CN106187838A - Arylalkyne hydrocarbon compound and its production and use - Google Patents

Arylalkyne hydrocarbon compound and its production and use Download PDF

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CN106187838A
CN106187838A CN201610556333.1A CN201610556333A CN106187838A CN 106187838 A CN106187838 A CN 106187838A CN 201610556333 A CN201610556333 A CN 201610556333A CN 106187838 A CN106187838 A CN 106187838A
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CN106187838B (en
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钟雪
刘兵
薛亚萍
李旭珂
王峰
何为
陈小燕
张英俊
郑常春
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Guangdong HEC Pharmaceutical
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Abstract

The present invention relates to a class arylalkyne hydrocarbon compound, and comprise the pharmaceutical composition of this compounds.Described compound or pharmaceutical composition can be as the inhibitor of the relevant lonely nuclear receptor γ t (Retinoid related orphan receptor gamma t, ROR γ t) of retinoic acid.The method that the invention still further relates to prepare this compounds and pharmaceutical composition, and they are in the inflammation mediated by ROR γ t or the purposes of autoimmune disease treating or preventing mammal, the particularly mankind.

Description

Arylalkyne hydrocarbon compound and its production and use
Technical field
The invention belongs to technical field of pharmaceuticals, be specifically related to a compounds, compositions and its production and use, its Described in compound or compositions can be as relevant lonely nuclear receptor γ t (the Retinoid-related orphan of retinoic acid Receptor gamma t, ROR γ t) inhibitor, and for prevention or treatment with Ia disease.
Background technology
Retinoic acid relevant lonely nuclear receptor γ t (Retinoid-related orphan receptor gamma t, ROR γ T) it is two kinds of the relevant lonely nuclear receptor γ of retinoic acid (Retinoid-related orphan receptor gamma, ROR γ) One of isoform, also referred to as ROR γ 2.There are some researches show, ROR γ t is only at lymphoid and bonnot's gland's inducer Cell is expressed (Sun et al., Science 288:2369-2372,2000；Eberl et al.,Nat Immunol.5: 64-73,2004).ROR γ t is as helper T lymphocyte (TH17) characteristic transcription factor, for TH17 cell differentiation all play Important function, is TH17 cells differentiation key regulator (Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A,Lafaille JJ,et al.Cell 2006；126(6):1121-33).
TH17 can secrete interleukin-17 (interleukin 17, IL-17) and other proinflammatory cytokines, exempt from self Epidemic disease disease and body defenses reaction have great importance.IL-17 is inflammatory development and the rush of various autoimmune disease Inflammatory cytokines, closely related with various autoimmune disease and inflammatory diseases, such as rheumatoid arthritis, psoriasis, silver bits Sick arthritis, spondylarthritis, asthma, inflammatory bowel disease, systemic lupus erythematosus (sle) and multiple sclerosis etc..
Therefore, suppression ROR γ t will effectively suppress THThe cell differentiation of 17, the generation of regulation and control IL-17 cytokine and secretion Level, thus regulate and control body immune system, treatment related immune and inflammatory diseases.
Brief summary of the invention
Hereinafter some aspects of the present invention are only summarized, it is not limited to this.These aspects and other parts are later There is more complete explanation.All lists of references in this specification are incorporated in this by entirety.Work as the disclosure of the specification With quote document variant time, be as the criterion with the disclosure of the specification.
The invention provides a class and there is relevant lonely nuclear receptor γ t (the Retinoid-related orphan of retinoic acid Receptor gamma t, ROR γ t) compound of inhibitory activity, for preparing prevention or treatment by the inflammation of ROR γ t mediation Or the medicine of autoimmune disease, such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle), multiple sclerosis, inflammation Property enteropathy, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or mucocutaneous lymphnode syndrome etc.；The compounds of this invention can press down well ROR γ t processed, has excellent physicochemical property and pharmacokinetic property simultaneously.
The preparation method that present invention provides these compounds and the pharmaceutical composition that comprises these compounds and make The method treating the above-mentioned disease of mammal, the especially mankind by these compounds or compositions.
Specifically:
On the one hand, the present invention relates to the stereoisomerism of compound shown in a kind of compound as shown in formula (I) or formula (I) Body, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable Salt or its prodrug,
Wherein:
W ring is phenyl ring, naphthalene nucleus, pyrrole ring, furan nucleus, thiphene ring, pyrazole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine Ring, pyrazine ring, pyridazine ring, quinoline ring or indole ring；
L is-C (=O)-N (R4)-CR5R6-、-N(R7)-C (=O)-CR8R9-or-N (R10)-CR11R12-；
R4、R7And R10It is each independently hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl or C1-6Hydroxy alkyl；R5、R6、R8、 R9、R11And R12It is each independently hydrogen, deuterium, hydroxyl, halogen atom, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkane Epoxide, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Alkoxy-C1-6Alkyl-, C3-6Carbocylic radical or C3-6Halo carbocylic radical；Or R5 And R6、R8And R9、R11And R12With and they carbon atoms of being jointly connected together with form C3-6Carbocyclic ring or C2-6Heterocycle；
A is-S (O)2-R14；Wherein, R14For ethyl；
R1And R2It is each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Alkyl halide Base, C1-6Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxy-C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo Carbocylic radical, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxy-C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo carbocylic radical, C2-9Heterocycle Base, C6-10Aryl and C1-9Heteroaryl individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, nitro, cyanogen Base, amino, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl and C1-6The group of alkoxyl is replaced；Or,
R1、R2And form C together with the carbon atom being jointly connected with them3-6Carbocyclic ring or C2-6Heterocycle；Described C3-6Carbocyclic ring and C2-6Heterocycle individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, amino, nitro, cyano group, methyl and The group of trifluoromethyl is replaced；
Each R3Independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6 Alkoxyl, C1-6Halogenated alkoxy, C1-6Hydroxy alkyl or C1-6Alkylamino；
T ring is C3-10Carbocyclic ring, C2-9Heterocycle, C6-10Aromatic ring or C1-9Hetero-aromatic ring；
Each J independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl alkane Base, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbocyclic ring, aldehyde radical or carboxyl；
R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl or C1-6 Alkylamino；
M is 0,1,2,3 or 4；With
N is 0,1,2 or 3.
In certain embodiments, R5、R6、R8、R9、R11And R12It is each independently hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, iodine, first Base, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group, difluoromethyl epoxide, three Methyl fluoride epoxide, methylamino, dimethylamino, methyl epoxide methyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；Or R5And R6、 R8And R9、R11And R12With and they carbon atoms of being jointly connected together with form cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, epoxy Ethyl group, tetrahydrofuran base or pyrrolidinyl；
Each R3Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano group, methyl, ethyl, n-pro-pyl, different Propyl group, difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro-methoxy, trifluoromethoxy, hydroxyl first Base, 2-hydroxyethyl, methylamino, dimethylamino or diethylamino.
In certain embodiments, R1And R2It is each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-3 Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkoxy-C1-3Alkyl-, C3-6Carbon Ring group, C3-6Halo carbocylic radical, C2-6Heterocyclic radical, C6-10Aryl or C1-5Heteroaryl；Described C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkoxy-C1-3Alkyl-, C3-6Carbocylic radical, C3-6Halo carbocyclic ring Base, C2-6Heterocyclic radical, C6-10Aryl and C1-5Heteroaryl individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl Base, nitro, cyano group, amino, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl and C1-3The group of alkoxyl is replaced；Or Person,
R1、R2And form C together with the carbon atom being jointly connected with them3-6Carbocyclic ring or C2-6Heterocycle；Described C3-6Carbocyclic ring and C2-6Heterocycle individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, amino, nitro, cyano group, methyl and The group of trifluoromethyl is replaced.
In further embodiments, R1And R2It is each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyanogen Base, methyl, ethyl, n-pro-pyl, isopropyl, trifluoromethyl, hydroxymethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro first Epoxide, trifluoromethoxy, methoxy, acetyl group, carboxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 2-hydroxyl ring third Base, Oxyranyle, azepine butane group, pyrrolidinyl, tetrahydrofuran base, piperazinyl, morpholinyl, phenyl, pyrrole radicals, thiophene Base, furyl, imidazole radicals, oxazolyl, pyridine radicals or pyrimidine radicals；Or R1、R2With and they carbon atoms of being jointly connected together with group Become cyclopropane, Tetramethylene., oxirane, azepine butane or expoxy propane.
In certain embodiments, T ring is C3-6Carbocyclic ring, C2-6Heterocycle, C6-10Aromatic ring or C1-5Hetero-aromatic ring；
Each J independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxyl alkane Base, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbocyclic ring, aldehyde radical or carboxyl；
R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, C1-3Alkyl, C1-3Haloalkyl, C1-3Alkoxyl or C1-3 Alkylamino.
In further embodiments, T ring is cyclopropane, Tetramethylene., Pentamethylene., hexamethylene, azetidine, tetrahydrochysene furan Mutter, pyrrolidine, piperidines, piperazine, morpholine, Pentamethylene oxide., thiomorpholine, pyrroles, thiophene, furan, imidazoles, oxazole, thiazole, pyrrole Pyridine, pyrimidine, pyrazine, pyridazine, benzene, naphthalene or 3,4-dihydro-2H-benzo [b] [1,4] piperazine；
Each J independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano group, methyl, ethyl, n-pro-pyl, isopropyl, Methylol, 1-ethoxy, 2-ethoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxyl group, isopropyl epoxide, Difluoro-methoxy, trifluoromethoxy, methylamino, dimethylamino ,-C (=O)-R15、-S(O)2-R16, cyclopropyl, cyclobutyl, ring penta Base, cyclohexyl, aldehyde radical or carboxyl；
R15And R16Be each independently hydrogen, deuterium, hydroxyl, amino, methyl, ethyl, n-pro-pyl, isopropyl, difluoromethyl, Trifluoromethyl, methoxyl group, isopropyl epoxide, methylamino, dimethylamino or diethylamino.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound shown in formula (I) of the present invention or it is three-dimensional Isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or their prodrug, and pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof；
Described pharmaceutical composition comprise further other preventions or treatment inflammatory syndrome, obstacle or the medicine of disease or Their combination in any.
On the other hand, the present invention relates to compound shown in formula (I) or its pharmaceutical composition purposes in preparing medicine, institute State medicine for preventing or treating mammal, including the mankind by the inflammation of ROR γ t mediation or autoimmune disease.
In certain embodiments, the present invention relates to compound or its pharmaceutical composition shown in formula (I) in preparing medicine Purposes, described medicine be used for preventing or treat psoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle), multiple sclerosis, Inflammatory bowel, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or mucocutaneous lymphnode syndrome.
On the other hand, the present invention relates to the preparation of compound shown in formula (I), separation and the method for purification.
Biological results shows, the compound that the present invention provides has preferable inhibitory activity to ROR γ t, has simultaneously There is good Pharmacokinetic Characteristics.
Any embodiment of the either side of the present invention, can be combined with other embodiment, as long as they are not There will be contradiction.Additionally, in any embodiment of either side of the present invention, it is real that arbitrary technical characteristic goes for other Execute this technical characteristic in scheme, as long as they do not have contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
Certain embodiments of the present invention be will now be described in more detail, and the example is by the structural formula enclosed and chemical formula explanation.This Invention intention contains all of replacement, amendment and equivalent technical solutions, and they are included in such as the present invention of claim definition In the range of.Those skilled in the art will appreciate that many similar with the described herein or method of equivalent and material can be used in reality Trample the present invention.The present invention is not limited to method described herein and material.At the document combined, patent and similar material one Or many different from the application or conflicting in the case of (include but not limited to defined term, term application, described Technology, etc.), be as the criterion with the application.
It will further be appreciated that some feature of the present invention, for clearly visible, carry out in multiple independent embodiments Describe but it also may provide in combination in single embodiment.Otherwise, the various features of the present invention, for brevity, Single embodiment is described but it also may individually or with the sub-portfolio being arbitrarily suitable for provide.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's It is generally understood that identical implication.The all patents that the present invention relates to and public publication are integrally incorporated this by reference Bright.
Unless otherwise indicated, it should apply following definition used herein.For purposes of the present invention, chemical element with Periodic table of elements CAS version, and " Handbook of Chemistry and Physics ", the 75th edition, 1994 is consistent.Additionally, organic chemistry General Principle can be joined Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Description in Wiley&Sons, NewYork:2007, entire contents is incorporated herein by.
Context except as otherwise noted or has significantly conflict, article used herein " ", " one (kind) " " described " is intended to include " at least one " or " one or more ".Therefore, these articles used herein refer to one or The article of more than one (i.e. at least one) object.Such as, " component " refers to one or more component, it is possible to have more than one Component be taken into account in the embodiment of described embodiment and use or use.
Term used in the present invention " study subject " refers to animal.Typical described animal is mammal.Tested right As, the most also refer to primate (the such as mankind, sex), cattle, sheep, goat, horse, dog, cat, rabbit, rat, little Mus, fish, bird etc..In certain embodiments, described study subject is primate.In other embodiments, described it is subject to Try liking people.
Term used in the present invention " patient " refers to people's (including adult and child) or other animals.Implement at some In scheme, " patient " refers to people.
It is open language that term " comprises ", i.e. includes the content specified by the present invention, but is not precluded from otherwise Content.
" stereoisomer " refers to have identical chemical constitution, but the change that atom or group spatially arrangement mode is different Compound.Stereoisomer includes enantiomer, diastereomer, conformer (rotamer), geometric isomer (cis/trans) isomer, atropisomer, etc..
" chirality " is that have can not the molecule of overlapping character with its mirror image；And " achirality " refer to can be overlapping with its mirror image Molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror image relationship.
" diastereomer " refers to two or more chiral centre and the stereoisomerism of its molecule mirror image the most each other Body.Diastereomer has different physical propertys, such as fusing point, boiling point, spectral quality and reactivity.Diastereomer mixes Compound can be separated by high resolution analysis operation such as electrophoresis and chromatograph, such as HPLC.
Stereochemical definitions used in the present invention and rule typically follow S.P.Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York；and Eliel, E.and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley&Sons, Inc., New York, 1994.
Many organic compound exist with optical active forms, and i.e. they have and make the plane of linearly polarized light rotate Ability.When describing optically active compound, prefix D and L or R and S is used to represent that molecule is about one or more hands The absolute configuration at property center.Prefix d and l or (+) and (-) are the symbols rotated for linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix for (+) or the compound of d be dextrorotation.A kind of concrete stereoisomerism Body is enantiomer, and the mixture of this isomer is referred to as enantiomeric mixture.The 50:50 mixture of enantiomer Be referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereo selectivity or stereospecificity time, May occur in which this situation.
Come into the open any asymmetric atom (such as, carbon etc.) of compound of the present invention can be enriched with raceme or enantiomer Presented in, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration aspect there is at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomer mistake Amount, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomer Excess.
According to starting material and the selection of method, the compounds of this invention can with in possible isomer or they Mixture, the such as form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) is deposited ?.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent to prepare, or use routine techniques to tear open Point.If compound contains a double bond, substituent group may be E or Z configuration；If containing dibasic cycloalkanes in compound Base, the substituent group of cycloalkyl may have cis or trans configuration.
The mixture of any stereoisomer of gained can be separated into according to the difference in component physicochemical properties Pure or the purest geometric isomer, enantiomer, diastereomer, such as, by chromatography and/or fractional crystallization Method.
By known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art The method being familiar with splits into optical antipode, e.g., by separating its diastereoisomeric salt obtained.Racemic product Thing can also be separated by chiral chromatogram, e.g., uses the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomer can be prepared by asymmetric synthesis, such as, refers to Jacques, et al., Enantiomers, Racemates and Resolutions(Wiley Interscience,New York,1981)；Principles of Asymmetric Synthesis(2ndEd.Robert E.Gawley,JeffreyAubé,Elsevier,Oxford,UK,2012)；Eliel, E.L.Stereochemistry ofCarbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany, 2007)。
As described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as General formula compound above, or as example special inside embodiment, subclass, and the compounds that the present invention is comprised.
It is said that in general, term " substituted " represents that the one or more hydrogen atoms in given structure are taken by concrete substituent group Generation.Unless other aspects show, a substituted group can have a substituent group to carry out in each commutable position of group Replace.When in given structural formula, more than one position can be selected from one or more substituent groups of concrete group and replaced, So substituent group can replace in each position identical or differently.
Term " unsubstituted ", represents and specifies group without substituent group.
Term " optionally by ... replaced ", can with term " unsubstituted or quilt ... replaced " exchange use, i.e. Described structure is unsubstituted or is replaced by one or more substituent groups of the present invention.Substituent group bag of the present invention Include, but be not limited to D, oxo (=O), F, Cl, Br, I, N3、CN、NO2、OH、SH、NH2, carboxyl, aldehyde radical, alkyl, haloalkyl, Thiazolinyl, alkynyl, alkoxyl, halogenated alkoxy, alkyl amino, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, etc..
In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode used in the present invention " each ... to independently be " and " ... be each independently " and " ... independently be " can exchange, and all should be interpreted broadly, and it both may be used To refer in different groups, do not affect mutually between concrete option expressed between same-sign, it is also possible to represent in phase In same group, do not affect mutually between concrete option expressed between same-sign.
At each several part of this specification, the come into the open substituent group of compound of the present invention is open according to radical species or scope.Special Not pointing out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.Such as, term “C1-6Alkyl " refer in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
At each several part of the present invention, describe connection substituent group.When this structure clearly needs linking group, for this Ma Kushi variable cited by group is interpreted as linking group.Such as, if this structure needs linking group and for this The Ma Kushi group definition of variable lists " alkyl " or " aryl ", then it should be understood that should " alkyl " or " aryl " represent respectively The alkylidene group connected or arylene group.
Terminology used in the present invention " alkyl " or " alkyl group ", represent saturated straight or branched univalent hydrocarbyl group, Wherein, the substituent group that described alkyl group can optionally be described by one or more present invention replaces.Unless it is the most detailed Illustrating, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；At another In embodiment, alkyl group contains 3-12 carbon atom；In another embodiment, alkyl group contains 1-6 carbon atom； In yet another embodiment, alkyl group contains 1-3 carbon atom.
The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-pro-pyl (n- Pr、-CH2CH2CH3), isopropyl (i-Pr ,-CH (CH3)2), normal-butyl (n-Bu ,-CH2CH2CH2CH3), isobutyl group (i-Bu ,- CH2CH(CH3)2), sec-butyl (s-Bu ,-CH (CH3)CH2CH3), the tert-butyl group (t-Bu ,-C (CH3)3), n-pentyl (- CH2CH2CH2CH2CH3), 2-amyl group (-CH (CH3)CH2CH2CH3), 3-amyl group (-CH (CH2CH3)2), 2-methyl-2-butyl (-C (CH3)2CH2CH3), 3-methyl-2-butyl (-CH (CH3)CH(CH3)2), 3-methyl isophthalic acid-butyl (-CH2CH2CH(CH3)2), 2-first Base-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3)(CH2CH2CH3)), 2-methyl-2-amyl group (-C (CH3)2CH2CH2CH3), 3-first Base-2-amyl group (-CH (CH3)CH(CH3)CH2CH3), 4-methyl-2-amyl group (-CH (CH3)CH2CH(CH3)2), 3-methyl-3-penta Base (-C (CH3)(CH2CH3)2), 2-methyl-3-amyl group (-CH (CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C (CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH (CH3)C(CH3)3), n-heptyl, n-octyl, etc..
Term " alkylidene " represents remove obtained by two hydrogen atoms from saturated straight or branched alkyl saturated Bivalent hydrocarbon radical group.Unless otherwise detailed instructions, alkylidene group contains 1-12 carbon atom.In one embodiment, alkylene Base group contains 1-6 carbon atom；In another embodiment, alkylidene group contains 1-4 carbon atom；Another embodiment party In case, alkylidene group contains 1-3 carbon atom；The most in one embodiment, alkylidene group contains 1-2 carbon atom.This The example of sample includes methylene (-CH2-), ethylidene (-CH2CH2-), isopropylidene (-CH (CH3)CH2-) etc..
Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.An embodiment party In case, alkoxy base contains 1-6 carbon atom；In another embodiment, alkoxy base contains 1-4 carbon atom；? In another embodiment, alkoxy base contains 1-3 carbon atom.Described alkoxy base can be the most one or more The substituent group that the present invention describes is replaced.
The example of alkoxy base includes, but is not limited to, methoxyl group (MeO ,-OCH3), ethyoxyl (EtO ,- OCH2CH3), 1-propoxyl group (n-PrO, n-propoxyl group ,-OCH2CH2CH3), 2-propoxyl group (i-PrO, i-propoxyl group ,-OCH (CH3)2), 1-butoxy (n-BuO, n-butoxy ,-OCH2CH2CH2CH3), 2-methyl-l-propoxyl group (i-BuO, i-fourth oxygen Base ,-OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH3)CH2CH3), 2-methyl-2-propoxyl group (t- BuO, t-butoxy ,-OC (CH3)3), 1-amoxy (n-amoxy ,-OCH2CH2CH2CH2CH3), 2-amoxy (-OCH (CH3) CH2CH2CH3), 3-amoxy (-OCH (CH2CH3)2), 2-methyl-2-butoxy (-OC (CH3)2CH2CH3), 3-methyl-2-fourth Epoxide (-OCH (CH3)CH(CH3)2), 3-methyl-l-butoxy (-OCH2CH2CH(CH3)2), 2-methyl-l-butoxy (- OCH2CH(CH3)CH2CH3), etc..
