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WO2015064714A1 - 1-substituted imidazopyrimidinone derivative having autotaxin-inhibiting activity - Google Patents

1-substituted imidazopyrimidinone derivative having autotaxin-inhibiting activity Download PDF

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Publication number
WO2015064714A1
WO2015064714A1 PCT/JP2014/078963 JP2014078963W WO2015064714A1 WO 2015064714 A1 WO2015064714 A1 WO 2015064714A1 JP 2014078963 W JP2014078963 W JP 2014078963W WO 2015064714 A1 WO2015064714 A1 WO 2015064714A1
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Prior art keywords
substituted
unsubstituted
aromatic heterocyclic
aromatic
group
Prior art date
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PCT/JP2014/078963
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French (fr)
Japanese (ja)
Inventor
哲雄 長野
岡部　隆義
宏建 小島
充康 川口
理 濡木
隆一郎 石谷
弘志 西増
青木　淳賢
遠藤　毅
佑介 舘野
泰彦 神田
直也 浅田
千明 藤越
俊博 和田
田中　伸幸
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Tohoku University NUC
Shionogi and Co Ltd
University of Tokyo NUC
Original Assignee
Tohoku University NUC
Shionogi and Co Ltd
University of Tokyo NUC
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Publication of WO2015064714A1 publication Critical patent/WO2015064714A1/en
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Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an imidazopyrimidinone derivative having autotaxin inhibitory activity, and a pharmaceutical comprising the imidazopyrimidinone derivative as an active ingredient.
  • Lysophosphatidic acid is a lipid mediator that exhibits various functions such as cell proliferation, intracellular calcium influx, cytoskeletal changes, and cell migration, and is a G protein-coupled receptor expressed on the surface of cell membrane ( Information is transmitted through LPA1-6). It has been reported that this lipid is involved in biological abnormalities such as fibrosis, pain, cancer, inflammation, arteriosclerosis (Non-patent Document 1).
  • LPA can be biosynthesized by several metabolic routes, but the main route is that lysophosphatidylcholine is produced by hydrolysis by autotaxin (ENPP2, ATX).
  • ATX is also called ENPP2 be secretory proteins belonging to ENPP (E cto n ucleotide p yrophosphatase and p hosphodiesterase) Family (ENPP1-7), among the family, LPA production in a lysophospholipase D activity Only ATX is involved. It has been reported that inhibiting the enzyme activity of ATX to suppress the production of LPA is effective in treating fibrotic diseases (Non-patent Document 1).
  • Fibrosis can occur in any tissue, but can progress by a common mechanism, regardless of the type of trigger for its onset.
  • structures and structures of animal tissues and organs are maintained by fibers such as collagen.
  • fibers such as collagen.
  • the tissues are damaged in some way, they are restored to the original tissues by a wound healing process accompanied by collagen production.
  • excessive fibrous connective tissue accumulation may occur.
  • Such accumulation of connective tissue is irreversible, and when fibers increase abnormally, a fibrotic disease is caused in which tissues and organs do not function normally.
  • pathological features of chronic kidney disease include glomerular and tubulointerstitial fibrosis.
  • the pathological features of end stage renal failure are markedly parenchymal cell loss and fibrosis. It is known that patients who show tubulointerstitial fibrosis in patients with chronic kidney disease progress more rapidly in renal function deterioration than patients who do not show fibrosis.
  • Patent Document 1 discloses an imidazopyrimidinone derivative having an inhibitory action on gonadotropin-releasing hormone, but does not describe anything about whether the compound has an inhibitory action on autotaxin or a therapeutic agent for chronic kidney disease. There is no suggestion.
  • Patent Documents 2 to 15 describe polycyclic compounds having an autotaxin inhibitory effect, but do not describe or suggest any imidazopyrimidinone derivatives of the present application.
  • Patent Documents 16 to 23 describe monocyclic compounds having an autotaxin inhibitory activity, but do not describe or suggest any imidazopyrimidinone derivatives of the present application.
  • Non-Patent Document 2 describes monocyclic and polycyclic compounds having an autotaxin inhibitory effect, but does not describe or suggest any imidazopyrimidinone derivatives of the present application.
  • An object of the present invention is to provide a novel imidazopyrimidinone derivative having excellent autotaxin inhibitory activity.
  • R 1 , R 2 , R 3 And R 4 are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic
  • An autotaxin inhibitor characterized by comprising: (2) Formula (I): (Where R 1 , R 2 And R 3 Are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic
  • R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or
  • R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted
  • R 1 Is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group ( 2) to (5) or a pharmaceutically acceptable salt thereof.
  • R 1 Is substituted with one or more substituents selected from substituent group A (alkylcarbonyloxy, alkyloxycarbonyl and aromatic carbocyclic group), and one or more substituents selected from substituent group A Alkenyl substituted with, alkynyl substituted with one or more substituents selected from substituent group A, substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted Substituted with one or more substituents selected from alkyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl) Aromatic carbocyclic group, non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group B, 1 selected from substituent group B (2) to (5) above, which is a non-arar
  • R 2 Is hydrogen, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, or substituted or unsubstituted alkynyl
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (8), which is carbonyl.
  • R 2 Or a pharmaceutical product thereof according to any one of (2) to (8) above, wherein is hydrogen, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted alkyloxycarbonyl Acceptable salt.
  • R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (10), wherein is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
  • R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (10), wherein is hydrogen or substituted or unsubstituted alkyl.
  • R 4 Is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy
  • R 4 Is substituted group D (halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl and An alkyl substituted with one or more substituents selected from substituted or unsubstituted aromatic carbocyclic sulfonyl), an alkenyl substituted with one or more substituents selected from substituent group D, from substituent group D Alkyloxy substituted with one or more selected substituents, non-aromatic carbon substituted with one or
  • R 4 Is substituted group D ′ (substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted Alkyloxy substituted with one or more substituents selected from aromatic heterocyclic groups), alkenyloxy substituted with one or more substituents selected from substituent group D ′, from substituent group D ′
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (12), which is alkynyloxy substituted with one or more selected substituents.
  • a pharmaceutical composition comprising the compound according to any one of (2) to (15) above or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a method for treating or preventing a disease involving autotaxin which comprises administering the compound according to any one of (2) to (15) above or a pharmaceutically acceptable salt thereof.
  • R 1 , R 2 , R 3 And R 4 are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted
  • An autotaxin inhibitor characterized by comprising: (2 ′) Formula (I): (Where R 1 , R 2 And R 3 Are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carb
  • R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy,
  • R 5 The compound or a pharmaceutically acceptable salt thereof according to (2 ′) above, wherein is substituted or unsubstituted C5-C10 alkyl, substituted or unsubstituted C4-C10 alkenyl, or substituted or unsubstituted alkynyl.
  • R 5 The compound or a pharmaceutically acceptable salt thereof according to (2 ′) above, wherein is C4-C10 alkyl substituted with halogen or cyano, substituted or unsubstituted C4-C10 alkenyl or substituted or unsubstituted alkynyl.
  • R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted
  • the compound or a pharmaceutically acceptable salt thereof according to any one of (2 ′) to (5 ′) above, which is a substituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 1 Is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group ( 2 ') to (5') or a pharmaceutically acceptable salt thereof.
  • R 1 An alkyl substituted with one or more substituents selected from substituent group A (alkylcarbonyloxy, alkyloxycarbonyl and aromatic carbocyclic group), one or more substituents selected from substituent group A Substituted alkenyl, alkynyl substituted with one or more substituents selected from substituent group A, substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl Aromatic substituted with one or more substituents selected from oxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted carbamoyl) A non-aromatic carbocyclic group substituted with one or more substituents selected from a carbocyclic group, substituent group B, one or more selected from substituent group B Or a non-aromatic hetero
  • R 1 Is substituted with a substituent group C (hydroxy, carboxy, carboxyalkyl, carboxyalkyloxy, alkylcarbonylamino, non-aromatic heterocyclic alkylaminocarbonyl, alkylsulfonyloxy, unsubstituted non-aromatic heterocyclic group and non-substituted with oxo.
  • Non-aromatic carbocyclic group substituted with one or more substituents selected from aromatic heterocyclic groups aromatic carbocyclic substituted with one or more substituents selected from substituent group C Group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group C, or an aromatic heterocyclic group substituted with one or more substituents selected from substituent group C
  • aromatic carbocyclic substituted with one or more substituents selected from substituent group C a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group C
  • an aromatic heterocyclic group substituted with one or more substituents selected from substituent group C The compound or a pharmaceutically acceptable salt thereof according to any one of (2 ′) to (5 ′) above.
  • R 2 Is hydrogen, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, or substituted or unsubstituted alkynyl
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (9 ′), which is carbonyl.
  • (11 ') R 2 Or a compound thereof according to any one of (2 ′) to (9 ′) above, wherein is hydrogen, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted alkyloxycarbonyl Pharmaceutically acceptable salt.
  • (12 ') R 3 Or a pharmaceutically acceptable compound thereof according to any one of (2 ′) to (11 ′) above, wherein is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl salt.
  • R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (11 ′), wherein is hydrogen or substituted or unsubstituted alkyl.
  • R 4 Is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy
  • R 4 Is substituted group D (halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl and An alkyl substituted with one or more substituents selected from substituted or unsubstituted aromatic carbocyclic sulfonyl), an alkenyl substituted with one or more substituents selected from substituent group D, from substituent group D Alkyloxy substituted with one or more selected substituents, non-aromatic carbon substituted with
  • R 4 Is substituted group D ′ (substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted Alkyloxy substituted with one or more substituents selected from aromatic heterocyclic groups), alkenyloxy substituted with one or more substituents selected from substituent group D ′, from substituent group D ′
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (13 ′), which is alkynyloxy substituted with one or more selected substituents.
  • (17 ′) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (2 ′) to (16 ′) or a pharmaceutically acceptable salt thereof.
  • (18 ′) The pharmaceutical composition according to the above (17 ′), which is an autotaxin inhibitor.
  • (19 ′) The pharmaceutical composition according to the above (17 ′) for the prevention or treatment of a disease involving autotaxin.
  • (20 ′) Use of the compound according to any one of (2 ′) to (16 ′) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving autotaxin. .
  • 21 ′) A method for treating or preventing a disease involving autotaxin, which comprises administering the compound according to any one of (2 ′) to (16 ′) or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention exhibits autotaxin inhibitory activity, and is a drug, particularly diseases involving autotaxin, such as urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or pulmonary fibrosis, scleroderma, pain, Fibromyalgia, rheumatoid arthritis, angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis, eye disease, choroidal neovascularization and diabetic retinopathy, inflammatory disease, arthritis, neurodegeneration, restenosis, wound healing It is very useful as a medicament for the treatment or prevention of transplant rejection, multiple sclerosis or endometriosis.
  • diseases involving autotaxin such as urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or pulmonary fibrosis, scleroderma, pain, Fibromyalgia, rheumatoid arthritis, angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis,
  • Halogen includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable. “Halogen” in R 4 includes chlorine.
  • Alkyl means a straight or branched hydrocarbon group having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like.
  • Alkyl in R 1 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl, ethyl, and n-propyl are preferable.
  • Alkyl in R 2 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl is preferred.
  • Alkyl in R 3 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl, ethyl and the like are preferable.
  • Alkyl in R 4 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl, ethyl, propyl and the like are preferable.
  • alkyl in R 5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isohexyl, n -Hexyl, n-heptanyl, n-octanyl and the like.
  • methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl are preferable, and n-pentyl, n-hexyl and the like are more preferable.
  • alkyl part of “alkyloxy”, “alkylthio”, “alkylcarbonyl”, “alkyloxycarbonyl”, “alkylsulfinyl” and “alkylsulfonyl” has the same meaning as the above “alkyl”.
  • alkyl moiety of “alkyloxy” in R 4 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyloxy, ethyloxy, n-propyloxy and isopropyloxy are preferable.
  • Haloalkyl and “haloalkyloxy” are any positions where 1 to 5 (preferably 1 to 3) of the above “halogens” can be substituted on the alkyl part of the above “alkyl” and “alkyloxy”. Means a group substituted by.
  • haloalkyl for R 5 include monohaloalkyl, dihaloalkyl, trihalomethylalkyl and the like. In particular, trifluoropropyl and the like are preferable.
  • Alkenyl means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
  • alkenyl examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl and the like.
  • propenyl, t-butylpropenyl, isobutenyl and the like are preferable.
  • alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylcarbonyl”, “alkenyloxycarbonyl”, “alkenylsulfinyl” and “alkenylsulfonyl” has the same meaning as the above “alkenyl”.
  • Alkynyl means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
  • alkynyl examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In particular, propynyl is preferred.
  • the alkynyl part of “alkynyloxy”, “alkynylthio”, “alkynylcarbonyl”, “alkynyloxycarbonyl”, “alkynylsulfinyl”, “alkynylsulfonyl” has the same meaning as the above “alkynyl”.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, a group in which one or two 3- to 8-membered rings are condensed to these cyclic saturated hydrocarbon groups, and It means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups.
  • cyclic saturated hydrocarbon group having 3 to 8 carbon atoms examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms and a cyclic saturated hydrocarbon group having 5 or 6 carbon atoms are preferable.
  • Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • the bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
  • Examples of the ring condensed with the C 3-8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring).
  • aromatic carbocycles eg, benzene ring, naphthalene ring etc.
  • non-aromatic carbocycles eg cycloalkane ring.
  • cyclohexane ring, cyclopentane ring, etc. examples include cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.)
  • the bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .
  • non-aromatic carbocyclic groups are also exemplified as non-aromatic carbocyclic groups and are included in non-aromatic carbocyclic groups. These groups may be substituted at any substitutable position.
  • non-aromatic carbocyclic group for R 1 include cycloalkyl, cycloalkenyl and the like. In particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are preferable.
  • Non-aromatic carbocyclic oxy “Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic thio”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfinyl”, “non-aromatic The non-aromatic carbocyclic moiety of “carbocycle sulfonyl” has the same meaning as the above “non-aromatic carbocycle”.
  • Examples of the “non-aromatic carbocyclic oxy” in R 4 include cycloalkyloxy and cycloalkenyloxy.
  • cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, decahydronaphthyloxy, dihydroindenyloxy and the like are preferable.
  • “Aromatic carbocyclic group” means a monocyclic or polycyclic aromatic carbocyclic group, and these monocyclic or polycyclic aromatic carbocyclic groups are further substituted with one or more 3- to 8-membered rings. It means a group condensed with two. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
  • Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • the bond is assumed to be from a monocyclic or polycyclic aromatic carbocyclic group.
  • the following groups are also exemplified as the aromatic carbocyclic group, and are included in the aromatic carbocyclic group. These groups may be substituted at any substitutable position.
  • Examples of the “aromatic carbocyclic group” for R 1 include phenyl, naphthyl, anthryl, phenanthryl and the like. In particular, phenyl is preferred.
  • Examples of the “aromatic carbocyclic group” for R 4 include phenyl, naphthyl, anthryl, phenanthryl and the like. In particular, phenyl is preferred.
  • Aromatic carbocyclic oxy "aromatic carbocyclic thio”, “aromatic carbocyclic carbonyl”, “aromatic carbocyclic oxycarbonyl”, “aromatic carbocyclic sulfinyl”, “aromatic carbocyclic sulfonyl”
  • aromatic carbocyclic moiety has the same meaning as the above “aromatic carbocycle”.
  • “Aromatic heterocyclic group” means a monocyclic or polycyclic aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these monocyclic rings Alternatively, it means a group obtained by further condensing one or two 3- to 8-membered rings on a polycyclic aromatic heterocyclic group.
  • a 5-membered or 6-membered aromatic heterocyclic group is particularly preferable, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, Examples include tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
  • an aromatic heterocyclic group in which a 5- or 6-membered ring is condensed is particularly preferable.
  • any ring may have a bond.
  • Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene). Ring, cyclopentene ring, etc.)) and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.).
  • the bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
  • the following groups are also exemplified as the aromatic heterocyclic group, and are included in the aromatic heterocyclic group. These groups may be substituted at any substitutable position.
  • Aromatic heterocyclic groups '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, isoindolyl , Indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl,
  • Examples of the “aromatic heterocyclic group” in R 1 include furyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothiophenyl, and the like. In particular, pyridyl and the like are preferable.
  • Examples of the “aromatic heterocyclic group” in R 4 include furyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothiophenyl, and the like. In particular, pyridyl and the like are preferable.
  • Non-aromatic heterocyclic group means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic rings This means a group obtained by further condensing one or two 3- to 8-membered rings to the formula group, and includes a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
  • ⁇ monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
  • polycyclic non-aromatic heterocyclic group examples include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.
  • the following groups are also included in the non-aromatic heterocyclic group.
  • non-aromatic heterocyclic group examples include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazinoyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, Examples include dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl
  • non-aromatic heterocyclic group examples include pyrrolidinyl, tetrahydrofuranyl, piperidino, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, morpholino, morpholinyl and the like. Particularly preferred is piperidinyl.
  • Non-aromatic heterocyclic oxy has the same meaning as the above “non-aromatic heterocyclic ring”.
  • non-aromatic heterocyclic oxy in R 4 , azetidinyloxy, piperidinyloxy, tetrahydropyranyloxy and the like are preferable.
  • the substituted or unsubstituted non-aromatic carbocyclic group or the substituted or unsubstituted non-aromatic heterocyclic group may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino.
  • Substituted alkyl “Substituted alkenyl”, “Substituted alkynyl”, “Substituted non-aromatic carbocyclic group”, “Substituted aromatic carbocyclic group”, “Substituted aromatic heterocyclic group” or “Substituted non-aromatic”
  • Substituents for ⁇ heterocyclic group '' include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic Carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, substituted carbamoyl, substituted sulfamoyl, substituted amidino, group represented by the formula: —O—R x , formula: —O—C ( ⁇ O ) -R
  • substituent of “substituted alkyl” in R 1 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl
  • substituent of “substituted alkyl” in R 1 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl Examples include oxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. In particular, an aromatic carbocyclic group, alkyloxycarbonyl, alkylcarbonyloxy and the like are preferable.
  • the substituent of the "substituted alkyl" for R 2 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, alkyl Examples include oxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. Aromatic carbocyclic groups are preferred, and phenyl and the like are particularly preferred.
  • substituent of “substituted alkyl” in R 3 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl
  • substituent of “substituted alkyl” in R 3 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl Examples include oxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. In particular, hydroxy, alkyloxycarbonyl and the like are preferable.
  • substituent of “substituted alkyl” in R 4 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl
  • substituent of “substituted alkyl” in R 4 halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl Examples include oxy, aromatic carbocyclic alkyloxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. In particular, hydroxy, aromatic carbocyclic alkyloxy, alkyloxycarbonyl and the like are preferable.
  • the substituent of “substituted alkyl” in R 5 is particularly preferably a halogen, an aromatic carbocyclic group or a haloaromatic carbocyclic group, more preferably halogen, phenyl, halophenyl or the like.
  • non-aromatic carbocyclic group haloaromatic carbocyclic group, cyanoaromatic carbocyclic group, alkyloxyaromatic carbocyclic group, haloalkylaromatic group
  • substituent of “substituted alkyloxy” in R 4 non-aromatic carbocyclic group, haloaromatic carbocyclic group, cyanoaromatic carbocyclic group, alkyloxyaromatic carbocyclic group, haloalkylaromatic group
  • examples thereof include carbocyclic groups, and spiro [2.5] octyl, halophenyl, cyanophenyl, methyloxyphenyl, trifluoromethylphenyl and the like are particularly preferable.
  • the substituent of “substituted alkenyl” in R 4 is preferably an aromatic carbocyclic group or the like.
  • substituent of the “substituted aromatic carbocyclic group” include cyano, halogen, hydroxy, carboxy, sulfo, amino, alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxy, hydroxyalkyloxy, haloaromatic carbocyclic group, Alkyl non-aromatic heterocyclic group, alkylcarbonylaminoalkyl non-aromatic heterocyclic group, alkylthio, alkylcarbonyl, alkyloxycarbonyl, non-aromatic heterocyclic carbonyl, alkyloxy non-aromatic heterocyclic carbonyl, alkylcarbonyl non-aromatic Aromatic heterocyclic carbonyl, hydroxy non-aromatic heterocyclic carbonyl, alkylsulfonyl non-aromatic heterocyclic carbonyl,
  • Examples of the substituent of the “substituted aromatic carbocyclic group” in R 1 include halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic ring Examples include a formula group, alkyloxy, alkyloxycarbonyl, alkylamino, alkylcarbonylamino, and non-aromatic heterocyclic alkylcarbamoyl.
  • halogen, hydroxy, carboxy, aromatic carbocyclic group, non-aromatic heterocyclic group, alkyloxy, alkyloxycarbonyl, alkylamino, alkylcarbonylamino, and non-aromatic heterocyclic alkylcarbamoyl are preferable.
  • Examples of the substituent of the “substituted aromatic heterocyclic group” in R 4 include halogen, cyano, trihalomethyl, alkenyl and the like.
  • Substituents of “substituted non-aromatic heterocyclic group” include cyano, hydroxy, carboxy, alkyl, hydroxyalkyl, alkyloxyalkyl, carboxyalkyl, non-aromatic carbocyclic group alkyl, aromatic carbocyclic alkyl, alkyloxy Carbonylalkyl, alkyloxycarbonylaminoalkyl, aminoalkyl, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl, carboxyalkylaminocarbonyl, non-aromatic heterocyclic carbonyl, nitroaromatic carbocyclic carbonyl, aromatic carbocyclic carbamoyl, non-alkyl Aromatic heterocyclic carbamoyl, alkylamino, alkylcarbonylamino, alkylsulfonylamino, dialkylaminosulfonyl, hydroxyaminosulfonyl, non-aromatic heterocyclic
  • Examples of the substituent of the “non-aromatic heterocyclic group” in R 1 include alkyloxycarbonyl and the like.
  • non-aromatic heterocyclic group examples include hydroxy, halogen, aromatic carbocyclic alkyl, aromatic heterocyclic group, alkyloxycarbonyl, carbamoyl, carboxyalkylcarbamoyl and the like.
  • R 4 examples include cyano, alkyloxycarbonyl and the like.
  • Substituents for “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino” include hydroxy, cyano, formyl, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic Group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R, formula: —C ( ⁇ O) — A group represented by R, a group represented by the formula: —C ( ⁇ O) —O—R, or a group represented by the formula: —SO 2 —R, wherein R is alkyl, haloalkyl, alkenyl, alkynyl, non- Aromatic carbocyclic group, aromatic carb
  • substituent of “substituted amino” in R 4 alkyl, hydroxyalkyl, alkyloxyalkyl, carboxyalkyl, alkylaminoalkyl, aromatic carbocyclic alkyl, alkyloxy aromatic carbocyclic alkyl, alkyloxycarbonylalkyl, carboxy aromatic Aromatic carbocyclic group alkyl, alkylamino aromatic carbocyclic alkyl, methylenedioxy aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, alkyl aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, alkyl non-aromatic heterocyclic ring Examples include amino, alkylcarbonylaminoalkyl, non-aromatic carbocyclic group, alkylaminosulfonyl and the like. Examples of the substituent of “substituted amino” in R 4 include haloaromatic carbocyclic alkyl, cyanoaromatic carbocyclic s
  • R 1 is (Ia) substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group Group or a substituted or unsubstituted aromatic heterocyclic group is preferred, and (Ib) a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted group And a non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group of (Ic) substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, carboxyalkyl, Carboxyalkyloxy, alkylsulfonyloxy, substituted or unsubstituted alkyloxycarbon
  • R 2 is preferably (Ie) hydrogen, halogen, hydroxy, formyl, carboxy, cyano, substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted alkyl, and (If) hydrogen, halogen, alkyloxycarbonyl or substituted Alternatively, unsubstituted alkyl is more preferable, and (Ig) hydrogen is particularly preferable.
  • R 3 is preferably (Ih) hydrogen, halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted amino, and (Ii) hydrogen More preferably, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, particularly (Ij) hydrogen.
  • R 4 represents (Ik) substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbon Cyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic hetero Ring oxy or substituted or unsubstituted amino is preferred, and (Il) substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocycle A cyclic group or a substituted or unsubstituted aromatic heterocyclic group is more preferable
  • R 5 represents (In) substituent group E (halogen, cyano, hydroxy, formyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic Aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio Substituted or
  • the compound of the present invention is not limited to a specific isomer, but all possible isomers (eg, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ), Racemates or mixtures thereof.
  • One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively.
  • 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 compounds of the present invention also include compounds substituted with such isotopes.
  • the compound substituted with the isotope is useful as a pharmaceutical and includes all radiolabeled compounds of the present invention.
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • the radioactive label of the compound of the present invention can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • 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 of the present invention include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.). , Magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) And salts with amino acids, or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoro Acetic acid, citric acid, lactic acid, tartaric acid, Salts with
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs.
  • the “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention.
  • solvent molecules for example, water molecules
  • the compound of the present invention or a pharmaceutically acceptable salt thereof When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate.
  • the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the compound 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 invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions.
  • Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed and converted to the compounds of the present invention under physiological conditions in vivo, compounds that are hydrolyzed by gastric acid, etc., and converted to the compounds of the present invention, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion.
  • a compound having a hydroxyl group and an appropriate acyl halide an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion.
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with hydride or reacting with a condensing agent.
  • CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p— CH 3 —O—PhSO 3 —, PhSO 3 —, and p-CH 3 PhSO 3 — can be mentioned.
  • this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below.
  • Process 1 Compound a2 can be obtained by reacting a solution of compound a1 with bromoethanone in the presence of a base.
  • bromoethanone include halides, alkyloxysulfonyl compounds and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a1.
  • the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a1.
  • the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound a3 can be obtained by reacting a solution of compound a2 with an alkylating agent in the presence of a base.
  • alkylating agent include haloalkyl, alkyl triflate and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a2.
  • base include cesium carbonate, potassium carbonate, sodium hydride, tetrabutylammonium fluoride and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a2.
  • the solvent examples include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Process 1 Compound a5 can be obtained by reacting the solution of compound a4 with bromoethanone in the presence of a base.
  • bromoethanone include halides, alkyloxysulfonyl compounds and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
  • the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
  • the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound a6 can be obtained by reacting a solution of compound a5 with an alkylating agent in the presence of a base.
  • alkylating agent include haloalkyl, alkyl triflate, etc., and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a5.
  • base include cesium carbonate, potassium carbonate, sodium hydride, tetrabutylammonium fluoride and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a5.
  • the solvent examples include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound a7 can be obtained by reacting a solution of compound a6 with a nucleophile in the presence of a base.
  • the nucleophilic agent include alcohols and amines, and 1 to 10 equivalents, preferably 1 to 3 equivalents can be used.
  • the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a6.
  • the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
  • the reaction temperature is ⁇ 20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Process 1 Compound a8 can be obtained by reacting the solution of compound a4 with bromoethanone in the presence of a base.
  • bromoethanone include halides, alkyloxysulfonyl compounds and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
  • the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
  • the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound a9 can be obtained by reacting a solution of compound a8 with an alkylating agent in the presence of a base.
  • the alkylating agent can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound a8.
  • the base include cesium carbonate, potassium carbonate, sodium hydride, tetrabutylammonium fluoride and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a8.
  • the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound a10 can be obtained by reacting a solution of compound a9 with boronic acid or a boronic acid ester in the presence of a base and a metal catalyst.
  • boronic acids include aromatic carbocyclic boronic acids, non-aromatic carbocyclic boronic acids, aromatic heterocyclic boronic acids, non-aromatic heterocyclic boronic acids or boronic acid esters thereof. 1 to 10 equivalents, preferably 1 to 3 equivalents can be used.
  • the metal catalyst include 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, palladium acetate and the like. 0.05 to 0.2 equivalent can be used.
  • Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate and the like, and 1 to 10 equivalents, preferably 3 to 5 equivalents, can be used with respect to compound a9.
  • Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like.
  • the reaction temperature is from room temperature to heating under reflux, preferably from room temperature to 100 ° C.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Compound a11 can be obtained by reacting a solution of compound a10 with a base.
  • the base include sodium hydroxide and lithium hydroxide, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a10.
  • the solvent include tetrahydrofuran, ethanol, methanol and the like.
  • the reaction temperature is ⁇ 20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
  • the reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • the compound of the present invention thus obtained can be purified by crystallization with various solvents.
  • Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N—
  • Examples include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water, or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.
  • the compound according to the present invention has autotaxin inhibitory activity.
  • the pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diseases involving autotaxin.
  • diseases involving autotaxin include cancer. More preferable are urinary drainage disorder, interstitial pneumonia or pulmonary fibrosis, renal fibrosis, liver fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis and the like.
  • the pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for these diseases.
  • the compound of the present invention has not only autotaxin inhibitory activity but also usefulness as a pharmaceutical, and may have any or all of the following excellent characteristics.
  • CYP1A2, CYP2C9, CYP3A4, etc. The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak. b) Good pharmacokinetics such as high bioavailability and moderate clearance. c) Low toxicity such as anemia-inducing action. d) High metabolic stability. e) High water solubility. f) High brain transferability. g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).
  • the compound of the present invention has low affinity for ENPP1, 3-7 receptors and may have high ENPP2 receptor selectivity.
  • Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods.
  • parenteral administration any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered.
  • отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • excipients such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.
  • Excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like.
  • binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone.
  • disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate.
  • the lubricant include talc, magnesium stearate, and macrogol.
  • cacao butter, macrogol, methyl cellulose or the like can be used as a suppository base.
  • solubilizers when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in 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.
  • Step 3 To a mixed solution of the compound ( 144 , 60 mg, 0.12 mmol) in ethanol (150 uL) and tetrahydrofuran (300 ul), add 2 mol / L-sodium hydroxide aqueous solution (300 ul, 0.60 mmol) at room temperature. Stir for 2 hours. To the reaction solution was added 1 mol / L hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Test Example 1 Evaluation of Autotaxin Inhibitor A solution A consisting of 25 mM Tris-HCl buffer (pH 7.5), 100 mM NaCl, 5 mM MgCl 2 , 0.1% BSA was prepared. 5 ⁇ l of mouse autotaxin enzyme (R & D systems) diluted with solution A was added. Further, 5 ⁇ l of 0.5 ⁇ M TG-mTMP diluted with solution A was added and reacted at room temperature for 2 hours. After completion of the reaction, 5 ⁇ l of 150 mM EDTA diluted with solution A was added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction was detected.
  • mouse autotaxin enzyme R & D systems
  • fluorescence was measured under the conditions of an excitation wavelength of 480 nm / fluorescence wavelength of 540 nm using a measuring device ViewLux (manufactured by PerkinElmer).
  • a concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition.
  • the compound concentration showing 50% inhibition was defined as the IC50 value.
  • Test Example 2 Evaluation of autotaxin inhibitor Solution A consisting of 25 mM Tris-HCl buffer (pH 7.5), 100 mM NaCl, 5 mM MgCl 2 , and 0.1% BSA was prepared. 5 ⁇ l of human autotaxin enzyme (manufactured by R & D systems) diluted with solution A was added. Further, 5 ⁇ l of 0.5 ⁇ M TG-mTMP diluted with solution A was added and reacted at room temperature for 2 hours. After completion of the reaction, 5 ⁇ l of 150 mM EDTA diluted with solution A was added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction was detected.
  • human autotaxin enzyme manufactured by R & D systems
  • fluorescence was measured under the conditions of an excitation wavelength of 480 nm / fluorescence wavelength of 540 nm using a measuring device ViewLux (manufactured by PerkinElmer).
  • a concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition.
  • the compound concentration showing 50% inhibition was defined as the IC50 value.
  • Test Example 3 Evaluation of autotaxin inhibitor Solution B consisting of 100 mM Tris-HCl buffer (pH 7.5), 150 mM NaCl, 5 mM MgCl 2 and 0.05% Triton X-100 was prepared and dissolved in DMSO. To the compound, 2.5 ⁇ l of human autotaxin enzyme (R & D systems) diluted with solution B was added. Further, 200 ⁇ M 18: 0 Lyso PC diluted by solution B (manufactured by Avanti Polar Lipids) was added by 2.5 ⁇ l and reacted at room temperature for 2 hours.
  • human autotaxin enzyme R & D systems
  • 200 ⁇ M 18: 0 Lyso PC diluted by solution B manufactured by Avanti Polar Lipids
  • resorufin For the detection of resorufin, a measuring instrument ViewLux (manufactured by PerkinElmer) was used, and fluorescence was measured under conditions of excitation wavelength 531 nm / fluorescence wavelength 598 nm. A concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition. The compound concentration showing 50% inhibition was defined as the IC50 value.
  • Test Example 4 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human 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 was inhibited by the test compound was 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; test compound concentration 1, 5, 10, 20 ⁇ mol / L (4 points).
  • reaction solution in a 96-well plate 5 kinds of each substrate, human liver microsome, and test compound are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin (CYP1A2 metabolite) in the centrifugal supernatant was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
  • the control system (100%) was obtained by adding only DMSO, which is the solvent in which the test compound was dissolved, to the reaction system, and calculated the residual activity (%) at each concentration with the test compound solution added. Using the rate, IC 50 was calculated by inverse estimation with a logistic model.
  • NADPH final concentration 1 mM, in the case of oxidative metabolism
  • liver microsomes final concentration 0.5 mg protein
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Starch 15mg Lactose 15mg Crystalline cellulose 19mg Polyvinyl alcohol 3mg 30ml distilled water Calcium stearate 3mg Ingredients other than calcium stearate are uniformly 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 Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg The above ingredients 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 Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g The above ingredients are mixed well, compression molded, pulverized, sized, and sieved to give granules of appropriate size.
  • the present invention can be used in the field of pharmaceuticals, for example, in the field of development and production of therapeutic agents for fibrotic diseases and the like.

