CN105085427B - A kind of benzo [d] isoxazole class compound and its application - Google Patents

Abstract

The present invention relates to technical field of chemical medicine, specifically disclose a kind of benzo [d] isoxazole class compound and its application shown in general formula (A).Such compound can effectively inhibit the bromine structural domain (bromodomain) of BET family proteins, so as to block the interaction between BET family proteins and chromatin histone, and then genetic transcription is adjusted, cause the variation of downstream signaling pathway, and a variety of diseases are had an important influence on.Therefore compound provided by the invention and composition can be used for preparing the drug for treating or preventing the diseases such as tumour formation, inflammation, viral infection, cell proliferation sexual disorder, autoimmune disease, septicemia.

Description

A kind of benzo [d] isoxazole class compound and its application

Technical field

The present invention relates to technical field of chemical medicine, and in particular to a kind of benzo [d] isoxazole class compound and its application.

Background technology

The acetylation of lysine is to adjust the important mechanisms of chromatin Structure；Abnormal Acetylation Level with a variety of diseases Development it is related.Acetyl-lysine is modified to the albumen comprising bromine structural domain and creates docking site, these sites are in difference Protein in the small interaction module that finds, some of transcriptional regulatory compounds assemblings relied in acetylation Middle performance key effect.These compounds can initialize transducer and then cause the change of phenotype.Find recently for Bromine structural domain BET (bromine structural domain and outer-end) family has the inhibitor of potent high degree of specificity, has evoked it and has been controlled in difference The in-depth study in treatment field, particularly in oncology, BET albumen adjusts the expression of crucial oncogene and anti-apoptotic proteins.This Outside, the treatment that targeting BET bromines structural domain also infects for inflammation and virus provides potentially possible.

Epigenetic regulation gene expression is the focus of genome times afterwards comprehensively research, on a molecular scale, the table of gene Seeing science of heredity regulation and control includes to DNA and is wound in the histone of DNA and carries out dynamically and reversible modification.Histone is dyeing The core of matter participates in posttranscriptional modification, mainly includes：Acetylation methylates, phosphorylation and ubiquitination.It is different on histone Covalent modification combines, and (histone end can change in modifying upon translation, be other so as to provide a kind of distinguishing mark The combination generation of albumen and DNA cooperate with or antagonistic effect, it is a kind of dynamic transcriptional control ingredient) it is known as Histone Code, it We are understood with gene expression pattern and is much not changed by the dominant inheritance of DNA sequence encoding most important.

Bromodomain families are the epigenetics readers of a kind of identification acetylated lysine.By identifying ε-N- second Acylated lysine residue, mediating proteins interaction, and then influence transcription.Bromodomain albumen is in 20th century 90 It is accredited out from Drosophila melanogaster Buddhist day gene at the beginning of age.Human protein organizes 61 kinds of bromodomain of coding, is present in In 46 different cores and cytoplasmic protein.This protein families is divided into nine groups, wherein BET according to the difference of sequence Bromodomain is one kind therein.There are four types of BET bromodomain albumen tools, and hypotype is respectively：BRD2、BRD3、BRD4 And BRDT.BRD2, BRD3 are located at after being combined with histone on active transcription gene, it is thus possible to it participates in promoting transcription extension, BRD4 can recruit PTEF- β, and the phosphorylation and enhancing for causing RNA polymerase are transcribed.BRD4 and BRD3 can be with nucleoprotein (NUT) New oncogenic fusion gene, i.e. BRD4-NUT and BRD3-NUT are formed, there is data to suggest that BRD-NUT is main carcinogenic factor. BRDT is mainly expressed in testis and ovary.

The wider biological function of bromine structural domain is reported in many documents.Albumen comprising bromine structural domain participates in turning Program calling and controlling is recorded, oncogene is caused to be reset, obtains high carcinogenic fusion protein, this plays weight in the development of a variety of malignant cancers It acts on.In addition, bromine structural domain also adjusts nuclear Factor-Kappa B (NF- κ B) comprising albumen, this is that a kind of inflammatory reaction of mediation is crucial Transcription factor.They also participate in virus genomic duplication and adjust the transcription of some virus proteins.In conclusion target these For albumen for developing target on cancer, the new therapeutic strategy that inflammation and virus infect may be beneficial.It is existing at present to be directed to this The micromolecular inhibitor of one receptor enters clinical stage, is mainly used for the treatment of cancer and autoimmune disease.

The content of the invention

The technical problem to be solved by the invention is to provide a kind of benzo [d] isoxazole class compounds, such compound can Effectively inhibit BET bromodomain receptors, more properly, the present invention provides include BET families bromo-structural domain for destroying Domain and the compound with the interaction of the acetyl-lysine of chromatin histone polypeptide.Treating cancer, inflammatory disease can be used as Disease, cell proliferation sexual disorder, autoimmune disease, septicemia, the medicine of virus infection.

The present invention to be solved the above problems and will be achieved by the following technical programs：

A kind of benzo [d] isoxazole class compound or its pharmaceutically acceptable salt, isomers, racemic modification, precursor medicine Object cocrystallization compound, hydrate or solvate have the general formula structure shown in formula A：

In formula A,

X is selected from O or S；

W is selected from H, hydroxyl, alkyl, alkoxy, hydroxyalkyl, alkylhalide group, aminoalkyl or alkoxyalkyl；

Any functional group of Y1, Y2 in following (i) or (ii) group：

(i) H, halogen, amino, alkyl, nitro, carboxyl, cyano, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkylhalide group, When hydroxyl, alkoxy, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl, Y1 or Y2 are selected from more than functional group, R1 and R2 groups are not In the presence of；

(ii)-N(R4)SO₂-、-SO₂N(R4)-、-N(R4)CO-、-CON(R4)-、-N(R4)CH₂-、-NHCH(R4)-、-N (R4)-,-CH (R4)-,-CO- ,-COO- ,-OCO- ,-S- or-O-；

Y3 is selected from any functional group in following (iii) or (iv) group：

(iii) H, halogen, alkyl, nitro, carboxyl, cyano, amino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, alkyl halide Base, hydroxyl or alkoxy, when Y3 is selected from more than functional group, R3 groups are not present；

(iv)-N(R4)SO₂-、-SO₂N(R4)-、-N(R4)CO-、-CON(R4)-、-N(R4)CH₂-、-NHCH(R4)-、-N (R4)-、-CH(R4)-、-CO-、-COO-、-OCO-、-S-、-O-；

Any functional group of R1, R2, R3 in following (v), (vi), (vii) or (viii) group：

(v) aryl, heteroaryl, the aryl being substituted or the heteroaryl being substituted；

(vi) cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, the cycloalkyl being substituted, the cycloalkenyl group being substituted or it is substituted miscellaneous Cycloalkyl；The cycloalkyl forms cycloalkyl by 3-10 carbon atom；The cycloalkenyl group is by 3-10 carbon atom group Into cycloalkenyl group, the Heterocyclylalkyl is the Heterocyclylalkyl of 1-3 hetero atom (O, S or N) composition by 3-10 carbon atom；

(vii) alkenyl or alkynyl that the straight or branched alkyl of 1-8 carbon composition, 2-8 carbon form；The carbochain The hetero atom for being selected from O, S or N comprising 0,1,2 or 3；

(viii)-(CH₂)_n-R5,-(CH2)_n-Y4-(CH₂)_m- R5, wherein n, m 0-4；Wherein Y4 is selected from-N (R4) SO₂-、-SO₂N(R4)-、-N(R4)CO-、-CON(R4)-、-N(R4)CH₂-、-NHCH(R4)-、-N(R4)-、-CH(R4)-、- CO- ,-COO- ,-OCO- ,-S- or-O-；

R4 is selected from H, C1~C6 straight or branched alkyls, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl or-(CH2)_n- R5, wherein n For 0-4；

R5 be selected from C1~C8 linear chain or branch chains or cycloalkyl, cycloalkenyl group, Heterocyclylalkyl, aryl, heteroaryl, alkenyl ,- CONH₂,-CONHR6 ,-NHCOR6 ,-COR6 ,-COOR6 ,-OCOR6 or-OR6；

R6 is selected from C1~C8 linear chain or branch chains or cycloalkyl, cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl, alkenyl.

Preferably, the linear chain or branch chain or cycloalkyl, cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl and alkenyl are Linear chain or branch chain or cycloalkyl, cycloalkenyl group, aryl, heteroaryl, Heterocyclylalkyl and the alkenyl being substituted.

Most preferably, it is described be substituted refer to through H, D, halogen, alkyl, nitro, carboxyl, cyano, amino, hydroxyalkyl, Aminoalkyl, alkoxyalkyl, alkylhalide group, hydroxyl ,-CONH₂,-COOR7 ,-COR7 ,-OR7 ,-NHCOR7 ,-NHCOOR7, ring Alkyl, Heterocyclylalkyl, aryl or heteroaryl substitution, R7 optionally from C1~C4 straight chained alkyls, branched alkyl or cycloalkyl, halogen, Acetyl group or alkoxy.

In certain embodiments, W is methyl, and H is optional on methyl is substituted by halogen, hydroxyl, amino, D.

In certain embodiments, R1 is aryl or heteroaryl, cycloalkyl, Heterocyclylalkyl, and each can be optional Ground is substituted.

In certain embodiments, Y1 is amine sulphonyl linking group (- NH-SO₂-), the sulfonamide that can be reversed replace (- SO₂-NH-)。

In certain embodiments, Y1, Y2, Y3 are oxygen or nitrogen, and are optionally replaced by conventional hetero atom (such as S).

Preferably, the aryl is phenyl ring or naphthalene nucleus group；

The heteroaryl is 5-8 unit monocycles, 8-12 membered bicyclics or the 11-14 membered tricyclic systems of aromatics；Described is monocyclic With 1-4 hetero atom, described is bicyclic with 1-6 hetero atom, and the tricyclic is with 1-9 hetero atom, the miscellaneous original Son is selected from O, N or S；

The Heterocyclylalkyl is heteroatomic organises in a cyclic structure comprising at least one in addition to carbon Close object；Cyclic structure in the organic compound is non-aromatic.

Most preferably, the aryl is selected from：Phenyl, tolyl, anthryl, fluorenyl, indenyl, azulenyl and naphthalene or 5,6, 7,8- tetralyls；Aryl group is unsubstituted or optionally substitutes through one or more substituent groups, for example, (including but not limited to alkyl (is preferably low alkyl group or through one to substituent group described herein for aryl group The alkyl of a or multiple halogens substitution), hydroxyl, alkoxy (preferably lower alkoxy), alkylthio group, cyano, halogen, amino, Boric acid-B (OH)₂。

The heteroaryl is selected from：Pyridyl group, furyl, thienyl, pyrrole radicals, pyrimidine radicals, oxazolyl, isoxazolyls, Oxadiazolyl, imidazole radicals, thiazolyl, isothiazolyl, quinolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazine radical, triazolyl, thiophene Di azoly, isoquinolyl, indazolyl, benzoxazolyl, benzofuranyl, indolizine base, imidazopyridyl, tetrazole radical, benzo Imidazole radicals, benzothiazolyl, diazosulfide base, Ben Bing oxadiazolyl and 1,3- dioxolanyls, isoquinolyl, indoles Quinoline base, 1H- indazolyls, 1H- benzos [d] imidazole radicals, 1H- indyls, benzo [d] [1,3] dioxa cyclopentenyl, benzo [d] Thiazolyl or H- pyrazoles -3 (2H) -one base；

The Heterocyclylalkyl is selected from morpholinyl, piperazinyl, piperidyl, nafoxidine base, THP trtrahydropyranyl, tetrahydrochysene furan It mutters, thiophane Huo dioxanes.

Most preferably, the alkyl, it is meant that the non-cyclic hydrocarbon of linear chain or branch chain of saturation, the hydrocarbon typically have 1-10 Carbon atom.The straight chained alkyl of representative saturation includes methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, positive heptan Base, n-octyl, n-nonyl and positive decyl；And the branched alkyl of saturation includes isopropyl, sec-butyl, isobutyl group, tert-butyl, different Amyl, 2- methyl butyls, 3- methyl butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2- methylhexyls, 3- methyl Hexyl, 4- methylhexyls, 5- methylhexyls, 2,3- dimethylbutyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,3- Dimethylhexanyl, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethyl amyl groups, 2,2- dimethylhexanyls, 3,3- bis- Methyl amyl, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls, 2- ethyl pentyl groups, 3- ethyl pentyl groups, 2- ethylhexyls, 3- second Base hexyl, 4- ethylhexyls, 2- methyl -2- ethyl pentyl groups, 2- methyl -3- ethyl pentyl groups, 2- methyl -4- ethyl pentyl groups, 2- first Base -2- ethylhexyls, 2- methyl -3- ethylhexyls, 2- methyl -4- ethylhexyls, 2,2- diethyl amyl groups, 3,3- diethyl oneself Base, 2,2- diethylhexyls, 3,3- diethylhexyls etc..Be included in the alkyl group in the compound of the present invention can be without Substitution or optionally through one or more substituent groups substitute, such as amino, alkylamino, fragrant amino, heteroaryl amino, alkane Oxygroup, alkylthio group, oxygroup, halogen, acyl group, nitro, hydroxyl, cyano, aryl, heteroaryl, alkaryl, miscellaneous alkyl aryl, fragrant oxygen Base, heteroaryloxy, arylthio, heteroarylthio, fragrant amino, heteroaryl amino, carbocylic radical, carbocyclic ring epoxide, carbocyclylthio, carbocyclic ring ammonia Base, heterocycle, heterocyclic oxy group, heterocyclic amino group, heterocyclethio etc..Typically preferred low alkyl group.

So-called " compound (compound) " means the chemical compound, antibody, nucleic acid molecules or more of any small molecule Peptide or its segment.

Described benzo [d] the isoxazole class compound, also covers its simple isotope derivatives, and such as H is taken by D thereon Generation, C¹²By C¹³Substitution.

Term " halogen (halogen) " refers to-F ,-Cl ,-Br or-I.

Term " alkylhalide group (haloalkyl) " is intended to include as defined above, through halogen is single, double or polysubstituted alkyl base Group, for example, methyl fluoride and trifluoromethyl.

Term " halogenated alkoxy " refers to through halogen is single, double or polysubstituted alkoxy base, such as trifluoromethoxy.

Term " hetero atom (heteroatom) " as used in this means any element in addition to carbon or hydrogen Atom.It is preferred that hetero atom is nitrogen, oxygen, sulphur and phosphorus.

On the name of chiral centre, term " d " and " l " configuration are as International Federation of Theoretical and Applied Chemistry (IUPAC) defined in.On term diastereoisomer, raceme, epimer and enantiomter, these will be It uses to describe the spatial chemistry of product in their common linguistic context.

