CN108218845A - A kind of chroman -6- sulfonamide ROR gamma modulators and application thereof - Google Patents

A kind of chroman -6- sulfonamide ROR gamma modulators and application thereof Download PDF

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CN108218845A
CN108218845A CN201611195147.6A CN201611195147A CN108218845A CN 108218845 A CN108218845 A CN 108218845A CN 201611195147 A CN201611195147 A CN 201611195147A CN 108218845 A CN108218845 A CN 108218845A
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alkyl
cycloalkyl
heterocyclylalkyl
ring
halogen
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CN108218845B (en
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金秋
秦引林
苏梅
马瑞
仇亚男
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Jiangsu Carephar Pharmaceutical Co ltd
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Nanjing Carefree Shenghui Pharmaceutical Co Ltd
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Abstract

The present invention relates to structure such as formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, preparation method, the pharmaceutical composition containing these conditioning agents and its purposes in the inflammatory, metabolic and autoimmune disease for the treatment of ROR γ mediations.

Description

A kind of chroman -6- sulfonamide ROR gamma modulators and application thereof
Technical field
The present invention relates to novel retinoic acid-related orphan receptor y (ROR γ) conditioning agent, preparation method, contain these The pharmaceutical composition of conditioning agent and its purposes in the inflammatory, metabolic and autoimmune disease for the treatment of ROR γ mediations.
Background technology
The relevant orphan receptor of retinoid receptor (retinoic acid receptor-related orphan Receptors, RORs) be a kind of ligand-dependent transcription factor, reproductive development, circadian rhythm adjusting, metabolic disturbance, It plays an important role during the series of physiological and pathological such as inflammation generation and immune system.RORs is nuclear receptor superfamily In a member, including ROR α, ROR β, ROR γ.ROR α be mainly distributed on liver, skeletal muscle, skin, lung, adipose tissue, kidney, It is related with the pathological processes such as hepatic gluconeogenesis, lipid metaboli, atherosclerosis in thymus gland, brain and blood.ROR β are main It is distributed in central nervous system, including brain, retina and pineal body, mainly sensitivity is believed with spinal cord, thalamus, cerebellar cortex It is related in terms of the processing of breath.ROR γ high are expressed in thymus gland, in kidney, liver, heart, skeletal muscle, adipose tissue, testis, preceding It is also distributed in row gland, pancreas, it is related with the autoimmunity diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis.
ROR γ include two hypotypes of ROR γ 1 and ROR γ 2 (ROR γ t).ROR γ 1 are including thymus gland, muscle, kidney and liver It is expressed in Various Tissues inside；ROR γ t are only uniquely expressed in immune system cell, and in thymus gland generation, the leaching of several two levels Bar tissue development and Th17 lineages in play a crucial role.Studies have shown that ROR γ t are that the crucial of Th17 cell differentiations is adjusted Save agent.Th17 cells are the hypotypes of t helper cell, generate IL-17 and other proinflammatory cytokines.Th17 cells are several Mouse Autoimmune Disease Models (including：Encephalomyelitis (EAE) and Collagen-Induced Arthritis (CIA)) in there is crucial make With.In addition, studies have shown that Th17 cells or its product and multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn disease, A variety of human inflammations including asthma are related with the pathology of autoimmune disease.The main reason for autoimmune disease is fallen ill It is the development to the automatic aggressive effector T cell for not tolerating and infiltrating tissue of self-antigen.Th17 cells are tissue spies One of driven factor important in inflammatory processes in different in nature autoimmunity, in disease progression, Th17 cells are activated And be responsible for raising other inflammatory cells (neutrophil leucocyte), so as to mediate the lesion of target tissue.
It is reported that ROR γ t are the key regulator of Th17 cell differentiations, it has recently been found that Th17 cells are preferential generate carefully The subgroup of the t helper cell of intracellular cytokine IL-17A, IL-17F, IL-21 and IL-22.ROR γ t induction codings IL-17A and IL- Transcription of the gene of 17F in initial CD4+T auxiliary cells.The mouse of ROR γ t defects shows considerably less Th17 cells.ROR Inhibition, the missing of γ t is so that EAE is improved.
In asthmatic patient, show ROR γ t and IL-17A expressions in saliva, lung, bronchoalveolar lavage (BAL) increase in liquid and peripheral blood, and horizontal directly related with disease severity.In addition to IL-17A, research recently has been shown Another cell factor IL-17F for showing IL-17 families can play an important roll, and therefore in air flue in allergic airway inflammation There is great influence in disease such as asthma.Overexpression of the IL-17F genes in airway of mice increases with air flue neutrocyte More diseases, cytokine induction, the increase of airway hyperreactivity are related to Polyblennia.
In view of effects of the ROR γ played in the pathogenesis of disease, it is expected to prepare adjusting ROR gamma activities and be accordingly used in The compound of inflammatory, metabolic and autoimmune disease that ROR γ are mediated is treated, the disease such as respiratory disease is roared Asthma, chronic obstructive pulmonary disease (COPD) and bronchitis, the anaphylactia including allergic rhinitis and Atopic dermatitis, capsule Property fibrosis and lung allograft rejection.
Invention content
According to the present invention, novel retinoic acid-related orphan receptor y (ROR γ) conditioning agent, preparation method, packet are provided Pharmaceutical composition containing these conditioning agents and its diseases such as inflammatory, metabolic and autoimmune in treatment ROR γ mediations In purposes.
More specifically, on the one hand, the present invention relates to structure such as formula (I) compound represented or its stereoisomer, changes Isomers or its pharmaceutically acceptable salt or its solvate or prodrug：
Wherein,
R1、R2It is independently selected from hydrogen, halogen, hydroxyl, amino, C1-6Alkyl, C1-C6Alkyl amine group, C1-C6Alkoxy, Or R1、R2Merge into oxo base；
R4Selected from hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl or-CH2C3-C8Cycloalkyl, wherein the alkyl, cycloalkyl can be with By one or more selected from hydrogen, halogen, hydroxyl, amino, C1-C6The substituent group substitution of alkyl；
R5Selected from C6-C10Aryl or C2-C10Heteroaryl；Wherein C6-C10Aryl, C2-C10Heteroaryl can be by one or more It is a to be selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C1-C6Alkoxy, C1-C6Alkyl halide Base, C1-C6The substituent group substitution of alkyl sulphonyl；
R3For group-(CHR6)s-(Y)t-(CHR7)u-R8；
R6、R7It is independently selected from hydrogen, C1-6Alkyl, hydroxyl；
Y is selected from C1-6Alkyl, NH or O；
R8Selected from C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C6-C10Aryl, C2-C10Heteroaryl, wherein the C2-C8Heterocycle Alkyl, C3-C8Cycloalkyl, C6-C10Aryl, C2-C10Heteroaryl can be selected from H, C by one or more1-6Alkyl, C2-C8Heterocycle Alkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)mC2-C8Heterocycle alkane Base ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6- C10The substituent group substitution of aryl, hydroxyl, halogen；
M is selected from 0,1,2；
S, t, u are independently selected from 0,1,2；
X is selected from O, NR9、CR9；
R9Selected from hydrogen, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl；
N is selected from 0,1.
On the other hand, the present invention provides a kind of pharmaceutical composition, it includes：Formula (I) compound or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug；It is one or more pharmaceutically acceptable auxiliary Material.
On the other hand, offer formula (I) compound of the present invention or its stereoisomer, tautomer or its can pharmaceutically connect Its disease for being used to treat ROR γ mediations of the salt received or its solvate or prodrug, such as inflammatory, metabolic or autoimmune Purposes in disease.
On the other hand, offer formula (I) compound of the present invention or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug its be used to treat asthma, chronic obstructive pulmonary disease (COPD), bronchitis, anaphylaxis Disease is (such as：Allergic rhinitis), Atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis, Rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic loupus erythematosus, silver bits Disease, Hashimoto's disease, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, Crohn's disease, inflammation Property enteropathy (IBS), inflammatory bowel syndrome (IBD), siogren's syndrome, optic neuritis, type-1 diabetes mellitus, optic nerve spinal cord Use in inflammation, myasthenia gravis, uveitis, actue infectious polyradiculoneuritis, psoriatic arthritis, lattice Lei's disease or sclerotitis etc. On the way.
On the other hand, offer formula (I) compound of the present invention or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug its be used to treating asthma, rheumatoid arthritis, psoriasis, ulcerative colitis or Purposes in Crohn's disease.
Detailed description of the invention：
The present invention relates to structure such as formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutically Acceptable salt or its solvate or prodrug：
Wherein,
R1、R2It is independently selected from hydrogen, halogen, hydroxyl, amino, C1-6Alkyl, C1-C6Alkyl amine group, C1-C6Alkoxy, Or R1、R2Merge into oxo base；
R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl, the C arbitrarily replaced3-C8Cycloalkyl or the-CH arbitrarily replaced2C3-C8 Cycloalkyl, substituent group are selected from hydrogen, halogen, hydroxyl, amino or C1-C6Alkyl；
R5It is selected from：The C arbitrarily replaced6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group be selected from hydrogen, halogen, Cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or-S (O2)C1-6Alkane Base；
R3For group-(CHR6)s-(Y)t-(CHR7)u-R8；
R6、R7It is independently selected from hydrogen, C1-6Alkyl, hydroxyl；
Y is selected from C1-6Alkyl, NH or O；
R8Selected from arbitrary substituted C2-C8Heterocyclylalkyl, the C arbitrarily replaced3-C8Cycloalkyl, the C arbitrarily replaced6-C10Aryl Or the C arbitrarily replaced2-C10Heteroaryl, substituent group are selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6 Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen；
M is selected from 0,1,2；
S, t, u are independently selected from 0,1,2；
X is selected from O, NR9、CR9；
R9Selected from hydrogen, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl；
N is selected from 0,1.
In a kind of preferred embodiment, structure of the present invention such as formula (I) compound represented or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug, wherein R5Selected from arbitrary substituted following base Group：Phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, quinoline, isoquinolin, pyrrole ring, pyrazole ring, imidazole ring, thiphene ring, Thiazole ring, furan nucleus Huo oxazole rings；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkanes Base, C1-C6Alkoxy, C1-C6Halogenated alkyl or C1-C6Alkyl sulphonyl.
Preferably, R5Selected from arbitrary substituted phenyl ring or the pyridine ring arbitrarily replaced；Substituent group be selected from hydrogen, halogen, cyano, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or C1-C6Alkyl sulphonyl；Substituent group more preferably selected from hydrogen, halogen, Cyano, C1-C3Alkyl, C1-C3Alkoxy, C1-C3Halogenated alkyl or-S (O2)C1-3Alkyl.
In a kind of preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomer, changes Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, wherein R8Selected from arbitrary substituted following group： Oxirane, oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, azetidine, pyrrolidines, piperidines, morpholine, pyridine, Morpholine -3- ketone or thiomorpholine 1,1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkanes Base ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkane Base ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or Halogen.
