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WO2023033018A1 - Dérivé hétérocyclique condensé présentant une action inhibitrice de la réplication du vih - Google Patents

Dérivé hétérocyclique condensé présentant une action inhibitrice de la réplication du vih 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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Prior art keywords
substituted
unsubstituted
aromatic
aromatic heterocyclic
aromatic carbocyclic
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English (en)
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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Shionogi and Co Ltd
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Shionogi and Co Ltd
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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.

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Abstract

La présente invention concerne un composé représenté par la formule (I). (Dans la formule, A1, A2 ou A3 représentent chacun indépendamment un atome de carbone ou un atome d'azote, B1, B2, B3 ou B4 représentent chacun indépendamment un atome de carbone ou un atome d'azote, X1 représente CR4R5, etc., R4 ou R5 représentent chacun indépendamment l'hydrogène, etc., X2 représente CR7R8, etc., R7 ou R8 représentent chacun indépendamment l'hydrogène etc., R1 représente un groupe carboxylique aromatique substitué ou non substitué, etc., R2 représentent chacun indépendamment un groupe hydroxyle, etc., R3 représentent chacun indépendamment un groupe hydroxy, etc., n représente un entier de 0 à 3 et m représente un entier de 0 à 4).
PCT/JP2022/032701 2021-08-31 2022-08-31 Dérivé hétérocyclique condensé présentant une action inhibitrice de la réplication du vih Ceased WO2023033018A1 (fr)

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* 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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