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Abstract

The present invention provides a compound that has autotaxin-inhibiting activity and is represented by formula (I) (where R1, R2, R3, R4, and R5 are as defined in the description), a drug comprising the compound as an active ingredient, and a method that is for treating or preventing autotaxin-related disease and that is characterized by administration of the compound.

Description

オートタキシン阻害活性を有する１－置換イミダゾピリミジノン誘導体1-Substituted imidazopyrimidinone derivatives having autotaxin inhibitory activity

　本発明はオートタキシン阻害活性を有するイミダゾピリミジノン誘導体、ならびに該イミダゾピリミジノン誘導体を有効成分とする医薬に関する。 The present invention relates to an imidazopyrimidinone derivative having autotaxin inhibitory activity, and a pharmaceutical comprising the imidazopyrimidinone derivative as an active ingredient.

　リゾホスファチジン酸（Lysophosphatidic acid、LPA）は、細胞増殖、細胞内カルシウム流入、細胞骨格変化、細胞遊走など多彩な作用を発揮する脂質メディエーターであり、細胞膜表面上に発現するＧ蛋白質共役型受容体（LPA1-6）を介して情報伝達がなされている。この脂質は、線維化、疼痛、癌、炎症、動脈硬化などの生体の異常に関与することが報告されている（非特許文献１）。 Lysophosphatidic acid (LPA) is a lipid mediator that exhibits various functions such as cell proliferation, intracellular calcium influx, cytoskeletal changes, and cell migration, and is a G protein-coupled receptor expressed on the surface of cell membrane ( Information is transmitted through LPA1-6). It has been reported that this lipid is involved in biological abnormalities such as fibrosis, pain, cancer, inflammation, arteriosclerosis (Non-patent Document 1).

　LPAはいくつかの代謝経路により生合成されうるが、主な経路はリゾホスファチジルコリンがオートタキシン（autotaxin、ENPP2、ATX）によって加水分解されて産生されることによる。ATXはENPP（Ectonucleotide pyrophosphatase and phosphodiesterase）ファミリー（ENPP1-7）に属する分泌型蛋白でありENPP2とも呼ばれているが、ファミリーのうち、リゾホスホリパーゼD活性を有してLPA産生に関わるのはATXのみである。ATXの酵素活性を阻害してLPAの生成を抑えることが線維化疾患の治療に有効であることが報告されている（非特許文献１）。 LPA can be biosynthesized by several metabolic routes, but the main route is that lysophosphatidylcholine is produced by hydrolysis by autotaxin (ENPP2, ATX). Although ATX is also called ENPP2 be secretory proteins belonging to ENPP (E cto n ucleotide p yrophosphatase and p hosphodiesterase) Family (ENPP1-7), among the family, LPA production in a lysophospholipase D activity Only ATX is involved. It has been reported that inhibiting the enzyme activity of ATX to suppress the production of LPA is effective in treating fibrotic diseases (Non-patent Document 1).

　線維化はあらゆる組織で起こりうるが、その発症の引き金の種類に関わらず、共通した機序で進行しうる。
　一方、動物の組織や臓器は、コラーゲン等の線維により構造が維持されているが、組織が何らかの傷害を受けると、コラーゲン産生を伴う創傷治癒の過程により元の組織に修復される。しかしながら、組織が免疫的、化学的、機械的、代謝的、あるいはその他の傷害を複数回にわたって受けたり、その傷害の程度が大きいと、過剰な線維性結合組織の蓄積が生じる場合がある。このような結合組織の蓄積は不可逆的であり、線維が異常に増えてしまうと、組織や臓器が正常な機能を果たさなくなる線維化疾患が引き起こされる。 Fibrosis can occur in any tissue, but can progress by a common mechanism, regardless of the type of trigger for its onset.
On the other hand, structures and structures of animal tissues and organs are maintained by fibers such as collagen. However, when the tissues are damaged in some way, they are restored to the original tissues by a wound healing process accompanied by collagen production. However, if the tissue is subjected to multiple immunological, chemical, mechanical, metabolic, or other injuries or the extent of the injuries is large, excessive fibrous connective tissue accumulation may occur. Such accumulation of connective tissue is irreversible, and when fibers increase abnormally, a fibrotic disease is caused in which tissues and organs do not function normally.

　例えば、慢性腎臓病の病理学的特徴として糸球体や尿細管間質の線維化が挙げられる。末期腎不全の病理像は実質細胞の脱落と線維化が顕著である。慢性腎臓病患者において尿細管間質の線維化を示す患者は、線維化を示さない患者と比較してより腎機能悪化の進行が早いことが知られている。 For example, pathological features of chronic kidney disease include glomerular and tubulointerstitial fibrosis. The pathological features of end stage renal failure are markedly parenchymal cell loss and fibrosis. It is known that patients who show tubulointerstitial fibrosis in patients with chronic kidney disease progress more rapidly in renal function deterioration than patients who do not show fibrosis.

　慢性腎臓病の予防・治療法としては、生活指導・食事指導に加えて、アンギオテンシン受容体拮抗薬やカルシウム拮抗薬などの降圧療法による治療が行われている。しかし、既存の治療法によって得られる効果は十分とは言えず、より優れた腎機能障害の予防・治療剤が求められている。 As a preventive and therapeutic method for chronic kidney disease, in addition to lifestyle guidance and dietary guidance, treatment with antihypertensive therapies such as angiotensin receptor antagonists and calcium antagonists is performed. However, the effects obtained by existing therapies cannot be said to be sufficient, and there is a demand for better preventive / therapeutic agents for renal dysfunction.

　特許文献１には、ゴナドトロピン放出ホルモン阻害作用を有するイミダゾピリミジノン誘導体が開示されているが、当該化合物がオートタキシン阻害作用を有することや慢性腎臓病の治療剤になるうることについては何ら記載も示唆もされていない。 Patent Document 1 discloses an imidazopyrimidinone derivative having an inhibitory action on gonadotropin-releasing hormone, but does not describe anything about whether the compound has an inhibitory action on autotaxin or a therapeutic agent for chronic kidney disease. There is no suggestion.

　特許文献２～１５には、オートタキシン阻害作用を有する多環性化合物が記載されているが、本願イミダゾピリミジノン誘導体については何ら記載も示唆もされていない。
　特許文献１６～２３には、オートタキシン阻害作用を有する単環性化合物が記載されているが、本願イミダゾピリミジノン誘導体については何ら記載も示唆もされていない。
　非特許文献２には、オートタキシン阻害作用を有する単環および多環性化合物が記載されているが、本願イミダゾピリミジノン誘導体については何ら記載も示唆もされていない。 Patent Documents 2 to 15 describe polycyclic compounds having an autotaxin inhibitory effect, but do not describe or suggest any imidazopyrimidinone derivatives of the present application.
Patent Documents 16 to 23 describe monocyclic compounds having an autotaxin inhibitory activity, but do not describe or suggest any imidazopyrimidinone derivatives of the present application.
Non-Patent Document 2 describes monocyclic and polycyclic compounds having an autotaxin inhibitory effect, but does not describe or suggest any imidazopyrimidinone derivatives of the present application.

国際公開第２００３／５１８８５号International Publication No. 2003/51885 国際公開第２０１２／１２７８８５号International Publication No. 2012/12785 国際公開第２０１２／５２２７号International Publication No. 2012/5227 国際公開第２０１１／１１６８６７号International Publication No. 2011/116867 国際公開第２０１１／５６６９号International Publication No. 2011/5669 国際公開第２０１０／６０５３２号International Publication No. 2010/60532 国際公開第２０１２／１０００１８号International Publication No. 2012/100018 米国特許出願公開第２０１２／１００５９２号明細書US Patent Application Publication No. 2012/100592 国際公開第２０１２／２４６２０号International Publication No. 2012/24620 国際公開第２０１１／５３５９７号International Publication No. 2011/53597 国際公開第２０１０／１１５４９１号International Publication No. 2010/115491 国際公開第２０１０／１１２１２４号International Publication No. 2010/112124 国際公開第２００９／４６８４１号International Publication No. 2009/46841 国際公開第２００９／４６８４２号International Publication No. 2009/46842 国際公開第２０１０／６３３５２号International Publication No. 2010/63352 国際公開第２０１２／１３８６４８号International Publication No. 2012/138648 国際公開第２０１１／４１４６２号International Publication No. 2011/41462 国際公開第２０１１／４１６９４号International Publication No. 2011/41694 国際公開第２０１１／１７３５０号International Publication No. 2011/17350 国際公開第２０１０／１１２１１６号International Publication No. 2010/112116 国際公開第２０１０／６８７７５号International Publication No. 2010/68775 米国特許出願公開第２０１０／１６２５８号明細書US Patent Application Publication No. 2010/16258 国際公開第２００９／４６８０４号International Publication No. 2009/46804

Nature, 411巻、494-498頁、2001年Nature, Vol.411, 494-498, 2001 ACS Chemical Biology, 411巻、1713-1721頁、2013年ACS Chemical Biology, Vol.411, pp.1713-1721, 2013

　本発明の目的は、優れたオートタキシン阻害活性を有する新規イミダゾピリミジノン誘導体を提供することにある。 An object of the present invention is to provide a novel imidazopyrimidinone derivative having excellent autotaxin inhibitory activity.

　本発明者らは、鋭意研究の結果、優れたオートタキシン阻害活性を有する１－置換イミダゾピリミジノン誘導体を見出し、本願発明を達成した。 As a result of intensive studies, the present inventors have found a 1-substituted imidazopyrimidinone derivative having excellent autotaxin inhibitory activity, and achieved the present invention.

　すなわち、本発明は、以下に関する。
（１）式（Ｉ）：

Figure JPOXMLDOC01-appb-C000010
（式中、
　Ｒ１、Ｒ２、Ｒ３およびＲ４はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ５はハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルである）で示される化合物またはその製薬上許容される塩を含有することを特徴とする、オートタキシン阻害剤。
（２）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000011
 （式中、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立して水素、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ４は水素、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換アミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ５は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の芳香族複素環式基であり；
ただし、下記（ｉ）～（ｘ）の化合物を除く、
（ｉ）Ｒ４が、非置換４－チオモルホリノ、非置換４－テトラヒドロピラニル、非置換４－ジヒドロピラニル、非置換４－モルホリノまたは置換された４－モルホリノ（置換基は、メチル）であり、かつＲ５が置換若しくは非置換のフェニルメチルである化合物、
（ｉｉ）Ｒ３が置換若しくは非置換の含窒素非芳香族複素環式基で置換されたエチルである化合物、
（ｉｉｉ）Ｒ１が水素であり、かつＲ４が（ａ）水素、（ｂ）置換されたチアゾリル（置換基は、カルボキシ；非置換アミノ；非置換メチル；非置換メチルオキシ；非置換アルキルオキシカルボニル；非置換フェニル；非置換ピリジル；非置換ピリミジニル；置換もしくは非置換のフェニルメチルから選択される１以上の基）、または（ｃ）置換もしくは非置換のフェニルメチルで置換されたオキサゾリルである化合物、
（ｉｖ）Ｒ１が水素であり、かつ、Ｒ２が（ａ）置換されたアルキル（置換基は、非置換アルキルチオ；非置換アルキルスルホニルから選択される１以上の基）、または（ｂ）式：
Figure JPOXMLDOC01-appb-C000012
で示される基である化合物、
（ｖ）Ｒ３が置換若しくは非置換のフェニルであり、かつＲ４が非置換４－ピリジルである化合物、
（ｖｉ）Ｒ１が水素または非置換メチルであり、かつＲ４が非置換４－ピリジルである化合物、
（ｖｉｉ）Ｒ１が水素であり、Ｒ２が水素であり、Ｒ３が水素であり、かつＲ５が置換テトラヒドロフラニルである化合物、
（ｖｉｉｉ）Ｒ１が水素であり、かつＲ４がカルボキシ、または非置換メチルオキシカルボニルである化合物、
（ｉｘ）Ｒ１が水素であり、Ｒ２が水素であり、Ｒ３が水素、非置換メチルまたは非置換エチルであり、Ｒ４が非置換メチルまたは非置換エチルであり、かつＲ５が置換フェニルメチルである化合物、および
（ｘ）以下に示す化合物
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
 ）で示される化合物またはその製薬上許容される塩。
（３）Ｒ１が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり、
Ｒ５が置換もしくは非置換のC５-C１０アルキル、置換もしくは非置換のC４-C１０アルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である、上記（２）記載の化合物またはその製薬上許容される塩。
（４）Ｒ５が置換もしくは非置換のC５-C１０アルキル、置換もしくは非置換のC４-C１０アルケニルまたは置換もしくは非置換のアルキニルである、上記（２）記載の化合物またはその製薬上許容される塩。
（５）Ｒ５がハロゲンまたはシアノで置換されたＣ４-Ｃ１０アルキル、置換もしくは非置換のＣ４-Ｃ１０アルケニルまたは置換もしくは非置換のアルキニルである、上記（２）記載の化合物またはその製薬上許容される塩。
（６）Ｒ１が置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基または置換若しくは非置換の非芳香族複素環式基である、上記（２）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（７）Ｒ１が置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、または置換若しくは非置換の芳香族複素環式基である、上記（２）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（８）Ｒ１が置換基群Ａ（アルキルカルボニルオキシ、アルキルオキシカルボニルおよび芳香族炭素環式基）から選択される１以上の置換基で置換されたアルキル、置換基群Ａからから選択される１以上の置換基で置換されたアルケニル、置換基群Ａから選択される１以上の置換基で置換されたアルキニル、置換基群Ｂ（ヒドロキシ、アルコキシ、カルボキシ、ハロゲン、置換若しくは非置換のアミノ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル）から選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｂから選択される１以上の置換基で置換された芳香族複素環式基である、上記（２）～（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（９）Ｒ２が水素、ホルミル、カルボキシ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニルまたは置換若しくは非置換のアルキニルカルボニルである、上記（２）～（８）のいずれかに記載の化合物またはその製薬上許容される塩。
（１０）Ｒ２が水素、ホルミル、置換若しくは非置換のアルキル、置換若しくは非置換のアルキルカルボニルまたは置換もしくは非置換のアルキルオキシカルボニルである、上記（２）～（８）のいずれかに記載の化合物またはその製薬上許容される塩。
（１１）Ｒ３が水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルである、上記（２）～（１０）のいずれかに記載の化合物またはその製薬上許容される塩。
（１２）Ｒ３が水素または置換若しくは非置換のアルキルである、上記（２）～（１０）のいずれかに記載の化合物またはその製薬上許容される塩。
（１３）Ｒ４が水素、ハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換若しくは非置換のアミノである、上記（２）～（１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（１４）Ｒ４が置換基群Ｄ（ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイルおよび置換もしくは非置換の芳香族炭素環スルホニル）から選択される１以上の置換基で置換されたアルキル、置換基群Ｄから選択される１以上の置換基で置換されたアルケニル、置換基群Ｄから選択される１以上の置換基で置換されたアルキルオキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族炭素環オキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族複素環オキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｄから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｄから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｄから選択される１以上の置換基で置換されたアミノである、上記（２）～（１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（１５）Ｒ４が置換基群Ｄ’（置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基および置換もしくは非置換の芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルオキシ、置換基群Ｄ’から選択される１以上の置換基で置換されたアルケニルオキシ、置換基群Ｄ’から選択される１以上の置換基で置換されたアルキニルオキシである、上記（２）～（１２）のいずれかに記載の化合物またはその製薬上許容される塩。
（１６）上記（２）～（１５）のいずれかに記載の化合物またはその製薬上許容される塩を有効成分として含有する医薬組成物。
（１７）オートタキシン阻害剤である、上記（１６）記載の医薬組成物。
（１８）オートタキシンが関与する疾患の予防または治療のための、上記（１６）記載の医薬組成物。
（１９）オートタキシンの関与する疾患の治療剤又は予防剤を製造するための、上記（２）～（１５）のいずれかに記載の化合物、又はその製薬上許容される塩の使用。
（２０）上記（２）～（１５）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とするオートタキシンの関与する疾患の治療又は予防方法。
（１’）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000017
 （式中、
　Ｒ１、Ｒ２、Ｒ３およびＲ４はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ５はハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルである）で示される化合物またはその製薬上許容される塩を含有することを特徴とする、オートタキシン阻害剤。
（２’）式（Ｉ）：
Figure JPOXMLDOC01-appb-C000018
 （式中、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立して水素、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ４は水素、シアノ、ホルミル、カルボキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換若しくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ５は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の芳香族複素環式基であり；
ただし、下記（ｉ）～（ｘ）の化合物を除く、
（ｉ）Ｒ４が非置換４－チオモルホリノ、非置換４－テトラヒドロピラニル、非置換４－ジヒドロピラニル、非置換４－モルホリノまたは置換された４－モルホリノ（置換基は、非置換メチル）であり、かつＲ５が置換若しくは非置換のフェニルメチルである化合物、
（ｉｉ）Ｒ３が置換若しくは非置換の含窒素非芳香族複素環式基で置換されたエチルである化合物、
（ｉｉｉ）Ｒ１が水素であり、かつＲ４が（ａ）水素、（ｂ）置換されたチアゾリル（置換基は、カルボキシ；非置換アミノ；非置換メチル；非置換メチルオキシ；非置換アルキルオキシカルボニル；非置換フェニル；非置換ピリジル；非置換ピリミジニル；置換もしくは非置換のフェニルメチルの１以上の基）、または（ｃ）置換もしくは非置換のフェニルメチルで置換されたオキサゾリルである化合物、
（ｉｖ）Ｒ１が水素であり、かつＲ２が（ａ）置換されたアルキル（置換基は、非置換アルキルチオ；非置換アルキルスルホニルから選択される１以上の基）、または（ｂ）式：
Figure JPOXMLDOC01-appb-C000019
で示される基である化合物、
（ｖ）Ｒ３が置換若しくは非置換のフェニルであり、かつＲ４が非置換４－ピリジルである化合物、
（ｖｉ）Ｒ１が水素または非置換メチルであり、かつＲ４が非置換４－ピリジルまたは非置換２，４－ピリミジニルである化合物、
（ｖｉｉ）Ｒ１が水素であり、Ｒ２が水素であり、Ｒ３が水素であり、かつＲ５が置換テトラヒドロフラニルである化合物、
（ｖｉｉｉ）Ｒ１が水素であり、かつＲ４がカルボキシまたは非置換メチルオキシカルボニルである化合物、
（ｉｘ）Ｒ１が水素であり、Ｒ２が水素であり、Ｒ３が水素、非置換Ｃ１－Ｃ３アルキルであり、Ｒ４が非置換メチルまたは非置換エチルであり、かつＲ５が置換フェニルメチルである化合物、および
（ｘ）以下に示す化合物
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025

