CN104860869B

CN104860869B - Compound with MEK kinase inhibition functions and preparation method and application

Info

Publication number: CN104860869B
Application number: CN201510158186.8A
Authority: CN
Inventors: 徐萍; 牛彦; 黄文杰; 许凤荣
Original assignee: Peking University
Current assignee: Peking University
Priority date: 2015-04-03
Filing date: 2015-04-03
Publication date: 2017-11-03
Anticipated expiration: 2035-04-03
Also published as: CN104860869A

Abstract

The invention discloses compound with MEK kinase inhibition functions and preparation method and application.The compounds of this invention, its chemical constitution is shown in formula I.In addition, the invention also provides the method for preparing the compound, research shows, compound of the invention has preferable MEK kinase inhibiting activities, in MEK kinase inhibitors association area by with wide application value.

Description

Compound with MEK kinase inhibition functions and preparation method and application

Technical field

The present invention relates to compound and preparation method and application, the more particularly to change with MEK kinase inhibition functions Compound and preparation method and application.Belong to medicinal chemistry arts.

Background technology

During MAPK (mitogen-activated protein kinase, MAPK) was the 1980's The protein kinase played an important roll that phase finds, is important core signal path in cell.MAPK paths are broadly divided into four Class subtribe：Extracellular signal-regulated kinase ERK (extracellular signal-regulated kinase) path, JNK Path, p38 paths and ERK5 paths.ERK paths are an important families in MAPK paths, mainly by three core proteins Kinases RAF, MEK (Mitogen-activated and Extracellular signal-regulated Kinase) and ERK Composition, mutual Sequential Activation, the signal transmission network for collectively constituting a precise and high efficiency plays its adjustment effect.In tranquillization Intracellular ERK is silent oscillation, and active state is become after it receives the phosphorylation of upstream activator molecule.ERK connects The signal with transmission is changed by membrane receptor and bring signal in nucleus into, makes some transcription factors (such as Elk-1, c- in core Fos etc.) phosphorylation, eventually through the phosphorylation level and then the expression of regulatory gene of regulation transcription factor；In addition, ERK Many substrate phosphorylations in cytoplasm can also be made, and then influence the construction and other signal transduction pathways of cytoskeleton.

RAF/MEK/ERK signal paths are primarily involved in the significant process such as cell development, growth, differentiation, its function up-regulation with The generation of tumour is closely related.So suppressing the path one of research focus as new type antineoplastic medicine already, such as RAF Inhibitor Sorafenib was ratified to list in 2005 by FDA, the treatment for entity tumors such as advanced renal cell cancers.Also have at present Some RAF inhibitor and mek inhibitor are in antitumor clinical trial.Moreover, increasing research is confirmed, this path Extremely important effect is also played in virus infection and in replicating.This path of selective exclusion can prevent a variety of viral numerous Grow, including influenza virus, herpes simplex virus, hepatitis viruse, vaccinia virus, HIV, vesicular stomatitis virus etc. Deng.In addition, inflammation and many other diseases such as neuropathic pain, COPD, hypertrophic cardiomyopathy, heart method west Generation, the development of skin (CFC) syndrome difficult to understand, Huntington chorea etc. are also relevant with the up-regulation of ERK paths.

MEK1 and MEK2 be two and be closely related, tyrosine/Serineprotein kinase with bispecific, Vital effect is played in RAF/MEK/ERK signal paths.MEK1 and MEK2 has 79% amino acid identity, and Ability with equal phosphorylated CREB substrate.Known ERK1/2 is MEK1/2 unique substrate, and MEK1/2 is unique energy ERK1/2 enzyme is activated, MEK1 and MEK2 are the important tie points of ERK paths.This point is very special, imply that MEK Inhibitor blocks the effect of ERK paths to be high degree of specificity.Therefore, the suppression to MEK1/2 activity turns into new drug development In very promising strategy.

Reported is mek inhibitor with the MEK compounds specifically bound, can be divided into two classes by mechanism of action： ATP competitive inhibitors and ATP noncompetitive inhibitors.

ATP competitiveness mek inhibitors act on same binding site with ATP, are vied each other with ATP, action effect is easy Influenceed by ATP concentration.Because this inhibitor molecules amount is larger, the selectivity to kinases is not high, it is impossible to produce specificity Effect, it is possible that toxic side effect can be made larger.ATP competitiveness mek inhibitor mainly includes cyano quinolines class and natural production Thing.

