WO2021047407A1 - 联芳基类化合物，包含其的药物组合物，其制备方法及其用途 - Google Patents

联芳基类化合物，包含其的药物组合物，其制备方法及其用途 Download PDF

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WO2021047407A1
WO2021047407A1 PCT/CN2020/112483 CN2020112483W WO2021047407A1 WO 2021047407 A1 WO2021047407 A1 WO 2021047407A1 CN 2020112483 W CN2020112483 W CN 2020112483W WO 2021047407 A1 WO2021047407 A1 WO 2021047407A1
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compound
alkyl
pharmaceutically acceptable
alkylene
formula
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PCT/CN2020/112483
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English (en)
French (fr)
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刘金明
唐建川
任云
田强
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202311202216.1A priority Critical patent/CN117229215A/zh
Priority to CN202080050297.6A priority patent/CN114096525B/zh
Publication of WO2021047407A1 publication Critical patent/WO2021047407A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a novel compound with ROR ⁇ regulating activity, a preparation method thereof, a pharmaceutical composition containing the same, and medical use thereof.
  • the nuclear receptor superfamily is a type of ligand-dependent transcription factor, with 48 family members (ZHANG Y, LUO X Y, WU D H, et al., ROR nuclear receptors: structures, related diseases, and drug discovery[ J], Acta Pharmacologica Sinica, 2015, 36(1): 71-87). According to the different types of nuclear receptor ligands, the 48 superfamily members can be divided into three main types: steroid hormone receptors, non-steroid hormone receptors and orphan receptors.
  • steroid hormone receptors include glucocorticoid receptor (GR), mineralcorticoid receptor (MR), androgen receptor (AR), estrogen receptor (estrone receptor, ER), progestogen receptor (progestogen receptor, PR), etc.; non-steroid hormone receptors include thyroid hormone receptor (thyroid hormone receptor, TR), retinoic acid receptor (or called retinoic acid receptor, retinoic acid receptor) Body) (retinoic acid receptor, RAR), retinoic acid X receptor (retinoid X receptor, RXR) and vitamin D3 receptor (vitamin D3 receptor, VDR), etc.; orphan receptor, because its endogenous ligand has not yet been found Named after the body.
  • thyroid hormone receptor thyroid hormone receptor, TR
  • retinoic acid receptor or called retinoic acid receptor, retinoic acid receptor
  • Body retinoic acid receptor
  • RAR retinoic acid X receptor
  • vitamin D3 receptor vitamin D3 receptor
  • ROR retinoic acid receptor-related orphan receptors
  • FXR farnesoid X receptors
  • PPAR peroxisome proliferator activated receptor
  • LXR liver X receptor
  • the members of the ROR superfamily include three subtypes, ROR ⁇ , ROR ⁇ and ROR ⁇ , which play a regulatory role in a variety of physiological processes. Recent studies have found that, compared with retinoic acid, members of the ROR family have a higher affinity for oxidized steroid derivatives and are regulated by them.
  • ROR is widely distributed in various tissues of the body, can directly enter the nucleus to regulate the transcription of target genes, and then participate in different physiological processes, showing different tissue specificities.
  • ROR ⁇ is expressed in various tissues, but is highly expressed in the brain, and plays an important role in the development of the cerebellum and bone formation.
  • ROR ⁇ has a small range of action, mainly expressed in the brain, and plays a role in the development of the retina and cerebral cortex. ROR ⁇ can be expressed in many tissues, including thymus, liver and skeletal muscle, and plays a key role in the development of secondary lymphoid tissues.
  • ROR ⁇ has two subtypes: ROR ⁇ 1 and ROR ⁇ 2 (ROR ⁇ t).
  • ROR ⁇ 1 is expressed in a variety of tissues, while ROR ⁇ 2 is specifically expressed on immune cells.
  • ROR ⁇ 2 is a key transcription factor for the differentiation and maintenance of Th17 and Tc17 effector T cells. It regulates the secretion of the effector IL-17 by Th17 cells and plays an important role in the differentiation of NK cells, ⁇ T cells and iNKT cells. These cells can mediate the immune system.
  • NK cells ⁇ T cells and iNKT cells.
  • iNKT cells iNKT cells.
  • NK cells ⁇ T cells
  • iNKT cells iNKT cells.
  • NK cells ⁇ T cells
  • iNKT cells iNKT cells
  • cancer is the disease with the highest mortality rate, and the morbidity and mortality rates are still increasing.
  • the therapeutic drugs for tumors are not effective for all tumor patients, and the development of ROR ⁇ modulators has gradually gained attention in the pharmaceutical industry, such as WO2017157332A1, WO2011115892A1, etc. Therefore, research and development of compounds with high ROR ⁇ regulatory activity, fewer side effects, strong resistance to drug resistance, and improved pharmacokinetics may be beneficial to the treatment of tumors and provide more options for the treatment of tumor patients.
  • the purpose of the present invention is to provide a novel compound having a regulatory effect on ROR ⁇ activity, a preparation method of the compound, a pharmaceutical composition containing the compound, and medical use of the compound.
  • the present invention provides a compound having the structure of Formula I or a pharmaceutically acceptable form thereof,
  • Ring A 1 is selected from phenyl and 5-6 membered heteroaryl
  • Ring A 2 is selected from phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group;
  • Ring A 3 is selected from phenyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 4-10 membered heterocyclic group;
  • Z 1 , Z 2 and Z 3 are each independently selected from CR 4 and N;
  • R 1 is selected from hydrogen and C 1-6 alkyl
  • Each R 2 is independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy and C 3-6 cycloalkoxy;
  • Each R 4 is independently selected from hydrogen, halogen, cyano, C 1-6 alkyl and C 1-6 alkoxy;
  • Each R 6 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, solvates, N-oxides, isotopic labels , Metabolites and prodrugs.
  • the present invention provides a method for preparing the compound having the structure of formula I, which comprises the following steps:
  • ring A 1 , ring A 2 , ring A 3 , Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 5 , m, n, and q are as defined in formula I;
  • X represents Degroups, including (but not limited to) halogen atoms, methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • ring A 1 , ring A 2 , ring A 3 , Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 5 , m, n, and q are as defined in formula I;
  • X represents Degroups, including (but not limited to) halogen atoms, methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • Hal represents a halogen atom, including (but not limited to) F, Cl, Br and I, preferably F and Cl .
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound having the structure of Formula I or a pharmaceutically acceptable form thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides the above-mentioned compound having the structure of Formula I, or a pharmaceutically acceptable form thereof, or the above-mentioned pharmaceutical composition, which is used as a ROR ⁇ modulator.
  • the present invention provides the use of the above-mentioned compound having the structure of formula I or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition as a ROR ⁇ modulator.
  • the ROR ⁇ modulator is used to prevent and/or treat diseases at least partly mediated by ROR ⁇ .
  • the application provides the use of the compound having the structure of Formula I, or a pharmaceutically acceptable form thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of diseases mediated at least in part by ROR ⁇ .
  • the disease mediated at least in part by ROR ⁇ is selected from cancer, inflammation and autoimmune diseases.
  • the present invention provides a method for preventing and/or treating diseases at least partly mediated by ROR ⁇ , which comprises the following steps: a therapeutically effective amount of the compound having the structure of formula I or its pharmaceutically acceptable
  • a therapeutically effective amount of the compound having the structure of formula I or its pharmaceutically acceptable is administered to patients in need thereof.
  • the present invention provides a drug combination composition
  • a drug combination composition comprising the above-mentioned compound having the structure of formula I or a pharmaceutically acceptable form thereof or the above-mentioned pharmaceutical composition, and at least one other co-directional ROR ⁇ modulator .
  • the present invention provides a method for preventing and/or treating cancer, which comprises the following steps: a therapeutically effective amount of the compound having the structure of formula I as a ROR ⁇ agonist or a pharmaceutically acceptable compound thereof
  • a therapeutically effective amount of the compound having the structure of formula I as a ROR ⁇ agonist or a pharmaceutically acceptable compound thereof The form or the above-mentioned pharmaceutical composition or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the present invention provides a method for preventing and/or treating inflammation, which comprises the following steps: a therapeutically effective amount of the compound having the structure of formula I as a ROR ⁇ antagonist or a pharmaceutically acceptable compound thereof
  • a therapeutically effective amount of the compound having the structure of formula I as a ROR ⁇ antagonist or a pharmaceutically acceptable compound thereof The accepted form or the above-mentioned pharmaceutical composition or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the present invention provides a method for the prevention and/or treatment of autoimmune diseases, which comprises the following steps: a therapeutically effective amount of the compound having the structure of formula I as a ROR ⁇ antagonist or its
  • a therapeutically effective amount of the compound having the structure of formula I as a ROR ⁇ antagonist or its The pharmaceutically acceptable form or the above-mentioned pharmaceutical composition or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the present invention provides a compound of formula I with a novel structure, which can be used as a high-efficiency ROR ⁇ modulator, has various pharmacological activities such as anti-tumor, anti-autoimmune diseases, anti-inflammatory, etc., and has fewer side effects, strong resistance to drug resistance, Pharmacokinetics and other properties have been effectively improved.
  • the synthesis method is gentle, the operation is simple and easy, and it is suitable for industrial large-scale production.
  • compositions, methods, or device that includes a series of elements is not necessarily limited to the explicitly listed elements, but may also include other elements that are not explicitly listed or elements inherent in the above-mentioned composition, method, or device.
  • “Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention that is substantially non-toxic to living organisms.
  • Pharmaceutically acceptable salts generally include (but are not limited to) the salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases. Such salts are also called acid addition salts or Base addition salt.
  • isomers refers to compounds that have the same molecular weight because of the same number of atoms and atomic types, but differ in the arrangement or configuration of the atoms in space.
  • stereoisomer refers to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.) resulting in a vertical asymmetric plane, So that it can rotate the stable isomer of plane polarized light. Since the compounds of the present invention have asymmetric centers and other chemical structures that may lead to stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can be in the form of single stereoisomers, racemates, enantiomers, and mixtures of diastereomers Form exists. Generally, these compounds can be prepared as racemates.
  • stereoisomers that is, single enantiomers or diastereomers, or enrichment of single stereoisomers (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%).
  • a single stereoisomer of a compound is synthetically prepared from an optically active starting material containing the desired chiral center, or is prepared by preparing a mixture of enantiomeric products and then separating or resolving.
  • the obtained for example, is converted into a mixture of diastereomers and then subjected to separation or recrystallization, chromatographic treatment, chiral resolution reagents, or direct separation of the enantiomers on a chiral chromatography column.
  • Starting compounds with specific stereochemistry are either commercially available, or they can be prepared according to the methods described below and then resolved by methods well known in the art.
  • enantiomers refers to a pair of stereoisomers that have non-superimposable mirror images of each other.
  • diastereomer or “diastereomer” refers to optical isomers that do not constitute mirror images of each other.
  • racemic mixture or “racemate” refers to a mixture containing equal parts of a single enantiomer (ie, a mixture of two R and S enantiomers in equimolar amounts).
  • non-racemic mixture refers to a mixture containing unequal parts of single enantiomers. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
  • tautomers refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers include (but are not limited to) interconversion through proton migration, such as keto-enol isomerization, imine-enamine isomerization Isomerization, amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • cis-trans isomer refers to the stereoisomers formed by the atoms (or groups) located on both sides of the double bond or the ring system due to different positions relative to the reference plane; in the cis-isomer, the atom ( Or group) is located on the same side of the double bond or ring system, and the atom (or group) is located on the opposite side of the double bond or ring system in the trans isomer. Unless otherwise indicated, all cis-trans isomer forms of the compounds of the present invention are within the scope of the present invention.
  • polymorph refers to a solid crystal form of a compound or complex.
  • Those skilled in the art can obtain molecular polymorphs by many known methods. These methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, gas phase diffusion, and sublimation.
  • well-known techniques can be used to detect, classify and identify polymorphs.
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • XRPD X-ray Powder Diffraction
  • SCXRD Single crystal X-ray diffraction
  • NMR solid-state nuclear magnetic resonance
  • IR infrared spectroscopy
  • Raman spectroscopy and scanning electron microscopy (SEM), etc.
  • solvate refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces.
  • N-oxide refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen-containing (aromatic) heterocyclic compound.
  • Common N-oxides include (but are not limited to) trimethylamine-N-oxide, 4-methylmorpholine-N-oxide, pyridine-N-oxide and the like.
  • the 1a position in the nucleus of the formula I compound of the present invention is a tertiary amine nitrogen atom, which can form the corresponding N-oxide; in addition, when the group directly connected to the nitrogen atom at the 3 position in the nucleus is not a (sulfon) acyl group , Then the 3-position is also a tertiary amine nitrogen atom, which can also form the corresponding N-oxide.
  • isotopic label refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotope atom.
  • the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H (D), 3 H (T), 13 C, 14 C, 15 N , 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.
  • metabolite refers to a derivative compound formed after the compound of the present invention is metabolized.
  • metabolized refers to a derivative compound formed after the compound of the present invention is metabolized.
  • prodrug refers to a derivative compound capable of directly or indirectly providing the compound of the present invention after administration to a patient.
  • Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to a patient (for example, more easily absorbed into the blood), or promote the delivery of the parent compound to the site of action (for example, the lymphatic system) compound of.
  • all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are well known in the art.
  • the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl, or aryl.
  • the substituent Y can be either hydrogen or halogen. Hydroxy, cyano, alkyl or aryl; in the same way, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxy, cyano, alkyl or aryl.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • alkyl refers to a monovalent linear or branched alkane group composed of carbon atoms and hydrogen atoms, without unsaturation, and connected to other groups through a single bond, such as C 1- 6 Alkyl refers to an alkyl group containing 1-6 carbon atoms, and C 1-4 alkyl refers to an alkyl group containing 1-4 carbon atoms; common alkyl groups include (but are not limited to) methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), sec-butyl (-CH(CH 3 )CH 2 CH 3 ), isobutyl (-CH 2 CH(CH 3 ) 2 ), tert-butyl (-C(CH 3 ) 3 ), n-pentyl Group (-CH 2 CH 2 CH 2
  • alkylene refers to a divalent linear or branched alkane group composed of carbon atoms and hydrogen atoms, without unsaturation, and connected to one group through a single bond, and through another A single bond is connected to other groups (or ring systems).
  • C 0-6 alkylene refers to an alkylene group containing 0-6 carbon atoms, and an alkylene group with 0 carbon atoms represents a total of Valence bond, for example, C 1-6 alkylene refers to an alkylene group containing 1-6 carbon atoms, and C 1-4 alkylene refers to an alkylene group containing 1-4 carbon atoms; common alkylene Groups include (but are not limited to) methylene (-CH 2 -), 1,2-ethylene (-CH 2 CH 2 -), 1,3-propylene (-CH 2 CH 2 CH 2 -) , 1-methyl-1,2-ethylene (-CH(CH 3 )CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), 1-methyl-1 ,3-propylene (-CH(CH 3 )CH 2 CH 2 -), 1,1-dimethyl-1,2-ethylene (-C(CH 3 ) 2 CH 2 -), 1, 2-Dimethyl-1,2-ethylene
  • haloalkyl refers to a monovalent linear or branched alkyl group, which is substituted by at least one atom selected from fluorine, chlorine, bromine and iodine, does not contain unsaturation, and is connected to the other through a single bond group, for example C 1-6 haloalkyl with at least one means selected from fluorine, chlorine, bromine and iodine atoms substituted C 1-6 alkyl, C 1-4 haloalkyl with at least one means selected from fluoro, C 1-4 alkyl substituted by chlorine, bromine and iodine atoms; common halogenated alkyl groups include (but are not limited to) fluoromethyl (-CH 2 F), difluoromethyl (-CHF 2 ), trifluoromethyl (-CF 3 ), 1-fluoroethyl (-CHFCH 3 ), 2-fluoroethyl (-CH 2 CH 2 F), 1,2-difluoroethyl (-
  • cycloalkyl refers to a monovalent monocyclic or polycyclic (including bridged ring and spiro ring forms) non-aromatic cyclic hydrocarbon group, which consists only of carbon atoms and hydrogen atoms, does not contain unsaturation, and is A single bond is connected to other groups.
  • C 3-10 cycloalkyl refers to a cycloalkyl containing 3-10 carbon atoms
  • C 3-6 cycloalkyl refers to a cycloalkane containing 3-6 carbon atoms Group
  • common cycloalkyl groups include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl (also known as decalin, naphthyl), adamantyl, etc. .
  • Suitable cycloalkyl groups include, but are not limited to, spiropentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, two Cyclo[5.1.0]octyl, spiro[2.6]nonyl, bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl, and spiro[3.5]nonyl. Cycloalkyl groups are optionally substituted with one or more substituents described in this invention.
  • cycloalkylene refers to a divalent monocyclic or polycyclic (including bridged ring and spiro ring forms) non-aromatic cyclic hydrocarbon group, which is composed only of carbon atoms and hydrogen atoms, does not contain unsaturation, and Connect to a group through a single bond, and to other groups through another single bond, for example, C 3-10 cycloalkylene, cycloalkylene containing 3-10 carbon atoms, C 3-6 cycloalkylene Cycloalkylene groups containing 3-6 carbon atoms; common cycloalkylene groups include (but are not limited to) cyclopropane-1,1-ylidene, cyclopropane-1,2-ylidene, cyclobutane- 1,1-subunit, cyclobutane-1,2-subunit, cyclobutane-1,3-subunit, etc.
  • heterocyclic group refers to a monovalent monocyclic or polycyclic (including bridged ring and spiro ring forms) non-aromatic ring system, the ring atoms of which consist of carbon atoms and are selected from boron, nitrogen, oxygen, sulfur, and phosphorus.
  • heterocyclic group is composed of heteroatoms of arsenic and arsenic, and is connected to other groups through a single bond, such as 3-10 membered heterocyclic group, 3-7 membered heterocyclic group or 4-10 membered heterocyclic group; common heterocyclic groups include ( But not limited to) oxirane, oxetan-3-yl, azetidine-3-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, Tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidin-4-yl, tetrahydropyridinyl and the like.
  • the heterocyclic group is optionally substituted with one or more substituents described in the present invention.
  • heterocyclylene refers to a bivalent monocyclic or polycyclic (including bridged ring and spiro ring forms) non-aromatic ring system, the ring atoms of which consist of carbon atoms and are selected from boron, nitrogen, oxygen, sulfur, It is composed of heteroatoms of phosphorus and arsenic, and is connected to one group through a single bond and to other groups (or ring systems) through another single bond, such as 3-10 membered heterocyclylene, 3-7 membered Heterocyclyl or 4-10 membered heterocyclylene; common heterocyclylenes include (but are not limited to) oxirane-2,2-ylidene, oxirane-2,3-ylidene, nitrogen Etidine-2,2-ylidene, azetidine-2,3-ylidene, azetidine-2,4-ylidene, tetrahydrofuran-2,5-ylidene, tetrahydro-
  • aryl refers to a monovalent monocyclic or polycyclic (including fused form) all-carbon aromatic ring system, the ring atoms of which are composed only of carbon atoms and are connected to other groups through a single bond, such as C 6-10 aryl groups; common aryl groups include (but are not limited to) phenyl, naphthyl, anthracenyl, phenanthryl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, etc.
  • Aryl groups are optionally substituted with one or more substituents described in this invention.
  • heteroaryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system, the ring atoms of which consist of carbon atoms and a heterocyclic group selected from boron, nitrogen, oxygen, sulfur, phosphorus and arsenic. It is composed of atoms and is connected to other groups through a single bond.
  • 5-10 membered heteroaryl refers to a monocyclic or polycyclic (including fused form) with a total of 5-10 ring atoms Aromatic ring system; common heterocyclic groups include (but are not limited to) benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, imidazopyridine Group, acridinyl, carbazolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indazinyl, Indolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pterridinyl, puriny
  • alkoxy refers to a monovalent linear or branched alkyl-O- group, which consists only of carbon atoms, hydrogen atoms and oxygen atoms, may contain unsaturation, and is connected to an oxygen atom by one The connected single bond is connected to other groups, such as C 1-6 alkoxy, C 1-4 alkoxy; common alkoxy groups include (but are not limited to) methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 )CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), normal Pentyloxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), neopent
  • haloalkoxy refers to a monovalent linear or branched haloalkyl-O- group, which is substituted by at least one atom selected from fluorine, chlorine, bromine and iodine, may contain unsaturation, and is A single bond connected to the oxygen atom is connected to other groups, such as C 1-6 haloalkoxy, C 1-4 haloalkoxy; common haloalkoxy groups include (but are not limited to) fluoromethoxy (-OCH 2 F), difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), 1-fluoroethoxy (-OCHFCH 3 ), 2-fluoroethoxy (-OCH 2 CH 2 F ), 1,2-difluoroethoxy (-OCHFCH 2 F), 2,2-difluoroethoxy (-OCH 2 CHF 2 ), 1,2,2-trifluoroethoxy (-OCHFCHF 2 ), 2,2,2-trifluoroethoxy
  • cycloalkoxy refers to a monovalent group composed of a cycloalkyl group and an oxygen atom, and is connected to other groups through a single bond to the oxygen atom, such as a C 3-6 cycloalkoxy group; common
  • the cycloalkoxy group includes (but is not limited to) cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, decahydronaphthyloxy, adamantyloxy and the like.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable form thereof,
  • Ring A 1 is selected from phenyl and 5-6 membered heteroaryl
  • Ring A 2 is selected from phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group;
  • Ring A 3 is selected from phenyl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl and 4-10 membered heterocyclic group;
  • Z 1 , Z 2 and Z 3 are each independently selected from CR 4 and N;
  • R 1 is selected from hydrogen and C 1-6 alkyl
  • Each R 2 is independently selected from halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 1-6 Haloalkoxy and C 3-6 cycloalkoxy;
  • Each R 4 is independently selected from hydrogen, halogen, cyano, C 1-6 alkyl and C 1-6 alkoxy;
  • each R a is independently selected from hydrogen and C 1-6 alkyl
  • each R b is independently selected from hydrogen and C 1-6 alkyl
  • a nitrogen atom, R a and R b, together with which they are attached form a 3-7 membered heterocyclyl
  • Each R 6 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl
  • n 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, solvates, N-oxides, isotopic labels, Metabolites and prodrugs.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula I-A or a pharmaceutically acceptable form thereof
  • ring A 1 , ring A 2 , ring A 3 , R 2 , R 3 , R 5 , m, n, and q are as defined above.
