WO2018079759A1 - Hétérocycle fusionné ayant une activité inhibitrice de trka et dérivé carbocycle fusionné - Google Patents

Hétérocycle fusionné ayant une activité inhibitrice de trka et dérivé carbocycle fusionné Download PDF

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WO2018079759A1
WO2018079759A1 PCT/JP2017/039043 JP2017039043W WO2018079759A1 WO 2018079759 A1 WO2018079759 A1 WO 2018079759A1 JP 2017039043 W JP2017039043 W JP 2017039043W WO 2018079759 A1 WO2018079759 A1 WO 2018079759A1
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substituted
unsubstituted
compound
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aromatic
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一也 鹿野
裕樹 山口
透 堀口
和也 安尾
佳世子 畑
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塩野義製薬株式会社
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to a compound having a TrkA inhibitory activity and useful in the treatment and / or prevention of diseases caused by TrkA, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them.
  • Trk The Tropomyosin receptor kinase family belongs to a receptor tyrosine kinase and functions as a receptor for humoral factors collectively called neurotrophic factor (neurotrophin; NT).
  • the Trk family includes TrkA, a high affinity receptor for nerve growth factor (NGF), TrkB, a high affinity receptor for brain-derived trophic factor (BDNF) and NT-4 / 5, and high levels of NT-3.
  • NNF nerve growth factor
  • TrkB a high affinity receptor for brain-derived trophic factor
  • BDNF brain-derived trophic factor
  • Trk-4 Three subtypes of TrkC, which is an affinity receptor, are known and are known to exhibit various functions in vivo.
  • TrkA is mainly expressed in peripheral nerves and brain neurons and is known to play an important role in the generation, differentiation and maintenance of neurons in vivo.
  • Non-Patent Documents 1 and 2 Non-Patent Documents 1-3. It is known that hypersensitivity is induced when NGF activates TrkA in peripheral nerves (Non-Patent Documents 4-6). Pain associated with osteoarthritis, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis, prostatitis based on the results of clinical and nonclinical studies using anti-NGF antibodies or nonclinical studies using Trk inhibitors In addition, NGF- for various pains such as chronic low back pain, diabetic peripheral neuropathic pain, postoperative pain, pelvic pain, cancer pain, nociceptive pain, neuropathic pain, acute pain, and chronic pain.
  • TrkA signal or NT-Trk signal is involved (Patent Documents 1 and 2, Non-Patent Documents 7 and 8). Trk is also expressed in various cancer cells such as neuroblastoma, prostate cancer, lung cancer, breast cancer, stomach cancer, and pancreatic cancer, and has been reported to be associated with the proliferation and migration of cancer cells. Yes.
  • lung cancer it has been reported that a protein in which the kinase domain of TrkA is fused is involved in the growth of cancer cells.
  • Trk inhibitors suppress cancer growth and metastasis (Patent Documents 1 and 2, Non-Patent Documents 9-12).
  • TrkA is also expressed in mast cells, eosinophils, immunocompetent cells such as T cells and B cells, keratinocytes, etc., and NGF-TrkA signal or NT-Trk signal is detected in ulcerative colitis. It has been reported that it may be involved in inflammatory bowel diseases such as Crohn's disease, allergic diseases such as asthma and rhinitis, and skin diseases such as psoriasis, atopic dermatitis and pruritus (Patent Documents 1 and 2). . In addition, it has been reported that NGF-TrkA signal inhibition improves overactive bladder due to cystitis (Patent Document 1).
  • TrkA is considered to be important in the infection process of a cruise trypanosoma infection (Chagas disease) (Patent Document 1). Therefore, compounds that inhibit the kinase activity of TrkA are used as therapeutic agents for various pains such as nociceptive pain and neuropathic pain and various diseases such as cancer, inflammatory diseases, allergic diseases and skin diseases. Useful. Compounds having a TrkA inhibitory action are disclosed in Patent Document 1-20 and Non-Patent Documents 6 and 13-14. However, none of the documents describes or suggests compounds related to the present invention.
  • An object of the present invention is to provide a compound having TrkA inhibitory activity or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them.
  • the present invention relates to a compound having a TrkA inhibitory activity and useful for treating and / or preventing a disease caused by TrkA or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the following items 1) to 27) and 101) to 107).
  • R 2 represents a hydrogen atom, cyano, carboxy, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted carbamoyl) Is;
  • —Z— is —NR 5 —, —O— or —CR 6 R 7 —;
  • —Z A — is —NR 5A — or —CR 6A R 7A —;
  • R 5 and R 5A are each independently a hydrogen atom or substituted or unsubstituted alkyl;
  • R 6 , R 6A , R 7 and R 7A are each independently a hydrogen atom, halogen, hydroxy, substituted or un
  • Ring C is of the formula: Wherein R 13 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic group A carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group; R 14 represents a hydrogen atom, hydroxy, halogen, cyano, 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 carbamoyl, substituted or unsubstituted alkylsulfonyl, substituted or un
  • R 13 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic carbocyclic group
  • R 14 is a substituted or unsubstituted aromatic heterocyclic group
  • R 15 is a hydrogen atom or a substituted or unsubstituted group
  • B 1 is substituted or unsubstituted phenyl
  • R 2 is a hydrogen atom
  • R 3 is a hydrogen atom
  • R 4 is a hydrogen atom
  • ring D is a substituted or unsubstituted benzene ring or substituted Or the compound of the said item 16) which is an unsubstituted pyridine ring, or its pharmaceutically acceptable salt.
  • a method for treating or preventing a disease involving TrkA which comprises administering the compound according to any one of the above items 1) to 22) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition for oral administration comprising the compound according to any one of the above items 1) to 22), or a pharmaceutically acceptable salt thereof. 102) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions or tinctures, The pharmaceutical composition according to item 101) above.
  • a pharmaceutical composition for parenteral administration comprising the compound according to any one of the above items 1) to 22), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition according to the above item 104 for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.
  • the present invention provides a compound or a pharmaceutically acceptable salt thereof useful in the treatment and / or prevention of a TrkA-dependent disease.
  • the compound of the present invention exhibits an excellent TrkA kinase activity inhibitory action as described in Test Examples described later. Therefore, the pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof is effective for osteoarthritis, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis, pain associated with prostatitis, and chronic low back pain.
  • the compound of the present invention is a compound having utility as a medicine.
  • the usefulness as a medicine includes good solubility, good metabolic stability, little induction of drug metabolizing enzymes, small inhibition of drug metabolizing enzymes that metabolize other drugs, oral absorption
  • the compound includes a highly active compound, a small hERG inhibition, a small clearance, and / or a sufficiently long half-life for exhibiting a medicinal effect.
  • Halogen includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • Alkylene is a straight or branched divalent hydrocarbon having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • aromatic carbocyclic group means a cyclic aromatic hydrocarbon group having one or more rings.
  • aromatic carbocyclic group includes phenyl.
  • “Aromatic carbocycle” means a monocyclic or two or more cyclic aromatic hydrocarbon rings. For example, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, etc. are mentioned. Preferred embodiments of the “aromatic carbocycle” include a benzene ring and a naphthalene ring.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • non-aromatic carbocycle means a monocyclic ring or two or more cyclic saturated hydrocarbon rings or cyclic non-aromatic unsaturated hydrocarbon rings.
  • the two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
  • the “non-aromatic carbocycle” includes a ring that is bridged as follows, or a spiro ring.
  • the monocyclic non-aromatic carbocycle preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
  • the two or more non-aromatic carbocycles include indane, indene, acenaphthalene, tetrahydronaphthalene, and fluorene.
  • Examples of the non-aromatic carbocyclic ring formed by R C and R D together include the following rings.
  • non-aromatic carbocycle formed by R 14 and R 15 together include the following ring Q B.
  • the ring Q B include non-aromatic carbocyclic ring, for example, 5 to 8-membered.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Examples include dazinyl, oxazolopyridyl, thiazolopyridyl and the like.
  • R represents a hydrogen atom, CH 3 , CH 2 CF 3, and when one of the bonds is bonded to one ring, the bond is bonded to any ring-constituting atom of the ring. And when one of the bonds is bonded to two rings, the bond may be present at any of the ring-constituting atoms of the two rings.
  • the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • 6-membered aromatic heterocyclic group examples include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.
  • “Aromatic heterocycle” means a single ring or two or more aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
  • Two or more aromatic heterocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more aromatic heterocycles.
  • the monocyclic aromatic heterocyclic ring is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples thereof include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
  • bicyclic aromatic heterocycle examples include indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, Benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine, etc. Is mentioned.
  • the three or more aromatic heterocycles include carbazole, acridine, xanthene, phenothiazine, phenoxathiin, phen
  • 6-membered aromatic heterocycle examples include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.
  • the aromatic heterocyclic ring formed together with the carbon atom to which R 14 and R 15 are adjacent together for example, the following rings Q C.