Most preferably, the compound is any in following compounds：

The chloro- N- of 4- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

The chloro- N- of 2- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- fluorobenzenesulfonamides,

The chloro- N- of 5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- fluorobenzenesulfonamides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) thiophene -2- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- nitrobenzene sulfonamides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) butane -1- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) naphthalene -1- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- methoxybenzenesulphoismides,

2- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl benzoate,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) pentamethylene sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -1- (3- fluorophenyls) Methanesulfomide,

Methyl -4- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl benzoate,

N- (4- chlorobenzyls) -3,6- dimethylbiphenyls [d] isoxazole -5- amine,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- (4- fluorophenyls) acetamide,

2- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) benzoic acid,

4- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) benzoic acid,

Methyl 4- ((N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl) methyl benzoate,

The chloro- N- of 2- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

The chloro- N- of 3- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- fluorobenzenesulfonamides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) propane -1- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) ethyl sulfonamide,

4- ((N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl) benzoic acid,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- (p-methylphenyl) acetamide,

The bromo- N- of 5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxybenzenes sulphur,

The bromo- N- of 2- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 3,5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 2,6- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2,5- dimethoxy benzenesulfonamides,

Bis- chloro- N- of 2,3- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 2,5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2,3- dihydrobenzos [b] [1,4] dioxine -6- Sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) hexamethylene alkyl sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxyl group -5- methylbenzenes sulphur,

N- (2- chlorobenzyls) -3,6- dimethylbiphenyls [d] isoxazole -5- amine,

The bromo- 2- methoxyl groups-N- of 5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- ((4- (trifluoromethyl) benzyl) oxygroup) benzo [d] isoxazole -5- Base)-N- (4- (trifluoromethyl) benzyl) benzsulfamide,

The bromo- N- of 5- (6- ethyoxyl -3- methyl benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides,

The chloro- 2- methoxyl groups-N- of 5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The chloro- N- of 2- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- propoxyl group benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- ((4- (trifluoromethyl) benzyl) oxygroup) benzo [d] isoxazole -5- bases) Benzsulfamide,

Ethyl -2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygen Base) ethyl acetate,

5- (N- ((the bromo- 2- methoxyphenyls of 5-) sulfonyl) acetylamino) -3- methyl benzo [d] isoxazole -6- base second Acid esters,

Tertiary butyl -2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) Oxygroup) ethyl acetate,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup) second Acid,

The bromo- N- of 2- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The fluoro- N- of the chloro- 2- of 3- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 2,5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) propane -1- sulfonamide,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -2,3- dihydrobenzos [b] [1,4] dioxa hexamethylene Alkene -6- sulfonamide,

Bis- chloro- N- of 3,5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

2- methoxyl groups-N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -5- methyl benzenesulfonamides,

6- methoxyl group -3- methyl-N- (1- phenethyls) benzo [d] isoxazole -5- amine,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) thiophene -2- sulfonamide,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -5- methylthiophene -2- sulfonamide,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup)-N- Ethyl acetamide,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygen)-N- oneself Yl acetamide,

N- (2- acetamidoethyls) -2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzos [d] Isoxazole -6- bases) oxygen) acetamide,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup)-N- (2- morpholinoethyls) acetamide,

Tertiary butyl -4- (2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- Base) oxygroup) acetylamino) piperidines -1- carboxylic acid tert-butyl esters,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- 2- methoxy-. N-methyls-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzene sulfonyl Amine

N- (5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases)-N- methyl second Amide,

The bromo- N- of 5- (6- (ethylamino) -3- methyl benzo [d] isoxazole -5- bases) -2- methoxy-benzenesulfonamides,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- ((tetrahydrochysene -2H- pyrans -4- bases) amino) benzo [d] isoxazole -5- Base) benzsulfamide,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- ((2- morpholinoethyls) amino) benzo [d] isoxazole -5- bases) benzene sulphur Amide,

The chloro- N- of 2- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

The chloro- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases)-N- (2- morpholino second Base) benzsulfamide,

Bis- chloro- N- of 2,5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

N- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide,

3- methyl -5- (4- morpholino -3- nitrobenzophenones) benzo [d] isoxazole,

5- (3- methyl benzo [d] isoxazole -5- bases) -2- morpholinoes aniline,

The chloro- N- of 4- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide,

The fluoro- N- of the chloro- 4- of 2- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide,

N- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) thiophene -2- sulfonamide,

N- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) butane -1- sulfonamide,

The chloro- N- of 2- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide,

N- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) pentane amide,

The fluoro- N- of 4- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzamide,

N- (4- chlorobenzyls) -5- (3- methyl benzo [d] isoxazole -5- bases) -2- morpholinoes aniline,

The fluoro- N- of 4- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide,

N- (2- chlorphenyls) -6- methoxyl group -3- methyl benzo [d] isoxazole -7- sulfonamide,

N- hexyl -6- methoxyl group -3- methyl benzo [d] isoxazole -7- sulfonamide,

N- ethyls -6- methoxyl groups -3- methyl benzo [d] isoxazole -7- sulfonamide.

A kind of benzo [d] isoxazole class compound pharmaceutically acceptable salt of the present invention, isomers, racemic Body, pro-drug, cocrystallization compound, hydrate or solvate.

Term " isomers " refers to thering is identical chemical component, but the change that the spatial arrangement of atom or group is different Close object.Mainly there are diastereoisomer (diastereomers) and enantiomter (enantiomers).

Term " diastereoisomer (diastereomers) " refer to have two or more asymmetric centers and Its molecule is not the stereoisomer of mirror images of each other.

Term " enantiomter (enantiomers) " refer to two kinds of a kind of compound each other non-superimposable mirror image stand Body isomers.The equimolar mixture of two kinds of enantiomters is referred to as " racemic mixture " or " raceme ".

Term " pro-drug (prodrug) " includes the compound with the part that can be metabolized in vivo.In general, before drug Body is metabolized as active medicine by esterase or other mechanism in vivo.It can in situ be made when compound is finally recovered and is purified These standby prodrugs or by the compound of purifying in the form of sour or hydroxyl is respectively reacted with suitable esterifying agent.

A kind of benzo [d] isoxazole class compound or its pharmaceutically acceptable salt, isomers, racemic modification, precursor medicine The application of object, cocrystallization compound, hydrate or solvate in BET bromodomain acceptor inhibitors are prepared.

A kind of benzo [d] isoxazole class compound or its pharmaceutically acceptable salt, isomers, racemic modification, precursor medicine Object, cocrystallization compound, hydrate or solvate are preparing treatment, prevention or are improving cancer, cell proliferation sexual disorder, inflammation Application in the drug that disease, autoimmune disease, septicemia or virus infect.

One kind is used to treating, prevent or improving cancer, cell proliferation sexual disorder, inflammation, autoimmune disease, septicemia Or the pharmaceutical composition of virus infection, which is characterized in that contain benzo of the present invention [d] isoxazole class compound or its medicine Acceptable salt, isomers, racemic modification, pro-drug, cocrystallization compound, hydrate or solvate on.

So-called " improve (ameliorate) " means to reduce, inhibits, weakens, reducing, retardance or the development of stable disease Or progress.

In certain embodiments, the compounds of this invention is attached to BET bromo-base structure domains, so as to compete histone H 4 Kac The combination of peptide inhibits the function of bromine structural domain.

In certain embodiments, detected and combined using Alphascreen methods.

In certain embodiments, experiment (TSA) is migrated using thermostabilization to measure binding specificity.

In certain embodiments, which forms hydrogen bond with the asparagine guarded in the bromine structural domain.

Term " BET bromines structural domain ".Refer to the protein domain being made of about 110 amino acid, this structural domain A kind of left-handed bundle mainly is formed by four α spirals, which can interact with chromatin.Common BET family protein bags Two bromo-base structure domains and a kind of polypeptide or segment of additional terminal domains are included, with transcriptional regulatory activity or identification and are tied Close acetylation-lysine-reactive.Illustrative BET family members include BRD2, BRD3, BRD4 and BRDT.

Being applicable in the exemplary knurl that the compound of the present invention is treated includes, but is not limited to, and leukaemia is (for example, acute Leukaemia, acute lymphatic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute preceding marrow Cell leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, Di Guglielmo syndrome, mixing Property leukaemia, chronic leukemia, chronic granulocytic leukemia, chronic lymphocytic leukemia), it is Huppert's disease, true Property erythremia, T-cell lymphoma,cutaneous (CTCL), lymthoma (Hodgkin's disease, non-Hodgkin lymphoma), Wall Dan Sitelunshi Macroglobulinemia, heavy chain disease and solid tumor, if sarcoma and cancer are (for example, fibrosarcoma, myxosarcoma, sarcolipoma, cartilage Sarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangioendothelial sarcoma, lymphangioendothelial sarcoma, synovialoma, celiothelioma, Ewing' s tumor, leiomyosarcoma, rhabdomyosarcoma, colon tumor, colorectal cancer, cancer of pancreas, breast cancer, oophoroma, prostate Cancer, squamous cell carcinoma, basal-cell carcinoma, gland cancer, syringocarcinoma, carcinoma of sebaceous glands, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, marrow sample Cancer, bronchiolar carcinoma, clear-cell carcinoma, liver cancer, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, kidney mother cell

The cancer is：Adrenal tumor, acoustic neurinoma, acral lentiginous melanoma, acrospiroma, acute acidophilia are white Blood disease, the leukaemia of acute red, acute lymphoblastic leukemia, acute megakaryocytic leukemia, Acute monocytic Leukaemia, acute promyelocytic leukemia, gland cancer, adenoid cystic carcinoma, adipose tissue neoplasms, adrenocortical carcinoma, into The soft sarcoma of human T cell leukemia/lymthoma, aids related lymphoma, alveolar rhabdomyosarcoma, alveolar, the fibre of ameloblast Tie up knurl, primary cutaneous type, undifferentiated thyroid carcinoma, Angiomyolipoma, angiosarcoma, astrocytoma, SARS The rod-shaped tumour of type deformity, B cell chronic lymphocytic leukemia, B cell prolymphocyte leukaemia, B cell lymphoma, base Floor cells cancer, cancer of bile ducts, carcinoma of urinary bladder, enblastoma, bone tumour, brown tumor, Burkitt lymphoma, breast cancer, the cancer of the brain, original position Cancer, chondroma, cementoma, medullary system sarcoma, chondroma, chordoma, choriocarcinoma, papilloma choroideum, kidney hyaline cell Sarcoma, craniopharyngioma, Cutaneous T-cell Lymphoma, cervical carcinoma, colon cancer, small round cell neoplasm, cell diffuse type B cell lymph Knurl, neurepithelial tumour, dysgerminoma, embryonal carcinoma endocrine disrupting effects, endodermal sinus tumor, cancer of the esophagus, fibroma, Fibrosarcoma, follicular lymphoma, folliculus neuroastrocytoma, thyroid cancer gastrointestinal cancer, germinoma, the gestational period Choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, neurogliocytoma, glioblastoma multiforme, nerve Outside glioma, granular cell tumor, masculinoma, gall-bladder cancer, stomach cancer, hemangioblastoma, head and neck cancer, blood vessel Chrotoplast knurl malignant tumour, liver mother cell cancer, cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, wellability leaflet Cancer, intestinal tract, kidney, laryngocarcinoma, fatal center line cancer, leukaemia, Leydig cell tumor, embryonal-cell lipoma, lung cancer, lymphatic vessel Knurl, lymphoepithelioma, lymthoma, acute lymphoblastic pipe sarcoma, lymphocytic leukemia, chronic lymphocytic leukemia, liver cancer, Small Cell Lung Cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, marginal zone B cell lymphomas, mast cell leukemia, Germ Cell Tumors of Mediastinum, medullary carcinoma of breast, medullary thyroid carcinoma, into nerve channel Cytoma, melanoma, meningioma, merkel's cells cancer, celiothelioma, metastatic cell cancer, mixing Miao Shi tumours, mucus Tumour, Huppert's disease, muscle tissue tumor, gill fungus sample mucoid embryonal-cell lipoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, nerve Blastoma, neurofibroma, neuroma, eye cancers, acidophilia, vagina nervi optici meningioma, tumour, carcinoma of mouth, osteosarcoma, Oophoroma, papillary thyroid carcinoma, tumour Chromaffionoma, pineoblastoma, pituicytoma, precursor T- lymphs are female thin Born of the same parents' property lymthoma, primary central nervous system lymphoma, peritoneal cancer, prostate cancer, cancer of pancreas, pharynx cancer, clear-cell carcinoma, kidney marrow Sample cancer, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, the carcinoma of the rectum, sarcoma, seminoma, trophoblastic tumor, Cutaneum carcinoma, small round cell neoplasm, small cell carcinoma, soft tissue sarcoma, somatostatinoma, tumor of spinal cord, Splenic marginal zone lymphoma, squama Shape cell cancer, synovial sarcoma, squamous cell carcinoma, stomach cancer, t cell lymphoma, carcinoma of testis, thyroid cancer, transfer small bowel cancer Cell cancer, laryngocarcinoma, carcinoma of urachus, urogenital cancer, uterine cancers, verrucous carcinoma, visual pathway glioma, carcinoma of vulva or Carcinoma of vagina.

The cell proliferation sexual disorder disease includes：Benign soft tissue neoplasm, brain and tumor of spinal cord, eyelid and track swell Knurl, granuloma, lipoma, meningioma, Multiple Endocrine knurl, nasal polyp, pituitary tumor, prolactinoma, seborrheica cutin, Polyp of stomach, thyroid nodule, hepatic hemangioma, singer's node, polyp, tumour, pilonidal disease, histiocytoma, Pi Laer tumours or Pyogenic granuloma.

The inflammation disease includes：Inflammation pelvic conditions, urethritis, skin sunburn, nasosinusitis, pneumonia, encephalitis, meninx Inflammation, myocarditis, ephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, pancreatitis, psoriasis, allergy, Crow It is engler's disease, bowel syndrome, ulcerative colitis, tissue transplantation rejection, organ-graft refection, asthma, allergic rhinitis, chronic Obstructive disease of lung, autoimmune disease, autoimmune alopecia, anaemia, glomerulonephritis, dermatomyositis, multiple sclerosis Disease, chorionitis, vasculitis, Autoimmune hemolytic and decrease of platelet, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, infectious shock, systemic loupus erythematosus, rheumatoid Property arthritis, psoriatic arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, myasthenia gravis, bridge this first shape Adenositis, allergic dermatitis, degenerative joint disease, actue infectious polyradiculoneuritis, mycosis fungoides or acute inflammatory reaction.

The virus infection includes：Human papilloma virus, herpesviral, epstein-Barr virus, human immunodeficiency virus, Hepatitis type B virus or infection with hepatitis C virus.

Advantageous effect：The present invention provides a kind of structure novel as BET bromodomain acceptor inhibitors Compound, such compound can effectively inhibit the bromine structural domain (bromodomain) of BET family proteins, so as to block BET families Interaction between albumen and chromatin histone, and then genetic transcription is adjusted, cause the variation of downstream signaling pathway, and it is right A variety of diseases have an important influence on.Therefore compound provided by the invention and composition, which can be used for preparing, treats or prevents tumour shape Into the drug of the diseases such as, inflammation, viral infection, cell proliferation sexual disorder, autoimmune disease, septicemia.

Specific embodiment

The present invention is explained further below in conjunction with specific embodiment, but embodiment does not do any type of limit to the present invention It is fixed.

The preparation scheme of compound of the present invention

For the ease of statement, the compound according to preparation method by claim is divided into four classes, but to former general formula and Entire invention does not limit in any form.

When structure type as shown is following I, compound can be passed through by 4- methoxyl groups -2-aminotoluene for starting material 6 steps are obtained by the reaction：

The synthesis of the chloro- N- of 1 4- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide

The synthesis of step 1.N- (4- methoxyl group -2- aminomethyl phenyls) acetamide

4- methoxyl groups -2-aminotoluene (10g, 72.9mmol) and triethylamine (11.8g, 116.64,1.6eq) are dissolved in Under condition of ice bath, acetic anhydride (10.42g, 1.4eq) is added dropwise in 30ml dichloromethane, and 80min -2h, TLC prisons is then stirred at room temperature Survey reaction.After reaction, 10% aqueous citric acid solution is added in into reaction system, is then extracted with ethyl acetate, organic layer Dilute hydrochloric acid, saturated sodium bicarbonate, saturated common salt water washing are used successively, and anhydrous sodium sulfate drying is concentrated under reduced pressure, obtains product 8.89g.