  • m is 1 or 2, preferably 2.
  • n is 1 or 2, preferably 1.
  • q is 0, 1, or 2.
  • q is 1 or 2.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl and pyridyl.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is a phenyl group.
  • each R 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is independently selected from halogen, cyano, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 3-6 cycloalkoxy.
  • each R 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is independently selected from halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy.
  • each R 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is independently selected from halogen, cyano, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy.
  • each R 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is independently selected from fluorine, chlorine, cyano, methoxy and di Fluoromethoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl and pyridyl, and each R 2 is independently selected from halogen and cyano. , Hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 3-6 cycloalkoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl, and each R 2 is independently selected from halogen, cyano, C 1-3 haloalkyl, C 3-6 cycloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl, and each R 2 is independently selected from halogen, cyano, C 1-4 alkyl, C 1-3 alkoxy and C 1-3 haloalkoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is a phenyl group; each R 2 is independently selected from fluorine, chlorine, and cyanide. Group, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is phenyl; each R 2 is independently selected from fluorine, chlorine, methyl Group, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is a phenyl group; each R 2 is independently selected from fluorine, chlorine, and cyanide. Group, methoxy and difluoromethoxy.
  • the ring A 1 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is phenyl, and each R 2 is independently selected from fluorine and difluoro Methoxy.
  • the compound of the above formula I or formula IA or a pharmaceutically acceptable form thereof Selected from
  • the ring A 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl and 5-6 membered heteroaryl.
  • the ring A 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl and pyridyl.
  • the ring A 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is a phenyl group.
  • pharmaceutically Formula I or Formula IA compound or a pharmaceutically acceptable form of R 3 is C 1- 4 haloalkyl, preferably, R 3 is trifluoromethyl.
  • each R 3 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is independently selected from fluorine, cyano, methyl, trifluoromethyl And methylsulfonyl.
  • R 3 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is trifluoromethyl.
  • ring A 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl and pyridyl, and R 3 is C 1-4 haloalkyl.
  • ring A 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is selected from phenyl, and each R 3 is independently selected from fluorine, cyano, methyl Group, trifluoromethyl and methylsulfonyl.
  • ring A 2 in the compound of formula I or formula IA or a pharmaceutically acceptable form thereof is phenyl; R 3 is trifluoromethyl.
  • Ring A 1 is a phenyl group and a 5-6 membered heteroaryl group
  • Each R 2 is independently selected from halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 Haloalkoxy and C 3-6 cycloalkoxy;
  • Ring A 2 is selected from phenyl and 5-6 membered heteroaryl
  • Ring A 3 is selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group;
  • q 0, 1 or 2;
  • n 1 or 2;
  • n 1 or 2.
  • Ring A 1 is phenyl
  • Each R 2 is independently selected from fluorine, chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy;
  • Ring A 2 is selected from phenyl and 5-6 membered heteroaryl
  • R 3 is trifluoromethyl
  • Ring A 3 is selected from pyrazolyl, tetrahydropyridyl, thiazolyl, piperazinyl, morpholinyl and piperidinyl;
  • q 0, 1 or 2;
  • n 2;
  • n 1.
  • the above-mentioned compound of formula I or formula I-A or a pharmaceutically acceptable form thereof is a compound of formula I-B1 or a pharmaceutically acceptable form thereof,
  • rings A 3 , R 2 , R 5 , m and q are as defined above.
  • each R 2 in the compound of formula I, formula IA, or formula I-B1 or a pharmaceutically acceptable form thereof is independently selected from fluorine, chlorine, methyl, and methoxy , Ethoxy, difluoromethoxy and trifluoromethoxy.
  • Each R 2 is independently selected from halogen, cyano, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, C 1-4 Haloalkoxy and C 3-6 cycloalkoxy;
  • Ring A 3 is selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group;
  • q 0, 1 or 2;
  • n 1 or 2.
  • Each R 2 is independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy and C 1-4 haloalkoxy;
  • Ring A 3 is selected from 5-6 membered heteroaryl and 5-6 membered heterocyclic group
  • q 0, 1 or 2;
  • Each R 2 is independently selected from fluorine, chlorine, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy;
  • Ring A 3 is selected from pyrazolyl, tetrahydropyridyl, thiazolyl, piperazinyl, morpholinyl and piperidinyl;
  • q 0, 1 or 2;
  • the above-mentioned compound of formula I, formula I-A or formula I-B1 or a pharmaceutically acceptable form thereof is a compound of formula I-B or a pharmaceutically acceptable form thereof
  • rings A 3 , R 5 and q are as defined above.
  • the ring A 3 in the compound of formula I, formula IA, formula I-B1 or formula IB or a pharmaceutically acceptable form thereof is selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group.
  • the ring A 3 in the compound of formula I, formula IA, formula I-B1 or formula IB or a pharmaceutically acceptable form thereof is selected from 5-6 membered heteroaryl groups and 5-6 membered heteroaryl groups. Membered heterocyclic group.
  • the ring A 3 in the compound of formula I, formula IA, formula I-B1 or formula IB or a pharmaceutically acceptable form thereof is selected from pyrazolyl, tetrahydropyridyl, Thiazolyl, piperazinyl, morpholinyl and piperidinyl.
  • the ring A 3 in the compound of formula I, formula IA, formula I-B1 or formula IB or a pharmaceutically acceptable form thereof is selected from
  • the present invention also provides the following compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, cis-trans isomers, polymorphs, solvates, N-oxides, isotopic labels
  • the structure and name of the substance, metabolite or prodrug are shown in the following table:
  • the present invention provides a preparation method of the above-mentioned compound of formula I, which comprises the following steps:
  • ring A 1 , ring A 2 , ring A 3 , Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 5 , m, n, and q are as defined in formula I;
  • X represents Degroups, including but not limited to halogen atoms, methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • ring A 1 , ring A 2 , ring A 3 , Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , R 5 , m, n, and q are as defined in formula I;
  • X represents Degroups, including (but not limited to) halogen atoms, methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • Hal represents a halogen atom, including (but not limited to) F, Cl, Br and I, preferably F and Cl .
  • step (1) of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the solvent used includes (but is not limited to) N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • step (1) of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • step (1) of the above preparation method is carried out in an alkaline environment, and suitable reagents for providing an alkaline environment include (but are not limited to) potassium phosphate, potassium acetate, sodium bicarbonate, and sodium carbonate. And potassium carbonate, preferably potassium carbonate.
  • suitable reaction temperature in step (1) of the above preparation method is 60-120°C.
  • suitable reaction time in step (1) of the above preparation method is 2-8 hours.
  • step (2) of the above preparation method is carried out in a suitable organic solvent, and the organic solvent used includes (but is not limited to) acetonitrile, dichloromethane, chloroform, N,N-dimethylformaldehyde Amide and any combination thereof, preferably acetonitrile.
  • step (2) of the above preparation method is carried out in the presence of a suitable nitrite, and the nitrite used includes (but is not limited to) isoamyl nitrite and tert-butyl nitrite.
  • step (2) of the above preparation method is carried out in the presence of a suitable bromination reagent, and the bromination reagent used includes (but is not limited to) cuprous bromide, copper bromide and N-bromo Succinimide, preferably cuprous bromide.
  • the suitable reaction temperature in step (2) of the above preparation method is -10 to 80°C.
  • the suitable reaction time in step (2) of the above preparation method is 2-8 hours.
  • the reduction reaction in step (3) of the above preparation method is carried out in a suitable solvent.
  • the solvent used includes (but is not limited to) methanol, ethanol, tetrahydrofuran, water and any combination thereof, preferably ethanol Mixed solvent with water.
  • the reduction reaction in step (3) of the above preparation method is carried out in the presence of a suitable reducing agent.
  • the reducing agent used includes (but is not limited to) iron powder, zinc powder, sodium dithionite, chlorine Stannous and hydrazine hydrate, iron powder is preferred.
  • the reduction reaction in step (3) of the above preparation method is carried out in the presence of a suitable inorganic salt.
  • the inorganic salt used includes (but is not limited to) ammonium chloride and ammonium formate, preferably ammonium chloride .
  • the suitable reaction temperature of the reduction reaction in step (3) of the above preparation method is 20-100°C.
  • the suitable reaction time of the reduction reaction in step (3) of the above preparation method is 2-8 hours.
  • the N-alkylation reaction in step (3) of the above preparation method is carried out in the presence of a suitable alkylating agent, and the alkylating agent used includes (but is not limited to) halogenated alkanes, alcohols and Alkyl sulfates, preferably halogenated alkanes.
  • the N-alkylation reaction in step (3) of the above preparation method is carried out in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) sodium hydroxide, Sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate and potassium carbonate, potassium carbonate is preferred.
  • step (4) of the above preparation method is carried out in a suitable organic solvent.
  • the organic solvent used includes (but is not limited to) acetonitrile, dichloromethane, chloroform, tetrahydrofuran and any combination thereof, preferably two Methyl chloride.
  • step (4) of the above preparation method is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) triethylamine, N,N-dimethylethyl Base amine, pyridine, sodium bicarbonate, sodium carbonate and potassium carbonate, preferably pyridine.
  • the suitable reaction temperature in step (4) of the above preparation method is 20-80°C.
  • the suitable reaction time in step (4) of the above preparation method is 2-8 hours.
  • step (5) of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene, Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene, Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • step (5) of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • step (5) of the above preparation method is carried out in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) potassium phosphate, potassium acetate, sodium bicarbonate, and sodium carbonate. And potassium carbonate, preferably potassium carbonate.
  • suitable reaction temperature in step (5) of the above preparation method is 60-120°C.
  • suitable reaction time in step (5) of the above preparation method is 2-8 hours.
  • step (1') of the above preparation method is carried out in a suitable organic solvent, and the organic solvent used includes (but is not limited to) acetonitrile, N,N-dimethylformamide, dimethylformamide, and dimethylformamide. Sulfoxide, 1,4-dioxane and any combination thereof, preferably N,N-dimethylformamide.
  • step (1') of the above preparation method is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) diisopropylethylamine, triethylamine, Sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
  • the suitable reaction temperature of step (1') of the above preparation method is 40-80°C.
  • the suitable reaction time of step (1') of the above preparation method is 2-24 hours.
  • the reduction reaction in step (2') of the above preparation method is carried out in a suitable organic solvent.
  • the organic solvent used includes (but is not limited to) alcoholic protic solvents, tetrahydrofuran, ethyl acetate, and Any combination of it.
  • the reduction reaction in step (2') of the above preparation method is carried out in the presence of a suitable metal reagent and acid.
  • the metal reagents used include (but are not limited to) Raney nickel, palladium carbon, iron Powder and zinc powder, preferably iron powder
  • the acid used includes (but not limited to) hydrochloric acid, formic acid and acetic acid, preferably acetic acid.
  • the suitable reaction temperature of the reduction reaction in step (2') of the above preparation method is 40-80°C. In some embodiments of the present invention, the suitable reaction time of the reduction reaction in step (2') of the above preparation method is 2-12 hours. In some embodiments of the present invention, the N-alkylation reaction in step (2') of the above preparation method is carried out in the presence of a suitable alkylating agent, and the alkylating agent used includes (but is not limited to) alkyl halides, Alcohols and alkyl sulfates, preferably alkyl halides.
  • the N-alkylation reaction in step (2') of the above preparation method is carried out in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) sodium hydroxide , Sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate and potassium carbonate, potassium carbonate is preferred.
  • step (3') of the above preparation method is carried out in a suitable organic solvent, and the organic solvent used includes (but is not limited to) triethylamine, N,N-diisopropylethylamine , Pyridine and any combination thereof, preferably pyridine.
  • the suitable reaction temperature in step (3') of the above preparation method is 40-80°C.
  • the suitable reaction time of step (3') of the above preparation method is 2-8 hours.
  • step (4') of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene , Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene , Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • step (4') of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, Palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, preferably [1,1'-bis(diphenylphosphine) ferrocene] palladium dichloride Methane complex.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, Palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, preferably [1,1'-bis(diphenylphosphine) ferrocene] palladium dichloride Methane complex.
  • step (4') of the above preparation method is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) potassium phosphate, potassium carbonate, cesium carbonate, and sodium carbonate. , Sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate.
  • suitable reaction temperature in step (4') of the above preparation method is 60-100°C.
  • suitable reaction time of step (4') of the above preparation method is 2-8 hours.
  • the method for preparing the compound of formula I-A includes the following steps:
  • ring A 1 , ring A 2 , ring A 3 , R 2 , R 3 , R 5 , m, n and q are as defined in formula I;
  • X represents a leaving group, including (but not limited to) a halogen atom , Methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • ring A 1 , ring A 2 , ring A 3 , R 2 , R 3 , R 5 , m, n and q are as defined in formula I;
  • X represents a leaving group, including (but not limited to) a halogen atom , Methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • Hal represents a halogen atom, including but not limited to F, Cl, Br and I, preferably F and Cl.
  • step (1) of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the solvent used includes (but is not limited to) N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • step (1) of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • step (1) of the above preparation method is carried out in an alkaline environment, and suitable reagents for providing an alkaline environment include (but are not limited to) potassium phosphate, potassium acetate, sodium bicarbonate, and sodium carbonate. And potassium carbonate, preferably potassium carbonate.
  • suitable reaction temperature in step (1) of the above preparation method is 60-120°C.
  • suitable reaction time in step (1) of the above preparation method is 2-8 hours.
  • step (2) of the above preparation method is carried out in a suitable organic solvent, and the organic solvent used includes (but is not limited to) acetonitrile, dichloromethane, chloroform, N,N-dimethylformaldehyde Amide and any combination thereof, preferably acetonitrile.
  • step (2) of the above preparation method is carried out in the presence of a suitable nitrite.
  • the nitrite used includes but is not limited to isoamyl nitrite and tert-butyl nitrite.
  • step (2) of the above preparation method is carried out in the presence of a suitable bromination reagent, and the bromination reagent used includes (but is not limited to) cuprous bromide, copper bromide and N-bromo Succinimide, preferably cuprous bromide.
  • the suitable reaction temperature in step (2) of the above preparation method is -10 to 80°C.
  • the suitable reaction time in step (2) of the above preparation method is 2-8 hours.
  • step (3) of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) methanol, ethanol, tetrahydrofuran, water and any combination thereof, preferably a mixture of ethanol and water Solvent.
  • step (3) of the above preparation method is carried out in the presence of a suitable reducing agent.
  • the reducing agent used includes (but is not limited to) iron powder, zinc powder, sodium dithionite, stannous chloride and Hydrazine hydrate is preferably iron powder.
  • step (3) of the above preparation method is carried out in the presence of a suitable inorganic salt.
  • the inorganic salt used includes (but is not limited to) ammonium chloride and ammonium formate, preferably ammonium chloride.
  • the suitable reaction temperature in step (3) of the above preparation method is 20-100°C.
  • the suitable reaction time in step (3) of the above preparation method is 2-8 hours.
  • step (4) of the above preparation method is carried out in a suitable organic solvent.
  • the organic solvent used includes (but is not limited to) acetonitrile, dichloromethane, chloroform, tetrahydrofuran and any combination thereof, preferably two Methyl chloride.
  • step (4) of the above preparation method is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) triethylamine, N,N-dimethylethyl Base amine, pyridine, sodium bicarbonate, sodium carbonate and potassium carbonate, preferably pyridine.
  • the suitable reaction temperature in step (4) of the above preparation method is 20-80°C.
  • the suitable reaction time in step (4) of the above preparation method is 2-8 hours.
  • step (5) of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene, Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene, Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • step (5) of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, acetic acid Palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane Complex.
  • step (5) of the above preparation method is carried out in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) potassium phosphate, potassium acetate, sodium bicarbonate, and sodium carbonate. And potassium carbonate, preferably potassium carbonate.
  • suitable reaction temperature in step (5) of the above preparation method is 60-120°C.
  • suitable reaction time in step (5) of the above preparation method is 2-8 hours.
  • step (1') of the above preparation method is carried out in a suitable organic solvent, and the organic solvent used includes (but is not limited to) acetonitrile, N,N-dimethylformamide, dimethylformamide, and dimethylformamide. Sulfoxide, 1,4-dioxane and any combination thereof, preferably N,N-dimethylformamide.
  • step (1') of the above preparation method is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) diisopropylethylamine, triethylamine, Sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate.
  • the suitable reaction temperature of step (1') of the above preparation method is 40-80°C.
  • the suitable reaction time of step (1') of the above preparation method is 2-24 hours.
  • step (2') of the above preparation method is carried out in a suitable organic solvent.
  • the organic solvent used includes (but is not limited to) alcoholic protic solvents, tetrahydrofuran, ethyl acetate and any combination thereof.
  • step (2') of the above preparation method is carried out in the presence of a suitable metal reagent and acid.
  • the metal reagents used include (but are not limited to) Raney nickel, palladium carbon, iron powder and zinc powder.
  • the acid used includes but is not limited to hydrochloric acid, formic acid and acetic acid, preferably acetic acid.
  • the suitable reaction temperature in step (2') of the above preparation method is 40-80°C.
  • the suitable reaction time of step (2') of the above preparation method is 2-12 hours.
  • step (3') of the above preparation method is carried out in a suitable organic solvent, and the organic solvent used includes (but is not limited to) triethylamine, N,N-diisopropylethylamine , Pyridine and any combination thereof, preferably pyridine.
  • the suitable reaction temperature in step (3') of the above preparation method is 40-80°C.
  • the suitable reaction time of step (3') of the above preparation method is 2-8 hours.
  • step (4') of the above preparation method is carried out in a suitable solvent, and the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene , Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the solvent used includes (but is not limited to) N,N-dimethylformamide, N-methylpyrrolidone, toluene , Ethanol, ethylene glycol dimethyl ether, water, 1,4-dioxane and any combination thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • step (4') of the above preparation method is carried out in the presence of a suitable catalyst, and the catalyst used is a palladium catalyst, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, Palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, preferably [1,1'-bis(diphenylphosphine) ferrocene] palladium dichloride Methane complex.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, Palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride, preferably [1,1'-bis(diphenylphosphine) ferrocene] palladium dichloride Methane complex.
  • step (4') of the above preparation method is performed in an alkaline environment, and suitable reagents that provide an alkaline environment include (but are not limited to) potassium phosphate, potassium carbonate, cesium carbonate, and sodium carbonate. , Sodium bicarbonate and potassium bicarbonate, preferably potassium carbonate.
  • suitable reaction temperature in step (4') of the above preparation method is 60-100°C.
  • suitable reaction time of step (4') of the above preparation method is 2-8 hours.
  • composition refers to a composition that can be used as a medicine, which comprises a pharmaceutical active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to pharmaceutical excipients that are compatible with the active ingredients of the drug and are harmless to the subject, including (but not limited to) diluents (or fillers), binders, and disintegrants Agents, lubricants, wetting agents, thickeners, glidants, flavors, odorants, preservatives, antioxidants, pH regulators, solvents, cosolvents, surfactants, etc.
  • the present invention provides a pharmaceutical composition, which comprises the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof.
  • the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned compound of formula I, or a pharmaceutically acceptable form thereof, or the above-mentioned pharmaceutical composition as a ROR ⁇ modulator.
  • the ROR ⁇ modulator is used to prevent and/or treat diseases at least partly mediated by ROR ⁇ .
  • this application also provides the use of the compound of formula I, or a pharmaceutically acceptable form thereof, or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases mediated at least in part by ROR ⁇ .
  • disease mediated at least in part by ROR ⁇ refers to a disease that includes at least part of the factors related to ROR ⁇ in its pathogenesis.
  • diseases include (but are not limited to) cancers (such as leukemia, lymphoma, myeloma, breast cancer, ovarian cancer, etc.). Cancer, cervical cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, colorectal cancer, stomach cancer, esophageal cancer, oral cancer, pancreatic cancer, liver cancer, lung cancer, kidney cancer, skin cancer, bone cancer, brain cancer, nerve glue Tumor, melanoma, etc.), inflammation (e.g.