  • the ring Q C such as O, having one or more identical or different hetero atoms in the ring is selected arbitrarily from S and N, an aromatic 5- or 6-membered heterocyclic ring.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • non-aromatic heterocyclic group having two or more rings is the same as the above-mentioned “non-aromatic carbocyclic group” and / or “non-aromatic heterocyclic group”. Also included are those in which each ring in the “group” is condensed. Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • Non-aromatic heterocycle means a monocyclic or bicyclic or more cyclic non-aromatic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring .
  • the non-aromatic heterocyclic ring having two or more rings is the above-mentioned “aromatic carbocycle”, “non-aromatic carbocycle”, and / or “aromatic heterocycle” in addition to a single ring or two or more non-aromatic heterocyclic rings. Also included are those in which each ring is condensed.
  • the “non-aromatic heterocyclic ring” includes a ring that is bridged as follows, or a spiro ring.
  • the non-bridged non-aromatic heterocyclic ring is preferably 3 to 8 members, more preferably 4 to 8 members, still more preferably 5 or 6 members.
  • the bridged non-aromatic heterocyclic ring preferably has 6 to 10 members, more preferably 8 or 9 members.
  • the number of members shown here means the total number of atoms constituting the bridged non-aromatic heterocycle.
  • the monocyclic non-aromatic heterocyclic ring is preferably 3 to 8 members, more preferably 5 or 6 members.
  • Examples include dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thio
  • R C and R D examples include the following rings.
  • R AA includes substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxycarbonyl, or substituted or unsubstituted alkylcarbonyl.
  • the non-aromatic heterocyclic ring formed together with the carbon atom to which R 14 and R 15 are adjacent together for example, the following rings Q D.
  • the ring Q D includes, for example, a 5- to 8-membered non-aromatic heterocyclic ring having one or more hetero atoms selected from O, S and N in the ring.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • Alkyloxy means a group wherein the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl For example, vinyl carbonyl, allyl carbonyl, etc. are mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • Alkylamino means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N, N-diisopropylamino, N-methyl-N-ethylamino and the like can be mentioned.
  • Preferable embodiments of “alkylamino” include methylamino and ethylamino.
  • Alkenylamino means a group in which the above “alkenyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • alkenyl For example, vinylamino, allylamino and the like can be mentioned.
  • Alkynylamino means a group in which the above “alkynyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • alkynyl is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • ethynylamino and the like can be mentioned.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl For example, vinyl sulfonyl, allyl sulfonyl, etc. are mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • Alkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Alkenylcarbonylamino means a group in which the above “alkenylcarbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • alkenylcarbonyl For example, vinyl carbonylamino, allyl carbonylamino, etc. are mentioned.
  • Alkynylcarbonylamino means a group in which the above “alkynylcarbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • alkynylcarbonylamino ethynylcarbonylamino, propynylcarbonylamino and the like can be mentioned.
  • Alkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Preferable embodiments of “alkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Alkenylsulfonylamino means a group in which the above “alkenylsulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • alkenylsulfonyl For example, vinyl sulfonylamino, allyl sulfonylamino, etc. are mentioned.
  • Alkynylsulfonylamino means a group in which the above “alkynylsulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • alkynylsulfonylamino ethynylsulfonylamino, propynylsulfonylamino and the like can be mentioned.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like. Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
  • Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • Alkylcarbamoyl means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl and the like can be mentioned.
  • Alkenylcarbamoyl means a group in which the above “alkenyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • alkenyl for example, vinyl carbamoyl, allyl carbamoyl, etc. are mentioned.
  • Alkynylcarbamoyl means a group in which the above “alkynyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • alkynyl ethynylcarbamoyl, propynylcarbamoyl and the like can be mentioned.
  • Alkylsulfamoyl means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include methylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.
  • Alkenylsulfamoyl means a group in which the above “alkenyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group.
  • alkenyl for example, vinyl sulfamoyl, allyl sulfamoyl, etc. are mentioned.
  • Alkynylsulfamoyl means a group in which the above “alkynyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. For example, ethynyl sulfamoyl, propynyl sulfamoyl, etc. are mentioned.
  • Trialkylsilyl means a group in which the above three “alkyls” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • Non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxycarbonyl, morpholinylethyloxycarbonyl, piperidinylmethyloxycarbonyl, piperazinylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • the “aromatic carbocyclic” moiety is the same as the above “aromatic carbocyclic group”.
  • “Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
  • “Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
  • “Aromatic carbocyclic carbonyloxy” means a group in which the above “aromatic carbocyclic carbonyl” is bonded to an oxygen atom. For example, phenylcarbonyloxy, naphthylcarbonyloxy and the like can be mentioned.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • Aromatic carbocyclic sulfanyl means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • Aromatic carbocyclic sulfonyl means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom.
  • Non-aromatic carbocycle carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • Non-aromatic carbocyclic carbonyloxy means a group in which the above “non-aromatic carbocyclic carbonyl” is bonded to an oxygen atom.
  • non-aromatic carbocyclic oxycarbonyl means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • Aromatic heterocyclic oxy means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • Aromatic heterocycle carbonyl means a group in which “aromatic heterocycle” is bonded to a carbonyl group.
  • “Aromatic heterocyclic carbonyloxy” means a group in which the above “aromatic heterocyclic carbonyl” is bonded to an oxygen atom.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
  • “Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • Non-aromatic heterocyclic carbonyloxy means a group in which the above “non-aromatic heterocyclic carbonyl” is bonded to an oxygen atom.
  • piperidinylcarbonyloxy, tetrahydrofurylcarbonyloxy and the like can be mentioned.
  • non-aromatic heterocyclic oxycarbonyl means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • non-aromatic heterocyclic for example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • Acyl means “formyl”, “alkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic carbonyl”, “aromatic heterocyclic carbonyl” and Includes “non-aromatic heterocyclic carbonyl”.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, dialkylamino, alkylsulfonyl, alkenyl
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl” and “substituted or unsubstituted sulfamoyl” include the following substituents.
  • One or two hydrogen atoms bonded to the nitrogen atom of the amino group may be replaced with a group selected from the following substituents.
  • Substituents alkyl, alkenyl, alkynyl, halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl , Cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylamino, dialkylamino, alkylsulfonyl , Alkenylsulfonyl, al
  • Aromatic heterocyclic group ", "Substituted or unsubstituted aromatic carbocyclic oxy", “Substituted or unsubstituted non-aromatic carbocyclic oxy", “Substituted or unsubstituted aromatic heterocyclic oxy", and “Substituted or unsubstituted non-aromatic Heterocyclic oxy ", "Substituted or unsubstituted aromatic carbocyclic carbonyl", “Substituted or unsubstituted non-aromatic carbocyclic carbonyl", “Substituted or unsubstituted aromatic
  • An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkylcarbonyl, alkyl,
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • substituents of “substituted or unsubstituted alkyl” in R A include alkyloxy; haloalkyloxy; cyano; halogen; It may be substituted with one or more groups selected from these.
  • R A ′ examples include alkyloxy; haloalkyloxy; cyano; halogen; It may be substituted with one or more groups selected from these.
  • Ring D examples include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Ring D examples include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Substituents for “substituted or unsubstituted phenyl” in B 1 include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted 6-membered aromatic heterocyclic group” in B 1 include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic carbocyclic group” in B 2 include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in B 2 include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted non-aromatic carbocyclic group” in B 2 include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted non-aromatic heterocyclic group” in B 2 include halogen; alkyl; hydroxy; haloalkyl; hydroxyalkyl; It may be substituted with one or more groups selected from these.
  • substituents of “substituted or unsubstituted aromatic heterocyclic ring” in ring C include, for example: Substituted or unsubstituted aromatic carbocyclic groups; A substituted or unsubstituted aromatic heterocyclic group; A substituted or unsubstituted non-aromatic heterocyclic group; A substituted or unsubstituted non-aromatic carbocyclic group; Substituted or unsubstituted alkyl; Substituted or unsubstituted alkyloxy; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 13 include halogen and alkyl. It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 13 include halogen and alkyl. It may be substituted with one or more groups selected from these.
  • R 15 examples include halogen and hydroxy. It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 14 include alkyl; haloalkyl; alkyloxy; alkylcarbamoyl; substituted (alkyl as a substituent) or unsubstituted nonaromatic heterocycle. Carbamoyl substituted with a ring; hydroxyalkyl; substituted (alkyl as a substituent) or unsubstituted non-aromatic heterocyclic group; alkylsulfinylimine; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted non-aromatic carbocyclic group” in R 14 include alkyl and oxo. It may be substituted with one or more groups selected from these.
  • R 14 examples include substituted (non-aromatic heterocyclic group as a substituent) or unsubstituted alkyloxycarbonyl;
  • substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 14 for example, alkyloxycarbonyl; carboxy; substituted (alkyl as a substituent) or substituted with an unsubstituted non-aromatic heterocyclic ring Carbamoyl; It may be substituted with one or more groups selected from these.
  • R 14 examples include oxo; alkyl; It may be substituted with one or more groups selected from these.
