WO2017097182A1 - 喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 - Google Patents

喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 Download PDF

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WO2017097182A1
WO2017097182A1 PCT/CN2016/108688 CN2016108688W WO2017097182A1 WO 2017097182 A1 WO2017097182 A1 WO 2017097182A1 CN 2016108688 W CN2016108688 W CN 2016108688W WO 2017097182 A1 WO2017097182 A1 WO 2017097182A1
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substituted
unsubstituted
group
aryl
cycloalkyl
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English (en)
French (fr)
Inventor
樊磊
杜武
李兴海
陈元伟
胥珂馨
陈锞
张少华
罗潼川
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Hinova Pharmaceuticals Inc
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Hinova Pharmaceuticals Inc
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Priority to CA3007783A priority Critical patent/CA3007783C/en
Priority to BR112018011390-5A priority patent/BR112018011390B1/pt
Priority to EP16872373.2A priority patent/EP3388420B1/en
Priority to JP2018529587A priority patent/JP6752888B2/ja
Priority to ES16872373T priority patent/ES2926781T3/es
Priority to RU2018120242A priority patent/RU2715229C2/ru
Priority to DK16872373.2T priority patent/DK3388420T3/da
Priority to US15/781,997 priority patent/US10450274B2/en
Priority to PL16872373.2T priority patent/PL3388420T3/pl
Priority to AU2016368240A priority patent/AU2016368240B2/en
Publication of WO2017097182A1 publication Critical patent/WO2017097182A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/04—Drugs for disorders of the urinary system for urolithiasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • 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
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to quinoline compounds, processes for their preparation and use as urate transporter inhibitors.
  • Urate transporter (URAT1) inhibitors are used to treat diseases such as hyperuricemia and gout.
  • the present invention provides a class of quinoline compounds and their use as urate transporter inhibitors.
  • the present invention provides a compound represented by the formula (A), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,
  • Z is selected from O, S or -NH-;
  • W 1 is selected from N or CR a ;
  • W 2 is selected from N or CR b ;
  • W 3 is selected from N or CR c ;
  • R a , R b , R c , R 2 , R 3 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -OR d , -S(O) m R d , -C(O)R d , C(O)OR d , -C(O)NR e R f , -NR e R f or NR e C (O)R f , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is independently independently optionally further selected from one or more selected from the group consisting of halogen and cyano , nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkyny
  • R d is selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted with a substituent of an aryl group, a carboxyl group, a carboxylate group, -C(O)NR e R f , -NR e R f or NR e C(O)R f ;
  • R e and R f are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl
  • alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl independently, further selected from one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group, or a carboxylate group; and m is 0, 1 or 2;
  • X and Y are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkyl, haloalkyl or hydroxyalkyl;
  • R 4 is selected from hydrogen or alkyl or cycloalkyl; when Z is selected from -NH-, R 4 is selected from hydrogen, aryl or heteroaryl, preferably pyridyl.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (I):
  • R 1 is selected from the group consisting of hydrogen, halogen, trifluoromethyl, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR d , - S(O) m R d , -C(O)R d , C(O)OR d , -C(O)NR e R f , -NR e R f or NR e C(O)R f , wherein
  • the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, Alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,
  • R 2 , R 3 , R 4 , R d , R e , R f and m all have the meanings described for the formula (A).
  • R 1 is selected from halogen, substituted or unsubstituted alkyl, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl;
  • R 2 and R 3 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkane. base;
  • R 4 is selected from hydrogen or a C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group.
  • R 1 is selected from the group consisting of halogen, trifluoromethyl, and substituted Or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted Furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiyl Azolyl or a C 3 -C 6 cycloalkyl group.
  • R 1 is selected from the group consisting of F, Br, Cl, and trifluoro Methyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further further selected from one or more selected from the group consisting of methoxy, ethoxy, fluoro, chloro, Substituted by a substituent of bromo or trifluoromethyl.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • R 2 is selected from hydrogen and R 3 is selected from methyl
  • R 2 is selected from hydrogen and R 3 is selected from ethyl;
  • R 2 is selected from hydrogen and R 3 is selected from isopropyl
  • R 2 and R 3 are each selected from a methyl group
  • R 2 and R 3 are each selected from the group consisting of ethyl
  • both R 2 and R 3 are selected from n-propyl.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Ia):
  • R 1 has the meaning set forth in claim 2.
  • R 1 is selected from the group consisting of halogen, trifluoromethyl, and substituted Or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted Furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiyl Azolyl or a C 3 -C 6 cycloalkyl group.
  • R 1 is selected from the group consisting of F, Br, Cl, and trifluoro Methyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further further selected from one or more selected from the group consisting of methoxy, ethoxy, fluoro, chloro, Substituted by a substituent of bromo or trifluoromethyl.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof has a structure represented by the formula (Ib):
  • R 1 has the meaning set forth in claim 2.
  • R 1 is selected from the group consisting of halogen, trifluoromethyl, and substituted Or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted Furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiyl Azolyl or a C 3 -C 6 cycloalkyl group.
  • R 1 is selected from the group consisting of F, Br, Cl, and trifluoro Methyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further further selected from one or more selected from the group consisting of methoxy, ethoxy, fluoro, chloro, Substituted by a substituent of bromo or trifluoromethyl.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof has a structure represented by the formula (Ic):
  • R 1 has the meaning set forth in claim 2.
  • R 1 is selected from the group consisting of halogen, trifluoromethyl, and substituted Or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted Furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiyl Azolyl or a C 3 -C 6 cycloalkyl group.
  • R 1 is selected from the group consisting of F, Br, Cl, and trifluoro Methyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further further selected from one or more selected from the group consisting of methoxy, ethoxy, fluoro, chloro, Substituted by a substituent of bromo or trifluoromethyl.
  • R 1 has the meaning set forth in claim 2.
  • R 1 is selected from the group consisting of halogen, trifluoromethyl, and substituted Or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted Furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted thiadiyl Azolyl or a C 3 -C 6 cycloalkyl group.
  • R 1 is selected from the group consisting of F, Br, Cl, and trifluoro Methyl, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, phenyl or cyclopropyl, wherein said phenyl is optionally further further selected from one or more selected from the group consisting of methoxy, ethoxy, fluoro, chloro, Substituted by a substituent of bromo or trifluoromethyl.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 1 is selected from cyclopropyl; R 2 and R 3 has the meanings described in the formula (A).
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • R 1 is selected from one or two methoxy groups Substituted phenyl; both R 2 and R 3 have the meanings indicated in formula (A).
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • R 1 is selected from fluorophenyl
  • R 2 and R 3 has the meanings described in the formula (A).
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof wherein R 2 and R 3 are each independently selected from hydrogen, Halogen or a C 1 -C 6 alkyl group.
  • the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable thereof a salt, or a prodrug thereof which is one of the following compounds:
  • the invention also provides a process for the preparation of the compound, comprising the steps carried out according to the following route:
  • the present invention also provides the use of the compound, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, for the preparation of a URAT1 inhibitor.
  • the drug is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kay- Sai's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyl transfer
  • a drug for enzyme deficiency preferably a drug for preventing and/or treating gout or hyperuricemia.
  • the present invention also provides a pharmaceutical composition which is active with a compound as defined, or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof
  • the invention also provides the use of the pharmaceutical composition for the preparation of a URAT1 inhibitor.
  • the medicament is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kai- ⁇ Second syndrome, kidney disease, kidney Stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency, preferably prevention and / or drugs for the treatment of gout or hyperuricemia.