The synthesis of step 2.N- (5- acetyl group -4- hydroxy-2-methyls phenyl) acetamide

N- (4- methoxyl group -1- aminomethyl phenyls) acetamide 2-2 (8.89g, 49.6mmol) is dissolved in 35ml dichloromethane, Ice-water bath condition is slowly added dropwise chloroacetic chloride (11.68g, 148.8mmol), is vigorously stirred, then alchlor is added portionwise successively (26.45g, 198.4mmol).2h is heated to reflux after reaction system stabilization.TLC monitoring reactions.After reaction, it is cooled to room Reaction system is slowly added dropwise and is quenched into trash ice by temperature.It is extracted afterwards with dichloromethane (30ml x 3), water washing once, is satisfied It washed once with sodium chloride solution, anhydrous Na₂SO₄It is dry.Sand core funnel is taken, spreads enough silica whites, is filtered, a small amount of dichloromethane It rinses, merging filtrate is concentrated under reduced pressure, and petroleum ether recrystallization obtains product 2-3 (8g, 77%).¹H NMR(400MHz,DMSO)δ 11.80(s,1H),9.31(s,1H),7.77(s,1H),6.83(s,1H),2.57(s,3H),2.19(s,3H),2.03(s, 3H).MM-MS+APCI m/z[M+H]⁺=208.0, m/z [M-H]^-=206.0

The synthesis of step 3.N- (4- hydroxyls -5- (1- (oxyimino) methyl) -2- aminomethyl phenyls) acetamide

It is water-soluble that N- (5- acetyl group -4- hydroxy-2-methyls phenyl) acetamide 2-3 (8g, 38.6mmol) is dissolved in 160ml ethyl alcohol Liquid (absolute ethyl alcohol：Water=3:1, V/V), add in hydrochloric acid hydroxyl by (4.3g, 61.76mmol) and sodium acetate (5.0g, 61.76mmol), 80 DEG C of reflux 70min.TLC monitoring reactions.Reaction finishes, and is cooled to room temperature, and reduction vaporization is concentrated into about 60ml adds in 125ml elutriations and goes out solid, be filtered under diminished pressure, washes, dry, obtains pink solid 2-4 (8.9g, 90%).¹H NMR(400MHz,DMSO)δ11.49(s,1H),11.37(s,1H),9.22(s,1H),7.34(s,1H),6.72(s,1H), 2.19(s,3H),2.12(s,3H),2.01(s,3H).

The synthesis of step 4.N- (3-6- dimethyl -1,2- benzoisoxazole -5- bases) acetamide

N- (4- hydroxyls -5- (1- (oxyimino) methyl) -2- aminomethyl phenyls) acetamide 2-4 (8.5g, 38.6mmol) 25ml Isosorbide-5-Nitraes-dioxane is dissolved in, is vigorously stirred lower instillation n,N-Dimethylformamide dimethylacetal (DMF-DMA) (23ml). After reaction system stabilization, 100 DEG C of reaction 7min are warming up to.It is cooled to room temperature.Add water, ethyl acetate into reaction system (30ml x 3) is extracted, and washed once respectively with water, saturated salt solution, and anhydrous sodium sulfate drying is concentrated under reduced pressure, obtains brownish black Solid (4.5g).¹H NMR(400MHz,DMSO)δ9.41(s,1H),7.77(s,1H),7.56(s,1H),2.50(s,3H), 2.35(s,3H),2.09(s,3H).MM-MS+APCI m/z[M+H]⁺=205.0, m/z [M-H]^-=203.1

The synthesis of step 5. 3,6- dimethyl -1,2- benzoisoxazole -5- amine

((3,6- dimethyl -1,2- benzoisoxazole -5- bases) acetamide 2-5 (3.5g, 17.3mmol) is dissolved in 3mol/L to N- Hydrochloric acid, flow back 80min.TLC monitoring reactions.Reaction finishes, and adds in sodium hydroxide solution tune PH to neutrality, precipitation, decompression is precipitated Filtering, a small amount of water washing is dry, obtains sepia solid 2-6 (2.7g, 97%).¹H NMR(400MHz,DMSO)δ7.29(s, 1H),6.83(s,1H),4.89(s,2H),2.41(s,3H),2.21(s,3H).MM-MS+APCI m/z[M+H]⁺=163.0

The chloro- N- of step 6. 4- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide

3,6- dimethyl -1,2- benzoisoxazole -5- amine (50mg, 0.308mmol) and 4- chlorobenzene sulfonyl chlorides (97.7mg, 6mL dichloromethane 0.463mmol) is dissolved in, adds in 0.5ml pyridines, 45 DEG C of reaction 1.5h.TLC monitoring reactions.After reaction, add in 20ml water and 3~5ml dilute hydrochloric acid, ethyl acetate (15ml x 2) extraction, once, saturated salt solution washed once, anhydrous slufuric acid for washing Sodium is dried, and is concentrated under reduced pressure, column chromatography for separation (PE:EA=2:1v/v), white solid (73mg, 70%) is obtained.¹H NMR(400MHz, DMSO)δ9.88(s,1H),7.74–7.57(m,4H),7.51(s,1H),7.40(s,1H),2.46(s,3H),2.05(s,3H).

2 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.75 (s, 1H), 7.64 (dd, J=17.5, 7.6Hz, 3H), 7.54 (t, J=7.6Hz, 2H), 7.48 (s, 1H), 7.36 (s, 1H), 2.44 (s, 3H), 2.02 (s, 3H)

The chloro- N- of 3 2- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- fluorobenzenesulfonamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.13 (s, 1H), 7.86 (dd, J=8.8, 6.1Hz, 1H), 7.77 (dd, J=8.7,2.2Hz, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.33 (td, J=8.5, 2.3Hz,1H),2.44(s,3H),2.24(s,3H).

The chloro- N- of 4 5- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.77 (s, 1H), 7.68 (dd, J=8.9, 2.5Hz, 1H), 7.53 (d, J=2.5Hz, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.29 (d, J=8.9Hz, 1H), 3.83 (s,3H),2.45(s,3H),2.22(s,3H).

5 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- fluorobenzenesulfonamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.82 (s, 1H), 7.67 (dd, J=8.6, 5.3Hz, 2H), 7.51 (s, 1H), 7.39 (dd, J=10.7,6.8Hz, 3H), 2.46 (s, 3H), 2.05 (s, 3H)

6 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) thiophene -2- sulfonamide

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 7.94 (d, J=4.8Hz, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.38 (d, J=3.2Hz, 1H), 7.14 (t, J=4.3Hz, 1H), 2.47 (s, 3H), 2.08 (s, 3H)

7 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- nitrobenzene sulfonamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.19 (s, 1H), 8.38 (d, J=8.6Hz, 2H), 7.87 (d, J=8.6Hz, 2H), 7.53 (s, 1H), 7.42 (s, 1H), 2.46 (s, 3H), 2.06 (s, 3H)

8 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) butane -1- sulfonamide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.21(s,1H),7.65(s,1H),7.60(s, 1H),3.20–3.07(m,2H),2.53(s,3H),2.46(s,3H),1.81–1.63(m,2H),1.51–1.33(m,2H), 0.89 (t, J=7.3Hz, 3H)

9 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) naphthalene -1- sulfonamide

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.07 (s, 1H), 8.68 (d, J=8.8Hz, 1H), 8.24 (d, J=8.2Hz, 1H), 8.17-8.08 (m, 1H), 7.99 (d, J=7.3Hz, 1H), 7.74-7.62 (m, 2H), 7.56 (t, J=7.8Hz, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 2.38 (s, 3H), 1.90 (s, 3H)

10 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- methoxybenzenesulphoismides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.58 (s, 1H), 7.53 (d, J=8.6Hz, 2H), 7.48 (s, 1H), 7.38 (s, 1H), 7.05 (d, J=8.6Hz, 2H), 3.81 (s, 3H), 2.45 (s, 3H), 2.05 (s, 3H)

11 2- of embodiment (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl benzoate

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.50 (s, 1H), 7.73 (dd, J=10.5, 5.3Hz, 1H), 7.64 (d, J=4.7Hz, 3H), 7.49 (d, J=6.3Hz, 2H), 3.69 (s, 3H), 2.47 (s, 3H), 2.08 (s, 3H)

12 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) pentamethylene sulfonamide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.18(s,1H),7.66(s,1H),7.59(s, 1H), 3.64 (p, J=7.6Hz, 1H), 2.53 (s, 3H), 2.47 (s, 3H), 1.93 (d, J=5.5Hz, 4H), 1.72-1.63 (m,2H),1.62–1.53(m,2H).

13 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -1- (3- fluorophenyls) Methanesulfomide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.30(s,1H),7.59(s,1H),7.53(s, 1H), 7.43 (dd, J=14.4,7.5Hz, 1H), 7.23 (dt, J=15.5,7.7Hz, 3H), 4.59 (s, 2H), 2.50 (s, 3H),2.41(s,3H).

14 methyl -4- of embodiment (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl benzoate

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.00 (s, 1H), 8.10 (d, J=8.2Hz, 2H), 7.75 (d, J=8.2Hz, 2H), 7.50 (s, 1H), 7.43 (s, 1H), 3.88 (s, 3H), 2.46 (s, 3H), 2.00 (s, 3H)

15 N- of embodiment (4- chlorobenzyls) -3,6- dimethylbiphenyls [d] isoxazole -5- amine

3,6- dimethyl -1,2- benzoisoxazole -5- amine (referring to embodiment 1) (70mg, 0.432mmol) are dissolved in 15ml third Ketone then adds in K₂CO₃(178.8mg, 1.30mmol), 4- benzyl chlorides chlorine (69.5mg, 0.432mmol) and KI (7.17mg, 0.043mmol), 50 DEG C of stirring 4h.After reaction, acetone vacuum is spin-dried for, and adds water, ethyl acetate extraction, organic layer saturation Brine It 1 time, anhydrous sodium sulfate drying, is concentrated under reduced pressure, silica gel column chromatography obtains white solid (63mg).¹H NMR (400MHz, DMSO) δ 7.43 (d, J=8.3Hz, 2H), 7.38 (s, 1H), 7.37 (d, J=5.4Hz, 2H), 6.56 (s, 1H), 5.69 (s, 1H), 4.39 (d, J=5.2Hz, 2H), 2.35 (s, 3H), 2.32 (s, 3H)

16 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- (4- fluorophenyls) acetamide

3,6- dimethyl -1,2- benzoisoxazole -5- amine (referring to embodiment 1) (50mg, 0.308mmol) and triethylamine (93.5mg, 0.924mmol) dissolves in methylene chloride, and is cooled to 0 DEG C.Under nitrogen protection, by 2- (4- fluorophenyls) second Acyl chlorides (53.2mg, 0.308mmol) is slowly added into the mixture, and by reaction be stirred at room temperature 2 it is small when.Reaction terminates After use NaHCO₃(1N) is quenched, and is washed with brine.Concentration and dry (sodium sulphate), column chromatography (silica gel, ethyl acetate/oil Ether mixture=1:2 elutions), obtain pure amide product.¹H NMR(400MHz,DMSO)δ9.64(s,1H),7.76(s,1H), 7.56 (s, 1H), 7.45-7.36 (m, 2H), 7.17 (t, J=8.7Hz, 2H), 3.70 (s, 2H), 2.49 (s, 3H), 2.31 (s, 3H)

17 2- of embodiment (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) benzoic acid

2- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl benzoate (comes from embodiment 11) (70mg, 0.19mmol) is dissolved in 5ml methanol, adds in the NaOH of 15ml 2M, 2h is stirred at room temperature.Reaction terminates, and is spin-dried for methanol, uses 1M dilute hydrochloric acid tune PH filter to neutrality, obtain white solid (52.5mg).¹H NMR(400MHz,DMSO)δ13.66(s,1H), 9.21 (s, 1H), 7.71 (d, J=3.9Hz, 2H), 7.66-7.53 (m, 2H), 7.48 (s, 1H), 7.46 (s, 1H), 2.45 (s, 3H),2.12(s,3H).

18 4- of embodiment (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) benzoic acid

Synthetic method such as embodiment 17.¹H NMR(400MHz,DMSO)δ13.46(s,1H),9.97(s,1H),8.07(d, J=8.2Hz, 2H), 7.73 (d, J=8.1Hz, 2H), 7.50 (s, 1H), 7.41 (s, 1H), 2.45 (s, 3H), 2.01 (s, 3H)

19 methyl 4- of embodiment ((N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl) methyl benzoate

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.32 (s, 1H), 7.96 (d, J=8.0Hz, 2H), 7.59 (s, 1H), 7.56 (d, J=8.1Hz, 2H), 7.48 (s, 1H), 4.66 (s, 2H), 3.86 (s, 3H), 2.49 (s, 3H), 2.41(s,3H).MM-MS+APCIm/z[M+H]⁺=375.0, m/z [M-H]^-=373.0

The chloro- N- of 20 2- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.06 (s, 1H), 7.80 (d, J=7.8Hz, 1H), 7.72 (d, J=7.8Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.52 (s, 1H), 7.45 (t, J=7.6Hz, 1H), 7.36(s,1H),2.42(s,3H),2.22(s,3H).

The chloro- N- of 21 3- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- fluorobenzenesulfonamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.37 (s, 1H), 7.93 (t, J=7.3Hz, 1H), 7.61 (t, J=7.0Hz, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.35 (t, J=8.0Hz, 1H), 2.45 (s, 3H), 2.19(s,3H).

22 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) propane -1- sulfonamide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.20(s,1H),7.65(s,1H),7.60(s, 1H), 3.17-3.08 (m, 2H), 2.53 (s, 3H), 2.46 (s, 3H), 1.82-1.69 (m, 2H), 1.00 (t, J=7.4Hz, 3H)

23 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) ethyl sulfonamide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.19(s,1H),7.66(s,1H),7.60(s, 1H), 3.16 (q, J=7.3Hz, 2H), 2.53 (s, 3H), 2.47 (s, 3H), 1.28 (t, J=7.3Hz, 3H)

24 4- of embodiment ((N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl) benzoic acid

Synthetic method such as embodiment 17.¹H NMR (400MHz, DMSO) δ 7.85 (d, J=7.8Hz, 2H), 7.49 (s, 1H), 7.33 (s, 1H), 7.30 (d, J=7.8Hz, 2H), 4.42 (s, 2H), 2.45 (s, 3H), 2.34 (s, 3H) .MM-MS+ APCI m/z[M-H]^-=359.0

25 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- (p-methylphenyl) acetamide

2- (p-methylphenyl) acetic acid (138.88mg, 0.93mmol) is dissolved in dichloromethane (15mL), adds in HATU (281.00mg, 0.74mmol) and DIPEA (238.85mg, 1.85mmol), 15min is stirred at room temperature in mixture.3 are then added in, 6- dimethyl -1,2- benzoisoxazole -5- amine (referring to embodiment 1) (100mg, 0.62mmol) and a small amount of DMAP (0.1eq), It is stirred overnight at room temperature.Reaction terminates, and adds water, with dichloromethane extraction three times, merges organic layer, saturated sodium-chloride washes one time, nothing Aqueous sodium persulfate is dried, and is spin-dried for, column chromatography, is obtained white solid (52mg).¹H NMR(400MHz,DMSO)δ9.60(s,1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.26 (d, J=7.6Hz, 2H), 7.15 (d, J=7.6Hz, 2H), 3.64 (s, 2H), 2.50 (s,3H),2.30(s,3H),2.29(s,3H).MM-MS+APCI m/z[M+H]⁺=295.0, m/z [M-H]^-=293.0

The bromo- N- of 26 5- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 9.77 (s, 1H), 7.80 (d, J=8.8Hz, 1H), 7.64 (d, J=0.9Hz, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 7.24 (d, J=8.9Hz, 1H), 3.83 (s, 3H), 2.46 (s,3H),2.22(s,3H).