  • substituents of “substituted or unsubstituted alkyloxy” in R 14 include halogen; alkylamino; substituted (alkyl as substituent) or unsubstituted non-aromatic heterocyclic group; alkyloxy; alkyloxy Alkyloxy; haloalkyloxy; hydroxy; amino; alkylsulfonyl; alkylsulfinylimine; It may be substituted with one or more groups selected from these.
  • substituents of “substituted or unsubstituted alkyl” in R 14 include hydroxy; halogen; substituted or unsubstituted non-aromatic carbocyclic group; It may be substituted with one or more groups selected from these.
  • substituents of “substituted or unsubstituted carbamoyl” in R 14 include substituted (alkyl as the substituent) or unsubstituted non-aromatic heterocyclic group.
  • ring D is a substituted or unsubstituted benzene ring or substituted or unsubstituted Pyridine ring. (Hereafter referred to as A-2)
  • R A , R A ′ , W, U and t are as defined above, and R B is independently halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy, n is an integer of 0 to 4, and n hydrogen atoms bonded to the ring-constituting atoms of the benzene ring can be replaced by R B. ).
  • A-3 (Hereafter referred to as A-3)
  • U includes —O— or —CR C R D — (wherein R C and R D are each independently a hydrogen atom, halogen, or substituted or unsubstituted alkyl).
  • B-1 U includes —CR C R D — (wherein R C and R D are each independently a hydrogen atom, halogen, or substituted or unsubstituted alkyl).
  • B-2 U includes -CR C R D- (wherein R C and R D are each independently a hydrogen atom or halogen).
  • B-3 U includes —CR C R D — (where R C and R D are hydrogen atoms).
  • t is an integer of 1 to 3.
  • C-1 t is an integer of 1 or 2.
  • C-2 t may be an integer of 2 or 3.
  • C-3 Examples of t include 1.
  • C-4 Examples of t include 2.
  • C-5 Examples of t include 3.
  • C-6 Examples of t include 3.
  • R A and R A ′ include substituted or unsubstituted alkyl.
  • D-1 R A and R A ′ include alkyl substituted with substituted or unsubstituted alkyloxy.
  • D-2 R A and R A ′ include alkyl substituted with alkyloxy.
  • D-3 R A and R A ′ include C2-C6 alkyl substituted with substituted or unsubstituted C1-C3 alkyloxy.
  • R A and R A ′ include C2-C6 alkyl substituted with C1-C3 alkyloxy.
  • Examples of R A include substituted or unsubstituted alkyl.
  • Examples of RA include alkyl substituted with substituted or unsubstituted alkyloxy.
  • Examples of RA include alkyl substituted with substituted or unsubstituted alkyloxy.
  • D-7 RA includes alkyl substituted with alkyloxy.
  • D-8 RA includes C2-C6 alkyl substituted with substituted or unsubstituted C1-C3 alkyloxy.
  • RA includes C2-C6 alkyl substituted with C1-C3 alkyloxy.
  • R A ′ examples include substituted or unsubstituted alkyl.
  • R A ′ includes alkyl substituted with substituted or unsubstituted alkyloxy.
  • R A ′ includes alkyl substituted with alkyloxy.
  • R A ′ includes C2-C6 alkyl substituted with substituted or unsubstituted C1-C3 alkyloxy.
  • D-14 R A ′ includes C2-C6 alkyl substituted with C1-C3 alkyloxy.
  • the R B include halogen. (Hereafter referred to as F-1)
  • n is an integer of 0 to 3.
  • G-1 n is an integer of 0 to 2.
  • G-2 n may be 0.
  • G-3 As n, 1 is mentioned.
  • G-4 n may be 2.
  • Ring C includes a substituted or unsubstituted aromatic heterocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring.
  • E-1 Ring C includes a substituted or unsubstituted aromatic heterocycle.
  • E-2 Ring C includes substituted or unsubstituted pyrazole.
  • E-3 Ring C includes pyrazole substituted with substituted or unsubstituted phenyl.
  • Ring C includes pyrazole substituted with substituted or unsubstituted alkyl.
  • Ring C includes pyrazole substituted with substituted or unsubstituted pyrazolyl.
  • E-6 As ring C, Wherein R 13 is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic carbocyclic group, and R 14 is a substituted or unsubstituted aromatic carbocyclic group.
  • An aromatic heterocyclic group a substituted or unsubstituted alkyloxy, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group, and R 15 is a hydrogen atom, substituted or unsubstituted Substituted alkyl or halogen).
  • E-7 As ring C, (Where R 13 is a substituted or unsubstituted aromatic carbocyclic group, R 14 is a substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alkyloxy, and R 15 is substituted. Or unsubstituted alkyl).
  • E-8 As ring C, (Where R 13 is substituted or unsubstituted phenyl, R 14 is substituted or unsubstituted pyrazolyl, and R 15 is substituted or unsubstituted alkyl).
  • E-9 As ring C, (Where R 13 is substituted or unsubstituted phenyl, R 14 is pyrazolyl or unsubstituted pyrazolyl substituted with C1-C3 alkyl or C1-C3 haloalkyl, and R 15 is substituted or unsubstituted alkyl. .).
  • R 13 is substituted or unsubstituted phenyl
  • R 14 is pyrimidyl or unsubstituted pyrimidyl substituted with alkyloxy, alkyl or hydroxyalkyl
  • R 15 is substituted or unsubstituted alkyl. .).
  • R 13 is unsubstituted phenyl
  • R 14 is pyrimidyl substituted with methyloxy, ethyloxy, methyl or hydroxymethyl
  • R 15 is unsubstituted C1-C3 alkyl. It is done.
  • the compound of formula (I) or formula (IA) is not limited to a specific isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer) Isomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) or formula (IA) may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
  • Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I) or the formula (IA) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by formula (I) or formula (IA).
  • a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
  • the radiolabeled compound of the compound represented by formula (I) or formula (IA) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) or the formula (IA) is introduced into the specific compound represented by the formula (I) or the formula (IA) by a catalytic dehalogenation reaction using tritium.
  • This method comprises a precursor and tritium in which the compound of formula (I) or formula (IA) is appropriately halogenated in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. It includes reacting with a gas.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) or the formula (IA) include a compound represented by the formula (I) or the formula (IA) and an alkali metal (for example, lithium, sodium, potassium). Etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanol) Amines, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acid salts, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic Acids (e.g.
  • solvate for example, hydrate etc.
  • co-crystal and / or a crystal polymorph a co-crystal and / or a crystal polymorph.
  • the present invention also encompasses such various solvates, co-crystals and crystal polymorphs.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I) or the formula (IA).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing the compound represented by formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof.
  • “Co-crystal” means that the compound or salt represented by formula (I) or formula (IA) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules. .
  • the compound represented by the formula (I) or the formula (IA) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is hydrolyzed by a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted to a compound represented by formula (I) or formula (IA), gastric acid, etc. The compound etc.
  • the compound represented by formula (I) or formula (IA) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable acid anhydride, Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl chloride, a suitable sulfonyl anhydride and mixed anhydride, or by reacting with a condensing agent.
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl chloride, a suitable sulfonyl anhydride and mixed anhydride, or by reacting with a condensing agent.
  • a general synthesis method of the compound of the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds. Extraction, purification, and the like may be performed by ordinary processing performed in organic chemistry experiments.
  • the compound represented by the general formula (I) of the present invention can be produced, for example, by the following synthesis route.
  • Compound (A-3) can be obtained by reacting compound (A-1) with compound (A-2) in the presence of pyrrolidine.
  • Compound (A-1) is commercially available or can be synthesized by a known method.
  • Compound (A-2) is commercially available or can be synthesized by a known method.
  • 1-3 mole equivalents can be used with respect to (A-1).
  • Pyrrolidine can be used in an amount of 1 to 1.5 molar equivalents relative to compound (A-1).
  • the reaction temperature is ⁇ 20 ° C.
  • Compound (A-5) can be obtained by reacting compound (A-3) with compound (A-4) in the presence of an acid and a reducing agent.
  • Compound (A-4) is commercially available or can be synthesized by a known method. It can be used at 1 to 3 molar equivalents relative to (A-3).
  • the acid include acetic acid and the like, and can be used at 1 to 3 molar equivalents relative to (A-3).
  • the reaction temperature is 0 ° C.
  • Compound (A-7) can be obtained by reacting compound (A-5) with compound (A-6) in the presence of a base.
  • Compound (A-6) is commercially available or can be synthesized by a known method. It can be used at 1 to 3 molar equivalents relative to (A-5).
  • the base include lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and can be used at 1 to 3 molar equivalents relative to (A-5).
  • the reaction temperature is -78 ° C to -45 ° C, preferably -78 ° C to -65 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • Examples of the reaction solvent include tetrahydrofuran and the like.
  • Examples of the reagent used for the Curtius rearrangement include DPPA and the like, and can be used at 1 to 5 molar equivalents relative to (A-8). Benzyl alcohol can be used at 1 to 10 molar equivalents relative to (A-8).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from 50 to 100 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include toluene, xylene and the like, and they can be used alone or in combination.