）で示される化合物またはその製薬上許容される塩。
（３’）Ｒ１が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり、
Ｒ５が置換もしくは非置換のC５-C１０アルキル、置換もしくは非置換のC４-C１０アルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である、上記（２’）記載の化合物またはその製薬上許容される塩。
（４’）Ｒ５が置換もしくは非置換のC５-C１０アルキル、置換もしくは非置換のC４-C１０アルケニルまたは置換もしくは非置換のアルキニルである、上記（２’）記載の化合物またはその製薬上許容される塩。
（５’）Ｒ５がハロゲンまたはシアノで置換されたＣ４-Ｃ１０アルキル、置換もしくは非置換のＣ４-Ｃ１０アルケニルまたは置換もしくは非置換のアルキニルである、上記（２’）記載の化合物またはその製薬上許容される塩。
（６’）Ｒ１が置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基または置換若しくは非置換の非芳香族複素環式基である、上記（２’）～（５’）のいずれかに記載の化合物またはその製薬上許容される塩。
（７’）Ｒ１が置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、または置換若しくは非置換の芳香族複素環式基である、上記（２’）～（５’）のいずれかに記載の化合物またはその製薬上許容される塩。
（８’）Ｒ１が置換基群Ａ（アルキルカルボニルオキシ、アルキルオキシカルボニルおよび芳香族炭素環式基）から選択される１以上の置換基で置換されたアルキル、置換基群Ａから選択される１以上の置換基で置換されたアルケニル、置換基群Ａから選択される１以上の置換基で置換されたアルキニル、置換基群Ｂ（ヒドロキシ、アルコキシ、カルボキシ、ハロゲン、置換若しくは非置換のアミノ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基および置換若しくは非置換のカルバモイル）から選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｂから選択される１以上の置換基で置換された芳香族複素環式基である、上記（２’）～（５’）のいずれかに記載の化合物またはその製薬上許容される塩。
（９’）Ｒ１が置換基群Ｃ（ヒドロキシ、カルボキシ、カルボキシアルキル、カルボキシアルキルオキシ、アルキルカルボニルアミノ、非芳香族複素環アルキルアミノカルボニル、アルキルスルホニルオキシ、非置換非芳香族複素環式基およびオキソで置換された非芳香族複素環式基）から選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｃから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｃから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｃから選択される１以上の置換基で置換された芳香族複素環式基である、上記（２’）～（５’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１０’）Ｒ２が水素、ホルミル、カルボキシ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニルまたは置換若しくは非置換のアルキニルカルボニルである、上記（２’）～（９’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１１’）Ｒ２が水素、ホルミル、置換若しくは非置換のアルキル、置換若しくは非置換のアルキルカルボニルまたは置換もしくは非置換のアルキルオキシカルボニルである、上記（２’）～（９’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１２’）Ｒ３が水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルである、上記（２’）～（１１’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１３’）Ｒ３が水素または置換若しくは非置換のアルキルである、上記（２’）～（１１’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１４’）Ｒ４が水素、ハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換若しくは非置換のアミノである、上記（２’）～（１３’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１５’）Ｒ４が置換基群Ｄ（ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイルおよび置換もしくは非置換の芳香族炭素環スルホニル）から選択される１以上の置換基で置換されたアルキル、置換基群Ｄから選択される１以上の置換基で置換されたアルケニル、置換基群Ｄから選択される１以上の置換基で置換されたアルキルオキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族炭素環オキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族複素環オキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｄから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｄから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｄから選択される１以上の置換基で置換されたアミノである、上記（２’）～（１３’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１６’）
Ｒ４が置換基群Ｄ’（置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基および置換もしくは非置換の芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルオキシ、置換基群Ｄ’から選択される１以上の置換基で置換されたアルケニルオキシ、置換基群Ｄ’から選択される１以上の置換基で置換されたアルキニルオキシである、上記（２’）～（１３’）のいずれかに記載の化合物またはその製薬上許容される塩。
（１７’）上記（２’）～（１６’）のいずれかに記載の化合物またはその製薬上許容される塩を有効成分として含有する医薬組成物。
（１８’）オートタキシン阻害剤である、上記（１７’）記載の医薬組成物。
（１９’）オートタキシンが関与する疾患の予防または治療のための、上記（１７’）記載の医薬組成物。
（２０’）オートタキシンの関与する疾患の治療剤又は予防剤を製造するための、上記（２’）～（１６’）のいずれかに記載の化合物、又はその製薬上許容される塩の使用。
（２１’）上記（２’）～（１６’）のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とするオートタキシンの関与する疾患の治療又は予防方法。
That is, the present invention relates to the following.
(1) Formula (I):
Figure JPOXMLDOC01-appb-C000010
 (Where
R 1 , R 2 , R 3 And R 4 Are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, Substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted nonaromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted nonaromatic heterocyclic thio Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, Substituted or unsubstituted alkynyloxycar Nyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxy Carbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted nonaromatic carbocycle Sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl Rusulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted An aromatic heterocyclic sulfonyl of
R 5 Is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or non-substituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or Unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkyl Nilthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or non-substituted Non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or Is substituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic And a pharmaceutically acceptable salt thereof. An autotaxin inhibitor, characterized by comprising:
(2) Formula (I):
Figure JPOXMLDOC01-appb-C000011
 (Where
R 1 , R 2 And R 3 Are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, Substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted nonaromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted nonaromatic heterocyclic thio Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, Substituted or unsubstituted alkynyloxycar Nyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxy Carbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted nonaromatic carbocycle Sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl Rusulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted An aromatic heterocyclic sulfonyl of
R 4 Is hydrogen, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic Carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic Ring oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted Lucinylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or Unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted Non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic oxycarboni Substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted Sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted Or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, Substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic sulfonyl;
R 5 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A substituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
However, the following compounds (i) to (x) are excluded,
(I) R 4 Is unsubstituted 4-thiomorpholino, unsubstituted 4-tetrahydropyranyl, unsubstituted 4-dihydropyranyl, unsubstituted 4-morpholino or substituted 4-morpholino (substituent is methyl), and R 5 Wherein is a substituted or unsubstituted phenylmethyl,
(Ii) R 3 A compound in which is substituted with a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group,
(Iii) R 1 Is hydrogen and R 4 (A) hydrogen, (b) substituted thiazolyl (substituent is carboxy; unsubstituted amino; unsubstituted methyl; unsubstituted methyloxy; unsubstituted alkyloxycarbonyl; unsubstituted phenyl; unsubstituted pyridyl; unsubstituted pyrimidinyl One or more groups selected from substituted or unsubstituted phenylmethyl), or (c) a compound that is oxazolyl substituted with substituted or unsubstituted phenylmethyl,
(Iv) R 1 Is hydrogen and R 2 (A) substituted alkyl (substituent is unsubstituted alkylthio; one or more groups selected from unsubstituted alkylsulfonyl), or (b) formula:
Figure JPOXMLDOC01-appb-C000012
A compound which is a group represented by:
(V) R 3 Is substituted or unsubstituted phenyl and R 4 A compound in which is unsubstituted 4-pyridyl,
(Vi) R 1 Is hydrogen or unsubstituted methyl and R 4 A compound in which is unsubstituted 4-pyridyl,
(Vii) R 1 Is hydrogen and R 2 Is hydrogen and R 3 Is hydrogen and R 5 Wherein is a substituted tetrahydrofuranyl;
(Viii) R 1 Is hydrogen and R 4 A compound wherein is carboxy, or unsubstituted methyloxycarbonyl,
(Ix) R 1 Is hydrogen and R 2 Is hydrogen and R 3 Is hydrogen, unsubstituted methyl or unsubstituted ethyl, and R 4 Is unsubstituted methyl or unsubstituted ethyl and R 5 Wherein is a substituted phenylmethyl, and
(X) Compounds shown below
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000016
 Or a pharmaceutically acceptable salt thereof.
(3) R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted Or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic Group carbocyclic oxycarbonyl, substituted or non-substituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or non-substituted Substituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-substituted Aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted A non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl or a substituted or unsubstituted aromatic heterocyclic sulfonyl,
R 5 Is substituted or unsubstituted C5-C10 alkyl, substituted or unsubstituted C4-C10 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted aromatic heterocyclic The compound according to (2) above or a pharmaceutically acceptable salt thereof, which is a group.
(4) R 5 Or a pharmaceutically acceptable salt thereof, wherein is a substituted or unsubstituted C5-C10 alkyl, a substituted or unsubstituted C4-C10 alkenyl, or a substituted or unsubstituted alkynyl.
(5) R 5 Or a pharmaceutically acceptable salt thereof, wherein is a C4-C10 alkyl substituted with halogen or cyano, a substituted or unsubstituted C4-C10 alkenyl, or a substituted or unsubstituted alkynyl.
(6) R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (5), which is a substituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
(7) R 1 Is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group ( 2) to (5) or a pharmaceutically acceptable salt thereof.
(8) R 1 Is substituted with one or more substituents selected from substituent group A (alkylcarbonyloxy, alkyloxycarbonyl and aromatic carbocyclic group), and one or more substituents selected from substituent group A Alkenyl substituted with, alkynyl substituted with one or more substituents selected from substituent group A, substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted Substituted with one or more substituents selected from alkyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl) Aromatic carbocyclic group, non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group B, 1 selected from substituent group B (2) to (5) above, which is a non-aromatic heterocyclic group substituted with the above substituent or an aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group B Or a pharmaceutically acceptable salt thereof.
(9) R 2 Is hydrogen, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, or substituted or unsubstituted alkynyl The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (8), which is carbonyl.
(10) R 2 Or a pharmaceutical product thereof according to any one of (2) to (8) above, wherein is hydrogen, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted alkyloxycarbonyl Acceptable salt.
(11) R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (10), wherein is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl.
(12) R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (10), wherein is hydrogen or substituted or unsubstituted alkyl.
(13) R 4 Is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy A substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted amino, 2) The compound according to any one of (12) or a pharmaceutically acceptable salt thereof.
(14) R 4 Is substituted group D (halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl and An alkyl substituted with one or more substituents selected from substituted or unsubstituted aromatic carbocyclic sulfonyl), an alkenyl substituted with one or more substituents selected from substituent group D, from substituent group D Alkyloxy substituted with one or more selected substituents, non-aromatic carbon substituted with one or more substituents selected from substituent group D Oxy, non-aromatic heterocyclic oxy substituted with one or more substituents selected from substituent group D, Non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group D An aromatic carbocyclic group substituted with one or more substituents selected from substituent group D, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group D, or The compound or a pharmaceutically acceptable salt thereof according to any one of (2) to (12) above, which is amino substituted with one or more substituents selected from Substituent Group D.
(15) R 4 Is substituted group D ′ (substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted Alkyloxy substituted with one or more substituents selected from aromatic heterocyclic groups), alkenyloxy substituted with one or more substituents selected from substituent group D ′, from substituent group D ′ The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (12), which is alkynyloxy substituted with one or more selected substituents.
(16) A pharmaceutical composition comprising the compound according to any one of (2) to (15) above or a pharmaceutically acceptable salt thereof as an active ingredient.
(17) The pharmaceutical composition according to the above (16), which is an autotaxin inhibitor.
(18) The pharmaceutical composition according to the above (16), for the prevention or treatment of a disease involving autotaxin.
(19) Use of the compound according to any one of (2) to (15) above or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving autotaxin.
(20) A method for treating or preventing a disease involving autotaxin, which comprises administering the compound according to any one of (2) to (15) above or a pharmaceutically acceptable salt thereof.
(1 ′) Formula (I):
Figure JPOXMLDOC01-appb-C000017
 (Where
R 1 , R 2 , R 3 And R 4 Are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, Substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted nonaromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted nonaromatic heterocyclic thio Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, Substituted or unsubstituted alkynyloxycar Nyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxy Carbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted nonaromatic carbocycle Sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl Rusulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted An aromatic heterocyclic sulfonyl of
R 5 Is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or non-substituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or Unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkyl Nilthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or non-substituted Non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or Is substituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or substituted or unsubstituted aromatic heterocyclic And a pharmaceutically acceptable salt thereof. An autotaxin inhibitor, characterized by comprising:
(2 ′) Formula (I):
Figure JPOXMLDOC01-appb-C000018
 (Where
R 1 , R 2 And R 3 Are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic Group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, Substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted nonaromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted nonaromatic heterocyclic thio Substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or Unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, Substituted or unsubstituted alkynyloxycar Nyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxy Carbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted nonaromatic carbocycle Sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenyl Rusulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted An aromatic heterocyclic sulfonyl of
R 4 Is hydrogen, cyano, formyl, carboxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or non-substituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or Unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenyl O, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or unsubstituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl Substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic Carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted Substituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted aromatic heterocyclic sulfonyl Is;
R 5 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A substituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
However, the following compounds (i) to (x) are excluded,
(I) R 4 Is unsubstituted 4-thiomorpholino, unsubstituted 4-tetrahydropyranyl, unsubstituted 4-dihydropyranyl, unsubstituted 4-morpholino or substituted 4-morpholino (substituent is unsubstituted methyl), and R 5 Wherein is a substituted or unsubstituted phenylmethyl,
(Ii) R 3 A compound in which is substituted with a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group,
(Iii) R 1 Is hydrogen and R 4 (A) hydrogen, (b) substituted thiazolyl (substituent is carboxy; unsubstituted amino; unsubstituted methyl; unsubstituted methyloxy; unsubstituted alkyloxycarbonyl; unsubstituted phenyl; unsubstituted pyridyl; unsubstituted pyrimidinyl One or more groups of substituted or unsubstituted phenylmethyl), or (c) a compound that is oxazolyl substituted with substituted or unsubstituted phenylmethyl,
(Iv) R 1 Is hydrogen and R 2 (A) substituted alkyl (substituent is unsubstituted alkylthio; one or more groups selected from unsubstituted alkylsulfonyl), or (b) formula:
Figure JPOXMLDOC01-appb-C000019
A compound which is a group represented by:
(V) R 3 Is substituted or unsubstituted phenyl and R 4 A compound in which is unsubstituted 4-pyridyl,
(Vi) R 1 Is hydrogen or unsubstituted methyl and R 4 A compound in which is unsubstituted 4-pyridyl or unsubstituted 2,4-pyrimidinyl,
(Vii) R 1 Is hydrogen and R 2 Is hydrogen and R 3 Is hydrogen and R 5 Wherein is a substituted tetrahydrofuranyl;
(Viii) R 1 Is hydrogen and R 4 A compound wherein is carboxy or unsubstituted methyloxycarbonyl;
(Ix) R 1 Is hydrogen and R 2 Is hydrogen and R 3 Is hydrogen, unsubstituted C1-C3 alkyl, R 4 Is unsubstituted methyl or unsubstituted ethyl and R 5 Wherein is a substituted phenylmethyl, and
(X) Compounds shown below
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025

Or a pharmaceutically acceptable salt thereof.
(3 ') R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted Substituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted Or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic Group carbocyclic oxycarbonyl, substituted or non-substituted Aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or non-substituted Substituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-substituted Aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted A non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl or a substituted or unsubstituted aromatic heterocyclic sulfonyl,
R 5 Is substituted or unsubstituted C5-C10 alkyl, substituted or unsubstituted C4-C10 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted aromatic heterocyclic The compound of the above (2 ′) or a pharmaceutically acceptable salt thereof, which is a group.
(4 ') R 5 The compound or a pharmaceutically acceptable salt thereof according to (2 ′) above, wherein is substituted or unsubstituted C5-C10 alkyl, substituted or unsubstituted C4-C10 alkenyl, or substituted or unsubstituted alkynyl.
(5 ') R 5 The compound or a pharmaceutically acceptable salt thereof according to (2 ′) above, wherein is C4-C10 alkyl substituted with halogen or cyano, substituted or unsubstituted C4-C10 alkenyl or substituted or unsubstituted alkynyl.
(6 ') R 1 Is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of (2 ′) to (5 ′) above, which is a substituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
(7 ') R 1 Is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group ( 2 ') to (5') or a pharmaceutically acceptable salt thereof.
(8 ') R 1 An alkyl substituted with one or more substituents selected from substituent group A (alkylcarbonyloxy, alkyloxycarbonyl and aromatic carbocyclic group), one or more substituents selected from substituent group A Substituted alkenyl, alkynyl substituted with one or more substituents selected from substituent group A, substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted alkyl Aromatic substituted with one or more substituents selected from oxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted carbamoyl) A non-aromatic carbocyclic group substituted with one or more substituents selected from a carbocyclic group, substituent group B, one or more selected from substituent group B Or a non-aromatic heterocyclic group substituted with one or more substituents or an aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group B. ) Or a pharmaceutically acceptable salt thereof.
(9 ') R 1 Is substituted with a substituent group C (hydroxy, carboxy, carboxyalkyl, carboxyalkyloxy, alkylcarbonylamino, non-aromatic heterocyclic alkylaminocarbonyl, alkylsulfonyloxy, unsubstituted non-aromatic heterocyclic group and non-substituted with oxo. Non-aromatic carbocyclic group substituted with one or more substituents selected from aromatic heterocyclic groups), aromatic carbocyclic substituted with one or more substituents selected from substituent group C Group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group C, or an aromatic heterocyclic group substituted with one or more substituents selected from substituent group C The compound or a pharmaceutically acceptable salt thereof according to any one of (2 ′) to (5 ′) above.
(10 ') R 2 Is hydrogen, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, or substituted or unsubstituted alkynyl The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (9 ′), which is carbonyl.
(11 ') R 2 Or a compound thereof according to any one of (2 ′) to (9 ′) above, wherein is hydrogen, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted alkyloxycarbonyl Pharmaceutically acceptable salt.
(12 ') R 3 Or a pharmaceutically acceptable compound thereof according to any one of (2 ′) to (11 ′) above, wherein is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl salt.
(13 ') R 3 The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (11 ′), wherein is hydrogen or substituted or unsubstituted alkyl.
(14 ') R 4 Is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy A substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted amino, 2 ') to (13') or a pharmaceutically acceptable salt thereof.
(15 ') R 4 Is substituted group D (halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl and An alkyl substituted with one or more substituents selected from substituted or unsubstituted aromatic carbocyclic sulfonyl), an alkenyl substituted with one or more substituents selected from substituent group D, from substituent group D Alkyloxy substituted with one or more selected substituents, non-aromatic carbon substituted with one or more substituents selected from substituent group D Oxy, non-aromatic heterocyclic oxy substituted with one or more substituents selected from substituent group D, Non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group D An aromatic carbocyclic group substituted with one or more substituents selected from substituent group D, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group D, or The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (13 ′), which is amino substituted with one or more substituents selected from Substituent Group D.
(16 ')
R 4 Is substituted group D ′ (substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or unsubstituted Alkyloxy substituted with one or more substituents selected from aromatic heterocyclic groups), alkenyloxy substituted with one or more substituents selected from substituent group D ′, from substituent group D ′ The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (13 ′), which is alkynyloxy substituted with one or more selected substituents.
(17 ′) A pharmaceutical composition comprising as an active ingredient the compound according to any one of (2 ′) to (16 ′) or a pharmaceutically acceptable salt thereof.
(18 ′) The pharmaceutical composition according to the above (17 ′), which is an autotaxin inhibitor.
(19 ′) The pharmaceutical composition according to the above (17 ′) for the prevention or treatment of a disease involving autotaxin.
(20 ′) Use of the compound according to any one of (2 ′) to (16 ′) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for a disease involving autotaxin. .
(21 ′) A method for treating or preventing a disease involving autotaxin, which comprises administering the compound according to any one of (2 ′) to (16 ′) or a pharmaceutically acceptable salt thereof.

　本発明化合物はオートタキシン阻害活性を示し、医薬品、特にオートタキシンの関与する疾患、例えば、尿排泄障害、慢性腎臓病もしくは腎線維症、間質性肺炎もしくは肺線維症、強皮症、疼痛、線維筋痛症、関節炎リウマチ、血管新生、癌、腫瘍の形成、成長および伝播、動脈硬化症、眼疾患、脈絡膜血管新生および糖尿病網膜症、炎症性疾患、関節炎、神経変性、再狭窄、創傷治癒、移植片拒絶反応、多発性硬化症もしくは子宮内膜症等の治療または予防のための医薬として非常に有用である。 The compound of the present invention exhibits autotaxin inhibitory activity, and is a drug, particularly diseases involving autotaxin, such as urinary excretion disorder, chronic kidney disease or renal fibrosis, interstitial pneumonia or pulmonary fibrosis, scleroderma, pain, Fibromyalgia, rheumatoid arthritis, angiogenesis, cancer, tumor formation, growth and spread, arteriosclerosis, eye disease, choroidal neovascularization and diabetic retinopathy, inflammatory disease, arthritis, neurodegeneration, restenosis, wound healing It is very useful as a medicament for the treatment or prevention of transplant rejection, multiple sclerosis or endometriosis.

　以下に本明細書中で使用する各用語を説明する。なお、本明細書中、各用語は単独で使用されている場合もまたは他の用語と一緒になって使用されている場合も、特に記載の無い限り、同一の意義を有する。 The terms used in this specification are explained below. In addition, in this specification, each term has the same meaning, unless otherwise specified, when used alone or in combination with other terms.

　「ハロゲン」とは、フッ素、塩素、臭素およびヨウ素を包含する。特にフッ素および塩素が好ましい。
　Ｒ４における「ハロゲン」としては、塩素が挙げられる。 “Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.
“Halogen” in R 4 includes chlorine.