  • the various compounds provided by the present invention, and salts, hydrates thereof, or optical isomers thereof, or solvates thereof, or pharmaceutically acceptable salts thereof, or prodrugs thereof, are a selective uric acid
  • the absorption inhibitor can treat hyperuricemia and gout by promoting excretion of uric acid from the body and reducing serum uric acid, and has an effect of reducing uric acid in animals and in humans.
  • an isotope substituent can replace hydrogen with hydrazine and/or hydrazine.
  • the natural abundance of 12 C can be replaced by 13 C or 14 C
  • the natural abundance of 14 N can be replaced by 15 N
  • the C 1 -C 6 alkyl group means a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkyl group, that is, a straight chain or a branch having 1 to 6 carbon atoms.
  • Alkyl of the chain such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, tert-butyl, sec-butyl, tert-butylmethyl, and the like.
  • the C 3 -C 6 cycloalkyl group means a C 3 , C 4 , C 5 , C 6 cycloalkyl group, that is, a cycloalkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group. , cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and the like.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • the "salt" is an acid form and/or a base salt which forms a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitter ion salt (internal salt), and also includes a season.
  • An ammonium salt such as an alkylammonium salt.
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • the acid salt, oxalate salt, malate salt, succinate salt, fumarate salt, maleate salt, tartrate salt or trifluoroacetate salt may also be an alkali metal ion salt such as a sodium salt or a potassium salt of the compound.
  • the target products 23, 24, 83, 93, 94, 95, 96, 114, 128, 129 were synthesized in the same manner using the corresponding reagents.
  • the target products 88, 89, 90, 91, 92 were synthesized in the same manner using the corresponding reagents.
  • Compound 1;2;3;4;5;6;7;8;9;10;11;12;13;14;15;16;17;18;20;21;25;26;27;28;29;29; ;30;31;32;33;34;35;36;37;38;39;40;41;42;84;85;86;100;101;102;103;104;108;109;110;111; ;112;113;115;116;117;118;119;120;121;122;123;124;125;126;127;138;139;140;141;142 are all in accordance with the same method
  • the reagents are decomposed.
  • Test Example Determination of the inhibitory activity of the compound of the present invention on URAT1
  • Penicillin-Streptomycin (Invitrogen, Cat. No. 15070-063)
  • Isoplate-96Microplate (PERKIN ELMER, Cat. No. 6005040)
  • HEK-293T cells stably expressing hURAT1 were cultured in 10% FBS and 1% P/S DMEM medium, and cultured overnight in a 37-degree incubator with 5% carbon dioxide.
  • the medium was removed, washed once with PBS, and then trypsinized for 2 minutes. After the cells were separated in a Petri dish, 10 ml of the medium was added to terminate the digestion.
  • test compound was dissolved in DMSO and then the same concentration of DMSO was added to the wells of HEK293/hURAT1 cells containing no test compound. Uric acid uptake of cells at each test concentration was expressed as the average percent inhibition of the DMSO control. The radioactivity value obtained for the wells containing DMSO is considered to be 100% uptake of the cells. The IC50 value of a compound can be calculated from the inhibition rate at different concentrations.
  • the IC50 (nM) of the inhibition of hURAT1 activity by the compound of the present invention is shown in Table 1.
  • the reference compound 1 was synthesized in accordance with the method described in the patent WO 2011/159839 A2.
  • Reference compound 2 and reference compound 3 were synthesized according to the method described in the patent WO 2014/183555 A1 and tested head-to-head under the same conditions as the compounds 83 and 129, respectively.
  • the IC50 of reference compounds 2 and 83 is the average of multiple head-to-head comparison experiments.
  • the IC50 of reference compounds 3 and 129 is the average of two comparative experiments.
  • the compounds of the present invention have a significant inhibitory effect on the uric acid transporter URAT1.
  • Reference compounds 1 and 2 are known high activity uric acid transporter URAT1 inhibitors.
  • Compound 83 exhibited better urate transporter inhibitory activity than reference compound 1.
  • the multiple pairs of compound 83 and reference compound 2 The statistical analysis of the head activity measurement data is shown in Table 2, and the results demonstrate that the activity of the compound 83 is significantly different from the activity data of the reference compound 2. Comparing the structure and activity of the binding compound 129 with the reference compound 3, it is apparent that the present invention significantly improves the compound after the cycloalkyl substitution at a specific position is changed to a ring-opened alkyl group, especially a bis-ethyl substitution.
  • the uric acid transporter URAT1 inhibitory activity of the compound is described in Table 2, and the results demonstrate that the activity of the compound 83 is significantly different from the activity data of the reference compound 2. Comparing the structure and activity of the binding compound 129 with the reference compound 3, it is apparent that the present invention significantly improves the compound after the cycloalkyl substitution at a specific position is changed to
  • the various compounds and salts, hydrates or solvates thereof provided by the present invention are selective uric acid reuptake inhibitors which are more biologically active than the compounds represented in the art, and can excrete uric acid from the body and reduce serum.
  • Uric acid is used to treat or prevent conditions characterized by abnormal levels of uric acid.
  • the condition is selected from the group consisting of gout, recurrent gout attack, hyperuricemia, cardiovascular disease, Ly-Naphthalene syndrome, Kay-Sei's syndrome, kidney disease, arthritis, urolithiasis, lead poisoning, Hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency have the effect of reducing uric acid in animals and in humans.

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Abstract

本发明公开了喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途。本发明提供的各种化合物及其盐类、水合物或溶剂合物，是一种选择性尿酸再吸收抑制剂，可以通过促进尿酸从体内排泄并减少血清尿酸来治疗高尿酸血症和痛风，具有在动物体内和人体内具有降低尿酸的效果。

Description

喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途 技术领域。
本发明涉及喹啉类化合物及其制备方法和作为尿酸盐转运体抑制剂类药物的用途。
背景技术
尿酸盐转运体(URAT1)抑制剂类药物以用于治疗高尿酸血症、痛风等疾病。
发明内容
本发明提供了一类喹啉类化合物，以及它们作为尿酸盐转运体抑制剂类药物的用途。
本发明提供了式(A)所示的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，
Figure PCTCN2016108688-appb-000001
其中：
Z选自O，S或-NH-；
W1选自N或CRa；W2选自N或CRb；W3选自N或CRc；
Ra、Rb、Rc、R2、R3分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；
Rd选自氢、卤素、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧 基、羧酸酯基、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；