  • Step 6 Compound (A-10) can be obtained by reacting compound (A-9) with a reducing agent.
  • Examples of the reducing agent include borane-THF complex and lithium aluminum hydride.
  • the reducing agent can be used at 1 to 5 molar equivalents relative to (A-9).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from 50 ° C. to the reflux temperature of the solvent.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • Examples of the reaction solvent include tetrahydrofuran and the like.
  • Step 7) Compound (A-11) can be obtained by deprotecting the amine protecting group of compound (A-10) obtained in the above Step 6. For example, the method described in the above document A can be used.
  • Compound (IA) can be obtained by reacting compound (A-11) with compound (A-12) in the presence of a base.
  • Compound (A-12) can be synthesized by the method described in WO2012 / 158413. 1 to 1.5 molar equivalents can be used with respect to compound (A-11).
  • the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, and the like, and 1 to 5 molar equivalents can be used with respect to compound (A-11).
  • the reaction temperature is 0 ° C. to the reflux temperature of the solvent, preferably room temperature to 50 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include dichloromethane, chloroform, THF, toluene, DMF, DMSO, dioxane and the like, and these can be used alone or in combination.
  • Compound (B-2) can be obtained by reacting compound (B-1) with 2-methylpropane-2-sulfinamide in the presence of a dehydrating agent.
  • Compound (B-1) is commercially available or can be synthesized by a known method.
  • 2-Methylpropane-2-sulfinamide can be used in an amount of 1 to 1.5 molar equivalents with respect to compound (B-1).
  • the dehydrating agent include magnesium sulfate and copper sulfate, and can be used at 1 to 3 molar equivalents relative to (B-1).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably room temperature to 50 ° C.
  • the reaction time is 12 to 96 hours, preferably 24 to 48 hours.
  • Examples of the reaction solvent include chloroform, dichloromethane, toluene and the like, and these can be used alone or in combination.
  • Compound (B-3) can be obtained by reacting compound (B-2) with ethynyltrimethylsilane in the presence of a base. Ethynyltrimethylsilane can be used at 1 to 3 molar equivalents relative to (B-2).
  • Examples of the base include lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide and the like, and can be used at 1 to 3 molar equivalents relative to (B-2).
  • the reaction temperature is -78 ° C to 40 ° C, preferably -78 ° C to room temperature.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • Examples of the reaction solvent include tetrahydrofuran, hexane, toluene and the like, and they can be used alone or in combination.
  • Compound (B-4) can be obtained by reacting compound (B-3) with TBAF.
  • TBAF can be used at 1 to 3 molar equivalents relative to (B-3).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably room temperature to 50 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • Examples of the reaction solvent include tetrahydrofuran and the like.
  • Compound (B-5) can be obtained by subjecting compound (B-4) to a catalytic hydrogenation reaction in the presence of quinoline and Lindlar catalyst.
  • Quinoline can be used in an amount of 0.01 to 0.1 molar equivalents relative to (B-4).
  • the Lindlar catalyst can be used in an amount of 0.01 to 0.1 molar equivalents relative to (B-4).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably room temperature to 50 ° C.
  • the reaction time is 0.5 to 72 hours, preferably 0.5 to 24 hours.
  • the reaction solvent include tetrahydrofuran, methanol, ethyl acetate and the like, and these can be used alone or in combination.
  • Compound (B-6) can be obtained by reacting compound (B-5) with an acid.
  • the acid include hydrochloric acid (dioxane solution), trifluoroacetic acid and the like, and 3 to 20 molar equivalents can be used with respect to (B-5).
  • the reaction temperature is ⁇ 20 ° C.
  • Step 6 Compound (B-7) can be obtained by reacting compound (B-6) with di-tert-butyl dicarbonate in the presence of a base. Di-tert-butyl dicarbonate can be used at 1 to 2 molar equivalents relative to (B-6). Examples of the base include sodium carbonate and potassium carbonate, and 1 to 10 molar equivalents can be used with respect to (B-6).
  • the reaction temperature is ⁇ 20 ° C.
  • Step 7 Compound (B-8) can be obtained by reacting compound (B-7) with 9-borabicyclo [3.3.1] nonane and then treating with sodium hydroxide and aqueous hydrogen peroxide.
  • 9-borabicyclo [3.3.1] nonane can be used at 1 to 3 molar equivalents relative to (B-7).
  • Sodium hydroxide can be used at 5 to 10 molar equivalents relative to (B-7).
  • the hydrogen peroxide solution can be used in an amount of 5 to 150 molar equivalents relative to (B-7).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably ⁇ 20 ° C. to room temperature.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours. Examples of the reaction solvent include tetrahydrofuran, water and the like, and these can be used alone or in combination.
  • Compound (B-9) can be obtained by reacting compound (B-8) with triphenylphosphine and iodine in the presence of imidazole. Triphenylphosphine can be used at 1 to 2 molar equivalents relative to (B-8).
  • Iodine can be used at 1 to 2 molar equivalents relative to (B-8).
  • Imidazole can be used at 1 to 3 molar equivalents relative to (B-8).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably ⁇ 20 ° C. to room temperature.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours. Examples of the reaction solvent include dichloromethane, tetrahydrofuran, toluene and the like, and these can be used alone or in combination.
  • Compound (B-10) can be obtained by reacting compound (B-9) with sodium nitrite. Sodium nitrite can be used at 1 to 10 molar equivalents relative to (B-9).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably ⁇ 20 ° C. to room temperature.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include DMF, NMP and the like, and these can be used alone or in combination.
  • Compound (B-11) can be obtained by deprotecting the amine protecting group of compound (B-10) obtained in the above Step 9.
  • the method described in the above document A can be used.
  • Compound (B-13) can be obtained by reacting compound (B-11) with compound (B-12) in the presence of a dehydrating agent and a base.
  • Compound (B-12) can be commercially available or synthesized by a known method, and can be used at 1 to 2 molar equivalents relative to (B-11).
  • the dehydrating agent include magnesium sulfate and sodium sulfate, and 1 to 3 mole equivalents can be used with respect to (B-11).
  • the base include triethylamine, diisopropylethylamine and the like, and the base can be used in an amount of 0.1 to 3 mol equivalent to (B-11).
  • the reaction temperature is from ⁇ 20 ° C. to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent.
  • the reaction time is 0.5 to 96 hours, preferably 0.5 to 24 hours.
  • reaction solvent examples include dichloromethane, toluene and the like, and they can be used alone or in combination.
  • Compound (B-15) can be obtained by reacting compound (B-13) with compound (B-14) in the presence of a base.
  • Compound (B-14) can be commercially available or synthesized by a known method, and can be used in an amount of 1 to 5 mole equivalents relative to (B-13).
  • Examples of the base include triethylamine and diisopropylethylamine, and the base can be used in an amount of 1 to 10 mol equivalent to (B-13).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably 0 ° C. to the reflux temperature of the solvent.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 5 hours.
  • the reaction solvent include toluene, dichloromethane, acetonitrile and the like, and these can be used alone or in combination.
  • Compound (B-16) can be obtained by reacting compound (B-15) with a second generation Grubbs catalyst.
  • the second generation Grubbs catalyst can be used in an amount of 0.01-0.1 mole equivalent to (B-16).
  • the reaction temperature is 50 ° C. to the reflux temperature of the solvent, preferably 80 ° C. to the reflux temperature of the solvent.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent examples include toluene, xylene and the like, and they can be used alone or in combination.
  • Compound (B-17) can be obtained by reacting compound (B-16) with zinc in the presence of ammonium chloride. Zinc can be used in an amount of 5 to 20 mole equivalents relative to (B-16). Ammonium chloride can be used in an amount of 10 to 100 mole equivalents relative to (B-16).
  • the reaction temperature is from ⁇ 20 ° C. to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • the reaction solvent examples include methanol, ethanol, tetrahydrofuran and the like, and these can be used alone or in combination.
  • the compound (B-18) can be obtained by stirring the compound (B-17) in the presence of a catalyst in a hydrogen atmosphere.
  • the catalyst include palladium-carbon, platinum oxide, palladium hydroxide and the like, and it can be used in an amount of 0.01 to 0.1 mole equivalent to (B-18).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50 ° C.
  • the reaction time is 0.5 to 96 hours, preferably 0.5 to 18 hours.
  • Step 16 Compound (IB) can be obtained from Compound (B-18) obtained in Step 15 above according to Step 8 of Method A above.
  • Compound (C-2) can be obtained by protecting the hydroxyl group of compound (C-1) which can be synthesized commercially or by a known method with a THP group. For example, the method described in the above document A can be used.
  • Compound (C-4) can be obtained by treating compound (C-2) with magnesium and iodine and then reacting with compound (C-3). Magnesium can be used at 1 to 2 molar equivalents relative to (C-2).
  • Iodine can be used in an amount of 0.001 to 0.01 molar equivalents relative to compound (C-2).
  • Compound (C-3) is commercially available or can be synthesized by a known method.
