WO2020108538A1 - 含有磺酰基结构的RORγ抑制剂 - Google Patents

含有磺酰基结构的RORγ抑制剂 Download PDF

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WO2020108538A1
WO2020108538A1 PCT/CN2019/121306 CN2019121306W WO2020108538A1 WO 2020108538 A1 WO2020108538 A1 WO 2020108538A1 CN 2019121306 W CN2019121306 W CN 2019121306W WO 2020108538 A1 WO2020108538 A1 WO 2020108538A1
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alkyl
compound
pharmaceutically acceptable
methyl
membered
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PCT/CN2019/121306
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English (en)
French (fr)
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王小龙
阳安乐
姜洪建
蒋晓龙
陈磊
周建
徐宏江
宋伟
王晓金
耿晓函
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正大天晴药业集团股份有限公司
南京格亚医药科技有限公司
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Priority to CN201980076661.3A priority Critical patent/CN113166061B/zh
Priority to CN202311636222.8A priority patent/CN117800904A/zh
Publication of WO2020108538A1 publication Critical patent/WO2020108538A1/zh

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Definitions

  • the present application relates to a class of ROR ⁇ inhibitors containing a sulfonyl structure, methods for their preparation, pharmaceutical compositions containing these compounds, and their use in the treatment of diseases mediated by ROR ⁇ receptors.
  • Retinoic acid-related orphan nuclear receptor is a member of the nuclear receptor family, which can regulate various physiological and biochemical processes.
  • the ROR family includes three types, ROR ⁇ , ROR ⁇ , and ROR ⁇ . Three different RORs can be expressed in different tissues and regulate different physiological processes.
  • ROR ⁇ is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain; ROR ⁇ mainly acts on the central nervous system; ROR ⁇ can be expressed in many tissues, including liver, animal fat and skeletal muscle.
  • ROR ⁇ 1 is expressed in many tissues such as thymus, muscle, kidney and liver, while ROR ⁇ t is expressed only in immune cells.
  • ROR ⁇ t is thought to regulate the differentiation of T cell helper T cells 17 ((Th17).
  • Th17 is a type of helper T cell cell that can produce interleukin 17 (IL-17) and other cytokines.
  • Th17 cells and many other Immunity is related to the pathology of inflammatory diseases, including but not limited to psoriasis, multiple sclerosis, rheumatoid arthritis, Crohn's disease, asthma, chronic obstructive pulmonary disease, Behcet's disease and Irritable bowel syndrome and so on.
  • Patent applications of Vitae Pharmaceuticals Inc in the prior art such as WO2014179564, WO2015116904, WO2016061160, etc.; and patent applications of GlaxoSmithKline, such as WO2013045431, WO2013160418, WO2013160419, etc.; and such as WO2015116904, WO2016061160, US20160122318, WO2017024018, WO2017087608, WO2017132432
  • the present application provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
  • U, V, W, Z are each independently selected from CH or N;
  • R 1 is selected from Or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with m R 4 ;
  • R 2 is independently selected from halogen, hydroxyl, amino, cyano, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 3-6 membered cycloalkyl, wherein the C 1 -C 6 alkyl, C 1 -C 6 alkoxy or 3-6 membered ring
  • the alkyl group is optionally substituted with one or two or three substituents selected from halogen, hydroxy, amino, cyano;
  • R 3 is independently selected from halogen, hydroxy, amino, cyano, nitro, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl , 3-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the C 1 -C 6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered Cycloalkenyl, 3-6 membered heterocycloalkenyl or 5-6 membered heteroaryl is optionally selected from one, two or three selected from halogen, hydroxyl, amino, cyano, Substitution of halogenated C 1 -C 3 alkyl substituents;
  • R 4 is independently selected from halogen, hydroxy, amino, cyano, nitro or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally selected from one or two or three from halogen , Hydroxy, amino, cyano substituents;
  • p is selected from 1, 2 or 3;
  • q is selected from 1, 2 or 3;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1, 2, 3, 4, 5, or 6.
  • R 1 when R 1 is selected from R 3 is selected from halogen, cyano, 3-6 membered cycloalkyl, C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl, 3-6 membered cycloalkyl is optionally substituted by one or two One or three selected from halogen, hydroxyl, amino, cyano, When substituted with a halogenated C 1 -C 3 alkyl substituent, at least one R 2 is selected from 3-6 membered cycloalkyl;
  • R 1 when R 1 is selected from R 3 is selected from chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, -CF 3 , -CH 2 CF 3 , -CF 2 CH 3 , -C(OH)(CH 3 ) 2 , at least one R 2 is selected from 3-6 membered cycloalkyl;
  • R 1 when R 1 is selected from R 3 is selected from halogen, cyano, 3-6 membered cycloalkyl, C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl, 3-6 membered cycloalkyl is optionally substituted by one or two One or three selected from halogen, hydroxyl, amino, cyano, When substituted with a halogenated C 1 -C 3 alkyl substituent, at least one R 2 is selected from 3-6 membered cycloalkyl;
  • R 3 is not methyl, ethyl, isopropyl and cyclobutyl.
  • R 1 when R 1 is selected from R 3 is selected from chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, -CF 3 , -CH 2 CF 3 , -CF 2 CH 3 , -C(OH)(CH 3 ) 2 , at least one R 2 is selected from 3-6 membered cycloalkyl; meanwhile, when q is 1, R 3 is not methyl, ethyl, isopropyl and Cyclobutyl.
  • At least one of U, V, W, and Z is CH.
  • At most one of U, V, W, and Z is N.
  • U, V, W, and Z are all CH.
  • V, W, and Z are CH and U is N.
  • U, V, and Z are CH, and W is C(R 3 ).
  • R 1 is selected from
  • R 1 is selected from Furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2, 4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl , Tetrazolyl or triazinyl, of which furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl , Isoxazolyl, 1,2,4-triazolyl,
  • R 1 is selected from Isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, The isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl Optionally substituted with m R 4 .
  • R 1 is selected from Isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl, The isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyrazinyl or pyridazinyl Optionally substituted with m R 4 . In some typical embodiments, R 1 is selected from Where Optionally substituted with m R 4 .
  • R 1 is selected from Where Optionally substituted with m R 4 .
  • R 4 is independently selected from C 1 -C 4 alkyl.
  • R 4 is independently selected from methyl, ethyl, isopropyl, or tert-butyl.
  • R 4 is independently selected from methyl.
  • R 1 is selected from
  • R 1 is selected from
  • R 2 is independently selected from C 1 -C 4 alkyl, or 3-6 membered cycloalkyl, wherein the C 1 -C 4 alkyl or 3-6 membered cycloalkyl is optionally selected from one, two, or three selected from halogen, Substitution of hydroxyl, amino and cyano groups;
  • R 2 is independently selected from C 1 -C 4 alkyl, or 3-6 membered cycloalkyl.
  • R 2 is independently selected from ethyl, Or cyclopropyl.
  • R 2 is independently selected from ethyl or cyclopropyl.
  • At least one R 2 is selected from 3-6 membered cycloalkyl.
  • At least one R 2 is selected from cyclopropyl.
  • R 3 is independently selected from C 1 -C 4 alkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl, or 5-6 membered Heteroaryl, wherein the C 1 -C 4 alkyl, 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl or 5-6 membered heteroaryl are optional One or two or three are selected from halogen, hydroxyl, amino, cyano, Substitution of halogenated C 1 -C 3 alkyl substituents;
  • R 3 is independently selected from C 1 -C 4 alkyl.
  • R 3 is independently selected from methyl, ethyl, and a hydrogen atom is lost at any position The formed group, or oxazolyl, wherein said R 3 is optionally selected from one or two or three selected from halogen, hydroxyl, amino, cyano, Of substituents.
  • R 3 is independently selected from methyl, ethyl, Where R 3 is optionally selected from one, two or three selected from halogen, hydroxyl, amino, cyano, Of substituents.
  • R 3 is independently selected from —CHF 2 , —CF 3 , ethyl, —C(O)CH 3 ,
  • p is 1.
  • q is 1 or 2.
  • n 0, 1, 2, or 3.
  • n 0, 1, or 2.
  • R 1 when R 1 is selected from R 3 is independently selected from 3-6 membered heterocycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl or 5-6 membered heteroaryl, wherein the 3-6 membered hetero Cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered heterocycloalkenyl or 5-6 membered heteroaryl are optionally selected from one, two or three selected from halogen, hydroxyl, amino, cyano, Substitution of halogenated C 1 -C 3 alkyl substituents.
  • R 1 is selected from R 3 is independently selected from Where R 3 is optionally selected from one, two or three selected from halogen, hydroxyl, amino, cyano, Of substituents.
  • R 1 when R 1 is selected from At least one R 2 is selected from 3-6 membered cycloalkyl.
  • R 1 when R 1 is selected from When R 3 is selected from one or two or three selected from halogen, hydroxyl, amino, cyano, Of C 1 -C 4 alkyl.
  • R 1 is selected from V, W, and Z are all C, U is N, and R 3 is selected from unsubstituted C 1 -C 4 alkyl.
  • R 1 when R 1 is selected from When R 3 is selected from unsubstituted C 1 -C 4 alkyl, q is 2.
  • the compound of the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof has the structure represented by the formula (II),
  • the compound of the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof has the structure represented by the formula (III),
  • the compound of the above formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof has the structure represented by the formula (IV),
  • the compound referred to in this application is selected from the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:
  • the compound referred to in the present application is selected from the following compounds or pharmaceutically acceptable salts thereof:
  • the present application also provides a compound of formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof,
  • X, Y, Q, P are each independently selected from CH or N, wherein said X, Y, Q, P may be optionally substituted with R 6 ;
  • U', V', W', Z' are each independently selected from CH or N, wherein the U', V', W', Z'may be optionally substituted by R 7 ;
  • L 1 , L 2 and L 3 are each independently selected from a single bond, CH 2 , NH, C(O) or S(O) 2 , wherein the L 1 , L 2 and L 3 may optionally be one or two selected from R 4 'substituent groups, and L 1, L 2, L 3 are different;
  • R 1' is selected from C 1 -C 6 alkyl optionally substituted with one or two or three substituents selected from halogen, hydroxy or C 3 -C 6 cycloalkyl;
  • R 2' is selected from H, halogen, hydroxy, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl or hydroxy C 1 -C 6 alkyl;
  • R 3' is selected from H, C 1 -C 6 alkyl or C 1 -C 6 alkyl C(O)-;
  • R 4' is independently selected from halogen, hydroxy, amino or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl may be optionally selected from one, two or three selected from halogen, hydroxy, cyanide Substituent group or amino group substitution;
  • R 5 is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the 3-6 membered cycloalkyl, 3-6 membered heterocycloalkane
  • the radical, phenyl or 5-6 membered heteroaryl can be optionally selected from one, two or three selected from halogen, hydroxy, cyano, nitro, amino, C 1 -C 3 alkyl or halo C 1 -C 3 alkyl substituent substitution;
  • R 6 is selected from halogen, hydroxyl, amino, nitro or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl can be optionally selected from one, two or three selected from halogen, hydroxyl, cyanide Substituent group or amino group substitution;
  • R 7 is selected from halogen, hydroxy, amino, nitro, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, wherein the C 1 -C 6 alkyl or C 1 -C 6 alkoxy may be Optionally substituted with one or two or three substituents selected from halogen, hydroxyl, cyano or amino.
  • At least one of X, Y, Q, and P is CH, wherein said X, Y, Q, and P can be optionally substituted with R 6 .
  • At most one of X, Y, Q, and P is N, wherein said X, Y, Q, and P may be optionally substituted with R 6 .
  • X, Q, and P are selected from CH, and Y is selected from CH or N, wherein the X, Y, Q, and P may be optionally substituted with R 6 .
  • U ', V', W ', Z' at least one of CH, wherein said U ', V', W ' , Z' may optionally be substituted with R 7.
  • U ', V', W ', Z' most one is N, wherein said U ', V', W ' , Z' may optionally be substituted with R 7.
  • Z ', U' is selected from CH
  • W' is selected from CH or N, wherein said U ', V', W ' , Z' may optionally be substituted with R 7.
  • U ', V', W ', Z' are both CH, wherein said U ', V', W ' , Z' may optionally be substituted with R 7.
  • U ', W', Z ' is CH, V' is N, wherein said U ', W', Z 'may optionally be substituted with R 7.
  • R 7 is selected from -F, -Cl, -Br, methoxy, ethoxy, isopropyloxy, or tert-butyloxy.
  • R 7 is selected from -F or methoxy.
  • U', Z'are selected from CH, W'is selected from N, and V'is selected from C(F), wherein U', Z'are not substituted by R 7 .
  • R 1' is selected from methyl, ethyl, isopropyl, or tert-butyl.
  • R 1' is selected from ethyl.
  • R 2' is selected from H, methyl, ethyl, isopropyl, or t-butyl, wherein the methyl, ethyl, isopropyl, or t-butyl can be optionally substituted by a hydroxyl group Replace.
  • R 2' is selected from H or -CH 2 OH.
  • the R 2 'configuration of the chiral C atoms attached to the R-type is not limited.
  • R 2' is selected from -CH 2 OH, and the chiral configuration of the C atom to which R 2'is attached is R type.
  • R 3' is selected from H, methyl, ethyl, isopropyl, or tert-butyl.
  • R 3' is selected from H or methyl.
  • R 4' is selected from methyl, ethyl, isopropyl, or tert-butyl.
  • R 4' is selected from ethyl or isopropyl.
  • L 1 is selected from CH 2 or NH, wherein L 1 may be optionally substituted with one or two groups selected from R 4′ .
  • L 1 is selected from CH 2 , wherein L 1 is substituted with isopropyl. In some embodiments, L 1 is selected from NH, where L 1 is substituted with isopropyl or ethyl.
  • L 2 is selected from a single bond, NH, or C(O), wherein L 2 can be optionally substituted with one or two groups selected from R 4 .
  • L 2 is selected from single bonds, NH, or C(O).
  • L 3 is selected from CH 2 or C(O), wherein L 3 may be optionally substituted with one or two groups selected from R 4 .
  • L 3 is selected from CH 2 or C(O).
  • R 5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, Pyridazinyl, pyrazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl or Triazinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl , Pyrazinyl, thiazo
  • R 5 is selected from cyclohexyl, phenyl, or pyridyl, wherein the cyclohexyl, phenyl, or pyridyl can be optionally selected from one, two, or three selected from halogen, hydroxy, cyano , Nitro, amino, C 1 -C 3 alkyl or halogenated C 1 -C 3 alkyl substituents.
  • R 5 is selected from cyclohexyl, phenyl, or pyridyl, and the cyclohexyl, phenyl, or pyridyl can be optionally selected from one, two, or three selected from F, Cl, trifluoromethyl Substituent substitution.
  • R 5 is selected from
  • R 5 is selected from
  • the compound of formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof has the structure represented by formula (VI),
  • the compound of formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof has the structure represented by formula (VII),
  • the compound of formula (V), its stereoisomer, or a pharmaceutically acceptable salt thereof has the structure represented by formula (VIII),
  • the present application prefers the following compounds or pharmaceutically acceptable salts thereof:
  • the C 1 -C 6 alkyl groups described herein are selected from C 1 -C 4 alkyl groups or C 1 -C 3 alkyl groups. In some embodiments, the C 1 -C 6 alkyl group is selected from methyl, ethyl, isopropyl, tert-butyl.
  • the C 1 -C 6 alkoxy groups described herein are selected from C 1 -C 4 alkoxy groups or C 1 -C 3 alkoxy groups. In some embodiments, the C 1 -C 6 alkoxy group is selected from methoxy, ethoxy, isopropoxy, tert-butoxy.
  • the halogenated C 1 -C 6 alkyl groups described herein are selected from halogenated C 1 -C 4 alkyl groups or halogenated C 1 -C 3 alkyl groups. In some embodiments, the halogenated C 1 -C 6 alkyl is selected from fluoro C 1 -C 4 alkyl or fluoro C 1 -C 3 alkyl. In some embodiments, the halogenated C 1 -C 6 alkyl group is selected from fluoromethyl or fluoroethyl.
  • the halogenated C 1 -C 6 alkyl group is selected from -CF 3 , -CF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CHFCH 3 , -CF 2 CF 3 .
  • the halogenated C 1 -C 3 alkyl groups described herein are selected from fluoro C 1 -C 3 alkyl groups. In some embodiments, the halogenated C 1 -C 3 alkyl group is selected from fluoromethyl or fluoroethyl.
  • the halogen described herein is selected from fluorine or chlorine.
  • the hydroxy C 1 -C 6 alkyl groups described herein are selected from hydroxy C 1 -C 4 alkyl groups or hydroxy C 1 -C 3 alkyl groups. In some embodiments, the hydroxy C 1 -C 6 alkyl group is selected from hydroxymethyl, hydroxyethyl.
  • the 3-6 membered cycloalkyl described herein is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the 3-6 membered heterocycloalkyl groups described herein are selected from those that lose a hydrogen atom The formed group.
  • the 3-6 membered cycloalkenyl group described in the present application is selected from those that lose a hydrogen atom at any position The formed group.
  • the 3-6 membered heterocycloalkenyl group described in the present application is selected from the group that loses a hydrogen atom at any position The formed group.
  • the hetero atoms in the 5-6 membered heteroaryl group described herein are selected from O, S, or N, and the number of hetero atoms is 1, 2, or 3.
  • the 5-6 membered heteroaryl groups described herein are selected from furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazole Group, isothiazolyl, oxazolyl, isoxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, 1,3,4-oxadiazolyl, 1, 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, tetrazolyl or triazinyl.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a compound of formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • suitable pharmaceutically acceptable excipients for example, can be formulated into solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes for administering the compounds of the present application or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous and intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compound of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
  • the solid oral composition can be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by mixing the active compound with solid auxiliary materials, optionally grinding the resulting mixture, adding other suitable auxiliary materials if necessary, and then processing the mixture into granules to obtain tablets Or the core of sugar coating.
  • suitable excipients include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the compound of formula (I) or the compound of formula (V), the stereoisomer thereof or the pharmaceutically acceptable salt thereof of the present application can be used for medical purposes.
  • the present application relates to a method for preventing or treating a mammal-mediated disease mediated by ROR ⁇ receptors, which includes administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of a compound of formula (I) or formula of the present application (V) The compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition.
  • the ROR ⁇ receptor is a ROR ⁇ t receptor.
  • the daily dose is 0.01 to 100 mg/kg body weight, preferably 0.05 To 50 mg/kg body weight, more preferably 0.1 to 5 mg/kg body weight, in separate or divided doses.
  • the present application relates to the preparation of a compound of formula (I) or a compound of formula (V), a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the prevention or treatment of ROR ⁇ receptor-mediated diseases Use in medicine.
  • the ROR ⁇ receptor is a ROR ⁇ t receptor.
  • the present application relates to a compound of formula (I) or a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating ROR ⁇ receptor-mediated diseases.
  • the ROR ⁇ receptor is a ROR ⁇ t receptor.
  • the ROR ⁇ receptor-mediated diseases include immune-related diseases, such as tumors and arthritis.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced with a substituent, as long as the valence state of the specific atom is normal and the compound after substitution is stable.
  • ethyl is "optionally” substituted with halogen, meaning that ethyl can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • halogen meaning that ethyl can be unsubstituted (CH 2 CH 3 ), mono-substituted (such as CH 2 CH 2 F), poly-substituted (such as CHFCH 2 F, CH 2 CHF 2 etc.) or completely substituted (CF 2 CF 3 ).
  • C m -C n in this text is an integer number of carbon atoms in a given range in this part.
  • C 1 -C 6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to the -OH group.
  • cyano refers to a -CN group.
  • amino refers to -NH 2 groups, -NH (alkyl) and -N (alkyl) 2 , specific examples of amino groups include but are not limited to -NH 2 , -NHCH 3 , -NHCH(CH 3 ) 2 , -N(CH 3 ) 2 , -NHC 2 H 5 , -N(CH 3 )C 2 H 5 and so on.
  • nitro refers to the -NO 2 group.
  • alkyl refers to a hydrocarbon group of the formula C n H 2n +.
  • the alkyl group may be linear or branched.
  • C 1 -C 6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl) , Tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • the alkyl portion (ie, alkyl) of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio groups has the same definition as above.
  • haloalkyl is meant to include monohaloalkyl and polyhaloalkyl; for example, the term “halo C 1 -C 3 alkyl” is meant to include, but are not limited to trifluoromethyl, 2,2,2-trifluoroethyl And 3-bromopropyl, etc.
  • haloalkyl include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy refers to -O-alkyl
  • cycloalkyl refers to an all-carbon monocyclic saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as C 3 -C 20 cycloalkyl, preferably C 3 -C 6 cycloalkyl, such as cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the cycloalkyl group may be unsubstituted or substituted, and the substituents include but are not limited to alkyl, alkyloxy, cyano, carboxyl, aryl, heteroaryl, amino, halogen, sulfonyl , Sulfinyl, phosphoryl and hydroxyl.
  • cycloalkenyl refers to an all-carbon monocyclic partially saturated hydrocarbon group composed of carbon atoms and hydrogen atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, and the like.
  • heterocycloalkyl refers to a cyclic group that is fully saturated and can exist as a monocyclic, bridged or spiro ring. Unless otherwise indicated, the heterocycle is usually a 3 to 7 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen.
  • 3-membered heterocyclic alkyl groups include, but are not limited to, ethylene oxide, epithioethyl, and cyclic azetyl groups
  • 4-membered heterocyclic alkyl groups include, but are not limited to, azetidinyl, oxinyl
  • cyclic groups, thibutane, 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine
  • groups, imidazolidinyl, tetrahydropyrazolyl, and 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazin
  • heterocyclenyl refers to a partially saturated heterocycloalkyl group, for example, the heterocycloalkyl group contains at least one double bond.
  • heteroaryl refers to the group remaining after a hydrogen atom is removed from a "heteroaryl ring" molecule. Heteroaryl groups may be unsubstituted or substituted. The substituents include but are not limited to alkyl, alkyl Oxygen, aryl, aralkyl, amino, halogen, hydroxyl, cyano, nitro, carbonyl and heteroalicyclic.
  • Non-limiting examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, iso Quinolinyl, tetrazolyl, triazinyl.
  • treatment means the administration of a compound or formulation described herein to prevent, ameliorate or eliminate one or more symptoms associated with the disease or diseases, and includes:
  • terapéuticaally effective amount means (i) treatment or prevention of a specific disease, condition or disorder, (ii) reduction, improvement or elimination of one or more symptoms of a specific disease, condition or disorder, or (iii) prevention or delay
  • the amount of the compound of the present application constituting the “therapeutically effective amount” depends on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art Determined by its own knowledge and the content of this application.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues without Multiple toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like can be mentioned .
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant stimulating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • °C refers to degrees Celsius
  • DCM dichloromethane
  • MeOH refers to methanol
  • THF tetrahydrofuran
  • TEA triethylamine
  • DIAD diisopropyl azodicarboxylate
  • PPh 3 refers to triphenylphosphine
  • PdCl 2 (PPh 3 ) 2 refers to bis(triphenylphosphine) palladium chloride
  • NaBH 4 refers to sodium borohydride
  • LC- MS refers to liquid chromatography coupled with mass spectrometry
  • PE refers to petroleum ether
  • EA refers to ethyl acetate
  • CsF refers to cesium fluoride
  • TLC refers to thin layer chromatography
  • M refers to the molar concentration unit mol/L, such as 2M Refers to 2mol/L
  • mM refers to the
  • tautomer or "tautomeric form” refers to structural isomers of different energies that can be interconverted via a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • proton tautomers include tautomerization via proton migration, such as keto-enol and imine-enamine isomerization.
  • proton tautomers is an imidazole moiety, where protons can migrate between two ring nitrogens.
  • Valence tautomers include interconversion through the recombination of some bonding electrons.
  • Non-limiting examples of tautomers include, but are not limited to.
  • the present application also includes compounds of the present application that are the same as those described herein, but one or more atoms are replaced by an isotope labeled with an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature.
  • isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, 36 Cl, etc.
  • Certain isotopically-labeled compounds of the present application can be used in the analysis of compound and/or substrate tissue distribution. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • PET positron emission tomography
  • the isotopically labeled compounds of the present application can generally be prepared by isotopically labeled reagents instead of unisotopically labeled reagents by the following procedures similar to those disclosed in the schemes and/or examples below.
  • substitution with heavier isotopes can provide certain therapeutic advantages resulting from higher metabolic stability (eg, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations
  • deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present application may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the compounds containing asymmetric carbon atoms of the present application can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using chiral raw materials or chiral reagents.
  • Post-treatment add 100ml of water, extract three times with ethyl acetate (30ml ⁇ 3), combine the organic phases, wash with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain an oil, which is purified through a column. The product was collected and concentrated under reduced pressure to give 1-(2-amino-5-ethylphenyl)-pent-1-yn-3-ol (1.3g).
  • Post-treatment quench with saturated ammonium chloride solution (30mL), add methyl tert-butyl ether (25mL ⁇ 2) to the system, combine organic phases, wash once with saturated brine (20mL ⁇ 1), anhydrous sulfuric acid Sodium was dried and concentrated to obtain 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-ol (1.2g, crude product), which was directly used in the next reaction.
  • Post-treatment Add saturated ammonium chloride aqueous solution to quench the reaction, extract with ethyl acetate (50mL ⁇ 3), rinse with saturated brine (20mL), dry over anhydrous sodium sulfate, concentrate, and distill under reduced pressure to obtain 1-(trimethyl Silyl)-1-pentyn-3-ol (6.96g).
  • the 0.15g of the title compound was prepared according to the synthesis method of steps 1.2-1.3 in Example 1.
