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WO2011024987A1 - Dérivé hétérocyclique aromatique condensé et composition pharmaceutique associée - Google Patents

Dérivé hétérocyclique aromatique condensé et composition pharmaceutique associée Download PDF

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Publication number
WO2011024987A1
WO2011024987A1 PCT/JP2010/064665 JP2010064665W WO2011024987A1 WO 2011024987 A1 WO2011024987 A1 WO 2011024987A1 JP 2010064665 W JP2010064665 W JP 2010064665W WO 2011024987 A1 WO2011024987 A1 WO 2011024987A1
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substituted
unsubstituted
compound
aromatic heterocyclic
group
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Japanese (ja)
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裕樹 立花
努 桝田
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塩野義製薬株式会社
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Publication of WO2011024987A1 publication Critical patent/WO2011024987A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
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    • A61P17/00—Drugs for dermatological disorders
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/06—Peri-condensed systems

Definitions

  • the present invention relates to a compound useful for treating a disease or condition involving histamine H4 receptor, a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutical composition containing them.
  • Histamine interacts with four receptors of the G-protein coupled superfamily (histamine H1, H2, H3 and H4 receptors), allergic reaction through H1 receptor, gastric acid secretion through H2 receptor, H3 receptor It expresses various physiological functions such as neurotransmission in the central nervous system through the body.
  • the histamine H4 receptor is a 7-transmembrane G protein-coupled receptor consisting of 390 amino acids with about 40% homology to the H3 receptor. It is mainly expressed in blood cells such as eosinophils, mast cells, dendritic cells, and T cells, and particularly highly expressed in eosinophils and mast cells (Non-patent Documents 1 and 2). .
  • histamine H4 receptor has been confirmed to be expressed in synovial cells collected from rheumatic patients (Non-patent Documents 3 and 4), and is also expressed in synovial cells collected from osteoarthritis patients. It has been confirmed (Non-Patent Document 5), and expression has also been confirmed in intestinal cells (Non-Patent Document 6). Furthermore, it has been reported that the expression level of histamine H4 receptor is also increased in intranasal polyps (Non-patent Document 7). The pharmacological properties of the histamine H4 receptor have also been revealed by several specific ligands.
  • eosinophil migration and morphological changes, and increased expression of CD11b / CD18 and CD54 are known to be effects caused by binding of histamine to the H4 receptor (Non-patent Document 8).
  • the histamine H4 receptor is also known to be involved in calcium influx in mast cells (Non-patent Document 9), to be involved in regulation of cytokine production in dendritic cells (Non-patent Document 10), and the like. The action is various.
  • histamine H4 receptor is involved in the accumulation of mast cells induced by histamine (Non-patent document 9), peritonitis model induced by zymosan (Non-patent document 11) and pleurisy model (non-patent document) Involvement in neutrophil infiltration in literature 12), involvement in eosinophil infiltration in an asthma model by ovalbumin (Non-patent document 10), and involvement in itch (non-patent document 13) have been reported. Yes. It is described in Patent Documents 1, 2, 3 and 4 that an aromatic heterocyclic derivative acts on a histamine H4 receptor, but neither compound describes nor suggests the compound of the present invention.
  • the present invention provides a novel compound having an action of regulating histamine H4 receptor.
  • the present inventors have an action of regulating histamine H4 receptor, and are useful for the prevention and / or treatment of diseases mediated by histamine H4 receptor.
  • the inventors discovered a new compound and completed the invention described below.
  • a histamine H4 modulator comprising a salt or a solvate thereof.
  • R 1a is halogen
  • R 1b are each independently halogen, 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 alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, formyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, aryloxycarbonyl, Carbamoyl, sulfamoyl, sulfonyloxy, sulfinyl
  • R a and R b come together
  • R 4 is substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy or substituted or unsubstituted amino
  • Z represents —C (R 11 ) — or —N—
  • R 11 is hydrogen or substituted or unsubstituted alkyl
  • Each R 5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstituted alkynyloxy, hydroxy, cyano
  • R a and R b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group,
  • R a is hydrogen;
  • R b is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, (3) - The compound according to any one of (7) or a pharmaceutically acceptable salt thereof or a solvate thereof. (9) The compound according to any one of (3) to (8) above, wherein X is —O—, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, sulfonyl, carbamoyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or The compound or a pharmaceutically acceptable salt thereof according to any one of (3) to (10) above, which is an unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl Or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (3) to (11) above, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Prevention of a disease involving a histamine H4 receptor comprising administering the compound according to any one of (3) to (11), a pharmaceutically acceptable salt thereof, or a solvate thereof. Or treatment method.
  • the compound according to any one of (3) to (11), a pharmaceutically acceptable salt thereof or a compound thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease involving histamine H4 receptor Use of solvates.
  • a histamine H4 modulator comprising a salt or a solvate thereof.
  • a method for treating and / or preventing a disease or condition involving histamine H4 receptor which comprises administering the compound according to (1 ⁇ ) above, a pharmaceutically acceptable salt thereof or a solvate thereof. .
  • R a and R b come together
  • R 4 is hydrogen, substituted or unsubstituted alkyl, halogen, hydroxy, substituted or unsubstituted alkyloxy or substituted or unsubstituted amino
  • —Z— represents —C (R 11 ) — or —N—
  • R 11 is hydrogen or substituted or unsubstituted alkyl
  • Each R 5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstituted alky
  • R a and R b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group,
  • R a is hydrogen;
  • R b is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, the (3.alpha.) ⁇
  • (10 ⁇ ) -X— is —O—, the compound according to any one of the above (3 ⁇ ) to (9 ⁇ ), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, sulfonyl, carbamoyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or The compound or a pharmaceutically acceptable salt thereof according to any one of the above (3 ⁇ ) to (10 ⁇ ), which is an unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl Or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (3 ⁇ ) to (11 ⁇ ), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (14 ⁇ ) a disease involving histamine H4 receptor comprising administering a compound according to any one of (3 ⁇ ) to (11 ⁇ ), a pharmaceutically acceptable salt thereof, or a solvate thereof, or How to treat and / or prevent a condition.
  • histamine H4 receptor agonist, partial agonist, inverse agonist and antagonist, particularly antagonist
  • histamine H4 receptor is It is useful as a therapeutic agent for diseases involved.
  • respiratory diseases such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD); rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus Inflammatory diseases such as atherosclerosis; effective for pain relief including neuropathic pain and nociceptive pain.
  • the compounds of the present invention have a high affinity for histamine receptors, in particular histamine H4 receptors, subtype selectivity (selectivity for histamine H1, H2, and H3 receptors, in particular selectivity for H3 receptors) and Since it has high selectivity for other receptors, it can be a medicament with reduced side effects (for example, influence on motor function).