  • the disease mediated at least in part by ROR ⁇ is selected from cancer, inflammation and autoimmune diseases.
  • the present invention provides a method for preventing and/or treating diseases at least partly mediated by ROR ⁇ , which comprises the following steps: a therapeutically effective amount of the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof, or a combination of the above-mentioned drugs
  • a therapeutically effective amount of the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof, or a combination of the above-mentioned drugs The substance is administered to patients who need it.
  • terapéuticaally effective amount refers to a dose of a pharmaceutical active ingredient that can induce a biological or medical response in cells, tissues, organs or organisms (such as patients).
  • administration refers to the application of pharmaceutical active ingredients (such as the compound of the present invention) or a pharmaceutical composition containing the pharmaceutical active ingredient (such as the pharmaceutical composition of the present invention) to a patient or its cells, tissues, organs, biological fluids, etc. , In order to make the active ingredient of the medicine or the medicine composition come into contact with the patient or its cell, tissue, organ, biological fluid and other parts.
  • pharmaceutical active ingredients such as the compound of the present invention
  • a pharmaceutical composition containing the pharmaceutical active ingredient such as the pharmaceutical composition of the present invention
  • Common modes of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration and the like.
  • the term "has a need for it” refers to the judgment of the doctor or other nursing staff on the needs of the patient or the benefit from the prevention and/or treatment process. This judgment is based on the doctors or other nursing staff’s expertise in their fields of expertise. Kind of factors.
  • patient refers to a human or non-human animal (e.g., a mammal).
  • the present invention provides a drug combination composition, which comprises the above-mentioned compound of formula I or its pharmaceutically acceptable form or the above-mentioned pharmaceutical composition, and at least one other co-directional ROR ⁇ modulator.
  • the term "in the same direction" means that when at least two modulators are administered to a certain target, their adjustment directions should be substantially the same, or both exhibit agonistic effects or simultaneously exhibit antagonistic effects.
  • the above-mentioned drug combination composition contains the compound of formula I as a ROR ⁇ agonist or a pharmaceutically acceptable form or pharmaceutical composition thereof, it also contains at least one other ROR ⁇ agonist, and the drug combination is used
  • the composition is suitable for the prevention and/or treatment of cancer; similarly, when the above-mentioned drug combination composition contains the compound of formula I as a ROR ⁇ antagonist or a pharmaceutically acceptable form or pharmaceutical composition thereof, it also contains at least one For other ROR ⁇ antagonists, the drug combination composition is suitable for preventing and/or treating inflammation and/or autoimmune diseases.
  • the present invention provides a method for the prevention and/or treatment of cancer, inflammation or autoimmune diseases, which comprises the following steps: a therapeutically effective amount of the above-mentioned compound of formula I or its pharmaceutically acceptable form or a combination of the above-mentioned drugs
  • a therapeutically effective amount of the above-mentioned compound of formula I or its pharmaceutically acceptable form or a combination of the above-mentioned drugs The drug or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the present invention provides a method for the prevention and/or treatment of cancer, which comprises the following steps: a therapeutically effective amount of the compound of the above formula I or its pharmaceutically acceptable form or the above pharmaceutical composition as a ROR ⁇ agonist Or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the present invention provides a method for preventing and/or treating inflammation, which comprises the following steps: a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable form thereof, or the above-mentioned pharmaceutical composition as a ROR ⁇ antagonist Or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the present invention provides a method for the prevention and/or treatment of autoimmune diseases, which comprises the following steps: a therapeutically effective amount of the compound of formula I or its pharmaceutically acceptable form or the above as a ROR ⁇ antagonist
  • a therapeutically effective amount of the compound of formula I or its pharmaceutically acceptable form or the above as a ROR ⁇ antagonist The pharmaceutical composition or the above-mentioned drug combination composition is administered to patients in need thereof.
  • the structural formulas of the compounds described in the following examples were confirmed by 1 H-NMR or MS.
  • the measuring instrument of 1 H-NMR is a Bruker 400MHz nuclear magnetic resonance instrument, the measuring solvent is CD 3 OD, CDCl 3 or DMSO-d 6 , the internal standard substance is TMS, and all ⁇ values are expressed in ppm.
  • the measuring instrument of MS is Agilent 6120B mass spectrometer, and the ion source is ESI.
  • the reaction process is monitored by TLC or LC-MS.
  • the developing solvent system includes dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system.
  • the solvent can be adjusted according to the polarity of the compound.
  • the volume ratio In order to obtain a suitable ratio shift value (Rf) or retention time (RT), an appropriate amount of triethylamine, etc. can also be added to the developing agent.
  • TLC uses aluminum plates (20 ⁇ 20cm) produced by Merck and GF254 silica gel (0.4 ⁇ 0.5mm) for thin layer chromatography produced by Qingdao Ocean Chemical.
  • CC uses 200-300 mesh silica gel as a carrier.
  • the eluent system includes: dichloromethane and methanol system, petroleum ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • PHPLC uses two conditions: 1) Instrument model: Agilent 1260, chromatographic column: Waters XBridge Prep C 18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); chromatographic column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm ; Mobile phase A: 100% acetonitrile; Mobile phase B: 0.05% ammonium bicarbonate aqueous solution; Elution gradient: 0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B; 2) Instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C 18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; mobile phase A: 100% acetonitrile; mobile phase B: 100% water (containing 0.05% formic acid); elution gradient: 0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B.
  • the first step preparation of 3'-(difluoromethoxy)-5'-fluoro-3-nitrobenzidine-4-amine.
  • reaction solution was poured into water (150 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound of this step (2.42g, yield: 88.1%) .
  • the second step preparation of 4-bromo-3'-(difluoromethoxy)-5'-fluoro-3-nitrobiphenyl.
  • the third step preparation of 4-bromo-3'-(difluoromethoxy)-5'-fluorobiphenyl-3-amine.
  • the fourth step preparation of N-(4-bromo-3'-(difluoromethoxy)-5'-fluorobiphenyl-3-yl)-3-(trifluoromethyl)benzenesulfonamide.
  • the first step preparation of tert-butyl 4-(4-methoxy-4-oxobutyryl)piperazine-1-carboxylate.
  • the second step preparation of methyl 4-oxo-4-(piperazin-1-yl)butyrate.
  • Example 1 2-(3-(3'-(Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)- Preparation of 1H-pyrazol-1-yl)acetic acid (compound 1).
  • the first step 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl ) Preparation of ethyl acetate.
  • the second step 2-(3-(3'-(difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)- Preparation of 1H-pyrazol-1-yl) ethyl acetate.
  • the third step 2-(3-(3'-(difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)- Preparation of 1H-pyrazol-1-yl)acetic acid.
  • Example 2 N-(3'-(Difluoromethoxy)-5'-fluoro-4-(1-(2-methoxyethyl)-1H-pyrazol-3-yl)biphenyl- Preparation of 3-yl)-3-(trifluoromethyl)benzenesulfonamide (Compound 2).
  • Example 3 2-(3-(3'-(Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)- Preparation of 1H-pyrazol-1-yl)-N,N-dimethylacetamide (Compound 3).
  • Example 5 N-(3'-(Difluoromethoxy)-4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-5'-fluoro Preparation of phenyl-3-yl)-3-(trifluoromethyl)benzenesulfonamide (compound 5).
  • the first step N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Preparation of 1H-pyrazol-1-yl)ethylamine.
  • reaction solution was poured into water (100 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain the title compound of this step (1.8 g, yield: 88.2%) .
  • the second step N-(3'-(difluoromethoxy)-4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-5'-fluoro Preparation of phenyl-3-yl)-3-(trifluoromethyl)benzenesulfonamide.
  • the reaction solution was poured into water (50 mL), extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the concentrate was purified by preparative high performance liquid chromatography (condition 1) to obtain The title compound (8 mg, yield: 5.9%).
  • Example 7 (S)-N-(3'-(Difluoromethoxy)-5'-fluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) Preparation of phenyl-3-yl)-3-(trifluoromethyl)benzenesulfonamide (compound 7).
  • Example 8 (R)-N-(3'-(Difluoromethoxy)-5'-fluoro-4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl) Preparation of phenyl-3-yl)-3-(trifluoromethyl)benzenesulfonamide (compound 8).
  • Example 10 2-(4-(3'-(Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)- Preparation of 5,6-dihydropyridine-1(2H)-yl)acetic acid (compound 10).
  • Example 11 N-(3'-(Difluoromethoxy)-5'-fluoro-4-(thiazol-4-yl)biphenyl-3-yl)-3-(trifluoromethyl)benzenesulfonate Preparation of amide (compound 11).
  • Example 12 N-(4-(4-(cyclopropanoyl)piperazin-1-yl)-3'-(difluoromethoxy)-5'-fluorobiphenyl-3-yl)-3 -Preparation of (trifluoromethyl)benzenesulfonamide (Compound 12).
  • the first step preparation of (4-(4-bromo-2-nitrophenyl)piperazin-1-yl)(cyclopropyl)methanone.
  • the second step preparation of (4-(2-amino-4-bromophenyl)piperazin-1-yl)(cyclopropyl)methanone.
  • the third step preparation of N-(5-bromo-2-(4-cyclopropanoyl)piperazin-1-yl)phenyl)-3-(trifluoromethyl)benzenesulfonamide.
  • the fourth step N-(4-(4-(cyclopropanoyl)piperazin-1-yl)-3'-(difluoromethoxy)-5'-fluorobiphenyl-3-yl)-3 -Preparation of (trifluoromethyl)benzenesulfonamide.
  • Example 13 4-(4-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)piperazine Preparation of -1-yl)-4-oxobutanoic acid (Compound 13).
  • the first step 4-(4-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperazine Preparation of methyl -1-yl)-4-oxobutanoate.
  • Step 2 4-(4-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperazine Preparation of -1-yl)-4-oxobutanoic acid.
  • Example 14 1-(4-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperazine Preparation of -1-formyl)cyclopropanoic acid (Compound 14).
  • Example 16 1-(3'-(Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)piperidine-4 -Preparation of methyl formate (compound 16).
  • Example 17 1-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)piperidine-4- Preparation of formic acid (compound 17).
  • Example 18 2-(1-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)piperidine Preparation of -4-yl)acetic acid (compound 18).
  • the first step preparation of methyl 2-(1-(4-bromo-2-nitrophenyl)piperidin-4-yl)acetate.
  • the second step preparation of methyl 2-(1-(2-amino-4-bromophenyl)piperidin-4-yl)acetate.
  • the third step preparation of methyl 2-(1-(4-bromo-2-(3-(trifluoromethyl)benzenesulfonyl)phenyl)piperidin-4-yl)acetate.
  • the fourth step 2-(1-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperidine Preparation of -4-yl) methyl acetate.
  • Step 5 2-(1-(3'-Difluoromethoxy)-5'-fluoro-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperidine Preparation of -4-yl)acetic acid.
  • Example 20 N-(3'-(Difluoromethoxy)-5'-fluoro-4-(4-(methylsulfonyl)piperidin-1-yl)biphenyl-3-yl)-3- Preparation of (trifluoromethyl)benzenesulfonamide (Compound 20).
  • Example 21 N-(3'-(Difluoromethoxy)-5'-fluoro-4-(4-(2-methoxyethoxy)piperidin-1-yl)biphenyl-3- Preparation of yl)-3-(trifluoromethyl)benzenesulfonamide (Compound 21).
  • Example 22 2-(1-(3'-Chloro-5'-methoxy-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperidine-4- Preparation of methyl)acetic acid (compound 22).
  • Example 23 2-(1-(3'-Fluoro-5'-methoxy-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperidine-4- Preparation of methyl)acetic acid (compound 23).
  • Example 24 2-(1-(3'-Methoxy-5'-methyl-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperidine-4 Preparation of -yl)acetic acid (compound 24).
  • Example 25 2-(1-(3'-Chloro-5'-(difluoromethoxy)-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piper Preparation of pyridin-4-yl)acetic acid (compound 25).
  • Example 26 2-(1-(3'-Chloro-5'-ethoxy-3-(3-(trifluoromethyl)benzenesulfonylamino)biphenyl-4-yl)piperidine-4- Preparation of methyl)acetic acid (compound 26).
  • Example 27 2-(1-(3'-Chloro-5'-(trifluoromethoxy)-3-(3-(trifluoromethyl)benzenesulfonamido)biphenyl-4-yl)piper Preparation of pyridin-4-yl)acetic acid (compound 27).
  • Experimental example 1 Time-resolved fluorescence resonance energy transfer (TR-FRET) experiment of ROR ⁇ -LBD.
  • the compound to be tested was diluted with DMSO, starting with 5 ⁇ M, using a 4-fold dilution, and taking 10 concentration points.
  • Seal the plate with sealing tape shake for 2 minutes, and mix the reaction solution. Place the 384-well plate at 4°C overnight, take out the 384-well plate to room temperature equilibrium, centrifuge, and read the plate with a microplate reader (detection wavelength 665nm/615nm).
  • the activation rate of the compound (FI ratio compound- FI ratio solvent control )/(FI ratio solvent control- FI ratio negative control ) ⁇ 100%;
  • FI ratio represents the ratio of the fluorescence value (665nm) read by the microplate reader to the fluorescence value (615nm) of the microplate reader;
  • EC 50 values were calculated by GraphPad Prism software.
  • Maximum activation rate the activation rate of the corresponding concentration point when the curve obtained by the above activation rate formula is in the upper plateau; when the maximum activation rate is greater than 0, it indicates that the test compound has an agonistic effect on ROR ⁇ .
  • the compound of the present invention has a significant agonistic effect on ROR ⁇ , with an EC 50 of , for example, less than 110 nM, preferably less than 20 nM, more preferably less than 10 nM, and the maximum activation rate is above 50%.
  • Experimental example 2 ROR ⁇ -luciferase reporter gene experiment.
  • Plasmids pcDNA3.1 GAL4DBD/ROR ⁇ LBD
  • pGL4.35 luc2P/9XGAL4UAS/Hygro
  • 293T cells (purchased from ATCC);
  • 293T cells were cultured in T25 cell culture flasks with DMEM high-sugar medium (containing 10% FBS), and when they had grown to a confluency of about 80%, liposomes containing plasmids were prepared according to the Lipofectamine 3000 instructions.
  • the liposomes are mixed with a certain volume of DMEM high glucose medium (containing 10% FBS), the original medium in the T25 culture flask is removed, and the mixture of the liposome and DMEM high glucose medium is added to transfect 293T cells. 24h after transfection, the cells were digested and counted.
  • DMEM medium containing 10% FBS, 2 ⁇ M ursolic acid
  • DMSO test compound stock solution and solvent control
  • DMEM high-sugar medium containing 10% FBS, 2 ⁇ M ursic acid
  • 100 ⁇ M as the starting concentration
  • use 3-fold dilution and take 10 concentration points.
  • Add the diluted test compound and solvent control to the experimental wells and solvent control wells of a 96-well cell culture plate, respectively. Shake the cell culture plate for 2 minutes to thoroughly mix the test compound with the culture medium, and continue culturing in a 37°C, 5% CO 2 incubator for 24 hours.
  • Activation rate luminescence value of experimental wells/average luminescence value of solvent control wells ⁇ 100%.
  • the average luminescence value of the solvent control well is defined as 100%, and Graphpad Prism 5 software is used for data analysis and mapping.
  • the EC 50 value is calculated by the four-parameter fitting curve with the logarithm of the activation rate and the compound concentration; the maximum activation rate is the fitting curve The activation rate of the corresponding concentration point in the upper plateau phase; when the maximum activation rate is greater than 100%, it indicates that the test compound has an agonistic effect on ROR ⁇ .
  • Table 2 shows the results of the agonistic activity of the compounds of the present invention on ROR ⁇ in cells.
  • the compound of the present invention has a significant agonistic effect on ROR ⁇ in cells, with, for example, an EC 50 of less than 2000 nM and a maximum activation rate of greater than 300%.