  • Example 3 The procedure of Example 3 was followed to prepare 40 mg of the title compound (MS (ESI) m/z: 508.0 [M+H] + ).
  • Example 3 The procedure of Example 3 was followed to prepare 54 mg of the title compound (MS (ESI) m/z: 480 [M+H] + ).
  • the reaction solution was diluted with ethyl acetate (60 mL), the organic phase was washed with water (20 mL ⁇ 2), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure to obtain the title compound (90 mg) , The crude product is directly invested in the next step.
  • reaction solution was quenched with water (20 ⁇ L), the reaction solution was diluted with tetrahydrofuran (30 mL), 10% sodium hydroxide solution (20 ⁇ L) was added, stirred for 5 minutes, water (60 ⁇ L) was added, and anhydrous magnesium sulfate was added and stirred for 10 minutes. It was filtered through celite, and the filtrate was dried under reduced pressure, and purified by Prep-HPLC to obtain the title compound 27 mg (HPLC purity 99.28%, MS (ESI) m/z 497.1 [M+1] + ).
  • Example 11 5-((2-cyclopropyl-6-ethyl-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-((1,4-dimethyl -1H-1,2,3-triazol-5-yl)methoxy)benzyl alcohol
  • the 720 mg of the title compound was prepared by referring to the synthesis method of steps 1.2-1.3 in Example 1.
  • Post-treatment add 50ml of water, extract three times with ethyl acetate (20ml ⁇ 3), combine the organic phases, wash with aqueous sodium sulfite, aqueous sodium carbonate, saturated brine, dry over anhydrous sodium sulfate, and remove the solvent by rotary evaporation under reduced pressure
  • the title compound 660mg.
  • reaction solution was diluted with dichloromethane (100 mL), washed with saturated brine (30 mL ⁇ 2), the organic phase was spin-dried under reduced pressure, and separated by silica gel column chromatography to obtain N-(4-bromophenyl)-2,2,2-tris Fluoroacetamide 7.42g.
  • N-(4-bromophenyl)-2,2,2-trifluoroacetamide (7.42g) was put into a 250mL three-necked bottle, and anhydrous tetrahydrofuran (80mL) was added to dissolve and protected by nitrogen.
  • the reaction system was cooled to -78°C, and n-butyllithium (24.5 mL) was added dropwise thereto, and stirred at this temperature for 30 minutes.
  • 3-oxetanone (4.4 g) was added dropwise thereto. After the resulting mixture was stirred at -78°C for 2 hours, it was gradually raised to room temperature and stirred for 1 hour. Sampling, TLC detection, the raw material point disappeared.
  • the reaction system was cooled to -78°C, diethylaminosulfur trifluoride (1.85 g) was added dropwise thereto, and stirred at this temperature for 30 minutes. Sampling and delivering LC-MS, the product peak 261.9 [M-1] -.
  • reaction solution was quenched with saturated ammonium chloride solution (15 mL), diluted with dichloromethane (300 mL), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure, silica gel column layer After analysis, 625 mg of N-(4-(3-fluorooxetan-3-yl)phenyl)trifluoroacetamide (MS(ESI)m/z 261.9[M-1] - ) was obtained.
  • N-(4-(3-fluorooxetan-3-yl)phenyl)trifluoroacetamide 400mg
  • add palladium hydroxide carbon 192mg
  • ethanol 14mL
  • Put on a hydrogen balloon replace with hydrogen three times, and react at room temperature for 3 hours.
  • Sampling and delivering LC-MS the product peak 243.9 [M-1] -.
  • Diatomaceous earth was filtered and concentrated to obtain N-(4-(oxetan-3-yl)phenyl)trifluoroacetamide (400 mg, crude product), which was directly put into the next step.
  • N-(4-(oxetan-3-yl)phenyl)trifluoroacetamide 400mg was dissolved in ethanol (14mL), and an aqueous solution of sodium hydroxide (3.3mL, 1N) was added to it. The mixture was heated and stirred at 80°C for 3 hours. Sampling and sending to LC-MS, the product peak 150.1[M+1] + was detected.
  • reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with organic phase saturated brine (30 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation under reduced pressure, and the title compound was separated by 90 mg of silica gel column chromatography (MS(ESI)m/z 542.3[M+1] + ).
  • Post-treatment add 50ml of water, extract with ethyl acetate (30mL ⁇ 3), combine organic phases, adjust pH to neutral with aqueous sodium carbonate solution, use 50mL of saturated table salt It was washed with water, dried over anhydrous sodium sulfate, and filtered to remove the solvent by rotary evaporation under reduced pressure to obtain 1.4 g of 5-ethyl-3-iodo-2-pyridylamine.
  • Post-treatment add 50ml of water, extract three times with ethyl acetate (20ml ⁇ 3), combine the organic phases, wash with 50mL of saturated brine, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation under reduced pressure to obtain an oil, and separate by column chromatography. The product points were collected and concentrated under reduced pressure to give the title compound (120mg).
  • Methyl-4-yl)methoxybenzoate 500 mg was dissolved in 6 ml of dichloromethane, cooled in an ice bath, diethylaminosulfur trifluoride was added dropwise, and the solution was stirred overnight at room temperature. TLC detected a small amount of raw material remaining, and LC-MS detected a product peak, 536.1 [M+1] + .
  • Post-treatment add 50 ml of aqueous solution to quench, extract three times with dichloromethane (20 ml ⁇ 3), combine organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain the title compound (crude product, 500 mg, MS ( ESI)m/z 536.1[M+1] + ).
  • Example 21 4-((4-((2-cyclopropyl-6-ethyl-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-(hydroxymethyl) Synthesis of phenoxy)methyl)dihydrofuran-2(3H)-one
  • Example 22 4-((4-((2-cyclopropyl-6-ethyl-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-(hydroxymethyl) Synthesis of phenoxy)methyl)-1-methylpyrrolidin-2-one
  • Example 3 The procedure of Example 3 was followed to obtain 15.3 mg of the title compound (MS (ESI) m/z: 499.3 [M+H] + ).
  • Example 18 The procedure of Example 18 was followed to obtain 7.0 mg of the title compound (MS (ESI) m/z: 527.1 [M+H] + ).
  • Example 26 1-(2-cyclopropyl-1-((3-(hydroxymethyl)-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)sulfonyl )-1,2,3,4-Tetrahydroquinolin-6-yl)pyrrolidin-2-one
  • Example 18 The procedure of Example 18 was followed to obtain 7.0 mg of the title compound (MS (ESI) m/z: 541.2 [M+H] + ).
  • Example 14 The procedure of Example 14 was followed to obtain 20.5 mg of the title compound (MS (ESI) m/z: 525.1 [M+H] + ).
  • Example 28 (5-((2-cyclopropyl-6-morpholino-3,4-dihydroquinolin-1(2H)-yl)sulfonyl)-2-((tetrahydro-2H- Synthesis of pyran-4-yl)methoxy)phenyl)methanol
  • Example 30 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-4-(2-methyl-1-(((trans-4 -Synthesis of (trifluoromethyl)cyclohexyl)methyl)amino)propyl)benzamide
  • Methyl 4-isobutyrylbenzoate (350 mg) was dissolved in methanol (2 mL) and water (1 mL), lithium hydroxide monohydrate (214 mg) was added thereto, and the resulting mixture was stirred at room temperature for 3 hours. Sampling and sending to LC-MS, the product molecular weight was detected to be 193.0[M+1] + .
  • reaction solution was spin-dried under reduced pressure, water (10 mL) was added, the pH was adjusted to 3 with 1N hydrochloric acid, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to give 330 mg of 4-isobutyrylbenzoic acid.
  • reaction solution was methanol ( 15mL) was quenched, the resulting reaction solution was spin-dried under reduced pressure, and silica gel column chromatography gave 80 mg of the title compound (yield 41.5%, MS (ESI) m/z 374.0 [M+1] + ).
  • reaction solution was diluted with ethyl acetate (100 mL), washed with saturated brine (30 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and silica gel column chromatography gave the title compound 200 mg (MS (ESI )m/z502.1[M+1] + ).
  • reaction solution was diluted with water (30 mL), ethanol was removed under reduced pressure, pH was adjusted to 3 with 1N hydrochloric acid, the aqueous layer was extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, and washed with saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain 174 mg of the title compound (MS (ESI) m/z 445.9 [M+1] + ).
  • reaction solution was diluted with ethyl acetate (150 mL), washed with saturated brine (40 mL ⁇ 4), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was vortexed under reduced pressure, silica gel column chromatography to obtain 3-fluoro-4-methyl 600 mg of methyl acylbenzoate.
  • Example 33 For the remaining synthetic steps, the intermediate compound in Example 33 was used as a raw material, and the title compound 42.1 mg (MS (ESI) m/z 554.9 [M+1] + ) was prepared by referring to the synthesis method in steps 30.4-30.5 in Example 30.
  • Example 36 N-((R)-1-(4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-6-(2-methyl-1-(((trans-4 -Synthesis of (trifluoromethyl)cyclohexyl)methyl)amino)propyl)nicotinamide
  • reaction solution was diluted with water (20 mL), extracted with ethyl acetate (40 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure.
  • the crude product was sent to pre.HPLC to prepare 42 mg of light yellow oily liquid.
  • reaction solution was spin-dried under reduced pressure, water (10 mL) was added, the pH was adjusted to 3 with 1N hydrochloric acid, extracted with ethyl acetate (30 mL ⁇ 3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered The filtrate was spin-dried under reduced pressure to obtain 40 mg of white solid, and the crude product was directly put into the next step.
  • reaction solution was diluted with dichloromethane (100 mL), washed with saturated brine (30 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was vortexed under reduced pressure to obtain a brown oily liquid 2.82 g (MS (ESI) m/ z 256.1[M+1] + ).
  • the crude product was directly put into the next step.
  • Example 33 The procedure of Example 33 was followed to obtain 32.6 mg of the title compound (MS (ESI) m/z: 548.3 [M+H] + ).
  • This test method uses luciferase as a reporter gene to detect the expression of cells transfected with a gene recombinant plasmid at the level of gene transcription.
  • the recombinant plasmid is constructed from the promoter of the target gene and the luciferase gene.
  • the experiment is mainly about the transfection of recombinant plasmid hROR ⁇ t (“RORgt”). Transfection requires 27.75 ⁇ g of DNA, an 18 ml volume of cells and culture fluid, and a 125 ml shake flask.
  • Cells Chinese hamster ovary cells (CHO-S, Invitrogen, Cat#R80007), suspended in CD-CHO culture medium, containing 8mM L-glutamine (L-glutamine) and 1 ⁇ HT.
  • CD-CHO Invitrogen, Cat#10743029
  • HT Invitrogen, Cat#11067030
  • L-glutamine Invitrogen, Cat#25030149
  • Penicillin-streptomycin 100X (Invitrogen, Cat#10378016) is only used for passaging, not for transfection.
  • Opti-MEM (Invitrogen, Cat# 51985034) is used in the process of reducing the formation of serum culture medium, ie transfection complex.
  • Luciferase reporter gene plasmid pG5-luc:reporter plasma Promega.
  • Transfection reagent TransIT-CHO transfection kit (Mirus Bio), containing Trans-It reagent and Mojo reagent (Mirus, MIR2170).
  • Culture plate white cell culture plate (VWR, Catalog#29444-041).
  • Compound plate polypropylene 96-well round bottom plate (VWR, Catalog#29444-104).
  • Luciferase kit (Promega 1Glo, 100 ml, Catalog#E6120): Contains luciferase substrate (CoA, ATP, and luciferin) and reaction buffer.
  • Cell plating 18-24 hours before transfection, add a concentration of 0.5-0.6 ⁇ 10 ⁇ 6 cells/ml CHO-S cells to a 125-ml shake flask, and add CD-CHO medium (the medium only contains L -Glutamine and HT additives) to a final volume of 18 ml.
  • the shake flask was placed on a shaker and subcultured overnight at 120 rpm, 37°C and 8% carbon dioxide.
  • the cell concentration of the above solution should be 1.2-1.5 ⁇ 10 ⁇ 6 cells/ml.
  • the cell concentration was diluted to 1 ⁇ 10 ⁇ 6 cells/ml using CD-CHO medium (containing L-glutamine and HT supplement).
  • Transfection reagent preparation (TransIT-CHO: Mojo: DNA complex), prepared before transfection.
  • the cell density should be 3x10 ⁇ 6 cells/ml.
  • Cell count If the cells are fully alive, 6 ⁇ 10 ⁇ 5 cells/ml should be obtained. In general, a survival rate of 65% to 70% should be obtained.
  • the cell density should be 4 ⁇ 10 ⁇ 5 cells/ml, such as It is necessary to use culture medium for dilution.
  • test compound plate prepared in advance.
  • the culture solution was diluted with 1GLO luciferase (4:1), transferred 50 ⁇ l to the cell plate, and mixed with a gun.
  • Reading time 1 sec/well, 6 wells/read
  • B1 refers to the blank control group: sterile deionized water
  • S refers to the positive control group (100% inhibition): 2uM ursolic acid in DMSO
  • D refers to the negative control group (100% activity): DMSO
  • C1-C8 refers to the compound group to be tested: the compound to be tested at different dilution concentrations or the repeated test group.
  • Each well in this experiment contains: 1 microliter of the test compound (dissolved in DMSO), 100 microliters of cells, and 50 microliters of luciferase reagent.
  • CytoStim stimulates the inhibition of human PBMC cells
  • PBMCs (Sai Li) (5*10 7 cells/branch) were recovered. After mixing, the appropriate amount of 1640 (5% human serum) culture medium was added, and the horizontal rotor was centrifuged at 1500 rpm for 5 minutes. The cell pellet was taken and added. 10 ml of medium was diluted to obtain a cell suspension. Adjust the cell density to about 1.12*10 7 cells/ml, add 90 ⁇ l of cell suspension (1*10 6 cells/well) to each well in the 96-well culture plate, and incubate overnight.
  • 1640 5% human serum
  • a control group without compound and CytoStim added
  • CytoStim stimulation group example compound (100 nM) were set.
  • the total amount of liquid in each well was 100 ⁇ l.
  • the cell supernatant was taken at 48h, centrifuged at 2000g for 5min, and the supernatant collected.
  • Streptavidin-HRP was diluted 40-fold as the detection third antibody, 100 ⁇ l per well, incubated at 25 ⁇ 2°C for 30min; added TMB for color development, and the reaction was terminated by 1M H2SO4.
  • the absorbance value is read at 450/630nm wavelength on the plate reader, the curve fitting adopts 4parameter logisticfit, and the final OD value is OD450nm-OD630nm.
  • PBMC cells The inhibition of IL-17 secretion by PBMC cells is as follows:

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Abstract

一类含有磺酰基结构的RORγ抑制剂，其制备方法，以及含有这些化合物的药物组合物。所述抑制剂具有式（I）或式（V）所示结构，式（I）化合物和式（V）化合物具有良好的RORγ抑制活性，有望用于治疗哺乳动物由RORγ受体介导的疾病。

Description

含有磺酰基结构的RORγ抑制剂
相关申请的交叉引用
本申请要求于2018年11月27日向中国国家知识产权局提交的第201811426060.4号中国专利申请、于2019年03月28日向中国国家知识产权局提交的第201910243555.1号中国专利申请、于2019年03月28日向中国国家知识产权局提交的第201910243579.9号中国专利申请的优先权和权益，所有申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及一类含有磺酰基结构的RORγ抑制剂、其制备方法、含有这些化合物的药物组合物、以及其在治疗RORγ受体介导的疾病中的用途。
背景技术
维甲酸相关孤儿核受体(ROR)是核受体家族的成员之一，它能够调控多种生理和生化过程。ROR家族包括三种类型，RORα、RORβ以及RORγ。三种不同的ROR可以在不同的组织中表达并且调控不同的生理过程。RORα主要分布在肝脏，骨骼肌，皮肤，肺，脂肪组织，肾脏，胸腺和大脑；RORβ主要作用于中枢神经系统；RORγ可以在许多组织中表达，包括肝脏，动物脂肪和骨骼肌。
RORγ有两种亚型：RORγ1和RORγt(RORγ2)。RORγ1在许多组织，如：胸腺，肌肉，肾脏和肝脏中表达，而RORγt则只在免疫细胞内表达。RORγt被认为能够调控T细胞辅助T细胞17((Th17)的分化。Th17是一类辅助T细胞的细胞，这种细胞可以产生白介素17(IL-17)和其他细胞激素。Th17细胞与众多自身免疫性和炎性疾病的病理学有关系，所述疾病包括但不限于银屑病、多发性硬化症、类风湿性关节炎、克罗恩病、哮喘、慢性阻塞性肺病、Behcet’sdisease和肠易激综合征等。
现有技术中Vitae Pharmaceuticals Inc的专利申请，如WO2014179564、WO2015116904、WO2016061160等；以及葛兰素史克公司的专利申请，如WO2013045431、WO2013160418、WO2013160419等；以及如WO2015116904、WO2016061160、US20160122318、WO2017024018、WO2017087608、WO2017132432均公开了一系列可作为RORγ抑制剂的化合物。鉴于RORγ抑制剂具有很大的潜在价值，进一步寻找具有RORγ抑制功能的化合物是十分必要的。