The bromo- N- of 27 2- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.02 (s, 1H), 7.90 (d, J=7.7Hz, 1H), 7.84 (d, J=7.6Hz, 1H), 7.55 (t, J=7.5Hz, 1H), 7.52 (s, 1H), 7.49 (t, J=7.4Hz, 1H), 7.35(s,1H),2.42(s,3H),2.23(s,3H).

28 3,5- of embodiment, bis- chloro- N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ10.10(s,1H),8.02(s,1H),7.57(s, 3H),7.36(s,1H),2.46(s,3H),2.13(s,3H).

29 2,6- of embodiment, bis- chloro- N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.28 (s, 1H), 7.64 (d, J=7.6Hz, 2H), 7.58 (t, J=6.7Hz, 1H), 7.55 (s, 1H), 7.39 (s, 1H), 2.43 (s, 3H), 2.26 (s, 3H)

30 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2,5- dimethoxy benzenesulfonamides

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.54(s,1H),7.49(s,1H),7.42(s, 1H),7.18(s,2H),7.10(s,1H),3.77(s,3H),3.66(s,3H),2.44(s,3H),2.23(s,3H).

31 2,3- of embodiment, bis- chloro- N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.27 (s, 1H), 7.95 (d, J=8.0Hz, 1H), 7.80 (d, J=7.8Hz, 1H), 7.53 (s, 1H), 7.47 (t, J=8.0Hz, 1H), 7.39 (s, 1H), 2.43 (s, 3H), 2.23(s,3H).

32 2,5- of embodiment, bis- chloro- N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 1.¹H NMR (400MHz, DMSO) δ 10.28 (s, 1H), 7.77 (d, J=3.9Hz, 3H),7.55(s,1H),7.40(s,1H),2.45(s,3H),2.23(s,3H).MM-MS+APCI m/z[M+H]⁺=371.0, m/z[M-H]^-=369.0

33 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2,3- dihydrobenzos [b] [1,4] dioxa Cyclohexene -6- sulfonamide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.60(s,1H),7.50(s,1H),7.36(s, 1H), 7.05 (d, J=12.2Hz, 2H), 6.98 (d, J=8.2Hz, 1H), 4.29 (d, J=14.0Hz, 4H), 2.45 (s, 3H), 2.09(s,3H).

34 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) hexamethylene alkyl sulfonamide

Synthetic method such as embodiment 1.¹H NMR(400MHz,DMSO)δ9.11(s,1H),7.63(s,1H),7.59(s, 1H), 3.06 (t, J=11.6Hz, 1H), 2.53 (s, 3H), 2.47 (s, 3H), 2.11 (d, J=11.6Hz, 2H), 1.79 (d, J =9.2Hz, 2H), 1.63 (d, J=12.4Hz, 1H), 1.41 (q, J=12.4Hz, 2H), 1.29 (m, 2H), 1.71 (t, J= 12.4Hz,1H).MM-MS+APCI m/z[M-H]^-=307.0

35 N- of embodiment (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxyl group -5- methyl benzenesulfonamides

Synthetic method such as embodiment 1.¹H NMR(400MHz,CDCl₃) δ 7.59 (d, J=1.7Hz, 1H), 7.45 (s, 1H), 7.32 (dd, J=8.4,1.6Hz, 1H), 7.28 (s, 1H), 6.95 (d, J=8.4Hz, 1H), 6.87 (s, 1H), 4.00 (s, 3H),2.46(s,3H),2.35(s,3H),2.26(s,3H).

36 N- of embodiment (2- chlorobenzyls) -3,6- dimethylbiphenyls [d] isoxazole -5- amine

Synthetic method such as embodiment 15.¹H NMR(500MHz,DMSO)δ7.50–7.45(m,1H),7.41(s,1H), 7.38 (dd, J=5.7,3.7Hz, 1H), 7.32-7.25 (m, 2H), 6.51 (s, 1H), 5.71 (t, J=6.0Hz, 1H), 4.47 (d, J=5.9Hz, 2H), 2.35 (s, 6H) tables, 1 I class embodiment chemical constitutions

Note：1 embodiment preparation method of table is referring especially to embodiment 1；Band *：Preparation method is with reference to described in specific embodiment

When structure type is II as shown in scheme, wherein Y2=O, compound can be starting by 2,4- dimethoxyanilines Raw material is obtained by the reaction by 6-10 steps：

The bromo- 2- methoxyl groups-N- of embodiment 375- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide

The synthesis of step 1.N- (2,4- dimethoxy phenyls) acetamide

2,4- dimethoxyanilines (10g, 65.28mmol) and triethylamine (10.56g, 104.4mmol) are dissolved in 40ml bis- Chloromethanes under the conditions of ice-water bath, is added dropwise acetic anhydride (9.33g, 91.4mmol), is then stirred overnight at room temperature, TLC monitoring reactions. After reaction, 10% aqueous citric acid solution (or dilute hydrochloric acid) is added in into reaction system, is then extracted with dichloromethane, it is organic Layer uses dilute hydrochloric acid, saturated sodium bicarbonate, saturated common salt water washing successively, and anhydrous sodium sulfate drying is concentrated under reduced pressure, obtains brown and consolidate Body (10g).¹H NMR (400MHz, DMSO) δ 8.99 (s, 1H), 7.64 (d, J=8.7Hz, 1H), 6.59 (s, 1H), 6.45 (d, J=8.8Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 2.01 (s, 3H) .MM-MS+APCI m/z [M+H]⁺=196.1, m/z [M-H]^-=194.2

The synthesis of step 2.N- (5- acetyl group -4- hydroxyl -2- methoxyphenyls) acetamide

N- (2,4- dimethoxy phenyl) acetamides (10g, 51.22mmol) are dissolved in 35ml dichloromethane, in ice-water bath item Part is slowly added dropwise chloroacetic chloride (12.6g, 153.67mmol), is vigorously stirred successively, then be added portionwise alchlor (27.32g, 204.88mmol).After reaction system stabilization, 43 DEG C of oil bath heating reflux 3h are transferred to.TLC monitoring reactions.After reaction, It is cooled to room temperature, reaction system is slowly added dropwise and is quenched into trash ice, stir 1.5h.Extracted afterwards with dichloromethane (30ml x 3) It takes, water washing 2 times, saturated nacl aqueous solution washs 1 time, anhydrous Na₂SO₄It is dry.Sand core funnel is taken, spreads enough silica gel, is filtered, A small amount of dichloromethane rinses, and merging filtrate is concentrated under reduced pressure.Obtained solid petroleum ether recrystallizes, and obtains yellow-white product (8g).¹H NMR(500MHz,DMSO)δ12.54(s,1H),9.17(s,1H),8.26(s,1H),6.59(s,1H),3.88(s,3H),2.52 (s,3H),2.05(s,3H).MM-MS+APCI m/z[M+H]⁺=224.1, m/z [M-H]^-=222.1

The synthesis of step 3. (E)-N- (4- hydroxyls -5- (1- (oxyimino) ethyl) -2- methoxyphenyls) acetamide

N- (5- acetyl group -4- hydroxyl -2- methoxyphenyls) acetamide 2-3 (8g, 35.8mmol) is dissolved in 133ml ethanol waters Solution (absolute ethyl alcohol：Water=3:1, v/v), add in hydrochloric acid hydroxyl by (3.98g, 57.3mmol) and sodium acetate (4.7g, 57.3mmol), 78 DEG C of reflux 70min.TLC monitoring reactions.Reaction finishes, and is cooled to room temperature, and reduction vaporization is concentrated into about 40ml, It adds in 125ml elutriations and goes out solid, be filtered under diminished pressure, wash, it is dry, obtain red brown solid (8g).¹H NMR(500MHz,DMSO) δ11.74(s,1H),11.33(s,1H),9.03(s,1H),7.84(s,1H),6.54(s,1H),3.80(s,3H),2.17(s, 3H),2.02(s,3H).MM-MS+APCI m/z[M+H]⁺=239.1, m/z [M-H]^-=237.2

The synthesis of step 4.N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) acetamide

(E)-N- (4- hydroxyls -5- (1- (oxyimino) ethyl) -2- methoxyphenyls) acetamide (8g, 30ml Isosorbide-5-Nitraes-dioxane 33.58mmol) is dissolved in, is vigorously stirred down and is slowly dropped into n,N-Dimethylformamide dimethylacetal (DMF-DMA)(20.5ml).After reaction system stabilization, 100 DEG C of reaction 7min are warming up to.It is cooled to room temperature.To reaction system Middle addition about 30ml water, ethyl acetate (30ml x 3) extraction washed once, anhydrous sodium sulfate with water, saturated salt solution respectively It is dry, it is concentrated under reduced pressure, obtains pale brown, orange crystal (6.2g).¹H NMR(500MHz,DMSO)δ9.26(s,1H),8.24(s, 1H),7.36(s,1H),3.94(s,3H),2.47(s,3H),2.11(s,3H).MM-MS+APCI m/z[M+H]⁺=221.1, m/z[M-H]^-=219.1

The synthesis of step 5. 6- methoxyl groups -3- methyl benzo [d] isoxazole -5- amine

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) acetamide (6.2g, 28.15mmol) is dissolved in 169ml Hydrochloric acid (3mol/L), 90 DEG C of reflux 3h.TLC monitoring reactions.Reaction finishes, addition sodium hydroxide solution tune PH to neutral (7-9), Precipitation is precipitated, is filtered under diminished pressure, a small amount of water washing, it is dry, obtain sepia solid (4.8g).¹H NMR(500MHz,DMSO)δ 7.14(s,1H),6.80(s,1H),4.80(s,2H),3.88(s,3H),2.39(s,3H).

The conjunction of the bromo- 2- methoxyl groups-N- of step 6 5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide Into

6- methoxyl groups -3- methyl benzo [d] isoxazole -5- amine (50mg, 0.28mmol) and 4- chlorobenzene sulfonyl chlorides (96.14mg, 0.337mmol) is dissolved in 6ml dichloromethane, adds in 0.5ml pyridines, 45 DEG C of reaction 1.5h.TLC monitoring reactions.Instead After answering, 20ml water and 3~5ml dilute hydrochloric acid are added in, ethyl acetate (15ml x 2) extraction is washed once, saturated salt solution It washed once, anhydrous sodium sulfate drying is concentrated under reduced pressure, column chromatography for separation (PE:EA=1:1v/v), white solid is obtained (100mg, 84%).¹H NMR (500MHz, DMSO) δ 9.31 (s, 1H), 7.75 (dd, J=8.8,2.5Hz, 1H), 7.64 (d, J =2.5Hz, 1H), 7.62 (s, 1H), 7.24 (s, 1H), 7.20 (d, J=8.9Hz, 1H), 3.84 (s, 3H), 3.63 (s, 3H), 2.48(s,3H).MM-MS m/z[M+H]⁺=165.0, m/z [M-H]^-=163.1

The bromo- N- of 38 5- of embodiment (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides

The synthesis of step 1. 5- amino -3- methyl benzo [d] isoxazole -6- alcohol

6- methoxyl group -3- methyl benzo [d] isoxazole -5- amine (comes from 37 step 5) of embodiment (800mg, 4.49mmol) 15ml dichloromethane is dissolved in, takes BBr₃(2.8g, 11.22mmol) is dissolved in 10ml dichloromethane, and reaction system is added dropwise under ice bath, After go to room temperature reaction, TLC monitorings.Reaction terminates, and methanol and NH is slowly added dropwise₄Cl aqueous solutions are quenched, and add water, adjust PH to 6-8, Ethyl acetate extracts (30mlx3), saturated common salt water washing, and anhydrous sodium sulfate drying is spin-dried for, recrystallizes, obtain brown solid 670mg。¹H NMR(500MHz,DMSO)δ6.85(s,1H),6.76(s,1H),2.36(s,3H).

The synthesis of the bromo- N- of step 2. 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides

5- amino -3- methyl benzo [d] isoxazole -6- alcohol (840mg, 5.11mmol) and the bromo- 2- methoxybenzenes sulphonyl of 5- Chlorine (1.32g, 5.11mmol) is dissolved in 20ml dichloromethane, adds in 1ml pyridines, reacts at room temperature 3.5h.TLC monitoring reactions.Reaction After, add water, dichloromethane (15mlx 3) extraction, dilute hydrochloric acid is washed once, and saturated salt solution washed once, anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, column chromatography (PE:EA=1:2v/v), white solid (1.5g) is obtained.¹H NMR(500MHz,DMSO)δ 10.70 (s, 1H), 9.09 (s, 1H), 7.74 (dd, J=8.8,2.5Hz, 1H), 7.69 (d, J=2.5Hz, 1H), 7.54 (s, 1H), 7.18 (d, J=8.9Hz, 1H), 6.88 (s, 1H), 3.82 (s, 3H), 2.44 (s, 3H)

(3- methyl -6- ((4- (trifluoromethyl) benzyl) oxygroup) benzo [d] is different by the bromo- 2- methoxyl groups-N- of 39 5- of embodiment Oxazole -5- bases)-N- (4- (trifluoromethyl) benzyl) benzsulfamide

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides (come from embodiment 37) (50mg, 0.12mmol) is dissolved in 10ml DMF, then adds in K₂CO₃(49.6mg, 0.36mmol) aqueous solution, 1- (bromine first Base) -4- (trifluoromethyl) benzene (57.36mg, 0.24mmol), KI (8.03mg) is stirred overnight at room temperature.After reaction, water is added, Ethyl acetate extracts, organic layer saturated common salt water washing, and anhydrous sodium sulfate drying is concentrated under reduced pressure, and silica gel column chromatography separation obtains To white solid (60mg).¹H NMR (500MHz, DMSO) δ 7.73 (d, J=8.1Hz, 2H), 7.65 (d, J=2.5Hz, 1H), 7.62 (dd, J=8.8,2.5Hz, 1H), 7.59 (d, J=6.5Hz, 3H), 7.51 (d, J=8.1Hz, 2H), 7.41 (d, J= 8.0Hz, 2H), 7.38 (s, 1H), 6.99 (d, J=8.9Hz, 1H), 5.13 (s, 4H), 3.62 (s, 3H), 2.43 (s, 3H)

The bromo- N- of 40 5- of embodiment (6- ethyoxyl -3- methyl benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides (come from embodiment 37) (200mg, 0.484mmol) is dissolved in 10ml acetone, then adds in K₂CO₃(200.37mg, 1.45mmol), iodoethane (121.23mg, 0.725mmol) and KI (8.03mg, 0.048mmol), 50 DEG C are stirred overnight.After reaction, acetone vacuum is revolved It is dry, add water, ethyl acetate extracts, organic layer saturated common salt water washing, and anhydrous sodium sulfate drying is concentrated under reduced pressure, silica gel column layer Analysis separation, obtains white solid (100mg).¹H NMR (500MHz, DMSO) δ 9.25 (s, 1H), 7.76 (dd, J=8.9, 2.6Hz, 1H), 7.70 (d, J=2.5Hz, 1H), 7.63 (s, 1H), 7.24 (s, 1H), 7.18 (d, J=8.9Hz, 1H), 3.94 (q, J=7.0Hz, 2H), 3.74 (s, 3H), 2.48 (s, 3H), 1.09 (t, J=7.0Hz, 3H)

The chloro- 2- methoxyl groups-N- of 41 5- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 37.¹H NMR (500MHz, DMSO) δ 9.32 (s, 1H), 7.65 (dd, J=8.5, 2.5Hz, 1H), 7.63 (s, 1H), 7.52 (d, J=2.7Hz, 1H), 7.25 (d, J=9.7Hz, 1H), 7.24 (s, 1H), 3.85 (s,3H),3.62(s,3H),2.48(s,3H).