Preferably, R3For-CH2R8Or-R8。R8Selected from arbitrary substituted following group：Oxirane, oxetanes, Tetrahydrofuran, tetrahydrochysene -2H- pyrans, azetidine, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thiomorpholine 1, 1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2) (CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkanes Base ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen.It is furthermore preferred that R8Selected from appoint The following group of meaning substitution：Oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, pyrrolidines, piperidines, morpholine, pyridine；Substitution Base is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkanes Base ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)m C2- C8Heterocyclylalkyl, hydroxyl or halogen, substituent group preferably are selected from H, C1-3Alkyl, C2-C6Heterocyclylalkyl, C3-C6Cycloalkyl ,-S (O2)C1-3 Alkyl ,-S (O2)C3-C6Cycloalkyl ,-S (O2)CH2C3-C6Cycloalkyl ,-S (O2)C2-C6Heterocyclylalkyl ,-S (O2)CH2C2-C6Heterocycle Alkyl ,-C (O) C1-3Alkyl ,-C (O) C3-C6Cycloalkyl ,-C (O) CH2C3-C6Cycloalkyl ,-C (O) C2-C6Heterocyclylalkyl ,-C (O) CH2C2-C6Heterocyclylalkyl, hydroxyl or halogen；Substituent group is further preferably from H, C1-3Alkyl ,-S (O2)C1-3Alkyl ,-S (O2)C3- C6Cycloalkyl ,-S (O2)CH2C3-C6Cycloalkyl ,-S (O2)C2-C6Heterocyclylalkyl ,-S (O2)CH2C2-C6Heterocyclylalkyl ,-C (O) C1-3 Alkyl, hydroxyl or halogen；Substituent group is still more preferably from H, hydroxyl, halogen, C1-3Alkyl ,-S (O2)C1-3Alkyl ,-S (O2) C3-C4Cycloalkyl ,-S (O2)CH2C3-C4Cycloalkyl ,-S (O2)C2-C4Heterocyclylalkyl ,-S (O2)CH2C2-C4Heterocyclylalkyl or-C (O)C1-3Alkyl.
In a kind of preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomer, changes Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, wherein X are selected from O, NH or CH2；Preferred X choosings From O or NH, further preferred X is O.
In a kind of preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomer, changes Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, R1、R2It is independently selected from hydrogen, hydroxyl, halogen Element, amino, C1-3Alkyl, C1-C3Alkoxy or R1、R2Merge into oxo base.
In a kind of preferred embodiment, the present invention relates to structure such as formula (I) compound represented or its stereoisomer, changes Isomers or its pharmaceutically acceptable salt or its solvate or prodrug, R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl or The C arbitrarily replaced3-C8Cycloalkyl, substituent group are selected from hydrogen, halogen, hydroxyl, amino or C1-C6Alkyl.
It should be appreciated that the arbitrary combination the invention further relates to above-mentioned preferred embodiment.Some examples of combination given below. It is combined however, the present invention is not restricted to these.
In a preferred embodiment：The present invention relates to structure such as formula (I) compound represented or its alloisomerisms Body, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, wherein X are selected from O or NH；R5Selected from appoint The phenyl ring of meaning substitution or the pyridine ring arbitrarily replaced；Wherein substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkyl, C1-C6Alcoxyl Base, C1-C6Halogenated alkyl or C1-C6Alkyl sulphonyl；R3For-CH2R8Or-R8；R8Selected from arbitrary substituted following group：Oxa- Cyclopropane, oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thio Morpholine 1,1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkanes Base ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen；M is selected from 0,1,2.
In a preferred embodiment：The present invention relates to structure such as formula (I) compound represented or its alloisomerisms Body, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, wherein X are selected from O, R5Selected from arbitrarily taking The phenyl ring in generation or the pyridine ring arbitrarily replaced；Wherein substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkyl, C1-C6Alkoxy, C1- C6Halogenated alkyl or C1-C6Alkyl sulphonyl；R3For-CH2R8Or-R8；R8Selected from arbitrary substituted following group：Oxirane, Oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thiomorpholine 1, 1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2) (CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkanes Base ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen；M is selected from 0,1,2.
In a preferred embodiment：The present invention relates to structure such as formula (I) compound represented or its alloisomerisms Body, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug, wherein：X is O；N is 0 or 1；R1、R2 It is independently selected from hydrogen, hydroxyl, halogen, amino, C1-3Alkyl, C1-C3Alkoxy or R1、R2Merge into oxo base；R4Choosing The C from hydrogen, arbitrarily replaced1-C6Alkyl or the C arbitrarily replaced3-C6Cycloalkyl, substituent group be selected from hydrogen, halogen, hydroxyl, amino or C1-C3Alkyl；R5Selected from arbitrary substituted phenyl ring or the pyridine ring arbitrarily replaced；Substituent group is selected from hydrogen, halogen, cyano, C1-C3Alkane Base, C1-C3Alkoxy, C1-C3Halogenated alkyl or C1-C3Alkyl sulphonyl；R3For-CH2R8Or-R8；R8Selected from arbitrary substituted four Hydrogen -2H- pyrans or the piperidines arbitrarily replaced；Substituent group is selected from H, C1-3Alkyl ,-S (O2)C1-3Alkyl, hydroxyl or halogen.
In a kind of preferred embodiment, the present invention also provides the compound of formula (Ia-Ij) or its stereoisomer, changes Isomers or its pharmaceutically acceptable salt or the subgroup of its solvate or prodrug：
Wherein：R3、R4、R5It is as defined above with n.
Some examples of combination given below.It is combined however, the present invention is not restricted to these.
In a kind of preferred assembled scheme, the compound of formula (Ia-Ij) or its stereoisomer, tautomer or its Pharmaceutically acceptable salt or the subgroup of its solvate or prodrug, wherein：
R3Selected from group-(CHR6)s-(Y)t-(CHR7)u-R8。R6、R7It is independently selected from hydrogen, C1-6Alkyl, hydroxyl；Y is selected from C1-6 Alkyl, NH or O；S, t, u are independently selected from 0,1,2；R8Selected from arbitrary substituted following group：Oxirane, oxa- ring fourth Alkane, tetrahydrofuran, tetrahydrochysene -2H- pyrans, azetidine, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thiomorpholine 1,1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2) (CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)m C2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkanes Base ,-C (O) (CH2)m C2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen；
R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl, the C arbitrarily replaced3-C8Cycloalkyl or the-CH arbitrarily replaced2C3-C8 Cycloalkyl, substituent group are selected from hydrogen, halogen, hydroxyl, amino or C1-C6Alkyl；
R5Selected from arbitrary substituted following group：Phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, quinoline, isoquinoline Quinoline, pyrrole ring, pyrazole ring, imidazole ring, thiphene ring, thiazole ring, furan nucleus Huo oxazole rings；Substituent group be selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or C1-C6Alkyl sulphonyl.
Further, in a kind of preferred embodiment, the compound of offer formula (Ia-Ie, Ih, Ii, Ij) of the present invention or it is vertical Body isomers, tautomer or its pharmaceutically acceptable salt or the subgroup of its solvate or prodrug：
Wherein：R3、R4、R5It is as defined above with n.
Further, in a kind of preferred embodiment, the compound or its alloisomerism of offer formula (Ia-Ie, Ij) of the present invention Body, tautomer or its pharmaceutically acceptable salt or the subgroup of its solvate or prodrug：
Wherein：R3、R4、R5It is as defined above with n.
Some examples of combination given below.It is combined however, the present invention is not restricted to these.
In a kind of preferred assembled scheme, the compound of formula (Ia-Ie, Ij) or its stereoisomer, tautomer or Its pharmaceutically acceptable salt or the subgroup of its solvate or prodrug, wherein：
R5Selected from arbitrary substituted phenyl ring or the pyridine ring arbitrarily replaced；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkane Base, C1-C6Alkoxy, C1-C6Halogenated alkyl or C1-C6Alkyl sulphonyl；
R3For-CH2R8Or-R8。R8Selected from arbitrary substituted following group：Oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrroles It mutters, azetidine, pyrrolidines, piperidines, morpholine, pyridine；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Ring Alkyl ,-S (O2)C1-6Alkyl, hydroxyl or halogen.
In a kind of preferred assembled scheme, the compound of formula (Ia-Ie) or its stereoisomer, tautomer or its Pharmaceutically acceptable salt or the subgroup of its solvate or prodrug, wherein：
R5Selected from arbitrary substituted phenyl ring or the pyridine ring arbitrarily replaced；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkane Base, C1-C6Alkoxy, C1-C6Halogenated alkyl or C1-C6Alkyl sulphonyl；
R3For-CH2R8Or-R8。R8Selected from arbitrary substituted tetrahydrochysene -2H- pyrans or the piperidines arbitrarily replaced；Substituent group is selected from H、C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl, hydroxyl or halogen.
On the other hand, more specific scheme, the present invention relates to structure compound as follows or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug：
On the other hand, the present invention provides a kind of pharmaceutical composition, it includes：Formula (I) compound or its stereoisomer, mutually Tautomeric or its pharmaceutically acceptable salt or its solvate or prodrug；It is one or more pharmaceutically acceptable auxiliary Material.
On the other hand, offer formula (I) compound of the present invention or its stereoisomer, tautomer or its can pharmaceutically connect Its purposes for being used in the disease for treating ROR γ mediations of the salt received or its solvate or prodrug and prepare treatment ROR γ Application in the drug of the disease of mediation.The disease of wherein ROR γ mediations includes but not limited to inflammatory, metabolic or autoimmunity Property disease etc..
On the other hand, offer formula (I) compound of the present invention or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug its be used to treat asthma, chronic obstructive pulmonary disease (COPD), bronchitis, anaphylaxis Disease (such as：Allergic rhinitis), Atopic dermatitis, cystic fibrosis, lung allograft rejection, multiple sclerosis Disease, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic loupus erythematosus, Psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, ulcerative colitis, Chron Disease, inflammatory bowel disease (IBS), inflammatory bowel syndrome (IBD), siogren's syndrome, optic neuritis, type-1 diabetes mellitus, optic nerve In myelitis, myasthenia gravis, uveitis, actue infectious polyradiculoneuritis, psoriatic arthritis, lattice Lei's disease or sclerotitis etc. Purposes, preferably its be used to treat the use in asthma, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease On the way.
On the other hand, the present invention also provides the preparation methods of compound of the present invention.
The compounds of this invention can be prepared by the method as shown in following synthetic route.In following reaction route and hereafter In, unless otherwise indicated, all groups are as defined in aforementioned.It will also be appreciated that in all routes being described below, many institute's weeks Know, according to the General Principle of organic synthesis, when necessary using sensitive or reactive group protecting group (T.W.Greene and P.G.M.Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley＆Sons)；Changing Close object synthesis appropriate stage, using one skilled in the art will readily appreciate that method remove these groups；The choosing of this method Select and reaction condition and they execution sequence be considered as being consistent with the preparation method of the compounds of this invention.
General reactions route：
Route 1：
Route 2：
Wherein R1、R2、R3、R4、R5, X and n it is defined as described above.
The term of the present invention in the specification and in the claims has following meanings.
" alkyl " refers to the aliphatic hydrocarbon group of saturation.Include the linear chain or branch chain group of 1 to 20 carbon atom.C1-6Alkyl refers to Median size alkyl containing 1 to 6 carbon atom, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group, tertiary fourth Base, amyl etc..Low alkyl group preferably containing 1 to 4 carbon atom, the more preferably lower alkyl containing 1 to 4 carbon atom Base, such as methyl, ethyl, propyl, 2- propyl, normal-butyl, isobutyl group or tertiary butyl etc..Alkyl can be substitution or unsubstituted , when substituted, preferred group is：Halogen, C2-C6Alkenyl, C6-C10Aryl, C5-C10Heteroaryl, halogenated C1-C6Alkyl, 4 to 8 yuan of heteroalicyclyls, hydroxyl, C1-C6Alkoxy, C6-C10Aryloxy group.