  • the base can be used at 1 to 5 molar equivalents relative to compound (C-2).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably 0 ° C. to 60 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 2 hours. Examples of the reaction solvent include THF.
  • Compound (C-5) can be obtained by reacting compound (C-4) with p-toluenesulfonyl chloride in the presence of a base.
  • Paratoluenesulfonyl chloride can be used at 1 to 3 molar equivalents relative to (C-4).
  • the base include triethylamine, pyridine and the like, and 1 to 3 molar equivalents can be used with respect to (C-4).
  • DMAP can be added in an amount of 0.01 to 0.1 mole equivalent.
  • the reaction temperature is ⁇ 20 ° C. to room temperature, preferably ⁇ 10 ° C. to 10 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include dichloromethane and dichloroethane.
  • Compound (C-6) can be obtained by deprotecting the THP group of compound (C-5) obtained in Step 3 above.
  • Compound (C-7) can be obtained by treating compound (C-6) with manganese dioxide.
  • Manganese dioxide can be used at 5 to 30 molar equivalents relative to (C-6).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from room temperature to 50 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. Examples of the reaction solvent include dichloromethane and the like.
  • the compound (C-8) can be obtained from the compound (C-7) obtained in the step 5 and the compound (B-11) obtained in the step 10 of the method B according to the step 11 of the method B. .
  • Step 7 Compound (C-9) can be obtained from Compound (C-8) obtained in Step 6 above according to Step 14 of Method B above.
  • Step 8 Compound (IC) can be obtained from compound (C-9) obtained in the above step 7 according to step 8 of the above-mentioned Method A.
  • Compound (D-2) can be obtained by reacting compound (D-1) with an acrylate ester in the presence of a palladium catalyst and a base. Ligand can also be added.
  • Compound (D-1) is commercially available or can be synthesized by a known method.
  • the palladium catalyst include palladium acetate, bis (tri-tert-butylphosphine) palladium, and the like, and 0.01 to 0.1 molar equivalent can be used with respect to compound (D-1).
  • Examples of the ligand include triphenylphosphine, tri (o-tolyl) phosphine, and the like, and it can be used at 0.02 to 0.2 molar equivalent relative to compound (D-1).
  • Examples of the base include triethylamine, potassium carbonate, sodium acetate and the like, and the base can be used at 1 to 5 molar equivalents relative to the compound (D-1).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from 80 ° C. to the reflux temperature of the solvent.
  • the reaction time is 1 to 96 hours, preferably 3 to 12 hours.
  • Examples of the reaction solvent include N-methylpyrrolidone and dimethylacetamide, which can be used alone or in combination.
  • Compound (D-4) can be obtained by reacting compound (D-2) with compound (D-3) in the presence of a rhodium catalyst and a base.
  • Compound (D-3) is commercially available or can be synthesized by a known method. It can be used at 1 to 3 molar equivalents relative to (D-2).
  • the rhodium catalyst include chloro (1,5-cyclooctadiene) rhodium dimer, and the like can be used in an amount of 0.01 to 0.1 molar equivalents relative to (D-2).
  • the reaction temperature is room temperature to 120 ° C, preferably 40 to 80 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 1 to 5 hours.
  • reaction solvent examples include methanol, ethanol and the like, and these can be used alone or in combination.
  • Compound (D-5) can be obtained by treating compound (D-4) with a base.
  • the base include lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and can be used at 1 to 3 molar equivalents relative to (D-4).
  • the reaction temperature is -78 ° C to room temperature, preferably -20 to 0 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • the reaction solvent include tetrahydrofuran and the like.
  • Compound (D-6) can be obtained by deprotecting the carboxylic acid protecting group of compound (D-5) obtained in Step 3 above.
  • the method described in the above document A can be used.
  • the carboxyl group of the compound (D-6) obtained in the above step 4 is converted to an amino group by Curtius rearrangement.
  • the reagent used for the Curtius rearrangement include DPPA, and can be used at 1 to 5 molar equivalents relative to (D-6).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from 50 to 100 ° C.
  • the reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • reaction solvent 2- (trimethylsilyl) ethanol, t-BuOH, benzyl alcohol, or the like can be used.
  • Toluene, benzene or the like can also be used as a reaction solvent.
  • the carbamate can be obtained by adding the alcohol.
  • the alcohol can be used at 1 to 5 molar equivalents relative to (D-6).
  • the obtained carbamate can be deprotected according to the method described in the above-mentioned document A and the like to obtain compound (D-7).
  • Step 6 Compound (ID) can be obtained from Compound (D-7) obtained in Step 5 above according to Step 8 of Method A above.
  • Compound (E-3) can be obtained by reacting compound (E-1) with compound (E-2) in the presence of a catalyst.
  • Compound (E-1) is commercially available or can be synthesized by a known method.
  • Compound (E-2) can be commercially available or synthesized by a known method, and can be used at 1 to 3 mole equivalents relative to (E-1).
  • the catalyst includes 3,5-di-tert-butyl-N ((S-((1S, 2S, 4S, 5R) -5-methylquinuclidin-2-yl) (6-methylquinolin-4-yl ) Methyl) benzamide and the like, and 0.05 to 0.15 molar equivalent can be used with respect to (E-1).
  • the reaction temperature is 0 ° C. to the reflux temperature of the solvent, preferably room temperature to 50 ° C.
  • the reaction time is 12 to 96 hours, preferably 24 to 48 hours. Examples of the reaction solvent include toluene.
  • Compound (E-4) can be obtained by reacting compound (E-3) with Raney nickel.
  • Raney nickel can be used at 1 to 5 molar equivalents relative to (E-3).
  • the reaction temperature is from ⁇ 20 ° C. to the reflux temperature of the solvent, preferably from room temperature to the reflux temperature of the solvent.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • Examples of the reaction solvent include tetrahydrofuran, methanol, ethanol and the like, and these can be used alone or in combination.
  • Compound (E-5) can be obtained by reacting compound (E-4) with di-tert-butyl dicarbonate in the presence of a base. Di-tert-butyl dicarbonate can be used at 1 to 2 molar equivalents relative to (E-4).
  • Examples of the base include sodium carbonate and potassium carbonate, and 1 to 10 molar equivalents can be used with respect to (E-4).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably room temperature to 50 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include tetrahydrofuran, dichloromethane, methanol, water and the like, and these can be used alone or in combination.
  • Compound (E-6) can be obtained by reacting compound (E-5) with a reducing agent.
  • Examples of the reducing agent include lithium aluminum hydride and lithium borohydride. The reducing agent can be used at 1 to 3 molar equivalents relative to (E-5).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably 0 ° C. to 50 ° C.
  • the reaction time is 0.5 to 72 hours, preferably 0.5 to 24 hours.
  • Examples of the reaction solvent include tetrahydrofuran and the like.
  • Compound (E-7) can be obtained by reacting compound (E-6) with 2-nitrophenyl selenocyanate and tributylphosphine.
  • 2-Nitrophenyl selenocyanate can be used at 1 to 3 molar equivalents relative to (E-6).
  • Tributylphosphine can be used at 1 to 3 molar equivalents relative to (E-6).
  • the reaction temperature is ⁇ 20 ° C.
  • Step 6 Compound (E-8) can be obtained by reacting compound (E-7) with a peroxide.
  • the peroxide include aqueous hydrogen peroxide and metachloroperbenzoic acid, and 5 to 30 molar equivalents can be used with respect to (E-7).
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 72 hours, preferably 0.5 to 18 hours.
  • reaction solvent examples include tetrahydrofuran and the like.
  • Step 7 Compound (E-9) can be obtained by deprotecting the amine protecting group of compound (E-8) obtained in the above Step 6.
  • the method described in the above document A can be used.
  • Step 8) Compound (E-10) can be obtained from compound (E-9) obtained in the above Step 7 according to Step 8 of Method A above.
  • Step 9) Compound (E-11) can be obtained by reacting compound (E-10) with potassium osmium (VI) dihydrate in the presence of a reoxidant. Osmium (VI) potassium dihydrate can be used in an amount of 0.01 to 0.1 molar equivalents relative to (E-10).
  • Examples of the reoxidizing agent include NMO and can be used at 1 to 3 molar equivalents relative to (E-10).
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 72 hours, preferably 0.5 to 18 hours.
  • Examples of the reaction solvent include tetrahydrofuran, acetone, t-butanol, water and the like, and these can be used alone or in combination.
  • Compound (E-12) can be obtained by reacting compound (E-11) with methanesulfonyl chloride in the presence of a base. Methanesulfonyl chloride can be used at 1 to 2 molar equivalents relative to (E-11).
  • Examples of the base include triethylamine, diisopropylethylamine and the like, and 1 to 3 molar equivalents can be used with respect to (E-11).
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 72 hours, preferably 0.5 to 3 hours.
  • Examples of the reaction solvent include tetrahydrofuran, dichloromethane and the like, and these can be used alone or in combination.
  • Compound (E-13) can be commercially available or synthesized by a known method, and can be used at 1 to 5 molar equivalents relative to (E-12).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 72 hours, preferably 0.5 to 3 hours. Examples of the reaction solvent include tetrahydrofuran and DMF, and these can be used alone or in combination.
