CN106187838B - Aryl alkynes compound and its preparation method and application - Google Patents

Aryl alkynes compound and its preparation method and application Download PDF

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CN106187838B
CN106187838B CN201610556333.1A CN201610556333A CN106187838B CN 106187838 B CN106187838 B CN 106187838B CN 201610556333 A CN201610556333 A CN 201610556333A CN 106187838 B CN106187838 B CN 106187838B
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phenyl
alkyl
propyl
methoxy
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CN106187838A (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 kind of aryl alkynes compound, and the pharmaceutical composition comprising such compound.The compound or pharmaceutical composition can be used as the inhibitor of vitamin A acid correlation orphan nuclear receptor γ t (Retinoid related orphan receptor gamma t, ROR γ t).The invention further relates to the method for preparing such compound and pharmaceutical composition, and they are treating or preventing mammal, the particularly inflammation mediated by ROR γ t of the mankind or the purposes of autoimmune disease.

Description

Aryl alkynes compound and its preparation method and application
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of compound, composition and its preparation method and application, its Described in compound or composition can be used as vitamin A acid correlation orphan nuclear receptor γ t (Retinoid-related orphan Receptor gamma t, ROR γ t) inhibitor, and for preventing or treat and immune-related disease.
Background technology
Vitamin A acid correlation orphan nuclear receptor γ t (Retinoid-related orphan receptor gamma t, ROR γ T) it is two kinds of vitamin A acid correlation orphan nuclear receptor γ (Retinoid-related orphan receptor gamma, ROR γ) One of isoform, also referred to as ROR γ 2.Some researches show that ROR γ t are only in lymphoid and bonnot's gland's inducer (Sun et al., Science 288 is expressed in cell:2369-2372,2000；Eberl et al.,Nat Immunol.5: 64-73,2004).ROR γ t are as helper T lymphocyte (TH17) characteristic transcription factor, for TH17 cell differentiations all play Important function, is TH17 cell differentiations 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 itself Have great importance in epidemic disease disease and body defenses reaction.IL-17 is the rush of inflammatory development and various autoimmune diseases Inflammatory cytokines, it is closely related with various autoimmune disease and inflammatory disease, such as rheumatoid arthritis, psoriasis, silver bits Sick arthritis, arthritis vertebralis, asthma, inflammatory bowel disease, systemic loupus erythematosus and multiple sclerosis etc..
Therefore, T will effectively be suppressed by suppressing ROR γ tH17 cell differentiation, regulates and controls the generation and secretion of IL-17 cell factors Level, so as to regulate and control body immune system, treats related immune and inflammatory disease.
Brief summary of the invention
Only summarize some aspects of the present invention below, it is not limited to this.These aspects and other parts are later There is more complete explanation.All bibliography in this specification are incorporated in this by overall.Work as the disclosure of the specification With citation it is variant when, be subject to the disclosure of the specification.
The present invention provides one kind to have vitamin A acid correlation orphan nuclear receptor γ t (Retinoid-related orphan Receptor gamma t, ROR γ t) inhibitory activity compound, be used to prepare prevention or treatment by ROR γ t mediate inflammation Or the medicine of autoimmune disease, such as psoriasis, rheumatoid arthritis, systemic loupus erythematosus, multiple sclerosis, inflammation Property enteropathy, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or Kawasaki disease etc.；The compounds of this invention can press down well ROR γ t processed, while there is excellent physicochemical property and pharmacokinetic property.
Preparation method present invention provides these compounds and the pharmaceutical composition comprising these compounds and make With the method for the above-mentioned disease of these compound or compositions treatment mammal, the especially mankind.
Specifically：
On the one hand, the present invention relates to the alloisomerism of compound shown in compound or formula (I) of the one kind as shown in formula (I) Body, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, ester are pharmaceutically acceptable Salt or its prodrug,
Wherein：
W rings are phenyl ring, naphthalene nucleus, pyrrole ring, furan nucleus, thiphene ring, pyrazole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine Ring, pyridine 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 R12C is formed with together with the carbon atom being connected jointly with them3-6Carbocyclic 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, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkoxy -C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo Carbocylic radical, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；The C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkoxy -C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo carbocylic radical, C2-9Heterocycle Base, C6-10Aryl and C1-9Heteroaryl is 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 alkoxy is substituted；Alternatively,
R1、R2C is formed with together with the carbon atom that they are connected jointly3-6Carbocyclic ring or C2-6Heterocycle；The 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 substituted；
Each R3It independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6 Alkoxy, C1-6Halogenated alkoxy, C1-6Hydroxy alkyl or C1-6Alkylamino；
T rings are C3-10Carbocyclic ring, C2-9Heterocycle, C6-10Aromatic ring or C1-9Hetero-aromatic ring；
Each J independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl alkane Base, C1-6Alkoxy, 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, C1-6Alkoxy 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- hydroxyethyls, 2- hydroxyethyls, 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 forming cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, epoxy together with the carbon atom being connected jointly with them Ethyl group, tetrahydrofuran base or pyrrolidinyl；
Each R3It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano group, methyl, ethyl, n-propyl, different Propyl group, difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro-methoxy, trifluoromethoxy, hydroxyl first Base, 2- hydroxyethyls, 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, C1-3Alkoxy, C1-3Halogenated alkoxy, C1-3Alkoxy -C1-3Alkyl-, C3-6Carbon Ring group, C3-6Halo carbocylic radical, C2-6Heterocyclic radical, C6-10Aryl or C1-5Heteroaryl；The C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxy, C1-3Halogenated alkoxy, C1-3Alkoxy -C1-3Alkyl-, C3-6Carbocylic radical, C3-6Halo carbocyclic ring Base, C2-6Heterocyclic radical, C6-10Aryl and C1-5Heteroaryl is 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 alkoxy is substituted；Or Person,
R1、R2C is formed with together with the carbon atom that they are connected jointly3-6Carbocyclic ring or C2-6Heterocycle；The 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 substituted.
In further embodiments, R1And R2It is each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyanogen Base, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxymethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro first Epoxide, trifluoromethoxy, methoxy, acetyl group, carboxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 2- hydroxyls 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 group together with the carbon atom being connected jointly with them Into cyclopropane, cyclobutane, ethylene oxide, azepine butane or propylene oxide.
In certain embodiments, T rings are C3-6Carbocyclic ring, C2-6Heterocycle, C6-10Aromatic ring or C1-5Hetero-aromatic ring；
Each J independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxyl alkane Base, C1-3Alkoxy, 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, C1-3Alkoxy or C1-3 Alkylamino.
In further embodiments, T rings are cyclopropane, cyclobutane, pentamethylene, hexamethylene, azetidine, tetrahydrochysene furan Mutter, pyrrolidines, piperidines, piperazine, morpholine, oxinane, thiomorpholine, pyrroles, thiophene, furans, imidazoles, oxazole, thiazole, pyrrole Pyridine, pyrimidine, pyrazine, pyridazine, benzene, naphthalene or 3,4- dihydro -2H- benzos [b] [1,4] oxazines；
Each J independently be hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano group, methyl, ethyl, n-propyl, isopropyl, Methylol, 1- ethoxys, 2- ethoxys, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyls, 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-propyl, 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 includes compound shown in formula (I) of the present invention or its solid It is isomers, geometric isomer, dynamic isomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable Salt or their prodrug, and pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof；
The pharmaceutical composition further include other preventions or treatment inflammatory syndrome, obstacle or disease medicine or Their any combination.
On the other hand, the present invention relates to the purposes of compound or its pharmaceutical composition in medicine preparation, institute shown in formula (I) State medicine to be used to prevent or treat mammal, include the inflammation or autoimmune disease by ROR γ t mediations of the mankind.
In certain embodiments, the present invention relates to compound shown in formula (I) or its pharmaceutical composition in medicine preparation Purposes, the medicine be used for prevent or treat psoriasis, rheumatoid arthritis, systemic loupus erythematosus, multiple sclerosis, Inflammatory bowel disease, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or Kawasaki disease.
On the other hand, the present invention relates to the method for preparation, separation and the purifying of compound shown in formula (I).
Biological results show that compound provided by the invention has preferable inhibitory activity to ROR γ t, has at the same time There are good Pharmacokinetic Characteristics.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic can be adapted for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.
Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspect and its The content of his aspect will make more specific complete description below.
Detailed description of the invention book
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation enclosed.This Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim In the range of.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method described herein and material Trample the present invention.The present invention is not limited to method described herein and material.The one of document, patent and the similar material combined Or more it is different from the application or in the case of contradicting it is (including but not limited to defined term, term application, described Technology, etc.), be subject to the application.
It will further be appreciated that some features of the present invention, are clearly visible, are carried out in multiple independent embodiments Description, but can also be provided in combination in single embodiment.Conversely, the various features of the present invention, for brevity, It is described, but can also be provided individually or with any suitable sub-portfolio in single embodiment.
Unless otherwise stated, 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.All patents of the present invention and public publication are integrally incorporated this hair by reference It is bright.
Unless otherwise stated, following definition used herein should be applied.For purposes of the present invention, chemical element with Periodic table of elements CAS editions, and《Handbook of Chemistry and Physics》, the 75th edition, 1994 is consistent.In addition, organic chemistry General Principle can join Examine " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, With " March's Advanced Organic Chemistry " by Michael B.Smith and Jerry March, John Wiley&Sons,NewYork:Description in 2007, entire contents are incorporated herein by reference.
There is obvious conflict unless otherwise indicated or in context, article " one " 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.For example, " component " refers to one or more components, it is possible to has more than one Component be taken into account in the embodiment of the embodiment and use or use.
Term " study subject " used in the present invention refers to animal.The typical animal is mammal.It is tested right As, such as also refer to primate (such as mankind, male or female), ox, sheep, goat, horse, dog, cat, rabbit, rat, small Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by It is people to try object.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations In scheme, " patient " refers to people.
Term "comprising" is open language, that is, includes the content specified by the present invention, but be not precluded from otherwise Content.
" stereoisomer " refers to there is identical chemical constitution, but the spatially different change of arrangement mode of atom or group Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer (cis/trans) isomers, atropisomer, etc..
" chirality " be with its mirror image cannot overlapping property molecule；And " achirality " refer to can be overlapping with its mirror image Molecule.
" enantiomter " refers to that two of a compound cannot isomers that is overlapping but being mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer mixes Compound can be operated such as electrophoresis and chromatography, such as HPLC by high resolution analysis to separate.
Stereochemical definitions used in the present invention and rule generally 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 compounds exist with optical active forms, i.e., they, which have, rotates the plane of linearly polarized light Ability.When describing optically active compound, represent molecule on one or more hand using prefix D and L or R and S The absolute configuration at property center.Prefix d and l or (+) and (-) are to be used for the rotating symbol of linearly polarized light caused by appointed compound, Wherein (-) or l represent that compound is left-handed.Prefix is dextrorotation for the compound of (+) or d.A kind of specific alloisomerism Body is enantiomter, and the mixture of this isomers is referred to as enantiomeric mixture.The 50 of enantiomter:50 mixtures Referred to as racemic mixture or racemic modification, when chemical reaction or during there is no stereoselectivity or stereospecificity when, It may occur in which such case.
Any asymmetric atom (for example, carbon etc.) that the present invention discloses compound can be enriched with racemic or enantiomer Form exist, such as (R)-, (S)-or (R, S)-configuration exist.In certain embodiments, each asymmetric atom exists (R)-or (S)-configuration in terms of there is at least 50% enantiomeric excess, at least at least 60% enantiomeric excess, 70% enantiomer mistake Amount, at least at least 80% enantiomeric excess, at least 90% enantiomeric excess, 95% enantiomeric excess, or at least 99% enantiomer It is excessive.
According to the selection of starting material and method, the compounds of this invention can with one in possible isomers or they Mixture, such as the form of racemic modification and non-enantiomer mixture (this depends on the quantity of asymmetric carbon atom) deposits .Chiral synthon or chiral reagent can be used to prepare for optically active (R)-or (S)-isomers, or be torn open using routine techniques Point.If compound contains a double bond, substituent may be E or Z configurations；If contain dibasic cycloalkanes in compound Base, the substituent 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 substantially pure geometric isomer, enantiomter, diastereoisomer, for example, passing through chromatography and/or fractional crystallization Method.
The racemic modification of any gained end-product or intermediate can be passed through into those skilled in the art with known method Known method splits into optical antipode, e.g., is separated by its diastereoisomeric salt to acquisition.Racemic production Thing can also be separated by chiral chromatogram, e.g., use the high performance liquid chromatography (HPLC) of chiral sorbent.Especially, mapping Isomers can be prepared by asymmetric syntheses, for example, Jacques is referred to, 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, compound of the invention can optionally be substituted by one or more substituents, such as General formula compound above, or as example special inside embodiment, subclass, and a kind of compound that the present invention is included.
In general, term is " substituted " to represent that institute is taken to one or more of structure hydrogen atom by specific substituent Generation.Unless otherwise indicated, the group of a substitution can have a substituent to be carried out in each commutable position of group Substitution.When more than one position can be substituted by one or more substituents selected from specific group in given structural formula, So substituent can substitute in each position identical or differently.
Term " unsubstituted ", represents specified group without substituent.
Term " optionally by ... substitute ", can exchange use, i.e., with term " unsubstituted or by ... substitute " The structure is unsubstituted or is substituted by one or more substituents of the present invention.Substituent 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, Alkenyl, alkynyl, alkoxy, halogenated alkoxy, alkyl amino, carbocylic radical, cycloalkyl, heterocyclic radical, aryl, heteroaryl, etc..
In addition, it is necessary to explanation, unless otherwise explicitly point out, used describing mode in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can exchange, and should all be interpreted broadly, it both may be used To refer in different groups, do not influence mutually, can also represent in phase between expressed specific option between same-sign In same group, do not influenced mutually between expressed specific option between same-sign.
In each several part of this specification, the substituent that the present invention discloses compound is disclosed according to radical species or scope.It is special Do not point out, the present invention includes each independent sub-combinations thereof of each member of these radical species and scope.For example, term “C1-6Alkyl " refers in particular to individually disclosed methyl, ethyl, C3Alkyl, C4Alkyl, C5Alkyl and C6Alkyl.
In each several part of the present invention, connect substituent is described.When the structure clearly needs linking group, for this Markush variable cited by group is interpreted as linking group.If for example, the structure needs linking group and is directed to be somebody's turn to do The Markush group definition of variable lists " alkyl " or " aryl ", then is represented respectively it should be understood that being somebody's turn to do " alkyl " or " aryl " The alkylidene group or arylene group of connection.
Terminology used in the present invention " alkyl " or " alkyl group ", represent the straight or branched univalent hydrocarbyl group of saturation, Wherein, the alkyl group can optionally be substituted by the substituent that one or more present invention describe.Unless in addition in detail Illustrate, alkyl group contains 1-20 carbon atom.In one embodiment, alkyl group contains 1-12 carbon atom；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 includes, but is not limited to, methyl (Me ,-CH3), ethyl (Et ,-CH2CH3), n-propyl (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 groups (- CH (CH3)CH2CH2CH3), 3- amyl groups (- CH (CH2CH3)2), 2- methyl -2- butyl (- C (CH3)2CH2CH3), 3- methyl -2- butyl (- CH (CH3)CH(CH3)2), 3- methyl isophthalic acids-butyl (- CH2CH2CH(CH3)2), 2- first Base -1- butyl (- CH2CH(CH3)CH2CH3), n-hexyl (- CH2CH2CH2CH2CH2CH3), 2- hexyls (- CH (CH3) CH2CH2CH2CH3), 3- hexyls (- CH (CH2CH3)(CH2CH2CH3)), 2- methyl -2- amyl groups (- C (CH3)2CH2CH2CH3), 3- first Base -2- amyl groups (- CH (CH3)CH(CH3)CH2CH3), 4- methyl -2- amyl groups (- CH (CH3)CH2CH(CH3)2), 3- methyl -3- penta Base (- C (CH3)(CH2CH3)2), 2- methyl -3- amyl groups (- 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 to remove two obtained saturations of hydrogen atom from the straight or branched alkyl of saturation 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；In another embodiment party In case, alkylidene group contains 1-3 carbon atom；Also 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 " alkoxy " represents that alkyl group is connected by oxygen atom with molecule remainder, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, the alkoxy base contains 1-12 carbon atom.In 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.The alkoxy base can be optionally one or more The substituent that the present invention describes is substituted.