Term " alkyl amino " includes " N-alkyl amino " and " N, N-dialkyl amido ", and wherein amino group is independently Ground is replaced by one or two alkyl group；Described alkyl has implication described in the invention.Some of them embodiment is, Alkyl amino is one or two C1-6What alkyl was connected on nitrogen-atoms to be formed the alkylamino group of lower level.Other one A little embodiments are that alkyl amino is one or two C1-3The alkyl of lower level be connected on nitrogen-atoms the alkyl amino that formed Group.Suitably alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but do not limits In, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-lignocaine etc..
Term " haloalkyl ", " halogenated alkoxy " or " haloalkylamino " represents alkyl, alkoxyl or alkyl amino Group is replaced by one or more halogen atoms, wherein alkyl, and alkoxyl or alkylamino group have as described herein Implication, such example comprises, but is not limited to, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyls, 2,2,3,3-tetra- Fluoropropyl, difluoro-methoxy, trifluoromethoxy, trifluoromethyl amino etc..
Term " hydroxy alkyl " represents that alkyl group is replaced by one or more hydroxyls, and wherein alkyl group has such as this Implication described in invention, such example comprises, but is not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl etc..
Term " alkoxyalkyl " represents that alkoxy base is connected with molecule remainder by alkyl, wherein alkoxyl with Alkyl group has implication as described in the present invention.Such example comprises, but is not limited to, methoxy, (ethoxymethyl) Base, i-propoxymethyl, 1-methoxy ethyl, 2-methoxy ethyl etc..
Term " cycloalkyl " represents containing 3-12 carbon atom, unit price or the saturated monocycle of multivalence, dicyclo or three rings Hydrocarbyl group.In one embodiment, cycloalkyl comprises 7-12 carbon atom；In yet another embodiment, cycloalkyl comprises 3-8 Individual carbon atom；In yet another embodiment, cycloalkyl comprises 3-6 carbon atom.Described group of naphthene base can the most not by Replace or replaced by one or more substituent groups described in the invention.
Term " carbocyclic ring " or " carbocylic radical " expression contain the nonaromatic saturated of 3-12 carbon atom, unit price or multivalence Or the unsaturated monocycle of part, dicyclo or the hydrocarbyl group of three rings.Carbon bicyclic group includes spiral shell carbon bicyclic group and condenses carbon bicyclic group, Suitably carbocylic radical group includes, but is not limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.In one embodiment, carbocylic radical bag Containing 3-10 carbon atom；In one embodiment, carbocylic radical comprises 3-8 carbon atom；In yet another embodiment, carbocylic radical bag Containing 3-6 carbon atom.The example of carbocylic radical group farther includes, cyclopropyl, cyclobutyl, cyclopenta, 1-cyclopenta-1-alkene Base, 1-cyclopenta-2-thiazolinyl, 1-cyclopenta-3-thiazolinyl, cyclohexyl, 1-cyclohexyl-1-thiazolinyl, 1-cyclohexyl-2-thiazolinyl, 1- Cyclohexyl-3-thiazolinyl, cyclohexadienyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl, etc. Deng.Described carbocylic radical group can be the most unsubstituted or replaced by one or more substituent groups described in the invention.
Term " heterocyclic radical " and " heterocycle " are used interchangeably herein, all referring to comprising the saturated of 3-12 annular atoms or portion Dividing undersaturated nonaromatic unit price or multivalence monocycle, dicyclo or three rings, at least one of which annular atoms is selected from nitrogen, sulfur and oxygen Atom；Heterocyclic radical includes spiro heterocyclic radical and annelated heterocycles base.Wherein, in some embodiments, 3-12 ring of heterocyclic radical is former Containing 2-9 carbon atom in son；In other embodiment, containing 2-8 carbon atom in 3-12 annular atoms of heterocyclic radical； In other embodiment, containing 2-6 carbon atom in 3-12 annular atoms of heterocyclic radical；In other embodiment, Containing 2-5 carbon atom in 3-12 annular atoms of heterocyclic radical.Unless otherwise indicated, heterocyclic radical can pass through carbon atom and molecule In other groups connect, it is also possible to be connected with other groups in molecule by nitrogen-atoms, and-CH2-group can be optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.The example of heterocyclic radical includes, but are not limited to: Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring Butyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrochysene Furyl, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3-dioxy cyclopenta, two sulfur cyclopenta, THP trtrahydropyranyl, Dihydro pyranyl, 2H-pyranose, 4H-pyranose, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, two Alkyl, dithiane base, thiophene alkyl, homopiperazine base, homopiperidinyl, Diazesuberane base, oxepane alkyl, thia ring Heptane base, oxygen azepineBase, diazaBase, sulfur azepineBase, 2-oxa--5-azabicyclo [2.2.1] hept-5-base.Heterocyclic radical In-CH2-group is included, but not limited to 2-oxo-pyrrolidine base, oxo-1,3-thiazoles alkane by the example of-C (=O)-replacement Base, 2-piperidone base, 3,5-dioxy piperazine piperidinyl and hybar X base.The example that in heterocyclic radical, sulphur atom is oxidized includes, but It is not limited to, sulfolane base, 1,1-dioxothiomorpholinyl.Described heterocyclyl groups can be optionally by one or more Substituent group described by invention is replaced.
Term " t former molecular ", wherein t is integer, typically describes the number of ring member nitrogen atoms in molecule, described In molecule, the number of ring member nitrogen atoms is t.Such as, piperidyl is 6 former molecular heterocyclic radicals, and decahydro naphthyl is 10 atoms The carbocylic radical group of composition.
The term " undersaturated " used in the present invention represents in group containing one or more degrees of unsaturation.
Term " hetero atom " refers to O, S, N, P and Si, including the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that in heterocycle, the hydrogen on nitrogen-atoms is replaced, such as, N is (as 3, in 4-dihydro-2 h-pyrrole base N), NH (NH as in pyrrolidinyl) or NR (NR as in the substituted pyrrolidinyl of N-).
Term " halogen " or " halogen atom " refer to fluorine atom (F), chlorine atom (Cl), bromine atoms (Br) or atomic iodine (I).
Term " cyano group " or " CN " represent a cyano group structure, and this group can be connected with other groups.
Term " nitro " or " NO2" representing a nitro structure, this group can be connected with other groups.
Term " aryl " represents containing 6-14 annular atoms, or 6-12 annular atoms, or the monocycle of 6-10 annular atoms, double Ring or the full carbocyclic ring system of three rings, wherein, at least one ring is aromatic, and has one or more attachment point and molecule its Remaining part split-phase is even.Term " aryl " can use with term " aromatic rings " exchange.In one embodiment, aryl is by 6-10 Annular atoms forms, and at least a part of which contains the carbocyclic ring system of an aromatic rings.The example of aromatic yl group can include phenyl, naphthalene Base and anthryl.Described aromatic yl group can be replaced by one or more substituent groups described in the invention individually optionally.
Term " heteroaryl " represents containing the monocycle of 5-12 annular atoms, dicyclo or three rings, and at least one of which ring is virtue Fragrant race, and at least one ring comprises one or more hetero atom, and have one or more attachment point and molecule remainder phase Even.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.Wherein, in some embodiments In, containing 1-9 carbon atom in 5-12 annular atoms of heteroaryl；In other embodiment, 5-12 ring of heteroaryl Containing 1-7 carbon atom in atom；In other embodiment, former containing 1-5 carbon in 5-12 annular atoms of heteroaryl Son；Described heteroaryl groups is optionally replaced by one or more substituent groups described in the invention.In one embodiment, Heteroaryl is the heteroaryl comprising 1,2,3 or 4 heteroatomic 5-12 annular atoms compositions being independently selected from O, S and N；At another In embodiment, heteroaryl is comprise 1,2,3 or 4 heteroatomic 5-6 annular atoms compositions being independently selected from O, S and N miscellaneous Aryl.
The example of heteroaryl groups includes, but is not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazole radicals, 4-imidazole radicals, 5-imidazole radicals, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-azoles Base, di azoly (such as 1,2,3-di azoly, 1,2,5-di azoly, 1,2,4-di azoly), triazolyl (such as 1,2,3, 4-triazolyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, isothiazolyl, 2-thiadiazolyl group (as 1,3,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, 1,2,5-thiadiazolyl group), thiatriazole base (such as 1,2,3,4-thiatriazole base), tetrazole radical (such as 2H-1,2, 3,4-tetrazole radical, 1H-1,2,3,4-tetrazole radical), triazolyl (such as 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1, 2,4-triazolyl), 2-thienyl, 3-thienyl, 1H-pyrazolyl (as 1H-pyrazole-3-yl, 1H-pyrazoles-4-base, 1H-pyrazoles- 5-yl), 1,2,3-thio biphosphole base, 1,3,4-thio biphosphole base, 1,2,5-thio biphosphole base, N-pyrrole radicals, 2-pyrrole radicals, 3- Pyrrole radicals, 2-pyridine radicals, 3-pyridine radicals, 4-pyridine radicals, 2-pyrimidine radicals, 4-pyrimidine radicals, 5-pyrimidine radicals, pyridazinyl are (such as 3-pyridazine Base, 4-pyridazinyl), 2-pyrazinyl, triazine radical (such as 1,3,5-triazine), tetrazine base is (such as 1,2,4,5-tetrazine, 1,2,3,5-tetra- Piperazine)；Also include following dicyclo, but be not limited to these dicyclos: benzimidazolyl, benzofuranyl, benzothienyl, indole Base (such as 2-indyl), purine radicals, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl are (such as 1-isoquinoline Quinoline base, 3-isoquinolyl or 4-isoquinolyl), imidazo [1,2-a] pyridine radicals, pyrazolo [1,5-a] pyridine radicals, pyrazolo [1,5-a] pyrimidine radicals, imidazo [1,2-b] pyridazinyl, [1,2,4] triazol [4,3-b] pyridazinyl, [1,2,4] triazol [1, 5-a] pyrimidine radicals, [1,2,4] triazol [1,5-a] pyridine radicals, etc..
Term " carboxyl ", is either used alone and is still used in conjunction, such as " carboxyl ", expression-CO with other terms2H；Term " carbonyl ", is either used alone and is still used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represent-(C=O)-.
As described in the invention, substituent group draws the member ring systems formed on a ring being bonded the center of receiving (such as formula b institute Show) represent substituent group any commutable position on this ring and can replace.Such as, formula b represent substituent R can be on C ring On any position that may be replaced monosubstituted or polysubstituted, as shown in formula c1～formula c19.
As described in the invention, a connecting key is connected to member ring systems (as shown in the formula d) generation formed in the heart in ring Table connecting key can be connected with molecule remainder any attachable position in member ring systems.Formula d represents any possibility on D ring The position connected all can be connected with molecule remainder.
The when that term " blocking group " or " PG " referring to a substituent group and other reacted with functional groups, it is commonly used to resistance Disconnected or protect special functional.Such as, " blocking group of amino " refers to that a substituent group is connected with amino group and blocks Or amino functional in protection compound, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9-fluorenes Asia methoxycarbonyl group (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent group of base is used for blocking or protect the functional of hydroxyl, suitable blocking group to include acetyl group and silicyl." carboxyl Blocking group " refer to the substituent group of carboxyl for blocking or protect the functional of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2-(TMS) ethyl, 2-(TMS) ethoxyl methyl, 2-is (to toluene Sulfonyl) ethyl, 2-(p-nitrophenyl sulfonyl) ethyl, 2-(diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The description that group is general refers to document: T W.Greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme, Stuttgart,2005.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo. Such conversion is hydrolyzed in blood by prodrug or is that precursor structure is affected through enzymatic conversion in blood or tissue.This Bright prodrug compounds can be ester, and in existing invention, ester can have phenyl ester class, aliphatic as prodrug (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as in the present invention one Compound comprises hydroxyl, i.e. can be acylated the compound obtaining prodrug form.Other prodrug form includes Phosphate ester, if these phosphate compounds are that the di on parent obtains.About complete the begging for of prodrug Discuss and be referred to documents below: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
" metabolite " refers to that concrete compound or its salt is in vivo by the product obtained by metabolism.One change The metabolite of compound can be identified by technology known to art, and its activity can be retouched by such as the present invention Adopt as stating and experimentally characterize.Such product can be by passing through oxidation, reduction, water to drug compound Solving, amidated, desamido-effect, esterification, degreasing, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes compound Metabolite, be fully contacted metabolite produced by a period of time including by the compound of the present invention and mammal.
" pharmaceutically acceptable salt " used in the present invention refers to organic salt and the inorganic salt of the compound of the present invention.Medicine On, acceptable salt is known to us at art, such as document: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, with amino base The inorganic acid salt that group's reaction is formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange obtain these salt.Other pharmaceutically acceptable salts include adipate, alginate, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, Camphora sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxy-ethanesulfonic acid Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2-naphthalene sulfonate, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, special penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By suitable alkali The salt obtained includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any comprised N's The quaternary ammonium salt that the compound of group is formed.Water solublity or oil-soluble or dispersion product can be obtained by quaternization.Alkali Metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..It is suitable, nontoxic that pharmaceutically acceptable salt farther includes Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, hydrosulphate, phosphoric acid Compound, nitric acid compound, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
" solvate " of the present invention refers to the association that the compound of one or more solvent molecule and the present invention is formed Thing.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, second Acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
When described solvent is water, it is possible to use term " hydrate ".In certain embodiments, a compounds of this invention Molecule can combine with a hydrone, such as monohydrate；In other embodiment, a compounds of this invention divides Son can combine with more than one hydrone, such as dihydrate, in further embodiments, and a compounds of this invention Molecule can combine with the hydrone less than, such as semihydrate.It should be noted that hydrate of the present invention remains with The biological effectiveness of the described compound of nonhydrated form.
As used in the present invention any disease or disease " treated " in term, refer to all can to slow down, interrupt, stop, Controlling or stop disease or the progress of disease, but not necessarily representing that the symptom of all diseases or disease all disappears, it also includes Prophylactic treatment to described symptom, especially in easily suffering from the patient of such disease or obstacle.Some are implemented wherein Scheme middle finger improves disease or disease (i.e. slow down or stop or palliate a disease or the development of its at least one clinical symptoms).Separately In some embodiments, " treatment " refers to relax or improve at least one body parameter, including the body may not discovered by patient Body parameter.In other embodiments, " treat " and refer to (such as stablize perceptible symptom) from health or physiologically (example Parameter such as stable health) or above-mentioned two in terms of regulate disease or disease.In other embodiments, " treat " refer to prevention or Postpone disease or the outbreak of disease, occur or deteriorate.
Term " therapeutically effective amount " or " treatment effective dose " refer to cause individual life as used in the present invention Thing or medicinal response (such as reduce or inhibitory enzyme or protein active, or improve symptom, alleviate disease, slow down or postpone disease Sick development, or prevention disease etc.) the amount of the compounds of this invention.In the embodiment of an indefiniteness, " treatment has term Effect amount " refer to when using the compounds of this invention to individuality, amount effective to situations below: (1) is alleviated at least in part, pressed down Make, prevent and/or improve (i) to be mediated by ROR γ t, or (ii) is relevant to ROR γ t activity, or (iii) is by ROR γ t's The disease of abnormal activity sign or disease；Or (2) reduce or suppress the activity of ROR γ t；Or (3) reduce or suppress ROR γ The expression of t.In another embodiment, term " therapeutically effective amount " refers to when to cell or organ or acellular organism thing When matter or medium are used, can reduce or suppress ROR γ t activity at least in part；Or reduce at least in part or suppress ROR The amount of the effective the compounds of this invention that γ t expresses.
Term compound " gives " and " administration " compound should be understood to needing the individual of its as used in the present invention Body provides compound or the prodrug of the compounds of this invention of the present invention.Will be appreciated that those skilled in the art are by using effectively The compounds of this invention treatment of amount suffers from the patient of this obstacle at present or prophylactically treats the patient suffering from this obstacle.
Term " compositions " refers to the product of the predetermined component comprising ormal weight, and ormal weight as used in the present invention The spawn that produces directly or indirectly of the combination of predetermined component.The implication of this term relevant to pharmaceutical composition Including the product of the inert fraction (single or multiple) comprising active component (single or multiple) and composition carrier, Yi Jiyou Any two or Multiple components mixing, compound or gathering, or by one or more ingredient breakdown, or become by one or more Point other kinds of reaction or interaction and the spawn that directly or indirectly produces.Therefore, pharmaceutical composition of the present invention Including any compositions prepared by the compounds of this invention is mixed with pharmaceutically suitable carrier.
The description of the compound of the present invention
The invention discloses (miscellaneous) aromatic ring analog derivative of a class carboxylic acid-substituted, its pharmaceutically acceptable salt, medicine system Agent and combinations thereof thing, can be as ROR γ t inhibitor, to the inflammation mediated by ROR γ t or autoimmune disease, and such as silver bits Disease, rheumatoid arthritis, systemic lupus erythematosus (sle), multiple sclerosis, inflammatory bowel, ankylosing spondylitis, asthma, bone close The treatment of joint inflammation, Crohn disease and mucocutaneous lymphnode syndrome has potential purposes.
On the one hand, the present invention relates to the stereoisomerism of compound shown in a kind of compound as shown in formula (I) or formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein:
W ring is phenyl ring, naphthalene nucleus, pyrrole ring, furan nucleus, thiphene ring, pyrazole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine Ring, pyrazine ring, pyridazine ring, quinoline ring or indole ring；
L is-C (=O)-N (R4)-CR5R6-、-N(R7)-C (=O)-CR8R9-or-N (R10)-CR11R12-；
R4、R7And R10It is each independently hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl or C1-6Hydroxy alkyl；R5、R6、R8、 R9、R11And R12It is each independently hydrogen, deuterium, hydroxyl, halogen atom, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkane Epoxide, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Alkoxy-C1-6Alkyl-, C3-6Carbocylic radical or C3-6Halo carbocylic radical；Or R5 And R6、R8And R9、R11And R12With and they carbon atoms of being jointly connected together with form C3-6Carbocyclic ring or C2-6Heterocycle；
A is-S (O)2-R14；Wherein, R14For ethyl；
R1And R2It is each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Alkyl halide Base, C1-6Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxy-C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo Carbocylic radical, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxy-C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo carbocylic radical, C2-9Heterocycle Base, C6-10Aryl and C1-9Heteroaryl individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, nitro, cyanogen Base, amino, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl and C1-6The group of alkoxyl is replaced；Or,
R1、R2And form C together with the carbon atom being jointly connected with them3-6Carbocyclic ring or C2-6Heterocycle；Described C3-6Carbocyclic ring and C2-6Heterocycle individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, amino, nitro, cyano group, methyl and The group of trifluoromethyl is replaced；
Each R3Independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6 Alkoxyl, C1-6Halogenated alkoxy, C1-6Hydroxy alkyl or C1-6Alkylamino；
T ring is C3-10Carbocyclic ring, C2-9Heterocycle, C6-10Aromatic ring or C1-9Hetero-aromatic ring；
Each J independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl alkane Base, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbocyclic ring, aldehyde radical or carboxyl；
R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl or C1-6 Alkylamino；
M is 0,1,2,3 or 4；With
N is 0,1,2 or 3.
In certain embodiments, R5、R6、R8、R9、R11And R12It is each independently hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, iodine, first Base, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group, difluoromethyl epoxide, three Methyl fluoride epoxide, methylamino, dimethylamino, methyl epoxide methyl, cyclopropyl, cyclobutyl, cyclopenta or cyclohexyl；Or R5And R6、 R8And R9、R11And R12With and they carbon atoms of being jointly connected together with form cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, epoxy Ethyl group, tetrahydrofuran base or pyrrolidinyl.
In certain embodiments, each R3Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano group, first Base, ethyl, n-pro-pyl, isopropyl, difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro-methoxy, Trifluoromethoxy, hydroxymethyl, 2-hydroxyethyl, methylamino, dimethylamino or diethylamino.
In certain embodiments, R1And R2It is each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-3 Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkoxy-C1-3Alkyl-, C3-6Carbon Ring group, C3-6Halo carbocylic radical, C2-6Heterocyclic radical, C6-10Aryl or C1-5Heteroaryl；Described C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkoxy-C1-3Alkyl-, C3-6Carbocylic radical, C3-6Halo carbocyclic ring Base, C2-6Heterocyclic radical, C6-10Aryl and C1-5Heteroaryl individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl Base, nitro, cyano group, amino, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl and C1-3The group of alkoxyl is replaced；Or Person,
R1、R2And form C together with the carbon atom being jointly connected with them3-6Carbocyclic ring or C2-6Heterocycle；Described C3-6Carbocyclic ring and C2-6Heterocycle individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, amino, nitro, cyano group, methyl and The group of trifluoromethyl is replaced.