Re、Rf分别独立选自氢、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基、羧酸酯基的取代基所取代；且m为0、1或2；
X、Y分别独立地选自氢、卤素、氰基、硝基、烷基、烷基、卤代烷基或羟烷基；
当Z选自O或S时，R4选自氢或烷基或环烷基；当Z选自-NH-时，R4选自氢、芳基或杂芳基，优选吡啶基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(I)所示的结构：
Figure PCTCN2016108688-appb-000002
其中，R1选自氢、卤素、三氟甲基、氰基、硝基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；
R2、R3、R4、Rd、Re、Rf、m均具有式(A)所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中：
R1选自卤素、取代或未被取代的烷基、三氟甲基、取代或未被取代的芳基、取代或未被取代的杂芳基、取代或未被取代的环烷基；
R2、R3分别独立地选自氢、卤素、取代或未被取代的烷基、取代或未被取代的芳基、取代或未被取代的杂芳基、取代或未被取代的环烷基；
R4选自氢或C1～C6的烷基或C3～C6的环烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，当Z选自O时，R4选自氢。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、三氟甲基、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自F、Br、Cl、三氟甲基、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，
R2选自氢且R3选自甲基；
或，R2选自氢且R3选自乙基；
或，R2选自氢且R3选自异丙基；
或，R2和R3均选自甲基；
或，R2和R3均选自乙基；
或，R2和R3均选自正丙基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ia)所示的结构：
Figure PCTCN2016108688-appb-000003
其中，R1具有权利要求2中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、三氟甲基、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代 的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自F、Br、Cl、三氟甲基、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐，所述化合物具有如式(Ib)所示的结构：
Figure PCTCN2016108688-appb-000004
其中，R1具有权利要求2中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、三氟甲基、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自F、Br、Cl、三氟甲基、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Ic)所示的结构：
Figure PCTCN2016108688-appb-000005
其中，R1具有权利要求2中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、三氟甲基、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自F、Br、Cl、三氟甲基、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Id)或(Ie)所示的结构：
Figure PCTCN2016108688-appb-000006
其中，R1具有权利要求2中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、三氟甲基、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自F、Br、Cl、三氟甲基、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自环丙基；R2和R3均具有式(A)中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自吡啶基；R2和R3均具有式(A)中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自被一个或两个甲氧基取代的苯基；R2和R3均具有式(A)中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自Br；R2和R3均具有式(A)中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自氟苯基；R2和R3均具有式(A)中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自三氟甲基苯基；R2和R3均具有式(A)中所述的含义。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基。
进一步地，所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的 盐、或其前体药物，所述化合物为如下化合物之一：
Figure PCTCN2016108688-appb-000007
Figure PCTCN2016108688-appb-000008
Figure PCTCN2016108688-appb-000009
Figure PCTCN2016108688-appb-000010
Figure PCTCN2016108688-appb-000011
本发明还提供了所述化合物的制备方法，包括按照下述路线进行的步骤：
Figure PCTCN2016108688-appb-000012
或者，包括按照下述路线进行的步骤：
Figure PCTCN2016108688-appb-000013
本发明还提供了所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物在制备URAT1抑制剂类药物中的用途。
进一步地，所述是药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
本发明还提供了一种药物组合物，它是以权利要所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物为活性成分，加上药学上可接受的辅料制备而成的制剂。
本发明还提供了所述的药物组合物在制备URAT1抑制剂类药物中的用途。
进一步地，所述药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾 结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
本发明提供的各种化合物及其盐类、水合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，是一种选择性尿酸再吸收抑制剂，可以通过促进尿酸从体内排泄并减少血清尿酸来治疗高尿酸血症和痛风，具有在动物体内和人体内具有降低尿酸的效果。
此外，对于本发明的化合物而言，其同位素取代物，如氘代、氚代、14C代以及15N代也具有相同的活性和用途。例如，同位素取代物可以将氢置换为氘和/或氚。同样的，天然丰度的12C可被13C或14C置换、天然丰度的14N可被15N置换，天然丰度的16O被17O或18O置换等或任何组合。
本发明中，所述C1～C6的烷基是指C1、C2、C3、C4、C5、C6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、丁基，戊基，己基，异丙基、异丁基、叔丁基、仲丁基，叔丁基甲基，等等。
本发明中，所述C3～C6的环烷基是指C3、C4、C5、C6的环烷基，即具有3～6个碳原子的环烷基，例如环丙基、环丁基，环戊基，环己基，环丙基甲基、环丁基甲基、环戊基甲基等等。
本发明中，“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
本发明中，“盐”是将化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐，也可以是化合物的碱金属离子盐如钠盐，钾盐。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
反应通式如下：
Figure PCTCN2016108688-appb-000014
实施例1
Figure PCTCN2016108688-appb-000015
2-(6-溴喹啉-4-硫)-2-甲基丙酸乙酯(中间体2)的合成
Figure PCTCN2016108688-appb-000016
向100mL的反应瓶中加入6-溴-4-氯喹啉(2.42g，10mmol)，硫化钠(1.17g，15mmol)，N-甲基吡咯烷酮(30mL)，加热到120℃搅拌反应2个小时，然后向反应瓶中加入碳酸铯(6.52g，20mmol)和2-溴异丁酸乙酯(2.15g，11mmol)，继续在100℃反应2个小时，反应完毕后，加入水(150mL)，用乙酸乙酯萃取三次(3×100ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体2(2.1g)，收率60％。MS:354,356(M+H+)。
2-(6-溴喹啉-4-硫)-2-甲基丙酸(22)的合成
Figure PCTCN2016108688-appb-000017
向100mL的反应瓶中加入中间体2(354mg，1mmol)，甲醇(5mL)，水(5mL)，室温反应16个小时。反应完毕后，在冰水浴条件下，用2N盐酸中和至PH为5左右，然后过滤，滤饼用10mL水洗，滤饼烘干得化合物22(228mg)，收率70％。1H NMR(400MHz,DMSO):δ(ppm)13.09(s,1H),8.89(d,J＝4.0Hz,1H),8.51(d,J＝4.0Hz,1H),7.96(m,2H),7.64(d,J＝4.0Hz,1H),1.55(s,6H).质谱:326.1,328.1(M+H+)。
目标产物23，24，83，93，94，95，96，114，128，129用同样的方法，用与之相对应的试剂合成。
Figure PCTCN2016108688-appb-000018
产物23(2-(6-溴喹啉-4-硫)-丙酸)：312.0，314.0(M+H+)。
Figure PCTCN2016108688-appb-000019
产物24(2-(6-溴喹啉-4-硫)-丁酸)：1H NMR(DMSO,400MHz)：δ(ppm)13.22(s,1H),8.81(d,J＝4.8Hz,1H),8.28(d,J＝1.2Hz,1H),7.99-7.94(m,2H),7.65(d,J＝4.8Hz,1H),4.29(t,J＝7.2Hz,1H),2.01-1.90(m,2H),1.06(t,J＝7.2Hz,3H)；质谱：325.9,327.9(M+H+)。
Figure PCTCN2016108688-appb-000020
产物83(2-(6-溴喹啉-4-硫)-2-乙基丁酸)：1H NMR(DMSO,400MHz)：δ(ppm)13.09(s,1H),8.87(d,J＝4.0Hz,1H),8.56(d,J＝4.0Hz,1H),7.96(m,2H),7.61(d,J＝4.0Hz,1H),1.84-1.77(m,4H),0.92(t,6H).质谱：354.0,356.0(M+H+)。
Figure PCTCN2016108688-appb-000021
产物93(2-(喹啉-4-硫)-2-甲基丙酸)：1H NMR(CDCl3,400MHz)：δ(ppm)8.60(d,J＝4.0Hz,1H),8.35(d,J＝4.0Hz,1H),8.07(d,J＝4.0Hz,1H),7.65(m,2H),7.51(t,J＝4.0Hz,1H),1.81(t,6H).质谱：324.1(M+H+)。
Figure PCTCN2016108688-appb-000022
产物94(2-(6-溴喹啉-4-硫)-3-甲基丁酸)：1H NMR(DMSO,400MHz)：δ(ppm)13.10(s,1H),8.79(d,J＝8.0Hz,1H),8.29(d,J＝4.0Hz,1H),7.96(m,2H),7.61(d,J＝8.0Hz,1H),4.13(d,J＝7.6Hz,1H),2.27-2.24(m,1H),1.14-1.10(t,6H).质谱：340.0,342.0(M+H+)。
Figure PCTCN2016108688-appb-000023
产物95(2-(6,7-二甲氧基喹啉-4-硫)-2-甲基丙酸)：1H NMR(DMSO,400MHz)：δ(ppm)8.62(d,J＝4.0Hz,1H),7.67(s,1H),7.45(d,J＝4.0Hz,1H),7.40(1H,s),3.94(6H,s),1.51(6H,s)；质谱：308.1(M+H+)。
Figure PCTCN2016108688-appb-000024
产物96(2-(6-三氟甲基喹啉-4-硫)-2-甲基丙酸)：1H NMR(DMSO,400MHz)：δ(ppm)13.10(s,1H),8.96(d,J＝8.0Hz,1H),8.28(d,J＝4.0Hz,1H),8.05(m,2H),7.40(d,J＝8.0Hz,1H),1.5(s,6H)；质谱：316.0(M+H+)。
Figure PCTCN2016108688-appb-000025
产物114(2-(6-溴喹啉-4-硫)-2-丙基戊酸)：1H NMR(DMSO,400MHz)：δ(ppm):8.84(d,J＝4.0Hz,1H),8.54(d,J＝4.0Hz,1H),7.94(m,2H),7.61(d,J＝4.0Hz,1H),1.78-1.65(m,4H),1.46-1.29(m,4H),0.89-0.82(m,6H)；质谱：381.9,383.9(M+H+)。
Figure PCTCN2016108688-appb-000026
产物128(2-(6-三氟甲基-喹啉-4-硫)-2-丙基戊酸)：1H NMR(DMSO,400MHz)：δ(ppm):13.01(s,1H),8.81(d,J＝4.0Hz,1H),8.47(d,J＝4.0Hz,1H),7.94(m,2H),7.59(d,J＝4.0Hz,1H),1.77-1.62(m,4H),1.45-1.27(m,4H),0.87-0.80(m,6H)；质谱：344.1(M+H+)。
Figure PCTCN2016108688-appb-000027
产物129(2-喹啉-4-硫)-2-丙基戊酸)：质谱：276.1(M+H+)
实施例2
Figure PCTCN2016108688-appb-000028
(产物87)的合成
向100mL的反应瓶中加入中间体2(325mg,1mmol)，二氯甲烷(10mL)，DMF(20mg)，然后加入草酰氯(1g，8mmol)加热到40度反应1个小时，浓缩至干，然后用加入二氯甲烷(10mL)，加入三乙胺(500mg,5mmol)，最后加入4-氨基吡啶(190mg,2mmol)，加热到40 度反应1个小时。反应完毕后，加入水(50mL)，用乙酸乙酯萃取三次(3×50ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得化合物87(160mg)收率40％。MS:401.0,403.0(M+H+).