　「アルキル」とは、炭素数１～１０の直鎖または分枝状の炭化水素基を意味する。炭素数１～６のアルキル、炭素数１～４のアルキル、炭素数１～３のアルキル等を包含する。例えば、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル、ｎ－へプチル、イソヘプチル、ｎ－オクチル、イソオクチル、ｎ－ノニル、ｎ－デシル等が挙げられる。
　Ｒ１における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。特に、メチル、エチル、ｎ－プロピルが好ましい。
　Ｒ２における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。特に、メチルが好ましい。
　Ｒ３における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。特に、メチル、エチル等が好ましい。
　Ｒ４における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。特に、メチル、エチル、プロピル等が好ましい
　Ｒ５における「アルキル」としては、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、イソヘキシル、ｎ－ヘキシル、ｎ－ヘプタニル、ｎ－オクタニル等が挙げられる。特に、メチル、エチル、ｎ－プロピル、ｎ－ブチル、ｎ－ペンチル、ｎ－ヘキシルが好ましく、ｎ－ペンチル、ｎ－ヘキシル等がさらに好ましい。 “Alkyl” means a straight or branched hydrocarbon group having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.
“Alkyl” in R 1 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl, ethyl, and n-propyl are preferable.
“Alkyl” in R 2 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl is preferred.
“Alkyl” in R 3 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl, ethyl and the like are preferable.
“Alkyl” in R 4 includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyl, ethyl, propyl and the like are preferable. As “alkyl” in R 5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isohexyl, n -Hexyl, n-heptanyl, n-octanyl and the like. In particular, methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl are preferable, and n-pentyl, n-hexyl and the like are more preferable.

　「アルキルオキシ」、「アルキルチオ」、「アルキルカルボニル」、「アルキルオキシカルボニル」、「アルキルスルフィニル」および「アルキルスルホニル」のアルキル部分は、上記「アルキル」と同意義である。
　Ｒ４における「アルキルオキシ」のアルキル部分としては、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル等が挙げられる。特に、メチルオキシ、エチルオキシ、ｎ－プロピルオキシ、イソプロピルオキシが好ましい。 The alkyl part of “alkyloxy”, “alkylthio”, “alkylcarbonyl”, “alkyloxycarbonyl”, “alkylsulfinyl” and “alkylsulfonyl” has the same meaning as the above “alkyl”.
Examples of the alkyl moiety of “alkyloxy” in R 4 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like. In particular, methyloxy, ethyloxy, n-propyloxy and isopropyloxy are preferable.

　「ハロアルキル」および「ハロアルキルオキシ」とは、上記「アルキル」および「アルキルオキシ」のアルキル部分に、１～５個（好ましくは、１～３個）の上記「ハロゲン」が置換可能な任意の位置に置換した基を意味する。
Ｒ５における「ハロアルキル」としては、モノハロアルキル、ジハロアルキル、トリハロメチルアルキル等が挙げられる。特に、トリフルオロプロピル等が好ましい。 “Haloalkyl” and “haloalkyloxy” are any positions where 1 to 5 (preferably 1 to 3) of the above “halogens” can be substituted on the alkyl part of the above “alkyl” and “alkyloxy”. Means a group substituted by.
Examples of “haloalkyl” for R 5 include monohaloalkyl, dihaloalkyl, trihalomethylalkyl and the like. In particular, trifluoropropyl and the like are preferable.

　「アルケニル」とは、任意の位置に１以上の二重結合を有する炭素数２～１０の直鎖または分枝状の炭化水素基を意味する。炭素数２～８のアルケニル、炭素数３～６のアルケニル等を包含する。例えば、ビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デセニル等が挙げられる。
Ｒ４における「アルケニル」としては、ビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル等が挙げられる。特に、プロペニル、ｔ－ブチルプロペニル、イソブテニル等が好ましい。
　「アルケニルオキシ」、「アルケニルチオ」、「アルケニルカルボニル」、「アルケニルオキシカルボニル」、「アルケニルスルフィニル」、「アルケニルスルホニル」のアルケニル部分は、上記「アルケニル」と同意義である。 “Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
Examples of “alkenyl” in R 4 include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl and the like. In particular, propenyl, t-butylpropenyl, isobutenyl and the like are preferable.
The alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylcarbonyl”, “alkenyloxycarbonyl”, “alkenylsulfinyl” and “alkenylsulfonyl” has the same meaning as the above “alkenyl”.

　「アルキニル」とは、任意の位置に１以上の三重結合を有する炭素数２～１０の直鎖状または分枝状の炭化水素基を意味する。炭素数２～６のアルキニル、炭素数２～４のアルキニル等を包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等が挙げられる。アルキニルは任意の位置の１以上の三重結合の他、さらに二重結合を有していてもよい。
Ｒ３における「アルキニル」としては、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニニル、デシニル等が挙げられる。特に、プロピニルが好ましい。
　「アルキニルオキシ」、「アルキニルチオ」、「アルキニルカルボニル」、「アルキニルオキシカルボニル」、「アルキニルスルフィニル」、「アルキニルスルホニル」のアルキニル部分は、上記「アルキニル」と同意義である。 “Alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.
Examples of “alkynyl” in R 3 include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In particular, propynyl is preferred.
The alkynyl part of “alkynyloxy”, “alkynylthio”, “alkynylcarbonyl”, “alkynyloxycarbonyl”, “alkynylsulfinyl”, “alkynylsulfonyl” has the same meaning as the above “alkynyl”.

　「非芳香族炭素環式基」とは、炭素数３～８の環状飽和炭化水素基、およびこれらの環状飽和炭化水素基にさらに３～８員の環が１または２個縮合した基、ならびに炭素数３～８個の環状不飽和脂肪族炭化水素基、およびこれらの環状不飽和脂肪族炭化水素基にさらに３～８員の環が１または２個縮合した基を意味する。
　炭素数３～８の環状飽和炭化水素基としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロへプチル、シクロオクチル等が挙げられる。特に、炭素数３～６の環状飽和炭化水素基、炭素数５または６の環状飽和炭化水素基が好ましい。
　炭素数３～８の環状飽和炭化水素基に縮合する環としては、非芳香族炭素環（例えば、シクロアルカン環（例：シクロヘキサン環、シクロペンタン環等）、シクロアルケン環（例：シクロヘキセン環、シクロペンテン環）等）、非芳香族複素環（例えば、ピペリジン環、ピペラジン環、モルホリン環等）が挙げられる。なお、結合手は、炭素数３～８の環状飽和炭化水素基から出ているものとする。
　炭素数３～８の環状不飽和脂肪族炭化水素基に縮合する環としては、炭素環（芳香族炭素環（例えば、ベンゼン環、ナフタレン環等）、非芳香族炭素環（例えば、シクロアルカン環（例：シクロヘキサン環、シクロペンタン環等）、シクロアルケン環（例：シクロヘキセン環、シクロペンテン環等）等））、複素環（芳香族複素環（ピリジン環、ピリミジン環、ピロール環、イミダゾール環等）、非芳香族複素環（例えば、ピペリジン環、ピペラジン環、モルホリン環等）が挙げられる。なお、結合手は、炭素数３～８の環状不飽和脂肪族炭化水素基から出ているものとする。 The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, a group in which one or two 3- to 8-membered rings are condensed to these cyclic saturated hydrocarbon groups, and It means a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups.
Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. In particular, a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms and a cyclic saturated hydrocarbon group having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
Examples of the ring condensed with the C 3-8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring). (Example: cyclohexane ring, cyclopentane ring, etc.), cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.) The bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .

　例えば、以下の基も非芳香族炭素環式基に例示され、非芳香族炭素環式基に含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。

Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
 　Ｒ１における「非芳香族炭素環式基」としては、シクロアルキル、シクロアルケニル等が挙げられる。特に、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル等が好ましい。
　「非芳香族炭素環オキシ」、「非芳香族炭素環チオ」、「非芳香族炭素環カルボニル」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環スルフィニル」、「非芳香族炭素環スルホニル」の非芳香族炭素環部分は、上記「非芳香族炭素環」と同意義である。
　Ｒ４における「非芳香族炭素環オキシ」としては、シクロアルキルオキシ、シクロアルケニルオキシ等が挙げられる。特に、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロヘプチルオキシ、シクロオクチルオキシ、デカヒドロナフチルオキシ、ジヒドロインデニルオキシ等が好ましい。 For example, the following groups are also exemplified as non-aromatic carbocyclic groups and are included in non-aromatic carbocyclic groups. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000032
 Examples of the “non-aromatic carbocyclic group” for R 1 include cycloalkyl, cycloalkenyl and the like. In particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are preferable.
“Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic thio”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfinyl”, “non-aromatic The non-aromatic carbocyclic moiety of “carbocycle sulfonyl” has the same meaning as the above “non-aromatic carbocycle”.
Examples of the “non-aromatic carbocyclic oxy” in R 4 include cycloalkyloxy and cycloalkenyloxy. In particular, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, decahydronaphthyloxy, dihydroindenyloxy and the like are preferable.

　「芳香族炭素環式基」とは、単環または多環の芳香族炭素環式基、およびこれらの単環または多環の芳香族炭素環式基にさらに３～８員の環が１または２個縮合した基を意味する。単環または多環の芳香族炭素環式基としては、例えば、フェニル、ナフチル、アントリル、フェナントリルが挙げられる。特にフェニルが好ましい。
　単環または多環の芳香族炭素環式基に縮合する環としては、非芳香族炭素環（例えば、シクロアルカン環（例：シクロヘキサン環、シクロペンタン環等）、シクロアルケン環（例：シクロヘキセン環、シクロペンテン環等）等）、非芳香族複素環（例えば、ピペリジン環、ピペラジン環、モルホリン環等）が挙げられる。なお、結合手は、単環または多環の芳香族炭素環式基から出ているものとする。
　例えば、以下の基も芳香族炭素環式基として例示され、芳香族炭素環式基に含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。

Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
 　Ｒ１における「芳香族炭素環式基」としては、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。特に、フェニルが好ましい。
　Ｒ４における「芳香族炭素環式基」としては、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。特に、フェニルが好ましい。
　「芳香族炭素環オキシ」、「芳香族炭素環チオ」、「芳香族炭素環カルボニル」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環スルフィニル」、「芳香族炭素環スルホニル」の非芳香族炭素環部分は、上記「芳香族炭素環」と同意義である。 “Aromatic carbocyclic group” means a monocyclic or polycyclic aromatic carbocyclic group, and these monocyclic or polycyclic aromatic carbocyclic groups are further substituted with one or more 3- to 8-membered rings. It means a group condensed with two. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic carbocyclic group.
For example, the following groups are also exemplified as the aromatic carbocyclic group, and are included in the aromatic carbocyclic group. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
 Examples of the “aromatic carbocyclic group” for R 1 include phenyl, naphthyl, anthryl, phenanthryl and the like. In particular, phenyl is preferred.
Examples of the “aromatic carbocyclic group” for R 4 include phenyl, naphthyl, anthryl, phenanthryl and the like. In particular, phenyl is preferred.
"Aromatic carbocyclic oxy", "aromatic carbocyclic thio", "aromatic carbocyclic carbonyl", "aromatic carbocyclic oxycarbonyl", "aromatic carbocyclic sulfinyl", "aromatic carbocyclic sulfonyl" The aromatic carbocyclic moiety has the same meaning as the above “aromatic carbocycle”.

　「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する単環または多環の芳香族へテロ環式基、およびこれらの単環または多環の芳香族へテロ環式基にさらに３～８員の環が１または２個縮合した基を意味する。
　「単環の芳香族ヘテロ環式基」としては、特に５員または６員の芳香族複素環式基が好ましく、例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリル、チエニル等が挙げられる。
　「多環の芳香族ヘテロ環式基」としては、特に５員または６員の環が縮合した芳香族複素環式基が好ましく、例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等の２環の芳香族へテロ環式基；カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチニル、フェノキサジニル、ジベンゾフリル等の３環の芳香族へテロ環式基等が挙げられる。多環の芳香族へテロ環式基である場合、結合手をいずれの環に有していてもよい。
　単環または多環の芳香族へテロ環式基に縮合する環としては、非芳香族炭素環（例えば、シクロアルカン環（例：シクロヘキサン環、シクロペンタン環等）、シクロアルケン環（例：シクロヘキセン環、シクロペンテン環等）等）、非芳香族複素環（例えば、ピペリジン環、ピペラジン環、モルホリン環等）が挙げられる。なお、結合手は、単環または多環の芳香族へテロ環式基から出ているものとする。 “Aromatic heterocyclic group” means a monocyclic or polycyclic aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these monocyclic rings Alternatively, it means a group obtained by further condensing one or two 3- to 8-membered rings on a polycyclic aromatic heterocyclic group.
As the “monocyclic aromatic heterocyclic group”, a 5-membered or 6-membered aromatic heterocyclic group is particularly preferable, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, Examples include tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
As the “polycyclic aromatic heterocyclic group”, an aromatic heterocyclic group in which a 5- or 6-membered ring is condensed is particularly preferable. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, Phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzo Bicyclic aromatic heterocyclic groups such as thienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazopyridyl; carbazolyl Acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, cycloalkenyl, phenoxazinyl, heterocyclic groups such as the aromatic tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.
Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene). Ring, cyclopentene ring, etc.)) and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.

　例えば、以下の基も芳香族複素環式基として例示され、芳香族複素環式基に含まれる。なお、これらの基は置換可能な任意の位置で置換されていてもよい。

Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000036
 For example, the following groups are also exemplified as the aromatic heterocyclic group, and are included in the aromatic heterocyclic group. These groups may be substituted at any substitutable position.
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000036

　「芳香族複素環式基」としては、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル、フリル、チエニル、インドリル、イソインドリル、インダゾリル、インドリジニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、オキサゾロピリジル、チアゾロピリジル等の２環の芳香族へテロ環式基；カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチニル、フェノキサジニル、ジベンゾフリル等が挙げられる。特に、フリル、チアゾリル、ピラゾリル、ピリジル、ピリミジニル、ピラジニル、ベンゾフリル、ベンゾチオフェニル等が好ましい。 `` Aromatic heterocyclic groups '' include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, isoindolyl , Indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl Thiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as ryl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazopyridyl; carbazolyl, acridinyl, xanthenyl, phenothiazinyl, Examples include phenoxatinyl, phenoxazinyl, dibenzofuryl and the like. Particularly preferred are furyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothiophenyl and the like.

　Ｒ１における「芳香族複素環式基」としては、フリル、チアゾリル、ピラゾリル、ピリジル、ピリミジニル、ピラジニル、ベンゾフリル、ベンゾチオフェニル等が挙げられる。特に、ピリジル等が好ましい。
　Ｒ４における「芳香族複素環式基」としては、フリル、チアゾリル、ピラゾリル、ピリジル、ピリミジニル、ピラジニル、ベンゾフリル、ベンゾチオフェニル等が挙げられる。特に、ピリジル等が好ましい。 Examples of the “aromatic heterocyclic group” in R 1 include furyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothiophenyl, and the like. In particular, pyridyl and the like are preferable.
Examples of the “aromatic heterocyclic group” in R 4 include furyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothiophenyl, and the like. In particular, pyridyl and the like are preferable.

　「芳香族複素環オキシ」、「芳香族複素環チオ」、「芳香族複素環カルボニル」、「芳香族複素環オキシカルボニル」、「芳香族複素環スルフィニル」、「芳香族複素環スルホニル」の芳香族複素環部分は、上記「芳香族複素環」と同意義である。 "Aromatic heterocyclic oxy", "aromatic heterocyclic thio", "aromatic heterocyclic carbonyl", "aromatic heterocyclic oxycarbonyl", "aromatic heterocyclic sulfinyl", "aromatic heterocyclic sulfonyl" The group heterocyclic moiety has the same meaning as the above “aromatic heterocyclic ring”.

　「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択されるヘテロ原子を環内に１以上有する非芳香族へテロ環式基、およびこれらの非芳香族へテロ環式基にさらに３～８員の環が１または２個縮合した基を意味し、単環の非芳香族へテロ環式基または多環の非芳香族へテロ環式基を包含する。 “Non-aromatic heterocyclic group” means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic rings This means a group obtained by further condensing one or two 3- to 8-membered rings to the formula group, and includes a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.

　「単環の非芳香族複素環式基」として、具体的には、ジオキサニル、チイラニル、オキシラニル、オキサチオラニル、アゼチジニル、チアニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペリジノ、ピペラジニル、ピペラジノ、モルホリニル、モルホリノ、オキサジアジニル、ジヒドロピリジル、チオモルホリニル、チオモルホリノ、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、オキサゾリジル、チアゾリジル等が挙げられる。 Specific examples of the `` monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.

　「多環の非芳香族複素環式基」として、具体的には、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。多環の非芳香族へテロ環式基である場合、結合手をいずれの環に有していてもよい。 Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.

　例えば、以下の基も非芳香族複素環式基に含まれる。

Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000040
 For example, the following groups are also included in the non-aromatic heterocyclic group.
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000040

　「非芳香族複素環式基」としては、ジオキサニル、チイラニル、オキシラニル、オキサチオラニル、アゼチジニル、チアニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペリジノ、ピペラジニル、ピペラジノ、モルホリニル、モルホリノ、オキサジアジニル、ジヒドロピリジル、チオモルホリニル、チオモルホリノ、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、オキサゾリジル、チアゾリジル、アゼパニル等が挙げられる。特に、アゼチジニル、ピペリジニル、ピペラジニル、モルホリニル、モルホリノ、アゼパニル等が好ましい。 Examples of the “non-aromatic heterocyclic group” include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazinoyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, morpholinyl, Examples include dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl, azepanyl and the like. In particular, azetidinyl, piperidinyl, piperazinyl, morpholinyl, morpholino, azepanyl and the like are preferable.

　Ｒ４における「非芳香族複素環式基」としては、ピロリジニル、テトラヒドロフラニル、ピペリジノ、ピペリジニル、ピペラジニル、テトラヒドロピラニル、モルホリニル、モルホリノ、モルホリニル等が挙げられる。特にピペリジニル等が好ましい。 Examples of the “non-aromatic heterocyclic group” for R 4 include pyrrolidinyl, tetrahydrofuranyl, piperidino, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, morpholino, morpholinyl and the like. Particularly preferred is piperidinyl.

　「非芳香族複素環オキシ」、「非芳香族複素環チオ」、「非芳香族複素環カルボニル」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環スルフィニル」、「非芳香族複素環スルホニル」の非芳香族複素環部分は、上記「非芳香族複素環」と同意義である。 "Non-aromatic heterocyclic oxy", "Non-aromatic heterocyclic thio", "Non-aromatic heterocyclic carbonyl", "Non-aromatic heterocyclic oxycarbonyl", "Non-aromatic heterocyclic sulfinyl", "Non-aromatic The non-aromatic heterocyclic part of “heterocyclic sulfonyl” has the same meaning as the above “non-aromatic heterocyclic ring”.

　Ｒ４における「非芳香族複素環オキシ」としては、アゼチジニルオキシ、ピペリジニルオキシ、テトラヒドロピラニルオキシ等が好ましい。 As the “non-aromatic heterocyclic oxy” in R 4 , azetidinyloxy, piperidinyloxy, tetrahydropyranyloxy and the like are preferable.

　置換もしくは非置換の非芳香族炭素環式基または置換もしくは非置換の非芳香族複素環式基は、１または２個のオキソ、チオキソまたは置換もしくは非置換のイミノで置換されていてもよい。 The substituted or unsubstituted non-aromatic carbocyclic group or the substituted or unsubstituted non-aromatic heterocyclic group may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino.

　「置換アルキル」、「置換アルケニル」、「置換アルキニル」、「置換非芳香族炭素環式基」、「置換芳香族炭素環式基」、「置換芳香族複素環式基」または「置換非芳香族複素環式基」の置換基としては、ハロゲン、ヒドロキシ、メルカプト、ニトロ、ニトロソ、シアノ、アジド、ホルミル、アミノ、カルボキシ、アルキル、ハロアルキル、アルケニル、アルキニル、非芳香族炭素環式基、芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、置換カルバモイル、置換スルファモイル、置換アミジノ、式：－Ｏ－Ｒｘで示される基、式：－Ｏ－Ｃ（＝Ｏ）－Ｒｘで示される基、式：－Ｃ（＝Ｏ）－Ｒｘで示される基、式：－Ｃ（＝Ｏ）－Ｏ－Ｒｘで示される基、式：－Ｓ－Ｒｘで示される基または式：－ＳＯ２－Ｒｘで示される基（ここでＲｘは、アルキル、ハロアルキル、アルケニル、アルキニル、非芳香族炭素環式基、芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、カルバモイル、スルファモイルまたはアミジノ）が挙げられる。これらの置換基で、置換可能な任意の位置が１～数個、置換されていてもよい。 “Substituted alkyl”, “Substituted alkenyl”, “Substituted alkynyl”, “Substituted non-aromatic carbocyclic group”, “Substituted aromatic carbocyclic group”, “Substituted aromatic heterocyclic group” or “Substituted non-aromatic” Substituents for `` heterocyclic group '' include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic Carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, substituted carbamoyl, substituted sulfamoyl, substituted amidino, group represented by the formula: —O—R x , formula: —O—C (═O ) -R x group, formula: -C (= O) -R x group, formula: -C (= O) -O-R x group, formula: -S-R x a group represented by or the formula: represented by -SO 2 -R x That group (wherein R x is alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, carbamoyl, sulfamoyl Or amidino). With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.

　Ｒ１における「置換アルキル」の置換基としては、ハロゲン、ヒドロキシ、カルボキシ、非芳香族炭素環式基、芳香族炭素環式基、非芳香族複素環式基、芳香族複素環式基、アルキルオキシ、アルキルオキシカルボニル、アルキルカルボニルオキシ等が挙げられる。特に芳香族炭素環式基、アルキルオキシカルボニル、アルキルカルボニルオキシ等が好ましい。 As the substituent of “substituted alkyl” in R 1 , halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl Examples include oxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. In particular, an aromatic carbocyclic group, alkyloxycarbonyl, alkylcarbonyloxy and the like are preferable.

　Ｒ２における「置換アルキル」の置換基としては、ハロゲン、ヒドロキシ、カルボキシ、非芳香族炭素環式基、芳香族炭素環式基、非芳香族複素環式基、芳香族複素環式基、アルキルオキシ、アルキルオキシカルボニル、アルキルカルボニルオキシ等が挙げられる。芳香族炭素環式基が好ましく、特にフェニル等が好ましい。 The substituent of the "substituted alkyl" for R 2, halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, a non-aromatic heterocyclic group, an aromatic heterocyclic group, alkyl Examples include oxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. Aromatic carbocyclic groups are preferred, and phenyl and the like are particularly preferred.

　Ｒ３における「置換アルキル」の置換基としては、ハロゲン、ヒドロキシ、カルボキシ、非芳香族炭素環式基、芳香族炭素環式基、非芳香族複素環式基、芳香族複素環式基、アルキルオキシ、アルキルオキシカルボニル、アルキルカルボニルオキシ等が挙げられる。特に、ヒドロキシ、アルキルオキシカルボニル等が好ましい。 As the substituent of “substituted alkyl” in R 3 , halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl Examples include oxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. In particular, hydroxy, alkyloxycarbonyl and the like are preferable.

　Ｒ４における「置換アルキル」の置換基としては、ハロゲン、ヒドロキシ、カルボキシ、非芳香族炭素環式基、芳香族炭素環式基、非芳香族複素環式基、芳香族複素環式基、アルキルオキシ、芳香族炭素環アルキルオキシ、アルキルオキシカルボニル、アルキルカルボニルオキシ等が挙げられる。特に、ヒドロキシ、芳香族炭素環アルキルオキシ、アルキルオキシカルボニル等が好ましい。 As the substituent of “substituted alkyl” in R 4 , halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic group, alkyl Examples include oxy, aromatic carbocyclic alkyloxy, alkyloxycarbonyl, alkylcarbonyloxy and the like. In particular, hydroxy, aromatic carbocyclic alkyloxy, alkyloxycarbonyl and the like are preferable.

　Ｒ５における「置換アルキル」の置換基としては、特に、ハロゲン、芳香族炭素環式基、ハロ芳香族炭素環式基が好ましく、ハロゲン、フェニル、ハロフェニル等がさらに好ましい。 The substituent of “substituted alkyl” in R 5 is particularly preferably a halogen, an aromatic carbocyclic group or a haloaromatic carbocyclic group, more preferably halogen, phenyl, halophenyl or the like.

　Ｒ４における「置換アルキルオキシ」の置換基としては、非芳香族炭素環式基、ハロ芳香族炭素環式基、シアノ芳香族炭素環式基、アルキルオキシ芳香族炭素環式基、ハロアルキル芳香族炭素環式基等が挙げられ、特に、スピロ[２．５]オクチル、ハロフェニル、シアノフェニル、メチルオキシフェニル、トリフルオロメチルフェニル等が好ましい。 As the substituent of “substituted alkyloxy” in R 4 , non-aromatic carbocyclic group, haloaromatic carbocyclic group, cyanoaromatic carbocyclic group, alkyloxyaromatic carbocyclic group, haloalkylaromatic group Examples thereof include carbocyclic groups, and spiro [2.5] octyl, halophenyl, cyanophenyl, methyloxyphenyl, trifluoromethylphenyl and the like are particularly preferable.