  • the compound of the present invention has high stability, high oral absorption, high solubility, good bioavailability, low clearance, long half-life, high sustained efficacy, and / or liver enzyme There are also advantages such as low inhibitory activity.
  • the present invention provides a pharmaceutical composition comprising a combination of an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier.
  • compositions for example, excipients, binders, disintegrants, lubricants, colorants, flavoring agents, flavoring agents, surfactants, and the like
  • pharmaceutically acceptable carriers well known in the art Can be used to produce a pharmaceutical composition according to a conventional method.
  • the dosage unit dosage form can be appropriately selected depending on the therapeutic purpose and administration route. Specifically, oral preparations such as tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions, and parenterals such as injections, suppositories, ointments, patches, aerosols, etc. Agents. These dosage unit forms are formulated according to methods well known in the art.
  • the amount of the compound of the present invention to be contained in the above preparation can be appropriately changed depending on the dosage form, administration route, administration schedule and the like.
  • the administration method of the pharmaceutical composition according to the present invention is appropriately determined according to the dosage form of the preparation, the age, sex, weight, symptom level and other conditions of the patient, and is oral, subcutaneous, transdermal, rectal, nasal It can be selected from various routes such as inner and oral cavity.
  • the dose of the compound of the present invention contained in the pharmaceutical composition of the present invention depends on the selected route of administration, patient age, sex, weight, disease state, type of the compound administered, other conditions, etc. Although it is appropriately selected, in the case of oral administration to adults, it is usually 0.05 to 1000 mg / kg / day, preferably 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 100 mg / kg / day, preferably 0.01 to 1 mg / kg / day. These pharmaceutical compositions of the present invention can be administered once a day or divided into a plurality of times.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • Alkyl includes linear or branched monovalent hydrocarbon groups having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. 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 moieties such as “haloalkyl”, “alkylamino”, “alkylimino”, “alkylsulfonyl”, “alkylsulfamoyl”, “alkylcarbamoyl”, “arylalkyl”, “arylalkylamino”, “alkylsulfinyl”, etc. Is as defined above for “alkyl”.
  • alkyl part of “alkyloxy” has the same meaning as the above “alkyl”. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • alkyloxy moiety such as “haloalkyloxy” and “alkyloxyimino” has the same meaning as the above “alkyloxy”.
  • alkyl part of “alkylthio” has the same meaning as the above “alkyl”. Examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like.
  • alkyloxycarbonyl has the same meaning as the above “alkyloxy”. Examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
  • alkyl part of “alkylcarbamoyl” has the same meaning as the above “alkyl”.
  • Examples thereof include mono- or dialkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and dipropylcarbamoyl groups.
  • Alkenyl includes straight or branched alkenyl having 2 to 6, preferably 2 to 3, carbon atoms having one or more double bonds at any position. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl and the like.
  • alkenyl part of “alkenyloxy” has the same meaning as the above “alkenyl”.
  • alkenyl part of “alkenylthio” has the same meaning as the above “alkenyl”. Examples thereof include vinylthio, propenylthio, isopropenylthio, butenylthio, isobutenylthio, prenylthio, butadienylthio, pentenylthio, isopentenylthio, pentadienylthio, hexenylthio, isohexenylthio, hexadienylthio and the like.
  • Alkynyl includes linear or branched alkynyl having 2 to 6, preferably 2 to 3, carbon atoms having one or more triple bonds at any position. These have one or more triple bonds at arbitrary positions, and may further have a double bond. Examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, various pentynyl isomers, and the like.
  • alkynyl part of “alkynyloxy” has the same meaning as the above “alkynyl”.
  • alkynyl For example, ethynyloxy, propynyloxy, butynyloxy, pentynyloxy and the like can be mentioned.
  • C2-C6 alkynyloxy is used.
  • Alkynylthio has the same meaning as the above “alkynyl” in the alkynyl moiety.
  • alkynyl in the alkynyl moiety.
  • ethynylthio, propynylthio, butynylthio, pentynylthio and the like can be mentioned.
  • C2-C6 alkynylthio is used.
  • “Acyl” refers to R—C ( ⁇ O) — (for example, R is “alkyl” or “alkenyl”, or “aryl”, “heteroaryl”, “non-aromatic carbocyclic group”, “ A non-aromatic heterocyclic group, “arylalkyl” or “heteroarylalkyl”, which is hydroxy, carboxy, “alkyl”, “alkenyl”, “alkynyl”, “halogen”, as described above or below, respectively.
  • “Sulfonyloxy” means —O—S ( ⁇ O) 2 —R (for example, R is “alkyl” or “alkenyl” as described above, or “aryl”, “heteroaryl”, “non-aromatic carbocycle” described later.
  • acyl part of “acylamino” and “acylimino” has the same meaning as the above “acyl”.
  • Carbamoyl refers to —C ( ⁇ O) —NR X R Y (eg, R X and R Y are each independently hydrogen, the above “alkyl” or “alkenyl”, or “aryl” described below, “Heteroaryl”, “non-aromatic carbocyclic group”, “non-aromatic heterocyclic group”, “arylalkyl” or “heteroarylalkyl”, which are each independently hydroxy, carboxy, or “Alkyl”, “alkenyl”, “alkynyl”, “halogen”, “alkyloxy”, “alkenyloxy”, “alkynyloxy”, “alkylthio”, “carbamoyl”, “alkyloxycarbonyl”, “aryl” described later A group which may be substituted with “oxycarbonyl” or the like.
  • “Sulfinyl” refers to —S ( ⁇ O) —R (R represents the above “alkyl” or “alkenyl”, or “aryl”, “heteroaryl”, “non-aromatic carbocyclic group”, “non- An aromatic heterocyclic group, “arylalkyl” or “heteroarylalkyl.” These are each independently hydroxy, carboxy, “alkyl”, “alkenyl”, “alkynyl”, “halogen” as described above or below.
  • “Sulfonyl” refers to —S ( ⁇ O) 2 —R (wherein R is “alkyl” or “alkenyl”, or “aryl”, “heteroaryl”, “non-aromatic carbocyclic group”, “ A non-aromatic heterocyclic group, “arylalkyl” or “heteroarylalkyl”, each independently of hydroxy, carboxy, “alkyl”, “alkenyl”, “alkynyl”, “ A group which may be substituted with “halogen”, “alkyloxy”, “alkenyloxy”, “alkynyloxy”, “alkylthio”, “carbamoyl”, “alkyloxycarbonyl”, “aryloxycarbonyl” and the like) Is included.
  • sulfamoyl refers to —S ( ⁇ O) 2 —NR X R Y (for example, R X and R Y are each independently hydrogen, the above “alkyl” or “alkenyl”, or the “aryl” described below.
