WO2023033018A1 - Fused heterocyclic derivative having hiv replication inhibitory action - Google Patents

Fused heterocyclic derivative having hiv replication inhibitory action Download PDF

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Publication number
WO2023033018A1
WO2023033018A1 PCT/JP2022/032701 JP2022032701W WO2023033018A1 WO 2023033018 A1 WO2023033018 A1 WO 2023033018A1 JP 2022032701 W JP2022032701 W JP 2022032701W WO 2023033018 A1 WO2023033018 A1 WO 2023033018A1
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substituted
unsubstituted
aromatic
aromatic heterocyclic
aromatic carbocyclic
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PCT/JP2022/032701
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French (fr)
Japanese (ja)
Inventor
元太 只野
和也 安尾
梓 岡野
善史 楠本
宗大 正門
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塩野義製薬株式会社
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Publication of WO2023033018A1 publication Critical patent/WO2023033018A1/en

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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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • 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
    • C07D513/12—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 three hetero rings
    • C07D513/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to novel compounds with antiviral activity, more specifically to anti-HIV drugs.
  • HIV Human Immunodeficiency Virus
  • AIDS Acquired Immunodeficiency Syndrome
  • Reverse transcriptase inhibitors AKT, 3TC, etc.
  • protease inhibitors Indinavir, etc.
  • integrase inhibitors Raltegravir, etc.
  • Patent Document 1 HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex allosteric inhibitors are attracting attention as anti-HIV drugs with a novel mechanism (Non-Patent Document 1).
  • Patent Documents 1 to 42 have reported anti-HIV drugs having the same action.
  • a compound in which a carboxy group is directly bonded to the condensed ring mother nucleus of the present invention has not been reported so far.
  • An object of the present invention is to provide novel compounds with antiviral activity.
  • the present invention preferably provides an anti-HIV drug having HIV replication inhibitory activity. More preferably, it provides a novel anti-HIV drug that has a different basic skeleton from conventional anti-HIV drugs and is effective against HIV mutant strains and resistant strains. Furthermore, the present invention also provides synthetic intermediates and production methods thereof.
  • the present inventors have found that fused heterocyclic derivatives are useful as HIV replication inhibitors.
  • the compounds of the present invention and pharmaceuticals containing them are antiviral agents (e.g., antiretroviral agents, anti-HIV agents, anti-HTLV-1 (Human T cell leukemia virus type 1: human T cell leukemia virus type 1) agents).
  • antiviral agents e.g., antiretroviral agents, anti-HIV agents, anti-HTLV-1 (Human T cell leukemia virus type 1: human T cell leukemia virus type 1) agents.
  • anti-FIV Feine immunodeficiency virus: feline AIDS virus
  • anti-SIV Seimian immunodeficiency virus: monkey AIDS virus
  • the inventors have completed the present invention described below.
  • the present invention relates to:
  • a 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 1
  • B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms
  • the number of nitrogen atoms is 0 to 2
  • X 1 is CR 4 R 5 , NR 6 , O or S
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl
  • R 6 is hydrogen or substituted or unsubstituted alkyl
  • X 2 is CR 7 R
  • R 1 is (wherein R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl)
  • R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl
  • each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl
  • ring C is an aromatic carbocyclic ring optionally substituted with R 2A , an aromatic heterocyclic ring optionally substituted with R 2A , a non-aromatic carbocyclic ring optionally substituted with R 2A , or a non-aromatic heterocyclic ring optionally substituted with R 2A
  • R 1 has the same meaning as [1]; n-2 is 0 or 1; R2 is hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkyloxy; R 2A is halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyny
  • each R 2A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubsti
  • Each R 2A is independently hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic , a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, the compound according to [1] to [9] or a pharmaceutically acceptable salt thereof.
  • ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring;
  • m ⁇ 2 is an integer of 0 to 2
  • each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted al
  • each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy, q is an integer of 0 to 5.
  • X 1 is NR 6 ;
  • R 6 is hydrogen or substituted or unsubstituted alkyl,
  • X 2 is CR 7 R 8 , O or S;
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl; Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted
  • the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [13], which may form a substituted non-aromatic carbocyclic ring.
  • [15] Compounds I-0015, I-0019, I-0045, I-0048, I-0049, I-0056, I-0073, I-0075, I-0078, I-0079, I-0084, I- 1.
  • the compound or pharmaceutical of claim 1 which is selected from the group consisting of 0092, 1-0097, 1-0098, 1-0118, 1-0146, 1-0151, 1-0172, 1-0189 and 1-0190 Salts tolerable above.
  • the pharmaceutical composition of [16] which is an antiviral agent.
  • the pharmaceutical composition of [16] which is an anti-HIV agent.
  • a method for treating and/or preventing HIV infection which comprises administering the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof.
  • a 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 2
  • B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms the number of nitrogen atoms is 0 to 2
  • X 1 is CR 4 R 5 , NR 6 , O or S
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl
  • R 6 is hydrogen or substituted or unsubstituted alkyl
  • X 2 is CR 7
  • [2'] The compound of [1'], wherein R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof .
  • [3'] The compound of [1'] or a pharmaceutically acceptable salt thereof, wherein R1 is substituted or unsubstituted phenyl or substituted or unsubstituted piperidinyl.
  • [4′]R 1 is (wherein R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl)
  • R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl
  • each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl
  • ring C is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring;
  • R 1 has the same meaning as [1′], n ⁇ 2 is 0 or 1
  • R 2 is hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsul
  • Ring C is substituted or unsubstituted pyrrole ring, substituted or unsubstituted pyrazole ring, substituted or unsubstituted thiophene ring, substituted or unsubstituted furan ring, substituted or unsubstituted imidazole ring, substituted or unsubstituted
  • the compound of [5'] which is a substituted thiazole ring, substituted or unsubstituted oxazole ring, or substituted or unsubstituted triazole ring, or a pharmaceutically acceptable salt thereof.
  • each R 2A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubsti
  • R 2A are each independently hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocycle
  • the compound of [9'] which is a formula group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
  • ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring;
  • m ⁇ 2 is an integer of 0 to 2
  • each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted
  • each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy, q is an integer of 0 to 5.)
  • R 6 is hydrogen or C1-C6 alkyl optionally substituted with halogen
  • R 1 is an aromatic carbocyclic group optionally substituted with substituent group F, a non-aromatic carbocyclic group optionally substituted with substituent group F, substituted with substituent group F is an aromatic heterocyclic group which may be substituted, or a non-aromatic heterocyclic group which may be substituted with substituent group F
  • R 2A is amino optionally substituted with C1-C3 alkyl, C1-C6 alkyl optionally substituted with halogen, 6-membered aromatic carbocyclic group optionally substituted with substituent group G, substituent 6-membered aromatic heterocyclic group optionally substituted by group G, 3-6 membered non-aromatic carbocyclic group optionally substituted with halogen, or 4-6 membered optionally substituted with halogen
  • R 1 is The compound of [14′] or a pharmaceutically acceptable salt thereof, which is a group represented by (wherein R 1A is hydrogen, halogen or C1-C6 alkyl).
  • R 1A is hydrogen, halogen or C1-C6 alkyl.
  • R 2A is a 6-membered aromatic carbocyclic group optionally substituted by Substituent Group G, or a pharmaceutically acceptable salt thereof.
  • X 1 is NR 6 ;
  • R 6 is hydrogen or substituted or unsubstituted alkyl,
  • X 2 is CR 7 R 8 , O or S;
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl; Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted
  • the compound or a pharmaceutically acceptable salt thereof according to any one of [1′] to [13′], which may form a substituted non-aromatic carbocyclic ring.
  • a method for treating and/or preventing HIV infection which comprises administering the compound according to any one of [1'] to [20'] or a pharmaceutically acceptable salt thereof.
  • the present invention further provides the following inventions.
  • a method for treating and/or preventing a viral infection eg, HIV infection
  • a viral infection eg, HIV infection
  • a compound or a pharmaceutically acceptable salt thereof for the treatment and/or prevention of viral infections eg, HIV infection.
  • the compound of the present invention has replication-inhibitory activity against viruses, especially HIV (eg, HIV-1), its mutant viruses, and resistant viruses. Therefore, it is useful for prevention and/or treatment of viral infections (eg, AIDS).
  • viruses especially HIV (eg, HIV-1), its mutant viruses, and resistant viruses. Therefore, it is useful for prevention and/or treatment of viral infections (eg, AIDS).
  • Halogen includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • a fluorine atom and a chlorine atom are particularly preferred.
  • Alkyl includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms. do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • alkenyl refers to a group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. straight or branched chain hydrocarbon groups.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • alkynyl refers to a group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. It includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. These may further have a double bond at any position. Preferred embodiments of "alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene means a linear or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms. contains groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • aromatic carbocyclic group means a monocyclic or bicyclic or more aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like. A preferred embodiment of the "aromatic carbocyclic group” is phenyl.
  • Aromatic carbocyclic ring means a ring derived from the above “aromatic carbocyclic group”.
  • non-aromatic carbocyclic group means a monocyclic or bicyclic or more ring saturated cyclic hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group.
  • the "non-aromatic carbocyclic group” having two or more rings also includes a monocyclic or non-aromatic carbocyclic group having two or more rings condensed with the above “aromatic carbocyclic group”.
  • the "non-aromatic carbocyclic group” also includes a group that forms a bridge or a spiro ring as shown 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 cycloalkyl, cycloalkenyl and the like.
  • Cycloalkyl preferably has 3 to 10 carbon atoms, more preferably 3 to 7 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • Cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • the bicyclic or more non-aromatic carbocyclic group preferably has 8 to 13 carbon atoms, more preferably 9 to 10 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, dihydroindenyl and the like.
  • Non-aromatic carbocyclic ring means a ring derived from the above “non-aromatic carbocyclic group”.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms which are the same or different and are arbitrarily selected from O, S and N in the ring. do.
  • An aromatic heterocyclic group with two or more rings includes a monocyclic or an aromatic heterocyclic group with two or more rings condensed with the ring in the above "aromatic carbocyclic group", and the bond is Either ring may have it.
  • the monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered.
  • Five-membered aromatic heterocyclic groups include, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • the bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered.
  • indolyl isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl.
  • Ryl benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. are mentioned.
  • the aromatic heterocyclic group having 3 or more rings is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.
  • Aromatic heterocyclic ring means a ring derived from the above “aromatic heterocyclic group”.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more heteroatoms in the ring that are the same or different and arbitrarily selected from O, S and N.
  • a bicyclic or more non-aromatic heterocyclic group is a monocyclic or bicyclic or more non-aromatic heterocyclic group, the above "aromatic carbocyclic group", “non-aromatic carbocyclic group”, and / Or a ring in which each ring in the "aromatic heterocyclic group” is condensed, and a ring in the above "aromatic heterocyclic group” is condensed to a monocyclic or bicyclic or more non-aromatic carbocyclic group and the bond may be in any ring.
  • non-aromatic heterocyclic group also includes a group that forms a bridge or a spiro ring as shown below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3- to 8-membered, more preferably 5- or 6-membered.
  • Three-membered non-aromatic heterocyclic groups include, for example, thiiranyl, oxiranyl, aziridinyl.
  • Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl.
  • Five-membered non-aromatic heterocyclic groups include, for example, oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, and the like. mentioned.
  • 6-membered non-aromatic heterocyclic groups include, for example, dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl and the like.
  • Seven-membered non-aromatic heterocyclic groups include, for example, hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl.
  • the non-aromatic heterocyclic group having two or more rings is preferably 8- to 20-membered, more preferably 8- to 10-membered. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • Non-aromatic heterocyclic ring means a ring derived from the above “non-aromatic heterocyclic group”.
  • substituent group ⁇ means “optionally substituted with one or more groups selected from substituent group ⁇ ".
  • substituent groups ⁇ , ⁇ , ⁇ ', E, F and G are same applies to the substituent groups ⁇ , ⁇ , ⁇ ', E, F and G.
  • a carbon atom at any position may be bonded to one or more groups selected from Substituent Group A below.
  • Substituent group A halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl, alkyloxy optionally substituted with substituent group ⁇ , alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylcarbonyloxy optionally substituted with substituent group ⁇ , alkenylcarbonyloxy optionally substituted with substituent group ⁇ , alky
  • Substituent group ⁇ halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
  • Substituent group ⁇ halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alken
  • Substituent Group ⁇ Substituent Group ⁇ , alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, amino, alkylamino, alkylsulfonyl, alkyloxycarbonyl and cyclo propanyl.
  • Substituent group ⁇ ' Substituent group ⁇ and oxo.
  • Substituent group B halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , alkynyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkyloxy, alkenyloxy optionally substituted with substituent group ⁇ , alkynyloxy optionally substituted with substituent group ⁇ , alkylcarbon
  • non-aromatic carbocycle and “non-aromatic heterocycle” are substituted with “oxo” they mean rings in which two hydrogens on a carbon atom are replaced as follows.
  • Substituted aromatic carbocyclic ring and “substituted aromatic heterocyclic ring” formed together with the ring-constituting atoms to which two adjacent R 2 are bonded and "substituted aromatic carbocyclic ring” and “substituted aromatic carbocyclic ring” in Ring C
  • Substituents on the ring of the “aromatic carbocyclic ring” and “aromatic heterocyclic ring” of “heterocyclic ring” include Substituent Group B and the following formulas.
  • ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group ⁇ , an aromatic heterocyclic ring optionally substituted with a substituent group ⁇ , substituted with a substituent group ⁇ ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group ⁇ '
  • ring G is an aromatic carbocyclic ring which may be substituted with a substituent group B , an aromatic heterocyclic ring optionally substituted with a substituent group B, a non-aromatic carbocyclic ring optionally substituted with a substituent group C or a non-aromatic heterocyclic ring optionally substituted with a substituent group C and L is a single bond, C1-C3 al
  • Substituted non-aromatic carbocyclic ring and “substituted non-aromatic heterocyclic ring” formed together with the ring-constituting atoms to which two adjacent R 2 are bonded and "substituted non-aromatic carbocyclic ring” and " Examples of substituents on the ring of the “non-aromatic carbocyclic ring” and “non-aromatic heterocyclic ring” of the substituted non-aromatic heterocyclic ring include Substituent Group C and the following formulas.
  • ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group ⁇ , an aromatic heterocyclic ring optionally substituted with a substituent group ⁇ , substituted with a substituent group ⁇ ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group ⁇ '
  • ring G is an aromatic carbocyclic ring which may be substituted with a substituent group B , an aromatic heterocyclic ring optionally substituted with a substituent group B, a non-aromatic carbocyclic ring optionally substituted with a substituent group C or a non-aromatic heterocyclic ring optionally substituted with a substituent group C and L is a single bond, C1-C3 al
  • Substituents of “substituted amino”, “substituted carbamoyl” and “substituted sulfamoyl” include Substituent Group D below. It may be substituted with one or two groups selected from Substituent Group D.
  • Substituent group D halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group ⁇ , alkenyl optionally substituted with substituent group ⁇ , optionally substituted with substituent group ⁇ alkynyl, alkylcarbonyl optionally substituted with substituent group ⁇ , alkenylcarbonyl optionally substituted with substituent group ⁇ , alkynylcarbonyl optionally substituted with substituent group ⁇ , substituted with substituent group ⁇ alkylsulfanyl optionally substituted with substituent group ⁇ , alkenylsulfanyl optionally substituted with substituent group ⁇ , alkynylsulfanyl optionally substituted with substituent group ⁇ , alkylsulfinyl optionally substituted with substituent group ⁇ , alkenylsulfinyl optionally substituted with substituent group ⁇ , alkynylsulfinyl optionally substituted with substituent group ⁇ , alkeny
  • a 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 2.
  • a 1 , A 2 and A 3 are preferably each independently a carbon atom or a nitrogen atom, wherein a nitrogen atom of a ring-constituting atom of a ring containing A 1 , A 2 and A 3 as constituent atoms is one or two.
  • a 1 , A 2 and A 3 are more preferably each independently a carbon atom or a nitrogen atom, where the nitrogen atom is a ring-constituting atom of a ring containing A 1 , A 2 and A 3 as constituent atoms is 0 or 1. More preferably, A 1 is a carbon atom, A 2 is a carbon atom and A 3 is a nitrogen atom.
  • the group represented by is preferably the following groups. More preferably and more preferably is. Another preferred aspect is as follows. Another preferred aspect is as follows. A more preferred embodiment is as follows.
  • Ring C is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • Ring C preferably includes a substituted or unsubstituted 5-membered aromatic heterocyclic ring, more preferably a substituted or unsubstituted pyrrole ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted thiophene ring , substituted or unsubstituted furan ring, substituted or unsubstituted imidazole ring, substituted or unsubstituted thiazole ring, substituted or unsubstituted oxazole ring, substituted or unsubstituted triazole ring and the like.
  • the substituent of ring C is R 2A .
  • R 2 is each independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfony
  • Each R 2 is preferably independently a group selected from R 2A , or a substituted or unsubstituted aromatic heterocyclic ring (substituted group: R 2A ).
  • the other R 2 is preferably hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl
  • the other R 2 is more preferably hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen, aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or It is unsubstituted alkynyl or substituted or unsubstituted alkyloxy (example of substituent: halogen). More preferred are hydroxy, alkylamino, alkyl or haloalkyl.
  • Each R 2A is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfon
  • Each R 2A is independently preferably halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substitute
  • R 2A is more preferably each independently hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (substituent Examples of: halogen, aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen) , substituted or unsubstituted aromatic carbocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted Aromatic heterocyclic groups (example
  • R 2A are each independently substituted or unsubstituted amino (example of substituent: C1-C3 alkyl), substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen), substituted or an unsubstituted 6-membered aromatic carbocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, halo C1-C3 alkyloxy, C1-C3 alkylamino) , a substituted or unsubstituted 6-membered aromatic heterocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy, C1-C3 alkyl amino), a substituted or unsubstituted amino (
  • R 2A is each independently any of the formulas below.
  • X 3 is CH or N
  • X 4 is CH or N
  • X 5 is CH or N
  • R b is a substituent group ⁇
  • R c is a substituent group ⁇
  • Ring F is a 6-membered aromatic carbocyclic ring optionally substituted with a substituent group ⁇
  • a 6-membered aromatic heterocyclic ring optionally substituted with a substituent group ⁇
  • substituted with a substituent group ⁇ ' a 6-membered non-aromatic carbocyclic ring which may be substituted or a 6-membered non-aromatic heterocyclic ring which may be substituted with a substituent group ⁇ '
  • ring G may be substituted with a substituent group B 6- or 10-membered aromatic carbocyclic ring, 5-, 6- or 10-membered aromatic heterocyclic ring optionally substituted by substituent group B, 4- to 6-membered non-cyclic ring
  • R 2A is each independently any of the formulas below.
  • X 3 is CH or N
  • X 4 is CH or N
  • X 5 is CH or N
  • R b is hydrogen, alkyl or haloalkyl
  • R c is hydrogen, alkyl or haloalkyl
  • ring F is a substituted or unsubstituted piperidine (substituent: halogen, alkyloxyalkyl)
  • ring G is a substituted or unsubstituted 5-, 6- or 10-membered aromatic heterocyclic ring or a substituted or unsubstituted 4- to 6-membered non-aromatic heterocyclic ring (substituent: haloalkyl, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl)
  • R 2A is preferably substituted or unsubstituted amino (example of substituent: C1-C3 alkyl), substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen), substituted or unsubstituted 6-membered aromatic carbocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy, C1-C3 alkylamino), substituted or unsubstituted 6 membered aromatic heterocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy, C1-C3 alkylamino), substituted or unsubstituted A 3- to
  • B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms
  • the number of nitrogen atoms is 0-2.
  • B 1 , B 2 , B 3 and B 4 are preferably each independently a carbon atom or a nitrogen atom, wherein the ring of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms
  • the number of nitrogen atoms in the constituent atoms is 0 or 1. More preferably, B 1 , B 2 , B 3 and B 4 are carbon atoms.
  • the group represented by preferably includes the following groups. Another preferred aspect is as follows.
  • Ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • Ring D is preferably a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 6-membered aromatic heterocyclic ring, a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring or a substituted Or an unsubstituted 5- to 6-membered non-aromatic heterocyclic ring, more preferably a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted cyclopentane ring, a substituted or unsubstituted A substituted cyclohexane ring, a substituted or unsubstituted cycloheptane ring, and the like are included.
  • the substituent of ring D is R 3A .
  • Each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfony
  • R 3 is preferably each independently halogen, cyano, hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl), substituted or unsubstituted alkyl (examples of substituents: hydroxy, alkylamino, alkyl (benzyl)amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkenyl (examples of substituents: hydroxy, alkylamino, alkyl(benzyl) ) amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen) , substituted or unsubstituted alkenyloxy (example of substituent
  • Each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy.
  • R 3A is preferably each independently halogen, cyano, hydroxy, substituted or unsubstituted amino (example of substituent: alkyl), substituted or unsubstituted alkyl (example of substituent: halogen), substituted or unsubstituted substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.
  • X 1 is CR 4 R 5 , NR 6 , O or S; X 1 is preferably NR 6 .
  • R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • R 4 and R 5 are preferably each independently hydrogen or substituted or unsubstituted C1-C4 alkyl (example of substituent: halogen).
  • R6 is hydrogen or substituted or unsubstituted alkyl.
  • R 6 is preferably hydrogen or substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen).
  • X2 is CR7R8 , NR9 , O or S ; X2 is preferably O or S, more preferably O. Another embodiment of X 2 is CR 7 R 8 , O or S, more preferably CR 7 R 8 or O.
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl; R 7 and R 8 together may form a substituted or unsubstituted exomethylene, or together with the carbon atom bonded to the carbon atom to which R 7 and R 8 are bonded, a substituted or unsubstituted It may form a substituted non-aromatic carbocyclic ring.
  • R 7 and R 8 are preferably each independently hydrogen, substituted or unsubstituted alkyl (example of substituent: halogen) or substituted or unsubstituted alkenyl (example of substituent: halogen), together with the carbon atom to which R 7 and R 8 are attached may form a substituted or unsubstituted exomethylene (examples of substituents: alkyl, haloalkyl), or the carbon atom to which R 7 and R 8 are attached Together with the atoms, they may form a substituted or unsubstituted C3-C6 non-aromatic carbocyclic ring (example of substituent: halogen).
  • R9 is hydrogen or substituted or unsubstituted alkyl.
  • R 9 is preferably hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen).
  • R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group It is a cyclic group.
  • R 1 is preferably a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, preferably 5- to 7-membered, but optionally fused , may have a crosslinked structure.
  • the fused ring moieties are 5- to 10-membered and may be monocyclic or bicyclic.
  • substituted or unsubstituted aromatic carbocyclic groups include phenyl groups represented by the following formulae.
  • Another preferred embodiment of R 1 is an aromatic carbocyclic group optionally substituted with a substituent group F, a non-aromatic carbocyclic group optionally substituted with a substituent group F, a substituent group It is an aromatic heterocyclic group optionally substituted with F or a non-aromatic heterocyclic group optionally substituted with a substituent group F.
  • a more preferred embodiment of R 1 is an optionally substituted aromatic carbocyclic group with substituent group F or a non-aromatic heterocyclic group optionally substituted with substituent group F.
  • Substituent group F halogen, hydroxy, alkoxy, amino, alkylamino, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, oxo, cyano.
  • R 11 , R 12 , R 13 , R 14 and R 15 are each independently preferably hydrogen, halogen, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxyhaloalkyl , haloalkyloxy, carboxy, carbamoyl or alkylamino, more preferably hydrogen, halogen, cyano, amino, alkyl or alkyloxy, more preferably hydrogen, fluoro, chloro, bromo, cyano, amino, methyl , ethyl or methyloxy, particularly preferably hydrogen, halogen, cyano, methyl or ethyl.
  • R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , and R 14 and R 15 are each independently taken together with adjacent atoms to form a substituted or unsubstituted aromatic carbocyclic ring; It may form a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • These rings are preferably 5- to 8-membered, more preferably 5- or 6-membered, with 6-membered being more preferred.
  • R 1 is more preferably a phenyl or non-aromatic carbocyclic group optionally fused with 1 to 2 carbocyclic or heterocyclic rings (eg, 5- to 7-membered rings), more preferably It is a cyclic group exemplified below.
  • the carbocycle, heterocycle, phenyl, non-aromatic carbocycle, or the following cyclic groups have 1 to 4 substituents (e.g., halogen, hydroxy, alkoxy, amino, alkylamino, alkyl , haloalkyl, hydroxyalkyl, aminoalkyl, oxo, cyano) may be present.
  • R 1 is more preferably the following groups.
  • R 1 may also be a cyclic amine having a bond on the N atom, preferably a saturated cyclic amine.
  • the cyclic amine is a 5- to 7-membered heterocyclic ring which may be substituted, condensed and/or bridged, and may contain N, O and/or S atoms as ring-constituting atoms.
  • Preferred substituents are alkyl, cycloalkyl, oxo, hydroxy, halogen, alkoxy and the like. Examples of the cyclic amine include the following.
  • R 1 is a substituted or unsubstituted non-aromatic carbocyclic group having 1 or 2 double bonds in the ring, having 1 or 2 double bonds in the ring, as exemplified below It may be a substituted or unsubstituted non-aromatic heterocyclic group.
  • Said carbocyclic group or said heterocyclic group is preferably 5- to 7-membered.
  • Preferred substituents are alkyl, cycloalkyl, oxo, hydroxy, halogen, alkoxy and the like.
  • R 1 may be selected from the following group.
  • R 1 may be selected from the following group. (wherein R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl.) R 1A is preferably hydrogen, halogen, C1-C3 alkyl or haloC1-C3 alkyl. Methyl or ethyl is more preferred. Each R 1B is preferably independently hydrogen, halogen, C1-C3 alkyl or haloC1-C3 alkyl. Methyl is more preferred.
  • X 1 is NR 6 ;
  • R 6 is hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen);
  • X 2 is CR 7 R 8 , O or S;
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl (example of substituent: halogen) or substituted or unsubstituted alkenyl (example of substituent: halogen), together with the carbon atom to which R 7 and R 8 are attached may form a substituted or unsubstituted exomethylene (examples
  • the compounds of formula (I) are not limited to any particular isomer, but include all possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers, atropisomers , optical isomers, rotational isomers, etc.), racemates or mixtures thereof. These isomers can be easily separated in many cases by, for example, optical resolution, crystallization, chromatographic separation, etc. However, for convenience, they are sometimes represented by the same planar structural formula.
  • One aspect of the isomers of compound (I) includes stereoisomers specified by the ring orientation of R 1 , but the present invention includes all isomers and racemates thereof.
  • One or more hydrogen, carbon and/or other atoms of the compounds of Formula (I) may be substituted with isotopes of hydrogen, carbon and/or other atoms, respectively.
  • isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O , 31 P, 32 P, 35 S, 18 F, 123 I and Included are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, as in 36 Cl.
  • the compounds of formula (I) also include such isotopically substituted compounds.
  • the isotopically substituted compounds are also useful as pharmaceuticals and include all radiolabeled compounds of formula (I).
  • a "radiolabeling method" for producing the "radiolabel” is also encompassed by the present invention, and the “radiolabel” is useful as a research and/or diagnostic tool in metabolic pharmacokinetic studies, binding assays. is.
  • Radiolabeled compounds of formula (I) can be prepared by methods well known in the art.
  • a tritium-labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) through a catalytic dehalogenation reaction using tritium.
  • This method comprises reacting a suitably halogenated precursor of a compound of formula (I) with tritium gas in the presence or absence of a base, in the presence of a suitable catalyst such as Pd/C.
  • a suitable catalyst such as Pd/C.
  • 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
  • Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid) , trifluoroacetic acid, citric acid, lactic acid, tarta
  • the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form solvates (e.g., hydrates, etc.), co-crystals and/or crystal polymorphs, and the present invention also includes such various solvates, co-crystals and polymorphs.
  • a "solvate” may be coordinated with any number of solvent molecules (eg, water molecules, etc.) to a compound of formula (I).
  • solvent molecules eg, water molecules, etc.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water, attach adsorbed water, or form a hydrate. Also, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form polymorphs.
  • “Co-crystal” means that a compound or salt of formula (I) and a counter molecule are present in the same crystal lattice, and may contain any number
  • the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs.
  • Prodrugs are derivatives of the compounds of the invention having groups which are chemically or metabolically degradable, and which, upon solvolysis or under physiological conditions, become pharmaceutically active compounds of the invention in vivo.
  • a prodrug is a compound that undergoes enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo and is converted into a compound represented by formula (I), or a compound that is hydrolyzed by gastric acid or the like to form formula (I). It includes compounds that are converted to the indicated compounds, and the like. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with sulfonyl anhydrides and mixed anhydrides or by using condensing agents are exemplified.
  • the compound of the present invention Since the compound of the present invention has HIV replication inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for viral infections such as AIDS.
  • the compounds represented by formula (I) according to the present invention can be produced, for example, by the general synthetic methods shown below. Extraction, purification, and the like may be carried out in the same manner as in ordinary organic chemistry experiments.
  • the compounds of the present invention can be synthesized with reference to methods known in the art.
  • Process 1 Compound a3 can be obtained by reacting compounds a1 and a2.
  • Compound a2 can be used in an amount of 1 to 5 equivalents relative to compound a1.
  • the reaction temperature is room temperature to 150°C, preferably room temperature to 100°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • Examples of the reaction solvent include methanol, THF, and the like, which can be used singly or in combination.
  • Process 2 Compound a4 can be obtained by reacting compound a3 with isocyanide in the presence of an acid. Examples of the acid include acetic acid and TFA, which can be used in an amount of 1 to 5 molar equivalents relative to compound a3.
  • the isocyanide includes alkyl isocyanide and the like, and can be used in an amount of 1 to 2 molar equivalents relative to compound a3.
  • the reaction temperature is -10 to 80°C, preferably room temperature to 60°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • Examples of the reaction solvent include methanol, THF, and the like, which can be used singly or in combination.
  • Compound a5 can be obtained by protecting the amino of the amide group of compound a4.
  • a reagent Boc 2 O, Ac 2 O, acetyl chloride, etc. can be used, and 1 to 3 molar equivalents can be used with respect to compound a4.
  • the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP and the like, and it can be used in an amount of 1 to 5 molar equivalents relative to compound a4.
  • the reaction temperature is room temperature to 150°C, preferably 60 to 110°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • reaction solvent examples include toluene, xylene, THF, and the like, which can be used singly or in combination.
  • Step 4 Compound a6 can be obtained by hydrolyzing compound a5.
  • the base examples include an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and the like, which can be used in an amount of 1 to 5 molar equivalents relative to the compound a5.
  • the reaction temperature is room temperature to 150°C, preferably 60 to 110°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include dioxane, THF, and the like, which can be used alone or in combination.
  • Step 5 Compound a7 can be obtained by alkylating compound a6.
  • reagents include TMS diazomethane, O-tert-butyl-N,N'-diisopropylisourea, and the like, which can be used in an amount of 1 to 5 molar equivalents relative to compound a6.
  • the reaction temperature is -10 to 50°C, preferably 0°C to room temperature.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • a reaction solvent a mixed solvent such as methanol, dioxane, and THF can be used.
  • Process 6 Compound a9 can be obtained by subjecting compounds a7 and a8 to a coupling reaction.
  • reaction examples include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, Buchwald-Hartwig coupling and the like.
  • Metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium and the like. and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a7.
  • Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound a7.
  • Compound a8 includes substituted boronic acid, substituted boronate ester, substituted tin alkyl, substituted zinc halide and the like, and can be used in an amount of 1 to 10 molar equivalents relative to compound a7.
  • Additives include CuI, CsF, etc., and can be used in an amount of 0.05 to 1 molar equivalent relative to compound a7, if necessary.
  • the reaction temperature is 0 to 150°C, preferably 50 to 120°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • Examples of the reaction solvent include dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
  • Step 7 Compound a10 can be obtained by subjecting compound a9 to alkylation such as reductive amination.
  • reagents include acetaldehyde and the like, which can be used in an amount of 1 to 20 molar equivalents relative to compound a9.
  • the reaction temperature is -10 to 40°C, preferably 0°C to room temperature.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include chloroform, dichloromethane, THF, water, and the like, which can be used singly or in combination.
  • Step 8 Compound Ia can be obtained by deprotecting compound a10.
  • Examples of the base include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and the like, and can be used in an amount of 1 to 50 molar equivalents relative to the compound a10.
  • the reaction temperature is 10-110°C, preferably 30-90°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • Examples of the reaction solvent include methanol, THF, dioxane, water, and the like, which can be used singly or in combination.
  • metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, [ 1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride and the like can be mentioned, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a4′.
  • Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound a4'.
  • Examples of compound a5′ include amines, substituted boronic acids, substituted boronic esters, substituted tin alkyls, substituted zinc halides, etc., and can be used in an amount of 1 to 10 molar equivalents relative to compound a4′.
  • Examples of the additive include copper (I) iodide, cesium fluoride, and the like, and if necessary, 0.05 to 1 molar equivalent can be used with respect to compound a4'.
  • the reaction temperature is 0 to 250° C., preferably 50 to 220° C., and can be carried out under microwave irradiation.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include NMP, dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
  • Compound a7' can be obtained by subjecting compound a6' to alkylation such as nucleophilic substitution reaction or reductive amination.
  • alkylation such as nucleophilic substitution reaction or reductive amination.
  • reagents include ethyl iodide and acetaldehyde, which can be used in an amount of 1 to 20 molar equivalents relative to compound a6'.
  • the reaction temperature is -78 to 40°C, preferably -50°C to room temperature.
  • the reaction time is 0.05 to 24 hours, preferably 0.1 to 12 hours.
  • the reaction solvent include chloroform, dichloromethane, THF, water, and the like, which can be used singly or in combination.
  • Compound a8' can be obtained by protecting the amino of the amide group of compound a7'.
  • a reagent Boc 2 O, Ac 2 O, acetyl chloride, etc. can be used, and 1 to 3 molar equivalents can be used with respect to compound a7′.
  • the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP and the like, and it can be used in an amount of 1 to 5 molar equivalents relative to compound a7'.
  • the reaction temperature is room temperature to 180°C, preferably 60 to 150°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • reaction solvent examples include toluene, xylene, THF, and the like, which can be used singly or in combination.
  • Step 4 Compound Ia can be obtained by hydrolyzing compound a8'.
  • the base examples include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and the like, and can be used in an amount of 1 to 50 molar equivalents relative to the compound a8'.
  • the reaction temperature is 10-150°C, preferably 30-110°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include methanol, THF, dioxane, water, and the like, which can be used singly or in combination.
  • Compound h3 can be obtained by reacting compounds h1, h2, acid and isocyanide.
  • Compound h2 can be used in an amount of 1 to 5 molar equivalents relative to compound h1.
  • the acid include acetic acid and TFA, and 1 to 5 molar equivalents can be used with respect to compound h1.
  • the isocyanide includes alkylisocyanide and the like, and can be used in an amount of 1 to 3 molar equivalents relative to compound h1.
  • the reaction temperature is -10 to 80°C, preferably room temperature to 70°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include methanol, THF, and the like, which can be used singly or in combination.
  • Compound h4 can be obtained by subjecting compound h3 to an intramolecular coupling reaction.
  • the coupling reaction is exemplified by the Mizoroki-Heck reaction.
  • metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium (II) dichloride, bis(tri-tert-butylphosphine)palladium, [ 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and the like can be mentioned, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound h3.
  • Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound h3.
  • the reaction temperature is 0 to 180°C, preferably 50 to 150°C. It is preferably carried out under microwave irradiation.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • Examples of the reaction solvent include acetonitrile, hexafluoroisopropanol, NMP, dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
  • Compound h5 can be obtained by subjecting compound h4 to alkylation such as nucleophilic substitution reaction or reductive amination.
  • alkylation such as nucleophilic substitution reaction or reductive amination.
  • reagents include ethyl iodide and acetaldehyde, which can be used in an amount of 1 to 20 molar equivalents relative to compound h4.
  • the reaction temperature is -78 to 40°C, preferably -50°C to room temperature.
  • the reaction time is 0.05 to 24 hours, preferably 0.1 to 12 hours.
  • the reaction solvent include chloroform, dichloromethane, THF, water, and the like, which can be used singly or in combination.
  • Step 4 Compound h6 can be obtained by protecting the amino of the amide group of compound h5.
  • Boc 2 O, Ac 2 O, acetyl chloride, etc. can be used, and 1 to 3 molar equivalents can be used with respect to compound h5.
  • the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP and the like, and it can be used in an amount of 1 to 5 molar equivalents relative to compound h5.
  • the reaction temperature is room temperature to 180°C, preferably 60 to 150°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • reaction solvent examples include toluene, xylene, THF, and the like, which can be used singly or in combination.
  • Step 5 Compound h7 can be obtained by hydrolyzing compound h6.
  • the base examples include an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound h6.
  • the reaction temperature is room temperature to 150°C, preferably 60 to 110°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • examples of the reaction solvent include dioxane, THF, and the like, which can be used alone or in combination.
  • Process 6 Compound h8 can be obtained by alkylating compound h7.
  • reagents examples include TMS diazomethane, O-tert-butyl-N,N'-diisopropylisourea, and the like, which can be used in an amount of 1 to 5 molar equivalents relative to compound h7.
  • the reaction temperature is -10 to 50°C, preferably 0°C to room temperature.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • a reaction solvent a mixed solvent such as methanol, dioxane, and THF can be used.
  • Step 7 Compound h10 can be obtained by subjecting compounds h8 and h9 to an aromatic nucleophilic substitution reaction or coupling reaction.
  • Examples of coupling reactions include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, and Buchwald-Hartwig coupling.
  • Metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, Xphos Pd G3, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, etc., can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound h8.
  • Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound h8.
  • Compound h9 includes amines, substituted boronic acids, substituted boronic esters, substituted tin alkyls, substituted zinc halides, etc., and can be used in an amount of 1 to 10 molar equivalents relative to compound h8.
  • Examples of the additive include copper (I) iodide, cesium fluoride, and the like, and if necessary, 0.05 to 1 molar equivalent can be used with respect to compound h8.
  • the reaction temperature is 0-250° C., preferably 50-220° C., and can be carried out under microwave irradiation.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include NMP, dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
  • Step 8 Compound Ih can be obtained by hydrolyzing compound h10.
  • the base include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and the like.
  • the reaction temperature is 10-150°C, preferably 30-110°C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
  • the reaction solvent include methanol, ethanol, THF, dioxane, water, and the like, which can be used singly or in combination.
  • the compound of the present invention Since the compound of the present invention has HIV replication inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for viral infections such as AIDS.
  • the HIV replication inhibitory action of the compound of the present invention is preferably 100 nM or less, more preferably 50 nM or less, still more preferably 20 nM or less, particularly preferably 10 nM, in Test Example 1 and/or Test Example 2 described later. It is below. EC90 values can also be used as an assessment of the same effect.
  • the compounds of the present invention have not only replication-inhibitory activity against viruses, particularly HIV (e.g., HIV-1), its mutant viruses, and resistant viruses, but also are useful as pharmaceuticals. It has excellent characteristics.
  • a) Good antiviral activity eg, PA-EC50, PA-EC90, etc. in the presence of serum proteins.
  • b) It has a weak inhibitory effect on CYP enzymes eg, CYP1A2, CYP2C9, CYP3A4, CYP2D6, CYP2C19, etc.
  • c) Good pharmacokinetics such as high blood concentration, long duration of effect, moderate clearance, and moderate bioavailability.
  • CYP3A4 No irreversible inhibitory effect on CYP enzymes (eg, CYP3A4) within the concentration range of the measurement conditions described herein, and low MBI activity.
  • the stability of the compound (for example, solution stability in various liquids, light stability, color stability, etc.) is high.
  • i) The frequency/probability of emergence of resistant viruses due to the compound of the present application itself or in combination with other drugs is low. j) It exhibits strong efficacy even against resistant viruses.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally.
  • parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear and intravaginal administration.
  • internal solid preparations e.g., tablets, powders, granules, capsules, pills, films, etc.
  • internal liquid preparations e.g., suspensions, emulsions, elixirs, syrups, etc.
  • Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules may be dry syrups.
  • the capsules may be soft capsules, microcapsules or sustained release capsules.
  • injections In the case of parenteral administration, injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, Any commonly used dosage form such as ointments, plasters, jellies, creams, patches, poultices, powders for external use, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O/W, W/O, O/W/O and W/O/W types.
  • a pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, if necessary. Furthermore, by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can be used as a pharmaceutical composition for children, the elderly, critically ill patients, or for surgery. You can also For example, a pediatric pharmaceutical composition can be used for neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old) infants (1 to 7 years old), children (7 to 15 years old) or 15 Patients between the ages of 18 and 18 can be administered. For example, geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, administration route, etc., but when administered orally, it is usually 0.05 to 100 mg / kg/day, preferably within the range of 0.1 to 10 mg/kg/day. In the case of parenteral administration, it is generally 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day, although it varies greatly depending on the route of administration. It may be administered once to several times a day.
  • the compound of the present invention can be used as a reverse transcriptase inhibitor, ribonuclease H inhibitor, protease inhibitor, integrase inhibitor, adsorption/invasion inhibitor, It can be used in combination with budding inhibitors, maturation inhibitors, capsid inhibitors, broadly neutralizing antibodies, other anti-HIV drugs, and the like (hereinafter abbreviated as concomitant drugs).
  • the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times.
  • the compound of the present invention and the concomitant drug may be administered as two or more formulations containing each active ingredient, or may be administered as a single formulation containing those active ingredients.
  • the dosage of the concomitant drug can be appropriately selected based on the clinically used dosage.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • Reverse transcriptase inhibitors include AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, emtricitabine, nevirapine, efavirenz, capravirine, etravirine, delavirdine, delavirdine mesylate, rilpivirine, rilpivirine hydrochloride, VM-1500A, VM-1500, doravirine, MK-8507, MK-8504, MK-8583 and the like.
  • ribonuclease H inhibitors examples include compounds described below. compounds described in WO2008/010964; Compounds described in WO2011/075747
  • Reverse transcriptase inhibitors include indinavir, indinavir sulfate ethanolate, ritonavir, saquinavir, saquinavir mesylate, nelfinavir, nelfinavir mesylate, amprenavir, atazanavir, atazanavir sulfate, lopinavir, fosamprenavir, fosamprenavir calcium hydrate, darunavir, darunavir ethanol adduct, etc.
  • Integrase inhibitors include raltegravir, raltegravir potassium, elvitegravir, JTK-656, dolutegravir, dolutegravir sodium, cabotegravir, cabotegravir sodium, victegravir, victegravir sodium, S-365598, and the like.
  • Adsorption/entry inhibitors include Maraviroc, Enfuvirtide, Ibalizumab, PRO-140, Temsavir, Fostemsavir Tromethamine, Combinectin, and the like.
  • Maturation inhibitors include GSK-2838232, GSK-3640254, and the like.
  • Capsid inhibitors include GS-6207 and the like.
  • Examples of broadly neutralizing antibodies include Leronlimab, UB-421, VRC01, 10E8, PGDM1400, PGT121, N6LS (GSK3810109A), Teropavimab (3BNC117-LS, GS-5423), GS-2872 (10-1074-LS), and the like. be done.
  • the compound of the present invention can also be used in the field of gene therapy to prevent the spread of retroviral vector infection to tissues other than the target tissue when using retroviral vectors based on HIV or MLV. can be done.
  • pre-administration of the compound of the present invention can prevent unnecessary infection in the body.
  • NMR analyzes obtained in each example were performed at 300 MHz or 400 MHz and measured using DMSO-d 6 , CDCl 3 . Moreover, when NMR data are shown, there are cases where not all measured peaks are described.
  • “No.” represents the compound number
  • "Structure” represents the chemical structure
  • “MS” represents the mass in LC/MS (liquid chromatography/mass spectrometry). MS (m/z) can be measured under the following measurement conditions, but is not limited to these conditions.
  • Step 5 Meta-chloroperbenzoic acid (about 30% water content, 58 g, 240 mmol) was added to a solution of compound b6 (39 g, 78 mmol) in chloroform (310 mL) and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (200 mL) and aqueous sodium thiosulfate solution (2 mM, 200 mL, 400 mmol) were added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure.
  • Step 9 Benzoyl isothiocyanate (0.21 mL, 1.6 mmol) was added to a THF (10 mL) solution of compound b10 (1.0 g, 1.6 mmol) and stirred at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b11 (1.1 g, yield 86%).
  • step 11 Hydrochloric acid-dioxane solution (4.0 M, 13 mL, 50 mmol) was added to compound b12 (680 mg, 1.0 mmol), and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution and a saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the resulting solid was collected by filtration. The solid was washed with diisopropyl ether and hexane to obtain compound b13 (580 mg, yield 100%).
  • Step 13 Concentrated sulfuric acid (98%, 60 mL) was added at 0°C to a mixed solution of compound b14 (8.2 g, 14 mmol) in methanol and water (21 mL, 21 mL), and the mixture was stirred at 80°C for 3 hours and 30 minutes.
  • THF (80 mL), methanol (80 mL) and sodium hydroxide aqueous solution (10 M, 240 mL, 2.4 mol) were added to the reaction solution, and the mixture was stirred at 80° C. for 2 hours.
  • Concentrated hydrochloric acid was added to the reaction solution, and the resulting solid was collected by filtration. The solid was washed with water to give compound b15 (6.2 g, yield 92%).
  • Step 15 To a DMF (12 mL) solution of tert-butyl nitrite (2.6 ml, 22 mmol) and diiodomethane (1.8 ml, 22 mmol) was added a DMF (12 mL) solution of compound b16 (1.20 g, 2.2 mmol) under ice cooling. , and stirred at room temperature for 15 minutes. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b17 (0.86 g, yield 59%).
  • Step 17 Hydrochloric acid-ethyl acetate solution (4.0 M, 2.7 mL, 11 mmol) was added to compound b18 (100 mg, 0.15 mmol), and the mixture was stirred at room temperature for 15 hours. An aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and ethyl acetate and hexane were added to the obtained residue to solidify to obtain compound I-0075 (71 mg, yield 78%).
  • Step 3 Compound d2 was reacted in the same manner as in Step 12 of Example 1.
  • 2M aqueous sodium hydroxide solution (1.4 ml, 2.8 mmol) was added to a solution of the obtained crude product (338 mg) in THF (2.5 ml) and methanol (0.5 ml), and the mixture was stirred at 80°C for 4 hours.
  • Methanol (1.5 ml) and 2M aqueous sodium hydroxide solution (0.55 ml, 1.1 mmol) were added to the reaction mixture, and the mixture was stirred for 2.5 hours.
  • 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Step 3 Sodium hydride (containing about 40% liquid paraffin, 280 mg, 7.0 mmol) was added to a DMF (25 mL) solution of compound e2, and the mixture was stirred at room temperature for 10 minutes. Methyl iodide (0.88 mL, 14 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e3 (930 mg, yield 73%).
  • Step 7 Bis(pinacolato)diboron (0.43g, 1.7mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) (dimer) (74mg, 0.11mmol), 4,4'-di-tert -Butyl-2,2′-bipyridyl (90 mg, 0.33 mmol) in THF (6.0 mL) was stirred at room temperature for 5 minutes, and compound e6 (0.58 g, 1.1 mmol) in THF (11 mL) was added to the reaction mixture. ) solution and stirred at 80° C. for 30 minutes.
  • Step 7 Compound f7 (0.13 g, 0.37 mmol) in water (1.0 mL)-tetrahydrofuran (2.0 mL) solution, 4-methylphenylboronic acid (0.15 g, 1.1 mmol), Xphos G3 (0.032 g , 0.037 mmol), potassium phosphate (0.16 g, 0.75 mmol) and stirred at 50° C. for 30 minutes.
  • the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound f8 (0.13 g, yield 89%).
  • Step 3 Diisopropylethylamine (18 mL, 0.10 mol) was added to a solution of compound g3 (28 g, 84 mmol) and 1-aminonaphthalen-2-ol (16 g, 0.10 mol) in DMA (140 mL) and stirred at 100° C. for 3 hours. . Water (140 mL) was added dropwise to the reaction solution, and the mixture was allowed to cool and stirred. The precipitated solid was collected by filtration, washed with water and methanol, and dried to obtain compound g4 (34 g, yield 92%).
  • Step 5 To a solution of compound g5 (23 g, 40 mmol), acetaldehyde (11 mL, 0.20 mol) and acetic acid (12 mL, 0.20 mol) in dichloromethane (230 mL) was added sodium triacetoxyborohydride (26 g, 0.12 mol) in an ice bath. The mixture was added and stirred at room temperature for 1 hour. Water (500 mL) and sodium hydrogen carbonate (61 g, 0.73 mol) were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 7 2-tert-butyl-1,3-diisopropylisourea (34 mL, 138 mmol) was added to a solution of compound g7 (18 g, 35 mmol) in chloroform (180 mL), and the mixture was stirred at 50° C. for 2.5 hours. Water (3.1 mL, 170 mmol) was added to the reaction and filtered. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), the obtained solid was washed with hexane-diisopropyl ether, and compound g8 (16 g, yield 82%) was obtained. Obtained.
  • Step 9 Compound g9 (40 mg, 0.071 mmol), 4-methoxyphenylboronic acid (16 mg, 0.11 mmol), tripotassium phosphate (45 mg, 0.21 mmol) in THF (1.0 mL) - water (0.10 mL) XPhos G3 (6.0 mg, 7.1 ⁇ mol) was added to the solution and stirred at 65° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound g10 (40 mg, yield 95%).
  • the compounds of the invention can be tested essentially as described in the Test Examples below.
  • the compound represented by formula (I) according to the present invention may have an HIV replication inhibitory effect and inhibit HIV replication.
  • the EC50 is preferably 1000 nM or less, more preferably 100 nM or less, and even more preferably 50 nM or less.
  • Test Example 1 HIV Replication Inhibition Test Plasmids of HIV-1 NL432 recombinant molecular clones were transfected into 293T cells.
  • polymorphic mutations in the 124th and 125th amino acids on the HIV-1 integrase (IN) gene have been confirmed in HIV-1 infected patients. Mutations were introduced on the IN gene of the clones to generate mutant virus plasmids for amino acids 124 and 125, and HIV-containing supernatants were prepared as described above.
  • EC50 was defined as the compound concentration that inhibits cytotoxicity caused by the virus by 50%. (Result) EC50 is shown below.
  • Test Example 2 Calculation of Potency Shift Value
  • human serum was added and EC50 was calculated.
  • HIV HTLV-IIIB strain
  • persistently infected human T cell line Molt-4 clone 8 was cultured, and the supernatant was filtered to obtain a virus solution and stored at -80°C.
  • 20 ⁇ L of RPMI 1640 medium supplemented with 50% human serum/10% fetal bovine serum was added to each anti-HIV active substance previously dispensed to a 384-well microplate at a predetermined concentration, and allowed to stand at room temperature for 1 hour. .
  • RPMI 1640 medium supplemented with 10% fetal bovine serum was added to the plate for which no human serum was added.
  • 3 ⁇ 10 4 cells/well of MT-4 cells and 3 ⁇ L/well of HIV solution diluted to an appropriate concentration (multiplicity of infection 0.005-0.025 TCID 50 ) were mixed for the required number of wells and kept at 37° C. for 1 hour. reacted.
  • non-infected cells were prepared at 3 ⁇ 10 4 cells/well for the required number of wells.
  • the compound may bind to serum proteins and reduce the amount of free body in the blood, resulting in decreased antiviral activity.
  • PA-EC 90 Protein adjusted-EC 90
  • the drug is effective.
  • PA-EC potency shift value when adding 25% human serum calculated above
  • PA-EC PA-EC when adding 100% human serum is calculated according to the formula shown below. 50 values were extrapolated.
  • PA-EC 50 EC 50 ⁇ (potency shift value when 25% human serum is added) ⁇ 4
  • the compounds of the present invention showed good PA-EC 50 values.
  • Test Example 3 CYP Inhibition Test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin, which is a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4). (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. is inhibited by the compounds of the present invention.
  • CYP1A2 methyl-hydroxylation of tolbutamide
  • CYP2C19 4′-hydroxylation of mephenytoin
  • CYP2D6 O-demethylation of dextromethorphan
  • CYP3A4 hydroxylation of terfenad
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol/L ethoxyresorufin (CYP1A2), 100 ⁇ mol/L tolbutamide (CYP2C9), 30 ⁇ mol/L or 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 microsomes 0.2 mg protein/mL; (4 points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the centrifugation supernatant was quantified using a fluorescence multi-label counter or LC/MS/MS, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4'-hydroxylation. body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), terfenadine alcohol (CYP3A4 metabolite) are quantified by LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.
  • the compounds of the invention were tested essentially as described above.
  • Test Example 3-2 CYP3A4 (MDZ) MBI Test Regarding CYP3A4 inhibition of the compounds of the present invention, this is a test to evaluate the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory action caused by the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes as an index of 1-hydroxylation of midazolam (MDZ).
  • Reaction conditions were as follows: substrate, 10 ⁇ mol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; 0.05 mg/mL at the time of reaction (at 10-fold dilution); concentration at the time of pre-reaction of the compound of the present invention, 0.83, 5, 10, 20 ⁇ mol/L or 1, 5, 10, 20 ⁇ mol/L (4 points).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved instead of the compound of the present invention, to the reaction solution, and the residual activity (%) was calculated when the compound of the present invention was added at each concentration, IC is calculated by inverse estimation by logistic model using concentration and inhibition rate.
  • Preincubation IC of 0 min/Preincubation IC of 30 min is taken as the Shifted IC value, and if the Shifted IC is 1.5 or more, it is positive, and if the Shifted IC is 1.0 or less, it is negative.
  • Test Example 5 Metabolic Stability Test
  • Commercially available pooled human liver microsomes and the compound of the present invention are reacted for a certain period of time, the residual rate is calculated by comparing the reacted sample and the unreacted sample, and the degree of metabolism of the compound of the present invention in the liver is evaluated. .
  • the compound of the present invention in the centrifugation supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the residual amount of the compound of the present invention after the reaction was determined assuming that the amount of the compound at the time of 0 minute reaction was 100%. calculate.
  • the hydrolysis reaction was carried out in the absence of NADPH, and the glucuronidation reaction was carried out in the presence of 5 mmol/L UDP-glucuronic acid instead of NADPH.
  • the dilution concentration and dilution solvent are changed as necessary.
  • the compounds of the invention were tested essentially as described above.
  • 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, Tricitrate Suspend the bacteria in sodium dihydrate: 0.25 g/L, MgSO 4 7H 2 0: 0.1 g/L) and add 120 mL of Exposure medium (biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, Glucose: MicroF buffer containing 8 mg/mL).
  • Exposure medium biotin: 8 ⁇ g/mL
  • histidine 0.2 ⁇ g/mL
  • Glucose MicroF buffer containing 8 mg/mL.
  • 3.10 to 3.42 mL of bacterial solution is added to 120 to 130 mL of Exposure medium to prepare a test bacterial solution.
  • DMSO solution of the compound of the present invention (several dilutions from the highest dose of 50 mg/mL to 2- to 3-fold common ratio), DMSO as a negative control, and 50 ⁇ g/mL of 4- Nitroquinoline-1-oxide in DMSO, 0.25 ⁇ g/mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide in DMSO for strain TA100, TA98 in metabolic activation conditions 12 ⁇ L of 40 ⁇ g/mL 2-aminoanthracene DMSO solution for the strain, 12 ⁇ L of 20 ⁇ g/mL 2-aminoanthracene DMSO solution for the TA100 strain, and 588 ⁇ L of the test bacterial solution (under metabolic activation conditions, 498 ⁇ L of the test bacterial solution and S9 90 ⁇ L of the mixture) is mixed, and cultured with shaking at 37° C.
  • Test Example 7 For the purpose of evaluating the risk of electrocardiographic QT interval prolongation of the compound of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to test the The effect of the compounds of the invention on the delayed rectifier K + current (I Kr ) that plays a role is investigated. Using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S), cells were held at a membrane potential of ⁇ 80 mV by the whole-cell patch clamp method, and a leak potential of ⁇ 50 mV was applied, followed by +20 mV depolarization stimulation. for 2 seconds, followed by a repolarizing stimulus of ⁇ 50 mV for 2 seconds.
  • QPatch fully automated patch clamp system
  • analysis software (QPatch Assay software; Sophion Bioscience A/S) is used to measure the absolute value of the maximum tail current based on the current value at the retained membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the vehicle is calculated as the inhibition rate, and the effect of the compound of the present invention on I Kr is evaluated. Note that the dilution concentration and dilution solvent are changed as necessary.
  • Test Example 8 Ames test The mutagenicity of the compounds of the present invention was evaluated by the Ames test using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA strains as test strains. To 0.1 mL of DMSO solution of the compound of the present invention, 0.5 mL of S9mix under metabolic activation conditions, and 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution under non-metabolic activation conditions were mixed, and histidine and biotin were mixed. , or overlay minimal glucose agar plates with 2 mL soft overlay agar containing tryptophan.
  • negative controls DMSO
  • positive controls (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) was similarly performed.
  • the revertant colonies that appear are counted and evaluated in comparison with the negative control group. If the number of revertant colonies increases in a concentration-dependent manner and is at least twice the number of colonies in the negative control group, it is determined as positive (+). Note that the dilution concentration and dilution solvent are changed as necessary.
  • the formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
  • the compounds of the invention can be administered topically by any conventional route, especially enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions.
  • it can be administered as a pharmaceutical composition in the form of lotions, gels, ointments or creams, or in nasal or suppository form.
  • a pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing, mixing, It can be manufactured by a granulation or coating method.
  • oral compositions can be tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients.
  • injectable compositions may be in the form of solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffers and the like.
  • the compound according to the present invention is useful as a therapeutic and/or prophylactic agent for viral infections such as AIDS, or an intermediate thereof.