　Ｒ４における「置換アルケニル」の置換基としては、芳香族炭素環式基等が好ましい。
　「置換芳香族炭素環基」の置換基としては、シアノ、ハロゲン、ヒドロキシ、カルボキシ、スルホ、アミノ、アルキル、ヒドロキシアルキル、アルキルオキシアルキル、アルキルオキシ、ヒドロキシアルキルオキシ、ハロ芳香族炭素環式基、アルキル非芳香族複素環式基、アルキルカルボニルアミノアルキル非芳香族複素環式基、アルキルチオ、アルキルカルボニル、アルキルオキシカルボニル、非芳香族複素環カルボニル、アルキルオキシ非芳香族複素環カルボニル、アルキルカルボニル非芳香族複素環カルボニル、ヒドロキシ非芳香族複素環カルボニル、アルキルスルホニル非芳香族複素環カルボニル、ハロアルキルアミノカルボニル、ヒドロキシアルキルアミノカルボニル、アルキルアミノカルボニル、アミノアルキルアミノカルボニル、ヒドロキシアルキルアミノカルボニル、アミノスルホニルアルキルアミノカルボニル、アルキルスルホニルアルキルアミノカルボニル、カルバモイル、アルキルカルバモイル、ハロアルキルカルバモイル、シアノアルキルカルバモイル、ヒドロキシアルキルカルバモイル、非芳香族複素環アルキルカルバモイル、アルキル非芳香族複素環アルキルカルバモイル、アルキニルカルバモイル、非芳香族炭素環アルキルカルバモイル、アミノアルキルカルバモイル、ヒドロキシアルキルシクロアルキルカルバモイル、非芳香族複素環アミノアルキルカルバモイル、アルキルオキシアルキルカルバモイル、アルキルアミノアルキルカルバモイル、ヒドロキシアルキルカルバモイル、ヒドロキシアルキルオキシアルキルカルバモイル、ヒドロキシアルキル（アルキル）カルバモイル、ジヒドロキシアルキルカルバモイル、アルキルカルボニルアルキルカルバモイル、非芳香族複素環カルボニルアルキルカルバモイル、アルキルカルボニルアミノアルキルカルバモイル、アルキルスルホニルアルキルカルバモイル、スルファモイル芳香族炭素環アルキル、アルキルスルホニル芳香族複素環アルキル、芳香族複素環-芳香族複素環アルキル、非芳香族複素環スルホニルアルキルカルバモイル、スルファモイルアルキルカルバモイル、ニトロ芳香族炭素環アルキル、非芳香族炭素環カルバモイル、アルキルオキシ芳香族炭素環カルバモイル、芳香族複素環アルキルカルバモイル、アルキル非芳香族炭素環カルバモイル、ヒドロキシアルキル非芳香族炭素環カルバモイル、非芳香族複素環カルバモイル、アルキルスルホニル、アミノスルホニル、アルキルアミノスルホニル、ヒドロキシアルキルアミノスルホニル、非芳香族複素環スルホニル、アルキルアミノ、アルキルカルボニルアミノ、非芳香族複素環カルボニルアミノ、アルキルスルホニルアミノ等が挙げられる。 The substituent of “substituted alkenyl” in R 4 is preferably an aromatic carbocyclic group or the like.
Examples of the substituent of the “substituted aromatic carbocyclic group” include cyano, halogen, hydroxy, carboxy, sulfo, amino, alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxy, hydroxyalkyloxy, haloaromatic carbocyclic group, Alkyl non-aromatic heterocyclic group, alkylcarbonylaminoalkyl non-aromatic heterocyclic group, alkylthio, alkylcarbonyl, alkyloxycarbonyl, non-aromatic heterocyclic carbonyl, alkyloxy non-aromatic heterocyclic carbonyl, alkylcarbonyl non-aromatic Aromatic heterocyclic carbonyl, hydroxy non-aromatic heterocyclic carbonyl, alkylsulfonyl non-aromatic heterocyclic carbonyl, haloalkylaminocarbonyl, hydroxyalkylaminocarbonyl, alkylaminocarbonyl, aminoalkylaminocarbonyl , Hydroxyalkylaminocarbonyl, aminosulfonylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl, carbamoyl, alkylcarbamoyl, haloalkylcarbamoyl, cyanoalkylcarbamoyl, hydroxyalkylcarbamoyl, non-aromatic heterocyclic alkyl carbamoyl, alkyl non-aromatic heterocyclic alkyl carbamoyl , Alkynyl carbamoyl, non-aromatic carbocyclic alkyl carbamoyl, aminoalkyl carbamoyl, hydroxyalkyl cycloalkyl carbamoyl, non-aromatic heterocyclic aminoalkyl carbamoyl, alkyloxyalkyl carbamoyl, alkylaminoalkyl carbamoyl, hydroxyalkyl carbamoyl, hydroxyalkyloxyalkyl carbamoyl , Hydroxya Kill (alkyl) carbamoyl, dihydroxyalkylcarbamoyl, alkylcarbonylalkylcarbamoyl, non-aromatic heterocyclic carbonylalkylcarbamoyl, alkylcarbonylaminoalkylcarbamoyl, alkylsulfonylalkylcarbamoyl, sulfamoyl aromatic carbocyclic alkyl, alkylsulfonyl aromatic heterocyclic alkyl, Aromatic heterocycle-aromatic heterocycle alkyl, non-aromatic heterocycle sulfonylalkylcarbamoyl, sulfamoylalkylcarbamoyl, nitroaromatic carbocyclic alkyl, nonaromatic carbocyclic carbamoyl, alkyloxy aromatic carbocyclic carbamoyl, aromatic Heterocyclic alkylcarbamoyl, alkyl non-aromatic carbocyclic carbamoyl, hydroxyalkyl non-aromatic carbocyclic carbamoyl, non-aromatic heterocyclic carbamoyl , Alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, hydroxyalkyl aminosulfonyl, non-aromatic heterocyclic sulfonyl, alkylamino, alkylcarbonylamino, non-aromatic heterocyclic carbonylamino, alkylsulfonylamino, and the like.

　Ｒ１における「置換芳香族炭素環基」の置換基としては、ハロゲン、ヒドロキシ、カルボキシ、非芳香族炭素環式基、芳香族炭素環式基、非芳香族複素環式基、芳香族複素環式基、アルキルオキシ、アルキルオキシカルボニル、アルキルアミノ、アルキルカルボニルアミノ、非芳香族複素環アルキルカルバモイルが挙げられる。特に、ハロゲン、ヒドロキシ、カルボキシ、芳香族炭素環式基、非芳香族複素環式基、アルキルオキシ、アルキルオキシカルボニル、アルキルアミノ、アルキルカルボニルアミノ、非芳香族複素環アルキルカルバモイルが好ましい。 Examples of the substituent of the “substituted aromatic carbocyclic group” in R 1 include halogen, hydroxy, carboxy, non-aromatic carbocyclic group, aromatic carbocyclic group, non-aromatic heterocyclic group, aromatic heterocyclic ring Examples include a formula group, alkyloxy, alkyloxycarbonyl, alkylamino, alkylcarbonylamino, and non-aromatic heterocyclic alkylcarbamoyl. In particular, halogen, hydroxy, carboxy, aromatic carbocyclic group, non-aromatic heterocyclic group, alkyloxy, alkyloxycarbonyl, alkylamino, alkylcarbonylamino, and non-aromatic heterocyclic alkylcarbamoyl are preferable.

　Ｒ４における「置換芳香族複素環基」の置換基としては、ハロゲン、シアノ、トリハロメチル、アルケニル等が挙げられる。 Examples of the substituent of the “substituted aromatic heterocyclic group” in R 4 include halogen, cyano, trihalomethyl, alkenyl and the like.

　「置換非芳香族複素環基」の置換基としては、シアノ、ヒドロキシ、カルボキシ、アルキル、ヒドロキシアルキル、アルキルオキシアルキル、カルボキシアルキル、非芳香族炭素環式基アルキル、芳香族炭素環アルキル、アルキルオキシカルボニルアルキル、アルキルオキシカルボニルアミノアルキル、アミノアルキル、アルキルカルボニル、アルキルオキシカルボニル、アルキルアミノカルボニル、カルボキシアルキルアミノカルボニル、非芳香族複素環カルボニル、ニトロ芳香族炭素環カルボニル、芳香族炭素環カルバモイル、アルキル非芳香族複素環カルバモイル、アルキルアミノ、アルキルカルボニルアミノ、アルキルスルホニルアミノ、ジアルキルアミノスルホニル、ヒドロキシアミノスルホニル、非芳香族複素環スルホニル、非芳香族炭素環式基、芳香族炭素環式基、ハロ芳香族炭素環式基、非芳香族複素環式基、アルキルオキシカルボニル非芳香族複素環式基等が挙げられる。 Substituents of “substituted non-aromatic heterocyclic group” include cyano, hydroxy, carboxy, alkyl, hydroxyalkyl, alkyloxyalkyl, carboxyalkyl, non-aromatic carbocyclic group alkyl, aromatic carbocyclic alkyl, alkyloxy Carbonylalkyl, alkyloxycarbonylaminoalkyl, aminoalkyl, alkylcarbonyl, alkyloxycarbonyl, alkylaminocarbonyl, carboxyalkylaminocarbonyl, non-aromatic heterocyclic carbonyl, nitroaromatic carbocyclic carbonyl, aromatic carbocyclic carbamoyl, non-alkyl Aromatic heterocyclic carbamoyl, alkylamino, alkylcarbonylamino, alkylsulfonylamino, dialkylaminosulfonyl, hydroxyaminosulfonyl, non-aromatic heterocyclic sulfonyl, Aromatic carbocyclic group, aromatic carbocyclic group, a halo-aromatic carbocyclic groups, non-aromatic heterocyclic group, such as an alkyloxycarbonyl non-aromatic heterocyclic group.

　Ｒ１における「非芳香族複素環式基」の置換基としては、アルキルオキシカルボニル等が挙げられる。 Examples of the substituent of the “non-aromatic heterocyclic group” in R 1 include alkyloxycarbonyl and the like.

　Ｒ４における「非芳香族複素環式基」の置換基としては、ハロゲン、シアノ、ヒドロキシ、アルキル、ヒドロキシアルキル、トリフルオロアルキル、アルキルオキシカルボニルアルキル、置換もしくは非置換の芳香族炭素環式基、ヒドロキシ、ハロゲン、芳香族炭素環アルキル、芳香族複素環式基、アルキルオキシカルボニル、カルバモイル、カルボキシアルキルカルバモイル等が挙げられる。 As the substituent of the “non-aromatic heterocyclic group” in R 4 , halogen, cyano, hydroxy, alkyl, hydroxyalkyl, trifluoroalkyl, alkyloxycarbonylalkyl, substituted or unsubstituted aromatic carbocyclic group, Examples include hydroxy, halogen, aromatic carbocyclic alkyl, aromatic heterocyclic group, alkyloxycarbonyl, carbamoyl, carboxyalkylcarbamoyl and the like.

　Ｒ４における「置換非芳香族複素環オキシ」の置換基としては、シアノ、アルキルオキシカルボニル等が挙げられる。 Examples of the substituent of “substituted non-aromatic heterocyclic oxy” in R 4 include cyano, alkyloxycarbonyl and the like.

　「置換アミノ」、「置換カルバモイル」、「置換スルファモイル」、「置換アミジノ」または「置換イミノ」の置換基としては、ヒドロキシ、シアノ、ホルミル、アルキル、ハロアルキル、アルケニル、アルキニル、非芳香族炭素環式基、芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、カルバモイル、スルファモイル、アミジノ、式：－Ｏ－Ｒで示される基、式：－Ｃ（＝Ｏ）－Ｒで示される基、式：－Ｃ（＝Ｏ）－Ｏ－Ｒで示される基、または式：－ＳＯ２－Ｒで示される基（ここでＲは、アルキル、ハロアルキル、アルケニル、アルキニル、非芳香族炭素環式基、芳香族炭素環式基、芳香族複素環式基または非芳香族複素環式基）が挙げられる。これらの置換基で、置換可能な任意の位置が１～２個、置換されていてもよい。 Substituents for “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino” include hydroxy, cyano, formyl, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic Group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R, formula: —C (═O) — A group represented by R, a group represented by the formula: —C (═O) —O—R, or a group represented by the formula: —SO 2 —R, wherein R is alkyl, haloalkyl, alkenyl, alkynyl, non- Aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group or non-aromatic heterocyclic group). With these substituents, 1 to 2 arbitrary positions where substitution is possible may be substituted.

　Ｒ４における「置換アミノ」の置換基としては、アルキル、ヒドロキシアルキル、アルキルオキシアルキル、カルボキシアルキル、アルキルアミノアルキル、芳香族炭素環アルキル、アルキルオキシ芳香族炭素環アルキル、アルキルオキシカルボニルアルキル、カルボキシ芳香族炭素環式基アルキル、アルキルアミノ芳香族炭素環アルキル、メチレンジオキシ芳香族炭素環アルキル、芳香族複素環アルキル、アルキル芳香族複素環アルキル、非芳香族複素環アルキル、アルキル非芳香族複素環アミノ、アルキルカルボニルアミノアルキル、非芳香族炭素環式基、アルキルアミノスルホニル等が挙げられる。
　Ｒ４における「置換アミノ」の置換基としては、ハロ芳香族炭素環アルキル、シアノ芳香族炭素環スルホニル等が挙げられる。 As the substituent of “substituted amino” in R 4 , alkyl, hydroxyalkyl, alkyloxyalkyl, carboxyalkyl, alkylaminoalkyl, aromatic carbocyclic alkyl, alkyloxy aromatic carbocyclic alkyl, alkyloxycarbonylalkyl, carboxy aromatic Aromatic carbocyclic group alkyl, alkylamino aromatic carbocyclic alkyl, methylenedioxy aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, alkyl aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, alkyl non-aromatic heterocyclic ring Examples include amino, alkylcarbonylaminoalkyl, non-aromatic carbocyclic group, alkylaminosulfonyl and the like.
Examples of the substituent of “substituted amino” in R 4 include haloaromatic carbocyclic alkyl, cyanoaromatic carbocyclic sulfonyl and the like.

　本発明化合物において、特に好ましい態様を以下に示す。
　一般式（Ｉ）で示される化合物において、Ｒ１～Ｒ５の好ましい置換基の群を（Ｉａ）～（Ｉｏ）で示す。それらの可能な組合せの化合物が好ましい。 In the compound of the present invention, particularly preferred embodiments are shown below.
In the compounds represented by the general formula (I), preferred substituent groups of R 1 to R 5 are represented by (Ia) to (Io). Those possible combinations of compounds are preferred.

　Ｒ１は、（Ｉａ）置換もしくは非置換のアルキル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の芳香族複素環式基が好ましく、さらに、（Ｉｂ）置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の芳香族複素環式基がより好ましく、（Ｉｃ）置換基群B（ヒドロキシ、アルコキシ、カルボキシ、ハロゲン、置換若しくは非置換のアミノ、カルボキシアルキル、カルボキシアルキルオキシ、アルキルスルホニルオキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換のカルバモイル）から選択される１以上の置換基で置換されていてもよい非芳香族炭素環式基、置換基群Bから選択される１以上の置換基で置換されていてもよい芳香族炭素環式基、置換基群Bから選択される１以上の置換基で置換されていてもよい非芳香族複素環式基または置換基群Bから選択される１以上の置換基で置換されていてもよい芳香族複素環式基、（Ｉｄ）置換基群Ｃ（ヒドロキシ、カルボキシ、カルボキシアルキル、カルボキシアルキルオキシ、アルキルカルボニルアミノ、非芳香族複素環アルキルアミノカルボニル、アルキルスルホニルオキシ、非置換非芳香族複素環式基およびオキソで置換された非芳香族複素環式基）から選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｃから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｃから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｃから選択される１以上の置換基で置換された芳香族複素環式基が特に好ましい。 R 1 is (Ia) substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group Group or a substituted or unsubstituted aromatic heterocyclic group is preferred, and (Ib) a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted group And a non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group of (Ic) substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, carboxyalkyl, Carboxyalkyloxy, alkylsulfonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Is selected from a non-aromatic carbocyclic group optionally substituted with one or more substituents selected from an unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted carbamoyl, and substituent group B An aromatic carbocyclic group optionally substituted with one or more substituents, a non-aromatic heterocyclic group or substituent optionally substituted with one or more substituents selected from substituent group B An aromatic heterocyclic group optionally substituted with one or more substituents selected from group B, (Id) substituent group C (hydroxy, carboxy, carboxyalkyl, carboxyalkyloxy, alkylcarbonylamino, non-aromatic Non-aromatic substituted with one or more substituents selected from the group consisting of aromatic heterocyclic alkylaminocarbonyl, alkylsulfonyloxy, unsubstituted non-aromatic heterocyclic group and oxo-substituted non-aromatic heterocyclic group) Aromatic carbocyclic group, aromatic carbocyclic group substituted with one or more substituents selected from substituent group C, non-aromatic substituted with one or more substituents selected from substituent group C Particularly preferred is an aromatic heterocyclic group substituted with one or more substituents selected from a heterocyclic group or substituent group C.

　Ｒ２は、（Ｉｅ）水素、ハロゲン、ヒドロキシ、ホルミル、カルボキシ、シアノ、置換もしくは非置換のアルキルオキシカルボニルまたは置換もしくは非置換のアルキルが好ましく、さらに（Ｉｆ）水素、ハロゲン、アルキルオキシカルボニルまたは置換もしくは非置換のアルキルがより好ましく、特に（Ｉｇ）水素が好ましい。 R 2 is preferably (Ie) hydrogen, halogen, hydroxy, formyl, carboxy, cyano, substituted or unsubstituted alkyloxycarbonyl or substituted or unsubstituted alkyl, and (If) hydrogen, halogen, alkyloxycarbonyl or substituted Alternatively, unsubstituted alkyl is more preferable, and (Ig) hydrogen is particularly preferable.

　Ｒ３は、（Ｉｈ）水素、ハロゲン、シアノ、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニルまたは置換もしくは非置換のアミノが好ましく、さらに（Ｉｉ）水素、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニルまたは置換もしくは非置換のアルキニルがより好ましく、特に（Ｉｊ）水素が好ましい。 R 3 is preferably (Ih) hydrogen, halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted amino, and (Ii) hydrogen More preferably, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, particularly (Ij) hydrogen.

　Ｒ４は、（Ｉｋ）置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシまたは置換もしくは非置換のアミノが好ましく、さらに（Ｉｌ）置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基また置換もしくは非置換の芳香族複素環式基がより好ましく、特に（Ｉｍ）置換もしくは非置換の芳香族炭素環式基また置換もしくは非置換の芳香族複素環式基が好ましい。 R 4 represents (Ik) substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbon Cyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic hetero Ring oxy or substituted or unsubstituted amino is preferred, and (Il) substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocycle A cyclic group or a substituted or unsubstituted aromatic heterocyclic group is more preferable, and in particular, (Im) a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic ring. Formula groups are preferred.

　Ｒ５は、（Ｉｎ）置換基群Ｅ（ハロゲン、シアノ、ヒドロキシ、ホルミル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニル、置換もしくは非置換の芳香族複素環スルホニルおよび置換もしくは非置換のアミノ）から選択される１以上の置換基で置換されたＣ１－Ｃ３アルキルまたは置換もしくは非置換のＣ４－Ｃ８アルキルが好ましく、さらに（Ｉｏ）置換基群Ｅ’（ハロゲン、シアノ、置換もしくは非置換のアルキルカルボニルおよび置換もしくは非置換のアルキルオキシカルボニル）から選択される１以上の置換基で置換されていてもよいＣ１－Ｃ８アルキルが好ましく、特に、（Ｉｐ）置換基群Ｅ’から選択される１以上の置換基で置換されていてもよいＣ４－Ｃ８アルキルが好ましい。 R 5 represents (In) substituent group E (halogen, cyano, hydroxy, formyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted Aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic Aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio Substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted Non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic Carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted Alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic Ring oxycarbonyl, Or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted Or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl, substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted C4-C8 alkyl substituted with one or more substituents selected from aromatic heterocyclic sulfonyl and substituted or unsubstituted amino) is preferred, and (Io) substituent group C1-C8 alkyl optionally substituted with one or more substituents selected from E ′ (halogen, cyano, substituted or unsubstituted alkylcarbonyl and substituted or unsubstituted alkyloxycarbonyl) is preferred, Ip) C4-C8 alkyl optionally substituted with one or more substituents selected from substituent group E ′ is preferred.

　本発明化合物は、特定の異性体に限定するものではなく、全ての可能な異性体（例えば、ケト－エノール異性体、イミン－エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等）、ラセミ体またはそれらの混合物を含む。 The compound of the present invention is not limited to a specific isomer, but all possible isomers (eg, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ), Racemates or mixtures thereof.

　本発明化合物の一つ以上の水素、炭素および／または他の原子は、それぞれ水素、炭素および／または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれ２Ｈ、３Ｈ、１１Ｃ、１３Ｃ、１４Ｃ、１５Ｎ、１８Ｏ、１７Ｏ、３１Ｐ、３２Ｐ、３５Ｓ、１８Ｆ、123Ｉおよび３６Ｃｌのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。本発明化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、本発明化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究および／または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compounds of the present invention 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 compounds of the present invention also include compounds substituted with such isotopes. The compound substituted with the isotope is useful as a pharmaceutical and includes all radiolabeled compounds of the present invention. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

　本発明化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式（Ｉ）で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式（Ｉ）で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばＰｄ／Ｃの存在下、塩基の存在下または非存在下で、式（Ｉ）で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）を参照にできる。１４Ｃ－標識化合物は、１４Ｃ炭素を有する原料を用いることによって調製できる。 The radioactive label of the compound of the present invention can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.

　本発明化合物の製薬上許容される塩としては、例えば、式（Ｉ）で示される化合物と、アルカリ金属（例えば、リチウム、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム、バリウム等）、マグネシウム、遷移金属（例えば、亜鉛、鉄等）、アンモニア、有機塩基（例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等）およびアミノ酸との塩、または無機酸（例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等）、および有機酸（例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等）との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。 Examples of the pharmaceutically acceptable salt of the compound of the present invention include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.). , Magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) And salts with amino acids, or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoro Acetic acid, citric acid, lactic acid, tartaric acid, Salts with oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Can be mentioned. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

　本発明化合物またはその製薬上許容される塩は、溶媒和物（例えば、水和物等）および／または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、本発明化合物に対し、任意の数の溶媒分子（例えば、水分子等）と配位していてもよい。本発明化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、本発明化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。 The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.

　本発明化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的または代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解によりまたは生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて本発明化合物に変換される化合物、胃酸等により加水分解されて本発明化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばＤｅｓｉｇｎ　ｏｆ　Ｐｒｏｄｒｕｇｓ，　Ｅｌｓｅｖｉｅｒ，　Ａｍｓｔｅｒｄａｍ　１９８５に記載されている。プロドラッグは、それ自身が活性を有する場合がある。 The compound 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 invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed and converted to the compounds of the present invention under physiological conditions in vivo, compounds that are hydrolyzed by gastric acid, etc., and converted to the compounds of the present invention, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

　本発明化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えばヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロライド、適当なスルホニルアンハイドライドおよびミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えばＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、p-ＣＨ３-Ｏ-ＰｈＳＯ３－、ＰｈＳＯ３－、p-ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion. Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with hydride or reacting with a condensing agent. For example, CH 3 COO—, C 2 H 5 COO—, t-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p— CH 3 —O—PhSO 3 —, PhSO 3 —, and p-CH 3 PhSO 3 — can be mentioned.

　以下に、本発明化合物の一般的な製造方法を説明する。なお、本発明化合物は以下に示す合成方法以外の方法でも、有機化学の知識に基づいて、製造することができる。 Hereinafter, a general method for producing the compound of the present invention will be described. In addition, this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below.