  • Heteroaryl “non-aromatic carbocyclic group”, “non-aromatic heterocyclic group”, “arylalkyl” or “heteroarylalkyl”, each independently hydroxy, carboxy, or “Alkyl”, “alkenyl”, “alkynyl”, “halogen”, “alkyloxy”, “alkenyloxy”, “alkynyloxy”, “alkylthio”, “carbamoyl”, “alkyloxycarbonyl”, “aryl” described later A group which may be substituted with “oxycarbonyl” or the like.
  • “Cycloalkane” includes monocyclic or polycyclic saturated carbocyclic rings having 3 to 10 carbon atoms.
  • Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.
  • Examples of the polycyclic cycloalkane include norbornane and tetrahydronaphthalene.
  • Cycloalkyl includes a monovalent group derived from the above “cycloalkane”.
  • monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl and the like.
  • “Cycloalkanediyl” includes a divalent group derived from the above “cycloalkane”.
  • Examples of the monocyclic cycloalkanediyl include cyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, cycloheptanediyl, cyclooctanediyl, cyclononanediyl, cyclodecandidiyl and the like.
  • Examples of polycyclic cycloalkanediyl include norbornanediyl.
  • cycloalkyl part of “cycloalkyloxy” has the same meaning as the above “cycloalkyl”.
  • cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclononyloxy, cyclodecyloxy and the like can be mentioned.
  • polycyclic cycloalkyloxy include norbornyloxy, tetrahydronaphthalen-5-yloxy, tetrahydronaphthalen-6-yloxy and the like.
  • “Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond.
  • Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene.
  • Examples of the polycyclic cycloalkene include norbornene and indene.
  • Cycloalkenyl includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like.
  • Cycloalkenediyl includes a divalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenediyl include cyclopentenediyl, cyclohexenediyl and the like. Examples of polycyclic cycloalkenediyl include norbornene diyl.
  • cycloalkenyl part of “cycloalkenyloxy” has the same meaning as the above “cycloalkenyl”.
  • cycloalkenyloxy examples include norbornenyloxy and indenyloxy.
  • non-aromatic carbocycle includes a ring selected from the above “cycloalkane” and the above “cycloalkene”. Examples thereof include monocyclic rings such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, and cyclohexene, and polycyclic rings such as norbornane, tetrahydronaphthalene, norbornene, and indene.
  • monocyclic rings such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, and cyclohexene
  • polycyclic rings such as norbornane, tetrahydronaphthal
  • non-aromatic carbocyclic group includes a monovalent group derived from the above “non-aromatic carbocyclic group”. For example, it contains a group selected from “cycloalkyl” and “cycloalkenyl”.
  • non-aromatic carbocyclic moiety of “non-aromatic carbocyclic oxy” has the same meaning as the above “non-aromatic carbocycle”. For example, it contains a group selected from “cycloalkyloxy” and “cycloalkenyloxy”.
  • aromatic carbocycle includes a monocyclic or condensed aromatic hydrocarbon ring.
  • a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned.
  • Aryl means a monovalent group derived from the above “aromatic carbocycle”. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like.
  • aryl part of “arylsulfonyloxy” has the same meaning as the above “aryl”.
  • aryl For example, phenylsulfonyloxy, 1-naphthylsulfoneoxy and the like can be mentioned.
  • Arylalkyl includes a group in which the above “alkyl” is substituted with the above “aryl”. For example, benzyl, phenethyl and the like can be mentioned.
  • the aryl part of “aryloxy”, “aryloxycarbonyl”, “arylalkylamino”, “arylsulfinyl” and “arylalkyl” has the same meaning as the above “aryl”.
  • “Aromatic carbocyclic diyl” includes a divalent group derived from the above “aromatic carbocycle”. For example, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like can be mentioned.
  • Heterocycle means a 5- to 7-membered ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring, A ring in which two or more of them are independently fused, or A 5- to 7-membered ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the “aromatic carbocycle”, the “cycloalkane” or the “cycloalkene”.
  • An aromatic or non-aromatic fused ring derived from the above ring.
  • monocyclic non-aromatic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorphone, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc.
  • heterocyclic group includes a monovalent group derived from the above “heterocycle”.
  • Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl
  • a ring group For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo Examples include condensed heterocyclic groups
  • the “aromatic heterocycle” includes the above “heterocycle” which is an aromatic ring.
  • a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring An aromatic ring in which two or more of them are independently fused, An aromatic ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
  • indole isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo
  • examples thereof include condensed aromatic heterocycles such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.
  • non-aromatic heterocyclic ring of A ring triazole, pyrazole, imidazole and pyrrole are preferable.
  • Heteroaryl includes a monovalent group derived from the above “aromatic heterocycle”.
  • a 5- to 7-membered aromatic cyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring An aromatic cyclic group in which two or more of them are independently fused, An aromatic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
  • Aryl For example, isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoxiazozolyl, benzothiazozolyl Condensation such as ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl Heteroaryl.
  • non-aromatic heterocycle includes those that are non-aromatic rings among the above-mentioned “heterocycle”.
  • a 5- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring A non-aromatic ring in which two or more of them are independently fused,
  • a ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “cycloalkane” or “cycloalkene”;
  • a 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”.
  • fused rings For example, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydro Monocyclic non-aromatic heterocycles such as thiazoline, tetrahydroisothiazoline, Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, tetrahydrobenzothiophen
  • non-aromatic heterocyclic group includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
  • non-aromatic heterocyclic moiety of “non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic alkylamino” and “non-aromatic heterocyclic alkyl” has the same meaning as the above “non-aromatic heterocyclic”.
  • Substituents for “substituted amino” include, but are not limited to, one or more of the same or different substituents selected from the following group: Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy) Etc.), haloalkyloxy (eg CF 3 O), alkenyloxy (eg vinyloxy,
  • Substituted non-aromatic carbocyclic group “substituted aryl”, “substituted non-aromatic heterocyclic group”, “substituted heteroaryl”, “substituted arylalkyl”, “substituted heteroarylalkyl”, “substituted non-aromatic carbon” ”Ring oxy”, “substituted non-aromatic heterocyclic oxy”, “substituted aryloxy”, “substituted aryloxycarbonyl”, “substituted heteroaryloxy”, “substituted non-aromatic carbocycle”, and “substituted non-aromatic heterocyclic”
  • Substituents for “ring” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of: Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.),
  • the present invention includes all possible isomers, including these, and their Includes mixtures.
  • one or more hydrogen, carbon or other atoms of the compound of general formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms.
  • the compound of general formula (I) includes all radiolabeled compounds of the compound of general formula (I). Such “radiolabeled”, “radiolabeled” and the like of compounds of general formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. is there. Examples of isotopes that can be incorporated into the compound of the general formula (I) of the present invention include 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, and 35, respectively.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium-labeled compound of general formula (I) can be prepared by introducing tritium into a specific compound of formula I, for example, by a catalytic dehalogenation reaction using tritium. This process comprises reacting a compound of general formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base. It may be included.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • solvate includes, for example, solvates with organic solvents, hydrates, and the like. When forming a hydrate, it may be coordinated with any number of water molecules.