发明内容
一方面，本申请提供式(I)化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2019121306-appb-000001
其中，
U、V、W、Z各自独立地选自CH或N；
R 1选自
Figure PCTCN2019121306-appb-000002
Figure PCTCN2019121306-appb-000003
Figure PCTCN2019121306-appb-000004
Figure PCTCN2019121306-appb-000005
或5-6元杂芳基，其中所述5-6元杂芳基任选地被m个R 4取代；
R 2独立地选自卤素、羟基、氨基、氰基、硝基、
Figure PCTCN2019121306-appb-000006
C 1-C 6烷基、C 1-C 6烷氧基或3-6元环烷基，其中所述C 1-C 6烷基、C 1-C 6烷氧基或3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基的取代基取代；
R 3独立地选自卤素、羟基、氨基、氰基、硝基、C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基，其中所述C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000007
卤代C 1-C 3烷基的取代基取代；
R 4独立地选自卤素、羟基、氨基、氰基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基的取代基取代；
p选自1、2或3；
q选自1、2或3；
n选自0、1、2、3、4或5；
m选自0、1、2、3、4、5或6。
在一些实施方案中：当R 1选自
Figure PCTCN2019121306-appb-000008
R 3选自卤素、氰基、3-6元环烷基、C 1-C 6烷基，其中所述C 1-C 6烷基、3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000009
卤代C 1-C 3烷基的取代基取代时，至少有一个R 2选自3-6元环烷基；
同时不包括以下化合物：
Figure PCTCN2019121306-appb-000010
Figure PCTCN2019121306-appb-000011
在一些实施方案中：当R 1选自
Figure PCTCN2019121306-appb-000012
R 3选自氯、氰基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、-CF 3、-CH 2CF 3、-CF 2CH 3、-C(OH)(CH 3) 2时，至少有一个R 2选自3-6元环烷基；
同时不包括以下化合物：
Figure PCTCN2019121306-appb-000013
在一些实施方案中，当R 1选自
Figure PCTCN2019121306-appb-000014
R 3选自卤素、氰基、3-6元环烷基、C 1-C 6烷基，其中所述C 1-C 6烷基、3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000015
卤代C 1-C 3烷基的取代基取代时，至少有一个R 2选自3-6元环烷基；
同时，当q为1时，R 3不为甲基、乙基、异丙基和环丁基。
在一些实施方案中：当R 1选自
Figure PCTCN2019121306-appb-000016
R 3选自氯、氰基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、-CF 3、-CH 2CF 3、-CF 2CH 3、-C(OH)(CH 3) 2时，至少有一个R 2选自3-6元环烷基；同时，当q为1时，R 3不为甲基、乙基、异丙基和环丁基。
在一些实施方案中，U、V、W、Z中至少有一个为CH。
在一些实施方案中，U、V、W、Z中至多有一个为N。
在一些典型的实施方案中，U、V、W、Z均为CH。
在一些典型的实施方案中，V、W、Z为CH，U为N。
在一些典型的实施方案中，U、V、Z为CH，W为C(R 3)。
在一些实施方案中，R 1选自
Figure PCTCN2019121306-appb-000017
在一些实施方案中，R 1选自
Figure PCTCN2019121306-appb-000018
Figure PCTCN2019121306-appb-000019
Figure PCTCN2019121306-appb-000020
呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、四唑基或三嗪基，其中呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、四唑基或三嗪基任选地被m个R 4取代。
在一些实施方案中，R 1选自
Figure PCTCN2019121306-appb-000021
Figure PCTCN2019121306-appb-000022
异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基、吡嗪基或哒嗪基，其中所述异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基、吡嗪基或哒嗪基任选地被m个R 4取代。
在一些实施方案中，R 1选自
Figure PCTCN2019121306-appb-000023
Figure PCTCN2019121306-appb-000024
异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基、吡嗪基或哒嗪基，其中所述异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基、 吡嗪基或哒嗪基任选地被m个R 4取代。在一些典型的实施方案中，R 1选自
Figure PCTCN2019121306-appb-000025
Figure PCTCN2019121306-appb-000026
Figure PCTCN2019121306-appb-000027
其中所述
Figure PCTCN2019121306-appb-000028
Figure PCTCN2019121306-appb-000029
任选地被m个R 4取代。
在一些典型的实施方案中，R 1选自
Figure PCTCN2019121306-appb-000030
Figure PCTCN2019121306-appb-000031
Figure PCTCN2019121306-appb-000032
其中所述
Figure PCTCN2019121306-appb-000033
Figure PCTCN2019121306-appb-000034
任选地被m个R 4取代。
在一些实施方案中，R 4独立地选自C 1-C 4烷基。
在一些实施方案中，R 4独立地选自甲基、乙基、异丙基或叔丁基。
在一些典型的实施方案中，R 4独立地选自甲基。
在一些更典型的实施方案中，R 1选自
Figure PCTCN2019121306-appb-000035
Figure PCTCN2019121306-appb-000036
在一些更典型的实施方案中，R 1选自
Figure PCTCN2019121306-appb-000037
Figure PCTCN2019121306-appb-000038
在一些实施方案中，R 2独立地选自
Figure PCTCN2019121306-appb-000039
C 1-C 4烷基、或3-6元环烷基，其中所述C 1-C 4烷基或3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基的取代基取代；
在一些典型的实施方案中，R 2独立地选自
Figure PCTCN2019121306-appb-000040
C 1-C 4烷基、或3-6元环烷基。
在一些典型的实施方案中，R 2独立地选自乙基、
Figure PCTCN2019121306-appb-000041
或环丙基。
在一些典型的实施方案中，R 2独立地选自乙基或环丙基。
在一些实施方案中，至少有一个R 2选自3-6元环烷基。
在一些实施方案中，至少有一个R 2选自环丙基。
在一些实施方案中，R 3独立地选自C 1-C 4烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基，其中所述C 1-C 4烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000042
卤代C 1-C 3烷基的取代基取代；
在一些实施方案中，R 3独立地选自C 1-C 4烷基。
在一些实施方案中，R 3独立地选自甲基、乙基、任意位置失去一个氢原子的
Figure PCTCN2019121306-appb-000043
Figure PCTCN2019121306-appb-000044
所形成的基团、或噁唑基，其中所述R 3任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000045
的取代基取代。
在一些典型的实施方案中，R 3独立地选自甲基、乙基、
Figure PCTCN2019121306-appb-000046
Figure PCTCN2019121306-appb-000047
其中R 3任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000048
的取代基取代。
在一些更典型的实施方案中，R 3独立地选自-CHF 2、-CF 3、乙基、-C(O)CH 3、
Figure PCTCN2019121306-appb-000049
Figure PCTCN2019121306-appb-000050
在一些实施方案中，p为1。
在一些实施方案中，q为1或2。
在一些实施方案中，n为0、1、2、或3。
在一些实施方案中，m为0、1或2。
在一些实施方案中，当R 1选自
Figure PCTCN2019121306-appb-000051
时，R 3独立地选自3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基，其中所述3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000052
卤代C 1-C 3烷基的取代基取代。
在一些典型的实施方案中，R 1选自
Figure PCTCN2019121306-appb-000053
R 3独立地选自
Figure PCTCN2019121306-appb-000054
Figure PCTCN2019121306-appb-000055
其中R 3任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000056
的取代基取代。
在一些实施方案中，当R 1选自
Figure PCTCN2019121306-appb-000057
时，至少有一个R 2选自3-6元环烷基。
在一些实施方案中，当R 1选自
Figure PCTCN2019121306-appb-000058
时，R 3选自被一个或两个或三个选自卤素、羟基、氨基、氰基、
Figure PCTCN2019121306-appb-000059
的取代基取代C 1-C 4烷基。
在一些实施方案中，R 1选自
Figure PCTCN2019121306-appb-000060
V、W、Z均为C，U为N，R 3选自未取代C 1-C 4烷基。
在一些实施方案中，当R 1选自
Figure PCTCN2019121306-appb-000061
R 3选自未取代C 1-C 4烷基时，q为2。
在一些实施方案中，上述式(I)化合物、其立体异构体或其药学上可接受的盐具有式(II)所示的结构，
Figure PCTCN2019121306-appb-000062
其中，U、R 1、R 2、R 3、n、p、q如前述式(I)化合物中所定义。
在一些实施方案中，上述式(I)化合物、其立体异构体或其药学上可接受的盐具有式(III)所示的结构，
Figure PCTCN2019121306-appb-000063
其中，U、R 1、R 2、R 3、n、q如前述式(I)化合物中所定义。
在一些实施方案中，上述式(I)化合物、其立体异构体或其药学上可接受的盐具有式(IV)所示的结构，
Figure PCTCN2019121306-appb-000064
其中，U、R 1、R 2、R 3、n如前述式(I)化合物中所定义。
在一些实施方案中，本申请涉及的化合物选自以下化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2019121306-appb-000065
Figure PCTCN2019121306-appb-000066
Figure PCTCN2019121306-appb-000067
Figure PCTCN2019121306-appb-000068
在一些典型的实施方案中，本申请涉及的化合物选自以下化合物或其药学上可接受的盐：
Figure PCTCN2019121306-appb-000069
Figure PCTCN2019121306-appb-000070
Figure PCTCN2019121306-appb-000071
Figure PCTCN2019121306-appb-000072
Figure PCTCN2019121306-appb-000073
Figure PCTCN2019121306-appb-000074
另一方面，本申请还提供式(V)化合物、其立体异构体或其药学上可接受的盐，
Figure PCTCN2019121306-appb-000075
其中，
X、Y、Q、P各自独立地选自CH或N，其中所述X、Y、Q、P可任选地被R 6取代；
U＇、V＇、W＇、Z＇各自独立地选自CH或N，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代；
L 1、L 2、L 3各自独立地选自单键、CH 2、NH、C(O)或S(O) 2，其中所述L 1、L 2、L 3可任选地被一个或两个选自R 4＇的基团取代，且L 1、L 2、L 3各不相同；
R 1＇选自任选地被一个或两个或三个选自卤素、羟基或C 3-C 6环烷基的取代基取代的C 1-C 6烷基；
R 2＇选自H、卤素、羟基、C 1-C 6烷基、卤代C 1-C 6烷基或羟基C 1-C 6烷基；
R 3＇选自H、C 1-C 6烷基或C 1-C 6烷基C(O)-；
R 4＇独立地选自卤素、羟基、氨基或C 1-C 6烷基，其中所述C 1-C 6烷基可任选地被一个或两个或三个选自卤素、羟基、氰基或氨基的取代基取代；
R 5选自3-6元环烷基、3-6元杂环烷基、苯基或5-6元杂芳基，其中所述3-6元环烷基、3-6元杂环烷基、苯基或5-6元杂芳基可任选地被一个或两个或三个选自卤素、羟基、氰基、硝基、氨基、C 1-C 3烷基或卤代C 1-C 3烷基的取代基取代；
R 6选自卤素、羟基、氨基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基可任选地被一个或两个或三个选自卤素、羟基、氰基或氨基的取代基取代；
R 7选自卤素、羟基、氨基、硝基、C 1-C 6烷基或C 1-C 6烷氧基，其中所述C 1-C 6烷基或C 1-C 6烷氧基可任选地被一个或两个或三个选自卤素、羟基、氰基或氨基的取代基取代。
在一些实施方案中，X、Y、Q、P中至少有一个为CH，其中所述X、Y、Q、P可任选地被R 6取代。
在一些实施方案中，X、Y、Q、P中至多有一个为N，其中所述X、Y、Q、P可任选地被R 6取代。
在一些典型的实施方案中，X、Q、P选自CH，Y选自CH或N，其中所述X、Y、Q、P可任选地被R 6取代。
在一些实施方案中，U＇、V＇、W＇、Z＇中至少有一个为CH，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代。
在一些实施方案中，U＇、V＇、W＇、Z＇中至多有一个为N，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代。
在一些实施方案中，Z＇、U＇选自CH，V＇、W＇选自CH或N，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代。
在一些实施方案中，U＇、V＇、W＇、Z＇均为CH，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代。
在一些实施方案中，U＇、W＇、Z＇为CH，V＇为N，其中所述U＇、W＇、Z＇可任选地被R 7取代。
在一些实施方案中，U＇、V＇、Z＇为CH，W＇为N，其中所述U＇、V＇、Z＇可任选地被R 7取代。
在一些实施方案中，R 7选自-F、-Cl、-Br、甲氧基、乙氧基、异丙基氧基或叔丁基氧基。
在一些典型的实施方案中，R 7选自-F或甲氧基。
在一些典型的实施方案中，U＇、V＇、W＇、Z＇均为CH，其中U＇、V＇、W＇、Z＇未被R 7取代。
在一些典型的实施方案中，U＇、W＇、Z＇选自CH，V＇选自C(F)或C(OCH 3)，其中U＇、W＇、Z＇未被R 7取代。
在一些典型的实施方案中，U＇、W＇、Z＇选自CH，V＇选自N，其中U＇、W＇、Z＇未被R 7取代。
在一些典型的实施方案中，U＇、Z＇选自CH，W＇选自N，V＇选自C(F)，其中U＇、Z＇未被R 7取代。
在一些实施方案中，R 1＇选自甲基、乙基、异丙基或叔丁基。
在一些典型的实施方案中，R 1＇选自乙基。
在一些实施方案中，R 2＇选自H、甲基、乙基、异丙基或叔丁基，其中所述甲基、乙基、异丙基或叔丁基可任选地被一个羟基取代。
在一些典型的实施方案中，R 2＇选自H或-CH 2OH。
在一些典型的实施方案中，与R 2＇连接的C原子的手性构型为R型。
在一些更典型的实施方案中，R 2＇选自-CH 2OH，且与R 2＇连接的C原子的手性构型为R型。
在一些实施方案中，R 3＇选自H、甲基、乙基、异丙基或叔丁基。
在一些典型的实施方案中，R 3＇选自H或甲基。
在一些实施方案中，R 4＇选自甲基、乙基、异丙基或叔丁基。
在一些典型的实施方案中，R 4＇选自乙基或异丙基。
在一些实施方案中，L 1选自CH 2或NH，其中所述L 1可任选地被一个或两个选自R 4＇的基团取代。
在一些实施方案中，L 1选自CH 2，其中L 1被异丙基取代。在一些实施方案中，L 1选自NH，其中L 1被异丙基或乙基取代。
在一些实施方案中，L 2选自单键、NH或C(O)，其中所述L 2可任选地被一个或两个选自R 4的基团取代。
在一些典型的实施方案中，L 2选自单键、NH或C(O)。
在一些实施方案中，L 3选自CH 2或C(O)，其中所述L 3可任选地被一个或两个选自R 4的基团取代。
在一些典型的实施方案中，L 3选自CH 2或C(O)。
在一些更典型的实施方案中，
Figure PCTCN2019121306-appb-000076
选自
Figure PCTCN2019121306-appb-000077
Figure PCTCN2019121306-appb-000078
在一些实施方案中，R 5选自环丙基、环丁基、环戊基、环己基、苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四唑基或三嗪基，其中所述环丙基、环丁基、环戊基、环己基、苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四唑基或三嗪基可任选地被一个或两个或三个选自卤素、羟基、氰基、硝基、氨基、C 1-C 3烷基或卤代C 1-C 3烷基的取代基取代。
在一些实施方案中，R 5选自环己基、苯基或吡啶基，其中所述环己基、苯基或吡啶基可任选地被一个或两个或三个选自卤素、羟基、氰基、硝基、氨基、C 1-C 3烷基或卤代C 1-C 3烷 基的取代基取代。
在一些实施方案中，R 5选自环己基、苯基或吡啶基，所述环己基、苯基或吡啶基可任选地被一个或两个或三个选自F、Cl、三氟甲基的取代基取代。
在一些典型的实施方案中，R 5选自
Figure PCTCN2019121306-appb-000079
Figure PCTCN2019121306-appb-000080
在一些更典型的实施方案中，R 5选自
Figure PCTCN2019121306-appb-000081
Figure PCTCN2019121306-appb-000082
在一些实施方案中，式(V)化合物、其立体异构体或其药学上可接受的盐具有式(VI)所示的结构，
Figure PCTCN2019121306-appb-000083
其中，X、Y、Q、P、U＇、V＇、W＇、Z＇、L 1、L 2、L 3、R 2＇、R 3＇和R 5如前述式(V)化合物中所定义。
在一些实施方案中，式(V)化合物、其立体异构体或其药学上可接受的盐具有式(VII)所示的结构，
Figure PCTCN2019121306-appb-000084
其中，U＇、V＇、W＇、Z＇、L 1、L 2、L 3、R 2＇、R 3＇和R 5如前述式(V)化合物中所定义。
在一些实施方案中，式(V)化合物、其立体异构体或其药学上可接受的盐具有式(VIII)所示的结构，
Figure PCTCN2019121306-appb-000085
其中，U＇、V＇、W＇、Z＇、L 1、L 2、L 3、R 2＇、R 3＇和R 5如前述式(V)化合物中所定义。 在一些实施方案中，本申请优选下述化合物、其立体异构体或其药学上可接受的盐：
Figure PCTCN2019121306-appb-000086
Figure PCTCN2019121306-appb-000087
在一些实施方案中，本申请优选下述化合物或其药学上可接受的盐：
Figure PCTCN2019121306-appb-000088
Figure PCTCN2019121306-appb-000089
Figure PCTCN2019121306-appb-000090
在一些实施方案中，本申请所述C 1-C 6烷基选自C 1-C 4烷基或C 1-C 3烷基。在一些实施方案中，所述C 1-C 6烷基选自甲基、乙基、异丙基、叔丁基。
在一些实施方案中，本申请所述C 1-C 6烷氧基选自C 1-C 4烷氧基或C 1-C 3烷氧基。在一些实施方案中，所述C 1-C 6烷氧基选自甲氧基、乙氧基、异丙氧基、叔丁氧基。
在一些实施方案中，本申请所述卤代C 1-C 6烷基选自卤代C 1-C 4烷基或卤代C 1-C 3烷基。在一些实施方案中，所述卤代C 1-C 6烷基选自氟代C 1-C 4烷基或氟代C 1-C 3烷基。在一些实施方案中，所述卤代C 1-C 6烷基选自氟代甲基或氟代乙基。在一些实施方案中，所述卤代C 1-C 6烷基选自-CF 3、-CF 2、-CH 2CF 3、-CF 2CH 3、-CHFCH 3、-CF 2CF 3。
在一些实施方案中，本申请所述卤代C 1-C 3烷基选自氟代C 1-C 3烷基。在一些实施方案中，所述卤代C 1-C 3烷基选自氟代甲基或氟代乙基。
在一些实施方案中，本申请所述卤素选自氟或氯。
在一些实施方案中，本申请所述羟基C 1-C 6烷基选自羟基C 1-C 4烷基或羟基C 1-C 3烷基。在一些实施方案中，所述羟基C 1-C 6烷基选自羟甲基、羟乙基。
在一些实施方案中，本申请所述3-6元环烷基选自环丙基、环丁基、环戊基、环己基。
在一些实施方案中，本申请所述3-6元杂环烷基选自任意位置失去一个氢原子的
Figure PCTCN2019121306-appb-000091
Figure PCTCN2019121306-appb-000092
Figure PCTCN2019121306-appb-000093
所形成的基团。
在一些实施方案中，本申请所述3-6元环烯基选自任意位置失去一个氢原子的
Figure PCTCN2019121306-appb-000094
Figure PCTCN2019121306-appb-000095
所形成的基团。
在一些实施方案中，本申请所述3-6元杂环烯基选自任意位置失去一个氢原子的
Figure PCTCN2019121306-appb-000096
Figure PCTCN2019121306-appb-000097
所形成的基团。
在一些实施方案中，本申请所述5-6元杂芳基中的杂原子选自O、S或N，杂原子数目为1、2或3。
在一些实施方案中，本申请所述5-6元杂芳基选自呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、四唑基或三嗪基。
另一方面，本申请涉及药物组合物，其包含本申请的式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐。
在一些实施方案中，本申请涉及药物组合物，其包含治疗有效量的本申请的式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐。
在另一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产 品。
另一方面，本申请的式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐可用于医药用途。
另一方面，本申请涉及预防或者治疗哺乳动物由RORγ受体介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。在一些实施方案中，所述RORγ受体为RORγt受体。
本申请的式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐的所有施用方法中，每天给药的剂量为0.01到100mg/kg体重，优选为0.05到50mg/kg体重，更优选0.1到5mg/kg体重，以单独或分开剂量的形式。
另一方面，本申请涉及式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗RORγ受体介导的疾病的药物中的用途。在一些实施方案中，所述RORγ受体为RORγt受体。
另一方面，本申请涉及预防或者治疗RORγ受体介导的疾病的式(I)化合物或式(V)化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，所述RORγ受体为RORγt受体。
所述RORγ受体介导的疾病包括免疫相关性疾病，例如肿瘤和关节炎。
定义
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。
本文中的C m-C n，是该部分具有给定范围中的整数个碳原子。例如“C 1-C 6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。
术语“卤”或“卤素”是指氟、氯、溴和碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“氨基”指-NH 2基团、-NH(烷基)和-N(烷基) 2，氨基的具体例子包括但不限于-NH 2、-NHCH 3、-NHCH(CH 3) 2、-N(CH 3) 2、-NHC 2H 5、-N(CH 3)C 2H 5等。
术语“硝基”指-NO 2基团。
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1-C 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。
术语“卤代烷基”意在包括单卤代烷基和多卤代烷基；例如，术语“卤代C 1-C 3烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基和3-溴丙基等等。卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基和五氯乙基。
术语“烷氧基”指-O-烷基。
术语“环烷基”是指由碳原子和氢原子组成的全碳单环的饱和烃基团，如C 3-C 20环烷基，优选为C 3-C 6环烷基，例如环丙基、环丁基、环戊基、环己基等。所述环烷基可以是非取代的或是被取代的，所述的取代基包括但不限于烷基、烷基氧基、氰基、羧基、芳基、杂芳基、氨基、卤素、磺酰基、亚磺酰基、磷酰基和羟基。
术语“环烯基”是指由碳原子和氢原子组成的全碳单环的部分饱和烃基团，例如环丁烯基、环戊烯基、环己烯基等。
术语“杂环烷基”是指完全饱和的并且可以以单环、桥环或螺环存在的环状基团。除非另有指示，该杂环通常为含有1至3个独立地选自硫、氧和/或氮的杂原子(优选1或2个杂原子)的3至7元环。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基、，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“杂环烯基”是指部分饱和的杂环烷基，例如杂环烷基含有至少一个双键。
术语“杂芳基”是指“杂芳环”分子去掉1个氢原子后余下的基团，杂芳基可以是非取代的或取代的，所述的取代基包括但不限于烷基、烷基氧基、芳基、芳烷基、氨基、卤素、羟基、氰基、硝基、羰基和杂脂环基。非取代的杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三嗪基。
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本申请内容而确定。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
在本申请中，除非特别定义，所采用的缩略语的含义如下所示：℃是指摄氏度；DCM是指二氯甲烷；MeOH是指甲醇；THF是指四氢呋喃；TEA是指三乙胺；DIAD是指偶氮二甲 酸二异丙酯；PPh 3是指三苯基膦；PdCl 2(PPh 3) 2是指双(三苯基膦)氯化钯；NaBH 4是指硼氢化钠；LC-MS是指液相色谱与质谱联用；PE是指石油醚；EA是指乙酸乙酯；CsF是指氟化铯；TLC是指薄层色谱；M是指摩尔浓度单位mol/L，例如2M是指2mol/L；mM是指摩尔浓度单位毫摩尔/升，例如2mM是指2mmol/L；N是指当量浓度，例如1N HCl是指浓度为1mol/L的盐酸；2N NaOH是指浓度为2mol/L的氢氧化钠；LAH或LiAlH 4是指氢化铝锂；PCC是指吡啶氯铬酸盐；mCPBA是指间氯过氧苯甲酸；(S,S)-Noyori’s催化剂是指[(1S,2S)-N-(对甲苯磺酰基)-1,2-二苯基-1,2-乙二胺](对异丙基甲苯)钌；DMF是指N,N-二甲基甲酰胺；TMS是指四甲基硅烷基；TBAF是指四丁基氟化铵；rt是指室温；Py是指吡啶；NIS是指N-碘代琥珀酰亚胺；TFA或TFAA是指三氟乙酸酐；Pd(PPh 3) 4是指四三苯基膦钯；dioxane是指二氧六环；Pd(OAc) 2是指醋酸钯；Bu 4NBr是指四丁基溴化胺；BAST是指二乙胺基三氟化硫。
本申请的中间体和化合物还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。互变异构体的非限制性实例包括但不限于。
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。
某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见地。
中间体1：1-(2-氨基-5-乙基苯基)-3-戊醇的合成
Figure PCTCN2019121306-appb-000098
1.1 4-乙基-2-碘苯胺
向250mL单口瓶中投入4-乙基苯胺(10.0g)，加二氯甲烷(50ml)溶解，加入100ml水溶解的碳酸氢钠(10.4g)溶液，分批次加入碘(22.0g)，室温搅拌过夜，TLC检测原料消失。后处理：加饱和亚硫酸钠水溶液，分液，水相用二氯甲烷萃取(50mL×2)，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂得油状物，过柱纯化，收集产物点减压浓缩得4-乙基-2-碘苯胺(12.7g)。
1.2 1-(2-氨基-5-乙基苯基)-戊-1-炔-3-醇
向单口瓶中投入4-乙基-2-碘苯胺(5.0g)，加60ml三乙胺溶解，加入戊-1-炔-3醇(2.0g)，加入碘化亚铜(183mg)，双(三苯基膦)二氯化钯(673mg)，氮气置换三次，室温搅拌过夜，取样，TLC检测，原料反应完全。后处理：加水100ml，用乙酸乙酯(30ml×3)萃取三次，合并有机相，用饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，滤液减压浓缩得油状物，过柱纯化，收集产物点减压浓缩，得1-(2-氨基-5-乙基苯基)-戊-1-炔-3-醇(1.3g)。
1.3 1-(2-氨基-5-乙基苯基)-3-戊醇
于单口瓶中加入1-(2-氨基-5-乙基苯基)-戊-1-炔-3-醇(1.3g)，甲醇溶解，加入钯碳(260mg)，氢气置换三次，加氢气，室温搅拌过夜。TLC检测反应完全。过滤减压浓缩得1-(2-氨基-5-乙基苯基)-3-戊醇(1.0g)。
中间体2：3-(2-氨基-5-乙基苯基)-1-环丙基丙烷-1-醇
Figure PCTCN2019121306-appb-000099
2.1 1-环丙基-3-(三甲基硅基)丙-2-炔-1-醇
向50mL单口瓶中投入三甲基硅乙炔(1.0g)，反应溶剂四氢呋喃(10mL)，氮气保护，于-40℃条件下加入正丁基锂(2.5M，8mL)，加毕，保持该温度反应0.5小时。滴加环丙烷甲醛(0.7g)，加毕，该温度下反应1小时，取样，TLC检测，原料点消失，反应完全。后处理：用饱和氯化铵溶液(30mL)淬灭，向体系中加入甲基叔丁基醚(25mL×2)，合并有机相，用饱和食盐水(20mL×1)洗涤一次，无水硫酸钠干燥，浓缩，得1-环丙基-3-(三甲基硅基)丙-2-炔-1-醇(1.2g,粗品)，直接用于下一步反应。
2.2 1-环丙基丙-2-炔-1-醇
向50mL单口反应瓶中投入化合物1-环丙基-3-(三甲基硅基)丙-2-炔-1-醇(1.2g，粗品)，加入甲醇(15mL)，加入氟化铯(1.63g)，室温反应16小时。取样，TLC检测，原料点消失，反应完全。后处理：向反应体系中加入甲基叔丁基醚(80mL)稀释，用饱和食盐水(30mL×2)洗涤两次，无水硫酸钠干燥，浓缩，得1-环丙基丙基-2-炔-1-醇(1.0g)。
2.3 3-(2-氨基-5-乙基苯基)-1-环丙基丙烷-1-醇
参照中间体1中步骤1.1-1.3的合成方式制得标题化合物。
中间体3：(S)-1-(2-氨基-5-乙基苯基)-3-戊醇的合成
Figure PCTCN2019121306-appb-000100
3.1 1-(三甲基硅基)-1-戊炔-3-醇
向500mL三口瓶中依次投入三甲基硅乙炔(7.00g)，无水四氢呋喃(100mL)，氮气置换三次，乙醇-干冰浴降温至低于-70℃，滴加正丁基锂正己烷溶液(31.4mL，2.5M)，滴加完毕，低温搅拌约30分钟，滴加正丙醛(5.7mL)，滴加完毕，自然升温至室温。后处理：加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取(50mL×3)，饱和食盐水(20mL)润洗，无水硫酸钠干燥，浓缩，减压蒸馏得1-(三甲基硅基)-1-戊炔-3-醇(6.96g)。
1H NMR(400MHz,CDCl 3)δ4.30(d,J＝4.8Hz,1H),1.91(d,J＝4.8Hz,1H),1.76–1.66(m,2H),1.00(t,J＝7.4Hz,3H),0.23–0.03(m,9H)。