In further embodiments, R1And R2It is each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyanogen Base, methyl, ethyl, n-pro-pyl, isopropyl, trifluoromethyl, hydroxymethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro first Epoxide, trifluoromethoxy, methoxy, acetyl group, carboxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 2-hydroxyl ring third Base, Oxyranyle, azepine butane group, pyrrolidinyl, tetrahydrofuran base, piperazinyl, morpholinyl, phenyl, pyrrole radicals, thiophene Base, furyl, imidazole radicals, oxazolyl, pyridine radicals or pyrimidine radicals；Or R1、R2With and they carbon atoms of being jointly connected together with group Become cyclopropane, Tetramethylene., oxirane, azepine butane or expoxy propane.
In certain embodiments, T ring is C3-6Carbocyclic ring, C2-6Heterocycle, C6-10Aromatic ring or C1-5Hetero-aromatic ring.
In further embodiments, T ring is cyclopropane, Tetramethylene., Pentamethylene., hexamethylene, azetidine, tetrahydrochysene furan Mutter, pyrrolidine, piperidines, piperazine, morpholine, Pentamethylene oxide., thiomorpholine, pyrroles, thiophene, furan, imidazoles, oxazole, thiazole, pyrrole Pyridine, pyrimidine, pyrazine, pyridazine, benzene, naphthalene or 3,4-dihydro-2H-benzo [b] [1,4] piperazine.
In certain embodiments, each J independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Halo Alkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbon Ring, aldehyde radical or carboxyl；
Wherein R15And R16There is implication as described in the present invention.
In further embodiments, each J independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano group, methyl, second Base, n-pro-pyl, isopropyl, methylol, 1-ethoxy, 2-ethoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, first Epoxide, isopropyl epoxide, difluoro-methoxy, trifluoromethoxy, methylamino, dimethylamino ,-C (=O)-R15、-S(O)2-R16, ring Propyl group, cyclobutyl, cyclopenta, cyclohexyl, aldehyde radical or carboxyl；
Wherein R15And R16There is implication as described in the present invention.
In certain embodiments, R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, C1-3Alkyl, C1-3Alkyl halide Base, C1-3Alkoxyl or C1-3Alkylamino.
In further embodiments, R15And R16Be each independently hydrogen, deuterium, hydroxyl, amino, methyl, ethyl, n-pro-pyl, Isopropyl, difluoromethyl, trifluoromethyl, methoxyl group, isopropyl epoxide, methylamino, dimethylamino or diethylamino.
The most in certain embodiments, the present invention relates to compound or its stereoisomer, the nitrogen oxygen of one of Compound, solvate, metabolite, pharmaceutically acceptable salt or its prodrug, but it is not limited to these compounds:
Unless otherwise mentioned, the stereoisomer of compound shown in formula (I), solvate, metabolite, salt and pharmaceutically Acceptable prodrug is intended to be included within the scope of the present invention.
On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises compound shown in formula (I) of the present invention or it is three-dimensional Isomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or their prodrug, and pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof.
In certain embodiments, pharmaceutical composition comprises other preventions or treatment inflammatory syndrome, obstacle or disease further Sick medicine or their combination in any.
In one embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray-type.
On the other hand, the present invention relates to compound shown in formula (I) or its pharmaceutical composition purposes in preparing medicine, institute State medicine for preventing or treating mammal, including the mankind by the inflammation of ROR γ t mediation or autoimmune disease.
In certain embodiments, the present invention relates to compound or its pharmaceutical composition shown in formula (I) in preparing medicine Purposes, described medicine be used for preventing or treat psoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle), multiple sclerosis, Inflammatory bowel, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or mucocutaneous lymphnode syndrome.
On the other hand, the present invention relates to the preparation of compound shown in formula (I), separation and the method for purification.
On the other hand, the present invention relates to prepare the intermediate of compound shown in formula (I).
Present invention compound of coming into the open can contain asymmetric or chiral centre, therefore can deposit by different stereoisomer forms ?.It is contemplated that all stereoisomer forms of compound shown in formula (I), include but not limited to diastereomer, Enantiomer, atropisomer and geometry (or conformation) isomer, and their mixture such as racemic mixture, become The ingredient of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicates, then this structure All stereoisomers all consider within the present invention, and be included in the invention as present invention compound of coming into the open.When Spatial chemistry is expressed the real wedge shape line (solid wedge) of particular configuration or time dotted line indicates, then the stereoisomerism of this structure Body clearly and defines with regard to this.
Compound shown in formula (I) can exist with different tautomeric forms, and all these tautomer, It is included within the scope of the present invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, described salt refers to pharmaceutically can connect The salt being subject to.Term " pharmaceutically acceptable " refers to that material or compositions must be with other compositions comprising preparation and/or use it The mammal for the treatment of is in chemistry and/or compatible in toxicology.In another embodiment, described salt is not necessarily pharmaceutically Acceptable salt, could be for preparation and/or purifies compound shown in formula formula (I) and/or be used for separating shown in Ben Shishi (I) The intermediate of the enantiomer of compound.
Pharmaceutically useful acid-addition salts can be come into the open compound and mineral acid by the present invention or organic acid effect is formed, such as acetic acid Salt, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulphuric acid Salt, camsilate, chloride/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, Gluconate, glucuronate, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, Lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoic acid The acid of salt, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor Hydrogen salt/dihydric phosphate, poly-galactose hydrochlorate, propionate, stearate, succinate, sulfosalicylate, tartrate, Toluene fulfonate and trifluoroacetate.
Pharmaceutically acceptable base addition salts can be come into the open compound and inorganic base by the present invention or organic base effect is formed.
Can be included by its derivative inorganic base obtaining salt, the metal of the I race of such as ammonium salt and periodic chart to XII race.? In some embodiment, this salt is derived from sodium, potassium, ammonium, calcium, magnesium, ferrum, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salt.
Can be included that primary amine, secondary amine and tertiary amine, substituted amine include naturally occurring by its derivative organic base obtaining salt Substituted amine, cyclic amine, deacidite etc..Some organic amine includes, such as, and 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine And trometamol.
The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. It is said that in general, such salt can free acid form Yu stoichiometry by making these compounds suitable alkali (as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need to use non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack Publishing Company, Easton, Pa., (1985)；" pharmaceutical salts handbook: character, select and apply (Handbook ofPharmaceutical Salts:Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) list of the suitable salt of other can be found in.
It addition, compound disclosed by the invention, include their salt, it is also possible to their hydrate forms or comprise it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention comes into the open compound can be with pharmacy Upper acceptable solvent (including water) inherently or passes through design forming solvate；Therefore, it is contemplated that include the present invention The compound solvation that comes into the open and unsolvated form.
Any structural formula that the present invention is given be also intended to represent these compounds not by isotope enrichment form and with The form of position element enrichment.The compound of isotope enrichment has the structure of the formula description that the present invention provides, except one or many Individual atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes in the compounds of this invention can be introduced Including the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
On the other hand, compound of the present invention includes compound defined in the present invention of isotope enrichment, such as, and its In there is radiosiotope, as3H、14C and18Those compounds of F, or wherein there is non radioactive isotope, as2H and13Those compounds of C.The compound of such isotope enrichment can be used for metabolism research and (uses14C), kinetics research (use such as2H or3H), detection or imaging technique, such as positron emission tomography (PET) or include medicine or substrate group Knit the SPECT (single photon emission computed tomography) (SPECT) of measure of spread, or can be used in the radiotherapy of patient.18The change of F enrichment Compound is especially desirable for PET or SPECT studies.Compound shown in the formula formula (I) of isotope enrichment can be by this Embodiment in routine techniques that skilled person is familiar with or the present invention and preparation process is described uses suitable isotope Labelled reagent substitutes original used unmarked reagent to be prepared.
Additionally, higher isotope particularly deuterium is (i.e.,2H or D) replacement can provide some treat advantage, these advantages are Brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index obtains improving band Come.Should be appreciated that the deuterium in the present invention is counted as the substituent group of compound shown in formula formula (I).Can use isotope enrichment because of Son defines the concentration of such higher isotope particularly deuterium.Term used in the present invention " the isotope enrichment factor " refers to institute Specify the ratio between isotopic isotope abundance and natural abundance.If the substituent group of the compounds of this invention is designated as Deuterium, this compound has at least 3500 (each specify the deuterium of 52.5% at D-atom to mix), extremely for each D-atom specified Few 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 The deuterium of 82.5% (mix), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), at least 6600 (deuterium of 99% mixes) or the isotope enrichment of at least 6633.3 (deuterium of 99.5% mixes) The factor.The pharmaceutically useful solvate of the present invention includes that wherein recrystallisation solvent can be the substituted such as D of isotope2O, acetone-d6、 DMSO-d6Those solvates.
The pharmaceutical composition of the compounds of this invention, preparation and administration
The present invention provides a kind of pharmaceutical composition, and it comprises the present invention and comes into the open listed chemical combination in compound, such as embodiment Thing；With pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof.
The present invention provides treatment, the method preventing or improving disease or disease, including giving comprising originally of safe and effective amount Disclosure of the invention compound and the combination medicine of one or more therapeutically active agents.Wherein, combination medicine comprises one or more its He prevents or treatment inflammatory syndrome, obstacle or the medicine of disease.
In pharmaceutical composition disclosed by the invention, the amount of compound refers to suppression biological specimen or patient effectively be detected The relevant lonely nuclear receptor γ t of internal retinoic acid.In the present composition, the dosage of active component can change, but, active component Amount must be the amount that can obtain appropriate dosage forms.Active component can be to provide the dosed administration of optimal drug effect in needs The patient (animal and people) of this treatment.Selected dosage depends on desired therapeutic effect, depends on route of administration and controls Treat the persistent period.Dosage will be different with patient, this attribute depending on disease and the order of severity, the weight of patient, patient Concrete diet, the medicine simultaneously used and the other factors that it will be recognized by those skilled in the art.Dosage range is usually Each patient's every day, about 0.5mg to 1.0g, can be administered with the form of single dose or multi-agent.In one embodiment, dosage range For about 0.5mg to 500mg each patient's every day；It is about 0.5mg to 200mg each patient's every day in another embodiment；? Still another embodiment is about 5mg to 50mg each patient's every day.
It will also be appreciated that some compound of the present invention can exist in a free form and be used for treating, if or suitable When can be presented in its pharmaceutically acceptable derivates.Pharmaceutically acceptable derivates includes pharmaceutically acceptable Prodrug, salt, ester, the salt of these esters, or when patient in need is administered, can directly or indirectly provide of the present inventionization Compound or its metabolite or any other adduct of residue or derivant.
Medicine disclosed by the invention or pharmaceutical composition can prepare and be packaged as (bulk) in bulk form, wherein can extract peace The compound shown in formula (I) of full effective dose, then gives patient with powder or syrup form.Generally, to arrive every day 0.0001 Dosage level between 10mg/kg body weight, to patient, is administered and effectively suppresses to make to retinoic acid relevant orphan nuclear receptor γ t to obtain With.Or, pharmaceutical composition disclosed by the invention can be prepared and be packaged as unit dosage forms, the most discrete the most each unit The compound shown in formula (I) containing safe and effective amount.When preparing with unit dosage forms, pharmaceutical composition disclosed by the invention leads to Chang Kehan, such as, the compound disclosed by the invention of 0.5mg to 1g or 1mg to 700mg or 5mg to 100mg.
When the pharmaceutical composition of the present invention in addition to containing the compounds of this invention possibly together with one or more other activity group Timesharing, the compound weight ratio of the compounds of this invention and the second active component can change and depend on the effective of every kind of component Dosage.Generally, the effective dose of every kind is used.It is therefoie, for example, when the compounds of this invention mixes with another kind of medicament, this The weight ratio of bright compound and another kind of medicament is typically about 1000: 1 to about 1: 1000, e.g., from about 200: 1 to about 1: 200.The mixture of the compounds of this invention and other active component the most within the above range, but in each case, all The effective dose of every kind of active component should be used.
The present invention " pharmaceutically acceptable excipient " used means relevant to form of administration or pharmaceutical composition concordance Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient must become with other of pharmaceutical composition when mixing Split-phase is held, and can be substantially reduced the present invention and come into the open the interaction of effect of compound and causing not during to avoid being administered patient It it is the interaction of pharmaceutically acceptable pharmaceutical composition.Additionally, every kind of excipient must be pharmaceutically acceptable, example As, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected concrete dosage form.Additionally, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.Such as, optional can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.Optional some pharmaceutically acceptable figuration that can help to produce stabilizer type Agent.Optional contribute to time patient is administered carrying or transport the present invention come into the open compound from health organ or part to Another organ of health or some pharmaceutically acceptable excipient of part.Optional some medicine strengthening patient compliance Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient: diluent, filler, binding agent, Disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, rectify Taste agent, odor mask, coloring agent, anticaking agent, wetting agent, chelating agen, plasticiser, viscosifier, antioxidant, preservative, stable Agent, surfactant and buffer agent.Technical staff it can be appreciated that, some pharmaceutically acceptable excipient can provide more than one Function, and alternative function is provided, this depend on preparation exists which there is in how many these excipient and preparation other Excipient.
Technical staff grasps the knowledge and skills of this area, so that they can select the suitable of the appropriate amount for the present invention Pharmaceutically acceptable excipient.Additionally, there are the obtainable resource of a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and be used for selecting suitable pharmaceutically acceptable excipient.Example includes Remington's Pharmaceutical Sciences(Mack Publishing Company),The Handbook of Pharmaceutical Additives(Gower Publishing Limited),and The Handbook of Pharmaceutical Excipients(theAmerican Pharmaceutical Association and the Pharmaceutical Press)。
At Remington:The Science and Practice ofPharmacy, 21st edition, 2005, ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker, New York discloses the various carriers for configuring pharmaceutically acceptable compositions, and is used for what it was prepared Known technology, the respective content of these documents is incorporated by reference into the present invention.Except any such as because producing any less desirable life Thing effect, or so that other composition any in harmful way and pharmaceutically acceptable compositions occurs to interact and the present invention Outside any commonly employed carrier that compound of coming into the open is incompatible, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention uses technology well known by persons skilled in the art and method to prepare.This area The description of some common methods can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company)。
Therefore, on the other hand, the present invention relates to prepare the technique of pharmaceutical composition, described pharmaceutical composition comprises the present invention Come into the open compound and pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof, and this technique includes mixing various one-tenth Point.Comprise the present invention to come into the open the pharmaceutical composition of compound, can mix under such as ambient temperature and atmospheric pressure and prepare.
Compound disclosed by the invention is usually formulated as being adapted to pass through the dosage form that patient is administered by required approach.Example As, dosage form includes that those are suitable for the dosage form of following route of administration: (1) oral administration, such as tablet, capsule, caplet agent, ball Agent, containing tablet, powder, syrup, elixir, suspensoid, solution, Emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, suspensoid and redissolution powder；(3) transdermal administration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) topical, such as ointment, ointment, lotion, molten Liquor, paste, spray, foam and gel.
In one embodiment, compound disclosed by the invention can be configured to peroral dosage form.In another embodiment, Compound disclosed by the invention can be configured to inhalant dosage form.In another embodiment, compound disclosed by the invention is permissible It is configured to nose administration dosage form.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. The most in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
The present invention provide pharmaceutical composition can with compressed tablet, develop sheet, can chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are to dissolve or the material bag of disintegrate in intestinal with being resistant to gastric acid effect The compressed tablet of clothing, thus prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to fatty acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Coated tablet is the compacting that sugar-coat surrounds Sheet, it can be beneficial to cover taste beastly or abnormal smells from the patient and can prevent tablet from aoxidizing.Thin membrane coated tablet is for using water solublity The compressed tablet that the thin layer of material or thin film cover.Film coating includes, but not limited to hydroxyethyl cellulose, carboxymethyl cellulose Sodium, Macrogol 4000 and cellulose acetate phthalate ester.Film coating possesses the general characteristic identical with sweet tablet.Multiple Tabletting is the compressed tablet through preparing more than a press cycles, including multilayer tablet and pressed coated or dry coated tablet.
Tabules can by powder, the one that individually or describes with the present invention of crystallization or granular active component Or prepared by variety carrier or excipient composition, described carrier and excipient include binding agent, disintegrating agent, controlled release polymer, profit Lubrication prescription, diluent and/or coloring agent.Fumet and sweeting agent are particularly useful when forming chewable tablet and lozenge.
The pharmaceutical composition that the present invention provides can provide with soft capsule or hard capsule, and it can be by gelatin, methyl fibre Prepared by dimension element, starch or calcium alginate.Described hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, enclose active component the most completely.SEC (SEC) is soft, spherical shell, such as gelatin shell, It plastifies by adding glycerol, sorbitol or similar polyhydric alcohol.Soft gelatin shell can comprise preservative and carry out prophylaxis of microbial life Long.Suitably preservative be as described in the present invention those, including methyl hydroxybenzoate and propylparaben, and sorbic acid.This Liquid, semisolid and solid dosage forms that invention provides can be encapsulated in capsule.Suitably liquid and semisolid dosage form is included in Solution in Allyl carbonate, vegetable oil or triglyceride and suspensoid.The capsule comprising such solution can be as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.Described capsule can also be adopted Use coating as is known to persons skilled in the art, thus improve or maintain the dissolution of active component.
The pharmaceutical composition that the present invention provides can provide with liquid and semisolid dosage form, including Emulsion, solution, suspendible Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another kind of liquid in pellet form, It can be oil-in-water type or water-in-oil type.Emulsion can include pharmaceutically acceptable on-aqueous liquid and solvent, emulsifying agent and Preservative.Suspensoid can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used The acetal accepted, two (low alkyl group) acetal of such as low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With there is one or many The water-soluble solvent of individual hydroxyl, such as propylene glycol and ethanol.Elixir is transparent, the water-alcohol solution of sweet taste.Syrup is dense The aqueous solution of sugar such as sucrose, and also preservative can be comprised.For liquid dosage form, such as, the solution in Polyethylene Glycol Can be with enough pharmaceutically acceptable liquid-carrier such as water dilutions, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to comprise the active component and two grades that the present invention provides Change list-or those dosage forms of poly-alkylene glycol, described list-or poly-alkylene glycol include: 1,2-dimethoxymethane, diethylene glycol Dimethyl ether, triethylene glycol dimethyl ether., tetraethylene glycol dimethyl ether, Polyethylene Glycol-350-dimethyl ether, Polyethylene Glycol-550-dimethyl ether, poly-second Glycol-750-dimethyl ether, wherein 350,550,750 refer to the approximation mean molecule quantity of Polyethylene Glycol.These preparations can be further Including one or more antioxidant, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydrogen Quinone, Hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and ester thereof and dithiocarbamate.
Time suitably, can be by the dosage unit preparations microencapsulation of oral administration.Can also be prepared into extending or dimension Hold the compositions of release, such as by by microparticle material coating or be embedded in polymer, wax or the like.
The combination of oral medication that the present invention provides can also carry with the form of liposome, micelle, microsphere or nanometer system Supply.Micelle dosage form can be prepared by the method that U.S.Pat.No.6,350,458 describes.
The pharmaceutical composition that the present invention provides can provide with non-effervescent or the granule of effervescent and powder, to reconstruct Liquid dosage form.The pharmaceutically acceptable carrier used in non-effervescent granule or powder and excipient can include dilution Agent, sweeting agent and wetting agent.The pharmaceutically acceptable carrier and the excipient that use in effervescent granule or powder can wrap Include organic acid and carbon dioxide source.
Coloring agent and flavoring agent can be used in all above-mentioned dosage forms.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.Such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl Radix Asparagi acyl Amine phenol or the substituted oxide polylysine of palmitoyl residues.Additionally, compound disclosed in this invention can with in reality The class Biodegradable polymeric controlling to use in release of existing medicine combines, such as, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are altogether Polymers.
The present invention provide pharmaceutical composition can be configured to immediately or Modified release dosage forms, including postpone-, slow release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
The pharmaceutical composition that the present invention provides can be common with other active component without compromising on intended therapeutical effect Preparation, or with supplement the material co-formulation of intended effect.
The pharmaceutical composition that the present invention provides can be by injection, infusion or implantation parenteral, for local or complete Body is administered.As the present invention use parenteral include intravenous, intra-arterial, intraperitoneal, sheath in, in ventricle, in urethra, breast In bone, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical composition that the present invention provides can be configured to be suitable to any dosage form of parenteral, including solution, mixes Suspension, Emulsion, micelle, liposome, microsphere, nanometer system and being suitable to makes consolidating of solution or suspension the most in a liquid Bodily form formula.Such dosage form can be prepared according to the conventional method known to the skilled person in pharmaceutical science field and (sees Remington:The Science and Practice ofPharmacy, ibid).