目标产物88，89，90，91，92用同样的方法，用与之相对应的试剂合成。
Figure PCTCN2016108688-appb-000029
产物88(2-(6-溴喹啉-4-硫)-2-甲基丙酰-(2-氨基吡啶))：质谱：401.0,403.0(M+H+)。
Figure PCTCN2016108688-appb-000030
产物89(2-(6-溴喹啉-4-硫)-2-甲基丙酰-(3-氨基吡啶))：质谱：401.0,403.0(M+H+)。
Figure PCTCN2016108688-appb-000031
产物90(2-(喹啉-4-硫)-2-甲基丙酰-(4-氨基吡啶))：质谱：324.1(M+H+)。
Figure PCTCN2016108688-appb-000032
产物91(2-(喹啉-4-硫)-2-甲基丙酰-(2-氨基吡啶))质谱：324.1(M+H+)。
Figure PCTCN2016108688-appb-000033
产物92(2-(喹啉-4-硫)-2-甲基丙酰-(3-氨基吡啶))：质谱：324.1(M+H+)。
实施例3
Figure PCTCN2016108688-appb-000034
向50mL的反应瓶中加入中间体A-1(112mg，0.33mmol)，环丙基磺酰胺(52mg，0.43mmol)，HATU(163mg，0.43mmol)，DIPEA(129mg，1mmol)，DMF(3mL)，反应液在室温下搅拌16个小时。反应完毕后，加入20mL水，然后用EA萃取(15mL×3)，干燥，旋干后的粗品用prep-HPLC纯化，干燥得到化合物105(50mg)，收率34％。1H NMR(400MHz,CDCl3)δ8.70(d,J＝4.6Hz，1H),8.23(d,J＝2.0Hz,1H),8.01(d,J＝8.8Hz,1H),7.85(m,1H),6.95(d,J＝4.8Hz,1H),3.18-3.10(m,2H),2.83-2.73(m,2H),2.42(dd,J＝11.2Hz,2H),2.26-2.14(m,1H),1.18-1.12(m,2H),0.91-0.84(m,2H).质谱：440.8,442.8(M+H+)
化合物106，107采用相应的原料和与105相同的制备方式制得。
Figure PCTCN2016108688-appb-000035
产物106 2-(6-溴喹啉-4-硫)-N-(环丙基磺酰基)-2-甲基丙酰胺:1H NMR(400MHz,CDCl3)δ8.78(d,J＝4.7Hz,1H),8.41(d,J＝2.1Hz,1H),8.02(d,J＝8.9Hz,1H),7.85(m,1H,),7.33(d,J＝4.6Hz,1H),2.98-2.90(m,2H),1.73(s,6H),2.26-2.14(m,1H),1.38-1.31(m,2H)；质谱：428.8,430.8(M+H+)
Figure PCTCN2016108688-appb-000036
产物107 1-(6-溴喹啉-4-硫)-N-(甲基磺酰基)环丁基甲酰胺:质谱：414.8,416.8(M+H+)。
实施例4
Figure PCTCN2016108688-appb-000037
(中间体4)的合成
Figure PCTCN2016108688-appb-000038
向50mL的反应瓶中加入中间体3(241mg,1mmol)，2-甲氧基苯硼酸(152mg,1mmol)，碳酸钠(212mg,2mmol)，双二苯基膦二茂铁二氯化钯(37mg,0.05mmol)，二氧六环(6mL)，水(3mL)，然后氮气置换，在氮气保护条件下加热到110℃反应2个小时，反应完毕后，加入水(50mL)，用乙酸乙酯萃取三次(3×50ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体4(190mg)，收率50％。质谱:270.0,272.0(M+H+)
(中间体5)的合成
Figure PCTCN2016108688-appb-000039
向100mL的反应瓶中加入中间体4(2.69g,10mmol)，硫化钠(1.17g,15mmol)，N-甲基吡咯烷酮(30mL)，加热搅拌到120℃反应2个小时，然后向反应瓶中加入碳酸铯(6.52g,20mmol)和2-溴异丁酸乙酯(2.15g,11mmol)，继续在100℃反应2个小时，反应完毕后，加入水(150mL)，用乙酸乙酯萃取三次(3×100ml)，有机层合并，饱和食盐水洗，无水硫酸钠干燥，过滤，旋蒸后过柱得中间体5(2.1g)，收率60％。质谱:382.0(M+H+)
(19)的合成
Figure PCTCN2016108688-appb-000040
向100mL的反应瓶中加入中间体5(381mg,1mmol)，甲醇(5mL)，水(5mL)，室温反应16个小时。反应完毕后，在冰水浴条件下，用2N盐酸中和至PH为5左右，然后过滤，滤饼用10mL水洗，滤饼烘干得产物19(247mg)，收率70％。质谱:354.1(M+H+)
化合物1；2；3；4；5；6；7；8；9；10；11；12；13；14；15；16；17；18；20；21；25；26；27；28；29；30；31；32；33；34；35；36；37；38；39；40；41；42；84；85；86；100；101；102；103；104；108；109；110；111；112；113；115；116；117；118；119；120；121；122；123；124；125；126；127；138；139；140；141；142都按照同样的方法，用与之对应的试剂去合成。
Figure PCTCN2016108688-appb-000041
产物1(2-(6-环丙基喹啉-4-硫)-2-甲基丙酸)：1H NMR(400MHz,DMSO):δ(ppm)12.97(s,1H),8.72(d,J＝4.0Hz,1H),8.03(d,J＝4.0Hz,1H),7.93(d,J＝4.0Hz,1H),7.52-7.47(m,2H),2.20-2.09(m,1H),1.55(s,6H),1.10-1.02(m,2H),0.83-0.75(m,2H).质谱：288.1(M+H+)。
Figure PCTCN2016108688-appb-000042
产物2(2-(6-(2-吡啶)-喹啉-4-硫)-2-甲基丙酸)：质谱：325.1(M+H+)。
Figure PCTCN2016108688-appb-000043
产物3(2-(6-(3-吡啶)-喹啉-4-硫)-2-甲基丙酸)：1H NMR(400MHz,DMSO):δ(ppm)12.94(s,1H),9.04(d,J＝4.0Hz,1H),8.88(m,1H),8.66-8.62(m,2H),8.22-8.16(m,3H),7.66(d,J＝4.0 Hz,1H),7.58(m,1H),1.58(s,6H).质谱：325.1(M+H+)。
Figure PCTCN2016108688-appb-000044
产物4(2-(6-(4-吡啶)-喹啉-4-硫)-2-甲基丙酸)：1H NMR(400MHz,DMSO):δ(ppm)13.00(s,1H),8.90(d,J＝4.0Hz,1H),8.74-8.70(m,3H),8.22-8.20(m,2H),7.86(m,2H),7.67(d,J＝4.0Hz,1H),1.58(s,6H).质谱：325.1(M+H+)。
Figure PCTCN2016108688-appb-000045
产物5(2-(6-环丙基喹啉-4-硫)-丙酸)：质谱：274.1(M+H+)。
Figure PCTCN2016108688-appb-000046
产物6(2-(6-环丙基喹啉-4-硫)-丙酸)：质谱：288.1(M+H+)。
Figure PCTCN2016108688-appb-000047
产物7(2-(6-(2-吡啶)-喹啉-4-硫)-丙酸)：质谱：311.1(M+H+)。
Figure PCTCN2016108688-appb-000048
产物8(2-(6-(2-吡啶)-喹啉-4-硫)-丁酸)：质谱：325.1(M+H+)。
Figure PCTCN2016108688-appb-000049
产物9(2-(6-(3-吡啶)-喹啉-4-硫)-丙酸)：质谱：311.1(M+H+)。
Figure PCTCN2016108688-appb-000050
产物10(2-(6-(3-吡啶)-喹啉-4-硫)-丁酸)：质谱：325.1(M+H+)。
Figure PCTCN2016108688-appb-000051
产物11(2-(6-(4-吡啶)-喹啉-4-硫)-丙酸)：质谱：311.1(M+H+)。
Figure PCTCN2016108688-appb-000052
产物12(2-(6-(4-吡啶)-喹啉-4-硫)-丁酸)：质谱：325.1(M+H+)。
Figure PCTCN2016108688-appb-000053
产物13(2-(6-(2-甲氧基苯基)-喹啉-4-硫)-丙酸)：质谱：340.1(M+H+)。
Figure PCTCN2016108688-appb-000054
产物14(2-(6-(2-甲氧基苯基)-喹啉-4-硫)-丁酸)：质谱：354.1(M+H+)。
Figure PCTCN2016108688-appb-000055