式ａ３で示される化合物の製造方法

Figure JPOXMLDOC01-appb-C000041
（式中、各記号は前記と同意義である）
工程１
　化合物ａ１の溶液に、塩基存在下で、ブロモエタノンを反応させることにより、化合物ａ２を得ることができる。
　ブロモエタノンとしては、ハロゲン化物、アルキルオキシスルホニル化合物等が挙げられ、化合物ａ１に対して、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、水素化ナトリウム等が挙げられ、化合物ａ１に対して、１～５当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Method for producing compound represented by formula a3
Figure JPOXMLDOC01-appb-C000041
 (Wherein each symbol is as defined above)
Process 1
Compound a2 can be obtained by reacting a solution of compound a1 with bromoethanone in the presence of a base.
Examples of bromoethanone include halides, alkyloxysulfonyl compounds and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a1.
Examples of the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a1.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

工程２
　化合物ａ２の溶液に、塩基存在下、アルキル化剤を反応させることにより、化合物ａ３を得ることができる。
　アルキル化剤としては、ハロアルキル、アルキルトリフラート等が挙げられ、化合物ａ２に対して、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、炭酸セシウム、炭酸カリウム、水素化ナトリウム、テトラブチルアンモニウムフロリド等が挙げられ、化合物ａ２に対して、１～１０当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、テトラヒドロフラン等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Process 2
Compound a3 can be obtained by reacting a solution of compound a2 with an alkylating agent in the presence of a base.
Examples of the alkylating agent include haloalkyl, alkyl triflate and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a2.
Examples of the base include cesium carbonate, potassium carbonate, sodium hydride, tetrabutylammonium fluoride and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a2.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

式ａ７で示される化合物の製造方法

Figure JPOXMLDOC01-appb-C000042
（式中、各記号は前記と同意義である）
工程１
　化合物ａ４の溶液に、塩基存在下で、ブロモエタノンを反応させることにより、化合物ａ５を得ることができる。
　ブロモエタノンとしては、ハロゲン化物、アルキルオキシスルホニル化合物等が挙げられ、化合物ａ４に対して、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、水素化ナトリウム等が挙げられ、化合物ａ４に対して、１～５当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Method for producing compound represented by formula a7
Figure JPOXMLDOC01-appb-C000042
 (Wherein each symbol is as defined above)
Process 1
Compound a5 can be obtained by reacting the solution of compound a4 with bromoethanone in the presence of a base.
Examples of bromoethanone include halides, alkyloxysulfonyl compounds and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
Examples of the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

工程２
　化合物ａ５の溶液に、塩基存在下、アルキル化剤を反応させることにより、化合物ａ６を得ることができる。
　アルキル化剤としては、ハロアルキル、アルキルトリフラート等が挙げられ、化合物ａ５に対して、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、炭酸セシウム、炭酸カリウム、水素化ナトリウム、テトラブチルアンモニウムフロリド等が挙げられ、化合物ａ５に対して、１～１０当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、テトラヒドロフラン等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Process 2
Compound a6 can be obtained by reacting a solution of compound a5 with an alkylating agent in the presence of a base.
Examples of the alkylating agent include haloalkyl, alkyl triflate, etc., and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a5.
Examples of the base include cesium carbonate, potassium carbonate, sodium hydride, tetrabutylammonium fluoride and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a5.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

工程３
　化合物ａ６の溶液に、塩基存在下で、求核剤を反応させることにより化合物ａ７を得ることができる。
　求核剤としては、アルコール、アミン等が挙げられ、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、水素化ナトリウム等が挙げられ、化合物ａ６に対して、１～５当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン等が挙げられる。
　反応温度は、－２０℃～５０℃、好ましくは０℃～室温である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Process 3
Compound a7 can be obtained by reacting a solution of compound a6 with a nucleophile in the presence of a base.
Examples of the nucleophilic agent include alcohols and amines, and 1 to 10 equivalents, preferably 1 to 3 equivalents can be used.
Examples of the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a6.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
The reaction temperature is −20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

式ａ１１で示される化合物の製造方法

Figure JPOXMLDOC01-appb-C000043
（式中、各記号は前記と同意義である）
工程１
　化合物ａ４の溶液に、塩基存在下で、ブロモエタノンを反応させることにより、化合物ａ８を得ることができる。
　ブロモエタノンとしては、ハロゲン化物、アルキルオキシスルホニル化合物等が挙げられ、化合物ａ４に対して、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、水素化ナトリウム等が挙げられ、化合物ａ４に対して、１～５当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Method for producing compound represented by formula a11
Figure JPOXMLDOC01-appb-C000043
 (Wherein each symbol is as defined above)
Process 1
Compound a8 can be obtained by reacting the solution of compound a4 with bromoethanone in the presence of a base.
Examples of bromoethanone include halides, alkyloxysulfonyl compounds and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
Examples of the base include sodium hydride and the like, and 1 to 5 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a4.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

工程２
　化合物ａ８の溶液に、塩基存在下、アルキル化剤を反応させることにより、化合物ａ９を得ることができる。
　アルキル化剤は、化合物ａ８に対して、１～１０当量、好ましくは１～３当量用いることができる。
　塩基としては、炭酸セシウム、炭酸カリウム、水素化ナトリウム、テトラブチルアンモニウムフロリド等が挙げられ、化合物ａ８に対して、１～１０当量、好ましくは１～３当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、テトラヒドロフラン等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Process 2
Compound a9 can be obtained by reacting a solution of compound a8 with an alkylating agent in the presence of a base.
The alkylating agent can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound a8.
Examples of the base include cesium carbonate, potassium carbonate, sodium hydride, tetrabutylammonium fluoride and the like, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a8.
Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

工程３
　化合物ａ９の溶液に、塩基および金属触媒存在下で、ボロン酸又はボロン酸エステルを反応させることにより化合物ａ１０を得ることができる。
　ボロン酸としては、芳香族炭素環ボロン酸、非芳香族炭素環ボロン酸、芳香族複素環ボロン酸、非芳香族複素環ボロン酸又はそれらのボロン酸エステルが挙げられ、１～１０当量、好ましくは１～３当量用いることができる。
　金属触媒としては、１,１'－ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体、酢酸パラジウム等が挙げられ、化合物ａ９に対して、０．０１～０．５当量、好ましくは０．０５～０．２当量用いることができる。
　塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム等が挙げられ、化合物ａ９に対して、１～１０当量、好ましくは３～５当量用いることができる。
　溶媒としては、Ｎ，Ｎ－ジメチルホルムアミド、テトラヒドロフラン、１，４－ジオキサン等が挙げられる。
　反応温度は、室温～加熱還流下、好ましくは室温～１００℃である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Process 3
Compound a10 can be obtained by reacting a solution of compound a9 with boronic acid or a boronic acid ester in the presence of a base and a metal catalyst.
Examples of boronic acids include aromatic carbocyclic boronic acids, non-aromatic carbocyclic boronic acids, aromatic heterocyclic boronic acids, non-aromatic heterocyclic boronic acids or boronic acid esters thereof. 1 to 10 equivalents, preferably 1 to 3 equivalents can be used.
Examples of the metal catalyst include 1,1′-bis (diphenylphosphino) ferrocene-palladium (II) dichloride-dichloromethane complex, palladium acetate and the like. 0.05 to 0.2 equivalent can be used.
Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate and the like, and 1 to 10 equivalents, preferably 3 to 5 equivalents, can be used with respect to compound a9.
Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane and the like.
The reaction temperature is from room temperature to heating under reflux, preferably from room temperature to 100 ° C.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

工程４
　化合物ａ１０の溶液に、塩基を反応させることにより化合物ａ１１を得ることができる。
　塩基としては、水酸化ナトリウム、水酸化リチウム等が挙げられ、化合物ａ１０に対して、１～１０当量、好ましくは１～３当量用いることができる。
　溶媒としては、テトラヒドロフラン、エタノール、メタノール等が挙げられる。
　反応温度は、－２０℃～２００℃、好ましくは０℃～加熱還流下である。
　反応時間は、０．１時間～２４時間、好ましくは１時間～１２時間である。 Process 4
Compound a11 can be obtained by reacting a solution of compound a10 with a base.
Examples of the base include sodium hydroxide and lithium hydroxide, and 1 to 10 equivalents, preferably 1 to 3 equivalents, can be used with respect to compound a10.
Examples of the solvent include tetrahydrofuran, ethanol, methanol and the like.
The reaction temperature is −20 ° C. to 200 ° C., preferably 0 ° C. to heating under reflux.
The reaction time is 0.1 hour to 24 hours, preferably 1 hour to 12 hours.

　このようにして得られた本発明化合物は、各種の溶媒で結晶化させて精製することができる。用いられる溶媒としては、アルコール（メタノール、エタノール、イソプロピルアルコール、ｎ－ブタノール等）、エーテル（ジエチルエーテル、ジイソプロピルエーテル等）、酢酸メチルエステル、酢酸エチルエステル、クロロホルム、塩化メチレン、テトラヒドロフラン、Ｎ，Ｎ－ジメチルホルムアミド、トルエン、ベンゼン、キシレン、アセトニトリル、ヘキサン、ジオキサン、ジメトキシエタン、水またはそれらの混合溶媒等が挙げられる。これらの溶媒に加温下で溶解し、不純物を除去した後、徐々に温度を下げて、析出した固形物または結晶を濾取すればよい。 The compound of the present invention thus obtained can be purified by crystallization with various solvents. Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N— Examples include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water, or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.

　本発明に係る化合物は、オートタキシン阻害活性を有する。本発明に係る化合物を含有する医薬組成物は、オートタキシンの関与する疾患の治療剤及び／又は予防剤として有用である。オートタキシンが関与する疾患とは、具体的には、癌、等が挙げられる。さらに好ましくは、尿排出障害、間質性肺炎もしくは肺線維症、腎線維症、肝線維症、強皮症、疼痛、線維筋痛症または関節炎リウマチ等である。本発明に係る化合物を含有する医薬組成物は、それら疾患の治療剤及び／又は予防剤として有用である。
　本発明化合物は、オートタキシン阻害活性のみならず、医薬としての有用性を備えており、下記いずれか、あるいは全ての優れた特徴を有し得る。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ３Ａ４等) に対する阻害作用が弱い。
ｂ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｃ）貧血誘発作用等の毒性が低い。
ｄ）代謝安定性が高い。
ｅ）水溶性が高い。
ｆ）脳移行性が高い。
ｇ）消化管障害（例えば、出血性腸炎、消化管潰瘍、消化管出血等）を起こさない。 The compound according to the present invention has autotaxin inhibitory activity. The pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for diseases involving autotaxin. Specific examples of diseases involving autotaxin include cancer. More preferable are urinary drainage disorder, interstitial pneumonia or pulmonary fibrosis, renal fibrosis, liver fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis and the like. The pharmaceutical composition containing the compound according to the present invention is useful as a therapeutic and / or prophylactic agent for these diseases.
The compound of the present invention has not only autotaxin inhibitory activity but also usefulness as a pharmaceutical, and may have any or all of the following excellent characteristics.
a) The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) Low toxicity such as anemia-inducing action.
d) High metabolic stability.
e) High water solubility.
f) High brain transferability.
g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).

　さらに、本発明化合物はＥＮＰＰ１、３～７受容体に対する親和性は低く、高いＥＮＰＰ２受容体選択性を有し得る。 Furthermore, the compound of the present invention has low affinity for ENPP1, 3-7 receptors and may have high ENPP2 receptor selectivity.

　本発明の医薬組成物を投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤、丸剤、液剤、シロップ剤、バッカル剤または舌下剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、例えば筋肉内投与、静脈内投与等の注射剤、坐剤、経皮吸収剤、吸入剤等、通常用いられるいずれの剤型でも好適に投与することができる。 When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered.

　本発明化合物の有効量にその剤型に適した賦形剤、結合剤、湿潤剤、崩壊剤、滑沢剤、希釈剤等の各種医薬用添加剤を必要に応じて混合し医薬組成物とすることができる。注射剤の場合には適当な担体と共に滅菌処理を行なって製剤とすればよい。 Various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.

　賦形剤としては乳糖、白糖、ブドウ糖、デンプン、炭酸カルシウムまたは結晶セルロ－ス等が挙げられる。結合剤としてはメチルセルロ－ス、カルボキシメチルセルロ－ス、ヒドロキシプロピルセルロ－ス、ゼラチンまたはポリビニルピロリドン等が挙げられる。崩壊剤としてはカルボキシメチルセルロ－ス、カルボキシメチルセルロ－スナトリウム、デンプン、アルギン酸ナトリウム、カンテン末またはラウリル硫酸ナトリウム等が挙げられる。滑沢剤としてはタルク、ステアリン酸マグネシウムまたはマクロゴ－ル等が挙げられる。坐剤の基剤としてはカカオ脂、マクロゴ－ルまたはメチルセルロ－ス等を用いることができる。また、液剤または乳濁性、懸濁性の注射剤として調製する場合には通常使用されている溶解補助剤、懸濁化剤、乳化剤、安定化剤、保存剤、等張剤等を適宜添加しても良い。経口投与の場合には嬌味剤、芳香剤等を加えても良い。 Excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like. Examples of the binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate. Examples of the lubricant include talc, magnesium stearate, and macrogol. As a suppository base, cacao butter, macrogol, methyl cellulose or the like can be used. In addition, when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.

　本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常０．０５～１００ｍｇ／ｋｇ／日であり、好ましくは０．１～１０ｍｇ／ｋｇ／日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常０．００５～１０ｍｇ／ｋｇ／日であり、好ましくは０．０１～１ｍｇ／ｋｇ／日の範囲内である。これを１日１回～数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in 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.

　以下に本発明の実施例および試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples and test examples of the present invention, but the present invention is not limited thereto.

　また、本明細書中で用いる略語は以下の意味を表す。
Ｍｅ：メチル
Ｅｔ：エチル
Ｂｕ：ブチル
Ｐｈ：フェニル
ＰＰｈ３、ＴＰＰ：トリフェニルホスフィン
ＡｃＯＥｔ：酢酸エチル
ＤＭＦ：Ｎ，Ｎ－ジメチルホルムアミド
ＴＦＡ：トリフルオロ酢酸
ＤＭＳＯ：ジメチルスルホキシド
ＴＨＦ：テトラヒドロフラン
ＤＩＥＡ、Ｈｕｎｉｇ‘ｓ　Ｂａｓｅ：Ｎ，Ｎ－ジイソプロピルエチルアミン
ＴＢＡＦ：テトラブチルアンモニウムフルオライド
ＳＥＭ：２－（トリメチルシリル）エトキシメチル
ＯＡｃ：酢酸基
ｍＣＰＢＡ：メタクロロ過安息香酸
ＮＭＰ：１－メチルピロリジン－２－オン
ＬＡＨ：水素化リチウムアルミニウム
ＤＢＵ：１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン
ＤＣＭ：塩化メチレン
ＴＥＡ：トリエチルアミン
ＴＭＳ：テトラメチルシラン Moreover, the abbreviation used in this specification represents the following meaning.
Me: methyl Et: ethyl Bu: butyl Ph: phenyl PPh 3 , TPP: triphenylphosphine AcOEt: ethyl acetate DMF: N, N-dimethylformamide TFA: trifluoroacetic acid DMSO: dimethyl sulfoxide THF: tetrahydrofuran DIEA, Hunig's Base : N, N-diisopropylethylamine TBAF: tetrabutylammonium fluoride SEM: 2- (trimethylsilyl) ethoxymethyl OAc: acetate group mCPBA: metachloroperbenzoic acid NMP: 1-methylpyrrolidin-2-one LAH: lithium aluminum hydride DBU : 1,8-diazabicyclo [5.4.0] undec-7-ene DCM: methylene chloride TEA: triethylamine TMS: tetramethylsilane

　各実施例で得られたＮＭＲ分析は４００ＭＨｚで行い、重ジメチルスルホキシド（ｄ６－ＤＭＳＯ）あるいは重クロロホルム（ＣＤＣｌ３）を用いて測定した。
　ＬＣ／ＭＳは以下の条件で測定した。
（Method A）
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ　ＢＥＨ　Ｃ１８　（１．７μｍ　ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
流速：０．８ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３．５分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、０．５分間、１００％溶媒［Ｂ］を維持した。
（Method B）
カラム：Ｓｈｉｍ－ｐａｃｋ　ＸＲ－ＯＤＳ　（２．２μｍ、ｉ．ｄ．５０ｘ３．０ｍｍ）　（Ｓｈｉｍａｄｚｕ）
流速：１．６ｍＬ／分
ＵＶ検出波長：２５４ｎｍ
移動相：［Ａ］は０．１％ギ酸含有水溶液、［Ｂ］は０．１％ギ酸含有アセトニトリル溶液
グラジェント：３分間で１０％－１００％溶媒［Ｂ］のリニアグラジエントを行い、１分間、１００％溶媒［Ｂ］を維持した。 The NMR analysis obtained in each example was carried out at 400 MHz and measured using deuterated dimethyl sulfoxide (d 6 -DMSO) or deuterated chloroform (CDCl 3 ).
LC / MS was measured under the following conditions.
(Method A)
Column: ACQUITY UPLC BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.
(Method B)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.

実施例1
7-アミノ-2-(4-クロロフェニル)-1-ペンチルイミダゾ[1,2-a]ピリミジン-5(1H)-オン(3)の合成

Figure JPOXMLDOC01-appb-C000044
第一工程
　2,6-ジアミノピリミジン-4-オール(1, 200 mg, 1.59 mmol)のN,N-ジメチルホルムアミド(6 mL)溶液に、氷冷下で水素化ナトリウム(60wt%, 70 mg, 1.74 mmol)を加え、室温で30分間攪拌した。氷冷下で、反応液に2-ブロモ-1-(4-クロロフェニル)エタノン(370 mg, 1.59 mmol)のN,N-ジメチルホルムアミド(3 mL)溶液を加え、室温で24時間攪拌した。反応液に水酸化ナトリウム溶液(2 mol/L, 1 mL)を加え、室温で30分間攪拌した。反応液に水を加え、酢酸エチルで2回洗浄した。その水層に塩酸(2 mol/L, 1 mL)を加え、析出した固体を濾取することにより、7-アミノ-2-(4-クロロフェニル)イミダゾ[1,2-a]ピリミジン-5(8H)-オン(2, 179 mg, 収率: 43％)を無色固体として得た。
1H-NMR (δppm TMS/DMSO-d6) 12.42 (s, 1H), 7.93 (s, 1H), 7.85 (d, 2H, J = 7.3 Hz), 7.49 (d, 2H, J = 7.5 Hz), 6.33 (s, 2H), 4.84 (s, 1H).

第二工程
　化合物(2, 53 mg, 0.20 mmol)のN,N-ジメチルホルムアミド(1 mL)溶液に、炭酸セシウム(265 mg, 0.81 mmol)および1-ブロモペンタン(37 mg, 0.24 mmol)を加え、50℃で2時間攪拌した。反応液を室温まで冷却後、反応液に水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、7-アミノ-2-(4-クロロフェニル)-1-ペンチルイミダゾ[1,2-a]ピリミジン-5(1H)-オン(3, 9.0 mg, 収率: 13％)を無色固体として得た。
1H-NMR (δppm TMS/CDCl3) 7.48 (d, 2H, J = 8.0 Hz), 7.43 (s, 1H), 7.37 (d, 2H, J = 8.0 Hz), 5.22 (s, 1H), 4.61 (s, 2H), 3.98 (t, 2H, J = 7.6 Hz), 1.61 (t, 2H, J = 7.4 Hz), 1.25-1.14 (m, 4H), 0.82 (t, 3H, J = 7.1 Hz). Example 1
Synthesis of 7-amino-2- (4-chlorophenyl) -1-pentylimidazo [1,2-a] pyrimidin-5 (1H) -one ( 3 )
Figure JPOXMLDOC01-appb-C000044
 First Step To a solution of 2,6-diaminopyrimidin-4-ol ( 1 , 200 mg, 1.59 mmol) in N, N-dimethylformamide (6 mL), sodium hydride (60 wt%, 70 mg, 70 mg, 1.74 mmol) was added and stirred at room temperature for 30 minutes. Under ice cooling, a solution of 2-bromo-1- (4-chlorophenyl) ethanone (370 mg, 1.59 mmol) in N, N-dimethylformamide (3 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. Sodium hydroxide solution (2 mol / L, 1 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was washed twice with ethyl acetate. Hydrochloric acid (2 mol / L, 1 mL) was added to the aqueous layer, and the precipitated solid was collected by filtration to give 7-amino-2- (4-chlorophenyl) imidazo [1,2-a] pyrimidine-5 ( 8H) -one ( 2 , 179 mg, yield: 43%) was obtained as a colorless solid.
1H-NMR (δppm TMS / DMSO-d6) 12.42 (s, 1H), 7.93 (s, 1H), 7.85 (d, 2H, J = 7.3 Hz), 7.49 (d, 2H, J = 7.5 Hz), 6.33 (s, 2H), 4.84 (s, 1H).

Second Step To a solution of the compound ( 2 , 53 mg, 0.20 mmol) in N, N-dimethylformamide (1 mL), add cesium carbonate (265 mg, 0.81 mmol) and 1-bromopentane (37 mg, 0.24 mmol). And stirred at 50 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give 7-amino-2- (4-chlorophenyl) -1-pentylimidazo [1,2-a] pyrimidine-5 (1H)- On ( 3 , 9.0 mg, yield: 13%) was obtained as a colorless solid.
1H-NMR (δppm TMS / CDCl3) 7.48 (d, 2H, J = 8.0 Hz), 7.43 (s, 1H), 7.37 (d, 2H, J = 8.0 Hz), 5.22 (s, 1H), 4.61 (s , 2H), 3.98 (t, 2H, J = 7.6 Hz), 1.61 (t, 2H, J = 7.4 Hz), 1.25-1.14 (m, 4H), 0.82 (t, 3H, J = 7.1 Hz).

同様にして、化合物(4)～(9)を合成した。

Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046
 Similarly, compounds ( 4 ) to ( 9 ) were synthesized.
Figure JPOXMLDOC01-appb-T000045
Figure JPOXMLDOC01-appb-T000046

実施例2
3-(2-(4-クロロフェニル)-5-オキソ-1-ペンチル-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-7-イルオキシ)アゼチジン-1-カルボン酸t-ブチルエステル(13)の合成

Figure JPOXMLDOC01-appb-C000047
第一工程
　2-アミノ-6-クロロピリミジン-4-オール(10, 25 g, 172 mmol)のN,N-ジメチルホルムアミド(250 mL)溶液に、氷冷下で水素化ナトリウム(60wt%, 7.56 g, 189 mmol)を加え、室温で30分間攪拌した。反応液に氷冷下で、2-ブロモ-1-(4-クロロフェニル)エタノン(40 g, 172 mmol)のN,N-ジメチルホルムアミド(100 mL)溶液を加え、室温で2時間攪拌した。反応液に水酸化ナトリウム溶液(2 mol/L, 125 mL)を加え、室温で45分間攪拌した。反応液に塩酸(2 mol/L, 138 mL)および水(250 mL)を加え、析出した固体を濾取することにより、7-クロロ-2-(4-クロロフェニル)イミダゾ[1,2-a]ピリミジン-5(8H)-オン(11)の粗生成物(20 g)を得た。

第二工程
　化合物(11)の粗生成物(20 g)のN,N-ジメチルホルムアミド(300 mL)溶液に、水素化ナトリウム(60wt%、3.43 g, 86.0 mmol)および1-ブロモペンタン(32.4 g, 214 mmol)を加え、100℃で6時間攪拌した。反応液を室温まで冷却後、水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、7-クロロ-2-(4-クロロフェニル)-1-ペンチルイミダゾ[1,2-a]ピリミジン-5(1H)-オン(12, 12.9 g, 化合物(10)からの換算収率: 21％)を無色固体として得た。
LC/MS (Method B) Retention Time = 2.61 min, Found Mass [M+H] = 350

第三工程
　化合物(12, 100 mg, 0.286 mmol)のN,N-ジメチルホルムアミド(2 mL)溶液に、3-ヒドロキシアゼチジン-1-カルボン酸t-ブチルエステル(99 mg, 0.57 mmol)および水素化ナトリウム(60wt%, 34 mg, 0.86 mmol)を加え、室温で6時間攪拌した。反応液に水を加えて酢酸エチルで抽出した。有機層を水洗して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(クロロホルム/メタノール)で精製することにより、3-(2-(4-クロロフェニル)-5-オキソ-1-ペンチル-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-7-イルオキシ)アゼチジン-1-カルボン酸t-ブチルエステル(13, 11 mg, 収率: 8％)を無色固体として得た。
LC/MS (Method B) Retention Time = 2.71 min, Found Mass [M+H] = 487 Example 2
3- (2- (4-Chlorophenyl) -5-oxo-1-pentyl-1,5-dihydroimidazo [1,2-a] pyrimidin-7-yloxy) azetidine-1-carboxylic acid t-butyl ester (13 )
Figure JPOXMLDOC01-appb-C000047
 First Step 2-Amino-6-chloropyrimidin-4-ol ( 10 , 25 g, 172 mmol) in N, N-dimethylformamide (250 mL) was added to sodium hydride (60 wt%, 7.56) under ice-cooling. g, 189 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of 2-bromo-1- (4-chlorophenyl) ethanone (40 g, 172 mmol) in N, N-dimethylformamide (100 mL) was added to the reaction solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. Sodium hydroxide solution (2 mol / L, 125 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 45 minutes. Hydrochloric acid (2 mol / L, 138 mL) and water (250 mL) were added to the reaction solution, and the precipitated solid was collected by filtration to give 7-chloro-2- (4-chlorophenyl) imidazo [1,2-a ] A crude product (20 g) of pyrimidin-5 (8H) -one ( 11 ) was obtained.