Be intended for the pharmaceutical composition of parenteral can include one or more pharmaceutically acceptable carriers and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or anti-micro-life Preservative, stabilizer, dissolution enhancers, isotonic agent, buffer agent, antioxidant, local anesthetic, suspending agent and the dispersion of thing growth Agent, wetting agent or emulsifying agent, chelating agent, sequestering agent or chelating agen, antifreezing agent, cryoprotective agent, thickening agent, pH adjusting agent And noble gas.
Suitably include, but are not limited to containing transporter: water, saline, normal saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers injection, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers injection.Non-transporter includes, but not limited to the fixed oil of plant origin, Oleum Ricini, Semen Maydis oil, Semen Gossypii The middle chain of oil, olive oil, Oleum Arachidis hypogaeae semen, Oleum menthae, safflower oil, Oleum sesami, Oleum Glycines, hydrogenated vegetable oil, hydrogenated soybean oil and Oleum Cocois Triglyceride and palm seed oil.Water miscibility carrier includes, but not limited to ethanol, 1,3 butylene glycol, the poly-second of liquid two Alcohol (such as Liquid Macrogol and PEG400), propylene glycol, glycerol, METHYLPYRROLIDONE, N, N-dimethylacetamide Amine and dimethyl sulfoxide.
Suitably antimicrobial or preservative include, but not limited to phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, Methyl parahydroxybenzoate and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylparaben and sorbic acid.Suitably isotonic agent includes, but not limited to sodium chloride, glycerol and glucose.Suitably buffer agent Include, but not limited to phosphate and citrate.Suitably antioxidant is as the present invention describes, including sulfurous acid Hydrogen salt and sodium metabisulfite.Suitably local anesthetic includes, but are not limited to procaine hydrochloride.Suitably suspending agent and point Powder is as the present invention describes, including sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitably emulsifying agent includes those that the present invention describes, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene moves back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitably sequestering agent or chelating agen includes, but are not limited to EDTA. Suitably pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitably chelating agent includes, but does not limits In cyclodextrin, including alpha-cyclodextrin, beta-schardinger dextrin-, HP-β-CD, Sulfobutylether-beta-schardinger dextrin-and sulfobutyl group Ether 7-beta-schardinger dextrin-(CyDex,Lenexa,KS)。
The pharmaceutical composition that the present invention provides can be configured to single dose or multiple dose administration.Described single-dose preparations is wrapped It is contained in ampulla, bottle or syringe.Described multiple dose parenteral administration must comprise the anti-micro-of antibacterial or fungistatic concentrations Biological agent.All of parenteral administration must be all aseptic, as known in the art with practice.
In one embodiment, pharmaceutical composition provides with instant sterile solution.In another embodiment, medicine Compositions provides with aseptic dried soluble product, and including freeze-dried powder and hypodermic tablet, it uses carrier before use Reconstruct.In yet another embodiment, pharmaceutical composition is formulated into instant sterile suspensions.In yet another embodiment, medicine The aseptic dry insolubility product that compositions reconstructs with carrier before being formulated into use.The most in one embodiment, Pharmaceutical composition is formulated into the aseptic Emulsion of instant.
Pharmaceutical composition can be configured to suspensoid, solid, semisolid or thixotropic liquid, and the reservoir being used as to implant is administered. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior substrate, its be insoluble to body fluid but The outside polymeric membrane allowing the active component in pharmaceutical composition to diffuse through is surrounded.
Be suitable for internal matrix include polymethyl methacrylate, poly-butyl methacrylate, plasticising or unplasticizied Polrvinyl chloride, the nylon of plasticising, the polyethylene terephthalate of plasticising, the polyethylene terephthalate of plasticising, natural rubber, Polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, poly-diformazan silica Alkane, silicone carbonate copolymer, the hydrogel of ester of hydrophilic polymer such as acrylic acid and methacrylic acid, collagen, crosslinking The polyvinyl acetate of the partial hydrolysis of polyvinyl alcohol and coach.
The outside polymeric membrane being suitable for includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polychlorostyrene second Alkene, ethlyene dichloride gather benzene two with the copolymer of vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer Formic acid second diester, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymer, Ethylene/vinyl acetate/vinyl alcohol trimer and Ethylene/vinyl ethoxy-ethanol copolymer.
On the other hand, pharmaceutical composition disclosed in this invention can be configured to be suitable to any dose to patient's inhalation Type, such as dry powder doses, aerosol, suspensoid or liquid composite.In one embodiment, drug regimen disclosed in this invention Thing can be configured to be suitable to by the dry powder doses dosage form to patient's inhalation.In yet another embodiment, disclosed in this invention Pharmaceutical composition can be configured to be suitable to by the aerosol apparatus dosage form to patient's inhalation.Dry powder by inhalation delivery to lung Compositions generally comprises fine powdered that compound disclosed in this invention is fine powdered pharmaceutically with one or more Acceptable excipient.The pharmaceutically acceptable excipient being especially suitable for use as dry powder doses is known to those skilled in the art Dawn, it includes lactose, starch, mannitol and single-, two-and polysaccharide.Fine powder can be by such as micronization and grinding preparation Obtain.In general, reduced size of (as micronized) compound can be by the D of about 1 to 10 micron50Value is (such as, with swashing Optical diffraction method is measured) define.
Aerosol can be by being suspended or dissolved in liquefied propellant preparation by compound disclosed in this invention.It is suitable for Propellant include chlorohydrocarbon, hydro carbons and other liquid gas.Representational propellant includes: Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoro Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.The aerosol comprising compound disclosed in this invention generally passes through Patient is administered by metered dose inhaler (MDI).Such device dawn known to those skilled in the art.
Aerosol can comprise pharmaceutically acceptable excipient extra, that can be used, such as surface activity by MDIs Agent, lubricant, cosolvent and other excipient, with improve preparation physical stability, improve valve characteristic, improve dissolubility, Or improve taste.
The pharmaceutical composition being suitable for transdermal administration can be prepared as discontinuous paster agent, it is intended that keeps with the epidermis of patient It is in close contact the time of an elongated segment.Such as, delivering active ingredients from paster agent can be permeated by ion, as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of topical can be formulated into ointment, ointment, suspensoid, lotion, powder, Solution, paste, gel, spray, aerosol or oil preparation.Such as, ointment, ointment and gel can be with water or oil Substrate, and the thickening agent and/or gel and/or the solvent that are suitable for configure.Such substrate can include, water, and/or oil example Such as liquid-liquid paraffin and vegetable oil (such as Oleum Arachidis hypogaeae semen or Oleum Ricini), or solvent such as Polyethylene Glycol.Make according to medium property Thickening agent and gel include soft paraffin, aluminium stearate, cetearyl alcohol, Polyethylene Glycol, lanoline, Cera Flava, poly-carboxylic second Alkene and cellulose derivative, and/or glyceryl monostearate and/or nonionic emulsifier.
Lotion can be prepared with water or oil matrix, and generally also contains one or more emulsifying agents, stabilizer, dispersion Agent, suspending agent or thickening agent.
Externally-applied powder can molding in the presence of powder the substrate such as Pulvis Talci, lactose or starch being arbitrarily suitable for.Drop Can be formulated with the water or non-aqueous matrix comprising one or more dispersants, solubilizing agent, suspending agent or preservative.
Topical formulations can be by applying one or many to be administered every day in affected part；The impermeable plastic wound dressing covering skin is preferential Used.The administration that adhesiveness store system can realize continuously or extend.
The compounds of this invention and the purposes of compositions
Compound disclosed in this invention or pharmaceutical composition may be used for preparing for treating, prevent, improve, control or Alleviate mammal, including the inflammation mediated by ROR γ t or the medicine of autoimmune disease of the mankind, it is also possible to be used for preparing For suppressing other medicines of ROR γ t.
Specifically, in the compositions of the present invention, the amount of compound can the most detectably suppress ROR γ t, this Bright compound can as prevention or treatment people's parapsoriasis, rheumatoid arthritis, systemic lupus erythematosus (sle), multiple firmly Change disease, inflammatory bowel, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or the medicine of mucocutaneous lymphnode syndrome.
Compound or the compositions of the present invention can apply to, but are not limited to, and use compound or the combination of the present invention Patient is administered and prevents, treat or alleviate mammal, including psoriasis, the rheumatoid joint of the mankind by the effective dose of thing Inflammation, systemic lupus erythematosus (sle), multiple sclerosis, inflammatory bowel, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease and Mucocutaneous lymphnode syndrome.
The compound of the present invention and pharmaceutical composition, in addition to useful to human treatment, apply also for veterinary treatment and dote on Mammal in the animal on thing, the animal of introduced variety and farm.The example of other animal includes horse, Canis familiaris L. and cat.? This, the compound of the present invention includes its pharmaceutically acceptable derivates.
General synthesis step
For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method putting into practice the present invention is provided.
Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (I).Following reaction scheme and embodiment are used for being further illustrated by this The content of invention.
The professional of art is it will be appreciated that chemical reaction described in the invention can be used to prepare perhaps suitably Other compounds of many present invention, and it is considered as the model in the present invention for other method of the compound of preparing the present invention Within enclosing.Such as, the synthesis according to the compound of those non-illustrations of the present invention can be successfully by those skilled in the art Completed by method of modifying, as group is disturbed in suitable protection, by utilizing reagent known to other except described in the invention , or reaction condition is made the amendment of some routines.It addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applicable to the preparation of other compounds of the present invention.
The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company andAlfa Chemical Company, the most not through being further purified, unless other aspects show during use.General reagent is western Gansu Province chemical industry from Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune chemistry in morning Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao purchase Can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide and N, N- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.
Hereinafter reaction is usually and overlaps a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb the most suitable rubber closure, substrate is squeezed into by syringe.Glass drying oven is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
NMR (Nuclear Magnetic Resonance) spectrum uses Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer record, with CDC13、DMSO-d6、 CD3OD or acetone-d6For solvent (in units of ppm), with TMS (0ppm) or chloroform (7.26ppm) as reference standard.When going out The when of existing multiplet, by use following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t (triplet, three Weight peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet ofdoublets, double doublet), Dt (doublet oftriplets, double triplets).Coupling constant, represents with hertz (Hz).
The condition determination of Algorithm (MS) data is: Agilent 6120 level Four bar HPLC-M (pillar model: Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity is 0.6mL/min.Phase: 5%-95% is (containing 0.1% in flowing The CH of formic acid3CN) at (H containing 0.1% formic acid2O) ratio in), use electron spray ionisation (ESI), under 210nm/254nm, Detect with UV.
Compound purity uses high performance liquid chromatography (HPLC) to measure, use Agilent 1260HPLC (pillar model: Agilent zorbax Eclipse Plus C18), and detect with DAD detector, final employing area normalization method calculates To compound purity.
The use of brief word below runs through the present invention:
NaNO2Sodium nitrite； NH4F ammonium fluoride；
Na2CO3Sodium carbonate；MeONa Feldalat NM；
KOH sodium hydroxide； Et3N TEA triethylamine；
MeCN acetonitrile；HOBt I-hydroxybenzotriazole；
K2CO3Potassium carbonate；EDCI 1-ethyl-(3-dimethylaminopropyl) Phosphinylidyne two is sub-
CH2Cl2DCM dichloromethane；Amine hydrochlorate；
Na2SO4Sodium sulfate；MeMgBr methyl-magnesium-bromide；
M-CPBA metachloroperbenzoic acid； H2O water；
TLC thin layer chromatography； InCl3Indium chloride；
NaHCO3Sodium bicarbonate；PhMgBr phenyl-magnesium-bromide；
NaCl sodium chloride；NaH sodium hydride；
PE petroleum ether；Pd/C palladium/carbon
EtOAc EA ethyl acetate； BH3Borine
NaOH sodium hydroxide；Dess-Martin reagent Dai Si-Martin reagent；
EtOH ethanol；DAST diethylin sulfur trifluoride；
THF oxolane；MsCl methylsufonyl chloride；
NH4Cl ammonium chloride； Me2S methyl sulfide；
Pd(PPh3)2Cl2Bis-triphenylphosphipalladium palladium dichloride；I-PrMgBr isopropyl magnesium bromide；
CuI Hydro-Giene (Water Science).； CDC13Deuterochloroform
MeOH methanol；DMSO dimethyl sulfoxide
HATU 2-(7-azo BTA)-N, N, N', N'-tetramethyl DMSO-d6Deuterated dimethyl sulfoxide
Base urea hexafluorophosphoric acid ester；G gram
DIPEA N, N-diisopropyl ethyl amine；H hour
Et3SiH triethyl silicane；Min minute
TFA trifluoroacetic acid；Mmol mM
M mole every liter RT, rt, r.t. room temperature
DEG C degree Celsius rpm rpm
ML, ml milliliter Rt retention time
The preparation present invention comes into the open the typical synthesis step of compound as shown in following synthetic schemes.Unless otherwise indicated, T、W、J、A、R1、R2, each R3、R5、R6、R8、R9, m and n there is as described in the present invention definition.
Synthetic schemes 1
In formula, X represent leaving group, described leaving group include but not limited to halogen atom, mesyl epoxide, To Methyl benzenesulfonyl base epoxide etc..
Compound (6a) can be prepared by following process:
Reacting generating compound is there is in acetylene hydrocarbon compound (1a) and compound (2a) under the effect of palladium catalyst and alkali (3a), then compound (3a) reduction obtaining compound (4a), finally, compound (4a) and carboxylic acid compound (5a) are in condensation Reacting generating compound (6a) under the effect of agent.
Synthetic schemes 2
In formula, X represent leaving group, described leaving group include but not limited to halogen atom, mesyl epoxide, To Methyl benzenesulfonyl base epoxide etc..
Compound (6a) can also be prepared by following process:
Amino-compound (7a) and carboxylic acid compound (5a) occur condensation reaction to generate compound (8a), and compound (8a) is Under the effect of palladium catalyst and alkali, compound (6a) is generated eventually with acetylene hydrocarbon compound (1a).
Synthetic schemes 3
In formula, X represent leaving group, described leaving group include but not limited to halogen atom, mesyl epoxide, To Methyl benzenesulfonyl base epoxide etc.；R0Represent C1-6Alkyl.
Compound (13a) can be prepared by following process:
Acetylene hydrocarbon compound (1a) and compound (9a) reacting generating compound (10a) under the effect of palladium catalyst and alkali, Then compound (10a) occurs ester hydrolysis reaction to generate carboxylic acid compound (11a) under the effect of alkali, and compound (11a) is final Condensation reaction is occurred to generate compound (13a) with amino-compound (12a).
Synthetic schemes 4
In formula, X represent leaving group, described leaving group include but not limited to halogen atom, mesyl epoxide, To Methyl benzenesulfonyl base epoxide etc..
Compound (17a) can be prepared by following process:
Amino-compound (7a) and carboxylic acid compound (14a) occur condensation reaction to generate compound (15a), then compound (15a) being reduced generation compound (16a), compound (16a) is final and acetylene hydrocarbon compound (1a) occurs palladium catalysed cross coupling reaction Generate compound (17a).
The compound, pharmaceutical composition and the application thereof that there is provided the present invention below in conjunction with embodiment are further described.
The synthesis of embodiment 1:2-(4-(ethylsulfonyl) phenyl)-N-(4-iodobenzene) acetamide
By 2-(4-ethylsulfonyl phenyl) acetic acid (5.04g, 22.1mmol) (referenced patent WO2014125426 page 29 Synthetic method), 4-iodobenzene (5.34g, 24.4mmol), EDCI (6.33g, 33.0mmol) and HOBT (3.57g, 26.4mmol) It is dissolved in DCM (50mL), 10h is stirred at room temperature.Concentrating under reduced pressure, residue CH2Cl2(120mL) dissolve, the most successively with saturated NaHCO3Solution (40mL) and NaCl solution (40mL) washing, aqueous phase merges, uses CH2Cl2(120mL) extraction (50mL × 2), closes And organic facies use Na2SO4Be dried, concentrating under reduced pressure, crude product by silica gel column chromatography separate (eluent: PE/EtOAc (v/v)= 1/1), obtaining product is white solid powder (7.9g, 83%).MS(ESI,pos.ion)m/z:429.9[M+1]+；
1H NMR (400MHz, DMSO) δ (ppm): 10.36 (s, 1H), 7.85 (d, J=8.2Hz, 2H), 7.62 (m, 4H), 7.44 (d, J=8.6Hz, 2H), 3.80 (s, 2H), 3.27 (q, J=7.3Hz, 2H), 1.10 (t, J=7.3Hz, 3H).
Embodiment 2:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynyl) phenyl)-2-(4-(ethylsulfonyl) Phenyl) synthesis of acetamide (compound 1)
The synthesis of step one: 1-[4-(difluoro-methoxy) phenyl] Propargyl-1-alcohol
Under the conditions of anhydrous and oxygen-free, in dry single port flask by 4-(difluoro-methoxy) benzaldehyde (18mL, 136.2mmol) it is dissolved in anhydrous THF (32mL), and cools down in-20 DEG C of cryostats, in reaction system, then drip acetenyl The THF solution (0.5M, 300mL, 200mmol) of magnesium bromide, finishes, and reaction is stirred in reaction at such a temperature, TLC follow the tracks of anti- Should.After raw material converts completely, under ice bath cools down, in system, drip NH4Cl solution (15mL) cancellation is reacted, concentrating under reduced pressure Remove THF, remain aqueous phase CH2Cl2(20mL × 3) extract, and merge organic facies and use anhydrous Na2SO4It is dried, concentrates, crude product Being separated (eluent: PE/EtOAc (v/v)=5/1) by silica gel column chromatography, obtaining product is colourless liquid (19.3g, 72%).
The synthesis of step 2: 1-[4-difluoro-methoxy) phenyl]-3-(4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol
Under nitrogen protection, by 1-[4-(difluoro-methoxy) phenyl] Propargyl-1-alcohol (266mg, 1.34mmol), Pd(PPh3)2Cl2(95mg, 0.13mmol), CuI (12.5mg, 2.2 μ L, 0.0643mmol), 1-bromo-4-Nitrobenzol (256mg, 1.27mmol) it is dissolved in THF (8mL) with triethylamine (0.40mL, 2.8mmol), 3h is stirred at room temperature, is filtered to remove insoluble matter, filter After liquid concentrates, silica gel column chromatography separating (eluent: PE/EtOAc (v/v)=4/1), obtaining product is yellow liquid (189mg, 44%).
The synthesis of step 3: 3-(4-aminophenyl)-1-(4-(difluoro-methoxy) phenyl) acrylate-2-alkynes-1-alcohol
It is stirred at room temperature down, by NH4The aqueous solution of Cl (0.50g, 330 μ L, 9.34mmol) and iron powder (0.19g, 3.40mmol) add 1-[4-difluoro-methoxy) phenyl]-3-(4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol (189mg, 0.59mmol) MeOH (5mL) solution in, back flow reaction 4h.Kieselguhr filters, and it is yellow oil that removal of solvent under reduced pressure obtains crude product (76mg, 44%).
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl)-3-hydroxypropyl-1-alkynes-1-base) phenyl)-2-(4-(second Base sulfonvlphenyl) synthesis of acetamide
By molten for 3-(4-aminophenyl)-1-(4-(difluoro-methoxy) phenyl) acrylate-2-alkynes-1-alcohol (72mg, 0.25mmol) In dichloromethane (5mL), sequentially add HATU (95mg, 0.24mmol), DIPEA (0.05mL, 0.3mmol) and 2-(4- Ethanesulfonylphenyl) acetic acid (64mg, 0.28mmol), stirred overnight at room temperature.After reactant liquor concentrates, crude product is by silica gel column chromatography Separating (eluent: DCM/MeOH (v/v)=40/1), obtaining product is yellow oily solid (59mg, 47%).
Step 5: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base) phenyl)-2-(4-(ethylsulfonyl) Phenyl) synthesis of acetamide
Under nitrogen protection, by N-(4-(3-(4-(difluoro-methoxy) phenyl)-3-hydroxypropyl-1-propargyl) phenyl)- (4-(ethylsulfonyl phenyl) acetamide (55mg, 0.11mmol) is dissolved in DCM (5mL) 2-, and reaction system is cooled to-5 DEG C, add Et the most with stirring3SiH (27 μ L, 0.17mmol) and NH4F (6.4mg, 0.17mmol), reaction is at such a temperature Stirring 0.5h, is subsequently adding TFA (35 μ L, 0.47mmol), continues stirring 2h, then warms naturally to room temperature reaction overnight.To Reaction system adds NaHCO3(5mL) solution, separatory, organic facies anhydrous Na2SO4Being dried, concentrate, crude product is by silicagel column Chromatography (eluent: PE/EtOAc (v/v)=1/1), obtaining product is yellow solid (19mg, 36%).