3.2 1-(三甲基硅基)-1-戊炔-3-酮
向250mL单口瓶中投入1-(三甲基硅基)-1-戊炔-3-醇(6.00g)，100mL二氯甲烷稀释，冰浴冷却，加入硅胶(20g)，分批加入氯铬酸吡啶(9.10g)，滴加完毕，室温反应16小时。TLC检测，原料点消失，硅藻土过滤，减压蒸馏得1-(三甲基硅基)-1-戊炔-3-酮(5.00g)。
1H NMR(400MHz,CDCl 3)δ2.57(q,J＝7.4Hz,2H),1.12(t,J＝7.4Hz,3H),0.22(s,9H)。
3.3(S)-1-(三甲基硅基)-1-戊炔-3-醇
向250mL单口瓶中投入1-(三甲基硅基)-1-戊炔-3-酮(2.00g)和无水异丙醇(12mL)，加入溶于6mL无水异丙醇的(S,S)-Noyori’s催化剂(1.02g,参照文献Chem.Eur.J.21(32),11387-11392,2015制得)溶液，室温反应0.5小时。TLC检测，原料点消失，减压旋蒸除去溶剂，重复三批次，合并柱层析纯化得(S)-1-(三甲基硅基)-1-戊炔-3-醇(7.50g)。 1H NMR(400MHz,CDCl 3)δ4.29(t,J＝6.4Hz,1H),2.16(s,1H),1.75–1.62(m,2H),0.98(t,J＝7.4Hz,3H),0.15(s,9H)。
3.4(S)-1-戊炔-3-醇
向100mL单口瓶中投入(S)-1-(三甲基硅基)-1-戊炔-3-醇(7.50g)和甲醇(50mL)，分批加入氟化铯(8.00g)，加毕，室温反应16小时。TLC检测，原料点消失，减压旋蒸除去溶剂，柱层析得(S)-1-戊炔-3-醇(4.50g)。
3.5(S)-1-(2-氨基-5-乙基苯基)-3-戊醇的合成
参照中间体1中步骤1.1-1.3的合成方式制得标题化合物。
中间体4：(R)-3-(2-氨基-5-乙基苯基)-1-环丙基丙烷-1-醇
Figure PCTCN2019121306-appb-000101
Figure PCTCN2019121306-appb-000102
参照中间体3的合成方式制得标题化合物。
实施例1：5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((嘧啶-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000103
1.1 5-氯磺酰-2-羟基苯甲酸甲酯
将2mL氯化亚砜，6mL氯磺酸投入反应瓶中，用冰水浴将其冻至0-5℃。称取2g水杨酸甲酯并缓慢滴入反应瓶中，滴加完毕，继续于室温搅拌反应16小时。将反应液缓慢滴加至冰水中，析出白色固体，待冰完全融化后抽滤得产品，自然风干得到5-氯磺酰-2-羟基苯甲酸甲酯3.0克。
1.2 5-(N-(4-乙基-2-(3-羟基戊基)苯基)氨基磺酰基)-2-羟基苯甲酸甲酯
向25mL单口反应瓶中投入1-(2-氨基-5-乙基苯基)-3-戊醇(0.3g)，加入反应溶剂吡啶(5mL)，冰浴搅拌下，分批加入5-氯磺酰-2-羟基苯甲酸甲酯(0.47g)，加毕，撤掉冰浴，室温反应16小时。取样，TLC监测，原料点消失，送检LC-MS，检测到产物峰420[M-H] -。反应液减压浓缩除去吡啶，残留物用乙酸乙酯(50mL)稀释，用水(20mL×2)洗涤两次，饱和食盐水(20mL×2)洗涤两次，无水硫酸钠干燥，浓缩，残留物柱层析纯化，得标题化合物360mg(MS(ESI)m/z：[M-H] -420.0)。
1.3 5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯
向10mL三口瓶中投入三苯基磷(0.67g)，加入四氢呋喃(4mL)，氮气置换三次，冰浴条件下，滴加偶氮二甲酸二异丙酯(0.43g)，加毕，该温度下搅拌0.5小时；滴加5-(N-(4-乙基-2-(3-羟基戊基)苯基)氨基磺酰基)-2-羟基苯甲酸甲酯(0.36g)的四氢呋喃溶液(4mL)，加毕，自然升温反应16小时。取样，TLC检测，原料点消失，送检LC-MS，检测到产物峰402[M-H] -。向反应体系加入乙酸乙酯(60mL)稀释，用水(20mL×2)洗涤两次，饱和食盐水(20mL×3)洗涤三次，无水硫酸钠干燥，浓缩，残留物经柱层析纯化，得标题化合物0.25g(MS(ESI)m/z：402[M-H] -)。
1.4 5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((嘧啶-4-基)甲氧基)苯甲酸甲酯
向10mL三口瓶中投入5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯(0.25g)，4-羟甲基嘧啶(0.1g)和三苯基磷(0.49g)，加入四氢呋喃(6mL)，氮气置换三次，冰浴条件下，滴加偶氮二甲酸二异丙酯(0.31g)，加毕，自然升温反应16小时。取样，TLC检测，原料点消失，送检LC-MS，检测到产物峰496[M+H] +。向反应体系加入乙酸乙酯(60mL)稀释，用水(20mL×2)洗涤两次，饱和食盐水(20mL×3)洗涤三次，无水硫酸钠干燥，浓缩，残留物经柱层析纯化，得标题化合物0.6g(MS(ESI)m/z：496[M+H] +)，包含部分三苯基氧磷，直接用于下一步还原。
1.5 5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((嘧啶-4-基)甲氧基)苯甲醇
向25mL单口瓶中投入5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((嘧啶-4-基)甲氧基)苯甲酸甲酯(0.60g)，无水甲醇(8mL)，冰浴冷却至0℃；分批加入硼氢化钠(0.07g)，加毕，自然升温反应16小时。取样，TLC监测，原料点消失。送检LC-MS，检测到产物峰468[M+H] +。冰浴条件下，用1N盐酸淬灭，用乙酸乙酯(20mL×3)萃取三次，合并有机相，饱和食盐水(20mL×2)洗涤两次，无水硫酸钠干燥，浓缩，得残留物300mg，直接送perp-HPLC制备，最终制得标题化合物24mg(MS(ESI)m/z：[M+H] +468)。
1H NMR(400MHz,CDCl 3)δ9.21(s,1H),8.78(d,J＝5.1Hz,1H),7.64(d,J＝8.3Hz,1H),7.51(d,J＝2.3Hz,1H),7.47(d,J＝5.1Hz,1H),7.40(dd,J＝8.6,2.3Hz,1H),7.06(dd,J＝8.2,1.8Hz,1H),6.81(d,J＝8.7Hz,1H),6.79(s,1H),5.23(s,2H),4.72(s,2H),4.20–4.12(m,1H),2.60(q,J＝7.6Hz,2H),2.54(m,1H),2.42–2.34(m,1H),1.86–1.69(m,2H),1.65–1.61(m,1H),1.42(ddt,J＝32.3,13.2,6.5Hz,2H),1.22(t,J＝7.6Hz,3H),0.94(t,J＝7.4Hz,3H)。
实施例2：5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(甲磺酰基)乙氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000104
2.1 5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(甲硫基)乙氧基)苯甲酸甲酯
向10mL三口瓶中投入5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯(0.25g)，2-(甲硫基)-乙醇(0.068g)和三苯基磷(0.39g)，加入四氢呋喃(5mL)，氮气置换三次，冰浴条件下，滴加偶氮二甲酸二异丙酯(0.25g)，加毕，自然升温反应16小时。取样，TLC检测，原料点消失，送检LC-MS，检测到产物峰478[M+H] +。向反应体系加入乙酸乙酯(60mL)稀释，用水(10mL×2)洗涤两次，饱和食盐水(15mL×2)洗涤三次，无水硫酸钠干燥，浓缩，残留物柱层析纯化，得标题化合物0.5g，(MS(ESI)m/z：478.0[M+H] +)。
2.2 5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(甲硫基)乙氧基)苯甲醇
向25mL单口瓶中投入5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(甲硫基)乙氧基)苯甲酸甲酯(0.5g)，无水四氢呋喃(5mL)，冰浴冷却至0℃；分批加入四氢铝锂(0.07g)，加毕，该温度下反应1小时。取样，TLC监测，原料点消失。送检LC-MS，检测到产物峰449.8[M+H] +。冰浴条件下，用1N HCl淬灭，用乙酸乙酯(10mL×3)萃取三次，合并有机相，饱和食盐水(15mL×2)洗涤两次，无水硫酸钠干燥，浓缩，得标题化合物(500mg，粗品)，直接用于下一步反应(MS(ESI)m/z：449.8[M+H] +)。
2.3 5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(甲磺酰基)乙氧基)苯甲醇
向25mL单口瓶中投入5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(甲硫基)乙氧基)苯甲醇(0.50g，粗品)，二氯甲烷(5mL)，冰浴冷却至0℃；分批加入间氯过氧苯甲酸(0.34g)，加毕，自然升温反应16小时。取样，TLC监测，原料点消失。送检LC-MS，检测到产物峰481.9[M+H] +。向反应体系中加入乙酸乙酯(60mL)，用水(20mL×2)洗涤两次，饱和碳酸氢钠溶液(20mL×2)洗涤两次，饱和食盐水(20mL×2)洗涤两次，无水硫酸钠干燥，浓缩，得粗品固体600mg，直接送perp-HPLC制备，最终制得标题化合物96mg(MS(ESI)m/z：482.0[M+H] +)。
1H NMR(400MHz,CDCl 3)：δ7.59(d,J＝8.3Hz,1H),7.42(d,J＝1.9Hz,1H),7.30–7.26(m,1H),7.08–7.00(m,1H),6.80(s,1H),6.72(d,J＝8.7Hz,1H),4.50(d,J＝2.0Hz,2H),4.46(t, J＝5.2Hz,2H),4.17–4.07(m,1H),3.59–3.44(m,2H),3.06(s,3H),2.93(m,1H),2.59(q,J＝7.6Hz,2H),2.43–2.32(m,1H),1.88–1.79(m,1H),1.70(td,J＝13.7,6.0Hz,1H),1.57(td,J＝14.4,7.4Hz,1H),1.42(dtt,J＝19.4,13.0,6.7Hz,2H),1.21(t,J＝7.6Hz,3H),0.92(t,J＝7.4Hz,3H)。
实施例3：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(3-(甲磺酰基)丙氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000105
3.1 5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯
参照实施例1中步骤1.2-1.3的合成方式制得标题化合物0.15g。
3.2 5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(3-(甲磺酰基)丙氧基)苯甲醇
参照实施例2的步骤2.1-2.3制得标题化合物62mg(MS(ESI)m/z：508[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.61(d,J＝8.3Hz,1H),7.46(d,J＝2.0Hz,1H),7.31(dd,J＝8.6,2.2Hz,1H),7.04(d,J＝7.0Hz,1H),6.82(s,1H),6.71(d,J＝8.7Hz,1H),4.55(d,J＝5.1Hz,2H),4.14(t,J＝5.9Hz,2H),3.62(dt,J＝8.3,5.6Hz,1H),3.25(t,J＝7.4Hz,2H),2.96(s,3H),2.59(dd,J＝15.2,7.6Hz,2H),2.56–2.48(m,2H),2.40–2.31(m,2H),1.96(dt,J＝16.2,6.1Hz,1H),1.71(ddd,J＝19.8,8.6,6.0Hz,1H),1.58(td,J＝12.0,6.1Hz,1H),1.21(t,J＝7.6Hz,3H),0.95–0.83(m,1H),0.52–0.42(m,3H),0.34(dd,J＝10.6,5.2Hz,1H)。
实施例4：3-(4-(((R)-2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)四氢噻吩1,1-二氧化物的合成
Figure PCTCN2019121306-appb-000106
参照实施例3的步骤制得标题化合物60mg(MS(ESI)m/z：494.0[M+H] +)。
1H NMR(400MHz,CDCl3)δ7.62(d,J＝8.3Hz,1H),7.59–7.31(m,2H),7.05(d,J＝8.3Hz,1H),6.80(s,1H),6.72(dd,J＝10.2,8.7Hz,1H),4.64–4.50(m,2H),4.16(dd,J＝6.5,4.0Hz,1H),3.43–3.30(m,3H),3.30–3.17(m,1H),2.71–2.36(m,6H),1.89–1.70(m,2H),1.58(d,J＝6.4Hz,2H),1.50–1.37(m,2H),1.22(t,J＝7.6Hz,3H),0.94(t,J＝7.4Hz,3H)。
实施例5：3-((4-(((R)-2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)甲基)四氢噻吩1,1-二氧化物的合成
Figure PCTCN2019121306-appb-000107
参照实施例3的步骤制得标题化合物40mg(MS(ESI)m/z：508.0[M+H] +)。
1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.3Hz,1H),7.49(t,J＝2.1Hz,1H),7.42–7.37(m,1H),7.06(dd,J＝8.3,2.0Hz,1H),6.82–6.71(m,2H),4.60(s,2H),4.17(dd,J＝12.9,6.4Hz,1H),4.14–4.04(m,2H),3.29(ddd,J＝12.6,10.6,6.3Hz,2H),3.10(ddd,J＝21.4,13.1,9.1Hz,2H),3.03–2.93(m,1H),2.59(q,J＝7.6Hz,2H),2.42(ddd,J＝23.2,14.9,7.4Hz,2H),2.27–2.14(m,1H),1.94–1.68(m,2H),1.67–1.58(m,2H),1.43(ddd,J＝24.4,13.6,7.0Hz,2H),1.22(t,J＝7.6Hz,3H),0.94(t,J＝7.4Hz,3H)。
实施例6：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((4-甲基-4H-1,2,4-三唑-3-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000108
参照实施例1的步骤制得标题化合物33mg(MS(ESI)m/z：483.0[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.59(d,J＝8.3Hz,1H),7.48(d,J＝2.1Hz,1H),7.29–7.24(m,1H),7.03(dd,J＝8.3,1.5Hz,1H),6.94(d,J＝8.7Hz,1H),6.83(s,1H),5.25(s,2H),4.53(s,2H),3.75(s,3H),3.65–3.52(m,2H),2.59(dd,J＝15.1,7.6Hz,2H),2.52(dd,J＝8.7,7.0Hz,1H),1.96(dt,J＝16.3,6.1Hz,1H),1.71(dq,J＝8.6,5.9Hz,1H),1.58(td,J＝12.0,6.1Hz,1H),1.21(t,J＝7.6Hz,3H),0.94–0.83(m,1H),0.53–0.40(m,3H),0.37–0.29(m,1H)。
实施例7：5-(((S)-2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((嘧啶-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000109
Figure PCTCN2019121306-appb-000110
参照实施例1的步骤制得标题化合物11mg(MS(ESI)m/z：480[M+H] +)。
1H NMR(400MHz,CDCl 3)δ9.20(s,1H),8.77(d,J＝5.1Hz,1H),7.64(d,J＝8.3Hz,1H),7.53(d,J＝2.0Hz,1H),7.47(d,J＝5.0Hz,1H),7.39(dd,J＝8.6,2.2Hz,1H),7.07–7.02(m,1H),6.80(d,J＝8.9Hz,2H),5.23(s,2H),4.72(s,2H),3.65(dt,J＝8.4,5.7Hz,1H),2.59(dd,J＝15.1,7.6Hz,2H),2.56–2.50(m,1H),1.96(dt,J＝16.2,6.1Hz,2H),1.74(ddd,J＝19.8,8.5,5.9Hz,1H),1.65–1.57(m,1H),1.22(t,J＝7.6Hz,3H),0.90(ddd,J＝16.4,10.8,6.0Hz,1H),0.49(ddd,J＝19.2,9.5,3.8Hz,3H),0.35(dd,J＝10.3,5.5Hz,1H)。
实施例8：3-((4-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)甲基)硫杂环丁烷1,1-二氧化物的合成
Figure PCTCN2019121306-appb-000111
参照实施例3的步骤制得标题化合物32mg(MS(ESI)m/z：506[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.62(d,J＝8.3Hz,1H),7.45(d,J＝2.1Hz,1H),7.31(dd,J＝8.6,2.3Hz,1H),7.04(dd,J＝8.3,1.5Hz,1H),6.83(s,1H),6.70(d,J＝8.7Hz,1H),4.63–4.52(m,2H),4.34(dd,J＝14.6,10.1Hz,2H),4.21(dd,J＝5.6,2.8Hz,1H),4.18(d,J＝5.1Hz,2H),3.63(dt,J＝8.4,5.6Hz,1H),3.10–2.99(m,1H),2.74(s,1H),2.59(q,J＝7.5Hz,2H),2.53(dd,J＝8.7,6.9Hz,1H),1.97(dt,J＝16.3,6.1Hz,1H),1.71(t,J＝6.6Hz,2H),1.59(dt,J＝19.5,6.1Hz,1H),1.22(t,J＝7.6Hz,3H),0.89(ddd,J＝13.2,8.8,6.7Hz,1H),0.54–0.42(m,3H),0.34(dd,J＝10.8,5.2Hz,1H)。
实施例9：3-((4-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)硫杂环丁烷1,1-二氧化物的合成
Figure PCTCN2019121306-appb-000112
参照实施例3的步骤制得标题化合物54mg(MS(ESI)m/z：480[M+H] +)。
1H NMR(400MHz,CDCl 3)δ:7.63(d,J＝8.3Hz,1H),7.55(d,J＝2.0Hz,1H),7.40(dd,J＝8.5,2.2Hz,1H),7.06(d,J＝8.2Hz,1H),6.80(s,1H),6.57(d,J＝8.6Hz,1H),5.16–5.09(m,1H),4.60(ddd,J＝11.2,6.6,3.4Hz,4H),4.24(dd,J＝15.4,2.6Hz,2H),4.20–4.10(m,1H),2.59(q,J＝7.6Hz,2H),2.45–2.34(m,1H),2.19(dt,J＝13.2,6.9Hz,1H),1.87–1.68(m,2H),1.63 (d,J＝7.2Hz,1H),1.51–1.36(m,2H),1.22(t,J＝7.6Hz,3H),0.94(t,J＝7.4Hz,3H)。
实施例10：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((1,5-二甲基-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲醇的合成
实施例11：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((1,4-二甲基-1H-1,2,3-三氮唑-5-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000113
10.1 2-(丁-2-炔-1-基氧基)-5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)苯甲酸甲酯
向50mL原底烧瓶中加入5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯(250mg)，1-溴-2-丁炔(95.4mg)，碘化钾(10mg)和N,N-二甲基甲酰胺(12mL)，混合液在室温搅拌12小时。取样，送检LC-MS，检测到产物峰468.2[M+1] +。反应液冷却到室温，乙酸乙酯(100mL)稀释，有机相饱和食盐水(30mL×3)洗，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，硅胶柱层析得到标题化合物280mg(MS(ESI)m/z 468.2[M+1] +)。
10.2 5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((5-甲基-1-((三甲硅基)甲基)-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲酸甲酯和5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((4-甲基-1-((三甲硅基)甲基)-1H-1,2,3-三氮唑-5-基)甲氧基)苯甲酸甲酯
向50mL圆底烧瓶中投入2-(丁-2-炔-1-基氧基)-5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)苯甲酸甲酯(150mg)，用N,N-二甲基甲酰胺(4.5mL)和甲醇(0.5mL)溶解，向其中加入碘化亚铜(4.5mL)和三甲基硅基叠氮甲烷(249mg)，所得反应混合物在氮气氛围下加热搅拌三天。取样，送检LC-MS，检测到产物峰597.2[M+1] +。反应液冷却到室温，乙酸乙酯(120mL)稀释，有机相用饱和食盐水(30mL×3)洗，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，经Prep-HPLC纯化得到的120mg粗品(MS(ESI)m/z 596.8[M+1] +)后，再经过制备TLC板分离分别得到5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((5-甲基-1-((三甲硅基)甲基)-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲酸甲酯(72mg)和5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((4-甲基-1-((三甲硅基)甲基)-1H-1,2,3-三氮唑-5-基)甲氧基)苯甲酸甲酯(49.6mg)。
10.3 5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((1,5-二甲基-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲酸甲酯
向25mL圆底烧瓶中投入5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((5-甲基-1-((三甲硅基)甲基)-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲酸甲酯(89mg)和四氢呋喃(2mL)，向其中加入四丁基氟化铵(58.4mg)，所得混合液室温搅拌3小时。取样，送检LC-MS，检测到产物峰525.1[M+1] +。将反应液用乙酸乙酯(60mL)稀释，有机相用水(20mL×2)洗，饱和食盐水(20mL)洗，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂得到标题化合物(90mg)，粗品直接投入下一步。
10.4 5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((1,5-二甲基-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲醇
向25mL圆底烧瓶中投入5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((1,5-二甲基-1H-1,2,3-三氮唑-4-基)甲氧基)苯甲酸甲酯(80mg)和四氢呋喃(2mL)，于0℃冷却，向其中加入四氢铝锂(17.4mg)，所得混合液于0℃搅拌30分钟。取样，送检LC-MS，检测到产物峰497.1[M+1] +。将反应液用水(20μL)淬灭，反应液用四氢呋喃(30mL)稀释，加入10％的氢氧化钠溶液(20μL)，搅拌5分钟，加入水(60μL)，加入无水硫酸镁搅拌10分钟，硅藻土过滤，滤液减压旋干，经Prep-HPLC纯化得标题化合物27mg(HPLC纯度99.28％，MS(ESI)m/z 497.1[M+1] +)。
1H NMR(400MHz,CDCl 3):δ7.66(d,J＝8.4Hz,1H),7.48(d,J＝2.4Hz,1H),7.40(dd,J＝8.4,2.4Hz,1H),7.06(dd,J＝8.4,1.6Hz,1H),7.01(d,J＝8.8Hz,1H),6.85(s,1H),5.18(s,2H),4.55(d,J＝5.6Hz,2H),3.98(s,3H),3.66(dt,J＝8.4,5.6Hz,1H),2.65–2.59(m,2H),2.58–2.51(m,1H),2.40(br.s,1H),2.34(s,3H),2.06–1.97(m,1H),1.80–1.72(m,1H),1.66–1.56(m,1H),1.24(t,J＝7.6Hz,3H),0.98–0.88(m,1H),0.56–0.45(m,3H),0.40–0.34(m,1H).
实施例11：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((1,4-二甲基-1H-1,2,3-三氮唑-5-基)甲氧基)苯甲醇
参照实施例10的步骤10.3和10.4以同样的方式合成标题化合物9mg(HPLC纯度99.02％，MS(ESI)m/z 497.1[M+1] +).
1H NMR(400MHz,CDCl 3):δ7.65(d,J＝8.4Hz,1H),7.53(d,J＝2.0Hz,1H),7.41(d,J＝8.4Hz,1H),7.07(dd,J＝8.4,1.6Hz,1H),6.89(d,J＝8.8Hz,1H),6.86(s,1H),5.10(s,2H),4.56(d,J＝5.2Hz,2H),4.07(s,3H),3.72–3.60(m,1H),2.65–2.54(m,3H),2.36(s,3H),2.05–1.96(m,1H),1.80–1.73(m,1H),1.67–1.59(m,1H),1.24(t,J＝7.6Hz,3H),0.97–0.88(m,1H),0.57–0.43(m,3H),0.40–0.33(m,1H).
实施例12：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((3,5-二甲基异恶唑-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000114
参照实施例1中步骤1.4-1.5的合成方式制得标题化合物82.21mg(HPLC纯度98.46％,MS(ESI)m/z：497.1[M+1] +)。
1H NMR(400MHz,CDCl 3)δ7.64(d,J＝8.3Hz,1H),7.51(d,J＝2.3Hz,1H),7.39(dd,J＝8.6,2.4Hz,1H),7.04(dd,J＝8.3,1.9Hz,1H),6.86(d,J＝8.7Hz,1H),6.84(s,1H),4.84(s,2H),4.55(d,J＝5.6Hz,2H),3.65(dt,J＝8.5,5.6Hz,1H),2.60(dd,J＝9.4,5.7Hz,2H),2.55(dd,J＝8.0,5.8Hz,1H),2.40(s,3H),2.27(s,3H),2.21(t,J＝5.7Hz,1H),2.00(dt,J＝16.3,6.1Hz,1H),1.76–1.69(m,1H),1.67–1.56(m,1H),1.22(t,J＝7.6Hz,3H),0.91(dt,J＝8.2,5.2Hz,1H),0.55–0.41(m,3H),0.39–0.29(m,1H).
实施例13：5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((嘧啶-5-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000115
参照实施例1中步骤1.4-1.5的合成方式制得标题化合物43mg(MS(ESI)m/z：480.0 [M+H] +)。
1H NMR(400MHz,CDCl 3)δ9.23(s,1H),8.82(s,2H),7.64(d,J＝8.3Hz,1H),7.55(d,J＝1.8Hz,1H),7.39(dd,J＝8.6,2.1Hz,1H),7.05(d,J＝8.2Hz,1H),6.86(d,J＝8.6Hz,1H),6.83(s,1H),5.14(s,2H),4.63(s,2H),3.65(dt,J＝8.3,5.7Hz,1H),2.63–2.50(m,3H),2.21(s,1H),1.97(dt,J＝16.3,6.1Hz,1H),1.76(dd,J＝8.4,5.7Hz,1H),1.60(td,J＝12.3,6.1Hz,1H),1.22(t,J＝7.6Hz,3H),0.96–0.85(m,1H),0.55–0.42(m,3H),0.35(dd,J＝10.5,5.6Hz,1H).
实施例14：5-((6-(环戊-1-烯-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000116
14.1 5-((2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯
参照实施例1中步骤1.2-1.3的合成方式制得标题化合物720mg。
14.2 5-((2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向50mL单口瓶中投入5-((2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯(720mg)，加15ml N,N-二甲基甲酰胺溶解，加入对甲苯磺酸-4-吡喃甲酯(650mg)，碳酸钾(514mg)，加入碘化钾(15mg)，油浴70℃反应16小时，取样，TLC检测，原料点消失。后处理：加水100ml，用乙酸乙酯(30ml×3)萃取三次，合并有机相，用50mL饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂得标题化合物1.1g(粗品)。
14.3 5-((2-环丙基-6-碘-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向50mL单口瓶中投入5-((2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(600mg)，加5ml三氟乙酸溶解，冰浴降温，分批加入N-碘代丁二酰亚胺(292mg)，加料毕升至室温搅拌过夜，取样，TLC检测，原料点消失，送检LC-MS，无MS信号。后处理：加水50ml，用乙酸乙酯(20ml×3)萃取三次，合并有机相，用亚硫酸钠水溶液洗，碳酸钠水溶液洗，饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂得标题化合物660mg。
14.4 5-((6-(环戊-1-烯-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向单口瓶中投入5-((2-环丙基-6-碘-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(140mg)、1-环戊烯硼酸频哪醇酯(67mg)，用1,4-二氧六环(4ml)溶解，加入150mg碳酸铯，水(31mL)，四三苯基磷钯(13mg)，氮气置换并保护，80℃搅拌过夜。TLC检测反应完全，LC-MS检测到产物峰552.1[M+1] +。加水(50ml)，用乙酸乙酯(20ml×3)萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂得标题化合物220mg(粗品，MS(ESI)m/z 552.1[M+1] +)。
14.5 5-((6-(环戊-1-烯-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇
于100ml单口瓶中加入5-((6-(环戊-1-烯-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(220mg)，加无水THF 5ml溶解，冰浴降温，分 批加入四氢铝锂(44mg)，加料完毕，冰浴下搅拌30min，TLC检测反应完全，LC-MS:524.0[M+1] +。加1ml水淬灭，补加10ml乙酸乙酯，无水硫酸钠干燥。过滤，减压浓缩得220mg粗品。分析制备得12.63mg(HPLC纯度：99.3％,MS(ESI)m/z：524.0[M+1] +)。
1H NMR(400MHz,CDCl 3)δ7.71(d,J＝8.5Hz,1H),7.55(d,J＝2.2Hz,1H),7.37(dd,J＝8.6,2.3Hz,1H),7.30(dd,J＝8.5,1.7Hz,1H),7.06(s,1H),6.75(d,J＝8.7Hz,1H),6.14(s,1H),4.61(d,J＝5.9Hz,2H),4.01(dd,J＝11.3,3.7Hz,2H),3.85(d,J＝6.3Hz,2H),3.68(dt,J＝8.6,5.5Hz,1H),3.44(t,J＝11.0Hz,2H),2.63(ddd,J＝15.9,10.7,6.8Hz,3H),2.55–2.42(m,2H),2.22–1.95(m,5H),1.68(dd,J＝12.2,3.1Hz,2H),1.62(dd,J＝13.3,5.7Hz,1H),1.47(qd,J＝12.4,4.4Hz,2H),0.96–0.84(m,1H),0.49(qd,J＝12.4,5.6Hz,3H),0.35(dd,J＝9.1,4.1Hz,1H).