产物15(2-(6-(3-甲氧基苯基)-喹啉-4-硫)-丙酸)：质谱：340.1(M+H+)。
Figure PCTCN2016108688-appb-000056
产物16(2-(6-(3-甲氧基苯基)-喹啉-4-硫)-丁酸)：质谱：354.1(M+H+)。
Figure PCTCN2016108688-appb-000057
产物17(2-(6-(4-甲氧基苯基)-喹啉-4-硫)-丙酸)：质谱：340.1(M+H+)。
Figure PCTCN2016108688-appb-000058
产物18(2-(6-(4-甲氧基苯基)-喹啉-4-硫)-丁酸)：质谱：354.1(M+H+)。
Figure PCTCN2016108688-appb-000059
产物19(2-(6-(2-甲氧基苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm)12.98(s,1H),8.84(d,J＝4.0Hz,1H),8.43(d,J＝4.0Hz,1H),8.06(d,J＝4.0Hz,1H),7.95(m,1H),7.58(d,J＝4.0Hz,1H),7.44-7.41(m,2H),7.19(d,J＝4.0Hz,1H),7.13-7.09(m,1H),3.87(s,3H),1.56(s,6H)；质谱：354.1(M+H+)。
Figure PCTCN2016108688-appb-000060
产物20(2-(6-(3-甲氧基苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm) 8.92(d,J＝4.9Hz,1H),8.55(d,J＝1.8Hz,1H),8.22(dt,J＝22.3,5.3Hz,2H),7.67(d,J＝4.9Hz,1H),7.49(t,J＝7.9Hz,1H),7.42-7.31(m,2H),7.05(dd,J＝8.1,1.8Hz,1H),3.87(s,3H),1.64(s,6H)；质谱：354.1(M+H+)。
Figure PCTCN2016108688-appb-000061
产物21(2-(6-(4-甲氧基苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm)12.99(s,1H),8.81(d,J＝4.0Hz,1H),8.51(d,J＝4.0Hz,1H),8.10(m,2H),7.77(d,J＝4.0Hz,2H),7.60(d,J＝4.0Hz,1H),7.11(d,J＝4.0Hz,2H),3.84(s,3H),1.57(s,6H)；质谱：354.1(M+H+)。
Figure PCTCN2016108688-appb-000062
产物25(2-(6-(2-氟-苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm)13.02(s,1H),8.88(d,J＝4.0Hz,1H),8.52(d,J＝4.0Hz,1H),8.15(d,J＝8.0Hz,1H),8.02-8.0(m,1H),8.00-7.99(m,1H),7.72(d,J＝8.0Hz,1H),7.54-7.49(m,1H),7.43-7.38(m,2H),1.57(s,6H)；质谱：342.0(M+H+)。
Figure PCTCN2016108688-appb-000063
产物26(2-(6-(2-氟-苯基)-喹啉-4-硫)-丙酸):质谱：328.0(M+H+)。
Figure PCTCN2016108688-appb-000064
产物27(2-(6-(2-氟-苯基)-喹啉-4-硫)-丁酸):质谱：342.0(M+H+)。
Figure PCTCN2016108688-appb-000065
产物28(2-(6-(3-氟-苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm)12.97(s,1H),8.87(d,J＝8.0Hz,1H),8.59(s,1H),8.18-8.13(m,2H),7.69-7.60(m,4H),7.32-7.27(m,1H),1.58(s,6H)；质谱：342.0(M+H+)。
Figure PCTCN2016108688-appb-000066
产物29(2-(6-(3-氟-苯基)-喹啉-4-硫)-丙酸):质谱：328.0(M+H+)。
Figure PCTCN2016108688-appb-000067
产物30(2-(6-(3-氟-苯基)-喹啉-4-硫)-丁酸):质谱：342.0(M+H+)。
Figure PCTCN2016108688-appb-000068
产物31(2-(6-(4-氟-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：342.0(M+H+)。
Figure PCTCN2016108688-appb-000069
产物32(2-(6-(4-氟-苯基)-喹啉-4-硫)-丙酸):质谱：328.0(M+H+)。
Figure PCTCN2016108688-appb-000070
产物33(2-(6-(4-氟-苯基)-喹啉-4-硫)-丁酸):质谱：342.0(M+H+)。
Figure PCTCN2016108688-appb-000071
产物34(2-(6-(4-三氟甲基-苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm)12.98(s,1H),8.89(d,J＝4.0Hz,1H),8.64(s,1H),8.19(d,J＝4.0Hz,2H),8.06(d,J＝4.0Hz,2H),7.91(d,J＝4.0Hz,2H),7.66(d,J＝4.0Hz,1H),1.57(s,6H)；质谱：392.0(M+H+)。
Figure PCTCN2016108688-appb-000072
产物35(2-(6-(4-三氟甲基-苯基)-喹啉-4-硫)-丙酸):质谱：378.0(M+H+)。
Figure PCTCN2016108688-appb-000073
产物36(2-(6-(4-三氟甲基-苯基)-喹啉-4-硫)-丁酸):质谱：392.0(M+H+)。
Figure PCTCN2016108688-appb-000074
产物37(2-(6-(2-三氟甲基-苯基)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm)13.02(s,1H),8.89(d,J＝4.0Hz,1H),8.25(d,J＝4.0Hz,1H),8.12(d,J＝8.0Hz,1H),7.91(d,J＝4.0Hz,1H),7.78-7.70(m,3H),7.61-7.55(m,2H),1.53(s,6H)；质谱：392.0(M+H+)。
Figure PCTCN2016108688-appb-000075
产物38(2-(6-(2-三氟甲基-苯基)-喹啉-4-硫)-丙酸):质谱：378.0(M+H+)。
Figure PCTCN2016108688-appb-000076
产物39(2-(6-(2-三氟甲基-苯基)-喹啉-4-硫)-丁酸):质谱：392.0(M+H+)。
产物40(2-(6-(3-三氟甲基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：392.0(M+H+)。
Figure PCTCN2016108688-appb-000078
产物41(2-(6-(3-三氟甲基-苯基)-喹啉-4-硫)-丙酸):质谱：378.0(M+H+)。
Figure PCTCN2016108688-appb-000079
产物42(2-(6-(3-三氟甲基-苯基)-喹啉-4-硫)-丁酸):质谱：392.0(M+H+)。
Figure PCTCN2016108688-appb-000080
产物84(2-(6-(3,4-二甲氧基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：384.0(M+H+)。
Figure PCTCN2016108688-appb-000081
产物85(2-(6-(3,4-二甲氧基-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：412.0(M+H+)。
Figure PCTCN2016108688-appb-000082
产物86(2-(6-环丙基喹啉-4-硫)-2-乙基丁酸):质谱：316.0(M+H+)。
Figure PCTCN2016108688-appb-000083
产物100(2-(6-(4-氰基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：349.0(M+H+)。
Figure PCTCN2016108688-appb-000084
产物101(2-(6-(3-三氟甲氧基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：408.0(M+H+)。
Figure PCTCN2016108688-appb-000085
产物102(2-(6-(3-乙氧基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：368.0(M+H+)。