Step 2 To a solution of the crude product of compound ( 11 ) (20 g) in N, N-dimethylformamide (300 mL) was added sodium hydride (60 wt%, 3.43 g, 86.0 mmol) and 1-bromopentane (32.4 g , 214 mmol) and stirred at 100 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give 7-chloro-2- (4-chlorophenyl) -1-pentylimidazo [1,2-a] pyrimidine-5 (1H)- On ( 12 , 12.9 g, conversion yield from compound ( 10 ): 21%) was obtained as a colorless solid.
LC / MS (Method B) Retention Time = 2.61 min, Found Mass [M + H] = 350

Step 3 To a solution of the compound ( 12 , 100 mg, 0.286 mmol) in N, N-dimethylformamide (2 mL), add 3-hydroxyazetidine-1-carboxylic acid t-butyl ester (99 mg, 0.57 mmol) and hydrogen. Sodium chloride (60 wt%, 34 mg, 0.86 mmol) was added and stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform / methanol) to give 3- (2- (4-chlorophenyl) -5-oxo-1-pentyl-1,5-dihydroimidazo [1,2-a ] Pyrimidin-7-yloxy) azetidine-1-carboxylic acid t-butyl ester ( 13 , 11 mg, yield: 8%) was obtained as a colorless solid.
LC / MS (Method B) Retention Time = 2.71 min, Found Mass [M + H] = 487

同様にして、化合物(14)～(82)を合成した。

Figure JPOXMLDOC01-appb-T000048
Similarly, the compounds ( 14 ) to ( 82 ) were synthesized.
Figure JPOXMLDOC01-appb-T000048

Figure JPOXMLDOC01-appb-T000049
Figure JPOXMLDOC01-appb-T000049

Figure JPOXMLDOC01-appb-T000050
Figure JPOXMLDOC01-appb-T000050

Figure JPOXMLDOC01-appb-T000051
Figure JPOXMLDOC01-appb-T000051

Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052

Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053

Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054

Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055

Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056

Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057

Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058

Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059

Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060

Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000061

Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062

実施例3
4-(7-(4-クロロフェニル)-5-オキソ-1-ペンチル-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-2-イル)安息香酸(86)の合成

Figure JPOXMLDOC01-appb-C000063

第一工程
　2-アミノ-6-クロロピリミジン-4-オール(10, 1.50 g, 10.3 mmol)のN,N-ジメチルホルムアミド(15 mL)溶液に、氷冷下で水素化ナトリウム(60wt%, 453 mg, 11.3 mmol)を加え、室温で30分間攪拌した。氷冷下で、反応液に4-(2-ブロモアセチル)安息香酸エチル(2.79 g, 10.3 mmol)のN,N-ジメチルホルムアミド(5 mL)溶液を加え、室温で2時間攪拌した。反応液に水酸化ナトリウム溶液(2 mol/L, 4.5 mL)を加え、室温で30分間攪拌した。反応液に塩酸(1 mol/L, 10 mL)および水(10 mL)を加えた。析出した固体を濾取することにより、4-(7-クロロ-5-オキソ-5,8-ジヒドロイミダゾ[1,2-a]ピリミジン-2-イル)安息香酸エチル(83, 2.39 g, 収率: 73％)を黄色固体として得た。
LC/MS (Method B) Retention Time = 1.71 min, Found Mass [M+H] = 318

第二工程
　化合物(83, 900 mg, 2.83 mmol)のN,N-ジメチルホルムアミド(1 mL)溶液に、水素化ナトリウム(60wt%, 136 mg, 3.40 mmol)および1-ブロモペンタン(1.28 g, 8.50 mmol)を加え、100℃で4時間攪拌した。反応液を室温まで冷却後、反応液に水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、4-(7-クロロ-5-オキソ-1-ペンチル-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-2-イル)安息香酸エチル(84, 283 mg, 収率: 26％)を無色油状物として得た。
LC/MS (Method B) Retention Time = 2.48 min, Found Mass [M+H] = 389

第三工程
　化合物(84, 250 mg, 0.645 mmol)のN,N-ジメチルホルムアミド(5 mL)溶液に、4-クロロフェニルボロン酸(151 mg, 0.967 mmol)、1,1'-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロリド-ジクロロメタン錯体(53 mg, 0.064 mmol)および炭酸ナトリウム水溶液(2 mol/L, 1.3 mL)を加え、100℃で2時間攪拌した。反応液を室温まで冷却後、反応液に水を加えて酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、4-(7-(4-クロロフェニル)-5-オキソ-1-ペンチル-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-2-イル)安息香酸エチル(85, 220 mg, 収率: 74％)を無色固体として得た。
LC/MS (Method B) Retention Time = 2.89 min, Found Mass [M+H] = 464

第四工程
　化合物(85, 160 mg, 0.345 mmol)のテトラヒドロフラン(3.2 mL)溶液に、水酸化ナトリウム溶液(2 mol/L, 1.7 mL)を加え、80℃で3時間攪拌した。反応液を室温まで冷却後、反応液に塩酸(1 mol/L)を加えて酢酸エチルで抽出した。有機層を水洗し、無水硫酸ナトリウムで乾燥して減圧濃縮した。得られた残渣をクロロホルム/メタノール/ヘキサンから固化することにより、4-(7-(4-クロロフェニル)-5-オキソ-1-ペンチル-1,5-ジヒドロイミダゾ[1,2-a]ピリミジン-2-イル)安息香酸(86, 139 mg, 収率: 93％)を無色固体として得た。
LC/MS (Method B) Retention Time = 2.39 min, Found Mass [M+H] = 436 Example 3
Synthesis of 4- (7- (4-chlorophenyl) -5-oxo-1-pentyl-1,5-dihydroimidazo [1,2-a] pyrimidin-2-yl) benzoic acid ( 86 )
Figure JPOXMLDOC01-appb-C000063
First Step 2-Amino-6-chloropyrimidin-4-ol ( 10 , 1.50 g, 10.3 mmol) in N, N-dimethylformamide (15 mL) was added to sodium hydride (60 wt%, 453) under ice-cooling. mg, 11.3 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Under ice cooling, a solution of ethyl 4- (2-bromoacetyl) benzoate (2.79 g, 10.3 mmol) in N, N-dimethylformamide (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Sodium hydroxide solution (2 mol / L, 4.5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Hydrochloric acid (1 mol / L, 10 mL) and water (10 mL) were added to the reaction solution. The precipitated solid was collected by filtration to give ethyl 4- (7-chloro-5-oxo-5,8-dihydroimidazo [1,2-a] pyrimidin-2-yl) benzoate ( 83 , 2.39 g, yield). Rate: 73%) as a yellow solid.
LC / MS (Method B) Retention Time = 1.71 min, Found Mass [M + H] = 318

Second Step A solution of the compound ( 83 , 900 mg, 2.83 mmol) in N, N-dimethylformamide (1 mL) was added to sodium hydride (60 wt%, 136 mg, 3.40 mmol) and 1-bromopentane (1.28 g, 8.50). mmol) was added, and the mixture was stirred at 100 ° C. for 4 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give 4- (7-chloro-5-oxo-1-pentyl-1,5-dihydroimidazo [1,2-a] pyrimidine- Ethyl 2-yl) benzoate ( 84 , 283 mg, yield: 26%) was obtained as a colorless oil.
LC / MS (Method B) Retention Time = 2.48 min, Found Mass [M + H] = 389

Step 3 To a solution of the compound ( 84 , 250 mg, 0.645 mmol) in N, N-dimethylformamide (5 mL), add 4-chlorophenylboronic acid (151 mg, 0.967 mmol), 1,1'-bis (diphenylphosphino ) Ferrocene-palladium (II) dichloride-dichloromethane complex (53 mg, 0.064 mmol) and aqueous sodium carbonate (2 mol / L, 1.3 mL) were added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane / ethyl acetate) to give 4- (7- (4-chlorophenyl) -5-oxo-1-pentyl-1,5-dihydroimidazo [1,2- a] Pyrimidin-2-yl) ethyl benzoate ( 85 , 220 mg, yield: 74%) was obtained as a colorless solid.
LC / MS (Method B) Retention Time = 2.89 min, Found Mass [M + H] = 464

Fourth Step To a solution of the compound ( 85 , 160 mg, 0.345 mmol) in tetrahydrofuran (3.2 mL) was added sodium hydroxide solution (2 mol / L, 1.7 mL), and the mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, hydrochloric acid (1 mol / L) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was solidified from chloroform / methanol / hexane to give 4- (7- (4-chlorophenyl) -5-oxo-1-pentyl-1,5-dihydroimidazo [1,2-a] pyrimidine- 2-yl) benzoic acid ( 86 , 139 mg, yield: 93%) was obtained as a colorless solid.
LC / MS (Method B) Retention Time = 2.39 min, Found Mass [M + H] = 436

同様にして、化合物(87)～(130)を合成した。

Figure JPOXMLDOC01-appb-T000064
Similarly, the compounds ( 87 ) to ( 130 ) were synthesized.
Figure JPOXMLDOC01-appb-T000064

Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065

Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066

Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067

Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068

Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069

Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070

Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071

Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072

実施例４
2-(((1r,4r)-4-(7-(4-クロロフェニル)-5-オキソ-8-ペンチルl-5,8-ジヒドロイミダゾ [1,2-a]ピリミジン -2-イル)シクロヘキシル)オキシ)酢酸(134)の合成

Figure JPOXMLDOC01-appb-C000073

第一工程
　化合物 (142, 282 mg, 0.43 mmol)のテトラヒドロフラン(3 mL)溶液に、テトラブチルアンモニウムフルオリドのテトラヒドロフラン溶液 (1mol/L, 8.65 ml, 8.65 mmol)を加え、室温で14時間攪拌した。反応液に水を加え、酢酸エチルで2回洗浄した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(クロロホルム/メタノール)で精製することにより、7-(4-クロロフェニル)-2-((1r,4r)-4-ヒドロキシシクロヘキシル)-8-ペンチルイミダゾ[1,2-a]ピリミジン -5(8H)-オン(143, 160 mg, 収率: 89％)を白色固体として得た。
LC/MS (Method B) Retention Time =  2.41min, Found Mass [M+H] = 414
1H-NMR (δppm TMS/DMSO-d6) 12.42 (s, 1H), 7.93 (s, 1H), 7.85 (d, 2H, J = 7.3 Hz), 7.49 (d, 2H, J = 7.5 Hz), 6.33 (s, 2H), 4.84 (s, 1H).

第二工程
　化合物(143, 50 mg, 0.12 mmol)のトルエン (2 mL)溶液に、ロジウム（II）アセテートダイマー(107 mg, 0.24 mmol)を加え、室温で2時間攪拌した。エチル 2-ジアゾアセテート（127 ul, 1.208 mmol）を加え、室温で1日攪拌した。反応液に水を加え、酢酸エチルで2回洗浄した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して減圧濃縮した。得られた残渣をジオールシリカゲルクロマトグラフィー(ヘキサン/酢酸エチル)で精製することにより、エチル 2-(((1r,4r)-4-(7-(4-クロロフェニル)-5-オキソ-8-ペンチル-5,8-ジヒドロイミダゾ[1,2-a]ピリミジン-2-イル)シクロヘキシル)オキシ)アセテート (144, 42.9 mg, 収率: 71％)を茶色液体として得た。
LC/MS (Method B) Retention Time = 2.83 min, Found Mass [M+H] = 500
1H-NMR (δppm TMS/CDCl3).0.81-095(m, 3H), 1.17-1.62(m, 14H), 1.87(d, 1H, J = 8.5Hz), 2.01-2.30(m, 3H), 3.44(t, 2H, J = 4.4Hz), 4.10-4.37(m, 6H), 6.47(s, 1H)7.43(d, 2H, J =4.4Hz), 7.96(d, 2H, J = 4.4Hz).

第三工程
　化合物(144, 60 mg, 0.12 mmol)のエタノール (150 uL)およびテトラヒドロフラン（300 ul）の混合溶液に、2mol/L-水酸化ナトリウム水溶液(300 ul, 0.60 mmol)を加え、室温で2時間攪拌した。反応液に1mol/L 塩酸を加えて酢酸エチルで2回抽出した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥して減圧濃縮した。得られた残渣をジオールシリカゲルクロマトグラフィー(クロロホルム/メタノール)で精製することにより、2-(((1r,4r)-4-(7-(4-クロロフェニル)-5-オキソ-8-ペンチルl-5,8-ジヒドロイミダゾ [1,2-a]ピリミジン -2-イル)シクロヘキシル)オキシ)酢酸 (134, 17.5 mg, 収率: 31％)を茶色固体として得た。
LC/MS (Method B) Retention Time = 2.45 min, Found Mass [M+H] = 472
1H-NMR (δppm TMS/CDCl3). .0.81-095(m, 3H), 1.21-1.54(m, 8H), 1.87(dd, 2H, J = 13.9, 6.9Hz), 2.13(s, 1H), 2.28(s, 1H), 2.60(s, 1H), 3.52(t, 2H, J = 4.4Hz), 3.65(s, 1H), 4.11-4.20(m, 4H), 6.51(s, 1H), 7.43(ｄ, 2H, J = 4.4Hz), 7.96(d, 2H, J = 4.4Hz).
Example 4
2-((((1r, 4r) -4- (7- (4-chlorophenyl) -5-oxo-8-pentyll-5,8-dihydroimidazo [1,2-a] pyrimidin-2-yl) cyclohexyl Synthesis of oxy) acetic acid ( 134 )
Figure JPOXMLDOC01-appb-C000073
First Step Tetrabutylammonium fluoride in tetrahydrofuran (1 mol / L, 8.65 ml, 8.65 mmol) was added to a solution of the compound ( 142 , 282 mg, 0.43 mmol) in tetrahydrofuran (3 mL) and stirred at room temperature for 14 hours. . Water was added to the reaction mixture, and the mixture was washed twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform / methanol) to give 7- (4-chlorophenyl) -2-((1r, 4r) -4-hydroxycyclohexyl) -8-pentylimidazo [1,2 -a] pyrimidin-5 (8H) -one ( 143 , 160 mg, yield: 89%) was obtained as a white solid.
LC / MS (Method B) Retention Time = 2.41min, Found Mass [M + H] = 414
1H-NMR (δppm TMS / DMSO-d6) 12.42 (s, 1H), 7.93 (s, 1H), 7.85 (d, 2H, J = 7.3 Hz), 7.49 (d, 2H, J = 7.5 Hz), 6.33 (s, 2H), 4.84 (s, 1H).

Second Step Rhodium (II) acetate dimer (107 mg, 0.24 mmol) was added to a toluene (2 mL) solution of the compound ( 143 , 50 mg, 0.12 mmol), and the mixture was stirred at room temperature for 2 hours. Ethyl 2-diazoacetate (127 ul, 1.208 mmol) was added, and the mixture was stirred at room temperature for 1 day. Water was added to the reaction mixture, and the mixture was washed twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by diol silica gel chromatography (hexane / ethyl acetate) to give ethyl 2-(((1r, 4r) -4- (7- (4-chlorophenyl) -5-oxo-8-pentyl]. -5,8-dihydroimidazo [1,2-a] pyrimidin-2-yl) cyclohexyl) oxy) acetate ( 144 , 42.9 mg, yield: 71%) was obtained as a brown liquid.
LC / MS (Method B) Retention Time = 2.83 min, Found Mass [M + H] = 500
1H-NMR (δppm TMS / CDCl3) .0.81-095 (m, 3H), 1.17-1.62 (m, 14H), 1.87 (d, 1H, J = 8.5Hz), 2.01-2.30 (m, 3H), 3.44 (t, 2H, J = 4.4Hz), 4.10-4.37 (m, 6H), 6.47 (s, 1H) 7.43 (d, 2H, J = 4.4Hz), 7.96 (d, 2H, J = 4.4Hz).

Step 3 To a mixed solution of the compound ( 144 , 60 mg, 0.12 mmol) in ethanol (150 uL) and tetrahydrofuran (300 ul), add 2 mol / L-sodium hydroxide aqueous solution (300 ul, 0.60 mmol) at room temperature. Stir for 2 hours. To the reaction solution was added 1 mol / L hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by diol silica gel chromatography (chloroform / methanol) to give 2-(((1r, 4r) -4- (7- (4-chlorophenyl) -5-oxo-8-pentyl-l- 5,8-Dihydroimidazo [1,2-a] pyrimidin-2-yl) cyclohexyl) oxy) acetic acid ( 134 , 17.5 mg, yield: 31%) was obtained as a brown solid.
LC / MS (Method B) Retention Time = 2.45 min, Found Mass [M + H] = 472
1H-NMR (δppm TMS / CDCl3) .0.81-095 (m, 3H), 1.21-1.54 (m, 8H), 1.87 (dd, 2H, J = 13.9, 6.9Hz), 2.13 (s, 1H), 2.28 (s, 1H), 2.60 (s, 1H), 3.52 (t, 2H, J = 4.4Hz), 3.65 (s, 1H), 4.11-4.20 (m, 4H), 6.51 (s, 1H), 7.43 (d, 2H, J = 4.4Hz), 7.96 (d, 2H, J = 4.4Hz).

同様にして、化合物(131)～(141)を合成した。

Figure JPOXMLDOC01-appb-T000074

Figure JPOXMLDOC01-appb-I000075
Similarly, the compounds ( 131 ) to ( 141 ) were synthesized.
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-I000075

試験例１（Method A）オートタキシン阻害剤の評価
　25mM Tris-HCl緩衝液 (pH7.5)、100mM NaCl、5mM MgCl2、0.1% BSAからなる溶液Ａを調製し、DMSOに溶解した化合物に、溶液Ａで希釈したマウスオートタキシン酵素（R＆D systems社製）5μlを添加した。さらに、溶液Ａで希釈した0.5μM TG-mTMPを5μl添加し、室温で2時間反応させた。反応終了後、反応液に、溶液Ａで希釈した150mM EDTAを5μl添加して反応を停止させ、反応により生成される蛍光色素TokyoGreenを検出した。
　TokyoGreenの検出には測定機器ViewLux（PerkinElmer社製）を用い、励起波長480nm/蛍光波長540nmの条件で蛍光を測定した。
　化合物を含まない時の値を0%阻害、酵素添加なしの時の値を100%阻害とし、化合物の各濃度での阻害率をプロットした濃度依存性曲線を作成した。50%阻害を示す化合物濃度をIC50値とした。

Figure JPOXMLDOC01-appb-C000076
Test Example 1 (Method A) Evaluation of Autotaxin Inhibitor A solution A consisting of 25 mM Tris-HCl buffer (pH 7.5), 100 mM NaCl, 5 mM MgCl 2 , 0.1% BSA was prepared. 5 μl of mouse autotaxin enzyme (R & D systems) diluted with solution A was added. Further, 5 μl of 0.5 μM TG-mTMP diluted with solution A was added and reacted at room temperature for 2 hours. After completion of the reaction, 5 μl of 150 mM EDTA diluted with solution A was added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction was detected.
For detection of TokyoGreen, fluorescence was measured under the conditions of an excitation wavelength of 480 nm / fluorescence wavelength of 540 nm using a measuring device ViewLux (manufactured by PerkinElmer).
A concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition. The compound concentration showing 50% inhibition was defined as the IC50 value.
Figure JPOXMLDOC01-appb-C000076

試験例２（Method B）オートタキシン阻害剤の評価
　25mM Tris-HCl緩衝液 (pH7.5)、100mM NaCl、5mM MgCl2、0.1% BSAからなる溶液Ａを調製し、DMSOに溶解した化合物に、溶液Ａで希釈したヒトオートタキシン酵素（R＆D systems社製）を5μl添加した。さらに、溶液Ａで希釈した0.5μM TG-mTMPを5μl添加し、室温で2時間反応させた。反応終了後、反応液に、溶液Ａで希釈した150mM EDTAを5μl添加して反応を停止させ、反応により生成される蛍光色素TokyoGreenを検出した。
　TokyoGreenの検出には測定機器ViewLux（PerkinElmer社製）を用い、励起波長480nm/蛍光波長540nmの条件で蛍光を測定した。
　化合物を含まない時の値を0%阻害、酵素添加なしの時の値を100%阻害とし、化合物の各濃度での阻害率をプロットした濃度依存性曲線を作成した。50%阻害を示す化合物濃度をIC50値とした。 Test Example 2 (Method B) Evaluation of autotaxin inhibitor Solution A consisting of 25 mM Tris-HCl buffer (pH 7.5), 100 mM NaCl, 5 mM MgCl 2 , and 0.1% BSA was prepared. 5 μl of human autotaxin enzyme (manufactured by R & D systems) diluted with solution A was added. Further, 5 μl of 0.5 μM TG-mTMP diluted with solution A was added and reacted at room temperature for 2 hours. After completion of the reaction, 5 μl of 150 mM EDTA diluted with solution A was added to the reaction solution to stop the reaction, and the fluorescent dye TokyoGreen produced by the reaction was detected.
For detection of TokyoGreen, fluorescence was measured under the conditions of an excitation wavelength of 480 nm / fluorescence wavelength of 540 nm using a measuring device ViewLux (manufactured by PerkinElmer).
A concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition. The compound concentration showing 50% inhibition was defined as the IC50 value.

試験例３（Method C）オートタキシン阻害剤の評価
　100mM Tris-HCl緩衝液 (pH7.5)、150mM NaCl、5mM MgCl2、0.05% Triton X-100からなる溶液Ｂを調製し、DMSOに溶解した化合物に、溶液Ｂで希釈したヒトオートタキシン酵素（R＆D systems社製）を2.5μl添加した。さらに、溶液Ｂで希釈した200μM 18:0 Lyso PC（Avanti Polar Lipids社製）を2.5μl添加し、室温で2時間反応させた。反応終了後、100mM Tris-HCl緩衝液(pH7.5)、5mM MgCl2、77μg/mlコリンオキシダーゼ、10μg/ml ペルオキシダーゼ、25μM 10-アセチル-3,7-ジヒドロキシフェノキサジン、過剰のオートタキシン阻害剤からなるコリン定量試薬を15μl添加して室温で20分間反応させた。反応により生成される蛍光色素レゾルフィンを検出した。
　レゾルフィンの検出には測定機器ViewLux（PerkinElmer社製）を用い、励起波長531nm/蛍光波長598nmの条件で蛍光を測定した。
　化合物を含まない時の値を0%阻害、酵素添加なしの時の値を100%阻害とし、化合物の各濃度での阻害率をプロットした濃度依存性曲線を作成した。50%阻害を示す化合物濃度をIC50値とした。 Test Example 3 (Method C) Evaluation of autotaxin inhibitor Solution B consisting of 100 mM Tris-HCl buffer (pH 7.5), 150 mM NaCl, 5 mM MgCl 2 and 0.05% Triton X-100 was prepared and dissolved in DMSO. To the compound, 2.5 μl of human autotaxin enzyme (R & D systems) diluted with solution B was added. Further, 200 μM 18: 0 Lyso PC diluted by solution B (manufactured by Avanti Polar Lipids) was added by 2.5 μl and reacted at room temperature for 2 hours. After completion of the reaction, 100 mM Tris-HCl buffer (pH 7.5), 5 mM MgCl 2 , 77 μg / ml choline oxidase, 10 μg / ml peroxidase, 25 μM 10-acetyl-3,7-dihydroxyphenoxazine, excess autotaxin inhibitor 15 μl of a choline assay reagent consisting of was added and reacted at room temperature for 20 minutes. The fluorescent dye resorufin produced by the reaction was detected.
For the detection of resorufin, a measuring instrument ViewLux (manufactured by PerkinElmer) was used, and fluorescence was measured under conditions of excitation wavelength 531 nm / fluorescence wavelength 598 nm.
A concentration-dependent curve was prepared by plotting the inhibition rate at each concentration of the compound, assuming that the value when no compound was contained was 0% inhibition and the value when no enzyme was added was 100% inhibition. The compound concentration showing 50% inhibition was defined as the IC50 value.

本発明化合物について、上記試験例に記載した試験方法により得られた結果を以下の表に示す。
アッセイ方法：
Method A：試験例１；Method B：試験例２；Method C：試験例３
酵素阻害活性：
A:IC50 < 10 nM, B:10 nM ≦ IC50 < 100 nM, C:100 nM ≦ IC50 < 1000 nM, 
D:1000 nM ≦ IC50

Figure JPOXMLDOC01-appb-T000077

Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
 About this invention compound, the result obtained by the test method described in the said test example is shown in the following table | surfaces.
Assay method:
Method A: Test Example 1; Method B: Test Example 2; Method C: Test Example 3
Enzyme inhibitory activity:
A: IC50 <10 nM, B: 10 nM ≤ IC50 <100 nM, C: 100 nM ≤ IC50 <1000 nM,
D: 1000 nM ≤ IC50
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079

試験例４　ＣＹＰ阻害試験
　市販のプールドヒト肝ミクロソームを用いて、ヒト主要ＣＹＰ５分子種（ＣＹＰ１Ａ２、２Ｃ９、２Ｃ１９、２Ｄ６、３Ａ４）の典型的基質代謝反応として７－エトキシレゾルフィンのＯ－脱エチル化（ＣＹＰ１Ａ２）、トルブタミドのメチル－水酸化（ＣＹＰ２Ｃ９）、メフェニトインの４’－水酸化（ＣＹＰ２Ｃ１９）、デキストロメトルファンのＯ脱メチル化（ＣＹＰ２Ｄ６）、テルフェナジンの水酸化（ＣＹＰ３Ａ４）を指標とし、それぞれの代謝物生成量が被検化合物によって阻害される程度を評価した。 Test Example 4 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human 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 was inhibited by the test compound was evaluated.