实施例15：5-((2-环丙基-6-(2,3-二氢呋喃-2-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000117
15.1 5-((2-环丙基-6-(2,3-二氢呋喃-2-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向单口瓶中投入5-((2-环丙基-6-碘-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(实施例26.3,270mg)、2,3-二氢呋喃(310mg)，用N,N-二甲基甲酰胺(2ml)溶解，加入110mg醋酸钾，354mg四丁基溴化胺，5mg醋酸钯，氮气置换并保护，35℃搅拌过夜。TLC检测反应完全，LC-MS检测到产物峰,554.1[M+1] +。体系加水和乙酸乙酯萃取，有机层干燥浓缩得标题化合物450mg(粗品,MS(ESI)m/z 554.1[M+1] +)。
15.2 5-((2-环丙基-6-(2,3-二氢呋喃-2-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇
于100ml单口瓶中加入原料12(450mg)，加重蒸THF 10ml溶解，冰浴降温，分批加入四氢铝锂(93mg)，加料完毕，冰浴下搅拌30min，TLC检测反应完全，LC-MS，526.3[M+1]+。加1ml水淬灭，补加10ml乙酸乙酯，无水硫酸钠干燥。过滤，减压浓缩得300mg油状物。分析制备得标题化合物92.12mg(HPLC纯度：96.7％,MS(ESI)m/z：526.3[M+1] +)。
1H NMR(400MHz,CDCl 3)δ7.76(d,J＝8.5Hz,1H),7.45(d,J＝8.8Hz,1H),7.41(dd,J＝8.0,4.4Hz,1H),7.19(dd,J＝11.1,4.2Hz,1H),7.03(d,J＝6.3Hz,1H),6.76(d,J＝8.5Hz,1H),6.42(d,J＝1.8Hz,1H),5.45(ddd,J＝10.5,8.8,4.9Hz,1H),5.03–4.94(m,1H),4.59(d,J＝5.9Hz,2H),4.02(dd,J＝11.3,3.9Hz,2H),3.85(d,J＝6.3Hz,2H),3.69(dt,J＝8.6,5.5Hz,1H),3.44(t,J＝11.1Hz,2H),3.05(ddd,J＝15.2,10.7,2.3Hz,1H),2.69–2.51(m,2H),2.18–1.98(m,3H),1.74(t,J＝6.6Hz,2H),1.68–1.57(m,2H),1.47(qd,J＝12.4,4.5Hz,2H),0.97–0.83(m,1H),0.59–0.42(m,3H),0.34(dd,J＝7.4,5.3Hz,1H)。
实施例16：5-((2-环丙基-6-(氧杂环丁-3-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000118
Figure PCTCN2019121306-appb-000119
16.1 N-(4-溴苯基)-2,2,2-三氟乙酰胺
向100mL单口瓶中投入对溴苯胺(5.0g)和二氯甲烷(25mL)，向其中加入三乙胺(2.96g),混合液于0℃冷却，滴入三氟乙酸酐(6.14g)，所得反应液逐渐升至室温搅拌5小时。取样，TLC检测，原料点消失。将反应液用二氯甲烷(100mL)稀释，饱和食盐水(30mLx2)洗，有机相减压旋干，硅胶柱层析分离得N-(4-溴苯基)-2,2,2-三氟乙酰胺7.42g。
16.2 N-(4-(3-羟基氧杂环丁-3-基)苯基)三氟乙酰胺
将N-(4-溴苯基)-2,2,2-三氟乙酰胺(7.42g)投入250mL三口瓶中，加入无水四氢呋喃(80mL)溶解，氮气保护。将反应体系冷却到-78℃，向其中滴加入正丁基锂(24.5mL)，并于该温度下搅拌30分钟。向其中滴加入3-氧杂环丁酮(4.4g)。所得混合物液在-78℃搅拌2小时后，逐渐升至室温搅拌1小时。取样，TLC检测，原料点消失。用饱和氯化铵溶液(50mL)淬灭反应，乙酸乙酯(80mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，硅胶柱层析分离得N-(4-(3-羟基氧杂环丁-3-基)苯基)三氟乙酰胺(6.56g)。
16.3 N-(4-(3-氟氧杂环丁-3-基)苯基)三氟乙酰胺
向250mL单口瓶中投入N-(4-(3-羟基氧杂环丁-3-基)苯基)三氟乙酰胺(2.0g)，四氢呋喃(7mL)和二氯甲烷(70mL)。将反应体系冷却到-78℃，向其中滴加入二乙胺基三氟化硫(1.85g)，并于该温度下搅拌30分钟。取样，送检LC-MS，检测到产物峰261.9[M-1] -。将反应液用饱和氯化铵溶液(15mL)淬灭，用二氯甲烷(300mL)稀释，饱和食盐水(100mL)洗，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，硅胶柱层析分离得N-(4-(3-氟氧杂环丁-3-基)苯基)三氟乙酰胺625mg(MS(ESI)m/z 261.9[M-1] -)。
16.4 N-(4-(氧杂环丁-3-基)苯基)三氟乙酰胺
向50mL单口瓶中投入N-(4-(3-氟氧杂环丁-3-基)苯基)三氟乙酰胺(400mg)，加入氢氧化钯碳(192mg)和乙醇(14mL)，加上氢气球，氢气置换三次，室温反应3小时。取样，送检LC-MS，检测到产物峰243.9[M-1] -。硅藻土过滤，浓缩得N-(4-(氧杂环丁-3-基)苯基)三氟乙酰胺(400mg,粗品)，直接投入下一步。
16.5 4-(氧杂环丁-3-基)苯胺
将N-(4-(氧杂环丁-3-基)苯基)三氟乙酰胺(400mg)溶于乙醇(14mL)中，向其中加入氢氧化钠的水溶液(3.3mL,1N)，所得混合液于80℃加热搅拌3小时。取样，送检LC-MS， 检测到产物峰150.1[M+1] +。减压旋除乙醇，用水(15mL)稀释，乙酸乙酯(40mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，硅胶柱层析(PE:EA＝10:0至1:1洗脱)，得黄色固体4-(氧杂环丁-3-基)苯胺140mg
16.6 5-((2-环丙基-6-(氧杂环丁-3-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯
参照中间体1中步骤1.1-1.3以及实施例1中步骤1.2-1.3的合成方式制得标题化合物239mg(MS(ESI)m/z 444.2[M+1] +)。
16.7 5-((2-环丙基-6-(氧杂环丁-3-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向25mL单口瓶中投入5-((2-环丙基-6-(氧杂环丁-3-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-羟基苯甲酸甲酯(209mg)，对甲苯磺酸-4-吡喃甲酯(255mg)，碳酸钾(130mg)，碘化钾(7.8mg)和N,N-二甲基甲酰胺(14mL)，70℃反应24小时。取样，送检LC-MS，检测到产物峰542.2[M+1] +。反应液冷却到室温，乙酸乙酯(100mL)稀释，有机相饱和食盐水(30mL×3)洗，无水硫酸钠干燥，过滤，减压旋蒸除去溶剂，硅胶柱层析分离得到标题化合物90mg(MS(ESI)m/z 542.3[M+1] +)。
16.8 5-((2-环丙基-6-(氧杂环丁-3-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇
向25mL三口瓶中投入5-((2-环丙基-6-(氧杂环丁-3-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(60mg)，无水四氢呋喃(4mL)，氮气置换3次，冰浴冷却至0℃。分批将氢化铝锂(8.4mg)加入到反应液中，保持0℃反应1小时。取样，送检LC-MS，检测到产物峰514.2[M+1] +。在冰浴下用水(0.02mL)淬灭反应，再滴入10％的氢氧化钠水溶液(0.01mL)，继续滴入水(0.06mL)，室温搅拌5分钟。反应液用四氢呋喃(30mL)稀释，加入适量无水硫酸镁，搅拌15分钟。硅藻土过滤，滤液减压浓缩，粗品经PREP-HPLC纯化得标题化合物18.73mg(HPLC纯度99.95％，MS(ESI)m/z 514.2[M+1] +.
1H NMR(400MHz,CDCl 3):δ7.76(d,J＝8.4Hz,1H),7.55(d,J＝2.4Hz,1H),7.42(dd,J＝8.4,2.4Hz,1H),7.22(dd,J＝8.4,2.0Hz,1H),7.08(s,1H),6.79(d,J＝8.4Hz,1H),5.11-5.02(m,2H),4.75(dd,J＝12.0,6.0Hz,2H),4.63(d,J＝6.0Hz,2H),4.23-4.11(m,1H),4.09-3.98(m,2H),3.88(d,J＝6.4Hz,2H),3.74-3.63(m,1H),3.45(t,J＝11.2Hz,2H),2.73-2.60(m,1H),2.26-2.04(m,3H),1.79-1.71m,3H),1.70-1.62(m,1H),1.58-1.38(m,2H),0.97-0.85(m,1H),0.59-0.42(m,3H),0.41-0.31(m,1H)。
实施例17：(S)-5-((2-环丙基-6-乙基-3,4-二氢-1,8-萘啶-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000120
17.1 5-乙基-3-碘-2-吡啶胺
向100mL单口瓶中投入5-乙基-2-吡啶胺(1.1g)，加10ml三氟乙酸溶解，冰浴降温，分批加入碘代丁二酰亚胺(2.1g)加料毕升至室温搅拌过夜，取样，TLC检测，原料消失。LC-MS检测到产物峰248.8[M+1] +.后处理：加水50ml，用乙酸乙酯萃取(30mL×3)，合并有机相，用碳酸钠水溶液调PH至中性,用50mL饱和食盐水洗涤，无水硫酸钠干燥，过滤减压旋蒸除 去溶剂得5-乙基-3-碘-2-吡啶胺1.4g。
17.2(S)-3-(2-氨基-5-乙基吡啶-3-基)-1-环丙基-2-丙炔-1-醇
向单口瓶中投入5-乙基-3-碘-2-吡啶胺(680mg)，加10ml三乙胺溶解，加入(S)-1-环丙基-2-丙炔-1-醇(394mg)，加入碘化亚铜(26mg)，95mg二-三苯基膦二氯化钯，氮气置换三次，室温搅拌过夜，取样，TLC检测，原料反应完全。LC-MS检测217.1[M+1] +，后处理：加水100ml，用乙酸乙酯(50mlx3)萃取三次，合并有机相，用饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，滤液减压浓缩得油状物，过柱纯化，收集产物点减压浓缩，得(S)-3-(2-氨基-5-乙基吡啶-3-基)-1-环丙基-2-丙炔-1-醇(630mg)。
17.3(R)-3-(2-氨基-5-乙基吡啶-3-基)-1-环丙基-1-丙醇
于单口瓶中加入(S)-3-(2-氨基-5-乙基吡啶-3-基)-1-环丙基-2-丙炔-1-醇(630mg),15ml甲醇,5ml乙酸乙酯溶解，加入120mg氢氧化钯碳，氢气置换三次，加氢气，油浴45℃搅拌过夜。LC-MS检测221.1[M+1] +。原料反应完全,过滤减压浓缩得标题化合物(510mg)。
17.4(R)-1-环丙基-3-(5-乙基-2-碘吡啶-3-基)-1-丙醇
向单口瓶中加入(R)-3-(2-氨基-5-乙基吡啶-3-基)-1-环丙基-1-丙醇(470mg)，加亚硝酸钠(295mg),加二甲亚砜(3ml)溶解搅拌,滴加二甲亚砜(2ml)溶解的碘化钾(1.77g),氢碘酸(1.1g)溶液,滴加毕,氮气置换三次，油浴55℃搅拌过夜。取样，TLC检测，原料点消失,LC-MS检测331.6[M+1] +。后处理:将反应液倒入50ml饱和碳酸钾冰水溶液中,用乙酸乙酯30mlx3萃取三次,合并有机相,食盐水洗,无水硫酸钠干燥,过滤,减压浓缩,得油状物,柱层析分离，收集产物点，减压浓缩得标题化合物(140mg).
17.5(R)-5-(N-(3-(3-环丙基-3-羟基丙基)-5-乙基吡啶-2-基)氨基磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向50mL单口瓶中投入(R)-1-环丙基-3-(5-乙基-2-碘吡啶-3-基)-1-丙醇(140mg)，加5-胺磺酰基-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(210mg，其合成详见专利CN201710913429.3)，加1,4-二氧六环(2ml)溶解，加入碘化亚铜(16mg)，N，N’-二甲基乙二胺(8mg),室温搅拌过夜，取样，TLC检测，原料点少量剩余，送检LC-MS，检测到产物峰，532.9[M+1] +。后处理：加水50ml，用乙酸乙酯(20ml×3)萃取三次，合并有机相，用50mL饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂得油状物，柱层析分离，收集产物点，减压浓缩得标题化合物(120mg).
17.6(S)-5-((2-环丙基-6-乙基-3,4-二氢-1,8-萘啶-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向250mL三口瓶中加入三苯基膦(180mg)，加3ml重蒸四氢呋喃溶解，氮气置换三次，冰浴降温至0℃，滴加116mg偶氮二甲酸二异丙酯，滴加完毕，冰浴下搅拌30分钟，滴加(R)-5-(N-(3-(3-环丙基-3-羟基丙基)-5-乙基吡啶-2-基)氨基磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(120mg)的四氢呋喃(2ml)溶液，滴加完毕升至室温搅拌过夜。取样，TLC检测，原料点少量剩余。硅胶拌样，柱层析分离，收集产物点，减压浓缩得标题化合物(粗品，140mg)。
17.7(S)-5-((2-环丙基-6-乙基-3,4-二氢-1,8-萘啶-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇
于100ml单口瓶中加入(S)-5-((2-环丙基-6-乙基-3,4-二氢-1,8-萘啶-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(140mg)，加甲醇5ml溶解，加热回流，分批加入硼氢化钠(56mg)，加料完毕，回流30min，TLC检测反应完全，LC-MS，487.3[M+1] +。加水50ml，用乙酸乙酯(20ml×3)萃取三次，合并有机相，用50mL饱和食盐水洗涤，无水硫酸钠干燥。过滤，减压浓缩得200mg油状物。Prep-HPLC制备得标题化合物2.1mg(HPLC纯度：98.57％,MS(ESI)m/z：487.3[M+1] +)。
1H NMR(400MHz,CDCl 3)δ8.15–8.07(m,2H),7.92(d,J＝2.0Hz,1H),7.20(s,1H),6.88(d,J＝8.4Hz,1H),4.70(d,J＝6.1Hz,2H),4.16(dt,J＝9.5,3.5Hz,1H),4.02(dd,J＝11.1,3.7 Hz,2H),3.90(d,J＝6.4Hz,2H),3.44(td,J＝11.9,1.8Hz,2H),3.02(ddd,J＝30.4,15.6,9.1Hz,1H),2.74(dd,J＝17.0,4.8Hz,1H),2.50(q,J＝7.6Hz,2H),2.12(dd,J＝15.8,3.9Hz,2H),2.08–2.03(m,1H),1.98(dd,J＝13.3,5.7Hz,1H),1.73(d,J＝13.1Hz,2H),1.47(ddd,J＝25.4,12.3,4.6Hz,2H),1.16(t,J＝7.6Hz,3H),1.00–0.85(m,2H),0.75(dt,J＝9.2,4.6Hz,1H),0.55(q,J＝5.8Hz,2H),0.35–0.25(m,1H).
实施例18：5-((6-(氮杂环丁烷-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000121
18.1 5-((6-(氮杂环丁烷-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向闷罐中投入5-((2-环丙基-6-碘-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(实施例26.3,160mg)、氮杂环丁烷盐酸盐(254mg)，N,N-二甲基甲酰胺(5ml)，碳酸铯(678mg),碘化亚铜(2.5mg),，2-异丁酰基环己酮(13mg),80℃搅拌过夜。TLC检测少量原料剩余,LC-MS检测到产物峰:541.1[M+1] +。后处理:加水50ml，用乙酸乙酯(20ml×3)萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩得标题化合物(粗品,390mg,MS(ESI)m/z 541.1)。
18.2 5-((6-(氮杂环丁烷-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇
于100ml单口瓶中加入5-((6-(氮杂环丁烷-1-基)-2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(390mg)，加无水四氢呋喃10ml溶解，冰浴降温，分批加入四氢铝锂(82mg)，加料完毕，冰浴下搅拌30min，TLC检测反应完全，LC-MS，513.3[M+1] +。加1ml水淬灭，补加10ml乙酸乙酯，无水硫酸钠干燥。过滤，减压浓缩得370mg油状物。HPLC分析制备得标题化合物(9.87mg,HPLC纯度99.2％,MS(ESI)m/z：513.3[M+1] +)。
1H NMR(400MHz,CDCl 3)δ7.52(d,J＝8.7Hz,1H),7.37(d,J＝2.3Hz,1H),7.28(dd,J＝8.6,2.4Hz,1H),6.72(d,J＝8.7Hz,1H),6.31(dd,J＝8.7,2.7Hz,1H),6.00(d,J＝2.6Hz,1H),4.57(s,2H),4.00(dd,J＝11.3,3.6Hz,2H),3.86–3.76(m,6H),3.60(dd,J＝14.4,6.4Hz,1H),3.41(td,J＝11.9,1.8Hz,2H),2.39–2.28(m,3H),2.06(td,J＝11.5,5.7Hz,1H),1.80–1.60(m,5H),1.44(qd,J＝12.2,4.4Hz,3H),0.86(ddt,J＝10.7,8.1,3.9Hz,1H),0.45(dddd,J＝12.8,10.6,8.2,3.0Hz,3H),0.37–0.28(m,1H).
实施例19：5-((2-环丙基-6-二氟甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇的合成
Figure PCTCN2019121306-appb-000122
19.1 5-((2-环丙基-6-甲酰基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向50mL单口瓶中投入5-((2-环丙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(实施例26.2，370mg)，加二氯甲烷(9ml)溶解，氮气保护，降温至-20℃，滴加四氯化钛(434mg)，滴加毕，-20℃搅拌1小时，滴加二氯甲基甲醚(263mg)，滴加 毕-20℃下搅拌16小时，取样，TLC检测，原料点消失。后处理：加氯化铵水溶液50ml淬灭，用乙酸乙酯(20ml×3)萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，减压旋蒸除去溶剂得标题化合物500mg。
19.2 5-((2-环丙基-6-二氟甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯
向单口瓶中投入5-((2-环丙基-6-甲酰基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(500mg)，用6ml二氯甲烷溶解，冰浴降温，滴加二乙胺基三氟化硫，滴加毕室温搅拌过夜。TLC检测少量原料剩余，LC-MS检测到产物峰,536.1[M+1] +。后处理：加水溶液50ml淬灭，用二氯甲烷(20ml×3)萃取三次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤减压浓缩得标题化合物(粗品,500mg，MS(ESI)m/z 536.1[M+1] +)。
19.3 5-((2-环丙基-6-二氟甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲醇
于100ml单口瓶中加入5-((2-环丙基-6-二氟甲基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯甲酸甲酯(500mg)，加无水四氢呋喃10ml溶解，冰浴降温，分批加入四氢铝锂(75mg)，加料完毕，冰浴下搅拌30分钟，TLC检测反应完全，LC-MS，508.2[M+1] +。加1ml水淬灭，补加10ml乙酸乙酯，无水硫酸钠干燥。过滤，减压浓缩得470mg油状物，经HPLC分析制备得标题化合物(17.7mg，HPLC纯度97.8％,MS(ESI)m/z：508.2[M+1] +)。
1H NMR(400MHz,CDCl 3)δ7.88(d,J＝8.5Hz,1H),7.58(d,J＝2.4Hz,1H),7.42(dd,J＝8.6,2.4Hz,1H),7.33(d,J＝8.5Hz,1H),7.19(s,1H),6.79(d,J＝8.7Hz,1H),6.60(t,J＝56.6Hz,1H),4.64(d,J＝4.7Hz,2H),4.03(dd,J＝11.2,3.5Hz,2H),3.87(d,J＝6.4Hz,2H),3.80–3.66(m,1H),3.44(td,J＝11.9,1.9Hz,2H),2.74(dt,J＝16.6,8.2Hz,1H),2.26(dt,J＝16.6,5.5Hz,1H),2.16–2.03(m,1H),1.94(s,1H),1.71(dt,J＝7.6,5.2Hz,4H),1.48(ddd,J＝25.0,12.4,4.5Hz,2H),0.97–0.82(m,1H),0.51(tdd,J＝16.5,7.5,3.9Hz,3H),0.40–0.30(m,1H).
实施例20：3-((4-(((S)-2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)甲基)四氢噻吩1,1-二氧化物的合成
Figure PCTCN2019121306-appb-000123
参照实施例3的步骤得到标题化合物36mg(MS(ESI)m/z:520.2[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.64(d,J＝8.3Hz,1H),7.49(d,J＝2.1Hz,1H),7.37(dd,J＝8.6,2.4Hz,1H),7.05(dd,J＝8.3,1.9Hz,1H),6.83(s,1H),6.72(d,J＝8.7Hz,1H),4.65–4.52(m,2H),4.13–4.03(m,2H),3.69–3.60(m,1H),3.28(ddd,J＝12.8,10.5,6.2Hz,2H),3.16–3.02(m,2H),3.01–2.92(m,1H),2.63–2.51(m,3H),2.49–2.38(m,1H),2.26–2.12(m,2H),1.99(dt,J＝16.3,6.1Hz,1H),1.73(ddt,J＝8.8,6.0,4.4Hz,1H),1.65–1.60(m,1H),1.22(t,J＝7.6Hz,3H),0.96–0.84(m,1H),0.57–0.41(m,3H),0.40–0.30(m,1H)。
实施例21：4-((4-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)甲基)二氢呋喃-2(3H)-酮的合成
Figure PCTCN2019121306-appb-000124
参照实施例3的步骤得到标题化合物14.3mg(MS(ESI)m/z:486.2[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.64(d,J＝8.3Hz,1H),7.49(dd,J＝6.3,2.3Hz,1H),7.39–7.31(m,1H),7.05(dd,J＝8.3,1.9Hz,1H),6.83(s,1H),6.72(d,J＝8.7Hz,1H),4.55(d,J＝3.6Hz,2H),4.53–4.48(m,1H),4.32(ddd,J＝9.5,4.0,2.1Hz,1H),4.07(qd,J＝9.3,5.7Hz,2H),3.64(dt,J＝8.5,5.6Hz,1H),3.05(ddq,J＝13.8,9.3,4.7Hz,1H),2.78(dd,J＝17.6,9.1Hz,1H),2.59(q,J＝7.7Hz,2H),2.50(ddd,J＝17.6,4.5,1.7Hz,1H),2.11–1.92(m,2H),1.78–1.66(m,1H),1.66–1.55(m,2H),1.22(t,J＝7.6Hz,3H),0.95–0.82(m,1H),0.56–0.42(m,3H),0.38–0.30(m,1H)。
实施例22：4-((4-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(羟甲基)苯氧基)甲基)-1-甲基吡咯烷-2-酮的合成
Figure PCTCN2019121306-appb-000125
参照实施例3的步骤得到标题化合物15.3mg(MS(ESI)m/z:499.3[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.64(d,J＝8.3Hz,1H),7.52(d,J＝1.3Hz,1H),7.34(d,J＝8.6Hz,1H),7.05(dd,J＝8.3,1.5Hz,1H),6.84(s,1H),6.72(d,J＝8.7Hz,1H),4.64–4.46(m,2H),4.09–3.91(m,2H),3.64(td,J＝8.5,4.2Hz,2H),3.31(ddd,J＝10.1,4.3,1.5Hz,1H),2.87(s,4H),2.69–2.45(m,5H),2.30(dd,J＝17.0,5.2Hz,1H),2.00(dt,J＝16.4,6.0Hz,1H),1.72(dt,J＝14.3,7.0Hz,1H),1.60(td,J＝11.9,6.1Hz,1H),1.22(t,J＝7.6Hz,3H),0.90(ddd,J＝16.1,8.2,5.2Hz,1H),0.56–0.40(m,3H),0.40–0.26(m,1H)。
实施例23：(5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(哒嗪-4-基甲氧基)苯基)甲醇的合成
Figure PCTCN2019121306-appb-000126
参照实施例3的步骤得到标题化合物15.9mg(MS(ESI)m/z:480.0[M+H] +)。
1H NMR(400MHz,CDCl 3)δ9.25(s,1H),9.21(dd,J＝5.3,1.0Hz,1H),7.63(d,J＝8.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.56(dd,J＝5.3,2.3Hz,1H),7.36(dd,J＝8.6,2.3Hz,1H),7.05(dd,J＝8.3,1.9Hz,1H),6.83(s,1H),6.78(d,J＝8.7Hz,1H),5.18(s,2H),4.71(s,2H),3.65(dt,J＝8.5,5.7Hz,1H),2.59(q,J＝7.5Hz,2H),2.55–2.51(m,1H),1.96(dt,J＝16.3,6.2Hz,1H),1.82–1.69(m,2H),1.60(td,J＝12.0,6.2Hz,1H),1.22(t,J＝7.6Hz,3H),0.96–0.84(m,1H),0.57–0.40(m,3H),0.40–0.28(m,1H)。
实施例24：(5-((2-环丙基-6-乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((5-甲基-1,3,4-恶二唑-2-基)甲氧基)苯基)甲醇的合成
Figure PCTCN2019121306-appb-000127
参照实施例3的步骤得到标题化合物6.5mg(MS(ESI)m/z:484.2[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.64(d,J＝8.3Hz,1H),7.53(d,J＝2.2Hz,1H),7.39(dd,J＝8.6,2.3Hz,1H),7.05(dd,J＝8.3,1.6Hz,1H),6.93(d,J＝8.7Hz,1H),6.83(s,1H),5.28(s,2H),4.62(s,2H),3.64(dt,J＝8.5,5.6Hz,1H),2.63–2.58(m,2H),2.56(s,3H),2.56–2.50(m,1H),2.35(s,1H),1.97(dt,J＝16.3,6.1Hz,1H),1.77–1.68(m,1H),1.64–1.56(m,1H),1.22(t,J＝7.6Hz,3H),0.95–0.85(m,1H),0.55–0.41(m,3H),0.34(dd,J＝10.3,5.5Hz,1H).