Figure PCTCN2016108688-appb-000086
产物103(2-(6-(3-异丙氧基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：382.0(M+H+)。
Figure PCTCN2016108688-appb-000087
产物104(2-(6-(3-二氟甲氧基-苯基)-喹啉-4-硫)-2-甲基丙酸):质谱：390.0(M+H+)。
Figure PCTCN2016108688-appb-000088
产物108(2-(6-(3-乙氧基-苯基)-喹啉-4-硫)-2-丙基戊酸):质谱：424.1(M+H+)。
Figure PCTCN2016108688-appb-000089
产物109(2-(6-(3-环丙基氧基-苯基)-喹啉-4-硫)-2-丙基戊酸):质谱：436.1(M+H+)。
Figure PCTCN2016108688-appb-000090
产物110(2-(6-(3-环丁基氧基-苯基)-喹啉-4-硫)-2-丙基戊酸):质谱：450.1(M+H+)。
Figure PCTCN2016108688-appb-000091
产物111(2-(6-(3-环丁基氧基-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：422.1(M+H+)。
Figure PCTCN2016108688-appb-000092
产物112(2-(6-(3-环丙基氧基-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：408.1(M+H+)。
Figure PCTCN2016108688-appb-000093
产物113(2-(6-(3-乙氧基-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：396.1(M+H+)。
Figure PCTCN2016108688-appb-000094
产物115(2-(6-(2-甲氧基吡啶-4-)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm):13.02(s,1H),8.95(d,J＝4.0Hz,1H),8.77(d,J＝4.0Hz,1H),8.36(d,J＝4.0Hz,1H),8.20(m,2H),7.66(d,J＝4.0Hz,1H),7.47(m,1H),7.24(s,1H),3.94(s,3H),0.95-0.85(m,6H)；质谱：355.1(M+H+)。
Figure PCTCN2016108688-appb-000095
产物116(2-(6-(2-甲氧基吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):1H NMR(DMSO,400MHz)：δ(ppm):12.96(s,1H),8.87(d,J＝4.0Hz,1H),8.74(d,J＝4.0Hz,1H),8.33(d,J＝4.0Hz,1H),8.18(m,2H),7.64(d,J＝4.0Hz,1H),7.44(m,1H),7.24(s,1H),3.94(s,3H),1.91-1.82(m,4H),0.95-0.85(m,6H)；质谱：383.2(M+H+)。
Figure PCTCN2016108688-appb-000096
产物117(2-(6-(2-氟吡啶-4-)-喹啉-4-硫)-2-甲基丙酸):1H NMR(DMSO,400MHz)：δ(ppm):13.02(s,1H),8.95(d,J＝4.0Hz,1H),8.77(d,J＝4.0Hz,1H),8.36(d,J＝4.0Hz,1H),8.20(m,2H),7.66(d,J＝4.0Hz,1H),7.47(m,1H),7.24(s,1H),0.93(m,6H)；质谱：343.0(M+H+)。
Figure PCTCN2016108688-appb-000097
产物118(2-(6-(2-氟吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):1H NMR(DMSO,400MHz)：δ(ppm):12.96(s,1H),8.87(d,J＝4.0Hz,1H),8.74(d,J＝4.0Hz,1H),8.33(d,J＝4.0Hz,1H),8.18(m,2H),7.64(d,J＝4.0Hz,1H),7.44(m,1H),7.24(s,1H),3.94(s,3H),1.89(m,4H),0.91(m,6H)；质谱：371.0(M+H+)。
Figure PCTCN2016108688-appb-000098
产物119(2-(6-(吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):1H NMR(DMSO,400MHz)：δ(ppm):13.00(s,1H),8.90(d,J＝8.0Hz,1H),8.72(m,3H),8.21(m,2H),7.86(m,2H),7.67(d,J＝4.0Hz,1H),1.93(m,4H),1.58(m,6H)；质谱：353.1(M+H+)。
Figure PCTCN2016108688-appb-000099
产物120(2-(6-(2-甲基吡啶-4-)-喹啉-4-硫)-2-甲基丙酸):13.03(s,1H),8.87(d,J＝4.0Hz,1H),8.74(d,J＝4.0Hz,1H),8.33(d,J＝4.0Hz,1H),8.18(m,2H),7.64(d,J＝4.0Hz,1H),7.44(m,1H),7.24(s,1H),2.71(s,3H),1.52(m,6H)；质谱：339.1(M+H+)。
Figure PCTCN2016108688-appb-000100
产物121(2-(6-(2-甲基吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):1H NMR(DMSO,400MHz)：δ(ppm):12.99(s,1H),8.85(d,J＝4.0Hz,1H),8.77(d,J＝4.0Hz,1H),8.35(d,J＝4.0Hz,1H),8.15(m,2H),7.69(d,J＝4.0Hz,1H),7.47(m,1H),7.26(s,1H),3.94(s,3H),1.92(m,4H),0.9(m,6H)；质谱：367.1(M+H+)。
Figure PCTCN2016108688-appb-000101
产物122(2-(6-(3-氟吡啶-4-)-喹啉-4-硫)-2-甲基丙酸):质谱：343.1(M+H+)。
Figure PCTCN2016108688-appb-000102
产物123(2-(6-(3-氟吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):质谱：371.1(M+H+)。
Figure PCTCN2016108688-appb-000103
产物124(2-(6-(3-氯吡啶-4-)-喹啉-4-硫)-2-甲基丙酸):质谱：359.0(M+H+)。
Figure PCTCN2016108688-appb-000104
产物125(2-(6-(3-氯吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):质谱：387.0(M+H+)。
Figure PCTCN2016108688-appb-000105
产物126(2-(6-(2-羟基吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):质谱：369.0(M+H+)。
Figure PCTCN2016108688-appb-000106
产物127(2-(6-(1-甲基-2-氧-1,2-二氢吡啶-4-)-喹啉-4-硫)-2-乙基丁酸):质谱：383.0(M+H+)。
Figure PCTCN2016108688-appb-000107
产物138(2-(6-(3-氰基-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：377.1(M+H+)。
Figure PCTCN2016108688-appb-000108
产物139(2-(6-(3-三氟甲基-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：420.1(M+H+)。
Figure PCTCN2016108688-appb-000109
产物140(2-(6-(3-氟-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：370.1(M+H+)。
Figure PCTCN2016108688-appb-000110
产物141(2-(6-(2-氟-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：370.1(M+H+)。
Figure PCTCN2016108688-appb-000111
产物142(2-(6-(4-氟-苯基)-喹啉-4-硫)-2-乙基丁酸):质谱：370.1(M+H+)。