" alkyl amine group " refers to one or two hydrogen atom in amino by alkyl-substituted group.Including by direct-connected, branch Chain or the amino group of cyclic alkyl substitution, such as methylamino, dimethylamino, ethylamino, n-propylamine base, isopropylamino, n-butyl amine Base, i-butylamino, tertiary fourth amino, cyclopropylamino, ring fourth amino, penta amino etc..It is preferably low containing 1 to 4 carbon atom The direct-connected, branch of grade or the amino of cyclic alkyl substitution.
" cycloalkyl " refers to monocyclic 3 to 8 yuan of full carbon, 5 yuan/6 yuan of full carbon or 6 yuan/6 yuan thick and rings or polycyclic thick and ring is (" thick With " ring means that each ring in system shares a pair of of the carbon atom adjoined with other rings in system) group, one of them or Multiple rings have the pi-electron system being fully connected, and the example (being not limited to) of cycloalkyl is cyclopropane, cyclobutane, pentamethylene, ring Amylene, hexamethylene, adamantane, cyclohexadiene, cycloheptane or cycloheptatriene.Cycloalkyl is commutable and unsubstituted.Work as quilt During substitution, substituent group is preferably that one or more each is selected from following group, including：Hydrogen, hydroxyl, sulfydryl, oxo, lower alkyl Base, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, lower halogenated alkane Base, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, Alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, Arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" aryl " represents the pi-electron system that full carbon is monocyclic or fused polycycle group, has total conjugated of 6 to 14 carbon atoms System." aryl " includes：
Hexa-atomic carbon aromatic rings, e.g., benzene；
Bicyclic, wherein at least one ring is carbon aromatic rings, e.g., naphthalene, indenes or 1,2,3,4- tetrahydroquinolines；And
Tricyclic, wherein at least one ring are carbon aromatic rings, e.g., fluorenes.
For example, aryl is included containing hexa-atomic carbon aromatic rings and a hexa-member heterocycle, this heterocycle includes one or more select From the hetero atom of nitrogen, oxygen and sulphur, condition is tie point on carbon aromatic rings.But aryl does not include, not by any mode yet It is Chong Die with the heterocyclic aryl defined separately below.Therefore, it defines herein, if one or more carbon aromatic rings and a heteroaryl perfume (or spice) Ring and ring, resulting loop system is heteroaryl rather than aryl.The non-limiting examples of aryl have phenyl, naphthalene.Aryl It can be substituted or unsubstituted.When substituted, preferred group is：Hydrogen, hydroxyl, nitro, cyano, oxo, lower alkyl Base, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, lower halogenated alkane Base, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, Alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, Arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" heteroaryl " represents the monocyclic or fused ring group of 5 to 14 annular atoms, containing there are one, two, three or four Ring hetero atom selected from N, O or S, remaining annular atom are C, in addition the pi-electron system with total conjugated.Heteroaryl refers to：
The mononuclear aromatics of 5-8 members, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, in some realities It applies in scheme, 1-3 hetero atom, other atoms are carbon atoms on ring；
The double ring arene of 8-12 members, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, at some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings；And
The thrcylic aromatic hydrocarbon of 11-14 members, containing one or more hetero atoms for being selected from N, O and S, such as 1-4 hetero atom, at some In embodiment, 1-3 hetero atom, other atoms are carbon atoms on ring；Wherein at least one ring is aromatic rings.
For example, heteroaryl includes the miscellaneous aromatic rings of a 5-6 member and the cycloalkyl of a 5-6 member.For such bicyclic And the heteroaryl to get up, only one of which ring contain one or more hetero atoms, connection site is on miscellaneous aromatic rings.
When the sulphur atom on heteroaryl and oxygen atom sum are more than 1, these hetero atoms will not be adjacent one by one.In some realities It applies in scheme, the sum of sulphur atom and oxygen atom in heteroaryl is no more than 2.In some embodiments, sulphur atom and oxygen are former Sum of the son in heteroaryl is no more than 1.
The example of heteroaryl, including but not limited to, pyrroles, furans, thiophene, imidazoles, oxazoles, thiazole, pyrazoles, triazole, Pyrimidine, pyridine, pyridone, miaow pyridine, pyrazine, pyridazine, indoles, azaindole, benzimidazole, benzotriazole, indoline, indoles Ketone, quinoline, isoquinolin, quinazoline, thienopyridine, Thienopyrimidine etc..The preferred embodiment of such group is phenyl ring, pyrrole Pyridine, pyrimidine, pyridazine, pyrazine, quinoline, isoquinolin, pyrroles, pyrazoles, imidazoles, thiophene, thiazole, furans Huo oxazoles.In heteroaryl One or all hydrogen atom can be replaced by following groups：Hydrogen, hydroxyl, nitro, cyano, oxo, low alkyl group, lower alkoxy, It is low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen, low-grade halogenated alkyl, Lower hydroxy alkyl, low Grade naphthenic base alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alkoxy carbonyl, amino, alkyl amino, alkyl sulfonyl Base, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl sulfonyl-amino, arlysulfonylamino, alkane Base amino carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl-amino-carbonyl.
" Heterocyclylalkyl " is represented by one or more rings, the monovalence saturation of preferably 1 to 2 ring (including spiral ring system) composition Cyclic group, each 3 to 8 atoms of ring are combined with one or more ring hetero atoms (selected from N, O or S (O)0-2), and its Can be optionally independently one or more, preferably 1 or the substitution of 2 substituent groups, the substituent group are selected from:Hydrogen, hydroxyl, mercapto Base, oxo, low alkyl group, lower alkoxy, low-grade cycloalkyl, rudimentary Heterocyclylalkyl, elementary halogenated alkoxy, alkylthio group, halogen Element, low-grade halogenated alkyl, Lower hydroxy alkyl, low-grade cycloalkyl alkylidene, rudimentary Heterocyclylalkyl alkylene, aryl, heteroaryl, alcoxyl Base carbonyl, amino, alkyl amino, alkyl sulphonyl, aryl sulfonyl, alkyl amino sulfonyl, n-aryl sulfonyl, alkyl Sulfuryl amino, arlysulfonylamino, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkyl-carbonyl-amino, aryl carbonyl ammonia Base.Unless otherwise noted.
The example of Heterocyclylalkyl includes but not limited to oxirane, aziridine, pyridine, morpholine -3- ketone, Thiomorpholine 1,1- dioxide, morpholinyl, piperazinyl, piperidyl, azetidinyl, pyrrolidinyl, hexahydro azepine Careless base, oxetanyl, tetrahydrofuran base, tetrahydro-thienyl, oxazole alkyl, thiazolidinyl, isoxazole alkyl, tetrahydrochysene -2H- Pyranose, thio Lin Ji, quininuclidinyl and imidazolinyl, preferably W is selected from O, S or NR12, each group as previously mentioned, example can also be bicyclic, Such as, for example, 3,8- diazas-bicyclic [3.2.1] octane, 2,5- diazabicyclos [2.2.2] octane or octahydro-pyrazine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines；It is preferred that oxirane, oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, aziridine, Azetidine, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thiomorpholine 1,1- dioxide；Its Heterocyclylalkyl (and derivative) includes its ionic species.
" alkoxy " expression-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl).Representative example include but It is not limited to methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..
" aryloxy group " expression-O- aryl and-O- heteroaryls.Representative example include but not limited to phenoxy group, pyridine oxygroup, Furans oxygroup, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygroup etc. and its derivative.
" aryl alkylene " represents alkyl, and low alkyl group preferably as defined above, it is substituted as described above for aryl groups, Such as-CH2Phenyl ,-(CH2)2Phenyl ,-(CH2)3Phenyl, CH3CH(CH3)CH2Phenyl and its derivative.
" heteroarylalkylenyl " represents alkyl, and low alkyl group preferably as defined above, it is by heteroaryl as described above Substitution, such as-CH2Pyridyl group ,-(CH2)2Pyrimidine radicals ,-(CH2)3Imidazole radicals etc. and its derivative.
" oxo base " expression=O groups.
" hydroxyl " expression-OH groups.
" sulfydryl " expression-SH groups.
" halogen " represents fluorine, chlorine, preferably bromine or iodine, fluorine or chlorine.
The alkyl that " halogenated alkyl " expression is optionally substituted by halogen, low alkyl group preferably as defined above, it is by one or more A identical or different halogen atom substitution, such as-CH2Cl、-CF3、-CCl3、-CH2CF3、-CH2CCl3Deng.
" cyano " expression-CN groups.
" amino " expression-NH2Group.
" nitro " expression-NO2Group.
" tetrahydrochysene -2H- pyrans " represents
" alkyl sulphonyl " expression-S (O2)C1-6Alkyl, wherein alkyl are as defined above.
The situation and unsubstituted situation that " arbitrarily replacing " replaces including one or more substituent groups, as arbitrarily replaced Alkyl includes unsubstituted alkyl and the alkyl being substituted by one or more substituents.
The event for being meant that subsequent descriptions or situation of so-called " optionally " may may also will not occur, and should Description, which includes things or situation, may also will not occur, and the description includes things or situation occurs and do not occur two Kind situation.
In some embodiments, one referred in specified atom or group " is replaced " by one or more groups It is a, two, three or four hydrogen atoms identical or different group that is designated to select in the group of range respectively replaces.
Wave represents connection site；
" pharmaceutically acceptable salt " represents to retain the biological effectiveness of parent compound and those salt of property.This kind of salt Including：
(1) with acid into salt, by the free alkali of parent compound and inorganic acid or organic acid react and must, inorganic acid packet Hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc. are included, organic acid includes acetic acid, propionic acid, propylene Acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, adjacent benzene Dioctyl phthalate, methanesulfonic acid, ethanesulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, breast Acid, mandelic acid, succinic acid or malonic acid etc..
(2) acid proton being present in parent compound is replaced or given birth to organic base ligand compound by metal ion Into salt, metal ion such as alkali metal ion, alkaline-earth metal ions or aluminium ion, organic bases for example ethanol amine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
" pharmaceutical composition " refers to one or more of compound in the present invention or its pharmaceutically acceptable salt, molten The combination of agent compound, hydrate or prodrug and one or more pharmaceutically acceptable auxiliary materials.Wherein " auxiliary material " generally selects this Invent other chemical composition except the compound, for example, pharmaceutically acceptable pharmaceutical carrier or other imitated with drug The mixing of the compound of fruit etc..The purpose of pharmaceutical composition can be that administration is promoted to be assisted to the process or drug of animal Same-action.
" pharmaceutical carrier " refers to not causing apparent irritation to organism and does not interfere the biology of given compound Non-active ingredient in the pharmaceutical composition of activity and property, such as, but not limited to：Calcium carbonate, calcium phosphate, it is various sugar (such as breast Sugar, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or methacrylic polymeric Object, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or rilanit special or more ethoxy aluminium castor oil, sesame Oil, corn oil, peanut oil etc..
