WO2021047406A1 - Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée - Google Patents

Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée Download PDF

Info

Publication number
WO2021047406A1
WO2021047406A1 PCT/CN2020/112479 CN2020112479W WO2021047406A1 WO 2021047406 A1 WO2021047406 A1 WO 2021047406A1 CN 2020112479 W CN2020112479 W CN 2020112479W WO 2021047406 A1 WO2021047406 A1 WO 2021047406A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
alkylene
alkyl
Prior art date
Application number
PCT/CN2020/112479
Other languages
English (en)
Chinese (zh)
Inventor
刘春池
唐建川
任云
刘金明
田强
宋宏梅
薛彤彤
王晶翼
Original Assignee
四川科伦博泰生物医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川科伦博泰生物医药股份有限公司 filed Critical 四川科伦博泰生物医药股份有限公司
Priority to CN202080050294.2A priority Critical patent/CN114096533B/zh
Publication of WO2021047406A1 publication Critical patent/WO2021047406A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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 been found And got the name.
  • 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 5-10 membered heteroaryl groups
  • Ring A 2 is selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group;
  • X 1 , X 2 and X 3 are each independently selected from N and CR 4 ;
  • 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, C 1-6 haloalkyl and C 1-6 alkoxy;
  • R 5a and R 5b are each independently selected from hydrogen and C 1-6 alkyl, or R 5a and R 5b together with the nitrogen atom to which they are connected form a 3-7 membered heterocyclic group;
  • Each R 6 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n 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 , X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , m and n are as defined in formula I;
  • X represents a leaving group, selected from halogen Atom, methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • Hal represents halogen, selected from F and Cl;
  • PG represents protecting group, selected from benzyloxycarbonyl and tert-butoxycarbonyl.
  • 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 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 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. Common solvates include (but are not limited to) hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, etc.), ethanolate, acetonate, and the like.
  • 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), for example, C 1-6 alkylene refers to an alkylene containing 1-6 carbon atoms, and C 1-4 alkylene refers to containing 1-4 carbons Atom alkylene; common alkylene includes (but is 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-di
  • 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 refers to a monocyclic or polycyclic (including fused form) aromatic ring system containing 6-10 carbon atoms; common aryl groups include (but are not limited to) phenyl, naphthyl, anthracene Base, 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.
  • a 5-10 membered heteroaryl group refers to a monocyclic or polycyclic (including fused form) aromatic ring system with a total of 5-10 ring atoms;
  • common Heterocyclic groups include (but are not limited to) benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, imidazopyridyl, acridinyl, carb Azolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indazinyl, indolyl, quinolinyl , Isoquinolinyl, quinoxalinyl, phenazinyl, phenoxazinyl, phenothiazinyl, pterridiny
  • 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 5-10 membered heteroaryl groups
  • Ring A 2 is selected from phenyl, 5-10 membered heteroaryl and 4-10 membered heterocyclic group;
  • X 1 , X 2 and X 3 are each independently selected from N and CR 4 ;
  • 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, C 1-6 haloalkyl and C 1-6 alkoxy;
  • R 5a and R 5b are each independently selected from hydrogen and C 1-6 alkyl, or R 5a and R 5b together with the nitrogen atom to which they are connected form a 3-7 membered heterocyclic group;
  • Each R 6 is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl
  • n 0, 1, 2 or 3;
  • n 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 ring A 1 in the compound of formula I or a pharmaceutically acceptable form thereof is selected from phenyl, pyridyl, isoxazolyl, pyrazolyl and imidazo [1,2- a] Pyridyl.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ia-1 or a pharmaceutically acceptable form thereof
  • rings A 2 , X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , m, and n are as defined above.
  • each R 2 in the compound of formula I or formula Ia-1 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-1 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-1 or a pharmaceutically acceptable form thereof is independently selected from fluorine, chlorine, cyano, methyl, methyl Oxy, ethoxy, difluoromethoxy and trifluoromethoxy.
  • each R 2 in the compound of formula I or formula Ia-1 or a pharmaceutically acceptable form thereof is independently selected from fluorine, chlorine, cyano, methyl, methyl Oxy and difluoromethoxy.