  • Compound (E-15) can be obtained by reacting compound (E-14) with magnesium under ultrasonic irradiation. Magnesium can be used at 5 to 20 molar equivalents relative to (E-14).
  • the reaction temperature is 0 ° C.
  • Step 13 Compound (E-17) can be obtained by reacting compound (E-15) with compound (E-16) in the presence of an acid and a reducing agent.
  • Compound (E-16) can be commercially available or synthesized by a known method, and can be used at 1 to 3 molar equivalents relative to (E-15).
  • the reducing agent include sodium triacetoxyborohydride and sodium cyanoborohydride. The reducing agent can be used in an amount of 1 to 10 mole equivalents relative to (E-15).
  • Examples of the acid include acetic acid and the like, and can be used in an amount of 0.1 to 1 mole equivalent to (E-15).
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include tetrahydrofuran, dichloromethane, methanol and the like, and these can be used alone or in combination.
  • Compound (IE) can be obtained by reacting compound (E-17) with sodium iodide. Sodium iodide can be used in an amount of 1-30 mol equivalent to (E-17).
  • the reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from 50 ° C to 100 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • Examples of the reaction solvent include DMF, NMP and the like, and these can be used alone or in combination.
  • Compound (F-3) can be obtained by reacting compound (F-1) with compound (F-2) in the presence of a base.
  • Compound (F-1) is commercially available or can be synthesized by a known method.
  • Compound (F-2) can be commercially available or synthesized by a known method, and can be used at 1 to 3 molar equivalents relative to (F-1).
  • Examples of the base include sodium hydride, sodium methoxide and the like, and 1 to 3 molar equivalents can be used with respect to (F-1).
  • the reaction temperature is 0 ° C. to the reflux temperature of the solvent, preferably 40 ° C. to 70 ° C.
  • the reaction time is 1 to 24 hours, preferably 2 to 8 hours.
  • Examples of the reaction solvent include tetrahydrofuran and DMF, and these can be used alone or in combination.
  • Compound (F-4) can be obtained by reacting compound (F-3) with samarium iodide. Samarium iodide can be used at 1 to 5 molar equivalents relative to (F-3).
  • the reaction temperature is ⁇ 20 ° C.
  • reaction time is 0.5 to 24 hours, preferably 0.5 to 6 hours.
  • An example of the reaction solvent is tetrahydrofuran.
  • Compound (F-5) can be obtained by reacting compound (F-4) with trimethyloxonium tetrafluoroborate and then with a reducing agent.
  • Trimethyloxonium tetrafluoroborate can be used at 1 to 2 molar equivalents relative to (F-4).
  • the reducing agent include sodium cyanoborohydride, diborane and the like, and 1 to 10 molar equivalents can be used with respect to (F-4).
  • the reaction temperature is ⁇ 20 ° C.
  • Compound (F-7) can be obtained by reacting compound (F-5) with compound (F-6) in the presence of a base.
  • Compound (F-6) can be commercially available or synthesized by a known method, and can be used at 1 to 2 molar equivalents relative to (F-5).
  • Examples of the base include diisopropylethylamine, potassium carbonate and the like, and 1 to 5 molar equivalents can be used with respect to (F-5).
  • the reaction temperature is ⁇ 20 ° C. to the reflux temperature of the solvent, preferably room temperature to 80 ° C.
  • the reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • the reaction solvent include tetrahydrofuran, acetonitrile, DMF and the like, and these can be used alone or in combination.
  • Compound (F-8) can be obtained by deprotecting the carboxylic acid protecting group of compound (F-7) obtained in Step 4 above. For example, the method described in the above document A can be used.
  • Step 6 In the presence of benzyl alcohol, compound (F-8) can be converted to compound (F-9) by Curtius rearrangement.
  • Step 7 Compound (IF) can be obtained from Compound (F-9) obtained in Step 6 above according to Steps 7 and 8 of Method A above.
  • the compound represented by the formula (I) or formula (IA) obtained by the above general synthesis method can be isolated and purified by known means (for example, chromatography, recrystallization, etc.).
  • the compound according to the present invention has a TrkA inhibitory action, pain associated with osteoarthritis, rheumatoid arthritis, fracture, interstitial cystitis, chronic pancreatitis, and prostatitis; chronic low back pain, diabetic peripheral neuropathic pain , Postoperative pain, pelvic pain, nociceptive pain typified by cancer pain, neuropathic pain, acute pain and chronic pain; and treatment of cancer, inflammatory diseases, allergic diseases and skin diseases It is useful as an agent and / or preventive agent.
  • the compound of the present invention has not only a TrkA inhibitory action but also a usefulness as a medicine, and has any or all of the following excellent features.
  • CYP enzymes for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.
  • Good pharmacokinetics such as high bioavailability and moderate clearance.
  • e Not mutagenic.
  • composition of the present invention can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • a solid preparation for internal use for example, tablets, powders, granules, capsules, pills, films, etc.
  • a liquid for internal use for example, suspension
  • Preparations, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions, tinctures, etc. may be prepared and administered.
  • the tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • injections When the pharmaceutical composition of the present invention is administered parenterally, injections, drops, external preparations (for example, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings) Any of the commonly used dosage forms such as gargle, enema, ointment, plaster, jelly, cream, patch, patch, external powder, suppository, etc.).
  • the injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
  • Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. Also, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 17 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the compound of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, route of administration, etc., but usually 0.05 to 100 mg / kg / day when administered orally. Preferably, it is within the range of 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 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the compound of the present invention is used in combination with a pain treatment agent, an anti-inflammatory agent, an anticancer agent or the like (hereinafter referred to as a concomitant drug) for the purpose of enhancing the action of the compound or reducing the dose of the compound.
  • a concomitant drug for the purpose of enhancing the action of the compound or reducing the dose of the compound.
  • Can do a pain treatment agent, an anti-inflammatory agent, an anticancer agent or the like
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • pain treatment agents examples include cyclooxygenase inhibitors (eg, ketoprofen, celecoxib), neuropathy treatment agents (eg, pregabalin), antidepressants (eg, duloxetine, amitriptyline), opioid receptor agonists (eg, morphine, Tramadol), local anesthetics (eg, lidocaine), ketamine, acetaminophen and the like.
  • neuropathy treatment agents eg, pregabalin
  • antidepressants eg, duloxetine, amitriptyline
  • opioid receptor agonists eg, morphine, Tramadol
  • local anesthetics eg, lidocaine
  • ketamine acetaminophen and the like.
  • anti-inflammatory agent examples include steroid agents (eg, prednisolone), antihistamine agents (eg, loratadine) and the like.
  • Anticancer agents include, for example, molecular targeting agents (eg, lapatinib, rituximab), alkylating agents (eg, cyclophosphamide), antimetabolites (eg, methotrexate), alkaloid agents (eg, paclitaxel), platinum Agents (eg, oxaliplatin), hormone agents (eg, tamoxifen, leuprorelin) and the like.
  • molecular targeting agents eg, lapatinib, rituximab
  • alkylating agents eg, cyclophosphamide
  • antimetabolites eg, methotrexate
  • alkaloid agents eg, paclitaxel
  • platinum Agents eg, oxaliplatin
  • hormone agents eg, tamoxifen, leuprorelin
  • Step 5 Synthesis of Compound 6 To a solution of compound 5 (801 mg, 3.65 mmol) in dichloromethane (2 mL) was added hydrochloric acid 5 mL (4 mol / L, 1,4-dioxane solution), and the mixture was stirred at room temperature. The reaction solution was concentrated to obtain compound 6 (421 mg, yield 100%).
  • Step 6 Synthesis of Compound 7 Compound 6 (5.11 g, 33.7 mmol) and sodium carbonate (17.86 g, 169 mmol) were dissolved in THF (20 mL) and water (20 mL). -Tert-Butyl (8.61 mL, 37.1 mmol) was added. The mixture was stirred at room temperature overnight.
  • Step 7 Synthesis of Compound 8 9-BBN (169 mL, 85 mmol) was added dropwise to a solution of compound 7 (6.5 g, 30.2 mmol) in THF (65 mL) under ice cooling, and the mixture was stirred at room temperature for 4 hours and a half.
  • 2 mol / L sodium hydroxide (106 mL, 211 mmol) and then 30% aqueous hydrogen peroxide (100 mL, 3263 mmol) were added under ice cooling, and the mixture was further stirred for 1.5 hours.
  • a saturated sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 9 Synthesis of Compound 10 Sodium nitrite (619 mg, 8.97 mmol) was added to a DMF (0.5 mL) solution of compound 9 (385 mg, 1.12 mmol), and the mixture was stirred at room temperature for 1 hour under light shielding. Water was added to the reaction solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 10 (197 mg, yield 67%).