In aforementioned pharmaceutical composition, other than including pharmaceutically acceptable carrier etc., medicine (agent) can also be included in Common adjuvant on, such as：Antibacterial agent, antifungal agent, antimicrobial, preservative, toner, solubilizer, thickener, Surfactant, complexing agent, protein, amino acid, fat, carbohydrate, vitamin, minerals, trace element, sweetener, pigment, Essence or their combination etc..
Formula (I) compound of the present invention has apparent inhibiting effect to ROR γ t, and ROR γ t are in inflammatory, metabolic And have very important effect in autoimmune disease, inhibit ROR γ t that these diseases will be caused to be eased or effectively control It treats.
Specific embodiment
With reference to embodiments for further describing the present invention, but these embodiments are not to limit the model of the present invention It encloses.Embodiment 1：N- (4- ethylphenyls)-N- isobutyl group -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulfonamide The preparation of compound EXP 1
1) synthesis of compound 2
Compound 1 (10.0g, 73.5mmol, 1.0eq) is dissolved at room temperature in MeCN (200mL), adds in K2CO3 (32.0g, 220.5mmol, 3.0eq) is stirred at room temperature 30 minutes, adds MeI (21.0g, 147.0mmol, 2.0eq), room Temperature stirring 16 hours.The reaction was complete for LCMS detections.Solvent is spin-dried for, silica gel mixed sample, crosses column (PE:EA=40:1) chemical combination, is obtained Object 2 (2.8g, yield：25%).
TLC:PE/EA=10:1,UV 254nm
Rf(Compound 1)=0.6
Rf(Compound 2)=0.5
2) synthesis of compound 3
ClSO is added in single port bottle3H (30mL, 0.46mol, 24.6eq), is cooled to 0 DEG C, adds compound 2 (2.8g, 18.7mmol, 1.0eq) is stirred 20 minutes, is removed ice-water bath, is reacted at room temperature 16 hours.The display reaction of TLC contact plates Completely, there is new point generation.It is quenched in the ice water that reaction solution is poured into stirring, add methylene chloride extraction, anhydrous sodium sulfate drying, Organic phase is spin-dried for, crosses column (PE/EA=20:1-10:1) compound as white solid 3 (3.6g, yield, are obtained：78%).
TLC:PE/EA=3:1,UV 254nm
Rf(Compound 2)=0.8
Rf(Compound 3)=0.4
3) synthesis of compound 5
By compound 3 (1.0g, 4.32mmol, 1.0eq), compound 4 (0.78g, 4.44mmol, 1.1eq) adds at room temperature Enter in 20mL pyridines, stir two hours at room temperature, TLC shows that the reaction was complete.Pyridine is spin-dried for, crosses column (PE:EA=20:1-15: 1) compound 5 (1.4g, yield are obtained：89%).
TLC:PE/EA=3:1,UV 254nm
Rf(Compound 3)=0.4
Rf(Compound 5)=0.5
4) synthesis of compound 6
Compound 5 (0.97g, 2.48mmol, 1.0eq) is dissolved in 100mL DCM, 0 DEG C of is cooled to and is slowly added dropwise BBr3(7.3mL, 0.68M in DCM, 5.0mmol, 2.0eq).1h. is reacted at 0 DEG C and is spin-dried for solvent, crosses column (PE:EA=20:1) Obtain compound 6 (0.33g, yield：33%).
TLC:PE/EA=3:1,UV 254nm
Rf(Compound 5)=0.5
Rf(Compound 6)=0.7
5) synthesis of Exp 1
At room temperature, compound 6 (170mg, 0.45mmol, 1.0eq) is dissolved in MeOH (10mL), adds in compound 7 (62mg, 0.54mmol, 1.2eq), pyrrolidines (40mg, 0.54mmol, 1.2eq) are stirred 3 hours at 80 DEG C.TLC display reactions Completely, solvent is spin-dried for, solid chemical compound is prepared in prep-HPLC separation
Exp1 (70mg, yield:33%)
TLC:PE/EA=5:1,UV 254nm
Rf(Compound 6)=0.7
Rf(Compound Exp1)=0.1
LC-MS:[M+1]=472.2
1H NMR(400MHz,CDCl3) δ 8.13 (d, J=2.0Hz, 1H), 7.48 (dd, J=8.8,2.4Hz, 1H), 7.05 (d, J=8.0Hz, 2H), 6.92 (d, J=8.8Hz, 1H), 6.89 (d, J=8.4Hz, 2H), 4.26-4.22 (m, 1H), 4.02- 3.98 (m, 2H), 3.41-3.33 (m, 2H), 3.22 (d, J=7.2Hz, 2H), 2.69 (d, J=7.6Hz, 2H), 2.57 (q, J= 7.6Hz, 2H), 1.96-1.93 (m, 1H), 1.84-1.80 (m, 1H), 1.55-1.52 (m, 7H), 1.16 (t, J=7.2Hz, 3H), 0.83 (d, J=6.8Hz, 6H)
Embodiment 2：N- (4- ethylphenyls) -4 hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide compound EXP 2
At room temperature, Exp1 (40mg, 0.09mmol, 1.0eq) is dissolved in MeOH (5mL), adds in compound N aBH4 (10mg, 0.25mmol, 3.0eq) is stirred 2 hours at room temperature.TLC shows that the reaction was complete, is spin-dried for solvent, prep-HPLC separation Solid chemical compound Exp 2 (21mg, yield is prepared:52%)
TLC:PE/EA=3:1,UV 254nm
Rf(Compound Exp1)=0.3
Rf(Compound Exp 2)=0.1
LC-MS:[M+1]=474.2
1H NMR(400MHz,CDCl3) δ 7.60 (s, 1H), 7.27 (dd, J=8.0,2.0Hz, 1H), 7.05 (d, J= 8.0Hz, 2H), 6.91 (d, J=8.0Hz, 2H), 6.72 (d, J=8.4Hz, 1H), 4.84-4.80 (m, 1H), 3.99-3.90 (m, 3H), 3.39-3.33 (m, 2H), 3.22-3.15 (m, 2H), 2.56 (q, J=7.6Hz, 2H), 2.28-2.23 (m, 1H), 1.91-1.66 (m, 4H), 1.49-1.40 (m, 4H), 1.16 (t, J=7.6Hz, 3H), 0.84-0.81 (m, 6H)
Embodiment 3：N- (4- ethylphenyls) -4 hydroxy-ns-isobutyl group -4- methyl -2- (tetrahydrochysene -2H- pyrans -4- bases) color The preparation of full -6- sulfonamide compounds EXP 3
Compound Exp 1 (50mg, 0.67mmol, 1.0eq) is dissolved at room temperature in tetrahydrofuran (3mL), at 0 DEG C When, MeMgBr (1.0ml, 1.6mmol, 2.5eq), stirring at normal temperature 1 hour is slowly added dropwise.TLC contact plates show that the reaction was complete, have new Point generation.It is quenched with saturated aqueous ammonium chloride (5mL), with ethyl acetate (30mL) extraction three times, merges organic phase, use is anhydrous Sodium sulphate is dried, and filtering is concentrated to give crude product.Through prep-HPLC preparative separation (mobile phases：0.1%TFA/CH3CN/H2O it) obtains Compound as white solid Exp 3 (11mg, yield：12%).
TLC:PE/EA=5:1,UV 254nm
Rf(Exp 1)=0.40
Rf(Exp 3)=0.20
LC-MS:[M+1]=488
1H NMR(400MHz,CDCl3) δ 7.58 (s, 1H), 7.41 (dd, J=8.0,2.4Hz, 1H), 7.11 (d, J= 8.4Hz, 2H), 6.95 (d, J=8.0Hz, 2H), 6.82 (d, J=8.4Hz, 1H), 4.09-4.05 (m, 2H), 3.98-3.94 (m, 1H), 3.43-3.40 (m, 2H), 3.33-3.27 (m, 1H), 3.23-3.17 (m, 1H), 2.63 (q, J=7.6Hz, 2H), 2.10-2.06 (m, 1H), 1.95-1.85 (m, 5H), 1.50 (s, 3H), 1.25 (s, 2H), 1.22 (t, J=7.6Hz, 3H), 0.92-0.88(m,6H).
Embodiment 4：N- (4- ethylphenyls)-N- isobutyl group -4- methyl -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide compound EXP 4
Compound Exp 3 (110mg, 0.23mmol, 1.0eq) is dissolved at room temperature in DCM (5mL), adds in Et3SH At 0 DEG C, BF is added dropwise in (1mL, 2.3mmol, 10.0eq)3Diethyl ether solution (1mL, 2.3mmol, 10.0eq), stirring at normal temperature 1 are small When.LCMS shows that raw material has reacted, and has product generation.It is quenched with saturated aqueous ammonium chloride (5mL), with ethyl acetate (30mL) Extraction three times, merges organic phase, is dried with anhydrous sodium sulfate, filters, is concentrated to give crude product.(0.1%TFA/ is detached through machine CH3CN/H2O compound as white solid Exp 4 (12mg, yield) are obtained：11%).