  • the ring A 1 in the compound of formula I or its pharmaceutically acceptable form is selected from phenyl and 5-10 membered heteroaryl, and each R 2 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 base.
  • the ring A 1 in the compound of formula I or its pharmaceutically acceptable form is selected from phenyl, pyridyl, isoxazolyl, pyrazolyl and imidazo [1,2 -a] Pyridyl, each R 2 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.
  • the ring A 1 in the compound of formula I or its pharmaceutically acceptable form is phenyl, and each R 2 is independently selected from fluorine, chlorine, cyano, methyl, Methoxy, ethoxy, difluoromethoxy and trifluoromethoxy.
  • the ring A 2 in the compound of formula I 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 a pharmaceutically acceptable form thereof is selected from phenyl, pyridyl, isoxazolyl and pyrazolyl.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ib-1 or a pharmaceutically acceptable form thereof
  • rings A 1 , X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , m, and n are as defined above.
  • the ring A 2 in the compound of formula I or its pharmaceutically acceptable form is phenyl, and each R 3 is independently selected from fluorine, cyano, methyl, and trifluoro Methyl and methylsulfonyl, preferably trifluoromethyl.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ic or a pharmaceutically acceptable form thereof
  • ring A 1 , ring A 2 , X 3 , L, R 1 , R 2 , R 3 , m and n are as defined above.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ic-1 or a compound of formula Ic'-1 or a pharmaceutically acceptable form thereof,
  • ring A 1 , ring A 2 , L, R 1 , R 2 , R 3 , m, and n are as defined above.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ic-2 or a compound of formula Ic'-2 or a pharmaceutically acceptable form thereof,
  • rings A 2 , L, R 1 , R 2 , R 3 , m and n are as defined above.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ic-3 or a compound of formula Ic'-3 or a pharmaceutically acceptable form thereof,
  • rings A 1 , L, R 1 , R 2 , R 3 , m and n are as defined above.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ic-4 or Ic'-4 or a pharmaceutically acceptable form thereof,
  • L, R 1 , R 2 , R 3 , m and n are as defined above.
  • the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is a compound of formula Ic-4 or Ic'-4 or a pharmaceutically acceptable form thereof, wherein,
  • 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;
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3.
  • the above-mentioned compound of formula I is a compound of formula Ic-4 or Ic'-4, wherein,
  • Each R 2 is independently selected from fluorine, chlorine, cyano, methyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy, preferably fluorine, chlorine, cyano, methyl, Methoxy and difluoromethoxy, more preferably fluorine and difluoromethoxy;
  • Each R 3 is independently selected from fluorine, cyano, methyl, trifluoromethyl and methylsulfonyl, preferably trifluoromethyl;
  • n 0, 1 or 2, preferably 2;
  • n 0, 1, or 2, preferably 1.
  • 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 , X 1 , X 2 , X 3 , L, R 1 , R 2 , R 3 , m and n are as defined in formula I;
  • X represents a leaving group, including (but Not limited to) halogen atoms, methanesulfonyloxy and trifluoromethanesulfonyloxy;
  • Hal represents halogen, including (but not limited to) F and Cl;
  • PG represents a protecting group, including (but not limited to) benzyloxycarbonyl ( Cbz) and tert-butoxycarbonyl (Boc).
  • step 1) of the above preparation method is carried out in an alkaline environment, and reagents that provide an alkaline environment include (but are not limited to) diisopropylethylamine (DIPEA), triethylamine (TEA) ), sodium carbonate, potassium carbonate, cesium carbonate, preferably cesium carbonate.
  • step 1) of the above preparation method is carried out in a solvent, and the solvent used includes (but is not limited to) acetonitrile, dimethyl sulfoxide (DMSO), 1,4-dioxane, N , N-Dimethylformamide (DMF) and combinations thereof, preferably DMF.
  • the reaction temperature in step 1) of the above preparation method is 40-80° C., and the reaction time is 2-24 hours.
  • step 2) of the above preparation method is carried out in the presence of metal and acid.
  • the metal used includes (but is not limited to) zinc powder and iron powder, preferably iron powder;
  • the acid used includes (but not Limited to) hydrochloric acid and acetic acid, preferably acetic acid.
  • step 2) of the above preparation method is carried out in a solvent, and the solvent used includes (but is not limited to) alcohols.
  • step 3) of the above preparation method is carried out by reducing the lactam carbonyl group to methylene by a metal hydride or borane reagent.
  • the metal hydride used includes (but is not limited to) tetrahydro
  • the borane reagents used include (but are not limited to) borane dimethyl sulfide, borane tetrahydrofuran, and borane tetrahydrofuran is preferred.