The chloro- N- of 42 2- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 37.¹H NMR (500MHz, DMSO) δ 9.75 (s, 1H), 7.74 (dd, J=7.9, 1.5Hz, 1H), 7.67 (dd, J=8.0,1.1Hz, 1H), 7.62 (s, 1H), 7.61 (td, J=7.8,1.2Hz, 1H), 7.39 (td, J=7.8,1.2Hz, 1H), 7.20 (s, 1H), 3.49 (s, 3H), 2.47 (s, 3H)

The bromo- 2- methoxyl groups-N- of 43 5- of embodiment (3- methyl -6- propoxyl group benzo [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 40.¹H NMR (500MHz, DMSO) δ 9.26 (s, 1H), 7.75 (dd, J=8.7, 2.6Hz, 1H), 7.73 (d, J=2.5Hz, 1H), 7.61 (s, 1H), 7.25 (s, 1H), 7.16 (d, J=8.8Hz, 1H), 3.84 (t, J=6.6Hz, 2H), 3.68 (s, 3H), 2.48 (s, 3H), 1.54-1.45 (m, 2H), 0.82 (t, J=7.4Hz, 3H)

(3- methyl -6- ((4- (trifluoromethyl) benzyl) oxygroup) benzo [d] is different by the bromo- 2- methoxyl groups-N- of 44 5- of embodiment Oxazole -5- bases) benzsulfamide

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides (come from embodiment 38) (100mg, 0.24mmol) is dissolved in 10ml acetone, then adds in K₂CO₃(100mg, 0.726mmol), 1- (bromomethyl) -4- (trifluoromethyl) benzene (57.8mg, 0.24mmol), KI (10mg), is stirred overnight at room temperature.After reaction, dry solvent is selected, adds water, Ethyl acetate extracts, organic layer saturated common salt water washing, and anhydrous sodium sulfate drying is concentrated under reduced pressure, and silica gel column chromatography separation obtains To white solid (60mg).¹H NMR (500MHz, DMSO) δ 10.73 (s, 1H), 7.80 (dd, J=8.9,2.6Hz, 1H), 7.65 (d, J=8.2Hz, 2H), 7.60 (d, J=2.5Hz, 1H), 7.52 (d, J=8.1Hz, 2H), 7.45 (s, 1H), 7.27 (d, J=9.0Hz, 1H), 6.88 (s, 1H), 5.03 (s, 2H), 3.87 (s, 3H), 2.37 (s, 3H)

45 ethyl -2- of embodiment ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] different evils Azoles -6- bases) oxygroup) ethyl acetate

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides (come from embodiment 38) (200mg, 0.484mmol) is dissolved in 15ml acetone, then adds in K₂CO₃(200mg, 1.45mmol), ethyl chloroacetate (71.2mg, 0.58mmol) and KI (8.03mg, 0.048mmol), return stirring 4h.After reaction, acetone vacuum is spin-dried for, and is added Water, ethyl acetate extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure, silica gel column chromatography point From obtaining white solid (80mg).¹H NMR (500MHz, DMSO) δ 9.18 (s, 1H), 7.73 (dd, J=8.8,2.6Hz, 1H), 7.69 (d, J=2.5Hz, 1H), 7.67 (s, 1H), 7.27 (s, 1H), 7.16 (d, J=8.9Hz, 1H), 4.75 (s, 2H), 4.11 (q, J=7.1Hz, 2H), 3.82 (s, 3H), 2.48 (s, 3H), 1.17 (t, J=7.1Hz, 3H)

46 5- of embodiment (N- ((the bromo- 2- methoxyphenyls of 5-) sulfonyl) acetylamino) -3- methyl benzo [d] different evil Azoles -6- yl acetates

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides (come from embodiment 38) (100mg, 0.242mmol) and triethylamine (98.0mg, 0.968mmol) dissolve in methylene chloride, and are cooled to 0 DEG C. Nitrogen protection under, chloroacetic chloride (38.00mg, 0.484mmol) is slowly added into the mixture, and be stirred at room temperature 2 it is small when.Instead NaHCO is used after answering₃(1N) is quenched, and is washed with brine.Concentration and drying (sodium sulphate), column chromatography obtain pure amide Product (80mg).¹H NMR (500MHz, DMSO) δ 8.14 (s, 1H), 8.01 (d, J=2.4Hz, 1H), 7.92 (dd, J=8.9, 2.5Hz, 1H), 7.87 (s, 1H), 7.34 (d, J=9.0Hz, 1H), 3.93 (s, 3H), 2.63 (s, 3H), 2.34 (s, 3H), 1.87(s,3H).

47 tertiary butyl -2- of embodiment ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] different evils Azoles -6- bases) oxygroup) ethyl acetate

Synthetic method such as embodiment 45.¹H NMR (400MHz, DMSO) δ 9.10 (s, 1H), 7.72 (dd, J=8.6, 2.6Hz, 1H), 7.70 (d, J=2.4Hz, 1H), 7.66 (s, 1H), 7.22 (s, 1H), 7.16 (d, J=8.7Hz, 1H), 4.66 (s,2H),3.83(s,3H),2.48(s,3H),1.39(s,9H).

48 2- of embodiment ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- Base) oxygroup) acetic acid

Ethyl -2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygen Base) ethyl acetate (embodiment 45) (35mg, 0.08mmol) is dissolved in 5ml methanol, and the NaOH of 5ml 2M is added in, 2h is stirred at room temperature. Reaction terminates, and is spin-dried for methanol, with the dilute hydrochloric acid tune PH of 1M to neutrality, filters, obtains white solid (25mg).¹H NMR (400MHz, DMSO) δ 13.10 (s, 1H), 9.15 (s, 1H), 7.73 (dd, J=8.8,2.6Hz, 1H), 7.70 (d, J= 2.5Hz, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 7.15 (d, J=8.8Hz, 1H), 4.68 (s, 2H), 3.82 (s, 3H), 2.48(s,3H).

The bromo- N- of 49 2- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 37.¹H NMR(500MHz,CDCl₃) δ 7.96 (dd, J=7.4,2.1Hz, 1H), 7.71 (dd, J=7.5,1.8Hz, 1H), 7.70 (s, 1H), 7.63 (s, 1H), 7.38-7.29 (m, 2H), 6.85 (s, 1H), 3.78 (s, 3H),2.51(s,3H).

The fluoro- N- of the chloro- 2- of 50 3- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 37.¹H NMR(500MHz,CDCl₃) δ 7.71 (s, 1H), 7.58 (dddd, J=9.9, 8.3,6.5,1.6Hz, 2H), 7.25 (s, 1H), 7.07 (td, J=8.0,0.9Hz, 1H), 6.85 (s, 1H), 3.78 (s, 3H), 2.53(s,3H).

51 2,5- of embodiment, bis- chloro- N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 37.¹H NMR (500MHz, DMSO) δ 10.07 (s, 1H), 7.73 (d, J=6.9Hz, 3H),7.67(s,1H),7.25(s,1H),3.52(s,3H),2.49(s,3H).

52 N- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) propane -1- sulfonamide

Synthetic method such as embodiment 37.¹H NMR(500MHz,DMSO)δ9.08(s,1H),7.63(s,1H),7.39(s, 1H), 3.92 (s, 3H), 3.04-2.94 (m, 2H), 2.49 (s, 3H), 1.81-1.68 (m, 2H), 0.95 (t, J=7.4Hz, 3H)

53 N- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -2,3- dihydrobenzos [b] [1,4] two Oxa- cyclohexene -6- sulfonamide

Synthetic method such as embodiment 37.¹H NMR(500MHz,DMSO)δ9.50(s,1H),7.59(s,1H),7.22(s, 1H), 7.12 (d, J=2.2Hz, 1H), 7.08 (dd, J=8.5,2.2Hz, 1H), 6.93 (d, J=8.5Hz, 1H), 4.33- 4.24(m,4H),3.56(s,3H),2.48(s,3H).

54 3,5- of embodiment, bis- chloro- N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 37.¹H NMR (500MHz, DMSO) δ 10.10 (s, 1H), 7.96 (t, J=1.7Hz, 1H), 7.68 (s, 1H), 7.62 (d, J=1.8Hz, 2H), 7.27 (s, 1H), 3.53 (s, 3H), 2.50 (s, 3H)

55 2- methoxyl groups-N- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -5- methyl benzenesulfonamides

Synthetic method such as embodiment 37.¹H NMR(500MHz,DMSO)δ8.86(s,1H),7.60(s,1H),7.42(s, 1H), 7.36 (d, J=8.4Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=8.4Hz, 1H), 3.83 (s, 3H), 3.67 (s, 3H), 2.46(s,3H),2.19(s,3H).

Embodiment 56 6- methoxyl group -3- methyl-N- (1- phenethyls) benzo [d] isoxazole -5- amine

6- methoxyl group -3- methyl benzo [d] isoxazole -5- amine (100mg, 0.56mmol) is dissolved in 10ml acetonitriles, then adds Enter (1- bromoethyls) benzene (135mg, 0.73mmol), K₂CO₃(231.84mg, 1.68mmol) and KI (9.2mg, 0.056mmol), 80 DEG C of stirring 4h.After reaction, acetonitrile vacuum is spin-dried for, and adds water, and ethyl acetate extracts, organic layer saturated common salt water washing, Anhydrous sodium sulfate is dried, and is concentrated under reduced pressure, and silica gel column chromatography separation obtains white solid (89mg).¹H NMR(500MHz,DMSO) δ 7.41 (d, J=7.6Hz, 2H), 7.30 (t, J=7.5Hz, 2H), 7.19 (t, J=7.4Hz, 1H), 7.17 (s, 1H), 6.45 (s, 1H), 5.22 (d, J=7.3Hz, 1H), 4.58 (p, J=6.7Hz, 1H), 3.94 (s, 3H), 2.28 (s, 3H), 1.49 (d, J =6.7Hz, 3H)

57 N- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) thiophene -2- sulfonamide

Synthetic method such as embodiment 37.¹H NMR (500MHz, DMSO) δ 9.80 (s, 1H), 7.88 (dd, J=5.0, 1.3Hz, 1H), 7.64 (s, 1H), 7.36 (dd, J=3.7,1.3Hz, 1H), 7.26 (s, 1H), 7.09 (dd, J=5.0, 3.8Hz,1H),3.56(s,3H),2.49(s,3H).

58 N- of embodiment (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -5- methylthiophene -2- sulfonamide

Synthetic method such as embodiment 37.¹H NMR(500MHz,DMSO)δ9.70(s,1H),7.63(s,1H),7.28(s, 1H), 7.18 (d, J=3.6Hz, 1H), 6.80 (d, J=2.8Hz, 1H), 3.62 (s, 3H), 2.50 (s, 3H), 2.46 (s, 3H)

2.1 II class embodiment chemical constitution (1) of table

Note：2.1 embodiment preparation method of table is referring especially to embodiment 37；Band *：Preparation method is with reference to described in specific embodiment

59 2- of embodiment ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- Base) oxygroup)-N- ethyl acetamides

By 2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup) Acetic acid (48 product of embodiment) (80.0mg, 0.17mmol) is dissolved in DMF (5mL), adds in HATU (197.0mg, 0.26mmol) With DIPEA (87.89mg, 0.68mmol), 15min is stirred at room temperature in mixture.Then add in 2M ethamine tetrahydrofuran solutions (0.255mmol, 0.13ml) and a small amount of DMAP (0.1eq), it is closed to be stirred overnight at room temperature.Reaction terminates, and adds water, uses dichloromethane Alkane extracts three times, merges organic layer, and saturated sodium-chloride is washed one time, and anhydrous sodium sulfate drying is spin-dried for, column chromatography, it is solid to obtain white Body (45mg).¹H NMR(400MHz,CDCl₃) δ 7.95 (d, J=2.4Hz, 1H), 7.64 (dd, J=8.8,2.4Hz, 1H), 7.55 (s, 1H), 7.38 (s, 1H), 6.94 (d, J=8.4Hz, 1H), 6.94 (s, 1H), 6.64 (s, 1H), 4.53 (s, 2H), 3.97 (s, 3H), 3.41-3.31 (m, 2H), 2.50 (s, 3H), 1.14 (t, J=7.3Hz, 3H)

60 2- of embodiment ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- Base) oxygen)-N- hexyl acetamides

Synthetic method such as embodiment 59.¹H NMR(400MHz,DMSO)δ9.67(s,1H),8.02(s,1H),7.77– 7.64 (m, 3H), 7.29 (s, 1H), 7.10 (d, J=9.5Hz, 1H), 4.40 (s, 2H), 3.57 (s, 3H), 3.08 (q, J= 6.8Hz, 2H), 1.40-1.31 (m, 2H), 1.20 (s, 6H), 0.82 (t, J=6.5Hz, 3H)

61 N- of embodiment (2- acetamidoethyls) -2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- first Base benzo [d] isoxazole -6- bases) oxygen) acetamide

Synthetic method such as embodiment 59.¹H NMR(400MHz,CDCl₃)δ8.69(s,1H),8.20(s,1H),8.00(d,J =2.4Hz, 1H), 7.73 (s, 1H), 7.56 (dd, J=8.8,2.4Hz, 1H), 6.89 (s, 1H), 6.80 (d, J=8.8Hz, 1H), 6.19 (s, 1H), 4.34 (s, 2H), 3.61 (s, 3H), 3.42 (t, J=5.6Hz, 4H), 2.54 (s, 3H), 2.07 (s, 3H).MM-MS+APCI m/z[M+H]⁺=554.8＆555.9, m/z [M-H]^-=553.0＆554.1

62 2- of embodiment ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- Base) oxygroup)-N- (2- morpholinoethyls) acetamide

Synthetic method such as embodiment 59.¹H NMR(400MHz,CDCl₃) δ 7.99 (d, J=2.4Hz, 1H), 7.68-7.55 (m, 2H), 7.09 (s, 1H), 6.94 (s, 1H), 6.90 (d, J=8.8Hz, 1H), 4.55 (s, 2H), 3.91 (s, 3H), 3.68- 3.55 (m, 4H), 3.45 (q, J=5.5Hz, 2H), 2.57-2.52 (m, 2H), 2.51 (s, 3H), 2.46 (t, 4H)

63 tertiary butyl -4- of embodiment (2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzos [d] Isoxazole -6- bases) oxygroup) acetylamino) piperidines -1- carboxylic acid tert-butyl esters

Synthetic method such as embodiment 59.¹H NMR(400MHz,CDCl₃) δ 7.93 (d, J=2.5Hz, 1H), 7.66 (dd, J =8.8,2.5Hz, 1H), 7.39 (s, 1H), 7.15 (s, 1H), 6.97 (d, J=8.8Hz, 1H), 6.96 (s, 1H), 6.85 (d, J =7.9Hz, 1H), 4.56 (s, 2H), 4.08 (m, 2H), 3.99 (s, 4H), 2.83 (t, J=12.4Hz, 2H), 2.48 (s, 3H), 1.86 (d, J=10.6Hz, 2H), 1.43 (s, 9H), 1.36 (d, J=3.5Hz, 2H) .MM-MS+APCI m/z [M-H]^-= 651.1&653.1

2.2 II class embodiment chemical constitution (2) of table

Note：2.2 embodiment preparation method of table is referring especially to embodiment 59

When structure type as shown is II, wherein Y2=-N (R4)-, compound can be led to by 3- fluorophenols for starting material 8-10 steps are crossed to be obtained by the reaction：

The bromo- 2- methoxyl groups-N- of 64 5- of embodiment (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzene sulphur The preparation of amide