  • the compound according to the present invention includes a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt for example, alkali metals (such as lithium, sodium or potassium), alkaline earth metals (such as magnesium or calcium), ammonium, salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphorus Acid or hydroiodic acid) and organic acids (acetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, and salts with p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.).
  • hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable.
  • prodrug of the present invention any form known in the art can be adopted.
  • Prodrugs take the metabolic mechanism of the body in reverse, and in their original form do not show drug action or only show very weak activity, but they show pharmacological activity only after being metabolized in vivo Or it has been modified to increase its pharmacological activity.
  • salts and solvates, esters, amides and the like can also be mentioned as examples of prodrugs.
  • “Modulators” include agonists, partial agonists, inverse agonists and antagonists.
  • “Histamine H4 modulator” includes histamine H4 receptor modulators, ie, histamine H4 receptor agonists, histamine H4 receptor partial agonists, histamine H4 receptor inverse agonists, histamine H4 receptor antagonists To do.
  • R 2 is Rather than the group indicated by —X— is —O—, and R a and R b are R 1 is a group represented by It is not a group indicated by A compound represented by (however, The following compounds: Or a pharmaceutically acceptable salt or solvate thereof, a histamine H4 modulator.
  • Formula (I ′) And the compounds represented by (I′-A) to (I′-E).
  • Compound (I′-A): In the above formula (I ′), R a and R b are taken together C (R 3a ) (R 3b ); R 1 , R 2 , R 3a , R 3b and n are as defined above (3 ⁇ ), Or a pharmaceutically acceptable salt or solvate thereof according to (3) or (3 ⁇ ), wherein Compound (I′-B): In the above formula (I ′), R a and R b come together —Z— represents —C (R 11 ) —; Each R 5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstit
  • R a is hydrogen
  • R b is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • R 1 , R 2 and n are as defined above (3 ⁇ ), Or a pharmaceutically acceptable salt or solvate thereof according to (3) or (3 ⁇ ), wherein
  • R a is hydrogen
  • R b is a substituted or unsubstituted non-aromatic carbocyclic group, or a substituted or unsubstituted non-aromatic heterocyclic group
  • R 1 , R 2 and n are as defined above (3 ⁇ )
  • a pharmaceutically acceptable salt or solvate thereof according to (3) or (3 ⁇ ) wherein
  • R 2 is hydrogen
  • R a , R b , R 1 and n are as defined above (3 ⁇ ), Or a pharmaceutically acceptable salt or solvate thereof according to the above (3) or (3 ⁇ ).
  • One embodiment of the compound of the present invention represented by the formula (I) includes compounds represented by the following general formulas (II-A) and (II-B).
  • R 1a is halogen (hereinafter, R 1a is assumed to be a1). 2) R 1a is a fluorine atom or a chlorine atom (hereinafter, R 1a is assumed to be a2). 3) R 1a is a chlorine atom (hereinafter, R 1a is a3).
  • each R 1b is independently halogen, 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 alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, formyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, aryloxy Carbonyl, carbamoyl, sulfamoyl, sulfonyloxy, sulfinyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbo
  • R 1b is each independently halogen, carboxy, unsubstituted C1-C3 alkyl, unsubstituted C1-C3 alkyloxy, substituted or unsubstituted amino (hereinafter, R 1b is b2) To do).
  • q is an integer of 0 to 3 (hereinafter, q is assumed to be q1).
  • q is 0 or 1 (hereinafter, q is assumed to be q2).
  • q is 0 (hereinafter, q is assumed to be q3).
  • R 2 is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl (wherein substituted C1-C3 alkyl, substituted C2- Substituents for C4 alkenyl and substituted C2-C4 alkynyl include amino, heteroaryl (eg thienyl) or aryl (eg phenyl)) (hereinafter R 2 is assumed to be c1). 10) R 2 is hydrogen (hereinafter, R 2 is c2).
  • R 3a is substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or An unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl (hereinafter, R 3a is d1).
  • R 3a is a substituted or unsubstituted C1-C3 alkyl (wherein the substituent includes alkylamino) or a substituted or unsubstituted non-aromatic heterocyclic group (eg, pyrrolidinyl) (hereinafter referred to as “pyrrolidinyl”).
  • R 3a is d2).
  • R 3a is an unsubstituted non-aromatic heterocyclic group (eg, pyrrolidinyl) (hereinafter, R 3a is d3).
  • -X- is -O- or -S- (hereinafter, X is x1).
  • -X- is -O- (hereinafter, X is x2). (However, R 3a can take a cis or trans position with respect to X.)
  • Examples of the group represented by the general formula (II-A) include the following combinations.
  • (R 1a , R 1b , q, R 2 , R 3a , X) (a1, b1, q1, c1, d1, x1), (a1, b1, q1, c1, d1, x2), (a1, b1, q1, c1, d2, x1), (a1, b1, q1, c1 , d2, x2), (a1, b1, q1, c1, d3, x1), (a1, b1, q1, c1, d3, x2), (a1, b1, q1, c2, d1, x1), (a1 , b1, q1, c2, d1, x2), (a1, b1, q1, c2, d2, x1), (a1, b1, q1, c2, d2, x2), (a1, b1, q1, c2,
  • each R 1 is independently halogen, 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 alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, acyl, hydroxy, formyl, carboxy, substituted or unsubstituted alkyloxycarbonyl, aryloxy Carbonyl, carbamoyl, sulfamoyl, sulfonyloxy, sulfinyl, cyano, nitro, substituted or unsubstituted amino, substituted or unsubstit
  • R 1 is each independently halogen (eg, fluorine atom, chlorine atom or bromine atom), substituted or unsubstituted C1-C3 alkyl (wherein the substituent includes cycloalkyl, halogen, hydroxy) ), Substituted or unsubstituted C2-C4 alkenyl (wherein the substituents include cycloalkyl, halogen, hydroxy), substituted or unsubstituted C2-C4 alkynyl (wherein the substituent is cycloalkyl, halogen, , Hydroxy), unsubstituted C1-C3 alkyloxy, unsubstituted C2-C4 alkenyloxy, unsubstituted C2-C4 alkynyloxy, hydroxy, cyano, nitro, substituted or unsubstituted amino (substituted here) Groups such as aryl (eg phenyl), arylalkyl, unsubstitute
  • Each R 1 is independently halogen, cyano, or substituted or unsubstituted C1-C3 alkyl (wherein the substituent includes halogen or hydroxy) (hereinafter, R 1 is aa3) To do).
  • n is an integer of 0 to 2 (hereinafter, n is assumed to be n1).
  • n is 1 (hereinafter, n is assumed to be n2).