Abstract

The present invention provides a compound represented by formula (I). (In the formula, A1, A2, or A3 each independently is a carbon atom or a nitrogen atom, B1, B2, B3, or B4 each independently is a carbon atom or a nitrogen atom, X1 is CR4R5, etc., R4 or R5 each independently is hydrogen, etc., X2 is CR7R8, etc., R7 or R8 each independently is hydrogen, etc., R1 is a substituted or unsubstituted aromatic carbocyclic group, etc., R2 each independently is hydroxy, etc., R3 each independently is hydroxy, etc., n is an integer of 0-3, and m is an integer of 0-4.)

Description

ＨＩＶ複製阻害作用を有する縮合複素環誘導体Fused heterocyclic derivative having HIV replication inhibitory activity
　本発明は、抗ウイルス作用を有する新規化合物、更に詳しくは、抗ＨＩＶ薬に関する。 The present invention relates to novel compounds with antiviral activity, more specifically to anti-HIV drugs.
　ウイルスのなかでも、レトロウイルスの一種であるヒト免疫不全ウイルス（Ｈｕｍａｎ　Ｉｍｍｕｎｏｄｅｆｉｃｉｅｎｃｙ　Ｖｉｒｕｓ、以下ＨＩＶと略す）は、後天性免疫不全症候群（Ａｃｑｕｉｒｅｄ　ｉｍｍｕｎｏｄｅｆｉｃｉｅｎｃｙ　ｓｙｎｄｒｏｍｅ、以下エイズ（ＡＩＤＳ）と略す）の原因となることが知られている。そのエイズの治療薬としては、これまでのところ逆転写酵素阻害剤（ＡＺＴ、３ＴＣ等）、プロテアーゼ阻害剤（インディナビル等）、およびインテグラーゼ阻害剤（ラルテグラビル等）が主流であるが、腎臓障害等の副作用や耐性ウイルスの出現等の問題が判明しており、それらとは異なる作用メカニズムを有する抗ＨＩＶ薬の開発が期待されている。 Among viruses, Human Immunodeficiency Virus (hereinafter abbreviated as HIV), which is a type of retrovirus, causes Acquired Immunodeficiency Syndrome (hereinafter abbreviated as AIDS). It has been known. Reverse transcriptase inhibitors (AZT, 3TC, etc.), protease inhibitors (Indinavir, etc.), and integrase inhibitors (Raltegravir, etc.) have been the mainstream of AIDS therapeutic drugs so far. Problems such as side effects such as disorders and emergence of resistant viruses have been clarified, and the development of anti-HIV drugs having different mechanisms of action is expected.
　また、エイズの治療においては、耐性ウイルスが容易に出現するという理由から、現在、多剤併用療法が効果的であると報告されている。抗ＨＩＶ薬としては、逆転写酵素阻害剤、プロテアーゼ阻害剤、インテグラーゼ阻害剤の３種が臨床で使用されているが、同じ作用メカニズムを有する薬剤はしばしば交叉耐性を示し、または付加的な効果を示すに過ぎず、異なった作用メカニズムの抗ＨＩＶ薬の開発が要望されている。 Also, in the treatment of AIDS, it is currently reported that multidrug therapy is effective because resistant viruses emerge easily. Three types of anti-HIV drugs, reverse transcriptase inhibitors, protease inhibitors, and integrase inhibitors, are used clinically, but drugs with the same mechanism of action often show cross-resistance or have additive effects. There is a demand for the development of anti-HIV drugs with different mechanisms of action.
　このような状況下、新規メカニズムの抗ＨＩＶ薬として、ＨＩＶ－１　Ｉｎｔｅｇｒａｓｅ（ＩＮ）－Ｌｅｎｓ　ｅｐｉｔｈｅｒｉｕｍ-ｄｅｒｉｖｅｄ　ｇｒｏｗｔｈ ｆａｃｔｏｒ（ＬＥＤＧＦ）複合体アロステリック阻害剤が注目されている（非特許文献１)。また同作用を有する抗ＨＩＶ薬として、特許文献１～４２が報告されている。しかし、本発明の縮合環母核に直接カルボキシ基が結合している化合物は、これまで報告されていない。 Under these circumstances, HIV-1 Integrase (IN)-Lens epitherium-derived growth factor (LEDGF) complex allosteric inhibitors are attracting attention as anti-HIV drugs with a novel mechanism (Non-Patent Document 1). In addition, Patent Documents 1 to 42 have reported anti-HIV drugs having the same action. However, a compound in which a carboxy group is directly bonded to the condensed ring mother nucleus of the present invention has not been reported so far.
国際公開第2015/147247号WO2015/147247 国際公開第2015/174511号WO2015/174511 国際公開第2015/179448号WO2015/179448 国際公開第2015/126376号WO2015/126376 国際公開第2015/126737号WO2015/126737 国際公開第2015/126726号WO2015/126726 国際公開第2015/126743号WO2015/126743 国際公開第2015/126758号WO2015/126758 国際公開第2015/127003号WO2015/127003 国際公開第2015/126765号WO2015/126765 国際公開第2015/126751号WO2015/126751 国際公開第2015/123230号WO2015/123230 国際公開第2015/123182号WO2015/123182 国際公開第2016/033009号WO2016/033009 国際公開第2016/005878号WO 2016/005878 国際公開第2016/012930号WO 2016/012930 国際公開第2016/012913号WO2016/012913 国際公開第2016/194806号WO2016/194806 国際公開第2017/006260号WO2017/006260 国際公開第2017/006261号WO2017/006261 国際公開第2017/006280号WO2017/006280 国際公開第2017/006281号WO2017/006281 国際公開第2017/025914号WO2017/025914 国際公開第2017/025915号WO2017/025915 国際公開第2017/025916号WO2017/025916 国際公開第2017/025917号WO2017/025917 国際公開第2017/025864号WO2017/025864 国際公開第2017/025913号WO2017/025913 国際公開第2017/029631号WO2017/029631 国際公開第2017/046707号WO2017/046707 国際公開第2017/093938号International Publication No. 2017/093938 国際公開第2017/093937号WO2017/093937 国際公開第2017/093932号WO2017/093932 国際公開第2017/093930号WO2017/093930 国際公開第2017/195111号WO2017/195111 国際公開第2017/195112号WO2017/195112 国際公開第2017/195113号WO2017/195113 国際公開第2018/020357号WO 2018/020357 国際公開第2018/064080号WO2018/064080 国際公開第2018/127801号WO 2018/127801 国際公開第2018/127800号WO 2018/127800 国際公開第2018/174320号WO2018/174320
　本発明の目的は、抗ウイルス活性を有する新規化合物を提供することである。本発明は、好ましくは、ＨＩＶ複製阻害作用を有する抗ＨＩＶ薬を提供する。より好ましくは、従来の抗ＨＩＶ薬とは基本骨格が異なり、またＨＩＶの変異株や耐性株にも有効な新規の抗ＨＩＶ薬を提供する。さらに本発明は、それらの合成中間体や製法も提供する。 An object of the present invention is to provide novel compounds with antiviral activity. The present invention preferably provides an anti-HIV drug having HIV replication inhibitory activity. More preferably, it provides a novel anti-HIV drug that has a different basic skeleton from conventional anti-HIV drugs and is effective against HIV mutant strains and resistant strains. Furthermore, the present invention also provides synthetic intermediates and production methods thereof.
　本発明者らは鋭意検討した結果、縮合複素環誘導体がＨＩＶ複製阻害剤として有用であることを見出した。さらに、本発明化合物およびそれらを含有する医薬が、抗ウイルス薬（例：抗レトロウイルス薬、抗ＨＩＶ薬、抗ＨＴＬＶ－１（Ｈｕｍａｎ　Ｔ　ｃｅｌｌ　ｌｅｕｋｅｍｉａ　ｖｉｒｕｓ　ｔｙｐｅ　１：ヒトＴ細胞白血病ウイルス１型）薬、抗ＦＩＶ（Ｆｅｌｉｎｅ　ｉｍｍｕｎｏｄｅｆｉｃｉｅｎｃｙ　ｖｉｒｕｓ　：ネコエイズウイルス）薬、抗ＳＩＶ（Ｓｉｍｉａｎ　ｉｍｍｕｎｏｄｅｆｉｃｉｅｎｃｙ　ｖｉｒｕｓ　：サルエイズウイルス）薬）、特に抗ＨＩＶ薬、抗ＡＩＤＳ薬、またはその関連疾患の治療薬等として有用であることを見出し、以下に示す本発明を完成した。
　本発明は以下に関する。 As a result of extensive studies, the present inventors have found that fused heterocyclic derivatives are useful as HIV replication inhibitors. Furthermore, the compounds of the present invention and pharmaceuticals containing them are antiviral agents (e.g., antiretroviral agents, anti-HIV agents, anti-HTLV-1 (Human T cell leukemia virus type 1: human T cell leukemia virus type 1) agents). , anti-FIV (Feline immunodeficiency virus: feline AIDS virus) drug, anti-SIV (Simian immunodeficiency virus: monkey AIDS virus) drug), especially anti-HIV drug, anti-AIDS drug, or therapeutic drug for related diseases etc. The inventors have completed the present invention described below.
The present invention relates to:
［１］式（Ｉ）：
Figure JPOXMLDOC01-appb-C000013
（式中、
　Ａ１、Ａ２およびＡ３はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ａ１、Ａ２およびＡ３を構成原子として含む環の環構成原子の窒素原子の数は、０～１個であり、
　Ｂ１、Ｂ２、Ｂ３およびＢ４はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
　Ｘ１は、ＣＲ４Ｒ５、ＮＲ６、ＯまたはＳであり、
　Ｒ４およびＲ５は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のアルキニルであり、
　Ｒ６は水素または置換もしくは非置換のアルキルであり、
　Ｘ２は、ＣＲ７Ｒ８、ＮＲ９、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、または
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよく、
　Ｒ９は水素または置換もしくは非置換のアルキルであり、
　Ｒ１は、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基であり、
隣接する２つのＲ２が結合する環構成原子と一緒になって、置換若しくは非置換の芳香族炭素環、置換若しくは非置換の芳香族複素環、置換若しくは非置換の非芳香族炭素環または置換若しくは非置換の非芳香族複素環を形成し、
ｎが３の場合はさらに、
　Ｒ２は、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
Figure JPOXMLDOC01-appb-C000014
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－であり、
置換基群γ：ハロゲン、ヒドロキシ、カルボキシ、アルキルオキシ、ハロアルキルオキシ、アルケニルオキシ、アルキニルオキシ、スルファニル、シアノ、アルキル、ハロアルキル、ヒドロキシアルキル、アルケニル、アルキニル、アルキルオキシアルキル、アルキルカルボニル、ハロアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アミノ、アルキルアミノ、アルキルスルホニル、アルキルオキシカルボニルおよびシクロプロパニル；
置換基群γ’：置換基群γおよびオキソ）であり、
　Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、または置換もしくは非置換のスルファモイルであり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく、
　ｎは２～３の整数であり、
　ｍは０～４の整数である）で示される化合物またはその製薬上許容される塩。
［２］Ｒ１が、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である、［１］記載の化合物またはその製薬上許容される塩。
［３］Ｒ１が、置換もしくは非置換のフェニルまたは置換もしくは非置換のピペリジニルである、［１］記載の化合物またはその製薬上許容される塩。
［４］Ｒ１が、
Figure JPOXMLDOC01-appb-C000015
（式中、Ｒ１Ａは、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルであり、Ｒ１Ｂは、それぞれ独立して、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルである）で示される基である、［１］記載の化合物またはその製薬上許容される塩。
［５］
Figure JPOXMLDOC01-appb-C000016
で示される基が、
Figure JPOXMLDOC01-appb-C000017
（式中、環ＣはＲ２Ａで置換されていてもよい芳香族炭素環、Ｒ２Ａで置換されていてもよい芳香族複素環、Ｒ２Ａで置換されていてもよい非芳香族炭素環またはＲ２Ａで置換されていてもよい非芳香族複素環であり、
　Ｒ１は［１］と同意義であり、
　ｎ－２は０または１であり、
　Ｒ２はヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニルまたは置換もしくは非置換のアルキルオキシであり、
Ｒ２Ａはハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、または以下の式：
Figure JPOXMLDOC01-appb-C000018
（式中、各記号は［１］と同意義）で示される基である、［１］～［４］のいずれか記載の化合物またはその製薬上許容される塩。
［６］環ＣがＲ２Ａで置換されていてもよい単環の芳香族複素環である、［５］記載の化合物またはその製薬上許容される塩。
［７］環ＣがＲ２Ａで置換されていてもよい５員の芳香族複素環である、［５］記載の化合物またはその製薬上許容される塩。
［８］環ＣがＲ２Ａで置換されていてもよいピロール環、Ｒ２Ａで置換されていてもよいピラゾール環、Ｒ２Ａで置換されていてもよいチオフェン環、Ｒ２Ａで置換されていてもよいフラン環、Ｒ２Ａで置換されていてもよいイミダゾール環、Ｒ２Ａで置換されていてもよいチアゾール環、Ｒ２Ａで置換されていてもよいオキサゾール環、またはＲ２Ａで置換されていてもよいトリアゾール環である、［５］記載の化合物またはその製薬上許容される塩。
［９］
Figure JPOXMLDOC01-appb-C000019
で示される基が、
Figure JPOXMLDOC01-appb-C000020
（式中、Ｒ２Ａは、それぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
Figure JPOXMLDOC01-appb-C000021
（式中、各記号は［１］と同意義）であり、
ｐは０～４の整数であり、Ｒ１は［１］と同意義である。）で示される基である、［１］～［４］のいずれかに記載の化合物またはその製薬上許容される塩。
［１０］Ｒ２Ａが、それぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である、［１］～［９］記載の化合物またはその製薬上許容される塩。
［１１］
Figure JPOXMLDOC01-appb-C000022
で示される基が、
Figure JPOXMLDOC01-appb-C000023
（式中、環Ｄは置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、ｍ－２は０～２の整数であり、Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルである）で示される基である、［１］～［１０］のいずれかに記載の化合物またはその製薬上許容される塩。
［１２］環Ｄが置換もしくは非置換のベンゼン環、置換もしくは非置換のピリジン環、置換もしくは非置換のシクロペンタン環、置換もしくは非置換のシクロヘキサン環または置換もしくは非置換のシクロヘプタン環である、［１１］記載の化合物またはその製薬上許容される塩。
［１３］
Figure JPOXMLDOC01-appb-C000024
で示される基が、
Figure JPOXMLDOC01-appb-C000025
（式中、Ｒ３Ａはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、または置換もしくは非置換のアルキニルオキシであり、ｑは０～５の整数である。）で示される基である、［１１］記載の化合物またはその製薬上許容される塩。
［１４］Ｘ１は、ＮＲ６であり、
　Ｒ６は水素または置換もしくは非置換のアルキルであり、
　Ｘ２は、ＣＲ７Ｒ８、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよい、［１］～［１３］のいずれかに記載の化合物またはその製薬上許容される塩。
［１５］化合物Ｉ－００１５、Ｉ－００１９、Ｉ－００４５、Ｉ－００４８、Ｉ－００４９、Ｉ－００５６、Ｉ－００７３、Ｉ－００７５、Ｉ－００７８、Ｉ－００７９、Ｉ－００８４、Ｉ－００９２、Ｉ－００９７、Ｉ－００９８、Ｉ－０１１８、Ｉ－０１４６、Ｉ－０１５１、Ｉ－０１７２、Ｉ－０１８９およびＩ－０１９０からなる群から選択される、請求項１記載の化合物またはその製薬上許容される塩。
［１６］［１］～［１５］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［１７］抗ウイルス剤である、［１６］記載の医薬組成物。
［１８］抗ＨＩＶ剤である、［１６］記載の医薬組成物。
［１９］［１］～［１５］のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、ＨＩＶ感染症の治療および/または予防方法。
［２０］ＨＩＶ感染症の治療および/または予防に使用するための、［１］～［１５］のいずれかに記載の化合物またはその製薬上許容される塩。
［２１］ＨＩＶ感染症の治療剤および/または予防剤を製造するための、［１］～［１５］のいずれかに記載の化合物またはその製薬上許容される塩の使用。 [1] Formula (I):
Figure JPOXMLDOC01-appb-C000013
(In the formula,
A 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 1,
B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms The number of nitrogen atoms is 0 to 2,
X 1 is CR 4 R 5 , NR 6 , O or S;
R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R 6 is hydrogen or substituted or unsubstituted alkyl,
X 2 is CR 7 R 8 , NR 9 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl, or together with the carbon atom to which R 7 and R 8 are attached, substituted or unsubstituted may form a substituted exomethylene or together with the carbon atom to which R7 and R8 are attached may form a substituted or unsubstituted non-aromatic carbocyclic ring,
R9 is hydrogen or substituted or unsubstituted alkyl;
R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group is a cyclic group;
A substituted or unsubstituted aromatic carbocyclic ring , a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, or a substituted or to form an unsubstituted non-aromatic heterocycle,
Further, when n is 3,
R 2 is hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenyl sulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyl oxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or non- substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or the following formulas:
Figure JPOXMLDOC01-appb-C000014
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring that may be substituted or a non-aromatic heterocyclic ring that may be substituted with a substituent group γ', and ring G is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted non-aromatic carbocyclic ring or substituted or unsubstituted non-aromatic heterocyclic ring, L is a single bond, C1-C3 alkylene, —C(=O)— or —SO 2 - and
Substituent group γ: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, cyano, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl , alkynylcarbonyl, amino, alkylamino, alkylsulfonyl, alkyloxycarbonyl and cyclopropanyl;
Substituent group γ': substituent group γ and oxo),
Each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl and/or a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted may form a non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
n is an integer of 2 to 3,
m is an integer of 0 to 4) or a pharmaceutically acceptable salt thereof.
[2] The compound of [ 1 ] or a pharmaceutically acceptable salt thereof, wherein R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
[3] The compound of [ 1] or a pharmaceutically acceptable salt thereof, wherein R1 is substituted or unsubstituted phenyl or substituted or unsubstituted piperidinyl.
[4] R 1 is
Figure JPOXMLDOC01-appb-C000015
(wherein R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl) The compound of [1] or a pharmaceutically acceptable salt thereof, which is a group.
[5]
Figure JPOXMLDOC01-appb-C000016
The group represented by
Figure JPOXMLDOC01-appb-C000017
(Wherein, ring C is an aromatic carbocyclic ring optionally substituted with R 2A , an aromatic heterocyclic ring optionally substituted with R 2A , a non-aromatic carbocyclic ring optionally substituted with R 2A , or a non-aromatic heterocyclic ring optionally substituted with R 2A ,
R 1 has the same meaning as [1];
n-2 is 0 or 1;
R2 is hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkyloxy;
R 2A is halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or the following formulas:
Figure JPOXMLDOC01-appb-C000018
(wherein each symbol has the same meaning as in [1]) or a pharmaceutically acceptable salt thereof according to any one of [1] to [4].
[6] The compound of [5] or a pharmaceutically acceptable salt thereof, wherein Ring C is a monocyclic aromatic heterocyclic ring optionally substituted with R2A .
[7] The compound of [5] or a pharmaceutically acceptable salt thereof, wherein ring C is a 5-membered aromatic heterocyclic ring optionally substituted with R2A .
[8] Pyrrole ring optionally substituted with R 2A , pyrazole ring optionally substituted with R 2A , thiophene ring optionally substituted with R 2A , ring C optionally substituted with R 2A furan ring optionally substituted with R2A , imidazole ring optionally substituted with R2A, thiazole ring optionally substituted with R2A , oxazole ring optionally substituted with R2A , or optionally substituted with R2A The compound of [5] or a pharmaceutically acceptable salt thereof, which is a triazole ring.
[9]
Figure JPOXMLDOC01-appb-C000019
The group represented by
Figure JPOXMLDOC01-appb-C000020
(wherein each R 2A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or the following formulas:
Figure JPOXMLDOC01-appb-C000021
(Wherein, each symbol has the same meaning as [1]),
p is an integer of 0 to 4, and R 1 has the same meaning as [1]. ), the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
[10] Each R 2A is independently hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic , a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, the compound according to [1] to [9] or a pharmaceutically acceptable salt thereof.
[11]
Figure JPOXMLDOC01-appb-C000022
The group represented by
Figure JPOXMLDOC01-appb-C000023
(Wherein, ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; , m−2 is an integer of 0 to 2, and each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyl oxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocycle formula group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy , substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon ring sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl) The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [10], which is a group represented by
[12] Ring D is a substituted or unsubstituted benzene ring, substituted or unsubstituted pyridine ring, substituted or unsubstituted cyclopentane ring, substituted or unsubstituted cyclohexane ring or substituted or unsubstituted cycloheptane ring; [11] The compound of the description or a pharmaceutically acceptable salt thereof.
[13]
Figure JPOXMLDOC01-appb-C000024
The group represented by
Figure JPOXMLDOC01-appb-C000025
(wherein each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy, q is an integer of 0 to 5.) The compound according to [11] or a pharmaceutical product thereof Salt tolerable above.
[14] X 1 is NR 6 ;
R 6 is hydrogen or substituted or unsubstituted alkyl,
X 2 is CR 7 R 8 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [13], which may form a substituted non-aromatic carbocyclic ring.
[15] Compounds I-0015, I-0019, I-0045, I-0048, I-0049, I-0056, I-0073, I-0075, I-0078, I-0079, I-0084, I- 1. The compound or pharmaceutical of claim 1, which is selected from the group consisting of 0092, 1-0097, 1-0098, 1-0118, 1-0146, 1-0151, 1-0172, 1-0189 and 1-0190 Salts tolerable above.
[16] A pharmaceutical composition containing the compound of any one of [1] to [15] or a pharmaceutically acceptable salt thereof.
[17] The pharmaceutical composition of [16], which is an antiviral agent.
[18] The pharmaceutical composition of [16], which is an anti-HIV agent.
[19] A method for treating and/or preventing HIV infection, which comprises administering the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof.
[20] The compound of any one of [1] to [15] or a pharmaceutically acceptable salt thereof for use in treating and/or preventing HIV infection.
[21] Use of the compound according to any one of [1] to [15] or a pharmaceutically acceptable salt thereof for manufacturing a therapeutic and/or preventive agent for HIV infection.
［１’］式（Ｉ）：
Figure JPOXMLDOC01-appb-C000026
（式中、
　Ａ１、Ａ２およびＡ３はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ａ１、Ａ２およびＡ３を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
　Ｂ１、Ｂ２、Ｂ３およびＢ４はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
　Ｘ１は、ＣＲ４Ｒ５、ＮＲ６、ＯまたはＳであり、
　Ｒ４およびＲ５は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のアルキニルであり、
　Ｒ６は水素または置換もしくは非置換のアルキルであり、
　Ｘ２は、ＣＲ７Ｒ８、ＮＲ９、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよく、
　Ｒ９は水素または置換もしくは非置換のアルキルであり、
　Ｒ１は、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基であり、
　Ｒ２はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
Figure JPOXMLDOC01-appb-C000027
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－であり、
置換基群γ：ハロゲン、ヒドロキシ、カルボキシ、アルキルオキシ、ハロアルキルオキシ、アルケニルオキシ、アルキニルオキシ、スルファニル、シアノ、アルキル、ハロアルキル、ヒドロキシアルキル、アルケニル、アルキニル、アルキルオキシアルキル、アルキルカルボニル、ハロアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アミノ、アルキルアミノ、アルキルスルホニル、アルキルオキシカルボニルおよびシクロプロパニル；
置換基群γ’：置換基群γおよびオキソ）であり、および／または、隣接する２つのＲ２が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく、
　Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、または置換もしくは非置換のスルファモイルであり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく、
　ｎは０～３の整数であり、
　ｍは０～４の整数である）で示される化合物またはその製薬上許容される塩。
［２’］Ｒ１が、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である、［１’］記載の化合物またはその製薬上許容される塩。
［３’］Ｒ１が、置換もしくは非置換のフェニルまたは置換もしくは非置換のピペリジニルである、［１’］記載の化合物またはその製薬上許容される塩。
［４’］Ｒ１が、
Figure JPOXMLDOC01-appb-C000028
（式中、Ｒ１Ａは、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルであり、Ｒ１Ｂは、それぞれ独立して、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルである）で示される基である、［１’］記載の化合物またはその製薬上許容される塩。
［５’］
Figure JPOXMLDOC01-appb-C000029
で示される基が、
Figure JPOXMLDOC01-appb-C000030
（式中、環Ｃは置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、Ｒ１は［１’］と同意義であり、ｎ－２は０または１であり、Ｒ２はヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルである）で示される基である、［１’］～［４’］のいずれか記載の化合物またはその製薬上許容される塩。
［６’］環Ｃが置換もしくは非置換の芳香族複素環である、［５’］記載の化合物またはその製薬上許容される塩。
［７’］環Ｃが置換もしくは非置換の５員の芳香族複素環である、［５’］記載の化合物またはその製薬上許容される塩。
［８’］環Ｃが置換もしくは非置換のピロール環、置換もしくは非置換のピラゾール環、置換もしくは非置換のチオフェン環、置換もしくは非置換のフラン環、置換もしくは非置換のイミダゾール環、置換もしくは非置換のチアゾール環、置換もしくは非置換のオキサゾール環、または置換もしくは非置換のトリアゾール環である、［５’］記載の化合物またはその製薬上許容される塩。
［９’］
Figure JPOXMLDOC01-appb-C000031
で示される基が、
Figure JPOXMLDOC01-appb-C000032
（式中、Ｒ２Ａは、それぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
Figure JPOXMLDOC01-appb-C000033
（式中、各記号は［１’］と同意義）であり、
ｐは０～４の整数であり、Ｒ１は［１’］と同意義である。）で示される基である、［１’］～［８’］のいずれかに記載の化合物またはその製薬上許容される塩。
［１０’］Ｒ２Ａが、それぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である、［９’］記載の化合物またはその製薬上許容される塩。
［１１’］
Figure JPOXMLDOC01-appb-C000034
で示される基が、
Figure JPOXMLDOC01-appb-C000035
（式中、環Ｄは置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、ｍ－２は０～２の整数であり、Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルである）で示される基である、［１’］～［１０’］のいずれかに記載の化合物又はその製薬上許容される塩。
［１２’］環Ｄが置換もしくは非置換のベンゼン環、置換もしくは非置換のピリジン環、置換もしくは非置換のシクロペンタン環、置換もしくは非置換のシクロヘキサン環または置換もしくは非置換のシクロヘプタン環である、［１１’］記載の化合物またはその製薬上許容される塩。
［１３’］
Figure JPOXMLDOC01-appb-C000036
で示される基が、
Figure JPOXMLDOC01-appb-C000037
（式中、Ｒ３Ａはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシであり、ｑは０～５の整数である。）で示される基である、［１１’］記載の化合物またはその製薬上許容される塩。
［１４’］以下のいずれかの式：
Figure JPOXMLDOC01-appb-C000038
（式中、
　Ｒ６は、水素またはハロゲンで置換されてもよいＣ１－Ｃ６アルキルであり、
　Ｒ１は、置換基群Ｆで置換されていてもよい芳香族炭素環式基、置換基群Ｆで置換されていてもよい非芳香族炭素環式基、置換基群Ｆで置換されていてもよい芳香族複素環式基、または置換基群Ｆで置換されていてもよい非芳香族複素環式基であり、
　置換基群Ｆ：ハロゲン、アルキルおよびアルキルオキシであり、
　Ｒ２Ａは、Ｃ１－Ｃ３アルキルで置換されてもよいアミノ、ハロゲンで置換されてもよいＣ１－Ｃ６アルキル、置換基群Ｇで置換されてもよい６員の芳香族炭素環式基、置換基群Ｇで置換されてもよい６員の芳香族複素環式基、ハロゲンで置換されてもよい３～６員の非芳香族炭素環式基、またはハロゲンで置換されてもよい４～６員の非芳香族複素環式基であり、
　置換基群Ｇ：ハロゲン、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３ハロアルキル、Ｃ１－Ｃ３アルキルオキシ、ハロＣ１－Ｃ３アルキルオキシおよびＣ１－Ｃ３アルキルアミノ、
　Ｒ２Ｂは、置換基群Ｅで置換されてもよいＣ１－Ｃ６アルキルであり、
　置換基群Ｅ：置換基群Ｇで置換されてもよい芳香族炭素環式基および置換基群Ｇで置換されてもよい芳香族複素環式基、
　Ｒ２Ｃは、水素、ハロゲンまたはＣ１－Ｃ６アルキルであり、
　Ｒ３は、それぞれ独立して、Ｃ１－Ｃ６アルキルであり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、Ｃ１－Ｃ６アルキルで置換されてもよい芳香族炭素環、Ｃ１－Ｃ６アルキルで置換されてもよい芳香族複素環またはＣ１－Ｃ６アルキルで置換されてもよい非芳香族炭素環を形成してもよく、
　ｍは０～４の整数である）で示される化合物またはその製薬上許容される塩。
［１５’］Ｒ１が、
Figure JPOXMLDOC01-appb-C000039
（式中、Ｒ１Ａは、水素、ハロゲンまたはＣ１－Ｃ６アルキルである）で示される基である、［１４’］記載の化合物またはその製薬上許容される塩。
［１６’］Ｒ２Ａが、置換基群Ｇで置換されてもよい６員の芳香族炭素環式基である、［１４］または［１５’］記載の化合物またはその製薬上許容される塩。
［１７’］隣接する２つのＲ３が結合する環構成原子と一緒になって、Ｃ１－Ｃ６アルキルで置換されてもよい６員の芳香族炭素環、またはＣ１－Ｃ６アルキルで置換されてもよい５～６員の非芳香族炭素環を形成し、更にＲ３が、それぞれ独立して、Ｃ１－Ｃ６アルキルであり、ｍは２～４の整数である、［１４’］～［１６’］のいずれかに記載の化合物またはその製薬上許容される塩。
［１８’］Ｒ３が、それぞれ独立して、Ｃ１－Ｃ６アルキルである、［１４’］～［１６’］のいずれかに記載の化合物またはその製薬上許容される塩。
［１９’］Ｘ１は、ＮＲ６であり、
　Ｒ６は水素または置換もしくは非置換のアルキルであり、
　Ｘ２は、ＣＲ７Ｒ８、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよい、［１’］～［１３’］のいずれかに記載の化合物またはその製薬上許容される塩。
［２０’］化合物Ｉ－００１５、Ｉ－００１９、Ｉ－００４５、Ｉ－００４８、Ｉ－００４９、Ｉ－００５６、Ｉ－００７３、Ｉ－００７５、Ｉ－００７８、Ｉ－００７９、Ｉ－００８４、Ｉ－００９２、Ｉ－００９７、Ｉ－００９８、Ｉ－０１１８、Ｉ－０１４６、Ｉ－０１５１、Ｉ－０１７２、Ｉ－０１８９、Ｉ－０１９０、Ｉ－０１２２’、Ｉ－０１３８’、Ｉ－０１３９’およびＩ－０１８９’からなる群から選択される、請求項１記載の化合物またはその製薬上許容される塩。
［２１’］［１’］～［２０’］のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
［２２’］抗ウイルス剤である、［２１’］記載の医薬組成物。
［２３’］抗ＨＩＶ剤である、［２１’］記載の医薬組成物。
［２４’］［１’］～［２０’］のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、ＨＩＶ感染症の治療および/または予防方法。
［２５’］ＨＩＶ感染症の治療および/または予防に使用するための、［１’］～［２０’］のいずれかに記載の化合物またはその製薬上許容される塩。
［２６’］ＨＩＶ感染症の治療剤および/または予防剤を製造するための、［１’］～［２０’］のいずれかに記載の化合物またはその製薬上許容される塩の使用。 [1′] Formula (I):
Figure JPOXMLDOC01-appb-C000026
(In the formula,
A 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 2,
B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms the number of nitrogen atoms is 0 to 2,
X 1 is CR 4 R 5 , NR 6 , O or S;
R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
R 6 is hydrogen or substituted or unsubstituted alkyl,
X 2 is CR 7 R 8 , NR 9 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted may form a substituted non-aromatic carbocycle,
R9 is hydrogen or substituted or unsubstituted alkyl;
R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group is a cyclic group;
R 2 is each independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or The formula below:
Figure JPOXMLDOC01-appb-C000027
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring that may be substituted or a non-aromatic heterocyclic ring that may be substituted with a substituent group γ', and ring G is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted non-aromatic carbocyclic ring or substituted or unsubstituted non-aromatic heterocyclic ring, L is a single bond, C1-C3 alkylene, —C(=O)— or —SO 2 - and
Substituent group γ: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, cyano, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl , alkynylcarbonyl, amino, alkylamino, alkylsulfonyl, alkyloxycarbonyl and cyclopropanyl;
Substituent Group γ′: Substituent Group γ and oxo) and/or together with the ring atoms to which two adjacent R 2 are bonded, a substituted or unsubstituted aromatic carbocyclic ring, substituted or may form an unsubstituted heteroaromatic ring, a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle,
Each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl and/or a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted may form a non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
n is an integer from 0 to 3,
m is an integer of 0 to 4) or a pharmaceutically acceptable salt thereof.
[2'] The compound of [1'], wherein R 1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof .
[3'] The compound of [1'] or a pharmaceutically acceptable salt thereof, wherein R1 is substituted or unsubstituted phenyl or substituted or unsubstituted piperidinyl.
[4′]R 1 is
Figure JPOXMLDOC01-appb-C000028
(wherein R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl) The compound of [1′] or a pharmaceutically acceptable salt thereof, which is a group.
[5']
Figure JPOXMLDOC01-appb-C000029
The group represented by
Figure JPOXMLDOC01-appb-C000030
(Wherein, ring C is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; , R 1 has the same meaning as [1′], n−2 is 0 or 1, R 2 is hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl , substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic ringsulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbon ring carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl) or a pharmaceutically acceptable salt thereof according to any one of [1′] to [4′].
[6'] The compound of [5'] or a pharmaceutically acceptable salt thereof, wherein Ring C is a substituted or unsubstituted aromatic heterocyclic ring.
[7'] The compound of [5'] or a pharmaceutically acceptable salt thereof, wherein ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic ring.
[8′] Ring C is substituted or unsubstituted pyrrole ring, substituted or unsubstituted pyrazole ring, substituted or unsubstituted thiophene ring, substituted or unsubstituted furan ring, substituted or unsubstituted imidazole ring, substituted or unsubstituted The compound of [5'], which is a substituted thiazole ring, substituted or unsubstituted oxazole ring, or substituted or unsubstituted triazole ring, or a pharmaceutically acceptable salt thereof.
[9']
Figure JPOXMLDOC01-appb-C000031
The group represented by
Figure JPOXMLDOC01-appb-C000032
(wherein each R 2A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or the following formulae:
Figure JPOXMLDOC01-appb-C000033
(Wherein, each symbol has the same meaning as [1']),
p is an integer of 0 to 4, and R 1 has the same meaning as [1']. ), the compound according to any one of [1′] to [8′] or a pharmaceutically acceptable salt thereof.
[10′]R 2A are each independently hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocycle The compound of [9'], which is a formula group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
[11']
Figure JPOXMLDOC01-appb-C000034
The group represented by
Figure JPOXMLDOC01-appb-C000035
(Wherein, ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; , m−2 is an integer of 0 to 2, and each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyl oxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocycle formula group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy , substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon ring sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl) The compound or a pharmaceutically acceptable salt thereof according to any one of [1′] to [10′], which is a group represented by
[12'] ring D is a substituted or unsubstituted benzene ring, substituted or unsubstituted pyridine ring, substituted or unsubstituted cyclopentane ring, substituted or unsubstituted cyclohexane ring or substituted or unsubstituted cycloheptane ring , [11′] or a pharmaceutically acceptable salt thereof.
[13']
Figure JPOXMLDOC01-appb-C000036
The group represented by
Figure JPOXMLDOC01-appb-C000037
(wherein each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy, q is an integer of 0 to 5.) The compound according to [11′] or a pharmaceutical product thereof Salt tolerable above.
[14′] Any of the following formulas:
Figure JPOXMLDOC01-appb-C000038
(In the formula,
R 6 is hydrogen or C1-C6 alkyl optionally substituted with halogen;
R 1 is an aromatic carbocyclic group optionally substituted with substituent group F, a non-aromatic carbocyclic group optionally substituted with substituent group F, substituted with substituent group F is an aromatic heterocyclic group which may be substituted, or a non-aromatic heterocyclic group which may be substituted with substituent group F,
Substituent group F: halogen, alkyl and alkyloxy,
R 2A is amino optionally substituted with C1-C3 alkyl, C1-C6 alkyl optionally substituted with halogen, 6-membered aromatic carbocyclic group optionally substituted with substituent group G, substituent 6-membered aromatic heterocyclic group optionally substituted by group G, 3-6 membered non-aromatic carbocyclic group optionally substituted with halogen, or 4-6 membered optionally substituted with halogen is a non-aromatic heterocyclic group of
Substituent Group G: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy and C1-C3 alkylamino,
R 2B is C1-C6 alkyl optionally substituted by substituent group E,
Substituent Group E: an aromatic carbocyclic group optionally substituted with Substituent Group G and an aromatic heterocyclic group optionally substituted with Substituent Group G;
R 2C is hydrogen, halogen or C1-C6 alkyl;
Each R 3 is independently C1-C6 alkyl, and/or an aromatic optionally substituted with C1-C6 alkyl together with the ring atoms to which the two adjacent R 3s are bonded may form a carbocyclic ring, an aromatic heterocyclic ring optionally substituted with C1-C6 alkyl or a non-aromatic carbocyclic ring optionally substituted with C1-C6 alkyl,
m is an integer of 0 to 4) or a pharmaceutically acceptable salt thereof.
[15′]R 1 is
Figure JPOXMLDOC01-appb-C000039
The compound of [14′] or a pharmaceutically acceptable salt thereof, which is a group represented by (wherein R 1A is hydrogen, halogen or C1-C6 alkyl).
[16'] The compound of [14] or [15'], wherein R 2A is a 6-membered aromatic carbocyclic group optionally substituted by Substituent Group G, or a pharmaceutically acceptable salt thereof.
[17′] A 6-membered aromatic carbocyclic ring optionally substituted with C1-C6 alkyl together with the ring-constituting atoms to which two adjacent R 3 are bonded, or optionally substituted with C1-C6 alkyl forming a good 5-6 membered non-aromatic carbocyclic ring, and each R 3 is independently C1-C6 alkyl, m is an integer of 2-4, [14′]-[16′ ] or a pharmaceutically acceptable salt thereof.
[18'] The compound or a pharmaceutically acceptable salt thereof according to any one of [14'] to [16'], wherein each R 3 is independently C1-C6 alkyl.
[19′]X 1 is NR 6 ;
R 6 is hydrogen or substituted or unsubstituted alkyl,
X 2 is CR 7 R 8 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of [1′] to [13′], which may form a substituted non-aromatic carbocyclic ring.
[20′] Compounds I-0015, I-0019, I-0045, I-0048, I-0049, I-0056, I-0073, I-0075, I-0078, I-0079, I-0084, I -0092, 1-0097, 1-0098, 1-0118, 1-0146, 1-0151, 1-0172, 1-0189, 1-0190, 1-0122', 1-0138', 1-0139' and The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of I-0189'.
[21'] A pharmaceutical composition containing the compound of any one of [1'] to [20'] or a pharmaceutically acceptable salt thereof.
[22'] The pharmaceutical composition of [21'], which is an antiviral agent.
[23'] The pharmaceutical composition of [21'], which is an anti-HIV agent.
[24'] A method for treating and/or preventing HIV infection, which comprises administering the compound according to any one of [1'] to [20'] or a pharmaceutically acceptable salt thereof.
[25'] The compound of any one of [1'] to [20'] or a pharmaceutically acceptable salt thereof for use in treating and/or preventing HIV infection.
[26'] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of [1'] to [20'] for producing a therapeutic and/or prophylactic agent for HIV infection.
　本発明は更に以下の発明を提供する。
　上記化合物またはその製薬上許容される塩をヒトに投与することを特徴とする、ウイルス感染症（例：ＨＩＶ感染症）の治療および／または予防方法。
ウイルス感染症（例：ＨＩＶ感染症）の治療および／または予防のための上記化合物またはその製薬上許容される塩。 The present invention further provides the following inventions.
A method for treating and/or preventing a viral infection (eg, HIV infection), which comprises administering the above compound or a pharmaceutically acceptable salt thereof to a human.
A compound or a pharmaceutically acceptable salt thereof for the treatment and/or prevention of viral infections (eg, HIV infection).
　本発明化合物は、ウイルス、特にＨＩＶ（例：ＨＩＶ－１）やその変異ウイルス、耐性ウイルスに対して複製阻害活性を有する。よって、ウイルス感染症（例：エイズ）等の予防および／または治療に有用である。 The compound of the present invention has replication-inhibitory activity against viruses, especially HIV (eg, HIV-1), its mutant viruses, and resistant viruses. Therefore, it is useful for prevention and/or treatment of viral infections (eg, AIDS).
　以下に本明細書において用いられる各用語の意味を説明する。各用語は特に断りのない限り、単独で用いられる場合も、または他の用語と組み合わせて用いられる場合も、同一の意味で用いられる。
　「からなる」という用語は、構成要件のみを有することを意味する。
　「含む」という用語は、構成要件に限定されず、記載されていない要素を排除しないことを意味する。
　以下、本発明について実施形態を示しながら説明する。本明細書の全体にわたり、単数形の表現は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。従って、単数形の冠詞（例えば、英語の場合は「ａ」、「ａｎ」、「ｔｈｅ」など）は、特に言及しない限り、その複数形の概念をも含むことが理解されるべきである。
　また、本明細書において使用される用語は、特に言及しない限り、当上記分野で通常用いられる意味で用いられることが理解されるべきである。したがって、他に定義されない限り、本明細書中で使用される全ての専門用語および科学技術用語は、本発明の属する分野の当業者によって一般的に理解されるのと同じ意味を有する。矛盾する場合、本明細書（定義を含めて）が優先する。 The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether it is used alone or in combination with other terms.
The term "consisting of" means having only constituent elements.
The term "comprising" is meant to be open to the elements and does not exclude elements not listed.
Hereinafter, the present invention will be described while showing embodiments. It should be understood that throughout this specification, expressions in the singular also include the concept of the plural unless specifically stated otherwise. Thus, articles in the singular (eg, “a,” “an,” “the,” etc. in the English language) should be understood to include their plural concepts as well, unless specifically stated otherwise.
In addition, it should be understood that the terms used in this specification have the meanings commonly used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present specification (including definitions) will control.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、およびヨウ素原子を包含する。特にフッ素原子、および塩素原子が好ましい。 "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom and a chlorine atom are particularly preferred.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖または分枝状の炭化水素基を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　「アルキル」の好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 "Alkyl" includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms. do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , isooctyl, n-nonyl, n-decyl and the like.
Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. More preferred embodiments include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
　「アルケニル」とは、任意の位置に１以上の二重結合を有する、炭素数２～１５、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖または分枝状の炭化水素基を包含する。例えば、ビニル、アリル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
　「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 The term “alkenyl” refers to a group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. straight or branched chain hydrocarbon groups. For example vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl etc.
Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl and butenyl.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖または分枝状の炭化水素基を包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等を包含する。これらはさらに任意の位置に二重結合を有していてもよい。
　「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 The term "alkynyl" refers to a group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. It includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. These may further have a double bond at any position.
Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl and pentynyl.
　「アルキレン」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖または分枝状の２価の炭化水素基を包含する。例えば、メチレン、エチレン、トリメチレン、プロピレン、テトラメチレン、ペンタメチレン、ヘキサメチレン等が挙げられる。 "Alkylene" means a linear or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms. contains groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
　「芳香族炭素環式基」とは、単環または２環以上の、芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
　「芳香族炭素環式基」の好ましい態様として、フェニルが挙げられる。 An "aromatic carbocyclic group" means a monocyclic or bicyclic or more aromatic hydrocarbon group. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
A preferred embodiment of the "aromatic carbocyclic group" is phenyl.
　「芳香族炭素環」とは、上記「芳香族炭素環式基」から導かれる環を意味する。 "Aromatic carbocyclic ring" means a ring derived from the above "aromatic carbocyclic group".
　「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の「非芳香族炭素環式基」は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000040
　単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。例えば、シクロアルキル、シクロアルケニル等が挙げられる。
　「シクロアルキル」としては、炭素数３～１０が好ましく、より好ましくは炭素数３～７であり、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル等が挙げられる。
　「シクロアルケニル」としては、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
　２環以上の非芳香族炭素環式基としては、炭素数８～１３が好ましく、より好ましくは炭素数９～１０である。例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル、ジヒドロインデニル等が挙げられる。 A "non-aromatic carbocyclic group" means a monocyclic or bicyclic or more ring saturated cyclic hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group. The "non-aromatic carbocyclic group" having two or more rings also includes a monocyclic or non-aromatic carbocyclic group having two or more rings condensed with the above "aromatic carbocyclic group".
Furthermore, the "non-aromatic carbocyclic group" also includes a group that forms a bridge or a spiro ring as shown below.
Figure JPOXMLDOC01-appb-C000040
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 cycloalkyl, cycloalkenyl and the like.
"Cycloalkyl" preferably has 3 to 10 carbon atoms, more preferably 3 to 7 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
"Cycloalkenyl" includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
The bicyclic or more non-aromatic carbocyclic group preferably has 8 to 13 carbon atoms, more preferably 9 to 10 carbon atoms. Examples include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl, dihydroindenyl and the like.
　「非芳香族炭素環」とは、上記「非芳香族炭素環式基」から導かれる環を意味する。 "Non-aromatic carbocyclic ring" means a ring derived from the above "non-aromatic carbocyclic group".
　「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。
　２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含し、該結合手はいずれの環に有していても良い。
　単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。５員芳香族複素環式基としては、例えば、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられる。６員芳香族複素環式基としては、例えば、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等が挙げられる。
　２環の芳香族複素環式基としては、８～１０員が好ましく、より好ましくは９員または１０員である。例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンズイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等が挙げられる。
　３環以上の芳香族複素環式基としては、１３～１５員が好ましい。例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms which are the same or different and are arbitrarily selected from O, S and N in the ring. do.
An aromatic heterocyclic group with two or more rings includes a monocyclic or an aromatic heterocyclic group with two or more rings condensed with the ring in the above "aromatic carbocyclic group", and the bond is Either ring may have it.
The monocyclic aromatic heterocyclic group is preferably 5- to 8-membered, more preferably 5- or 6-membered. Five-membered aromatic heterocyclic groups include, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like. Examples of 6-membered aromatic heterocyclic groups include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
The bicyclic aromatic heterocyclic group is preferably 8- to 10-membered, more preferably 9- or 10-membered. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl. Ryl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. are mentioned.
The aromatic heterocyclic group having 3 or more rings is preferably 13- to 15-membered. Examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.
　「芳香族複素環」とは、上記「芳香族複素環式基」から導かれる環を意味する。 "Aromatic heterocyclic ring" means a ring derived from the above "aromatic heterocyclic group".
　「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、非芳香族環式基を意味する。２環以上の非芳香族複素環式基は、単環または２環以上の非芳香族複素環式基に、上記「芳香族炭素環式基」、「非芳香族炭素環式基」、および／または「芳香族複素環式基」におけるそれぞれの環が縮合したもの、さらに、単環または２環以上の非芳香族炭素環式基に、上記「芳香族複素環式基」における環が縮合したものも包含し、該結合手はいずれの環に有していても良い。
　さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000041
　単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。
　３員非芳香族複素環式基としては、例えば、チイラニル、オキシラニル、アジリジニルが挙げられる。４員非芳香族複素環式基としては、例えば、オキセタニル、アゼチジニルが挙げられる。５員非芳香族複素環式基としては、例えば、オキサチオラニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、テトラヒドロフリル、ジヒドロチアゾリル、テトラヒドロイソチアゾリル、ジオキソラニル、ジオキソリル、チオラニル等が挙げられる。６員非芳香族複素環式基としては、例えば、ジオキサニル、チアニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロピラニル、ジヒドロオキサジニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキサジニル、チイニル、チアジニル等が挙げられる。７員非芳香族複素環式基としては、例えば、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、オキセパニルが挙げられる。
　２環以上の非芳香族複素環式基としては、８～２０員が好ましく、より好ましくは８～１０員である。例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 "Non-aromatic heterocyclic group" means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more heteroatoms in the ring that are the same or different and arbitrarily selected from O, S and N. means A bicyclic or more non-aromatic heterocyclic group is a monocyclic or bicyclic or more non-aromatic heterocyclic group, the above "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / Or a ring in which each ring in the "aromatic heterocyclic group" is condensed, and a ring in the above "aromatic heterocyclic group" is condensed to a monocyclic or bicyclic or more non-aromatic carbocyclic group and the bond may be in any ring.
Furthermore, the “non-aromatic heterocyclic group” also includes a group that forms a bridge or a spiro ring as shown below.
Figure JPOXMLDOC01-appb-C000041
The monocyclic non-aromatic heterocyclic group is preferably 3- to 8-membered, more preferably 5- or 6-membered.
Three-membered non-aromatic heterocyclic groups include, for example, thiiranyl, oxiranyl, aziridinyl. Examples of 4-membered non-aromatic heterocyclic groups include oxetanyl and azetidinyl. Five-membered non-aromatic heterocyclic groups include, for example, oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuryl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolyl, thiolanyl, and the like. mentioned. 6-membered non-aromatic heterocyclic groups include, for example, dioxanyl, thianyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl hexahydropyrimidinyl, dioxazinyl, thiinyl, thiazinyl and the like. Seven-membered non-aromatic heterocyclic groups include, for example, hexahydroazepinyl, tetrahydrodiazepinyl, oxepanyl.
The non-aromatic heterocyclic group having two or more rings is preferably 8- to 20-membered, more preferably 8- to 10-membered. Examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
　「非芳香族複素環」とは、上記「非芳香族複素環式基」から導かれる環を意味する。 "Non-aromatic heterocyclic ring" means a ring derived from the above "non-aromatic heterocyclic group".
　本明細書中、「置換基群αで置換されていてもよい」とは、「置換基群αから選択される1以上の基で置換されていてもよい」ことを意味する。置換基群β、γ、γ’、Ｅ、ＦおよびＧについても同様である。 In the present specification, "optionally substituted with substituent group α" means "optionally substituted with one or more groups selected from substituent group α". The same applies to the substituent groups β, γ, γ', E, F and G.
　「置換アルキル」、「置換アルケニル」、「置換アルキニル」、「置換エキソメチレン」、「置換アルキルオキシ」、「置換アルケニルオキシ」、「置換アルキニルオキシ」、「置換アルキルカルボニルオキシ」、「置換アルケニルカルボニルオキシ」、「置換アルキニルカルボニルオキシ」、「置換アルキルカルボニル」、「置換アルケニルカルボニル」、「置換アルキニルカルボニル」、「置換アルキルオキシカルボニル」、「置換アルケニルオキシカルボニル」、「置換アルキニルオキシカルボニル」、「置換アルキルスルファニル」、「置換アルケニルスルファニル」、「置換アルキニルスルファニル」、「置換アルキルスルフィニル」、「置換アルケニルスルフィニル」、「置換アルキニルスルフィニル」、「置換アルキルスルホニル」、「置換アルケニルスルホニル」、「置換アルキニルスルホニル」等の置換基としては、次の置換基群Ａが挙げられる。任意の位置の炭素原子が次の置換基群Ａから選択される１以上の基と結合していてもよい。
　置換基群Ａ：ハロゲン、ヒドロキシ、カルボキシ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、ペンタフルオロチオ、トリアルキルシリル、
置換基群αで置換されていてもよいアルキルオキシ、置換基群αで置換されていてもよいアルケニルオキシ、置換基群αで置換されていてもよいアルキニルオキシ、置換基群αで置換されていてもよいアルキルカルボニルオキシ、置換基群αで置換されていてもよいアルケニルカルボニルオキシ、置換基群αで置換されていてもよいアルキニルカルボニルオキシ、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルオキシカルボニル、置換基群αで置換されていてもよいアルケニルオキシカルボニル、置換基群αで置換されていてもよいアルキニルオキシカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群βで置換されていてもよいアミノ、置換基群βで置換されていてもよいイミノ、置換基群βで置換されていてもよいカルバモイル、置換基群βで置換されていてもよいスルファモイル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環オキシ、置換基群γ’で置換されていてもよい非芳香族炭素環オキシ、置換基群γで置換されていてもよい芳香族複素環オキシ、置換基群γ’で置換されていてもよい非芳香族複素環オキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族複素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシ、置換基群γで置換されていてもよい芳香族複素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシ、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族複素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted exomethylene", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyl"oxy","substitutedalkynylcarbonyloxy","substitutedalkylcarbonyl","substitutedalkenylcarbonyl","substitutedalkynylcarbonyl","substitutedalkyloxycarbonyl","substitutedalkenyloxycarbonyl","substitutedalkynyloxycarbonyl",""substitutedalkylsulfanyl","substitutedalkenylsulfanyl","substitutedalkynylsulfanyl","substitutedalkylsulfinyl","substitutedalkenylsulfinyl","substitutedalkynylsulfinyl","substitutedalkylsulfonyl","substitutedalkenylsulfonyl","substituted alkynyl Substituents such as "sulfonyl" include the following Substituent Group A. A carbon atom at any position may be bonded to one or more groups selected from Substituent Group A below.
Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl,
alkyloxy optionally substituted with substituent group α, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, substituted with substituent group α alkylcarbonyloxy optionally substituted with substituent group α, alkenylcarbonyloxy optionally substituted with substituent group α, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α , alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, substituted with substituent group α alkenyloxycarbonyl optionally substituted with substituent group α, alkynyloxycarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α sulfanyl, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, substituted with substituent group α alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,
amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, optionally substituted with substituent group β sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy optionally substituted with substituent group γ, aromatic heterocyclic oxy optionally substituted with substituent group γ', non-aromatic heterocyclic oxy optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic optionally substituted with substituent group γ ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic oxycarbonyl optionally substituted with, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxy which may be substituted with substituent group γ carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', substituent aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, substituent group γ' non-aromatic carbocyclic sulfanyl optionally substituted with, aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ , non-aromatic carbocyclic sulfinyl optionally substituted with substituent group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', non-substituted optionally substituted with substituent group γ' aromatic heterocyclic sulfinyl, aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', substituted with substituent group γ aromatic heterocyclic sulfonyl which may be optionally substituted and non-aromatic heterocyclic sulfonyl which may be substituted with substituent group γ';
置換基群α：ハロゲン、ヒドロキシ、カルボキシ、アルキルオキシ、ハロアルキルオキシ、アルケニルオキシ、アルキニルオキシ、スルファニル、およびシアノ。 Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.
置換基群β：ハロゲン、ヒドロキシ、カルボキシ、シアノ、置換基群αで置換されていてもよいアルキル、置換基群αで置換されていてもよいアルケニル、置換基群αで置換されていてもよいアルキニル、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環アルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキル、置換基群γで置換されていてもよい芳香族複素環アルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキル、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, optionally substituted with substituent group α alkynyl, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, substituted with substituent group α alkenylsulfonyl which may be substituted, alkynylsulfonyl which may be substituted with substituent group α,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyl optionally substituted with substituent group γ, aromatic heterocyclic alkyl optionally substituted with substituent group γ', non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ , non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic sulfanyl optionally substituted with, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, substituted non-aromatic heterocyclic sulfanyl optionally substituted with group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', optionally substituted with substituent group γ good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituted with substituent group γ' non-aromatic heterocyclic sulfonyl which may be
置換基群γ：置換基群α、アルキル、ハロアルキル、ヒドロキシアルキル、アルケニル、アルキニル、アルキルオキシアルキル、アルキルカルボニル、ハロアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アミノ、アルキルアミノ、アルキルスルホニル、アルキルオキシカルボニルおよびシクロプロパニル。 Substituent Group γ: Substituent Group α, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, amino, alkylamino, alkylsulfonyl, alkyloxycarbonyl and cyclo propanyl.
置換基群γ’：置換基群γおよびオキソ。 Substituent group γ': Substituent group γ and oxo.
　「置換芳香族炭素環」、「置換芳香族複素環」、「置換芳香族炭素環式基」、「置換芳香族複素環式基」、「置換芳香族炭素環オキシ」、「置換芳香族複素環オキシ」、「置換芳香族炭素環カルボニルオキシ」、「置換芳香族複素環カルボニルオキシ」、「置換芳香族炭素環カルボニル」、「置換芳香族複素環カルボニル」、「置換芳香族炭素環オキシカルボニル」、「置換芳香族複素環オキシカルボニル」、「置換芳香族炭素環スルファニル」、「置換芳香族複素環スルファニル」、「置換芳香族炭素環スルフィニル」、「置換芳香族複素環スルフィニル」、「置換芳香族炭素環スルホニル」および「置換芳香族複素環スルホニル」等の「芳香族炭素環」および「芳香族複素環」の環上の置換基としては、次の置換基群Ｂが挙げられる。環上の任意の位置の原子が次の置換基群Ｂから選択される１以上の基と結合していてもよい。
　置換基群Ｂ：ハロゲン、ヒドロキシ、カルボキシ、ホルミル、ホルミルオキシ、スルファニル、スルフィノ、スルホ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、ペンタフルオロチオ、トリアルキルシリル、
置換基群αで置換されていてもよいアルキル、置換基群αで置換されていてもよいアルケニル、置換基群αで置換されていてもよいアルキニル、置換基群αで置換されていてもよいアルキルオキシ、置換基群αで置換されていてもよいアルケニルオキシ、置換基群αで置換されていてもよいアルキニルオキシ、置換基群αで置換されていてもよいアルキルカルボニルオキシ、置換基群αで置換されていてもよいアルケニルカルボニルオキシ、置換基群αで置換されていてもよいアルキニルカルボニルオキシ、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルオキシカルボニル、置換基群αで置換されていてもよいアルケニルオキシカルボニル、置換基群αで置換されていてもよいアルキニルオキシカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群βで置換されていてもよいアミノ、置換基群βで置換されていてもよいイミノ、置換基群βで置換されていてもよいカルバモイル、置換基群βで置換されていてもよいスルファモイル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環オキシ、置換基群γ’で置換されていてもよい非芳香族炭素環オキシ、置換基群γで置換されていてもよい芳香族複素環オキシ、置換基群γ’で置換されていてもよい非芳香族複素環オキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族複素環カルボニルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環カルボニルオキシ、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環アルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキル、置換基群γで置換されていてもよい芳香族複素環アルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキル、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシ、置換基群γで置換されていてもよい芳香族複素環アルキルオキシ、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシ、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族複素環アルキルオキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環アルキルオキシアルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキルオキシアルキル、置換基群γで置換されていてもよい芳香族複素環アルキルオキシアルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキルオキシアルキル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 "substituted aromatic carbocyclic ring", "substituted aromatic heterocyclic ring", "substituted aromatic carbocyclic group", "substituted aromatic heterocyclic group", "substituted aromatic carbocyclic oxy", "substituted aromatic heterocyclic ring" ring oxy", "substituted aromatic carbocyclic carbonyloxy", "substituted aromatic heterocyclic carbonyloxy", "substituted aromatic carbocyclic carbonyl", "substituted aromatic heterocyclic carbonyl", "substituted aromatic carbocyclic oxycarbonyl ”, “substituted aromatic heterocycle oxycarbonyl”, “substituted aromatic carbocycle sulfanyl”, “substituted aromatic heterocycle sulfanyl”, “substituted aromatic carbocycle sulfinyl”, “substituted aromatic heterocycle sulfinyl”, “substituted Substituents on the ring of "aromatic carbocyclic ring" and "aromatic heterocyclic ring" such as "aromatic carbocyclic sulfonyl" and "substituted aromatic heterocyclic sulfonyl" include the following substituent group B. Any atom on the ring may be bonded to one or more groups selected from Substituent Group B below.
Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, penta fluorothio, trialkylsilyl,
alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, optionally substituted with substituent group α alkyloxy, alkenyloxy optionally substituted with substituent group α, alkynyloxy optionally substituted with substituent group α, alkylcarbonyloxy optionally substituted with substituent group α, substituent group α alkenylcarbonyloxy optionally substituted with, alkynylcarbonyloxy optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, even if substituted with substituent group α alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkyloxycarbonyl optionally substituted with substituent group α, alkenyloxycarbonyl optionally substituted with substituent group α, substituent alkynyloxycarbonyl optionally substituted with group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, substituted with substituent group α alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, substituent group alkylsulfonyl optionally substituted with α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α,
amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, optionally substituted with substituent group β sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic oxy optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic oxy optionally substituted with substituent group γ, aromatic heterocyclic oxy optionally substituted with substituent group γ', non-aromatic heterocyclic oxy optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyloxy optionally substituted with substituent group γ', aromatic heterocyclic optionally substituted with substituent group γ ring carbonyloxy, non-aromatic heterocyclic carbonyloxy optionally substituted with substituent group γ', aromatic carbocyclic carbonyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic oxycarbonyl optionally substituted with, non-aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic heterocyclic oxy which may be substituted with substituent group γ carbonyl, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic carbocyclic alkyl optionally substituted with substituent group γ, aromatic heterocyclic alkyl optionally substituted with substituent group γ', non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituted with substituent group γ optionally substituted aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy optionally substituted with substituent group γ′, aromatic heterocyclic alkyloxy optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxy optionally substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' good non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl optionally substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl optionally substituted by substituent group γ, substituted non-aromatic carbocyclic alkyloxyalkyl optionally substituted with group γ', aromatic heterocyclic alkyloxyalkyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic sulfanyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', substituent group γ aromatic heterocyclic sulfanyl optionally substituted with, non-aromatic heterocyclic sulfanyl optionally substituted with substituent group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, substituted non-aromatic carbocyclic sulfinyl optionally substituted with group γ', aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' heterocyclic sulfinyl, aromatic carbocyclic sulfonyl optionally substituted with substituent group γ, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', optionally substituted with substituent group γ aromatic heterocyclic sulfonyl and non-aromatic heterocyclic sulfonyl optionally substituted with a substituent group γ';
　「置換非芳香族炭素環」、「置換非芳香族複素環」、「置換非芳香族炭素環式基」、「置換非芳香族複素環式基」、「置換非芳香族炭素環オキシ」、「置換非芳香族複素環オキシ」、「置換非芳香族炭素環カルボニルオキシ」、「置換非芳香族複素環カルボニルオキシ」、「置換非芳香族炭素環カルボニル」、「置換非芳香族複素環カルボニル」、「置換非芳香族炭素環オキシカルボニル」、「置換非芳香族複素環オキシカルボニル」、「置換非芳香族炭素環スルファニル」、「置換非芳香族複素環スルファニル」、「置換非芳香族炭素環スルフィニル」、「置換非芳香族複素環スルフィニル」、「置換非芳香族炭素環スルホニル」、および「置換非芳香族複素環スルホニル」等の「非芳香族炭素環」および「非芳香族複素環」の環上の置換基としては、次の置換基群Ｃが挙げられる。環上の任意の位置の原子が次の置換基群Ｃから選択される１以上の基と結合していてもよい。
　置換基群Ｃ：置換基群Ｂおよびオキソ。 "substituted non-aromatic carbocyclic ring", "substituted non-aromatic heterocyclic ring", "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic oxy", "substituted non-aromatic carbocyclic carbonyloxy", "substituted non-aromatic heterocyclic carbonyloxy", "substituted non-aromatic carbocyclic carbonyl", "substituted non-aromatic heterocyclic carbonyl ", "substituted non-aromatic carbocyclic oxycarbonyl", "substituted non-aromatic heterocyclic oxycarbonyl", "substituted non-aromatic carbocyclic sulfanyl", "substituted non-aromatic heterocyclic sulfanyl", "substituted non-aromatic carbon "non-aromatic carbocycle" and "non-aromatic heterocycle" such as "ringsulfinyl", "substituted non-aromatic heterocyclesulfinyl", "substituted non-aromatic carbocyclesulfonyl" and "substituted non-aromatic heterocyclesulfonyl" The following substituent group C is mentioned as a substituent on the ring of ". An atom at any position on the ring may be bonded to one or more groups selected from Substituent Group C below.
Substituent Group C: Substituent Group B and oxo.
　「非芳香族炭素環」および「非芳香族複素環」が「オキソ」で置換されている場合、以下のように炭素原子上の２個の水素が置換されている環を意味する。
Figure JPOXMLDOC01-appb-C000042
 When "non-aromatic carbocycle" and "non-aromatic heterocycle" are substituted with "oxo" they mean rings in which two hydrogens on a carbon atom are replaced as follows.
Figure JPOXMLDOC01-appb-C000042
　隣接する２つのＲ２が結合する環構成原子と一緒になって形成する「置換芳香族炭素環」、並びに「置換芳香族複素環」および環Ｃにおける「置換芳香族炭素環」並びに「置換芳香族複素環」の「芳香族炭素環」および「芳香族複素環」の環上の置換基としては、置換基群Ｂおよび以下の式が挙げられる。環上の任意の位置の原子が置換基群Ｂから選択される１以上の基および／または以下の式：
Figure JPOXMLDOC01-appb-C000043
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換基群Ｂで置換されていてもよい芳香族炭素環、置換基群Ｂで置換されていてもよい芳香族複素環、置換基群Ｃで置換されていてもよい非芳香族炭素環または置換基群Ｃで置換されていてもよい非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－である）と結合してもよい。 "Substituted aromatic carbocyclic ring" and "substituted aromatic heterocyclic ring" formed together with the ring-constituting atoms to which two adjacent R 2 are bonded and "substituted aromatic carbocyclic ring" and "substituted aromatic carbocyclic ring" in Ring C Substituents on the ring of the “aromatic carbocyclic ring” and “aromatic heterocyclic ring” of “heterocyclic ring” include Substituent Group B and the following formulas. One or more groups in which atoms at arbitrary positions on the ring are selected from Substituent Group B and/or the following formulas:
Figure JPOXMLDOC01-appb-C000043
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group γ', and ring G is an aromatic carbocyclic ring which may be substituted with a substituent group B , an aromatic heterocyclic ring optionally substituted with a substituent group B, a non-aromatic carbocyclic ring optionally substituted with a substituent group C or a non-aromatic heterocyclic ring optionally substituted with a substituent group C and L is a single bond, C1-C3 alkylene, —C(═O)— or —SO 2 —).
　隣接する２つのＲ２が結合する環構成原子と一緒になって形成する「置換非芳香族炭素環」並びに「置換非芳香族複素環」および環Ｃにおける「置換非芳香族炭素環」並びに「置換非芳香族複素環」の「非芳香族炭素環」および「非芳香族複素環」の環上の置換基としては、置換基群Ｃおよび以下の式が挙げられる。環上の任意の位置の原子が置換基群Ｃから選択される１以上の基および／または以下の式：
Figure JPOXMLDOC01-appb-C000044
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換基群Ｂで置換されていてもよい芳香族炭素環、置換基群Ｂで置換されていてもよい芳香族複素環、置換基群Ｃで置換されていてもよい非芳香族炭素環または置換基群Ｃで置換されていてもよい非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－である）と結合してもよい。 "Substituted non-aromatic carbocyclic ring" and "substituted non-aromatic heterocyclic ring" formed together with the ring-constituting atoms to which two adjacent R 2 are bonded and "substituted non-aromatic carbocyclic ring" and " Examples of substituents on the ring of the “non-aromatic carbocyclic ring” and “non-aromatic heterocyclic ring” of the substituted non-aromatic heterocyclic ring include Substituent Group C and the following formulas. One or more groups in which atoms at arbitrary positions on the ring are selected from Substituent Group C and/or the following formulas:
Figure JPOXMLDOC01-appb-C000044
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group γ', and ring G is an aromatic carbocyclic ring which may be substituted with a substituent group B , an aromatic heterocyclic ring optionally substituted with a substituent group B, a non-aromatic carbocyclic ring optionally substituted with a substituent group C or a non-aromatic heterocyclic ring optionally substituted with a substituent group C and L is a single bond, C1-C3 alkylene, —C(═O)— or —SO 2 —).
　「置換アミノ」、「置換カルバモイル」および「置換スルファモイル」の置換基としては、次の置換基群Ｄが挙げられる。置換基群Ｄから選択される１または２の基で置換されていてもよい。
　置換基群Ｄ：ハロゲン、ヒドロキシ、カルボキシ、シアノ、置換基群αで置換されていてもよいアルキル、置換基群αで置換されていてもよいアルケニル、置換基群αで置換されていてもよいアルキニル、置換基群αで置換されていてもよいアルキルカルボニル、置換基群αで置換されていてもよいアルケニルカルボニル、置換基群αで置換されていてもよいアルキニルカルボニル、置換基群αで置換されていてもよいアルキルスルファニル、置換基群αで置換されていてもよいアルケニルスルファニル、置換基群αで置換されていてもよいアルキニルスルファニル、置換基群αで置換されていてもよいアルキルスルフィニル、置換基群αで置換されていてもよいアルケニルスルフィニル、置換基群αで置換されていてもよいアルキニルスルフィニル、置換基群αで置換されていてもよいアルキルスルホニル、置換基群αで置換されていてもよいアルケニルスルホニル、置換基群αで置換されていてもよいアルキニルスルホニル、
置換基群βで置換されていてもよいアミノ、置換基群βで置換されていてもよいイミノ、置換基群βで置換されていてもよいカルバモイル、置換基群βで置換されていてもよいスルファモイル、
置換基群γで置換されていてもよい芳香族炭素環式基、置換基群γ’で置換されていてもよい非芳香族炭素環式基、置換基群γで置換されていてもよい芳香族複素環式基、置換基群γ’で置換されていてもよい非芳香族複素環式基、置換基群γで置換されていてもよい芳香族炭素環アルキル、置換基群γ’で置換されていてもよい非芳香族炭素環アルキル、置換基群γで置換されていてもよい芳香族複素環アルキル、置換基群γ’で置換されていてもよい非芳香族複素環アルキル、置換基群γで置換されていてもよい芳香族炭素環カルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環カルボニル、置換基群γで置換されていてもよい芳香族複素環カルボニル、置換基群γ’で置換されていてもよい非芳香族複素環カルボニル、置換基群γで置換されていてもよい芳香族炭素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族炭素環オキシカルボニル、置換基群γで置換されていてもよい芳香族複素環オキシカルボニル、置換基群γ’で置換されていてもよい非芳香族複素環オキシカルボニル、置換基群γで置換されていてもよい芳香族炭素環スルファニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルファニル、置換基群γで置換されていてもよい芳香族複素環スルファニル、置換基群γ’で置換されていてもよい非芳香族複素環スルファニル、置換基群γで置換されていてもよい芳香族炭素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルフィニル、置換基群γで置換されていてもよい芳香族複素環スルフィニル、置換基群γ’で置換されていてもよい非芳香族複素環スルフィニル、置換基群γで置換されていてもよい芳香族炭素環スルホニル、置換基群γ’で置換されていてもよい非芳香族炭素環スルホニル、置換基群γで置換されていてもよい芳香族複素環スルホニルおよび置換基群γ’で置換されていてもよい非芳香族複素環スルホニル。 Substituents of “substituted amino”, “substituted carbamoyl” and “substituted sulfamoyl” include Substituent Group D below. It may be substituted with one or two groups selected from Substituent Group D.
Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, optionally substituted with substituent group α alkynyl, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, substituted with substituent group α alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, substituted with substituent group α alkenylsulfonyl which may be substituted, alkynylsulfonyl which may be substituted with substituent group α,
amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, optionally substituted with substituent group β sulfamoyl,
Aromatic carbocyclic group optionally substituted with substituent group γ, non-aromatic carbocyclic group optionally substituted with substituent group γ', aromatic optionally substituted with substituent group γ heterocyclic group, non-aromatic heterocyclic group optionally substituted with substituent group γ', aromatic carbocyclic alkyl optionally substituted with substituent group γ, substituted with substituent group γ' non-aromatic carbocyclic alkyl optionally substituted with substituent group γ, aromatic heterocyclic alkyl optionally substituted with substituent group γ', non-aromatic heterocyclic alkyl optionally substituted with substituent group γ', substituent aromatic carbocyclic carbonyl optionally substituted with substituent group γ, non-aromatic carbocyclic carbonyl optionally substituted with substituent group γ', aromatic heterocyclic carbonyl optionally substituted with substituent group γ , non-aromatic heterocyclic carbonyl optionally substituted with substituent group γ', aromatic carbocyclic oxycarbonyl optionally substituted with substituent group γ, optionally substituted with substituent group γ' non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ, non-aromatic heterocyclic oxycarbonyl optionally substituted with substituent group γ', substituent group γ aromatic carbocyclic sulfanyl optionally substituted with, non-aromatic carbocyclic sulfanyl optionally substituted with substituent group γ', aromatic heterocyclic sulfanyl optionally substituted with substituent group γ, substituted non-aromatic heterocyclic sulfanyl optionally substituted with group γ', aromatic carbocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic optionally substituted with substituent group γ' carbocyclic sulfinyl, aromatic heterocyclic sulfinyl optionally substituted with substituent group γ, non-aromatic heterocyclic sulfinyl optionally substituted with substituent group γ', optionally substituted with substituent group γ good aromatic carbocyclic sulfonyl, non-aromatic carbocyclic sulfonyl optionally substituted with substituent group γ', aromatic heterocyclic sulfonyl optionally substituted with substituent group γ, and substituted with substituent group γ' non-aromatic heterocyclic sulfonyl which may be
　式（Ｉ）で示される化合物における、各定義の好ましい態様を以下に示す。式（Ｉ）で示される化合物としては、以下に示される具体例のすべての組み合わせの態様が例示される。 Preferred embodiments of each definition in the compound represented by formula (I) are shown below. As the compound represented by formula (I), all combinations of specific examples shown below are exemplified.
　Ａ１、Ａ２およびＡ３はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ａ１、Ａ２およびＡ３を構成原子として含む環の環構成原子の窒素原子の数は、０～２個である。
　Ａ１、Ａ２およびＡ３は、好ましくは、それぞれ独立して、炭素原子または窒素原子であり、ここで、Ａ１、Ａ２およびＡ３を構成原子として含む環の環構成原子の窒素原子の数は、１または２個である。
　Ａ１、Ａ２およびＡ３は、より好ましくはそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ａ１、Ａ２およびＡ３を構成原子として含む環の環構成原子の窒素原子の数は、０または１個である。
　さらに好ましくは、Ａ１が炭素原子であり、Ａ２が炭素原子であり、Ａ３が窒素原子である。 A 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 2.
A 1 , A 2 and A 3 are preferably each independently a carbon atom or a nitrogen atom, wherein a nitrogen atom of a ring-constituting atom of a ring containing A 1 , A 2 and A 3 as constituent atoms is one or two.
A 1 , A 2 and A 3 are more preferably each independently a carbon atom or a nitrogen atom, where the nitrogen atom is a ring-constituting atom of a ring containing A 1 , A 2 and A 3 as constituent atoms is 0 or 1.
More preferably, A 1 is a carbon atom, A 2 is a carbon atom and A 3 is a nitrogen atom.
Figure JPOXMLDOC01-appb-C000045
で示される基は、好ましくは以下の基である。
Figure JPOXMLDOC01-appb-C000046
　より好ましくは、
Figure JPOXMLDOC01-appb-C000047
であり、更に好ましくは、
Figure JPOXMLDOC01-appb-C000048
である。
　別の好ましい態様は、以下である。
Figure JPOXMLDOC01-appb-C000049
　別の好ましい態様は、以下である。
Figure JPOXMLDOC01-appb-C000050
　更に好ましい態様は、以下である。
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000045
The group represented by is preferably the following groups.
Figure JPOXMLDOC01-appb-C000046
More preferably
Figure JPOXMLDOC01-appb-C000047
and more preferably
Figure JPOXMLDOC01-appb-C000048
is.
Another preferred aspect is as follows.
Figure JPOXMLDOC01-appb-C000049
Another preferred aspect is as follows.
Figure JPOXMLDOC01-appb-C000050
A more preferred embodiment is as follows.
Figure JPOXMLDOC01-appb-C000051
　環Ｃは、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環である。
　環Ｃは、好ましくは、置換もしくは非置換の５員の芳香族複素環が挙げられ、さらに好ましくは、置換もしくは非置換のピロール環、置換もしくは非置換のピラゾール環、置換もしくは非置換のチオフェン環、置換もしくは非置換のフラン環、置換もしくは非置換のイミダゾール環、置換もしくは非置換のチアゾール環、置換もしくは非置換のオキサゾール環、置換もしくは非置換のトリアゾール環等が挙げられる。
　環Ｃの置換基としては、Ｒ２Ａである。 Ring C is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
Ring C preferably includes a substituted or unsubstituted 5-membered aromatic heterocyclic ring, more preferably a substituted or unsubstituted pyrrole ring, a substituted or unsubstituted pyrazole ring, a substituted or unsubstituted thiophene ring , substituted or unsubstituted furan ring, substituted or unsubstituted imidazole ring, substituted or unsubstituted thiazole ring, substituted or unsubstituted oxazole ring, substituted or unsubstituted triazole ring and the like.
The substituent of ring C is R 2A .
　Ｒ２はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
Figure JPOXMLDOC01-appb-C000052
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換基群Ｂで置換されていてもよい芳香族炭素環、置換基群Ｂで置換されていてもよい芳香族複素環、置換基群Ｃで置換されていてもよい非芳香族炭素環または置換基群Ｃで置換されていてもよい非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－である）であり、および／または、隣接する２つのＲ２が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環（置換基の例：Ｒ２Ａ）、置換もしくは非置換の芳香族複素環（置換基の例：Ｒ２Ａ）、置換もしくは非置換の非芳香族炭素環（置換基の例：Ｒ２Ａ）または置換もしくは非置換の非芳香族複素環（置換基の例：Ｒ２Ａ）を形成してもよい。 R 2 is each independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or The formula below:
Figure JPOXMLDOC01-appb-C000052
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group γ', and ring G is an aromatic carbocyclic ring which may be substituted with a substituent group B , an aromatic heterocyclic ring optionally substituted with a substituent group B, a non-aromatic carbocyclic ring optionally substituted with a substituent group C or a non-aromatic heterocyclic ring optionally substituted with a substituent group C and L is a single bond, C1-C3 alkylene, —C(═O)— or —SO 2 —), and/or together with the ring atoms to which the two adjacent R 2 are attached Substituted or unsubstituted aromatic carbocyclic ring (example of substituent: R 2A ), substituted or unsubstituted aromatic heterocyclic ring (example of substituent: R 2A ), substituted or unsubstituted non-aromatic carbon A ring (example of substituent: R 2A ) or a substituted or unsubstituted non-aromatic heterocyclic ring (example of substituent: R 2A ) may be formed.
　Ｒ２は、好ましくはそれぞれ独立して、Ｒ２Ａから選択される基、または、隣接する２つのＲ２が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族複素環（置換基：Ｒ２Ａ）を形成する。 Each R 2 is preferably independently a group selected from R 2A , or a substituted or unsubstituted aromatic heterocyclic ring (substituted group: R 2A ).
　隣接する２つのＲ２が結合する環構成原子と一緒になって環を形成する時、その他のＲ２は、好ましくはヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルである。 When the ring-constituting atoms to which two adjacent R 2 are bonded together form a ring, the other R 2 is preferably hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl , substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenyl carbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group , substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic ringsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl.
　隣接する２つのＲ２が結合する環構成原子と一緒になって環を形成する時、その他のＲ２は、より好ましくはヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニルまたは置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）である。より好ましくは、ヒドロキシ、アルキルアミノ、アルキルまたはハロアルキルである。 When the ring-constituting atoms to which two adjacent R 2 are bonded together form a ring, the other R 2 is more preferably hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen, aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or It is unsubstituted alkynyl or substituted or unsubstituted alkyloxy (example of substituent: halogen). More preferred are hydroxy, alkylamino, alkyl or haloalkyl.
　Ｒ２Ａはそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
Figure JPOXMLDOC01-appb-C000053
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換もしくは非置換の芳香族炭素環（置換基の例：置換基群Ｂ）、置換もしくは非置換の芳香族複素環（置換基の例：置換基群Ｂ）、置換もしくは非置換の非芳香族炭素環（置換基の例：置換基群Ｃ）または置換もしくは非置換の非芳香族複素環（置換基の例：置換基群Ｃ）であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－である）である。 Each R 2A is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or the expression below:
Figure JPOXMLDOC01-appb-C000053
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group γ', wherein ring G is a substituted or unsubstituted aromatic carbocyclic ring (examples of substituents: Substituent Group B), substituted or unsubstituted aromatic heterocyclic ring (example of substituent: Substituent Group B), substituted or unsubstituted non-aromatic carbocyclic ring (example of substituent: Substituent Group C) or substituted or unsubstituted non-aromatic heterocyclic ring (example of substituent: substituent group C), L is a single bond, C1-C3 alkylene, -C(=O)- or -SO 2 -) .
　Ｒ２Ａはそれぞれ独立して、好ましくはハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、または以下の式：
Figure JPOXMLDOC01-appb-C000054
（式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換もしくは非置換の芳香族炭素環（置換基の例：置換基群Ｂ）、置換もしくは非置換の芳香族複素環（置換基の例：置換基群Ｂ）、置換もしくは非置換の非芳香族炭素環（置換基の例：置換基群Ｃ）または置換もしくは非置換の非芳香族複素環（置換基の例：置換基群Ｃ）であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－である）である。
　Ｒ２Ａは、より好ましくはそれぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の非芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）である。
　Ｒ２Ａの更に好ましい態様は、それぞれ独立して、置換もしくは非置換のアミノ（置換基の例：Ｃ１－Ｃ３アルキル）、置換もしくは非置換のＣ１－Ｃ６アルキル（置換基の例：ハロゲン）、置換もしくは非置換の６員の芳香族炭素環式基（置換基の例：ハロゲン、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３ハロアルキル、Ｃ１－Ｃ３アルキルオキシ、ハロＣ１－Ｃ３アルキルオキシ、Ｃ１－Ｃ３アルキルアミノ）、置換もしくは非置換の６員の芳香族複素環式基（置換基の例：ハロゲン、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３ハロアルキル、Ｃ１－Ｃ３アルキルオキシ、ハロＣ１－Ｃ３アルキルオキシ、Ｃ１－Ｃ３アルキルアミノ）、置換もしくは非置換の３～６員の非芳香族炭素環式基（置換基の例：ハロゲン）または置換もしくは非置換の４～６員の非芳香族複素環式基（置換基の例：ハロゲン）である。
　Ｒ２Ａの別の好ましい態様は、それぞれ独立して、以下のいずれかの式である。
Figure JPOXMLDOC01-appb-C000055
（式中、Ｘ３はＣＨまたはＮであり、Ｘ４はＣＨまたはＮであり、Ｘ５はＣＨまたはＮであり、Ｒｂは置換基群γであり、Ｒｃは置換基群γであり、環Ｆは置換基群γで置換されていてもよい６員の芳香族炭素環、置換基群γで置換されていてもよい６員の芳香族複素環、置換基群γ’で置換されていてもよい６員の非芳香族炭素環または置換基群γ’で置換されていてもよい６員の非芳香族複素環であり、環Ｇは置換基群Ｂで置換されていてもよい６もしくは１０員の芳香族炭素環、置換基群Ｂで置換されていてもよい５、６もしくは１０員の芳香族複素環、置換基群Ｃで置換されていてもよい４～６員の非芳香族炭素環または置換基群Ｃで置換されていてもよい４～６員の非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－である）。
　Ｒ２Ａの別のより好ましい態様は、それぞれ独立して、以下のいずれかの式である。
Figure JPOXMLDOC01-appb-C000056
（式中、Ｘ３はＣＨまたはＮであり、Ｘ４はＣＨまたはＮであり、Ｘ５はＣＨまたはＮであり、Ｒｂは水素、アルキルまたはハロアルキルであり、Ｒｃは水素、アルキルまたはハロアルキルであり、環Ｆは置換もしくは非置換のピペリジン（置換基：ハロゲン、アルキルオキシアルキル）であり、環Ｇは置換もしくは非置換の５、６もしくは１０員の芳香族複素環または置換もしくは非置換の４～６員の非芳香族複素環（置換基：ハロアルキル、アルキルカルボニル、アルキルオキシカルボニル、アルキルアミノカルボニル）であり、Ｌは単結合、メチレン、またはＣ（＝Ｏ）である）。 Each R 2A is independently preferably halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or the following formulae:
Figure JPOXMLDOC01-appb-C000054
(Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring which may be optionally substituted or a non-aromatic heterocyclic ring which may be substituted with a substituent group γ', wherein ring G is a substituted or unsubstituted aromatic carbocyclic ring (examples of substituents: Substituent Group B), substituted or unsubstituted aromatic heterocyclic ring (example of substituent: Substituent Group B), substituted or unsubstituted non-aromatic carbocyclic ring (example of substituent: Substituent Group C) or substituted or unsubstituted non-aromatic heterocyclic ring (example of substituent: substituent group C), L is a single bond, C1-C3 alkylene, -C(=O)- or -SO 2 -) .
R 2A is more preferably each independently hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (substituent Examples of: halogen, aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen) , substituted or unsubstituted aromatic carbocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted Aromatic heterocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted non-aromatic carbocyclic groups groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted non-aromatic heterocyclic groups ( Examples: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl).
Further preferred embodiments of R 2A are each independently substituted or unsubstituted amino (example of substituent: C1-C3 alkyl), substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen), substituted or an unsubstituted 6-membered aromatic carbocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, halo C1-C3 alkyloxy, C1-C3 alkylamino) , a substituted or unsubstituted 6-membered aromatic heterocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy, C1-C3 alkyl amino), a substituted or unsubstituted 3- to 6-membered non-aromatic carbocyclic group (example of substituent: halogen) or a substituted or unsubstituted 4- to 6-membered non-aromatic heterocyclic group (of the substituent example: halogen).
Another preferred embodiment of R 2A is each independently any of the formulas below.
Figure JPOXMLDOC01-appb-C000055
(Wherein, X 3 is CH or N, X 4 is CH or N, X 5 is CH or N, R b is a substituent group γ, R c is a substituent group γ , Ring F is a 6-membered aromatic carbocyclic ring optionally substituted with a substituent group γ, a 6-membered aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a 6-membered non-aromatic carbocyclic ring which may be substituted or a 6-membered non-aromatic heterocyclic ring which may be substituted with a substituent group γ', and ring G may be substituted with a substituent group B 6- or 10-membered aromatic carbocyclic ring, 5-, 6- or 10-membered aromatic heterocyclic ring optionally substituted by substituent group B, 4- to 6-membered non-cyclic ring optionally substituted by substituent group C an aromatic carbocyclic ring or a 4- to 6-membered non-aromatic heterocyclic ring optionally substituted by substituent group C, wherein L is a single bond, C1-C3 alkylene, -C(=O)- or -SO 2 -).
Another more preferred embodiment of R 2A is each independently any of the formulas below.
Figure JPOXMLDOC01-appb-C000056
where X 3 is CH or N, X 4 is CH or N, X 5 is CH or N, R b is hydrogen, alkyl or haloalkyl, R c is hydrogen, alkyl or haloalkyl and ring F is a substituted or unsubstituted piperidine (substituent: halogen, alkyloxyalkyl), and ring G is a substituted or unsubstituted 5-, 6- or 10-membered aromatic heterocyclic ring or a substituted or unsubstituted 4- to 6-membered non-aromatic heterocyclic ring (substituent: haloalkyl, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl), L is a single bond, methylene, or C(=O)).
Figure JPOXMLDOC01-appb-C000057
で示される基が、以下である時、
Figure JPOXMLDOC01-appb-C000058
　Ｒ２Ａは、好ましくは置換もしくは非置換のアミノ（置換基の例：Ｃ１－Ｃ３アルキル）、置換もしくは非置換のＣ１－Ｃ６アルキル（置換基の例：ハロゲン）、置換もしくは非置換の６員の芳香族炭素環式基（置換基の例：ハロゲン、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３ハロアルキル、Ｃ１－Ｃ３アルキルオキシ、ハロＣ１－Ｃ３アルキルオキシ、Ｃ１－Ｃ３アルキルアミノ）、置換もしくは非置換の６員の芳香族複素環式基（置換基の例：ハロゲン、Ｃ１－Ｃ３アルキル、Ｃ１－Ｃ３ハロアルキル、Ｃ１－Ｃ３アルキルオキシ、ハロＣ１－Ｃ３アルキルオキシ、Ｃ１－Ｃ３アルキルアミノ）、置換もしくは非置換の３～６員の非芳香族炭素環式基（置換基の例：ハロゲン）または置換もしくは非置換の４～６員の非芳香族複素環式基（置換基の例：ハロゲン）であり、
　Ｒ２Ｂは、好ましくは置換もしくは非置換のＣ１－Ｃ６アルキル（置換基の例：ハロゲン）であり、
　Ｒ２Ｃは、好ましくは水素、ハロゲンまたは置換もしくは非置換のＣ１－Ｃ６アルキル（置換基の例：ハロゲン）である。
Figure JPOXMLDOC01-appb-C000057
When the group represented by is
Figure JPOXMLDOC01-appb-C000058
R 2A is preferably substituted or unsubstituted amino (example of substituent: C1-C3 alkyl), substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen), substituted or unsubstituted 6-membered aromatic carbocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy, C1-C3 alkylamino), substituted or unsubstituted 6 membered aromatic heterocyclic group (examples of substituents: halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkyloxy, haloC1-C3 alkyloxy, C1-C3 alkylamino), substituted or unsubstituted A 3- to 6-membered non-aromatic carbocyclic group (example of substituent: halogen) or a substituted or unsubstituted 4- to 6-membered non-aromatic heterocyclic group (example of substituent: halogen) of
R 2B is preferably substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen),
R 2C is preferably hydrogen, halogen or substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen).
　Ｂ１、Ｂ２、Ｂ３およびＢ４はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０～２個である。
　Ｂ１、Ｂ２、Ｂ３およびＢ４は、好ましくはそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０または１個である。
　より好ましくは、Ｂ１、Ｂ２、Ｂ３およびＢ４が炭素原子である。 B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms The number of nitrogen atoms is 0-2.
B 1 , B 2 , B 3 and B 4 are preferably each independently a carbon atom or a nitrogen atom, wherein the ring of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms The number of nitrogen atoms in the constituent atoms is 0 or 1.
More preferably, B 1 , B 2 , B 3 and B 4 are carbon atoms.
Figure JPOXMLDOC01-appb-C000059
で示される基は、好ましくは以下の基が挙げられる。
Figure JPOXMLDOC01-appb-C000060
　別の好ましい態様は、以下である。
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000059
The group represented by preferably includes the following groups.
Figure JPOXMLDOC01-appb-C000060
Another preferred aspect is as follows.
Figure JPOXMLDOC01-appb-C000061
　より好ましくは、以下である。
Figure JPOXMLDOC01-appb-C000062
 More preferably, it is as follows.
Figure JPOXMLDOC01-appb-C000062
　環Ｄは、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環である。
　環Ｄは、好ましくは、置換もしくは非置換の６員の芳香族炭素環、置換もしくは非置換の６員の芳香族複素環、置換もしくは非置換の５～６員の非芳香族炭素環または置換もしくは非置換の５～６員の非芳香族複素環が挙げられ、さらに好ましくは、置換もしくは非置換のベンゼン環、置換もしくは非置換のピリジン環、置換もしくは非置換のシクロペンタン環、置換もしくは非置換のシクロヘキサン環、置換もしくは非置換のシクロヘプタン環等が挙げられる。
　環Ｄの置換基としては、Ｒ３Ａである。 Ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
Ring D is preferably a substituted or unsubstituted 6-membered aromatic carbocyclic ring, a substituted or unsubstituted 6-membered aromatic heterocyclic ring, a substituted or unsubstituted 5- to 6-membered non-aromatic carbocyclic ring or a substituted Or an unsubstituted 5- to 6-membered non-aromatic heterocyclic ring, more preferably a substituted or unsubstituted benzene ring, a substituted or unsubstituted pyridine ring, a substituted or unsubstituted cyclopentane ring, a substituted or unsubstituted A substituted cyclohexane ring, a substituted or unsubstituted cycloheptane ring, and the like are included.
The substituent of ring D is R 3A .
　Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、または置換もしくは非置換のスルファモイルであり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよい。
　Ｒ３は、好ましくはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル）、置換もしくは非置換のアルキル（置換基の例：ヒドロキシ、アルキルアミノ、アルキル（ベンジル）アミノ、アルキルオキシ、オキソで置換されてもよい非芳香族複素環式基、芳香族複素環オキシ）、置換もしくは非置換のアルケニル（置換基の例：ヒドロキシ、アルキルアミノ、アルキル（ベンジル）アミノ、アルキルオキシ、オキソで置換されてもよい非芳香族複素環式基、芳香族複素環オキシ）、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換のアルケニルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：アルキル）、置換もしくは非置換の芳香族複素環式基（置換基の例：アルキル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：アルキル）、置換もしくは非置換の非芳香族複素環式基（置換基の例：オキソ、アルキル）、または置換もしくは非置換のカルバモイル（置換基の例：アルキル）であり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環（置換基の例：Ｒ３Ａ）、置換もしくは非置換の芳香族複素環（置換基の例：Ｒ３Ａ）または置換もしくは非置換の非芳香族炭素環（置換基の例：Ｒ３Ａ）を形成してもよい。 Each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl and/or a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted Non-aromatic carbocycles or substituted or unsubstituted non-aromatic heterocycles may be formed.
R 3 is preferably each independently halogen, cyano, hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl), substituted or unsubstituted alkyl (examples of substituents: hydroxy, alkylamino, alkyl (benzyl)amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkenyl (examples of substituents: hydroxy, alkylamino, alkyl(benzyl) ) amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen) , substituted or unsubstituted alkenyloxy (example of substituent: halogen), substituted or unsubstituted aromatic carbocyclic group (example of substituent: alkyl), substituted or unsubstituted aromatic heterocyclic group (substituted Examples of groups: alkyl), substituted or unsubstituted non-aromatic carbocyclic groups (examples of substituents: alkyl), substituted or unsubstituted non-aromatic heterocyclic groups (examples of substituents: oxo, alkyl) , or substituted or unsubstituted carbamoyl (example of substituent: alkyl), and/or together with the ring atoms to which the two adjacent R 3 are bonded, a substituted or unsubstituted aromatic carbocyclic ring (Example of substituent: R 3A ), substituted or unsubstituted aromatic heterocyclic ring (example of substituent: R 3A ) or substituted or unsubstituted non-aromatic carbocyclic ring (example of substituent: R 3A ) is formed You may
　Ｒ３Ａはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、または置換もしくは非置換のアルキニルオキシである。
　Ｒ３Ａは、好ましくはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシである。 Each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted alkynyloxy.
R 3A is preferably each independently halogen, cyano, hydroxy, substituted or unsubstituted amino (example of substituent: alkyl), substituted or unsubstituted alkyl (example of substituent: halogen), substituted or unsubstituted substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy.
　Ｘ１は、ＣＲ４Ｒ５、ＮＲ６、ＯまたはＳである。
　Ｘ１は、好ましくは、ＮＲ６である。 X 1 is CR 4 R 5 , NR 6 , O or S;
X 1 is preferably NR 6 .
　Ｒ４およびＲ５は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のアルキニルである。
　Ｒ４およびＲ５は、好ましくはそれぞれ独立して、水素または置換もしくは非置換のＣ１－Ｃ４アルキル（置換基の例：ハロゲン）である。 R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
R 4 and R 5 are preferably each independently hydrogen or substituted or unsubstituted C1-C4 alkyl (example of substituent: halogen).
　Ｒ６は水素または置換もしくは非置換のアルキルである。
　Ｒ６は、好ましくは、水素または置換もしくは非置換のＣ１－Ｃ６アルキル（置換基の例：ハロゲン）である。 R6 is hydrogen or substituted or unsubstituted alkyl.
R 6 is preferably hydrogen or substituted or unsubstituted C1-C6 alkyl (example of substituent: halogen).
　Ｘ２は、ＣＲ７Ｒ８、ＮＲ９、ＯまたはＳである。
　Ｘ２は、好ましくは、ＯまたはＳであり、より好ましくはＯである。
　Ｘ２の別の態様として、ＣＲ７Ｒ８、ＯまたはＳであり、より好ましくはＣＲ７Ｒ８またはＯである。 X2 is CR7R8 , NR9 , O or S ;
X2 is preferably O or S, more preferably O.
Another embodiment of X 2 is CR 7 R 8 , O or S, more preferably CR 7 R 8 or O.
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、
　Ｒ７とＲ８が一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよい。
　Ｒ７およびＲ８は、好ましくはそれぞれ独立して、水素、置換もしくは非置換のアルキル（置換基の例：ハロゲン）または置換もしくは非置換のアルケニル（置換基の例：ハロゲン）であり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレン（置換基の例：アルキル、ハロアルキル）を形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のＣ３－Ｃ６の非芳香族炭素環（置換基の例：ハロゲン）を形成してもよい。 R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
R 7 and R 8 together may form a substituted or unsubstituted exomethylene, or together with the carbon atom bonded to the carbon atom to which R 7 and R 8 are bonded, a substituted or unsubstituted It may form a substituted non-aromatic carbocyclic ring.
R 7 and R 8 are preferably each independently hydrogen, substituted or unsubstituted alkyl (example of substituent: halogen) or substituted or unsubstituted alkenyl (example of substituent: halogen),
together with the carbon atom to which R 7 and R 8 are attached may form a substituted or unsubstituted exomethylene (examples of substituents: alkyl, haloalkyl), or the carbon atom to which R 7 and R 8 are attached Together with the atoms, they may form a substituted or unsubstituted C3-C6 non-aromatic carbocyclic ring (example of substituent: halogen).
　Ｒ９は水素または置換もしくは非置換のアルキルである。
　Ｒ９は、好ましくは、水素または置換もしくは非置換のアルキル（置換基の例：ハロゲン）である。 R9 is hydrogen or substituted or unsubstituted alkyl.
R 9 is preferably hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen).
　Ｒ１は、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である。
　Ｒ１は、好ましくは、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基であり、好ましくは５～７員であるが、縮合されていてもよく、架橋構造を有していてもよい。縮合環部分は、５～１０員で、単環でも２環性でも良い。置換もしくは非置換の芳香族炭素環式基としては、以下の式で示されるフェニル基が例示される。
　Ｒ１の別の好ましい態様としては、置換基群Ｆで置換されていてもよい芳香族炭素環式基、置換基群Ｆで置換されていてもよい非芳香族炭素環式基、置換基群Ｆで置換されていてもよい芳香族複素環式基、または置換基群Ｆで置換されていてもよい非芳香族複素環式基である。Ｒ１のより好ましい態様としては、置換基群Ｆで置換されていてもよい芳香族炭素環式基、または置換基群Ｆで置換されていてもよい非芳香族複素環式基である。
　置換基群Ｆ：ハロゲン、ヒドロキシ、アルコキシ、アミノ、アルキルアミノ、アルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、オキソ、シアノ。 R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group It is a cyclic group.
R 1 is preferably a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, preferably 5- to 7-membered, but optionally fused , may have a crosslinked structure. The fused ring moieties are 5- to 10-membered and may be monocyclic or bicyclic. Examples of substituted or unsubstituted aromatic carbocyclic groups include phenyl groups represented by the following formulae.
Another preferred embodiment of R 1 is an aromatic carbocyclic group optionally substituted with a substituent group F, a non-aromatic carbocyclic group optionally substituted with a substituent group F, a substituent group It is an aromatic heterocyclic group optionally substituted with F or a non-aromatic heterocyclic group optionally substituted with a substituent group F. A more preferred embodiment of R 1 is an optionally substituted aromatic carbocyclic group with substituent group F or a non-aromatic heterocyclic group optionally substituted with substituent group F.
Substituent group F: halogen, hydroxy, alkoxy, amino, alkylamino, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, oxo, cyano.
　Ｒ１のさらに別の好ましい態様としては、以下の基が挙げられる。
Figure JPOXMLDOC01-appb-C000063
　Ｒ１１、Ｒ１２、Ｒ１３、Ｒ１４およびＲ１５は、それぞれ独立して、好ましくは、水素、ハロゲン、シアノ、アルキル、シクロアルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシハロアルキル、ハロアルキルオキシ、カルボキシ、カルバモイル、またはアルキルアミノであり、より好ましくは、水素、ハロゲン、シアノ、アミノ、アルキルまたはアルキルオキシであり、さらに好ましくは、水素、フルオロ、クロロ、ブロモ、シアノ、アミノ、メチル、エチルまたはメチルオキシであり、特に好ましくは、水素、ハロゲン、シアノ、メチルまたはエチルである。
またＲ１１とＲ１２、Ｒ１２とＲ１３、Ｒ１３とＲ１４ならびにＲ１４とＲ１５は、それぞれ独立して、隣接する原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の非芳香族炭素環、置換もしくは非置換の芳香族複素環または置換もしくは非置換の非芳香族複素環を形成していても良い。これらの環は、好ましくは５～８員、より好ましくは５員または６員であり、６員がより好ましい。 Further preferred embodiments of R 1 include the following groups.
Figure JPOXMLDOC01-appb-C000063
R 11 , R 12 , R 13 , R 14 and R 15 are each independently preferably hydrogen, halogen, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxyhaloalkyl , haloalkyloxy, carboxy, carbamoyl or alkylamino, more preferably hydrogen, halogen, cyano, amino, alkyl or alkyloxy, more preferably hydrogen, fluoro, chloro, bromo, cyano, amino, methyl , ethyl or methyloxy, particularly preferably hydrogen, halogen, cyano, methyl or ethyl.
R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , and R 14 and R 15 are each independently taken together with adjacent atoms to form a substituted or unsubstituted aromatic carbocyclic ring; It may form a substituted or unsubstituted non-aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. These rings are preferably 5- to 8-membered, more preferably 5- or 6-membered, with 6-membered being more preferred.
　Ｒ１は、より好ましくは、１～２個の炭素環または複素環（例：５～７員環）と縮合していてもよい、フェニルまたは非芳香族炭素環式基であり、より好ましくは以下に例示される環式基である。該炭素環、複素環、フェニル、非芳香族炭素環、または以下の環式基上には、同一または異なる１～４個の置換基（例：ハロゲン、ヒドロキシ、アルコキシ、アミノ、アルキルアミノ、アルキル、ハロアルキル、ヒドロキシアルキル、アミノアルキル、オキソ、シアノ）が存在していてもよい。 R 1 is more preferably a phenyl or non-aromatic carbocyclic group optionally fused with 1 to 2 carbocyclic or heterocyclic rings (eg, 5- to 7-membered rings), more preferably It is a cyclic group exemplified below. The carbocycle, heterocycle, phenyl, non-aromatic carbocycle, or the following cyclic groups have 1 to 4 substituents (e.g., halogen, hydroxy, alkoxy, amino, alkylamino, alkyl , haloalkyl, hydroxyalkyl, aminoalkyl, oxo, cyano) may be present.
　Ｒ１は、さらに好ましくは、以下の基である。
Figure JPOXMLDOC01-appb-C000064
 R 1 is more preferably the following groups.
Figure JPOXMLDOC01-appb-C000064
　またＲ１は、結合手をＮ原子上に有する環状アミン、好ましくは飽和の環状アミンであってもよい。該環状アミンは、置換、縮合および/または架橋されていてもよい５～７員複素環であり、環構成原子としてＮ原子、Ｏ原子および／またはＳ原子が含まれていてもよい。置換基として好ましくは、アルキル、シクロアルキル、オキソ、ヒドロキシ、ハロゲン、アルコキシ等である。該環状アミンとしては、以下が例示される。
Figure JPOXMLDOC01-appb-C000065
 R 1 may also be a cyclic amine having a bond on the N atom, preferably a saturated cyclic amine. The cyclic amine is a 5- to 7-membered heterocyclic ring which may be substituted, condensed and/or bridged, and may contain N, O and/or S atoms as ring-constituting atoms. Preferred substituents are alkyl, cycloalkyl, oxo, hydroxy, halogen, alkoxy and the like. Examples of the cyclic amine include the following.
Figure JPOXMLDOC01-appb-C000065
　またＲ１は、以下に例示されるような、環内に２重結合を１または２本有する置換または非置換の非芳香族炭素環式基、環内に２重結合を１または２本有する置換または非置換の非芳香族複素環式基であってもよい。該炭素環式基または該複素環式基は、好ましくは５～７員である。置換基として好ましくは、アルキル、シクロアルキル、オキソ、ヒドロキシ、ハロゲン、アルコキシ等である。
Figure JPOXMLDOC01-appb-C000066
 R 1 is a substituted or unsubstituted non-aromatic carbocyclic group having 1 or 2 double bonds in the ring, having 1 or 2 double bonds in the ring, as exemplified below It may be a substituted or unsubstituted non-aromatic heterocyclic group. Said carbocyclic group or said heterocyclic group is preferably 5- to 7-membered. Preferred substituents are alkyl, cycloalkyl, oxo, hydroxy, halogen, alkoxy and the like.
Figure JPOXMLDOC01-appb-C000066
　さらにＲ１は以下の群から選択されてもよい。
Figure JPOXMLDOC01-appb-C000067
 Additionally, R 1 may be selected from the following group.
Figure JPOXMLDOC01-appb-C000067
　さらにＲ１は以下の群から選択されてもよい。
Figure JPOXMLDOC01-appb-C000068
（式中、Ｒ１Ａは、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルであり、Ｒ１Ｂは、それぞれ独立して、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルである。）
　Ｒ１Ａは、好ましくは水素、ハロゲン、Ｃ１－Ｃ３アルキルまたはハロＣ１－Ｃ３アルキルである。より好ましくはメチルまたはエチルである。
　Ｒ１Ｂは、好ましくはそれぞれ独立して、水素、ハロゲン、Ｃ１－Ｃ３アルキルまたはハロＣ１－Ｃ３アルキルである。より好ましくはメチルである。 Additionally, R 1 may be selected from the following group.
Figure JPOXMLDOC01-appb-C000068
(wherein R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and each R 1B is independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl.)
R 1A is preferably hydrogen, halogen, C1-C3 alkyl or haloC1-C3 alkyl. Methyl or ethyl is more preferred.
Each R 1B is preferably independently hydrogen, halogen, C1-C3 alkyl or haloC1-C3 alkyl. Methyl is more preferred.
　式（Ｉ）で示される化合物における、好ましい態様を以下に示す。
（実施態様１）
式：
Figure JPOXMLDOC01-appb-C000069
（式中、
Figure JPOXMLDOC01-appb-C000070
で示される基は
Figure JPOXMLDOC01-appb-C000071
であり、
　Ｂ１、Ｂ２、Ｂ３およびＢ４はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
　Ｘ１は、ＮＲ６であり、
　Ｒ６は水素または置換もしくは非置換のアルキル（置換基の例：ハロゲン）であり、
　Ｘ２は、ＣＲ７Ｒ８、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキル（置換基の例：ハロゲン）または置換もしくは非置換のアルケニル（置換基の例：ハロゲン）であり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレン（置換基の例：アルキル、ハロアルキル）を形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環（置換基の例：ハロゲン）を形成してもよく、
　Ｒ１は、置換もしくは非置換の芳香族炭素環式基（置換基の例：置換基群Ｆ）、置換もしくは非置換の芳香族複素環式基（置換基の例：置換基群Ｆ）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：置換基群Ｆ）または置換もしくは非置換の非芳香族複素環式基（置換基の例：置換基群Ｆ）であり、
　Ｒ２は、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニルまたは置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）であり、
　環ＣはＲ２Ａで置換されてもよい芳香族炭素環、Ｒ２Ａで置換されてもよい芳香族複素環、Ｒ２Ａで置換されてもよい非芳香族炭素環またはＲ２Ａで置換されてもよい非芳香族複素環であり、
　Ｒ２Ａはそれぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）または置換もしくは非置換の非芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）であり、
　Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、または置換もしくは非置換のスルファモイルであり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく、
　ｎは２～３の整数であり、
　ｍは０～４の整数である。）で示される化合物またはその製薬上許容される塩。 Preferred embodiments of the compound represented by formula (I) are shown below.
(Embodiment 1)
formula:
Figure JPOXMLDOC01-appb-C000069
(In the formula,
Figure JPOXMLDOC01-appb-C000070
The group represented by
Figure JPOXMLDOC01-appb-C000071
and
B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms The number of nitrogen atoms is 0 to 2,
X 1 is NR 6 ;
R 6 is hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen);
X 2 is CR 7 R 8 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl (example of substituent: halogen) or substituted or unsubstituted alkenyl (example of substituent: halogen),
together with the carbon atom to which R 7 and R 8 are attached may form a substituted or unsubstituted exomethylene (examples of substituents: alkyl, haloalkyl), or the carbon atom to which R 7 and R 8 are attached together with the atoms may form a substituted or unsubstituted non-aromatic carbocyclic ring (example of substituent: halogen);
R 1 is a substituted or unsubstituted aromatic carbocyclic group (example of substituent: Substituent Group F), a substituted or unsubstituted aromatic heterocyclic group (example of substituent: Substituent Group F), A substituted or unsubstituted non-aromatic carbocyclic group (example of substituent: substituent group F) or a substituted or unsubstituted non-aromatic heterocyclic group (example of substituent: substituent group F),
R 2 is hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen, aromatic carbon cyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkyloxy (example of substituent: halogen),
Ring C is an aromatic carbocyclic ring optionally substituted with R2A , an aromatic heterocyclic ring optionally substituted with R2A , a non-aromatic carbocyclic ring optionally substituted with R2A or optionally substituted with R2A is a good non-aromatic heterocycle,
Each R 2A is independently hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen , aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted Substituted aromatic carbocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted aromatic heterocycles Formula groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted non-aromatic carbocyclic groups (substituents Examples of: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl) or substituted or unsubstituted non-aromatic heterocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl),
Each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl and/or a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted may form a non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
n is an integer of 2 to 3,
m is an integer from 0 to 4; ) or a pharmaceutically acceptable salt thereof.
（実施態様２）
式：
Figure JPOXMLDOC01-appb-C000072
（式中、
Figure JPOXMLDOC01-appb-C000073
で示される基は
Figure JPOXMLDOC01-appb-C000074
であり、
　Ｂ１、Ｂ２、Ｂ３およびＢ４はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
　Ｘ１は、ＮＲ６であり、
　Ｒ６は水素または置換もしくは非置換のアルキル（置換基の例：ハロゲン）であり、
　Ｘ２は、ＣＲ７Ｒ８、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキル（置換基の例：ハロゲン）または置換もしくは非置換のアルケニル（置換基の例：ハロゲン）であり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレン（置換基の例：アルキル、ハロアルキル）を形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環（置換基の例：ハロゲン）を形成してもよく、
　Ｒ１は、置換もしくは非置換の芳香族炭素環式基（置換基の例：置換基群Ｆ）、置換もしくは非置換の芳香族複素環式基（置換基の例：置換基群Ｆ）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：置換基群Ｆ）または置換もしくは非置換の非芳香族複素環式基（置換基の例：置換基群Ｆ）であり、
　Ｒ２は、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニルまたは置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）であり、
　環ＣはＲ２Ａで置換されてもよい芳香族炭素環、Ｒ２Ａで置換されてもよい芳香族複素環、Ｒ２Ａで置換されてもよい非芳香族炭素環またはＲ２Ａで置換されてもよい非芳香族複素環であり、
　Ｒ２Ａはそれぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、または置換もしくは非置換の非芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）であり、
　Ｒ３はそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル）、置換もしくは非置換のアルキル（置換基の例：ヒドロキシ、アルキルアミノ、アルキル（ベンジル）アミノ、アルキルオキシ、オキソで置換されてもよい非芳香族複素環式基、芳香族複素環オキシ）、置換もしくは非置換のアルケニル（置換基の例：ヒドロキシ、アルキルアミノ、アルキル（ベンジル）アミノ、アルキルオキシ、オキソで置換されてもよい非芳香族複素環式基、芳香族複素環オキシ）、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換のアルケニルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：アルキル）、置換もしくは非置換の芳香族複素環式基（置換基の例：アルキル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：アルキル）、置換もしくは非置換の非芳香族複素環式基（置換基の例：オキソ、アルキル）または置換もしくは非置換のカルバモイル（置換基の例：アルキル）であり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、Ｒ３Ａで置換されてもよい芳香族炭素環、Ｒ３Ａで置換されてもよい芳香族複素環またはＲ３Ａで置換されてもよい非芳香族炭素環を形成してもよく、
　Ｒ３Ａはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシであり、
　ｎは２～３の整数であり、
　ｍは０～４の整数である。）で示される化合物またはその製薬上許容される塩。 (Embodiment 2)
formula:
Figure JPOXMLDOC01-appb-C000072
(In the formula,
Figure JPOXMLDOC01-appb-C000073
The group represented by
Figure JPOXMLDOC01-appb-C000074
and
B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms The number of nitrogen atoms is 0 to 2,
X 1 is NR 6 ;
R 6 is hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen);
X 2 is CR 7 R 8 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl (example of substituent: halogen) or substituted or unsubstituted alkenyl (example of substituent: halogen),
together with the carbon atom to which R 7 and R 8 are attached may form a substituted or unsubstituted exomethylene (examples of substituents: alkyl, haloalkyl), or the carbon atom to which R 7 and R 8 are attached together with the atoms may form a substituted or unsubstituted non-aromatic carbocyclic ring (example of substituent: halogen);
R 1 is a substituted or unsubstituted aromatic carbocyclic group (example of substituent: Substituent Group F), a substituted or unsubstituted aromatic heterocyclic group (example of substituent: Substituent Group F), A substituted or unsubstituted non-aromatic carbocyclic group (example of substituent: substituent group F) or a substituted or unsubstituted non-aromatic heterocyclic group (example of substituent: substituent group F),
R 2 is hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen, aromatic carbon cyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkyloxy (example of substituent: halogen),
Ring C is an aromatic carbocyclic ring optionally substituted with R2A , an aromatic heterocyclic ring optionally substituted with R2A , a non-aromatic carbocyclic ring optionally substituted with R2A or optionally substituted with R2A is a good non-aromatic heterocycle,
Each R 2A is independently hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen , aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted Substituted aromatic carbocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted aromatic heterocycles Formula groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted non-aromatic carbocyclic groups (substituents , halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), or substituted or unsubstituted non-aromatic heterocyclic groups (examples of substituents: halogen , cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl),
Each R 3 is independently halogen, cyano, hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl), substituted or unsubstituted alkyl (examples of substituents: hydroxy, alkylamino, alkyl (benzyl) amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkenyl (examples of substituents: hydroxy, alkylamino, alkyl(benzyl)amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or Unsubstituted alkenyloxy (example of substituent: halogen), substituted or unsubstituted aromatic carbocyclic group (example of substituent: alkyl), substituted or unsubstituted aromatic heterocyclic group (example of substituent : alkyl), substituted or unsubstituted non-aromatic carbocyclic group (example of substituent: alkyl), substituted or unsubstituted non-aromatic heterocyclic group (example of substituent: oxo, alkyl) or substituted or an aromatic carbocyclic ring that is unsubstituted carbamoyl (example of substituent: alkyl) and/or optionally substituted by R 3A together with the ring atoms to which two adjacent R 3s are bonded; may form an aromatic heterocyclic ring optionally substituted with R 3A or a non-aromatic carbocyclic ring optionally substituted with R 3A ,
Each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino (example of substituent: alkyl), substituted or unsubstituted alkyl (example of substituent: halogen), substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy,
n is an integer of 2 to 3,
m is an integer from 0 to 4; ) or a pharmaceutically acceptable salt thereof.
（実施態様３）
式：
Figure JPOXMLDOC01-appb-C000075
（式中、
Figure JPOXMLDOC01-appb-C000076
で示される基は
Figure JPOXMLDOC01-appb-C000077
であり、
　Ｘ１は、ＮＲ６であり、
　Ｒ６は水素または置換もしくは非置換のアルキル（置換基の例：ハロゲン）であり、
　Ｘ２は、ＣＲ７Ｒ８、ＯまたはＳであり、
　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキル（置換基の例：ハロゲン）または置換もしくは非置換のアルケニル（置換基の例：ハロゲン）であり、
　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレン（置換基の例：アルキル、ハロアルキル）を形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環（置換基の例：ハロゲン）を形成してもよく、
　Ｒ１は、置換もしくは非置換の芳香族炭素環式基（置換基の例：置換基群Ｆ）、置換もしくは非置換の芳香族複素環式基（置換基の例：置換基群Ｆ）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：置換基群Ｆ）または置換もしくは非置換の非芳香族複素環式基（置換基の例：置換基群Ｆ）であり、
　Ｒ２は、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニルまたは置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）であり、
　環ＣはＲ２Ａで置換されてもよい芳香族炭素環、Ｒ２Ａで置換されてもよい芳香族複素環、Ｒ２Ａで置換されてもよい非芳香族炭素環またはＲ２Ａで置換されてもよい非芳香族複素環であり、
　Ｒ２Ａはそれぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル、芳香族炭素環アルキル、芳香族炭素環カルボニル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン、芳香族炭素環式基、非芳香族炭素環式基）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）または置換もしくは非置換の非芳香族複素環式基（置換基の例：ハロゲン、シアノ、アルキル、ハロアルキル、アルキルオキシ、ハロアルキルオキシ、シクロプロパニル、アミノ、アルキルアミノ、アルキルスルホニル）であり、
Figure JPOXMLDOC01-appb-C000078
で示される基は、
Figure JPOXMLDOC01-appb-C000079
（式中、
　Ｒ３は、それぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル）、置換もしくは非置換のアルキル（置換基の例：ヒドロキシ、アルキルアミノ、アルキル（ベンジル）アミノ、アルキルオキシ、オキソで置換されてもよい非芳香族複素環式基、芳香族複素環オキシ）、置換もしくは非置換のアルケニル（置換基の例：ヒドロキシ、アルキルアミノ、アルキル（ベンジル）アミノ、アルキルオキシ、オキソで置換されてもよい非芳香族複素環式基、芳香族複素環オキシ）、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換のアルケニルオキシ（置換基の例：ハロゲン）、置換もしくは非置換の芳香族炭素環式基（置換基の例：アルキル）、置換もしくは非置換の芳香族複素環式基（置換基の例：アルキル）、置換もしくは非置換の非芳香族炭素環式基（置換基の例：アルキル）、置換もしくは非置換の非芳香族複素環式基（置換基の例：オキソ、アルキル）または置換もしくは非置換のカルバモイル（置換基の例：アルキル）であり、
　環ＤはＲ３Ａで置換されてもよい芳香族炭素環、Ｒ３Ａで置換されてもよい芳香族複素環、Ｒ３Ａで置換されてもよい非芳香族炭素環またはＲ３Ａで置換されてもよい非芳香族複素環であり、
　Ｒ３Ａはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ（置換基の例：アルキル）、置換もしくは非置換のアルキル（置換基の例：ハロゲン）、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ（置換基の例：ハロゲン）、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシであり、
　ｎは２～３の整数であり、
　ｍは２～４の整数である。）で示される化合物またはその製薬上許容される塩。 (Embodiment 3)
formula:
Figure JPOXMLDOC01-appb-C000075
(In the formula,
Figure JPOXMLDOC01-appb-C000076
The group represented by
Figure JPOXMLDOC01-appb-C000077
and
X 1 is NR 6 ;
R 6 is hydrogen or substituted or unsubstituted alkyl (example of substituent: halogen);
X 2 is CR 7 R 8 , O or S;
R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl (example of substituent: halogen) or substituted or unsubstituted alkenyl (example of substituent: halogen),
together with the carbon atom to which R 7 and R 8 are attached may form a substituted or unsubstituted exomethylene (examples of substituents: alkyl, haloalkyl), or the carbon atom to which R 7 and R 8 are attached together with the atoms may form a substituted or unsubstituted non-aromatic carbocyclic ring (example of substituent: halogen);
R 1 is a substituted or unsubstituted aromatic carbocyclic group (example of substituent: Substituent Group F), a substituted or unsubstituted aromatic heterocyclic group (example of substituent: Substituent Group F), A substituted or unsubstituted non-aromatic carbocyclic group (example of substituent: substituent group F) or a substituted or unsubstituted non-aromatic heterocyclic group (example of substituent: substituent group F),
R 2 is hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen, aromatic carbon cyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted alkyloxy (example of substituent: halogen),
Ring C is an aromatic carbocyclic ring optionally substituted with R2A , an aromatic heterocyclic ring optionally substituted with R2A , a non-aromatic carbocyclic ring optionally substituted with R2A or optionally substituted with R2A is a good non-aromatic heterocycle,