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- amoxys (n- amoxys ,-OCH2CH2CH2CH2CH3), 2- amoxys (- OCH (CH3) CH2CH2CH3), 3- amoxys (- OCH (CH2CH3)2), 2- methyl -2- butoxy (- OC (CH3)2CH2CH3), 3- methyl -2- fourths 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 aminos " and " N, N- dialkyl amido ", wherein amino group independently Ground is substituted by one or two alkyl group；The alkyl has implication described in the invention.Some of embodiments are, Alkyl amino is one or two C1-6Alkyl is connected to the alkylamino group of the lower level formed on nitrogen-atoms.Other one A little embodiments are that alkyl amino is one or two C1-3The alkyl of lower level be connected to the alkyl amino formed on nitrogen-atoms Group.Suitable alkylamino group can be alkyl monosubstituted amino or dialkyl amido, and such example includes, but and unlimited In, N- methylaminos, N- ethylaminos, N, N- dimethylaminos, N, N- lignocaines etc..
Term " haloalkyl ", " halogenated alkoxy " or " haloalkylamino " represent alkyl, alkoxy or alkyl amino Group is substituted by one or more halogen atoms, wherein alkyl, and alkoxy or alkylamino group have as described herein Implication, such example includes, 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 substituted by one or more hydroxyls, and wherein alkyl group has such as this The invention implication, such example includes, but is not limited to, hydroxymethyl, 1- hydroxyethyls, 2- hydroxyethyls etc..
Term " alkoxyalkyl " represent alkoxy base be connected by alkyl with molecule remainder, wherein alkoxy with Alkyl group has implication as described in the present invention.Such example includes, but is not limited to, methoxy, (ethoxymethyl) Base, i-propoxymethyl, 1- methoxy ethyls, 2- methoxy ethyls etc..
Term " cycloalkyl " represents that containing 3-12 carbon atom monovalent or multivalence saturation is monocyclic, bicyclic or tricyclic Hydrocarbyl group.In one embodiment, cycloalkyl includes 7-12 carbon atom；In yet another embodiment, cycloalkyl includes 3-8 A carbon atom；In yet another embodiment, cycloalkyl includes 3-6 carbon atom.The group of naphthene base can independently not by Substitution is substituted by one or more substituents described in the invention.
Term " carbocyclic ring " or " carbocylic radical " represented containing 3-12 carbon atom, monovalent or multivalence nonaromatic saturation Or unsaturated monocyclic, bicyclic or tricyclic the hydrocarbyl group in part.Carbon bicyclic group includes spiral shell carbon bicyclic group and fusion carbon bicyclic group, Suitable 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 includes 3-8 carbon atom；In yet another embodiment, carbocylic radical bag Containing 3-6 carbon atom.The example of carbocylic radical group further comprises, cyclopropyl, cyclobutyl, cyclopenta, 1- cyclopenta -1- alkene Base, 1- cyclopenta -2- alkenyls, 1- cyclopenta -3- alkenyls, cyclohexyl, 1- cyclohexyl -1- alkenyls, 1- cyclohexyl -2- alkenyls, 1- Cyclohexyl -3- alkenyls, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring undecyl, cyclo-dodecyl, etc. Deng.The carbocylic radical group can be independently unsubstituted or be substituted by one or more substituents described in the invention.
Term " heterocyclic radical " and " heterocycle " are used interchangeably here, all referring to the saturation comprising 3-12 annular atom or portion Point undersaturated nonaromatic unit price or multivalence are monocyclic, bicyclic or tricyclic, and wherein at least one annular atom is selected from nitrogen, sulphur 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 Contain 2-9 carbon atom in son；In other embodiment, 2-8 carbon atom is contained in 3-12 annular atom of heterocyclic radical； In other embodiment, 2-6 carbon atom is contained in 3-12 annular atom of heterocyclic radical；In other embodiment, Contain 2-5 carbon atom in 3-12 annular atom of heterocyclic radical.Unless otherwise stated, heterocyclic radical can pass through carbon atom and molecule Middle other groups connection, can also be connected by nitrogen-atoms with other groups in molecule, and-CH2- group can be optionally by-C (=O)-substitute.The sulphur atom of ring can optionally be oxidized to S- oxides.The nitrogen-atoms of ring can be optionally oxidized to N- oxygen compounds.The example of heterocyclic radical includes, but are not limited to：Oxyranyle, azelidinyl, oxetanylmethoxy, thia ring Butyl, pyrrolidinyl, 2- pyrrolinyls, 3- pyrrolinyls, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrochysene Furyl, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1,3- dioxies cyclopenta, two sulphur cyclopenta, THP trtrahydropyranyl, Dihydro pyranyl, 2H- pyranoses, 4H- pyranoses, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, two Oxane base, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, Diazesuberane base, oxepane alkyl, thia ring Heptane base, oxygen azepineBase, diazaBase, sulphur azepineBase, 2- oxa- -5- azabicyclos [2.2.1] hept- 5- bases.Heterocyclic radical In-CH2- group includes, but not limited to 2- oxo-pyrrolidines base, oxo -1,3-thiazoles alkane by the example of-C (=O)-replacement Base, 2- piperidone bases, 3,5- dioxy piperazines piperidinyl and hybar X base.The example that sulphur atom is aoxidized in heterocyclic radical includes, but It is not limited to, sulfolane base, 1,1- dioxothiomorpholinyls.The heterocyclyl groups can be optionally by one or more originally Described substituent is invented to be substituted.
Term " t former molecular ", wherein t is integer, the number of ring member nitrogen atoms in molecule is typically described, described The number of ring member nitrogen atoms is t in molecule.For example, piperidyl is 6 molecular heterocyclic radicals of original, and decahydro naphthyl is 10 atoms The carbocylic radical group of composition.
Used term is " undersaturated " 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, includes the form of any oxidation state of N, S and P；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the substituted form of hydrogen in heterocycle on nitrogen-atoms, for example, N is (as in 3,4- dihydro-2 h-pyrrole bases N), NH (as the NH in pyrrolidinyl) or NR (NR in the pyrrolidinyl substituted as N-).
Term " halogen " or " halogen atom " refer to fluorine atom (F), chlorine atom (Cl), bromine atoms (Br) or iodine atom (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 to contain 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, double The full carbocyclic ring system of ring or tricyclic, wherein, at least one ring is aromatic, and has its of one or more attachment points and molecule Remaining part split-phase connects.Term " aryl " can be exchanged with term " aromatic rings " and used.In one embodiment, aryl is by 6-10 Annular atom composition, and the carbocyclic ring system wherein at least containing an aromatic rings.The example of aromatic yl group can include phenyl, naphthalene Base and anthryl.The aromatic yl group can be substituted by one or more substituents described in the invention individually optionally.
Term " heteroaryl " represents monocyclic, bicyclic or tricyclic containing 5-12 annular atom, and wherein at least one ring is fragrant Fragrant race, and at least one ring includes one or more hetero atoms, and have one or more attachment points and molecule remainder phase Even.Term " heteroaryl " can exchange use with term " hetero-aromatic ring " or " heteroaromatics ".Wherein, in some embodiments In, 1-9 carbon atom is contained in 5-12 annular atom of heteroaryl；In other embodiment, 5-12 ring of heteroaryl Contain 1-7 carbon atom in atom；It is former containing 1-5 carbon in 5-12 annular atom of heteroaryl in other embodiment Son；The heteroaryl groups are optionally substituted by one or more substituents described in the invention.In one embodiment, Heteroaryl is the heteroaryl for including 1,2, the 3 or 4 heteroatomic 5-12 annular atom for being independently selected from O, S and N composition；Another In embodiment, heteroaryl is miscellaneous to be formed comprising 1,2,3 or 4 heteroatomic 5-6 annular atom for being independently selected from O, S and N Aryl.
The example of heteroaryl groups includes, but is not limited to, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyls, 4- isoxazolyls, 5- isoxazolyls, 2- oxazolyls, 4- oxazolyls, 5- oxazoles Ji, oxadiazolyls (such as 1,2,3- oxadiazolyls, 1,2,5- oxadiazolyls, 1,2,4- oxadiazolyl), oxatriazoles base (such as 1,2,3, 4- oxatriazoles base), 2- thiazolyls, 4- thiazolyls, 5- thiazolyls, isothiazolyl, 2- thiadiazolyl groups (such as 1,3,4- thiadiazolyl groups, 1,2,3- thiadiazolyl groups, 1,2,5- thiadiazolyl groups), thiatriazole base (such as 1,2,3,4- thiatriazoles base), tetrazole radical (such as 2H-1,2, 3,4- tetrazole radicals, 1H-1,2,3,4- tetrazole radicals), triazolyl (such as 2H-1,2,3- triazolyls, 1H-1,2,4- triazolyls, 4H-1, 2,4- triazolyls), 2- thienyls, 3- thienyls, 1H- pyrazolyls (such as 1H- pyrazole-3-yls, 1H- pyrazoles -4- bases, 1H- pyrazoles - 5- yls), 1,2,3- thio biphospholes base, 1,3,4- thio biphospholes base, 1,2,5- thio biphospholes 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 (such as 3- pyridazines Base, 4- pyridazinyls), 2- pyrazinyls, triazine radical (such as 1,3,5- triazines), tetrazine base (such as 1,2,4,5- tetrazines, 1,2,3,5- tetra- Piperazine)；Also include following bicyclic, but it is bicyclic to be not limited to these：Benzimidazolyl, benzofuranyl, benzothienyl, indoles Base (such as 2- indyls), purine radicals, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls), isoquinolyl (such as 1- isoquinolines Quinoline base, 3- isoquinolyls or 4- isoquinolyls), 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..
No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyl ", expression-CO2H；Term No matter " carbonyl ", be single use or be used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(C=O)-.
As described in the invention, the member ring systems formed in substituent one key connection of picture to the ring at center are (such as formula b institutes Show) represent substituent any commutable position on the ring and can substitute.For example, formula b represent substituent R can be on C rings It is monosubstituted or polysubstituted on any possible substituted position, 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 on the center of ring Table connecting key can be connected any attachable position in member ring systems with molecule remainder.Formula d represents any possibility on D rings The position of connection can be connected with molecule remainder.
When term " blocking group " or " PG " refer to a substituent with other reacted with functional groups, commonly used to hinder It is disconnected or protect special feature.For example, " blocking group of amino " refers to that a substituent is connected with amino group to block Or the feature of amino in compound is protected, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (BOC, Boc), benzyloxycarbonyl group (CBZ, Cbz) and 9- fluorenes methylene oxygen carbonyls (Fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl The substituent of base is used for blocking or protecting the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxyl Blocking group " refers to that the substituent of carboxyl is used for blocking or protect the feature of carboxyl, general carboxyl-protecting group includes- CH2CH2SO2Ph, cyano ethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group 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 " prodrug " used in the present invention, represents a compound and is converted into compound shown in formula (I) in vivo. Such conversion is hydrolyzed or influenced in blood or tissue through enzymatic conversion for precursor structure in blood by pro-drug.This hair Bright pro-drug compounds can be ester, and ester can be as the phenyl ester class that has of pro-drug, aliphatic in existing invention (C1-C24) esters, pivaloyloxymethyl esters, carbonic ester, carbamates and amino acid esters.Such as one in the present invention Compound includes hydroxyl, you can be acylated to obtain the compound of prodrug form.Other prodrug forms include Phosphate, if these phosphate compounds are being obtained through the di on parent.Completely begged on pro-drug By may 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 specific compound or its salt in vivo by the obtained product of metabolism.One change The metabolite of compound can be identified that its activity can be retouched by such as the present invention by technology well-known in the art Adopt as stating and experimentally characterized.Such product can be by, by aoxidizing, being reduced, water to drug compound The methods of solution, amidated, desamido- effect, esterification, degreasing, enzymatic lysis etc., obtains.Correspondingly, the present invention includes compound Metabolite, including compound and the mammal of the present invention are come into full contact with into metabolite caused by a period of time.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine Acceptable salt is known to us in fields on, such as document：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977,66:It is 1-19. 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 hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetic acid Salt, oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Other methods such as ion-exchanges obtain these salt.Other pharmaceutically acceptable salts include adipate, and alginates, resist Bad hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor sulphur Hydrochlorate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal Heptose hydrochlorate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonic acids Salt, lactobionate, lactate, laruate, lauryl sulfate, malate, mesylate, 2- naphthalene sulfonates, nicotinic acid Salt, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picrate, spy penta Hydrochlorate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..Pass through appropriate alkali Obtained salt includes alkali metal, alkaline-earth metal, ammonium and N+(C1-4Alkyl)4Salt.The present invention is also intended to contemplate any included N's The quaternary ammonium salt that the compound of group is formed.Water-soluble 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 appropriate, nontoxic that pharmaceutically acceptable salt further comprises Ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halide, 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 molecules and the present invention are formed Thing.The solvent for 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 matter that water is formed.
When the solvent is water, term " hydrate " can be used.In certain embodiments, a compounds of this invention Molecule can be combined with a hydrone, such as monohydrate；In other embodiments, a compounds of this invention point Son can be combined with more than one hydrone, such as dihydrate, in further embodiments, a compounds of this invention Molecule can be combined with the hydrone less than one, such as semihydrate.It should be noted that hydrate of the present invention remains with The biological effectiveness of the compound of nonhydrated form.
As used in the present invention any disease of term " treatment " or illness, refer to it is all can slow down, interrupt, preventing, Control or the progress for stopping disease or illness, but not necessarily represent that the symptom of all diseases or illness all disappears, it also includes To the prophylactic treatment of the symptom, especially in the patient of such disease or obstacle is easily suffered from.Some are implemented wherein Scheme middle finger improve disease or illness (slow down or prevent mitigate disease or the development of its at least one clinical symptoms).Another In some embodiments, " treatment " refers to mitigation or improves at least one body parameter, including the body that may not be discovered by patient Body parameter.In other embodiments, " treatment " refers to from body (such as stablizing perceptible symptom) or physiologically (example Such as stablize the parameter of body) or above-mentioned two aspect adjusting diseases or illness.In other embodiments, " treatment " refer to prevention or Postpone breaking-out, generation or the deterioration of disease or illness.
Term " therapeutically effective amount " as used in the present invention or " treatment effective dose " are the lifes for referring to trigger individual Thing or medicinal response (such as reduce or suppress enzyme or protein active, or improve symptom, alleviate illness, slow down or postpone disease Disease development, or prevention disease etc.) the compounds of this invention amount.In a non-limiting embodiment, " treatment has term Effect amount " refers to, when applying the compounds of this invention to individual, effectively measure situations below：(1) alleviate at least in part, press down System, prevention and/or improve (i) and mediated by ROR γ t, either (ii) and ROR γ t activity related or (iii) are by ROR γ t's The conditions or diseases of abnormal activity characterization；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 work as to cell or organ or acellular organism thing When matter or medium are applied, it can at least in part reduce or suppress ROR γ t activity；Or reduce at least in part or suppress ROR The amount of the effective the compounds of this invention of γ t expression.
Term compound " giving " and " administration " compound as used in the present invention should be understood to its of needs Body provides the compound of the present invention or the prodrug of the compounds of this invention.It should be appreciated that those skilled in the art are by using effective The compounds of this invention treatment of amount suffers from the patient of this obstacle or prophylactically treats the patient with this obstacle at present.
Term " composition " as used in the present invention refers to the product of the predetermined component comprising ormal weight, and ormal weight Predetermined component the spawn that directly or indirectly produces of combination.With the implication of the relevant this term of pharmaceutical composition Product including including active ingredient (single either multiple) and the inert fraction (single or multiple) for forming carrier, Yi Jiyou Any two or Multiple components mixing, it is compound or aggregation, either by one or more ingredient breakdowns or by one or more into Point other kinds of reaction or interaction and the spawn that directly or indirectly produces.Therefore, pharmaceutical composition of the present invention Including by the way that the compounds of this invention to be mixed to any composition to prepare with pharmaceutical acceptable carrier.
The description of the compound of the present invention
The invention discloses (miscellaneous) aromatic ring analog derivative of a kind of carboxylic acid-substituted, its pharmaceutically acceptable salt, medicine system Agent and combinations thereof, can be used as ROR γ t inhibitor, to the inflammation or autoimmune disease mediated by ROR γ t, such as silver bits Disease, rheumatoid arthritis, systemic loupus erythematosus, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, asthma, bone close Section is scorching, the treatment of Crohn disease and Kawasaki disease has potential purposes.
On the one hand, the present invention relates to the alloisomerism of compound shown in compound or formula (I) of the one kind as shown in formula (I) Body, nitrogen oxides, solvate, metabolite, pharmaceutically acceptable salt or its prodrug,
Wherein：
W rings are phenyl ring, naphthalene nucleus, pyrrole ring, furan nucleus, thiphene ring, pyrazole ring, thiazole ring, oxazole ring, pyridine ring, pyrimidine Ring, pyridine 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 R12C is formed with together with the carbon atom being connected jointly with them3-6Carbocyclic 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, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkoxy -C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo Carbocylic radical, C2-9Heterocyclic radical, C6-10Aryl or C1-9Heteroaryl；The C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxy, C1-6Halogenated alkoxy, C1-6Alkoxy -C1-6Alkyl-, C3-10Carbocylic radical, C3-10Halo carbocylic radical, C2-9Heterocycle Base, C6-10Aryl and C1-9Heteroaryl is 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 alkoxy is substituted；Alternatively,
R1、R2C is formed with together with the carbon atom that they are connected jointly3-6Carbocyclic ring or C2-6Heterocycle；The 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 substituted；
Each R3It independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, nitro, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6 Alkoxy, C1-6Halogenated alkoxy, C1-6Hydroxy alkyl or C1-6Alkylamino；
T rings are C3-10Carbocyclic ring, C2-9Heterocycle, C6-10Aromatic ring or C1-9Hetero-aromatic ring；
Each J independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxyl alkane Base, C1-6Alkoxy, 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, C1-6Alkoxy 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- hydroxyethyls, 2- hydroxyethyls, 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 forming cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, epoxy together with the carbon atom being connected jointly with them Ethyl group, tetrahydrofuran base or pyrrolidinyl.