MS(ESI,pos.ion)m/z:484.3[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.87 (d, J=7.9Hz, 2H), 7.53 (d, J=7.8Hz, 2H), 7.44 (d, J=7.8Hz, 2H), 7.38 (d, J=4.6Hz, 4H), 7.09 (d, J=8.2Hz, 2H), 6.49 (t, J=74.0Hz, 2H), 3.79 (s, 4H), 3.12 (q, J=7.3Hz, 2H), 1.29 (t, J=7.2Hz, 3H).
Embodiment 3:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-methoxyphenyl)-2-(4- (ethylsulfonyl) phenyl) synthesis of acetamide (compound 2)
The conjunction of step one: 1-(4-(difluoro-methoxy) phenyl)-3-(2-methoxyl group-4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol Become
By 1-[4-(difluoro-methoxy) phenyl] acrylate-2-alkynes-1-alcohol (529mg, 2.67mmol), 1-bromo-2-methoxyl group-4- Nitrobenzol (700mg, 3.02mmol), CuI (30mg, 0.16mmol) and Pd (PPh3)2Cl2(200mg, 0.30mmol) adds In two mouthfuls of flasks of 100mL, nitrogen is replaced three times, then under nitrogen is protected, is sequentially added into THF (40mL) and Et3N (0.8mL, 6mmol), reacts in 30 DEG C of oil baths and reacts overnight.Concentrating under reduced pressure, crude product is separated (drip washing by silica gel column chromatography Agent: PE/EtOAc (v/v)=4/1), obtaining product is yellow liquid (560mg, 60%).1H NMR(400MHz,CDCl3)δ (ppm): 7.84 (dd, J=8.4,1.8Hz, 1H), 7.76 (d, J=1.7Hz, 1H), 7.67 (d, J=8.6Hz, 2H), 7.58 (d, J=8.4Hz, 1H), 7.19 (d, J=8.5Hz, 2H), 6.55 (t, J=73.7Hz, 1H), 5.77 (d, J=6.0Hz, 1H), 4.01(s,3H)。
The synthesis of step 2: 1-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methoxyl group-4-Nitrobenzol
By 1-(4-(difluoro-methoxy) phenyl)-3-(2-methoxyl group-4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol (559mg, 1.60mmol) it is dissolved in CH2Cl2(40mL), it is cooled under 0 DEG C, stirring add Et3SiH (0.40mL, 3.00mmol) and NH4F (90mg, 2.43mmol), after 30min, dropping TFA (0.60mL, 8.00mmol), react on 0 DEG C of reaction 2h, be then slowly increased to Stirred overnight at room temperature.Saturated NaHCO is added in reaction system3(15mL) solution cancellation reaction, uses CH2Cl2(30mL × 3) extract Take, anhydrous Na2SO4It is dried, concentrating under reduced pressure, obtains crude product (520mg, 97%) and be directly used in next step reaction.
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-aminoanisole
By 1-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methoxyl group-4-Nitrobenzol (520mg, 1.57mmol) it is dissolved in MeOH/H2In O (3/1,40mL) mixed solvent, then it is sequentially added into NH4Cl (850mg, 15.89mmol) and Reduced iron powder (450mg, 8.04mmol), is heated to reflux 3h, filters, and washs filter cake with EtOAc (200mL), and filtrate is with anhydrous Na2SO4Being dried, concentrating under reduced pressure, obtaining crude product is red oil (450mg), is directly used in next step reaction.
MS(ESI,pos.ion)m/z:304.1[M+1]+。
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-methoxyphenyl)-2-(4- (ethylsulfonyl) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-aminoanisole (455mg, 1.50mmol), 2-(4-ethylsulfonyl phenyl) acetic acid (510mg, 2.23mmol) and HATU (1.7g, 4.5mmol) are dissolved in CH2Cl2(50mL), in, ice bath cools down, and then drips DIPEA (2.0mL, 12.1mmol), after 10min, stirred overnight at room temperature.Subtract Pressure concentrates, and crude product is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography, obtains crude product and is obtained by preparative separation It is white solid product (200mg, 26%) to product.
MS(ESI,pos.ion)m/z:514.1[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.88 (d, J=7.6Hz, 2H), 7.62 (s, 1H), 7.58-7.48 (m, 3H), 7.44 (d, J=8.1Hz, 2H), 7.33 (d, J=8.2Hz, 1H), 7.10 (d, J=8.1Hz, 2H), 6.81 (d, J= 8.2Hz, 1H), 6.51 (t, J=74.1Hz, 1H), 3.88 (s, 5H), 3.81 (s, 2H), 3.14 (q, J=7.3Hz, 2H), 1.30 (d, J=7.6Hz, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):167.67,160.62,149.87,140.67,138.71,137.53, 134.11,133.68,130.30,129.34,128.74,119.70,117.74,116.02,114.30,111.08,108.66, 102.59,90.91,78.84,55.94,50.66,44.27,25.44,7.41。
Embodiment 4:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methoxyphenyl)-2-(4- (ethylsulfonyl) phenyl) synthesis of acetamide (compound 3)
The synthesis of step one: 4-bromo-2-methoxyl group-1-Nitrobenzol
MeONa (1.0mL, 5.0mmol) is joined the MeOH of the bromo-2-of 4-fluoro-1-Nitrobenzol (1.01g, 4.58mmol) (10mL), in solution, stirring reaction 1h in 60 DEG C of oil baths is reacted on.Removal of solvent under reduced pressure, residue CH2Cl2(30mL) dissolve, Being filtered to remove insoluble matter, filtrate concentrates, and obtaining object is yellow solid (1.05g, 98%).
MS(ESI,pos.ion)m/z:232.1[M+1]+.
The conjunction of step 2: 1-(4-(difluoro-methoxy) phenyl)-3-(3-methoxyl group-4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol Become
Under nitrogen protection, by 1-(4-(difluoro-methoxy) phenyl) acrylate-2-alkynes-1-alcohol (802mg, 4.04mmol), 4- Bromo-2-methoxyl group-1-Nitrobenzol (1.05g, 4.52mmol), Pd (PPh3)2Cl2(289mg, 0.40mmol) and CuI (39.4mg, 0.20mmol) it is dissolved in THF (20mL), is subsequently adding Et3N (1.20mL, 8.44mmol), is stirred at room temperature reaction 5h.Cross and filter Removing insoluble matter, filtrate concentrates, and crude product is separated (eluent: PE/EtOAc (v/v)=4/1) by silica gel column chromatography, obtains target Thing is yellow liquid (1.22g, 86%).
MS(ESI,pos.ion)m/z:372.0[M+23]+。
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methoxyl group-1-Nitrobenzol
Under nitrogen protection, by 1-(4-(difluoro-methoxy) phenyl)-3-(3-methoxyl group-4-nitrobenzophenone) acrylate-2-alkynes- 1-alcohol (1.22g, 3.49mmol) is dissolved in CH2Cl2(10mL) it is cooled to-5 DEG C in and by reaction system, the most successively Add Et3SiH (0.69mL, 4.29mmol) and NH4F (159mg, 4.21mmol), after 30min, addition TFA (0.90mL, 12mmol), reactant liquor maintains low temperature to continue stirring 8h, and 3h is then stirred at room temperature.Saturated NaHCO is added in reaction system3 (30mL) solution, mixed liquor CH2Cl2(30mL × 3) extract, and merge organic facies and use anhydrous Na2SO4It is dried, concentrating under reduced pressure, Crude product is separated (eluent: PE) by silica gel column chromatography, and obtaining object is yellow oily liquid (167mg, 14%).
1H NMR(400MHz,CDCl3) δ (ppm): 7.83 (d, J=8.3Hz, 1H), 7.41 (d, J=8.4Hz, 2H), 7.15 (d, J=6.1Hz, 3H), 7.09 (t, J=6.9Hz, 1H), 6.73 6.33 (m, 1H), 3.98 (s, 3H), 3.86 (s, 2H)。
The synthesis of step 4: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-aminoanisole
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methoxyl group-1-Nitrobenzol (167mg, 0.50mmol) it is dissolved in MeOH (10mL), the most with stirring, is sequentially added into NH4The aqueous solution of Cl (264mg, 4.93mmol) (2mL) with reduced iron powder (175mg, 3.13mmol), back flow reaction 3h.Kieselguhr filters, concentrating under reduced pressure, aqueous phase CH2Cl2 (20mL × 3) extract, and merge organic facies, and use anhydrous Na2SO4Being dried, concentrating under reduced pressure, obtaining object is dark yellow solid (142mg, 93%).
MS(ESI,pos.ion)m/z:304.0[M+1]+.
Step 5: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methoxyphenyl)-2-(4- (ethylsulfonyl) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-aminoanisole (142mg, 0.47mmol), 2-(4-ethylsulfonyl phenyl) acetic acid (115mg, 0.50mmol) and HATU (546mg, 1.41mmol) are dissolved in CH2Cl2(15mL), then in reactant liquor, add DIPEA (0.15mL, 0.89mmol), reaction 6h is stirred at room temperature.Reactant liquor is direct Concentrate, by silica gel column chromatography separate (eluent: DCM/MeOH (v/v)=40/1), obtain object be white solid (158mg, 66%).
MS(ESI,pos.ion)m/z:514.0[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.31 (dd, J=8.2,4.1Hz, 1H), 7.93 (d, J=8.2Hz, 2H), 7.86 (d, J=9.8Hz, 1H), 7.58 (d, J=8.1Hz, 2H), 7.41 (d, J=8.5Hz, 2H), 7.12 (d, J= 8.5Hz, 2H), 7.08 (dt, J=5.8,2.9Hz, 1H), 6.93 (d, J=1.3Hz, 1H), 6.65 6.38 (m, 1H), 3.86 (s, 2H), 3.84 (s, 3H), 3.82 (s, 2H), 3.14 (q, J=7.4Hz, 2H), 1.31 (t, J=7.4Hz, 3H).
Embodiment 5:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluorophenyl)-2-(4-(second Base sulfonyl) phenyl) synthesis of acetamide (compound 4)
The synthesis of step one: 1-(4-(difluoro-methoxy) phenyl)-3-(3-fluoro-4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol
Under nitrogen protection, 1-(4-(difluoro-methoxy) phenyl) acrylate-2-alkynes-1-alcohol (507mg, 2.56mmol) is dissolved in In THF (20mL), then it is sequentially added into Pd (PPh3)2Cl2(181mg, 0.25mmol), CuI (25mg, 0.13mmol), 4-are bromo- 2-fluoro-1-Nitrobenzol (626mg, 2.85mmol) and Et3N (0.54g, 0.75mL, 5.3mmol), is stirred at room temperature, and reacts 4h, stops Only reaction.Being filtered to remove insoluble matter, filtrate concentrates, crude product by silica gel column chromatography separate (eluent: PE/EtOAc (v/v)= 4/1), obtaining product is yellow liquid (477mg, 55%).
MS(ESI,pos.ion)m/z:338.0[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.06 (t, J=8.2Hz, 1H), 7.61 (d, J=8.5Hz, 2H), 7.40 (d, J=4.0Hz, 1H), 7.37 (s, 1H), 7.20 (d, J=8.4Hz, 2H), 6.54 (t, J=73.6Hz, 1H), 5.74 (s,1H)。
The synthesis of step 2: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluoro-1-Nitrobenzol
Under nitrogen protection, by 1-(4-(difluoro-methoxy) phenyl)-3-(3-fluoro-4-nitrobenzophenone) acrylate-2-alkynes-1-alcohol (477mg, 1.41mmol) is dissolved in CH2Cl2(10mL) and be cooled to-5 DEG C, Et is added under stirring3SiH(0.489mL, 3.06mmol) and NH4F (124mg, 3.28mmol), after 0.5h, adds TFA (0.40mL, 5.40mmol), reacts overnight, then 2h is stirred at room temperature, stops stirring.Saturated NaHCO is added in reactant liquor3(15mL) solution, mixed liquor CH2Cl2(20mL× 3) extraction, organic facies anhydrous Na2SO4Being dried, concentrate, crude product is separated (eluent: PE) by silica gel column chromatography, obtains product For yellow liquid (158mg, 35%).
1H NMR(400MHz,CDCl3) δ (ppm): 8.04 (t, J=8.2Hz, 1H), 7.43 7.31 (m, 4H), 7.15 (d, J=8.4Hz, 2H), 6.73 6.33 (m, 1H), 3.87 (s, 2H).
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluoroaniline
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluoro-1-Nitrobenzol (158mg, 0.49mmol) it is dissolved in MeOH (10mL), under stirring, is sequentially added into NH4The aqueous solution of Cl (267mg, 0.175mL, 4.99mmol) With reduced iron powder (150mg, 2.68mmol), back flow reaction 3h.Question response system is cooled to room temperature, and kieselguhr filters, and filtrate is dense Contracting, residue CH2Cl2(50mL) dilution, uses saturated NaHCO successively3(15mL) solution and the washing of NaCl (15mL) solution, have Anhydrous Na used mutually by machine2SO4Being dried, concentrate, obtaining product is white solid (129mg, 90%).
MS(ESI,pos.ion)m/z:292.0[M+1]+。
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluorophenyl)-2-(4-(ethyl Sulfonyl) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluoroaniline (129mg, 0.44mmol), 2- (4-ethylsulfonyl phenyl) acetic acid (104mg, 0.46mmol) and HATU (596mg, 1.54mmol) are dissolved in CH2Cl2(15mL) In, it is subsequently adding DIPEA (0.15mL, 0.89mmol), 5h is stirred at room temperature.Concentrating under reduced pressure removes solvent, and crude product is by silicagel column Chromatography (eluent: CH2Cl2/ MeOH (v/v)=40/1), obtaining product is white solid (164mg, 74%).
MS(ESI,pos.ion)m/z:502.1[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.26 (t, J=8.3Hz, 1H), 7.93 (d, J=8.2Hz, 2H), 7.58 (d, J=8.1Hz, 2H), 7.52 (s, 1H), 7.39 (d, J=8.5Hz, 2H), 7.22 (d, J=8.4Hz, 1H), 7.18 7.14 (m, 1H), 7.12 (d, J=8.5Hz, 2H), 6.65 6.38 (t, J=73.8Hz, 1H), 3.86 (d, J=15.6Hz, 2H), 3.81 (s, 2H), 3.18 3.09 (m, 2H), 1.30 (t, J=7.4Hz, 3H).
Embodiment 6:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-fluorophenyl)-2-(4-(second Base sulfonyl) phenyl) synthesis of acetamide (compound 5)
The synthesis of step one: 1-(difluoro-methoxy)-4-(acrylate-2-alkynes-1-base) benzene
Under ice cooling, 4, by 1-(4-(difluoro-methoxy) phenyl) acrylate-2-alkynes-1-alcohol in dry single port flask (1.04g, 5.25mmol) is dissolved in CH2Cl2(30mL) in, by Et3SiH (2.9mL, 18mmol) is slowly dropped in reaction system, It is subsequently adding NH4F (0.40g, 11mmol), is stirred at room temperature 2h.Reaction bulb is cooled with an ice bath, and adds TFA in reaction system (1.50mL, 16.3mmol), then is slowly increased to 5h is stirred at room temperature by reaction system.Reactant liquor CH2Cl2(60mL) dilution, by Saturated NaCl solution (10mL × 2) is washed, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (drip washing by silica gel column chromatography Agent: PE/EtOAc (v/v)=1000/1) and separated by preparative hplc plate further, obtaining product is colourless transparent liquid (510mg, 53%).
1H NMR(600MHz,CDCl3) δ (ppm): 7.38 (d, J=8.6Hz, 2H), 7.11 (d, J=8.5Hz, 2H), 6.52 (t, J=74.0Hz, 1H), 3.62 (d, J=2.5Hz, 2H), 2.24 (t, J=2.7Hz, 1H), 1.05 (t, J=7.9Hz, 1H)。
The synthesis of step 2: 1-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluoro-4-Nitrobenzol
Under nitrogen protection, by 1-(difluoro-methoxy)-4-(acrylate-2-alkynes-1-base) benzene (600mg, 3.29mmol), 1- Bromo-2-fluoro-4-Nitrobenzol (1.00g, 4.55mmol), Pd (PPh3)2Cl2(245mg, 0.35mmol) and CuI (52mg, 0.27mmol) it is dissolved in THF (50mL), and adds DIPEA (0.90mL, 5.2mmol), be stirred at room temperature, TLC follow the tracks of reaction. After raw material is wholly absent, filter, concentrated filtrate.Residue EtOAc (60mL) dilutes, successively by saturated NaHCO3Solution (15mL) wash with saturated NaCl (15mL), anhydrous Na2SO4Be dried, concentrating under reduced pressure, obtain product be faint yellow solid (700mg, 66%).
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-fluoroaniline
By 1-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-fluoro-4-Nitrobenzol in single port bottle (391mg, 1.22mmol) is dissolved in MeOH (38mL) and adds NH4The aqueous solution (16mL) of Cl (241mg, 4.50mmol) and also Former iron powder (1.50g, 26.9mmol), reacts on reacting by heating in 50 DEG C of oil baths.After raw material disappears, reactant liquor is cooled to room Temperature, filters, and filtrate concentrates and removes MeOH, aqueous phase CH2Cl2(40mL × 3) extract, and organic facies is by anhydrous Na2SO4It is dried, decompression Concentrating, crude product is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography, and obtaining product is white solid (250mg, 70%).
MS(ESI,pos.ion)m/z:292.1[M+1]+。
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-fluorophenyl)-2-(4-(ethyl Sulfonyl) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-fluoroaniline (330mg, 1.13mmol), 2- (4-ethylsulfonyl phenyl) acetic acid (280mg, 1.23mmol), EDCI (330mg, 1.69mmol) and HOBt (200mg, 1.44mmol) it is dissolved in CH2Cl2(35mL), in, 6h is stirred at room temperature.Reactant liquor CH2Cl2(60mL) dilution, successively by saturated NaHCO3Solution (20mL) and saturated NaCl solution (20mL) washing, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is by silica gel Column chromatography for separation (eluent: PE/EA (v/v)=1/1), obtaining product is white solid (140mg, 25%).
MS(ESI,pos.ion)m/z:502.1[M+1]+；
1HNMR(600MHz,CDCl3)δ(ppm):7.87(d,2H),7.70(s,1H),7.52(m,4H),7.40(m,2H), 7.34 (m, 1H), 7.09 (s, 2H), 6.49 (t, J=74.1Hz, 2H), 3.84 (s, 2H), 3.80 (s, 2H), 3.12 (q, J= 7.4Hz, 2H), 1.29 (t, J=7.4Hz, 3H).
Embodiment 7:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-(trifluoromethyl) piperidin-1-yl) acrylate-1- Alkynes-1-base) phenyl) synthesis of acetamide (compound 6)
The synthesis of step one: 1-(acrylate-2-alkynes-1-base)-4-(trifluoromethyl) piperidines
In single port flask, by 4-(trifluoromethyl) piperidines (1.05g, 6.86mmol) and K2CO3(2.00g,11.2mmol) It is dissolved in MeCN (50mL), is then slowly added dropwise 3-bromine acrylate-1-alkynes (0.62mL, 7.19mmol), finishes, react on and be stirred at room temperature 10h.Reaction mixture filters, and filtrate concentrates, and crude product is separated (eluent: PE/EtOAc (v/v)=5/ by silica gel column chromatography 1) colourless transparent liquid (1.20g, 92%), is obtained.
MS(ESI,pos.ion)m/z:192.1[M+1]+。
Step 2: 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-(trifluoromethyl) piperidin-1-yl) acrylate-1-alkynes- 1-yl) phenyl) synthesis of acetamide
Under nitrogen protection, by 1-(acrylate-2-alkynes-1-base)-4-(trifluoromethyl) piperidines (520mg, 2.72mmol), 2- (4-ethylsulfonyl phenyl)-N-(4-iodobenzene) acetamide (250mg, 0.58mmol), Pd (PPh3)2Cl2(200mg, 0.28mmol) it is dissolved in THF (50mL) with CuI (25mg, 0.13mmol), adds DIPEA (0.70mL, 4.00mmol), reaction Heated and stirred 6h in 50 DEG C of oil baths.Stopping heating, question response liquid is cooled to room temperature, filters, and filtrate concentrates, and adds in residue Enter saturated NaHCO3Aqueous solution (30mL), then extracts with EtOAc (50mL × 3), merges organic facies, with saturated NaCl (30mL) Solution washs, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: CH by silica gel column chromatography2Cl2/EtOAc(v/ V)=1/1), obtaining object is white solid (270mg, 94%).
MS(ESI,pos.ion)m/z:493.2[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.87 (d, J=7.9Hz, 2H), 7.52 (d, J=7.8Hz, 2H), 7.44 (d, J=7.6Hz, 3H), 7.37 (d, J=8.3Hz, 2H), 3.79 (s, 2H), 3.51 (s, 2H), 3.12 (q, J= 7.4Hz, 2H), 3.05 (d, J=11.2Hz, 2H), 2.24 (t, J=11.6Hz, 2H), 2.07 1.96 (m, 1H), 1.90 (d, J =12.6Hz, 2H), 1.70 (dd, J=12.3,9.1Hz, 2H), 1.29 (t, J=7.4Hz, 3H).