Each R 2A is independently hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl, aromatic carbocyclic alkyl, aromatic carbocyclic carbonyl), substituted or unsubstituted alkyl (examples of substituents: halogen , aromatic carbocyclic group, non-aromatic carbocyclic group), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted Substituted aromatic carbocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted aromatic heterocycles Formula groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl), substituted or unsubstituted non-aromatic carbocyclic groups (substituents Examples of: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl) or substituted or unsubstituted non-aromatic heterocyclic groups (examples of substituents: halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, cyclopropanyl, amino, alkylamino, alkylsulfonyl),
Figure JPOXMLDOC01-appb-C000078
The group represented by
Figure JPOXMLDOC01-appb-C000079
(In the formula,
Each R 3 is independently halogen, cyano, hydroxy, substituted or unsubstituted amino (examples of substituents: alkyl), substituted or unsubstituted alkyl (examples of substituents: hydroxy, alkylamino, alkyl (benzyl ) amino, alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkenyl (examples of substituents: hydroxy, alkylamino, alkyl(benzyl)amino , alkyloxy, non-aromatic heterocyclic group optionally substituted with oxo, aromatic heterocyclic oxy), substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted Or unsubstituted alkenyloxy (example of substituent: halogen), substituted or unsubstituted aromatic carbocyclic group (example of substituent: alkyl), substituted or unsubstituted aromatic heterocyclic group (example of substituent Examples: alkyl), substituted or unsubstituted non-aromatic carbocyclic groups (examples of substituents: alkyl), substituted or unsubstituted non-aromatic heterocyclic groups (examples of substituents: oxo, alkyl) or substituted or unsubstituted carbamoyl (example of substituent: alkyl),
Ring D is an aromatic carbocyclic ring optionally substituted with R3A , an aromatic heterocyclic ring optionally substituted with R3A , a non-aromatic carbocyclic ring optionally substituted with R3A or optionally substituted with R3A is a good non-aromatic heterocycle,
Each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino (example of substituent: alkyl), substituted or unsubstituted alkyl (example of substituent: halogen), substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy (example of substituent: halogen), substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy,
n is an integer of 2 to 3,
m is an integer of 2-4. ) or a pharmaceutically acceptable salt thereof.
　式（Ｉ）で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、アトロプ異性体、光学異性体、回転異性体等）、ラセミ体またはそれらの混合物を含む。これらの異性体は、多くの場合、例えば光学分割、晶析、クロマト分離等により容易に分離可能であるが、便宜上、同一の平面構造式で表示される場合もある。
　化合物（Ｉ）の異性体の一態様は、Ｒ１の環の向きによって特定される立体異性体を包含するが、本発明はそれらのすべての異性体およびラセミ体を包含する。 The compounds of formula (I) are not limited to any particular isomer, but include all possible isomers (e.g. keto-enol isomers, imine-enamine isomers, diastereoisomers, atropisomers , optical isomers, rotational isomers, etc.), racemates or mixtures thereof. These isomers can be easily separated in many cases by, for example, optical resolution, crystallization, chromatographic separation, etc. However, for convenience, they are sometimes represented by the same planar structural formula.
One aspect of the isomers of compound (I) includes stereoisomers specified by the ring orientation of R 1 , but the present invention includes all isomers and racemates thereof.
　式（Ｉ）で示される化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式（Ｉ）で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式（Ｉ）で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、該「放射性標識体」は、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and/or other atoms of the compounds of Formula (I) may be substituted with isotopes of hydrogen, carbon and/or other atoms, respectively. Examples of such isotopes include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O , 31 P, 32 P, 35 S, 18 F, 123 I and Included are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, as in 36 Cl. The compounds of formula (I) also include such isotopically substituted compounds. The isotopically substituted compounds are also useful as pharmaceuticals and include all radiolabeled compounds of formula (I). A "radiolabeling method" for producing the "radiolabel" is also encompassed by the present invention, and the "radiolabel" is useful as a research and/or diagnostic tool in metabolic pharmacokinetic studies, binding assays. is.
　式（Ｉ）で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。トリチウム標識化合物を調製するための他の適切な方法は、“Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）”を参照することができる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 Radiolabeled compounds of formula (I) can be prepared by methods well known in the art. For example, a tritium-labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) through a catalytic dehalogenation reaction using tritium. This method comprises reacting a suitably halogenated precursor of a compound of formula (I) with tritium gas in the presence or absence of a base, in the presence of a suitable catalyst such as Pd/C. include Other suitable methods for preparing tritiated compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be prepared by using starting materials with a 14 C carbon.
　式（Ｉ）で示される化合物の製薬上許容される塩としては、例えば、式（Ｉ）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、コハク酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸、トリフルオロ酢酸等）との塩が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 Pharmaceutically acceptable salts of the compound represented by formula (I) include, for example, the compound represented by formula (I) and an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and organic acids (e.g., formic acid, acetic acid, propionic acid) , trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfone acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by a commonly used method.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）、共結晶および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物、共結晶および結晶多形も包含する。「溶媒和物」は、式（Ｉ）で示される化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。式（Ｉ）で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式（Ｉ）で示される化合物またはその製薬上許容される塩を、再結晶することで結晶多形を形成する場合がある。「共結晶」は、式（Ｉ）で示される化合物または塩とカウンター分子が同一結晶格子内に存在することを意味し、任意の数のカウンター分子を含んでいても良い。 The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form solvates (e.g., hydrates, etc.), co-crystals and/or crystal polymorphs, and the present invention also includes such various solvates, co-crystals and polymorphs. A "solvate" may be coordinated with any number of solvent molecules (eg, water molecules, etc.) to a compound of formula (I). When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb water, attach adsorbed water, or form a hydrate. Also, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form polymorphs. "Co-crystal" means that a compound or salt of formula (I) and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.
　本発明の式（Ｉ）で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式（Ｉ）で示される化合物に変換される化合物、胃酸等により加水分解されて式（Ｉ）で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えば “Ｄｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ，　１９８５”に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention also includes such various prodrugs. Prodrugs are derivatives of the compounds of the invention having groups which are chemically or metabolically degradable, and which, upon solvolysis or under physiological conditions, become pharmaceutically active compounds of the invention in vivo. A prodrug is a compound that undergoes enzymatic oxidation, reduction, hydrolysis, or the like under physiological conditions in vivo and is converted into a compound represented by formula (I), or a compound that is hydrolyzed by gastric acid or the like to form formula (I). It includes compounds that are converted to the indicated compounds, and the like. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.
　式（Ｉ）で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with sulfonyl anhydrides and mixed anhydrides or by using condensing agents are exemplified. For example, CH 3 COO-, C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 ) COO—, CH 2 N(CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3 -, PhSO 3 -, p-CH 3 PhSO 3 -.
　本発明化合物は、ＨＩＶ複製阻害作用を有するため、エイズ等、ウイルス感染症の治療剤および／または予防剤として有用である。 Since the compound of the present invention has HIV replication inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for viral infections such as AIDS.
（本発明の化合物の製造法）
　本発明に係る式（Ｉ）で示される化合物は、例えば、下記に示す一般的合成法によって製造することができる。抽出、精製等は、通常の有機化学の実験で行う処理を行えばよい。
　本発明の化合物は、当該分野において公知の手法を参考にしながら合成することができる。 (Method for producing the compound of the present invention)
The compounds represented by formula (I) according to the present invention can be produced, for example, by the general synthetic methods shown below. Extraction, purification, and the like may be carried out in the same manner as in ordinary organic chemistry experiments.
The compounds of the present invention can be synthesized with reference to methods known in the art.
（一般的合成法１）
Figure JPOXMLDOC01-appb-C000080
(式中、Ｘ１およびＸ２は、それぞれ独立してハロゲンなどの脱離基；Ｒは置換または非置換のアルキル基；Ｐ１はアミノ基の保護基；Ｐ２はカルボキシ基の保護基；その他の記号は前記と同意義）
Ｘ２がＯの場合を例として記載しているが、Ｘ２がＳでも同様に合成可能である。 (General Synthetic Method 1)
Figure JPOXMLDOC01-appb-C000080
(Wherein, X1 and X2 are each independently a leaving group such as halogen; R is a substituted or unsubstituted alkyl group; P1 is an amino group-protecting group; P2 is a carboxy group-protecting group; Same meaning as above)
Although the case where X2 is O is described as an example, even if X2 is S, synthesis is possible in the same way.
工程１
　化合物ａ１とａ２を反応させ、化合物ａ３を得ることができる。
　化合物ａ２は、化合物ａ１に対して１～５当量用いることができる。
　反応温度は、室温～１５０℃、好ましくは室温～１００℃である。
　反応時間は、０．５～２４時間、好ましくは１～１２時間である。
　反応溶媒としては、メタノール、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。
工程２
　化合物ａ３を酸存在下、イソシアニドと反応させることで、化合物ａ４を得ることができる。
　酸としては、酢酸、ＴＦＡ等が挙げられ、化合物ａ３に対して１～５モル当量用いることができる。
　イソシアニドとしては、アルキルイソシアニド等が挙げられ、化合物ａ３に対して１～２モル当量用いることができる。
　反応温度は、－１０～８０℃、好ましくは室温～６０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、メタノール、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。 Process 1
Compound a3 can be obtained by reacting compounds a1 and a2.
Compound a2 can be used in an amount of 1 to 5 equivalents relative to compound a1.
The reaction temperature is room temperature to 150°C, preferably room temperature to 100°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include methanol, THF, and the like, which can be used singly or in combination.
Process 2
Compound a4 can be obtained by reacting compound a3 with isocyanide in the presence of an acid.
Examples of the acid include acetic acid and TFA, which can be used in an amount of 1 to 5 molar equivalents relative to compound a3.
The isocyanide includes alkyl isocyanide and the like, and can be used in an amount of 1 to 2 molar equivalents relative to compound a3.
The reaction temperature is -10 to 80°C, preferably room temperature to 60°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include methanol, THF, and the like, which can be used singly or in combination.
工程３
　化合物ａ４のアミド基のアミノを保護することで、化合物ａ５を得ることができる。
　試薬としては、Ｂｏｃ２Ｏ、Ａｃ２Ｏ、アセチルクロライド等を用いることができ、化合物ａ４に対して１～３モル当量用いることができる。
　塩基としては、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウム、ピリジン、トリエチルアミン、ＤＭＡＰ等が挙げられ、化合物ａ４に対して１～５モル当量用いることができる。
　反応温度は、室温～１５０℃、好ましくは６０～１１０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、トルエン、キシレン、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。
工程４
　化合物ａ５を加水分解することで、化合物ａ６を得ることができる。
　塩基としては、水酸化リチウム水溶液、水酸化ナトリウム水溶液等が挙げられ、化合物ａ５に対して１～５モル当量用いることができる。
　反応温度は、室温～１５０℃、好ましくは６０～１１０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、ジオキサン、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。 Process 3
Compound a5 can be obtained by protecting the amino of the amide group of compound a4.
As a reagent, Boc 2 O, Ac 2 O, acetyl chloride, etc. can be used, and 1 to 3 molar equivalents can be used with respect to compound a4.
Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP and the like, and it can be used in an amount of 1 to 5 molar equivalents relative to compound a4.
The reaction temperature is room temperature to 150°C, preferably 60 to 110°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include toluene, xylene, THF, and the like, which can be used singly or in combination.
Step 4
Compound a6 can be obtained by hydrolyzing compound a5.
Examples of the base include an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and the like, which can be used in an amount of 1 to 5 molar equivalents relative to the compound a5.
The reaction temperature is room temperature to 150°C, preferably 60 to 110°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include dioxane, THF, and the like, which can be used alone or in combination.
工程５
　化合物ａ６をアルキル化することで、化合物ａ７を得ることができる。
　試薬として、ＴＭＳジアゾメタン、Ｏ－ｔｅｒｔ－ブチル－Ｎ，Ｎ’－ジイソプロピルイソ尿素等が挙げられ、化合物ａ６に対して１～５モル当量用いることができる。
　反応温度は、－１０～５０℃、好ましくは０℃～室温である。
　反応時間は、０．１～２４時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、メタノールとジオキサン、ＴＨＦ等の混合溶媒が用いることができる。
工程６
　化合物ａ７とａ８にカップリング反応を行うことにより、化合物ａ９を得ることができる。該反応としては、鈴木クロスカップリング、Ｕｌｌｍａｎｎクロスカップリング、根岸クロスカップリング、Ｓｔｉｌｌｅカップリング，　Ｂｕｃｈｗａｌｄ－Ｈａｒｔｗｉｇカップリング等が例示される。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム等が挙げられ、化合物ａ７に対して、０．００１～０．５モル当量用いることができる。
　塩基としては、炭酸カリウム、炭酸ナトリウム、リン酸カリウム等が挙げられ、化合物ａ７に対して、１～１０モル当量用いることができる。
　化合物ａ８としては、置換ボロン酸、置換ボロン酸エステル、置換スズアルキル、置換ハロゲン化亜鉛等が挙げられ、化合物ａ７に対して、１～１０モル当量用いることができる。
　添加剤としては、ＣｕＩ、ＣｓＦ等が挙げられ、必要に応じて化合物ａ７に対して、０．０５～１モル当量用いることができる。
　反応温度は、０～１５０℃、好ましくは５０～１２０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、ジオキサン、ＤＭＦ、ＤＭＥ、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。 Step 5
Compound a7 can be obtained by alkylating compound a6.
Examples of reagents include TMS diazomethane, O-tert-butyl-N,N'-diisopropylisourea, and the like, which can be used in an amount of 1 to 5 molar equivalents relative to compound a6.
The reaction temperature is -10 to 50°C, preferably 0°C to room temperature.
The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
As a reaction solvent, a mixed solvent such as methanol, dioxane, and THF can be used.
Process 6
Compound a9 can be obtained by subjecting compounds a7 and a8 to a coupling reaction. Examples of the reaction include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, Buchwald-Hartwig coupling and the like.
Metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium and the like. and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a7.
Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound a7.
Compound a8 includes substituted boronic acid, substituted boronate ester, substituted tin alkyl, substituted zinc halide and the like, and can be used in an amount of 1 to 10 molar equivalents relative to compound a7.
Additives include CuI, CsF, etc., and can be used in an amount of 0.05 to 1 molar equivalent relative to compound a7, if necessary.
The reaction temperature is 0 to 150°C, preferably 50 to 120°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
工程７
　化合物ａ９に還元的アミノ化等のアルキル化を行うことで、化合物ａ１０を得ることができる。
　試薬としては、アセトアルデヒド等が挙げられ、化合物ａ９に対して、１～２０モル当量用いることができる。
　反応温度は、－１０～４０℃、好ましくは０℃～室温である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、クロロホルム、ジクロロメタン、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。
工程８
　化合物ａ１０を脱保護することで、化合物Ｉ－ａを得ることができる。
　塩基として、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液等が挙げられ、化合物ａ１０に対して、１～５０モル当量用いることができる。
　反応温度は、１０～１１０℃、好ましくは３０～９０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、メタノ一ル、ＴＨＦ、ジオキサン、水等が挙げられ、単独又は混合して用いることができる。 Step 7
Compound a10 can be obtained by subjecting compound a9 to alkylation such as reductive amination.
Examples of reagents include acetaldehyde and the like, which can be used in an amount of 1 to 20 molar equivalents relative to compound a9.
The reaction temperature is -10 to 40°C, preferably 0°C to room temperature.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include chloroform, dichloromethane, THF, water, and the like, which can be used singly or in combination.
Step 8
Compound Ia can be obtained by deprotecting compound a10.
Examples of the base include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and the like, and can be used in an amount of 1 to 50 molar equivalents relative to the compound a10.
The reaction temperature is 10-110°C, preferably 30-90°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include methanol, THF, dioxane, water, and the like, which can be used singly or in combination.
（一般的合成法１－１）
Figure JPOXMLDOC01-appb-C000081
（式中、各記号は前記と同意義）
Ｘ２がＯの場合を例として記載しているが、Ｘ２がＳでも同様に合成可能である。
工程１
　化合物ａ４’とａ５’に芳香族求核置換反応またはカップリング反応を行うことにより、化合物ａ６’を得ることができる。カップリング反応としては、鈴木クロスカップリング、Ｕｌｌｍａｎｎクロスカップリング、根岸クロスカップリング、Ｓｔｉｌｌｅカップリング、Ｂｕｃｈｗａｌｄ－Ｈａｒｔｗｉｇカップリング等が例示される。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド等が挙げられ、化合物ａ４’に対して、０．００１～０．５モル当量用いることができる。
　塩基としては、炭酸カリウム、炭酸ナトリウム、リン酸カリウム等が挙げられ、化合物ａ４’に対して、１～１０モル当量用いることができる。
　化合物ａ５’としては、アミン、置換ボロン酸、置換ボロン酸エステル、置換スズアルキル、置換ハロゲン化亜鉛等が挙げられ、化合物ａ４’に対して、１～１０モル当量用いることができる。
　添加剤としては、ヨウ化銅（Ｉ）、フッ化セシウム等が挙げられ、必要に応じて化合物ａ４’に対して、０．０５～１モル当量用いることができる。
　反応温度は、０～２５０℃、好ましくは５０～２２０℃であり、マイクロ波照射下で行うこともできる。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、ＮＭＰ、ジオキサン、ＤＭＦ、ＤＭＥ、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。 (General Synthetic Method 1-1)
Figure JPOXMLDOC01-appb-C000081
(In the formula, each symbol has the same meaning as above)
Although the case where X2 is O is described as an example, even if X2 is S, synthesis is possible in the same way.
Process 1
Compound a6' can be obtained by subjecting compounds a4' and a5' to an aromatic nucleophilic substitution reaction or coupling reaction. Examples of coupling reactions include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, and Buchwald-Hartwig coupling.
Examples of metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, [ 1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride and the like can be mentioned, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound a4′.
Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound a4'.
Examples of compound a5′ include amines, substituted boronic acids, substituted boronic esters, substituted tin alkyls, substituted zinc halides, etc., and can be used in an amount of 1 to 10 molar equivalents relative to compound a4′.
Examples of the additive include copper (I) iodide, cesium fluoride, and the like, and if necessary, 0.05 to 1 molar equivalent can be used with respect to compound a4'.
The reaction temperature is 0 to 250° C., preferably 50 to 220° C., and can be carried out under microwave irradiation.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include NMP, dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
工程２
　化合物ａ６’に求核置換反応、還元的アミノ化等のアルキル化を行うことで、化合物ａ７’を得ることができる。
　試薬としては、ヨウ化エチル、アセトアルデヒド等が挙げられ、化合物ａ６’に対して、１～２０モル当量用いることができる。
　反応温度は、－７８～４０℃、好ましくは－５０℃～室温である。
　反応時間は、０．０５～２４時間、好ましくは０．１時間～１２時間である。
　反応溶媒としては、クロロホルム、ジクロロメタン、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。 Process 2
Compound a7' can be obtained by subjecting compound a6' to alkylation such as nucleophilic substitution reaction or reductive amination.
Examples of reagents include ethyl iodide and acetaldehyde, which can be used in an amount of 1 to 20 molar equivalents relative to compound a6'.
The reaction temperature is -78 to 40°C, preferably -50°C to room temperature.
The reaction time is 0.05 to 24 hours, preferably 0.1 to 12 hours.
Examples of the reaction solvent include chloroform, dichloromethane, THF, water, and the like, which can be used singly or in combination.
工程３
　化合物ａ７’のアミド基のアミノを保護することで、化合物ａ８’を得ることができる。
　試薬としては、Ｂｏｃ２Ｏ、Ａｃ２Ｏ、アセチルクロライド等を用いることができ、化合物ａ７’に対して１～３モル当量用いることができる。
　塩基としては、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウム、ピリジン、トリエチルアミン、ＤＭＡＰ等が挙げられ、化合物ａ７’に対して１～５モル当量用いることができる。
　反応温度は、室温～１８０℃、好ましくは６０～１５０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、トルエン、キシレン、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。
工程４
　化合物ａ８’を加水分解することで、化合物Ｉ－ａを得ることができる。
　塩基として、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液等が挙げられ、化合物ａ８’に対して、１～５０モル当量用いることができる。
　反応温度は、１０～１５０℃、好ましくは３０～１１０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、メタノ一ル、ＴＨＦ、ジオキサン、水等が挙げられ、単独又は混合して用いることができる。 Process 3
Compound a8' can be obtained by protecting the amino of the amide group of compound a7'.
As a reagent, Boc 2 O, Ac 2 O, acetyl chloride, etc. can be used, and 1 to 3 molar equivalents can be used with respect to compound a7′.
Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP and the like, and it can be used in an amount of 1 to 5 molar equivalents relative to compound a7'.
The reaction temperature is room temperature to 180°C, preferably 60 to 150°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include toluene, xylene, THF, and the like, which can be used singly or in combination.
Step 4
Compound Ia can be obtained by hydrolyzing compound a8'.
Examples of the base include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and the like, and can be used in an amount of 1 to 50 molar equivalents relative to the compound a8'.
The reaction temperature is 10-150°C, preferably 30-110°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include methanol, THF, dioxane, water, and the like, which can be used singly or in combination.
（一般的合成法２）
Figure JPOXMLDOC01-appb-C000082
(式中、各記号は前記と同意義） (General Synthetic Method 2)
Figure JPOXMLDOC01-appb-C000082
(In the formula, each symbol has the same meaning as above)
工程１
　化合物ｈ１、ｈ２、酸、イソシアニドを反応させ、化合物ｈ３を得ることができる。
　化合物ｈ２は、化合物ｈ１に対して１～５モル当量用いることができる。
　酸としては、酢酸、ＴＦＡ等が挙げられ、化合物ｈ１に対して１～５モル当量用いることができる。
　イソシアニドとしては、アルキルイソシアニド等が挙げられ、化合物ｈ１に対して１～３モル当量用いることができる。
　反応温度は、－１０～８０℃、好ましくは室温～７０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、メタノール、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。
工程２
　化合物ｈ３に分子内カップリング反応を行うことにより、化合物ｈ４を得ることができる。カップリング反応としては、溝呂木・ヘック反応が例示される。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム、［１，１’－ビス（ジ－ｔｅｒｔ－ブチルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）等が挙げられ、化合物ｈ３に対して、０．００１～０．５モル当量用いることができる。
　塩基としては、炭酸カリウム、炭酸ナトリウム、リン酸カリウム等が挙げられ、化合物ｈ３に対して、１～１０モル当量用いることができる。
　反応温度は、０～１８０℃、好ましくは５０～１５０℃である。マイクロ波照射下で行うことが好ましい。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、アセトニトリル、ヘキサフルオロイソプロパノール、ＮＭＰ、ジオキサン、ＤＭＦ、ＤＭＥ、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。 Process 1
Compound h3 can be obtained by reacting compounds h1, h2, acid and isocyanide.
Compound h2 can be used in an amount of 1 to 5 molar equivalents relative to compound h1.
Examples of the acid include acetic acid and TFA, and 1 to 5 molar equivalents can be used with respect to compound h1.
The isocyanide includes alkylisocyanide and the like, and can be used in an amount of 1 to 3 molar equivalents relative to compound h1.
The reaction temperature is -10 to 80°C, preferably room temperature to 70°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include methanol, THF, and the like, which can be used singly or in combination.
Process 2
Compound h4 can be obtained by subjecting compound h3 to an intramolecular coupling reaction. The coupling reaction is exemplified by the Mizoroki-Heck reaction.
Examples of metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium (II) dichloride, bis(tri-tert-butylphosphine)palladium, [ 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and the like can be mentioned, and can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound h3.
Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound h3.
The reaction temperature is 0 to 180°C, preferably 50 to 150°C. It is preferably carried out under microwave irradiation.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include acetonitrile, hexafluoroisopropanol, NMP, dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
工程３
　化合物ｈ４に求核置換反応、還元的アミノ化等のアルキル化を行うことで、化合物ｈ５を得ることができる。
　試薬としては、ヨウ化エチル、アセトアルデヒド等が挙げられ、化合物ｈ４に対して、１～２０モル当量用いることができる。
　反応温度は、－７８～４０℃、好ましくは－５０℃～室温である。
　反応時間は、０．０５～２４時間、好ましくは０．１時間～１２時間である。
　反応溶媒としては、クロロホルム、ジクロロメタン、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。 Process 3
Compound h5 can be obtained by subjecting compound h4 to alkylation such as nucleophilic substitution reaction or reductive amination.
Examples of reagents include ethyl iodide and acetaldehyde, which can be used in an amount of 1 to 20 molar equivalents relative to compound h4.
The reaction temperature is -78 to 40°C, preferably -50°C to room temperature.
The reaction time is 0.05 to 24 hours, preferably 0.1 to 12 hours.
Examples of the reaction solvent include chloroform, dichloromethane, THF, water, and the like, which can be used singly or in combination.
工程４
　化合物ｈ５のアミド基のアミノを保護することで、化合物ｈ６を得ることができる。
　試薬としては、Ｂｏｃ２Ｏ、Ａｃ２Ｏ、アセチルクロライド等を用いることができ、化合物ｈ５に対して１～３モル当量用いることができる。
　塩基としては、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸カルシウム、炭酸セシウム、ピリジン、トリエチルアミン、ＤＭＡＰ等が挙げられ、化合物ｈ５に対して１～５モル当量用いることができる。
　反応温度は、室温～１８０℃、好ましくは６０～１５０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、トルエン、キシレン、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。
工程５
　化合物ｈ６を加水分解することで、化合物ｈ７を得ることができる。
　塩基としては、水酸化リチウム水溶液、水酸化ナトリウム水溶液等が挙げられ、化合物ｈ６に対して１～１０モル当量用いることができる。
　反応温度は、室温～１５０℃、好ましくは６０～１１０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、ジオキサン、ＴＨＦ等が挙げられ、単独又は混合して用いることができる。
工程６
　化合物ｈ７をアルキル化することで、化合物ｈ８を得ることができる。
　試薬として、ＴＭＳジアゾメタン、Ｏ－ｔｅｒｔ－ブチル－Ｎ，Ｎ’－ジイソプロピルイソ尿素等が挙げられ、化合物ｈ７に対して１～５モル当量用いることができる。反応温度は、－１０～５０℃、好ましくは０℃～室温である。
　反応時間は、０．１～２４時間、好ましくは０．５時間～１２時間である。
　反応溶媒としては、メタノールとジオキサン、ＴＨＦ等の混合溶媒が用いることができる。
工程７
　化合物ｈ８とｈ９に芳香族求核置換反応またはカップリング反応を行うことにより、化合物ｈ１０を得ることができる。カップリング反応としては、鈴木クロスカップリング、Ｕｌｌｍａｎｎクロスカップリング、根岸クロスカップリング、Ｓｔｉｌｌｅカップリング、Ｂｕｃｈｗａｌｄ－Ｈａｒｔｗｉｇカップリング等が例示される。
　金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム、Ｘｐｈｏｓ　Ｐｄ　Ｇ３、［１，１’－ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド等が挙げられ、化合物ｈ８に対して、０．００１～０．５モル当量用いることができる。
　塩基としては、炭酸カリウム、炭酸ナトリウム、リン酸カリウム等が挙げられ、化合物ｈ８に対して、１～１０モル当量用いることができる。
　化合物ｈ９としては、アミン、置換ボロン酸、置換ボロン酸エステル、置換スズアルキル、置換ハロゲン化亜鉛等が挙げられ、化合物ｈ８に対して、１～１０モル当量用いることができる。
　添加剤としては、ヨウ化銅（Ｉ）、フッ化セシウム等が挙げられ、必要に応じて化合物ｈ８に対して、０．０５～１モル当量用いることができる。
　反応温度は、０～２５０℃、好ましくは５０～２２０℃であり、マイクロ波照射下で行うこともできる。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、ＮＭＰ、ジオキサン、ＤＭＦ、ＤＭＥ、ＴＨＦ、水等が挙げられ、単独又は混合して用いることができる。
工程８
　化合物ｈ１０を加水分解することで、化合物Ｉ－ｈを得ることができる。
　塩基として、水酸化ナトリウム水溶液、水酸化カリウム水溶液、水酸化リチウム水溶液等が挙げられ、化合物ｈ１０に対して、１～５０モル当量用いることができる。
　反応温度は、１０～１５０℃、好ましくは３０～１１０℃である。
　反応時間は、０．５～２４時間、好ましくは１時間～１２時間である。
　反応溶媒としては、メタノ一ル、エタノール、ＴＨＦ、ジオキサン、水等が挙げられ、単独又は混合して用いることができる。 Step 4
Compound h6 can be obtained by protecting the amino of the amide group of compound h5.
As a reagent, Boc 2 O, Ac 2 O, acetyl chloride, etc. can be used, and 1 to 3 molar equivalents can be used with respect to compound h5.
Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, calcium carbonate, cesium carbonate, pyridine, triethylamine, DMAP and the like, and it can be used in an amount of 1 to 5 molar equivalents relative to compound h5.
The reaction temperature is room temperature to 180°C, preferably 60 to 150°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include toluene, xylene, THF, and the like, which can be used singly or in combination.
Step 5
Compound h7 can be obtained by hydrolyzing compound h6.
Examples of the base include an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound h6.
The reaction temperature is room temperature to 150°C, preferably 60 to 110°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include dioxane, THF, and the like, which can be used alone or in combination.
Process 6
Compound h8 can be obtained by alkylating compound h7.
Examples of reagents include TMS diazomethane, O-tert-butyl-N,N'-diisopropylisourea, and the like, which can be used in an amount of 1 to 5 molar equivalents relative to compound h7. The reaction temperature is -10 to 50°C, preferably 0°C to room temperature.
The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
As a reaction solvent, a mixed solvent such as methanol, dioxane, and THF can be used.
Step 7
Compound h10 can be obtained by subjecting compounds h8 and h9 to an aromatic nucleophilic substitution reaction or coupling reaction. Examples of coupling reactions include Suzuki cross-coupling, Ullmann cross-coupling, Negishi cross-coupling, Stille coupling, and Buchwald-Hartwig coupling.
Metal catalysts include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, Xphos Pd G3, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, etc., can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound h8.
Examples of the base include potassium carbonate, sodium carbonate, potassium phosphate and the like, which can be used in an amount of 1 to 10 molar equivalents relative to compound h8.
Compound h9 includes amines, substituted boronic acids, substituted boronic esters, substituted tin alkyls, substituted zinc halides, etc., and can be used in an amount of 1 to 10 molar equivalents relative to compound h8.
Examples of the additive include copper (I) iodide, cesium fluoride, and the like, and if necessary, 0.05 to 1 molar equivalent can be used with respect to compound h8.
The reaction temperature is 0-250° C., preferably 50-220° C., and can be carried out under microwave irradiation.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include NMP, dioxane, DMF, DME, THF, water, and the like, which can be used singly or in combination.
Step 8
Compound Ih can be obtained by hydrolyzing compound h10.
Examples of the base include an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous lithium hydroxide solution, and the like.
The reaction temperature is 10-150°C, preferably 30-110°C.
The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.
Examples of the reaction solvent include methanol, ethanol, THF, dioxane, water, and the like, which can be used singly or in combination.
　本発明化合物は、ＨＩＶ複製阻害作用を有するため、エイズ等、ウイルス感染症の治療剤および／または予防剤として有用である。
　本発明化合物のＨＩＶ複製阻害作用は、例えば、後記試験例１および／または試験例２において、好ましくは、ＥＣ５０値が１００ｎＭ以下、より好ましくは５０ｎＭ以下、さらに好ましくは２０ｎＭ以下、特に好ましくは１０ｎＭ以下である。同作用の評価としては、ＥＣ９０値も使用可能である。
　本発明化合物は、ウイルス、特にＨＩＶ（例：ＨＩＶ－１）やその変異ウイルス、耐性ウイルスに対しての複製阻害活性のみならず、医薬としての有用性を備えており、下記の１つ以上の優れた特徴を有している。
ａ）血清タンパク存在下における抗ウイルス活性（例：ＰＡ－ＥＣ５０、ＰＡ－ＥＣ９０等）が良好である。
ｂ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２，ＣＹＰ２Ｃ９，ＣＹＰ３Ａ４，ＣＹＰ２Ｄ６，ＣＹＰ２Ｃ１９等）に対する阻害作用が弱い。
ｃ）血中濃度が高い、効果持続時間が長い、適度なクリアランス、適度なバイオアベイラビリティ等の良好な薬物動態を示す。
ｄ）光毒性（例：光溶血作用等）、変異原性、心毒性（例：ＱＴｃ延長等）、肝毒性、腎毒性、痙攣等の毒性を示さない。
ｅ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、本明細書に記載する測定条件の濃度範囲内で不可逆的阻害作用を示さず、ＭＢＩ能が低い。
ｆ）化合物の安定性（例えば、各種液性における溶液安定性、光安定性、着色安定性等）が高い。
ｇ）代謝安定性が高い。
ｈ）消化管障害（例：出血性腸炎、消化管潰瘍、消化管出血等）を起こさない。
ｉ）本願化合物自身または他剤との組み合わせによる耐性ウイルス出現の頻度・確率が低い。
ｊ）耐性ウイルスに対しても強い薬効を示す。 Since the compound of the present invention has HIV replication inhibitory activity, it is useful as a therapeutic and/or prophylactic agent for viral infections such as AIDS.
The HIV replication inhibitory action of the compound of the present invention is preferably 100 nM or less, more preferably 50 nM or less, still more preferably 20 nM or less, particularly preferably 10 nM, in Test Example 1 and/or Test Example 2 described later. It is below. EC90 values can also be used as an assessment of the same effect.
The compounds of the present invention have not only replication-inhibitory activity against viruses, particularly HIV (e.g., HIV-1), its mutant viruses, and resistant viruses, but also are useful as pharmaceuticals. It has excellent characteristics.
a) Good antiviral activity (eg, PA-EC50, PA-EC90, etc.) in the presence of serum proteins.
b) It has a weak inhibitory effect on CYP enzymes (eg, CYP1A2, CYP2C9, CYP3A4, CYP2D6, CYP2C19, etc.).
c) Good pharmacokinetics such as high blood concentration, long duration of effect, moderate clearance, and moderate bioavailability.
d) Does not exhibit toxicity such as phototoxicity (eg, photohemolysis, etc.), mutagenicity, cardiotoxicity (eg, QTc prolongation, etc.), hepatotoxicity, nephrotoxicity, convulsion, etc.
e) No irreversible inhibitory effect on CYP enzymes (eg, CYP3A4) within the concentration range of the measurement conditions described herein, and low MBI activity.
f) The stability of the compound (for example, solution stability in various liquids, light stability, color stability, etc.) is high.
g) high metabolic stability;
h) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
i) The frequency/probability of emergence of resistant viruses due to the compound of the present application itself or in combination with other drugs is low.
j) It exhibits strong efficacy even against resistant viruses.
　本発明の医薬組成物は、経口的、非経口的のいずれの方法でも投与することができる。非経口投与の方法としては、経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳、膣内投与等が挙げられる。 The pharmaceutical composition of the present invention can be administered orally or parenterally. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ocular, ear and intravaginal administration.
　経口投与の場合は常法に従って、内用固形製剤（例えば、錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤等）、内用液剤（例えば、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤、チンキ剤等）等の通常用いられるいずれの剤型に調製して投与すればよい。錠剤は、糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠または口腔内崩壊錠であってもよく、散剤および顆粒剤はドライシロップであってもよく、カプセル剤は、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤であってもよい。 For oral administration, internal solid preparations (e.g., tablets, powders, granules, capsules, pills, films, etc.), internal liquid preparations (e.g., suspensions, emulsions, elixirs, syrups, etc.) It may be prepared and administered in any commonly used dosage form such as a drug, limonade, alcohol, aromatic water, extract, decoction, tincture, and the like. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and powders and granules may be dry syrups. Alternatively, the capsules may be soft capsules, microcapsules or sustained release capsules.
　非経口投与の場合は、注射剤、点滴剤、外用剤（例えば、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤、坐剤等）等の通常用いられるいずれの剤型でも好適に投与することができる。注射剤は、Ｏ／Ｗ、Ｗ／Ｏ、Ｏ／Ｗ／Ｏ、Ｗ／Ｏ／Ｗ型等のエマルジョンであってもよい。 In the case of parenteral administration, injections, drops, external preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, Any commonly used dosage form such as ointments, plasters, jellies, creams, patches, poultices, powders for external use, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O/W, W/O, O/W/O and W/O/W types.
　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。さらに、該医薬組成物は、本発明化合物の有効量、剤型および／または各種医薬用添加剤を適宜変更することにより、小児用、高齢者用、重症患者用または手術用の医薬組成物とすることもできる。例えば、小児用医薬組成物は、新生児（出生後４週未満）、乳児（出生後４週～１歳未満）幼児（１歳以上７歳未満）、小児（７歳以上１５歳未満）若しくは１５歳～１８歳の患者に投与されうる。例えば、高齢者用医薬組成物は、６５歳以上の患者に投与されうる。 A pharmaceutical composition can be prepared by mixing an effective amount of the compound of the present invention with various pharmaceutical additives such as excipients, binders, disintegrants, and lubricants suitable for the dosage form, if necessary. Furthermore, by appropriately changing the effective amount, dosage form and/or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can be used as a pharmaceutical composition for children, the elderly, critically ill patients, or for surgery. You can also For example, a pediatric pharmaceutical composition can be used for neonates (less than 4 weeks after birth), infants (4 weeks after birth to less than 1 year old) infants (1 to 7 years old), children (7 to 15 years old) or 15 Patients between the ages of 18 and 18 can be administered. For example, geriatric pharmaceutical compositions may be administered to patients 65 years of age or older.
　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, administration route, etc., but when administered orally, it is usually 0.05 to 100 mg / kg/day, preferably within the range of 0.1 to 10 mg/kg/day. In the case of parenteral administration, it is generally 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day, although it varies greatly depending on the route of administration. It may be administered once to several times a day.
　本発明化合物は、該化合物の作用の増強または該化合物の投与量の低減等を目的として、逆転写酵素阻害剤、リボヌクレアーゼＨ阻害剤、プロテアーゼ阻害剤、インテグラーゼ阻害剤、吸着・侵入阻害剤、出芽阻害剤、成熟阻害剤、カプシド（Capsid）阻害剤、広域中和抗体、その他の抗ＨＩＶ薬等（以下、併用薬剤と略記する）と組み合わせて用いることができる。この際、本発明化合物と併用薬剤の投与時期は限定されず、これらを投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。さらに、本発明化合物と併用薬剤とは、それぞれの活性成分を含む２種類以上の製剤として投与されてもよいし、それらの活性成分を含む単一の製剤として投与されてもよい。 The compound of the present invention can be used as a reverse transcriptase inhibitor, ribonuclease H inhibitor, protease inhibitor, integrase inhibitor, adsorption/invasion inhibitor, It can be used in combination with budding inhibitors, maturation inhibitors, capsid inhibitors, broadly neutralizing antibodies, other anti-HIV drugs, and the like (hereinafter abbreviated as concomitant drugs). In this case, the timing of administration of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at different times. Furthermore, the compound of the present invention and the concomitant drug may be administered as two or more formulations containing each active ingredient, or may be administered as a single formulation containing those active ingredients.
　併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明化合物１重量部に対し、併用薬剤を０．０１～１００重量部用いればよい。 The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. In addition, the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination, and the like. For example, when the subject of administration is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
　逆転写酵素阻害剤としては、ＡＺＴ、３ＴＣ、ジダノシン、ザルシタビン、サニルブジン、アバカビル、アバカビル硫酸塩、テノホビル、テノホビル　ジソプロキシル、テノホビル　ジソプロキシルフマル酸塩、テノホビル　アラフェナミド、テノホビル　アラフェナミドフマル酸塩、エムトリシタビン、ネビラピン、エファビレンツ、カプラビリン、エトラビリン、デラビルジン、デラビルジンメシル酸塩、リルピビリン、リルピビリン塩酸塩、ＶＭ－１５００Ａ、ＶＭ－１５００、ドラビリン、ＭＫ－８５０７、ＭＫ－８５０４、ＭＫ－８５８３等が挙げられる。 Reverse transcriptase inhibitors include AZT, 3TC, didanosine, zalcitabine, sanilvudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, emtricitabine, nevirapine, efavirenz, capravirine, etravirine, delavirdine, delavirdine mesylate, rilpivirine, rilpivirine hydrochloride, VM-1500A, VM-1500, doravirine, MK-8507, MK-8504, MK-8583 and the like.
　リボヌクレアーゼＨ阻害剤としては、例えば以下に記載の化合物等が挙げられる。
WO2008/010964に記載の化合物;
WO2011/075747に記載の化合物 Examples of ribonuclease H inhibitors include compounds described below.
compounds described in WO2008/010964;
Compounds described in WO2011/075747
　逆転写酵素阻害剤としては、インジナビル、インジナビル硫酸塩エタノール付加物、リトナビル、サキナビル、サキナビルメシル酸塩、ネルフィナビル、ネルフィナビルメシル酸塩、アンプレナビル、アタザナビル、アタザナビル硫酸塩、ロピナビル、ホスアンプレナビル、ホスアンプレナビルカルシウム水和物、ダルナビル、ダルナビル　エタノール付加物等が挙げられる。 Reverse transcriptase inhibitors include indinavir, indinavir sulfate ethanolate, ritonavir, saquinavir, saquinavir mesylate, nelfinavir, nelfinavir mesylate, amprenavir, atazanavir, atazanavir sulfate, lopinavir, fosamprenavir, fosamprenavir calcium hydrate, darunavir, darunavir ethanol adduct, etc.
　インテグラーゼ阻害剤としては、ラルテグラビル、ラルテグラビルカリウム、エルビテグラビル、ＪＴＫ－６５６、ドルテグラビル、ドルテグラビルナトリウム、カボテグラビル、カボテグラビルナトリウム、ビクテグラビル、ビクテグラビルナトリウム、Ｓ－３６５５９８等が挙げられる。 Integrase inhibitors include raltegravir, raltegravir potassium, elvitegravir, JTK-656, dolutegravir, dolutegravir sodium, cabotegravir, cabotegravir sodium, victegravir, victegravir sodium, S-365598, and the like.
　吸着・侵入阻害剤としては、マラビロク、Ｅｎｆｕｖｉｒｔｉｄｅ、Ｉｂａｌｉｚｕｍａｂ、ＰＲＯ－１４０、テムサビル、ホステムサビル　トロメタミン、Ｃｏｍｂｉｎｅｃｔｉｎ等が挙げられる。 Adsorption/entry inhibitors include Maraviroc, Enfuvirtide, Ibalizumab, PRO-140, Temsavir, Fostemsavir Tromethamine, Combinectin, and the like.
　成熟阻害剤としては、ＧＳＫ－２８３８２３２、ＧＳＫ－３６４０２５４等が挙げられる。 Maturation inhibitors include GSK-2838232, GSK-3640254, and the like.
　カプシド（Capsid）阻害剤としては、ＧＳ－６２０７等が挙げられる。 Capsid inhibitors include GS-6207 and the like.
　広域中和抗体としては、Ｌｅｒｏｎｌｉｍａｂ、ＵＢ－４２１、ＶＲＣ０１、１０Ｅ８、ＰＧＤＭ１４００、ＰＧＴ１２１、Ｎ６ＬＳ（ＧＳＫ３８１０１０９Ａ）、Ｔｅｒｏｐａｖｉｍａｂ（３ＢＮＣ１１７－ＬＳ、ＧＳ－５４２３）、ＧＳ－２８７２（１０－１０７４－ＬＳ）等が挙げられる。 Examples of broadly neutralizing antibodies include Leronlimab, UB-421, VRC01, 10E8, PGDM1400, PGT121, N6LS (GSK3810109A), Teropavimab (3BNC117-LS, GS-5423), GS-2872 (10-1074-LS), and the like. be done.
　また、本発明化合物は、遺伝子治療の分野において、ＨＩＶやＭＬＶをもとにしたレトロウイルスベクターを用いる際に、目的の組織以外にレトロウイルスベクターの感染が広がるのを防止するために使用することができる。特に、試験管内で細胞等にベクターを感染しておいてから体内にもどすような場合に、本発明化合物を事前に投与しておくと、体内での余計な感染を防ぐことができる。 The compound of the present invention can also be used in the field of gene therapy to prevent the spread of retroviral vector infection to tissues other than the target tissue when using retroviral vectors based on HIV or MLV. can be done. In particular, when cells or the like are infected with a vector in vitro and then reintroduced into the body, pre-administration of the compound of the present invention can prevent unnecessary infection in the body.
　以下に実施例および参考例、ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 The present invention will be described in more detail below with examples, reference examples, and test examples, but the present invention is not limited by these.
　各実施例で得られたＮＭＲ分析は３００ＭＨｚまたは４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３を用いて測定した。また、ＮＭＲデータを示す場合は、測定した全てのピークを記載していない場合が存在する。
　実施例中、「Ｎｏ．」は化合物番号、「Ｓｔｒｕｃｔｕｒｅ」は化学構造、「ＭＳ」はＬＣ／ＭＳ（液体クロマトグラフィー／質量分析）での質量を表す。ＭＳ（ｍ／ｚ）は、以下の測定条件によって測定することができるが、これらの条件に限定されない。 NMR analyzes obtained in each example were performed at 300 MHz or 400 MHz and measured using DMSO-d 6 , CDCl 3 . Moreover, when NMR data are shown, there are cases where not all measured peaks are described.
In the examples, "No." represents the compound number, "Structure" represents the chemical structure, and "MS" represents the mass in LC/MS (liquid chromatography/mass spectrometry). MS (m/z) can be measured under the following measurement conditions, but is not limited to these conditions.
（LC/MS測定条件）　
（１）カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（登録商標）ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）（Ｗａｔｅｒｓ）
流速：０．８　ｍＬ／分；ＵＶ検出波長：２５４ｎｍ；
移動相：［Ａ］０．１％ギ酸含有水溶液、［Ｂ］０．１％ギ酸含有アセトニトリル溶液
３．５分間で５％－１００％溶媒［Ｂ］のリニアグラジエントを行った後、０．５分間、１００％溶媒［Ｂ］を維持した。 (LC/MS measurement conditions)
(1) Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1×50 mm) (Waters)
Flow rate: 0.8 mL/min; UV detection wavelength: 254 nm;
Mobile phase: [A] 0.1% formic acid-containing aqueous solution, [B] 0.1% formic acid-containing acetonitrile solution, linear gradient of 5%-100% solvent [B] over 3.5 minutes, followed by 0.5 100% solvent [B] was maintained for minutes.
（２）カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）　（Ｓｈｉｍａｄｚｕ）
流速：１．６　ｍＬ／分；ＵＶ検出波長：２５４ｎｍ；
移動相：［Ａ］０．１％ギ酸含有水溶液、［Ｂ］０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。 (2) Column: Shim-pack XR-ODS (2.2 μm, id 50×3.0 mm) (Shimadzu)
Flow rate: 1.6 mL/min; UV detection wavelength: 254 nm;
Mobile phase: [A] 0.1% formic acid-containing aqueous solution, [B] 0.1% formic acid-containing acetonitrile solution Gradient: 10%-100% solvent [B] linear gradient in 3 minutes, 0.5 minutes , 100% solvent [B] was maintained.
（略語）
Ａｃ２Ｏ：無水酢酸
Ｂｏｃ：ｔｅｒｔ－ブトキシカルボニル
ＤＭＥ：１，２－ジメトキシエタン
ＤＭＡＰ：Ｎ，Ｎ－ジメチル－４－アミノピリジン
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＤＭＳＯ：ジメチルスルホキシド
Ｍｅ：メチル
ｍｏｌ／Ｌ：Ｍ
ＮＭＰ：Ｎ－メチル－２－ピロリドン
Ｐｈ：フェニル
ｔＢｕ：ｔｅｒｔ－ブチル
ＴＨＦ：テトラヒドロフラン
ＴＦＡ：トリフルオロ酢酸
ＴＦＡＡ：無水トリフルオロ酢酸
ＴＭＳ：トリメチルシリル
ｘａｎｔｐｈｏｓ：４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチル－９Ｈ－キサンテン
ＸａｎｔＰｈｏｓ　Ｐｄ　Ｇ３：［（４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン）－２－（２′－アミノ－１，１′－ビフェニル）］パラジウム（ＩＩ）メタンスルホナート
ＸＰｈｏｓ　Ｐｄ　Ｇ３：（２－ジシクロヘキシルホスフィノ－２’，４’，６’－トリイソプロピル－１，１’－ビフェニル）［２－（２’－アミノ－１，１’－ビフェニル）］パラジウム（ＩＩ）メタンスルホン酸塩 (abbreviation)
Ac 2 O: acetic anhydride Boc: tert-butoxycarbonyl DME: 1,2-dimethoxyethane DMAP: N,N-dimethyl-4-aminopyridine DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide Me: methyl mol/L :M
NMP: N-methyl-2-pyrrolidone Ph: phenyl tBu: tert-butyl THF: tetrahydrofuran TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride TMS: trimethylsilyl xantphos: 4,5-bis(diphenylphosphino)-9,9 -dimethyl-9H-xanthene XantPhos Pd G3: [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium (II ) Methanesulfonate XPhos Pd G3: (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl) ] Palladium (II) methanesulfonate
（実施例１）
Figure JPOXMLDOC01-appb-C000083
 (Example 1)
Figure JPOXMLDOC01-appb-C000083
工程１
　化合物ｂ２（２０ｇ、１３０ｍｍｏｌ）のメタノール（３００ｍＬ）溶液に、化合物ｂ１（３３ｇ、１３０ｍｍｏｌ）を加え、６５℃で１時間撹拌した。生じた固体をろ過し、さらにメタノールで固体を洗浄し、化合物ｂ３（４３ｇ、収率９２％）を得た。
MS(m/z) = 373 [M+H]+
工程２
　化合物ｂ３（４３ｇ、１２０ｍｍｏｌ）、ＴＦＡ（１８ｍｌ、２３０ｍｍｏｌ）のジクロロエタン（３２０ｍＬ）溶液に、シクロヘキシルイソシアニド（２８ｍｌ、２３０ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に、メタノール（３２０ｍＬ）、水酸化ナトリウム水溶液（５Ｍ、７０ｍＬ、３５０ｍｍｏｌ）を加え、３０分撹拌した。減圧濃縮して生じた固体をろ過し、得られた個体を水、ジイソプロピルエーテル、ヘキサンで洗浄し、化合物ｂ４（５０ｇ、収率８７％）を得た。
MS(m/z) = 500 [M+H]+ Process 1
Compound b1 (33 g, 130 mmol) was added to a methanol (300 mL) solution of compound b2 (20 g, 130 mmol) and stirred at 65° C. for 1 hour. The resulting solid was filtered and washed with methanol to obtain compound b3 (43 g, yield 92%).
MS(m/z) = 373 [M+H] +
Process 2
Cyclohexyl isocyanide (28 ml, 230 mmol) was added to a solution of compound b3 (43 g, 120 mmol) and TFA (18 ml, 230 mmol) in dichloroethane (320 mL), and the mixture was stirred at room temperature for 1 hour. Methanol (320 mL) and aqueous sodium hydroxide solution (5 M, 70 mL, 350 mmol) were added to the reaction solution, and the mixture was stirred for 30 minutes. The solid obtained by concentration under reduced pressure was filtered, and the resulting solid was washed with water, diisopropyl ether and hexane to obtain compound b4 (50 g, yield 87%).
MS(m/z) = 500 [M+H]+
工程３
　化合物ｂ４（４９ｇ、９８ｍｍｏｌ）、ＤＭＡＰ（３．０ｇ、２５ｍｍｏｌ）のトルエン（４９０ｍＬ）溶液を１０５℃まで加熱し、Ｂｏｃ２Ｏ（１１０ｍｌ、４９０ｍｍｏｌ）を加え、１０５℃で３時間撹拌した。反応液を減圧濃縮した。
　得られた粗生成物のジオキサン（３４０ｍＬ）溶液に、水酸化リチウム水溶液（４．０Ｍ、１２０ｍＬ、４８０ｍｍｏｌ）を加え、１１０℃で４時間撹拌した。反応液を減圧濃縮し、得られた残渣を酢酸エチルで抽出した。水層を塩酸で中和し、酢酸エチルで抽出し、減圧濃縮して得られた残渣をろ過し、化合物ｂ５（４７ｇ、収率９２％）を得た。
MS(m/z) = 519 [M+H]+
工程４
　化合物ｂ５（４２ｇ、８０ｍｍｏｌ）のメタノールとＴＨＦ（２１０ｍＬ、２１０ｍＬ）の溶液にトリメチルシリルジアゾメタン（０．６Ｍヘキサン溶液、１５０ｍＬ、９０ｍｍｏｌ）を加え、室温で３０分撹拌した。反応液に、酢酸（１．４ｍＬ、２４ｍｍｏｌ）を加え、室温で１５分撹拌した。反応液を減圧濃縮した。
　得られた粗生成物のＤＭＦ（４３０ｍＬ）溶液に４－メチルフェニルボロン酸（１７ｇ、１２０ｍｍｏｌ）、［１，１’－ビス（ジ－ｔｅｒｔ－ブチルホスフィノ）フェロセン］パラジウム（ＩＩ）ジクロリド（５．３ｇ、８．２ｍｍｏｌ）、炭酸カリウム水溶液（２Ｍ、８０ｍＬ、１６０ｍｍｏｌ）を加え、１１０℃で１時間撹拌した。反応液に、酢酸エチル（４００ｍＬ）、水（４００ｍＬ）、活性炭（４４ｇ）を加え、５０℃で２０分撹拌した。反応液をセライト（登録商標）ろ過し、酢酸エチルで抽出した。減圧濃縮して生じた固体をトルエンとヘキサンの混合溶媒に懸濁し、ろ取し、化合物ｂ６（３９ｇ、収率９６％）を得た。
MS(m/z) = 497 [M+H]+ Process 3
A toluene (490 mL) solution of compound b4 (49 g, 98 mmol) and DMAP (3.0 g, 25 mmol) was heated to 105°C, Boc 2 O (110 ml, 490 mmol) was added, and the mixture was stirred at 105°C for 3 hours. The reaction solution was concentrated under reduced pressure.
An aqueous lithium hydroxide solution (4.0 M, 120 mL, 480 mmol) was added to a dioxane (340 mL) solution of the obtained crude product, and the mixture was stirred at 110° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was extracted with ethyl acetate. The aqueous layer was neutralized with hydrochloric acid, extracted with ethyl acetate, concentrated under reduced pressure, and the resulting residue was filtered to obtain compound b5 (47 g, yield 92%).
MS(m/z) = 519 [M+H]+
Step 4
Trimethylsilyldiazomethane (0.6M hexane solution, 150 mL, 90 mmol) was added to a solution of compound b5 (42 g, 80 mmol) in methanol and THF (210 mL, 210 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid (1.4 mL, 24 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure.
4-Methylphenylboronic acid (17 g, 120 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (5 .3 g, 8.2 mmol) and an aqueous solution of potassium carbonate (2 M, 80 mL, 160 mmol) were added and stirred at 110° C. for 1 hour. Ethyl acetate (400 mL), water (400 mL) and activated carbon (44 g) were added to the reaction solution, and the mixture was stirred at 50°C for 20 minutes. The reaction solution was filtered through Celite (registered trademark) and extracted with ethyl acetate. The solid produced by concentration under reduced pressure was suspended in a mixed solvent of toluene and hexane and collected by filtration to obtain compound b6 (39 g, yield 96%).
MS(m/z) = 497 [M+H]+
工程５
　化合物ｂ６（３９ｇ、７８ｍｍｏｌ）のクロロホルム（３１０ｍＬ）溶液にメタクロロ過安息香酸（約３０％水分含有物、５８ｇ、２４０ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に飽和重曹水（２００ｍＬ）、チオ硫酸ナトリウム水溶液（２ｍＭ、２００ｍＬ、４００ｍｍｏｌ）を加え、ジクロロメタンで抽出し、減圧濃縮した。
　２，６－ルチジン（１６ｍＬ、１４０ｍｍｏｌ）、オキシ塩化リン（２００ｍＬ、２．１ｍｏｌ）の混合物に、得られた粗生成物のジクロロメタン（７２ｍＬ）溶液を加え、室温で３０分撹拌した。反応液を減圧濃縮して得られた残渣を、水酸化ナトリウム水溶液（０．６Ｍ、３００ｍＬ）、エーテル（３００ｍＬ）混合溶液に加え、生じた固体をセライト（登録商標）ろ過で除去した。ろ液をエーテルで抽出し、減圧濃縮して生じた固体をヘキサンに懸濁し、ろ取し、化合物ｂ７（２５ｇ、収率６７％）を得た。
MS(m/z) = 531 [M+H]+
工程６
　化合物ｂ７（７．８ｇ、１５ｍｍｏｌ）のジオキサン（１２０ｍＬ）溶液に、ベンジルアミン（１６ｍＬ、１５０ｍｍｏｌ）、ＸａｎｔＰｈｏｓ　Ｐｄ　Ｇ３（１．４ｇ、１．５ｍｍｏｌ）、Ｘａｎｔｐｈｏｓ（８５０ｍｇ、１．５ｍｍｏｌ）、炭酸セシウム（９．５ｇ、２９ｍｍｏｌ）を加え、１２０℃で１時間撹拌した。反応液に酢酸エチル（１００ｍＬ）、水（１００ｍＬ）、活性炭（８ｇ）を加え、５０℃で３０分撹拌した。反応液をセライト（登録商標）ろ過し、酢酸エチルで抽出した。ろ液を、減圧濃縮して得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｂ８（６．１ｇ、収率７０％）を得た。
MS(m/z) = 602 [M+H]+ Step 5
Meta-chloroperbenzoic acid (about 30% water content, 58 g, 240 mmol) was added to a solution of compound b6 (39 g, 78 mmol) in chloroform (310 mL) and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (200 mL) and aqueous sodium thiosulfate solution (2 mM, 200 mL, 400 mmol) were added to the reaction solution, extracted with dichloromethane, and concentrated under reduced pressure.
A solution of the obtained crude product in dichloromethane (72 mL) was added to a mixture of 2,6-lutidine (16 mL, 140 mmol) and phosphorus oxychloride (200 mL, 2.1 mol) and stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was added to a mixed solution of sodium hydroxide solution (0.6 M, 300 mL) and ether (300 mL), and the resulting solid was removed by Celite (registered trademark) filtration. The filtrate was extracted with ether, concentrated under reduced pressure, and the resulting solid was suspended in hexane and collected by filtration to obtain compound b7 (25 g, yield 67%).
MS(m/z) = 531 [M+H]+
Process 6
To a solution of compound b7 (7.8 g, 15 mmol) in dioxane (120 mL) was added benzylamine (16 mL, 150 mmol), XantPhos Pd G3 (1.4 g, 1.5 mmol), Xantphos (850 mg, 1.5 mmol), cesium carbonate ( 9.5 g, 29 mmol) was added and stirred at 120° C. for 1 hour. Ethyl acetate (100 mL), water (100 mL) and activated carbon (8 g) were added to the reaction solution, and the mixture was stirred at 50°C for 30 minutes. The reaction solution was filtered through Celite (registered trademark) and extracted with ethyl acetate. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b8 (6.1 g, yield 70%).
MS(m/z) = 602 [M+H]+
工程７
　化合物ｂ８（６．１ｇ、１０ｍｍｏｌ）のＴＨＦ（９０ｍＬ）溶液に１０％パラジウム炭素（６．１ｇ）を加え、水素置換し、室温で５時間３０分撹拌した。反応液をセライト（登録商標）ろ過し、ろ液を減圧濃縮し、化合物ｂ９（５．２ｇ、収率１００％）を得た。
MS(m/z) = 512 [M+H]+
工程８
　化合物ｂ９（５．２ｇ、１０ｍｍｏｌ）のエタノール（８０ｍＬ）溶液に、ヨウ素（５．２ｇ、２０ｍｍｏｌ）、硝酸銀（３．５ｇ、２０ｍｍｏｌ）を加え、５０℃で３時間撹拌した。反応液にジクロロメタン（１００ｍＬ）、飽和重曹水（１００ｍＬ）、チオ硫酸ナトリウム（０．６ｍＭ、５０ｍＬ、３０ｍｍｏｌ）を加えた。生じた固体をセライト（登録商標）ろ過で除去した。ろ液をジクロロメタンで抽出し、減圧濃縮して生じた固体をジクロロメタンとヘキサンの混合溶媒に懸濁し、ろ取した。ヘキサンで固体を洗浄し、化合物ｂ１０（５．７ｇ、収率８７％）を得た。
MS(m/z) = 638 [M+H]+ Step 7
A solution of compound b8 (6.1 g, 10 mmol) in THF (90 mL) was added with 10% palladium on carbon (6.1 g), replaced with hydrogen, and stirred at room temperature for 5 hours and 30 minutes. The reaction solution was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain compound b9 (5.2 g, yield 100%).
MS(m/z) = 512 [M+H]+
Step 8
Iodine (5.2 g, 20 mmol) and silver nitrate (3.5 g, 20 mmol) were added to an ethanol (80 mL) solution of compound b9 (5.2 g, 10 mmol) and stirred at 50° C. for 3 hours. Dichloromethane (100 mL), saturated aqueous sodium bicarbonate (100 mL), and sodium thiosulfate (0.6 mM, 50 mL, 30 mmol) were added to the reaction solution. The resulting solid was removed by Celite® filtration. The filtrate was extracted with dichloromethane, and the solid produced by concentration under reduced pressure was suspended in a mixed solvent of dichloromethane and hexane and collected by filtration. The solid was washed with hexane to obtain compound b10 (5.7 g, yield 87%).
MS(m/z) = 638 [M+H]+
工程９
　化合物ｂ１０（１．０ｇ、１．６ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液に、イソチオシアン酸ベンゾイル（０．２１ｍＬ、１．６ｍｍｏｌ）を加え、５０℃で５時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｂ１１（１．１ｇ、収率８６％）を得た。
MS(m/z) = 801 [M+H]+
工程１０
　化合物ｂ１１（１．１ｇ、１．３ｍｍｏｌ）のジオキサン（１６ｍＬ）溶液に、ヨウ化銅（３８ｍｇ、０．２０ｍｍｏｌ）、Ｌ－プロリン（４７ｍｇ、０．４０ｍｍｏｌ）、炭酸カリウム（３７０ｍｇ、２．７ｍｍｏｌ）を加え、８０℃で３０分撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｂ１２（６８０ｍｇ、収率７５％）を得た。
MS(m/z) = 673 [M+H]+ Step 9
Benzoyl isothiocyanate (0.21 mL, 1.6 mmol) was added to a THF (10 mL) solution of compound b10 (1.0 g, 1.6 mmol) and stirred at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b11 (1.1 g, yield 86%).
MS(m/z) = 801 [M+H]+
step 10
To a solution of compound b11 (1.1 g, 1.3 mmol) in dioxane (16 mL), copper iodide (38 mg, 0.20 mmol), L-proline (47 mg, 0.40 mmol), potassium carbonate (370 mg, 2.7 mmol). was added and stirred at 80° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b12 (680 mg, yield 75%).
MS(m/z) = 673 [M+H]+
工程１１
　化合物ｂ１２（６８０ｍｇ、１．０ｍｍｏｌ）に塩酸－ジオキサン溶液（４．０Ｍ、１３ｍＬ、５０ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に水酸化ナトリウム水溶液、飽和重曹水を加え、生じた固体をろ取した。ジイソプロピルエーテル、ヘキサンで固体を洗浄し、化合物ｂ１３（５８０ｍｇ、収率１００％）を得た。
MS(m/z) = 573 [M+H]+
工程１２
　化合物ｂ１３（５８０ｍｇ、１．０ｍｍｏｌ）のジクロロメタン（１７ｍＬ）溶液に、アセトアルデヒド（１．１４ｍＬ、２０ｍｍｏｌ）、酢酸（１．７ｍＬ）を加え、氷冷下更にトリアセトキシ水素化ホウ素ナトリウム（４．２ｇ、２０ｍｍｏｌ）を加え、７時間撹拌した。反応液に飽和重曹水を加え、ジクロロメタンで抽出した。有機層を減圧濃縮して得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｂ１４（５４０ｍｇ、収率８８％）を得た。
MS(m/z) = 601 [M+H]+ step 11
Hydrochloric acid-dioxane solution (4.0 M, 13 mL, 50 mmol) was added to compound b12 (680 mg, 1.0 mmol), and the mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution and a saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the resulting solid was collected by filtration. The solid was washed with diisopropyl ether and hexane to obtain compound b13 (580 mg, yield 100%).
MS(m/z) = 573 [M+H]+
step 12
Acetaldehyde (1.14 mL, 20 mmol) and acetic acid (1.7 mL) were added to a solution of compound b13 (580 mg, 1.0 mmol) in dichloromethane (17 mL), and sodium triacetoxyborohydride (4.2 g, 20 mmol) was added and stirred for 7 hours. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with dichloromethane. The residue obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b14 (540 mg, yield 88%).
MS(m/z) = 601 [M+H]+
工程１３
　化合物ｂ１４（８．２ｇ、１４ｍｍｏｌ）のメタノールと水（２１ｍＬ、２１ｍＬ）の混合溶液に、０℃下濃硫酸（９８％、６０ｍＬ）を加え、８０℃で３時間３０分撹拌した。反応液にＴＨＦ（８０ｍＬ）、メタノール（８０ｍＬ）、水酸化ナトリウム水溶液（１０Ｍ、２４０ｍＬ、２．４ｍｏｌ）を加え、８０℃で２時間撹拌した。反応液に濃塩酸を加え、生じた固体をろ取した。水で固体を洗浄し、化合物ｂ１５（６．２ｇ、収率９２％）を得た。
MS(m/z) = 483 [M+H]+
工程１４
　化合物ｂ１５（７．０ｇ、１５ｍｍｏｌ）のクロロホルム（７０ｍＬ）溶液にＯ－ｔｅｒｔ－ブチル－Ｎ，Ｎ’－ジイソプロピルイソ尿素（１０ｍＬ、４４ｍｍｏｌ）を加え、５０℃で１時間撹拌した。生じた固体をセライト（登録商標）ろ過で除去した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（クロロホルム－メタノール）で精製し、ＳＦＣ光学分割し、化合物ｂ１６（８６０ｍｇ）を得た。
MS(m/z) = 539 [M+H]+