The mechanism of action of the noncompetitive kinase inhibitors of ATP can at least be divided into two kinds：A kind of inhibitor is directly and substrate Specific binding site is competed, it is another that inhibitory action is produced by allosterism.Allosteric inhibitor is not directly and substrate competition Binding site, and be incorporated in a position different from avtive spot of enzyme, make conformation transition and be fixed on one it is nonactive Conformational state, and then prevent the combination of protein and substrate.The existing noncompetitive mek inhibitors of ATP belong to allosteric suppression Agent, is characterized in：1. ATP-binding site not with ATP competitive target kinases, does not also compete MEK binding sites with ERK.2. with After MEK is combined, modification changes MEK three-dimensional structure so that MEK can not be by upstream kinases phosphorylation, or suppresses phosphate turn Move on to ERK avtive spot.3. its binding site does not have homologous sequence on other kinases, is spy in all kinase inhibitors Different in nature highest.4. inhibitory action is reversible, and kinases can be reactivated after deactivation.This kind of inhibitor generally possesses preferably thin Cytoactive, this is probably caused by they are not influenceed by the micromolar ATP concentration of cytosol.

The content of the invention

It is an object of the invention to provide a kind of novel compound with MEK kinase inhibition functions of structure and its preparation Method.

The compound with MEK1 inhibitory activity that the present invention is provided, and its pharmaceutically acceptable salt or prodrug, it is special Levy and be the structure of the compound shown in formula I：

Wherein, A rings are phenyl ring or cyclohexene；

R is hydrogen atom, C₁-C₁₀Straight chain, branched alkyl, substitution alkyl or cycloalkyl group, C₂-C₇Alkenyl or alkynyl, C₃-C₇Cycloalkyl, tertiary butyloxycarbonyl acyl group, benzyloxy carbonyl acyl group, benzyl, substituted benzyl, optional position is substituted or unsubstituted Aryl, heterocyclic radical, heteroaryl；

R₁For hydrogen, halogen, hydroxyl, cyano group, C₁-C₁₀Straight chain, branched alkyl, substitution alkyl or cycloalkyl group, C₂-C₇'s Alkenyl or alkynyl, substitution or unsubstituted cycloalkyl；

R₂For the substituted or unsubstituted aryl in optional position, heterocyclic radical, heteroaryl；

R₃For hydrogen, halogen, hydroxyl, C₁-C₁₀Straight chain, branched alkyl, substitution alkyl or cycloalkyl group, C₂-C₇Alkenyl or Alkynyl, substitution or unsubstituted cycloalkyl, the substituted or unsubstituted aryl in optional position, heterocyclic radical, heteroaryl；

X is oxygen, sulphur, carbon, NH, SO, SO₂；

N is 1,2,3 or 4；

R₄For hydroxyl, cyano group, carboxyl ,-COOR₇,-CONR₆R₇, 1,2,4- oxadiazole, 1,3,4- oxadiazole, tetrazole, 5- amino -1,3,4- oxadiazoles, the substituted or unsubstituted aryl in optional position, heterocyclic radical, heteroaryl；

R₆, R₇Hydrogen, C each are selected from respectively_1-3Alkyl.

In the present invention, it is preferred to, described C₁-C₁₀Straight chain, branched alkyl, substitution alkyl or cycloalkyl group include Methyl, ethyl, propyl group, isopropyl, normal-butyl, 2- methyl-propyls, 2- butyl, tertiary butyl, n-pentyl, methoxy methylol, ring third Base, Cvclopropvlmethvl, adamantyl and through halogen, hydroxyl, amino, cyano group, nitro, carboxyl it is monosubstituted or polysubstituted on State group.

In the present invention, it is preferred to, described C₂-C₇Alkenyl be containing C=C keys simultaneously in chain containing 2-7 carbon original The aliphatic alkyl of the straight or branched of son, including vinyl, acrylic, cyclobutenyl, isobutenyl, 3- methyl-2-butenes Base, n-pentene base, heptenyl, cyclopropylethenyl, cyclohexyl acrylic and by single or multiple halogens, hydroxyl, C₁-C₄ Alkoxy, amino, cyano group, nitro, carboxyl, aldehyde radical substitution above-mentioned group；Described alkynyl refers to same containing carbon-to-carbon triple bond When chain in the straight or branched containing 2-7 carbon atom aliphatic alkyl, it is including acetenyl, propinyl, positive butynyl, different Butynyl, 3- methyl -2- butynyls, positive pentynyl etc. and through single or multiple halogens, hydroxyl, C₁-C₄Alkoxy, ammonia Base, cyano group, nitro, carboxyl, the above-mentioned group of aldehyde radical substitution.