Embodiment 8:N-(4-(3-(4,4-difluoropiperdin-1-base) acrylate-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphonyl Base) phenyl) synthesis of acetamide (compound 7)
Step one: the synthesis of 4,4-difluoropiperdin-1-t-butyl formate
In 100mL single port bottle, 4-oxo-piperidine-1-t-butyl formate (1.81g, 9.08mmol) is dissolved in CH2Cl2 (42mL), in, under ice bath cooling and stirring, DAST (4.0mL, 29.4mmol) is slowly dropped in reaction system, reacts on this temperature Degree stirring 4h.Saturated NaHCO is added in reaction system3Aqueous solution (30mL) cancellation is reacted, and then uses CH2Cl2(50mL×3) Extraction, merges organic facies and washs by saturated NaCl solution (20mL), anhydrous Na2SO4It is dried, filters, concentrating under reduced pressure, crude product Being separated (eluent: PE/EtOAc (v/v)=5/1) by silica gel column chromatography, obtaining object is colourless liquid (1.21g, 60%).
Step 2: the synthesis of 4,4-difluoropiperdin
In single port bottle, 4,4-difluoropiperdin-1-t-butyl formate (650mg, 2.94mmol) is dissolved in CH2Cl2(20mL) With in TFA (5mL), 3h is stirred at room temperature.Concentrating under reduced pressure, obtains crude product and is directly used in next step reaction.
The synthesis of the fluoro-1-of step 3: 4,4-bis-(acrylate-2-alkynes-1-base) piperidines
In single port flask, by 4,4-difluoropiperdin and K2CO3(541mg, 3.02mmol) is dissolved in MeCN (50mL), then 3-propargyl bromide (304mg, 2.56mmol) is slowly added in reaction system, 5h is stirred at room temperature.Filtering, filtrate concentrates, crude product By silica gel column chromatography separate (eluent: PE/EtOAc (v/v)=1/1), obtain product be colourless transparent liquid (310mg, 76%).
MS(ESI,pos.ion)m/z:160.1[M+1]+。
Step 4: N-(4-(3-(4,4-difluoropiperdin-1-base) acrylate-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphonyl Base) phenyl) synthesis of acetamide
Under nitrogen protection, by 4, the fluoro-1-of 4-bis-(acrylate-2-alkynes-1-base) piperidines (220mg, 1.38mmol), 2-(4-second Base sulfonvlphenyl)-N-(4-iodobenzene) acetamide (250mg, 0.58mmol), Pd (PPh3)2Cl2(200mg, 0.28mmol) and CuI (25mg, 0.13mmol) is dissolved in THF (50mL), is subsequently adding DIPEA (0.70mL, 4.0mmol), reacts on 50 DEG C of oil Heated and stirred in bath, is followed the tracks of reaction by TLC.After reaction terminates, filtering, filtrate concentrates.Saturated NaHCO is added in residue3 Aqueous solution (20mL), then extracts with EtOAc (30mL × 3), and organic facies saturated NaCl solution (20mL) is washed, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: DCM/EtOAc (v/v)=3/1) by silica gel column chromatography, obtains mesh Mark thing is faint yellow solid (270mg, 42%).
MS(ESI,pos.ion)m/z:461.2[M+1]+；
1HNMR(600MHz,CDCl3) δ (ppm): 8.21 (s, 1H), 7.82 (d, J=8.2Hz, 2H), 7.50 7.47 (m, 4H), 7.33 (t, J=8.5Hz, 2H), 3.77 (s, 2H), 3.53 (s, 2H), 3.10 (q, J=7.4Hz, 2H), 2.72 (m, 4H), 2.07-2.02 (m, 4H), 1.27 (t, J=7.4Hz, 3H).
Embodiment 9:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-morpholine acrylate-1-alkynes-1-base) phenyl) acetamide The synthesis of (compound 8)
The synthesis of step one: 4-(acrylate-2-alkynes-1-base) morpholine
Acrylate-2-alkynes-1-alcohol (1.00g, 17.8mmol) is dissolved in CH2Cl2(30mL), and cooling under-20 DEG C of cryostats, so After with stirring, be sequentially added into NEt3(3.1mL, 22mmol) and MsCl (1.68mL, 21.7mmol), reactant liquor is at such a temperature Stirring, after 3h, in reaction system add morpholine (3.1mL, 35mmol), continue stirring 3h, be then stirred at room temperature, by TLC with Track reacts.Treat that intermediate is wholly absent, by reactant liquor concentrating under reduced pressure, and in residue, add saturated NaHCO3Aqueous solution (30mL), CH is used2Cl2(50mL × 3) extract, and merge organic facies and wash by saturated NaCl solution (20mL), anhydrous Na2SO4Dry Dry, filter, concentrating under reduced pressure, crude product is separated (eluent: PE/DCM (v/v)=1/1) by silica gel column chromatography, and obtaining product is nothing Color oily liquids (1.40g, 63%).
MS(ESI,pos.ion)m/z:126.1[M+1]+。
Step 2: 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-morpholine acrylate-1-alkynes-1-base) phenyl) acetamide Synthesis
Under nitrogen protection, by 4-(acrylate-2-alkynes-1-base) morpholine (420mg, 3.36mmol), 2-(4-ethylsulfonyl benzene Base)-N-(4-iodophenyl) acetamide (450mg, 1.05mmol), CuI (45mg, 0.23mmol) and Pd (PPh3)2Cl2(400mg, 0.56mmol) it is dissolved in THF (50mL), adds DIPEA (2.00mL, 11.4mmol), react under 50 DEG C of oil bath heating conditions Stirring reaction 8h.Reactant liquor being cooled to room temperature, is filtered to remove insoluble matter, filtrate concentrates.Add saturated in residue NaHCO3Aqueous solution (20mL), extracts with EtOAc (30mL × 3), and organic facies is washed with saturated NaCl aqueous solution (20mL), anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: DCM/EtOAc (v/v)=2/1) by silica gel column chromatography, obtains mesh Mark thing is faint yellow solid (470mg, 33%).
MS(ESI,pos.ion)m/z:427.2[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.35 (s, 1H), 7.79 (d, J=8.2Hz, 2H), 7.48 (d, J= 8.3Hz, 4H), 7.33 (d, J=8.5Hz, 2H), 3.80 (dd, 4H), 3.75 (s, 2H), 3.57 (s, 2H), 3.09 (q, J= 7.4Hz, 2H), 2.73 (m, 4H), 1.25 (t, J=7.4Hz, 3H).
Embodiment 10:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(piperidin-1-yl) acrylate-1-alkynes-1-base) phenyl) The synthesis of acetamide (compound 9)
The synthesis of step one: 1-(acrylate-2-alkynes-1-base) piperidines
At room temperature, in 100mL single port bottle, by Et3N (3.1mL, 22mmol) and MsCl (1.68mL, 21.7mmol) It is sequentially added into the CH of propargyl alcohol (1.00mL, 17.2mmol)2Cl2(30mL), in solution, after 0.5h, reaction system is cooled to-20 DEG C, under stirring, adding piperidines (3.3mL, 36mmol), reaction is stirred 3h under this condition, is then stirred at room temperature.By TLC with Track, after intermediate disappears, concentrating under reduced pressure, in residue, add saturated NaHCO3Aqueous solution (20mL), then uses CH2Cl2 (30mL × 3) extract, and organic facies saturated NaCl solution (20mL) is washed, anhydrous Na2SO4Be dried, filter, concentrate, crude product by Silica gel is through column chromatography for separation (eluent: PE/DCM (v/v)=1/1), and obtaining product is colourless transparent liquid (1.40g, 66%).
MS(ESI,pos.ion)m/z:124.1[M+1]+。
Step 2: 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(piperidin-1-yl) acrylate-1-alkynes-1-base) phenyl) second The synthesis of amide
Under nitrogen protection, by 1-(acrylate-2-alkynes-1-base) piperidines (220mg, 1.78mmol), 2-(4-ethylsulfonyl benzene Base)-N-(4-iodophenyl) acetamide (250mg, 0.58mmol), CuI (25mg, 0.13mmol) and Pd (PPh3)2Cl2(200mg, 0.28mmol) it is dissolved in THF (50mL), adds DIPEA (0.7mL, 4mmol).React on and stir under 50 DEG C of oil bath heating conditions Reaction 8h.Reactant liquor being cooled to room temperature, is filtered to remove insoluble matter, filtrate concentrates.Saturated NaHCO is added in residue3Water Solution (20mL), extracts with EtOAc (30mL × 3), and organic facies is washed with saturated NaCl aqueous solution (20mL), anhydrous Na2SO4Dry Dry, concentrating under reduced pressure, crude product is separated (eluent: DCM/EtOAc (v/v)=3/1) by silica gel column chromatography, and it is light for obtaining object Yellow solid (470mg, 62%).
MS(ESI,pos.ion)m/z:425.2[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.55 (s, 1H), 7.83 (d, J=7.9Hz, 2H), 7.53 (m, 4H), 7.33 (d, J=8.0Hz, 2H), 4.05 (s, 2H), 3.81 (s, 2H), 3.54 (d, J=10.2Hz, 2H), 3.12 (q, J= 7.4Hz, 2H), 2.95 (m, 2H), 2.04-1.86 (m, 4H), 1.30 1.25 (m, 2H), 1.27 (t, J=7.4Hz, 3H).
Embodiment 11:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-(trifluoromethoxy) phenyl) acrylate-1-alkynes- 1-yl) phenyl) synthesis of acetamide (compound 10)
The synthesis of step one: 1-(4-(trifluoromethoxy) phenyl) acrylate-2-alkynes-1-alcohol
At 0 DEG C, 4-(trifluoromethyl) benzaldehyde (3.01g, 15.8mmol) is dissolved in the THF of 15mL, by acetenyl Magnesium bromide (35mL, 17.5mmol) is slowly added to system, is warmed to room temperature reaction 3h.Reactant liquor is poured in water (25mL), use EtOAc (25mL × 3) extracts, and merges organic facies and washs by saturated NaCl solution (25mL), anhydrous Na2SO4It is dried, reduces pressure dense Contracting, crude product is separated (eluent: PE/EtOAc (v/v)=5/1) by silica gel column chromatography, and obtaining product is yellow oil (2.9g, 85%).
MS(ESI,pos.ion)m/z:199.0[M-18]+。
The synthesis of step 2: 1-(acrylate-2-alkynes-1-base)-4-(trifluoromethoxy) benzene
1-(4-(trifluoromethoxy) phenyl) acrylate-2-alkynes-1-alcohol (1.19g, 5.51mmol) is dissolved in CH2Cl2(10mL) in And it is cooled to-5 DEG C, in system, it is sequentially added into Et3SiH (2.1mL, 13mmol) and NH4F (450mg, 12.15mmol), 20min After, add TFA (1.4mL, 19mmol), room temperature reaction 2h.Reactant liquor is poured in water (30mL), with EtOAc (30mL × 3) Extraction, organic facies saturated NaCl solution (15mL) washing, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is by silica gel column chromatography Separating (eluent: PE), obtaining product is yellow oil (762mg, 69%).
The synthesis of step 3: 2-(4-(methyl sulphonyl) phenyl)-N-(4-iodophenyl) acetamide
By 4-Iodoaniline (303mg, 1.38mmol), 2-(4-ethylsulfonyl phenyl) acetic acid (345mg, 1.51mmol), EDCI (1.06g, 5.53mmol) and HOBT (280mg, 2.06mmol) is dissolved in CH2Cl2(15mL) in, and DIPEA is added (0.9mL, 5mmol), room temperature reaction 3h.Being poured into by reactant liquor in water (15mL), extract with EtOAc (15mL × 3), organic facies is used Saturated NaCl solution (15mL) is washed, anhydrous Na2SO4Be dried, concentrating under reduced pressure, crude product by silica gel column chromatography separate (eluent: PE/EtOAc (v/v)=1/1), obtaining product is colourless powder solid (491mg, 83%).
MS(ESI,pos.ion)m/z:429.80[M+1]+。
Step 4: compound 2-(4-(methyl sulphonyl) phenyl)-N-(4-(3-(4-(trifluoromethoxy) phenyl) acrylate-1- Alkynes-1-base) phenyl) synthesis of acetamide
Under nitrogen protection, by 1-(acrylate-2-alkynes-1-base)-4-(trifluoromethoxy) benzene (153mg, 0.76mmol), 2- (4-(methyl sulphonyl) phenyl)-N-(4-iodophenyl) acetamide (220mg, 0.51mmol), CuI (10mg, 0.052mmol) and Pd(PPh3)2Cl2(54mg, 0.076mmol) is dissolved in THF (10mL), adds Et3N (0.29mL, 2.1mmol), is stirred at room temperature 5h.Being filtered to remove insoluble matter, filtrate concentrates, silica gel column chromatography separate (eluent: PE/EtOAc (v/v)=1/5), obtain mesh Mark thing is yellow powdery solid (170mg, 44%).
MS(ESI,pos.ion)m/z:502.05[M+1]+；
1H NMR (600MHz, DMSO) δ (ppm): 10.40 (s, 1H), 7.85 (d, J=8.2Hz, 2H), 7.61 (dd, J= 8.5,2.7Hz, 4H), 7.53 (d, J=8.5Hz, 2H), 7.40 (d, J=8.6Hz, 2H), 7.36 (d, J=8.2Hz, 2H), 3.93 (s, 2H), 3.82 (s, 2H), 3.28 (d, J=7.4Hz, 2H), 1.10 (t, J=7.3Hz, 3H).
Embodiment 12:N-(4-(3-(4-(difluoro-methoxy) phenyl) butyl-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphur Acyl group) phenyl) synthesis of acetamide (compound 11)
The synthesis of step one: 1-(4-(difluoro-methoxy) phenyl) ethanol
4-(difluoro-methoxy) benzaldehyde (457mg, 2.66mmol) is dissolved in THF (40mL) and reaction system is cooled to 0 DEG C, under stirring, by the Et of MeMgBr2O solution (3.0M, 3.0mL) is added drop-wise in reaction system, after 30min, is warming up to room temperature And continue to be stirred overnight.Saturated NH is added in reactant liquor4Aqueous solution (20mL) the cancellation reaction of Cl, then with EtOAc (40mL × 3) extraction, merges organic facies, and uses anhydrous Na2SO4Be dried, concentrating under reduced pressure, crude product by silica gel column chromatography separate (eluent: PE/EtOAc (v/v)=4/1), obtaining object is colourless oil liquid (450mg, 90%).
The synthesis of step 2: 1-(difluoro-methoxy)-4-(4-(4-nitrobenzophenone) butyl-3-alkynes-2-base) benzene
Under nitrogen protection, by 1-(4-(difluoro-methoxy) phenyl) ethanol (102mg, 0.54mmol) and trimethyl ((4- Nitrobenzophenone) acetenyl) silane (233mg, 1.06mmol) is dissolved in 1,2-dichloroethanes (15mL), is subsequently adding InCl3 (20mg, 0.090mmol), reacts on stirring reaction 3h in 80 DEG C of oil baths, and concentrating under reduced pressure, mixture is separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=50/1), obtaining object is yellow oil (150mg, 87%).
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl) butyl-1-alkynes-1-base) aniline
1-(difluoro-methoxy)-4-(4-(4-nitrobenzophenone) butyl-3-alkynes-2-base) benzene (152mg, 0.48mmol) is dissolved in MeOH/H2In O (3/1,28mL), and add NH according to this4Cl solid (260mg, 4.86mmol) and reduced iron powder (150mg, 2.68mmol), react return stirring 3h, filter, wash filter cake, filtrate anhydrous Na with EtOAc (20mL)2SO4It is dried, decompression Concentrating, obtaining crude product is red oil (100mg, 73%).
MS(ESI,pos.ion)m/z:288.1[M+1]+。
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl) butyl-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphonyl Base) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) butyl-1-alkynes-1-base) aniline (403mg, 1.40mmol), 2-(4-second Base sulfonvlphenyl) acetic acid (500mg, 2.19mmol) and HATU (1.60g, 4.2mmol) be dissolved in DCM (15mL), and by ice bath Cooling, then drips DIPEA (1.2mL, 7.3mmol) in stirring in reaction system, reacts on and reaction is stirred at room temperature overnight, Concentrating under reduced pressure, mixture is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography and further preparative hplc is divided It is white solid (130mg, 18%) from obtaining object.
MS:(ESI,pos.ion)m/z:498.2[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.89 (d, J=8.1Hz, 2H), 7.54 (d, J=7.7Hz, 3H), 7.46 (t, J=9.4Hz, 4H), 7.39 (d, J=8.4Hz, 2H), 7.28 (s, 1H), 7.11 (d, J=8.4Hz, 2H), 6.51 (t, J=74.1Hz, 1H), 4.15 (q, J=7.1Hz, 1H), 3.98 (q, J=7.0Hz, 1H), 3.81 (s, 2H), 3.14 (q, J =7.4Hz, 2H), 1.58 (d, J=7.1Hz, 3H), 1.31 (t, 3H)；
13C NMR(151MHz,CDCl3)δ171.07,167.56,149.71,140.72,140.49,137.46, 137.08,132.38,130.27,128.75,128.30,119.73,119.47,117.72,116.00,114.20,92.03, 82.14,60.44,50.66,44.22,29.70,22.71,14.14。
Embodiment 13:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-formyl piperazine-1-base) acrylate-1-alkynes-1- Base) phenyl) synthesis of acetamide (compound 12)
The synthesis of step one: 4-(acrylate-2-alkynes-1-base) piperazine-1-Methanamide
Piperazine 1-Methanamide (580mg, 5.08mmol) is slowly added dropwise into 3-propargyl bromide (0.50mL, 5.80mmol) and K2CO3In MeCN (50mL) solution of (1.10g, 6.14mmol), 7h is stirred at room temperature.Concentrating under reduced pressure, residue CH2Cl2 (60mL) dissolve, the most successively by water (20mL) and saturated NaCl solution (20mL) washing, anhydrous Na2SO4It is dried, concentrating under reduced pressure, Obtaining product is yellow transparent liquid (519mg, 59%).
MS(ESI,pos.ion)m/z:153.1[M+1]+。
Step 2: 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-formyl piperazine-1-base) acrylate-1-alkynes-1- Base) phenyl) synthesis of acetamide
Under nitrogen protection, by 4-(acrylate-2-alkynes-1-base) piperazine-1-Methanamide (220mg, 1.45mmol), 2-(4-second Base sulfonvlphenyl)-N-(4-iodophenyl) acetamide (250mg, 0.58mmol), CuI (25mg, 0.13mmol) and Pd (PPh3)2Cl2(200mg, 0.28mmol) is dissolved in THF (50mL), adds DIPEA (0.7mL, 4mmol).React on 50 DEG C of oil bath heating Under the conditions of stirring reaction 8h.Reactant liquor being cooled to room temperature, is filtered to remove insoluble matter, filtrate concentrates.Add full in residue And NaHCO3Aqueous solution (20mL), extracts with EtOAc (30mL × 3), and organic facies is washed with saturated NaCl aqueous solution (20mL), nothing Water Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: DCM/EtOAc (v/v)=1/1) by silica gel column chromatography, obtains Object is white solid (270mg, 41%).
MS(ESI,pos.ion)m/z:454.2[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 8.55 (s, 1H), 8.04 (s, 1H), 7.82 (d, J=8.2Hz, 2H), 7.51 (t, J=7.8Hz, 4H), 7.34 (d, J=8.5Hz, 2H), 3.77 (s, 2H), 3.61 (m, 2H), 3.57 (s, 2H), 3.46 (dd, 2H), 3.11 (q, J=7.4Hz, 2H), 2.66 (dd, 2H), 2.61 (dd, 2H), 1.27 (t, J=7.4Hz, 3H).
Embodiment 14:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-(2,2,2-trifluoroethyl) piperazine-1-base) Acrylate-1-alkynes-1-base) phenyl) synthesis of acetamide (compound 13)
The synthesis of step one: 4-(2,2,2-trifluoroethyl) piperazine-1-t-butyl formate
To add TFA (1.5mL, 20mmol), the 1-piperazinecarboxylic acid tert-butyl ester (2.00g, 10.7mmol) and HATU (0.8g, 2mmol) it is dissolved in CH2Cl2(40mL), in, it is subsequently adding Et3N (1.50mL, 10.7mmol), is stirred at room temperature 8h.Use CH2Cl2 (40mL) dilute reaction solution, uses saturated NaHCO the most successively3Solution (30mL) and saturated NaCl solution (30mL) washing, anhydrous Na2SO4Being dried, filter, concentrating under reduced pressure, crude product is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography, It is faint yellow solid (1.50g, 50%) to product.