In certain embodiments, each R3It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyano group, first Base, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro-methoxy, Trifluoromethoxy, hydroxymethyl, 2- hydroxyethyls, 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, C1-3Alkoxy, C1-3Halogenated alkoxy, C1-3Alkoxy -C1-3Alkyl-, C3-6Carbon Ring group, C3-6Halo carbocylic radical, C2-6Heterocyclic radical, C6-10Aryl or C1-5Heteroaryl；The C1-3Alkyl, C1-3Haloalkyl, C1-3Hydroxy alkyl, C1-3Alkoxy, C1-3Halogenated alkoxy, C1-3Alkoxy -C1-3Alkyl-, C3-6Carbocylic radical, C3-6Halo carbocyclic ring Base, C2-6Heterocyclic radical, C6-10Aryl and C1-5Heteroaryl is 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 alkoxy is substituted；Or Person,
R1、R2C is formed with together with the carbon atom that they are connected jointly3-6Carbocyclic ring or C2-6Heterocycle；The 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 substituted.
In further embodiments, R1And R2It is each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, cyanogen Base, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxymethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro first Epoxide, trifluoromethoxy, methoxy, acetyl group, carboxyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, 2- hydroxyls 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 group together with the carbon atom being connected jointly with them Into cyclopropane, cyclobutane, ethylene oxide, azepine butane or propylene oxide.
In certain embodiments, T rings are C3-6Carbocyclic ring, C2-6Heterocycle, C6-10Aromatic ring or C1-5Hetero-aromatic ring.
In further embodiments, T rings are cyclopropane, cyclobutane, pentamethylene, hexamethylene, azetidine, tetrahydrochysene furan Mutter, pyrrolidines, piperidines, piperazine, morpholine, oxinane, thiomorpholine, pyrroles, thiophene, furans, imidazoles, oxazole, thiazole, pyrrole Pyridine, pyrimidine, pyrazine, pyridazine, benzene, naphthalene or 3,4- dihydro -2H- benzos [b] [1,4] oxazines.
In certain embodiments, each J independently is hydrogen, deuterium, halogen atom, hydroxyl, amino, cyano group, C1-3Alkyl, C1-3Halo Alkyl, C1-3Hydroxy alkyl, C1-3Alkoxy, C1-3Halogenated alkoxy, C1-3Alkylamino ,-C (=O)-R15、-S(O)2-R16、C3-6Carbon Ring, aldehyde radical or carboxyl；
Wherein R15And R16With implication as described in the present invention.
In further embodiments, each J independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, amino, cyano group, methyl, second Base, n-propyl, isopropyl, methylol, 1- ethoxys, 2- ethoxys, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyls, 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 R16With 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, C1-3Alkoxy or C1-3Alkylamino.
In further embodiments, R15And R16Be each independently hydrogen, deuterium, hydroxyl, amino, methyl, ethyl, n-propyl, Isopropyl, difluoromethyl, trifluoromethyl, methoxyl group, isopropyl epoxide, methylamino, dimethylamino or diethylamino.
Also in certain embodiments, the present invention relates to the compound of one of or its stereoisomer, nitrogen oxygen 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 includes compound shown in formula (I) of the present invention or its solid It is isomers, geometric isomer, dynamic isomer, 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 further includes other preventions or treatment inflammatory syndrome, obstacle or disease The medicine or their any combination of disease.
In one embodiment, pharmaceutical composition can be liquid, solid, semisolid, gel or spray-type.
On the other hand, the present invention relates to the purposes of compound or its pharmaceutical composition in medicine preparation, institute shown in formula (I) State medicine to be used to prevent or treat mammal, include the inflammation or autoimmune disease by ROR γ t mediations of the mankind.
In certain embodiments, the present invention relates to compound shown in formula (I) or its pharmaceutical composition in medicine preparation Purposes, the medicine be used for prevent or treat psoriasis, rheumatoid arthritis, systemic loupus erythematosus, multiple sclerosis, Inflammatory bowel disease, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or Kawasaki disease.
On the other hand, the present invention relates to the method for preparation, separation and the purifying of compound shown in formula (I).
On the other hand, the present invention relates to the intermediate for preparing compound shown in formula (I).
The present invention disclose compound can contain asymmetry or chiral centre, therefore can different stereoisomer forms deposit .It is contemplated that all stereoisomer forms of compound shown in formula (I), including but not limited to diastereoisomer, Enantiomter, atropisomer and geometry (or conformation) isomers, and their mixture such as racemic mixture, become The part of the present invention.
In structure disclosed by the invention, when the spatial chemistry of the chiral atom of any specific does not indicate, then the structure All stereoisomers all consider within the present invention, and disclose compound as the present invention and be included in the invention.When Spatial chemistry is expressed the real wedge-shaped line (solid wedge) of particular configuration or when dotted line indicates, then the alloisomerism of the structure Body clearly and is defined with regard to this.
Compound shown in formula (I) can exist with different tautomeric forms, and all these dynamic isomers, It is included within the scope of the present invention.
Compound shown in formula (I) can exist in a salt form.In one embodiment, the salt refers to pharmaceutically connect The salt received.Term " pharmaceutically acceptable " refers to that material or composition must be with other components comprising preparation and/or using it The mammal for the treatment of is compatible chemically and/or toxicologically.In another embodiment, the salt is not necessarily pharmaceutically Acceptable salt, can be used to prepare and/or purify compound shown in formula formula (I) and/or for separating shown in Ben Shishi (I) The intermediate of the enantiomer of compound.
Pharmaceutically useful acid-addition salts can be disclosed compound and acted on inorganic acid or organic acid and formed by the present invention, such as acetic acid Salt, aspartate, benzoate, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfuric acid Salt, camsilate, chloride/hydrochloride, 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 Salt, naphthalene sulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid Hydrogen salt/dihydric phosphate, poly- galactolipin hydrochlorate, propionate, stearate, succinate, sulfosalicylate, tartrate, Toluene fulfonate and trifluoroacetate.
Pharmaceutically acceptable base addition salts can be disclosed compound and acted on inorganic base or organic base and formed by the present invention.
The inorganic base that can obtain salt by its derivative includes, such as the metal of the I races of ammonium salt and periodic table to XII races. In some embodiments, which is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc and copper；Particularly suitable salt include ammonium, potassium, Sodium, calcium and magnesium salts.
The organic base that can obtain salt by its derivative includes primary amine, secondary amine and tertiary amine, and substituted amine includes naturally occurring Substituted amine, cyclic amine, deacidite etc..Some organic amines include, for example, isopropylamine, tardocillin (benzathine), choline salt (cholinate), diethanol amine, diethylamine, lysine, meglumine (meglumine), piperazine And tromethamine.
The officinal salt of the present invention can be synthesized with conventional chemical processes by parent compound, alkalescence or acidic moiety. In general, such salt can by make these compounds free acid form and stoichiometry suitable alkali (such as Na, Ca, The hydroxide of Mg or K, carbonate, bicarbonate etc.) reaction, or by making the free alkali form and chemistry of these compounds The suitable acid of metered amount is reacted to be prepared.Such reaction usually carries out in water or organic solvent or the mixture of the two. Usually, in appropriate cases, it is necessary 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：Property, selection and application (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.
In addition, compound disclosed by the invention including their salt, with their hydrate forms or can also include it The form of solvent (such as ethanol, DMSO, etc.) obtains, for their crystallization.The present invention discloses compound can be with pharmacy Upper acceptable solvent (including water) inherently or by design forms solvate；Therefore, it is contemplated that including the present invention Open compound solvated and unsolvated form.
Any structural formula that the present invention provides, which is also intended to, represents these compounds not by the form of isotope enrichment and same The form of position element enrichment.The structure that the general formula that there is the compound of isotope enrichment the present invention to provide is described, except one or more A atom is replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes that can be introduced into the compounds of this invention Include the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, such 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, for example, its In there are radio isotope, such as3H、14C and18Those compounds of F, or wherein there are non radioactive isotope, such as2H and13Those compounds of C.The compound of such isotope enrichment can be used for metabolism research (to use14C), Reaction kinetics research (using for example2H or3H), detection or imaging technique, such as positron emission tomography (PET) or including medicine or substrate group The single photon emission computed tomography (SPECT) of measure of spread is knitted, or available in the radiotherapy of patient.18The change of F enrichments Compound is especially desirable for PET or SPECT researchs.Compound shown in the formula formula (I) of isotope enrichment can pass through this Suitable isotope is used described by routine techniques known to field technology personnel or the embodiment in the present invention and preparation process Labelled reagent substitutes original used unmarked reagent to prepare.
In addition, higher isotope particularly deuterium is (i.e.,2H or D) substitution some treatment advantages can be provided, these advantages are Brought by metabolic stability higher.For example, Half-life in vivo increase or reduction of volume requirements or therapeutic index obtain improving band Come.It should be appreciated that the deuterium in the present invention is counted as the substituent of compound shown in formula formula (I).Can use isotope enrichment because Son defines the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to institute Specify the ratio between the isotope abundance and natural abundance of isotope.If the substituent of the compounds of this invention is designated as Deuterium, the compound have at least 3500 (at each specified D-atoms 52.5% deuterium incorporation), extremely for each D-atom specified Few 4000 (60% deuterium incorporations), at least 4500 (67.5% deuterium incorporations), at least 5000 (75% deuterium incorporations), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporations), at least 6333.3 (95% deuterium incorporations), at least 6466.7 The isotope enrichment of (97% deuterium incorporation), at least 6600 (99% deuterium incorporations) or at least 6633.3 (99.5% deuterium incorporations) The factor.The pharmaceutically useful solvate of the present invention includes such as D that wherein recrystallisation solvent can be isotope substitution2O, acetone-d6、 DMSO-d6Those solvates.
Pharmaceutical composition, preparation and the administration of the compounds of this invention
The present invention provides a kind of pharmaceutical composition, and it includes the present invention to disclose listed chemical combination in compound, such as embodiment Thing；With pharmaceutically acceptable excipient, carrier, adjuvant or combinations thereof.
Offer treatment, prevention or the method for improving disease or illness of the invention, including give including originally for safe and effective amount The combination medicine of disclosure of the invention compound and one or more therapeutically active agents.Wherein, combination medicine include it is one or more its He prevents or the medicine for the treatment of inflammatory syndrome, obstacle or disease.
The amount of compound, which refers to effectively to detect, in pharmaceutical composition disclosed by the invention suppresses biological specimen or patient Internal vitamin A acid correlation orphan nuclear receptor γ t.The dosage of active component can change in the present composition, still, active component Amount must can obtain the amount of appropriate dosage forms.Active component can deliver medicine to needs to provide the dosage of optimal drug effect The patient (animal and people) of this treatment.Selected dosage depends on desired therapeutic effect, depending on method of administration and controls Treat the duration.Dosage will be different with patient, this depends on the attribute of disease and the order of severity, the weight of patient, patient Specific diet, medicine used at the same time and it will be recognized by those skilled in the art other factors.Dosage range is usually Each patient about 0.5mg to 1.0g daily, can be administered in the form of single dose or multi-agent.In one embodiment, dosage range For each patient about 0.5mg to 500mg daily；It is each patient about 0.5mg to 200mg daily in another embodiment； It is each patient about 5mg to 50mg daily in still another embodiment.
It will also be appreciated that some compounds of the present invention can in a free form exist and for treating, or it is if suitable When can exist in the form of its pharmaceutically acceptable derivates.Pharmaceutically acceptable derivates include pharmaceutically acceptable Prodrug, salt, ester, the salt of these esters, or when patient in need is administered of the present inventionization can be directly or indirectly provided Any other adduct or derivative of compound or its metabolite or residue.
Medicine disclosed by the invention or pharmaceutical composition can prepare and be packaged as (bulk) form in bulk, wherein extractable peace Compound shown in complete a effective amount of formula (I), then gives patient with powder or syrup form.In general, arrived with daily 0.0001 Dosage level between 10mg/kg weight is administered and vitamin A acid correlation orphan nuclear receptor γ t is effectively suppressed to make to obtain to patient With.Alternatively, pharmaceutical composition disclosed by the invention can prepare and be packaged as unit dosage forms, wherein each physically discrete unit Compound shown in formula (I) containing safe and effective amount.When being prepared with unit dosage forms, pharmaceutical composition disclosed by the invention is led to Chang Kehan, for example, 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 also contains one or more other activearms in addition to containing the compounds of this invention The compound weight ratio of timesharing, the compounds of this invention and the second active component can change and depend on the effective of every kind of component Dosage.In general, use every kind of effective dose.Thus, for example, when the compounds of this invention is mixed with another medicament, this hair Bright compound and the weight ratio of another medicament generally range from 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 components generally also within the above range, but in each case, all The effective dose of every kind of active component should be used.
" pharmaceutically acceptable excipient " means related to form of administration or pharmaceutical composition uniformity used in the present invention Pharmaceutically acceptable material, mixture or solvent.Every kind of excipient mixing when must with pharmaceutical composition it is other into Split-phase is held, and to avoid the interaction that the effect of present invention discloses compound can be substantially reduced when administering to a patient and can cause not It is the interaction of pharmaceutically acceptable pharmaceutical composition.In addition, every kind of excipient must be pharmaceutically acceptable, example Such as, there is sufficiently high purity.
Suitable pharmaceutically acceptable excipient can be different according to selected specific formulation.In addition, can be according to them in group Specific function in compound selects pharmaceutically acceptable excipient.For example, it may be selected to can help to produce equal one dosage type low temperature Some pharmaceutically acceptable excipient.It may be selected to can help to some pharmaceutically acceptable figurations for producing stabilizer type Agent.Contribute to carry or transport when may be selected to administer to a patient the present invention disclose compound from an organ of body or partly to Another organ of body or partial some pharmaceutically acceptable excipient.Some medicines of enhancing patient compliance may be selected Acceptable excipient on.
Suitable pharmaceutically acceptable excipient includes following kind of excipient：Diluent, filler, adhesive, Disintegrant, lubricant, glidant, granulating agent, coating agent, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweetener, rectify Taste agent, odor mask, colouring agent, anticaking agent, moisturizer, chelating agent, plasticiser, tackifier, antioxidant, preservative, stabilization Agent, surfactant and buffer.Technical staff can be appreciated that some pharmaceutically acceptable excipient can provide more than one Function, and provide alternative function, this depends in preparation existing in how much excipient and preparation there are which 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 resource obtained by a large amount of technical staff, they describe pharmaceutically acceptable Excipient, and 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)。
In 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 The various carriers for configuring pharmaceutically acceptable composition are disclosed in Dekker, New York, and for its preparation Known technology, the respective content of these documents are incorporated by reference into the present invention.Except any such as because producing any undesirable life Thing acts on, or with interaction occurs for any other component in harmful way and pharmaceutically acceptable composition and with the present invention Outside the incompatible any commonly employed carrier of open compound, pay close attention to its application and belong to the scope of the present invention.
Pharmaceutical composition disclosed by the invention is prepared using technology well known by persons skilled in the art and method.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 the technique for preparing pharmaceutical composition, described pharmaceutical composition to include the present invention Open compound and pharmaceutically acceptable excipient, carrier, assistant agent or combinations thereof, the technique include mixing it is various into Point.The pharmaceutical composition of compound is disclosed comprising the present invention, can be mixed under such as environment temperature and atmospheric pressure to prepare.
Compound disclosed by the invention is usually formulated as being suitable for the formulation administered to a patient by required approach.Example Such as, formulation includes the formulation that those are suitable for following method of administration：(1) it is administered orally, such as tablet, capsule, caplet agent, ball Agent, containing tablet, pulvis, syrup, elixir, supensoid agent, solution, emulsion, sachet agent and cachet；(2) parenteral, example Such as sterile solution agent, supensoid agent and redissolution powder；(3) cutaneous penetration, such as transdermal patch tablet；(4) rectally, such as bolt Agent；(5) suck, such as aerosol, solution and dry powder doses；(6) local administration, for example, it is cream, ointment, lotion, molten Liquor, paste, spray, foaming agent and gelling agent.