Step 1：The preparation of 4- fluorophenyl acetates

3- fluorophenols (10g, 89mmol) are dissolved in 90mmol acetic anhydrides.The 3 drop concentrated sulfuric acids are added in, temperature rises to 120 DEG C.It is cold But after, mixture is poured into NaHCO containing 1g₃100ml ice water solutions in, and be extracted with ethyl acetate.By extract liquor saturation NaHCO₃Solution washs, and uses Na₂SO₄Dry, vacuum drying obtains 10.5g products, for next step.¹H NMR(400MHz, CDCl₃) δ 7.33 (td, J=8.2,6.6Hz, 1H), 6.95 (td, J=8.4,2.4Hz, 1H), 6.90 (d, J=8.1Hz, 1H), 6.86 (dt, J=9.6,2.4Hz, 1H), 2.30 (s, 3H)

Step 2：By the preparation of 4- fluorin-2-hydroxyacetophenones

Take 4- fluorophenyl acetates (10.5g, 68.1mmol), be added portionwise under ice bath aluminium chloride (12.7g, 95.3mmol, 1.4-2eq), stirred one hour at 190 DEG C, cool down, obtain solid.The mixture of ice, water, hydrochloric acid and dichloromethane is added to Solid.Gained mixture stirs several minutes, separates each phase.Organic phase washed with water, saturated sodium bicarbonate solution and salt water washing, It is dried over anhydrous sodium sulfate, and is concentrated in vacuo, obtain target product (7.5g), be yellow oil.¹H NMR(400MHz, CDCl₃) δ 12.57 (d, J=1.4Hz, 1H), 7.74 (dd, J=8.8,6.4Hz, 1H), 6.65 (dd, J=10.3,2.3Hz, 1H), 6.61 (td, J=8.4,2.4Hz, 1H), 2.60 (s, 3H)

Step 3：(E) preparation of -1- (4- fluoro-2-hydroxyphenyls) second -1- ketoximes

4- fluorin-2-hydroxyacetophenones (6.67g, 40mmol), hydroxylamine hydrochloride (5.56g, 80mmol) and sodium acetate (4.92g, Mixture 60mmol) is dissolved in EtOH (56ml)-water (24ml), mixture is heated under reflux 70 minutes.It will reaction System cools down, and adds in water (30ml), and (about 60ml) is concentrated into solid precipitation under reduced pressure by solution.Water (50ml) is added, The solid of precipitation filters, and washing is dried under reduced pressure, obtains target compound (6.5g), is white solid.¹H NMR(400MHz, CDCl₃) δ 11.48 (s, 1H), 7.39 (dd, J=8.8,6.4Hz, 1H), 7.21 (s, 1H), 6.67 (dd, J=10.4,2.6Hz, 1H), 6.62 (td, J=8.4,2.4Hz, 1H), 2.34 (s, 3H)

Step 4：The preparation of fluoro- 3- methyl benzo [d] isoxazoles of 6-

(E) -1- (4- fluoro-2-hydroxyphenyls) second -1- ketoximes (5.8g, 34.3mmol) are dissolved in DMF (70ml), add in acetic acid Sodium (6.36g, 77.52mmol), acetic anhydride (7.5ml, 79.8mmol).Be heated to reflux 4 it is small when, cooling, be poured into water and use second Acetoacetic ester extracts.It is washed with brine, sodium sulphate drying, and concentrates.It is purified by silica gel column chromatography, obtains product 4.7g, be White solid.¹H NMR(400MHz,CDCl₃) δ 7.57 (dd, J=8.6,5.1Hz, 1H), 7.23 (dd, J=8.5,1.8Hz, 1H), 7.07 (td, J=8.9,2.1Hz, 1H), 2.56 (s, 3H) .MM-MS+APCI m/z [M+H]⁺=154.1

Step 5：The preparation of fluoro- 3- methyl-5-nitros benzo [d] isoxazoles of 6-

Fluoro- 3- methyl benzo [d] isoxazoles (3.75g, 20mmol) of 6- are added into dense H under condition of ice bath₂SO₄(21ml) In, fuming nitric aicd (1.67ml) is added dropwise, while temperature of reaction system is kept to be stirred one hour under ice bath temperature less than 15 DEG C. After be stirred at room temperature 3 it is small when.It pours into ice and filters.Solid is dissolved in dichloromethane, and with the NaHCO of saturation₃Solution washs, Then it is washed with brine, through sewage NaSO₄It is dry, filtering, and concentrate, nitro compound is obtained as white solid (3.9g).¹H NMR(400MHz,CDCl₃) δ 8.45 (d, J=6.9Hz, 1H), 7.45 (d, J=10.0Hz, 1H), 2.65 (s, 3H)

Step 6：The preparation of N, 3- dimethyl -5- nitros benzo [d] isoxazole -6- amine

It is molten that fluoro- 3- methyl-5-nitros benzo [d] isoxazoles (1g, 5.1mmol) of 6- are dissolved in ethyl alcohol (20ml)-THF (10ml) Liquid adds in methylamine alcohol solution (2.64ml, 17.8mmol, 3.5 equivalent), and mixture is heated to what is sealed at one at 45 DEG C When stirring 3 is small in reaction vessel.Product is filtered, filtration cakes torrefaction is obtained as bright orange solid (1g).¹H NMR(400MHz, DMSO) δ 8.66 (s, 1H), 8.19 (d, J=4.2Hz, 1H), 6.94 (s, 1H), 2.97 (d, J=4.9Hz, 3H), 2.50 (s, 3H).

Step 7：N⁶, the preparation of 3 dimethylbiphenyls [d] isoxazole -5,6- diamines

Step 6 product N, 3- dimethyl -5- nitros benzo [d] isoxazole -6- amine (250mg, 1.21mmol) is dissolved in 40 DEG C In acetic acid (6ml).Stannous chloride dihydrate (952 grams, 4.22mmol) is added in concentrated hydrochloric acid (3ml).It is stirred at 50 DEG C Mix 2 it is small when, be allowed to cool, and pH5-6 be adjusted to NaOH aqueous solutions.Addition ethyl acetate simultaneously stirs, reject water layer, and organic layer is used Salt water washing.Fog sodium sulphate is dried, and concentration and silica gel column chromatography purifying obtain product as white solid (84mg).¹H NMR (400MHz, DMSO) δ 6.71 (s, 1H), 6.46 (s, 1H), 5.45 (d, J=4.4Hz, 1H), 4.54 (s, 2H), 2.78 (d, J= 4.8Hz,3H),2.33(s,3H).MM-MS+APCI m/z[M+H]⁺=178.1

Step 8：The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide Preparation

N⁶, 3 dimethylbiphenyls [d] isoxazole -5,6- diamines (73mg, 0.41mmol) and the bromo- 2- methoxybenzenes sulphonyl of 5- Chlorine (117.6mg, 0.41mmol) is dissolved in 6ml dichloromethane, adds in 0.5ml pyridines, reacts at room temperature 3.5h.TLC monitoring reactions.Instead After answering, add water, dichloromethane (15mlx 3) extraction, once, saturated salt solution washes twice, and anhydrous sodium sulfate is done for washing It is dry, it is concentrated under reduced pressure, column chromatography for separation (PE:EA=1:1v/v), white solid (63g) is obtained.¹H NMR(400MHz,DMSO)δ 9.51 (s, 1H), 7.81 (dd, J=8.9,2.5Hz, 1H), 7.62 (d, J=2.5Hz, 1H), 7.26 (d, J=8.9Hz, 1H), 7.00(s,1H),6.55(s,1H),5.69(s,1H),3.93(s,3H),2.72(s,3H),2.29(s,3H).MM-MS+APCI m/z[M+H]⁺=425.9＆427.9, m/z [M-H]^-=424.0＆426.0

The bromo- 2- methoxy-. N-methyls-N- of 65 5- of embodiment (3- methyl -6- (methylamino) benzo [d] isoxazole -5- Base) benzsulfamide

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide (comes from Embodiment 64) (100mg, 0.235mmol) be dissolved in 10ml acetone, then add in K₂CO₃(97.26mg, 0.704mmol), iodomethane (36.60mg, 0.258mmol) and KI (8mg, 0.047mmol), 50 DEG C of stirring 4h.After reaction, acetone vacuum is spin-dried for, and is added Water, ethyl acetate extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying are concentrated under reduced pressure, silica gel column chromatography point From obtaining white solid (89mg).¹H NMR (400MHz, DMSO) δ 7.89 (dd, J=8.9,2.5Hz, 1H), 7.59 (d, J= 2.5Hz, 1H), 7.36 (d, J=8.9Hz, 1H), 6.83 (s, 1H), 6.61 (s, 1H), 6.03 (d, J=4.9Hz, 1H), 3.98 (s, 3H), 3.17 (s, 3H), 2.80 (d, J=4.9Hz, 3H), 2.22 (s, 3H)

66 N- of embodiment (5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- Base)-N- methylacetamides

Acetic acid (21.0mg, 0.35mmol) is dissolved in dichloromethane (10mL), addition HATU (130.00mg, 0.35mmol) with DIPEA (121.5mg, 0.35mmol), 15min is stirred at room temperature in mixture.The bromo- 2- methoxyl groups of subsequent addition 5-- N- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide (coming from embodiment 59) (100mg, 0.235mmol) and a small amount of DMAP (0.1eq), it is stirred overnight at room temperature.Reaction terminates, and adds water, with dichloromethane extraction three times, Merge organic layer, saturated sodium-chloride is washed one time, and anhydrous sodium sulfate drying is spin-dried for, column chromatography, obtains white solid (50mg).¹H NMR (400MHz, DMSO) δ 9.91 (s, 1H), 7.82 (d, J=9.2,2.5Hz, 1H), 7.80 (s, 1H), 7.72 (d, J= 2.5Hz, 1H), 7.60 (s, 1H), 7.23 (d, J=9.0Hz, 1H), 3.86 (s, 3H), 3.31 (s, 3H), 2.93 (s, 3H), 1.51(s,3H).MM-MS+APCI m/z[M+H]⁺=467.9＆468.9, m/z [M-H]^-=467.0＆468.0

The bromo- N- of 67 5- of embodiment (6- (ethylamino) -3- methyl benzo [d] isoxazole -5- bases) -2- methoxyl groups-benzene sulphur Amide

Synthetic method reference implementation example 64 (step 6,7,8).¹H NMR(400MHz,CDCl₃) δ 7.88 (d, J=2.5Hz, 1H), 7.69 (dd, J=8.8,2.5Hz, 1H), 7.03 (d, J=8.8Hz, 1H), 6.79 (s, 1H), 6.57 (s, 1H), 6.45 (s, 1H), 5.00 (s, 1H), 4.09 (s, 3H), 3.23-3.11 (m, 2H), 2.29 (s, 3H), 1.28 (t, J=7.2Hz, 3H)

(3- methyl -6- ((tetrahydrochysene -2H- pyrans -4- bases) amino) benzo [d] is different by the bromo- 2- methoxyl groups-N- of 68 5- of embodiment Oxazole -5- bases) benzsulfamide

Synthetic method reference implementation example 64 (step 6,7,8).¹H NMR(400MHz,DMSO)δ9.68(s,1H),7.80 (dd, J=8.8,2.5Hz, 1H), 7.63 (d, J=2.5Hz, 1H), 7.28 (d, J=8.9Hz, 1H), 7.23 (s, 1H), 6.76 (s, 1H), 5.11 (d, J=7.7Hz, 1H), 3.90 (s, 3H), 3.83 (d, J=11.5Hz, 2H), 3.50 (d, J=3.5Hz, 1H), 3.41 (t, J=10.8Hz, 2H), 2.34 (s, 3H), 1.79 (d, J=12.7Hz, 2H), 1.15 (dt, J=15.1, 7.5Hz,2H).

The bromo- 2- methoxyl groups-N- of 69 5- of embodiment (3- methyl -6- ((2- morpholinoethyls) amino) benzo [d] isoxazole - 5- yls) benzsulfamide

Synthetic method reference implementation example 64 (step 6,7,8).¹H NMR (400MHz, DMSO) δ 7.82 (dd, J=8.9, 2.5Hz, 1H), 7.63 (d, J=2.5Hz, 1H), 7.28 (d, J=8.9Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 5.78 (s, 1H), 3.89 (s, 3H), 3.63-3.57 (m, 4H), 3.15 (d, J=4.9Hz, 2H), 2.46 (d, J=6.4Hz, 2H), 2.39(s,4H),2.26(s,3H).

The chloro- N- of 70 2- of embodiment (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide

Synthetic method such as embodiment 64.¹H NMR (400MHz, DMSO) δ 9.73 (s, 1H), 7.79 (dd, J=7.9, 1.3Hz, 1H), 7.74 (d, J=7.3Hz, 1H), 7.71-7.63 (m, 1H), 7.44 (t, J=7.6Hz, 1H), 6.81 (s, 1H), 6.56(s,1H),5.75(s,1H),2.72(s,3H),2.21(s,3H).

The chloro- 2- methoxyl groups-N- of 71 5- of embodiment (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzene sulphur Amide

Synthetic method such as embodiment 64.¹H NMR (400MHz, DMSO) δ 9.51 (s, 1H), 7.69 (dd, J=8.9, 2.7Hz, 1H), 7.51 (d, J=2.7Hz, 1H), 7.32 (d, J=8.9Hz, 1H), 7.00 (s, 1H), 6.55 (s, 1H), 5.69 (s,1H),3.94(s,3H),2.72(s,3H),2.29(s,3H).

The bromo- 2- methoxyl groups-N- of 72 5- of embodiment (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases)-N- (2- morpholinoethyls) benzsulfamide

The bromo- 2- methoxyl groups-N- of product 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) of embodiment 64 Benzsulfamide (126mg, 0.30mmol) and 4- (2- chloroethyls) morpholine hydrochloride (84.64mg, 0.45mmol) mixture are dissolved in In DMF (6mL), cesium carbonate (391.00mg, 1.20mmol) and sodium iodide (45.00mg, 0.30mmol) are added at room temperature.With Afterwards by mixture when 100 DEG C of heating 4 are small.Mixture with DCM is extracted, is washed with brine, is dried over anhydrous sodium sulfate, is filtered And it concentrates.Residue is washed into recrystallization with PE/EA, obtains white solid (100mg).¹H NMR(400MHz,CDCl₃)δ7.79 (d, J=2.5Hz, 1H), 7.65 (dd, J=8.8,2.5Hz, 1H), 6.97 (d, J=8.8Hz, 1H), 6.73 (s, 1H), 6.53 (s, 1H), 6.32 (d, J=5.0Hz, 1H), 4.51-4.39 (m, 1H), 3.98 (s, 3H), 3.76 (t, J=4.5Hz, 4H), 3.27-3.19 (m, 1H), 2.86 (d, J=5.0Hz, 3H), 2.70 (s, 2H), 2.49-2.40 (m, 1H), 2.33-2.27 (m, 2H), 2.26 (s, 3H), 2.23 (d, J=3.6Hz, 1H) .MM-MS+APCI m/z [M+H]⁺=539.0＆540.0

73 2,5- of embodiment, bis- chloro- N- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamides

Synthetic method such as embodiment 64.¹H NMR (400MHz, DMSO) δ 9.92 (s, 1H), 7.76 (d, J=5.9Hz, 3H),6.88(s,1H),6.59(s,1H),5.75(s,1H),2.72(s,3H),2.25(s,3H).

2.3 II class embodiment chemical constitution (3) of table

Note：2.3 embodiment preparation method of table is referring especially to embodiment 64

When structure type as shown is III, compound can be by 1- (the bromo- 2- hydroxy phenyls of 5-) second -1- ketone and the bromo- 1- of 4- Fluoro- 2- nitrobenzenes are obtained by the reaction for starting material by 7 steps, and synthetic method has route 1 or route 2 optionally.