  • step 3) of the above preparation method is carried out in a solvent, and the solvent used includes (but is not limited to) acetonitrile, tetrahydrofuran (THF) and a combination thereof, preferably THF.
  • the solvent used includes (but is not limited to) acetonitrile, tetrahydrofuran (THF) and a combination thereof, preferably THF.
  • step 4) of the above preparation method is carried out by sulfonylation in a solvent.
  • the solvent used includes (but is not limited to) TEA, DIPEA, pyridine (Pyr) and combinations thereof, preferably Pyr.
  • the reaction temperature in step 4) of the above preparation method is 40-80°C, and the reaction time is 2-8 hours.
  • the coupling reaction in step 5) or 7') of the above preparation method is carried out with the aid of a metal catalyst in an alkaline environment, and the coupling reaction used includes (but is not limited to) the Suzuki reaction (Suzuki reaction).
  • the metal catalysts used include (but are not limited to) palladium catalysts, such as tris(dibenzylideneacetone)dipalladium, triphenylphosphine palladium, palladium acetate, [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; reagents that provide an alkaline environment include (but are not limited to) ) Potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium carbonate.
  • the coupling reaction in step 5) or 7') of the above preparation method is carried out in a solvent, and the solvent used includes (but is not limited to) DMF, N-methylpyrrolidone, toluene, ethanol, Ethylene glycol dimethyl ether, water, 1,4-dioxane and combinations thereof, preferably a mixed solvent of 1,4-dioxane and water.
  • the reaction temperature of the coupling reaction in step 5) or 7') of the above preparation method is 60-100° C., and the reaction time is 2-8 hours.
  • step 6) or 5') of the above preparation method is carried out in the presence of a metal catalyst, acid or organic deprotection reagent, and the metal catalyst used includes (but is not limited to) palladium on carbon, hydrogen hydroxide Palladium, the acid used includes (but is not limited to) hydrobromic acid/acetic acid, hydrofluoric acid/pyridine, and the organic deprotection reagent used includes (but is not limited to) trimethylsilyl iodide, preferably palladium on carbon.
  • step 6) or 5') of the above preparation method is performed under a hydrogen atmosphere.
  • step 6) or 5') of the above preparation method is carried out in a solvent, and the solvent used includes (but is not limited to) alcohols, ethyl acetate (EtOAc), THF, toluene, dichloromethane (DCM), 1,4-dioxane and combinations thereof, preferably EtOAc.
  • the reaction temperature in step 6) or 5') of the above preparation method is 20-50°C, and the reaction time is 2-24 hours.
  • step 7) or 6') of the above preparation method may be carried out by substitution reaction or addition reaction.
  • step 7) or 6') of the above preparation method is carried out in a solvent in an alkaline environment, and reagents that provide an alkaline environment include (but are not limited to) potassium carbonate, cesium carbonate, TEA, DIPEA, preferably potassium carbonate; the solvent used includes (but is not limited to) methanol, DMF, N-methylpyrrolidone, THF, acetonitrile, DCM and combinations thereof, preferably DMF.
  • the reaction temperature in step 7) or 6') of the above preparation method is 25-100° C., and the reaction time is 2-12 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
  • a pharmaceutical composition comprising the above formula I, formula Ia-1, formula Ib-1, formula Ic, formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula A compound of Ic'-1, Formula Ic'-2, Formula Ic'-3, or Formula Ic'-4 or a pharmaceutically acceptable form thereof.
  • the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the present invention provides the above formula I, formula Ia-1, formula Ib-1, formula Ic, formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula Ic'-1, formula Use of a compound of Ic'-2, formula Ic'-3 or formula Ic'-4, 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 above formula I, formula Ia-1, formula Ib-1, formula Ic, formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula Ic'-1,
  • the compound of formula Ic'-2, formula Ic'-3 or formula Ic'-4, or a pharmaceutically acceptable form thereof, or the above-mentioned pharmaceutical composition is used in the preparation of a medicament for the prevention and/or treatment of diseases mediated at least in part by ROR ⁇ In the use.
  • 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.
  • ankylosing spondylitis chronic obstructive pulmonary disease, chronic bronchitis, asthma, mesangial capillary glomerulonephritis, allergic dermatitis, myocarditis, ulcerative colitis, Crohn Disease, etc.
  • autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, etc.
  • the present invention provides a method for preventing and/or treating diseases at least partly mediated by ROR ⁇ , which comprises the following steps: adding a therapeutically effective amount of the above formula I, formula Ia-1, formula Ib-1, and formula Ic , Formula Ic-1, Formula Ic-2, Formula Ic-3, Formula Ic-4, Formula Ic'-1, Formula Ic'-2, Formula Ic'-3 or Formula Ic'-4 compound or its pharmaceutically acceptable