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Abstract

一种联芳基类化合物，及其药物组合物，制备方法和用途。所述化合物具有式I所示结构，具有显著的RORγ调节作用，可以作为高效的RORγ调节剂，具有抗肿瘤、抗自身免疫性疾病、抗炎等多种药理活性。

Description

联芳基类化合物，包含其的药物组合物，其制备方法及其用途
相关申请的引用
本发明要求2019年9月10日在中国提交的，名称为“联芳基类化合物，包含其的药物组合物，其制备方法及其用途”、申请号为201910853525.2的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。
技术领域
本发明属于药物化学领域，涉及一种具有RORγ调节活性的新型化合物，其制备方法，包含其的药物组合物，及其医药用途。
背景技术
核受体超家族是一类配体依赖性的转录因子，共有48个家族成员(ZHANG Y,LUO X Y,WU D H,et al.,ROR nuclear receptors:structures,related diseases,and drug discovery[J],Acta Pharmacologica Sinica,2015,36(1):71-87)。根据核受体的配体类型不同，可将48个超家族成员分为：类固醇激素受体、非类固醇激素受体和孤儿受体等三种主要类型。其中，类固醇激素受体包括糖皮质激素受体(glucocorticoid receptor，GR)、盐皮质激素受体(mineralcorticoid receptor，MR)、雄激素受体(androgen receptor，AR)、雌激素受体(estrone receptor，ER)、孕激素受体(progestogen receptor，PR)等；非类固醇激素受体包括甲状腺激素受体(thyroid hormone receptor，TR)、维甲酸受体(或称维A酸受体、视黄酸受体)(retinoic acid receptor，RAR)、维甲酸X受体(retinoid X receptor，RXR)和维生素D3受体(vitamin D3 receptor，VDR)等；孤儿受体，因其目前尚未发现其内源性配体而得名。孤儿受体家族成员包括维甲酸受体相关孤儿受体(retinoic acid receptor-related orphan receptor，ROR)、法尼醇X受体(farnesoid X receptor，FXR)、过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor，PPAR)、肝X受体(liver X receptor，LXR)等。
ROR超家族成员中包括RORα、RORβ和RORγ三种亚型，在多种生理过程中发挥调控作用。近年来的研究发现，相较于维甲酸，ROR家族各成员与氧化类固醇衍生物的亲和力更高，并为其所调控。ROR广泛分布于机体的各个组织中，能够直接进入细胞核来调节靶基因的转录，进而参与不同的生理过程，表现出不同的组织特异性。其中，RORα在各种组织中均有表达，但在大脑中高表达，在小脑发展和骨形成中发挥重要作用。RORβ的作用范围较小，主要在大脑中表达，在视网膜、大脑皮层发展中发挥作用。RORγ可以在许多组织中表达，包括胸腺、肝脏和骨骼肌等，在次级淋巴组织发展中发挥关键作用。
RORγ有RORγ1和RORγ2(RORγt)两种亚型。RORγ1在多种组织中表达，而RORγ2特异性表达在免疫细胞上。RORγ2是Th17和Tc17效应T细胞分化与维持的关键转录因子，调节Th17细胞分泌效应因子IL-17，并在NK细胞、γδT细胞以及iNKT细胞的分化中发挥重要作用，这些细胞可介导免疫系统来对抗癌细胞以及细菌、真菌等病原微生物。在肿瘤微环境中，Thl7细胞和IL-17可招募自然杀伤细胞和细胞毒性CD8+T细胞对肿瘤细胞进行攻击和杀伤。一些研究显示，卵巢癌病人肿瘤部位浸润Thl7细胞水平和IL-17表达水平与良好的预后呈正相关关系。
针对癌症的治疗，尽管已进行了大量的研究，付出了巨大的努力，但其仍然是人类健康的一大威胁。无论在发达国家，还是在发展中国家，癌症都是死亡率最高的疾病，并且发病率和死亡率仍不断增高。目前，针对肿瘤的治疗药物并非对所有的肿瘤病人均有效，而RORγ调节剂的开发在医药工业界已逐渐得到重视，例如WO2017157332A1、WO2011115892A1等。因此，研究和开发RORγ调节活性高、副作用少、抗耐药性强、药代动力学等性质得到改善的化合物可能对肿瘤的治疗将有所助益，为肿瘤病人的治疗提供更多选择。
发明内容
发明要解决的问题
本发明旨在提供一种对于RORγ活性具有调节作用的新型化合物，该化合物的制备方法，包含该化合物的药物组合物，以及该化合物的医药用途。
用于解决问题的方案
第一方面，本发明提供了一种具有式I结构的化合物或其药学上可接受的形式，
Figure PCTCN2020112483-appb-000001
其中，
环A 1选自苯基和5-6元杂芳基；
环A 2选自苯基、5-6元杂芳基和3-6元杂环基；
环A 3选自苯基、5-10元杂芳基、3-10元环烷基和4-10元杂环基；
Z 1、Z 2和Z 3各自独立地选自CR 4和N；
R 1选自氢和C 1-6烷基；
每一个R 2各自独立地选自卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 3-6环烷氧基；
每一个R 3各自独立地选自卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6卤代烷氧基和-S(＝O) 2-R 6；
每一个R 4各自独立地选自氢、卤素、氰基、C 1-6烷基和C 1-6烷氧基；
每一个R 5各自独立地选自氢、卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、-C 0-6亚烷基-O-R a、-O-C 1-6亚烷基-O-R a、C 1-6卤代烷氧基、-C 0-6亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-6亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-C(＝O)-C 1-6烷基、-C 0-6亚烷基-S(＝O) 2-R 6、-C 0-6亚烷基-N(R a)(R b)、-C 0-6亚烷基-C(＝O)-N(R a)(R b)、-C 0-6亚烷基-N(R a)-C(＝O)-R 6、-C 0-6亚烷基-S(＝O) 2-N(R a)(R b)、-C 0-6亚烷基-N(R a)-S(＝O) 2-R 6、4-10元杂环基、苯基和5-10元杂芳基；其中：每一个R a各自独立地选自氢和C 1-6烷基；每一个R b各自独立地选自氢和C 1-6烷基；或者R a和R b连同与其相连的氮原子形成3-7元杂环基；
每一个R 6各自独立地选自C 1-6烷基和C 3-6环烷基；
m为1、2或3；
n为0、1、2或3；
q为0、1、2或3；
所述药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。
第二方面，本发明提供了具有式I结构的具体化合物，其包括：
(1)2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)乙酸；
(2)N-(3’-(二氟甲氧基)-5’-氟-4-(1-(2-甲氧基乙基)-1H-吡唑-3-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(3)2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)-N,N-二甲基乙酰胺；
(4)N-(3’-(二氟甲氧基)-5’-氟-4-(1-异丙基-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(5)N-(3’-(二氟甲氧基)-4-(1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(6)N-(3’-(二氟甲氧基)-5’-氟-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(7)(S)-N-(3’-(二氟甲氧基)-5’-氟-4-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(8)(R)-N-(3’-(二氟甲氧基)-5’-氟-4-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(9)N-(3’-(二氟甲氧基)-4-(1-乙基-1H-吡唑-4-基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(10)2-(4-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-5,6-二氢吡啶-1(2H)-基)乙酸；
(11)N-(3’-(二氟甲氧基)-5’-氟-4-(噻唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(12)N-(4-(4-(环丙甲酰基)哌嗪-1-基)-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(13)4-(4-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-基)-4-氧代丁酸；
(14)1-(4-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-甲酰基)环丙甲酸；
(15)N-(3’-(二氟甲氧基)-5’-氟-4-吗啉基联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(16)1-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-甲酸甲酯；
(17)1-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-甲酸；
(18)2-(1-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸；
(19)N-(3’-(二氟甲氧基)-5’-氟-4-(4-羟基-4-甲基哌啶-1-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(20)N-(3’-(二氟甲氧基)-5’-氟-4-(4-(甲磺酰基)哌啶-1-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(21)N-(3’-(二氟甲氧基)-5’-氟-4-(4-(2-甲氧基乙氧基)哌啶-1-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺；
(22)2-(1-(3’-氯-5’-甲氧基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸；
(23)2-(1-(3’-氟-5’-甲氧基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸；
(24)2-(1-(3’-甲氧基-5’-甲基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸；
(25)2-(1-(3’-氯-5’-(二氟甲氧基)-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸；
(26)2-(1-(3’-氯-5’-乙氧基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸；
(27)2-(1-(3’-氯-5’-(三氟甲氧基)-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸。
第三方面，本发明提供了上述具有式I结构的化合物的制备方法，其包括下列步骤：
(1)将化合物A与化合物B反应，得到化合物C；
Figure PCTCN2020112483-appb-000002
(2)化合物C发生取代反应，得到化合物D；
Figure PCTCN2020112483-appb-000003
(3)化合物D发生还原反应以及可选的N-烷基化反应，得到化合物E；
Figure PCTCN2020112483-appb-000004
(4)将化合物E与化合物F反应，得到化合物G；
Figure PCTCN2020112483-appb-000005
(5)将化合物G与化合物H反应，得到式I化合物；
Figure PCTCN2020112483-appb-000006
其中，环A 1、环A 2、环A 3、Z 1、Z 2、Z 3、R 1、R 2、R 3、R 5、m、n和q如式I中所定义；X表示离去基团，包括(但不限于)卤素原子、甲磺酰氧基和三氟甲磺酰氧基；
或者包括下列步骤：
(1’)将化合物A’与化合物B’反应，得到化合物C’；
Figure PCTCN2020112483-appb-000007
(2’)化合物C’发生还原反应以及可选的N-烷基化反应，得到化合物D’；
Figure PCTCN2020112483-appb-000008
(3’)将化合物D’与化合物F反应，得到化合物F’；
Figure PCTCN2020112483-appb-000009
(4’)将化合物F’与化合物B反应，得到式I化合物；
Figure PCTCN2020112483-appb-000010
其中，环A 1、环A 2、环A 3、Z 1、Z 2、Z 3、R 1、R 2、R 3、R 5、m、n和q如式I中所定义；X表示离去基团，包括(但不限于)卤素原子、甲磺酰氧基和三氟甲磺酰氧基；Hal表示卤素原子，包括(但不限于)F、Cl、Br和I，优选F和Cl。
第四方面，本发明提供了一种药物组合物，其包含上述具有式I结构的化合物或其药学上可接受的形式，以及药学上可接受的载体。
第五方面，本发明提供了上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物，其用作RORγ调节剂。
第六方面，本发明提供了上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物用作RORγ调节剂的用途。优选地，所述RORγ调节剂用于预防和/或治疗至少部分由RORγ介导的疾 病。
第七方面，本申请提供了上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物在制备用于预防和/或治疗至少部分由RORγ介导的疾病的药物中的用途。优选地，所述至少部分由RORγ介导的疾病选自癌症、炎症和自身免疫性疾病。
第八方面，本发明提供了一种用于预防和/或治疗至少部分由RORγ介导的疾病的方法，其包括下列步骤：将治疗有效量的上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物施用于对其有需求的患者。
第九方面，本发明提供了一种药物联用组合物，其包含上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物，以及至少一种其他的同向RORγ调节剂。
第十方面，本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的且作为RORγ激动剂的上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
第十一方面，本发明提供了一种用于预防和/或治疗炎症的方法，其包括下列步骤：将治疗有效量的且作为RORγ拮抗剂的上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
第十二方面，本发明提供了一种用于预防和/或治疗自身免疫性疾病的方法，其包括下列步骤：将治疗有效量的且作为RORγ拮抗剂的上述具有式I结构的化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
发明的效果
本发明提供了一种结构新颖的式I化合物，其可以作为高效的RORγ调节剂，具有抗肿瘤、抗自身免疫性疾病、抗炎等多种药理活性，且副作用少、抗耐药性强、药代动力学等性质得到有效改善。合成方法温和，操作简单易行，适合工业放大量生产。
具体实施方式
在进一步描述本发明之前，应当理解，本发明不限于文中所述的特定实施方案；还应该理解，文中所使用的术语仅用于描述而非限制特定实施方案。
[术语定义]
除非另有说明，下列术语在本发明中的含义如下。
术语“包含”、“包括”、“具有”或“含有”或其任何其他变体旨在涵盖非排他性的包含内容。例如，包含一系列元素的组合物、方法或装置不一定仅限于已明确列出的元素，而是可能还包含其他未明确列出的元素或上述组合物、方法或装置所固有的元素。
“药学上可接受的盐”是指对生物体基本上无毒性的，本发明的化合物的盐。药学上可接受的盐通常包括(但不限于)本发明的化合物与药学上可接受的无机/有机酸或无机/有机碱反应而形成的盐，此类盐又被称为酸加成盐或碱加成盐。
术语“异构体”是指因具有相同的原子数和原子类型而具有相同的分子量，但原子的空间排列或构型不同的化合物。
术语“立体异构体”(或称“旋光异构体”)是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面，从而能够使平面偏振光旋转的稳定异构体。由于本发明的化合物存在可能导致立体异构的不对称中心以及其他化学结构，因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物(或其药学上可接受的盐)包括不对称碳原子，因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常，这些化合物能够以外消旋物的形式制备。然而，如果需要的话，可以将这类化合物制备或分离后得到纯的立体异构体，即单一对映异构体或非对映异构体，或者单一立体异构体富集化(纯度≥98％、≥95％、≥93％、≥90％、≥88％、≥85％或≥80％)的混合物。如下文中所述，化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的，或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的，例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂， 或者在手性色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到，也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。术语“对映异构体”是指彼此具有不能重叠的镜像的一对立体异构体。术语“非对映异构体”或“非对映体”是指彼此不构成镜像的旋光异构体。术语“外消旋混合物”或“外消旋物”是指含有等份的单一对映异构体的混合物(即两种R和S对映体的等摩尔量混合物)。术语“非外消旋混合物”是指含有不等份的单一对映异构体的混合物。除非另外指出，本发明的化合物的所有立体异构体形式都在本发明的范围之内。
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的，可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化等。除非另外指出，本发明的化合物的所有互变异构体形式都在本发明的范围之内。
术语“顺反异构体”是指位于双键或环系两侧的原子(或基团)因相对于参考平面的位置不同而形成的立体异构体；在顺式异构体中原子(或基团)位于双键或环系的同侧，在反式异构体中原子(或基团)位于双键或环系的异侧。除非另外指出，本发明的化合物的所有顺反异构体形式都在本发明的范围之内。
术语“多晶型物”(或称“多晶型形式”)是指化合物或复合物的固体晶体形式。本领域技术人员可通过许多已知的方法获得分子的多晶型物。这些方法包括(但不限于)熔融重结晶、熔融冷却、溶剂重结晶、去溶剂化、快速蒸发、快速冷却、慢速冷却、气相扩散和升华。另外，可用熟知的技术检测、分类和鉴定多晶型物，这些技术包括(但不限于)差示扫描量热法(DSC)、热重分析法(TGA)、X射线粉末衍射法(XRPD)、单晶X射线衍射法(SCXRD)、固态核磁共振(NMR)、红外光谱法(IR)、拉曼光谱法和扫描电镜术(SEM)等。
术语“溶剂化物”是指由本发明的化合物(或其药学上可接受的盐)与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。
术语“N-氧化物”是指叔胺类或含氮(芳)杂环类化合物结构中的氮原子经氧化而形成的化合物。常见的N-氧化物包括(但不限于)三甲胺-N-氧化物、4-甲基吗啉-N-氧化物、吡啶-N-氧化物等。本发明的式I化合物母核中1a位是叔胺氮原子，可以形成相应的N-氧化物；另外，当母核中3位上与氮原子直接相连的基团不为(磺)酰基时，则3位也是叔胺氮原子，同样可以形成相应的N-氧化物。
术语“同位素标记物”是指将本发明的化合物中的特定原子替换为其同位素原子而形成的衍生化合物。除非另外指出，本发明的化合物包括H、C、N、O、F、P、S、Cl的各种同位素，如 2H(D)、 3H(T)、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S、 36S和 37Cl。
术语“代谢物”是指本发明的化合物经代谢后形成的衍生化合物。关于代谢的进一步信息可参见Goodman and Gilman’s:The Pharmacological Basis of Therapeutics(9 th ed.)[M],McGraw-Hill International Editions,1996。
术语“前药”是指在施用于患者后能够直接或间接地提供本发明的化合物的衍生化合物。特别优选的衍生化合物或前药是在施用于患者时可以提高本发明的化合物的生物利用度的化合物(例如，更易吸收入血)，或者促进母体化合物向作用位点(例如，淋巴系统)递送的化合物。除非另外指出，本发明的化合物的所有前药形式都在本发明的范围之内，且各种前药形式是本领域熟知的。
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如，取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当取代基X为氢时，取代基Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理，当取代基Y为氢时，取代基X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。
术语“烷基”是指一价的直链或支链的烷烃基团，其由碳原子和氢原子构成，不含不饱和度，并且通过一个单键连接至其他基团，例如C 1-6烷基是指含有1-6个碳原子的烷基，C 1-4烷基是指含有1-4个碳原子的烷基；常见的烷基包括(但不限于)甲基(-CH 3)、乙基(-CH 2CH 3)、正丙基(-CH 2CH 2CH 3)、异丙基(-CH(CH 3) 2)、正丁基(-CH 2CH 2CH 2CH 3)、仲丁基(-CH(CH 3)CH 2CH 3)、异丁基(-CH 2CH(CH 3) 2)、 叔丁基(-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、新戊基(-CH 2C(CH 3) 3)等。
术语“亚烷基”是指二价的直链或支链的烷烃基团，其由碳原子和氢原子构成，不含不饱和度，并且通过一个单键连接至一个基团，通过另一个单键连接至其他基团(或环系)，文中所使用的“C 0-6亚烷基”是指含有0-6个碳原子的亚烷基，0个碳原子的亚烷基表示共价键，例如C 1-6亚烷基是指含有1-6个碳原子的亚烷基，C 1-4亚烷基是指含有1-4个碳原子的亚烷基；常见的亚烷基包括(但不限于)亚甲基(-CH 2-)、1,2-亚乙基(-CH 2CH 2-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1-甲基-1,2-亚乙基(-CH(CH 3)CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)、1-甲基-1,3-亚丙基(-CH(CH 3)CH 2CH 2-)、1,1-二甲基-1,2-亚乙基(-C(CH 3) 2CH 2-)、1,2-二甲基-1,2-亚乙基(-CH(CH 3)CH(CH 3)-)等。
术语“卤代烷基”是指一价的直链或支链的烷基，其被至少一个选自氟、氯、溴和碘的原子取代，不含不饱和度，并且通过一个单键连接至其他基团，例如C 1-6卤代烷基是指被至少一个选自氟、氯、溴和碘的原子取代的C 1-6烷基，C 1-4卤代烷基是指被至少一个选自氟、氯、溴和碘的原子取代的C 1-4烷基；常见的卤代烷基包括(但不限于)氟甲基(-CH 2F)、二氟甲基(-CHF 2)、三氟甲基(-CF 3)、1-氟乙基(-CHFCH 3)、2-氟乙基(-CH 2CH 2F)、1,2-二氟乙基(-CHFCH 2F)、2,2-二氟乙基(-CH 2CHF 2)、1,2,2-三氟乙基(-CHFCHF 2)、2,2,2-三氟乙基(-CH 2CF 3)等。
术语“环烷基”是指一价的单环或多环(包含桥环和螺环形式)的非芳香族环烃基，其仅由碳原子和氢原子构成，不含不饱和度，并且通过一个单键连接至其他基团，例如C 3-10环烷基是指含有3-10个碳原子的环烷基，C 3-6环烷基是指含有3-6个碳原子的环烷基；常见的环烷基包括(但不限于)环丙基、环丁基、环戊基、环己基、十氢萘基(又称为十氢化萘基、萘烷基)、金刚烷基等。其他合适的环烷基包括(但不限于)螺戊基、二环[2.1.0]戊基、二环[3.1.0]己基、螺[2.4]庚基、螺[2.5]辛基、二环[5.1.0]辛基、螺[2.6]壬基、二环[2.2.0]己基、螺[3.3]庚基、二环[4.2.0]辛基、和螺[3.5]壬基。环烷基任选地被一个或多个本发明所描述的取代基所取代。
术语“亚环烷基”是指二价的单环或多环(包含桥环和螺环形式)的非芳香族环烃基，其仅由碳原子和氢原子构成，不含不饱和度，并且通过一个单键连接至一个基团，通过另一个单键连接至其他基团，例如C 3-10亚环烷基含有3-10个碳原子的亚环烷基，C 3-6亚环烷基含有3-6个碳原子的亚环烷基；常见的亚环烷基包括(但不限于)环丙烷-1,1-亚基、环丙烷-1,2-亚基、环丁烷-1,1-亚基、环丁烷-1,2-亚基、环丁烷-1,3-亚基等。
术语“杂环基”是指一价的单环或多环(包含桥环和螺环形式)的非芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成，并且通过一个单键连接至其他基团，例如3-10元杂环基、3-7元杂环基或4-10元杂环基；常见的杂环基包括(但不限于)环氧乙烷基、氧杂环丁烷-3-基、氮杂环丁烷-3-基、四氢呋喃-2-基、吡咯烷-1-基、吡咯烷-2-基、四氢-2H-吡喃-2-基、四氢-2H-吡喃-4-基、哌啶-2-基、哌啶-4-基、四氢吡啶基等。杂环基任选地被一个或多个本发明所描述的取代基所取代。
术语“亚杂环基”是指二价的单环或多环(包含桥环和螺环形式)的非芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成，并且通过一个单键连接至一个基团，通过另一个单键连接至其他基团(或环系)，例如3-10元亚杂环基、3-7元亚杂环基或4-10元亚杂环基；常见的亚杂环基包括(但不限于)氧杂环丙烷-2,2-亚基、氧杂环丙烷-2,3-亚基、氮杂环丁烷-2,2-亚基、氮杂环丁烷-2,3-亚基、氮杂环丁烷-2,4-亚基、四氢呋喃-2,5-亚基、四氢-2H-吡喃-2,3-亚基、四氢-2H-吡喃-2,4-亚基、四氢-2H-吡喃-2,5-亚基、四氢-2H-吡喃-2,6-亚基、吡咯烷-1,2-亚基、吡咯烷-1,3-亚基、吡咯烷-2,3-亚基、吡咯烷-2,4-亚基、吡咯烷-2,5-亚基、哌啶-1,2-亚基、哌啶-1,3-亚基、哌啶-1,4-亚基、哌啶-2,3-亚基、哌啶-2,4-亚基、哌啶-2,5-亚基、哌啶-2,6-亚基等。
术语“芳基”是指一价的单环或多环(包含稠合形式)的全碳芳香族环系，其环原子仅由碳原子构成，并且通过一个单键连接至其他基团，例如C 6-10芳基；常见的芳基包括(但不限于)苯基、萘基、蒽基、菲基、苊基、薁基、芴基、茚基、芘基等。芳基任选地被一个或多个本发明所描述的取代基所取代。
