WO2015064714A1 - Dérivé substitué en position 1 d'imidazopyrimidinone ayant une activité inhibitrice sur l'autotaxine - Google Patents

Dérivé substitué en position 1 d'imidazopyrimidinone ayant une activité inhibitrice sur l'autotaxine Download PDF

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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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substituted
unsubstituted
aromatic heterocyclic
aromatic
group
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PCT/JP2014/078963
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English (en)
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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国立大学法人東京大学
国立大学法人東北大学
塩野義製薬株式会社
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Publication of WO2015064714A1 publication Critical patent/WO2015064714A1/fr

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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

La présente invention concerne un composé présentant une activité inhibitrice sur l'autotaxine et qui est représenté par la formule (I) (dans laquelle R1, R2, R3, R4 et R5 sont tels que définis dans la description), un médicament contenant ledit composé en tant qu'ingrédient actif, et une méthode de traitement ou de prévention d'une maladie associée à l'autotaxine impliquant l'administration dudit composé.
PCT/JP2014/078963 2013-10-31 2014-10-30 Dérivé substitué en position 1 d'imidazopyrimidinone ayant une activité inhibitrice sur l'autotaxine WO2015064714A1 (fr)

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US20160002247A1 (en) * 2013-03-01 2016-01-07 The University Of Tokyo 8-substituted imidazopyrimidinone derivative having autotaxin inhibitory activity
WO2017033966A1 (fr) * 2015-08-26 2017-03-02 塩野義製薬株式会社 Dérivé de pyrazole condensé substitué par un 5-carbonylaminoalkyle ayant une activité inhibitrice d'autotaxine
US10183949B2 (en) 2014-08-29 2019-01-22 The University Of Tokyo Pyrimidinone derivative having autotaxin-inhibitory activity
JP2020504743A (ja) * 2016-12-22 2020-02-13 カデント セラピューティクス，インコーポレーテッド Ｎｍｄａ受容体モジュレーターおよびその使用
US11512097B2 (en) 2019-11-25 2022-11-29 Amgen Inc. Heterocyclic compounds as Delta-5 desaturase inhibitors and methods of use
US11542264B2 (en) 2018-08-03 2023-01-03 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
US20160002247A1 (en) * 2013-03-01 2016-01-07 The University Of Tokyo 8-substituted imidazopyrimidinone derivative having autotaxin inhibitory activity
US10183949B2 (en) 2014-08-29 2019-01-22 The University Of Tokyo Pyrimidinone derivative having autotaxin-inhibitory activity
WO2017033966A1 (fr) * 2015-08-26 2017-03-02 塩野義製薬株式会社 Dérivé de pyrazole condensé substitué par un 5-carbonylaminoalkyle ayant une activité inhibitrice d'autotaxine
JPWO2017033966A1 (ja) * 2015-08-26 2018-06-14 塩野義製薬株式会社 オートタキシン阻害活性を有する５位カルボニルアミノアルキル置換縮合ピラゾール誘導体
JP2020504743A (ja) * 2016-12-22 2020-02-13 カデント セラピューティクス，インコーポレーテッド Ｎｍｄａ受容体モジュレーターおよびその使用
US11274107B2 (en) 2016-12-22 2022-03-15 Cadent Therapeutics, Inc. NMDA receptor modulators and uses thereof
JP7332472B2 (ja) 2016-12-22 2023-08-23 ノバルティス アーゲー Ｎｍｄａ受容体モジュレーターおよびその使用
US11807650B2 (en) 2016-12-22 2023-11-07 Novartis Ag NMDA receptor modulators and uses thereof
US11542264B2 (en) 2018-08-03 2023-01-03 Cadent Therapeutics, Inc. Heteroaromatic NMDA receptor modulators and uses thereof
US11512097B2 (en) 2019-11-25 2022-11-29 Amgen Inc. Heterocyclic compounds as Delta-5 desaturase inhibitors and methods of use

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