实施例2本发明化合物的生物学测定
测试例：本发明化合物对URAT1抑制活性的测定
实验材料：
Figure PCTCN2016108688-appb-000112
FBS(Invitrogen,Cat.No.10099141)
Figure PCTCN2016108688-appb-000113
Trypsin(Invitrogen,Cat.No.25200056)
Figure PCTCN2016108688-appb-000114
DPBS(Invitrogen,Cat.No.14190250)
Figure PCTCN2016108688-appb-000115
DMEM(Invitrogen,Cat.No.10564)
Figure PCTCN2016108688-appb-000116
Penicillin-Streptomycin(Invitrogen,Cat.No.15070-063)
Figure PCTCN2016108688-appb-000117
TransIT-293Transfection Reagent(MIRUS BIO,Cat.No.MIR2706)
Figure PCTCN2016108688-appb-000118
Figure PCTCN2016108688-appb-000119
I Reduced Serum Medium(Invitrogen,Cat.No.31985-070)
Figure PCTCN2016108688-appb-000120
URAT1plasmid(Genecopoeia,Cat.No.EX-T4563-M03)
Figure PCTCN2016108688-appb-000121
Uric acid[8-14C](ARC,Cat.No.ARC0513-250UCI)
Figure PCTCN2016108688-appb-000122
Ultima GoldTM XR(PerkinElmer,Cat.No.6013111)
Figure PCTCN2016108688-appb-000123
Benzbromarone(百灵威科技,Cat.No.3562-84-3)
Figure PCTCN2016108688-appb-000124
D-Gluconic acid sodium salt(阿拉丁,Cat.No.527-07-1)
Figure PCTCN2016108688-appb-000125
Potassium D-gluconate(阿拉丁,Cat.No.299-27-4)
Figure PCTCN2016108688-appb-000126
Calcium gluconate(阿拉丁,Cat.No.299-28-5)
Figure PCTCN2016108688-appb-000127
DMSO(Sigma,Cat.No.D2650)
Figure PCTCN2016108688-appb-000128
Tube,15ml(Greiner,Cat.No.07030115)
Figure PCTCN2016108688-appb-000129
Tube,50ml(BD Falcon,Cat.No.352098)
Figure PCTCN2016108688-appb-000130
Poly-D-lysine 96-well microplates(BD,Cat.No.356461)
Figure PCTCN2016108688-appb-000131
Isoplate-96Microplate(PERKIN ELMER,Cat.No.6005040)
实验方法：
缓冲液配制
Figure PCTCN2016108688-appb-000132
细胞培养：
1.将稳定表达hURAT1的HEK-293T细胞培养于10％FBS和1％P/S的DMEM培养基中，在5％二氧化碳的37度培养箱中培养过夜。
2.将培养基去掉后用PBS清洗一次，然后加入胰酶消化2分钟，待细胞于培养皿分离后加入10毫升培养基终止消化。
3.把细胞放入离心机1000转离心2分钟，加入新的10毫升培养基来重悬细胞，并计算细胞个数。将细胞个数调整为4x105个细胞每毫升。
4.将上述计数好的细胞接种到96孔板中，每孔100微升。
5.将接种好细胞的96孔板放置于37度细胞培养箱中培养过夜。
同位素碳14标记的尿酸吸收实验：
1.在15毫升离心管中加入5毫升Cl-free HBSS缓冲液，然后加入碳14标记的尿酸，使尿酸的浓度达到2uCi/ml.
2.将之前培养过夜的96孔板中的培养基吸干净，加入100毫升预热过的Cl-free HBSS缓冲液清洗三次。
3.将清洗好后的96孔板中的所以缓冲液吸干净。
4.清洗好的96孔板上每孔中加入50微升含有碳14标记的尿酸的Cl-free HBSS缓冲液，然后加入需要测试的化合物的DMSO溶液。
5.把上述96孔板在室温下静置5分钟后，将里面所有的液体吸干。
6.加入100毫升预冷的Cl-free HBSS缓冲液清洗三次。
7.把板里残留的液体吸干净后，于每孔中加入50微升的细胞裂解液，在混匀器上以每分钟600转的速度振荡10分钟。
8.加入50微升Ultima GoldTM XR scitillation cocktail闪烁液后，继续振荡10分钟。将振荡好的板用封板膜贴好后，于MicroBeta Trilux上读数。
9.将测试化合物溶解在DMSO中，然后将相同浓度的DMSO加入不包含测试化合物的HEK293/hURAT1细胞孔中。将各测试浓度下的细胞的尿酸摄取表示为相对DMSO对照的平均百分比抑制率。将对包含DMSO的孔得到的放射性值视为细胞的100％摄取。化合物的IC50值可通过不同浓度下的抑制率计算得出。
本发明化合物对hURAT1的活性抑制的IC50(nM)，结果如表1所示。其中，参比化合物1按照专利WO 2011/159839A2中所述方法合成。参比化合物2和参比化合物3按照专利WO 2014/183555A1中所述方法合成.并分别与化合物83和129在同等条件下头对头地测试。参比化合物2和83的IC50为多次头对头对比试验的平均值。参比化合物3和129的IC50为两次对比试验的平均值。
表1
Figure PCTCN2016108688-appb-000133
Figure PCTCN2016108688-appb-000134
由上表可以发现，本发明的化合物对于尿酸转运体URAT1具有明显的抑制作用。
参比化合物1和2是已知的高活性尿酸转运体URAT1抑制剂。化合物83比参比化合物1展示了更好的尿酸转运体抑制活性。同时，化合物83与参照化合物2的多次头对 头活性测定数据的统计分析如表2所示，结果证明化合物83的活性与参照化合物2的活性数据具有显著性差异。结合化合物129与参照化合物3的结构与活性对比，显然，本发明将该类化合物在特定位置的环烷基取代改为开环的烷基取代后，尤其是双乙基取代，显著提高了该类化合物的尿酸转运体URAT1抑制活性。
表2
Figure PCTCN2016108688-appb-000135
本发明提供的各种化合物及其盐类、水合物或溶剂合物，是一种比本领域代表化合物生物活性更高的选择性尿酸再吸收抑制剂，可以通过促进尿酸从体内排泄并减少血清尿酸来治疗或预防以尿酸水平异常为特征的病症。其中所述病症选自痛风、复发性痛风发作、高尿酸血症、心血管疾病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症，具有在动物体内和人体内具有降低尿酸的效果。

Claims (10)

  1. 式(A)所示的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，
    Figure PCTCN2016108688-appb-100001
    其中：
    Z选自O,S或-NH-；
    W1选自N或CRa；W2选自N或CRb；W3选自N或CRc；
    Ra、Rb、Rc、R2、R3分别独立地选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；
    Rd选自氢、卤素、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基、羧酸酯基、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；
    Re、Rf分别独立选自氢、烷基、环烷基、杂环基、芳基或杂芳基，其中所述的烷基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基、羧酸酯基的取代基所取代；且m为0、1或2；
    X、Y分别独立地选自氢、卤素、氰基、硝基、烷基、环烷基、卤代烷基或羟烷基；
    当Z选自O或S时，R4选自氢或C1～C6的烷基；环烷基，其中所述的烷基、环烷基、独立地任选进一步被一个或多个选自卤素、氰基、硝基、羟基、氧代基、烷基、卤代烷基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、羧基、羧酸酯基、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；当Z选自-NH-时，R4选自氢、芳基或杂芳基，优选吡啶 基。