In the present invention, it is preferred to, described substituted or unsubstituted aryl refers to 6-14 unit monocycles or Bicyclic Group, including phenyl, naphthyl and through single or multiple halogens, hydroxyl, C₁-C₄Alkyl, C₁-C₄Alkoxy, amino, second Acylamino-, cyano group, nitro, carboxyl, the above-mentioned group of aldehyde radical substitution, wherein C₁-C₄Alkyl include methyl, ethyl.

In the present invention, it is preferred to, described substituted or unsubstituted heteroaryl refers to be independently selected from containing 1-5 N, O and S heteroatomic 4-10 unit monocycles or bicyclic aromatic group, including pyrrole radicals, pyridine radicals, imidazole radicals, indyl and Through single or multiple halogens, hydroxyl, C₁-C₄Alkyl, C₁-C₄Alkoxy, amino, cyano group, nitro, carboxyl, aldehyde radical substitution Above-mentioned group.

In the present invention, it is preferred to, described substituted or unsubstituted heterocyclic radical refers to contain in its ring structure One or more heteroatomic compounds, it is furthermore preferred that hetero atom includes N, O, S.

In the present invention, it is preferred to, described substituted or unsubstituted heterocyclic radical is saturation or fractional saturation Aromatic compound, it is furthermore preferred that five yuan and single six-membered rings heterocyclic radical and through single or multiple halogens, hydroxyl, C₁-C₄Alkane Base, C₁-C₄Alkoxy, amino, cyano group, nitro, carboxyl, aldehyde radical substitution above-mentioned group.

In the present invention, it is preferred to, described halogen includes fluorine, chlorine, bromine and iodine.

In the present invention, it is preferred to, described substitution or unsubstituted cycloalkyl refer to C₃-C₁₀Saturation it is monocyclic or many Ring ring system, including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, adamantyl and through single or multiple halogens, Hydroxyl, C₁-C₄Alkyl, C₁-C₄Alkoxy, amino, cyano group, nitro, carboxyl, aldehyde radical substitution above-mentioned group.

Prepare above-described compound, and its pharmaceutically acceptable salt or prodrug method, it is characterised in that it is described Formulas I structure in A rings be phenyl ring, R₃For the preparation method of the compound of hydroxyl, comprise the following steps：

1) diazo-reaction generation diazol occurs under the conditions of natrium nitrosum and concentrated hydrochloric acid for substituted aniline, then in chlorine The compound of Formula II structure is reduced under the conditions of change stannous；

2) in trifluoroacetic acid as the condition of solvent with hydroresorcinol Fischer Yin occur for Formula II structural compounds Diindyl ring closure reaction, obtains the compound of formula III structure；

3) chlorination occurs under conditions of copper chloride and lithium chloride for the compound of formula III structure, then in lithium chloride The compound of formula IV structure is obtained with generation elimination reaction under conditions of lithium carbonate；

4) compound of formula IV structure chlorination occurs under conditions of N- chlorosuccinimides obtains Formula V structure Compound；

5) compound of Formula V structure is oxidized to the compound of Formula IV structure under conditions of Fremy ' s Salt；

6) compound and sulfonamide of Formula IV structure use microwave heating response under conditions of titanium tetrachloride and triethylamine The compound of production VII structures；

7) compound of Formula VII structure then obtains Formulas I structure with nucleopilic reagent generation substitution reaction with sodium hydrosulfite reduction Middle A rings are phenyl ring, R₃For the compound of hydroxyl；

Wherein, R is hydrogen atom, C₁-C₁₀Straight chain, branched alkyl, substitution alkyl or cycloalkyl group, C2-C7 alkenyl or Alkynyl, substitution or unsubstituted cycloalkyl, tertiary butyloxycarbonyl acyl group, benzyloxy carbonyl acyl group, benzyl, substituted benzyl, optional position quilt Substitution or unsubstituted aryl, heterocyclic radical, heteroaryl；

X is oxygen, sulphur, carbon, NH, SO, SO₂；

N is 1,2,3 or 4；

R₄For hydroxyl, cyano group, carboxyl ,-COOR₇,-CONR₆R₇, 1,2,4- oxadiazole, 1,3,4- oxadiazole, tetrazole, 5- amino -1,3,4- oxadiazoles, the substituted or unsubstituted aryl in optional position, heterocyclic radical, heteroaryl；R₆, R₇It is each respectively From selected from hydrogen, C_1-3Alkyl.