术语“杂芳基”是指一价的单环或多环(包含稠合形式)的芳香族环系，其环原子由碳原子及选自硼、氮、氧、硫、磷和砷的杂原子构成，并且通过一个单键连接至其他基团，例如本文中所使用的“5-10元杂芳基”是指环原子总数为5-10的单环或多环(包括稠合形式)的芳香族环系；常见的杂环基包括 (但不限于)苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并噻唑基、咪唑并吡啶基、吖啶基、咔唑基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、吡唑基、异噁唑基、异噻唑基、吲唑基、吲嗪基、吲哚基、喹啉基、异喹啉基、喹喔啉基、吩嗪基、吩噁嗪基、吩噻嗪基、蝶啶基、嘌呤基、吡嗪基、嘧啶基、哒嗪基、吡啶基、三唑基、四唑基等。杂芳基任选地被一个或多个本发明所描述的取代基所取代。
术语“烷氧基”是指一价的直链或支链的烷基-O-基团，其仅由碳原子、氢原子和氧原子构成，可以含有不饱和度，并且通过一个与氧原子相连的单键连接至其他基团，例如C 1-6烷氧基、C 1-4烷氧基；常见的烷氧基包括(但不限于)甲氧基(-OCH 3)、乙氧基(-OCH 2CH 3)、正丙氧基(-OCH 2CH 2CH 3)、异丙氧基(-OCH(CH 3) 2)、正丁氧基(-OCH 2CH 2CH 2CH 3)、仲丁氧基(-OCH(CH 3)CH 2CH 3)、异丁氧基(-OCH 2CH(CH 3) 2)、叔丁氧基(-OC(CH 3) 3)、正戊氧基(-OCH 2CH 2CH 2CH 2CH 3)、新戊氧基(-OCH 2C(CH 3) 3)等。
术语“卤代烷氧基”是指一价的直链或支链的卤代烷基-O-基团，其被至少一个选自氟、氯、溴和碘的原子取代，可以含有不饱和度，并且通过一个与氧原子相连的单键连接至其他基团，例如C 1-6卤代烷氧基、C 1-4卤代烷氧基；常见的卤代烷氧基包括(但不限于)氟甲氧基(-OCH 2F)、二氟甲氧基(-OCHF 2)、三氟甲氧基(-OCF 3)、1-氟乙氧基(-OCHFCH 3)、2-氟乙氧基(-OCH 2CH 2F)、1,2-二氟乙氧基(-OCHFCH 2F)、2,2-二氟乙氧基(-OCH 2CHF 2)、1,2,2-三氟乙氧基(-OCHFCHF 2)、2,2,2-三氟乙氧基(-OCH 2CF 3)等。
术语“环烷氧基”是指由环烷基和氧原子构成的一价基团，并且通过一个与氧原子相连的单键连接至其他基团，例如C 3-6环烷氧基；常见的环烷氧基包括(但不限于)环丙氧基、环丁氧基、环戊氧基、环己氧基、十氢萘氧基、金刚烷氧基等。
[通式化合物]
本发明提供了一种式I化合物或其药学上可接受的形式，
Figure PCTCN2020112483-appb-000011
其中，
环A 1选自苯基和5-6元杂芳基；
环A 2选自苯基、5-6元杂芳基和3-6元杂环基；
环A 3选自苯基、5-10元杂芳基、3-10元环烷基和4-10元杂环基；
Z 1、Z 2和Z 3各自独立地选自CR 4和N；
R 1选自氢和C 1-6烷基；
每一个R 2各自独立地选自卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 3-6环烷氧基；
每一个R 3各自独立地选自卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6卤代烷氧基和-S(＝O) 2-R 6；
每一个R 4各自独立地选自氢、卤素、氰基、C 1-6烷基和C 1-6烷氧基；
每一个R 5各自独立地选自氢、卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、-C 0-6亚烷基-O-R a、-O-C 1-6亚烷基-O-R a、C 1-6卤代烷氧基、-C 0-6亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-6亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-C(＝O)-R 6、-C 0-6亚烷基-S(＝O) 2-R 6、-C 0-6亚烷基-N(R a)(R b)、-C 0-6亚烷基-C(＝O)-N(R a)(R b)、-C 0-6亚烷基-N(R a)-C(＝O)-R 6、-C 0-6亚烷基-S(＝O) 2-N(R a)(R b)、-C 0-6亚烷基-N(R a)-S(＝O) 2-R 6、4-10元杂环基、苯基和5-10元杂芳基；其中：每一个R a各自独立地选自氢和C 1-6烷基；每一个R b各自独立地选自氢和C 1-6烷基；或者R a和R b连同与其相连的氮原子形成3-7元杂环基；
每一个R 6各自独立地选自C 1-6烷基和C 3-6环烷基；
m为1、2或3；
n为0、1、2或3；
q为0、1、2或3；
该药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。
在本发明的一些实施方案中，上述式I化合物或其药学上可接受的形式为式I-A化合物或其药学上可接受的形式，
Figure PCTCN2020112483-appb-000012
其中，环A 1、环A 2、环A 3、R 2、R 3、R 5、m、n和q如上文中所定义。
在本发明的一些实施方案中，m为1或2，优选为2。
在本发明的一些实施方案中，n为1或2，优选为1。
在本发明的一些实施方案中，q为0、1或2。
在本发明的一些实施方案中，q为1或2。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1选自苯基和吡啶基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1为苯基。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 2各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 3-6环烷氧基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 2各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基和C 1-4卤代烷氧基。
在本发明的一些更优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 2各自独立地选自卤素、氰基、C 1-3卤代烷基、C 3-6环烷基、C 1-3烷氧基和C 1-3卤代烷氧基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 2各自独立地选自氟、氯、氰基、甲氧基和二氟甲氧基。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1选自苯基和吡啶基，每一个R 2各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 3-6环烷氧基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1选自苯基，每一个R 2各自独立地选自卤素、氰基、C 1-3卤代烷基、C 3-6环烷基、C 1-3烷氧基和C 1-3卤代烷氧基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1选自苯基，每一个R 2各自独立地选自卤素、氰基、C 1-4烷基、C 1-3烷氧基和C 1-3卤代烷氧基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1为苯基；每一个R 2各自独立地选自氟、氯、氰基、甲基、甲氧基、乙氧基、二氟甲氧基和三氟甲氧基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1为苯基；每一个R 2各自独立地选自氟、氯、甲基、甲氧基、乙氧基、二氟甲氧基和三氟甲氧基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环 A 1为苯基；每一个R 2各自独立地选自氟、氯、氰基、甲氧基和二氟甲氧基。
在本发明的一些更特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 1为苯基，每一个R 2各自独立地选自氟和二氟甲氧基。
在本发明的一些更特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的
Figure PCTCN2020112483-appb-000013
选自
Figure PCTCN2020112483-appb-000014
在本发明的一些更特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的
Figure PCTCN2020112483-appb-000015
为
Figure PCTCN2020112483-appb-000016
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2选自苯基和5-6元杂芳基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2选自苯基和吡啶基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2为苯基。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 3各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和-S(＝O) 2-C 1-4烷基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 3各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基和-S(＝O) 2-C 1-4烷基。
在本发明的一些优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的R 3为C 1- 4卤代烷基，优选地，R 3为三氟甲基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的每一个R 3各自独立地选自氟、氰基、甲基、三氟甲基和甲磺酰基。
在本发明的一些特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的R 3为三氟甲基。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2选自苯基和5-6元杂芳基；每一个R 3各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和-S(＝O) 2-C 1-4烷基。
在本发明的一些优选实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2选自苯基和吡啶基，每一个R 3各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 1-4卤代烷氧基和-S(＝O) 2-C 1-4烷基。
在本发明的一些优选实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2选自苯基和吡啶基，R 3为C 1-4卤代烷基。
在本发明的一些优选实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2选自苯基，每一个R 3各自独立地选自氟、氰基、甲基、三氟甲基和甲磺酰基。
在本发明的一些更特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的环A 2为苯基；R 3为三氟甲基。
在本发明的一些更特别优选的实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中的
Figure PCTCN2020112483-appb-000017
为
Figure PCTCN2020112483-appb-000018
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中，
环A 1为苯基和5-6元杂芳基；
每一个R 2各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、 C 1-4卤代烷氧基和C 3-6环烷氧基；
环A 2选自苯基和5-6元杂芳基；
每一个R 3各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和-S(＝O) 2-C 1-4烷基；
环A 3选自苯基、5-10元杂芳基和4-10元杂环基；
每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；
q为0、1或2；
m为1或2；
n为1或2。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式中，
环A 1为苯基；
每一个R 2各自独立地选自氟、氯、甲基、甲氧基、乙氧基、二氟甲氧基和三氟甲氧基；
环A 2选自苯基和5-6元杂芳基；
R 3为三氟甲基；
环A 3选自吡唑基、四氢吡啶基、噻唑基、哌嗪基、吗啉基和哌啶基；
每一个R 5各自独立地选自氢、羟基、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2COOH、-CH 2CH 2OCH 3、-CH 2C(＝O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、
Figure PCTCN2020112483-appb-000019
-C(＝O)CH 2CH 2COOH、
Figure PCTCN2020112483-appb-000020
-COOCH 3、-COOH、-S(＝O) 2-CH 3和-OCH 2CH 2OCH 3；
q为0、1或2；
m为2；
n为1。
在本发明的一些实施方案中，上述式I或式I-A化合物或其药学上可接受的形式为式I-B1化合物或其药学上可接受的形式，
Figure PCTCN2020112483-appb-000021
其中，环A 3、R 2、R 5、m和q如上文中所定义。
在本发明的一些实施方案中，上述式I、式I-A或式I-B1化合物或其药学上可接受的形式中的每一个R 2各自独立地选自氟、氯、甲基、甲氧基、乙氧基、二氟甲氧基和三氟甲氧基。
在本发明的一些实施方案中，上述式I、式I-A或式I-B1化合物或其药学上可接受的形式中，
每一个R 2各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 3-6环烷氧基；
环A 3选自苯基、5-10元杂芳基和4-10元杂环基；
每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；
q为0、1或2；
m为1或2。
在本发明的一些实施方案中，上述式I、式I-A或式I-B1化合物或其药学上可接受的形式中，
每一个R 2各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；
环A 3选自5-6元杂芳基和5-6元杂环基；
每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；
q为0、1或2；
m为2。
在本发明的一些实施方案中，上述式I、式I-A或式I-B1化合物或其药学上可接受的形式中，
每一个R 2各自独立地选自氟、氯、甲基、甲氧基、乙氧基、二氟甲氧基和三氟甲氧基；
环A 3选自吡唑基、四氢吡啶基、噻唑基、哌嗪基、吗啉基和哌啶基；
每一个R 5各自独立地选自氢、-OH、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2COOH、-CH 2CH 2OCH 3、-CH 2C(＝O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、
Figure PCTCN2020112483-appb-000022
-C(＝O)CH 2CH 2COOH、
Figure PCTCN2020112483-appb-000023
-COOCH 3、-COOH、-S(＝O) 2-CH 3和-OCH 2CH 2OCH 3；
q为0、1或2；
m为2。
在本发明的一些实施方案中，上述式I、式I-A或式I-B1化合物或其药学上可接受的形式为式I-B化合物或其药学上可接受的形式，
Figure PCTCN2020112483-appb-000024
其中，环A 3、R 5和q如上文中所定义。
在本发明的一些实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自苯基、5-10元杂芳基和4-10元杂环基。
在本发明的一些实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自5-6元杂芳基和5-6元杂环基。
在本发明的一些优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自吡唑基、四氢吡啶基、噻唑基、哌嗪基、吗啉基和哌啶基。
在本发明的一些特别优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自
Figure PCTCN2020112483-appb-000025
在本发明的一些实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的每一个R 5各自独立地选自氢、卤素、氰基、羟基、C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、-C 0-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、C 1-3卤代烷氧基、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-C(＝O)-R 6、-C 0-3亚烷基-S(＝O) 2-R 6、-C 0-3亚烷基-N(R a)(R b)、-C 0-3亚烷基-C(＝O)-N(R a)(R b)、-C 0-3亚烷基-N(R a)-C(＝O)-R 6、-C 0-3亚烷基-S(＝O) 2-N(R a)(R b)、-C 0-3亚烷基-N(R a)-S(＝O) 2-R 6、4-6元杂环基、苯基和5-6元杂芳基；其中：每一个R a各自独 立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；每一个R 6各自独立地选自C 1-3烷基和C 3-6环烷基。
在本发明的一些实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的每一个R 5各自独立地选自氢、卤素、氰基、羟基、C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、-C 0-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、C 1-3卤代烷氧基、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-C(＝O)-C 1-6烷基、-C 0-3亚烷基-S(＝O) 2-R 6、-C 0-3亚烷基-N(R a)(R b)、-C 0-3亚烷基-C(＝O)-N(R a)(R b)、-C 0-3亚烷基-N(R a)-C(＝O)-R 6、-C 0-3亚烷基-S(＝O) 2-N(R a)(R b)、-C 0-3亚烷基-N(R a)-S(＝O) 2-R 6、4-6元杂环基、苯基和5-6元杂芳基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；每一个R 6各自独立地选自C 1-3烷基和C 3-6环烷基。
在本发明的一些优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C(＝O)-O-R a、-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基。
在本发明的一些特别优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的每一个R 5各自独立地选自氢、羟基、甲基、乙基、异丙基、-CH 2CH 2-O-CH 3、-O-CH 2CH 2-O-CH 3、-C(＝O)-O-H、-C(＝O)-O-CH 3、-CH 2-C(＝O)-O-H、-C(＝O)-CH 2CH 2-C(＝O)-O-H、
Figure PCTCN2020112483-appb-000026
-S(＝O) 2-CH 3、-CH 2CH 2-N(CH 3) 2、-CH 2-C(＝O)-N(CH 3) 2和
Figure PCTCN2020112483-appb-000027
在本发明的一些实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自苯基、5-10元杂芳基和4-10元杂环基；每一个R 5各自独立地选自氢、卤素、氰基、羟基、C 1-3烷基、C 1-3卤代烷基、C 3-6环烷基、-C 0-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、C 1-3卤代烷氧基、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-C(＝O)-R 6、-C 0-3亚烷基-S(＝O) 2-R 6、-C 0-3亚烷基-N(R a)(R b)、-C 0-3亚烷基-C(＝O)-N(R a)(R b)、-C 0-3亚烷基-N(R a)-C(＝O)-R 6、-C 0-3亚烷基-S(＝O) 2-N(R a)(R b)、-C 0-3亚烷基-N(R a)-S(＝O) 2-R 6、4-6元杂环基、苯基和5-6元杂芳基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1- 3烷基；每一个R 6各自独立地选自C 1-3烷基和C 3-6环烷基。
在本发明的一些优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自吡唑基、四氢吡啶基、噻唑基、哌嗪基、吗啉基和哌啶基；每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C(＝O)-O-R a、-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基。
在本发明的一些特别优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的环A 3选自
Figure PCTCN2020112483-appb-000028
每一个R 5各自独立地选自氢、羟基、甲基、乙基、异丙基、-CH 2CH 2-O-CH 3、-O-CH 2CH 2-O-CH 3、-C(＝O)-O-H、-C(＝O)-O-CH 3、-CH 2-C(＝O)-O-H、-C(＝O)-CH 2CH 2-C(＝O)-O-H、
Figure PCTCN2020112483-appb-000029
-S(＝O) 2-CH 3、-CH 2CH 2-N(CH 3) 2、-CH 2-C(＝O)-N(CH 3) 2和
Figure PCTCN2020112483-appb-000030
在本发明的一些更特别优选的实施方案中，上述式I、式I-A、式I-B1或式I-B化合物或其药学上可接受的形式中的
Figure PCTCN2020112483-appb-000031
选自
Figure PCTCN2020112483-appb-000032
Figure PCTCN2020112483-appb-000033
另外，本发明还提供了如下化合物或其药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药，其结构及名称如下表所示：
Figure PCTCN2020112483-appb-000034
Figure PCTCN2020112483-appb-000035
Figure PCTCN2020112483-appb-000036
Figure PCTCN2020112483-appb-000037
[制备方法]
本发明提供了上述式I化合物的制备方法，其包括下列步骤：
(1)将化合物A与化合物B反应，得到化合物C；
Figure PCTCN2020112483-appb-000038
(2)化合物C发生取代反应，得到化合物D；
Figure PCTCN2020112483-appb-000039
(3)化合物D发生还原反应以及可选的N-烷基化反应，得到化合物E；
Figure PCTCN2020112483-appb-000040
(4)将化合物E与化合物F反应，得到化合物G；
Figure PCTCN2020112483-appb-000041
(5)将化合物G与化合物H反应，得到式I化合物；
Figure PCTCN2020112483-appb-000042
其中，环A 1、环A 2、环A 3、Z 1、Z 2、Z 3、R 1、R 2、R 3、R 5、m、n和q如式I中所定义；X表示离去基团，包括(但不限于)卤素原子、甲磺酰氧基和三氟甲磺酰氧基；
或者包括下列步骤：
(1’)将化合物A’与化合物B’反应，得到化合物C’；
Figure PCTCN2020112483-appb-000043
(2’)化合物C’发生还原反应以及可选的N-烷基化反应，得到化合物D’；
Figure PCTCN2020112483-appb-000044
(3’)将化合物D’与化合物F反应，得到化合物F’；
Figure PCTCN2020112483-appb-000045
(4’)将化合物F’与化合物B反应，得到式I化合物；
Figure PCTCN2020112483-appb-000046
其中，环A 1、环A 2、环A 3、Z 1、Z 2、Z 3、R 1、R 2、R 3、R 5、m、n和q如式I中所定义；X表示离去基团，包括(但不限于)卤素原子、甲磺酰氧基和三氟甲磺酰氧基；Hal表示卤素原子，包括(但不限于)F、Cl、Br和I，优选F和Cl。
在本发明的一些实施方案中，上述制备方法的步骤(1)在适合的溶剂中进行，所用溶剂包括(但不限于)N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(1)在适合的催化剂存在下进行，所用催化剂为钯催化剂，例如三(二亚苄基丙酮)二钯、 三苯基膦钯、醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯，优选[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。在本发明的一些实施方案中，上述制备方法的步骤(1)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)磷酸钾、醋酸钾、碳酸氢钠、碳酸钠和碳酸钾，优选碳酸钾。在本发明的一些实施方案中，上述制备方法的步骤(1)的适合的反应温度为60-120℃。在本发明的一些实施方案中，上述制备方法的步骤(1)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(2)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺及其任意组合，优选乙腈。在本发明的一些实施方案中，上述制备方法的步骤(2)在适合的亚硝酸酯存在下进行，所用亚硝酸酯包括(但不限于)亚硝酸异戊酯和亚硝酸叔丁酯。在本发明的一些实施方案中，上述制备方法的步骤(2)在适合的溴化试剂存在下进行，所用溴化试剂包括(但不限于)溴化亚铜、溴化铜和N-溴代丁二酰亚胺，优选溴化亚铜。在本发明的一些实施方案中，上述制备方法的步骤(2)的适合的反应温度为-10-80℃。在本发明的一些实施方案中，上述制备方法的步骤(2)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(3)中的还原反应在适合的溶剂中进行，所用溶剂包括(但不限于)甲醇、乙醇、四氢呋喃、水及其任意组合，优选乙醇和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(3)中的还原反应在适合的还原剂存在下进行，所用还原剂包括(但不限于)铁粉、锌粉、连二亚硫酸钠、氯化亚锡和水合肼，优选铁粉。在本发明的一些实施方案中，上述制备方法的步骤(3)中的还原反应在适合的无机盐存在下进行，所用无机盐包括(但不限于)氯化铵和甲酸铵，优选氯化铵。在本发明的一些实施方案中，上述制备方法的步骤(3)中的还原反应的适合的反应温度为20-100℃。在本发明的一些实施方案中，上述制备方法的步骤(3)中的还原反应的适合的反应时间为2-8小时。在本发明的一些实施方案中，上述制备方法的步骤(3)中的N-烷基化反应在适合的烷基化试剂存在下进行，所用烷基化试剂包括(但不限于)卤代烷、醇和烷基硫酸酯，优选卤代烷。在本发明的一些实施方案中，上述制备方法的步骤(3)中的N-烷基化反应在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)氢氧化钠、碳酸氢钠、碳酸钠、氢氧化钾、碳酸氢钾和碳酸钾，优选碳酸钾。