TLC:PE/EA=5:1,UV 254nm
Rf(Exp 3)=0.2
Rf(Exp 4)=0.4
LC-MS:[M+1]=472
1H NMR(400MHz,CDCl3) δ 7.34 (d, J=8.4Hz, 1H), 7.29 (s, 1H), 7.11 (d, J=8.0Hz, 2H), 6.97 (d, J=8.0Hz, 2H), 6.80 (d, J=8.4Hz, 1H), 4.06-4.02 (m, 2H), 3.90-3.83 (m, 2H), 3.46-3.40 (m, 2H), 3.28-3.33 (m, 2H), 3.21-3.16 (m, 1H), 2.94-2.89 (m, 1H), 2.62 (q, J= 7.6Hz,2H),2.07-2.01(m,1H),1.89-1.86(m,2H),1.62-1.60(m,2H),1.46-1.39(m,2H), 1.24 (s, 1H), 1.21 (d, J=7.6Hz, 6H), 0.90-0.86 (m, 6H)
Embodiment 5：4- amidos-N- (4- ethylphenyls)-N- isobutyl groups -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide trifluoroacetate EXP 5
1) preparation of compound 2
Hydroxylamine hydrochloride (20mg, 0.29mmol, 2.7eq) is dissolved in the absolute ethyl alcohol of 5mL, adds in sodium acetate at room temperature (50mg, 0.61mmol, 5.7eq) is stirred 15 minutes, is then dissolved in Exp 1 (50mg, 0.11mmol, 1.0eq) at room temperature 1.0mL absolute ethyl alcohols are simultaneously added in reaction solution.It is stirred overnight at room temperature, TLC shows the starting material left there are about 30%.Add hydrochloric acid Azanol (20mg, 0.29mmol, 2.7eq) and sodium acetate (50mg, 0.61mmol, 5.7eq) are added in reaction solution and at 30 DEG C Stirring 5 hours, TLC show that raw material reaction finishes.It is dissolved in the ethyl acetate of 10mL after reaction solution is spin-dried for, with a concentration of 0.5N The aqueous sodium carbonate of 5mL wash, then washed with saturated common salt, anhydrous sodium sulfate drying obtains white solid chemical combination after being spin-dried for Object 2 (50mg, 0.10mmol, yield：91%)
TLC:PE/EA=2:1,UV 254nm
Rf(Exp 1)=0.3
Rf(Compound 2)=0.6
2) preparation of Exp 5
Compound 2 (45mg, 0.09mmol, 1.0eq) is dissolved in 5mL methanol, then adds in Raney-Ni (20mg), instead The displacement of bottle nitrogen is answered to be replaced three times with hydrogen afterwards twice.It is reacted overnight with hydrogen balloon at room temperature.Filtering, filtrate are used after being spin-dried for DMSO dissolves, and then prep-HPLC prepares (mobile phase：+ 0.1% trifluoroacetic acid of acetonitrile+water) purifying obtain white solid chemical combination Object Exp 5 (35mg, 0.054mmol, yield：82%)
LC-MS:[M-16]=456.3
1H NMR(400MHz,DMSO-d6)δ8.53(s,1H),8.36(s,1H),7.95(s,0.5H),7.85(s, 0.5H), 7.35 (d, J=8.8Hz, 0.5H), 7.28 (d, J=6.8Hz, 0.5H), 7.19 (d, J=8.0Hz, 2H), 7.07- 6.87 (m, 3H), 4.71-4.57 (m, 1H), 4.15-4.10 (m, 1H), 3.93 (d, J=8.0Hz, 2H), 3.25-3.11 (m, 2H),2.69-2.54(m,3H),2.38-2.32(m,2H),2.05-1.72(m,3H),1.54(br s,1H),1.50-1.31 (m, 3H), 1.17 (t, J=7.6Hz, 3H), 0.87-0.84 (m, 6H)
Embodiment 6：N- (4- ethylphenyls)-N- isobutyl groups -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulfonamide EXP 6 preparation
Compound Exp 1 (53mg, 0.11mmol, 1.0eq) is added in 6mL ether, then adds in 2mL concentrated hydrochloric acids, it is cold But to addition zinc powder (588mg, 8.99mmol, 80eq) after zero degree.It is stirred at room temperature 3 hours after being raised to room temperature.Filtering, filtrate Crude material is obtained after being spin-dried for.Crude material prep-HPLC (mobile phases：+ 0.1% trifluoroacetic acid of acetonitrile+water) purifying obtain Compound as white solid Exp 6 (4mg, 0.054mmol, yield：8%)
LC-MS:[M+1]=458.3
1H NMR (400MHz, MeOD) δ 7.23-7.21 (m, 2H), 7.16 (d, J=8.4Hz, 2H), 6.95 (d, J= 8.4Hz, 2H), 6.82 (d, J=9.2Hz, 1H), 4.00 (d, J=8.0Hz, 2H), 3.89-3.85 (m, 1H), 3.47-3.45 (m, 2H), 3.30-3.28 (m, 2H), 2.86-2.71 (m, 2H), 2.64 (q, J=6.8Hz, 2H), 2.07-2.04 (m, 1H), 1.91-1.88 (m, 2H), 1.78-1.61 (m, 2H), 1.55-1.50 (m, 3H), 1.22 (t, J=7.2Hz, 3H), 0.89 (d, J =6.8Hz, 6H)
Embodiment 7：N- (4- ethylphenyls)-N- isobutyl group -4- methoxyl groups -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- The preparation of sulfonamide EXP 7
At room temperature, Exp 2 (80mg, 0.17mmol, 1.0eq) is dissolved in THF (5mL), adds in compound N aH (13mg, 60%in mineral oil, 0.34mmol, 2.0eq), at room temperature stir 0.5 hour after be added dropwise again MeI (100mg, 0.7mmol, 4eq), it is stirred at room temperature 1.5 hours.TLC shows that the reaction was complete, is spin-dried for solvent, prep-HPLC preparative separations (mobile phase：0.1%TFA/CH3CN/H2O systems) obtain solid chemical compound Exp 7 (31mg, yield:37%)
TLC:PE/EA=1:1,UV 254nm
Rf(Exp 2)=0.7
Rf(Exp 7)=0.9
LC-MS:[M+1]=488.2
1H NMR(400MHz,CDCl3) δ 7.60 (s, 1H), 7.23 (dd, J=8.6,2.0Hz, 1H), 7.05 (d, J= 8.0Hz, 2H), 6.91 (d, J=8.0Hz, 2H), 6.71 (d, J=8.4Hz, 1H), 4.45-4.41 (m, 1H), 3.99 (d, J= 10.8Hz, 2H), 3.97-3.87 (m, 1H), 3.40-3.35 (m, 5H), 3.21-3.18 (m, 2H), 2.56 (q, J=7.2Hz, 2H), 2.30-2.25 (m, 1H), 1.86-1.71 (m, 7H), 1.56-1.46 (m, 4H), 1.16 (t, J=7.6Hz, 3H), 0.83 (d, J=6.8Hz, 6H)
Embodiment 8：N- (2,4- 3,5-dimethylphenyls)-N- isobutyl group -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman - The preparation of 6- sulfonamide EXP8
1) preparation of compound 3
Compound 1 (5.0g, 41.3mmol, 1.0eq) is dissolved at room temperature in THF (100mL), addition 2 (2.9g, 41.3mmol, 1.0eq), 1h is stirred at room temperature, NaBH (OAc) is slowly added at 0 DEG C3(12.2g, 57.8mmol, 1.4eq), room temperature Stirring 16 hours.The reaction was complete for LCMS detections.Solvent is spin-dried for, silica gel mixed sample, crosses column (PE:EA=50:1) compound 3, is obtained (5.0g, yield：68%).
TLC:PE/EA=5:1,UV 254nm
Rf(Compound 1)=0.3
Rf(Compound 3)=0.7
2) preparation of EXP 8
Compound 4 (400mg, 1.21mmol, 1.0eq) is dissolved at room temperature in 15mL DCM and 3mL MeCN, then is added Enter compound 3 (236mg, 1.33mmol, 1.1eq), add in 1mL pyridines, react at room temperature 2 hours.The display of TLC contact plates has been reacted Entirely, there is new point generation.It is spin-dried for, adds methylene chloride and extracted with water, anhydrous sodium sulfate drying is spin-dried for organic phase, scraper plate (PE/EA= 2:1) compound as white solid 5 (194mg, yield, are obtained：34%).
TLC:PE/EA=3:1,UV 254nm
Rf(Compound 3)=0.8
Rf(Compound 4)=0.3
Rf(EXP 8)=0.4
LC-MS:[M+1]=472.6.
Embodiment 9：N- (2,4- 3,5-dimethylphenyls) -4- hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman - The preparation of 6- sulfonamide EXP9
By compound EXP 8 (130mg, 0.27mmol, 1.0eq), compound N aBH4(31.3mg, 0.81mmol, It 3.0eq) adds in 20mL MeOH, stirs two hours at room temperature, TLC shows that the reaction was complete at room temperature.MeOH is spin-dried for, scraper plate (PE:EA=2:1) solid chemical compound EXP 9 (63mg, yield are obtained：49%).
TLC:PE/EA=2:1,UV 254nm
Rf(EXP 8)=0.6
Rf(EXP 9)=0.3
1H NMR(400MHz,CDCl3) δ 7.67 (d, J=8.0Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 7.01 (s, 1H), 6.78-6.74 (m, 2H), 6.45 (t, J=8.4Hz, 1H), 4.84 (br s, 1H), 4.07-3.88 (m, 3H), 3.44- 3.27(m,3H),2.95-2.94(m,1H),2.30-2.27(m,3H),2.22(s,3H),1.97-1.68(m,5H),0.96- 0.91(m,3H),0.81-0.78(m,2H),0.73-0.72(m,3H).
Embodiment 10：N- (4- ethylphenyls)-N- isobutyl groups -2- (1- methyl piperidine -4- bases) -4- oxo -2,3- dihydros The preparation of benzopyran-4-one -6- sulfonamide EXP 10
With reference to the method for embodiment 1, compound EXP 10, LC-MS is prepared:[M+H]=485.4.
Embodiment 11：N- (4- ethylphenyls) -4- hydroxy-ns-isobutyl group -2- (1- methyl piperidine -4- bases) 2,3- dihydrobenzenes And the preparation of pyrans -4- ketone -6- sulfonamide EXP 11
With reference to the method for embodiment 2, compound EXP 11, LC-MS is prepared:[M+H]=487.3,1H NMR (400MHz,DMSO-d6) δ 9.18 (br s, 1H), 7.67 (s, 1H), 7.24 (d, J=8.4Hz, 1H), 7.18 (d, J= 8.0Hz, 2H), 6.97 (d, J=8.0Hz, 2H), 6.83 (d, J=8.4Hz, 1H), 5.75 (d, J=6.4Hz, 1H), 4.74- 4.82(m,1H),4.12-4.20(m,1H),3.43-3.51(m,2H),3.27-3.23(m,2H),3.00-2.89(m,2H), 2.77 (s, 3H), 2.60 (q, J=7.6Hz, 2H), 2.22-2.14 (m, 1H), 2.11-2.03 (m, 1H), 1.93-1.81 (m, 2H), 1.69-1.50 (m, 3H), 1.44-1.36 (m, 1H), 1.17 (t, J=7.6Hz, 3H), 0.83 (d, J=6.4Hz, 6H)
Embodiment 12：N- (4- fluorophenyls)-N- isobutyl group -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide EXP 12
With reference to the method for embodiment 1, compound EXP 12, LC-MS is prepared:[M+1]=462.5.
Embodiment 13：N- (4- fluorophenyls) -4- hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide EXP 13
With reference to the method for embodiment 2, compound EXP 13, LC-MS is prepared:[M+1]=464.2
1H NMR(400MHz,CDCl3) δ 7.69 (d, J=1.2Hz, 1H), 7.32 (dd, J=8.4Hz, J=2.0Hz, 1H), 7.06-6.97 (m, 4H), 6.80 (d, J=8.8Hz, 1H), 4.93-4.89 (m, 1H), 4.08-3.98 (m, 3H), 3.46- 3.40(m,2H),3.30-3.26(m,2H),2.36-2.32(m,1H),1.92-1.741(m,3H),1.63-1.48(m,3H), 0.92-0.89(m,6H).
Embodiment 14：N- isobutyl group -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases)-N- (2- (trifluoromethyl) benzyl) color The preparation of full -6- sulfonamide EXP 14
With reference to the method for embodiment 8, it is prepared for Exp14, LC-MS:[M+1]=525.6.