Prepare above-described compound, and its pharmaceutically acceptable salt or prodrug method, it is characterised in that it is described Formulas I structure in R₁, R₃For hydrogen atom, X is the preparation method of the compound of oxygen atom, is comprised the following steps：

1) amino metanitrophenol occurs under the conditions of potassium carbonate the chemical combination that alkylated reaction obtains Formula VIII structure Thing；

2) compound of Formula VIII structure obtains corresponding hydrazinobenzene hydrochloride salt after diazotising reduction reaction, then with The compound that Fischer indoles ring closure reactions obtain Formula IX structure occurs for cyclohexanone；

3) compound that aromatization obtains Formula X structure occurs under conditions of DDQ for the compound of Formula IX structure, saves Going this step, then A rings are cyclohexene ring；

4) compound of Formula X structure obtains corresponding amino-compound through catalytic hydrogenation, with obtaining Formulas I after acyl chloride reaction R in structure₃For hydrogen atom, X is the compound of oxygen atom；

Wherein, A rings are phenyl ring or cyclohexene；

R is hydrogen atom, C₁-C₁₀Straight chain, branched alkyl, substitution alkyl or cycloalkyl group, C₂-C₇Alkenyl or alkynyl, Substitution or unsubstituted cycloalkyl, tertiary butyloxycarbonyl acyl group, benzyloxy carbonyl acyl group, benzyl, substituted benzyl, optional position it is substituted or Unsubstituted aryl, heterocyclic radical, heteroaryl；

N is 1,2,3 or 4；

Prepare above-described compound, and its pharmaceutically acceptable salt or prodrug method, it is characterised in that it is described Formulas I structure in R₁, R₃For hydrogen atom, X is the preparation method of the compound of sulphur atom or sulfone, is comprised the following steps：

1) corresponding hydrazinobenzene hydrochloride salt is obtained after diazotising reduction reaction to amino metanitrophenol, then and ring The compound that Fischer indoles ring closure reactions obtain Formula X I structures occurs for hexanone；

2) with trifluoromethanesulfanhydride anhydride the compound that esterification obtains Formula X II structures occurs for the compound of Formula X I structures；

3) chemical combination that aromatization obtains Formula X III structures occurs under conditions of DDQ for the compound of Formula X II structures Thing, saving this step, then A rings are cyclohexene ring；

4) compound of Formula X III structures is in Pd₂(dba)₃Coupling reaction occurs under catalysis with XantPhos systems to obtain The compound of Formula X IV structures；

5) nitro is reduced to amino by the compound of Formula X IV structures using sodium hydrosulfite, is then passed through acylation reaction and is obtained formula R in the compound of XV structures, as Formulas I structure₃For hydrogen atom, X is the compound of sulphur atom；

If 6) X is sulfone, the oxidized reaction of compound of Formula X V structure can obtain R in Formulas I structure₃For hydrogen atom, X is sulfone Compound.

Wherein, A rings are phenyl ring or cyclohexene；

X is S or SO₂；

N is 1,2,3 or 4；

R₄For hydroxyl, cyano group, carboxyl ,-COOR₇,-CONR₆R₇, 1,2,4- oxadiazole, 1,3,4- oxadiazole, tetrazole, 5- amino -1,3,4- oxadiazoles, the substituted or unsubstituted aryl in optional position, heterocyclic radical, heteroaryl, R₆, R₇It is each respectively From selected from hydrogen, C_1-3Alkyl.

It should be noted that synthesis path described above is to illustrate the preparation of the compounds of this invention, and prepare This is by no means restricted to, i.e., other synthetic methods are equally possible, methods described refers to the synthesis side in skilled person's general knowledge Method.

If desired, the compounds of this invention can using methods known in the art be changed into they officinal salt or The form of ester.

It is a further object of the present invention to provide the purposes of the compounds of this invention.

Inventor is verified by experiments, and the compounds of this invention has good suppression MEK activity.

Therefore, the present invention proposes compound of the present invention or its salt pharmaceutically received in mek inhibitor is prepared Using.Wherein, described mek inhibitor has the inhibitory action to unactivated MEK.

Brief description of the drawings

Fig. 1 is experimental principle figure of the checking compound to non-phosphorylation MEK1 inhibitory action.

Embodiment

Below by experiment and the present invention will be further described in conjunction with the embodiments, it should be understood that these embodiments The purpose of illustration is only used for, protection scope of the present invention is never limited in.

Embodiment 1,2- ((4- hydroxyls -1- (4- tolysulfonyl amido) -9H- carbazole -3- bases) is thio) acetic acid (MI-1) Synthesis

The first step

N- chloro succinyl is slowly added into 9H-4- hydroxycarbazoles (918.2mg, 5mmol) acetonitrile (20mL) solution Imines (667.4mg, 5mmol), lasts 10 minutes.Reaction solution is stirred at room temperature 1.5 hours, is then boiled off with Rotary Evaporators molten Agent.Crude product separates (dichloromethane/petroleum ether=1 with silica gel column chromatography:5-1:2) product 3- chloro-4-hydroxyl carbazoles, are obtained, in vain Color solid (518.2mg), yield is 47.6%.