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 can be with It is configured to nose administration formulation.In yet another embodiment, compound disclosed by the invention can be configured to transdermal administration. Also in one embodiment, compound disclosed by the invention can be configured to Topical dosage forms.
Pharmaceutical composition provided by the invention can with compressed tablets, develop piece, chewable lozenge, rapidly dissolving tablet, multiple compressed tablet or Enteric coatel tablets, sugar-coat or Film coated tablets provide.Enteric coatel tablets are with the material bag for being resistant to hydrochloric acid in gastric juice effect but dissolving or being disintegrated in intestines The compressed tablets of clothing, so as to prevent the sour environment of active ingredient contacts stomach.Enteric coating includes, but not limited to aliphatic acid, fat Fat, phenyl salicylate, wax, lac, ammonification lac and cellulose acetate phthalate ester.Sugar coated tablet is the compacting that sugar-coat surrounds Piece, it can be beneficial to cover taste or smell beastly and can prevent tablet from aoxidizing.Thin membrane coated tablet is with water-soluble The compressed tablets of thin layer or the film covering of material.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.It is multiple Tabletting is by the compressed tablets of more than one press cycles preparation, including multilayer tablet and pressed coated or dry coating tablet.
Tabules can be by one kind that powder, crystallization or granular active ingredient are single or are described with the present invention Or prepared by variety carrier or excipient composition, the carrier and excipient include adhesive, disintegrant, controlled release polymer, profit Lubrication prescription, diluent and/or colouring agent.Fumet and sweetener are particularly useful when forming chewable tablets and lozenge.
Pharmaceutical composition provided by the invention can be provided with soft capsule or hard shell capsules, it can be fine by gelatin, methyl Element, starch or calcium alginate are tieed up to prepare.The hard gelatin capsule is also referred to as dry-filled capsules (DFC), is formed by two sections, one section Fill in another section, therefore enclose active ingredient completely.Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shell, It is plasticized by adding glycerine, sorbierite or similar polyalcohol.Soft gelatin shell can include the pre- preventing microorganism life of preservative It is long.Suitable preservative for as described in the present invention those, including methyl hydroxybenzoate and propylben, and sorbic acid.This Liquid, semisolid and the solid dosage forms that invention provides can be encapsulated in capsule.Suitable liquid and semisolid dosage form are included in Solution and supensoid agent in propene carbonate, vegetable oil or triglycerides.Capsule comprising such solution can be such as in the U.S. Patent U.S.Pat.Nos.4,328,245；Preparing described in 4,409,239 and 4,410,545.The capsule can also be adopted With coating as is known to persons skilled in the art, so as to improve or maintain the dissolution of active ingredient.
Pharmaceutical composition provided by the invention can be provided with liquid and semisolid dosage form, including emulsion, solution, suspension Agent, elixir and syrup.Emulsion is two-phase system, and one of which liquid is thoroughly dispersed in another 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.Supensoid agent can include pharmaceutically acceptable suspending agent and preservative.Aqueous alcohol solutions can include pharmaceutically may be used The acetal of receiving, such as two (low alkyl group) acetals of low alkyl group aldehyde, such as acetaldehyde diethyl acetal；With with one or more The water-soluble solvent of a hydroxyl, such as propane diols and ethanol.Elixir is transparent, sweet taste water-alcohol solution.Syrup is dense The aqueous solution of sugared such as sucrose, and preservative can also be included.For liquid dosage form, for example, the solution in polyethylene glycol It can be diluted with enough pharmaceutically acceptable liquid-carriers such as water, to be accurately, conveniently administered.
Other useful liquid and semisolid dosage form include, but are not limited to include active ingredient provided by the invention and two level Change those formulations of list-or poly- alkylene glycol, the list-or poly- alkylene glycol include：1,2- dimethoxymethane, diethylene glycol (DEG) Dimethyl ether, triglyme, tetraethylene glycol dimethyl ether, polyethylene glycol -350- dimethyl ether, polyethylene glycol -550- dimethyl ether, poly- second The approximate average molecular weight of glycol -750- dimethyl ether, wherein 350,550,750 finger 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, monoethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbierite, phosphoric acid, bisulfites, Jiao Sodium sulfite, thio-2 acid and its ester and dithiocarbamate.
Where appropriate, can be by the dosage unit preparations microencapsulation of oral administration.It can also be prepared into extending or tieing up The composition of release is held, such as by being coated or being embedded in polymer, wax or the like by microparticle material.
Combination of oral medication provided by the invention can also be carried in the form of liposome, micella, microballoon or nanometer system For.Micella formulation can be prepared with the method that U.S.Pat.No.6,350,458 is described.
Pharmaceutical composition provided by the invention can be provided with the granule and pulvis of non-effervesce or effervesce, to be reconstructed into Liquid dosage form.The pharmaceutically acceptable carrier and excipient used in non-effervescent or pulvis can include dilution Agent, sweetener and wetting agent.The pharmaceutically acceptable carrier and excipient used in effervescent or pulvis can wrap Include organic acid and carbon dioxide source.
Colouring agent and flavor enhancement can be used in all above-mentioned formulations.
Compound disclosed in this invention can also be combined with the soluble polymer as target medicine carrier.It is such Polymer includes polyvinylpyrrolidone, pyran co-polymer, poly- hydroxypropyhnethacrylamide-phenol, poly-hydroxyethyl asparagus fern acyl Amine phenol or the oxide polylysine of palmitoyl residues substitution.In addition, compound disclosed in this invention can with reality A kind of Biodegradable polymeric used in the control release of existing medicine combines, for example, polylactic acid, poly-epsilon-caprolactone, poly- Hydroxybutyric acid, polyorthoester, polyacetals, poly- dihydropyran, polybutylcyanoacrylate and the crosslinking of hydrogel or amphiphilic block are total to Polymers.
Pharmaceutical composition provided by the invention can be configured to immediately or Modified release dosage forms, including delay-, sustained release-, arteries and veins Punching-, control-, targeting-and sequencing releasing pattern.
Pharmaceutical composition provided by the invention can with will not to damage other active ingredients of expected therapeutic effect common Prepare, or with supplement expected from the material co-formulation that acts on.
Pharmaceutical composition provided by the invention can be by injecting, being transfused or be implanted into parenteral administration, for local or complete Body is administered.As the parenteral administration that uses of the present invention includes in intravenous, intra-arterial, peritonaeum, in intrathecal, intra-ventricle, urethra, chest In bone, encephalic, intramuscular, intrasynovial and subcutaneous administration.
Pharmaceutical composition provided by the invention can be configured to any formulation suitable for parenteral administration, including solution, mixed Suspension, emulsion, micella, liposome, microballoon, nanometer system and suitable for consolidating for solution or suspension is made in a liquid before the injection Body form.Such formulation can according to known to the technical staff in pharmaceutical science field conventional method come prepare (referring to Remington:The Science and Practice ofPharmacy, ibid).
Be intended for the pharmaceutical composition of parenteral administration can include one or more pharmaceutically acceptable carriers and Excipient, includes, but not limited to containing transporter, water miscibility carrier, non-transporter, antimicrobial or resists micro- life The preservative of thing growth, stabilizer, dissolution enhancers, isotonic agent, buffer, antioxidant, local anesthetic, suspending agent and scattered Agent, wetting agent or emulsifying agent, complexing agent, sequestering agent or chelating agent, antifreezing agent, cryoprotector, thickener, pH adjusting agent And inert gas.
Suitably include, but are not limited to containing transporter：Water, brine, physiological saline or phosphate buffered saline (PBS) (PBS), Sodium chloride injection, Ringers parenteral solutions, isotonic glucose injection, Sterile Water Injection, glucose and Lactated Ringers parenteral solutions.Non- transporter includes, but not limited to fixed oil, castor oil, corn oil, the cottonseed of plant origin Oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soya-bean oil, hydrogenated vegetable oil, the middle chain of hydrogenated soybean oil and coconut oil Triglycerides and palm seed oil.Water miscibility carrier includes, but not limited to the poly- second two of ethanol, 1,3-BDO, liquid Alcohol (such as Liquid Macrogol and polyethylene glycol 400), propane diols, glycerine, n-methyl-2-pyrrolidone, N, N- dimethylacetamides Amine and dimethyl sulfoxide.
Suitable antimicrobial or preservative include, but not limited to phenol, cresols, mercurial, phenmethylol, chlorobutanol, Methyl p-hydroxybenzoate and propylparaben, thimerosal, benzalkonium chloride (such as benzethonium chloride), methyl hydroxybenzoate and Propylben and sorbic acid.Suitable isotonic agent includes, but not limited to sodium chloride, glycerine and glucose.Suitable buffer Include, but not limited to phosphate and citrate.Suitable antioxidant is including the sulfurous acid as describing the present invention Hydrogen salt and sodium metabisulfite.Suitable local anesthetic includes, but are not limited to procaine hydrochloride.Suitable suspending agent and point Powder is including sodium carboxymethylcellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone as describing the present invention. Suitable emulsifying agent includes those that the present invention describes, including polyoxyethylene sorbitan monolaurate.Polyoxyethylene moves back Tax sorbitol monooleate 80 and triethanolamine oleate ester.Suitable sequestering agent or chelating agent include, but are not limited to EDTA. Suitable pH adjusting agent includes, but are not limited to sodium hydroxide, hydrochloric acid, citric acid and lactic acid.Suitable complexing agent includes, but unlimited In cyclodextrin, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutylether-beta-cyclodextrin and sulfobutyl group Ether 7- beta-cyclodextrins (CyDex,Lenexa,KS)。
Pharmaceutical composition provided by the invention can be configured to single dose or multiple dose administration.The single-dose preparations are wrapped In ampulla, bottle or syringe.The multiple dose parenteral administration must include antibacterial or fungistatic concentrations anti-micro- Biological agent.All parenteral administrations all must be it is sterile, as known in the art with practice.
In one embodiment, pharmaceutical composition is provided with instant sterile solution.In another embodiment, medicine Composition is provided with sterile dried soluble product, 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 Compositions are formulated into the sterile dry insolubility product reconstructed before use with carrier.Also in one embodiment, Pharmaceutical composition is formulated into instant without bacterial emulsion.
Pharmaceutical composition can be configured to supensoid agent, solid, semisolid or thixotropic liquid, the reservoir administration as implantation. In one embodiment, pharmaceutical composition disclosed in this invention is dispersed in solid interior matrix, its be insoluble to body fluid but The exterior polymeric membrane that the active ingredient in pharmaceutical composition diffuses through is allowed to be surrounded.
Suitable internal matrix include polymethyl methacrylate, poly- butyl methacrylate, plasticising or it is unplasticizied Polyvinyl chloride, plasticising nylon, plasticising polyethylene terephthalate, plasticising polyethylene terephthalate, natural rubber, Polyisoprene, polyisobutene, 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.
Suitable exterior polymeric membrane includes polyethylene, polypropylene, ethylene/propene copolymer, ethylene/ethyl acrylate copolymerization Thing, ethylene/vinyl acetate copolymer, silicone rubber, dimethyl silicone polymer, neoprene, haloflex, polychlorostyrene second Alkene, the copolymer of ethlyene dichloride and vinyl acetate, vinylidene chloride, ethene and propylene, ionomer gather to benzene two 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 for any dose to patient's inhalation Type, such as dry powder doses, aerosol, supensoid agent or liquid composite.In one embodiment, drug regimen disclosed in this invention Thing can be configured to be suitable for the formulation with dry powder doses to patient's inhalation.In yet another embodiment, it is disclosed in this invention Pharmaceutical composition can be configured to be suitable for the formulation by sprayer to patient's inhalation.Pass through the dry powder of inhalation delivery to lung Composition generally comprise fine powdered compound disclosed in this invention and it is one or more it is fine powdered pharmaceutically Acceptable excipient.Pharmaceutically acceptable excipient be especially suitable for 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 for example, by being micronized and grinding preparation Obtain.In general, (as being micronized) compound that size reduces can be by about 1 to 10 micron of D50Value is (for example, with sharp The measurement of optical diffraction method) define.
Aerosol can be prepared by the way that compound disclosed in this invention is suspended or dissolved in liquefied propellant.It is adapted to 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- difluoros Ethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, Perfluorinated butane, perflenapent, butane, iso-butane and pentane.Aerosol comprising compound disclosed in this invention usually passes through Metered dose inhaler (MDI) administers to a patient.Such device dawn known to those skilled in the art.
Aerosol can include pharmaceutically acceptable excipient that is extra, being used by MDIs, such as surface-active Agent, lubricant, cosolvent and other excipient, with improve the physical stability of preparation, improve valve characteristic, improve dissolubility, Or improve taste.
Discontinuous patch agent can be prepared into by being suitable for the pharmaceutical composition of cutaneous penetration, it is intended that be kept with the epidermis of patient It is in close contact the time of an elongated segment.For example, the delivering active ingredients from patch agent can be permeated by ion, such as Pharmaceutical Research, 3 (6), the general description in 318 (1986).
Be suitable for the pharmaceutical composition of local administration can be formulated into ointment, cream, supensoid agent, lotion, pulvis, Solution, paste, gelling agent, spray, aerosol or finish.For example, ointment, cream and gelling agent can use water or oil Matrix, and suitable thickener and/or gelling agent and/or solvent configure.Such matrix can include, water, and/or oily example Such as liquid-liquid paraffin and vegetable oil (such as peanut oil or castor oil), or solvent such as polyethylene glycol.Made according to medium property Thickener and gelling agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, poly- carboxylic second Alkene and cellulose derivative, and/or single stearic acid glycerine lipoprotein and/or nonionic emulsifier.
Lotion can use water or oil matrix to prepare, and generally also contain one or more emulsifying agents, stabilizer, disperse Agent, suspending agent or thickener.
Externally-applied powder can be molded in the presence of any suitable powder matrix such as talcum powder, lactose or starch.Drops It can be formulated with the water comprising one or more dispersing agents, solubilizer, suspending agent or preservative or non-aqueous matrix.
Topical formulations can be by being administered using one or many daily in affected part；The impermeable plastic wound dressing for covering skin is preferential Used.Adhesiveness store system can realize continuous or extended administration.
The purposes of the compounds of this invention and composition
Compound or pharmaceutical composition disclosed in this invention can be used for prepare be used for treat, prevent, improving, controlling or Mitigate mammal, including the inflammation mediated by ROR γ t of the mankind or the medicine of autoimmune disease, can be used for preparing For suppressing other medicines of ROR γ t.
Specifically, the amount of compound effectively can detectably suppress ROR γ t, this hair in composition of the invention Bright compound, which can be used as, prevents or treatment people parapsoriasis, rheumatoid arthritis, systemic loupus erythematosus, multiple hard Change the medicine of disease, inflammatory bowel disease, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or Kawasaki disease.
The compound or composition of the present invention can be applied to, but be not limited to, compound or combination using the present invention The effective dose of thing is administered to a patient to prevent, treat or mitigate mammal, including the psoriasis of the mankind, rheumatoid joint Inflammation, systemic loupus erythematosus, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease and Kawasaki disease.
The compound and pharmaceutical composition of the present invention to human treatment except beneficial in addition to, applying also for veterinary treatment and doting on Mammal in the animal of thing, the animal of introduced variety and farm.The example of other animal includes horse, dog and cat. This, compound of the invention includes its pharmaceutically acceptable derivates.
General synthesis step
For the description present invention, embodiment is listed below.But it is to be understood that the present invention is not limited to these Examples, simply The method that the practice present invention is provided.
Usually, compound of the invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent such as formula (I).Following reaction scheme and embodiment are used to this is further illustrated The content of invention.
The professional of fields will be recognized that：Chemical reaction described in the invention can be used for suitably preparing perhaps Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention Within enclosing.For example, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art according to the present invention Completed by method of modifying, such as appropriate protection interference group, by using other known reagent except described in the invention , or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is suitable for the preparation of other compounds of the invention.
The embodiments described below, unless other aspects show that all temperature are set to degree Celsius.Reagent is bought in business Product supplier such as Aldrich Chemical Company, Arco Chemical Company andAlfa Chemical Company, all without by not being further purified during use, unless other aspects show.General reagent is from the western Gansu Province chemical industry in Shantou Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Companies, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan developments in science and technology Co., Ltd, Qingdao Teng Long chemical reagent Co., Ltd, and Haiyang Chemical Plant, Qingdao's purchase It can buy.
Anhydrous tetrahydro furan, dioxane, toluene, ether are dried to obtain by metallic sodium reflux.Anhydrous methylene chloride With chloroform it is dried to obtain by calcium hydride reflux.Ethyl acetate, petroleum ether, n-hexane, n,N-dimethylacetamide and N, N- Dimethylformamide is used through anhydrous sodium sulfate is dry in advance.
Reaction is usually that a drying tube is covered under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects below Show), reaction bulb all by syringe squeezed into beyond the Great Wall by suitable rubber stopper, substrate.Glassware is all dried.
Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.
NMR spectrum is recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer, with CDC13、DMSO-d6、 CD3OD or acetone-d6For solvent (in units of ppm), reference standard is used as by the use of TMS (0ppm) or chloroform (7.26ppm).When going out When existing multiplet, following abbreviation will be used：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, is represented with hertz (Hz).
The determination condition of Algorithm (MS) data is：6120 level Four bar HPLC-M (pillar models of Agilent： Zorbax SB-C18,2.1x 30mm, 3.5 microns, 6min, flow velocity 0.6mL/min.Mobile phase：5%-95% (contains 0.1% The CH of formic acid3CN) (H of 0.1% formic acid is being contained2O the ratio in)), using electron spray ionisation (ESI), under 210nm/254nm, Detected with UV.
Compound purity is measured using high performance liquid chromatography (HPLC), uses Agilent 1260HPLC (pillar models： Agilent zorbax Eclipse Plus C18), and detected with DAD detectors, finally calculated using area normalization method To compound purity.
The use of brief word below is through the present invention：
NaNO2Sodium nitrite； NH4F ammonium fluorides；
Na2CO3Sodium carbonate；MeONa sodium methoxides；
KOH sodium hydroxides； Et3N TEA triethylamines；
MeCN acetonitriles；HOBt I-hydroxybenzotriazoles；
K2CO3Potassium carbonate；EDCI 1- ethyls-(3- dimethylaminos third Base) Asia of phosphinylidyne two
CH2Cl2DCM dichloromethane；Amine hydrochlorate；
Na2SO4Sodium sulphate；MeMgBr methyl-magnesium-bromides；
M-CPBA metachloroperbenzoic acids； H2O water；
TLC thin-layered chromatography； InCl3Inidum chloride；
NaHCO3Sodium acid carbonate；PhMgBr phenyl-magnesium-bromides；
NaCl sodium chloride；NaH sodium hydrides；
PE petroleum ethers；Pd/C palladiums/carbon
EtOAc EA ethyl acetate； BH3Borine
NaOH sodium hydroxides；Dess-Martin reagents Dai Si-Martin's examination Agent；
EtOH ethanol；DAST diethylin sulfur trifluorides；
THF tetrahydrofurans；MsCl methylsufonyl chlorides；
NH4Cl ammonium chlorides； Me2S methyl sulfides；
Pd(PPh3)2Cl2Bis-triphenylphosphipalladium palladium dichloride；I-PrMgBr isopropyl magnesium bromides；
CuI cuprous iodides； CDC13Deuterochloroform
MeOH methanol；DMSO dimethyl sulfoxide (DMSO)s
HATU 2- (7- azos benzotriazole)-N, N, N', N'- tetramethyls DMSO-d6Deuterated dimethyl sulfoxide
Base urea hexafluorophosphoric acid ester；G grams
DIPEA N, N- diisopropyl ethyl amines；When h is small
Et3SiH triethylsilanes；Min minutes
TFA trifluoroacetic acids；Mmol mMs
M moles of every liter of RT, rt, r.t. room temperature
DEG C degree Celsius rpm rpms
ML, ml milliliters of Rt retention times
Prepare the present invention and disclose the typical synthesis step of compound as shown in following synthetic schemes.Unless otherwise stated, T、W、J、A、R1、R2, each R3、R5、R6、R8、R9, m and n there is definition as described in the present invention.
Synthetic schemes 1
In formula, X represent leaving group, the 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：
Acetylene hydrocarbon compound (1a) reacts under the action of palladium catalyst and alkali with compound (2a) and generates compound (3a), then obtains compound (4a), finally, compound (4a) is being condensed with carboxylic acid compound (5a) by compound (3a) reduction Reaction generation compound (6a) under the action of agent.
Synthetic schemes 2
In formula, X represent leaving group, the 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：
With carboxylic acid compound (5a) condensation reaction generation compound (8a) occurs for amino-compound (7a), and compound (8a) is most Compound (6a) is generated under the action of palladium catalyst and alkali with acetylene hydrocarbon compound (1a) eventually.
Synthetic schemes 3
In formula, X represent leaving group, the 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) reacts generation compound (10a) with compound (9a) under the action of palladium catalyst and alkali, Then ester hydrolysis reaction generation carboxylic acid compound (11a) occurs under the action of alkali for compound (10a), and compound (11a) is final Condensation reaction generation compound (13a) occurs with amino-compound (12a).
Synthetic schemes 4
In formula, X represent leaving group, the 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：
With carboxylic acid compound (14a) condensation reaction generation compound (15a) occurs for amino-compound (7a), then compound (15a) is reduced generation compound (16a), and finally with acetylene hydrocarbon compound (1a) palladium catalysed cross coupling reaction occurs for compound (16a) Generate compound (17a).
Compound provided by the invention, pharmaceutical composition and its application are further described with reference to embodiments.
Embodiment 1：The synthesis of 2- (4- (ethylsulfonyl) phenyl)-N- (4- iodobenzenes) acetamide
By 2- (4- ethylsulfonyls phenyl) acetic acid (5.04g, 22.1mmol) (referenced patent WO2014125426 pages 29 Synthetic method), 4- iodobenzenes (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.It is concentrated under reduced pressure, residue CH2Cl2(120mL) dissolves, and then uses saturation successively NaHCO3Solution (40mL) and NaCl solution (40mL) washing, water mutually merge, and use CH2Cl2(120mL) extracts (50mL × 2), closes And organic phase and use Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)= 1/1) it is white solid powder (7.9g, 83%), to obtain product.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) propyl- 1- alkynyls) phenyl) -2- (4- (ethylsulfonyl) Phenyl) acetamide (compound 1) synthesis
Step 1：The synthesis of 1- [4- (difluoro-methoxy) phenyl] Propargyl -1- alcohol
Under the conditions of anhydrous and oxygen-free, in dry single-necked flask by 4- (difluoro-methoxy) benzaldehyde (18mL, 136.2mmol) it is dissolved in anhydrous THF (32mL), and is cooled down in -20 DEG C of cryostats, acetenyl is then added dropwise into reaction system The THF solution (0.5M, 300mL, 200mmol) of magnesium bromide, finishes, and reaction stirring reaction at such a temperature, is tracked anti-by TLC Should.After raw material completely conversion, under ice bath cooling, NH is added dropwise into system4Reaction is quenched in Cl solution (15mL), is concentrated under reduced pressure THF is removed, remaining water mutually uses CH2Cl2(20mL × 3) extract, and merge organic phase and use anhydrous Na2SO4It is dry, concentration, crude product (eluent is separated by silica gel column chromatography：PE/EtOAc (v/v)=5/1), it is colourless liquid (19.3g, 72%) to obtain product.
Step 2：The synthesis of 1- [4- difluoro-methoxies) phenyl] -3- (4- nitrobenzophenones) propyl- 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), the bromo- 4- nitrobenzenes of 1- (256mg, 1.27mmol) it is dissolved in triethylamine (0.40mL, 2.8mmol) in THF (8mL), 3h is stirred at room temperature, is filtered to remove insoluble matter, is filtered After liquid concentration, (eluent is separated by silica gel column chromatography：PE/EtOAc (v/v)=4/1), it is yellow liquid to obtain product (189mg, 44%).
Step 3：The synthesis of 3- (4- aminophenyls) -1- (4- (difluoro-methoxy) phenyl) propyl- 2- alkynes -1- alcohol
It is stirred at room temperature down, by NH4Cl (0.50g, 330 μ L, 9.34mmol) aqueous solution and iron powder (0.19g, 3.40mmol) add 1- [4- difluoro-methoxies) phenyl] -3- (4- nitrobenzophenones) propyl- 2- alkynes -1- alcohol (189mg, 0.59mmol) MeOH (5mL) solution in, back flow reaction 4h.Diatomite filters, and it is yellow oil that solvent, which is removed under reduced pressure, and obtains crude product (76mg, 44%).
Step 4：N- (4- (3- (4- (difluoro-methoxy) phenyl) -3- hydroxypropyl -1- alkynes -1- bases) phenyl) -2- (4- (second Base sulfonvlphenyl) acetamide synthesis
3- (4- aminophenyls) -1- (4- (difluoro-methoxy) phenyl) propyl- 2- alkynes -1- alcohol (72mg, 0.25mmol) is molten In dichloromethane (5mL), HATU (95mg, 0.24mmol), DIPEA (0.05mL, 0.3mmol) and 2- (4- are sequentially added Ethanesulfonylphenyl) acetic acid (64mg, 0.28mmol), it is stirred overnight at room temperature.After reaction solution concentration, crude product is by silica gel column chromatography Separate (eluent：DCM/MeOH (v/v)=40/1), it is yellow oily solid (59mg, 47%) to obtain product.
Step 5：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethylsulfonyl) Phenyl) acetamide synthesis
Under nitrogen protection, by N- (4- (3- (4- (difluoro-methoxy) phenyl) -3- hydroxypropyl -1- propargyls) phenyl) - (4- (ethylsulfonyl phenyl) acetamides (55mg, 0.11mmol) are dissolved in DCM (5mL) 2-, and reaction system is cooled to -5 DEG C, Et is then added with stirring3SiH (27 μ L, 0.17mmol) and NH4F (6.4mg, 0.17mmol), reaction is at such a temperature 0.5h is stirred, then adds TFA (35 μ L, 0.47mmol), continues to stir 2h, then warms naturally to room temperature reaction overnight.To NaHCO is added in reaction system3(5mL) solution, liquid separation, organic phase anhydrous Na2SO4Dry, concentration, crude product is by silicagel column Chromatography (eluent：PE/EtOAc (v/v)=1/1), it is yellow solid (19mg, 36%) to obtain product.
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) propyl- 1- alkynes -1- bases) -3- methoxyphenyls) -2- (4- (ethylsulfonyl) phenyl) acetamide (compound 2) synthesis
Step 1：The conjunction of 1- (4- (difluoro-methoxy) phenyl) -3- (2- methoxyl group -4- nitrobenzophenones) propyl- 2- alkynes -1- alcohol Into
By 1- [4- (difluoro-methoxy) phenyl] propyl- 2- alkynes -1- alcohol (529mg, 2.67mmol), the bromo- 2- methoxyl groups -4- of 1- Nitrobenzene (700mg, 3.02mmol), CuI (30mg, 0.16mmol) and Pd (PPh3)2Cl2(200mg, 0.30mmol) is added In the two mouth flask of 100mL, nitrogen displacement three times, then under nitrogen protection, sequentially adds THF (40mL) and Et3N (0.8mL, 6mmol), reacts in 30 DEG C of oil baths and reacts overnight.It is concentrated under reduced pressure, crude product separates (elution by silica gel column chromatography Agent：PE/EtOAc (v/v)=4/1), it is yellow liquid (560mg, 60%) to obtain product.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)。
Step 2：The synthesis of 1- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methoxyl group -4- nitrobenzenes
By 1- (4- (difluoro-methoxy) phenyl) -3- (2- methoxyl group -4- nitrobenzophenones) propyl- 2- alkynes -1- alcohol (559mg, 1.60mmol) it is dissolved in CH2Cl2(40mL), is cooled to 0 DEG C, stirs lower addition Et3SiH (0.40mL, 3.00mmol) and NH4F (90mg, 2.43mmol), after 30min, is added dropwise TFA (0.60mL, 8.00mmol), reacts on 0 DEG C of reaction 2h, is then slowly increased to It is stirred overnight at room temperature.Saturation NaHCO is added into reaction system3Reaction is quenched in (15mL) solution, uses CH2Cl2(30mL × 3) extract Take, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, obtains crude product (520mg, 97%) and be directly used in reaction in next step.
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- aminoanisoles
By 1- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methoxyl group -4- nitrobenzenes (520mg, 1.57mmol) it is dissolved in MeOH/H2O (3/1,40mL) in the mixed solvent, then sequentially adds NH4Cl (850mg, 15.89mmol) and Reduced iron powder (450mg, 8.04mmol), is heated to reflux 3h, filtering, and filter cake is washed with EtOAc (200mL), and filtrate is with anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, it is red oil (450mg) to obtain crude product, is directly used in and reacts in next step.
MS(ESI,pos.ion)m/z:304.1[M+1]+。
Step 4：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- methoxyphenyls) -2- (4- (ethylsulfonyl) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- aminoanisoles (455mg, 1.50mmol), 2- (4- ethylsulfonyls phenyl) acetic acid (510mg, 2.23mmol) and HATU (1.7g, 4.5mmol) are dissolved in CH2Cl2In (50mL), ice bath cools down, then dropwise addition DIPEA (2.0mL, 12.1mmol), after 10min, is stirred overnight at room temperature.Subtract Pressure concentration, crude product separate (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1), obtain crude product and 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) propyl- 1- alkynes -1- bases) -2- methoxyphenyls) -2- (4- (ethylsulfonyl) phenyl) acetamide (compound 3) synthesis
Step 1：The synthesis of the bromo- 2- methoxyl groups -1- nitrobenzenes of 4-
MeONa (1.0mL, 5.0mmol) is added to the MeOH of the fluoro- 1- nitrobenzenes (1.01g, 4.58mmol) of the bromo- 2- of 4- In (10mL) solution, stirring reaction 1h in 60 DEG C of oil baths is reacted on.Solvent, residue CH is removed under reduced pressure2Cl2(30mL) dissolves, Insoluble matter is filtered to remove, filtrate concentration, it is yellow solid (1.05g, 98%) to obtain object.
MS(ESI,pos.ion)m/z:232.1[M+1]+.
Step 2：The conjunction of 1- (4- (difluoro-methoxy) phenyl) -3- (3- methoxyl group -4- nitrobenzophenones) propyl- 2- alkynes -1- alcohol Into
Under nitrogen protection, by 1- (4- (difluoro-methoxy) phenyl) propyl- 2- alkynes -1- alcohol (802mg, 4.04mmol), 4- Bromo- 2- methoxyl groups -1- nitrobenzenes (1.05g, 4.52mmol), Pd (PPh3)2Cl2(289mg, 0.40mmol) and CuI (39.4mg, 0.20mmol) it is dissolved in THF (20mL), then adds Et3N (1.20mL, 8.44mmol), is stirred at room temperature reaction 5h.Cross and filter out Insoluble matter, filtrate concentration are removed, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=4/1), obtain target Thing is yellow liquid (1.22g, 86%).
MS(ESI,pos.ion)m/z:372.0[M+23]+。
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methoxyl group -1- nitrobenzenes
Under nitrogen protection, by 1- (4- (difluoro-methoxy) phenyl) -3- (3- methoxyl group -4- nitrobenzophenones) propyl- 2- alkynes - 1- alcohol (1.22g, 3.49mmol) is dissolved in CH2Cl2- 5 DEG C are cooled in (10mL) and by reaction system, then with stirring successively Add Et3SiH (0.69mL, 4.29mmol) and NH4After F (159mg, 4.21mmol), 30min, addition TFA (0.90mL, 12mmol), reaction solution maintains low temperature to continue to stir 8h, and 3h is then stirred at room temperature.Saturation NaHCO is added into reaction system3 (30mL) solution, mixed liquor CH2Cl2(30mL × 3) extract, and merge organic phase and use anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, Crude product separates (eluent by silica gel column chromatography：PE), it is yellow oily liquid (167mg, 14%) to obtain object.
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)。
Step 4：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- aminoanisoles
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methoxyl group -1- nitrobenzenes (167mg, MeOH (10mL) 0.50mmol) is dissolved in, then with stirring, sequentially adds NH4The aqueous solution of Cl (264mg, 4.93mmol) (2mL) and reduced iron powder (175mg, 3.13mmol), back flow reaction 3h.Diatomite filters, and is concentrated under reduced pressure, water mutually uses CH2Cl2 (20mL × 3) extract, and merge organic phase, and use anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, it is dark yellow solid to obtain object (142mg, 93%).
MS(ESI,pos.ion)m/z:304.0[M+1]+.
Step 5：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methoxyphenyls) -2- (4- (ethylsulfonyl) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- aminoanisoles (142mg, 0.47mmol), 2- (4- ethylsulfonyls phenyl) acetic acid (115mg, 0.50mmol) and HATU (546mg, 1.41mmol) are dissolved in CH2Cl2(15mL), then DIPEA (0.15mL, 0.89mmol) is added into reaction solution, reaction 6h is stirred at room temperature.Reaction solution is direct Concentration, (eluent is separated by silica gel column chromatography：DCM/MeOH (v/v)=40/1), obtain object for 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) propyl- 1- alkynes -1- bases) -2- fluorophenyls) -2- (4- (second Base sulfonyl) phenyl) acetamide (compound 4) synthesis
Step 1：The synthesis of 1- (4- (difluoro-methoxy) phenyl) -3- (the fluoro- 4- nitrobenzophenones of 3-) propyl- 2- alkynes -1- alcohol
Under nitrogen protection, 1- (4- (difluoro-methoxy) phenyl) propyl- 2- alkynes -1- alcohol (507mg, 2.56mmol) is dissolved in In THF (20mL), Pd (PPh are then sequentially added3)2Cl2(181mg, 0.25mmol), CuI (25mg, 0.13mmol), 4- are bromo- The fluoro- 1- nitrobenzenes (626mg, 2.85mmol) of 2- and Et3N (0.54g, 0.75mL, 5.3mmol), is stirred at room temperature, and reacts 4h, stops Only react.Insoluble matter, filtrate concentration are filtered to remove, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)= 4/1) it is yellow liquid (477mg, 55%), to obtain product.