Embodiment 15：4- hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases)-N- ((2- (trifluoromethyl) benzyl) The preparation of chroman -6- sulfonamide EXP 15
With reference to embodiment 9, it is prepared for Exp 15, LC-MS:[M+1]=528.2
1H NMR(400MHz,CDCl3) δ 7.98 (d, J=1.2Hz, 1H), 7.92 (d, J=7.6Hz, 1H), 7.65-7.55 (m, 3H), 7.37 (t, J=7.6Hz, 1H), 6.90 (d, J=8.4Hz, 1H), 4.99-4.95 (m, 1H), 4.46 (s, 2H), 4.08-4.01 (m, 2H), 3.47-3.41 (m, 2H), 2.94 (d, J=7.2Hz, 2H), 2.38-2.34 (m, 1H), 1.63-1.46 (m, 6H), 1.50-1.45 (m, 1H), 0.75 (d, J=6.8Hz, 6H)
Embodiment 16：N- cyclobutyl-N- (4- ethylphenyls) -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- The preparation of sulfonamide EXP16
With reference to the method for embodiment 8, it is prepared for Exp16.LC-MS:[M+1]=470.3
1H NMR(400MHz,CDCl3) δ 8.24 (d, J=2.0Hz, 1H), 7.62 (dd, J=8.8,2.4Hz, 1H), 7.12 (d, J=8.0Hz, 2H), 7.00 (d, J=8.8Hz, 1H), 6.85 (d, J=8.0Hz, 2H), 4.40-4.37 (m, 2H), 4.07 (d, J=11.6Hz, 2H), 3.46-3.43 (m, 2H), 2.77 (d, J=1.6Hz, 2H), 2.62 (q, J=7.6Hz, 2H), 1.91-1.86 (m, 6H), 1.63-1.57 (m, 2H), 1.55-1.50 (m, 2H), 1.24 (t, J=7.6Hz, 3H)
Embodiment 17：N- cyclobutyl-N- (4- ethylphenyls) -4- hydroxyls -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- The preparation of sulfonamide EXP17
With reference to embodiment 9, it is prepared for Exp 17, LC-MS:[M+1]=472.3
1H NMR(400MHz,CDCl3) δ 7.72 (d, J=1.2Hz, 1H), 7.39 (dd, J=8.8,2.0Hz, 1H), 7.12 (d, J=8.4Hz, 2H), 6.86 (d, J=8.8Hz, 2H), 6.80 (d, J=8.4Hz, 1H), 4.93-4.87 (m, 1H), 4.37- 4.31 (m, 1H), 4.07-3.98 (m, 2H), 3.46-3.40 (m, 2H), 2.67-2.61 (q, J=7.6Hz, 2H), 2.33-2.30 (m, 1H), 1.96-1.74 (m, 2H), 1.65-1.58 (m, 2H), 1.54-1.50 (m, 2H), 1.23 (t, J=7.6Hz, 3H)
Embodiment 18：N- (4- ethylphenyls) -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases)-N- (2,2,2- trifluoro second Base) chroman -6- sulfonamide EXP 18 preparation
With reference to the method for embodiment 8, it is prepared for Exp18, LC-MS:[M+1]=498.5
Embodiment 19：N- (4- ethylphenyls) -4- hydroxyls -2- (tetrahydrochysene -2H- pyrans -4- bases)-N- (2,2,2- trifluoro second Base) chroman -6- sulfonamide EXP 19 preparation
With reference to the method for embodiment 9, it is prepared for Exp19.
1H NMR(400MHz,CDCl3) δ 7.74 (s, 1H), 7.37 (d, J=8.4Hz, 1H), 7.14 (d, J=8.0Hz, 2H), 6.98 (d, J=8.0Hz, 2H), 6.81 (d, J=8.8Hz, 1H), 5.35 (br s, 1H), 4.91-4.87 (m, 1H), 4.18-3.99 (m, 5H), 3.46-3.40 (m, 2H), 2.64 (d, J=8.0Hz, 2H), 2.36-2.31 (m, 1H), 2.21 (d, J =7.7Hz, 1H), 2.03-1.73 (m, 4H), 1.24 (t, J=7.6Hz, 3H)
Embodiment 20：N- (4- ethylphenyls) -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulfonamide EXP 20 preparation
With reference to the method for embodiment 8, it is prepared for Exp20, LC-MS:[M+1]=416.5.
Embodiment 21：N- (4- ethylphenyls) -4- hydroxyls -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulfonamide EXP 21 preparation
With reference to the method for embodiment 9, it is prepared for Exp21.
1H NMR(400MHz,CDCl3) δ 7.98 (s, 1H), 7.46 (d, J=8.0Hz, 1H), 7.04 (d, J=8.0Hz, 2H), 6.98 (d, J=8.0Hz, 2H), 6.74 (d, J=8.8Hz, 1H), 4.88-4.86 (m, 1H), 4.09-3.93 (m, 4H), 3.42-3.37 (m, 2H), 2.84 (br s, 1H), 2.55 (q, J=7.6Hz, 2H), 2.26-2.30 (m, 1H), 1.85-1.75 (m, 2H), 1.54-1.43 (m, 2H), 1.26 (s, 2H), 1.17 (t, J=7.6Hz, 3H)
Embodiment 22：N- (2- fluorophenyls)-N- isobutyl group -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide EXP22
With reference to the method for embodiment 8, it is prepared for Exp22.
1H NMR(400MHz,CDCl3) δ 8.16 (d, J=2.0Hz, 1H), 7.60 (dd, J=8.4,2.4Hz, 1H),
7.27-7.22(m,2H),7.09-7.05(m,1H),6.95-6.91(m,2H),4.28-4.24(m,1H),4.01 (d, J=12.2Hz, 2H), 3.28 (d, J=7.6Hz, 2H), 2.69 (d, J=7.6Hz, 2H), 1.96-1.92 (m, 1H), 1.82 (d, J=14.0Hz, 1H), 1.64 (br s, 2H), 1.54-1.49 (m, 2H), 0.85 (d, J=6.4Hz, 6H)
Embodiment 23：N- (2- fluorophenyls) -4- hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide EXP23
With reference to the method for embodiment 9, it is prepared for Exp23.
1H NMR(400MHz,CDCl3) δ 7.71 (s, 1H), 7.36 (dd, J=8.4,2.4Hz, 1H), 7.22-7.19 (m, 2H), 7.05 (t, J=7.6Hz, 1H), 6.96 (t, J=9.6Hz, 1H), 6.74 (d, J=8.8Hz, 1H), 4.86-4.81 (m, 1H),4.00-3.91(m,3H),3.39-3.36(m,2H),3.30-3.22(m,2H),2.29-2.24(m,1H),1.88-1.66 (m,4H),1.55-1.45(m,4H),0.85-0.83(m,6H).
Embodiment 24：N- (4- cvano-phenyls)-N- isobutyl group -4- oxos -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- The preparation of sulfonamide EXP 24
With reference to the method for embodiment 8, it is prepared for Exp24.
1H NMR(400MHz,CDCl3) δ 8.16 (d, J=2.0Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.51 (dd, J =8.8,2.4Hz, 1H), 7.23 (d, J=8.8Hz, 2H), 7.01 (d, J=8.8Hz, 1H), 4.33-4.30 (m, 1H), 4.08 (d, J=12.4Hz, 2H), 3.46-3.41 (m, 2H), 3.36 (d, J=7.2Hz, 2H), 2.76 (d, J=7.6Hz, 2H), 2.04-2.00 (m, 2H), 1.98-1.90 (m, 2H), 1.62-1.55 (m, 2H), 0.90 (d, J=6.4Hz, 6H)
Embodiment 25：N- (4- cvano-phenyls) -4- hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- The preparation of sulfonamide EXP 25
With reference to the method for embodiment 9, it is prepared for Exp25.
1H NMR(400MHz,CDCl3) δ 7.60 (s, 1H), 7.54 (d, J=8.4Hz, 2H), 7.22-7.7.16 (m, 3H), 6.73 (d, J=8.8Hz, 1H), 4.85-4.80 (m, 1H), 3.99-3.91 (m, 3H), 3.39-3.35 (m, 2H), 3.26-3.22 (m,2H),2.28-2.23(m,1H),2.00(br s,2H),1.89-1.64(m,3H),1.51-1.43(m,2H),0.84- 0.82(m,6H).
Embodiment 26：N- ((5- (ethylsulfonyl) pyridine -2- bases) methylene) -4- oxos -2- (tetrahydrochysene -2H- pyrans - 4- yls) chroman -6- sulfonamide EXP 26 preparation
With reference to the method for embodiment 8, it is prepared for Exp26.
LC-MS:[M+1]=495.1
1H NMR(400MHz,CD3OD) δ 8.76 (d, J=1.6Hz, 1H), 8.10 (dd, J=8.0,2.0Hz, 1H), 8.06 (d, J=2.0Hz, 1H), 7.86 (dd, J=8.4,2.0Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.06 (d, J=8.4Hz, 1H), 4.36 (s, 3H), 4.03-4.00 (m, 2H), 3.47-3.45 (m, 2H), 3.23 (q, J=7.4Hz, 2H), 2.89-2.80 (m, 1H), 2.70-2.68 (m, 1H), 2.03 (br s, 1H), 1.90 (d, J=11.2Hz, 1H), 1.68-1.47 (m, 3H), 1.18 (t, J=7.6Hz, 3H)
Embodiment 27：N- ((5- (ethylsulfonyl) pyridine -2- bases) methylene) -4- hydroxyls -2- (tetrahydrochysene -2H- pyrans - 4- yls) chroman -6- sulfonamide EXP 27 preparation
With reference to the method for embodiment 9, it is prepared for Exp27.
LC-MS:[M+1]=497.2
1H NMR (400MHz, DMSO) δ 8.85 (d, J=1.6Hz, 1H), 8.29 (t, J=6.4Hz, 1H), 8.20 (dd, J =8.4,2.4Hz, 1H), 7.82 (d, J=1.2Hz, 1H), 7.61 (d, J=8.0Hz, 1H), 7.47 (dd, J=8.4,2.0Hz, 1H), 6.80 (d, J=8.4Hz, 1H), 4.76-4.72 (m, 1H), 4.19 (d, J=6.4Hz, 2H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 2H), 3.39-3.25 (m, 4H), 2.20-2.16 (m, 1H), 1.84 (br s, 1H), 1.76 (d, J= 13.2Hz, 1H), 1.60-1.58 (m, 2H), 1.49-1.22 (m, 3H), 1.11 (t, J=7.2Hz, 3H)
Embodiment 28：N- (4- ethylphenyls)-N- isobutyl group -4- oxos -2- ((tetrahydrochysene -2H- pyrans -4- bases) methylene) The preparation of chroman -6- sulfonamide EXP 28
With reference to the method for embodiment 1, it is prepared for Exp28.
LC-MS:[M+H]=486.4
1H NMR(400MHz,CDCl3) δ 8.20 (d, J=2.0Hz, 1H), 7.55 (d, J=11.2Hz, 1H), 7.13 (d, J =8.4Hz, 2H), 7.00-6.95 (m, 3H), 4.70-4.60 (m, 1H), 3.99 (d, J=14.0Hz, 2H), 3.43 (t, J= 12.0Hz, 2H), 3.29 (d, J=7.6Hz, 2H), 2.79-2.70 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 1.98-1.83 (m, 2H), 1.74-1.61 (m, 3H), 1.46-1.34 (m, 3H), 1.23 (t, J=7.6Hz, 3H), 0.91 (d, J=6.4Hz, 6H).
Embodiment 29：N- (4- ethylphenyls) -4- hydroxy-ns-isobutyl group -2- ((tetrahydrochysene -2H- pyrans -4- bases) methylene) The preparation of chroman -6- sulfonamide EXP 29
With reference to the method for embodiment 2, it is prepared for Exp29.