实施例25：(5-((2-环丙基-6-(吡咯烷-1-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(((四氢-2H-吡喃-4-基)甲氧基)苯基)甲醇的合成
Figure PCTCN2019121306-appb-000128
参照实施例18的步骤得到标题化合物7.0mg(MS(ESI)m/z:527.1[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.57(d,J＝8.8Hz,1H),7.43(d,J＝2.2Hz,1H),7.37(dd,J＝8.6,2.3Hz,1H),6.78(d,J＝8.6Hz,1H),6.49(dd,J＝8.8,2.7Hz,1H),6.16(d,J＝2.6Hz,1H),4.68–4.57(m,2H),4.04(dd,J＝11.2,3.6Hz,2H),3.88(d,J＝6.4Hz,2H),3.66(dd,J＝14.3,6.5Hz,1H),3.51–3.42(m,2H),3.28(dd,J＝9.7,6.5Hz,4H),2.40(dt,J＝15.4,6.3Hz,1H),2.11(dd,J＝9.6,5.8Hz,1H),2.02(dd,J＝7.9,5.1Hz,4H),1.85(ddd,J＝25.7,13.1,6.5Hz,2H),1.78–1.67(m,3H),1.56–1.43(m,3H),0.93–0.89(m,1H),0.60–0.36(m,4H)。
实施例26：1-(2-环丙基-1-((3-(羟甲基)-4-((四氢-2H-吡喃-4-基)甲氧基)苯基)磺酰基)-1,2,3,4-四氢喹啉-6-基)吡咯烷-2-酮的合成
Figure PCTCN2019121306-appb-000129
参照实施例18的步骤得到标题化合物7.0mg(MS(ESI)m/z:541.2[M+H] +)。
1H NMR(400MHz,CDCl3)δ7.77(d,J＝8.8Hz,1H),7.46–7.39(m,2H),7.32(d,J＝1.8Hz,1H),7.19(dd,J＝8.8,2.4Hz,1H),6.77(d,J＝8.7Hz,1H),4.59(dd,J＝40.7,14.4Hz,2H),4.01(dd,J＝11.3,3.6Hz,2H),3.95–3.76(m,4H),3.69(dd,J＝14.0,5.9Hz,1H),3.44(t,J＝11.0Hz,2H),2.74(s,1H),2.60(t,J＝8.1Hz,2H),2.56–2.44(m,1H),2.16(dt,J＝16.9,5.6Hz,2H),2.12–2.04(m,1H),1.89(dt,J＝12.8,6.2Hz,2H),1.78–1.68(m,3H),1.61–1.53(m,1H),1.47(ddd,J＝25.0,12.4,4.5Hz,2H),0.94–0.85(m,1H),0.57–0.43(m,3H),0.42–0.34(m,1H)。
实施例27：(5-((2-环丙基-6-(恶唑-5-基)-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(((四氢-2H-吡喃-4-基)甲氧基)苯基)甲醇的合成
Figure PCTCN2019121306-appb-000130
参照实施例14的步骤得到标题化合物20.5mg(MS(ESI)m/z:525.1[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.86(d,J＝8.6Hz,1H),7.61(d,J＝2.3Hz,1H),7.49(dd,J＝8.6,2.1Hz,1H),7.42(dd,J＝8.6,2.4Hz,1H),7.32(d,J＝1.8Hz,1H),7.30(s,1H),6.78(d,J＝8.7Hz,1H),4.63(s,2H),4.01(dd,J＝11.4,3.4Hz,2H),3.86(d,J＝6.3Hz,2H),3.73(dt,J＝8.8,5.2Hz,1H),3.43(td,J＝11.8,1.8Hz,2H),2.79–2.66(m,1H),2.29–2.17(m,1H),2.13–1.93(m,2H),1.71(dd,J＝13.2,4.3Hz,4H),1.47(ddd,J＝16.7,12.4,4.8Hz,2H),0.94–0.86(m,1H),0.60–0.44(m,3H),0.36(td,J＝6.6,2.3Hz,1H)。
实施例28：(5-((2-环丙基-6-吗啉代-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-((四氢-2H-吡喃-4-基)甲氧基)苯基)甲醇的合成
Figure PCTCN2019121306-appb-000131
参照实施例18的步骤得到标题化合物3.2mg(MS(ESI)m/z:543.1[M+H] +)。
1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.8Hz,1H),7.48(d,J＝2.4Hz,1H),7.39(dd,J＝8.4,2.4Hz,1H),6.82(dd,J＝8.8,2.8Hz,1H),6.78(d,J＝8.8Hz,1H),6.54(d,J＝2.8Hz,1H),4.63(s,2H),4.04(dd,J＝11.4,3.6Hz,2H),3.95-3.80(m,6H),3.69-3.62(m,1H),3.52-3.40(m,2H),3.20–3.09(m,4H),2.56–2.46(m,1H),2.16–2.05(m,1H),2.00–1.88(m,2H),1.79-1.69(m,3H),1.60–1.44(m,3H),0.93–0.88(m,1H),0.57–0.41(m,3H),0.40-0.33(m,1H)。
实施例29：(5-((2,6-二乙基-3,4-二氢喹啉-1(2H)-基)磺酰基)-2-(2-(吡嗪-2-基)乙氧基)苯基)甲醇的合成
Figure PCTCN2019121306-appb-000132
参照实施例1的步骤得到标题化合物36mg(MS(ESI)m/z:481.9[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.56(d,J＝0.9Hz,1H),8.53–8.49(m,1H),8.47(d,J＝2.5Hz,1H),7.62(d,J＝8.3Hz,1H),7.44(d,J＝2.1Hz,1H),7.34(dd,J＝8.6,2.3Hz,1H),7.03(dd,J＝8.3,1.5Hz,1H),6.79(s,1H),6.76(s,1H),4.54–4.44(m,2H),4.40(t,J＝5.9Hz,2H),4.18–4.09(m,1H),3.36(s,1H),3.31(t,J＝5.9Hz,2H),2.58(q,J＝7.6Hz,2H),2.42–2.32(m,1H),1.86(dt,J＝16.0,6.4Hz,1H),1.75–1.65(m,1H),1.58(td,J＝14.4,7.4Hz,1H),1.49–1.33(m,2H),1.21(t,J＝7.6Hz,3H),0.92(t,J＝7.4Hz,3H)。
实施例30：N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-(2-甲基-1-(((反式-4-(三氟甲基)环己 基)甲基)氨基)丙基)苯甲酰胺的合成
Figure PCTCN2019121306-appb-000133
30.1 4-(1-羟基-2-甲基丙基)苯甲酸甲酯
向150mL圆底烧瓶中投入4-甲酰基苯甲酸甲酯(3.0g)和四氢呋喃(60mL)，混合物在0℃搅拌。向其中加入异丙基溴化镁(18.3mL)，反应混合物在0℃搅拌1小时。将反应液逐渐升至室温搅拌3小时。取样，送检LC-MS，检测到产物分子量209.0[M+1] +。将反应用饱和氯化铵(20mL)淬灭，将反应液减压旋干，加入水(50mL)，用乙酸乙酯(50mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至10:3洗脱)得4-(1-羟基-2-甲基丙基)苯甲酸甲酯1.4g(MS(ESI)m/z 209.0[M+1] +)。
30.2 4-异丁酰基苯甲酸甲酯
将4-(1-羟基-2-甲基丙基)苯甲酸甲酯(445mg)溶于二氯甲烷(10mL)中，向其中加入氯铬酸吡啶盐(507mg)，所得混合物液在室温搅拌10小时。取样，送检LC-MS，检测到产物分子量207.0[M+1] +。将反应用硅藻土过滤，滤液减压旋干，粗品硅胶柱层析得4-异丁酰基苯甲酸甲酯356mg(MS(ESI)m/z 207.0[M+1] +)。
30.3 4-异丁酰基苯甲酸
将4-异丁酰基苯甲酸甲酯(350mg)溶于甲醇(2mL)和水(1mL)中，向其中加入一水合氢氧化锂(214mg)，所得混合物于室温搅拌3小时。取样，送检LC-MS，检测到产物分子量193.0[M+1] +。将反应液减压旋干，加入水(10mL)，用1N盐酸调节PH至3，用乙酸乙酯(20mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压旋干，得4-异丁酰基苯甲酸330mg。
30.4(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-异丁酰基苯甲酰胺
将4-异丁酰基苯甲酸(52mg)溶于N,N-二甲基甲酰胺(2mL)中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(150mg)和1-羟基苯并三唑(84.5mg)，所得混合物室温搅拌30分钟，加入(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(119.3mg)，搅拌5分钟，加入N-甲基吗啡啉(158mg)，所得混合物室温搅拌20.5小时。取样，送检LC-MS，检测到产物分子量403.9[M+1] +。将反应液用乙酸乙酯(100mL)稀释，用饱和食盐水(30mLx3)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析得标题化合物75mg(MS(ESI)m/z 403.8[M+1] +)。
30.5 N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)苯甲酰胺
向10mL圆底烧瓶中投入(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-4-异丁酰基苯甲酰胺(25mg)，反式-4-(三氟甲基)环己基)甲氨(13.5mg)和异丙醇(2mL),向其中加入钛酸异丙酯(52.9mg)，所得混合物回流搅拌4小时，后冷却至室温。向其中加入硼氢化钠(2.4mg)，室温搅拌1小时。取样，送检LC-MS，检测到产物分子量568.9[M+1] +。将反应用水(0.1mL)淬灭，将反应液用硅藻土过滤，滤液减压旋干，粗品送pre-HPLC制备，得标题化合物9mg(MS(ESI)m/z 568.9[M+1] +)。
1H NMR(400MHz,CDCl 3):δ7.89(d,J＝8.4Hz,2H),7.80(d,J＝8.0Hz,2H),7.61(d,J＝ 8.4Hz,2H),7.37(d,J＝8.0Hz,2H),7.13(d,J＝6.4Hz,1H),5.36-5.27(m,1H),4.12-3.97(m,2H),3.37(d,J＝6.4Hz,1H),3.11(q,J＝7.6Hz,2H),2.34-2.26(m,1H),2.19-2.12(m,1H),2.01-1.91(m,4H),1.89-1.80(m,2H),1.43-1.24(m,7H),0.97(d,J＝6.8Hz,3H),0.93-0.83(m,2H),0.77(d,J＝6.8Hz,3H)。
实施例31：N-((5-(乙基磺酰基)吡啶-2-基)甲基)-4-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)苯甲酰胺的合成
Figure PCTCN2019121306-appb-000134
参照实施例30中步骤30.4-30.5的合成方式制得标题化合物22mg(MS(ESI)m/z539.8[M+1] +)。
1H NMR(400MHz,CDCl 3):δ9.04(s,1H),8.15(d,J＝8.0Hz,1H),7.82(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,1H),7.48(s,1H),7.36(d,J＝8.0Hz,2H),4.87(d,J＝5.2Hz,2H),3.35(d,J＝6.8Hz,1H),3.16(q,J＝7.2Hz,2H),2.28(dd,J＝11.6,6.0Hz,1H),2.15(dd,J＝11.6,7.2Hz,1H),1.98-187(m,4H),1.87-1.75(m,2H),1.40-1.23(m,7H),0.95(d,J＝6.8Hz,3H),0.92-0.82(m,2H),0.75(d,J＝6.8Hz,3H).。
实施例32：6-(1-乙基-2-((反式-4-(三氟甲基)环己基)甲基)肼基)-N-((5-(乙基磺酰基)吡啶-2-基)甲基)烟酰胺的合成
Figure PCTCN2019121306-appb-000135
32.1 6-肼基烟酸叔丁酯
向250mL圆底烧瓶中投入6-氯烟酸叔丁酯(3.0g)和叔丁醇(60mL)，混合物回流搅拌至物料完全溶解。向其中加入水合肼(7.05g)，继续加热搅拌5小时。取样，送检LC-MS，检测到产物峰210.0[M+1] +。将反应液减压旋干，用甲基叔丁基醚(200mL)稀释，水(60mLx3)洗，饱和食盐水(60mL)洗。有机相无水硫酸钠干燥，过滤，滤液减压旋干，得6-肼基烟酸叔丁酯2.6g。
32.2 6-(2-((反式-4-(三氟甲基)环己烷羰基)肼基)烟酸叔丁酯
将反式-4-(三氟甲基)环己烷甲酸(2.25g)溶于N,N-二甲基甲酰胺(50mL)中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(2.75g)和1-羟基苯并三唑(1.55g),所得混合物室温搅 拌30分钟，加入6-肼基烟酸叔丁酯(2.0g)，搅拌5分钟，加入N-甲基吗啡啉(2.90g)，所得混合物室温搅拌22.5小时。取样，送检LC-MS，检测到产物分子量387.9[M+1] +。将反应液用乙酸乙酯(200mL)稀释，用饱和食盐水(50mLx3)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析得标题化合物2.6g(MS(ESI)m/z 388.0[M+1] +)。
32.3 6-(2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸叔丁酯
向50mL圆底烧瓶中投入6-(2-((反式-4-(三氟甲基)环己烷羰基)肼基)烟酸叔丁酯(200mg)和四氢呋喃(15mL),混合物在0℃搅拌。向其中加入1M硼烷四氢呋喃溶液(2mL)，所得反应液于室温搅拌24小时。取样，送检LC-MS，检测到产物分子量373.9[M+1] +。将反应液用甲醇(15mL)淬灭，所得反应液减压旋干，硅胶柱层析得标题化合物80mg(收率41.5％，MS(ESI)m/z374.0[M+1] +)。
32.4 6-(2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸叔丁酯
将6-(2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸叔丁酯(66mg)溶于二氯甲烷(1.5mL)中，向其中加入二碳酸二叔丁酯(38.6mg)，所得反应混合液室温搅拌4小时。取样，送检LC-MS，检测到产物分子量474.0[M+1] +。将反应液减压旋干，粗品经硅胶柱层析得标题化合物80mg。
32.5 6-(1-乙基-2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸叔丁酯
将6-(2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸叔丁酯(200mg)溶于N,N-二甲基甲酰胺(2.5mL)中，置于冰浴中冷却，向其中加入钠氢(17mg)搅拌30分钟。滴入碘乙烷(66mg),所得混合液逐渐升至室温搅拌4小时。取样，送检LC-MS，检测到产物分子量502.0[M+1] +。将反应液用乙酸乙酯(100mL)稀释，用饱和食盐水(30mLx3)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析得标题化合物200mg(MS(ESI)m/z502.1[M+1] +)。
32.6 6-(1-乙基-2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸
将6-(1-乙基-2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸叔丁酯200mg)溶于乙醇(10mL)和水(3mL)中，向其中加入氢氧化钠(48mg),所得混合液加热搅拌24小时。取样，送检LC-MS，检测到产物分子量445.9[M+1] +。将反应液用水(30mL)稀释，减压旋去乙醇，用1N盐酸调节pH＝3，水层用乙酸乙酯(50mLx3)萃取，合并有机相，饱和食盐水(50mL)洗。有机相用无水硫酸钠干燥，过滤，滤液减压旋干，得标题化合物174mg(MS(ESI)m/z 445.9[M+1] +)。
32.7 6-(1-乙基-2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)-N-((5-(乙基磺酰基)吡啶-2-基)甲基)烟酰胺
将6-(1-乙基-2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)烟酸(60mg)溶于N,N-二甲基甲酰胺(2mL)中，加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(56.5mg),搅拌5分钟，加入5-(乙基磺酰基)吡啶-2-基)甲胺(27mg)，搅拌5分钟，加入N,N-二异丙基乙胺(34.9mg),所得反应液室温搅拌4小时。取样，送检LC-MS，检测到产物分子量627.8[M+1] +。将反应液用乙酸乙酯(80mL)稀释，用水(30mLx3)洗，饱和食盐水(30mL)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，得标题化合物100mg(MS(ESI)m/z 627.8[M+1] +)。
32.8 6-(1-乙基-2-((反式-4-(三氟甲基)环己基)甲基)肼基)-N-((5-(乙基磺酰基)吡啶-2-基)甲基)烟酰胺
向25mL圆底烧瓶中投入6-(1-乙基-2-(叔丁氧羰基)-2-((反式-4-(三氟甲基)环己基)甲基)肼基)-N-((5-(乙基磺酰基)吡啶-2-基)甲基)烟酰胺(51mg),二氯甲烷(5mL)溶解，向其中加入三氟乙酸(463.5mg),所得反应液室温搅拌5小时。取样，送检LC-MS，检测到产物分子量527.9[M+1] +。将反应液用二氯甲烷(60mL)稀释，用饱和碳酸氢钠(10mLx3)洗，饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，送pre-HPLC制备，得标题化合物9.19mg(MS(ESI)m/z 527.8[M+1] +。
1H NMR(400MHz,MeOD):δ9.03(d,J＝1.6Hz,1H),8.58(s,1H),8.48(d,J＝9.2Hz,1H),8.38(d,J＝6.4Hz,1H),7.79(d,J＝8.2Hz,1H),7.39(d,J＝8.0Hz,1H),4.85(s,2H),3.93(q,J＝6.8Hz,2H),3.33-3.30(m,2H),2.87(d,J＝6.4Hz,2H),2.22-2.10(m,1H),2.09-1.95(m,4H),1.68-1.55(m,1H),1.43-1.32(m,5H),1.28(t,J＝7.2Hz,3H),1.21-1.07(m,2H).。
实施例33：N-((5-(乙基磺酰基)吡啶-2-基)甲基)-6-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)烟酰胺的合成
Figure PCTCN2019121306-appb-000136
33.1 6-二溴甲基烟酸甲酯
向100mL单口瓶中加入6-甲基烟酸甲酯(3.0g)，N-溴代丁二酰亚胺(7.42g)和偶氮二异丁腈(391mg)，混合物用二氯乙烷(45mL)溶解。所得反应液在氮气保护下回流搅拌反应8小时。取样，送检LC-MS，检测到产物峰309.7[M+1] +。将反应液用硅藻土过滤，滤液减压旋干，硅胶柱层析得6-二溴甲基烟酸甲酯2.1g。
33.2 6-甲酰基烟酸甲酯
向50mL圆底烧瓶中投入6-二溴甲基烟酸甲酯(1.88g)和乙腈(8mL),于室温搅拌，向其中加入硝酸银(4.14g)的水(8mL)溶液，所得混合物液于50℃加热搅拌24小时。取样，送检LC-MS，检测到产物峰165.9[M+1] +。将反应液冷却到室温，硅藻土过滤，滤液减压旋干，硅胶柱层析得6-甲酰基烟酸甲酯527mg。
33.3 N-((5-(乙基磺酰基)吡啶-2-基)甲基)-6-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)烟酰胺单甲酸盐
其余合成步骤参照实施例30所述的方式制得标题化合物3.5mg。
(MS(ESI)m/z 541.0[M+1] +。
1H NMR(400MHz,CDCl 3):δ9.18(s,1H),9.06(d,J＝2.0Hz,1H),8.29(d,J＝7.2Hz,1H),8.20(dd,J＝8.0,2.0Hz,1H),7.97(s,1H),7.60(d,J＝8.0Hz,1H),7.45(d,J＝7.6Hz,1H),4.90(d,J＝4.0Hz,2H),4.72(brs,3H),4.11(s,1H),3.17(q,J＝7.2Hz,2H),2.91(d,J＝7.2Hz,1H),2.72-2.54(m,1H),2.41-2.27(m,1H),2.14-2.03(m,1H),2.00-1.75(m,5H),1.33(t,J＝7.2Hz,3H),1.30-1.22(m,2H),1.02(d,J＝3.6Hz,3H),0.95-0.85(m,2H),0.82(d,J＝3.6Hz,3H).
实施例34：N-((5-(乙基磺酰基)吡啶-2-基)甲基)-3-氟-4-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)苯甲酰胺的合成
Figure PCTCN2019121306-appb-000137
Figure PCTCN2019121306-appb-000138
34.1 4-二溴甲基-3-氟苯甲酸
向100mL单口瓶中加入4-甲基-3-氟苯甲酸(3.0g)，N-溴代丁二酰亚胺(8.32g)和过氧化苯甲酰(236mg),混合物用二氯乙烷(40mL)溶解。所得反应液在氮气保护下回流搅拌反应12小时。取样，送检LC-MS，检测到产物峰310.8[M+1] +。将反应液用硅藻土过滤，滤液减压旋干得4-二溴甲基-3-氟苯甲酸6.04g。
34.2 3-氟-4-甲酰苯甲酸
向50mL圆底烧瓶中投入4-二溴甲基-3-氟苯甲酸(6.04g)和乙醇(50mL),于50℃搅拌，向其中加入硝酸银(6.04g)的水(10mL)溶液，所得混合物液于50℃加热搅拌5小时。取样，送检LC-MS，检测到产物峰166.9[M-1] -。将反应液冷却到室温，硅藻土过滤，滤液减压旋干，用水(50mL)稀释，混合液用1N的盐酸调节PH至3，用乙酸乙酯(60mLx3)萃取，合并有机相,无水硫酸钠干燥，过滤，滤液减压旋干得3-氟-4-甲酰苯甲酸5.0g(收率>100％,MS(ESI)m/z 166.9[M-1] -)。
34.3 3-氟-4-甲酰苯甲酸甲酯
向50mL圆底烧瓶中投入3-氟-4-甲酰苯甲酸(2.5g),碳酸氢钾(1.79g)和N,N-二甲基甲酰胺(20mL)，向其中加入碘甲烷(3.17g),所得反应混合物室温搅拌24小时。取样，送检LC-MS，检测到产物分子量183.0[M+1] +。将反应液用乙酸乙酯(150mL)稀释，用饱和食盐水(40mLx4)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析得3-氟-4-甲酰苯甲酸甲酯600mg。
34.4 N-((5-(乙基磺酰基)吡啶-2-基)甲基)-3-氟-4-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)苯甲酰胺
其余合成步骤参照实施例30所述的方式制得标题化合物15.63mg(MS(ESI)m/z557.9[M+1] +)。
1H NMR(400MHz,CDCl 3):δ9.05(d,J＝2.0Hz,1H),8.17(dd,J＝8.0,2.4Hz,1H),7.61(d,J＝8.0Hz,1H),7.58-7.52(m,2H),7.49-7.42(m,2H),4.87(d,J＝5.2Hz,2H),3.70(d,J＝7.2Hz,1H),3.16(q,J＝7.2Hz,2H),2.32-2.24(m,1H),2.20-2.12(m,1H),2.00-1.87(m,5H),1.87-1.79(m,1H),1.40-1.22(m,7H),0.99(d,J＝6.8Hz,3H),0.94-0.84(m,2H),0.80(d,J＝6.8Hz,3H)。
实施例35：N-((5-(乙基磺酰基)吡啶-2-基)甲基)-N-甲基-6-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)烟酰胺的合成
Figure PCTCN2019121306-appb-000139
35.1((5-(乙基磺酰基)吡啶-2-基)甲基)氨基甲酸叔丁酯
向100mL单口瓶中加入(5-(乙基磺酰基)吡啶-2-基)甲胺盐酸盐(1.57g)，二氯甲烷(15mL)和三乙胺(1.726g),向所得反应液中加入二碳酸二叔丁酯(1.24g),混合液室温搅拌5小时。取样，送检LC-MS，检测到产物峰300.9[M+1] +。将反应液旋干，硅胶柱层析得((5-(乙基磺酰基)吡啶-2-基)甲基)氨基甲酸叔丁酯1.24g(MS(ESI)m/z 300.9[M+1] +)。
35.2 ((5-(乙基磺酰基)吡啶-2-基)甲基)(甲基)氨基甲酸叔丁酯
向25mL圆底烧瓶中投入((5-(乙基磺酰基)吡啶-2-基)甲基)氨基甲酸叔丁酯(400mg)和N,N-二甲基甲酰胺(4mL)，于冰浴中冷却，向其中加入钠氢(59mg)，所得混合物液于0℃搅拌0.5小时。向其中加入硫酸二甲酯(252.2mg),反应液逐渐升至室温，搅拌3小时。取样，送检LC-MS，检测到产物峰314.9[M+1] +。将反应液用饱和氯化铵溶液(0.1mL)萃取，将反应液用乙酸乙酯(150mL)稀释，饱和氯化钠(40mLx3)洗，有机相无水硫酸钠干燥，过滤，滤液减压旋干，粗品硅胶柱层析(PE:EA＝10:0至5:1洗脱)得无色油状液体((5-(乙基磺酰基)吡啶-2-基)甲基)(甲基)氨基甲酸叔丁酯179mg(MS(ESI)m/z 314.9[M+1] +)。
35.3 1-(5-(乙基磺酰基)吡啶-2-基)N-甲基)甲氨盐酸盐
向25mL圆底烧瓶中投入((5-(乙基磺酰基)吡啶-2-基)甲基)(甲基)氨基甲酸叔丁酯(179mg),溶于二氯甲烷(5mL)中，向其中加入盐酸二氧六环溶液(4M,2.8mL)，所得混合物室温搅拌4小时。取样，送检LC-MS，检测到产物分子量214.9[M+1] +。将反应液减压旋干,得1-(5-(乙基磺酰基)吡啶-2-基)N-甲基)甲氨盐酸盐164mg。
35.4 N-((5-(乙基磺酰基)吡啶-2-基)甲基)-N-甲基-6-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)烟酰胺
其余合成步骤以实施例33中的中间体为原料参照实施例30中步骤30.4-30.5的合成方式制得标题化合物42.1mg(MS(ESI)m/z 554.9[M+1] +)。
1H NMR(400MHz,CDCl 3):δ9.06(s,1H),8.78-8.62(m,1H),8.19(d,J＝7.6Hz,1H),7.79(dd,J＝8.0,2.0Hz,1H),7.65-7.40(m,1H),7.39-7.29(m,1H),5.05-4.66(m,2H),3.24-3.05(m,1H),3.24-3.07(m,5H),2.33-2.20(m,1H),2.21-2.11(m,1H),2.00-1.90(m,5H),1.86-1.81(m,1H),1.46-1.15(m,7H),0.95(d,J＝5.6Hz,3H),0.91-0.81(m,2H),0.78(d,J＝6.4Hz,3H)。
实施例36：N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-6-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)烟酰胺的合成
Figure PCTCN2019121306-appb-000140
参照实施例33的合成方式制得标题化合物12.5mg(MS(ESI)m/z 570.3[M+1] +)。
1H NMR(400MHz,CDCl 3):δ9.01(s,1H),8.09(dd,J＝8.0,2.4Hz,1H),7.87(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),7.38(d,J＝8.0Hz,1H),7.24(d,J＝7.2Hz,1H),5.37-5.29(m,1H),4.13-3.97(m,2H),3.45(dd,J＝6.4,2.4Hz,1H),3.10(q,J＝7.2Hz,2H),2.31-2.25(m,1H),2.17-2.10(m,1H),1.99-1.91(m,4H),1.90-1.80(m,2H),1.41-1.20(m,7H),0.96(d,J＝6.8Hz,3H),0.91-0.82(m,2H),0.78(d,J＝6.8Hz,3H)。
实施例37：4-(1-((4-氯苯基)氨基)-2-甲基丙基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟苯甲酰胺的合成
Figure PCTCN2019121306-appb-000141
参照实施例34的合成方式制得标题化合物5.66mg(MS(ESI)m/z 547.2[M+1] +)。
1H NMR(400MHz,CDCl 3):δ7.87(d,J＝8.4Hz,2H),7.63(d,J＝8.0Hz,1H),7.60(d,J＝8.4Hz,2H),7.56(dd,J＝10.8,1.6Hz,1H),7.49(t,J＝7.6Hz,1H),7.31-7.27(m,2H),7.27-7.24(m,1H),7.21(d,J＝8.4Hz,2H),5.34-5.26(m,1H),4.14-3.95(m,2H),3.75(d,J＝7.2Hz,1H),3.60(d,J＝13.4Hz,1H),3.47(d,J＝13.4Hz,1H),3.11(q,J＝7.2Hz,2H),1.99-1.90(m,2H),1.29(t,J＝7.2Hz,3H),1.01(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,3H)。
实施例38：N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(2-甲基-1-(((反式-4-(三氟甲基)环己基)甲基)氨基)丙基)苯甲酰胺的合成
Figure PCTCN2019121306-appb-000142
参照实施例34的合成方式制得标题化合物9.77mg(MS(ESI)m/z 587.3[M+1] +)。
1H NMR(400MHz,CDCl 3):δ7.86(d,J＝8.4Hz,2H),7.62–7.56(t,J＝6.4Hz,3H),7.52(dd,J＝10.4,1.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.20(d,J＝7.2Hz,1H),5.30–5.25(m,1H),4.09–3.96(m,2H),3.70(d,J＝7.2Hz,1H),3.09(q,J＝7.2Hz,2H),2.30–2.22(m,1H),2.17–2.11(m, 1H),1.96–1.88(m,5H),1.84–1.80(m,1H),1.39–1.22(m,7H),0.98(d,J＝6.8Hz,3H),0.94–0.83(m,2H),0.79(d,J＝6.8Hz,3H).