  • Step 2 Synthesis of Compound 13 Under a nitrogen stream, granular magnesium (0.401 g, 16.5 mmol) and iodine (19 mg, 0.075 mmol) were mixed, and Compound 12 (4.07 g, 15 mmol) in anhydrous THF (20 mL) About 5 mL was dropped. The reaction solution was heated to 55 ° C., and after confirming the start of the reaction, the remaining THF solution of Compound 12 was added dropwise. After completion of dropping, the reaction solution was kept at 55 ° C. and stirred for 2 hours. After cooling to 0 ° C., ethylene oxide (1.1 mol / L THF solution, 54.5 mL, 60 mmol) was added dropwise.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate; 1: 1) to obtain Compound 16 as a crudely purified substance.
  • the obtained compound 16 was dissolved in methanol (55 mL) and THF (90 mL), NH 4 Cl (9.34 g, 175 mmol) and zinc powder (11.42 g, 175 mmol) were sequentially added, and the mixture was stirred at room temperature overnight.
  • the reaction solution was filtered through celite and washed with methanol, and the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of Compound 19
  • Compound 18 (1.94 g, 5.87 mmol) was dissolved in toluene (77.6 mL), and second generation Grubbs catalyst (249 mg, 0.294 mmol) was added. The mixture was stirred for 5 hours under reflux with heating in a nitrogen atmosphere. The reaction solution was removed from the oil bath, a second generation Grubbs catalyst (100 mg, 0.117 mmol) was added, and the mixture was stirred for 4.5 hours under heating and reflux in a nitrogen atmosphere. The reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 19 (918 mg, yield 52%).
  • Step 3 Synthesis of Compound 20
  • Compound 19 (59.7 mg, 0.197 mmol) was dissolved in THF (1.2 mL) and methanol (0.6 mL), and zinc (194 mg, 2.96 mmol) and sodium chloride (158 mg, 2 .96 mL) was added, and the mixture was stirred at room temperature for 9.5 hours and then allowed to stand overnight.
  • a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, the insoluble material was filtered off, and the solid was washed with ethyl acetate and water. The filtrate was extracted with ethyl acetate, and the organic layer was washed with saturated brine.
  • Step 4 Synthesis of Compound 21
  • Compound 20 (30 mg, 0.110 mmol) was dissolved in ethanol (2 mL), 10% palladium carbon (50% water-containing product, 24.8 mg, 0.005 mmol) was added, and room temperature under hydrogen atmosphere And stirred for 5.5 hours. Ethyl acetate was added to the reaction solution, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give compound 21 (23.9 mg, 79.1%).
  • Lithium aluminum hydride (4.77 mg, 0.126 mmol) was added, and the mixture was stirred for 3.5 hours under heating and reflux under a nitrogen atmosphere.
  • the reaction solution was returned to room temperature, sodium sulfate decahydrate (540 mg, 1.68 mmol) and ethyl acetate were added, and the mixture was stirred for 90 minutes.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give compound 22 (19.5 mg, 89%).
  • the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain an intermediate crude product (1.06 g, yield 107%).
  • the crude product was dissolved in THF (10 ml), 30% aqueous hydrogen peroxide solution (3.2 ml) was added under ice cooling, and the mixture was stirred for 3 days.
  • the precipitated solid was separated into a furnace, and a saturated sodium hydrogen carbonate solution (1 mol / L) was further added to the furnace liquid, followed by extraction with ethyl acetate.
  • the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate.
  • Trimethyloxonium tetrafluoroborate (212 mg, 1.43 mmol) was added and stirred overnight at room temperature.
  • the reaction solution was concentrated, dissolved in methanol (4 mL), and sodium cyanoborohydride (225 mg, 3.58 mmol) was added.
  • Bromocresol green was added as a pH indicator, and the mixture was stirred for 2 hours while appropriately adding a 2 mol / L hydrogen chloride-methanol solution to keep the reaction solution acidic.
  • Aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, and dried over anhydrous sodium sulfate.
  • Triethylamine (0.042 mL, 0.152 mmol) and Compound Y (56.8 mg, 0.152 mmol) that can be synthesized by a known method (WO2012158413) were added, and the mixture was stirred overnight at room temperature.
  • the reaction solution was directly purified by silica gel column chromatography (chloroform-methanol) to obtain compound (I-40) (racemate, 46.7 mg, yield 58%).
  • Step 2 Synthesis of Compound 59
  • the residue obtained in Step 1 above was dissolved in 1,4-dioxane (50 mL), and Compound V (the synthesis method is described in WO2012 / 158413) (5.08 g, 15.8 mmol), phosphorus Tripotassium acid (6.71 g, 31.6 mmol), XPhos aminobiphenyl palladium dichloride precatalyst (0.622 g, 0.790 mmol) and water (25 mL) were added and stirred at 90 ° C. for 4 hours. To the reaction solution was added saturated brine, and the mixture was extracted twice with ethyl acetate.
  • Test Example 1 Cell growth inhibitory activity (TF-1 assay) Human receptor genes (TrkA, TrkB, TrkC, p75) for each neurotrophic factor were introduced into TF-1 cells (ATCC Number: CRL-2003), a human erythroleukemia cell line, using retroviral vectors, Cells that stably express high levels of the receptor are produced. It should be noted that TF-1 cells introduced with TrkA and p75 were used for evaluation of inhibitory activity against NGF, TF-1 cells introduced with TrkB and p75 were used for evaluation of inhibitory activity against BDNF, and TrkC and p75 were used for evaluation of NT-3. TF-1 cells into which is introduced are used.
  • test substance (final concentration 20 ⁇ mol / L to 0.05 nmol / L) prepared in 200 nL DMSO is added to a white 384-well flat bottom plate.
  • Each TF-1 cell and each ligand in RPMI-1640 medium containing 10% fetal bovine serum were 400 TrkA and p75 expressing cells, 800 TrkC and p75 expressing cells, and 800 TrkB and p75 expressing cells per well.
  • human NGF is adjusted to a final concentration of 4 ng / mL
  • human BDNF and human NT-3 are adjusted to a final concentration of 8 ng / mL, and 40 ⁇ L is added to each well.
  • Inhibition rate (%) (1 ⁇ (Luminescence when test substance is added ⁇ Inhibitory activity 100% luminescence) / (Inhibitory activity 0% luminescence ⁇ Inhibitory activity 100% luminescence)) ⁇ 100
  • the inhibition rate was calculated for 10 points from a compound concentration of 20 ⁇ mol / L to a 3-fold dilution series of 1 nmol / L, or 10 points from 1 ⁇ mol / L to a 3-fold dilution series of 0.05 nmol / L, and an IC50 value (nmol was determined by logistic approximation). / L).
  • Test Example 1-1 Efficacy evaluation by Brennan postoperative pain model Under model anesthetized rats under anesthesia with isoflurane, the skin and fascia at the bottom of the hind limb were incised. Cut the skin with a scalpel from about 0.5 cm from the left hind limb to the tip of the foot using a scalpel, lift the plantar muscles and incise vertically with a scalpel, then cut the skin with 5-0 nylon thread. Two places were sutured. Evaluation (1) Randall-Selitto test The effect on mechanical hyperalgesia was evaluated by analgesiometer.
  • an analgesiometer was used to compress the hind limbs of the rat so that the stimulation pressure increased by 16g per second, and the pressure when the rat showed escape behavior was taken as the pain threshold. Pain thresholds were evaluated for the left and right hind limbs and used as pre-treatment pain thresholds. Animals with an operating pain threshold of 80 g or less and a preoperative pain threshold of 100 to 160 g were used. In order to train the animals, the same operation was performed before measuring the pre-treatment pain threshold. The compound of the present invention was administered to the adopted animals. The compound of the present invention was prepared as a suspension or solution and administered intravenously or subcutaneously.
  • the pain threshold value of the left and right hind limbs was evaluated and set as a post-treatment pain threshold value.
  • The% reversal value was calculated by the following method, and the analgesic action of the compounds was compared.
  • % reversal 100 ⁇ (post-treatment pain threshold minus pre-treatment pain threshold) / (pre-operative pain threshold ⁇ pre-treatment pain threshold) (result)
  • Compound I-15 31% reversal (4 mg / kg)
  • Compound I-63 33% reversal (6 mg / kg) Evaluation (2) Electric von Frey test After surgery, the effect on mechanical hyperalgesia is evaluated using an electric von Frey device.
  • the compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is prepared as a suspension or solution and administered intravenously or subcutaneously.
  • the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value.
  • the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value.
  • the compound represented by formula (I) or formula (IA) according to the present invention may be any compound that has a TrkA receptor inhibitory action and inhibits human TrkA receptor.
  • the IC50 is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.
  • Test Example 2 Measurement of chick TrkA inhibitory activity
  • a test substance final concentration 200 ⁇ M to 1 pM dissolved in 0.4 ⁇ L of DMSO was added.
  • the assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, 0.003 vol% Brij-35, 0.004 vol 7.5 ⁇ L of TrkA (TrkA, PV3144, Life Technologies, final concentration 1 nM) diluted with% Tween20 and 1 mmol / L dithiothreule] was added and pretreated at room temperature for 15 minutes.