  • R 2 is hydrogen, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C2-C4 alkenyl, substituted or unsubstituted C2-C4 alkynyl (wherein substituted C1-C3 alkyl, substituted C2- Substituents for C4 alkenyl and substituted C2-C4 alkynyl include amino, heteroaryl (eg, thienyl) or aryl (eg, phenyl) (hereinafter R 2 is cc1).
  • R 2 is hydrogen (hereinafter, R 2 is assumed to be cc2).
  • E is (Wherein —Z— represents —CH—; R 4 is hydrogen; Each R 5 is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or Unsubstituted alkynyloxy, hydroxy, cyano, nitro, substituted or unsubstituted amino; And / or Two R 5 bonded to the same carbon atom are ⁇ O or ⁇ NR 7 ; r is an integer from 0 to 4; R 6 and R 7 are the groups represented by the above (3 ⁇ ) (herein, E is e1).
  • each R 5 is independently an unsubstituted C1-C3 alkyl; r is 0 or 1; R 6 is hydrogen or a group represented by substituted or unsubstituted C1-C3 alkyl (wherein the substituent includes hydroxy and carbamoyl) (herein, E is e2).
  • E is (Here, E is e3).
  • —X— is —O— or —S—.
  • X is assumed to be x1)
  • —X— is —O—.
  • X is assumed to be x2)
  • Examples of the group represented by the general formula (II-B) include the following combinations.
  • (R 1 , n, R 2 , E, X) (aa1, n1, cc1, e1, x1), (aa1, n1, cc1, e1, x2), (aa1, n1, cc1, e2, x1), (aa1, n1, cc1, e2, x2), (aa1 , n1, cc1, e3, x1), (aa1, n1, cc1, e3, x2), (aa1, n1, cc2, e1, x1), (aa1, n1, cc2, e1, x2), (aa1, n1 , cc2, e2, x1), (aa1, n1, cc2, e2, x2), (aa1, n1 , cc2, e2, x1), (aa1, n1, cc2,
  • A, B, X, R a And R b Of the following (A, B, X, R a , R b ).
  • (A, B, X, R a , R b ) (A1, B1, X1, R a 1, R b 1), (A1, B1, X1, R a 1, R b 2), (A1, B1, X1, R a 1, R b 3), (A1, B1, X1, R a 1, R b 4), (A1, B1, X1, R a 1, R b 5), (A1, B1, X1, R a 1, R b 6), (A1, B1, X1, R a 1, R b 7), (A1, B1, X1, R a 1, R b 8), (A1, B1, X1, R a 1, R b 9), (A1, B1, X1, R a 2, R b 1), (A1, B1, X1, R a 2, R b 2), (A1, B1, X1, R a 2,
  • the compound whose combination of A, B, X, and C is the following (A, B, X, C).
  • (A, B, X, C) (A1, B1, X1, C1), (A1, B1, X1, C2), (A1, B1, X1, C3), (A1, B1, X1, C4), (A1, B1, X1, C5), (A1, B1, X1, C6), (A1, B1, X1, C7), (A1, B1, X1, C8), (A1, B1, X2, C1), (A1, B1, X2, C2), (A1, B1, X2, C3), (A1, B1, X2, C4), (A1, B1, X2, C5), (A1, B1, X2, C6), (A1, B1, X2, C7), (A1, B1, X2, C8), (A1, B2, X1, C1), (A1, B2, X1, C2), (A1, B2, X1, C3), (A1, B2,
  • the compound represented by the general formula (I) of the present invention can be produced, for example, by the following synthesis route.
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium hydride and the like, and 1 to 10 molar equivalents relative to compound (i) Can be used. With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (iii) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (v) can be synthesized by condensing the compound represented by the general formula (iii) and the compound represented by the general formula (iv) in the presence of a base.
  • the reaction solvent include THF, diethyl ether, hexane and the like, and these can be used alone or in combination.
  • Examples of the base include sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide and the like.
  • the reaction temperature is -78 to 40 ° C.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (v) can be isolated and purified by known means (for example, chromatography, recrystallization and the like).
  • a compound represented by general formulas (vi) and (vii) can be synthesized by allowing a halogenating reagent to act on the compound represented by general formula (v) in the presence of a base.
  • the reaction solvent include THF, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • the halogenating reagent include thionyl chloride, thionyl bromide, sulfuryl chloride and the like.
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, cesium carbonate and the like.
  • the reaction temperature it can be ⁇ 40 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compounds represented by the general formulas (vi) and (vii) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).
  • Method D (The symbols in the formula are as defined above.)
  • the compound represented by the general formula (iii) and the compound represented by the general formula (iv) are condensed, and then a halogenating reagent is allowed to act, whereby the compounds represented by the general formulas (vi) and (vii) are represented.
  • the reaction solvent include THF, diethyl ether, hexane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • halogenating reagent examples include thionyl chloride and thionyl bromide.
  • Bases include sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, potassium carbonate, sodium carbonate Sodium bicarbonate, pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, cesium carbonate and the like.
  • reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compounds represented by the general formulas (vi) and (vii) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).
  • a compound represented by the general formula (ix) can be synthesized by allowing an alkylating agent to act on the compound represented by the general formula (viii) in the presence of a base.
  • the reaction solvent include THF, diethyl ether, hexane, DMF, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • Bases include sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, hydrogen Potassium chloride, cesium carbonate, and the like, and can be used at 1 to 10 molar equivalents relative to compound (viii).
  • the alkylating agent include organic iodides such as methyl iodide and ethyl iodide, organic bromides, organic chlorides, dimethyl sulfate, and sulfonates.
  • the resulting compound represented by the general formula (ix) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • P 1 is hydrogen, substituted or unsubstituted alkyl, MOM group (2-methoxyethoxymethyl group), SEM group (2- (trimethylsilyl) ethoxymethyl group) or Boc group, and other symbols are as defined above.
  • a compound represented by the general formula (xi) can be synthesized by allowing a reducing agent to act on the nitro compound represented by the general formula (x).
  • reaction solvent examples include acetic acid, water, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
  • the reducing agent examples include zinc dust, iron / ammonium chloride, tin chloride and the like, and 1 to 20 molar equivalents can be used with respect to the compound (x). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xi) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • Examples of the metal halide include copper chloride and copper bromide, and 1 to 10 molar equivalents can be used with respect to the compound (xii). With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compounds represented by the general formulas (xiii) and (xiv) can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).
  • R 18 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted A non-aromatic heterocyclic group, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; each R 19 is independently hydrogen, a substituted or unsubstituted alkyl, or two R 19 are bonded together; (CR 20a R 20b ) t-, t is an integer of 1 to 3, R 20a and R 20b are each independently hydrogen, substituted or unsubstituted alkyl, and other symbols are as defined above.