LC-MS:[M+H]=488.4
1H NMR(400MHz,CDCl3) δ 7.67 (s, 1H), 7.34 (dd, J=8.5,2.0Hz, 1H), 7.12 (d, J= 8.0Hz, 2H), 6.97 (d, J=8.0Hz, 2H), 6.80 (d, J=8.8Hz, 1H), 4.91-4.87 (m, 1H), 4.33-4.28 (m, 1H), 3.98 (d, J=13.6Hz, 2H), 3.47-3.41 (m, 2H), 3.35-3.16 (m, 2H), 2.63 (q, J=7.6Hz, 2H), 2.32-2.27 (m, 1H), 1.81-1.28 (m, 10H), 1.23 (t, J=7.6Hz, 3H), 0.92-0.88 (m, 6H)
Embodiment 30：N- (3- fluorophenyls) -4- hydroxy-ns-isobutyl group -2- (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphurs The preparation of amide EXP 30
With reference to the method for embodiment 2, it is prepared for Exp30.
LC-MS:[M+1]=464.3
1H NMR(400MHz,CDCl3) δ 7.62 (d, J=1.2Hz, 1H), 7.26-7.21 (m, 2H), 7.22-7.16 (m, 1H), 6.94-6.90 (m, 1H), 6.85 (d, J=7.6Hz, 1H), 6.73 (d, J=8.8Hz, 2H), 4.84-4.79 (m, 1H), 3.99-3.91(m,3H),3.39-3.32(m,2H),3.22-3.18(m,2H),2.28-2.23(m,1H),1.85-1.65(m, 3H),1.59-1.40(m,4H),0.84-0.82(m,6H).
Embodiment 31：N- (4- ethylphenyls)-N- isobutyl groups -2- (1- (methyl sulphonyl) piperidin-4-yl) -4- oxo colors The preparation of full -6- sulfonamide EXP 31
With reference to the method for embodiment 1, it is prepared for Exp31.
LC-MS:[M+H]=449.4
1H NMR(400MHz,CDCl3) δ 8.20 (d, J=2.4Hz, 1H), 7.56 (dd, J=8.4,2.0Hz, 1H), 7.13 (d, J=8.0Hz, 2H), 7.00 (d, J=8.4Hz, 1H), 6.96 (d, J=8.4Hz, 2H), 4.38-4.35 (m, 1H), 3.94 (d, J=11.2Hz, 2H), 3.29 (d, J=7.6Hz, 2H), 2.81 (s, 3H), 2.78-2.61 (m, 6H), 2.10 (d, J= 12.9Hz, 1H), 1.86 (d, J=12.1Hz, 2H), 1.71-1.58 (m, 3H), 1.23 (t, J=7.6Hz, 3H), 0.91 (d, J =6.8Hz, 6H)
Embodiment 32：N- (4- ethylphenyls) -4- hydroxy-ns-isobutyl group -2- (1- (methyl sulphonyl) piperidin-4-yl) color The preparation of full -6- sulfonamide EXP 32
With reference to the method for embodiment 2, it is prepared for Exp32.
LC-MS:[M+H]=551.2
1H NMR(400MHz,CDCl3) δ 7.67 (s, 1H), 7.35 (dd, J=8.4,2.0Hz, 1H), 7.12 (d, J= 8.0Hz, 2H), 6.97 (d, J=8.4Hz, 2H), 6.80 (d, J=8.4Hz, 1H), 4.94-4.85 (m, 1H), 4.08-4.01 (m, 1H), 3.92 (d, J=11.4Hz, 2H), 3.33-3.18 (m, 2H), 2.80 (s, 3H), 2.71-2.59 (m, 4H), 2.36- 2.27 (m, 1H), 2.07 (d, J=11.7Hz, 1H), 1.90-1.75 (m, 4H), 1.68-1.57 (m, 2H), 1.23 (t, J= 7.6Hz,3H),0.92-0.88(m,6H).
Embodiment 33：N- (4- ethylphenyls) -4- hydroxy-ns-isobutyl group -2- (piperidin-4-yl) chroman -6- sulfonamide EXP 33 preparation
With reference to the method for embodiment 2, it is prepared for Exp33.
LC-MS:[M+H]=473.4
1H NMR(400MHz,CDCl3) δ 9.53 (br s, 1H), 8.97 (br s, 1H), 7.69 (s, 1H), 7.32 (d, J= 8.8Hz, 1H), 7.13 (d, J=8.4Hz, 2H), 6.97 (d, J=8.0Hz, 2H), 6.78 (d, J=8.4Hz, 1H), 4.95- 4.81(m,1H),4.09-3.98(m,1H),3.56-3.38(m,2H),3.32-3.19(m,2H),2.9-2.81(m,2H), 2.63 (q, J=7.2Hz, 2H), 2.33-2.18 (m, 2H), 2.12 (d, J=15.0Hz, 2H), 1.98-1.88 (m, 3H), 1.61-1.48 (m, 1H), 1.23 (t, J=7.6Hz, 3H), 0.92-0.88 (m, 6H)
Embodiment 34：- 4 fluoro- N- isobutyl groups -2- of N- (4- ethylphenyls) (tetrahydrochysene -2H- pyrans -4- bases) chroman -6- sulphonyl The preparation of amine compounds EXP 34
With reference to the method for embodiment 2, it is prepared for Exp34.
LC-MS:[M+1]=476.2
1H NMR(400MHz,CDCl3) δ 7.56 (s, 1H), 7.47 (d, J=8.8Hz, 1H), 7.13 (d, J=8.0Hz, 2H), 6.98 (d, J=5.2Hz, 2H), 6.92 (d, J=8.8Hz, 1H), 5.5 (m, 1H), 4.08-4.03 (m, 3H), 3.49- 3.41 (m, 2H), 3.26 (d, J=7.6Hz, 2H), 2.66 (q, J=8.0Hz, 2H), 2.3 (m, 1H), 1.94-1.81 (m, 3H), 1.66-1.51 (m, 4H), 1.23 (t, J=7.6Hz, 3H), 0.91-0.84 (m, 6H)
35 ROR γ t inhibitor luciferase reporter gene of embodiment is tested
Experiment material and instrument：
Wherein SR1001 is the inverse agonist of ROR γ t, and as positive control, structure is：
Experimental procedure：
1st, first day cell kind plate.293T attached cells add 1mL pancreatin digestion 5min or so, have been digested with pipettor absorption Good cell, is transferred in 15mL centrifuge tubes, 1000rpm, 5min centrifugations.Old culture medium is abandoned, cell is resuspended with fresh culture And it is diluted to required density.
2nd, cell count.By 1.5 ten thousand/hole of cell density, cell suspension is prepared.Kind plate, per 100 μ L cells of hole.In order to Edge effect is prevented, 96 porocyte culture plates only plant 60 holes among plate, and 36 holes of surrounding are used per 100 μ L PBS polishings of hole. 37 DEG C, 5%CO2Incubator culture cell.
3rd, cell transient transfection studies do in 24 hours sides after cell kind plate.Prepare wink Pignus pignoris grain (i.e. Gal4-ROR γ-LBD： 25ng/ holes；PgL4.3-luc：25ng/ holes), transfection reagent (2000 concentration of liposome is 3 times of DNA).
4th, 5min is incubated after reagent dilutions to be transfected, transfection reagent and plasmid is mixed and are incubated 20min, then adds 10 per hole μL.Micromolecular compound (compound of SR1001 or Exp1-Exp34) can be added by transiently transfecting more than 5h.
5th, as needed, first by DMEM cell culture medium 3 doubling dilution of the compound to be detected containing 10% fetal calf serum Then existing culture medium in tissue culture plate is sucked out, adds in prepared to be detectedization later by (100~0.195 μM) Close object and fresh culture.
6th, 37 DEG C are then placed in, 5%CO2Incubator culture cell.About cell is taken out afterwards for 24 hours, Microscopic observation cell Tissue culture plate is taken out iuntercellular by growing state.Then the double reporter gene test experiences of luciferase are done.
7th, cell culture medium suction is abandoned first, then adds in about 100 μ L PBS and wash remaining medium.By mother liquor 5 × Cell lysis buffer into 1 × after, add 20 μ L per hole, then vibrate about 20min by cell cracking.
8th, cell is transferred to white light tight 96 hole detection plate.Then 2390 homogeneous luminescents of En Spire Alpha are used Immune detection system test experiments result：The cell after configured good firefly luciferin substrate detection compound interference is added to live Property.
9th, the calculating of inhibitory activity：
10th, experimental result：
++++represent IC50<50nM；+++ represent IC50Ranging from 50~200nM；++ represent IC50Ranging from 200~ 1000nM；+ expression IC50>1000nM。
36 ROR γ t Binding experiments of embodiment
1. reagent and consumptive material：
2. compound management：
2.1 compounds store：Compound is dissolved in DMSO, 10mM liquid storages are made.
2.2 compounds preserve：All compounds being dissolved in DMSO, are stored in drier, room temperature does not surpass in a short time Spend 3 months.It is long-term then be stored in -20 DEG C.
2.3 prepare compound：
A) all compounds carry out 3 times of gradient dilutions, 10 dilution gradients, initial concentration 500uM with DMSO.
B) positive reference compound carries out 3 times of gradient dilutions, 10 dilution gradients, initial concentration 25uM with DMSO.
C) prepare the positive control (positive reference compound of 25uM) of 50x and the negative control (100%DMSO) of 50x.
D) compound plank is closed and shaken 5 minutes.
3. experimentation：
3.1 prepare reaction buffer：DTT and KF are dissolved in 1x buffer D.Final concentration：DTT 5mM, KF50mM.
3.2 detection compound:
A) prepare the compound of 2x gradient dilutions in buffer (see step 2.3).
B) compound of 10ul 2x gradient dilutions is added in (see step a) in the reaction plank in 384 holes.
C) reactant of 2x is prepared with the buffer of freezing：RORγ-LBD(40nM),SRC(100nM),anti-GST Eu (1:And chain enzyme penicillin-D2 (25nM) 200).
D) plank is reacted in 384 holes and (10ul 2x reactants are added in see step b) (see step c).
E) by 384 hole reaction plate centrifugations, 1000g, 1min.
F) room temperature is protected from light incubation 1 hour.
G) plank is detected：Wavelength 665nm and 615nm；Instrument：Multiple labeling micropore board detector.
4. data analysis
4.1 relative ratios (RR):Calculate the relative scale [(the 665nm responses/615nm responses-blank back of the body in each hole Scape response) * 1000].
The calculating of 4.2 percent inhibitions (%Inhibition) is as follows：
4.3 calculate the IC of compound50And amount effect curve:The inhibiting rate and compound concentration of compound obtained by calculation Log values, using Graphpad 5.0, obtain the IC50 and amount effect curve of compound.
4.4 audit report：
4.4.1 laboratory technician's completion report, another laboratory technician check again for reporting, to ensure the accuracy of data.
4.4.1.1 data are exported from detecting instrument and are analyzed manually.
4.4.1.2 it is percent inhibition by rate conversion.It is counted for the first time using Graphpad5.0 softwares and percent inhibition Calculate the IC of compound50。
4.4.1.3 with the IC of ratio calculation compound50, with this IC50Check the accuracy of data.
4.4.2 determine whether the title of all compounds is correct.
4.5 data standard：Z factor>0.5；S/B>3；
The IC of positive reference compound50In the range of 3 times of historical average value.