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)。
Step 2：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) fluoro- 1- nitrobenzenes of -2-
Under nitrogen protection, by 1- (4- (difluoro-methoxy) phenyl) -3- (the fluoro- 4- nitrobenzophenones of 3-) propyl- 2- alkynes -1- alcohol (477mg, 1.41mmol) is dissolved in CH2Cl2(10mL) and -5 DEG C are cooled to, addition Et under stirring3SiH(0.489mL, 3.06mmol) and NH4After F (124mg, 3.28mmol), 0.5h, TFA (0.40mL, 5.40mmol) is added, reaction is stayed overnight, then 2h is stirred at room temperature, stops stirring.Saturation NaHCO is added into reaction solution3(15mL) solution, mixed liquor CH2Cl2(20mL× 3) extract, organic phase anhydrous Na2SO4Dry, concentration, crude product separates (eluent by silica gel column chromatography：PE), product is obtained 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).
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- fluoroanilines
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) fluoro- 1- nitrobenzenes of -2- (158mg, 0.49mmol) it is dissolved in MeOH (10mL), NH is sequentially added under stirring4The 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, diatomite filtering, and filtrate is dense Contracting, residue CH2Cl2(50mL) dilutes, successively with saturation NaHCO3(15mL) solution and the washing of NaCl (15mL) solution, have Machine mutually uses anhydrous Na2SO4Dry, concentration, it is white solid (129mg, 90%) to obtain product.
MS(ESI,pos.ion)m/z:292.0[M+1]+。
Step 4：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- fluorophenyls) -2- (4- (ethyls Sulfonyl) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- fluoroanilines (129mg, 0.44mmol), 2- (4- ethylsulfonyls phenyl) acetic acid (104mg, 0.46mmol) and HATU (596mg, 1.54mmol) are dissolved in CH2Cl2(15mL) In, DIPEA (0.15mL, 0.89mmol) is then added, 5h is stirred at room temperature.It is concentrated under reduced pressure and removes solvent, crude product is by silicagel column Chromatography (eluent：CH2Cl2/ MeOH (v/v)=40/1), it is white solid (164mg, 74%) to obtain product.
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) propyl- 1- alkynes -1- bases) -3- fluorophenyls) -2- (4- (second Base sulfonyl) phenyl) acetamide (compound 5) synthesis
Step 1：The synthesis of 1- (difluoro-methoxy) -4- (propyl- 2- alkynes -1- bases) benzene
Under ice cooling, 4, by 1- (4- (difluoro-methoxy) phenyl) propyl- 2- alkynes -1- alcohol in dry single-necked flask (1.04g, 5.25mmol) is dissolved in CH2Cl2In (30mL), by Et3SiH (2.9mL, 18mmol) is slowly dropped in reaction system, Then NH is added4F (0.40g, 11mmol), is stirred at room temperature 2h.Reaction bulb is cooled with an ice bath, and TFA is added into reaction system Reaction system, is then slowly increased to that 5h is stirred at room temperature by (1.50mL, 16.3mmol).Reaction solution CH2Cl2(60mL) dilutes, by Saturation NaCl solution (10mL × 2) is washed, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (elution by silica gel column chromatography Agent：PE/EtOAc (v/v)=1000/1) and further by preparing chromatosheet separation, it is colourless transparent liquid to obtain product (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)。
Step 2：The synthesis of 1- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) fluoro- 4- nitrobenzenes of -2-
Under nitrogen protection, by 1- (difluoro-methoxy) -4- (propyl- 2- alkynes -1- bases) benzene (600mg, 3.29mmol), 1- The fluoro- 4- nitrobenzenes (1.00g, 4.55mmol) of bromo- 2-, 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, is tracked and reacted by TLC. After raw material is wholly absent, filtering, concentrates filtrate.Residue is diluted with EtOAc (60mL), successively by saturation NaHCO3Solution (15mL) and saturation NaCl (15mL) are washed, anhydrous Na2SO4It is dry, be concentrated under reduced pressure, obtain product for faint yellow solid (700mg, 66%).
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- fluoroanilines
By 1- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) the fluoro- 4- nitrobenzenes of -2- 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 and reaction is heated in 50 DEG C of oil baths.After raw material disappearance, reaction solution is cooled to room Temperature, filtering, filtrate concentration remove MeOH, and water mutually uses CH2Cl2(40mL × 3) extract, and organic phase is by anhydrous Na2SO4It is dry, decompression Concentration, crude product separate (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1), it is white solid to obtain product (250mg, 70%).
MS(ESI,pos.ion)m/z:292.1[M+1]+。
Step 4：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- fluorophenyls) -2- (4- (ethyls Sulfonyl) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- fluoroanilines (330mg, 1.13mmol), 2- (4- ethylsulfonyls phenyl) acetic acid (280mg, 1.23mmol), EDCI (330mg, 1.69mmol) and HOBt (200mg, 1.44mmol) it is dissolved in CH2Cl2In (35mL), 6h is stirred at room temperature.Reaction solution CH2Cl2(60mL) dilutes, successively by saturation NaHCO3Solution (20mL) and saturation NaCl solution (20mL) washing, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product is by silica gel Column chromatography for separation (eluent：PE/EA (v/v)=1/1), it is white solid (140mg, 25%) to obtain product.
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) propyl- 1- Alkynes -1- bases) phenyl) acetamide (compound 6) synthesis
Step 1：The synthesis of 1- (propyl- 2- alkynes -1- bases) -4- (trifluoromethyl) piperidines
In single-necked flask, by 4- (trifluoromethyl) piperidines (1.05g, 6.86mmol) and K2CO3(2.00g,11.2mmol) MeCN (50mL) is dissolved in, 3- bromine propyl- 1- alkynes (0.62mL, 7.19mmol) is then slowly added dropwise, finishes, reaction is stirred at room temperature 10h.Reaction mixture filters, and filtrate concentration, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=5/ 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) propyl- 1- alkynes- 1- yls) phenyl) acetamide synthesis
Under nitrogen protection, by 1- (propyl- 2- alkynes -1- bases) -4- (trifluoromethyl) piperidines (520mg, 2.72mmol), 2- (4- ethylsulfonyls phenyl)-N- (4- iodobenzenes) acetamide (250mg, 0.58mmol), Pd (PPh3)2Cl2(200mg, 0.28mmol) it is dissolved in CuI (25mg, 0.13mmol) in THF (50mL), adds DIPEA (0.70mL, 4.00mmol), reaction The heating stirring 6h in 50 DEG C of oil baths.Stop heating, question response liquid is cooled to room temperature, and is filtered, and filtrate concentration, adds into residue Enter saturation NaHCO3Aqueous solution (30mL), is then extracted with EtOAc (50mL × 3), merges organic phase, with saturation NaCl (30mL) Solution washs, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：CH2Cl2/EtOAc(v/ V)=1/1), it is white solid (270mg, 94%) to obtain object.
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- bases) propyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethyl sulphonyl Base) phenyl) acetamide (compound 7) synthesis
Step 1：The synthesis of 4,4- difluoropiperdin -1- t-butyl formates
In 100mL single port bottles, 4- oxo-piperidine -1- t-butyl formates (1.81g, 9.08mmol) are dissolved in CH2Cl2 In (42mL), under ice bath cooling and stirring, DAST (4.0mL, 29.4mmol) is slowly dropped in reaction system, reacts on the temperature Degree stirring 4h.Saturation NaHCO is added into reaction system3Reaction is quenched in aqueous solution (30mL), then uses CH2Cl2(50mL×3) Extraction, merges organic phase and is washed with saturation NaCl solution (20mL), anhydrous Na2SO4Dry, filtering, is concentrated under reduced pressure, crude product (eluent is separated by silica gel column chromatography：PE/EtOAc (v/v)=5/1), it is colourless liquid (1.21g, 60%) to obtain object.
Step 2：The synthesis of 4,4- difluoropiperdins
4,4- difluoropiperdin -1- t-butyl formates (650mg, 2.94mmol) are dissolved in CH in single port bottle2Cl2(20mL) In TFA (5mL), 3h is stirred at room temperature.It is concentrated under reduced pressure, obtains crude product and be directly used in reaction in next step.
Step 3：The synthesis of bis- fluoro- 1- of 4,4- (propyl- 2- alkynes -1- bases) piperidines
In single-necked flask, by 4,4- difluoropiperdins and K2CO3(541mg, 3.02mmol) is dissolved in MeCN (50mL), then 3- propargyl bromides (304mg, 2.56mmol) are slowly added in reaction system, 5h is stirred at room temperature.Filtering, filtrate concentration, crude product (eluent is separated by silica gel column chromatography：PE/EtOAc (v/v)=1/1), obtain product for colourless transparent liquid (310mg, 76%).
MS(ESI,pos.ion)m/z:160.1[M+1]+。
Step 4：N- (4- (3- (4,4- difluoropiperdin -1- bases) propyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethyl sulphonyl Base) phenyl) acetamide synthesis
Under nitrogen protection, by 4,4-, bis- fluoro- 1- (propyl- 2- alkynes -1- bases) piperidines (220mg, 1.38mmol), 2- (4- second Base sulfonvlphenyl)-N- (4- iodobenzenes) acetamide (250mg, 0.58mmol), Pd (PPh3)2Cl2(200mg, 0.28mmol) and CuI (25mg, 0.13mmol) is dissolved in THF (50mL), is then added DIPEA (0.70mL, 4.0mmol), is reacted on 50 DEG C of oil Heating stirring in bath, is tracked by TLC and reacted.After reaction, filter, filtrate concentration.Saturation NaHCO is added into residue3 Aqueous solution (20mL), is then extracted, organic phase is washed with saturation NaCl solution (20mL), anhydrous with EtOAc (30mL × 3) Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：DCM/EtOAc (v/v)=3/1), obtain 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 propyl- 1- alkynes -1- bases) phenyl) acetamide The synthesis of (compound 8)
Step 1：The synthesis of 4- (propyl- 2- alkynes -1- bases) morpholine
Propyl- 2- alkynes -1- alcohol (1.00g, 17.8mmol) is dissolved in CH2Cl2(30mL), and cooled down under -20 DEG C of cryostats, so Afterwards with stirring, NEt is sequentially added3(3.1mL, 22mmol) and MsCl (1.68mL, 21.7mmol), reaction solution is at such a temperature Stirring, after 3h, morpholine (3.1mL, 35mmol) is added into reaction system, is continued to stir 3h, is then stirred at room temperature, by TLC with Track reacts.Treat that intermediate is wholly absent, reaction solution is concentrated under reduced pressure, and saturation NaHCO is added into residue3Aqueous solution (30mL), uses CH2Cl2(50mL × 3) extract, and merge organic phase and are washed with saturation NaCl solution (20mL), anhydrous Na2SO4It is dry Dry, filtering, is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/DCM (v/v)=1/1), it is nothing to obtain product 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 propyl- 1- alkynes -1- bases) phenyl) acetamide Synthesis
Under nitrogen protection, by 4- (propyl- 2- alkynes -1- bases) morpholine (420mg, 3.36mmol), 2- (4- ethylsulfonyl benzene Base)-N- (4- iodophenyls) 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 the conditions of 50 DEG C of oil bath heatings Stirring reaction 8h.Reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate concentration.Saturation is added into residue NaHCO3Aqueous solution (20mL), is extracted, organic phase is washed with saturation NaCl aqueous solutions (20mL), anhydrous with EtOAc (30mL × 3) Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：DCM/EtOAc (v/v)=2/1), obtain 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) propyl- 1- alkynes -1- bases) phenyl) The synthesis of acetamide (compound 9)
Step 1：The synthesis of 1- (propyl- 2- alkynes -1- bases) piperidines
At room temperature, in 100mL single port bottles, by Et3N (3.1mL, 22mmol) and MsCl (1.68mL, 21.7mmol) Sequentially add the CH of propargyl alcohol (1.00mL, 17.2mmol)2Cl2In (30mL) solution, after 0.5h, reaction system is cooled to -20 DEG C, under stirring, piperidines (3.3mL, 36mmol) is added, reaction is stirred 3h, is then stirred at room temperature under this condition.By TLC with Track, after intermediate disappearance, is concentrated under reduced pressure, saturation NaHCO is added into residue3Aqueous solution (20mL), then uses CH2Cl2 (30mL × 3) extract, and organic phase is washed with saturation NaCl solution (20mL), anhydrous Na2SO4It is dry, filter, concentration, crude product by Silica gel is through column chromatography for separation (eluent：PE/DCM (v/v)=1/1), it is colourless transparent liquid (1.40g, 66%) to obtain product.
MS(ESI,pos.ion)m/z:124.1[M+1]+。
Step 2：2- (4- (ethylsulfonyl) phenyl)-N- (4- (3- (piperidin-1-yl) propyl- 1- alkynes -1- bases) phenyl) second The synthesis of acid amides
Under nitrogen protection, by 1- (propyl- 2- alkynes -1- bases) piperidines (220mg, 1.78mmol), 2- (4- ethylsulfonyl benzene Base)-N- (4- iodophenyls) 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 under the conditions of 50 DEG C of oil bath heatings and stir React 8h.Reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate concentration.Saturation NaHCO is added into residue3Water Solution (20mL), is extracted with EtOAc (30mL × 3), and organic phase is washed with saturation NaCl aqueous solutions (20mL), anhydrous Na2SO4It is dry It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：DCM/EtOAc (v/v)=3/1), it is light to obtain 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) propyl- 1- alkynes- 1- yls) phenyl) acetamide (compound 10) synthesis
Step 1：The synthesis of 1- (4- (trifluoromethoxy) phenyl) propyl- 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.Reaction solution is poured into water (25mL), is used EtOAc (25mL × 3) is extracted, and is merged organic phase and is washed with saturation NaCl solution (25mL), anhydrous Na2SO4Dry, decompression is dense Contracting, crude product separate (eluent by silica gel column chromatography：PE/EtOAc (v/v)=5/1), it is yellow oil to obtain product (2.9g, 85%).
MS(ESI,pos.ion)m/z:199.0[M-18]+。
Step 2：The synthesis of 1- (propyl- 2- alkynes -1- bases) -4- (trifluoromethoxy) benzene
1- (4- (trifluoromethoxy) phenyl) propyl- 2- alkynes -1- alcohol (1.19g, 5.51mmol) is dissolved in CH2Cl2In (10mL) And -5 DEG C are cooled to, Et is sequentially added into system3SiH (2.1mL, 13mmol) and NH4F (450mg, 12.15mmol), 20min Afterwards, TFA (1.4mL, 19mmol) is added, reacts at room temperature 2h.Reaction solution is poured into water (30mL), with EtOAc (30mL × 3) Extraction, organic phase are washed with saturation NaCl solution (15mL), anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product is by silica gel column chromatography Separate (eluent：PE), it is yellow oil (762mg, 69%) to obtain product.
Step 3：The synthesis of 2- (4- (methyl sulphonyl) phenyl)-N- (4- iodophenyls) acetamide
By 4- Iodoanilines (303mg, 1.38mmol), 2- (4- ethylsulfonyls phenyl) acetic acid (345mg, 1.51mmol), EDCI (1.06g, 5.53mmol) and HOBT (280mg, 2.06mmol) are dissolved in CH2Cl2In (15mL), and add DIPEA (0.9mL, 5mmol), reacts at room temperature 3h.Reaction solution is poured into water (15mL), is extracted with EtOAc (15mL × 3), organic phase is used Saturation NaCl solution (15mL) is washed, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography： PE/EtOAc (v/v)=1/1), it is colourless powder solid (491mg, 83%) to obtain product.
MS(ESI,pos.ion)m/z:429.80[M+1]+。
Step 4：Compound 2- (4- (methyl sulphonyl) phenyl)-N- (4- (3- (4- (trifluoromethoxy) phenyl) propyl- 1- Alkynes -1- bases) phenyl) acetamide synthesis
Under nitrogen protection, by 1- (propyl- 2- alkynes -1- bases) -4- (trifluoromethoxy) benzene (153mg, 0.76mmol), 2- (4- (methyl sulphonyl) phenyl)-N- (4- iodophenyls) 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.Insoluble matter is filtered to remove, filtrate concentration, (eluent is separated by silica gel column chromatography：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- bases) phenyl) -2- (4- (ethyl sulphurs Acyl group) phenyl) acetamide (compound 11) synthesis
Step 1：The synthesis of 1- (4- (difluoro-methoxy) phenyl) ethanol
4- (difluoro-methoxy) benzaldehyde (457mg, 2.66mmol) is dissolved in THF (40mL) and is cooled to reaction system 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.Saturation NH is added into reaction solution4Reaction is quenched in the aqueous solution (20mL) of Cl, then with EtOAc (40mL × 3) extract, merge organic phase, and use anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography： PE/EtOAc (v/v)=4/1), it is colourless oil liquid (450mg, 90%) to obtain object.