　反応条件は以下のとおり：基質、０．５　μｍｏｌ／Ｌ　エトキシレゾルフィン（ＣＹＰ１Ａ２）、１００　μｍｏｌ／Ｌ　トルブタミド（ＣＹＰ２Ｃ９）、５０　μｍｏｌ／Ｌ　Ｓ－メフェニトイン（ＣＹＰ２Ｃ１９）、５μｍｏｌ／Ｌ　デキストロメトルファン（ＣＹＰ２Ｄ６）、１　μｍｏｌ／Ｌ　テルフェナジン（ＣＹＰ３Ａ４）；反応時間、１５分；反応温度、３７℃；酵素、プールドヒト肝ミクロソーム　０．２ｍｇ　タンパク質／ｍＬ；被検化合物濃度、１、５、１０、２０　μｍｏｌ／Ｌ（４点）。 The reaction conditions were as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan ( CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; test compound concentration 1, 5, 10, 20 μmol / L (4 points).

　９６穴プレートに反応溶液として、５０ｍＭ　Ｈｅｐｅｓ　緩衝液中に各５種の基質、ヒト肝ミクロソーム、被検化合物を上記組成で加え、補酵素であるＮＡＤＰＨを添加して、指標とする代謝反応を開始し、３７℃、１５分間反応した後、メタノール／アセトニトリル＝１／１（ｖ／ｖ）溶液を添加することで反応を停止した。３０００ｒｐｍ、１５分間の遠心操作後、遠心上清中のレゾルフィン（ＣＹＰ１Ａ２代謝物）を蛍光マルチラベルカウンタで、トルブタミド水酸化体（ＣＹＰ２Ｃ９代謝物）、メフェニトイン４’水酸化体（ＣＹＰ２Ｃ１９代謝物）、デキストロルファン（ＣＹＰ２Ｄ６代謝物）、テルフェナジンアルコール体（ＣＹＰ３Ａ４代謝物）をＬＣ／ＭＳ／ＭＳで定量した。 As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsome, and test compound are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index. The mixture was reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugal supernatant was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

　被検化合物を溶解した溶媒であるＤＭＳＯのみを反応系に添加したものをコントロール（１００％）とし、被検化合物溶液を加えたそれぞれの濃度での残存活性（％）を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりＩＣ５０を算出した。 The control system (100%) was obtained by adding only DMSO, which is the solvent in which the test compound was dissolved, to the reaction system, and calculated the residual activity (%) at each concentration with the test compound solution added. Using the rate, IC 50 was calculated by inverse estimation with a logistic model.

試験例５　代謝安定性の評価
　ヒト肝ミクロソームによる代謝安定性評価：トリス塩酸バッファー（ｐＨ７．４）中にＮＡＤＰＨ（終濃度１ｍＭ，酸化的代謝の場合）、肝ミクロソーム（終濃度０．５ｍｇ　ｐｒｏｔｅｉｎ／ｍｌ）および被検化合物（終濃度２μＭ）を添加し、３７℃で０分および３０分間反応させた。グルクロン酸抱合の場合は、ＮＡＤＰＨに代えてＵＤＰＧＡ（終濃度５ｍＭ）を添加した。反応液の倍量のアセトニトリル／メタノール＝１／１（ｖ／ｖ）を添加し反応を停止した後、その遠心上清中の化合物をＨＰＬＣで測定した。０分および３０分の値の比較から代謝反応による消失量を算出し、本発明化合物の代謝安定性を確認した。 Test Example 5 Metabolic stability evaluation Metabolic stability evaluation by human liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein / in) in Tris-HCl buffer (pH 7.4). ml) and a test compound (final concentration 2 μM) were added and reacted at 37 ° C. for 0 and 30 minutes. In the case of glucuronidation, UDPGA (final concentration 5 mM) was added instead of NADPH. After the reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from a comparison of values of 0 minute and 30 minutes, and the metabolic stability of the compound of the present invention was confirmed.

試験例６　粉末溶解度試験
　適当な容器に検体を適量入れ、ＪＰ－１液（塩化ナトリウム２．０ｇ、塩酸７．０ｍＬに水を加えて１０００ｍＬとした）、ＪＰ－２液（ｐＨ６．８のリン酸塩緩衝液５００ｍＬに水５００ｍＬを加えた）、２０ｍｍｏｌ／Ｌ　ＴＣＡ（タウロコール酸ナトリウム）／ＪＰ－２液（ＴＣＡ　１．０８ｇに水を加え１００ｍＬとした）を２００μＬずつ添加した。試験液添加後に溶解した場合には、適宜原末を追加した。密閉し３７℃で１時間振とうした。濾過し、各濾液１００μＬにメタノール１００μＬを添加して２倍希釈を行った。希釈倍率は、必要に応じて変更した。気泡および析出物がないかを確認し、密閉して振とうした。絶対検量線法によりＨＰＬＣを用いて定量を行った。 Test Example 6 Powder Solubility Test An appropriate amount of a specimen is put in a suitable container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to make 1000 mL), JP-2 solution (pH 6.8 phosphorus) 200 mL of water was added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (1.08 g of TCA was added with water to make 100 mL). When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour. After filtration, 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. Quantification was performed using HPLC by the absolute calibration curve method.

製剤例
　以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例１　錠剤
　　本発明化合物　　　　　　　　　１５ｍｇ
　　デンプン　　　　　　　　　　　１５ｍｇ
　　乳糖　　　　　　　　　　　　　１５ｍｇ
　　結晶性セルロース　　　　　　　１９ｍｇ
　　ポリビニルアルコール　　　　　　３ｍｇ
　　蒸留水　　　　　　　　　　　　３０ｍｌ
　　ステアリン酸カルシウム　　　　　３ｍｇ
　ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。 Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Starch 15mg
Lactose 15mg
Crystalline cellulose 19mg
Polyvinyl alcohol 3mg
30ml distilled water
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

製剤例２　カプセル剤
　　本発明化合物　　　　　　　　　１０ｍｇ
　　ステアリン酸マグネシウム　　　１０ｍｇ
　　乳糖　　　　　　　　　　　　　８０ｍｇ
　上記成分を均一に混合して粉末または細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。 Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
The above ingredients are uniformly mixed to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.

製剤例３　顆粒剤
　　本発明化合物　　　　　　　　　　　３０ｇ
　　乳糖　　　　　　　　　　　　　　２６５ｇ
　　ステアリン酸マグネシウム　　　　　　５ｇ
　上記成分をよく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。 Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
The above ingredients are mixed well, compression molded, pulverized, sized, and sieved to give granules of appropriate size.

　本発明は、医薬品の分野、例えば線維化疾患等の治療薬の開発および製造の分野において利用可能である。 The present invention can be used in the field of pharmaceuticals, for example, in the field of development and production of therapeutic agents for fibrotic diseases and the like.

Claims (19)

式（Ｉ）：
Figure JPOXMLDOC01-appb-C000001
 （式中、
　Ｒ１、Ｒ２およびＲ３は、それぞれ独立して水素、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ４は水素、シアノ、ホルミル、カルボキシ、ハロゲン、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換若しくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ５は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換もしくは非置換の芳香族複素環式基であり；
ただし、下記（ｉ）～（ｘ）の化合物を除く、
（ｉ）Ｒ４が、非置換４－チオモルホリノ、非置換４－テトラヒドロピラニル、非置換４－ジヒドロピラニル、非置換４－モルホリノまたは置換された４－モルホリノ（置換基は、非置換メチル）であり、かつＲ５が置換若しくは非置換のフェニルメチルである化合物、
（ｉｉ）Ｒ３が置換若しくは非置換の含窒素非芳香族複素環式基で置換されたエチルである化合物、
（ｉｉｉ）Ｒ１が水素であり、かつＲ４が（ａ）水素、（ｂ）置換されたチアゾリル（置換基は、カルボキシ；非置換アミノ；非置換メチル；非置換メチルオキシ；非置換アルキルオキシカルボニル；非置換フェニル；非置換ピリジル；非置換ピリミジニル；置換もしくは非置換のフェニルメチルから選択される１以上の基）、または（ｃ）置換もしくは非置換のフェニルメチルで置換されたオキサゾリルである化合物、
（ｉｖ）Ｒ１が水素であり、かつＲ２が（ａ）置換されたアルキル（置換基は、非置換アルキルチオ；非置換アルキルスルホニルから選択される１以上の基）、または（ｂ）式：
Figure JPOXMLDOC01-appb-C000002
で示される基である化合物、
（ｖ）Ｒ３が置換若しくは非置換のフェニルであり、かつＲ４が非置換４－ピリジルである化合物、
（ｖｉ）Ｒ１が水素または非置換メチルであり、かつＲ４が非置換４－ピリジルまたは非置換２，４－ピリミジニルである化合物、
（ｖｉｉ）Ｒ１が水素であり、Ｒ２が水素であり、Ｒ３が水素であり、かつＲ５が置換テトラヒドロフラニルである化合物、
（ｖｉｉｉ）Ｒ１が水素であり、かつＲ４がカルボキシ、または非置換メチルオキシカルボニルである化合物、
（ｉｘ）Ｒ１が水素であり、Ｒ２が水素であり、Ｒ３が水素、非置換Ｃ１－Ｃ３アルキルであり、Ｒ４が非置換メチルまたは非置換エチルであり、かつＲ５が置換フェニルメチルである化合物、
および
（ｘ）以下に示す化合物
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000008
）で示される化合物またはその製薬上許容される塩。 Formula (I):
Figure JPOXMLDOC01-appb-C000001
 (Where
R 1 , R 2 and R 3 are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Substituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or non-substituted Substituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy Substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or Unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-substituted Aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbon Ring carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkenyloxycarbonyl, substituted or unsubstituted Alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic Ring oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted nonaromatic Carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted Or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted nonaromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted nonaromatic heterocyclic sulfonyl Or a substituted or unsubstituted aromatic heterocyclic sulfonyl;
R 4 is hydrogen, cyano, formyl, carboxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenyl Nilthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted nonaromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbon Ring carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyl Oxycarbonyl, substituted or unsubstituted Non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or Unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted aromatic heterocyclic Sulfonyl;
R 5 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted Or an unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
However, the following compounds (i) to (x) are excluded,
(I) R 4 is unsubstituted 4-thiomorpholino, unsubstituted 4-tetrahydropyranyl, unsubstituted 4-dihydropyranyl, unsubstituted 4-morpholino or substituted 4-morpholino (the substituent is unsubstituted methyl And R 5 is substituted or unsubstituted phenylmethyl,
(Ii) a compound wherein R 3 is ethyl substituted with a substituted or unsubstituted nitrogen-containing non-aromatic heterocyclic group,
(Iii) R 1 is hydrogen and R 4 is (a) hydrogen, (b) substituted thiazolyl (substituent is carboxy; unsubstituted amino; unsubstituted methyl; unsubstituted methyloxy; unsubstituted alkyloxy Carbonyl; unsubstituted phenyl; unsubstituted pyridyl; unsubstituted pyrimidinyl; one or more groups selected from substituted or unsubstituted phenylmethyl), or (c) a compound that is oxazolyl substituted with substituted or unsubstituted phenylmethyl ,
(Iv) R 1 is hydrogen and R 2 is (a) substituted alkyl (the substituent is one or more groups selected from unsubstituted alkylthio; unsubstituted alkylsulfonyl), or (b) formula:
Figure JPOXMLDOC01-appb-C000002
A compound which is a group represented by:
(V) a compound wherein R 3 is substituted or unsubstituted phenyl and R 4 is unsubstituted 4-pyridyl;
(Vi) the compound wherein R 1 is hydrogen or unsubstituted methyl and R 4 is unsubstituted 4-pyridyl or unsubstituted 2,4-pyrimidinyl;
(Vii) a compound wherein R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, and R 5 is substituted tetrahydrofuranyl;
(Viii) a compound wherein R 1 is hydrogen and R 4 is carboxy or unsubstituted methyloxycarbonyl;
(Ix) R 1 is hydrogen, R 2 is hydrogen, R 3 is hydrogen, unsubstituted C1-C3 alkyl, R 4 is unsubstituted methyl or unsubstituted ethyl, and R 5 is substituted phenyl A compound that is methyl,
And (x) the following compounds
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000008
Or a pharmaceutically acceptable salt thereof. Ｒ１が置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり、
Ｒ５が置換もしくは非置換のＣ５－Ｃ１０アルキル、置換もしくは非置換のＣ４－Ｃ１０アルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の芳香族炭素環式基または置換もしくは非置換の芳香族複素環式基である、請求項１記載の化合物またはその製薬上許容される塩。 R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted Or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or non-substituted Substituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy Substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, Substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic Aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic Group carbocyclic oxycarbonyl, substituted or Substituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or Unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted Non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or non-substituted Non-aromatic carbocyclic sulfonyl conversion, a substituted or unsubstituted aromatic carbocyclic ring sulfonyl, substituted or unsubstituted non-aromatic heterocyclic sulfonyl or substituted or unsubstituted aromatic heterocyclic sulfonyl,
R 5 is substituted or unsubstituted C5-C10 alkyl, substituted or unsubstituted C4-C10 alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted aromatic heterocycle The compound according to claim 1, which is a cyclic group, or a pharmaceutically acceptable salt thereof. Ｒ５が置換もしくは非置換のＣ５－Ｃ１０アルキル、置換もしくは非置換のＣ４－Ｃ１０アルケニルまたは置換もしくは非置換のアルキニルである、請求項１記載の化合物またはその製薬上許容される塩。 R 5 is a substituted or unsubstituted C5-C10 alkyl, substituted or unsubstituted C4-C10 alkenyl or a substituted or unsubstituted alkynyl, a compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein. Ｒ５がハロゲンまたはシアノで置換されたＣ４-Ｃ１０アルキル、置換もしくは非置換のＣ４-Ｃ１０アルケニルまたは置換もしくは非置換のアルキニルである、請求項１記載の化合物またはその製薬上許容される塩。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is C4-C10 alkyl substituted with halogen or cyano, substituted or unsubstituted C4-C10 alkenyl, or substituted or unsubstituted alkynyl. Ｒ１が置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基または置換若しくは非置換の非芳香族複素環式基である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。 R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted Alternatively, the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is an unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group. Ｒ１が置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、または置換若しくは非置換の芳香族複素環式基である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。 R 1 is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. Ｒ１が置換基群Ａ（アルキルカルボニルオキシ、アルキルオキシカルボニルおよび芳香族炭素環式基）から選択される１以上の置換基で置換されたアルキル、置換基群Ａから選択される１以上の置換基で置換されたアルケニル、置換基群Ａから選択される１以上の置換基で置換されたアルキニル、置換基群Ｂ（ヒドロキシ、アルコキシ、カルボキシ、ハロゲン、置換若しくは非置換のアミノ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基および置換若しくは非置換のカルバモイル）から選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｂから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｂから選択される１以上の置換基で置換された芳香族複素環式基である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。 R 1 is alkyl substituted with one or more substituents selected from substituent group A (alkylcarbonyloxy, alkyloxycarbonyl and aromatic carbocyclic group), one or more substitutions selected from substituent group A Alkenyl substituted with a group, alkynyl substituted with one or more substituents selected from substituent group A, substituent group B (hydroxy, alkoxy, carboxy, halogen, substituted or unsubstituted amino, substituted or unsubstituted Substituted with one or more substituents selected from alkyloxycarbonyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted nonaromatic heterocyclic group and substituted or unsubstituted carbamoyl) Aromatic carbocyclic group, non-aromatic carbocyclic group substituted with one or more substituents selected from substituent group B, selected from substituent group B The non-aromatic heterocyclic group substituted with one or more substituents or the aromatic heterocyclic group substituted with one or more substituents selected from Substituent Group B Or a pharmaceutically acceptable salt thereof. Ｒ１が置換基群Ｃ（ヒドロキシ、カルボキシ、カルボキシアルキル、カルボキシアルキルオキシ、アルキルカルボニルアミノ、非芳香族複素環アルキルアミノカルボニル、アルキルスルホニルオキシ、非置換非芳香族複素環式基およびオキソで置換された非芳香族複素環式基）から選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｃから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｃから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｃから選択される１以上の置換基で置換された芳香族複素環式基である、請求項１～４のいずれかに記載の化合物またはその製薬上許容される塩。 R 1 is substituted with substituent group C (hydroxy, carboxy, carboxyalkyl, carboxyalkyloxy, alkylcarbonylamino, non-aromatic heterocyclic alkylaminocarbonyl, alkylsulfonyloxy, unsubstituted non-aromatic heterocyclic group and oxo. A non-aromatic carbocyclic group substituted with one or more substituents selected from non-aromatic heterocyclic groups), an aromatic carbon substituted with one or more substituents selected from substituent group C A cyclic group, a non-aromatic heterocyclic group substituted with one or more substituents selected from substituent group C, or an aromatic heterocyclic ring substituted with one or more substituents selected from substituent group C The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a formula group. Ｒ２が水素、ホルミル、カルボキシ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルカルボニル、置換若しくは非置換のアルケニルカルボニルまたは置換若しくは非置換のアルキニルカルボニルである、請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩。 R 2 is hydrogen, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, or substituted or unsubstituted The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ｒ２が水素、ホルミル、置換若しくは非置換のアルキル、置換若しくは非置換のアルキルカルボニルまたは置換もしくは非置換のアルキルオキシカルボニルである、請求項１～８のいずれかに記載の化合物またはその製薬上許容される塩。 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, formyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, or substituted or unsubstituted alkyloxycarbonyl. Salt. Ｒ３が水素、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニルまたは置換若しくは非置換のアルキニルである、請求項１～１０のいずれかに記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. Ｒ３が水素または置換若しくは非置換のアルキルである、請求項１～１０のいずれかに記載の化合物またはその製薬上許容される塩。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 3 is hydrogen or substituted or unsubstituted alkyl. Ｒ４が水素、ハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基または置換若しくは非置換のアミノである、請求項１～１２のいずれかに記載の化合物またはその製薬上許容される塩。 R 4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic hetero Ring oxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted amino; The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. Ｒ４が置換基群Ｄ（ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のカルバモイル、および置換もしくは非置換の芳香族炭素環スルホニル）から選択される１以上の置換基で置換されたアルキル、置換基群Ｄから選択される１以上の置換基で置換されたアルケニル、置換基群Ｄから選択される１以上の置換基で置換されたアルキルオキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族炭素環オキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族複素環オキシ、置換基群Ｄから選択される１以上の置換基で置換された非芳香族炭素環式基、置換基群Ｄから選択される１以上の置換基で置換された芳香族炭素環式基、置換基群Ｄから選択される１以上の置換基で置換された非芳香族複素環式基または置換基群Ｄから選択される１以上の置換基で置換されたアミノである、請求項１～１２のいずれかに記載の化合物またはその製薬上許容される塩。 R 4 represents a substituent group D (halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle; Formula group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted Alkyl substituted with one or more substituents selected from carbamoyl and substituted or unsubstituted aromatic carbocyclic sulfonyl), alkenyl substituted with one or more substituents selected from Substituent Group D, substituent Alkyloxy substituted with one or more substituents selected from group D, non-aromatic substituted with one or more substituents selected from substituent group D Aromatic carbocyclic oxy, non-aromatic heterocyclic oxy substituted with one or more substituents selected from substituent group D, non-aromatic carbon substituted with one or more substituents selected from substituent group D A cyclic group, an aromatic carbocyclic group substituted with one or more substituents selected from substituent group D, and a non-aromatic heterocyclic ring substituted with one or more substituents selected from substituent group D The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is amino substituted with one or more substituents selected from the formula group or substituent group D. Ｒ４が置換基群Ｄ’（置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基および置換もしくは非置換の芳香族複素環式基）から選択される１以上の置換基で置換されたアルキルオキシ、置換基群Ｄ’から選択される１以上の置換基で置換されたアルケニルオキシ、置換基群Ｄ’から選択される１以上の置換基で置換されたアルキニルオキシである、請求項１～１２のいずれかに記載の化合物またはその製薬上許容される塩。 R 4 represents a substituent group D ′ (substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group and substituted or non-substituted Alkyloxy substituted with one or more substituents selected from substituted aromatic heterocyclic groups), alkenyloxy substituted with one or more substituents selected from substituent group D ′, substituent group D The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, which is alkynyloxy substituted with one or more substituents selected from: 請求項１～１５のいずれかに記載の化合物またはその製薬上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient. オートタキシン阻害剤である、請求項１６記載の医薬組成物。 The pharmaceutical composition according to claim 16, which is an autotaxin inhibitor. 請求項１～１５のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、オートタキシンの関与する疾患の治療又は予防方法。 A method for treating or preventing a disease involving autotaxin, which comprises administering the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof. 式（Ｉ）：
Figure JPOXMLDOC01-appb-C000009
 （式中、
　Ｒ１、Ｒ２、Ｒ３およびＲ４はそれぞれ独立して、水素、ハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルであり；
　Ｒ５はハロゲン、ヒドロキシ、シアノ、ホルミル、カルボキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換の芳香族複素環式基、置換もしくは非置換のアミノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換の非芳香族炭素環オキシ、置換もしくは非置換の芳香族炭素環オキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換の芳香族複素環オキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換の非芳香族炭素環チオ、置換もしくは非置換の芳香族炭素環チオ、置換もしくは非置換の非芳香族複素環チオ、置換もしくは非置換の芳香族複素環チオ、置換もしくは非置換のアルキルカルボニル、置換もしくは非置換のアルケニルカルボニル、置換もしくは非置換のアルキニルカルボニル、置換もしくは非置換の非芳香族炭素環カルボニル、置換もしくは非置換の芳香族炭素環カルボニル、置換もしくは非置換の非芳香族複素環カルボニル、置換もしくは非置換の芳香族複素環カルボニル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換の非芳香族炭素環オキシカルボニル、置換もしくは非置換の芳香族炭素環オキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換の芳香族複素環オキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアルキルスルフィニル、置換もしくは非置換のアルケニルスルフィニル、置換もしくは非置換のアルキニルスルフィニル、置換もしくは非置換の非芳香族炭素環スルフィニル、置換もしくは非置換の芳香族炭素環スルフィニル、置換もしくは非置換の非芳香族複素環スルフィニル、置換もしくは非置換の芳香族複素環スルフィニル、置換もしくは非置換のアルキルスルホニル、置換もしくは非置換のアルケニルスルホニル、置換もしくは非置換のアルキニルスルホニル、置換もしくは非置換の非芳香族炭素環スルホニル、置換もしくは非置換の芳香族炭素環スルホニル、置換もしくは非置換の非芳香族複素環スルホニルまたは置換もしくは非置換の芳香族複素環スルホニルである）で示される化合物またはその製薬上許容される塩を含有することを特徴とする、オートタキシン阻害剤。 Formula (I):
Figure JPOXMLDOC01-appb-C000009
 (Where
R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, A substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, Substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic Carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted Or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted nonaromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted Non-aromatic heterocyclic thio, substituted or unsubstituted aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic Aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or Unsubstituted alkenyloxycarbonyl, substituted or Unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted Aromatic heterocyclic oxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted Non-aromatic carbocyclic sulfinyl, substituted or unsubstituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl Substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclic sulfonyl, substituted or unsubstituted aromatic carbocyclic sulfonyl, substituted or unsubstituted non-aromatic heterocyclic ring Sulfonyl or substituted or unsubstituted aromatic heterocyclic sulfonyl;
R 5 is halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted Substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted Alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclic thio, substituted or unsubstituted aromatic carbocyclic thio, substituted or unsubstituted non-aromatic heterocyclic thio, substituted or unsubstituted Aromatic heterocyclic thio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic carbonyl, substituted or unsubstituted aromatic Carbocyclic carbonyl, substituted or unsubstituted non-aromatic heterocyclic carbonyl, substituted or unsubstituted aromatic heterocyclic carbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted Alkynyloxycarbonyl, substituted or Substituted non-aromatic carbocyclic oxycarbonyl, substituted or unsubstituted aromatic carbocyclic oxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aromatic heterocyclic oxycarbonyl, substituted or non-substituted Substituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclic sulfinyl, substituted or unsubstituted Substituted aromatic carbocyclic sulfinyl, substituted or unsubstituted non-aromatic heterocyclic sulfinyl, substituted or unsubstituted aromatic heterocyclic sulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted Or an unsubstituted alkynylsulfonyl, a substituted or unsubstituted non-aromatic carbocyclic sulfonyl, a substituted or unsubstituted aromatic carbocyclic sulfonyl, a substituted or unsubstituted non-aromatic heterocyclic sulfonyl, or a substituted or unsubstituted aromatic And a pharmaceutically acceptable salt thereof. An autotaxin inhibitor, characterized by comprising:
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