Route 1

Route 2

74 N- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide

Step 1：The preparation of the bromo- 2- of 4- (1- Iminoethyls) phenol

1- (the bromo- 2- hydroxy phenyls of 5-) second -1- ketone (2.15g, 10mmol), the ammonia MeOH (7ml, 49mmol) for adding in 7M are molten Liquid.Then 2h is stirred at room temperature, obtains yellow mercury oxide slurries.Slurries are filtered, filtration cakes torrefaction, obtain 2.03g yellow crystals, directly For the next step.

Step 2：The preparation of bromo- 3- methyl benzo [d] isoxazoles of 5-

The bromo- 2- of 4- (1- Iminoethyls) phenol (2.03g, 9.48mmol), NCS (14.22mmol) and K₂CO₃(2.62g, 18.96mmol) mixture is dissolved in 10ml THF, stirs 12h at room temperature.TLC monitoring reactions, after reaction, ethyl acetate (20ml) and water (30ml) are added in reaction mixture, organic layer are separated, anhydrous Na SO₄It is dry, and be concentrated in vacuo.Silica gel Column chromatography purifies (PE/EA=30:1) product 1.35g yellow solids are obtained.¹H NMR(400MHz,CDCl₃)δ7.77(s,1H), 7.63 (d, J=8.8Hz, 1H), 7.44 (d, J=8.8Hz, 1H), 2.56 (s, 3H)

Step 3：The preparation of 4- (the bromo- 2- nitrobenzophenones of 4-) morpholine

The fluoro- 2- nitrobenzenes (10.06g, 45.7mmol) of the bromo- 1- of 4- are dissolved in dimethyl sulfoxide (DMSO) (20.00ml, 282mmol), Add in morpholine solution (6.00ml, 68.6mmol).It is heated to 130 DEG C of reactions and treats that solution becomes orange red in 10 minutes.TLC shows nothing Initial substance remains.Reaction solution is poured into 200ml saturated bicarbonate solutions, is extracted with 200ml ethyl acetate, and organic layer is used again 100mL water, 100ml salt water washings, is then dried with anhydrous sodium sulfate, is filtered and is concentrated under reduced pressure, and obtains orange red oily mater 。¹H NMR(400MHz,CDCl₃) δ 7.91 (d, J=2.2Hz, 1H), 7.59 (s, 1H), 7.11-6.96 (m, 1H), 3.83 (s, 4H), 3.04 (d, J=3.5Hz, 4H) .MM-MS+APCI m/z [M+H]⁺=287.0＆289.0.

Step 4：The preparation of the bromo- 2- morpholines aniline of 5-

Iron powder (8.77g, 156.7mmol), ammonium chloride (465.5mg, 8.7mmol) and acetic acid (1.93ml, 38.28mmol) It is suspended in 45ml water, and 15min is stirred at 50 DEG C.4- (the bromo- 2- nitrobenzophenones of 4-) morpholine (5g, 17.4mmol) is dissolved in 15ml DMF, and be rapidly added in said mixture solution.After stirring 15 minutes, mixture is alkalized to PH9 with aqueous sodium carbonate. Remaining solid is filtered, and aqueous layer with ethyl acetate extraction merges organic layer salt water washing, with anhydrous Na SO₄It is dry, subtracting Pressure removes solvent, by crude product by being purified in silica gel column chromatography, obtains the bromo- 2- morpholines (4g) of 5-, is pale solid. MM-MS+APCI m/z[M+H]⁺=257.

Step 5：The preparation of 2- morpholinoes -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) aniline

The bromo- 2- morpholines aniline (8g) of 5-, connection boric acid pinacol ester (8.7g, 34.2mmol), KOAc (6.1g, 62.2mmol) With Pd (dppf) Cl₂(773.7mg) is dissolved in Isosorbide-5-Nitrae-dioxane (24ml) and DMSO (1.5mL), and is added under protection of argon gas Heat is refluxed overnight.After solvent is removed in vacuum, NaOH aqueous solutions (2M, 50ml) are added in residue, and by the mixture in room It is stirred under temperature 30 minutes.Mixture is extracted with EtOAc, is merged organic layer salt water washing, is used anhydrous Na₂SO ₄It is dry, subtracting Pressure removes solvent, by crude product by purifying (PE in silica gel column chromatography：EA=3：1) corresponding boric acid pinacol ester, is obtained (6.1g) directly uses it.¹H NMR(400MHz,CDCl₃) δ 7.24 (d, J=7.9Hz, 1H), 7.19 (s, 1H), 6.98 (d, J=7.8Hz, 1H), 3.89 (s, 2H), 3.86-3.83 (m, 4H), 2.98-2.92 (m, 4H), 1.32 (s, 12H)

Step 6：N- (2- morpholinoes -5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolane -2- bases) phenyl) benzene The preparation of sulfonamide

2- morpholinoes -5- (4,4,5,5- tetramethyls -1,3,2- dioxaborolane -2- bases) aniline (314mg, 1.03mmol) and benzene sulfonyl chloride (435mg, 2.06mmol) is dissolved in 6ml dichloromethane, adds in 0.5ml pyridines, 45 DEG C of reaction 2h. TLC monitoring reactions.After reaction, 20ml water and 3~5ml dilute hydrochloric acid, ethyl acetate (15ml x 2) extraction, washing one are added in Secondary, saturated salt solution washed once, and anhydrous sodium sulfate drying is concentrated under reduced pressure, column chromatography for separation (PE:EA=3:1v/v), obtain White solid (350mg).¹H NMR(400MHz,CDCl₃) δ 8.04 (s, 1H), 7.85-7.78 (m, 3H), 7.50 (dd, J= 7.6,4.0Hz, 2H), 7.41 (t, J=7.7Hz, 2H), 7.07 (d, J=7.9Hz, 1H), 3.75-3.70 (m, 4H), 2.49 (m, 4H),1.33(s,12H).

Step 7：The preparation of N- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide

Bromo- 3- methyl benzo [d] isoxazoles (147mg, 0.69mmol) of 5-, above-mentioned reaction borate (280mg, 0.63mmol), K₂CO₃(200mg, 1.58mmol) and Pd (PPh₃)₄The mixture of (72.80mg, 0.1eq) is dissolved in Isosorbide-5-Nitrae-dioxy Own ring (5ml) and water (0.5ml), mixture is heated to reflux under protection of argon gas.Reaction is monitored by TLC.After finishing, will mix Object filters, and filtrate is evaporated to dryness.Residue is extracted to distribution between EtOAc and water.Organic layer is washed with brine, is done Dry (Na₂SO₄), it concentrates in vacuum, and crude product is passed through into column chromatography (petroleum ether：Ethyl acetate 3:1) purify, obtain target Compound (50mg).¹H NMR(500MHz,CDCl₃) δ 7.99 (s, 1H), 7.89 (d, J=1.8Hz, 1H), 7.85 (d, J= 7.5Hz, 2H), 7.73 (d, J=8.8Hz, 2H), 7.61 (d, J=8.5Hz, 1H), 7.54 (t, J=7.4Hz, 1H), 7.45 (t, J=7.7Hz, 2H), 7.31 (dd, J=8.2,1.9Hz, 1H), 7.20 (d, J=8.2Hz, 1H), 3.81-3.74 (m, 4H), 2.64(s,3H),2.54(s,4H).

75 3- methyl -5- of embodiment (4- morpholino -3- nitrobenzophenones) benzo [d] isoxazole

Synthetic method is with reference to route 2, and specific steps are with reference to embodiment 74.¹H NMR(400MHz,CDCl₃)δ8.04(s, 1H), 7.76 (s, 3H), 7.63 (d, J=8.1Hz, 1H), 7.25-7.17 (m, 1H), 3.88 (s, 4H), 3.12 (s, 4H), 2.64 (s,3H).

76 5- of embodiment (3- methyl benzo [d] isoxazole -5- bases) -2- morpholino aniline

Synthetic method is with reference to route 2, and specific steps are with reference to embodiment 74.¹H NMR(400MHz,CDCl₃) δ 7.86 (d, J= 2.2Hz, 1H), 7.66 (dd, J=8.6,2.2Hz, 1H), 7.07 (d, J=8.5Hz, 1H), 7.03 (d, J=8.6Hz, 1H), 6.93 (dd, J=8.6Hz, 2.0Hz, 1H), 6.91 (d, J=2.0Hz, 1H), 4.09 (s, 2H), 3.87 (t, J=4.4Hz, 4H), 2.96 (t, J=4.8Hz, 4H), 2.68 (s, 3H)

The chloro- N- of 77 4- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide

Synthetic method such as embodiment 74.¹H NMR(400MHz,DMSO)δ9.39(s,1H),7.93(s,1H),7.86– 7.76 (m, 4H), 7.66 (d, J=8.6Hz, 2H), 7.53 (d, J=8.1Hz, 2H), 7.26 (d, J=8.0Hz, 1H), 3.62 (t, J=4.0Hz, 4H), 2.61 (s, 3H), 2.59 (t, J=4.3Hz, 4H) .MM-MS+APCI m/z [M-H]^-=482.0.

The fluoro- N- of the chloro- 4- of 78 2- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzene sulphur Amide

Synthetic method such as embodiment 74.¹H NMR(400MHz,CDCl₃) δ 8.80 (s, 1H), 8.22 (dd, J=8.9, 5.8Hz, 1H), 7.66 (d, J=1.7Hz, 1H), 7.63 (s, 1H), 7.60 (d, J=1.5Hz, 1H), 7.59 (s, 1H), 7.28 (s,1H),7.25–7.19(m,2H),7.11–7.05(m,1H),3.94–3.88(m,4H),2.91–2.83(m,4H),2.62 (s,3H).MM-MS+APCI m/z[M+H]⁺=502.0, m/z [M-H]^-=500.0.

79 N- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) thiophene -2- sulfonamide

Synthetic method such as embodiment 74.¹H NMR(400MHz,CDCl₃) δ 8.13 (s, 1H), 7.94 (d, J=1.8Hz, 1H), 7.75 (d, J=8.7Hz, 2H), 7.61 (d, J=8.5Hz, 1H), 7.57 (d, J=3.6Hz, 1H), 7.52 (d, J= 4.6Hz, 1H), 7.34 (dd, J=8.2,1.9Hz, 1H), 7.24 (d, J=8.4Hz, 1H), 7.04-6.98 (m, 1H), 3.84- 3.78(m,4H),2.64(s,3H),2.61(s,4H).

80 N- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) butane -1- sulfonamide

Synthetic method such as embodiment 74.¹H NMR(400MHz,CDCl₃) δ 7.84 (s, 1H), 7.77 (d, J=10.8Hz, 2H), 7.72 (d, J=5.6Hz, 1H), 7.60 (d, J=8.7Hz, 1H), 7.32 (s, 2H), 3.89-3.88 (m, 4H), 3.17 (dd, J=14.3,6.5Hz, 2H), 2.91-2.90 (m, 4H), 2.63 (s, 3H), 1.82 (dt, J=15.2,7.8Hz, 2H), 1.42 (dt, J=14.5,7.3Hz, 2H), 0.90 (t, J=7.3Hz, 3H) .MM-MS+APCI m/z [M+H]⁺=430.0, m/z [M-H]^-=428.0.

The chloro- N- of 81 2- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide

Synthetic method such as embodiment 74.¹H NMR(500MHz,CDCl₃) δ 8.81 (s, 1H), 8.22 (d, J=7.5Hz, 1H), 7.69 (d, J=1.8Hz, 1H), 7.65-7.55 (m, 3H), 7.51-7.44 (m, 2H), 7.40 (ddd, J=8.4,5.7, 3.0Hz, 1H), 7.25 (s, 1H), 7.22 (dd, J=8.2,1.9Hz, 1H), 3.96-3.88 (m, 4H), 2.92-2.80 (m, 4H),2.63(s,3H).

82 N- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) pentane amide

Synthetic method such as embodiment 74, final step is with reference to embodiment 69.¹H NMR(400MHz,CDCl₃)δ8.73(s, 1H), 8.57 (s, 1H), 7.79 (d, J=11.1Hz, 2H), 7.57 (d, J=8.6Hz, 1H), 7.32 (dd, J=8.2,2.0Hz, 1H), 7.24 (s, 1H), 3.98-3.88 (m, 4H), 2.97-2.89 (m, 4H), 2.61 (s, 3H), 2.46 (t, J=7.5Hz, 2H), 1.77 (dd, J=15.1,7.5Hz, 2H), 1.47 (dt, J=14.9,7.4Hz, 2H), 0.98 (t, J=7.3Hz, 3H) .MM-MS+APCI m/z[M+H]⁺=394.1.

The fluoro- N- of 83 4- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzamide

Synthetic method such as embodiment 82.¹H NMR (400MHz, DMSO) δ 9.73 (s, 1H), 8.41 (d, J=1.5Hz, 1H), 8.07 (dd, J=8.5,5.3Hz, 3H), 7.90 (d, J=8.7Hz, 1H), 7.78 (d, J=8.7Hz, 1H), 7.55 (dd, J=8.2,1.8Hz, 1H), 7.43 (t, J=8.7Hz, 2H), 7.38 (d, J=8.3Hz, 1H), 3.82-3.77 (m, 4H), 2.96–2.89(m,4H),2.62(s,3H).

84 N- of embodiment (4- chlorobenzyls) -5- (3- methyl benzo [d] isoxazole -5- bases) -2- morpholino aniline

Synthetic method such as embodiment 15.¹H NMR(500MHz,CDCl₃) δ 7.65 (dd, J=8.7,1.6Hz, 1H), 7.59 (d, J=0.8Hz, 1H), 7.53 (d, J=8.7Hz, 1H), 7.36-7.30 (m, 4H), 7.12 (d, J=8.0Hz, 1H), 6.94 (dd, J=8.0,1.9Hz, 1H), 6.73 (d, J=1.8Hz, 1H), 5.24 (s, 1H), 4.42 (d, J=4.8Hz, 2H), 3.87 (s, 4H), 2.98 (t, J=4.5Hz, 4H), 2.59 (s, 3H)

The fluoro- N- of 85 4- of embodiment (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide

Synthetic method such as embodiment 74.¹H NMR(400MHz,CDCl₃) δ 8.01 (s, 1H), 7.86 (dd, J=8.5, 4.7Hz, 3H), 7.72 (d, J=8.4Hz, 2H), 7.61 (d, J=8.6Hz, 1H), 7.32 (dd, J=8.2,1.8Hz, 1H), 7.22 (d, J=8.3Hz, 1H), 7.12 (t, J=8.5Hz, 2H), 3.83-3.77 (m, 4H), 2.64 (s, 3H), 2.61 (s, 4H).

3 III class embodiment chemical constitution of table

Note：3 embodiment preparation method of table is referring especially to embodiment 74；Band *：Preparation method is with reference to described in specific embodiment

As shown in scheme when structure type is IV, compound can be by 1- (2- hydroxyl -4- methoxyphenyls) ethyl -1- Ketone is obtained by the reaction for starting material by 4 steps.

The preparation of 86 N- of embodiment (2- chlorphenyls) -6- methoxyl groups -3- methyl benzo [d] isoxazole -7- sulfonamide

Step 1：The preparation of 2- (1- Iminoethyls) -5- metoxyphenols

1- (2- hydroxyl -4- methoxyphenyls) ethyl -1- ketone (5g, 30mmol), add in 7M ammonia MeOH (21ml, 147mmol) solution.Then it is stirred overnight at room temperature, obtains yellow mercury oxide slurries.Slurries are filtered, filtration cakes torrefaction, obtain yellow crystalline substance Body is directly used in the next step.