¹H NMR(400MHz,DMSO-d₆):δ 11.31 (s, 1H, NH), 9.78 (s, 1H, OH), 8.21 (d, J=8Hz, 1H, ArH), 7.46 (d, J=8Hz, 1H, ArH), 7.36 (td, J=1.16Hz J=8Hz, 1H, ArH), 7.30 (d, J= 8Hz, 1H, ArH), 7.16 (td, J=0.96Hz J=8Hz, 1H, ArH), 7.00 (d, J=8Hz, 1H, ArH)

Second step

Water (85mL) solution of nitroso potassium peroxydisulfate (1.4430g) and potassium dihydrogen phosphate (84.5mg) is added drop-wise to 3- In acetone (85mL) solution of chloro-4-hydroxyl carbazole (410mg, 1.88mmol).1.5 hours, Ran Houyong are stirred at room temperature in reaction solution Buchner funnel suction filtration, filter cake is washed with a small amount, infrared lower drying.Chloro- carbazole-Isosorbide-5-Nitrae-the diketone of 3- is obtained, is dark red solid (413.3mg), yield is 94.7%.

¹H NMR(400MHz,DMSO-d₆):δ 13.11 (s, 1H, NH), 8.05 (d, J=8Hz, 1H, ArH), 7.57 (d, J =8Hz, 1H, ArH), 7.43 (td, J=0.96Hz J=8Hz, 1H, ArH), 7.37 (td, J=0.96 Hz J=8Hz, 1H, ArH),7.18(s,1H,ArH).

3rd step

To the chloro- carbazole -1,4- diketone (116mg, 0.5mmol) of 3- and p-methylphenyl sulphonylamine (85.6 under condition of ice bath Mg, 0.5mmol) tetrahydrofuran solution (6mL) in the dichloromethane solution (1mL, 1 M) of titanium tetrachloride, and three second is added dropwise Amine (0.16mL).Mixed liquor heating response 15 minutes (150 watts, 65 degrees Celsius) in microwave reaction instrument, then uses short silicagel column Insoluble solid particle is filtered out, filtrate, which is mixed, uses silica gel post separation (ethyl acetate/petroleum ether=5 after sample:1-1:1), obtain coffee-like Solid (132.8mg), yield is 69.0%.

¹H NMR(400MHz,DMSO-d₆):δ12.87(s,1H,aromatic NH),8.11(s,1H,ArH), 8.00 (m, 3H, ArH), 7.54 (d, J=8Hz, 3H, ArH), 7.41 (t, J=8Hz, 1H, ArH), 7.33 (t, J=8 Hz, 1H, ArH),2.46(s,3H,CH₃).

4th step

Previous step product (77mg, 0.2mmol) is dissolved in tetrahydrofuran (6mL), add TGA (20.8 uL, 0.3mmol) with pyridine (24.2uL, 0.3mmol).Concentrated solvent after 40 minutes is stirred at room temperature in reaction solution.Mixture acetic acid second Ester (50mL) redissolves, and is transferred to 250mL separatory funnels, pyridine is washed away with the hydrogen potassium solution of sulfuric acid one (0.5 M, 20mL X 2).With After take a policy powder (204.7mg, 0.5mmol) and water (50mL), fierceness shaking is until ethyl acetate layer is changed into light yellow. Reject aqueous phase, washes organic phase with water (50mL X 2) and saturated aqueous common salt (50mL) respectively, then uses anhydrous sodium sulfate drying. Crude product is 21.3% through the isolated yellow solid of silicagel column (21mg), yield.

¹H NMR(400MHz,DMSO-d₆):δ13.33(br s,1H,COOH),11.06(s,1H,aromatic NH), 9.48(s,1H,SO₂NH), 8.17 (d, J=8Hz, 1H, ArH), 7.57-7.51 (m, 3H, ArH), 7.34-7.30 (m, 3H, ), ArH 7.14 (t, J=8Hz, 1H, ArH), 6.65 (s, 1H, ArH), 3.13 (s, 2H, CH₂), 2.36(s,3H,CH₃).

¹³C NMR(100MHz,DMSO-d₆)δ172.23,153.62,143.58,139.61,139.44,136.81, 130.76, 129.88,127.67,125.57,122.51,122.21,119.79,113.36,112.68,111.69, 106.30,21.44.

ESI-MS(C₂₁H₁₈N₂O₅S₂):m/z 441.0593(M-H⁺)；ESI-HRMS(C₂₁H₁₈N₂O₅S₂):m/z 441.05734(M-H⁺).