实施例39：4-(1-((4-氯苯基)氨基)-2-甲基丙基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-甲氧基苯甲酰胺的合成
Figure PCTCN2019121306-appb-000143
以4-甲基-3-甲氧基苯甲酸为原料参照实施例34的合成方式制得标题化合物19.7mg(MS(ESI)m/z 559.0[M+1] +)。
1H NMR(400MHz,CDCl 3):δ7.88(d,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,2H),7.44(s,1H),7.40-7.33(m,2H),7.27(d,J＝8.8Hz,2H),7.24-7.18(m,3H),5.34-5.26(m,1H),4.11-3.96(m,2H),3.85(s,3H),3.72(d,J＝7.2Hz,1H),3.57(d,J＝13.4Hz,1H),3.42(d,J＝13.4Hz,1H),3.11(q,J＝7.2Hz,2H),2.06-1.92(m,2H),1.29(t,J＝7.2Hz,3H),1.00(d,J＝6.8Hz,3H),0.76(d,J＝6.8Hz,3H)。
实施例40：6-(1-乙基-2-(((1R，4R)-4-(三氟甲基)环己基)甲基)肼基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)烟酰胺的合成
Figure PCTCN2019121306-appb-000144
40.1叔丁基2-乙基-2-(5-((((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)氨基甲酰基)吡啶-2-基)-1-(((1R，4R)-4-(三氟甲基)环己基)甲基)肼甲酸
将6-(2-(叔丁氧基羰基)-1-乙基-2-((((1R，4R)-4-(三氟甲基)环己基)甲基)肼基)烟酸(30mg)溶于N,N-二甲基甲酰胺(1.5mL)中，加入1-(3-二甲氨基丙基)-3-乙基碳二 亚胺盐酸盐(19.4mg)和1-羟基苯并三唑(11.0mg),所得混合物室温搅拌30分钟，加入(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(15.4g)，搅拌5分钟，加入N-甲基吗啡啉(20.4mg)，所得混合物室温搅拌23.5小时。取样，送检LC-MS，检测到产物分子量656.9[M+1] +。将反应液用乙酸乙酯(80mL)稀释，用水(30mLx2)洗，饱和食盐水(30mL)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，得淡黄色油状液体65mg(MS(ESI)m/z 656.9[M+1] +)。
40.2 6-(1-乙基-2-(((1R，4R)-4-(三氟甲基)环己基)甲基)肼基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)烟酰胺
向10mL圆底烧瓶中投入叔丁基2-乙基-2-(5-((((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)氨基甲酰基)吡啶-2-基)-1-(((1R，4R)-4-(三氟甲基)环己基)甲基)肼甲酸(65mg),二氯甲烷(3mL)溶解，向其中加入三氟乙酸(565mg),所得反应液室温搅拌5小时。取样，送检LC-MS，检测到产物分子量556.9[M+1] +。将反应液用二氯甲烷(80mL)稀释，用饱和碳酸氢钠(30mLx2)洗，饱和食盐水(30mL)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，送pre.HPLC制备，得白色固体5mg(MS(ESI)m/z 556.9[M+1] +。
1H NMR(400MHz,CDCl 3):δ8.63(s,1H),7.89(d,J＝2.4Hz,1H),7.86(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),6.96(d,J＝6.8Hz,1H),6.90(d,J＝9.2Hz,1H),5.29(dd,J＝9.2,6.4Hz,1H),4.08-3.95(m,2H),3.73(q,J＝7.2Hz,2H),3.09(q,J＝7.2Hz,2H),2.73(d,J＝6.4Hz,2H),2.08-1.89(m,6H),1.50-1.41(m,1H),1.38-1.30(m,2H),1.28(t,J＝7.2Hz,4H),1.19(t,J＝7.2Hz,3H),1.09-0.98(m,2H)。
实施例41：N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(1-(((4-氟苄基)氨基)-2-甲基丙基)苯甲酰胺的合成
Figure PCTCN2019121306-appb-000145
向10mL圆底烧瓶中投入(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-异丁酰基苯甲酰胺(45mg)，(4-氟苯基)甲胺(16.0mg)和异丙醇(2.5mL),向其中加入钛酸异丙酯(91.1mg)，所得混合物回流搅拌4小时，后冷却至室温。向其中加入硼氢化钠(4.0mg)，室温搅拌1小时。取样，送检LC-MS，检测到产物分子量531.0[M+1] +。将反应用水(0.2mL)淬灭，将反应液用硅藻土过滤，滤液减压旋干，粗品送pre.HPLC制备，得白色固体20.55mg(MS(ESI)m/z 531.0[M+1] +。
1H NMR(400MHz,CDCl 3):δ7.86(d,J＝8.0Hz,2H),7.63(d,J＝8.0Hz,1H),7.59(d,J＝8.0Hz,2H),7.56(d,J＝10.8Hz,1H),7.51(t,J＝7.6Hz,1H),7.27-7.20(m,3H),7.00(t,J＝8.8Hz,2H),5.32-5.26(m,1H),4.11-3.95(m,2H),3.76(d,J＝7.2Hz,1H),3.59(d,J＝13.2Hz,1H),3.46(d,J＝13.2Hz,1H),3.11(q,J＝7.2Hz,2H),1.99-1.92(m,1H),1.29(t,J＝7.2Hz,3H),1.01(d,J＝6.8Hz,3H),0.80(d,J＝6.8Hz,3H)。
实施例42：6-((S)-1-(4-氯苯甲酰胺基)-2-甲基丙基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-5-氟烟酰胺
Figure PCTCN2019121306-appb-000146
42.1 2,6-二氯-5-氟烟酸甲酯
向100mL单口瓶中加入2,6-二氯-5-氟烟酸(5.0g)和二氯甲烷(20mL)，滴入N,N-二甲基甲酰胺(1滴)，所得混合物室温搅拌1小时。减压旋干，再用二氯甲烷(10mL)稀释。向上述溶液中滴入二氯甲烷(20mL)与甲醇(20mL)的混合物液，所得混合液于室温搅拌1小时。将反应液减压旋干，硅胶柱层析(PE:EA＝10:0至10:1洗脱)得黄色油状液体5.516g(MS(ESI)m/z 223.9,225.9[M+1] +)。
42.2 2-氯-5-氟-6-甲基烟酸甲酯
向100mL圆底烧瓶中投入2,6-二氯-5-氟烟酸甲酯(2.8g),四三苯基膦钯(1.45g)，碳酸钾(4.68g)和二氧六环(32mL),向其中加入三甲基环三硼氧烷(3.1mL),所得混合物于100℃加热搅拌12小时。将反应液冷却到室温，硅藻土过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至10:1洗脱)得无色油状液体1.875g(MS(ESI)m/z 204.0[M+1] +)。
42.3 5-氟-6-甲基烟酸甲酯
向50mL圆底烧瓶中投入2-氯-5-氟-6-甲基烟酸甲酯(1.63g),氢氧化钯碳(0.33g)，醋酸钠(2.63g)和乙酸乙酯(20mL)，所得混合物液于氢气氛围下室温搅拌6小时。将反应液用硅藻土过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至10:1洗脱)得白色固体653mg(MS(ESI)m/z 170.1[M+1] +)。
42.4 6-(二溴甲基)-5-氟烟酸甲酯
向50mL圆底烧瓶中投入5-氟-6-甲基烟酸甲酯(650mg),二氯乙烷(12mL),N-溴代琥珀酰亚胺(1.45g)和偶氮二异丁腈(76mg)，所得混合物在氮气保护下回流搅拌2天。将反应液用硅藻土过滤，滤液减压旋干，粗品硅胶柱层析(PE:EA＝10:0至5:1洗脱)得无色油状液体958mg(MS(ESI)m/z 325.8,327.8，329.7[M+1] +)。
42.5 5-氟-6-甲酰基烟酸甲酯
向25mL圆底烧瓶中投入6-(二溴甲基)-5-氟烟酸甲酯(500mg)和乙腈(3mL)，于室温搅拌，向其中加入硝酸银(1.04g)的水(3mL)溶液，所得混合物液于50℃加热搅拌2 天。将反应液冷却到室温，硅藻土过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至3:1洗脱)得黄色固体135mg(MS(ESI)m/z 184.0[M+1] +)。
42.6 (S，E)-6-((((叔丁基亚磺酰基)亚氨基)亚氨基)甲基)-5-氟烟酸甲酯
将5-氟-6-甲酰基烟酸甲酯(135mg)和(S)-2-甲基丙烷-2-亚磺酰胺(121.1mg)溶于二氯乙烷(3mL)，向其中加入硫酸铜(352mg)，所得混合物于60℃加热搅拌24消失。将反应液冷却到室温，硅藻土过滤，滤液减压旋干,得黄色油状液体200mg，粗品直接投入下一步。
42.7 6-((S)-1-((S)-1,1-二甲基乙基亚磺酰胺基)-2-甲基丙基)-5-氟烟酸甲酯
向25mL圆底烧瓶中投入(S，E)-6-((((叔丁基亚磺酰基)亚氨基)亚氨基)甲基)-5-氟烟酸甲酯(133mg),溶于四氢呋喃(5mL)中，混合物于-78°冷却，向其中滴加入底物异丙基溴化镁的四氢呋喃溶液(0.51mL,1M),反应液逐渐升至室温，共搅拌24小时。将反应液用饱和氯化铵(1mL)淬灭。反应液用水(20mL)稀释，乙酸乙酯(40mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压旋干，粗品送pre.HPLC制备，得淡黄色油状液体42mg。
42.8 (S)6-(1-氨基-2-甲基丙基)-5-氟烟酸甲酯二盐酸盐
向25mL圆底烧瓶中投入6-((S)-1-((S)-1,1-二甲基乙基亚磺酰胺基)-2-甲基丙基)-5-氟烟酸甲酯(42mg),溶于二氯甲烷(2.5mL)中，向其中加入盐酸二氧六环溶液(0.16mL),所得混合物室温搅拌24小时。将反应液减压旋干，得乳白色固体(42mg),粗品直接投入下一步。
42.9 (S)-6-(1-(4-氯苯甲酰胺基)-2-甲基丙基)-5-氟烟酸甲酯
将(S)6-(1-氨基-2-甲基丙基)-5-氟烟酸甲酯二盐酸盐(42mg)溶于N,N-二甲基甲酰胺(2.5mL)中，加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(67mg),搅拌5分钟，加入4-氯苯甲酸(25mg)，搅拌5分钟，加入N,N-二异丙基乙胺(62mg),所得反应液室温搅拌4小时。将反应液用乙酸乙酯(60mL)稀释，用水(20mLx3)洗，饱和食盐水(20mL)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至2:1洗脱)得无色油状液体20mg(收率:34.3％)。
42.10 (S)-6-(1-(4-氯苯甲酰胺基)-2-甲基丙基)-5-氟烟酸
将(S)-6-(1-(4-氯苯甲酰胺基)-2-甲基丙基)-5-氟烟酸甲酯(20mg)溶于甲醇(1mL)和水(0.5mL)中，向其中加入一水合氢氧化锂(7mg),所得混合物于室温搅拌5小时。将反应液减压旋干，加入水(10mL)，用1N盐酸调节PH至3，用乙酸乙酯(30mLx3)萃取，合并有机相，饱和食盐水(10mL)洗,无水硫酸钠干燥，过滤，滤液减压旋干，得白色固体40mg,粗品直接投入下一步。
42.11 6-((S)-1-(4-氯苯甲酰胺基)-2-甲基丙基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-5-氟烟酰胺
将(S)-6-(1-(4-氯苯甲酰胺基)-2-甲基丙基)-5-氟烟酸(40mg)溶于N,N-二甲基甲酰胺(2.5mL)中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(32.9mg)和1-羟基苯并三唑(18.5mg),所得混合物室温搅拌30分钟，加入(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(26.2mg)，搅拌5分钟，加入N-甲基吗啡啉(34.6mg)，所得混合物室温搅拌5小时。将反应液用乙酸乙酯(60mL)稀释，用饱和食盐水(20mLx3)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，粗品送pre.HPLC制备，得白色固体10mg(收率15.6％，MS(ESI)m/z562.2[M+1] +，
1H NMR(400MHz,CDCl 3):δ9.09(d,J＝7.8Hz,1H),9.01(d,J＝8.0Hz,1H),8.88(s,1H),8.15(d,J＝10.2Hz,1H),7.90(d,J＝8.4Hz,2H),7.84(d,J＝8.4Hz,2H),7.68(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),5.22–5.03(m,3H),3.78–3.65(m,2H),3.27(q,J＝7.2Hz,2H),2.39–2.29(m,1H),1.15–1.02(m,6H),0.76(d,J＝6.8Hz,3H)。
实施例43：(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(异丙基((6-(三氟 甲基)吡啶-2-基)甲基)氨基)苯甲酰胺
Figure PCTCN2019121306-appb-000147
43.1 6-(三氟甲基)吡啶甲酸甲酯
向100mL单口瓶中加入6-(三氟甲基)吡啶甲酸(2.0g)和甲醇(25mL)，向其中滴入二氯亚砜(1.49g)，所得混合物于70℃加热搅拌4小时。将反应液减压旋干，乙酸乙酯(100mL)稀释，饱和碳酸氢钠水溶液(30mL)洗，饱和食盐水(30mL)洗。有机相无水硫酸钠干燥，过滤，滤液减压旋干，得白色固体1.9g(MS(ESI)m/z 206.1[M+1] +)。
43.2 (6-(三氟甲基)吡啶-2-基)甲醇
向150mL圆底烧瓶中加入6-(三氟甲基)吡啶甲酸甲酯(1.5g)，硼氢化钠(835mg)和四氢呋喃(30mL),混合物于50℃加热搅拌。向反应液中滴加甲醇(6mL),所得反应液于该温度搅拌4小时。将反应液冷却到室温，加入饱和氯化铵溶液(20mL)淬灭反应，减压旋蒸，除去有机溶剂，残留物用水(20mL)稀释，乙酸乙酯(50mLx3)萃取，饱和食盐水(30mLx2)洗，有机相无水硫酸钠干燥，过滤，滤液减压旋干，得无色油状液体1.22g(MS(ESI)m/z204.0[M+1] +)。
43.3 (6-(三氟甲基)吡啶-2-基)甲磺酸甲酯
向50mL圆底烧瓶中投入(6-(三氟甲基)吡啶-2-基)甲醇(1.216g),加入二氯甲烷(20mL)溶解。将反应液冷却至0℃，向其中依次滴加入三乙胺(0.834g)和甲烷磺酰氯(865mg)。所得混合物逐渐升至室搅拌24小时。将反应液用二氯甲烷(100mL)稀释，饱和食盐水(30mLx2)洗，有机相无水硫酸钠干燥，过滤，滤液减压旋干，得棕黄色油状液体2.82g(MS(ESI)m/z 256.1[M+1] +)。
43.4 (6-(三氟甲基)吡啶-2-基)甲胺
向50mL圆底烧瓶中加入(6-(三氟甲基)吡啶-2-基)甲磺酸甲酯(1.0g)用1.4-二氧六环(10mL)溶解，向混合液中滴加氨水(10mL,28％wt),所得反应混合物室温搅拌24小时。将反应液减压旋干，硅胶柱层析(PE:EA＝10:0至5:1洗脱)得白色固体245mg(MS(ESI)m/z177.1[M+1] +)。
43.5 3-氟-4-((((6-(三氟甲基)吡啶-2-基)甲基)氨基)苄腈
向25mL圆底烧瓶中投入(6-(三氟甲基)吡啶-2-基)甲胺(245mg)和3,4-二氟苄腈(193mg)用二甲亚砜(5mL)溶解。所得混合物在70℃加热搅拌9小时。将反应液用乙酸乙酯(100mL) 稀释，饱和食盐水(30mLx3)洗，有机相无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至3:1洗脱)得白色固体241mg(MS(ESI)m/z 296.1[M+1] +)。
43.6 3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苄腈
将3-氟-4-((((6-(三氟甲基)吡啶-2-基)甲基)氨基)苄腈(140mg)溶于N,N-二甲基甲酰胺(2.5mL)中，置于冰浴中冷却。向其中加入钠氢(19mg),所得混合物在0℃搅拌30分钟，向反应液中加入2-碘丙烷(242mg)，所得反应液在室温搅拌3小时。将反应液用饱和氯化铵溶液(5mL)淬灭，用乙酸乙酯(120mL)稀释，饱和食盐水(30mLx3)洗，有机相无水硫酸钠干燥，过滤，滤液减压旋干，硅胶柱层析(PE:EA＝10:0至2:1洗脱)得无色油状液体57mg(MS(ESI)m/z 338.1[M+1] +)。
43.7 3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苯甲酸甲酯
向25mL圆底烧瓶中投入3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苄腈(47mg),溶于甲醇(4mL)中。向反应液中加入浓硫酸(0.8mL)，所得混合物回流搅拌3天。将反应液冷却至室温，用饱和碳酸氢钠溶液调节PH＝7,减压旋除甲醇，残留液加入水(20mL)稀释，乙酸乙酯(40mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压旋干,得无色油状液体50mg,粗品直接投入下一步。
43.8 3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苯甲酸
向25mL圆底烧瓶中投入3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苯甲酸甲酯(50mg),溶于二氯甲烷(4mL)和水(2mL)中，向其中加入氢氧化锂(17mg)，所得混合物室温搅拌3小时。将反应液减压旋除甲醇，残留液用水(15mL)稀释，用1N盐酸调节PH＝3，用乙酸乙酯(30mLx3)萃取，合并有机相，饱和食盐水(30mL)洗，无水硫酸钠干燥，过滤，滤液减压旋干,得淡黄色油状液体50mg,粗品直接投入下一步。
43.9 (R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苯甲酰胺
将3-氟-4-(异丙基((6-(三氟甲基)吡啶-2-基)甲基)氨基)苯甲酸(50mg)溶于N,N-二甲基甲酰胺(2.5mL)中，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(40.3mg)和1-羟基苯并三唑(23mg),所得混合物室温搅拌30分钟，加入(R)-2-氨基-2-(4-(乙基磺酰基)苯基)乙醇(32mg)，搅拌5分钟，加入N-甲基吗啡啉(42.4mg)，所得混合物室温搅拌5小时。取样，送检LC-MS，检测到产物分子量568.3[M+1] +。将反应液用乙酸乙酯(100mL)稀释，用饱和食盐水(30mLx3)洗，有机相用无水硫酸钠干燥，过滤，滤液减压旋干，粗品送pre.HPLC制备，得白色固体12mg(MS(ESI)m/z 568.2[M+1] +，
1H NMR(400MHz,CDCl 3):δ7.82–7.69(m,3H),7.57–7.42(m,5H),7.40–7.31(m,1H),7.21–7.05m,1H),6.90–6.39(m,1H),5.19–5.08(m,1.7H),4.54(s,0.7H),4.45(t,J＝6.4Hz,0.7H),4.04–3.90(m,1H),3.89–3.83(m,1H),3.15–2.94(m,3H),2.39–1.94(m,1H),1.31–1.14(m,6H),1.02–0.92(m,3H))。
实施例44：(R)-4-(2-(4-氯苯基)-N-异丙基乙酰胺基)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟苯甲酰胺
Figure PCTCN2019121306-appb-000148
参照上述实施例43的步骤得到标题化合物13.2mg(MS(ESI)m/z:561.1[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.91(d,J＝8.1Hz,2H),7.74(d,J＝9.7Hz,1H),7.66(d,J＝8.1Hz,1H),7.62(d,J＝8.1Hz,2H),7.22(d,J＝8.3Hz,3H),7.15(td,J＝7.8,2.7Hz,1H),6.97(d,J＝8.3Hz,2H),5.40–5.32(m,1H),5.01(dt,J＝13.6,6.8Hz,1H),4.17–3.97(m,2H),3.30(dd,J＝44.1,16.1Hz,2H),3.13(q,J＝7.4Hz,2H),2.29(s,1H),1.31(t,J＝7.4Hz,3H),1.14(d,J＝6.7Hz,3H),1.03(d,J＝6.6Hz,3H)。
实施例45：(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(异丙基(吡啶-2-基甲基)氨基)苯甲酰胺
Figure PCTCN2019121306-appb-000149
参照上述实施例43的步骤得到标题化合物7.6mg(MS(ESI)m/z:500.2[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.44(d,J＝4.4Hz,1H),7.80(d,J＝8.4Hz,2H),7.57–7.47(m,4H),7.37–7.28(m,2H),7.20–7.05(m,2H),6.84(t,J＝8.4Hz,1H),5.24–5.17(m,1H),4.48(s,2H),4.08–3.86(m,3H),3.06(q,J＝7.2Hz,2H),1.26–1.22(m,9H)。
实施例46：(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(异丙基((6-(三氟甲基)吡啶-3-基)甲基)氨基)苯甲酰胺
Figure PCTCN2019121306-appb-000150
参照上述实施例43的步骤得到标题化合物38.7mg(MS(ESI)m/z:568.2[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.65(s,1H),7.86-7.76(m,3H),7.56(d,J＝8.0Hz,1H),7.52(d,J＝8.4Hz,2H),7.48(dd,J＝13.4,2.0Hz,1H),7.40(dd,J＝8.4,2.0Hz,1H),6.98(d,J＝7.2Hz,1H),6.88(t,J＝8.4Hz,1H),5.26–5.20(m,1H),4.46(s,2H),4.03–3.89(m,3H),3.07(q,J＝7.2Hz,2H),2.45(s,1H),1.28–1.24(m,9H)。
实施例47：N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(2-甲基-1-(((6-(三氟甲基)吡啶-2-基)甲基)氨基)丙基)苯甲酰胺
Figure PCTCN2019121306-appb-000151
参照上述实施例41的步骤得到标题化合物6.1mg(MS(ESI)m/z:582.1[M+H] +)。
1H NMR(400MHz,CDCl 3)δ7.89(d,J＝8.4Hz,2H),7.82(t,J＝7.6Hz,1H),7.61(d,J＝8.0Hz,3H),7.55(t,J＝8.4Hz,3H),7.47(d,J＝7.6Hz,1H),7.19(d,J＝7.2Hz,1H),5.34-5.27(m,1H),4.13-3.97(m,2H),3.85-3.69(m,3H),3.12(q,J＝7.2Hz,2H),2.43(br.s,1H),2.04-1.96(m,1H),1.29(t,J＝7.2Hz,3H),1.06(d,J＝6.8Hz,3H),0.83(d,J＝6.8Hz,3H)。
实施例48：(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(异丙基((2-(三氟甲基)吡啶-4-基)甲基)氨基)苯甲酰胺
Figure PCTCN2019121306-appb-000152
参照上述实施例43的步骤得到标题化合物7.0mg(MS(ESI)m/z:568.2[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.68(d,J＝4.4Hz,1H),7.87–7.74(m,2H),7.64(s,1H),7.59–7.47(m,3H),7.45(d,J＝4.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.03(s,1H),6.24(t,J＝8.3Hz,1H),5.20(s,1H),4.79(s,1H),4.32(t,J＝5.7Hz,1H),3.93(dd,J＝15.2,10.4Hz,2H),3.07(q,J＝7.3Hz,2H),2.19(dt,J＝13.1,6.6Hz,1H),1.29–1.22(m,4H),1.04(dd,J＝8.7,7.1Hz,6H)。
实施例49：6-(1-((4-氯苄基)氨基)-2-甲基丙基)-N-((R)-1-(4-(乙基磺酰基)苯基)-2-羟乙基)-5-氟烟酰胺
Figure PCTCN2019121306-appb-000153
参照实施例33的步骤得到标题化合物32.6mg(MS(ESI)m/z:548.3[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.88(s,1H),7.86(d,J＝8.4Hz,2H),7.80(dd,J＝9.6,1.6Hz,1H),7.59(d,J＝8.4Hz,2H),7.29(d,J＝6.8Hz,1H),7.25-7.17(m,4H),5.35-5.30(m,1H),4.12-3.96(m,2H),3.77(d,J＝7.2Hz,1H),3.57(dd,J＝13.6,2.0Hz,1H),3.41(d,J＝13.6Hz,1H),3.09(q,J＝7.2Hz,2H),2.23(br.s,1H),1.98(dd,J＝13.6,6.8Hz,1H),1.27(t,J＝7.2Hz,3H),1.02(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H)。
实施例50：(R)-N-(1-(4-(乙基磺酰基)苯基)-2-羟乙基)-3-氟-4-(异丙基((5-(三氟甲基)吡啶-2-基)甲基)氨基)苯甲酰胺
Figure PCTCN2019121306-appb-000154
参照上述步骤得到标题化合物4.3mg(MS(ESI)m/z:568.1[M+H] +)。
1H NMR(400MHz,CDCl 3)δ8.85(s,1H),8.05(dd,J＝8.4,2.0Hz,1H),7.85(dd,J＝8.4,2.4Hz,2H),7.69–7.59(m,3H),7.54(dt,J＝12.8,1.6Hz,1H),7.48(d,J＝8.4Hz,1H),6.64(t,J＝8.4Hz,1H),5.19(t,J＝6.4Hz,1H),4.56(s,1H),4.45(d,J＝7.8Hz,1H),3.85(d,J＝6.4Hz,2H),3.17(q,J＝7.6Hz,2H),2.34-2.19(m,1H),1.19(t,J＝7.6Hz,3H),1.12(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H)。
生物活性试验
荧光素酶检测(Luciferase assay)
本检验方法使用荧光素酶作为报告基因来检测转染了基因重组质粒的细胞在基因转录水平上的表达，该重组质粒由目的基因的启动子和荧光素酶基因构建而成。实验主要是有关重组质粒hRORγt(“RORgt”)的转染。转染需要27.75微克的DNA，18毫升体积的细胞和培养液以及125毫升的摇瓶。
一.试剂及材料：
1.细胞:中国仓鼠卵巢细胞(CHO-S,Invitrogen,Cat#R80007),悬浮培养在CD-CHO培养液中，包含8mM L-glutamine(L-谷氨酰胺)和1×HT。
2.培养液：
a)CD-CHO(Invitrogen,Cat#10743029)培养液[添加1×的HT(Invitrogen,Cat#11067030),L-谷氨酰胺(Invitrogen,Cat#25030149)]；
青霉素-链霉素100X(Invitrogen,Cat#10378016)仅在传代中使用，转染时不使用。
b)Opti-MEM(Invitrogen，Cat#51985034)是一种降低血清培养液即转染复合物的形成过程中使用。
3.DNA：
a)荧光素酶报告基因质粒pG5-luc:reporter plasmid(Promega)。
b)目的基因质粒pM-hRORγt:human RORgamma。
4.转染试剂：TransIT-CHO转染试剂盒(Mirus Bio公司),含有Trans-It试剂以及Mojo试剂(Mirus,MIR2170)。
5.培养板:白色细胞培养平板(VWR，Catalog#29444-041)。
6.化合物板：聚丙烯96孔圆底板(VWR，Catalog#29444-104)。
7.荧光素酶试剂盒：(Promega 1Glo，100毫升,Catalog#E6120):含有荧光素酶底物(辅酶A、ATP和荧光素)和反应缓冲液。
8.摇瓶。
二.实验具体步骤：
A细胞培养
1.细胞铺板：转染之前18-24小时，向125毫升摇瓶中加入浓度为0.5-0.6×10^6个细胞/毫升CHO-S细胞，加入CD-CHO培养液(培养液只含有L-谷氨酰胺和HT添加物)至最终体积为18毫升。摇瓶置于摇床上，在120转/分、37℃和8％二氧化碳条件下过夜传代。
2.细胞转染：此时上述溶液的细胞浓度应在1.2-1.5×10^6细胞/毫升。使用CD-CHO培养液(含有L-谷氨酰胺和HT添加物)将细胞浓度稀释到1×10^6细胞/毫升。
B转染试剂准备(TransIT-CHO:Mojo:DNA复合物)，转染之前现配。
1.预热trans-IT试剂到室温，使用前震荡混匀。
2.准备DNA转染：在1.5毫升无菌离心管里，混合以下试剂：
27微克荧光素酶报告基因质粒pG5-luc：27微升、1毫克/毫升溶液，
0.75微克目的基因表达质粒(pM-hRORγt，7.5微升、0.1毫克/毫升溶液)。
3.将以下试剂加入15毫升无菌离心管:
2.8毫升Opti-MEM
83微升Tansit-CHO试剂
步骤2准备好的DNA复合物
4.混合均匀，室温放置5分钟.