MS(ESI,pos.ion)m/z:283.3[M+1]+。
The synthesis of step 2: 4-(2,2,2-trifluoroethyl) piperazine-1-t-butyl formate
Under nitrogen protection, by 4-(2,2,2-trifluoroacetyl group) piperidines-1-t-butyl formate in single port flask (1.62g, 5.74mmol) is dissolved in anhydrous THF (32mL), under room temperature, by BH3·Me2The THF solution (2.0mol/L, 15mL) of S drips It is added in reaction system, 1h, back flow reaction 5h are stirred at room temperature.Reactant liquor is cooled to room temperature, under ice bath cooling, to reaction system Middle dropping NH4Cl solution (15mL) cancellation is reacted, and then concentrating under reduced pressure removes THF, remains aqueous phase CH2Cl2(30mL × 3) extract Take, organic facies anhydrous Na2SO4Being dried, concentrate, crude product is separated (eluent: PE/EtOAc (v/v)=5/ by silica gel column chromatography 1), obtaining product is brown oil (960mg, 62%).
MS(ESI,pos.ion)m/z:269.3[M+1]+。
The synthesis of step 3: 1-(2,2,2-trifluoroethyl) piperazine
4-(2,2,2-trifluoroethyl) piperazine-1-t-butyl formate (510mg, 1.90mmol) is dissolved in CH2Cl2(19mL) With TFA (5mL), under room temperature, stir 3h.Reacting liquid filtering, filtrate concentrates, and obtaining crude product is weak yellow liquid (300mg, 94%).
MS(ESI,pos.ion)m/z:169.3[M+1]+。
The synthesis of step 4: 1-(acrylate-2-alkynes-1-base)-4-(2,2,2-trifluoroethyl) piperazine
In single port flask, by 1-(2,2,2-trifluoroethyl) piperazine (1.55g, 8.32mmol) and K2CO3(1.00g, 5.58mmol) it is dissolved in MeCN (45mL), reactant liquor is cooled to-5 DEG C, in reaction system, then drip 3-propargyl bromide (1.20mL, 13.2mmol), finishes, and reacts on stirring reaction at a temperature of this, TLC follows the tracks of reaction.Treat that raw material converts completely, will Reacting liquid filtering, decompression removes MeCN, residue CH2Cl2(100mL) dissolve, the most successively with water (30mL) and saturated NaCl Solution (30mL) washs, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: PE/EtOAc by silica gel column chromatography (v/v)=5/1), obtaining product is yellow solid (383mg, 98%).
Step 5: 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-(4-(2,2,2-trifluoroethyl) piperazine-1-base) Acrylate-1-alkynes-1-base) phenyl) synthesis of acetamide
Under nitrogen protection, by 1-(acrylate-2-alkynes-1-base)-4-(2,2,2-trifluoroethyl) piperazine (290mg, 1.4063mmol), 2-(4-ethylsulfonyl phenyl)-N-(4-iodophenyl) acetamide (250mg, 0.58mmol), CuI (25mg, 0.13mmol) with Pd (PPh3)2Cl2(200mg, 0.28mmol) is dissolved in THF (50mL), adds DIPEA (0.7mL, 4mmol).Instead Should in 50 DEG C of oil baths relatively thermal agitation 6h.Reactant liquor being cooled to room temperature, is filtered to remove insoluble matter, filtrate concentrates.To residue The saturated NaHCO of middle addition3Aqueous solution (20mL), extracts with EtOAc (30mL × 3), and organic facies is with saturated NaCl aqueous solution (20mL) washing, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: DCM/EtOAc (v/ by silica gel column chromatography V)=15/1), obtaining object is faint yellow solid (170mg, 24%).
MS(ESI,pos.ion)m/z:508.6[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.86 (d, J=7.9Hz, 2H), 7.52 (d, J=7.9Hz, 2H), 7.46 (d, J=6.9Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.37 (d, J=8.2Hz, 2H), 3.79 (s, 2H), 3.50 (s, 2H), 3.12 (q, J=7.4Hz, 2H), 2.98 (q, J=9.6Hz, 2H), 2.76 (m, 4H), 2.68 (m, 4H), 1.28 (t, J =7.4Hz, 3H).
Embodiment 15:N-(4-(3-(4-(difluoro-methoxy) phenyl) amyl-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphur Acyl group) phenyl) synthesis of acetamide (compound 14)
The synthesis of step one: 1-(4-(difluoro-methoxy) phenyl) acrylate-1-alcohol
4-(difluoro-methoxy) benzaldehyde (1.57g, 9.12mmol) is dissolved in THF (100mL) and is cooled with an ice bath, so Backward system drips the Et of EtMgBr2O solution (3.0M, 10mL), after 30min, is warming up to room temperature reaction overnight.Ice bath cools down Under, in reaction system, drip saturated NH4Cl aqueous solution (50mL) cancellation is reacted, then EtOAc (100mL × 3) extraction, merges Organic facies also uses anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: PE/EA (v/v)=4/ by silica gel column chromatography 1), obtaining object is yellow oil (1.7g, 92%).
The synthesis of step 2: 1-(difluoro-methoxy)-4-(1-(4-nitrobenzophenone) amyl-1-alkynes-3-base) aniline
Under nitrogen protection, by 1-(4-(difluoro-methoxy) phenyl) acrylate-1-alcohol (463mg, 2.29mmol) and trimethyl (2-(4-nitrobenzophenone) acetenyl) silane (1.0g, 4.6mmol) is dissolved in 1, in 2-dichloroethanes (40mL), adds InCl3 (54mg, 0.24mmol), then stirring reaction 3h in 80 DEG C of oil baths, concentrating under reduced pressure, crude on silica gel column chromatography for separation (is drenched Lotion: PE/EtOAc (v/v)=50/1), obtaining object is yellow oil (0.70g, 92%).
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl) amyl-1-alkynes-1-base) aniline
By molten for 1-(difluoro-methoxy)-4-(1-(4-nitrobenzophenone) amyl-1-alkynes-3-base) aniline (702mg, 2.12mmol) In MeOH/H2In O (3/1) (40mL) mixed solvent, it is sequentially added into NH4Cl (1.2g, 22mmol) and reduced iron powder (600mg, 10.71mmol), back flow reaction 3h.Reacting liquid filtering, washs with EtOAc (200mL), filtrate anhydrous Na2SO4It is dried, decompression Concentrating, obtaining crude product is red oil (600mg, 94%), and this crude product is directly used in next step reaction.
MS(ESI,pos.ion)m/z:302.1[M+1]+。
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl) amyl-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphonyl Base) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) amyl-1-alkynes-1-base) aniline (602mg, 2.0mmol), 2-(4-ethyl Sulfonyl benzene) acetic acid (700mg, 3.07mmol) and HATU (2.3g, 6.0mmol) be dissolved in CH2Cl2(50mL), under ice bath cooling, Dropping DIPEA (2mL, 12.1mmol), is warmed to room temperature stirring reaction overnight after 10min.Concentrating under reduced pressure, crude product is by silica gel column layer Analysis separates (eluent: PE/EtOAc (v/v)=1/1) and preparative separation, and obtaining object is white solid (64mg, 6%).
MS(ESI,pos.ion)m/z:512.2[M+1]+；
1HNMR(400MHz,CDCl3) δ (ppm): 7.93 (d, J=7.9Hz, 2H), 7.57 (d, J=7.9Hz, 2H), 7.43 (dd, J=19.6,8.1Hz, 6H), 7.11 (d, J=8.4Hz, 2H), 6.42 (d, J=74.1Hz, 1H), 3.83 (s, 2H), 3.79 (t, J=7.0Hz, 1H), 3.15 (q, J=7.4Hz, 2H), 1.92 1.77 (m, 3H), 1.06 (t, J=7.3Hz, 6H)；
13C NMR(101MHz,CDCl3)δ(ppm):167.33,149.92,140.51,139.21,137.83,136.96, 132.41,130.27,128.86,119.92,119.59,119.46,118.58,116.01,113.43,90.93,83.04, 50.65,44.32,39.32,29.69,23.35,22.68,14.09,11.74,7.39。
Embodiment 16:N-(4-(3-(4-(difluoro-methoxy) phenyl)-3-phenyl acrylate-1-alkynes-1-base) phenyl)-2-(4- (ethylsulfonyl) phenyl) synthesis of acetamide (compound 15)
Step one: the synthesis of (4-(difluoro-methoxy) phenyl) (phenyl) methanol
4-(difluoro-methoxy) benzaldehyde (580mg, 3.37mmol) is dissolved in THF (40mL), and with ice bath, then will The THF solution (2M, 9.0mL) of PhMgBr is added drop-wise in system, after 30min, reaction is moved to room temperature, is stirred overnight.
Under ice bath cooling, in reaction system, drip saturated NH4Cl aqueous solution (30mL) cancellation is reacted, and mixed liquor is used EtOAc (50mL × 3) extracts, and merges organic facies, and uses anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is divided by silica gel column chromatography From (eluent: PE/EtOAc (v/v)=10/1), obtaining object is pale yellow oily liquid body (780mg, 93%).
1H NMR(400MHz,CDCl3) δ (ppm): 7.44 7.34 (m, 6H), 7.34 7.29 (m, 1H), 7.11 (d, J= 8.5Hz, 2H), 6.51 (t, J=74.0Hz, 1H), 5.86 (s, 1H), 2.28 (s, 1H).
The synthesis of step 2: 1-(difluoromethyl)-4-(3-(4-nitrobenzophenone)-1-phenyl acrylate-2-alkynes-1-base) benzene
Under nitrogen protection, by 4-(difluoro-methoxy) phenyl) (phenyl) methanol (781mg, 3.12mmol) and trimethyl (2-(4-nitrobenzophenone) acetenyl) silane (1.0g, 4.6mmol) is dissolved in 1, and 2-dichloroethanes (40mL) is subsequently adding InCl3 (70mg, 0.32mmol), reaction is by 80 DEG C of oil bath heated and stirred 3h.Concentrating under reduced pressure, mixture is separated (drip washing by silica gel column chromatography Agent: PE/EtOAc (v/v)=50/1), obtaining object is yellow oil (700mg, 59%).
The synthesis of step 3: 4-(3-(4-(difluoro-methoxy) phenyl)-3-phenyl acrylate-1-alkynes-1-base) aniline
By 1-(difluoromethyl)-4-(3-(4-nitrobenzophenone)-1-phenyl acrylate-2-alkynes-1-base) benzene (695mg, 1.83mmol) it is dissolved in MeOH/H2In O (3/1,40mL), then it is sequentially added into NH4Cl solid (1.0g, 18.70mmol) and reduction Iron powder (520mg, 9.29mmol), back flow reaction 3h.Filter, and wash with EtOAc (20mL), filtrate separatory, and with anhydrous Na2SO4Being dried organic facies, concentrating under reduced pressure, obtaining crude product is red oil (580mg, 91%), and crude product is directly used in down Single step reaction.
MS(ESI,pos.ion)m/z:350.1[M+1]+。
Step 4: N-(4-(3-(4-(difluoro-methoxy) phenyl)-3-phenyl acrylate-1-alkynes-1-base) phenyl)-2-(4-(second Base sulfonyl) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl)-3-phenyl acrylate-1-alkynes-1-base) aniline (580mg, 1.67mmol), 2-(4-ethylsulfonyl phenyl) acetic acid (600mg, 2.63mmol) and HATU (2.0g, 5.3mmol) are dissolved in DCM (50mL), ice Under bath cooling and stirring, adding DIPEA (2mL, 12.1mmol), after 10min, reaction moves to room temperature, is stirred overnight.Concentrating under reduced pressure, Crude product is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography and separates with further preparative hplc, obtains mesh Mark thing is white solid (200mg, 21%).
MS(ESI,pos.ion)m/z:560.2[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.92 (d, J=8.1Hz, 2H), 7.56 (d, J=8.0Hz, 2H), 7.44 (dd, J=8.7,7.6Hz, 8H), 7.35 (t, J=7.5Hz, 2H), 7.09 (d, J=8.5Hz, 2H), 6.41 (d, J= 74.0Hz, 1H), 5.21 (s, 1H), 3.83 (s, 2H), 3.15 (q, J=7.4Hz, 2H), 1.32-1.28 (m, 3H)；
13C NMR(151MHz,CDCl3)δ(ppm):167.01,149.95,141.21,140.05,138.85,137.57, 137.10,132.50,130.30,129.28,128.85,128.76,127.83,127.14,119.72,119.44,117.61, 115.81,114.06,89.48,84.45,50.66,44.31,43.09,7.43。
Embodiment 17:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-aminomethyl phenyl)-2-(4- (ethylsulfonyl) phenyl) synthesis of acetamide (compound 16)
The synthesis of step one: 1-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methyl-4-Nitrobenzol
Under nitrogen protection, by 1-(difluoro-methoxy)-4-(acrylate-2-alkynes-1-base) benzene (800mg, 4.39mmol) and 1- Bromo-2-methyl-4-Nitrobenzol (950mg, 4.39mmol) is dissolved in THF (50mL), be then sequentially added into CuI (45mg, 0.23mmol)、Pd(PPh3)2Cl2(400mg, 0.56mmol) and DIPEA (2.00mL, 11.4mmol), room temperature reaction, by TLC Follow the tracks of reaction.After reaction terminates, reactant liquor being cooled to room temperature, be filtered to remove insoluble matter, filtrate concentrates.Add in residue Saturated NaHCO3Aqueous solution (150mL), extracts with EtOAc (200mL × 3), and organic facies saturated NaCl solution (50mL) is washed, Anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: PE/CH by silica gel column chromatography2Cl2(v/v)=1/3), It is yellow-brown solid (270mg, 19%) to object.
The synthesis of step 2: 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-monomethylaniline.
1-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-2-methyl-4-is added in 100mL single port flask Nitrobenzol (191mg, 0.60mmol) also dissolves with MeOH (38mL), is then sequentially added into NH4The aqueous solution of Cl (141mg, 16mL, 2.63mmol) and reduced iron powder (0.50g, 9.0mmol), reactant liquor is reacting by heating 6h in 50 DEG C of oil baths.Then will be anti- Answering liquid to be cooled to room temperature, filter, filtrate concentrates, raffinate CH2Cl2(40mL × 3) extract, organic facies anhydrous Na2SO4Dry Dry, concentrating under reduced pressure, crude product is separated (eluent: PE/CH by silica gel column chromatography2Cl2(v/v) object=1/1), is obtained for Huang Brown solid (90mg, 52%).
MS(ESI,pos.ion)m/z:288.2[M+1]+。
Step 3: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-aminomethyl phenyl)-2-(4-(second Base sulfonyl) phenyl) synthesis of acetamide
By 4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base)-3-monomethylaniline. (41mg, 0.14mmol), 2- (4-ethylsulfonyl benzene) acetic acid (60mg, 0.26mmol), HOBt (50mg, 0.36mmol), EDCI (72mg, 0.37mmol) and CH2Cl2(5mL) it is sequentially added in the single port flask of 100mL, is stirred at room temperature, TLC follow the tracks of reaction.After 8h, stop stirring, reaction Liquid CH2Cl2(50mL) dilution, uses saturated NaHCO the most successively3Solution (10mL) and NaCl solution (10mL) washing, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography, obtains target Thing is faint yellow solid (65mg, 91%).
MS(ESI,pos.ion)m/z:498.2[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 7.86 (d, J=7.8Hz, 2H), 7.70 (m, 1H), 7.52 (d, J= 6.9Hz, 4H), 7.40 (d, J=8.5Hz, 2H), 7.33 (d, J=8.3Hz, 1H), 7.23 7.21 (m, 1H), 7.09 (d, J= 8.1Hz, 2H), 6.49 (t, J=74.1Hz, 1H), 3.84 (s, 2H), 3.78 (s, 2H), 3.11 (q, J=7.3Hz, 2H), 2.39 (s, 3H), 1.30 (t, J=7.3Hz, 3H).
Embodiment 18:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-((1r, 4r)-4-(trifluoromethyl) cyclohexyl) Acrylate-1-alkynes-1-base) phenyl) acetamide (compound 17a) and 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-((1s, 4s)- 4-(trifluoromethyl) cyclohexyl) acrylate-1-alkynes-1-base) phenyl) synthesis of acetamide (compound 17b)
The synthesis of step one: 2-(the sub-cyclohexyl of 4-(trifluoromethyl)) ethyl acetate
Under the conditions of anhydrous and oxygen-free, NaH (60%, 400mg, 10mmol) is placed in 100mL twoport flask, and uses THF (32mL) dissolve, and at-20 DEG C, drip ethyl 2-(diethoxy phosphinylidyne) acetas (2.05g, 9.14mmol), at a temperature of being somebody's turn to do Stirring 2h, is then slowly added into 4-(trifluoromethyl) Ketohexamethylene (1.20g, 7.22mmol), finishes, reactant liquor is slowly increased to room Temperature also stirs reaction 8h.After reaction terminates, decompression steams THF, residue CH2Cl2(20mL × 3) extract.Organic facies is with anhydrous Na2SO4Being dried, concentrate, crude on silica gel column chromatography for separation (eluent: PE/EA (v/v)=5/1), obtaining object is nothing Color transparency liquid (1.33g, 62%).
The synthesis of step 2: 2-(4-(trifluoromethyl) cyclohexyl) ethyl acetate
Add in 100mL single port flask 2-(4-(trifluoromethyl) sub-cyclohexyl) ethyl acetate (2.11g, 8.93mmol) and with MeOH (50mL) dissolving, be subsequently adding Pd/C (5%, 155mg, 1.46mmol), reaction mixture is at H2 55 DEG C of reaction 3h it are heated under the conditions of (balloon).Reacting liquid filtering, filtrate concentrate after, by silica gel column chromatography separate (eluent: PE/CH2Cl2(v/v)=5/1), obtaining object is colourless transparent liquid (1.30g, 61%).
The synthesis of step 3: 2-(4-(trifluoromethyl) cyclohexyl) ethanol
Under the conditions of anhydrous and oxygen-free, 2-(4-(trifluoromethyl) cyclohexyl) ethyl acetate (1.21g, 5.08mmol) is placed in In 100mL single port flask, and dissolve with THF (32mL), under ice bath cooling, by BH3THF solution (2.0mL, 20mmol, 10.0mol/L) it is added drop-wise in reaction system, after 1h is stirred at room temperature, back flow reaction 5h.After reaction terminates, reactant liquor is cooled to Room temperature, under ice bath cooling, drips NH in reaction system4Cl solution (15mL) cancellation react, decompression steam THF, residue by CH2Cl2(20mL × 3) extract, and merge organic facies and use anhydrous Na2SO4Being dried, concentrate, crude product is separated by silica gel column chromatography (eluent: PE/EtOAc (v/v)=5/1), obtaining object is colourless transparent liquid (887mg, 89%).
MS(ESI,pos.ion)m/z:197.1[M+1]+。
The synthesis of step 4: 2-(4-(trifluoromethyl) cyclohexyl) acetaldehyde
In 100mL single port bottle, 2-(4-(trifluoromethyl) cyclohexyl) ethanol (1.10g, 5.61mmol) is dissolved in CH2Cl2 (42mL), in and in-10 DEG C of coolings, it is subsequently adding Dess-Martin reagent (3.4g, 7.9mmol), after 10min, reaction is put Reaction 6h is stirred at room temperature.Reactant liquor is cooled down by ice bath, and slowly add water (10mL) cancellation, and decompression removes THF, adds in residue Enter saturated NaHCO3Aqueous solution (100mL), extracts (150mL × 3) with EtOAc, and organic facies saturated NaCl solution (50mL) is washed Wash, anhydrous Na2SO4Being dried, filter, concentrate, obtaining object is colourless transparent liquid (521mg, 48%).
The synthesis of step 5: 1-(acrylate-2-alkynes-1-base)-4-(trifluoromethyl) hexamethylene
Under ice cooling, 4, in 100mL single port flask add 2-(4-(trifluoromethyl) cyclohexyl) acetaldehyde (247mg, 1.27mmol) and with MeOH (38mL) dissolve, be sequentially added into K2CO3(360mg, 2.58mmol) and (1-diazonium-2-oxo-the third Alcohol)-dimethyl phosphonate (0.35mL, 2.0mmol), reaction is reacted at such a temperature, and is followed the tracks of by TLC.Reaction will be anti-after terminating Answering liquid to be cooled to room temperature, filter, filtrate concentrates, residue CH2Cl2(80mL) dilution, washes by saturated NaCl solution (20mL) Wash, anhydrous Na2SO4Being dried, filter, concentrate, obtaining object is colourless transparent liquid (210mg, 87%).
The synthesis of step 6: 2-(4-(ethylsulfonyl) phenyl)-N-(4-iodobenzene) acetamide
Under nitrogen protection, by molten for 1-(acrylate-2-alkynes-1-base)-4-(trifluoromethyl) hexamethylene (1.20g, 6.31mmol) In anhydrous THF (30mL), be sequentially added into 2-(4-ethylsulfonyl phenyl)-N-(4-iodophenyl) acetamide (3.10g, 7.22mmol)、CuI(55mg,0.28mmol)、Pd(PPh3)2Cl2(500mg, 0.71mmol) and DIPEA (2.7mL, 15mmol), then heated and stirred 8h in 50 DEG C of oil baths.Reactant liquor being cooled to room temperature, is filtered to remove insoluble matter, filtrate is dense Contracting.Saturated NaHCO is added in residue3Aqueous solution (30mL), extracts with EtOAc (50mL × 3), the saturated NaCl of organic facies Solution (30mL) washs, anhydrous Na2SO4It is dried, concentrates, crude on silica gel column chromatography for separation (eluent: DCM/EtOAc (v/ V)=5/1) obtain faint yellow solid (270mg, 48%), further through preparing plate and separate (developing solvent: DCM/EtOAc (v/v)= 2/1) 17a and 17b is obtained.