Embodiment 2,2- ((the bromo- 4- hydroxyls -1- of 6- (4- tolysulfonyl amido) -9H- carbazole -3- bases) is thio) acetic acid (MI-2) synthesis

The first step

The hydrochloride (222.8mg, 1mmol) and hydroresorcinol (125.9mg, 1.12 mmol) of 4- bromophenyl-hydrazines is molten In trifluoroacetic acid (1.5mL).Mixture uses microwave reaction instrument heating response 10 minutes (140 degrees Celsius, 50 watts).Revolving is removed Solvent is removed, solid is redissolved in ethyl acetate (60mL), (50mL) twice is washed with saturated sodium bicarbonate solution and removes trifluoroacetic acid, Reject aqueous phase.Revolving removes solvent, and gained solid is beaten in dichloromethane (20mL), then filtering.The a small amount of dichloro of filter cake Methane wash, obtains celadon solid (118.5mg), and yield is 44.9%.

¹H NMR(400MHz,DMSO-d₆):δ 12.07 (s, 1H, NH), 8.05 (d, J=1.92Hz, 1H, ArH), 7.38 (d, J=8.52Hz, 1H, ArH), 7.30 (dd, J=1.96Hz J=8.52Hz, 1H, ArH), 2.97 (t, 2H, ArCH ₂), 2.44(t,2H,COCH ₂),2.12(p,2H,CH₂CH ₂CH₂).

Second step

Anhydrous cupric chloride is added into DMF (12mL) solution of 6- bromine tetrahydro carbazole -4- ketone (1.055g, 4mmol) (2.689g, 20mmol), anhydrous Lithium chloride (512mg, 12mmol).Mixed liquor is in 105 degrees Centigrade 1 hour, then filtering Remove inorganic salts.Filtrate is diluted with 100mL water, is then extracted with ethyl acetate (50mL X 3).Organic phase after merging uses full With brine It (50mL X 3), anhydrous sodium sulfate drying obtains brown oil after concentration.

This brown oil is dissolved in DMF (15mL), anhydrous Lithium chloride (640.2mg, 15mmol) and lithium carbonate is added (1.1083g,15mmol).Mixture is heated to 150 degrees Celsius under nitrogen protective condition and reacted 4 hours.Then room is cooled to Temperature, is diluted with 100mL ethyl acetate, is filtered to remove inorganic salts, then washed with watery hydrochloric acid (2N, 50mL X 2) and saturated common salt Wash, then use anhydrous sodium sulfate drying.Crude product is through column chromatography (ethyl acetate/petroleum ether=1:5) isolated brown solid (403mg), yield is 34%.

¹H NMR(400MHz,DMSO-d₆):δ 11.29 (s, 1H, NH), 10.18 (s, 1H, OH), 8.23 (d, J= 1.32Hz, 1H, ArH), 7.44 (dd, J=1.76Hz J=8.56Hz, 1H, ArH), 7.39 (d, J=8.52Hz, 1H, ArH), (d, J=7.76Hz, 1H, the ArH) of 7.20 (t, 1H, ArH), 6.93 (d, J=8.04Hz, 1H, ArH), 6.59

¹³C NMR(100MHz,DMSO-d₆):δ154.19,142.53,138.20,127.81,127.01,124.52, 124.51,112.59,110.69,110.67,104.79,102.55.

3rd step

N- chlorine is slowly added into acetonitrile (4mL) solution of 9H-4- hydroxyl -6- bromines carbazoles (130.5mg, 0.5mmol l) For succimide (66.3mg, 0.5mmol), 10 minutes are lasted.Reaction solution is stirred at room temperature 1.5 hours, subsequent concentrated solvent. Crude product separates (dichloromethane/petroleum ether=1 with silica gel column chromatography:3) product 3- chloro-4-hydroxyl -6- bromine carbazoles, are obtained, silvery white Color solid (77.2mg), yield is 52.3%.

¹H NMR(400MHz,DMSO-d₆):δ 11.51 (s, 1H, NH), 10.02 (s, 1H, OH), 8.29 (d, J= 1.24Hz, 1H, ArH), 7.50 (dd, J=1.68Hz J=8.60Hz, 1H, ArH), 7.44 (d, J=8.60Hz, 1H, ArH), 7.35 (d, J=8.56Hz, 1H, ArH), 7.02 (d, J=8.56Hz, 1H, ArH)

¹³C NMR(100MHz,DMSO-d₆):δ148.83,140.86,138.64,127.89,127.80,124.70, 123.85,113.11,112.55,111.07,109.69,104.46.