SFC光学分割
カラム：CHIRALPAK IE/SFC　（5μｍ、ｉ．ｄ．250ｘ20ｍｍ）を2本直列で使用
流速：20 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：0.1% ジエチルアミンのMeOH溶液/CO2=50/50の組成比を維持して、30分間送液した。 Step 13
Concentrated sulfuric acid (98%, 60 mL) was added at 0°C to a mixed solution of compound b14 (8.2 g, 14 mmol) in methanol and water (21 mL, 21 mL), and the mixture was stirred at 80°C for 3 hours and 30 minutes. THF (80 mL), methanol (80 mL) and sodium hydroxide aqueous solution (10 M, 240 mL, 2.4 mol) were added to the reaction solution, and the mixture was stirred at 80° C. for 2 hours. Concentrated hydrochloric acid was added to the reaction solution, and the resulting solid was collected by filtration. The solid was washed with water to give compound b15 (6.2 g, yield 92%).
MS(m/z) = 483 [M+H]+
Step 14
O-tert-butyl-N,N'-diisopropylisourea (10 mL, 44 mmol) was added to a solution of compound b15 (7.0 g, 15 mmol) in chloroform (70 mL), and the mixture was stirred at 50°C for 1 hour. The resulting solid was removed by Celite® filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) and subjected to SFC optical resolution to obtain compound b16 (860 mg).
MS(m/z) = 539 [M+H]+