  • a compound represented by the general formula (xvii) is synthesized by allowing a metal catalyst and a boronic acid or boronic acid ester represented by the general formula (xvi) to act on the compound represented by the general formula (xv). can do.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF and the like, and these can be used alone or in combination.
  • the metal catalyst examples include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like.
  • the compound can be used in an amount of 0.001 to 0.5 molar equivalents relative to the compound (xv).
  • An organic phosphorus compound such as triphenylphosphine, tributylphosphine, or dppf can also be used as a ligand.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus
  • Examples thereof include potassium oxyhydrogen, cesium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to compound (xv).
  • Boronic acid or boronic ester (xvi) can be used in an amount of 1 to 10 molar equivalents relative to compound (xv).
  • the reaction temperature it can be 20 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xvii) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • R 21 and R 22 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • a compound represented by the general formula (xix) can be synthesized by condensing a compound represented by the general formula (xviii) with a compound represented by the general formula (xviii) in the presence or absence of a condensing agent.
  • a condensing agent examples include dichloromethane, 1,2-dichloroethane, chloroform, toluene and the like, and these can be used alone or in combination.
  • the condensing agent include acetic acid, hydrochloric acid, magnesium sulfate, molecular sieve, titanium tetrachloride, isopropyl orthotitanate, and the like can be used at 1 to 20 molar equivalents relative to compound (xi).
  • only solvent reflux may be used without using a condensing agent.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xix) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • An amine compound represented by the general formula (xx) can be synthesized by allowing a reducing agent to act on the imine compound represented by the general formula (xix).
  • the reaction solvent include acetic acid, water, methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
  • Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride, and the like (xix ) To 1 to 10 molar equivalents. With respect to the reaction temperature, it can be ⁇ 78 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xx) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (xxi) can be synthesized by allowing an alkylating agent to act on the compound represented by the general formula (xi) in the presence of a base.
  • the reaction solvent include THF, diethyl ether, hexane, DMF, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • Bases include sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, hydrogen And 1 to 10 molar equivalents can be used with respect to compound (xi).
  • the alkylating agent include organic iodides such as methyl iodide and ethyl iodide, organic bromides, organic chlorides, dimethyl sulfate and sulfonates, and 1 to 10 molar equivalents are used with respect to compound (xi). it can.
  • reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF and the like, and these can be used alone or in combination.
  • metal catalyst examples include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like.
  • the compound can be used in an amount of 0.001 to 0.5 molar equivalent based on the compound (xi).
  • an organic phosphorus compound such as triphenylphosphine, tributylphosphine, dppf, or xanthophos can also be used as a ligand.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus Examples thereof include potassium oxyhydrogen, cesium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to compound (xi).
  • Compound (xxvi) can be used at 1 to 10 molar equivalents relative to compound (ix).
  • reaction temperature it can be 20 ° C. to the reflux temperature of the solvent.
  • reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • Compound (xxiv) can be converted to alcohol compound (xxv) with a reducing agent.
  • a reducing agent include lithium borohydride, sodium borohydride, diisopropylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. be able to.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination.
  • the reaction temperature it can be ⁇ 78 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained alcohol compound (xxv) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • R 27 is halogen
  • R 28 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Of the above-mentioned cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • the compound represented by the general formula (xxviii) can be synthesized by allowing the acetylene compound represented by the general formula (xxvii) to act on the compound represented by the general formula (xxvi) in the presence of a base and a metal catalyst.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF and the like, and these can be used alone or in combination.
  • metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. Can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound (xxvi).
  • the base include triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, pyridine and the like, and 1 to 10 molar equivalents can be used with respect to compound (xxvi).
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound (xxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (xxix) can be synthesized by allowing a cyanide to act on the compound represented by the general formula (xxvi) in the presence of a base and a metal catalyst.
  • the reaction solvent include DMF, NMP, tetrahydrofuran, dioxane and the like, and these can be used alone or in combination.
  • the cyanide include copper cyanide and zinc cyanide.
  • the cyanide can be used in an amount of 1 to 10 molar equivalents relative to the compound (xxvi). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound (xxix) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 29 , R 30 and R 31 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl , Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • the compound represented by the general formula (xxxi) can be synthesized by allowing the compound represented by the general formula (xxx) to act on the compound represented by the general formula (xxxvi) in the presence of a base and a metal catalyst.
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, DMF and the like, and these can be used alone or in combination.
  • the metal catalyst examples include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. 0.001 to 0.5 molar equivalent can be used with respect to the compound ().
  • An organic phosphorus compound such as triphenylphosphine, tributylphosphine, or dppf can also be used as a ligand.
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound (xxxi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 33 and R 34 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, R 35 is a substituted or unsubstituted alkyl, and other symbols are: It is the same meaning as above.)
  • the compound represented by the general formula (xxxiii) can be synthesized by acid treatment of the compound represented by the general formula (xxxii).
  • reaction solvent examples include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
  • acid hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid and the like can be mentioned, and 1 molar equivalent to a solvent amount can be used with respect to compound (xxxii).
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the obtained compound (xxxiii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • Compound (xxxiii) can be converted to alcohol compound (xxxiv) with a reducing agent.
  • the reducing agent include lithium borohydride, sodium borohydride, diisopropylaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. be able to.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination. With respect to the reaction temperature, it can be ⁇ 78 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the obtained alcohol compound (xxxiv) can be isolated and purified by a known means (for example, chromatography, recrystallization, etc.).
  • R36 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic Heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and other symbols are as defined above.
  • the compound represented by the general formula (xxxvi) can be synthesized by allowing the organoboron compound represented by the general formula (xxxv) to act on the compound represented by the general formula (xxxvi).
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol, DMF and the like, and these can be used alone or in combination.
  • metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium and the like. Can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound (xxvi).
  • an organic phosphorus compound such as triphenylphosphine, tributylphosphine, dppf, xanthophos, butyldi-1-adamantylphosphine can be used as the ligand.
  • Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, phosphorus
  • Examples thereof include potassium oxyhydrogen, cesium carbonate and the like, and 1 to 10 molar equivalents can be used with respect to compound (xxvi).
  • the organoboron compound represented by the general formula (xxxv) can be used at 1 to 10 molar equivalents relative to the compound (xxxvi). With respect to the reaction temperature, it can be 20 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxxvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 37 is halogen
  • R 38 and R 39 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, Is the same meaning.
  • a compound represented by the general formula (xxxviii) can be synthesized by condensing a phosphate represented by the general formula (xxxvii) to the compound represented by the general formula (i).
  • the reaction solvent include acetonitrile, toluene, THF, DMF and the like, and they can be used alone or in combination.
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium hydride and the like, and 1 to 10 molar equivalents relative to compound (i) Can be used. With respect to the reaction temperature, it can be -20 ° C to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xxxviii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a compound represented by the general formula (xl) can be synthesized by condensing an acid chloride represented by the general formula (xxxix) to the compound represented by the general formula (i) in the presence of a base.