4th step

Acetone (33mL) solution of 3- chloro-4-hydroxyl -6- bromines carbazoles (213.5mg, 0.72mmol) is added drop-wise to nitroso In water (33mL) solution of potassium peroxydisulfate (563.5mg, 1.224mmol) and potassium dihydrogen phosphate (34.6mg, 0.24mmol).Instead Answer liquid to be stirred at room temperature 3 hours, then use Buchner funnel suction filtration, filter cake is washed with a small amount, infrared lower drying.Tied again with acetone Crystalline substance obtains the chloro- 6- bromines carbazole-Isosorbide-5-Nitrae-diketone of 3-, is dark red solid (75.0 mg), yield is 33.5%.

¹H NMR(400MHz,DMSO-d₆):δ 13.25 (s, 1H, carbazoleNH), 8.09 (d, J=8.0Hz, 1H, ), ArH 7.50 (m, 2H, ArH), 7.18 (d, J=8.0Hz, 1H, ArH)

5th step

To the chloro- 6- bromines carbazole -1,4- diketone (64mg, 0.21mmol) of 3- and p-methylphenyl sulphonylamine (35.2mg, 0.21 Mmol the dichloromethane solution (0.21mL, 1M) of titanium tetrachloride, and triethylamine are added dropwise in tetrahydrofuran (2.5mL) solution) (66uL).Mixed liquor heating response 15 minutes (150 watts, 65 degrees Celsius) in microwave reaction instrument, is then filtered out with short silicagel column Gained solid obtains coffee-like solid (56.9mg) with re-crystallizing in ethyl acetate after insoluble solid particle, concentration filtrate, and yield is 59.6%.

6th step

Previous step product (49mg, 0.1mmol) is dissolved in tetrahydrofuran (3mL), add TGA (11uL, 0.15mmol) with pyridine (12.5uL, 0.15mmol).Concentrated solvent after 30 minutes is stirred at room temperature in reaction solution.Mixture acetic acid Ethyl ester (20mL) redissolves, and is transferred to 100mL separatory funnels, pyridine is washed away with the hydrogen potassium solution of sulfuric acid one (0.5 M, 20mL X 2). Sodium hydrosulfite (102.4mg, 0.5mmol) and water (20mL) are subsequently added, fierceness shaking is until ethyl acetate layer is changed into pale yellow Color.Reject aqueous phase, washes organic phase with water (20mL X 2) and saturated aqueous common salt (20mL) respectively, then dry with anhydrous sodium sulfate It is dry.Crude product is through silicagel column (ethanol/methylene=1：8) isolated brown solid (9.7mg), yield is 18.6%.

¹H NMR(400MHz,DMSO-d₆):δ11.17(s,1H,carbazoleNH),9.46(s,1H,NHSO₂), 8.28 (d, 1H, ArH), 7.54 (d, J=7.2Hz, 2H, ArH), 7.44 (m, 2H, ArH), 7.33 (d, J=7.2Hz, 2H, ArH), 6.60(s,1H,ArH),3.02(s,2H,SCH₂),2.36(s,3H,CH₃).

ESI-MS(C21H17BrN2O5S2):m/z 518.9657520.9666(M-H+)；ESI-HRMS (C21H17BrN2O5S2):m/z 518.96895(M-H+).

Embodiment 3, ethyl 2- ((1- (4- p-methylphenyl sulphonylamines base) -9H- carbazole -3- bases) oxo) acetic acid esters (MI-3) Synthesis

First step intermediate compound I M1 synthesis

Added into 100mL round-bottomed bottles to amino metanitrophenol (4.9952g, 32.4mmol), potassium carbonate (4.9346g, 35.6mmol) and 60mL acetone.Bromoacetate (3.8mL, 34.0mmol) is then added dropwise.Reactant mixture It is stirred overnight at room temperature, filters out inorganic salts.Filtrate is concentrated to give yellow solid, and gained solid is in ethyl acetate and petroleum ether mixed liquor (1:3,50mL) it is beaten in, then uses Buchner funnel suction filtration, obtain yellow solid (5.8554 g), yield is 75.2%.

¹H NMR(400MHz,DMSO-d₆):δ 7.37 (d, J=2.24Hz, 1H, ArH), 7.27 (s, 2H, NH₂),7.22 (dd, J=2.68Hz J=9.24Hz, 1H, ArH), 7.01 (d, J=9.24Hz, 1H, ArH), 4.74 (s, 2H, OCH ₂CO), 4.17 (q, J=7.08Hz, 2H, COCH ₂CH₃), 1.21 (t, J=7.12Hz, 3H, CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.09,147.86,142.71,129.45,127.71,121.18, 107.47,65.97,61.11,14.50.