SFC optical resolution column: 2 CHIRALPAK IE/SFC (5 μm, id 250 x 20 mm) used in series Flow rate: 20 mL/min UV detection wavelength: 220 nm
Preparative conditions: 0.1% diethylamine in MeOH solution/CO2=50/50 composition ratio was maintained, and the solution was fed for 30 minutes.
工程１５
　亜硝酸ｔｅｒｔブチル（２．６ｍｌ、２２ｍｍｏｌ）、ジヨードメタン（１．８ｍｌ、２２ｍｍｏｌ）のＤＭＦ（１２ｍＬ）溶液に、氷冷下化合物ｂ１６（１．２０ｇ、２．２ｍｍｏｌ）のＤＭＦ（１２ｍＬ）溶液を加え、室温で１５分撹拌した。反応液にチオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出た。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｂ１７（０．８６ｇ、収率５９％）を得た。
MS(m/z) = 650 [M+H]+
工程１６
　化合物ｂ１７（１００ｍｇ、０．１５ｍｍｏｌ）のＴＨＦと水（２．０ｍＬ、１．０ｍｌ）の溶液に２－フルオロ－４－メトキシフェニルボロン酸（３９ｍｇ、０．２３ｍｍｏｌ）、ＸＰｈｏｓ　Ｐｄ　Ｇ３　（１３ｍｇ、０．０１５ｍｍｏｌ）、リン酸カリウム（６５ｍｇ、０．３１ｍｍｏｌ）を加え、５０℃で４０分撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｂ１８（１００ｍｇ、収率１００％）を得た。
MS(m/z) = 648 [M+H]+ Step 15
To a DMF (12 mL) solution of tert-butyl nitrite (2.6 ml, 22 mmol) and diiodomethane (1.8 ml, 22 mmol) was added a DMF (12 mL) solution of compound b16 (1.20 g, 2.2 mmol) under ice cooling. , and stirred at room temperature for 15 minutes. An aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b17 (0.86 g, yield 59%).
MS(m/z) = 650 [M+H]+
Step 16
To a solution of compound b17 (100 mg, 0.15 mmol) in THF and water (2.0 mL, 1.0 ml) was added 2-fluoro-4-methoxyphenylboronic acid (39 mg, 0.23 mmol), XPhos Pd G3 (13 mg, 0 .015 mmol) and potassium phosphate (65 mg, 0.31 mmol) were added and stirred at 50° C. for 40 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound b18 (100 mg, yield 100%).
MS(m/z) = 648 [M+H]+
工程１７
　化合物ｂ１８（１００ｍｇ、０．１５ｍｍｏｌ）に塩酸－酢酸エチル溶液（４．０Ｍ、２．７ｍＬ、１１ｍｍｏｌ）を加え、室温で１５時間撹拌した。反応液に水酸化ナトリウム水溶液を加え酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣に酢酸エチル、ヘキサンを加えて固体化し、化合物Ｉ－００７５（７１ｍｇ、収率７８％）を得た。
MS(m/z) = 592 [M+H]+
1H-NMR (CDCl3) δ: 0.84 (t, 3H, J=7.0Hz), 2.51 (s, 3H), 2.74 (dq, 1H, J=13.7, 7.0Hz), 3.07 (dq, 1H, J=13.7, 7.0Hz), 3.88 (s, 3H), 5.35 (s, 1H), 6.72 (dd, 1H, J=13.2, 2.3Hz), 6.88 (dd, 1H, J=8.9, 2.3Hz), 7.36-7.54 (m, 7H), 7.60 (d, 1H, J=8.9Hz), 7.78 (d, 1H, J=7.8Hz), 8.01 (d, 1H, J=8.3Hz), 8.52 (t, 1H, J=8.7Hz). Step 17
Hydrochloric acid-ethyl acetate solution (4.0 M, 2.7 mL, 11 mmol) was added to compound b18 (100 mg, 0.15 mmol), and the mixture was stirred at room temperature for 15 hours. An aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and ethyl acetate and hexane were added to the obtained residue to solidify to obtain compound I-0075 (71 mg, yield 78%).
MS(m/z) = 592 [M+H]+
1H-NMR (CDCl3) δ: 0.84 (t, 3H, J=7.0Hz), 2.51 (s, 3H), 2.74 (dq, 1H, J=13.7, 7.0Hz), 3.07 (dq, 1H, J=13.7 , 7.0Hz), 3.88 (s, 3H), 5.35 (s, 1H), 6.72 (dd, 1H, J=13.2, 2.3Hz), 6.88 (dd, 1H, J=8.9, 2.3Hz), 7.36-7.54 (m, 7H), 7.60 (d, 1H, J=8.9Hz), 7.78 (d, 1H, J=7.8Hz), 8.01 (d, 1H, J=8.3Hz), 8.52 (t, 1H, J= 8.7Hz).
（実施例２）
Figure JPOXMLDOC01-appb-C000084
工程１
　化合物ｂ１５（６５０ｍｇ、１．３ｍｍｏｌ）に、濃硫酸（０．７５ｍＬ、１３ｍｍｏｌ）のメタノール（５．５ｍＬ）溶液を加え、８５℃で４時間撹拌した。反応液に水酸化ナトリウム水溶液、飽和重曹水を加え、生じた固体をろ取した。水で固体を洗浄し、化合物ｃ１（５７０ｍｇ、収率８６％）を得た。
MS(m/z) = 497 [M+H]+
工程２
　化合物ｃ１を実施例１の工程１５と同様に反応を行い、化合物ｃ２を得た。
MS(m/z) = 608 [M+H]+ (Example 2)
Figure JPOXMLDOC01-appb-C000084
Process 1
A solution of concentrated sulfuric acid (0.75 mL, 13 mmol) in methanol (5.5 mL) was added to compound b15 (650 mg, 1.3 mmol), and the mixture was stirred at 85° C. for 4 hours. An aqueous sodium hydroxide solution and a saturated aqueous sodium bicarbonate solution were added to the reaction solution, and the resulting solid was collected by filtration. The solid was washed with water to obtain compound c1 (570 mg, yield 86%).
MS(m/z) = 497 [M+H]+
Process 2
Compound c1 was reacted in the same manner as in step 15 of Example 1 to obtain compound c2.
MS(m/z) = 608 [M+H]+
工程３
　化合物ｃ２（４０ｍｇ、０．０６６ｍｍｏｌ）のＤＭＦ（０．６０ｍＬ）溶液にジメチルアミン（２Ｍ ＴＨＦ溶液、０．０８２ｍＬ、０．１７ｍｍｏｌ）を加え、８０℃で２．５時間撹拌した。反応液に水を加え、生じた固体をろ過した。
　粗生成物のＴＨＦとメタノール（０．５２ｍＬ、０．５２ｍＬ）の混合溶液に、水酸化ナトリウム水溶液（２Ｍ、０．３３ｍＬ、０．６６ｍｍｏｌ）を加え、７５℃で２時間撹拌した。反応液に飽和クエン酸水溶液を加え、ジクロロメタンで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、ＳＦＣ光学分割し、化合物Ｉ－００１５（７．９ｍｇ）を得た。
MS(m/z) = 511 [M+H]+

SFC光学分割
カラム：CHIRALPAK IC/SFC　（5μｍ、ｉ．ｄ．250ｘ20ｍｍ）を2本直列で使用
流速：20 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：0.1% ジエチルアミンのMeOH溶液/CO2=70/30の組成比を維持して、30分間送液した。
1H-NMR (CDCl3) δ: 0.81 (3H, t, J=7.0Hz), 2.47 (3H, s), 2.75 (1H, dq, J=13.7, 7.0Hz), 3.02 (1H, dq, J=13.7, 7.0Hz), 3.20 (6H, s), 5.17 (1H, s), 7.47-7.30 (7H, m), 7.55 (1H, d, J=8.8Hz), 7.75 (1H, d, J=7.8Hz), 8.00 (1H, d, J=8.5Hz). Process 3
Dimethylamine (2M THF solution, 0.082 mL, 0.17 mmol) was added to a DMF (0.60 mL) solution of compound c2 (40 mg, 0.066 mmol) and stirred at 80° C. for 2.5 hours. Water was added to the reaction solution, and the resulting solid was filtered.
An aqueous sodium hydroxide solution (2M, 0.33 mL, 0.66 mmol) was added to a mixed solution of the crude product in THF and methanol (0.52 mL, 0.52 mL), and the mixture was stirred at 75° C. for 2 hours. A saturated aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and subjected to SFC optical resolution to obtain compound I-0015 (7.9 mg).
MS(m/z) = 511 [M+H]+

SFC optical resolution column: 2 CHIRALPAK IC/SFC (5 μm, id 250 x 20 mm) used in series Flow rate: 20 mL/min UV detection wavelength: 220 nm
Preparative conditions: 0.1% diethylamine in MeOH solution/CO2=70/30 composition ratio was maintained, and the solution was fed for 30 minutes.
1H-NMR (CDCl3) δ: 0.81 (3H, t, J=7.0Hz), 2.47 (3H, s), 2.75 (1H, dq, J=13.7, 7.0Hz), 3.02 (1H, dq, J=13.7 , 7.0Hz), 3.20 (6H, s), 5.17 (1H, s), 7.47-7.30 (7H, m), 7.55 (1H, d, J=8.8Hz), 7.75 (1H, d, J=7.8Hz ), 8.00 (1H, d, J=8.5Hz).
（実施例３）
Figure JPOXMLDOC01-appb-C000085
工程１
　化合物ｂ１０（１．５ｇ、２．４ｍｍｏｌ）のジクロロエタン（１２ｍＬ）溶液にピリジン（３．８ｍｌ、４７ｍｍｏｌ）を加え、氷冷下塩化ピバロイル（２．９ｍｌ、２４ｍｍｏｌ）を加え、８０℃で２．５時間撹拌した。反応液に水を加え、ジクロロメタンで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｄ１（１．１ｇ、収率６５％）を得た。
MS(m/z) = 722 [M+H]+
工程２
　化合物ｄ１（１．１ｇ、１．５ｍｍｏｌ）のトルエン（１１ｍＬ）溶液にローソン試薬（０．９３ｇ、２．３ｍｍｏｌ）を加え、１００℃で２時間撹拌した。反応液に炭酸カリウム（０．４３ｇ、３．１ｍｍｏｌ）、Ｌ－プロリン（５３ｍｇ、０．４６ｍｍｏｌ）、ヨウ化銅（４４ｍｇ、０．２３ｍｍｏｌ）を加え１００℃で１．５時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｄ２（０．２８ｇ、収率３６％）を得た。
MS(m/z) = 510 [M+H]+ (Example 3)
Figure JPOXMLDOC01-appb-C000085
Process 1
Pyridine (3.8 ml, 47 mmol) was added to a solution of compound b10 (1.5 g, 2.4 mmol) in dichloroethane (12 mL), and pivaloyl chloride (2.9 ml, 24 mmol) was added under ice-cooling. Stirred for an hour. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound d1 (1.1 g, yield 65%).
MS(m/z) = 722 [M+H]+
Process 2
Lawesson's reagent (0.93 g, 2.3 mmol) was added to a toluene (11 mL) solution of compound d1 (1.1 g, 1.5 mmol), and the mixture was stirred at 100° C. for 2 hours. Potassium carbonate (0.43 g, 3.1 mmol), L-proline (53 mg, 0.46 mmol) and copper iodide (44 mg, 0.23 mmol) were added to the reaction solution and stirred at 100° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound d2 (0.28 g, yield 36%).
MS(m/z) = 510 [M+H]+
工程３
　化合物ｄ２を実施例１の工程１２と同様に反応を行った。
　得られた粗生成物（３３８ｍｇ）のＴＨＦ（２．５ｍｌ）、メタノール（０．５ｍｌ）溶液に、２Ｍ水酸化ナトリウム水溶液（１．４ｍｌ、２．８ｍｍｏｌ）を加え、８０℃で４時間撹拌した。反応液にメタノール（１．５ｍｌ）、２Ｍ水酸化ナトリウム水溶液（０．５５ｍｌ、１．１ｍｍｏｌ）を加え、２．５時間撹拌した。反応液に２Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、ＳＦＣ光学分割し、化合物Ｉ－００１９（９２．３ｍｇ）を得た

SFC光学分割
カラム：CHIRALPAK  IC/SFC　（5μｍ、ｉ．ｄ．250ｘ20ｍｍ）
流速：30 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：MeOH+0.1% DEA/CO2=60/40の組成比を維持して、24分間送液した。
1H-NMR (CDCl3) δ: 0.81 (t, 3H, J=7.1Hz), 1.50 (s, 9H), 2.49 (s, 3H), 2.69 (dq, J=13.8, 7.1 Hz, 1H), 3.04 (dq, J=13.8, 7.1Hz, 1H), 5.32 (s, 1H), 7.31-7.52 (m, 7H), 7.57 (d, J=9.0Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.99 (d, J=8.3Hz, 1H). Step 3
Compound d2 was reacted in the same manner as in Step 12 of Example 1.
2M aqueous sodium hydroxide solution (1.4 ml, 2.8 mmol) was added to a solution of the obtained crude product (338 mg) in THF (2.5 ml) and methanol (0.5 ml), and the mixture was stirred at 80°C for 4 hours. . Methanol (1.5 ml) and 2M aqueous sodium hydroxide solution (0.55 ml, 1.1 mmol) were added to the reaction mixture, and the mixture was stirred for 2.5 hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) and subjected to SFC optical resolution to obtain compound I-0019 (92.3 mg).