Step 2：The preparation of 2- (1- Iminoethyls) -5- metoxyphenols

2- (1- Iminoethyls) -5- metoxyphenols (2.0g, 12mmol), NCS (18mmol) and K₂CO ₃(3.31g, 24mmol) mixture is dissolved in 10ml THF, stirs 12h at room temperature.TLC monitoring reactions, after reaction, ethyl acetate (15ml) It is added in reaction mixture, organic layer is separated, anhydrous Na with water (30ml)₂SO ₄It is dry, and be concentrated in vacuo.Silica gel column layer Analysis purifying (PE/EA=30:1) 300mg white powders are obtained.¹H NMR (400MHz, DMSO) δ 7.68 (d, J=8.7Hz, 1H), 7.23 (d, J=1.9Hz, 1H), 6.96 (dd, J=8.7,2.0Hz, 1H), 3.85 (s, 3H), 2.48 (s, 3H)

Step 3：The preparation of 6- methoxyl groups -3- methyl benzo [d] isoxazole -7- sulfonic acid chlorides

Under condition of ice bath, 2- ethyoxyl -4- methoxy benzoic acids (200mg, 1.22mmol) are added portionwise cold In chlorosulfonic acid (1.4ml), 15 minutes are lasted, and is slowly warmed to room temperature, is then heated to 60-65 DEG C of reaction 2h.Gained is dark Solution is carefully poured into substantial amounts of ice under stiring, then adds in 10ml dichloromethane solutions.Stirring 15 minutes, by organic layer point From, and water layer dichloromethane (3 × 10ml) is extracted.Organic layer is washed with brine, and is dried over anhydrous sodium sulfate, vacuum Concentration.It recrystallizes as white solid (200mg).¹H NMR (400MHz, DMSO) δ 7.72 (d, J=8.7Hz, 1H), 7.11 (d, J =8.7Hz, 1H), 3.86 (s, 3H), 2.47 (s, 3H)

Step 4：The preparation of N- (2- chlorphenyls) -6- methoxyl groups -3- methyl benzo [d] isoxazole -7- sulfonamide

2- chloroanilines (29mg, 0.23mmol) and 6- methoxyl group -3- methyl benzo [d] isoxazole -7- sulfonic acid chlorides (50mg, 6ml dichloromethane 0.19mmol) is dissolved in, adds in 0.5ml pyridines, 43 DEG C of reaction 2h.TLC monitoring reactions.After reaction, add in 20ml water and 3~5ml dilute hydrochloric acid, ethyl acetate (15ml x 2) extraction, once, saturated salt solution washed once, anhydrous for washing Sodium sulphate is dried, and is concentrated under reduced pressure, column chromatography for separation (PE:EA=3:1v/v), white solid (350mg) is obtained.¹H NMR (400MHz, DMSO) δ 9.88 (s, 1H), 8.05 (d, J=8.8Hz, 1H), 7.39 (d, J=7.8Hz, 1H), 7.34 (d, J= 8.0Hz, 1H), 7.29 (d, J=8.8Hz, 1H), 7.24 (t, J=7.5Hz, 1H), 7.15 (t, J=7.6Hz, 1H), 3.91 (s, 3H),2.49(s,3H).

The preparation of embodiment 87 N- hexyls -6- methoxyl groups -3- methyl benzo [d] isoxazole -7- sulfonamide

Synthetic method such as embodiment 86.¹H NMR(400MHz,CDCl₃) δ 7.74 (d, J=8.7Hz, 1H), 7.07 (d, J= 8.7Hz, 1H), 5.12 (t, J=6.1Hz, 1H), 4.09 (s, 3H), 3.02 (dd, J=13.4,6.9Hz, 2H), 2.56 (s, 3H), 1.47 (d, J=7.2Hz, 2H), 1.29-1.20 (m, 6H), 0.84 (t, J=6.9Hz, 3H)

The preparation of embodiment 88 N- ethyls -6- methoxyl groups -3- methyl benzo [d] isoxazole -7- sulfonamide

Synthetic method such as embodiment 86.¹H NMR(400MHz,CDCl₃) δ 7.73 (d, J=8.7Hz, 1H), 7.07 (d, J= 8.7Hz, 1H), 5.08 (t, J=5.7Hz, 1H), 4.09 (s, 3H), 3.20-3.01 (m, 2H), 2.56 (s, 3H), 1.14 (t, J =7.2Hz, 3H)

4 IV class embodiment chemical constitution of table

Note：4 embodiment preparation method of table is with reference to embodiment 86

Embodiment 89

External activity is tested：The present invention is using AlphaScreen detection techniques verification the compounds of this invention to BRD4 (1) Albumen rejection ability.

1st, experiment purpose

Measure inhibitory activity of the compounds of this invention to BRD4 (1) albumen.

2nd, experiment material

Destination protein BRD4 (1) 50nM；Test buffer (10 ×) MOPS (500mM), CHAPS (0.5mM), NaF (500mM), BSA (1mg/mL), PH7.4；5 μ g/mL of donor microballon in kit, 5 μ g/m of Acceptor beads；BRD4 (1) ligand, Peptide H4KAc4-biotin(SGRG{Lys-Ac}GG{Lys-Ac}GLG{Lys-Ac}GGA{Lys-Ac}RHR{Lys (biotin)})50nM；In 150 μ L reaction systems：BRD4(1):15 μ L, Peptide:15 μ L, test buffer：15 μ L, go from Sub- water：60 μ L, micromolecular compound：15 μ L, donor microballon：15 μ L, Acceptor beads：15μL.Positive inhibitor：(+)-JQ1.

3rd, experimental method

Albumen, Peotide are added in reaction solution, when 20 DEG C of incubations 1.5 are small, add in donor microballon and Acceptor beads, Be protected from light incubation 1 it is small when.384 orifice plates are transferred to, 40 μ L liquid are shifted per hole, 3 multiple holes are multi-functional by PE Envison2104 Detect microplate reader, excitation wavelength：680nM, launch wavelength 520-620nM detect reading.

Embodiment 90

External activity is tested, and the present invention inhibits BRD4 (1) albumen using TSA detection techniques verification the compounds of this invention Ability.

1st, experiment purpose

Measure inhibitory activity of the compounds of this invention to BRD4 (1) albumen.

2nd, experiment material

(1) 10 μM of destination protein BRD4；200 μM of micromolecular compound；Test buffer (10 ×) HEPES (100mM), NaCl (1500mM), glycerine 50%, pH7.5；Dyestuff,(SIGMA)(5000×)；In 20 μ L reaction systems： 2 μ L of albumen, 2 μ L of dyestuff, 10 μ L of micromolecular compound, 2 μ L of test buffer, 4 μ L of deionized water.Positive inhibitor：(+)- JQ1。

3rd, experimental method

Each component is added to 96 hole black PCR plates of BIO-RAD by above-mentioned volume, is protected from light incubation 30 minutes on ice, is used CFX-96 fluorescence quantitative PCR instruments are detected.Program is solubility curve, 30-75 DEG C, often raises 0.3 DEG C of reading once, final to survey Obtain temperature change value.

Embodiment 89 is using AlphaScreen detection techniques verification result and embodiment 90 using the verification of TSA detection techniques It the results are shown in Table 5：

5. protein level activity list of table

Compound	Alphascreen(μM)	TSA(℃)
			(+)-JQ1	0.14	11.0
Embodiment 1	>10	1.0
			Embodiment 2	4.13	2.0

Embodiment 3	1.48	5.5
			Embodiment 4	1.05	6.5
Embodiment 5	9.23	2.0
			Embodiment 6	3.21	4.5
Embodiment 7	>20	0.5
			Embodiment 8	3.11	5.0
Embodiment 9	2.95	4.5
			Embodiment 10	>10	1.5
Embodiment 11	5.51	3.0
			Embodiment 12	3.05	5.0
Embodiment 13	>20	0.5
			Embodiment 14	>20	0.5
Embodiment 15	>10	1.5
			Embodiment 16	>20	0.0
Embodiment 17	4.86	3.8
			Embodiment 18	>20	0.8
Embodiment 19	>20	0
			Embodiment 20	1.47	5.2
Embodiment 21	2.16	4.9
			Embodiment 22	2.47	4.55
Embodiment 23	5.75	3.0
			Embodiment 24	>10	1.1
Embodiment 25	>20	0.5
			Embodiment 26	0.56	8.0
Embodiment 27	1.84	4.4
			Embodiment 28	2.68	4.1
Embodiment 29	>10	1.1
			Embodiment 30	12.93	2.0
Embodiment 31	3.89	4.0
			Embodiment 32	3.00	5.0
Embodiment 33	2.12	4.0
			Embodiment 34	2.43	4.5
Embodiment 35	2.88	4.6
			Embodiment 36	4.47	4.2
Embodiment 37	0.13	9.4
			Embodiment 38	0.22	9.2
Embodiment 39	>10	1.4
			Embodiment 40	0.19	9.0
Embodiment 41	0.14	5.1
			Embodiment 42	0.28	7.8
Embodiment 43	0.51	6.0
			Embodiment 44	>20	0.3
Embodiment 45	>5	2.1
			Embodiment 46	>10	1.8
Embodiment 47	>5	2.7
			Embodiment 48	0.58	6.0
Embodiment 49	0.38	5.5
			Embodiment 50	0.49	6.0
Embodiment 51	0.35	7.3
			Embodiment 52	0.64	6.4
Embodiment 53	1.01	7.5

Embodiment 54	0.42	7.8
			Embodiment 55	0.49	7.8
Embodiment 56	>5	3.6
			Embodiment 57	0.50	3.6
Embodiment 58	0.94	4.5
			Embodiment 59	1.44	5.1
Embodiment 60	>20	0.5
			Embodiment 61	2.67	5.4
Embodiment 62	3.14	4.8
			Embodiment 63	3.45	4.5
Embodiment 64	0.18	9.2
			Embodiment 65	>20	0.2
Embodiment 66	>10	2.4
			Embodiment 67	>5	3.0
Embodiment 68	0.55	7.5
			Embodiment 69	2.66	5.7
Embodiment 70	3.18	1.5
			Embodiment 71	0.59	7.2
Embodiment 72	>20	0.0
			Embodiment 73	>20	-0.3
Embodiment 74	11.03	-0.6
			Embodiment 75	>20	0.5
Embodiment 76	>20	0.1
			Embodiment 77	>20	0.5
Embodiment 78	>20	0.2
			Embodiment 79	>20	0.5
Embodiment 80	34.43	0.2
			Embodiment 81	44.48	-0.1
Embodiment 82	>20	0.5
			Embodiment 83	>20	0.5
Embodiment 84	>20	0.0
			Embodiment 85	>20	0.5
Embodiment 86	>20	-0.1
			Embodiment 87	>20	0.5
Embodiment 88	>20	0.1

Note：More than activity data is directed to the BRD4 albumen of bromodomain families

Part of compounds in several tables show with the comparable activity of positive control JQ1, although lower slightly compared with JQ1, Show stronger activity.Particularly embodiment 26,37,38,40,41,42,43,48,49,50,51,52,53,54,55,58, 64th, 68,71 compounds introduced are suitable with positive compound activity, and have stable structure and easy than positive compound The advantages of preparation.5 molecular level activity data of table shows that these compounds can be combined effectively comprising bromodomain structures The albumen (BRD2, BRD3, BRD4 etc.) in domain.Therefore fully show that this kind of compound has as treating cancer, cell proliferation The potentiality of the diseases such as disorderly, inflammation disease and autoimmune disease, septicemia and virus infection.

Embodiment described above only expresses the several embodiments of the present invention, and description is more specific and detailed, but simultaneously Therefore the limitation to the scope of the claims of the present invention is not interpreted as it.It is in order to those of ordinary skill in the art to provide above example The method that how to be prepared, tested and screen of offer and to one complete disclosure and description of the present invention, it should be pointed out that It is that for those of ordinary skill in the art, without departing from the inventive concept of the premise, several deformations can also be made And improvement, these belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should using appended claims as It is accurate.

Claims (4)

1. a kind of benzo [d] isoxazole class compound, which is characterized in that any of the compound in following compounds It is a kind of：

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

The chloro- N- of 2- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- fluorobenzenesulfonamides,

The chloro- N- of 5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -4- fluorobenzenesulfonamides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) thiophene -2- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) butane -1- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) naphthalene -1- sulfonamide,

2- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) methyl benzoate,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) pentamethylene sulfonamide,

2- (N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) sulfonamides) benzoic acid,

The chloro- N- of 2- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

The chloro- N- of 3- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- fluorobenzenesulfonamides,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) propane -1- sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) ethyl sulfonamide,

The bromo- N- of 5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxybenzenes sulphur,

The bromo- N- of 2- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 3,5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2,5- dimethoxy benzenesulfonamides,

Bis- chloro- N- of 2,3- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 2,5- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) benzsulfamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2,3- dihydrobenzos [b] [1,4] dioxine -6- sulphonyl Amine,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) hexamethylene alkyl sulfonamide,

N- (3,6- dimethylbiphenyls [d] isoxazole -5- bases) -2- methoxyl group -5- methyl benzenesulfonamides,

N- (2- chlorobenzyls) -3,6- dimethylbiphenyls [d] isoxazole -5- amine,

The bromo- 2- methoxyl groups-N- of 5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- N- of 5- (6- hydroxy-3-methyls benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides,

The bromo- N- of 5- (6- ethyoxyl -3- methyl benzo [d] isoxazole -5- bases) -2- methoxybenzenesulphoismides,

The chloro- 2- methoxyl groups-N- of 5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The chloro- N- of 2- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- propoxyl group benzo [d] isoxazole -5- bases) benzsulfamide,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup) acetic acid,

The bromo- N- of 2- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

The fluoro- N- of the chloro- 2- of 3- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

Bis- chloro- N- of 2,5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) propane -1- sulfonamide,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -2,3- dihydrobenzos [b] [1,4] dioxine -6- Sulfonamide,

Bis- chloro- N- of 3,5- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) benzsulfamide,

2- methoxyl groups-N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -5- methyl benzenesulfonamides,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) thiophene -2- sulfonamide,

N- (6- methoxyl group -3- methyl benzo [d] isoxazole -5- bases) -5- methylthiophene -2- sulfonamide,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup)-N- ethyls Acetamide,

N- (2- acetamidoethyls) -2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] different evils Azoles -6- bases) oxygen) acetamide,

2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases) oxygroup)-N- (2- Morpholinoethyl) acetamide, tertiary butyl -4- (2- ((5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzos [d] Isoxazole -6- bases) oxygroup) acetylamino) piperidines -1- carboxylic acid tert-butyl esters,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

N- (5- ((the bromo- 2- methoxyphenyls of 5-) sulfonamido) -3- methyl benzo [d] isoxazole -6- bases)-N- methyl vinyls Amine,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- ((tetrahydrochysene -2H- pyrans -4- bases) amino) benzo [d] isoxazole -5- bases) benzene Sulfonamide,

The bromo- 2- methoxyl groups-N- of 5- (3- methyl -6- ((2- morpholinoethyls) amino) benzo [d] isoxazole -5- bases) benzene sulfonyl Amine,

The chloro- N- of 2- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

The chloro- 2- methoxyl groups-N- of 5- (3- methyl -6- (methylamino) benzo [d] isoxazole -5- bases) benzsulfamide,

N- (5- (3- methyl benzo [d] isoxazole -5- bases) -2- morphlinophenyls) benzsulfamide.

2. benzo [d] isoxazole class compound according to claim 1 is preparing BET bromodomain acceptor inhibitors In application.

3. one kind is used to treat, prevent or improve and the relevant cell proliferative disorders of bromodomain, inflammation, autoimmunity Property disease, septicemia or virus infection pharmaceutical composition, which is characterized in that contain benzo described in claim 1 [d] different evil Azole compounds.

4. a kind of be used to treat, prevent or improve and the pharmaceutical composition of the relevant cancers of bromodomain, which is characterized in that Contain benzo described in claim 1 [d] isoxazole class compound.