  • the accepted form or the above-mentioned pharmaceutical composition is administered to patients in need thereof.
  • 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
  • a drug combination composition comprising the above formula I, formula Ia-1, formula Ib-1, formula Ic, formula Ic-1, formula Ic-2, formula Ic-3, and formula Ic-4 , Formula Ic'-1, Formula Ic'-2, Formula Ic'-3 or Formula Ic'-4 compound 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 preventing and/or treating cancer, which comprises the following steps: a therapeutically effective amount of the above formula I, formula Ia-1, formula Ib-1, formula Ic, The compound of formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula Ic'-1, formula Ic'-2, formula Ic'-3 or formula Ic'-4 or pharmaceutically acceptable
  • a therapeutically effective amount of the above formula I formula Ia-1, formula Ib-1, formula Ic
  • the compound of formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula Ic'-1, formula Ic'-2, formula Ic'-3 or formula Ic'-4 or pharmaceutically acceptable 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 above formula I, formula Ia-1, formula Ib-1, formula Ic, The compound of formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula Ic'-1, formula Ic'-2, formula Ic'-3 or formula Ic'-4 or pharmaceutically acceptable
  • a therapeutically effective amount of the above formula I formula Ia-1, formula Ib-1, formula Ic
  • the compound of formula Ic-1, formula Ic-2, formula Ic-3, formula Ic-4, formula Ic'-1, formula Ic'-2, formula Ic'-3 or formula Ic'-4 or pharmaceutically acceptable 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 the prevention and/or treatment of autoimmune diseases, which comprises the following steps: a therapeutically effective amount of the above formula I, formula Ia-1, formula Ib-1, and ROR ⁇ antagonist Formula Ic, Formula Ic-1, Formula Ic-2, Formula Ic-3, Formula Ic-4, Formula Ic'-1, Formula Ic'-2, Formula Ic'-3 or Formula Ic'-4 Compound or its pharmacy
  • a therapeutically effective amount of the above formula I, formula Ia-1, formula Ib-1, and ROR ⁇ antagonist Formula Ic, Formula Ic-1, Formula Ic-2, Formula Ic-3, Formula Ic-4, Formula Ic'-1, Formula Ic'-2, Formula Ic'-3 or Formula Ic'-4 Compound or its pharmacy
  • the above acceptable form or the above-mentioned 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); Chromatographic 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 4-(benzyloxycarbonyl)-1-(4-bromo-2-nitrophenyl)piperazine-2-carboxylic acid.
  • the second step 8-bromo-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-carboxylic acid benzyl ester preparation.
  • the third step preparation of 8-bromo-4,4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-carboxylic acid benzyl ester.
  • the fourth step 8-bromo-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxa Preparation of benzyl phenoline-3(2H)-carboxylate.
  • the fifth step 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5,6-tetra Preparation of hydrogen-1H-pyrazino[1,2-a]quinoxaline-3(2H)-carboxylic acid benzyl ester.
  • the sixth step 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-2,3,4,4a,5 Preparation of ,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline.
  • the first step preparation of (S)-1-(4-bromo-2-nitrophenyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid.
  • the third step (R)-8-bromo-4,4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-carboxylic acid tert-butyl ester preparation.
  • the fifth step (S)-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5
  • the sixth step (S)-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-2,3,4 ,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline preparation.
  • the first step preparation of 4-(benzyloxycarbonyl)-1-(5-bromo-3-nitropyridin-2-yl)piperazine-2-carboxylic acid.
  • the third step 3-bromo-6a,7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-carboxylic acid Preparation of benzyl esters.
  • the fourth step 3-bromo-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido [3,2-e] Preparation of pyrazine-8(6H)-carboxylic acid benzyl ester.
  • the fifth step 3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetra Preparation of hydrogen-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-carboxylic acid benzyl ester.
  • the sixth step 3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6,6a,7,8,9 Preparation of ,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine.
  • the first step (S)-3-bromo-5-(3-(trifluoromethyl)phenylsulfonyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[ Preparation of 1,2-a]pyrido[3,2-e]pyrazine.
  • the second step (S)-4-(3-bromo-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro-5H-pyrazino[1 Preparation of ,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid.