Step 2：The synthesis of 1- (difluoro-methoxy) -4- (4- (4- nitrobenzophenones) butyl- 3- alkynes -2- bases) 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), then add InCl3 (20mg, 0.090mmol), reacts on stirring reaction 3h in 80 DEG C of oil baths, is concentrated under reduced pressure, mixture is separated by silica gel column chromatography (eluent：PE/EtOAc (v/v)=50/1), it is yellow oil (150mg, 87%) to obtain object.
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) butyl- 1- alkynes -1- bases) aniline
1- (difluoro-methoxy) -4- (4- (4- nitrobenzophenones) butyl- 3- alkynes -2- bases) benzene (152mg, 0.48mmol) is dissolved in MeOH/H2In O (3/1,28mL), and NH is added according to this4Cl solids (260mg, 4.86mmol) and reduced iron powder (150mg, 2.68mmol), reaction is refluxed 3h, filters, filter cake, filtrate anhydrous Na are washed with EtOAc (20mL)2SO4It is dry, decompression Concentration, it is red oil (100mg, 73%) to obtain crude product.
MS(ESI,pos.ion)m/z:288.1[M+1]+。
Step 4：N- (4- (3- (4- (difluoro-methoxy) phenyl) butyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethyl sulphonyl Base) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) butyl- 1- alkynes -1- bases) 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, is then added dropwise DIPEA (1.2mL, 7.3mmol) in stirring into reaction system, and reaction is stirred at room temperature overnight in reaction, It is concentrated under reduced pressure, mixture separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1) and further preparation chromatography is divided It is white solid (130mg, 18%) from object is obtained.
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- bases) propyl- 1- alkynes -1- Base) phenyl) acetamide (compound 12) synthesis
Step 1：The synthesis of 4- (propyl- 2- alkynes -1- bases) piperazine -1- formamides
Piperazine 1- formamides (580mg, 5.08mmol) are slowly added dropwise into 3- propargyl bromides (0.50mL, 5.80mmol) and K2CO3In MeCN (50mL) solution of (1.10g, 6.14mmol), 7h is stirred at room temperature.It is concentrated under reduced pressure, residue CH2Cl2 (60mL) dissolves, and is then washed successively with water (20mL) and saturation NaCl solution (20mL), anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, It is yellow transparent liquid (519mg, 59%) to obtain product.
MS(ESI,pos.ion)m/z:153.1[M+1]+。
Step 2：2- (4- (ethylsulfonyl) phenyl)-N- (4- (3- (4- formyl piperazine -1- bases) propyl- 1- alkynes -1- Base) phenyl) acetamide synthesis
Under nitrogen protection, by 4- (propyl- 2- alkynes -1- bases) piperazine -1- formamides (220mg, 1.45mmol), 2- (4- second Base sulfonvlphenyl)-N- (4- iodophenyls) 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 heatings Under the conditions of stirring reaction 8h.Reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate concentration.Added into residue full And NaHCO3Aqueous solution (20mL), is extracted with EtOAc (30mL × 3), and organic phase is washed with saturation NaCl aqueous solutions (20mL), nothing Water Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：DCM/EtOAc (v/v)=1/1), obtain 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- trifluoroethyls) piperazine -1- bases) Propyl- 1- alkynes -1- bases) phenyl) acetamide (compound 13) synthesis
Step 1：The synthesis of 4- (2,2,2- trifluoroethyls) piperazine -1- t-butyl formates
To add TFA (1.5mL, 20mmol), the 1- piperazinecarboxylic acids tert-butyl ester (2.00g, 10.7mmol) and HATU (0.8g, 2mmol) it is dissolved in CH2Cl2In (40mL), Et is then added3N (1.50mL, 10.7mmol), is stirred at room temperature 8h.Use CH2Cl2 (40mL) dilute reaction solution, then uses saturation NaHCO successively3Solution (30mL) and saturation NaCl solution (30mL) washing, it is anhydrous Na2SO4Dry, filtering, is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1), obtain It is faint yellow solid (1.50g, 50%) to product.
MS(ESI,pos.ion)m/z:283.3[M+1]+。
Step 2：The synthesis of 4- (2,2,2- trifluoroethyls) piperazine -1- t-butyl formates
Under nitrogen protection, by 4- (2,2,2- trifluoroacetyl groups) piperidines -1- t-butyl formates in single-necked flask (1.62g, 5.74mmol) is dissolved in anhydrous THF (32mL), at room temperature, by BH3·Me2THF solution (2.0mol/L, the 15mL) drop of S It is added in reaction system, 1h, back flow reaction 5h is stirred at room temperature.Reaction solution is cooled to room temperature, under ice bath cooling, to reaction system Middle dropwise addition NH4Reaction is quenched in Cl solution (15mL), is then concentrated under reduced pressure and removes THF, and remaining water mutually uses CH2Cl2(30mL × 3) extract Take, organic phase anhydrous Na2SO4Dry, concentration, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=5/ 1) it is brown oil (960mg, 62%), to obtain product.
MS(ESI,pos.ion)m/z:269.3[M+1]+。
Step 3：The synthesis of 1- (2,2,2- trifluoroethyls) piperazine
4- (2,2,2- trifluoroethyls) piperazine -1- t-butyl formates (510mg, 1.90mmol) are dissolved in CH2Cl2(19mL) With TFA (5mL), 3h is stirred at room temperature.Reacting liquid filtering, filtrate concentration, it is weak yellow liquid (300mg, 94%) to obtain crude product.
MS(ESI,pos.ion)m/z:169.3[M+1]+。
Step 4：The synthesis of 1- (propyl- 2- alkynes -1- bases) -4- (2,2,2- trifluoroethyls) piperazine
In single-necked flask, by 1- (2,2,2- trifluoroethyl) piperazine (1.55g, 8.32mmol) and K2CO3(1.00g, 5.58mmol) it is dissolved in MeCN (45mL), reaction solution is cooled to -5 DEG C, 3- propargyl bromides is then added dropwise into reaction system (1.20mL, 13.2mmol), finishes, and reacts on stirring reaction at this temperature, is tracked and reacted by TLC.Treat that raw material conversion is complete, will Reacting liquid filtering, is removed under reduced pressure MeCN, residue CH2Cl2(100mL) dissolves, and then uses water (30mL) and saturation NaCl successively Solution (30mL) washs, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=5/1 it is yellow solid (383mg, 98%)), to obtain product.
Step 5：2- (4- (ethylsulfonyl) phenyl)-N- (4- (3- (4- (2,2,2- trifluoroethyls) piperazine -1- bases) Propyl- 1- alkynes -1- bases) phenyl) acetamide synthesis
Under nitrogen protection, by 1- (propyl- 2- alkynes -1- bases) -4- (2,2,2- trifluoroethyl) piperazine (290mg, 1.4063mmol), 2- (4- ethylsulfonyls phenyl)-N- (4- iodophenyls) 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).Instead Should be in 50 DEG C of oil baths compared with thermal agitation 6h.Reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate concentration.To residue Middle addition saturation NaHCO3Aqueous solution (20mL), is extracted, organic phase saturation NaCl aqueous solutions with EtOAc (30mL × 3) (20mL) is washed, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：DCM/EtOAc(v/ V)=15/1), it is faint yellow solid (170mg, 24%) to obtain object.
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- bases) phenyl) -2- (4- (ethyl sulphurs Acyl group) phenyl) acetamide (compound 14) synthesis
Step 1：The synthesis of 1- (4- (difluoro-methoxy) phenyl) propyl- 1- alcohol
4- (difluoro-methoxy) benzaldehyde (1.57g, 9.12mmol) is dissolved in THF (100mL) and is cooled with an ice bath, so The Et of EtMgBr is added dropwise in backward system2O solution (3.0M, 10mL), after 30min, is warming up to room temperature reaction overnight.Ice bath cools down Under, saturation NH is added dropwise into reaction system4Reaction is quenched in Cl aqueous solutions (50mL), and then EtOAc (100mL × 3) is extracted, and merges Organic phase simultaneously uses anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/EA (v/v)=4/ 1) it is yellow oil (1.7g, 92%), to obtain object.
Step 2：The synthesis of 1- (difluoro-methoxy) -4- (the amyl- 1- alkynes -3- bases of 1- (4- nitrobenzophenones)) aniline
Under nitrogen protection, by 1- (4- (difluoro-methoxy) phenyl) propyl- 1- alcohol (463mg, 2.29mmol) and trimethyl (2- (4- nitrobenzophenones) acetenyl) silane (1.0g, 4.6mmol) is dissolved in 1,2- dichloroethanes (40mL), adds InCl3 (54mg, 0.24mmol), then the stirring reaction 3h in 80 DEG C of oil baths, is concentrated under reduced pressure, (the leaching of crude on silica gel column chromatography for separation Lotion：PE/EtOAc (v/v)=50/1), it is yellow oil (0.70g, 92%) to obtain object.
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) amyl- 1- alkynes -1- bases) aniline
1- (difluoro-methoxy) -4- (the amyl- 1- alkynes -3- bases of 1- (4- nitrobenzophenones)) aniline (702mg, 2.12mmol) is molten In MeOH/H2O (3/1) (40mL) in the mixed solvent, sequentially adds NH4Cl (1.2g, 22mmol) and reduced iron powder (600mg, 10.71mmol), back flow reaction 3h.Reacting liquid filtering, is washed, filtrate anhydrous Na with EtOAc (200mL)2SO4It is dry, decompression Concentration, it is red oil (600mg, 94%) to obtain crude product, which is directly used in reacts in next step.
MS(ESI,pos.ion)m/z:302.1[M+1]+。
Step 4：N- (4- (3- (4- (difluoro-methoxy) phenyl) amyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethyl sulphonyl Base) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) amyl- 1- alkynes -1- bases) aniline (602mg, 2.0mmol), 2- (4- ethyls Sulfonyl benzene) acetic acid (700mg, 3.07mmol) and HATU (2.3g, 6.0mmol) be dissolved in CH2Cl2(50mL), under ice bath cooling, DIPEA (2mL, 12.1mmol) is added dropwise, stirring reaction is warmed to room temperature after 10min overnight.It is concentrated under reduced pressure, crude product is by silica gel column layer Analysis separation (eluent：PE/EtOAc (v/v)=1/1) and preparative separation, it is white solid (64mg, 6%) to obtain object.
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 propyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethylsulfonyl) phenyl) acetamide (compound 15) synthesis
Step 1：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, saturation NH is added dropwise into reaction system4Reaction is quenched in Cl aqueous solutions (30mL), and mixed liquor is used EtOAc (50mL × 3) is extracted, and merges organic phase, and use anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product is by silica gel column chromatography point From (eluent：PE/EtOAc (v/v)=10/1), it is pale yellow oily liquid (780mg, 93%) to obtain object.
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).
Step 2：The synthesis of 1- (difluoromethyl) -4- (3- (4- nitrobenzophenones) -1- phenyl propyl- 2- alkynes -1- bases) benzene
Under nitrogen protection, by 4- (difluoro-methoxy) phenyl) (phenyl) methanol (781mg, 3.12mmol) and trimethyl (2- (4- nitrobenzophenones) acetenyl) silane (1.0g, 4.6mmol) is dissolved in 1,2- dichloroethanes (40mL), then adds InCl3 (70mg, 0.32mmol), reacts and stirs 3h by 80 DEG C of oil bath heatings.It is concentrated under reduced pressure, mixture separates (elution by silica gel column chromatography Agent：PE/EtOAc (v/v)=50/1), it is yellow oil (700mg, 59%) to obtain object.
Step 3：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) -3- phenyl propyl- 1- alkynes -1- bases) aniline
By 1- (difluoromethyl) -4- (3- (4- nitrobenzophenones) -1- phenyl propyl- 2- alkynes -1- bases) benzene (695mg, 1.83mmol) it is dissolved in MeOH/H2In O (3/1,40mL), NH is then sequentially added4Cl solids (1.0g, 18.70mmol) and reduction Iron powder (520mg, 9.29mmol), back flow reaction 3h.Filtering, and is washed, filtrate liquid separation with EtOAc (20mL), and with anhydrous Na2SO4Dry organic phase, is concentrated under reduced pressure, it is red oil (580mg, 91%) to obtain crude product, 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 propyl- 1- alkynes -1- bases) phenyl) -2- (4- (second Base sulfonyl) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) -3- phenyl propyl- 1- alkynes -1- bases) aniline (580mg, 1.67mmol), 2- (4- ethylsulfonyls phenyl) acetic acid (600mg, 2.63mmol) and HATU (2.0g, 5.3mmol) are dissolved in DCM (50mL), ice Bathe under cooling and stirring, after addition DIPEA (2mL, 12.1mmol), 10min, reaction moves to room temperature, is stirred overnight.It is concentrated under reduced pressure, Crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1) and chromatographic isolation is further prepared, obtain 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) propyl- 1- alkynes -1- bases) -3- aminomethyl phenyls) -2- (4- (ethylsulfonyl) phenyl) acetamide (compound 16) synthesis
Step 1：The synthesis of 1- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methyl -4- nitrobenzenes
Under nitrogen protection, by 1- (difluoro-methoxy) -4- (propyl- 2- alkynes -1- bases) benzene (800mg, 4.39mmol) and 1- Bromo- 2- methyl -4- nitrobenzenes (950mg, 4.39mmol) are dissolved in THF (50mL), then sequentially add CuI (45mg, 0.23mmol)、Pd(PPh3)2Cl2(400mg, 0.56mmol) and DIPEA (2.00mL, 11.4mmol), room temperature reaction, by TLC Tracking reaction.After reaction, reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate concentration.Added into residue Saturation NaHCO3Aqueous solution (150mL), is extracted with EtOAc (200mL × 3), and organic phase is washed with saturation NaCl solution (50mL), Anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/CH2Cl2(v/v)=1/3), obtain It is yellow-brown solid (270mg, 19%) to object.
Step 2：The synthesis of 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- methylanilines
1- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -2- methyl -4- is added in 100mL single-necked flasks Nitrobenzene (191mg, 0.60mmol) is simultaneously dissolved with MeOH (38mL), then sequentially adds NH4Cl aqueous solution (141mg, 16mL, 2.63mmol) and reduced iron powder (0.50g, 9.0mmol), reaction solution heats in 50 DEG C of oil baths reacts 6h.Then will be anti- Answer liquid to be cooled to room temperature, filter, filtrate concentration, raffinate CH2Cl2(40mL × 3) extract, organic phase anhydrous Na2SO4It is dry It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/CH2Cl2(v/v)=1/1 object), is obtained as Huang Brown solid (90mg, 52%).
MS(ESI,pos.ion)m/z:288.2[M+1]+。
Step 3：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- aminomethyl phenyls) -2- (4- (second Base sulfonyl) phenyl) acetamide synthesis
By 4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) -3- methylanilines (41mg, 0.14mmol), 2- (4- ethylsulfonyls benzene) acetic acid (60mg, 0.26mmol), HOBt (50mg, 0.36mmol), EDCI (72mg, 0.37mmol) and CH2Cl2(5mL) is sequentially added in the single-necked flask of 100mL, is stirred at room temperature, and is tracked and reacted by TLC.After 8h, stop stirring, reaction Liquid CH2Cl2(50mL) dilutes, and then uses saturation NaHCO successively3Solution (10mL) and NaCl solution (10mL) washing, it is anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1), obtain 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) Propyl- 1- alkynes -1- bases) phenyl) acetamide (compound 17a) and 2- (4- (ethylsulfonyl) phenyl)-N- (4- (3- ((1s, 4s) - 4- (trifluoromethyl) cyclohexyl) propyl- 1- alkynes -1- bases) phenyl) and acetamide (compound 17b) synthesis
Step 1：The synthesis of 2- (4- (trifluoromethyl) Asias cyclohexyl) ethyl acetate
Under the conditions of anhydrous and oxygen-free, NaH (60%, 400mg, 10mmol) is placed in 100mL twoport flasks, and use THF (32mL) dissolves, and ethyl 2- (diethoxy phosphinylidyne) acetic acid esters (2.05g, 9.14mmol) is added dropwise at -20 DEG C, at this temperature 2h is stirred, 4- (trifluoromethyl) cyclohexanone (1.20g, 7.22mmol) is then slowly added into, finishes, reaction solution is slowly increased to room Temperature simultaneously stirs reaction 8h.After reaction, decompression steams THF, residue CH2Cl2(20mL × 3) extract.Organic phase is with anhydrous Na2SO4It is dry, concentration, crude on silica gel column chromatography for separation (eluent：PE/EA (v/v)=5/1), it is nothing to obtain object Color transparency liquid (1.33g, 62%).