5.加入13.9微升Mojo试剂到一个无菌离心管，微微混匀，室温放置20分钟形成转染复合物。
C转染细胞：
1.缓慢摇动125毫升摇瓶的同时逐滴加入步骤B准备的转染复合物。
2. 37℃摇床、8％二氧化碳下，培养4小时。
3.四小时后转移细胞到50毫升无菌离心管，以1200rpm离心四分钟，吸走上清液体。
4.重新悬浮细胞至6毫升冷冻培养液(CD-CHO、L-谷氨酰胺、HT添加物和10％DMSO)中，此时细胞密度应在3x10^6细胞/毫升。
5.分装于12管，每管0.5毫升，置于零下80度冰箱缓慢冷冻过夜，然后转移到液氮长期储存。
D荧光素酶活性检测(96孔平板)
1. 37℃解冻细胞。
2.2毫升现配培养液(CD-CHO、L-谷氨酰胺和HT添加物)稀释细胞(1.5×10^6细胞/0.5毫升)到2.5毫升体积。转移到15毫升无菌离心管。
3.细胞计数，如果细胞完全存活，应该得到6×10^5个细胞/毫升，一般情况下应该得到65％～70％存活率，细胞密度应为4×10^5个细胞/毫升，如有必要，使用培养液进行稀释。
4.细胞铺板，每孔加入100微升细胞(4×10^4个细胞)。
5.每孔加入1微升待测化合物(溶解于100％DMSO)，使用预先准备好的100倍浓度待测化合物平板。
6. 37℃，5％二氧化碳过夜培养。
7.第二天，培养液稀释现配1GLO荧光素酶(4:1)，转移50微升到细胞平板，排枪混匀。
8.震荡混匀5分种。
9.荧光测定仪测定荧光素酶活性。
Wallac Trilux luminometer荧光测定仪设置：
Protocol：Luciferase luminescence
读取时间：1 sec/well,6 wells/read
96孔平板荧光素酶实验设计安排：
本实验使用白色不透明96孔平板，
B1是指空白对照组：无菌去离子水
S是指阳性对照组(100％抑制)：2uM乌索酸的DMSO溶液
D是指阴性对照组(100％活性)：DMSO
C1-C8是指待测试化合物组：不同稀释浓度的待测试化合物或者重复实验组。
  1 2 3 4 5 6 7 8 9 10 11 12
A Bl Bl Bl Bl Bl Bl Bl Bl Bl Bl Bl Bl
B Bl S D C1 C2 C3 C4 C5 C6 C7 C8 Bl
C Bl S D C1 C2 C3 C4 C5 C6 C7 C8 Bl
D Bl S D C1 C2 C3 C4 C5 C6 C7 C8 Bl
E Bl S D C1 C2 C3 C4 C5 C6 C7 C8 Bl
F Bl S D C1 C2 C3 C4 C5 C6 C7 C8 Bl
G Bl S D C1 C2 C3 C4 C5 C6 C7 C8 Bl
H Bl Bl Bl Bl Bl Bl Bl Bl Bl Bl Bl Bl
本实验每个孔含有：1微升待测化合物(溶于DMSO)，100微升细胞，50微升荧光素酶试剂。
荧光素酶检测结果如下表所示：
Figure PCTCN2019121306-appb-000155
Figure PCTCN2019121306-appb-000156
Figure PCTCN2019121306-appb-000157
CytoStim刺激人PBMC细胞的抑制作用
本实验通过检测体外CytoStim刺激人PBMC后IL-17的变化，进而验证化合物的抑制作用。在100nM化合物作用4小时后，以10ul/ml CytoStim作用48小时，ELISA法检测上清中细胞因子IL-17的含量。
一、试剂及材料：
1.1实验试剂
Figure PCTCN2019121306-appb-000158
1.2实验仪器
名称 生产厂家
细胞培养箱 Thermo
冷冻高速离心机 eppendorf
倒置显微镜 江南
超净台 苏净安泰
移液器 Raining
移液器 Thermo
移液器 Thermo
移液器 Thermo
电动移液器 Thermo
电动移液器 Eppendorf
纳升加样仪 Tecan
多功能酶标仪 TECAN
洗板机 BioTek
微孔板恒温振荡器 杭州米欧仪器有限公司
二、实验方法
2.1 PBMC培养、分组及上清收取
取冻存的PBMC(赛笠)共2支(5*10 7cells/支)复苏，混合后，加入适量1640(5％人血清)培养液，水平转子1500rpm离心5min，取细胞沉淀，再加入10ml培养基稀释，得到细胞悬液。调整细胞密度约为1.12*10 7个/ml，96孔培养板中每孔加入90μl细胞悬液(1*10 6cells/well)，培养过夜。
设置对照组(不加化合物和CytoStim)，CytoStim刺激组，实施例化合物(100nM)。纳升加样仪加样后培养4h，每孔再加入稀释后的10μl CytoStim刺激48h。每孔总液量为100μl，在48h取细胞上清液，2000g离心5min，收集上清。
2.2 ELISA法定量检测细胞上清中IL-17含量
使用Human IL-17 Capture Antibody 4μg/mL蛋白作为包被抗体，每孔100μl，2～8℃包被过夜。弃去板中液体，PBST洗3次，每孔加入200μl含1％BSA的PBST，25±2℃封闭1h。PBST洗板3次。加入50μl标准曲线等样品，25±2℃振荡孵育2h，用Human IL-17 Detection Antibody 60倍稀释作为检测二抗，每孔100μl，25±2℃孵育1h。Streptavidin-HRP 40倍稀释作为检测三抗，每孔100μl，25±2℃孵育30min；加入TMB显色，1M H2SO4终止反应。读板仪上在450/630nm波长处读吸光度值，曲线拟合采用4 parameter logistic fit，最终OD值为OD450nm-OD630nm。
三、实验结果
PBMC细胞IL-17分泌的抑制作用如下表：
化合物 剂量(nM) 抑制率(％)
实施例5 100 50-90
实施例19 100 50-90
实施例37 100 50-90
。

Claims (32)

  1. 式(I)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2019121306-appb-100001
    其中，
    U、V、W、Z各自独立地选自CH或N；
    R 1选自
    Figure PCTCN2019121306-appb-100002
    Figure PCTCN2019121306-appb-100003
    Figure PCTCN2019121306-appb-100004
    或5-6元杂芳基，其中所述5-6元杂芳基任选地被m个R 4取代；
    R 2独立地选自卤素、羟基、氨基、氰基、硝基、
    Figure PCTCN2019121306-appb-100005
    C 1-C 6烷基、C 1-C 6烷氧基或3-6元自环卤烷素、基，羟基其、中氨所基述、C 1-氰C 6基烷的基取、代C基 1-C取 6代烷；氧基或3-6元环烷基任选地被一个或两个或三个选
    R 3独立地选自卤素、羟基、氨基、氰基、硝基、C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基，其中所述C 1-C 6烷基、3-6元环烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100006
    卤代C 1-C 3烷基的取代基取代；
    R 4独立地选自卤素、羟基、氨基、氰基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基的取代基取代；
    p选自1、2或3；
    q选自1、2或3；
    n选自0、1、2、3、4或5；
    m选自0、1、2、3、4、5或6。
  2. 权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，当R 1选自
    Figure PCTCN2019121306-appb-100007
    R 3选自卤素、氰基、3-6元环烷基、C 1-C 6烷基，其中所述C 1-C 6烷基、3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100008
    卤代C 1-C 3烷基的取代基取代时，至少有一个R 2选自3-6元环烷基；同时不包括以下化合物：
    Figure PCTCN2019121306-appb-100009
    Figure PCTCN2019121306-appb-100010
    优选的，当R 1选自
    Figure PCTCN2019121306-appb-100011
    R 3选自氯、氰基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、-CF 3、-CH 2CF 3、-CF 2CH 3、-C(OH)(CH 3) 2时，至少有一个R 2选自3-6元环烷基；同时不包括以下化合物：
    Figure PCTCN2019121306-appb-100012
  3. 权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2019121306-appb-100013
    R 3选自卤素、氰基、3-6元环烷基、C 1-C 6烷基，其中所述C 1-C 6烷基、3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100014
    卤代C 1-C 3烷基的取代基取代时，至少有一个R 2选自3-6元环烷基；同时，当q为1时，R 3不为甲基、乙基、异丙基和环丁基；
    优选的，当R 1选自
    Figure PCTCN2019121306-appb-100015
    R 3选自氯、氰基、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、-CF 3、-CH 2CF 3、-CF 2CH 3、-C(OH)(CH 3) 2时，至少有一个R 2选自3-6 元环烷基；同时，当q为1时，R 3不为甲基、乙基、异丙基和环丁基。
  4. 权利要求1-3任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，U、V、W、Z中至少有一个为CH，或者，U、V、W、Z中至多有一个为N；优选的，U、V、W、Z均为CH，或者，V、W、Z为CH，U为N，或者U、V、Z为CH，W为C(R 3)。
  5. 权利要求1所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2019121306-appb-100016
    Figure PCTCN2019121306-appb-100017
    呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、四唑基或三嗪基，其中呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、四唑基或三嗪基任选地被m个R 4取代；优选的，R 1选自
    Figure PCTCN2019121306-appb-100018
    Figure PCTCN2019121306-appb-100019
    异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基或哒嗪基，其中所述异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基或哒嗪基任选地被m个R 4取代；更优选的，R 1选自
    Figure PCTCN2019121306-appb-100020
    Figure PCTCN2019121306-appb-100021
    Figure PCTCN2019121306-appb-100022
    其中所述
    Figure PCTCN2019121306-appb-100023
    Figure PCTCN2019121306-appb-100024
    任选地被m个R 4取代；最优选的，R 1选自
    Figure PCTCN2019121306-appb-100025
    Figure PCTCN2019121306-appb-100026
  6. 权利要求1-3任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2019121306-appb-100027
    异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基或哒嗪基，其中所述异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、1,3,4-噁二唑基、嘧啶基或哒嗪基任选地被m个R 4取代；优选的，R 1选自
    Figure PCTCN2019121306-appb-100028
    Figure PCTCN2019121306-appb-100029
    Figure PCTCN2019121306-appb-100030
    其中所述
    Figure PCTCN2019121306-appb-100031
    Figure PCTCN2019121306-appb-100032
    任选地被m个R 4取代；更优选的，R 1选自
    Figure PCTCN2019121306-appb-100033
    Figure PCTCN2019121306-appb-100034
  7. 权利要求1-3任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 2独立地选自
    Figure PCTCN2019121306-appb-100035
    C 1-C 4烷基、或3-6元环烷基，其中所述C 1-C 4烷基或3-6元环烷基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基的取代基取代；优选的，R 2独立地选自
    Figure PCTCN2019121306-appb-100036
    C 1-C 4烷基、或3-6元环烷基；更优选的，R 2独立地选自乙基、
    Figure PCTCN2019121306-appb-100037
    或环丙基；最优选的，R 2独立地选自乙基或环丙基。
  8. 权利要求1-3任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 3独立地选自C 1-C 4烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基，其中所述C 1-C 4烷基、3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100038
    卤代C 1-C 3烷基的取代基取代；优选的，R 3独立地选自甲基、乙基、任意位置失去一个氢原子的
    Figure PCTCN2019121306-appb-100039
    Figure PCTCN2019121306-appb-100040
    所形成的基团、或噁唑基，其中所述R 3任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100041
    的取代基取代；更优选的，R 3独立地选自甲基、乙基、
    Figure PCTCN2019121306-appb-100042
    其中R 3任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100043
    的取代基取代；最优选的，R 3独立地选自-CHF 2、-CF 3、乙基、-C(O)CH 3、
    Figure PCTCN2019121306-appb-100044
    Figure PCTCN2019121306-appb-100045
  9. 权利要求1-8任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，R 4独立地选自C 1-C 4烷基；优选的，R 4独立地选自甲基、乙基、异丙基或叔丁基；更优选的，R 4独立地选自甲基。
  10. 权利要求1-3任一项所述的式(I)化合物、其立体异构体或其药学上可接受的盐，其中，当R 1选自
    Figure PCTCN2019121306-appb-100046
    时，R 3独立地选自3-6元杂环烷基、3-6元环烯基、3-6元杂环烯基或5-6元杂芳基，其中所述3-6元杂环烷基、3-6元环烯基、3-6 元杂环烯基或5-6元杂芳基任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100047
    卤代C 1-C 3烷基的取代基取代；优选的，R 1选自
    Figure PCTCN2019121306-appb-100048
    R 3独立地选自
    Figure PCTCN2019121306-appb-100049
    Figure PCTCN2019121306-appb-100050
    其中R 3任选地被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100051
    的取代基取代。
  11. 权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，当R 1选自
    Figure PCTCN2019121306-appb-100052
    时，R 3选自被一个或两个或三个选自卤素、羟基、氨基、氰基、
    Figure PCTCN2019121306-appb-100053
    的取代基取代C 1-C 4烷基。
  12. 权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2019121306-appb-100054
    V、W、Z均为C，U为N，R 3选自未取代C 1-C 4烷基。
  13. 权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，式(I)化合物具有式(IV)所示的结构，
    Figure PCTCN2019121306-appb-100055
    其中，U、R 1、R 2、R 3、n如权利要求1中所定义。
  14. 以下化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2019121306-appb-100056
    Figure PCTCN2019121306-appb-100057
    Figure PCTCN2019121306-appb-100058
    Figure PCTCN2019121306-appb-100059
  15. 式(V)化合物、其立体异构体或其药学上可接受的盐，
    Figure PCTCN2019121306-appb-100060
    其中，
    X、Y、Q、P各自独立地选自CH或N，其中所述X、Y、Q、P可任选地被R 6取代；
    U＇、V＇、W＇、Z＇各自独立地选自CH或N，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代；
    L 1、L 2、L 3各自独立地选自单键、CH 2、NH、C(O)或S(O) 2，其中所述L 1、L 2、L 3可任选地被一个或两个选自R 4＇的基团取代，且L 1、L 2、L 3各不相同；
    R 1＇选自任选地被一个或两个或三个选自卤素、羟基或C 3-C 6环烷基的取代基取代的C 1-C 6烷基；
    R 2＇选自H、卤素、羟基、C 1-C 6烷基、卤代C 1-C 6烷基或羟基C 1-C 6烷基；
    R 3＇选自H、C 1-C 6烷基或C 1-C 6烷基C(O)-；
    R 4＇独立地选自卤素、羟基、氨基或C 1-C 6烷基，其中所述C 1-C 6烷基可任选地被一个或两个或三个选自卤素、羟基、氰基或氨基的取代基取代；
    R 5选自3-6元环烷基、3-6元杂环烷基、苯基或5-6元杂芳基，其中所述3-6元环烷基、3-6元杂环烷基、苯基或5-6元杂芳基可任选地被一个或两个或三个选自卤素、羟基、氰基、硝基、氨基、C 1-C 3烷基或卤代C 1-C 3烷基的取代基取代；
    R 6选自卤素、羟基、氨基、硝基或C 1-C 6烷基，其中所述C 1-C 6烷基可任选地被一个或两个或三个选自卤素、羟基、氰基或氨基的取代基取代；
    R 7选自卤素、羟基、氨基、硝基、C 1-C 6烷基或C 1-C 6烷氧基，其中所述C 1-C 6烷基或C 1-C 6烷氧基可任选地被一个或两个或三个选自卤素、羟基、氰基或氨基的取代基取代。
  16. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，X、Y、Q、P中至少有一个为CH，其中所述X、Y、Q、P可任选地被R 6取代，或者，X、Y、Q、P中至多有一个为N，其中所述X、Y、Q、P可任选地被R 6取代；优选的，X、Q、P选自CH，Y选自CH或N，其中所述X、Y、Q、P可任选地被R 6取代。
  17. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，U＇、V＇、W＇、Z＇中至少有一个为CH，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代，或者，U＇、 V＇、W＇、Z＇中至多有一个为N，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代；优选的，U＇、V＇、W＇、Z＇中至多有一个为N，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代；更优选的，U＇、V＇、W＇、Z＇均为CH，其中所述U＇、V＇、W＇、Z＇可任选地被R 7取代，或者，U＇、W＇、Z＇为CH，V＇为N，其中所述U＇、W＇、Z＇可任选地被R 7取代，或者U＇、V＇、Z＇为CH，W＇为N，其中所述U＇、V＇、Z＇可任选地被R 7取代；最优选的，U＇、V＇、W＇、Z＇均为CH，其中U＇、V＇、W＇、Z＇未被R 7取代，或者，U＇、W＇、Z＇选自CH，V选自C(F)或C(OCH 3)，其中U＇、W＇、Z＇未被R 7取代，或者，U＇、W＇、Z＇选自CH，V＇选自N，其中U＇、W＇、Z＇未被R 7取代，或者，U＇、Z＇选自CH，W＇选自N，V＇选自C(F)，其中U＇、Z＇未被R 7取代。
  18. 权利要求15-17任一项所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，R 7选自-F、-Cl、-Br、甲氧基、乙氧基、异丙基氧基或叔丁基氧基；优选的，R 7选自-F或甲氧基。
  19. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，R 1＇选自甲基、乙基、异丙基或叔丁基；优选的，R 1＇选自乙基。
  20. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，R 2＇选自H、甲基、乙基、异丙基或叔丁基，其中所述甲基、乙基、异丙基或叔丁基可任选地被一个羟基取代；优选的，R 2＇选自H或-CH 2OH；更优选的，R 2＇选自-CH 2OH，且与R 2＇连接的C原子的手性构型为R型。
  21. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，R 3＇选自H、甲基、乙基、异丙基或叔丁基；优选的，R 3＇选自H或甲基。
  22. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，R 4＇选自甲基、乙基、异丙基或叔丁基；优选的，R 4＇选自乙基或异丙基。
  23. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，L 1选自CH 2或NH，其中所述L 1可任选地被一个或两个选自R 4＇的基团取代；优选的，L 1选自CH 2，其中L 1被异丙基取代；或者优选的，L 1选自NH，其中L 1被异丙基或乙基取代。
  24. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，L 2选自单键、NH或C(O)，其中所述L 2可任选地被一个或两个选自R 4的基团取代；优选的，L 2选自单键、NH或C(O)。
  25. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，L 3选自CH 2或C(O)，其中所述L 3可任选地被一个或两个选自R 4的基团取代；优选的，L 3选自CH 2或C(O)。
  26. 权利要求15-25任一项所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，
    Figure PCTCN2019121306-appb-100061
    选自
    Figure PCTCN2019121306-appb-100062
  27. 权利要求15所述的式(V)化合物、其立体异构体或其药学上可接受的盐，其中，R 5选自环丙基、环丁基、环戊基、环己基、苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四唑基或三嗪基，其中所述环丙基、环丁基、环戊基、环己基、苯基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻唑基、异噻唑基、噁唑基、异噁唑基、1,2,4-三氮唑基、1,2,3-三氮唑基、四唑基或三嗪基可任选地被一个或两个或三个选自卤素、羟基、氰基、硝基、氨基、C 1-C 3烷基或卤代C 1-C 3烷基的取代基取代；优选的，R 5选自环己基、苯基或吡啶基，其中所述环己基、苯基或吡啶基可任选地被一个或两个或三个选自卤素、羟基、氰基、硝基、氨基、C 1-C 3烷基或卤代C 1-C 3烷基的取代基取代；更优选的，R 5选自环己基、苯基或吡啶基，所述环己 基、苯基或吡啶基可任选地被一个或两个或三个选自F、Cl、三氟甲基的取代基取代；最优选的，R 5选自
    Figure PCTCN2019121306-appb-100063
    Figure PCTCN2019121306-appb-100064
  28. 权利要求15所述的化合物、其立体异构体或其药学上可接受的盐，其中，式(V)化合物具有式(VII)所示的结构，
    Figure PCTCN2019121306-appb-100065
    其中，U＇、V＇、W＇、Z＇、L 1、L 2、L 3、R 2＇、R 3＇和R 5如权利要求15中所定义。
  29. 权利要求15所述的化合物、其立体异构体或其药学上可接受的盐，其中，式(V)化合物具有式(VIII)所示的结构，
    Figure PCTCN2019121306-appb-100066
    其中，U＇、V＇、W＇、Z＇、L 1、L 2、L 3、R 2＇、R 3＇和R 5如权利要求15中所定义。
  30. 下述化合物、其立体异构体或其药学上可接受的盐：
    Figure PCTCN2019121306-appb-100067
    Figure PCTCN2019121306-appb-100068
    Figure PCTCN2019121306-appb-100069
  31. 一种药物组合物，其包含治疗有效量的权利要求1-30所述的化合物、其立体异构体或其药学上可接受的盐；优选的，所述药物组合物还包含药学上可接受的辅料。
  32. 一种预防或者治疗RORγ受体介导的疾病的权利要求1-30所述的化合物、其立体异构体或其药学上可接受的盐或权利要求31所述的药物组合物，其中，所述RORγ受体为RORγt受体。
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