  • Example 1 3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5, Preparation of 6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionic acid (Compound 1).
  • the first step 3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5, Preparation of methyl 6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionate.
  • the second step 3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5, Preparation of 6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionic acid.
  • Example 2 8-(3-(Difluoromethoxy)-5-fluorophenyl)-3-(2,2,2-trifluoroethyl)-6-(3-(trifluoromethyl) (Phenylsulfonyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline (compound 2) preparation.
  • Example 3 8-(3-(Difluoromethoxy)-5-fluorophenyl)-3-(2-fluoroethyl)-6-(3-(trifluoromethyl)phenylsulfonyl) Preparation of -2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline (Compound 3).
  • Example 4 8-(3-(Difluoromethoxy)-5-fluorophenyl)-3-(2-methoxyethyl)-6-(3-(trifluoromethyl)phenylsulfonate Acyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline (compound 4) preparation.
  • Example 5 8-(3-(Difluoromethoxy)-5-fluorophenyl)-3-(2-(methylsulfonyl)ethyl)-6-(3-(trifluoromethyl) (Phenylsulfonyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline (compound 5) preparation.
  • Example 6 2-(8-(3-(Difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5, Preparation of 6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)-N,N-dimethylacetamide (compound 6).
  • Example 7 Cyclopropyl(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5 Preparation of ,6-Tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)methanone (Compound 7).
  • Example 8 4-(8-(3-(Difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5, Preparation of 6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)-4-oxobutanoic acid (Compound 8).
  • Example 9 3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4,4a,5, Preparation of 6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionitrile (compound 9).
  • Example 10 (S)-3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4, Preparation of 4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionic acid (compound 10).
  • the first step (S)-3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4, Preparation of 4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionic acid methyl ester.
  • the second step (S)-3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4, Preparation of 4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionic acid.
  • Example 11 (R)-3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-(3-(trifluoromethyl)phenylsulfonyl)-4, Preparation of 4a,5,6-tetrahydro-1H-pyrazino[1,2-a]quinoxaline-3(2H)-yl)propionic acid (Compound 11).
  • Example 12 3-(3-(3-(Difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 12).
  • the first step 3-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid methyl ester.
  • the second step 3-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid.
  • Example 13 (S)-3-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, Preparation of 7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 13).
  • Example 14 (R)-3-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, Preparation of 7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 14).
  • Example 15 (S)-4-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, 7,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 15 ) Preparation.
  • Example 16 (S)-4-(3-(3-chloro-5-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 16).
  • Example 17 (S)-4-(3-(2-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro Preparation of -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 17).
  • Example 18 (S)-4-(3-(3-ethoxy-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 18).
  • Example 19 (S)-4-(3-(3-fluoro-5-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 19).
  • Example 20 (S)-4-(3-(3-ethoxy-5-methylphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9 ,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 20) .
  • Example 21 (S)-4-(3-(3-chloro-5-(difluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, 7,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 21 ) Preparation.
  • Example 22 (S)-4-(3-(3-methoxy-5-methylphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9 ,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (Compound 22) .
  • Example 23 (S)-4-(3-(3-chloro-5-(trifluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, 7,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-4-oxobutanoic acid (compound 23 ) Preparation.
  • Example 24 (S)-2-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, 7,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropionic acid (Compound 24 ) Preparation.
  • the first step (S)-2-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, 7,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropanoate preparation.
  • the second step (S)-2-(3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, Preparation of 7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropionic acid.
  • Example 25 (S)-2-(3-(3-chloro-5-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropionic acid (Compound 25).