Step 2：The synthesis of 2- (4- (trifluoromethyl) cyclohexyl) ethyl acetate
Added in 100mL single-necked flasks 2- (4- (trifluoromethyl) Asia cyclohexyl) ethyl acetate (2.11g, 8.93mmol) and with MeOH (50mL) dissolve, then add Pd/C (5%, 155mg, 1.46mmol), reaction mixture is in H2 55 DEG C of reaction 3h are heated under the conditions of (balloon).Reacting liquid filtering, after filtrate concentration, (eluent is separated by silica gel column chromatography： PE/CH2Cl2(v/v)=5/1 it is colourless transparent liquid (1.30g, 61%)), to obtain object.
Step 3：The synthesis of 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-necked flasks, and dissolved 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, reaction solution is cooled to Room temperature, under ice bath cooling, NH is added dropwise into reaction system4Cl solution (15mL) is quenched reaction, and decompression steams THF, residue by CH2Cl2(20mL × 3) extract, and merge organic phase and use anhydrous Na2SO4Dry, concentration, crude product is separated by silica gel column chromatography (eluent：PE/EtOAc (v/v)=5/1), it is colourless transparent liquid (887mg, 89%) to obtain object.
MS(ESI,pos.ion)m/z:197.1[M+1]+。
Step 4：The synthesis of 2- (4- (trifluoromethyl) cyclohexyl) acetaldehyde
In 100mL single port bottles, 2- (4- (trifluoromethyl) cyclohexyl) ethanol (1.10g, 5.61mmol) is dissolved in CH2Cl2 Cool down in (42mL) and in -10 DEG C, then addition Dess-Martin reagents (3.4g, 7.9mmol), after 10min, reaction is put Reaction 6h is stirred at room temperature.Reaction solution is cooled down by ice bath, and slowly plus water (10mL) is quenched, and THF is removed under reduced pressure, and adds into residue Enter saturation NaHCO3Aqueous solution (100mL), is extracted (150mL × 3) with EtOAc, and organic phase is washed with saturation NaCl solution (50mL) Wash, anhydrous Na2SO4It is dry, filter, concentration, it is colourless transparent liquid (521mg, 48%) to obtain object.
Step 5：The synthesis of 1- (propyl- 2- alkynes -1- bases) -4- (trifluoromethyl) hexamethylene
Under ice cooling, 4, in 100mL single-necked flasks add 2- (4- (trifluoromethyl) cyclohexyl) acetaldehyde (247mg, 1.27mmol) and with MeOH (38mL) dissolve, sequentially add K2CO3(360mg, 2.58mmol) and (1- diazonium -2- oxos-the third Alcohol)-dimethyl phosphonate (0.35mL, 2.0mmol), reaction is reacted at such a temperature, and is tracked by TLC.After reaction will be anti- Answer liquid to be cooled to room temperature, filter, filtrate concentration, residue CH2Cl2(80mL) dilutes, and is washed with saturation NaCl solution (20mL) Wash, anhydrous Na2SO4It is dry, filter, concentration, it is colourless transparent liquid (210mg, 87%) to obtain object.
Step 6：The synthesis of 2- (4- (ethylsulfonyl) phenyl)-N- (4- iodobenzenes) acetamide
Under nitrogen protection, it is 1- (propyl- 2- alkynes -1- bases) -4- (trifluoromethyl) hexamethylene (1.20g, 6.31mmol) is molten In anhydrous THF (30mL), sequentially add 2- (4- ethylsulfonyls phenyl)-N- (4- iodophenyls) acetamide (3.10g, 7.22mmol)、CuI(55mg,0.28mmol)、Pd(PPh3)2Cl2(500mg, 0.71mmol) and DIPEA (2.7mL, 15mmol), the then heating stirring 8h in 50 DEG C of oil baths.Reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate is dense Contracting.Saturation NaHCO is added into residue3Aqueous solution (30mL), is extracted, organic phase saturation NaCl with EtOAc (50mL × 3) Solution (30mL) washs, anhydrous Na2SO4It is dry, concentration, crude on silica gel column chromatography for separation (eluent：DCM/EtOAc(v/ V) faint yellow solid (270mg, 48%)=5/1) is obtained, further through preparing plate separation (solvent：DCM/EtOAc (v/v)= 2/1) 17a and 17b are obtained.
17a：2- (4- (ethylsulfonyl) phenyl)-N- (4- (3- ((1r, 4r) -4- (trifluoromethyl) cyclohexyl) propyl- 1- Alkynes -1- bases) 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) propyl- 1- Alkynes -1- bases) 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- hydroxyls -3- (2- (trifluoromethyl) pyrimidines -5- Base) propyl- 1- alkynes -1- bases) phenyl) and acetamide (compound 18) synthesis
Step 1：The synthesis of 1- (2- (trifluoromethyl) pyrimidine -5- bases) propyl- 2- alkynes -1- alcohol
Under nitrogen protection, 2- (trifluoromethyl) pyrimidine -5-formaldehyde (5.04g, 28.6mmol) is dissolved in THF (50mL) And cooled down under -10 DEG C of cryostats, acetenyl magnesium bromide (0.5mol/L, 70mL, 40mmol) is slowly dropped in reaction system, Low temperature stirring 2h is reacted on, 18h is then stirred at room temperature.Saturation NaCl aqueous solutions (50mL) are added into reaction system to be quenched instead Should, then extracted with DCM (50mL × 3), organic phase anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product is by silica gel column chromatography point From (eluent：PE/EtOAc (v/v)=5/1), it is yellow solid (4.5g, 78%) to obtain product.
MS(ESI,pos.ion)m/z:203.1[M+1]+。
Step 2：2- (4- (ethylsulfonyl) phenyl)-N- (4- (3- hydroxyls -3- (2- (trifluoromethyl) pyrimidine -5- bases) Propyl- 1- alkynes -1- bases) phenyl) acetamide synthesis
Under nitrogen protection, by 1- (2- (trifluoromethyl) pyrimidine -5- bases) propyl- 2- alkynes -1- alcohol (498mg, 2.46mmol), 2- (4- ethylsulfonyls phenyl)-N- (4- iodophenyls) 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.It is filtered to remove insoluble matter, filtrate concentration.Crude product separates (eluent by silica gel column chromatography：DCM/EtOAc (v/v)=2/ 1) it is yellow solid (479mg, 39%), to obtain object.
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) propyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethyl sulphurs Acyl group) phenyl) -3- hydroxypropanamides (compound 19) synthesis
Step 1：The synthesis of 2- (4- (ethylsulfonyl) phenyl) -3- hydracrylic acids
Under nitrogen protection, 2- (4- ethylsulfonyls phenyl) acetic acid (670mg, 2.94mmol) is dissolved in anhydrous THF In (32mL), 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) is added in reaction system, and 3h is stirred at room temperature in reaction.Reaction solution is poured into saturation NH4Cl aqueous solutions In (15mL), vacuum rotary steam removes THF, and water mutually uses CH2Cl2(20mL × 3) extract, and merge organic phase and with saturation NaCl solution (20mL) is washed, anhydrous Na2SO4Dry, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=5/1), obtain It is weak yellow foam shape solid (590mg, 78%) to product.
MS(ESI,pos.ion)m/z:259.4[M+1]+。
Step 2：The synthesis of 2- (4- (ethylsulfonyl) phenyl) -3- hydroxy-ns-(4- iodobenzenes) propionamide
By 2- (4- (ethylsulfonyl) phenyl) -3- hydracrylic acids (500mg, 1.94mmol), 4- Iodoanilines (510mg, 2.33mmol), EDCI (800mg, 4.09mmol) and HOBT (500mg, 3.59mmol) are dissolved in CH2Cl2(15mL), is stirred at room temperature 8h.Reaction solution CH2Cl2(50mL) dilutes, successively with saturation NaHCO3Solution (20mL) and saturation NaCl solution (20mL) are washed Wash, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, crude product separates (eluent by silica gel column chromatography：PE/EtOAc (v/v)=1/1), It is faint yellow solid (200mg, 19%) to obtain product.
MS(ESI,pos.ion)m/z:460.3[M+1]+。
Step 3：N- (4- (3- (4- (difluoro-methoxy) phenyl) propyl- 1- alkynes -1- bases) phenyl) -2- (4- (ethyl sulphonyl Base) phenyl) -3- hydroxypropanamides synthesis
Under nitrogen protection, by 1- (difluoro-methoxy) -4- (propyl- 2- alkynes -1- bases) benzene (100mg, 0.55mmol), 2- (4- (ethylsulfonyl) phenyl) -3- hydroxy-ns-(4- iodobenzenes) propionamide (100mg, 0.22mmol), CuI (22mg, 0.11mmol) and Pd (PPh3)2Cl2(55mg, 0.077mmol) is dissolved in THF (25mL), then add DIPEA (0.30mL, 1.7mmol), heating stirring 6h in 70 DEG C of oil baths is reacted on.Reaction solution is cooled to room temperature, is filtered to remove insoluble matter, filtrate is dense Contracting.Saturation NaHCO is added into residue3Aqueous solution (15mL), is then extracted, organic phase saturation with EtOAc (20mL × 3) NaCl aqueous solutions (15mL) wash, anhydrous Na2SO4It is dry, it is concentrated under reduced pressure, it is faint yellow solid (30mg, 11%) to obtain crude product.
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) ROR γ test buffers and the DTT of 10mM are prepared
100mL 1x basic experiments buffer solution (HEPES (pH 7.4), 100mM NaCl, 0.01%BSA) is prepared, and is added 154.25mg DTT, fully mixes.
(2) compound gradient concentration is prepared
A. n-compound is prepared, 2.5mM is diluted to 100%DMSO, then 3 times of dilutions, 11 gradient dilutions are to most Final concentration of 42.34nM；
B. preparation experiment compound, reference standard compound.
(3) 1x protein solution mixtures are prepared
A. the desired amount of 2x B-ROR γ LBD/SA-APC protein mixtures are prepared.The concentration of B-ROR γ LBD is 40nM, The concentration of SA-APC is 20nM, and reverse mixing gently, is incubated at room temperature 15 minutes.Then the biotin of 400nM is added, is gently run Mix, be incubated at room temperature 10 minutes；
B. the desired amount of 2x Biotin-SRC1/SA-eu protein mixtures are prepared.The concentration of Bioin-SRC1 is 40nM, The concentration of SA-eu is 20nM, and reverse mixing gently, is incubated at room temperature 15 minutes.Then the biotin of 200nM is added, is gently run Mix, be incubated at room temperature 10 minutes；
c.1:1 mixes the protein mixture that step a and step b is prepared, and is incubated at room temperature 5 minutes；
D. the mixture in 25 μ L steps c is added into 384 orifice plates comprising test compound；
E.1000rpm centrifuge one minute；
F. when incubation at room temperature 1 is small.
(4) data acquisition is with calculating
Be incubated at room temperature 1 it is small when after, measure the fluorescence at 665nm and 615nm respectively with EnVision plate reader Value, and inhibiting rate is calculated, the IC finally obtained50Value is shown in Table 1；
Inhibiting rate (%)=[(X-Min)/(Max-Min)] × 100%
X is the numerical value of " 665/615 " of test compound；Min is the average value of " 665/615 " of DMSO blank controls； Max is the average value of " 665/615 " of 10 μM of SRC.
2) result of the test
Table 1TR-FRET result of the tests
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
By SD Rat Septal curfews eat 15 it is small when after weigh, be grouped at random according to weight, test-compound prepare solvent For 5%DMSO+5%Solutol+90%Saline.For the test group of intravenous injection administration, 1mg/kg is given to experimental animal Dosage；For the test group of oral administration, the dosage of 5mg/kg is given to experimental animal.Then, it is 0,0.083 at time point Extracting vein blood (about 0.2mL), is placed in EDTAK when (only intravenous injection group), 0.25,0.5,1.0,2.0,5.0,7.0 and 24 are small2It is anti- In solidifying pipe, centrifuged 2 minutes in 11000rpm, collect blood plasma, and preserved at -20 DEG C or -70 DEG C until carrying out LC/MS/MS points Analysis.Each time point blood plasma drug concentration is measured, pharmacokinetic parameters are calculated according to pharmaceutical concentration-time curve.
The pharmacokinetic property of the compounds of this invention is shown in Table 2 by above experimental test, pharmacokinetic parameter.
2. result of the test
The pharmacokinetic parameter of 2 the compounds of this invention of table
Conclusion：By table 2 as it can be seen that the compounds of this invention blood concentration and exposed amount are horizontal in rat body after oral administration Higher, clearance rate is low, and half-life period is longer, has good Pharmacokinetic Characteristics.
Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, the embodiment of the present invention is It will 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 Modification or the equivalents added in the claims.All publications or patent cited in the present invention will all be used as this hair Bright bibliography.

Claims (9)

1. a kind of compound, its for the enantiomter of compound shown in the compound or formula (I) shown in formula (I) or its pharmaceutically Acceptable salt,
Wherein：
W rings are phenyl ring；
L is-N (R7)-C (=O)-CR8R9-；
R7For hydrogen；R8And R9It is each independently hydrogen, deuterium, C1-6Alkyl, C1-6Haloalkyl, C1-6Hydroxy alkyl, C1-6Alkoxy- C1-6Alkyl；
A is-S (O)2-R14；Wherein, R14For ethyl；R1And R2It is each independently hydrogen, deuterium, halogen atom, hydroxyl, C1-3Alkyl, C1-3 Haloalkyl, C1-3Alkoxy, C1-3Halogenated alkoxy or C6-10Aryl；
Each R3It independently is hydrogen, deuterium, halogen atom, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxy or C1-6Halogenated alkoxy；
T rings are C3-6Carbocyclic ring, C2-6Heterocycle or C6-10Aromatic ring；
Each J independently is hydrogen, deuterium, halogen atom, hydroxyl, C1-6Alkyl, C1-6Haloalkyl, C1-6Alkoxy, C1-6Halogenated alkoxy Or aldehyde radical；
M is 0,1,2,3 or 4；With
N is 0,1,2 or 3；
The carbocyclic ring refers to unsaturated monocyclic, bicyclic or tricyclic the alkyl of the nonaromatic saturation of unit price or multivalence or part Group；The heterocycle refers to that the undersaturated nonaromatic unit price of saturation or part or multivalence are monocyclic, bicyclic or tricyclic, wherein extremely A few annular atom is selected from nitrogen, sulphur and oxygen atom.
2. compound according to claim 1, wherein, R8And R9Be each independently hydrogen, deuterium, methyl, ethyl, isopropyl, Trifluoromethyl, hydroxymethyl, 1- hydroxyethyls, 2- hydroxyethyls or methyl epoxide methyl；
Each R3It independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, first Epoxide, ethyoxyl, isopropyl epoxide, difluoro-methoxy or trifluoromethoxy.
3. compound according to claim 1, wherein, R1And R2Be each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, Methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropyl epoxide, difluoro-methoxy, trifluoro methoxy Base or phenyl.
4. compound according to claim 1, wherein, T rings are C3-6Carbocyclic ring, C2-6Heterocycle or C6-10Aromatic ring；
Each J independently is hydrogen, deuterium, halogen atom, C1-3Alkyl, C1-3Haloalkyl, C1-3Alkoxy, C1-3Halogenated alkoxy or aldehyde Base.
5. compound according to claim 1, wherein, T rings are cyclopropane, cyclobutane, pentamethylene, hexamethylene, piperidines, piperazine Piperazine, morpholine, oxinane, pyrimidine or benzene；
Each J independently is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, 2, 2,2- trifluoroethyls, methoxyl group, isopropyl epoxide, difluoro-methoxy or trifluoromethoxy.
6. compound according to claim 1, has the structure of one of：
Or its enantiomter or its pharmaceutically acceptable salt.
7. a kind of pharmaceutical composition, it includes the compound described in claim 1-6 any one, and pharmaceutically acceptable tax Shape agent, carrier, adjuvant or combinations thereof；Wherein,
Described pharmaceutical composition further include other preventions or treatment inflammatory syndrome, obstacle or disease medicine or they Any combination.
8. the pharmaceutical composition described in compound or claim 7 described in claim 1-6 any one is in medicine preparation Purposes, the medicine be used for prevent or treat mammal by ROR γ t mediation inflammation or autoimmune disease.
9. purposes according to claim 8, the inflammation or autoimmune disease are psoriasis, rheumatoid joint Inflammation, systemic loupus erythematosus, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, asthma, osteoarthritis, Crohn disease or Kawasaki disease.
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