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene ethyl acetate and the like, and these can be used alone or in combination.
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, sodium hydride and the like, and 1 to 10 molar equivalents relative to compound (i) Can be used.
  • the reaction temperature it can be -20 ° C to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xl) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (xli) can be synthesized by allowing a base to act on the compound represented by the general formula (xl).
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • the base include potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like, and the base can be used at 1 to 10 molar equivalents relative to the compound (xl). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xli) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (xli) can be synthesized by allowing a base to act on the compound represented by the general formula (xl).
  • the reaction solvent include tetrahydrofuran, dioxane, toluene, water, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • the base include potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like, and the base can be used at 1 to 10 molar equivalents relative to the compound (xl). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xli) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • a compound represented by the general formula (xlii) can be synthesized by allowing a halogenating agent to act on the compound represented by the general formula (xli) in the presence of dimethylformamide.
  • the reaction solvent include dichloromethane, 1,2-dichloroethane, chloroform, toluene ethyl acetate and the like, and these can be used alone or in combination.
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, and the like, and 1 equivalent to a solvent amount can be used with respect to the compound (xli).
  • the reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xlii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • a phosphoric acid ester compound represented by the general formula (xlib) is synthesized by condensing a phosphite ester represented by the general formula (xliii) to the compound represented by the general formula (xlii). Can do.
  • the phosphite (xliii) can be used at 1 molar equivalent to a solvent amount relative to the compound (xlii). With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xlib) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (xlvi) can be synthesized by allowing the compound represented by the general formula (xlv) to act on the phosphate ester represented by the general formula (xlib) in the presence of a base.
  • the reaction solvent include THF, diethyl ether, hexane, DMF, methanol, ethanol, propanol, isopropanol, butanol and the like, and these can be used alone or in combination.
  • Bases include sodium methoxide, potassium tert-butoxide, n-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium amide, lithium diisopropylamide, sodium hydride, hydrogen Potassium chloride, cesium carbonate, and the like, and can be used at 1 to 10 molar equivalents relative to the compound (xlib). With respect to the reaction temperature, it can be ⁇ 78 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 48 hours.
  • the resulting compound represented by the general formula (xlvi) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • Compound (xlvii) can be synthesized by reducing compound (xlvi) with hydrogen in the presence of a metal catalyst.
  • a metal catalyst examples include palladium-carbon, platinum oxide, chlorotris (triphenylphosphine) rhodium (I), and the like, and can be used in an amount of 0.01 to 0.5 weight percent with respect to the compound (xlvi).
  • the hydrogen pressure is 1 to 50 atm. With respect to the reaction temperature, it can be 0 ° C. to the reflux temperature of the solvent. An example of the reaction time is 0.5 to 72 hours.
  • the obtained compound (xlvii) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 46 and R 47 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, or R 46 and R 47 taken together to form a non-aromatic heterocycle (P 2 and P 3 may be a suitable protecting group for an amino group; u is an integer of 1 to 3, and other symbols are as defined above.) By subjecting compound (xlviii) to an acid treatment, an amine compound represented by the general formula (xlix) can be synthesized.
  • trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like can be used at 1 molar equivalent to a solvent amount.
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, dioxane, ethyl acetate, methylene chloride, chloroform, water and the like, and these can be used alone or in combination.
  • the reaction temperature include 0 ° C. to 100 ° C.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (xlix) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • R 46 and R 47 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, acyl, substituted or unsubstituted cycloalkyl, substituted Or an unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, or R 46 and R 47 taken together to form a non-aromatic heterocycle
  • P 2 and P 3 may be a suitable protecting group for an amino group; v is an integer of 1 to 3, w is an integer of 1 to 3, and other symbols are as defined above is there.
  • reaction solvent examples include methanol, ethanol, propanol, isopropanol, butanol, dioxane, ethyl acetate, methylene chloride, chloroform, water and the like, and these can be used alone or in combination.
  • reaction temperature examples include 0 ° C. to 100 ° C.
  • An example of the reaction time is 0.5 to 24 hours.
  • the obtained compound represented by the general formula (li) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (lii) can be converted into a carboxylic acid (liii) by hydrolysis.
  • the reactant include sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrochloric acid and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (lii).
  • the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, methylene chloride, water and the like, and these can be used alone or in combination.
  • the reaction temperature it can be -20 ° C to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 72 hours.
  • the obtained carboxylic acid compound (liiii) can be isolated and purified by a known means (for example, chromatography, recrystallization and the like).
  • the compound represented by the general formula (lib) can be synthesized by reacting the compound represented by the general formula (liiii) with a phosphoryl azide reagent in the presence of a base.
  • the phosphoryl azide reagent can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by the general formula (liiii).
  • the base include pyridine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine and the like, and 1 to 10 molar equivalents can be used with respect to the compound represented by the general formula (liii).
  • reaction solvent examples include tetrahydrofuran, diethyl ether, toluene, N, N-dimethylformamide, dichloromethane, 1,2-dichloroethane, chloroform and the like, and these can be used alone or in combination.
  • reaction temperature it can be 0 ° C. to the reflux temperature of the solvent.
  • reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lib) can be isolated and purified by the known means (eg chromatography, recrystallization etc.).
  • the compound represented by the general formula (lvi) By reacting the compound (lv) under acidic conditions, the compound represented by the general formula (lvi) can be synthesized.
  • the acid include hydrochloric acid, sulfuric acid, acetic acid, 4-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, and the like. it can.
  • the reaction solvent include tetrahydrofuran, diethyl ether, toluene, dichloromethane, 1,2-dichloroethane, chloroform, ethyl acetate and the like, and these can be used alone or in combination.
  • reaction temperature it can be -20 ° C to the reflux temperature of the solvent.
  • An example of the reaction time is 0.5 to 24 hours.
  • the resulting compound represented by the general formula (lvi) can be isolated and purified by the known means (for example, chromatography, recrystallization and the like).
  • reaction solution was poured into 2 mol / L hydrochloric acid and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine.
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Test Example Binding test of histamine H4 receptor Binding buffer solution 50 mM Tris-HCl
  • human-derived histamine H4 receptor forced expression CHO-K1 cell membrane fraction (PerkinElmer) and radioligand [3H] -Histine (PerkinElmer)
  • the receptor binding assay was performed in pH 7.4, 5 mM EDTA).
  • [3H] -Histamine having a final concentration of 15 nM was added to a binding buffer in which 15 ⁇ g of the histamine H4 receptor-expressing membrane fraction was suspended, and incubated at a reaction volume of 150 ⁇ L at room temperature for 60 minutes.