在本发明的一些实施方案中，上述制备方法的步骤(4)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)乙腈、二氯甲烷、氯仿、四氢呋喃及其任意组合，优选二氯甲烷。在本发明的一些实施方案中，上述制备方法的步骤(4)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)三乙胺、N,N-二甲基乙基胺、吡啶、碳酸氢钠、碳酸钠和碳酸钾，优选吡啶。在本发明的一些实施方案中，上述制备方法的步骤(4)的适合的反应温度为20-80℃。在本发明的一些实施方案中，上述制备方法的步骤(4)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(5)在适合的溶剂中进行，所用溶剂包括(但不限于)N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(5)在适合的催化剂存在下进行，所用催化剂为钯催化剂，例如三(二亚苄基丙酮)二钯、三苯基膦钯、醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯，优选[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。在本发明的一些实施方案中，上述制备方法的步骤(5)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)磷酸钾、醋酸钾、碳酸氢钠、碳酸钠和碳酸钾，优选碳酸钾。在本发明的一些实施方案中，上述制备方法的步骤(5)的适合的反应温度为60-120℃。在本发明的一些实施方案中，上述制备方法的步骤(5)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(1’)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)乙腈、N,N-二甲基甲酰胺、二甲基亚砜、1,4-二氧六环及其任意组合，优选N,N-二甲基甲酰胺。在本发明的一些实施方案中，上述制备方法的步骤(1’)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)二异丙基乙胺、三乙胺、碳酸钠、碳酸钾和碳酸铯，优选碳酸铯。在本发明的一些实施方案中，上述制备方法的步骤(1’)的适合的反应温度为40-80℃。在本发明的一些实施方案中，上述制备方法的步骤(1’)的适合的反应时间为2-24小时。
在本发明的一些实施方案中，上述制备方法的步骤(2’)中的还原反应在适合的有机溶剂中进行， 所用有机溶剂包括(但不限于)醇类质子溶剂、四氢呋喃、乙酸乙酯及其任意组合。在本发明的一些实施方案中，上述制备方法的步骤(2’)中的还原反应在适合的金属试剂和酸存在下进行，所用金属试剂包括(但不限于)雷尼镍、钯碳、铁粉和锌粉，优选铁粉，所用酸包括(但不限于)盐酸、甲酸和乙酸，优选乙酸。在本发明的一些实施方案中，上述制备方法的步骤(2’)中的还原反应的适合的反应温度为40-80℃。在本发明的一些实施方案中，上述制备方法的步骤(2’)中的还原反应的适合的反应时间为2-12小时。在本发明的一些实施方案中，上述制备方法的步骤(2’)中的N-烷基化反应在适合的烷基化试剂存在下进行，所用烷基化试剂包括(但不限于)卤代烷、醇和烷基硫酸酯，优选卤代烷。在本发明的一些实施方案中，上述制备方法的步骤(2’)中的N-烷基化反应在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)氢氧化钠、碳酸氢钠、碳酸钠、氢氧化钾、碳酸氢钾和碳酸钾，优选碳酸钾。
在本发明的一些实施方案中，上述制备方法的步骤(3’)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)三乙胺、N,N-二异丙基乙基胺、吡啶及其任意组合，优选吡啶。在本发明的一些实施方案中，上述制备方法的步骤(3’)的适合的反应温度为40-80℃。在本发明的一些实施方案中，上述制备方法的步骤(3’)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(4’)在适合的溶剂中进行，所用溶剂包括(但不限于)N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(4’)在适合的催化剂存在下进行，所用催化剂为钯催化剂，例如三(二亚苄基丙酮)二钯、三苯基膦钯、醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯，优选[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。在本发明的一些实施方案中，上述制备方法的步骤(4’)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)磷酸钾、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠和碳酸氢钾，优选碳酸钾。在本发明的一些实施方案中，上述制备方法的步骤(4’)的适合的反应温度为60-100℃。在本发明的一些实施方案中，上述制备方法的步骤(4’)的适合的反应时间为2-8小时。
在本发明的一些优选的实施方案中，上述式I-A化合物的制备方法包括下列步骤：
(1)将化合物A-A与化合物B反应，得到化合物C-A；
Figure PCTCN2020112483-appb-000047
(2)化合物C-A发生取代反应，得到化合物D-A；
Figure PCTCN2020112483-appb-000048
(3)化合物D-A发生还原反应，得到化合物E-A；
Figure PCTCN2020112483-appb-000049
(4)将化合物E-A与化合物F反应，得到化合物G-A；
Figure PCTCN2020112483-appb-000050
(5)将化合物G-A与化合物H反应，得到式I-A化合物；
Figure PCTCN2020112483-appb-000051
其中，环A 1、环A 2、环A 3、R 2、R 3、R 5、m、n和q如式I中所定义；X表示离去基团，包括(但不限于)卤素原子、甲磺酰氧基和三氟甲磺酰氧基；
或者包括下列步骤：
(1’)将化合物A’-A与化合物B’-A反应，得到化合物C’-A；
Figure PCTCN2020112483-appb-000052
(2’)化合物C’-A发生还原反应，得到化合物D’-A；
Figure PCTCN2020112483-appb-000053
(3’)将化合物D’-A与化合物F反应，得到化合物F’-A；
Figure PCTCN2020112483-appb-000054
(4’)将化合物F’-A与化合物B反应，得到式I-A化合物；
Figure PCTCN2020112483-appb-000055
其中，环A 1、环A 2、环A 3、R 2、R 3、R 5、m、n和q如式I中所定义；X表示离去基团，包括(但不限于)卤素原子、甲磺酰氧基和三氟甲磺酰氧基；Hal表示卤素原子，包括(但不限于)F、Cl、Br和I，优选F和Cl。
在本发明的一些实施方案中，上述制备方法的步骤(1)在适合的溶剂中进行，所用溶剂包括(但不限于)N,N-二甲基甲酰胺(DMF)、N-甲基吡咯烷酮(NMP)、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(1)在适合的催化剂存在下进行，所用催化剂为钯催化剂，例如三(二亚苄基丙酮)二钯、三苯基膦钯、醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯，优选[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。在本发明的一些实施方案中，上述制备方法的步骤(1)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)磷酸钾、醋酸钾、碳酸氢钠、碳酸钠和碳酸钾，优选碳酸钾。在本发明的一些实施方案中，上述制备方法的步骤(1)的适合的反应温度为60-120℃。在本发明的一些实施方案中，上述制备方法的步骤(1)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(2)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺及其任意组合，优选乙腈。在本发明 的一些实施方案中，上述制备方法的步骤(2)在适合的亚硝酸酯存在下进行，所用亚硝酸酯包括(但不限于)亚硝酸异戊酯和亚硝酸叔丁酯。在本发明的一些实施方案中，上述制备方法的步骤(2)在适合的溴化试剂存在下进行，所用溴化试剂包括(但不限于)溴化亚铜、溴化铜和N-溴代丁二酰亚胺，优选溴化亚铜。在本发明的一些实施方案中，上述制备方法的步骤(2)的适合的反应温度为-10-80℃。在本发明的一些实施方案中，上述制备方法的步骤(2)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(3)在适合的溶剂中进行，所用溶剂包括(但不限于)甲醇、乙醇、四氢呋喃、水及其任意组合，优选乙醇和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(3)在适合的还原剂存在下进行，所用还原剂包括(但不限于)铁粉、锌粉、连二亚硫酸钠、氯化亚锡和水合肼，优选铁粉。在本发明的一些实施方案中，上述制备方法的步骤(3)在适合的无机盐存在下进行，所用无机盐包括(但不限于)氯化铵和甲酸铵，优选氯化铵。在本发明的一些实施方案中，上述制备方法的步骤(3)的适合的反应温度为20-100℃。在本发明的一些实施方案中，上述制备方法的步骤(3)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(4)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)乙腈、二氯甲烷、氯仿、四氢呋喃及其任意组合，优选二氯甲烷。在本发明的一些实施方案中，上述制备方法的步骤(4)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)三乙胺、N,N-二甲基乙基胺、吡啶、碳酸氢钠、碳酸钠和碳酸钾，优选吡啶。在本发明的一些实施方案中，上述制备方法的步骤(4)的适合的反应温度为20-80℃。在本发明的一些实施方案中，上述制备方法的步骤(4)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(5)在适合的溶剂中进行，所用溶剂包括(但不限于)N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(5)在适合的催化剂存在下进行，所用催化剂为钯催化剂，例如三(二亚苄基丙酮)二钯、三苯基膦钯、醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯，优选[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。在本发明的一些实施方案中，上述制备方法的步骤(5)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)磷酸钾、醋酸钾、碳酸氢钠、碳酸钠和碳酸钾，优选碳酸钾。在本发明的一些实施方案中，上述制备方法的步骤(5)的适合的反应温度为60-120℃。在本发明的一些实施方案中，上述制备方法的步骤(5)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(1’)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)乙腈、N,N-二甲基甲酰胺、二甲基亚砜、1,4-二氧六环及其任意组合，优选N,N-二甲基甲酰胺。在本发明的一些实施方案中，上述制备方法的步骤(1’)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)二异丙基乙胺、三乙胺、碳酸钠、碳酸钾和碳酸铯，优选碳酸铯。在本发明的一些实施方案中，上述制备方法的步骤(1’)的适合的反应温度为40-80℃。在本发明的一些实施方案中，上述制备方法的步骤(1’)的适合的反应时间为2-24小时。
在本发明的一些实施方案中，上述制备方法的步骤(2’)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)醇类质子溶剂、四氢呋喃、乙酸乙酯及其任意组合。在本发明的一些实施方案中，上述制备方法的步骤(2’)在适合的金属试剂和酸存在下进行，所用金属试剂包括(但不限于)雷尼镍、钯碳、铁粉和锌粉，优选铁粉，所用酸包括(但不限于)盐酸、甲酸和乙酸，优选乙酸。在本发明的一些实施方案中，上述制备方法的步骤(2’)的适合的反应温度为40-80℃。在本发明的一些实施方案中，上述制备方法的步骤(2’)的适合的反应时间为2-12小时。
在本发明的一些实施方案中，上述制备方法的步骤(3’)在适合的有机溶剂中进行，所用有机溶剂包括(但不限于)三乙胺、N,N-二异丙基乙基胺、吡啶及其任意组合，优选吡啶。在本发明的一些实施方案中，上述制备方法的步骤(3’)的适合的反应温度为40-80℃。在本发明的一些实施方案中，上述制备方法的步骤(3’)的适合的反应时间为2-8小时。
在本发明的一些实施方案中，上述制备方法的步骤(4’)在适合的溶剂中进行，所用溶剂包括(但不限于)N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的混合溶剂。在本发明的一些实施方案中，上述制备方法的步骤(4’) 在适合的催化剂存在下进行，所用催化剂为钯催化剂，例如三(二亚苄基丙酮)二钯、三苯基膦钯、醋酸钯、[1,1’-双(二苯基膦基)二茂铁]二氯化钯，优选[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。在本发明的一些实施方案中，上述制备方法的步骤(4’)在碱性环境下进行，适合的提供碱性环境的试剂包括(但不限于)磷酸钾、碳酸钾、碳酸铯、碳酸钠、碳酸氢钠和碳酸氢钾，优选碳酸钾。在本发明的一些实施方案中，上述制备方法的步骤(4’)的适合的反应温度为60-100℃。在本发明的一些实施方案中，上述制备方法的步骤(4’)的适合的反应时间为2-8小时。
[药物组合物]
术语“药物组合物”是指可以用作药物的组合物，其包含药物活性成分(API)以及可选的一种或多种药学上可接受载体。术语“药学上可接受的载体”是指与药物活性成分相容并且对受试者无害的药用辅料，包括(但不限于)稀释剂(或称填充剂)、粘合剂、崩解剂、润滑剂、润湿剂、增稠剂、助流剂、矫味剂、矫嗅剂、防腐剂、抗氧化剂、pH调节剂、溶剂、助溶剂、表面活性剂等。
本发明提供了一种药物组合物，其包含上述式I化合物或其药学上可接受的形式。
在本发明的一些实施方案中，上述药物组合物还包含药学上可接受的载体。
[医药用途]
无论是上述式I化合物或其药学上可接受的形式，还是上述药物组合物，都能够对RORγ表现出调节作用(尤其是激动活性)，针对RORγ的EC 50值能够达到110nM以下，个别甚至达到10nM以下，可以用作RORγ调节剂。因此，本发明提供了上述式I化合物或其药学上可接受的形式或者上述药物组合物用作RORγ调节剂的用途。在本发明中，该RORγ调节剂用于预防和/或治疗至少部分由RORγ介导的疾病。
另外，本申请还提供了上述式I化合物或其药学上可接受的形式或者上述药物组合物在制备用于预防和/或治疗至少部分由RORγ介导的疾病的药物中的用途。
术语“至少部分由RORγ介导的疾病”是指发病机理中至少包含一部分与RORγ有关的因素的疾病，这些疾病包括(但不限于)癌症(例如白血病、淋巴瘤、骨髓瘤、乳腺癌、卵巢癌、宫颈癌、前列腺癌、膀胱癌、结肠癌、直肠癌、结直肠癌、胃癌、食管癌、口腔癌、胰腺癌、肝癌、肺癌、肾癌、皮肤癌、骨癌、脑癌、神经胶质瘤、黑色素瘤等)、炎症(例如强直性脊柱炎、慢性阻塞性肺病、慢性支气管炎、哮喘、系膜毛细血管性肾小球肾炎、过敏性皮炎、心肌炎、溃疡性结肠炎、克罗恩病等)以及自身免疫性疾病(例如银屑病、银屑病性关节炎、类风湿性关节炎、多发性硬化症、系统性红斑狼疮等)。在本发明中，该至少部分由RORγ介导的疾病选自癌症、炎症和自身免疫性疾病。
[治疗方法]
本发明提供了一种用于预防和/或治疗至少部分由RORγ介导的疾病的方法，其包括下列步骤：将治疗有效量的上述式I化合物或其药学上可接受的形式或者上述药物组合物施用于对其有需求的患者。
术语“治疗有效量”是指能够诱发细胞、组织、器官或生物体(例如患者)产生生物或医学反应的药物活性成分的剂量。
术语“施用”是指将药物活性成分(比如本发明的化合物)或包含药物活性成分的药物组合物(例如本发明的药物组合物)应用于患者或其细胞、组织、器官、生物流体等部位，以便使药物活性成分或药物组合物与患者或其细胞、组织、器官、生物流体等部位接触的过程。常见的施用方式包括(但不限于)口服施用、皮下施用、肌内施用、腹膜下施用、眼部施用、鼻部施用、舌下施用、直肠施用、阴道施用等。
术语“对其有需求”是指医生或其他护理人员对患者需要或者将要从预防和/或治疗过程中获益的判断，该判断的得出基于医生或其他护理人员在其专长领域中的各种因素。
术语“患者”(或称受试者)是指人类或非人类的动物(例如哺乳动物)。
[联合用药]
本发明提供了一种药物联用组合物，其包含上述式I化合物或其药学上可接受的形式或者上述药物组合物，以及至少一种其他的同向RORγ调节剂。
术语“同向”是指当针对某一靶点施用至少两种调节剂时，其调节方向应大体相同，或者同时表现出激动作用，或者同时表现出拮抗作用。具体而言，当上述药物联用组合物包含作为RORγ激动剂的 式I化合物或其药学上可接受的形式或者药物组合物时，其还包含至少一种其他的RORγ激动剂，该药物联用组合物适用于预防和/或治疗癌症；同理，当上述药物联用组合物包含作为RORγ拮抗剂的式I化合物或其药学上可接受的形式或者药物组合物时，其还包含至少一种其他的RORγ拮抗剂，该药物联用组合物适用于预防和/或治疗炎症和/或自身免疫性疾病。
本发明提供了一种用于预防和/或治疗癌症、炎症或自身免疫性疾病的方法，其包括下列步骤：将治疗有效量的上述式I化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的且作为RORγ激动剂的上述式I化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
本发明提供了一种用于预防和/或治疗炎症的方法，其包括下列步骤：将治疗有效量的且作为RORγ拮抗剂的上述式I化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
本发明提供了一种用于预防和/或治疗自身免疫性疾病的方法，其包括下列步骤：将治疗有效量的且作为RORγ拮抗剂的上述式I化合物或其药学上可接受的形式或者上述药物组合物或者上述药物联用组合物施用于对其有需求的患者。
以下将结合具体的实施例来进一步阐述本发明。应当理解，这些实施例仅用于说明本发明，而并不旨在限制本发明的范围。如果下列实施例中的实验方法未注明具体条件，则通常按照常规条件或生产厂商所建议的条件(例如，室温为20～30℃)。所使用的试剂购自Acros Organics、Aldrich Chemical Company、上海特伯化学科技有限公司等。除非另外说明，下列实施例中出现的百分比和份数均以重量计算。
本发明上下文中的缩写具有以下含义：
缩写 含义
TLC 薄层色谱法
CC 柱色谱法
PHPLC 制备型高效液相色谱法
LC-MS 液相色谱-质谱联用
Pd(dppf)Cl 2 [1,1’-双(二苯基膦基)二茂铁]二氯化钯
CD 3OD 氘代甲醇
CDCl 3 氘代氯仿
DMSO-d 6 六氘代二甲基亚砜
TMS 四甲基硅烷
NMR 核磁共振
MS 质谱
s 单峰
d 二重峰
t 三重峰
q 四重峰
dd 双二重峰
m 多重峰
br 宽峰
J 偶合常数
Hz 赫兹
h 小时
min 分钟
当下列实施例中化合物的化学名称和结构式不一致时，应当以结构式所示为准，除非根据上下文可以推断化学名称是正确的。下列实施例中记载的化合物的结构式通过 1H-NMR或MS来确证。 1H-NMR的测定仪器为Bruker 400MHz核磁共振仪，测定溶剂为CD 3OD、CDCl 3或DMSO-d 6，内标物质为TMS，全部δ值用ppm值表示。MS的测定仪器为Agilent 6120B质谱仪，离子源为ESI。
反应进程采用TLC或LC-MS进行监测，展开剂体系包括二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、石油醚和乙酸乙酯体系，可以根据化合物的极性不同来调节溶剂之间的体积比。为了获得适宜的比移值(Rf)或保留时间(RT)，也可以向展开剂中加入适量的三乙胺等。TLC采用Merck公司生产的铝板(20×20cm)以及青岛海洋化工生产的薄层层析用GF254硅胶(0.4～0.5mm)。
反应产物的分离纯化采用CC或PHPLC进行。CC使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。PHPLC使用两种条件：1)仪器型号：Agilent 1260，色谱柱：Waters XBridge Prep C 18OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；流动相A：100％乙腈；流动相B：0.05％碳酸氢铵水溶液；洗脱梯度：0min：10％A，90％B；16.0min：90％A，10％B；2)仪器型号：Agilent 1260，色谱柱：Waters SunFire Prep C 18OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；流动相A：100％乙腈；流动相B：100％水(含0.05％甲酸)；洗脱梯度：0min：10％A，90％B；16.0min：90％A，10％B。
[中间体的制备]
中间体制备例1：N-(4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺的制备。
第一步：3’-(二氟甲氧基)-5’-氟-3-硝基联苯-4-胺的制备。
Figure PCTCN2020112483-appb-000056
将4-溴-2-硝基苯胺(2.00g，9.22mmol)和2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(3.72g，12.90mmol)溶于1,4-二氧六环(20mL)和水(5mL)的混合溶剂中，加入碳酸钾(2.54g，18.43mmol)和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(376mg，0.46mmol)，氮气置换后加热至80℃反应2h。将反应液倾入水(150mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(2.42g，收率：88.1％)。
MS(ESI):m/z 297.1[M-H] -。
第二步：4-溴-3’-(二氟甲氧基)-5’-氟-3-硝基联苯的制备。
Figure PCTCN2020112483-appb-000057
将3’-(二氟甲氧基)-5’-氟-3-硝基联苯-4-胺(2.50g，8.38mmol)和溴化亚铜(1.20g，8.38mmol)加入乙腈(20mL)中，0℃下搅拌0.5h，缓慢滴加亚硝酸叔丁酯(2.59g，25.15mmol)后于25℃反应3h。将反应液倾入水(100mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(2.8g，收率：92.2％)。
第三步：4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-胺的制备。
Figure PCTCN2020112483-appb-000058
将4-溴-3’-(二氟甲氧基)-5’-氟-3-硝基联苯(2.40g，6.63mmol)、铁粉(3.70g，66.3mmol)和氯化铵(3.55g，66.3mmol)加入乙醇(20mL)和水(10mL)的混合溶剂中，升温至80℃下反应2h。将反应液倾入水(150mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(2.0g，收率：90.9％)。
MS(ESI):m/z 332.0[M+H] +。
第四步：N-(4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺的制备。
Figure PCTCN2020112483-appb-000059
将4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-胺(2.0g，6.02mmol)完全溶于二氯甲烷(50mL)中，室温下依次加入吡啶(2.38g，30.11mmol)和3-(三氟甲基)苯磺酰氯(2.95g，12.04mmol)，维持室温反应2h。减压浓缩后将剩余物倾入水(150mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(2.4g，收率：73.8％)。
MS(ESI):m/z 538.0[M-H] -。
中间体制备例2：4-氧代-4-(哌嗪-1-基)丁酸甲酯的制备。
第一步：4-(4-甲氧基-4-氧代丁酰)哌嗪-1-羧酸叔丁酯的制备。
Figure PCTCN2020112483-appb-000060
将哌嗪-1-羧酸叔丁酯(0.5g，2.69mmol)和三乙胺(0.82g，8.06mmol)溶于二氯甲烷(5mL)中，冰浴下滴加丁二酸单甲酯酰氯(0.61g，4.04mmol)，室温反应2h。将反应液倾入水(30mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(0.6g，收率：74.1％)。
MS(ESI):m/z 301.0[M+H] +。
第二步：4-氧代-4-(哌嗪-1-基)丁酸甲酯的制备。
Figure PCTCN2020112483-appb-000061
将4-(4-甲氧基-4-氧代丁酰)哌嗪-1-羧酸叔丁酯(0.6g，1.99mmol)溶于二氯甲烷(5mL)中，冰浴下滴加三氟醋酸(2.27g，19.9mmol)，室温反应2h。浓缩反应液，碳酸氢钠水溶液稀释，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到标题化合物(0.3g，收率：75.3％)。
MS(ESI):m/z 201.1[M+H] +。
中间体制备例3：1-哌嗪-1-羰基环丙基甲酸甲酯的制备。
Figure PCTCN2020112483-appb-000062
采用与中间体制备例2类似的合成方法，将第一步中的原料由丁二酸单甲酯酰氯替换为1-(氯甲酰基)环丙甲酸甲酯，得到标题化合物(0.25g，收率：73.5％)。
MS(ESI):m/z 213.1[M+H] +。
[化合物的制备]
实施例1：2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)乙酸(化合物1)的制备。
Figure PCTCN2020112483-appb-000063
第一步：2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-基)乙酸乙酯的制备。
将1H-吡唑-3-硼酸频哪醇酯(1.5g，7.73mmol)完全溶于乙腈(5mL)中，室温搅拌下依次加入碳酸钾(3.20g，23.19mmol)和溴乙酸乙酯(1.55g，9.28mmol)，维持室温反应2h。将反应液倾入水(100mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(2.0g，收率：92.4％)。
MS(ESI):m/z 281.1[M+H] +。
第二步：2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)乙酸乙酯的制备。