  2. 根据权利要求1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(I)所示的结构：
    Figure PCTCN2016108688-appb-100002
    其中，R1选自氢、卤素、氰基、硝基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf，其中所述的烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基分别独立地任选进一步被一个或多个选自卤素、氰基、硝基、氧代基、烷基、卤代烷基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-ORd、-S(O)mRd、-C(O)Rd、C(O)ORd、-C(O)NReRf、-NReRf或NReC(O)Rf的取代基所取代；
    R2、R3、R4、Rd、Re、Rf、m均具有权利要求1中所述的含义；
    优选的，
    R1选自卤素、取代或未被取代的烷基、取代或未被取代的芳基、取代或未被取代的杂芳基、取代或未被取代的环烷基；
    R2、R3分别独立地选自氢、卤素、取代或未被取代的烷基、取代或未被取代的芳基、取代或未被取代的杂芳基、取代或未被取代的环烷基；
    R4选自氢或C1～C6的烷基，C3～C6的环烷基，更优选氢。
  3. 根据权利要求1或2所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基；
    优选的，R1选自F、Br、Cl、吡啶基、嘧啶基、吡咯基、咪唑基、苯基、三氟甲基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代。
  4. 根据权利要求1-3任一项所述的化合物、或其光学异构体、或其溶剂合物、或其 药学上可接受的盐、或其前体药物，其中，R2、R3分别独立地选自氢、卤素或C1～C6的烷基；
    优选的，R2选自氢且R3选自甲基；
    或，R2选自氢且R3选自乙基；
    或，R2选自氢且R3选自异丙基；
    或，R2和R3均选自甲基；
    或，R2和R3均选自乙基；
    或，R2和R3均选自正丙基。
  5. 根据权利要4所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物具有如式(Id)或(Ie)所示的结构：
    Figure PCTCN2016108688-appb-100003
    其中，R1具有权利要求2中所述的含义。
  6. 根据权利要求5所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，其中，R1选自卤素、三氟甲基、取代或未被取代的芳基、取代或未被取代的吡啶基、取代或未被取代的嘧啶基、取代或未被取代的吡咯基、取代或未被取代的咪唑基、取代或未被取代的呋喃基，取代或未被取代的噻吩基，取代或未被取代的噁唑基，取代或未被取代的噻唑基,取代或未被取代的噁二唑基，取代或未被取代的噻二唑基或C3～C6的环烷基；
    优选的，R1选自F、Br、Cl、三氟甲基、吡啶基、嘧啶基、吡咯基、咪唑基、苯基或环丙基，其中所述的苯基任选进一步被一个或多个选自甲氧基、乙氧基、氟、氯、溴或三氟甲基的取代基所取代；
    其药学上可接受的盐包括和碱形成的盐，优选为钠盐；也包括和药学上可接受的酸形成的盐。
  7. 根据权利要求1所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物，所述化合物为如下化合物之一：
    Figure PCTCN2016108688-appb-100004
    Figure PCTCN2016108688-appb-100005
    Figure PCTCN2016108688-appb-100006
    Figure PCTCN2016108688-appb-100007
    Figure PCTCN2016108688-appb-100008
  8. 权利要求1-7任一项所述化合物的制备方法，其特征在于：包括按照下述路线进行的步骤：
    Figure PCTCN2016108688-appb-100009
    或者，包括按照下述路线进行的步骤：
    Figure PCTCN2016108688-appb-100010
  9. 权利要求1-8任一项所述的化合物、或其光学异构体、或其溶剂合物、或其药学上可接受的盐、或其前体药物在制备URAT1抑制剂类药物中的用途。
  10. 根据权利要求9所述的用途，所述是药物是预防和/或治疗痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱-萘二氏综合症、凯-赛二氏综合症、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿石症、铅中毒、甲状旁腺功能亢进、银屑病、结节病或次黄嘌呤-鸟嘌呤磷酸核糖转移酶缺乏症的药物，优选预防和/或治疗痛风或高尿酸血症的药物。
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DATABASE REGISTRY [O] American Chemical Society ACS; 13 February 2014 (2014-02-13), retrieved from STN Database accession no. 1542983-23-2 *
DATABASE REGISTRY [O] American Chemical Society ACS; 31 August 2016 (2016-08-31), retrieved from STN Database accession no. 1983708-93-5 *
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110467571A (zh) * 2018-05-11 2019-11-19 江苏恒瑞医药股份有限公司 一种制备环烷基甲酸类衍生物或其可药用盐的方法
CN110467571B (zh) * 2018-05-11 2021-02-26 江苏恒瑞医药股份有限公司 一种制备环烷基甲酸类衍生物或其可药用盐的方法
CN111943957A (zh) * 2019-05-17 2020-11-17 中国医学科学院药物研究所 喹啉甲酰胺类化合物及其制备方法和用途
US11926632B2 (en) 2020-06-22 2024-03-12 Pmv Pharmaceuticals, Inc. Methods and compounds for restoring mutant p53 function
EP4247375A4 (en) * 2020-11-18 2024-11-20 Southern Research Institute COMPOUNDS FOR THE TREATMENT OF ACUTE AND CHRONIC NEPHROPATHY
JP2024518849A (ja) * 2021-05-19 2024-05-07 チアンスー チアタイ チンチアン ファーマスーティカル カンパニー リミテッド キノリンメルカプト酢酸スルホンアミド系誘導体、中間体、薬学的誘導体又は製剤、並びにそれらの製造方法及び使用

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CN106831570B (zh) 2020-03-31
CA3007783C (en) 2021-06-08
AU2016368240B2 (en) 2020-01-02
TWI744264B (zh) 2021-11-01
PL3388420T3 (pl) 2022-12-05
JP6752888B2 (ja) 2020-09-09
TW201720797A (zh) 2017-06-16
CA3007783A1 (en) 2017-06-15
JP2019502673A (ja) 2019-01-31
EP3388420A1 (en) 2018-10-17
AU2016368240A1 (en) 2018-06-28
EP3388420A4 (en) 2019-05-22
BR112018011390B1 (pt) 2024-01-09
DK3388420T3 (da) 2022-09-26
PT3388420T (pt) 2022-09-20
US10450274B2 (en) 2019-10-22
BR112018011390A2 (zh) 2018-12-04
ES2926781T3 (es) 2022-10-28
CN106831570A (zh) 2017-06-13
CN106831569A (zh) 2017-06-13
RU2018120242A (ru) 2020-01-09
RU2715229C2 (ru) 2020-02-26
HUE059672T2 (hu) 2022-12-28

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