5. data result:
Compound ROR γ t activity half-inhibition concentrations (IC50)
Exp 1 17nM
Exp 2 2.6nM
Exp 6 25nM
Exp 32 6.6nM
SR1001 255nM
Can be seen that formula (I) compound by above-mentioned experimental result has ROR γ t an apparent inhibiting effect, and ROR γ t There is very important effect in inflammatory, metabolic and autoimmune disease, inhibit ROR γ t that these diseases will be caused to obtain Alleviate or effectively treat.Particularly ROR γ t inhibitor is used to treat respiratory disease (such as asthma, COPD), autoimmunity The purposes of property disease (such as rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease) is furtherd investigate and is recognized It can.

Claims (24)

1. structure such as formula (I) compound represented or its stereoisomer, tautomer or its pharmaceutically acceptable salt or Its solvate or prodrug：
Wherein,
R1、R2It is independently selected from hydrogen, halogen, hydroxyl, amino, C1-6Alkyl, C1-C6Alkyl amine group, C1-C6Alkoxy or R1、R2Merge into oxo base；
R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl, the C arbitrarily replaced3-C8Cycloalkyl or the-CH arbitrarily replaced2C3-C8Cycloalkanes Base, substituent group are selected from hydrogen, halogen, hydroxyl, amino or C1-C6Alkyl；
R5Selected from arbitrary substituted C6-C10Aryl or the C arbitrarily replaced2-C10Heteroaryl, substituent group be selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or-S (O2)C1-6Alkyl；
R3For group-(CHR6)s-(Y)t-(CHR7)u-R8；
R6、R7It is independently selected from hydrogen, C1-6Alkyl, hydroxyl；
Y is selected from C1-6Alkyl, NH or O；
R8Selected from arbitrary substituted C2-C8Heterocyclylalkyl, the C arbitrarily replaced3-C8Cycloalkyl, the C arbitrarily replaced6-C10Aryl is appointed Anticipate the C replaced2-C10Heteroaryl, substituent group are selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkane Base ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)mC2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8 Cycloalkyl ,-C (O) (CH2)mC2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen；
M is selected from 0,1,2；
S, t, u are independently selected from 0,1,2；
X is selected from O, NR9、CR9；
R9Selected from hydrogen, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl；
N is selected from 0,1.
2. according to formula (I) compound described in claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R5Selected from arbitrary substituted following group：Phenyl ring, pyridine Ring, pyrimidine ring, pyridazine ring, pyridine ring, quinoline, isoquinolin, pyrrole ring, pyrazole ring, imidazole ring, thiphene ring, thiazole ring, furan nucleus Huo oxazole rings；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or-S (O2)C1-6Alkyl.
3. according to formula (I) compound described in claim 2 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, it is characterised in that the R5Selected from arbitrary substituted phenyl ring or the pyridine arbitrarily replaced Ring；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or-S (O2)C1-6Alkyl.
4. according to formula (I) compound described in claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R8Selected from arbitrary substituted following group：Oxa- ring third Alkane, oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, azetidine, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- Ketone or thiomorpholine 1,1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2) C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)mC2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)mC2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl or halogen.
5. according to formula (I) compound described in claim 4 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R3For-CH2R8Or-R8；R8Selected from arbitrary substituted following Group：Oxirane, oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, azetidine, pyrrolidines, piperidines, Quinoline, pyridine, morpholine -3- ketone or thiomorpholine 1,1- dioxide；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3- C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)mC2-C8Heterocyclylalkyl ,-C (O) C1-6 Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)mC2-C8Heterocyclylalkyl, C2-C10Heteroaryl, C6-C10Aryl, hydroxyl Or halogen.
6. according to formula (I) compound described in claim 5 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the R8Selected from arbitrary substituted following group：Oxa- ring fourth Alkane, tetrahydrofuran, tetrahydrochysene -2H- pyrans, pyrrolidines, piperidines, morpholine, pyridine；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocycle alkane Base, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)mC2-C8Heterocyclylalkyl ,-C (O)C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)mC2-C8Heterocyclylalkyl, hydroxyl or halogen.
7. according to formula (I) compound described in claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that wherein X is selected from O, NH or CH2。
8. according to formula (I) compound described in claim 7 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that wherein X is O or NH.
9. according to formula (I) compound described in claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that R1、R2It is independently selected from hydrogen, hydroxyl, halogen, amino, C1-3 Alkyl, C1-C3Alkoxy or R1、R2Merge into oxo base.
10. according to formula (I) compound described in claim 1 or its stereoisomer, tautomer or its pharmaceutically may be used The salt of receiving or its solvate or prodrug, which is characterized in that R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl or arbitrary substitution C3-C8Cycloalkyl, substituent group are selected from hydrogen, halogen, hydroxyl, amino or C1-C6Alkyl.
11. formula (I) compound or its stereoisomer, tautomer described in claim 1 or its is pharmaceutically acceptable Salt or its solvate or prodrug, which is characterized in that wherein：
X is O；
N is 0 or 1；
R1、R2It is independently selected from hydrogen, hydroxyl, halogen, amino, C1-3Alkyl, C1-C3Alkoxy or R1、R2Merge into oxygen Dai Ji；
R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl or the C arbitrarily replaced3-C6Cycloalkyl, substituent group be selected from hydrogen, halogen, hydroxyl, Amino or C1-C3Alkyl；
R5Selected from arbitrary substituted phenyl ring or the pyridine ring arbitrarily replaced；Substituent group is selected from hydrogen, halogen, cyano, C1-C3Alkyl, C1- C3Alkoxy, C1-C3Halogenated alkyl or-S (O2)C1-3Alkyl；
R3For-CH2R8Or-R8；R8Selected from arbitrary substituted tetrahydrochysene -2H- pyrans or the piperidines arbitrarily replaced；Substituent group be selected from H, C1-3Alkyl ,-S (O2)C1-3Alkyl, hydroxyl or halogen.
12. structure such as Formulas I a-Ij any structures compound represented or its stereoisomer, tautomer or its pharmaceutically may be used The salt of receiving or its solvate or prodrug：
Wherein：R3、R4、R5Definition with n is as described in the appended claim 1.
13. compound according to claim 12 or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or prodrug, which is characterized in that wherein：
R3Selected from group-(CHR6)s-(Y)t-(CHR7)u-R8；
R6、R7It is independently selected from hydrogen, C1-6Alkyl, hydroxyl；
Y is selected from C1-6Alkyl, NH or O；
S, t, u are independently selected from 0,1,2；
R8Selected from arbitrary substituted following group：Oxirane, oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, azepine Cyclobutane, pyrrolidines, piperidines, morpholine, pyridine, morpholine -3- ketone or thiomorpholine 1,1- dioxide；Substituent group is selected from H, C1-6 Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl ,-S (O2)(CH2)mC3-C8Cycloalkyl ,-S (O2)(CH2)mC2-C8Heterocyclylalkyl ,-C (O) C1-6Alkyl ,-C (O) (CH2)mC3-C8Cycloalkyl ,-C (O) (CH2)mC2-C8Heterocyclylalkyl, C2-C10 Heteroaryl, C6-C10Aryl, hydroxyl or halogen；
R4The C selected from hydrogen, arbitrarily replaced1-C6Alkyl, the C arbitrarily replaced3-C8Cycloalkyl or the-CH arbitrarily replaced2C3-C8Cycloalkanes Base, substituent group are selected from hydrogen, halogen, hydroxyl, amino or C1-C6Alkyl；
R5Selected from arbitrary substituted following group：Phenyl ring, pyridine ring, pyrimidine ring, pyridazine ring, pyridine ring, quinoline, isoquinolin, pyrroles Ring, pyrazole ring, imidazole ring, thiphene ring, thiazole ring, furan nucleus Huo oxazole rings；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkane Base, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl, C1-C6Alkoxy, C1-C6Halogenated alkyl or-S (O2)C1-6Alkyl.
14. structure such as Formulas I a-Ie, Ih, Ii or Ij compounds represented or its stereoisomer, tautomer or its pharmaceutically Acceptable salt or its solvate or prodrug：
Wherein, R3、R4、R5It is as described in claim 1 with the definition of n.
15. the structure such as any compounds represented of Formulas I a-Ie or Ij or its stereoisomer, tautomer or its pharmaceutically may be used The salt of receiving or its solvate or prodrug：
Wherein：R3、R4、R5It is as defined above with n.
16. compound according to claim 15 or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or prodrug, which is characterized in that wherein：
R5Selected from arbitrary substituted phenyl ring or the pyridine ring arbitrarily replaced；Substituent group is selected from hydrogen, halogen, cyano, C1-C6Alkyl, C1- C6Alkoxy, C1-C6Halogenated alkyl or-S (O2)C1-6Alkyl；
R3For-CH2R8Or-R8；R8Selected from arbitrary substituted following group：Oxetanes, tetrahydrofuran, tetrahydrochysene -2H- pyrans, Azetidine, pyrrolidines, piperidines, morpholine, pyridine；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkanes Base ,-S (O2)C1-6Alkyl, hydroxyl or halogen.
17. compound according to claim 16 or its stereoisomer, tautomer or its is pharmaceutically acceptable Salt or its solvate or prodrug, which is characterized in that wherein：R8Selected from arbitrary substituted tetrahydrochysene -2H- pyrans or arbitrary substitution Piperidines；Substituent group is selected from H, C1-6Alkyl, C2-C8Heterocyclylalkyl, C3-C8Cycloalkyl ,-S (O2)C1-6Alkyl, hydroxyl or halogen.
18. formula (I) compound according to claim 1 or its stereoisomer, tautomer or its can pharmaceutically connect The salt received or its solvate or prodrug, which is characterized in that the compound is selected from：
The preparation method of formula described in claim 1 19. (I) compound, which is characterized in that the method is selected from route 1 or route 2：
Route 1：
Route 2：
Wherein, R1、R2、R3、R4、R5, X and n definition as described in the appended claim 1.
20. a kind of pharmaceutical composition, which is characterized in that it includes any one of one or more claim 1-18 chemical combination Object or its stereoisomer, tautomer or its pharmaceutically acceptable salt or its solvate or prodrug and it is a kind of or A variety of pharmaceutically acceptable auxiliary materials.
21. compound or stereoisomer, tautomer described in any one of claim 1-18 or its can pharmaceutically connect The salt received or its solvate or prodrug, the application in the drug of disease for the treatment of ROR γ mediations is used to prepare.
22. application according to claim 21, it is characterised in that the disease is inflammatory, metabolic or autoimmune disease Disease.
23. the application described in claim 22, it is characterised in that the inflammatory, metabolic or autoimmune disease for asthma, Chronic obstructive pulmonary disease, bronchitis, allergic rhinitis, Atopic dermatitis, cystic fibrosis, lung allograft row Reprimand multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, is System property lupus erythematosus, psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, Autoimmune ophthalmopathy, exedens knot Enteritis, inflammatory bowel disease, inflammatory bowel syndrome, siogren's syndrome, optic neuritis, type-1 diabetes mellitus, regards Crohn's disease Neuromyelities, myasthenia gravis, uveitis, actue infectious polyradiculoneuritis, psoriatic arthritis, lattice Lei's disease or sclerotitis.
24. application as claimed in claim 23, which is characterized in that the disease is asthma, rheumatoid arthritis, silver bits Disease, ulcerative colitis or Crohn's disease.
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