将N-(4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(200mg，0.37mmol)和2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-基)乙酸乙酯(207.4mg，0.74mmol)溶于1,4-二氧六环(8mL)和水(2mL)的混合溶剂中，加入碳酸钾(102.2mg，0.74mmol)和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(14mg，0.018mmol)，氮气置换后加热至80℃反应2h。将反应液倾入水(100mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，浓缩物经制备型高效液相色谱仪(条件1)纯化，得到本步的标题化合物(82mg，收率：36.1％)。
MS(ESI):m/z 614.1[M+H] +。
第三步：2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)乙酸的制备。
将2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)乙酸乙酯(70mg，0.11mmol)溶于乙醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化钠(10mg，0.23mmol)，继续于60℃搅拌反应1h。将反应液倾倒入水(50mL)中，2N稀盐酸调节pH＝2，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，浓缩物经制备型高效液相色谱仪(条件2)纯化，得到标题化合物(10mg，收率：15.0％)。
MS(ESI):m/z 586.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ7.97-7.95(m,1H),7.88-7.86(m,2H),7.81-7.80(m,1H),7.77-7.74(m,2H),7.62-7.60(m,1H),7.52-7.50(m,1H),7.42(t,J＝2.8Hz,1H),7.37-7.35(m,1H),7.26-7.17(m,2H),6.73-6.71(m,1H),4.90(s,2H)。
实施例2：N-(3’-(二氟甲氧基)-5’-氟-4-(1-(2-甲氧基乙基)-1H-吡唑-3-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物2)的制备。
Figure PCTCN2020112483-appb-000064
采用与实施例1类似的合成方法，将第一步中的原料由溴乙酸乙酯替换为2-溴乙基甲基醚，得到标题化合物(30mg，收率：21.5％)。
MS(ESI):m/z 586.1[M+H] +。
1H-NMR(400MHz,CDCl 3):δ11.23(s,1H),7.89-7.77(m,3H),7.64(d,J＝7.2Hz,1H),7.54-7.48(m,2H),7.39(t,J＝8.0Hz,1H),7.31-7.29(m,1H),7.17-7.13(m,2H),6.87(d,J＝9.2Hz,1H),6.76-6.58(m,1H),6.39(d,J＝2.8Hz,1H),4.37(t,J＝5.2Hz,2H),3.85(t,J＝4.8Hz,2H),3.40(s,3H)。
实施例3：2-(3-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-1H-吡唑-1-基)-N,N-二甲基乙酰胺(化合物3)的制备。
Figure PCTCN2020112483-appb-000065
采用与实施例1类似的合成方法，将第一步中的原料由溴乙酸乙酯替换为2-溴-N,N-二甲基乙酰胺，得到标题化合物(15mg，收率：21.2％)。
MS(ESI):m/z 613.1[M+H] +。
1H-NMR(400MHz,CDCl 3):δ10.98(s,1H),7.90-7.87(m,2H),7.77(d,J＝7.6Hz,1H),7.64(d,J＝7.6Hz,1H),7.55-7.53(m,2H),7.45-7.41(m,1H),7.31-7.29(m,1H),7.17-7.12(m,2H),6.89-6.86(m,1H),6.76-6.57(m,1H),6.46-6.39(m,1H),5.07(s,2H),3.22(s,3H),3.06(s,3H)。
实施例4：N-(3’-(二氟甲氧基)-5’-氟-4-(1-异丙基-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物4)的制备。
Figure PCTCN2020112483-appb-000066
将N-(4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(100mg，0.18mmol)和1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(87.4mg，0.37mmol)溶于1,4-二氧六环(4mL)和水(1mL)的混合溶剂中，加入碳酸钾(51mg，0.37mmol)和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(7mg，0.009mmol)，氮气置换后加热至80℃反应2h。将反应液倾入水(20mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，TLC纯化(洗脱剂：石油醚/乙酸乙酯(V/V)＝1/1)，得到标题化合物(20mg，收率：18.6％)。
MS(ESI):m/z 570.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ10.11(s,1H),8.12(s,1H),8.01-7.99(m,1H),7.93(d,J＝8.0Hz,1H),7.83(s,1H),7.78-7.74(m,2H),7.67-7.62(m,2H),7.56-7.38(s,1H),7.23-7.10(m,3H),7.08(s,1H),4.44-4.41(m,1H),1.42(d,J＝6.8Hz,6H)。
实施例5：N-(3’-(二氟甲氧基)-4-(1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物5)的制备。
Figure PCTCN2020112483-appb-000067
第一步：N,N-二甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-基)乙胺的制备。
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑(1.5g，7.73mmol)完全溶于乙腈(5mL)中，室温搅拌下依次加入碳酸钾(3.20g，23.19mmol)和2-氯-N,N-二甲基乙胺(998mg，9.28mmol)，80℃反应6h。将反应液倾入水(100mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，得到本步的标题化合物(1.8g，收率：88.2％)。
MS(ESI):m/z 266.0[M+H] +。
第二步：N-(3’-(二氟甲氧基)-4-(1-(2-(二甲氨基)乙基)-1H-吡唑-4-基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺的制备。
将N-(4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(200mg，0.37mmol)和N,N-二甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑-1-基)乙胺(196.1mg，0.74mmol)溶于1,4-二氧六环(8mL)和水(2mL)的混合溶剂中，加入碳酸钾(102.2mg，0.74mmol)和[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(14mg，0.018mmol)，氮气置换后加热至80℃反应2小时。将反应液倾入水(50mL)中，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，浓缩物经制备高效液相色谱仪(条件1)纯化，得到标题化合物(8mg，收率：5.9％)。
MS(ESI):m/z 599.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ8.19(s,1H),7.96(d,J＝7.6Hz,2H),7.89(s,1H),7.84(s,1H),7.76- 7.73(m,1H),7.59-7.52(m,2H),7.52-7.18(m,1H),7.15-7.07(m,3H),7.03(s,1H),4.21(t,J＝6.4Hz,2H),2.76(t,J＝6.4Hz,2H),2.26(s,6H)。
实施例6：N-(3’-(二氟甲氧基)-5’-氟-4-(1-(2-甲氧基乙基)-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物6)的制备。
Figure PCTCN2020112483-appb-000068
采用与实施例5类似的合成方法，将原料2-氯-N,N-二甲基乙胺替换为2-溴乙基甲基醚，得到标题化合物(30mg，收率：21.5％)。
MS(ESI):m/z 586.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ10.14(s,1H),8.11(s,1H),8.03-7.95(m,2H),7.89(s,1H),7.84-7.74(m,2H),7.66-7.61(m,2H),7.56-7.20(m,1H),7.16-7.13(m,2H),7.10-7.02(m,2H),4.26(t,J＝5.2Hz,2H),3.72(t,J＝5.2Hz,2H),3.28(s,3H)。
实施例7：(S)-N-(3’-(二氟甲氧基)-5’-氟-4-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物7)的制备。
Figure PCTCN2020112483-appb-000069
采用与实施例5类似的合成方法，将原料2-氯-N,N-二甲基乙胺替换为(S)-3-溴四氢呋喃，得到标题化合物(12mg，收率：39.1％)。
MS(ESI):m/z 598.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ10.13(s,1H),8.15(s,1H),8.02-7.92(m,2H),7.82-7.74(m,3H),7.72-7.60(m,2H),7.56-7.38(s,1H),7.23-7.11(m,3H),7.08(s,1H),5.01-4.96(m,1H),4.00-3.96(m,2H),3.93-3.80(m,2H),2.46-2.34(m,1H),2.28-2.21(m,1H)。
实施例8：(R)-N-(3’-(二氟甲氧基)-5’-氟-4-(1-(四氢呋喃-3-基)-1H-吡唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物8)的制备。
Figure PCTCN2020112483-appb-000070
采用与实施例5类似的合成方法，将原料2-氯-N,N-二甲基乙胺替换为(R)-3-溴四氢呋喃，得到标题化合物(42mg，收率：41.2％)。
MS(ESI):m/z 598.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ10.14(s,1H),8.23(s,1H),7.97-7.82(m,4H),7.77-7.57(m,3H),7.55-7.36(s,1H),7.23-7.09(m,3H),7.06(s,1H),5.01-4.96(m,1H),4.08-3.93(m,2H),3.93-3.77(m,2H),2.45-2.33(m,1H),2.28-2.20(m,1H)。
实施例9：N-(3’-(二氟甲氧基)-4-(1-乙基-1H-吡唑-4-基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物9)的制备。
Figure PCTCN2020112483-appb-000071
采用与实施例4类似的合成方法，将原料1-异丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑替换为1-乙基-1H-吡唑-4-硼酸频哪醇酯，得到标题化合物(30mg，收率：25.6％)。
MS(ESI):m/z 556.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ10.10(s,1H),8.08-7.98(m,2H),7.93(d,J＝7.6Hz,1H),7.85(s,1H),7.79-7.76(m,2H),7.69-7.67(m,1H),7.61-7.59(m,1H),7.56-7.38(m,1H),7.19-7.12(m,3H),7.07(s,1H),4.11(d,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H)。
实施例10：2-(4-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)-5,6-二氢吡啶-1(2H)-基)乙酸(化合物10)的制备。
Figure PCTCN2020112483-appb-000072
采用与实施例1类似的合成方法，将第一步中的原料由3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吡唑替换为4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶，得到标题化合物(8mg，收率：7.0％)。
MS(ESI):m/z 599.0[M-H] -。
1H-NMR(400MHz,CDCl 3):δ8.15-7.98(m,3H),7.83-7.80(m,1H),7.55-7.36(m,2H),7.23-7.12(m,4H),7.06(s,1H),5.38(s,1H),3.66-3.41(m,4H),2.87-2.84(m,2H),2.35-2.33(m,2H)。
实施例11：N-(3’-(二氟甲氧基)-5’-氟-4-(噻唑-4-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物11)的制备。
Figure PCTCN2020112483-appb-000073
将N-(4-溴-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(210mg，0.37mmol)、三丁基(噻唑-4-基)锡烷(210mg，0.56mmol)和氯化锂(71mg，1.66mmol)加入到1,4-二氧六环(6mL)溶剂中，室温搅拌溶解。加入四(三苯基膦)钯(46mg，0.04mmol)，氮气置换后于100℃搅拌4h。浓缩反应液，加入乙酸乙酯萃取，有机相干燥后，经制备型高效液相色谱仪(条件1)纯化，得到标题化合物(125mg，收率：63.7％)。
MS(ESI):m/z 545.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ11.36(s,1H),9.37(s,1H),8.17(s,1H),7.94-7.87(m,2H),7.78(d,J＝8.0Hz,1H),7.74-7.60(m,4H),7.44-7.41(m,1H),7.41(d,J＝9.6Hz,1H),7.30(s,1H),7.21-7.19(m,1H)。
实施例12：N-(4-(4-(环丙甲酰基)哌嗪-1-基)-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物12)的制备。
Figure PCTCN2020112483-appb-000074
第一步：(4-(4-溴-2-硝基苯基)哌嗪-1-基)(环丙基)甲酮的制备。
将4-溴-1-氟-2-硝基苯(0.50g，2.27mmol)、1-环丙甲酰基哌嗪(0.49g，3.18mmol)和碳酸铯(1.56g，4.55mmol)溶于N,N-二甲基甲酰胺(5mL)中，60℃下搅拌反应12h后，将反应液倒入水(60mL)中，乙酸乙酯(50mL×3)萃取，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，过滤，旋干溶剂，得到本步的标题化合物(0.65g，收率：81.2％)。
MS(ESI):m/z 354.1[M+H] +。
第二步：(4-(2-氨基-4-溴苯基)哌嗪-1-基)(环丙基)甲酮的制备。
将(4-(4-溴-2-硝基苯基)哌嗪-1-基)(环丙基)甲酮(0.65g，1.84mmol)溶于乙醇(8mL)和水(2mL)中，加入铁粉(0.31g，5.52mmol)和氯化铵(0.31g，5.52mmol)，80℃下搅拌2h后，过滤，浓缩，乙酸乙酯稀释，水洗，分液，干燥，过滤，浓缩，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯(V/V)＝3/1)，得到本步的标题化合物(0.29mg，收率：48.8％)。
MS(ESI):m/z 324.0[M+H] +。
第三步：N-(5-溴-2-(4-环丙甲酰基)哌嗪-1-基)苯基)-3-(三氟甲基)苯磺酰胺的制备。
将(4-(2-氨基-4-溴苯基)哌嗪-1-基)(环丙基)甲酮(0.29g，0.89mmol)溶于吡啶(5mL)中，缓慢加入3-(三氟甲基)苯磺酰氯(0.28g，1.13mmol)，60℃下反应4h，向反应液中加入适量的乙酸乙酯和水，分液，有机相用1N盐酸溶液洗一次，无水硫酸钠干燥有机相，过滤，旋干溶剂，得到本步的标题化合物(0.42g，收率：88.2％)。
MS(ESI):m/z 532.1[M+H] +。
第四步：N-(4-(4-(环丙甲酰基)哌嗪-1-基)-3’-(二氟甲氧基)-5’-氟联苯-3-基)-3-(三氟甲基)苯磺酰胺的制备。
将N-(5-溴-2-(4-环丙甲酰基)哌嗪-1-基)苯基)-3-(三氟甲基)苯磺酰胺(180mg，0.32mmol)、2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(108mg，0.35mmol)和碳酸钾(93.8mg，0.64mmol)溶于1,4-二氧六环(4mL)和水(1mL)中，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(13.8mg，0.16mmol)，氮气保护，80℃下反应2h，过滤除去反应液中不溶物，浓缩，加入乙酸乙酯和饱和食盐水，萃取，有机相用无水硫酸钠干燥，过滤，旋干溶剂，剩余物经制备型高效液相色谱仪(条件1)纯化，得到本步的标题化合物(17mg，收率：8.2％)。
MS(ESI):m/z 614.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ9.77(s,1H),8.09-8.03(m,3H),7.85-7.81(m,1H),7.58-7.39(m,3H),7.27-7.20(m,2H),7.15-7.11(m,2H),3.67(br,2H),3.45(br,2H),2.67(t,J＝2.0Hz,1H),2.52-2.50(m,2H),1.99-1.96(m,1H),0.74-0.69(m,4H)。
实施例13：4-(4-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-基)-4-氧代丁酸(化合物13)的制备。
Figure PCTCN2020112483-appb-000075
第一步：4-(4-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-基)-4-氧代丁酸甲酯的制备。
采用与实施例12类似的合成方法，将1-环丙甲酰基哌嗪替换为4-氧代-4-(哌嗪-1-基)丁酸甲酯，得到本步的标题化合物(350mg，收率：60.9％)。
MS(ESI):m/z 659.7[M+H] +。
第二步：4-(4-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-基)-4-氧代丁酸的制备。
将4-(4-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-基)-4-氧代丁酸甲酯(350mg，0.50mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化钠(61.7mg，1.50mmol)，室温搅拌反应2h。将反应液倾倒入水(30mL)中，用2N盐酸调节pH＝4，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，浓缩物经制备型高效液相色谱仪(条件2)纯化，得到标题化合物(138mg，收率：40.3％)。
MS(ESI):m/z 645.8[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ11.96(br,1H),9.66(br,1H),8.09-8.04(m,3H),7.86-7.82(m,1H),7.58-7.39(m,3H),7.27-7.11(m,4H),3.47-3.44(m,4H),3.34-3.28(m,4H),2.67-2.63(m,2H),2.67-2.42(m,2H)。
实施例14：1-(4-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌嗪-1-甲酰基)环丙甲酸(化合物14)的制备。
Figure PCTCN2020112483-appb-000076
采用与实施例13类似的合成方法，将4-氧代-4-(哌嗪-1-基)丁酸甲酯替换为1-(哌嗪-1-甲酰基)环丙甲酸甲酯，得到标题化合物(16mg，收率：5.2％)。
MS(ESI):m/z 658.0[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ8.07-8.05(m,2H),7.95-7.93(m,1H),7.77-7.75(m,1H),7.55-7.37(m,2H),7.32-7.29(m,1H),7.19-7.16(m,1H),7.09-7.02(m,3H),3.50-3.38(m,4H),2.77-2.67(m,4H),1.24(d,J＝2.8Hz,2H),1.10(d,J＝2.8Hz,2H)。
实施例15：N-(3’-(二氟甲氧基)-5’-氟-4-吗啉基联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物15)的制 备。
Figure PCTCN2020112483-appb-000077
采用与实施例12类似的合成方法，将1-环丙甲酰基哌嗪替换为吗啉，得到标题化合物(17mg，收率：9.1％)。
MS(ESI):m/z 545.0[M-H] -。
1H-NMR(400MHz,DMSO-d 6):δ9.65(s,1H),8.07-8.04(m,3H),7.84(d,J＝8.0Hz,1H),7.58-7.54(m,1H),7.45-7.44(m,1H),7.39-7.21(m,3H),7.14-7.11(m,2H),3.56-3.54(m,4H),2.62-2.59(m,4H)。
实施例16：1-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-甲酸甲酯(化合物16)的制备。
Figure PCTCN2020112483-appb-000078
采用与实施例12类似的合成方法，将1-环丙甲酰基哌嗪替换为哌啶-4-甲酸甲酯，得到标题化合物(219mg，收率：77.2％)。
MS(ESI):m/z 601.0[M-H] -。
1H-NMR(400MHz,DMSO-d 6):δ9.62(s,1H),8.10-8.03(m,3H),7.84-7.79(m,1H),7.57-7.39(m,3H),7.24-7.10(m,4H),3.63(s,3H),2.75-2.72(m,2H),2.55-2.52(m,2H),2.41-2.34(m,1H),1.77-1.62(m,4H)。
实施例17：1-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-甲酸(化合物17)的制备。
Figure PCTCN2020112483-appb-000079
将1-(3’-(二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-甲酸甲酯(162.1mg，0.26mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化钠(43.1mg，1.04mmol)，60℃搅拌反应1h。将反应液倾倒入水(10mL)中，用2N盐酸调节pH＝4，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤并将滤液减压浓缩，浓缩物经制备型高效液相色谱仪(条件2)纯化，得到标题化合物(79mg，收率：49.9％)。
MS(ESI):m/z 587.0[M-H] -。
1H-NMR(400MHz,DMSO-d 6):δ12.67(br,1H),9.60(br,1H),8.09-8.02(m,3H),7.83-7.79(m,1H),7.57-7.39(m,3H),7.23-7.10(m,4H),2.75-2.72(m,2H),2.54-2.52(m,2H),2.27-2.23(m,1H),1.77-1.62(m,4H)。
实施例18：2-(1-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物18)的制备。
Figure PCTCN2020112483-appb-000080
第一步：2-(1-(4-溴-2-硝基苯基)哌啶-4-基)乙酸甲酯的制备。
将4-溴-1-氟-2-硝基苯(0.50g，2.27mmol)、2-(4-哌啶基)乙酸甲酯(0.43g，2.73mmol)和碳酸铯(1.11g，3.41mmol)溶于N,N-二甲基甲酰胺(5mL)中，60℃下搅拌反应12h后，将反应液倒入水(60mL)中，乙酸乙酯(50mL×3)萃取，水洗，饱和食盐水洗，有机相用无水硫酸钠干燥，过滤，旋干溶剂，得到本步的标题化合物(0.60g，收率：75.0％)。
MS(ESI):m/z 357.0[M+H] +。
第二步：2-(1-(2-氨基-4-溴苯基)哌啶-4-基)乙酸甲酯的制备。
将2-(1-(4-溴-2-硝基苯基)哌啶-4-基)乙酸甲酯(0.60g，1.68mmol)溶于乙醇(8mL)和水(2mL)中，加入铁粉(0.47g，8.40mmol)和氯化铵(0.45g，8.40mmol)，80℃下搅拌2h后，过滤，浓缩，乙酸乙酯稀释，水洗，分液，干燥，过滤，浓缩，用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯(V/V)＝2/1)，得到本步的标题化合物(0.38g，收率：69.1％)。
MS(ESI):m/z 327.1[M+H] +。
第三步：2-(1-(4-溴-2-(3-(三氟甲基)苯磺胺基)苯基)哌啶-4-基)乙酸甲酯的制备。
将2-(1-(2-氨基-4-溴苯基)哌啶-4-基)乙酸甲酯(0.38g，1.16mmol)溶于吡啶(5mL)中，缓慢加入3-(三氟甲基)苯磺酰氯(0.30g，1.22mmol)，60℃下反应4h，向反应液中加入适量的乙酸乙酯和水，分液，有机相用1N盐酸溶液洗一次，无水硫酸钠干燥有机相，过滤，旋干溶剂，得到本步的标题化合物(0.60g，收率：96.8％)。
MS(ESI):m/z 535.0[M+H] +。
第四步：2-(1-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸甲酯的制备。
将2-(1-(4-溴-2-(3-(三氟甲基)苯磺胺基)苯基)哌啶-4-基)乙酸甲酯(600mg，1.12mmol)、2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(387mg，1.34mmol)和碳酸钾(310mg，2.24mmol)溶于1,4-二氧六环(10mL)和水(2mL)中，加入[1,1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(91mg，0.11mmol)，氮气保护，80℃下反应2h，过滤除去反应液中不溶物，浓缩，加入乙酸乙酯和饱和食盐水，萃取，有机相用无水硫酸钠干燥，过滤，旋干溶剂，剩余物经制备型高效液相色谱仪(条件1)纯化，得到本步的标题化合物(200mg，收率：28.9％)。