  • Example 26 (S)-2-(3-(3-methoxy-5-methylphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9 Preparation of ,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropionic acid (Compound 26) .
  • Example 27 (S)-2-(3-(3-chloro-5-(trifluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, 7,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropionic acid (Compound 27 ) Preparation.
  • Example 28 (S)-2-(3-(3-fluoro-5-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)-2-methylpropionic acid (Compound 28).
  • Example 29 (S)-3-(3-(3-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro Preparation of -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 29).
  • the first step (S)-3-(3-(3-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro Preparation of 5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid methyl ester.
  • the second step (S)-3-(3-(3-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro Preparation of -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid.
  • Example 30 (S)-3-(3-(2-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro Preparation of -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 30).
  • Example 31 (S)-3-(3-(3-ethoxy-5-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 31).
  • Example 32 (S)-3-(3-(3-fluoro-5-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 32).
  • Example 33 (S)-3-(3-(3-(difluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 33).
  • Example 34 (S)-3-(3-(3-chloro-5-methoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 34).
  • Example 35 (S)-3-(3-(3-cyanophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro- Preparation of 5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 35).
  • Example 36 (S)-3-(3-(2,6-difluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetra Preparation of Hydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 36).
  • Example 37 (S)-3-(3-(3,5-difluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetra Preparation of Hydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 37).
  • Example 38 (S)-3-(3-(3-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro-5H -Preparation of pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 38).
  • Example 39 (S)-3-(3-(2-fluorophenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro-5H -Preparation of pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (compound 39).
  • Example 40 (S)-3-(3-(3-(trifluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 40).
  • Example 41 (S)-3-(3-(3-ethoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9,10-tetrahydro Preparation of -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 41).
  • Example 42 (S)-3-(3-(3-chloro-5-(trifluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, Preparation of 7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 42).
  • Example 43 (S)-3-(3-(3-chloro-5-(difluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, Preparation of 7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 43).
  • Example 44 (S)-3-(3-(3-ethoxy-5-methylphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9 Preparation of ,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 44).
  • Example 45 (S)-3-(3-(3-fluoro-3-(trifluoromethoxy)phenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a, Preparation of 7,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 45).
  • Example 46 (S)-3-(3-(3-methoxy-5-methylphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9 Preparation of ,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 46).
  • Example 47 (S)-3-(3-(3-chloro-5-ethoxyphenyl)-5-(3-(trifluoromethyl)phenylsulfonyl)-6a,7,9, Preparation of 10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8(6H)-yl)propionic acid (Compound 47).
  • 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.
  • After placing the 384-well plate at 4°C overnight take out the 384-well plate to room temperature equilibrium, after centrifugation, 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 100 nM, preferably less than 20 nM, and more preferably less than 10 nM, and the maximum activation rate is all 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 an EC 50 of less than 1200 nM and a maximum activation rate of greater than 300%, for example.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé tricyclique représenté par la formule I, une composition pharmaceutique le contenant, un procédé de préparation correspondant et une utilisation associée. Le composé peut servir de modulateur de RORγ, et a diverses activités pharmacologiques, telles qu'une activité anti-tumorale, une activité contre des maladies auto-immunes et une activité anti-inflammatoire.
PCT/CN2020/112479 2019-09-10 2020-08-31 Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée WO2021047406A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202080050294.2A CN114096533B (zh) 2019-09-10 2020-08-31 一种三并环类化合物，包含其的药物组合物，其制备方法及其用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910853127 2019-09-10
CN201910853127.0 2019-09-10