SFC optical resolution column: CHIRALPAK IC/SFC (5 μm, id 250×20 mm)
Flow rate: 30 mL/min UV detection wavelength: 220 nm
Preparative conditions: MeOH + 0.1% DEA/CO2 = 60/40 composition ratio was maintained, and the solution was fed for 24 minutes.
1H-NMR (CDCl3) δ: 0.81 (t, 3H, J=7.1Hz), 1.50 (s, 9H), 2.49 (s, 3H), 2.69 (dq, J=13.8, 7.1 Hz, 1H), 3.04 ( dq, J=13.8, 7.1Hz, 1H), 5.32 (s, 1H), 7.31-7.52 (m, 7H), 7.57 (d, J=9.0Hz, 1H), 7.77 (d, J=7.8Hz, 1H ), 7.99 (d, J=8.3Hz, 1H).
（実施例４）
Figure JPOXMLDOC01-appb-C000086
工程１
　化合物ｂ１０（６００ｍｇ、０．９４ｍｍｏｌ）のジクロロメタン（７．２ｍＬ）溶液に、ピリジン（０．３０ｍＬ）、ＴＦＡＡ（０．２６ｍＬ、１．８ｍｍｏｌ）を加え、室温で３０分撹拌した。反応液を減圧濃縮して得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｅ１（６３０ｍｇ、収率９１％）を得た。
MS(m/z) = 734 [M+H]+
工程２
　化合物ｅ１（３．０ｇ、４．１ｍｍｏｌ）のアセトニトリル（４６ｍＬ）溶液に、トリメチルシリルアセチレン（２．４ｍＬ、１７ｍｍｏｌ）、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）ジクロリド（０．５８ｇ、０．８３ｍｍｏｌ）、ヨウ化銅（０．１６ｇ、０．８３ｍｍｏｌ）、トリエチルアミン（４．６ｍＬ、３３ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応液に酢酸エチル（４０ｍＬ）、水（４０ｍＬ）を加え、セライト（登録商標）ろ過した。ろ液を酢酸エチルで抽出し、水で洗浄した。有機層を減圧濃縮した。
　粗生成物のジグリム（１７ｍＬ）溶液に、酢酸銅（０．１５ｇ、０．８３ｍｍｏｌ）を加え、１２０℃で１時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｅ２（１．３ｇ、収率５６％）を得た。
MS(m/z) = 536 [M+H]+ (Example 4)
Figure JPOXMLDOC01-appb-C000086
Process 1
Pyridine (0.30 mL) and TFAA (0.26 mL, 1.8 mmol) were added to a solution of compound b10 (600 mg, 0.94 mmol) in dichloromethane (7.2 mL), and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e1 (630 mg, yield 91%).
MS(m/z) = 734 [M+H]+
Process 2
To a solution of compound e1 (3.0 g, 4.1 mmol) in acetonitrile (46 mL) was added trimethylsilylacetylene (2.4 mL, 17 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.58 g, 0.83 mmol), Copper iodide (0.16 g, 0.83 mmol) and triethylamine (4.6 mL, 33 mmol) were added and stirred at 80° C. for 1 hour. Ethyl acetate (40 mL) and water (40 mL) were added to the reaction solution, and the mixture was filtered through Celite (registered trademark). The filtrate was extracted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure.
Copper acetate (0.15 g, 0.83 mmol) was added to a solution of the crude product in diglyme (17 mL) and stirred at 120° C. for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e2 (1.3 g, yield 56%).
MS(m/z) = 536 [M+H]+
工程３
　化合物ｅ２のＤＭＦ（２５ｍＬ）溶液に、水素化ナトリウム（流動パラフィンを約４０％含む、２８０ｍｇ、７．０ｍｍｏｌ）を加え、室温で１０分撹拌した。反応液にヨウ化メチル（０．８８ｍＬ、１４ｍｍｏｌ）を加え、室温で３０分撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｅ３（９３０ｍｇ、収率７３％）を得た。
MS(m/z) = 550 [M+H]+
工程４
　化合物ｅ３を実施例１の工程１１および１２と同様に反応を行い、化合物ｅ４（６８０ｍｇ、収率８４％）を得た。
MS(m/z) = 478 [M+H]+
工程５
　化合物ｅ４（６８０ｍｇ、１．４ｍｍｏｌ）のＴＨＦ（６．８ｍＬ）、メタノール（６．８ｍＬ）混合溶液に、水酸化ナトリウム水溶液（２Ｍ、７．０ｍＬ、１４ｍｍｏｌ）を加え、７５℃で２時間３０分撹拌した。反応液に飽和クエン酸水溶液を加え、ジクロロメタンで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｅ５（６６０ｍｇ、収率１００％）を得た。
MS(m/z) = 464 [M+H]+
工程６
　化合物ｅ５を実施例１の工程１４と同様に反応を行い、SFC光学分割し、化合物ｅ６（265mg)を得た。
MS(m/z) = 520 [M+H]+

SFC光学分割
カラム：CHIRALPAK  IE/SFC　（5μｍ、ｉ．ｄ．250ｘ20ｍｍ）を2本直列で使用
流速：20 ｍＬ／分
ＵＶ検出波長：220ｎｍ
分取条件：0.1% ジエチルアミンのMeOH溶液/CO2=60/40の組成比を維持して、30分間送液した。 Step 3
Sodium hydride (containing about 40% liquid paraffin, 280 mg, 7.0 mmol) was added to a DMF (25 mL) solution of compound e2, and the mixture was stirred at room temperature for 10 minutes. Methyl iodide (0.88 mL, 14 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e3 (930 mg, yield 73%).
MS(m/z) = 550 [M+H]+
Step 4
Compound e3 was reacted in the same manner as steps 11 and 12 of Example 1 to obtain compound e4 (680 mg, yield 84%).
MS(m/z) = 478 [M+H]+
Step 5
An aqueous sodium hydroxide solution (2M, 7.0 mL, 14 mmol) was added to a mixed solution of compound e4 (680 mg, 1.4 mmol) in THF (6.8 mL) and methanol (6.8 mL), and the mixture was heated at 75°C for 2 hours and 30 minutes. Stirred. A saturated aqueous citric acid solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e5 (660 mg, yield 100%).
MS(m/z) = 464 [M+H]+
Process 6
Compound e5 was subjected to SFC optical resolution in the same manner as in step 14 of Example 1 to obtain compound e6 (265 mg).
MS(m/z) = 520 [M+H]+

SFC optical resolution column: 2 CHIRALPAK IE/SFC (5 μm, id 250 x 20 mm) used in series Flow rate: 20 mL/min UV detection wavelength: 220 nm
Preparative conditions: 0.1% diethylamine in MeOH solution/CO2=60/40 composition ratio was maintained, and the solution was fed for 30 minutes.
工程７
　ビス（ピナコラト）ジボロン（０．４３ｇ、１．７ｍｍｏｌ）、（１，５－シクロオクタジエン）（メトキシ）イリジウム（Ｉ）（ダイマー）（７４ｍｇ、０．１１ｍｍｏｌ）、４，４’－ジ－ｔｅｒｔ－ブチル－２，２’－ビピリジル（９０ｍｇ、０．３３ｍｍｏｌ）のＴＨＦ（６．０ｍＬ）溶液を室温で５分攪拌し、反応液に化合物ｅ６（０．５８ｇ、１．１ｍｍｏｌ）のＴＨＦ（１１ｍＬ）溶液を加え、８０℃で３０分撹拌した。反応液の溶媒を留去したのちに、臭化銅（ＩＩ）（０．６２ｇ、２．８ｍｍｏｌ）、ＭｅＯＨ（１２ｍＬ）、水（３．０ｍＬ）を加え８０℃で７０分撹拌した。反応液に水を加え、ジクロロメタンで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｅ７（０．２３ｇ、収率３４％）を得た。
MS(m/z) = 598 [M+H]+
工程８
　化合物ｅ７（６０ｍｇ、０．１０ｍｍｏｌ）のＴＨＦと水（１．２ｍＬ、０．６０ｍＬ）の溶液に、４－メトキシフェニルボロン酸（２３ｍｇ、０．１５ｍｍｏｌ）、ＸＰｈｏｓ　Ｇ３　（８．５ｍｇ、０．０１０ｍｍｏｌ）、リン酸カリウム（４３ｍｇ、０．２０ｍｍｏｌ）を加え、５０℃で１時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｅ８（５４ｍｇ、収率８６％）を得た。
MS(m/z) = 626 [M+H]+
工程９
化合物ｅ８を実施例１の工程１７と同様に反応を行い、化合物Ｉ－０１９０（３９ｍｇ、収率７９％）を得た。
MS(m/z) = 570 [M+H]+
1H-NMR (CDCl3) δ: 0.81 (t, 3H, J=7.1Hz), 2.48 (s, 3H), 2.71 (dq, 1H, J=14.1, 7.1Hz), 3.02 (dq, 1H, J=14.1, 7.1Hz), 3.86 (s, 3H), 3.86 (s, 3H), 5.40 (s, 1H), 6.26 (s, 1H), 6.96-7.00 (m, 2H), 7.31-7.52 (m, 9H), 7.58 (d, 1H, J=8.9Hz), 7.78 (d, 1H, J=8.0Hz), 8.00 (d, 1H, J=8.5Hz). Step 7
Bis(pinacolato)diboron (0.43g, 1.7mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) (dimer) (74mg, 0.11mmol), 4,4'-di-tert -Butyl-2,2′-bipyridyl (90 mg, 0.33 mmol) in THF (6.0 mL) was stirred at room temperature for 5 minutes, and compound e6 (0.58 g, 1.1 mmol) in THF (11 mL) was added to the reaction mixture. ) solution and stirred at 80° C. for 30 minutes. After distilling off the solvent of the reaction solution, copper (II) bromide (0.62 g, 2.8 mmol), MeOH (12 mL) and water (3.0 mL) were added and stirred at 80° C. for 70 minutes. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e7 (0.23 g, yield 34%).
MS(m/z) = 598 [M+H]+
Step 8
To a solution of compound e7 (60 mg, 0.10 mmol) in THF and water (1.2 mL, 0.60 mL) was added 4-methoxyphenylboronic acid (23 mg, 0.15 mmol), XPhos G3 (8.5 mg, 0.010 mmol). ), potassium phosphate (43 mg, 0.20 mmol) was added and stirred at 50° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound e8 (54 mg, yield 86%).
MS(m/z) = 626 [M+H]+
Step 9
Compound e8 was reacted in the same manner as in step 17 of Example 1 to obtain compound I-0190 (39 mg, yield 79%).
MS(m/z) = 570 [M+H]+
1H-NMR (CDCl3) δ: 0.81 (t, 3H, J=7.1Hz), 2.48 (s, 3H), 2.71 (dq, 1H, J=14.1, 7.1Hz), 3.02 (dq, 1H, J=14.1 , 7.1Hz), 3.86 (s, 3H), 3.86 (s, 3H), 5.40 (s, 1H), 6.26 (s, 1H), 6.96-7.00 (m, 2H), 7.31-7.52 (m, 9H) , 7.58 (d, 1H, J=8.9Hz), 7.78 (d, 1H, J=8.0Hz), 8.00 (d, 1H, J=8.5Hz).
（実施例５）
Figure JPOXMLDOC01-appb-C000087
 (Example 5)
Figure JPOXMLDOC01-appb-C000087
工程１
　化合物ｆ１（１２ｇ、５５ｍｍｏｌ）のメタノール（６６ｍＬ）溶液に、２－エテニル－６－メチルアニリン（７．４ｇ、５５ｍｍｏｌ）、ＴＦＡ（８．５ｍｌ、１１０ｍｍｏｌ）を加え、１時間還流撹拌した。反応液にシクロヘキシルイソシアニド（１３ｍｌ、１１０ｍｍｏｌ）を加え、２時間還流撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｆ２（５．５ｇ、収率２２％）を得た。
MS(m/z) = 462 [M+H]+
工程２
　化合物ｆ２（１．４ｇ、３．１ｍｍｏｌ）のアセトニトリル（１４ｍＬ）－ヘキサフルオロイソプロパノール（５．８ｍＬ）溶液に、［１，１’－ビス（ジ－ｔｅｒｔ－ブチルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）（０．２０ｇ、０．３１ｍｍｏｌ）、炭酸カリウム（１．３ｇ、９．２ｍｍｏｌ）を加え、マイクロ波照射下１２０℃で１時間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｆ３（０．６８ｇ、収率５８％）を得た。
MS(m/z) = 382 [M+H]+ Process 1
2-Ethenyl-6-methylaniline (7.4 g, 55 mmol) and TFA (8.5 ml, 110 mmol) were added to a solution of compound f1 (12 g, 55 mmol) in methanol (66 mL), and the mixture was stirred under reflux for 1 hour. Cyclohexyl isocyanide (13 ml, 110 mmol) was added to the reaction mixture, and the mixture was stirred under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound f2 (5.5 g, yield 22%).
MS(m/z) = 462 [M+H] +
Process 2
[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II ) (0.20 g, 0.31 mmol) and potassium carbonate (1.3 g, 9.2 mmol) were added and stirred at 120° C. for 1 hour under microwave irradiation. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound f3 (0.68 g, yield 58%).
MS(m/z) = 382 [M+H] +
工程３
　化合物ｆ３（０．５０ｇ、１．３ｍｍｏｌ）のジクロロメタン（７．５ｍＬ）、酢酸（０．７５ｍｌ）溶液に、氷冷下アセトアルデヒド（０．７４ｍＬ、１３ｍｍｏｌ）、ナトリウムトリアセトキシボロヒドリド（１．４ｇ、６．６ｍｍｏｌ）を加え、氷冷下で３０分間撹拌した。反応液に水酸化ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｆ４（０．３７ｇ、収率６８％）を得た。
MS(m/z) = 410 [M+H]+
工程４、５
　実施例１工程３と同様の反応を行うことで、化合物ｆ６（０．１８ｇ、２工程収率６１％）を得た。
MS(m/z) = 329 [M+H]+
工程６
　実施例１工程４の前半工程と同様の反応を行うことで、化合物ｆ７（０．１７ｇ、収率９１％）を得た。
MS(m/z) = 343 [M+H]+ Step 3
Acetaldehyde (0.74 mL, 13 mmol), sodium triacetoxyborohydride (1.4 g, 6.6 mmol) was added and stirred for 30 minutes under ice-cooling. An aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound f4 (0.37 g, yield 68%).
MS(m/z) = 410 [M+H] +
Steps 4 and 5
Compound f6 (0.18 g, 2-step yield: 61%) was obtained by performing the same reaction as in Example 1, Step 3.
MS(m/z) = 329 [M+H] +
Process 6
Compound f7 (0.17 g, yield 91%) was obtained by performing the same reaction as in the first half of Step 4 of Example 1.
MS(m/z) = 343 [M+H] +
工程７
　化合物ｆ７（０．１３ｇ、０．３７ｍｍｏｌ）の水（１．０ｍＬ）－テトラヒドロフラン（２．０ｍＬ）溶液に、４－メチルフェニルボロン酸（０．１５ｇ、１．１ｍｍｏｌ）、Ｘｐｈｏｓ　Ｇ３（０．０３２ｇ、０．０３７ｍｍｏｌ）、リン酸カリウム（０．１６ｇ、０．７５ｍｍｏｌ）を加え、５０℃で３０分間撹拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｆ８（０．１３ｇ、収率８９％）を得た。
MS(m/z) = 399 [M+H]+
1H-NMR (CDCl3) δ: 0.64 (t, 3H, J=7.2Hz), 2.24 (s, 3H), 2.43 (s, 3H), 2.59-2.76 (m, 2H), 3.50 (s, 3H), 5.28 (s, 1H), 5.65 (d, 1H, J=1.8Hz), 5.78 (d, 1H, J=1.8Hz), 6.95 (t, 1H, J=7.6Hz), 7.11-7.16 (m, 2H), 7.21-7.32 (m, 5H), 8.57 (d, 1H, J=4.9Hz).
工程８
　実施例４工程５と同様の反応を行うことで、化合物Ｉ－０１２２’（０．０２２ｇ、収率３０％）を得た。
MS(m/z) = 385 [M+H]+
1H-NMR (CDCl3) δ: 0.63 (t, 3H, J=7.2 Hz), 2.27 (s, 3H), 2.43 (s, 3H), 2.53-2.73 (m, 2H), 5.34 (s, 1H), 5.73 (d, 1H, J=1.2Hz), 5.75 (d, 1H, J=1.2Hz), 6.98 (t, 1H, J=7.4Hz), 7.15 (d, 1H, J=7.4Hz), 7.19 (d, 1H, J=5.0Hz), 7.27-7.31 (m, 4H), 7.35-7.39 (m, 1H), 8.59 (d, 1H, J=5.0Hz). Step 7
Compound f7 (0.13 g, 0.37 mmol) in water (1.0 mL)-tetrahydrofuran (2.0 mL) solution, 4-methylphenylboronic acid (0.15 g, 1.1 mmol), Xphos G3 (0.032 g , 0.037 mmol), potassium phosphate (0.16 g, 0.75 mmol) and stirred at 50° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound f8 (0.13 g, yield 89%).
MS(m/z) = 399 [M+H] +
1H-NMR (CDCl3) δ: 0.64 (t, 3H, J=7.2Hz), 2.24 (s, 3H), 2.43 (s, 3H), 2.59-2.76 (m, 2H), 3.50 (s, 3H), 5.28 (s, 1H), 5.65 (d, 1H, J=1.8Hz), 5.78 (d, 1H, J=1.8Hz), 6.95 (t, 1H, J=7.6Hz), 7.11-7.16 (m, 2H ), 7.21-7.32 (m, 5H), 8.57 (d, 1H, J=4.9Hz).
Step 8
Compound I-0122' (0.022 g, yield 30%) was obtained by the same reaction as in Step 5 of Example 4.
MS(m/z) = 385 [M+H] +
1H-NMR (CDCl3) δ: 0.63 (t, 3H, J=7.2 Hz), 2.27 (s, 3H), 2.43 (s, 3H), 2.53-2.73 (m, 2H), 5.34 (s, 1H), 5.73 (d, 1H, J=1.2Hz), 5.75 (d, 1H, J=1.2Hz), 6.98 (t, 1H, J=7.4Hz), 7.15 (d, 1H, J=7.4Hz), 7.19 ( d, 1H, J=5.0Hz), 7.27-7.31 (m, 4H), 7.35-7.39 (m, 1H), 8.59 (d, 1H, J=5.0Hz).
（実施例６）
Figure JPOXMLDOC01-appb-C000088
 (Example 6)
Figure JPOXMLDOC01-appb-C000088
工程１
　トリメチルスルホキソニウムヨージド（０．１１ｇ、０．５０ｍｍｏｌ）のＤＭＳＯ（１．０ｍＬ）溶液に、カリウム　ｔｅｒｔ－ブトキシド（０．０４２ｇ、０．３８ｍｍｏｌ）を加え、室温で２０分間撹拌した。反応液に化合物ｆ８（０．０５０ｇ、０．１３ｍｍｏｌ）を加え、室温で３０分間撹拌した。反応液に氷冷下クエン酸水溶液を加え、酢酸エチルで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｆ９（０．０２０ｇ、収率３９％）を得た。
MS(m/z) = 413 [M+H]+
工程２
　実施例４工程５と同様の反応を行うことで、化合物Ｉ－０１３８’（１．１ｍｇ、収率５．７％）を得た。
MS(m/z) = 399 [M+H]+
1H-NMR (CDCl3) δ: 0.79 (t, 3H, J=7.2Hz), 1.14-1.28 (m, 2H), 1.70-1.80 (m, 2H), 2.27 (s, 3H), 2.42 (s, 3H), 2.83 (q, 2H, J=7.2Hz), 5.38 (s, 1H), 6.93 (t, 1H, J=7.8Hz), 7.05 (d, 2H, J=5.0Hz), 7.13-7.16 (m, 1H), 7.31-7.22 (m, 4H), 8.44 (d, 1H, J=5.0Hz). Process 1
Potassium tert-butoxide (0.042 g, 0.38 mmol) was added to a solution of trimethylsulfoxonium iodide (0.11 g, 0.50 mmol) in DMSO (1.0 mL) and stirred at room temperature for 20 minutes. Compound f8 (0.050 g, 0.13 mmol) was added to the reaction solution and stirred at room temperature for 30 minutes. An aqueous citric acid solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound f9 (0.020 g, yield 39%).
MS(m/z) = 413 [M+H]+
Process 2
Compound I-0138′ (1.1 mg, yield 5.7%) was obtained by the same reaction as in Example 4, Step 5.
MS(m/z) = 399 [M+H] +
1H-NMR (CDCl3) δ: 0.79 (t, 3H, J=7.2Hz), 1.14-1.28 (m, 2H), 1.70-1.80 (m, 2H), 2.27 (s, 3H), 2.42 (s, 3H ), 2.83 (q, 2H, J=7.2Hz), 5.38 (s, 1H), 6.93 (t, 1H, J=7.8Hz), 7.05 (d, 2H, J=5.0Hz), 7.13-7.16 (m , 1H), 7.31-7.22 (m, 4H), 8.44 (d, 1H, J=5.0Hz).
（実施例７）
Figure JPOXMLDOC01-appb-C000089
 (Example 7)
Figure JPOXMLDOC01-appb-C000089
　化合物Ｉ－０１２２’（０．０１４ｇ、０．０３６ｍｍｏｌ）の酢酸エチル（１．４ｍＬ）溶液に、１０％パラジウム炭素（０．０１３ｇ）を加え、水素雰囲気下室温で４時間撹拌した。反応液をろ過し、ろ液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物Ｉ－０１３９’（２．６ｍｇ、収率１９％）を得た。
MS(m/z) = 387 [M+H]+
1H-NMR (CDCl3) δ: 0.75 (t, 3H, J=7.1Hz), 1.67 (d, 3H, J=7.7Hz), 2.25 (s, 3H), 2.42 (s, 3H), 2.61-2.80 (m, 2H), 4.87 (q, 1H, J=7.7Hz), 5.32 (s, 1H), 6.96-7.31 (m, 8H), 8.50 (d, 1H, J=5.0Hz). To a solution of compound I-0122′ (0.014 g, 0.036 mmol) in ethyl acetate (1.4 mL), 10% palladium on carbon (0.013 g) was added, and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound I-0139' (2.6 mg, yield 19%).
MS(m/z) = 387 [M+H] +
1H-NMR (CDCl3) δ: 0.75 (t, 3H, J=7.1Hz), 1.67 (d, 3H, J=7.7Hz), 2.25 (s, 3H), 2.42 (s, 3H), 2.61-2.80 ( m, 2H), 4.87 (q, 1H, J=7.7Hz), 5.32 (s, 1H), 6.96-7.31 (m, 8H), 8.50 (d, 1H, J=5.0Hz).
（実施例８）
Figure JPOXMLDOC01-appb-C000090
 (Example 8)
Figure JPOXMLDOC01-appb-C000090
工程１
　化合物ｇ１（１７ｇ、９６ｍｍｏｌ）のＤＭＦ（８５ｍＬ）溶液に、トリエチルアミン（４０ｍＬ、０．２９ｍｏｌ）、４，４－ジメチルピペリジン（１１ｇ、０．１０ｍｏｌ）を加え、室温で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｇ２（２１ｇ、収率８６％）を得た。
MS(m/z) = 253 [M+H]+
工程２
　化合物ｇ２（２１ｇ、８１ｍｍｏｌ）のＤＭＦ（４１０ｍＬ）溶液に、ジブロモイソシアヌル酸（２３ｇ、８１ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液、クロロホルムを加え、攪拌した。得られた混合液を濾過した。得られた有機層を水洗後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｇ３（１４ｇ、収率５３％）を得た。
MS(m/z) = 331 [M+H]+ Process 1
Triethylamine (40 mL, 0.29 mol) and 4,4-dimethylpiperidine (11 g, 0.10 mol) were added to a DMF (85 mL) solution of compound g1 (17 g, 96 mmol) and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound g2 (21 g, yield 86%).
MS(m/z) = 253 [M+H] +
Process 2
Dibromoisocyanuric acid (23 g, 81 mmol) was added to a DMF (410 mL) solution of compound g2 (21 g, 81 mmol) and stirred at room temperature for 2 hours. A saturated aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogencarbonate solution, and chloroform were added to the reaction solution, and the mixture was stirred. The resulting mixture was filtered. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound g3 (14 g, yield 53%).
MS(m/z) = 331 [M+H] +
工程３
　化合物ｇ３（２８ｇ、８４ｍｍｏｌ）、１－アミノナフタレン－２－オール（１６ｇ、０．１０ｍｏｌ）のＤＭＡ（１４０ｍＬ）溶液に、ジイソプロピルエチルアミン（１８ｍＬ、０．１０ｍｏｌ）を加え、１００℃で３時間攪拌した。反応液に水（１４０ｍＬ）を滴下し、放冷攪拌した。析出した固体を濾取し、水、メタノールで洗浄し、乾燥し、化合物ｇ４（３４ｇ、収率９２％）を得た。
MS(m/z) = 436 [M+H]+
工程４
　化合物ｇ４（３３ｇ、７５ｍｍｏｌ）、シクロヘキシルイソシアニド（４６ｍＬ、０．３８ｍｏｌ）のジクロロエタン（３００ｍＬ）溶液に、ＴＦＡ（４３ｇ、０．３８ｍｏｌ）のジクロロエタン（２７ｍＬ）溶液を、氷冷下加え、５０℃で４０分間攪拌した。反応液にメタノール（３３０ｍＬ）、２Ｍ水酸化ナトリウム水溶液（２６０ｍＬ）を、水浴下加え、５０℃で４０分間攪拌した。反応液に２Ｍ塩酸水溶液（７５ｍＬ）、水（３００ｍＬ）を加え、クロロホルムで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマ卜グラフィー（酢酸エチル－クロロホルム）で精製し、化合物ｇ５（２２ｇ、収率５３％）を得た。
MS(m/z) = 563 [M+H]+ Step 3
Diisopropylethylamine (18 mL, 0.10 mol) was added to a solution of compound g3 (28 g, 84 mmol) and 1-aminonaphthalen-2-ol (16 g, 0.10 mol) in DMA (140 mL) and stirred at 100° C. for 3 hours. . Water (140 mL) was added dropwise to the reaction solution, and the mixture was allowed to cool and stirred. The precipitated solid was collected by filtration, washed with water and methanol, and dried to obtain compound g4 (34 g, yield 92%).
MS(m/z) = 436 [M+H] +
Step 4
To a solution of compound g4 (33 g, 75 mmol) and cyclohexylisocyanide (46 mL, 0.38 mol) in dichloroethane (300 mL) was added a solution of TFA (43 g, 0.38 mol) in dichloroethane (27 mL) under ice cooling. Stir for a minute. Methanol (330 mL) and 2M aqueous sodium hydroxide solution (260 mL) were added to the reaction solution in a water bath, and the mixture was stirred at 50° C. for 40 minutes. A 2M hydrochloric acid aqueous solution (75 mL) and water (300 mL) were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-chloroform) to obtain compound g5 (22 g, yield 53%).
MS(m/z) = 563 [M+H] +
工程５
　化合物ｇ５（２３ｇ、４０ｍｍｏｌ）、アセトアルデヒド（１１ｍＬ、０．２０ｍｏｌ）および酢酸（１２ｍＬ、０．２０ｍｏｌ）のジクロロメタン（２３０ｍＬ）溶液に、氷浴下トリアセトキシ水素化ホウ素ナトリウム（２６ｇ、０．１２ｍｏｌ）を加え、室温で１時間攪拌した。反応液に水（５００ｍＬ）、炭酸水素ナトリウム（６１ｇ、０．７３ｍｏｌ）を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた固体をヘキサンで洗浄し、乾燥し、化合物ｇ６（２３ｇ、収率９５％）を得た。
MS(m/z) = 591 [M+H]+
工程６
　実施例１工程３と同様の反応を行うことで、化合物ｇ７（１８ｇ、７９％）を得た。
MS(m/z) = 510 [M+H]+ Step 5
To a solution of compound g5 (23 g, 40 mmol), acetaldehyde (11 mL, 0.20 mol) and acetic acid (12 mL, 0.20 mol) in dichloromethane (230 mL) was added sodium triacetoxyborohydride (26 g, 0.12 mol) in an ice bath. The mixture was added and stirred at room temperature for 1 hour. Water (500 mL) and sodium hydrogen carbonate (61 g, 0.73 mol) were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting solid was washed with hexane and dried to give compound g6 (23 g, 95% yield).
MS(m/z) = 591 [M+H] +
Process 6
Compound g7 (18 g, 79%) was obtained by the same reaction as in Example 1, Step 3.
MS(m/z) = 510 [M+H] +
工程７
　化合物ｇ７（１８ｇ、３５ｍｍｏｌ）のクロロホルム（１８０ｍＬ）溶液に、２－ｔｅｒｔ－ブチル－１，３－ジイソプロピルイソ尿素（３４ｍＬ、１３８ｍｍｏｌ）を加え、５０℃で２．５時間撹拌した。反応液に水（３．１ｍＬ、１７０ｍｍｏｌ）を加え、濾過した。ろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、得られた固体をヘキサン－ジイソプロピルエーテルで洗い、化合物ｇ８（１６ｇ、収率８２％）を得た。
MS(m/z) = 566 [M+H]+
工程８
　化合物ｇ８（１６ｇ、２８ｍｍｏｌ）をＳＦＣ光学分割し、化合物ｇ９を単一の立体異性体（７．１ｇ）として得た。

カラム：CHIRALPAK IE /SFC（5μｍ、ｉ．ｄ．250ｘ20ｍｍ）を2本直列で使用
移動相　A: MeOH+0.1%DEA 65%, B: CO2 35%
流速：20 mL／分
ＵＶ検出波長：220ｎｍ
分取条件：MeOH+0.1%DEA/CO2=65/35の組成比を維持して、18分間送液した。 Step 7
2-tert-butyl-1,3-diisopropylisourea (34 mL, 138 mmol) was added to a solution of compound g7 (18 g, 35 mmol) in chloroform (180 mL), and the mixture was stirred at 50° C. for 2.5 hours. Water (3.1 mL, 170 mmol) was added to the reaction and filtered. The filtrate was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), the obtained solid was washed with hexane-diisopropyl ether, and compound g8 (16 g, yield 82%) was obtained. Obtained.
MS(m/z) = 566 [M+H] +
Step 8
Compound g8 (16 g, 28 mmol) was subjected to SFC optical resolution to give compound g9 as a single stereoisomer (7.1 g).

Column: Two CHIRALPAK IE/SFC (5 μm, id 250×20 mm) used in series Mobile phase A: MeOH+0.1%DEA 65%, B: CO2 35%
Flow rate: 20 mL/min UV detection wavelength: 220 nm
Preparative conditions: MeOH+0.1%DEA/CO 2 =65/35 composition ratio was maintained, and the solution was fed for 18 minutes.
工程９
　化合物ｇ９（４０ｍｇ、０．０７１ｍｍｏｌ）、４－メトキシフェニルボロン酸（１６ｍｇ、０．１１ｍｍｏｌ）、リン酸三カリウム（４５ｍｇ、０．２１ｍｍｏｌ）のＴＨＦ（１．０ｍＬ）－水（０．１０ｍＬ）溶液に、ＸＰｈｏｓ　Ｇ３（６．０ｍｇ、７．１μｍｏｌ）を加え、６５℃で５時間攪拌した。反応液に水を加え、クロロホルムで抽出した。有機層を減圧濃縮し、得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物ｇ１０（４０ｍｇ、収率９５％）を得た。
MS(m/z) = 594 [M+H]+
工程１０
　化合物ｇ１０（４０ｍｇ、０．０６７ｍｍｏｌ）に、４Ｍ塩酸ジオキサン（１ｍＬ、４．００ｍｍｏｌ）および水（０．２０ｍＬ）を加え、室温で７時間攪拌した。反応液に２Ｎ水酸化ナトリウムを加え、酢酸エチルで抽出した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルカラムクロマ卜グラフィー（ヘキサン－酢酸エチル）で精製し、化合物Ｉ－０１８９’（３２ｍｇ、８７％）を得た。
MS(m/z) = 538 [M+H]+
1H NMR (CDCl3) δ: 0.81 (br.s, 6H) 1.16-1.33 (m, 7H) 2.25-3.03 (m, 4H), 2.89 (br dd, J=13.18, 6.78Hz, 1H) 3.12 (dd, J=13.05, 7.28Hz, 1H) 3.65 (s, 1H) 3.87 (s, 3H) 5.80 (s, 1H) 6.94-6.99 (m, 2H) 7.16-7.22 (m, 3H) 7.33-7.39 (m, 1H) 7.48 (ddd, J=8.31, 6.93, 1.19Hz, 1H) 7.53 (d, J=8.91Hz, 1H) 7.72 (d, J=7.91Hz, 1H) 7.88 (s, 1H) 8.29 (d, J=8.53Hz, 1H). Step 9
Compound g9 (40 mg, 0.071 mmol), 4-methoxyphenylboronic acid (16 mg, 0.11 mmol), tripotassium phosphate (45 mg, 0.21 mmol) in THF (1.0 mL) - water (0.10 mL) XPhos G3 (6.0 mg, 7.1 μmol) was added to the solution and stirred at 65° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound g10 (40 mg, yield 95%).
MS(m/z) = 594 [M+H] +
step 10
4M dioxane hydrochloride (1 mL, 4.00 mmol) and water (0.20 mL) were added to compound g10 (40 mg, 0.067 mmol) and stirred at room temperature for 7 hours. 2N sodium hydroxide was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound I-0189' (32 mg, 87%).
MS(m/z) = 538 [M+H] +
1 H NMR (CDCl3) δ: 0.81 (br.s, 6H) 1.16-1.33 (m, 7H) 2.25-3.03 (m, 4H), 2.89 (br dd, J=13.18, 6.78Hz, 1H) 3.12 (dd , J=13.05, 7.28Hz, 1H) 3.65 (s, 1H) 3.87 (s, 3H) 5.80 (s, 1H) 6.94-6.99 (m, 2H) 7.16-7.22 (m, 3H) 7.33-7.39 (m, 1H) 7.48 (ddd, J=8.31, 6.93, 1.19Hz, 1H) 7.53 (d, J=8.91Hz, 1H) 7.72 (d, J=7.91Hz, 1H) 7.88 (s, 1H) 8.29 (d, J =8.53Hz, 1H).
　上記実施例や一般合成法に記載の方法に従い、市販の化合物または上記中間体から以下の化合物を合成した。 The following compounds were synthesized from commercially available compounds or the above intermediates according to the methods described in the above examples and general synthesis method.
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000093
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
　更に以下の化合物も同様に合成できる。
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-T000108
Furthermore, the following compounds can be similarly synthesized.
Figure JPOXMLDOC01-appb-C000109
　各実施例化合物の物理化学データを以下に示す。表中に「ＭＳ」とあるのは、ＬＣ／ＭＳでの質量（Ｍ＋Ｈ）を表し、「Ｓｔｅｒｅｏ」とあるのは、化合物が単一のエナンチオマー（Single）であるか、ラセミ体（Racemate）であるのか、ジアステレオマー混合物(Stereomixture)であるか、不明(Unknown)を表す。
Figure JPOXMLDOC01-appb-T000110
 The physicochemical data of each example compound are shown below. "MS" in the table indicates mass (M+H) by LC/MS, "Stereo" indicates that the compound is a single enantiomer (Single) or racemate (Racemate). It is present, a diastereomeric mixture (Stereomixture), or unknown.
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
　以下に、本発明化合物の生物試験例を記載する。本発明化合物は、本質的に下記試験例のとおり試験することができる。
　本発明に係る式（Ｉ）で示される化合物は、ＨＩＶ複製阻害作用を有し、ＨＩＶ複製を阻害するものであればよい。
　具体的には、以下に記載する評価方法において、ＥＣ５０は１０００ｎＭ以下が好ましく、より好ましくは、１００ｎＭ以下、さらにより好ましくは５０ｎＭ以下である。 Biological test examples of the compound of the present invention are described below. The compounds of the invention can be tested essentially as described in the Test Examples below.
The compound represented by formula (I) according to the present invention may have an HIV replication inhibitory effect and inhibit HIV replication.
Specifically, in the evaluation method described below, the EC50 is preferably 1000 nM or less, more preferably 100 nM or less, and even more preferably 50 nM or less.
試験例１　ＨＩＶ複製阻害試験
　ＨＩＶ－１　ＮＬ４３２組み換え分子クローンのプラスミドを２９３Ｔ細胞に遺伝子導入し、培養２日後の上清を濾過してウイルス液とし、－８０℃保存した。また、ＨＩＶ－１のインテグラーゼ（ＩＮ）遺伝子上の１２４および１２５番目のアミノ酸はＨＩＶ－１感染患者において多型変異が確認されており、それらに対する薬効を確認するため、ＨＩＶ－１　ＮＬ４３２組み換え分子クローンのＩＮ遺伝子上に突然変異を導入して１２４および１２５番目のアミノ酸に関する変異ウイルスのプラスミドを作製し、上記の通りＨＩＶ含有上清を調製した。一方、各抗ＨＩＶ活性物質を所定の濃度になるようにあらかじめ分注した３８４ウェルマイクロプレートに、１０％牛胎児血清添加ＲＰＭＩ　１６４０培地で調製したＭＴ－４細胞浮遊液を２０μＬ（１２５０細胞）ずつ添加し、更に上記ＨＩＶ含有上清を上記の培養培地で希釈したものを２０μＬ（multiplicity of infection = 0.1～0.5 TCID50 [50% tissue culture infectious dose]）ずつ添加した。陽性コントロールとしてウイルスを添加しないウェルには培養培地のみを２０μＬずつ添加した。炭酸ガス培養器内で３７℃、４日間培養した後、すべてのウェルにＣｅｌｌＴｉｔｅｒ－Ｇｌｏ（登録商標）　２．０試薬を１０μＬずつ添加し、室温で２０分間プレートミキサーで混和し反応させた。マイクロプレートリーダーを用いて発光量を測定し、細胞生存率を指標に抗ＨＩＶ活性を評価した。ウイルスによる細胞障害を５０％抑制する化合物濃度をＥＣ５０とした。
（結果）ＥＣ５０を以下に示す。
Figure JPOXMLDOC01-appb-T000114
 Test Example 1 HIV Replication Inhibition Test Plasmids of HIV-1 NL432 recombinant molecular clones were transfected into 293T cells. In addition, polymorphic mutations in the 124th and 125th amino acids on the HIV-1 integrase (IN) gene have been confirmed in HIV-1 infected patients. Mutations were introduced on the IN gene of the clones to generate mutant virus plasmids for amino acids 124 and 125, and HIV-containing supernatants were prepared as described above. On the other hand, 20 μL (1250 cells) of MT-4 cell suspension prepared in RPMI 1640 medium supplemented with 10% fetal bovine serum was added to a 384-well microplate in which each anti-HIV active substance was previously dispensed at a predetermined concentration. 20 μL of the HIV-containing supernatant diluted with the culture medium (multiplicity of infection = 0.1 to 0.5 TCID 50 [50% tissue culture infectious dose]) was added. As a positive control, 20 μL of culture medium alone was added to each well to which virus was not added. After culturing for 4 days at 37° C. in a carbon dioxide gas incubator, 10 μL of CellTiter-Glo® 2.0 reagent was added to each well and mixed for 20 minutes at room temperature with a plate mixer for reaction. The amount of luminescence was measured using a microplate reader, and the anti-HIV activity was evaluated using the cell viability as an index. EC50 was defined as the compound concentration that inhibits cytotoxicity caused by the virus by 50%.
(Result) EC50 is shown below.
Figure JPOXMLDOC01-appb-T000114
試験例２　ポテンシーシフト値の算出
　ヒト血清による抗ＨＩＶ活性への影響を確認するために、ヒト血清を添加してＥＣ５０を算出した。ＨＩＶ（ＨＴＬＶ－ＩＩＩＢ株）持続感染ヒトＴ細胞株Ｍｏｌｔ－４　ｃｌｏｎｅ８を培養し、上清を濾過してウイルス液とし、－８０℃保存した。あらかじめ３８４ウェルマイクロプレートに所定の濃度になるように分注した各抗ＨＩＶ活性物質に、５０％ヒト血清／１０％牛胎児血清添加ＲＰＭＩ　１６４０培地を２０μＬずつ添加し、室温で１時間静置した。ヒト血清非添加用のプレートには１０％牛胎児血清添加ＲＰＭＩ　１６４０培地を添加した。３×１０４細胞／ｗｅｌｌのＭＴ－４細胞と、３μＬ／ｗｅｌｌの適度な濃度に希釈したＨＩＶ液（multiplicity of infection = 0.005～0.025 TCID50）を、必要ウェル数分混ぜ、３７℃で１時間反応させた。また、陽性コントロールとして非感染細胞を３×１０４細胞／ｗｅｌｌで必要ウェル数分調製した。感染細胞および非感染細胞を１２００　ｒｐｍで５分間遠心し、上清を廃棄後、１０％牛胎児血清添加ＲＰＭＩ　１６４０培地で再懸濁し、あらかじめ準備しておいた抗ＨＩＶ活性物質およびヒト血清が入った３８４ウェルマイクロプレートに２０μＬ（１５００細胞）ずつ添加した。プレートミキサーで混和し、炭酸ガス培養器内で３７℃、４日間培養した。試験例１と同様の方法にてヒト血清添加でのＥＣ５０を算出し、ヒト血清存在下のＥＣ５０／ヒト血清非存在下のＥＣ５０の比をポテンシーシフト値として算出した。
（結果）ヒト血清２５％添加時のポテンシーシフト値を以下に示す。
Figure JPOXMLDOC01-appb-T000115
　ヒトの血中において、化合物は血清タンパクと結合し血中のフリー体量が減少し、抗ウイルス活性が低下することがある。ＨＩＶの分野においては、血中化合物濃度のトラフ値がＰＡ－ＥＣ９０（Ｐｒｏｔｅｉｎ　ａｄｊｕｓｔｅｄ－ＥＣ９０）値を超えていれば薬効が出ることが知られている。臨床における抗ウイルス活性のより正確な予測を行うために、上記で算出したヒト血清２５％添加時のポテンシーシフト値を用いて、下式に示す計算式によりヒト血清１００％添加時のＰＡ－ＥＣ５０値を外挿した。
ＰＡ－ＥＣ５０＝ＥＣ５０×（ヒト血清２５％添加時のポテンシーシフト値）×４