MS(ESI):m/z 617.2[M+H] +。
第五步：2-(1-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸的制备。
将2-(1-(3’-二氟甲氧基)-5’-氟-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸甲酯(200mg，0.32mmol)溶于甲醇(5mL)和水(1mL)的混合溶剂中，加入氢氧化钠(51.2mg，1.28mmol)，室温搅拌反应2h。将反应液浓缩，然后向浓缩物中加水(15mL)中，用4N盐酸调节pH＝2，过滤，干燥滤饼，得到标题化合物(150mg，收率：76.9％)。
MS(ESI):m/z 603.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.09(s,1H),9.44(s,1H),8.12-8.01(m,3H),7.83(t,J＝7.6Hz,1H),7.59-7.38(m,3H),7.25(d,J＝9.6Hz,1H),7.20(d,J＝8.4Hz,1H),7.16-7.07(m,2H),2.70(d,J＝11.6Hz,2H),2.50-2.45(m,2H),2.15(d,J＝7.2Hz,2H),1.69-1.66(m,1H),1.58(d,J＝11.6Hz,2H),1.16-1.24 (m,2H)。
实施例19：N-(3’-(二氟甲氧基)-5’-氟-4-(4-羟基-4-甲基哌啶-1-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物19)的制备。
Figure PCTCN2020112483-appb-000081
采用与实施例12类似的合成方法，将第一步中的原料由1-环丙甲酰基哌嗪替换为4-甲基-4-羟基哌啶，得到标题化合物(26mg，收率：23.7％)。
MS(ESI):m/z 575.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ9.40(s,1H),8.08-8.01(m,3H),7.80(t,J＝7.6Hz,1H),7.64-7.54(m,1H),7.46-7.38(m,3H),7.28-6.99(m,4H),4.19(s,1H),2.79(t,J＝9.6Hz,2H),2.60-2.53(m,2H),1.59-1.35(m,4H),1.12(s,3H)。
实施例20：N-(3’-(二氟甲氧基)-5’-氟-4-(4-(甲磺酰基)哌啶-1-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物20)的制备。
Figure PCTCN2020112483-appb-000082
采用与实施例12类似的合成方法，将第一步中的原料由1-环丙甲酰基哌嗪替换为4-甲磺酰基哌啶，得到标题化合物(20mg，收率：22.8％)。
MS(ESI):m/z 623.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ9.70(s,1H),8.16-8.02(m,3H),7.84(t,J＝7.6Hz,1H),7.58-7.37(m,3H),7.24-7.08(m,4H),3.15-3.09(m,1H),2.96(s,3H),2.88-2.81(m,2H),2.62-2.54(m,2H),1.95-1.78(m,4H)。
实施例21：N-(3’-(二氟甲氧基)-5’-氟-4-(4-(2-甲氧基乙氧基)哌啶-1-基)联苯-3-基)-3-(三氟甲基)苯磺酰胺(化合物21)的制备。
Figure PCTCN2020112483-appb-000083
采用与实施例12类似的合成方法，将第一步中的原料由1-环丙甲酰基哌嗪替换为4-(2-甲氧基乙氧基)哌啶，得到标题化合物(48mg，收率：10.1％)。
MS(ESI):m/z 619.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ9.51(br,1H),8.11-8.04(m,3H),7.85-7.81(m,1H),7.57-7.39(m,3H),7.24-7.17(m,2H),7.13-7.10(m,2H),3.54-3.51(m,2H),3.45-3.43(m,2H),3.38-3.36(m,1H),3.26(s,3H),2.74-2.71(m,2H),2.53-2.51(m,2H),1.80-1.78(m,2H),1.55-1.51(m,2H)。
实施例22：2-(1-(3’-氯-5’-甲氧基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物22)的制备。
Figure PCTCN2020112483-appb-000084
采用与实施例18类似的合成方法，将第四步中的原料由2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替换为3-氯-5-甲氧基苯基硼酸，得到标题化合物(68mg，收率：91.4％)。
MS(ESI):m/z 583.3[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.08(s,1H),9.40(s,1H),8.08-8.04(m,3H),7.83(t,J＝8.0Hz,1H),7.48-7.46(m,1H),7.42-7.39(m,1H),7.18(d,J＝4.0Hz,1H),7.07-6.98(m,3H),3.83(s,3H),2.69-2.66(m,2H),2.50-2.46(m,2H),2.15(d,J＝8.8Hz,2H),1.74-1.57(m,3H),1.27-1.17(m,2H)。
实施例23：2-(1-(3’-氟-5’-甲氧基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物23)的制备。
Figure PCTCN2020112483-appb-000085
采用与实施例18类似的合成方法，将第四步中的原料由2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替换为3-氟-5-甲氧基苯基硼酸，得到标题化合物(92mg，收率：74.5％)。
MS(ESI):m/z 567.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.10(s,1H),9.40(s,1H),8.08-8.04(m,3H),7.83(t,J＝8.0Hz,1H),7.48-7.45(m,1H),7.42-7.40(m,1H),7.18(d,J＝8.4Hz,1H),6.89-6.80(m,3H),3.82(s,3H),2.68-2.65(m,2H),2.50-2.46(m,2H),2.15(d,J＝7.2Hz,2H),1.71-1.56(m,3H),1.27-1.17(m,2H)。
实施例24：2-(1-(3’-甲氧基-5’-甲基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物24)的制备。
Figure PCTCN2020112483-appb-000086
采用与实施例18类似的合成方法，将第四步中的原料由2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替换为3-甲氧基-5-甲基苯基硼酸，得到标题化合物(25mg，收率：32.5％)。
MS(ESI):m/z 563.2[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.04(s,1H),9.33(s,1H),8.09-8.05(m,3H),7.83(t,J＝7.6Hz,1H),7.48-7.39(m,2H),7.17(d,J＝8.0Hz,1H),6.84-6.75(m,3H),3.78(s,3H),2.68-2.65(m,2H),2.50-2.46(m,2H),2.33(s,3H),2.15(d,J＝6.8Hz,2H),1.71-1.58(m,3H),1.28-1.20(m,2H)。
实施例25：2-(1-(3’-氯-5’-(二氟甲氧基)-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物25)的制备。
Figure PCTCN2020112483-appb-000087
采用与实施例18类似的合成方法，将第四步中的原料由2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲 基-1,3,2-二氧杂硼杂环戊烷替换为3-氯-5-(二氟甲氧基)苯基硼酸，得到标题化合物(60mg，收率：53.8％)。
MS(ESI):m/z 619.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.04(s,1H),9.45(s,1H),8.07-8.05(m,3H),7.81(t,J＝8.0Hz,1H),7.58-7.40(m,4H),7.30-7.17(m,3H),2.73-2.67(m,2H),2.50-2.46(m,2H),2.14(d,J＝7.2Hz,2H),1.69-1.56(m,3H),1.23-1.15(m,2H)。
实施例26：2-(1-(3’-氯-5’-乙氧基-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物26)的制备。
Figure PCTCN2020112483-appb-000088
采用与实施例18类似的合成方法，将第四步中的原料由2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替换为3-氯-5-乙氧基苯基硼酸，得到标题化合物(25mg，收率：45.8％)。
MS(ESI):m/z 597.0[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.04(s,1H),9.40(s,1H),8.07-8.04(m,3H),7.85-7.81(m,1H),7.64-7.54(m,1H),7.47-7.38(m,2H),7.17-7.14(m,1H),7.05-6.95(m,3H),4.12-4.07(m,2H),2.68(d,J＝9.6Hz,2H),2.49-2.45(m,1H),2.15(d,J＝7.2Hz,2H),1.69-1.56(m,3H),1.35(t,J＝7.2Hz,3H),1.26-1.17(m,2H)。
实施例27：2-(1-(3’-氯-5’-(三氟甲氧基)-3-(3-(三氟甲基)苯磺酰氨基)联苯-4-基)哌啶-4-基)乙酸(化合物27)的制备。
Figure PCTCN2020112483-appb-000089
采用与实施例18类似的合成方法，将第四步中的原料由2-(3-(二氟甲氧基)-5-氟苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷替换为3-氯-5-三氟甲氧基苯硼酸，得到标题化合物(67mg，收率：48.6％)。
MS(ESI):m/z 637.1[M+H] +。
1H-NMR(400MHz,DMSO-d 6):δ12.08(s,1H),9.47(s,1H),8.08-8.05(m,3H),7.83(t,J＝8.0Hz,1H),7.64-7.60(m,1H),7.56-7.53(m,2H),7.41-7.39(m,2H),7.20(d,J＝8.8Hz,1H),2.76-2.73(m,2H),2.50-2.48(m,2H),2.15(d,J＝7.2Hz,2H),1.70-1.57(m,3H),1.25-1.19(m,2H)。
[生物学评价]
实验例1：RORγ-LBD的时间分辨荧光共振能量转移(TR-FRET)实验。
1、实验材料及仪器：
RORγ-LBD(辉源生物)；
生物素-SRC1(Perkin Elmer)；
LANCE Eu-抗-6×His抗体(Perkin Elmer)；
Figure PCTCN2020112483-appb-000090
Allophycocyanin-Streptavidin(Perkin Elmer)；
酶标仪(B MG Labtech)。
2、实验方法：
溶液配制：配制反应缓冲液(25mM HEPES，pH＝7.0，100mM NaCl，0.01％Tween 20，0.2％BSA，5mM DTT)。以反应缓冲液配制含1nM LANCE Eu-抗-6×His抗体的溶液A1，含1nM LANCE Eu-抗-6×His抗体和15nM RORγ-LBD的溶液A2，以及含200nM生物素-SRC1和15nM Allophycocyanin-Streptavidin的溶液B，均置于冰上，待用。
以DMSO稀释待测化合物，以5μM为起始浓度，采用4倍稀释，取10个浓度点。384孔板中的待测化合物孔加入0.25μL稀释后的待测化合物、15μL溶液A2，以及10μL溶液B；阴性对照孔加入0.25μL DMSO、15μL溶液A1，以及10μL溶液B；溶剂对照孔加入0.25μL DMSO、15μL溶液A2，以及10μL溶液B。封口胶带封板，震荡2min，混匀反应液。将384孔板置于4℃过夜后取出384孔板至室温平衡、离心后，采用酶标仪读板(检测波长665nm/615nm)。
3、数据处理：
化合物的激活率＝(FI比值 化合物-FI比值 溶剂对照)/(FI比值 溶剂对照-FI比值 阴性对照)×100％；
FI比值表示酶标仪读出荧光值(665nm)与酶标仪读出荧光值(615nm)的比值；
由GraphPad Prism软件计算EC 50值。
最大激活率：由上述激活率公式得到的曲线处于上平台期时对应浓度点的激活率；最大激活率大于0时，表明待测化合物对RORγ具有激动作用。
4、结果：
本发明的待测化合物对RORγ的激动活性结果见表1。
表1.本发明的化合物对RORγ的激动活性
化合物编号 EC 50(nM) 最大激活率(％)
1 2.1 70.7％
2 26.3 65.3％
3 59.1 69.4％
4 109.3 61.2％
5 87.7 70.7％
6 24.6 76.9％
7 29.2 92.3％
8 58.1 84.2％
9 89.8 69.9％
11 7.5 59.5％
12 12.3 82.1％
13 25.8 63.2％
15 25.3 51.2％
16 45.4 71.9％
17 19.0 54.6％
18 18.4 58.8％
19 8.5 59.5％
20 11.4 77.6％
21 14.5 61.7％
22 14.9 55.5％
23 12.6 57.2％
25 29.1 62.6％
26 66.2 64.1％
由此可见，本发明化合物对RORγ具有明显的激动作用，具有例如小于110nM，优选小于20nM，更优选小于10nM的EC 50，最大激活率均在50％以上。
实验例2：RORγ-荧光素酶报告基因实验。
1、实验材料及仪器：
质粒pcDNA3.1(GAL4DBD/RORγLBD)，pGL4.35(luc2P/9XGAL4UAS/Hygro)(南京科佰生物构建)；
Lipofectamine 3000(Invitrogen)；
Bright-Glo TM(Promega)；
乌苏酸(Cayman Chemical)；
酶标仪(BMG Labtech)；
293T细胞(购自ATCC)；
待测化合物(以DMSO配制为10mM储备液)。
2、实验方法：
293T细胞以DMEM高糖培养基(含10％FBS)培养于T25细胞培养瓶中，生长至融合度80％左右时，按Lipofectamine 3000说明书制备包载质粒的脂质体。将脂质体与一定体积的DMEM高糖培养基(含10％FBS)混合，去除T25培养瓶中原培养基，加入上述脂质体与DMEM高糖培养基的混合液转染293T细胞。转染后24h，消化细胞并计数。以DMEM高糖培养基(含10％FBS，2μM乌苏酸)稀释细胞至一定浓度，均匀铺至96孔培养板，每孔含细胞约10 5个。以DMEM高糖培养基(含10％FBS，2μM乌苏酸)稀释待测化合物储备液以及溶剂对照(DMSO)，以100μM为起始浓度，采用3倍稀释，取10个浓度点。将稀释后的待测化合物和溶剂对照分别加入96孔细胞培养板的实验孔和溶剂对照孔中。震荡细胞培养板2min，使待测化合物与培养基充分混合，于37℃，5％CO 2孵箱中继续培养24h。取出96孔细胞培养板至室温平衡10min，按照说明书加入Bright-Glo TM，充分混匀。快速转移混合液至检测板，采用酶标仪检测发光强度。
3、数据处理：
激活率＝实验孔发光值/溶剂对照孔平均发光值×100％。
溶剂对照孔平均发光值定义为100％，使用Graphpad Prism 5软件进行数据分析与作图，以激活率与化合物浓度的对数经四参数拟合曲线计算EC 50值；最大激活率为拟合曲线处于上平台期时对应浓度点的激活率；最大激活率大于100％时，表明待测化合物对RORγ具有激动作用。
4、结果：
本发明的化合物在细胞中对RORγ的激动活性结果见表2。
表2.本发明的化合物对RORγ的激动活性
化合物编号 EC 50(nM) 最大激活率(％)
4 930 302.0％
8 566 370.1％
11 1295 330.2％
12 517 489.7％
15 1184 312.8％
16 1368 354.2％
18 1075 488.3％
19 1260 388.7％
20 1245 412.3％
21 1528 342.2％
22 381 628.0％
23 1347 847.8％
24 768 694.1％
25 854 534.3％
26 1485 454.9％
27 929 653.8％
由此可见，本发明化合物在细胞中对RORγ具有明显的激动作用，具有例如小于2000nM的EC 50以及大于300％的最大激活率。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (16)

  1. 一种具有式I结构的化合物或其药学上可接受的形式，
    Figure PCTCN2020112483-appb-100001
    其中，
    环A 1选自苯基和5-6元杂芳基；
    环A 2选自苯基、5-6元杂芳基和3-6元杂环基；
    环A 3选自苯基、5-10元杂芳基、3-10元环烷基和4-10元杂环基；
    Z 1、Z 2和Z 3各自独立地选自CR 4和N；
    R 1选自氢和C 1-6烷基；
    每一个R 2各自独立地选自卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6卤代烷氧基和C 3-6环烷氧基；
    每一个R 3各自独立地选自卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、C 1-6烷氧基、C 1-6卤代烷氧基和-S(＝O) 2-R 6；
    每一个R 4各自独立地选自氢、卤素、氰基、C 1-6烷基和C 1-6烷氧基；
    每一个R 5各自独立地选自氢、卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基、-C 0-6亚烷基-O-R a、-O-C 1-6亚烷基-O-R a、C 1-6卤代烷氧基、-C 0-6亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-6亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-C(＝O)-C 1-6烷基、-C 0-6亚烷基-S(＝O) 2-R 6、-C 0-6亚烷基-N(R a)(R b)、-C 0-6亚烷基-C(＝O)-N(R a)(R b)、-C 0-6亚烷基-N(R a)-C(＝O)-R 6、-C 0-6亚烷基-S(＝O) 2-N(R a)(R b)、-C 0-6亚烷基-N(R a)-S(＝O) 2-R 6、4-10元杂环基、苯基和5-10元杂芳基；其中：每一个R a各自独立地选自氢和C 1-6烷基；每一个R b各自独立地选自氢和C 1-6烷基；或者R a和R b连同与其相连的氮原子形成3-7元杂环基；
    每一个R 6各自独立地选自C 1-6烷基和C 3-6环烷基；
    m为1、2或3；
    n为0、1、2或3；
    q为0、1、2或3；
    所述药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。
  2. 根据权利要求1所述的化合物或其药学上可接受的形式，其为具有式I-A结构的化合物或其药学上可接受的形式，
    Figure PCTCN2020112483-appb-100002
    其中，环A 1、环A 2、环A 3、R 2、R 3、R 5、m、n和q如权利要求1中所定义。
  3. 根据权利要求2所述的化合物或其药学上可接受的形式，其中，
    环A 1选自苯基和吡啶基；每一个R 2各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 3-6环烷氧基。
  4. 根据权利要求2或3所述的化合物或其药学上可接受的形式，其中，
    环A 2选自苯基和5-6元杂芳基；每一个R 3各自独立地选自卤素、氰基、C 1-4烷基、C 1-4卤代烷基、C 3- 6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和-S(＝O) 2-C 1-4烷基。
  5. 根据权利要求2所述的化合物或其药学上可接受的形式，其为具有式I-B1结构的化合物或其药学上可接受的形式，
    Figure PCTCN2020112483-appb-100003
    其中，环A 3、R 2、R 5、m和q如权利要求2所定义。
  6. 根据权利要求5所述的化合物或其药学上可接受的形式，
    其中，每一个R 2各自独立地选自卤素、氰基、羟基、C 1-4烷基、C 1-4卤代烷基、C 3-6环烷基、C 1-4烷氧基、C 1-4卤代烷氧基和C 3-6环烷氧基；
    环A 3选自苯基、5-10元杂芳基和4-10元杂环基；
    每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；
    q为0、1或2；
    m为1或2。
  7. 根据权利要求6所述的化合物或其药学上可接受的形式，
    其中，
    每一个R 2各自独立地选自卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基和C 1-4卤代烷氧基；
    环A 3选自5-6元杂芳基和5-6元杂环基；
    每一个R 5各自独立地选自氢、羟基、C 1-3烷基、-C 1-3亚烷基-O-R a、-O-C 1-3亚烷基-O-R a、-C 0-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 1-3亚烷基-C(＝O)-O-R a、-C(＝O)-C 3-6环烷基、-C(＝O)-C 3-6亚环烷基-C(＝O)-O-R a、-S(＝O) 2-C 1-3烷基、-C 1-3亚烷基-N(R a)(R b)、-C 1-3亚烷基-C(＝O)-N(R a)(R b)和4-6元杂环基；其中：每一个R a各自独立地选自氢和C 1-3烷基；每一个R b各自独立地选自氢和C 1-3烷基；
    q为0、1或2；
    m为2。
  8. 根据权利要求7所述的化合物或其药学上可接受的形式，
    其中，
    每一个R 2各自独立地选自氟、氯、甲基、甲氧基、乙氧基、二氟甲氧基和三氟甲氧基；
    环A 3选自吡唑基、四氢吡啶基、噻唑基、哌嗪基、吗啉基和哌啶基；
    每一个R 5各自独立地选自氢、-OH、-CH 3、-CH 2CH 3、-CH(CH 3) 2、-CH 2COOH、-CH 2CH 2OCH 3、-CH 2C(＝O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、
    Figure PCTCN2020112483-appb-100004
    -C(＝O)CH 2CH 2COOH、
    Figure PCTCN2020112483-appb-100005
    -COOCH 3、-COOH、-S(＝O) 2-CH 3和-OCH 2CH 2OCH 3；
    q为0、1或2；
    m为2。
  9. 根据权利要求5至8中任一项所述的化合物或其药学上可接受的形式，其为具有式I-B结构的化合物或其药学上可接受的形式，
    Figure PCTCN2020112483-appb-100006
    其中，环A 3、R 5和q如权利要求5至8中任一项所定义。
  10. 根据权利要求1所述的化合物或其药学上可接受的形式，其中所述化合物选自：
    Figure PCTCN2020112483-appb-100007
    Figure PCTCN2020112483-appb-100008
    所述药学上可接受的形式选自药学上可接受的盐、立体异构体、互变异构体、顺反异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物和前药。
  11. 根据权利要求1所述的具有式I结构的化合物的制备方法，其包括下列步骤：
    (1)将化合物A与化合物B反应，得到化合物C；
    Figure PCTCN2020112483-appb-100009
    (2)化合物C发生取代反应，得到化合物D；
    Figure PCTCN2020112483-appb-100010
    (3)化合物D发生还原反应以及可选的N-烷基化反应，得到化合物E；
    Figure PCTCN2020112483-appb-100011
    (4)将化合物E与化合物F反应，得到化合物G；
    Figure PCTCN2020112483-appb-100012
    (5)将化合物G与化合物H反应，得到式I化合物；
    Figure PCTCN2020112483-appb-100013
    其中，环A 1、环A 2、环A 3、Z 1、Z 2、Z 3、R 1、R 2、R 3、R 5、m、n和q如权利要求1中所定义；X表示离去基团，选自卤素原子、甲磺酰氧基和三氟甲磺酰氧基；
    或者包括下列步骤：
    (1’)将化合物A’与化合物B’反应，得到化合物C’；
    Figure PCTCN2020112483-appb-100014
    (2’)化合物C’发生还原反应以及可选的N-烷基化反应，得到化合物D’；
    Figure PCTCN2020112483-appb-100015
    (3’)将化合物D’与化合物F反应，得到化合物F’；
    Figure PCTCN2020112483-appb-100016
    (4’)将化合物F’与化合物B反应，得到式I化合物；
    Figure PCTCN2020112483-appb-100017
    其中，环A 1、环A 2、环A 3、Z 1、Z 2、Z 3、R 1、R 2、R 3、R 5、m、n和q如权利要求1中所定义；X表示离去基团，选自卤素原子、甲磺酰氧基和三氟甲磺酰氧基；Hal表示卤素原子，选自F、Cl、Br和I。
  12. 一种药物组合物，其包含根据权利要求1至10中任一项所述的化合物或其药学上可接受的形式，以及药学上可接受的载体。
  13. 一种药物联用组合物，其包含根据权利要求1至10中任一项所述的化合物或其药学上可接受的形式或者根据权利要求12所述的药物组合物，以及至少一种其他的同向RORγ调节剂。
  14. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的形式，或者根据权利要求12所述的药物组合物，或者根据权利要求13所述的药物联用组合物在制备用于预防和/或治疗至少部分由RORγ介导的疾病的药物中的用途。
  15. 根据权利要求1至10中任一项所述的化合物或其药学上可接受的形式，或者根据权利要求12所述的药物组合物，或者根据权利要求13所述的药物联用组合物，其用于预防和/或治疗至少部分由RORγ介导的疾病。
  16. 一种用于预防和/或治疗癌症、炎症或自身免疫性疾病的方法，其包括下列步骤：将治疗有效量的根据权利要求1至10中任一项所述的化合物或其药学上可接受的形式，或者根据权利要求12所述的药物组合物，或者根据权利要求13所述的药物联用组合物施用于对其有需求的患者。
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CN101679266A (zh) * 2007-03-01 2010-03-24 诺瓦提斯公司 Pim激酶抑制剂及其应用方法
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