Publications (1)

Publication Number Publication Date
WO2021047406A1 true WO2021047406A1 (fr) 2021-03-18

Family

ID=74866087

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/112479 WO2021047406A1 (fr) 2019-09-10 2020-08-31 Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée

Country Status (2)

Country Link
CN (1) CN114096533B (fr)
WO (1) WO2021047406A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012064744A2 (fr) * 2010-11-08 2012-05-18 Lycera Corporation Tétrahydroquinoline et composés bicycliques associés pour l'inhibition de l'activité rorγ et le traitement de maladies
WO2015171610A2 (fr) * 2014-05-05 2015-11-12 Lycera Corporation Sulfonamide de tétrahydroquinoline et composés apparentés destinés à servir d'agonistes de rory et pour le traitement de maladies
CN107980042A (zh) * 2015-06-11 2018-05-01 莱斯拉公司 用作RORγ激动剂和用于治疗疾病的芳基二氢-2H-苯并[b][1,4]噁嗪磺酰胺和相关化合物
WO2020151232A1 (fr) * 2019-01-23 2020-07-30 上海和誉生物医药科技有限公司 Dérivé de 1,2,3,4-tétrahydroquinoxaline, son procédé de préparation et son utilisation

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4032639A (en) * 1976-03-22 1977-06-28 American Home Products Corporation 2,3,4,4A-Tetrahydro-1H-pyrazino[1,2-a,]quinoxalin-5(6H)-ones and derivatives thereof for relieving hypertension
EP2846804B1 (fr) * 2012-05-08 2017-11-29 Merck Sharp & Dohme Corp. Tétrahydronaphtyridine et composés bicycliques apparentés pour l'inhibition de l'activité rorgamma et le traitement d'une maladie
US9809561B2 (en) * 2013-12-20 2017-11-07 Merck Sharp & Dohme Corp. Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease
CN104530014B (zh) * 2013-12-25 2018-03-20 中国科学院广州生物医药与健康研究院 2‑氧代‑1,2‑二氢苯并[cd]吲哚‑6‑磺酰胺类化合物及其组合物和应用
EP3377482B1 (fr) * 2015-11-20 2021-05-12 Vitae Pharmaceuticals, LLC Modulateurs de ror-gamma

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012064744A2 (fr) * 2010-11-08 2012-05-18 Lycera Corporation Tétrahydroquinoline et composés bicycliques associés pour l'inhibition de l'activité rorγ et le traitement de maladies
WO2015171610A2 (fr) * 2014-05-05 2015-11-12 Lycera Corporation Sulfonamide de tétrahydroquinoline et composés apparentés destinés à servir d'agonistes de rory et pour le traitement de maladies
CN107980042A (zh) * 2015-06-11 2018-05-01 莱斯拉公司 用作RORγ激动剂和用于治疗疾病的芳基二氢-2H-苯并[b][1,4]噁嗪磺酰胺和相关化合物
WO2020151232A1 (fr) * 2019-01-23 2020-07-30 上海和誉生物医药科技有限公司 Dérivé de 1,2,3,4-tétrahydroquinoxaline, son procédé de préparation et son utilisation

Also Published As

Publication number Publication date
CN114096533B (zh) 2024-03-08
CN114096533A (zh) 2022-02-25

Similar Documents

Publication Publication Date Title
KR20150131233A (ko) 치환된 트리아졸로피리딘 및 이의 사용 방법
JP6884800B2 (ja) メマンチン化合物及びその調整並びにその使用
WO2021249533A1 (fr) Composé modulateur du récepteur des oestrogènes et son utilisation
WO2023011513A1 (fr) Inhibiteur de shp2, composition pharmaceutique le comprenant et son application
WO2023041055A1 (fr) Inhibiteur de kif18a
WO2023088441A1 (fr) Inhibiteur de kif18a
WO2022166983A1 (fr) Dérivé d'hétéroaryloxypipéridine, composition pharmaceutique de celui-ci et son utilisation
WO2019149089A1 (fr) Composé benzohétérocycle contenant de l'azote comprenant un groupe acide carboxylique, son procédé de préparation et son utilisation
WO2020135454A1 (fr) Classe de composés stéroïdes et leur utilisation
WO2023125182A1 (fr) Dérivé d'acide propionique et son utilisation médicale
WO2021047406A1 (fr) Composé tricyclique, composition pharmaceutique le contenant, procédé de préparation correspondant et utilisation associée
WO2022222911A1 (fr) Composé pyrimidone et son utilisation
WO2021228217A1 (fr) COMPOSÉ ANILINE UTILISÉ COMME RÉGULATEUR DE RORγ
WO2022007659A1 (fr) Immunomodulateur hétérocyclique
WO2021228216A1 (fr) COMPOSÉ BIARYLE CAPABLE DE SERVIR DE MODULATEUR DE RORγ
WO2021228215A1 (fr) COMPOSÉ BIARYLE CAPABLE DE SERVIR DE RÉGULATEUR DE RORγ
RU2701861C1 (ru) Новое производное 3-азабицикло[3.1.0]гексана и его применение в медицинских целях
WO2020151232A1 (fr) Dérivé de 1,2,3,4-tétrahydroquinoxaline, son procédé de préparation et son utilisation
WO2021047407A1 (fr) Composé biaryle, composition pharmaceutique le comprenant, procédé de préparation correspondant et utilisation associée
WO2023143402A1 (fr) Composé stéroïde, son procédé de préparation et son utilisation
WO2023213264A1 (fr) Synthèse d'un composé amide et son utilisation
WO2023165574A1 (fr) Composé utilisé en tant qu'inhibiteur de tyk2, son procédé de préparation et son utilisation pharmaceutique
WO2024103400A1 (fr) Composé polycyclique utilisé en tant qu'activateur de gpr75, composition pharmaceutique le comprenant et son utilisation
WO2023236947A1 (fr) Composé pyridazine-3-carboxamide substitué servant d'inhibiteur de tyk2
WO2023083373A1 (fr) Composé utilisé comme inhibiteur de src

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20863045

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20863045

Country of ref document: EP

Kind code of ref document: A1