  • HEPES 2-hydroxyethyl) -1-piperazineethanesulfonic acid
  • Fluorescently labeled substrate FL-Peptide 27, 760424, Perkin Elmer, final concentration of 1.5 ⁇ M
  • ATP final concentration of 500 ⁇ M
  • ATP final concentration of 500 ⁇ M
  • a termination buffer [100 mmol / L HEPES, 40 mmol / L ethylenediaminetetraacetic acid (EDTA), 10 mmol / L magnesium chloride, 0.003 vol% Brij-35, 0.004 vol% Tween 20, The enzyme reaction was stopped by adding 15 ⁇ L of 1 mmol / L dithiothreule and 0.16 vol% Coating Reagent 3].
  • a mobility shift assay device (LabChip EZ Reader II, Caliper Life Sciences), the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured. Was calculated.
  • the phosphorylation inhibition rate of the test substance was determined by the following formula 2 using the well added with DMSO as a solvent as a negative control and the well not added with TrkA as a positive control.
  • Phosphorylation inhibition rate (%) (1 ⁇ (conversion rate at the time of addition of test substance ⁇ conversion rate of positive control) / (conversion rate of negative control ⁇ conversion rate of positive object)) ⁇ 100 10 points from a test substance concentration of 20 nmol / L to a 3-fold dilution series of 1 pmol / L, or 10 points from 2 ⁇ mol / L to a 3-fold dilution series of 0.1 nmol / L, or 200 ⁇ mol / L to a 3-fold dilution series of 10 nmol / L
  • the inhibition rate was determined for 10 points up to L, or 15 points from 200 ⁇ mol / L to 3-fold dilution series 0.04 nmol / L, and the IC50 value (nmol / L) was calculated by the logistic approximation method.
  • the evaluation results regarding the TrkA inhibitory activity of the compounds of the present invention are shown below.
  • the IC50 value is “A” when 0 nM or more and less than 100 nM, “B” when 100 nM or more and less than 1000 nM, and “C” when 1000 nM or more.
  • hERG Test Example 3 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, ventricle using Chinese hamster ovary cells (CHO) cells expressing human ether-a-go-related gene (hERG) channels.
  • CHO Chinese hamster ovary cells
  • hERG human ether-a-go-related gene
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • a medium an extracellular solution in which the medium and the compound of the present invention are dissolved at a target concentration is applied to the cells for 7 minutes or longer at room temperature.
  • the absolute value of the maximum tail current is measured based on the current value at the holding membrane potential by using analysis software (QPatch Assay software; Sophion Bioscience A / S). Further, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the medium is calculated as an inhibition rate, and the influence of the compound of the present invention on I Kr is evaluated.
  • Test Example 4 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production amount is inhibited by the compound of the present invention is evaluated.
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points) .
  • each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, is added as an indicator for metabolic reaction.
  • NADPH a coenzyme
  • resorufin CYP1A2 metabolite
  • a fluorescent multilabel counter or LC / MS / MS
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxylated The body CYP2C19 metabolite
  • dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC 50 was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.
  • CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction regarding CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes were used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsome, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when the compound of the present invention was added at each concentration was calculated.
  • IC was calculated by inverse estimation using a logistic model. Preincubation 0 min IC / Preincubation 30 min IC was defined as the Shifted IC value, and when the Shifted IC was 1.5 or more, Positive, and when the Shifted IC was 1.0 or less, it was defined as Negative.
  • Administration method Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle. (6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS. (7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated by the moment analysis method for the plasma concentration of the compound of the present invention, and the bio of the compound of the present invention is calculated from the AUC of the oral administration group and the intravenous administration group. Calculate availability (BA).
  • Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, citrate Bacteria were suspended in sodium dihydrate: 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L, and 120 mL Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, Glucose: MicroF buffer containing 8 mg / mL).
  • TA100 strain is prepared by adding a bacterial solution adjusted within the range of 3.1 to 3.42 mL to 130 mL of Exposure medium adjusted within the range of 120 to 130 mL.
  • Compound DMSO solution of the present invention maximal dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio
  • DMSO as a negative control
  • non-metabolic activation conditions as a positive control
  • Test Example 9 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention were reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. .
  • Test Example 10 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and each container is pH 4 citrate buffer (100 mmol / L citric acid / monohydrate aqueous solution and 100 mmol / L trisodium citrate / dihydrate). Mix an appropriate amount of aqueous solution and adjust to pH 4), JP-2 solution (dissolving 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to 1000 mL, add 1 volume of water to 1 volume) ) 200 ⁇ L at a time. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing and shaking at 25 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • SPE solid phase extraction
  • JP-2 liquid composition A: Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule The compound of the present invention, lactose and calcium stearate are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are uniformly mixed, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
  • Formulation Example 4 Orally disintegrating tablet The compound of the present invention and crystalline cellulose are mixed and tableted after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 5 Dry syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
  • Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to form an injection.
  • Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to form an instillation.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to make an inhalant.
  • Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A compound of the present invention and a base such as an adhesive plaster are mixed to obtain a patch.
  • the compounds of the present invention have TrkA inhibitory activity, and diseases associated with TrkA, such as osteoarthritis, rheumatoid arthritis, fractures, interstitial cystitis, pain associated with chronic pancreatitis and prostatitis; Diabetic peripheral neuropathic pain, postoperative pain, pelvic pain, nociceptive pain typified by cancer pain, neuropathic pain, acute pain and chronic pain; and cancer, inflammatory diseases, allergic diseases It is useful for skin diseases and the like.
  • diseases associated with TrkA such as osteoarthritis, rheumatoid arthritis, fractures, interstitial cystitis, pain associated with chronic pancreatitis and prostatitis
  • Diabetic peripheral neuropathic pain, postoperative pain, pelvic pain, nociceptive pain typified by cancer pain, neuropathic pain, acute pain and chronic pain
  • cancer inflammatory diseases, allergic diseases It is useful for skin diseases and the like.

Abstract

La présente invention concerne un composé ayant une activité inhibitrice de TrkA ou un sel pharmaceutiquement acceptable du composé. La présente invention concerne : un composé représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci; et une composition pharmaceutique contenant le composé ou le sel. (Dans la formule (I), un groupe représenté par la formule (II) est un groupe de formule (A1), (A2), (A3) ou (A4) (où W représente un atome d'azote ou similaire; chacun de R A et R A' représente un groupe alkyle substitué ou non substitué ou similaire; chacun de R 3 et R 4 représente un atome d'hydrogène ou similaire; le cycle D représente un cycle benzène substitué ou non substitué ou similaire; chacun de U A , U B et U représente -O- ou similaire; t représente un nombre entier de 1 à 4; B 1 représente un groupe phényle substitué ou non substitué ou similaire; B 2 représente un groupe carbocyclique aromatique substitué ou non substitué ou similaire; et R 2 représente un atome d'hydrogène ou similaire); -Z- représente -NR 5 - ou similaire; -L- représente -C (=X)- ou similaire; -Z A - représente -NR 5 - ou similaire; = X représente = O ou similaire; chacun de R 5 et R 5A représente un atome d'hydrogène ou similaire; et le cycle C représente un cycle hétérocyclique aromatique substitué ou non substitué ou similaire.)
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CN109053446A (zh) * 2018-09-13 2018-12-21 苏州大学张家港工业技术研究院 金属氢化物/钯化合物体系在缺电子烯化合物串联反应制备1,3-二羰基化合物中的应用
WO2020056565A1 (fr) * 2018-09-17 2020-03-26 南通纺织丝绸产业技术研究院 Utilisation d'un système de composé hydrure métallique/palladium dans la préparation d'un composé 1,3-dicarbonyle dans une réaction en cascade d'un composé alcène déficient en électrons
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
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CN108976122A (zh) * 2018-09-13 2018-12-11 南通纺织丝绸产业技术研究院 基于金属氢化物/钯化合物体系制备1,3-二羰基化合物的方法
CN109053446A (zh) * 2018-09-13 2018-12-21 苏州大学张家港工业技术研究院 金属氢化物/钯化合物体系在缺电子烯化合物串联反应制备1,3-二羰基化合物中的应用
CN109053446B (zh) * 2018-09-13 2021-01-01 苏州大学张家港工业技术研究院 金属氢化物/钯化合物体系在缺电子烯化合物串联反应制备1,3-二羰基化合物中的应用
CN108976122B (zh) * 2018-09-13 2021-01-12 南通纺织丝绸产业技术研究院 基于金属氢化物/钯化合物体系制备1,3-二羰基化合物的方法
WO2020056565A1 (fr) * 2018-09-17 2020-03-26 南通纺织丝绸产业技术研究院 Utilisation d'un système de composé hydrure métallique/palladium dans la préparation d'un composé 1,3-dicarbonyle dans une réaction en cascade d'un composé alcène déficient en électrons
US11795132B2 (en) 2018-09-17 2023-10-24 Soochow University Application of metal hydride/palladium compound system in preparation of 1,3-dicarbonyl compound in cascade reaction of electron-deficient alkene compound
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation

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