  • Nonspecific binding was determined by incubating in the presence of 100 ⁇ M unlabeled histamine dihydrochloride (Nacalai Tesque). Membrane fractions were collected on 0.5% PEI coated Unifilterplate GF / B (PerkinElmer) by rapid filtration using a PerkinElmer cell harvester and washed 6 times with 350 ⁇ L ice-cold 50 mM Tris-HCl, pH 7.4. The filter was air-dried, mixed with a scintillation cocktail Microscinti-MS (PerkinElmer), and the radioactivity trapped on the filter was measured with a Topcount liquid scintillation counter (PerkinElmer).
  • the CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, using 7-benzyloxytrifluoromethylcoumarin (BFC) as a CYP3A4 enzyme using E. coli-expressed CYP3A4 as an enzyme.
  • BFC 7-benzyloxytrifluoromethylcoumarin
  • HFC 7-hydroxytrifluoromethylcoumarin
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • DMSO a solvent in which the drug was dissolved
  • the residual activity (%) at each concentration with the test drug solution added was calculated.
  • IC 50 used to calculate IC 50 by inverse estimation with a logistic model. The case where the difference in IC 50 value is 5 ⁇ M or more is (+), and the case where it is 3 ⁇ M or less is ( ⁇ ).
  • Test Example CYP Inhibition Test O-deethylation of 7-ethoxyresorufin (CYP1A2) as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes ), Methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4). The degree to which the amount of product produced is inhibited by the test compound is evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan ( CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. Used to calculate IC 50 by inverse estimation with a logistic model.
  • Test example Metabolic stability test Using a pooled rat liver microsome prepared according to the literature (Japanese journal of pharmacology, 33 (1), p.41-56, Feb 1983) and a commercially available pooled human liver microsome, The reaction is performed for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • test compound in the centrifugal supernatant is quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction is calculated with the amount of the compound at 0 minute reaction as 100%.
  • the hydrolysis reaction is performed in the absence of NADPH, the glucuronic acid conjugation reaction is performed in the presence of 5 mM UDP-glucuronic acid instead of NADPH, and the same operation is performed thereafter.
  • Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution each 12 ⁇ L and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L of the mixture), and cultured with shaking at 37 ° C.
  • Test example hERG test A delay that plays an important role in the ventricular repolarization process using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel for the purpose of risk assessment of ECG QT interval prolongation
  • I Kr rectified K + current
  • a +50 mV depolarization stimulus was further applied for 2 seconds. Record the I Kr elicited when a 50 mV repolarization stimulus is applied for 2 seconds.
  • the absolute value of the maximum tail current is measured using the analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the test substance on I Kr is evaluated. (Result) The inhibition rate at a compound concentration of 1 ⁇ mol / l is shown. I-069: 1%
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • HPC-L low-viscosity hydroxypropylcellulose
  • aqueous solution to the powder mixture, knead, granulate (extruded granulation pore size 0.5-1mm), and dry.
  • the obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg
  • the compound of formula (I), lactose is passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • the compound of formula (Ia), lactose, microcrystalline cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.
  • Formulation Example 5 A haptic agent containing the following components is produced.
  • Ingredient Compound represented by formula (I) 50 mg Aqueous base (5% ethanol / 5% butylene glycol / 90% purified water) 950 mg Glycerin Kaolin
  • Polyvinyl alcohol aqueous solution Compound (I) is added to an aqueous base, and after ultrasonic irradiation for about 15 minutes, the solution is sufficiently stirred to obtain a solution. 5 parts of glycerin, 1 part of kaolin and 5 parts of an aqueous polyvinyl alcohol solution are uniformly mixed, and 1 part of the prepared solution is added.
  • the compound of the present invention has a modulatory action on the histamine H4 receptor, and diseases or conditions involving the histamine H4 receptor such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), etc. Diseases; rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus, atherosclerosis, and other inflammatory diseases; pain relief including neuropathic or nociceptive pain Useful for.
  • diseases or conditions involving the histamine H4 receptor such as bronchial asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), etc. Diseases; rheumatoid arthritis, atopic dermatitis, allergic conjunctivitis, psoriasis, inflammatory colitis, ulcerative colitis, lupus, atherosclerosis, and other inflammatory diseases; pain relief including

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Abstract

La présente invention concerne un composé possédant une activité de modulation du récepteur de l'histamine H4. L'invention concerne spécifiquement un composé représenté par la formule (I) [dans laquelle Ra et Rb représentent indépendamment un atome d'hydrogène, un groupe alkyle substitué ou non substitué, ou analogues ; X représente -O- ou -S(O)p- ; p représente un nombre entier de 0 à 2 ; Y représente =O ou =S ; R1 représente un atome d'halogène, un groupe alkyle substitué ou non substitué, ou analogues ; n représente un nombre entier de 0 à 4 ; et R2 représente un atome d'halogène, un groupe alkyle substitué ou non substitué, ou analogues], un sel pharmaceutiquement acceptable du composé ou un solvate du composé ou du sel pharmaceutiquement acceptable.
PCT/JP2010/064665 2009-08-31 2010-08-30 Dérivé hétérocyclique aromatique condensé et composition pharmaceutique associée WO2011024987A1 (fr)

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CN106674084A (zh) * 2016-12-20 2017-05-17 山东轩德医药科技有限公司 一种2‑异丙基氧基‑5‑甲基‑4‑(哌啶‑4‑基)苯胺二盐酸盐的制备方法
US9737516B2 (en) 2013-11-26 2017-08-22 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9777003B2 (en) 2013-12-19 2017-10-03 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US9834565B2 (en) 2014-09-15 2017-12-05 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
US9850257B2 (en) 2013-07-08 2017-12-26 Incyte Corporation Tricyclic heterocycles as BET protein inhibitors
US9918990B2 (en) 2013-11-26 2018-03-20 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US9957268B2 (en) 2014-04-23 2018-05-01 Incyte Corporation 1H-pyrrolo[2,3,c]pyridin-7(6H)-ones and pyrazolo[3,4-c]pyridin-7(6H)-ones as inhibitors of BET proteins
US10189832B2 (en) 2016-06-20 2019-01-29 Incyte Corporation Crystalline solid forms of a BET inhibitor
US10329305B2 (en) 2015-10-29 2019-06-25 Incyte Corporation Amorphous solid form of a BET protein inhibitor
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

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US9737516B2 (en) 2013-11-26 2017-08-22 Incyte Corporation Bicyclic heterocycles as bet protein inhibitors
US9918990B2 (en) 2013-11-26 2018-03-20 Incyte Corporation Substituted pyrrolo[2,3-c]pyridines and pyrazolo[3,4-c]pyridines as BET protein inhibitors
US10442803B2 (en) 2013-12-19 2019-10-15 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
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CN106674084B (zh) * 2016-12-20 2019-03-01 山东轩德医药科技有限公司 一种2-异丙基氧基-5-甲基-4-(哌啶-4-基)苯胺二盐酸盐的制备方法
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

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