17a:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-((1r, 4r)-4-(trifluoromethyl) cyclohexyl) acrylate-1- Alkynes-1-base) phenyl) acetamide: white solid (35mg).
MS(ESI,pos.ion)m/z:492.3[M+1]+；
1H NMR(600MHz,CDCl3) δ 7.89 (br, 1H), 7.80 (d, J=8.1Hz, 2H), 7.47 (d, J=7.9Hz, 2H), 7.44 (d, J=8.2Hz, 1H), 7.31 (d, J=8.2Hz, 1H), 3.74 (s, 2H), 3.10 (q, J=7.4Hz, 2H), 2.32 (d, J=6.4Hz, 2H), 1.99 (m, 4H), 1.76 (m, 1H), 1.59 1.50 (m, 1H), 1.34 (dd, J=24.5, 14.1Hz, 2H), 1.26 (t, J=7.4Hz, 3H), 1.16 1.05 (m, 2H)；
17b:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-((1s, 4s)-4-(trifluoromethyl) cyclohexyl) acrylate-1- Alkynes-1-base) phenyl) acetamide: faint yellow solid (28mg).
MS(ESI,pos.ion)m/z:492.3[M+1]+；
1H NMR(600MHz,CDCl3) δ (ppm): 7.82 (d, J=7.1Hz, 2H), 7.71 (s, 1H), 7.49 (d, J= 7.5Hz, 2H), 7.43 (d, J=7.7Hz, 2H), 7.32 (d, J=7.7Hz, 2H), 3.76 (s, 2H), 3.12 (q, J=7.2Hz, 2H), 2.42 (d, J=7.3Hz, 2H), 2.10 (m, 1H), 1.94 (m, 1H), 1.81 1.74 (m, 2H), 1.74 1.67 (m, 2H), 1.63 1.60 (m, 4H), 1.27 (t, J=7.2Hz, 3H).
Embodiment 19:2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-hydroxyl-3-(2-(trifluoromethyl) pyrimidine-5- Base) acrylate-1-alkynes-1-base) phenyl) synthesis of acetamide (compound 18)
The synthesis of step one: 1-(2-(trifluoromethyl) pyrimidine-5-base) acrylate-2-alkynes-1-alcohol
Under nitrogen protection, 2-(trifluoromethyl) pyrimidine-5-formaldehyde (5.04g, 28.6mmol) is dissolved in THF (50mL) And cool down under-10 DEG C of cryostats, acetenyl magnesium bromide (0.5mol/L, 70mL, 40mmol) is slowly dropped in reaction system, React on low temperature stirring 2h, 18h is then stirred at room temperature.The cancellation of saturated NaCl aqueous solution (50mL) is added anti-in reaction system Should, then extract with DCM (50mL × 3), organic facies anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is divided by silica gel column chromatography From (eluent: PE/EtOAc (v/v)=5/1), obtaining product is yellow solid (4.5g, 78%).
MS(ESI,pos.ion)m/z:203.1[M+1]+。
Step 2: 2-(4-(ethylsulfonyl) phenyl)-N-(4-(3-hydroxyl-3-(2-(trifluoromethyl) pyrimidine-5-base) Acrylate-1-alkynes-1-base) phenyl) synthesis of acetamide
Under nitrogen protection, by 1-(2-(trifluoromethyl) pyrimidine-5-base) acrylate-2-alkynes-1-alcohol (498mg, 2.46mmol), 2-(4-ethylsulfonyl phenyl)-N-(4-iodophenyl) acetamide (1.15g, 2.68mmol), CuI (34mg, 0.18mmol) and Pd(PPh3)2Cl2(185mg, 0.26mmol) is dissolved in THF (15mL), adds TEA (0.7mL, 5.0mmol), is stirred at room temperature anti- Answer 8h.Being filtered to remove insoluble matter, filtrate concentrates.Crude product is separated (eluent: DCM/EtOAc (v/v)=2/ by silica gel column chromatography 1), obtaining object is yellow solid (479mg, 39%).
MS(ESI,pos.ion)m/z:504.5[M+1]+；
1H NMR (400MHz, DMSO) δ (ppm): 10.56 (s, 1H), 9.64 (s, 2H), 7.91 (d, J=8.6Hz, 2H), 7.86 (d, J=8.3Hz, 2H), 7.84 (d, J=2.0Hz, 2H), 7.73 (d, J=8.5Hz, 2H), 7.62 (d, J=8.1Hz, 2H), 3.86 (s, 2H), 3.28 (q, J=7.4Hz, 2H), 1.11 (t, J=7.3Hz, 3H).
Embodiment 20:N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphur Acyl group) phenyl) synthesis of-3-hydroxypropanamide (compound 19)
The synthesis of step one: 2-(4-(ethylsulfonyl) phenyl)-3-hydracrylic acid
Under nitrogen protection, 2-(4-ethylsulfonyl phenyl) acetic acid (670mg, 2.94mmol) is dissolved in anhydrous THF (32mL) in, and by reaction system in-20 DEG C of coolings, under stirring, by the Et of i-PrMgBr2O solution (3.0mol/L, 9.5mL, 29mmol) it is added dropwise in reaction system, reacts on-20 DEG C of stirring 3h, 3h is then stirred at room temperature, then by paraformaldehyde (800mg, 8.70mmol) joins in reaction system, reacts on and 3h is stirred at room temperature.Reactant liquor is poured into saturated NH4Cl aqueous solution (15mL), in, vacuum rotary steam removes THF, aqueous phase CH2Cl2(20mL × 3) extract, and merge organic facies and use saturated NaCl solution (20mL) washing, anhydrous Na2SO4Being dried, crude product is separated (eluent: PE/EtOAc (v/v)=5/1) by silica gel column chromatography, It is weak yellow foam shape solid (590mg, 78%) to product.
MS(ESI,pos.ion)m/z:259.4[M+1]+。
The synthesis of step 2: 2-(4-(ethylsulfonyl) phenyl)-3-hydroxy-n-(4-iodobenzene) propionic acid amide.
By 2-(4-(ethylsulfonyl) phenyl)-3-hydracrylic acid (500mg, 1.94mmol), 4-Iodoaniline (510mg, 2.33mmol), EDCI (800mg, 4.09mmol) and HOBT (500mg, 3.59mmol) is dissolved in CH2Cl2(15mL), it is stirred at room temperature 8h.Reactant liquor CH2Cl2(50mL) dilution, uses saturated NaHCO successively3Solution (20mL) and saturated NaCl solution (20mL) are washed Wash, anhydrous Na2SO4Being dried, concentrating under reduced pressure, crude product is separated (eluent: PE/EtOAc (v/v)=1/1) by silica gel column chromatography, Obtaining product is faint yellow solid (200mg, 19%).
MS(ESI,pos.ion)m/z:460.3[M+1]+。
Step 3: N-(4-(3-(4-(difluoro-methoxy) phenyl) acrylate-1-alkynes-1-base) phenyl)-2-(4-(ethyl sulphonyl Base) phenyl) synthesis of-3-hydroxypropanamide
Under nitrogen protection, by 1-(difluoro-methoxy)-4-(acrylate-2-alkynes-1-base) benzene (100mg, 0.55mmol), 2- (4-(ethylsulfonyl) phenyl)-3-hydroxy-n-(4-iodobenzene) propionic acid amide. (100mg, 0.22mmol), CuI (22mg, 0.11mmol) with Pd (PPh3)2Cl2(55mg, 0.077mmol) is dissolved in THF (25mL), be subsequently adding DIPEA (0.30mL, 1.7mmol), heated and stirred 6h in 70 DEG C of oil baths is reacted on.Reactant liquor being cooled to room temperature, is filtered to remove insoluble matter, filtrate is dense Contracting.Saturated NaHCO is added in residue3Aqueous solution (15mL), then extracts with EtOAc (20mL × 3), and organic facies is with saturated NaCl aqueous solution (15mL) washs, anhydrous Na2SO4Being dried, concentrating under reduced pressure, obtaining crude product is faint yellow solid (30mg, 11%).
MS(ESI,pos.ion)m/z:514.6[M+1]+；
1H NMR(400MHz,CDCl3) δ (ppm): 8.32 (s, 1H), 7.77 (d, J=7.7Hz, 2H), 7.51 (d, J= 7.7Hz, 2H), 7.47 (d, J=8.1Hz, 2H), 7.37 (m, 4H), 7.08 (d, J=8.1Hz, 2H), 6.49 (t, J= 74.0Hz, 1H), 4.14 (t, J=9.8Hz, 1H), 3.92 (d, J=6.3Hz, 2H), 3.78 (s, 2H), 3.08 (q, J= 7.0Hz, 2H), 1.25 (t, J=7.1Hz, 3H).
Biological activity test
Test example 1TR-FRET is tested
1. test method
(1) preparation ROR γ test buffer and the DTT of 10mM
Preparation 100mL 1x basic experiment buffer (HEPES (pH 7.4), 100mM NaCl, 0.01%BSA), and add 154.25mg DTT, fully mix.
(2) preparation compound gradient concentration
A. preparing n-compound, be diluted to 2.5mM with 100%DMSO, then 3 times of dilutions, 11 gradient dilutions are to Final concentration of 42.34nM；
B. preparation experiment compound, reference standard compound.
(3) preparation 1x protein solution mixture
A. the desired amount of 2x B-ROR γ LBD/SA-APC protein mixture is prepared.The concentration of B-ROR γ LBD is 40nM, The concentration of SA-APC is 20nM, reverse mixing gently, incubated at room 15 minutes.It is subsequently adding the biotin of 400nM, runs gently Fall to mix, incubated at room 10 minutes；
B. the desired amount of 2x Biotin-SRC1/SA-eu protein mixture is prepared.The concentration of Bioin-SRC1 is 40nM, The concentration of SA-eu is 20nM, reverse mixing gently, incubated at room 15 minutes.It is subsequently adding the biotin of 200nM, runs gently Fall to mix, incubated at room 10 minutes；
C.1:1 mixing step a and the protein mixture of step b preparation, incubated at room 5 minutes；
D. the mixture in 25 μ L steps c is added to comprising in 384 orifice plates testing compound；
E.1000rpm one minute it is centrifuged；
F. incubated at room 1 hour.
(4) data acquisition and calculating
After incubated at room 1 hour, measure the fluorescence at 665nm and 615nm respectively with EnVision plate reader Value, and calculate suppression ratio, the final IC obtained50Value is shown in Table 1；
Suppression ratio (%)=[(X-Min)/(Max-Min)] × 100%
X is the numerical value of " 665/615 " of test compound；Min is the meansigma methods of " 665/615 " of DMSO blank； Max is the meansigma methods of " 665/615 " of 10 μMs of SRC.
2) result of the test
Table 1TR-FRET result of the test
Numbering IC50(nM)
Compound 1 22
Compound 2 26
Compound 4 23
Compound 5 41
Compound 10 26
Compound 14 40
Compound 16 15
Compound 17a 19
Compound 17b 19
Compound 19 51
Conclusion: the compounds of this invention has preferable inhibitory activity to ROR γ t.
Pharmacokinetic Evaluation
1. test method
Weigh after SD Rat Septal curfew is eaten 15 hours, carry out random packet, test-compound preparation solvent according to body weight For 5%DMSO+5%Solutol+90%Saline.For the test group of intravenous administration, give 1mg/kg to experimental animal Dosage；For the test group of oral administration, experimental animal is given the dosage of 5mg/kg.Then, it is 0,0.083 at time point (only intravenous injection group), 0.25,0.5,1.0,2.0,5.0,7.0 and 24 hours extracting vein bloods (about 0.2mL), be placed in EDTAK2Anti- In solidifying pipe, it is centrifuged 2 minutes at 11000rpm, collects blood plasma, and preserve at-20 DEG C or-70 DEG C until carrying out LC/MS/MS and dividing Analysis.Measure each time point blood plasma drug concentration, calculate pharmacokinetic parameters according to pharmaceutical concentration-time curve.
The pharmacokinetic property of the compounds of this invention passes through above experimental test, and pharmacokinetic parameter is shown in Table 2.
2. result of the test
The pharmacokinetic parameter of table 2 the compounds of this invention
Conclusion: from table 2, in the compounds of this invention rat body after oral administration, blood drug level and exposed amount level are equal Higher, clearance rate is low, and the half-life is longer, has good Pharmacokinetic Characteristics.
Finally it should be noted that also have other modes to be used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention, it is also possible to be made within the scope of the present invention Amendment or the equivalents added in the claims.All publications or patent cited in the present invention all will be as these Bright list of references.

Claims (10)

1. a compound, it is the stereoisomer of compound shown in the compound shown in formula (I) or formula (I), geometrical isomerism Body, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or it before Medicine,
Wherein:
W ring is phenyl ring, naphthalene nucleus, pyrrole ring, furan nucleus, thiphene ring, pyrazole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine ring, pyrrole Piperazine ring, pyridazine ring, quinoline ring or indole ring；
L is-C (=O)-N (R4)-CR5R6-、-N(R7)-C (=O)-CR8R9-or-N (R10)-CR11R12-；
R4、R7And R10It is each independently hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl or C1-6Hydroxy alkyl；R5、R6、R8、R9、R11 And R12It is each independently hydrogen, deuterium, hydroxyl, halogen atom, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino, C1-6Alkoxy-C1-6Alkyl-, C3-6Carbocylic radical or C3-6Halo carbocylic radical；Or R5And R6、 R8And R9、R11And R12With and they carbon atoms of being jointly connected together with form C3-6Carbocyclic ring or C2-6Heterocycle；
A is-S (O)2-R14；Wherein, R14For ethyl；
R1And R2It is each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6 Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkoxy-C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo carbocylic radical, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；Described C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alcoxyl Base, C1-6Halogenated alkoxy, C1-6Alkoxy-C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo carbocylic radical, C2-9Heterocyclic radical, C6-10Virtue Base and C1-9Heteroaryl individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, nitro, cyano group, amino, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl and C1-6The group of alkoxyl is replaced；Or,
R1、R2And form C together with the carbon atom being jointly connected with them3-6Carbocyclic ring or C2-6Heterocycle；Described C3-6Carbocyclic ring and C2-6Miscellaneous Ring individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, amino, nitro, cyano group, methyl and fluoroform The group of base is replaced；
Each R3Independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Alcoxyl Base, C1-6Halogenated alkoxy, C1-6Hydroxy alkyl or C1-6Alkylamino；
T ring is C3-10Carbocyclic ring, C2-9Heterocycle, C6-10Aromatic ring or C1-9Hetero-aromatic ring；
Each J independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxyl, C1-6Halogenated alkoxy, C1-6Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbocyclic ring, aldehyde radical or carboxyl；
R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxyl or C1-6Alkane ammonia Base；
M is 0,1,2,3 or 4；With
N is 0,1,2 or 3.
Compound the most according to claim 1, wherein, R5、R6、R8、R9、R11And R12Be each independently hydrogen, deuterium, hydroxyl, Fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyl group, Difluoromethyl epoxide, trifluoromethyl epoxide, methylamino, dimethylamino, methyl epoxide methyl, cyclopropyl, cyclobutyl, cyclopenta or Cyclohexyl；Or R5And R6、R8And R9、R11And R12With and they carbon atoms of being jointly connected together with form cyclopropyl, cyclobutyl, ring Amyl group, cyclohexyl, Oxyranyle, tetrahydrofuran base or pyrrolidinyl；
Each R3Independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano group, methyl, ethyl, n-pro-pyl, isopropyl, Difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro-methoxy, trifluoromethoxy, hydroxymethyl, 2- Hydroxyethyl, methylamino, dimethylamino or diethylamino.
Compound the most according to claim 1, wherein, R1And R2Be each independently hydrogen, deuterium, halogen atom, hydroxyl, amino, Nitro, cyano group, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkoxyl- C1-3Alkyl-, C3-6Carbocylic radical, C3-6Halo carbocylic radical, C2-6Heterocyclic radical, C6-10Aryl or C1-5Heteroaryl；Described C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkoxy-C1-3Alkyl-, C3-6Carbocylic radical, C3-6Halo carbocylic radical, C2-6Heterocyclic radical, C6-10Aryl and C1-5Heteroaryl individually optionally by one or more selected from halogen atom, Oxo (=O), hydroxyl, nitro, cyano group, amino, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl and C1-3The base of alkoxyl Group is replaced；Or,
R1、R2And form C together with the carbon atom being jointly connected with them3-6Carbocyclic ring or C2-6Heterocycle；Described C3-6Carbocyclic ring and C2-6Miscellaneous Ring individually optionally by one or more selected from halogen atom, oxo (=O), hydroxyl, amino, nitro, cyano group, methyl and fluoroform The group of base is replaced.
4. according to the compound described in claim 1 or 3, wherein, R1And R2It is each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl Base, amino, nitro, cyano group, methyl, ethyl, n-pro-pyl, isopropyl, trifluoromethyl, hydroxymethyl, methoxyl group, ethyoxyl, different Propyl group epoxide, difluoro-methoxy, trifluoromethoxy, methoxy, acetyl group, carboxyl, cyclopropyl, cyclobutyl, cyclopenta, ring Hexyl, 2-hydroxycyclopropyl, Oxyranyle, azepine butane group, pyrrolidinyl, tetrahydrofuran base, piperazinyl, morpholinyl, benzene Base, pyrrole radicals, thienyl, furyl, imidazole radicals, oxazolyl, pyridine radicals or pyrimidine radicals；Or R1、R2With and they be jointly connected Carbon atom makeup ring propane together, Tetramethylene., oxirane, azepine butane or expoxy propane.
Compound the most according to claim 1, wherein, T ring is C3-6Carbocyclic ring, C2-6Heterocycle, C6-10Aromatic ring or C1-5Hetero-aromatic ring；
Each J independently be hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxyl, C1-3Halogenated alkoxy, C1-3Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbocyclic ring, aldehyde radical or carboxyl；
R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, C1-3Alkyl, C1-3Haloalkyl, C1-3Alkoxyl or C1-3Alkane ammonia Base.
Compound the most according to claim 1, wherein, T ring is cyclopropane, Tetramethylene., Pentamethylene., hexamethylene, azacyclo- Butane, oxolane, pyrrolidine, piperidines, piperazine, morpholine, Pentamethylene oxide., thiomorpholine, pyrroles, thiophene, furan, imidazoles, evil Azoles, thiazole, pyridine, pyrimidine, pyrazine, pyridazine, benzene, naphthalene or 3,4-dihydro-2H-benzo [b] [1,4] piperazine；
Each J independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano group, methyl, ethyl, n-pro-pyl, isopropyl, hydroxyl first Base, 1-ethoxy, 2-ethoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxyl group, isopropyl epoxide, difluoro Methoxyl group, trifluoromethoxy, methylamino, dimethylamino ,-C (=O)-R15、-S(O)2-R16, cyclopropyl, cyclobutyl, cyclopenta, Cyclohexyl, aldehyde radical or carboxyl；
R15And R16It is each independently hydrogen, deuterium, hydroxyl, amino, methyl, ethyl, n-pro-pyl, isopropyl, difluoromethyl, fluoroform Base, methoxyl group, isopropyl epoxide, methylamino, dimethylamino or diethylamino.
Compound the most according to claim 1, has a structure of one of:
Or its stereoisomer, geometric isomer, tautomer, nitrogen oxygen Compound, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug.
8. a pharmaceutical composition, it comprises the compound described in claim 1-7 any one, and pharmaceutically acceptable tax Shape agent, carrier, adjuvant or combinations thereof；Wherein,
Described pharmaceutical composition comprise further other preventions or treatment inflammatory syndrome, obstacle or the medicine of disease or they Combination in any.
9. the compound described in claim 1-7 any one or the pharmaceutical composition described in claim 8 are in preparing medicine Purposes, described medicine for prevent or treat mammal by ROR γ t mediation inflammation or autoimmune disease.
Purposes the most according to claim 9, described inflammation or autoimmune disease are psoriasis, rheumatoid joint Inflammation, systemic lupus erythematosus (sle), multiple sclerosis, inflammatory bowel, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or Mucocutaneous lymphnode syndrome.
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CN113072542A (en) * 2020-01-06 2021-07-06 广东东阳光药业有限公司 ROR gamma t inhibitor and preparation method and application thereof
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CN110724076A (en) * 2018-07-16 2020-01-24 四川科伦博泰生物医药股份有限公司 Para-aryl dicarboxamide compound, pharmaceutical composition containing same, preparation method and application thereof
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