その結果、本発明化合物は良好なＰＡ－ＥＣ５０値を示した。 Test Example 2 Calculation of Potency Shift Value In order to confirm the effect of human serum on anti-HIV activity, human serum was added and EC50 was calculated. HIV (HTLV-IIIB strain) persistently infected human T cell line Molt-4 clone 8 was cultured, and the supernatant was filtered to obtain a virus solution and stored at -80°C. 20 μL of RPMI 1640 medium supplemented with 50% human serum/10% fetal bovine serum was added to each anti-HIV active substance previously dispensed to a 384-well microplate at a predetermined concentration, and allowed to stand at room temperature for 1 hour. . RPMI 1640 medium supplemented with 10% fetal bovine serum was added to the plate for which no human serum was added. 3×10 4 cells/well of MT-4 cells and 3 μL/well of HIV solution diluted to an appropriate concentration (multiplicity of infection = 0.005-0.025 TCID 50 ) were mixed for the required number of wells and kept at 37° C. for 1 hour. reacted. As a positive control, non-infected cells were prepared at 3×10 4 cells/well for the required number of wells. Infected and uninfected cells were centrifuged at 1200 rpm for 5 minutes, the supernatant was discarded, resuspended in RPMI 1640 medium supplemented with 10% fetal bovine serum, and pre-prepared anti-HIV active substances and human serum were added. 20 µL (1500 cells) was added to each 384-well microplate. The mixture was mixed with a plate mixer and cultured in a carbon dioxide incubator at 37° C. for 4 days. The EC50 with the addition of human serum was calculated in the same manner as in Test Example 1, and the ratio of EC50 in the presence of human serum/ EC50 in the absence of human serum was calculated as a potency shift value.
(Results) Potency shift values when 25% human serum was added are shown below.
Figure JPOXMLDOC01-appb-T000115
In human blood, the compound may bind to serum proteins and reduce the amount of free body in the blood, resulting in decreased antiviral activity. In the field of HIV, it is known that if the trough value of the blood compound concentration exceeds the PA-EC 90 (Protein adjusted-EC 90 ) value, the drug is effective. In order to make a more accurate prediction of clinical antiviral activity, using the potency shift value when adding 25% human serum calculated above, PA-EC when adding 100% human serum is calculated according to the formula shown below. 50 values were extrapolated.
PA-EC 50 =EC 50 × (potency shift value when 25% human serum is added) × 4

As a result, the compounds of the present invention showed good PA-EC 50 values.
試験例３　ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応である７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価する。 Test Example 3 CYP Inhibition Test Using commercially available pooled human liver microsomes, O-deethylation of 7-ethoxyresorufin, which is a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4). (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. is inhibited by the compounds of the present invention.
　反応条件は以下のとおり：基質、０．５μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、３０μｍｏｌ／Ｌあるいは５０μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム０．２ｍｇ　タンパク質／ｍＬ；本発明化合物濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions are as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 30 μmol/L or 50 μmol/L S-mephenytoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 µmol/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37°C; enzyme, pooled human liver microsomes 0.2 mg protein/mL; (4 points).
　９６穴プレートに５０ｍｍｏｌ／Ｌ　Ｈｅｐｅｓ緩衝液中に各５種の基質、ヒト肝ミクロソーム、本発明化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始する。３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を添加することで反応を停止する。３０００ｒｐｍ、１５分間の遠心後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタまたはＬＣ／ＭＳ／ＭＳで定量し、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量する。なお、希釈濃度や希釈溶媒は、必要に応じて変更する。 Five types of substrates, human liver microsomes, and the compound of the present invention are added to a 96-well plate in a 50 mmol/L Hepes buffer with the above composition, and the coenzyme NADPH is added to initiate a metabolic reaction as an indicator. After reacting at 37° C. for 15 minutes, the reaction is terminated by adding a methanol/acetonitrile=1/1 (V/V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified using a fluorescence multi-label counter or LC/MS/MS, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4'-hydroxylation. body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), terfenadine alcohol (CYP3A4 metabolite) are quantified by LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.
　本発明化合物の代わりに化合物を溶解した溶媒であるＤＭＳＯのみを反応溶液に添加したものをコントロール（１００％）とし、残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出する。
　本発明化合物を本質的に上記のとおり試験した。 A control (100%) obtained by adding only DMSO, which is a solvent in which the compound is dissolved instead of the compound of the present invention, to the reaction solution, calculates the residual activity (%), and uses the concentration and the inhibition rate. Calculate the IC50 by inverse estimation.
The compounds of the invention were tested essentially as described above.
試験例３－２　ＣＹＰ３Ａ４（ＭＤＺ）ＭＢＩ試験
　本発明化合物のＣＹＰ３Ａ４阻害に関して、本発明化合物の代謝反応に起因した阻害作用の増強からＭｅｃｈａｎｉｓｍ　ｂａｓｅｄ　ｉｎｈｉｂｉｔｉｏｎ（ＭＢＩ）能を評価する試験である。プールドヒト肝ミクロソームを用いてミダゾラム（ＭＤＺ）の１－水酸化反応を指標としてＣＹＰ３Ａ４阻害を評価する。 Test Example 3-2 CYP3A4 (MDZ) MBI Test Regarding CYP3A4 inhibition of the compounds of the present invention, this is a test to evaluate the mechanism based inhibition (MBI) ability from the enhancement of the inhibitory action caused by the metabolic reaction of the compounds of the present invention. CYP3A4 inhibition is evaluated using pooled human liver microsomes as an index of 1-hydroxylation of midazolam (MDZ).
　反応条件は以下のとおり：基質、１０μｍｏｌ／Ｌ　ＭＤＺ；プレ反応時間、０または３０分；基質代謝反応時間、２分；反応温度、３７℃；プールドヒト肝ミクロソーム、プレ反応時０．５ｍｇ／ｍＬ、反応時０．０５ｍｇ／ｍＬ（１０倍希釈時）；本発明化合物プレ反応時の濃度、０．８３、５、１０、２０μｍｏｌ／Ｌあるいは１、５、１０、２０μｍｏｌ／Ｌ（４点）。 Reaction conditions were as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate metabolism reaction time, 2 minutes; reaction temperature, 37°C; 0.05 mg/mL at the time of reaction (at 10-fold dilution); concentration at the time of pre-reaction of the compound of the present invention, 0.83, 5, 10, 20 μmol/L or 1, 5, 10, 20 μmol/L (4 points).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中にプールドヒト肝ミクロソーム、本発明化合物溶液を上記のプレ反応の組成で加え、別の９６穴プレートに基質を含むＫ－Ｐｉ緩衝液で１／１０希釈されるようにその一部を移行し、補酵素であるＮＡＤＰＨを添加して指標とする反応を開始し（Ｐｒｅｉｎｃｕｂａｔａｉｏｎ　０ｍｉｎ）、所定の時間反応後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を加えることによって反応を停止する。また残りのプレ反応液にもＮＡＤＰＨを添加しプレ反応を開始し（Ｐｒｅｉｎｃｕｂａｔａｉｏｎ　３０ｍｉｎ）、所定時間プレ反応後、別のプレートに基質を含むＫ－Ｐｉ緩衝液で１／１０希釈されるように一部を移行し指標とする反応を開始する。所定の時間反応後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを３０００ｒｐｍ、１５分間の遠心後、遠心上清中の１－水酸化ミダゾラム　をＬＣ／ＭＳ／ＭＳで定量する。なお、希釈濃度や希釈溶媒は、必要に応じて変更する。
　本発明化合物を本質的に上記のとおり試験した。 Add pooled human liver microsomes and the compound solution of the present invention in K-Pi buffer (pH 7.4) as a pre-reaction solution to a 96-well plate in the above pre-reaction composition, and add K-Pi containing the substrate to another 96-well plate. A portion thereof was transferred so as to be diluted 1/10 with a buffer solution, a coenzyme NADPH was added to initiate an index reaction (Preincubation 0 min), and after a predetermined time of reaction, methanol/acetonitrile = 1. /1 (V/V) solution to stop the reaction. In addition, NADPH was added to the remaining pre-reaction solution to initiate the pre-reaction (Preincubation 30 min), and after pre-reaction for a predetermined time, another plate was added to the K-Pi buffer solution containing the substrate so as to be diluted 1/10. Initiate a response that shifts the part and serves as an index. After reacting for a predetermined time, the reaction is stopped by adding methanol/acetonitrile=1/1 (V/V) solution. The plate on which each index reaction was performed is centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifugation supernatant is quantified by LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.
The compounds of the invention were tested essentially as described above.
　本発明化合物の代わりに化合物を溶解した溶媒であるＤＭＳＯのみを反応液に添加したものをコントロール（１００％）とし、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と阻害率を用いて、ロジスティックモデルによる逆推定によりＩＣを算出する。Ｐｒｅｉｎｃｕｂａｔａｉｏｎ　０ｍｉｎのＩＣ／Ｐｒｅｉｎｃｕｂａｔａｉｏｎ　３０ｍｉｎのＩＣをＳｈｉｆｔｅｄ　ＩＣ値とし，Ｓｈｉｆｔｅｄ　ＩＣが１．５以上であればＰｏｓｉｔｉｖｅとし、Ｓｈｉｆｔｅｄ　ＩＣが１．０以下であればＮｅｇａｔｉｖｅとする。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound was dissolved instead of the compound of the present invention, to the reaction solution, and the residual activity (%) was calculated when the compound of the present invention was added at each concentration, IC is calculated by inverse estimation by logistic model using concentration and inhibition rate. Preincubation IC of 0 min/Preincubation IC of 30 min is taken as the Shifted IC value, and if the Shifted IC is 1.5 or more, it is positive, and if the Shifted IC is 1.0 or less, it is negative.
試験例４　静脈内投与試験
実験材料と方法
（１）使用動物：ＳＤラットを使用する。
（２）飼育条件：ＳＤラットは、飼料および水は自由摂取とする。
（３）投与量、群分けの設定：静脈内投与を所定の投与量により投与する。以下のように群を設定する。
　静脈内投与　１μｍｏｌ／ｋｇ（ｎ＝２）
（４）投与液の調製：ジメチルスルホキシド／プロピレングリコール＝１／１溶媒を用いて可溶化して投与する。
（５）投与方法：注射針を付けたシリンジにより尾静脈から投与する。
（６）評価項目：経時的に採血し、血漿中本発明化合物濃度をＬＣ／ＭＳ／ＭＳを用いて測定する。なお、希釈濃度や希釈溶媒は、必要に応じて変更する。
（７）統計解析：血漿中本発明化合物濃度推移について、モーメント解析法により全身クリアランス（CLtot）、半減期(T1/2)を算出した。
　本発明化合物を本質的に上記のとおり試験した。 Test Example 4 Intravenous Administration Test Experimental Materials and Methods (1) Animal used: SD rats are used.
(2) Breeding conditions: SD rats are allowed free access to food and water.
(3) Dose and grouping setting: Intravenous administration is administered at a predetermined dose. Set up the group as follows.
Intravenous administration 1 μmol/kg (n=2)
(4) Preparation of administration solution: Solubilize with a solvent of dimethyl sulfoxide/propylene glycol = 1/1 and administer.
(5) Administration method: Administer through the tail vein using a syringe with an injection needle.
(6) Evaluation item: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC/MS/MS. Note that the dilution concentration and dilution solvent are changed as necessary.
(7) Statistical analysis: Concerning changes in plasma concentration of the compound of the present invention, systemic clearance (CLtot) and half-life (T1/2) were calculated by the moment analysis method.
The compounds of the invention were tested essentially as described above.
試験例５　代謝安定性試験
　市販のプールドヒト肝ミクロソームと本発明化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、本発明化合物が肝で代謝される程度を評価する。 Test Example 5 Metabolic Stability Test Commercially available pooled human liver microsomes and the compound of the present invention are reacted for a certain period of time, the residual rate is calculated by comparing the reacted sample and the unreacted sample, and the degree of metabolism of the compound of the present invention in the liver is evaluated. .
　ヒト肝ミクロソーム０．５ｍｇタンパク質／ｍＬを含む０．２ｍＬの緩衝液（５０ｍｍｏｌ／Ｌ　Ｔｒｉｓ－ＨＣｌ　ｐＨ７．４、１５０ｍｍｏｌ／Ｌ　塩化カリウム、１０ｍｍｏｌ／Ｌ　塩化マグネシウム）中で、１ｍｍｏｌ／Ｌ　ＮＡＤＰＨ存在下で３７℃、０分あるいは３０分間反応させる（酸化反応）。反応後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液の１００μＬに反応液５０μＬを添加、混合し、３０００ｒｐｍで１５分間遠心する。その遠心上清中の本発明化合物をＬＣ／ＭＳ／ＭＳまたは固相抽出(ＳＰＥ)／ＭＳにて定量し、０分反応時の化合物量を１００％として反応後の本発明化合物の残存量を計算する。なお、加水分解反応はＮＡＤＰＨ非存在下で、グルクロン酸抱合反応はＮＡＤＰＨに換えて５ｍｍｏｌ／Ｌ　ＵＤＰ－グルクロン酸の存在下で反応を行い、以後同じ操作を実施する。希釈濃度や希釈溶媒は、必要に応じて変更する。
　本発明化合物を本質的に上記のとおり試験した。 In 0.2 mL of buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL human liver microsomes, in the presence of 1 mmol/L NADPH. React at 37° C. for 0 minute or 30 minutes (oxidation reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of methanol/acetonitrile=1/1 (v/v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugation supernatant was quantified by LC/MS/MS or solid phase extraction (SPE)/MS, and the residual amount of the compound of the present invention after the reaction was determined assuming that the amount of the compound at the time of 0 minute reaction was 100%. calculate. The hydrolysis reaction was carried out in the absence of NADPH, and the glucuronidation reaction was carried out in the presence of 5 mmol/L UDP-glucuronic acid instead of NADPH. The dilution concentration and dilution solvent are changed as necessary.
The compounds of the invention were tested essentially as described above.
試験例６　Ｆｌｕｃｔｕａｔｉｏｎ　Ａｍｅｓ　Ｔｅｓｔ
　本発明化合物の変異原性を評価する。
　凍結保存しているネズミチフス菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ　ＴＡ９８株、ＴＡ１００株）２０μＬを１０ｍＬ液体栄養培地（２．５％　Ｏｘｏｉｄ　ｎｕｔｒｉｅｎｔ　ｂｒｏｔｈ　Ｎｏ．２）に接種し３７℃にて１０時間、振盪前培養した。ＴＡ９８株は７．７０～８．００ｍＬの菌液を遠心（２０００×ｇ、１０分間）して培養液を除去する。遠心に用いた菌液と同容量のＭｉｃｒｏ　Ｆ緩衝液（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／Ｌ）に菌を懸濁し、１２０ｍＬのＥｘｐｏｓｕｒｅ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）に添加する。ＴＡ１００株は３．１０～３．４２ｍＬの菌液をＥｘｐｏｓｕｒｅ培地１２０～１３０ｍＬに添加し試験菌液を調製する。本発明化合物ＤＭＳＯ溶液（最高用量５０ｍｇ／ｍＬから２～３倍公比で数段階希釈）、陰性対照としてＤＭＳＯ、陽性対照として非代謝活性化条件ではＴＡ９８株に対しては５０μｇ／ｍＬの４－ニトロキノリン－１－オキシドＤＭＳＯ溶液、ＴＡ１００株に対しては０．２５μｇ／ｍＬの２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミドＤＭＳＯ溶液、代謝活性化条件ではＴＡ９８株に対して４０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液、ＴＡ１００株に対しては２０μｇ／ｍＬの２－アミノアントラセンＤＭＳＯ溶液それぞれ１２μＬと試験菌液５８８μＬ（代謝活性化条件では試験菌液４９８μＬとＳ９　ｍｉｘ　９０μＬの混合液）を混和し、３７℃にて９０分間、振盪培養する。本発明化合物を曝露した菌液４６０μＬを、Ｉｎｄｉｃａｔｏｒ培地（ビオチン：８μｇ／ｍＬ、ヒスチジン：０．２μｇ／ｍＬ、グルコース：８ｍｇ／ｍＬ、ブロモクレゾールパープル：３７．５μｇ／ｍＬを含むＭｉｃｒｏＦ緩衝液）２３００μＬに混和し、５０μＬずつマイクロプレート４８ウェル／用量に分注し、３７℃にて３日間、静置培養する。アミノ酸（ヒスチジン）合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、ｐＨ変化により紫色から黄色に変色するため、１用量あたり４８ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。変異原性が陰性のものを（－）、陽性のものを（＋）として示す。
なお、希釈濃度や希釈溶媒は、必要に応じて変更する。 Test Example 6 Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and cultured at 37° C. for 10 hours before shaking. For the TA98 strain, 7.70 to 8.00 mL of the bacterial solution is centrifuged (2000×g, 10 minutes) to remove the culture medium. 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, Tricitrate Suspend the bacteria in sodium dihydrate: 0.25 g/L, MgSO 4 7H 2 0: 0.1 g/L) and add 120 mL of Exposure medium (biotin: 8 μg/mL, histidine: 0.2 μg/mL, Glucose: MicroF buffer containing 8 mg/mL). For the TA100 strain, 3.10 to 3.42 mL of bacterial solution is added to 120 to 130 mL of Exposure medium to prepare a test bacterial solution. DMSO solution of the compound of the present invention (several dilutions from the highest dose of 50 mg/mL to 2- to 3-fold common ratio), DMSO as a negative control, and 50 μg/mL of 4- Nitroquinoline-1-oxide in DMSO, 0.25 μg/mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide in DMSO for strain TA100, TA98 in metabolic activation conditions 12 μL of 40 μg/mL 2-aminoanthracene DMSO solution for the strain, 12 μL of 20 μg/mL 2-aminoanthracene DMSO solution for the TA100 strain, and 588 μL of the test bacterial solution (under metabolic activation conditions, 498 μL of the test bacterial solution and S9 90 μL of the mixture) is mixed, and cultured with shaking at 37° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added to 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, and bromocresol purple: 37.5 μg/mL). , aliquots of 50 μL are dispensed into 48 wells/dose of a microplate, and statically cultured at 37° C. for 3 days. Wells containing bacteria that have acquired growth ability due to mutation of the amino acid (histidine) synthase gene change color from purple to yellow due to changes in pH. , evaluated in comparison with the negative control group. Negative mutagenicity is indicated by (-), and positive one by (+).
Note that the dilution concentration and dilution solvent are changed as necessary.
試験例７　ｈＥＲＧ試験
　本発明化合物の心電図ＱＴ間隔延長リスク評価を目的として、ｈｕｍａｎ　ｅｔｈｅｒ－ａ－ｇｏ－ｇｏ　ｒｅｌａｔｅｄ　ｇｅｎｅ　（ｈＥＲＧ）チャネルを発現させたＣＨＯ細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流Ｋ＋電流（ＩＫｒ）への本発明化合物の作用を検討する。
　全自動パッチクランプシステム（ＱＰａｔｃｈ；Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ　Ａ／Ｓ）を用い、ホールセルパッチクランプ法により、細胞を－８０ｍＶの膜電位に保持し、－５０ｍＶのリーク電位を与えた後、＋２０ｍＶの脱分極刺激を２秒間、さらに－５０ｍＶの再分極刺激を２秒間与えた際に誘発されるＩＫｒを記録する。ジメチルスルホキシドを０．１％に調整した細胞外液（ＮａＣｌ：１４５　ｍｍｏｌ／Ｌ、ＫＣｌ：４　ｍｍｏｌ／Ｌ、ＣａＣｌ２：２　ｍｍｏｌ／Ｌ、ＭｇＣｌ２：１　ｍｍｏｌ／Ｌ、グルコース：１０　ｍｍｏｌ／Ｌ、ＨＥＰＥＳ（４－（２－ｈｙｄｒｏｘｙｅｔｈｙｌ）－１－ｐｉｐｅｒａｚｉｎｅｅｔｈａｎｅｓｕｌｆｏｎｉｃ　ａｃｉｄ、４－（２－ヒドロキシエチル）－１－ピペラジンエタンスルホン酸）：１０ｍｍｏｌ／Ｌ、ｐＨ＝７．４）を媒体とし、媒体及び本発明化合物を目的の濃度で溶解させた細胞外液をそれぞれ室温条件下で、７分以上細胞に適用させる。得られたＩＫｒから、解析ソフト（ＱＰａｔｃｈ　Ａｓｓａｙ　ｓｏｆｔｗａｒｅ；Ｓｏｐｈｉｏｎ　Ｂｉｏｓｃｉｅｎｃｅ　Ａ／Ｓ）を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、媒体適用後の最大テール電流に対する本発明化合物適用後の最大テール電流を阻害率として算出し、本発明化合物のＩＫｒへの影響を評価する。なお、希釈濃度や希釈溶媒は、必要に応じて変更する。 Test Example 7 hERG test For the purpose of evaluating the risk of electrocardiographic QT interval prolongation of the compound of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to test the The effect of the compounds of the invention on the delayed rectifier K + current (I Kr ) that plays a role is investigated.
Using a fully automated patch clamp system (QPatch; Sophion Bioscience A/S), cells were held at a membrane potential of −80 mV by the whole-cell patch clamp method, and a leak potential of −50 mV was applied, followed by +20 mV depolarization stimulation. for 2 seconds, followed by a repolarizing stimulus of −50 mV for 2 seconds. Extracellular solution adjusted to 0.1% dimethyl sulfoxide (NaCl: 145 mmol/L, KCl: 4 mmol/L, CaCl 2 : 2 mmol/L, MgCl 2 : 1 mmol/L, glucose: 10 mmol/L , HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH = 7.4), and An extracellular solution in which the compound of the invention is dissolved at a desired concentration is applied to the cells for 7 minutes or more under room temperature conditions. From the obtained IKr , analysis software (QPatch Assay software; Sophion Bioscience A/S) is used to measure the absolute value of the maximum tail current based on the current value at the retained membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the vehicle is calculated as the inhibition rate, and the effect of the compound of the present invention on I Kr is evaluated. Note that the dilution concentration and dilution solvent are changed as necessary.
試験例８　Ａｍｅｓ試験
　サルモネラ菌（Ｓａｌｍｏｎｅｌｌａ　ｔｙｐｈｉｍｕｒｉｕｍ）ＴＡ９８株、ＴＡ１００株、ＴＡ１５３５株、ＴＡ１５３７株および大腸菌（Ｅｓｃｈｅｒｉｃｈｉａ　ｃｏｌｉ）ＷＰ２ｕｖｒＡ株を試験菌株としたＡｍｅｓ試験により、本発明化合物の変異原性を評価した。本発明化合物のＤＭＳＯ溶液０．１ｍＬに、代謝活性化条件ではＳ９ｍｉｘを０．５ｍＬ、非代謝活性化条件ではリン酸緩衝液を０．５ｍＬと試験菌液０．１ｍＬを混和し、ヒスチジン及びビオチン、またはトリプトファン含有の重層用軟寒天２ｍＬと共に最少グルコース寒天平板に重層する。同時に、陰性対照物質（ＤＭＳＯ）および陽性対照物質（２－（２－フリル）－３－（５－ニトロ－２－フリル）アクリルアミド、アジ化ナトリウム、９－アミノアクリジン、または２－アミノアントラセン）についても同様に実施した。３７℃で４８時間培養した後、出現した復帰変異コロニーを計数し、陰性対照群と比較して評価する。復帰変異コロニー数が濃度依存的に増加し、かつ陰性対照群のコロニー数の２倍以上となる場合を陽性（＋）と判断する。なお、希釈濃度や希釈溶媒は、必要に応じて変更する。 Test Example 8 Ames test The mutagenicity of the compounds of the present invention was evaluated by the Ames test using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA strains as test strains. To 0.1 mL of DMSO solution of the compound of the present invention, 0.5 mL of S9mix under metabolic activation conditions, and 0.5 mL of phosphate buffer and 0.1 mL of test bacterial solution under non-metabolic activation conditions were mixed, and histidine and biotin were mixed. , or overlay minimal glucose agar plates with 2 mL soft overlay agar containing tryptophan. Simultaneously, negative controls (DMSO) and positive controls (2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide, sodium azide, 9-aminoacridine, or 2-aminoanthracene) was similarly performed. After culturing at 37° C. for 48 hours, the revertant colonies that appear are counted and evaluated in comparison with the negative control group. If the number of revertant colonies increases in a concentration-dependent manner and is at least twice the number of colonies in the negative control group, it is determined as positive (+). Note that the dilution concentration and dilution solvent are changed as necessary.
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
　本発明の化合物は、任意の従来の経路により、特に、経腸、例えば、経口で、例えば、錠剤またはカプセル剤の形態で、または非経口で、例えば注射液剤または懸濁剤の形態で、局所で、例えば、ローション剤、ゲル剤、軟膏剤またはクリーム剤の形態で、または経鼻形態または座剤形態で医薬組成物として投与することができる。少なくとも１種の薬学的に許容される担体または希釈剤と一緒にして、遊離形態または薬学的に許容される塩の形態の本発明の化合物を含む医薬組成物は、従来の方法で、混合、造粒またはコーティング法によって製造することができる。例えば、経口用組成物としては、賦形剤、崩壊剤、結合剤、滑沢剤等および有効成分等を含有する錠剤、顆粒剤、カプセル剤とすることができる。また、注射用組成物としては、溶液剤または懸濁剤とすることができ、滅菌されていてもよく、また、保存剤、安定化剤、緩衝化剤等を含有してもよい。 The formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention in any way.
The compounds of the invention can be administered topically by any conventional route, especially enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injection solutions or suspensions. For example, it can be administered as a pharmaceutical composition in the form of lotions, gels, ointments or creams, or in nasal or suppository form. A pharmaceutical composition comprising a compound of the invention in free form or in pharmaceutically acceptable salt form together with at least one pharmaceutically acceptable carrier or diluent can be prepared by mixing, mixing, It can be manufactured by a granulation or coating method. For example, oral compositions can be tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients. Injectable compositions may be in the form of solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffers and the like.
　本発明に係る化合物は、エイズ等、ウイルス感染症の治療および／または予防剤、またはその中間体として有用である。 The compound according to the present invention is useful as a therapeutic and/or prophylactic agent for viral infections such as AIDS, or an intermediate thereof.

Claims (20)

  1. 式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、
    　Ａ１、Ａ２およびＡ３はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ａ１、Ａ２およびＡ３を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
    　Ｂ１、Ｂ２、Ｂ３およびＢ４はそれぞれ独立して、炭素原子または窒素原子であり、ここで、Ｂ１、Ｂ２、Ｂ３およびＢ４を構成原子として含む環の環構成原子の窒素原子の数は、０～２個であり、
    　Ｘ１は、ＣＲ４Ｒ５、ＮＲ６、ＯまたはＳであり、
    　Ｒ４およびＲ５は、それぞれ独立して、水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のアルキニルであり、
    　Ｒ６は水素または置換もしくは非置換のアルキルであり、
    　Ｘ２は、ＣＲ７Ｒ８、ＮＲ９、ＯまたはＳであり、
    　Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、
    　Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよく、
    　Ｒ９は水素または置換もしくは非置換のアルキルであり、
    　Ｒ１は、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基であり、
    　Ｒ２はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
    Figure JPOXMLDOC01-appb-C000002
    （式中、環Ｅおよび環Ｆは、置換基群γで置換されていてもよい芳香族炭素環、置換基群γで置換されていてもよい芳香族複素環、置換基群γ’で置換されていてもよい非芳香族炭素環または置換基群γ’で置換されていてもよい非芳香族複素環であり、環Ｇは、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、Ｌは単結合、Ｃ１－Ｃ３アルキレン、－Ｃ（＝Ｏ）－または－ＳＯ２－であり、
    置換基群γ：ハロゲン、ヒドロキシ、カルボキシ、アルキルオキシ、ハロアルキルオキシ、アルケニルオキシ、アルキニルオキシ、スルファニル、シアノ、アルキル、ハロアルキル、ヒドロキシアルキル、アルケニル、アルキニル、アルキルオキシアルキル、アルキルカルボニル、ハロアルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アミノ、アルキルアミノ、アルキルスルホニル、アルキルオキシカルボニルおよびシクロプロパニル；
    置換基群γ’：置換基群γおよびオキソ）であり、および／または、隣接する２つのＲ２が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく、
    　Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、または置換もしくは非置換のスルファモイルであり、および／または、隣接する２つのＲ３が結合する環構成原子と一緒になって、置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環を形成してもよく、
    　ｎは０～３の整数であり、
    　ｍは０～４の整数である。）で示される化合物またはその製薬上許容される塩。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001
    (In the formula,
    A 1 , A 2 and A 3 are each independently a carbon atom or a nitrogen atom, wherein the number of ring-constituting nitrogen atoms in the ring containing A 1 , A 2 and A 3 as constituent atoms is 0 to 2,
    B 1 , B 2 , B 3 and B 4 are each independently a carbon atom or a nitrogen atom, wherein the ring-constituting atoms of the ring containing B 1 , B 2 , B 3 and B 4 as constituent atoms The number of nitrogen atoms is 0 to 2,
    X 1 is CR 4 R 5 , NR 6 , O or S;
    R 4 and R 5 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
    R 6 is hydrogen or substituted or unsubstituted alkyl,
    X 2 is CR 7 R 8 , NR 9 , O or S;
    R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
    Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted may form a substituted non-aromatic carbocycle,
    R9 is hydrogen or substituted or unsubstituted alkyl;
    R 1 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group is a cyclic group;
    R 2 is each independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or The formula below:
    Figure JPOXMLDOC01-appb-C000002
    (Wherein, ring E and ring F are an aromatic carbocyclic ring optionally substituted with a substituent group γ, an aromatic heterocyclic ring optionally substituted with a substituent group γ, substituted with a substituent group γ' a non-aromatic carbocyclic ring that may be substituted or a non-aromatic heterocyclic ring that may be substituted with a substituent group γ', and ring G is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted non-aromatic carbocyclic ring or substituted or unsubstituted non-aromatic heterocyclic ring, L is a single bond, C1-C3 alkylene, —C(=O)— or —SO 2 - and
    Substituent group γ: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, cyano, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, alkyloxyalkyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl , alkynylcarbonyl, amino, alkylamino, alkylsulfonyl, alkyloxycarbonyl and cyclopropanyl;
    Substituent Group γ′: Substituent Group γ and oxo) and/or together with the ring atoms to which two adjacent R 2 are bonded, a substituted or unsubstituted aromatic carbocyclic ring, substituted or may form an unsubstituted heteroaromatic ring, a substituted or unsubstituted non-aromatic carbocycle or a substituted or unsubstituted non-aromatic heterocycle,
    Each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic ring formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclesulfinyl, substituted or unsubstituted aromatic carbocyclesulfonyl, substituted or unsubstituted aromatic heterocyclesulfonyl, substituted or unsubstituted non-aromatic carbocyclesulfonyl, substituted or unsubstituted non-aromatic heterocyclesulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl , substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl and/or a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted may form a non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
    n is an integer from 0 to 3,
    m is an integer from 0 to 4; ) or a pharmaceutically acceptable salt thereof.
  2. Ｒ１が、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である、請求項１記載の化合物またはその製薬上許容される塩。
    2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R1 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
  3. Ｒ１が、置換もしくは非置換のフェニルまたは置換もしくは非置換のピペリジニルである、請求項１記載の化合物またはその製薬上許容される塩。
    2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is substituted or unsubstituted phenyl or substituted or unsubstituted piperidinyl.
  4. Ｒ１が、
    Figure JPOXMLDOC01-appb-C000003
    （式中、Ｒ１Ａは、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルであり、Ｒ１Ｂは、それぞれ独立して、水素、ハロゲン、シアノまたは置換もしくは非置換のアルキルである。）で示される基である、請求項１記載の化合物またはその製薬上許容される塩。
    R 1 is
    Figure JPOXMLDOC01-appb-C000003
    (In the formula, R 1A is hydrogen, halogen, cyano or substituted or unsubstituted alkyl, and R 1B is each independently hydrogen, halogen, cyano or substituted or unsubstituted alkyl.) The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is a group.
  5. Figure JPOXMLDOC01-appb-C000004
    で示される基が、
    Figure JPOXMLDOC01-appb-C000005
    （式中、環Ｃは置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、Ｒ１は請求項１と同意義であり、ｎ－２は０または１であり、Ｒ２はヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、または置換もしくは非置換のスルファモイルである）で示される基である、請求項１～４のいずれか記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000004
    The group represented by
    Figure JPOXMLDOC01-appb-C000005
    (Wherein, ring C is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring; , R 1 has the same meaning as in claim 1, n-2 is 0 or 1, R 2 is hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbon ring carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a group represented by ).
  6. 環Ｃが置換もしくは非置換の芳香族複素環である、請求項５記載の化合物またはその製薬上許容される塩。
    6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein Ring C is a substituted or unsubstituted aromatic heterocyclic ring.
  7. 環Ｃが置換もしくは非置換の５員の芳香族複素環である、請求項５記載の化合物またはその製薬上許容される塩。
    6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein Ring C is a substituted or unsubstituted 5-membered aromatic heterocyclic ring.
  8. 環Ｃが置換もしくは非置換のピロール環、置換もしくは非置換のピラゾール環、置換もしくは非置換のチオフェン環、置換もしくは非置換のフラン環、置換もしくは非置換のイミダゾール環、置換もしくは非置換のチアゾール環、置換もしくは非置換のオキサゾール環、または置換もしくは非置換のトリアゾール環である、請求項５記載の化合物またはその製薬上許容される塩。
    Ring C is substituted or unsubstituted pyrrole ring, substituted or unsubstituted pyrazole ring, substituted or unsubstituted thiophene ring, substituted or unsubstituted furan ring, substituted or unsubstituted imidazole ring, substituted or unsubstituted thiazole ring , a substituted or unsubstituted oxazole ring, or a substituted or unsubstituted triazole ring, or a pharmaceutically acceptable salt thereof according to claim 5.
  9. Figure JPOXMLDOC01-appb-C000006
    で示される基が、
    Figure JPOXMLDOC01-appb-C000007
    （式中、Ｒ２Ａは、それぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイルまたは以下の式：
    Figure JPOXMLDOC01-appb-C000008
    （式中、各記号は請求項１と同意義）であり、
    ｐは０～４の整数であり、Ｒ１は請求項１と同意義である。）で示される基である、請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000006
    The group represented by
    Figure JPOXMLDOC01-appb-C000007
    (wherein each R 2A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl or the following formulae:
    Figure JPOXMLDOC01-appb-C000008
    (wherein each symbol has the same meaning as in claim 1),
    p is an integer of 0 to 4, and R 1 has the same meaning as in claim 1; ), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8.
  10. Ｒ２Ａが、それぞれ独立して、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基である、請求項９記載の化合物またはその製薬上許容される塩。
    Each R 2A is independently hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted 10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, which is an unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
  11. Figure JPOXMLDOC01-appb-C000009
    で示される基が、
    Figure JPOXMLDOC01-appb-C000010
    （式中、環Ｄは置換もしくは非置換の芳香族炭素環、置換もしくは非置換の芳香族複素環、置換もしくは非置換の非芳香族炭素環または置換もしくは非置換の非芳香族複素環であり、ｍ－２は０～２の整数であり、Ｒ３はそれぞれ独立して、ヒドロキシ、シアノ、ハロゲン、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルスルファニル、置換もしくは非置換のアルケニルスルファニル、置換もしくは非置換のアルキニルスルファニル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換のアルキルカルボニルオキシ、置換もしくは非置換のアルケニルカルボニルオキシ、置換もしくは非置換のアルキニルカルボニルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族炭素環スルファニル、置換もしくは非置換の芳香族複素環スルファニル、置換もしくは非置換の非芳香族炭素環スルファニル、置換もしくは非置換の非芳香族複素環スルファニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の芳香族複素環スルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニルオキシ、置換もしくは非置換の芳香族複素環カルボニルオキシ、置換もしくは非置換の非芳香族炭素環カルボニルオキシ、置換もしくは非置換の非芳香族複素環カルボニルオキシ、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイルまたは置換もしくは非置換のスルファモイルである）で示される基である、請求項１～１０のいずれかに記載の化合物又はその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000009
    The group represented by
    Figure JPOXMLDOC01-appb-C000010
    (Wherein, ring D is a substituted or unsubstituted aromatic carbocyclic ring, a substituted or unsubstituted aromatic heterocyclic ring, a substituted or unsubstituted non-aromatic carbocyclic ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; , m−2 is an integer of 0 to 2, and each R 3 is independently hydroxy, cyano, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl , substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyl oxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocycle formula group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy , substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic heterocyclic sulfanyl, substituted or unsubstituted substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic carbon ring sulfonyl, substituted or unsubstituted aromatic heterocyclic sulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyloxy, substituted or unsubstituted aromatic heterocyclic carbonyloxy, substituted or unsubstituted non-aromatic carbocyclic carbonyloxy, substituted or unsubstituted non-aromatic heterocyclic carbonyloxy, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl) The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, which is a group represented by
  12. 環Ｄが置換もしくは非置換のベンゼン環、置換もしくは非置換のピリジン環、置換もしくは非置換のシクロペンタン環、置換もしくは非置換のシクロヘキサン環または置換もしくは非置換のシクロヘプタン環である、請求項１１記載の化合物またはその製薬上許容される塩。
    11. Ring D is a substituted or unsubstituted benzene ring, substituted or unsubstituted pyridine ring, substituted or unsubstituted cyclopentane ring, substituted or unsubstituted cyclohexane ring or substituted or unsubstituted cycloheptane ring. A compound as described or a pharmaceutically acceptable salt thereof.
  13. Figure JPOXMLDOC01-appb-C000011
    で示される基が、
    Figure JPOXMLDOC01-appb-C000012
    （式中、Ｒ３Ａはそれぞれ独立して、ハロゲン、シアノ、ヒドロキシ、置換もしくは非置換のアミノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシまたは置換もしくは非置換のアルキニルオキシであり、ｑは０～５の整数である。）で示される基である、請求項１１記載の化合物またはその製薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000011
    The group represented by
    Figure JPOXMLDOC01-appb-C000012
    (wherein each R 3A is independently halogen, cyano, hydroxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted is an alkyloxy, substituted or unsubstituted alkenyloxy or substituted or unsubstituted alkynyloxy, q is an integer of 0 to 5.), the compound according to claim 11 or a pharmaceutical preparation thereof acceptable salt.
  14. Ｘ１は、ＮＲ６であり、
    Ｒ６は水素または置換もしくは非置換のアルキルであり、
    Ｘ２は、ＣＲ７Ｒ８、ＯまたはＳであり、
    Ｒ７およびＲ８は、それぞれ独立して、水素、置換もしくは非置換のアルキルまたは置換もしくは非置換のアルケニルであり、
    Ｒ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換のエキソメチレンを形成してもよく、またはＲ７とＲ８が結合する炭素原子と一緒になって、置換もしくは非置換の非芳香族炭素環を形成してもよい、請求項１～１３のいずれかに記載の化合物またはその製薬上許容される塩。
    X 1 is NR 6 ;
    R 6 is hydrogen or substituted or unsubstituted alkyl,
    X 2 is CR 7 R 8 , O or S;
    R 7 and R 8 are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkenyl;
    Together with the carbon atom to which R 7 and R 8 are attached, they may form a substituted or unsubstituted exomethylene, or together with the carbon atom to which R 7 and R 8 are attached, a substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, which may form a substituted non-aromatic carbocyclic ring.
  15. 化合物Ｉ－００１５、Ｉ－００１９、Ｉ－００４５、Ｉ－００４８、Ｉ－００４９、Ｉ－００５６、Ｉ－００７３、Ｉ－００７５、Ｉ－００７８、Ｉ－００７９、Ｉ－００８４、Ｉ－００９２、Ｉ－００９７、Ｉ－００９８、Ｉ－０１１８、Ｉ－０１４６、Ｉ－０１５１、Ｉ－０１７２、Ｉ－０１８９、Ｉ－０１９０、Ｉ－０１２２’、Ｉ－０１３８’、Ｉ－０１３９’およびＩ－０１８９’からなる群から選択される、請求項１記載の化合物またはその製薬上許容される塩。
    Compounds I-0015, I-0019, I-0045, I-0048, I-0049, I-0056, I-0073, I-0075, I-0078, I-0079, I-0084, I-0092, I -0097, 1-0098, 1-0118, 1-0146, 1-0151, 1-0172, 1-0189, 1-0190, 1-0122', 1-0138', 1-0139' and 1-0189' 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  16. 請求項１～１５のいずれかに記載の化合物またはその製薬上許容される塩を含有する、医薬組成物。
    A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
  17. 抗ウイルス剤である、請求項１６記載の医薬組成物。
    17. The pharmaceutical composition according to claim 16, which is an antiviral agent.
  18. 抗ＨＩＶ剤である、請求項１６記載の医薬組成物。
    17. The pharmaceutical composition according to claim 16, which is an anti-HIV agent.
  19. 請求項１～１５のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、ＨＩＶ感染症の治療および/または予防方法。
    A method for treating and/or preventing HIV infection, which comprises administering a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.
  20. ＨＩＶ感染症の治療の治療および/または予防に使用するための、請求項１～１５のいずれかに記載の化合物またはその製薬上許容される塩。 A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prophylaxis of treatment of HIV infection.
PCT/JP2022/032701 2021-08-31 2022-08-31 Fused heterocyclic derivative having hiv replication inhibitory action WO2023033018A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070249583A1 (en) * 2006-04-25 2007-10-25 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070249583A1 (en) * 2006-04-25 2007-10-25 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STORCK, P. ; AUBERTIN, A.M. ; GRIERSON, D.S.: "Tosylation/mesylation of 4-hydroxy-3-nitro-2-pyridinones as an activation step in the construction of dihydropyrido[3,4-b] benzo[f][1,4]thiazepin-1-one based anti-HIV agents", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM , NL, vol. 46, no. 16, 18 April 2005 (2005-04-18), Amsterdam , NL , pages 2919 - 2922, XP027863019, ISSN: 0040-4039 *

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