Second step intermediate compound I M2 synthesis

Intermediate compound I M1 (5.8554g, 24.4mmol) is dissolved in concentrated hydrochloric acid (40mL), -10 degrees Celsius are cooled to.It is added dropwise sub- Water (3mL) solution of sodium nitrate (2.027g, 29.28mmol) carries out diazotising.Stannous chloride is added dropwise after reaction half an hour Concentrated hydrochloric acid (10mL) solution of (11.04g, 48.8mmol) carries out reduction reaction, completes to keep -10 degrees Celsius of reactions 1 after being added dropwise Hour, room temperature is then warming up to, is stirred at room temperature overnight.

Above-mentioned concentrated hydrochloric acid solution is diluted with ethanol (50mL), cyclohexanone (2.5mL, 24.4mmol) is slowly added to.Mixing Liquid flows back 3 hours at 90 degrees Celsius, is then down to room temperature.Buchner funnel suction filtration is used, three times, gained are washed with a small amount in filter cake The infrared lower drying of solid.Red solid (3.2376g) is obtained, yield is 41.7%.

¹H NMR(400MHz,CDCl₃):δ9.34(s,1H,indole NH),7.66(s,1H,ArH),7.38(s, 1H, ArH),4.72(s,2H,OCH ₂), CO 4.32 (q, J=7.12Hz, 2H, COCH ₂CH₃),2.79(t,2H, 1-CH₂),2.67(t, 2H,4-CH₂),1.93(m,4H,2,3-CH₂CH₂) 1.34 (t, J=7.08Hz, 3H, CH₂CH ₃).

¹³C NMR(100MHz,CDCl₃):δ168.83,150.81,138.51,132.31,131.41,125.74, 112.82,111.13,105.03,66.90,61.45,23.17,22.86,22.80,20.56,14.18.

3rd step intermediate compound I M3 synthesis

Intermediate compound I M2 (3.2376g, 10.17mmol) and DDQ are heated under conditions of toluene (50mL) is as solvent Backflow 2 hours, then cools to room temperature.Mixture is diluted with 100mL ethyl acetate, is transferred to 250mL separatory funnels, organic (100mL X 5) is washed with saturated sodium bicarbonate solution, until aqueous phase is colourless.Reject aqueous phase, organic phase anhydrous slufuric acid Sodium is dried, and is concentrated to give red brown solid (3.4166g), quantitative reaction.

¹H NMR(400MHz,DMSO-d₆):δ 11.97 (s, 1H, NH), 8.37 (s, 1H, ArH), 8.23 (d, J= 7.76Hz, 1H, ArH), 7.86 (s, 1H, ArH), 7.71 (d, J=8.16Hz, 1H, ArH), 7.51 (t, 1H, ArH), 7.27 (t,1H,ArH),4.98(s,2H,OCH ₂), CO 4.21 (q, J=7.08Hz, 2H, COCH ₂CH₃), 1.24 (t, J=7.16Hz, 3H,CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.15,150.61,141.93,131.35,129.40,128.26, 128.06,121.81,121.46,120.69,116.03,113.05,108.62,66.58,61.18,14.51.

4th step intermediate compound I M4 synthesis

Previous step aromatization products IM3 (315.1mg, 1mmol) is dissolved in methanol (25mL), add palladium carbon (20%, 65.7mg).Mixture is stirred overnight at room temperature in hydrogenation instrument (40psi).Filter out palladium carbon, be directly used in after concentration filtrate next Step.

5th step

Intermediate compound I M4 obtained by previous step is dissolved in pyridine (10mL), be added portionwise p-methyl benzene sulfonic chloride (263.1 mg, 1.38mmol).Mixture is stirred overnight at room temperature.Solvent pyridine is steamed with membrane pump, crude product separates (stone with silica gel column chromatography Oily ether/acetone=3:1) white solid (221.1mg) is obtained, yield is 50.4%.

¹H NMR(400MHz,DMSO-d₆):δ10.75(s,1H,carbazoleNH),10.00(s,1H, NHSO₂), 8.02 (d, J=7.80Hz, 1H, ArH), 7.68 (d, J=8.24Hz, 2H, ArH), 7.54 (d, J=8.16Hz, 1H, ArH), 7.49 (d, J=2.24Hz, 1H, ArH), 7.37 (td, 1H, ArH), 7.33 (d, J=8.08 Hz, 2H, ArH), 7.12 (t, 1H, ), ArH 6.68 (d, J=2.32Hz, 1H, ArH), 4.70 (s, 2H, OCH ₂CO), 4.17 (q, J=7.12Hz, 2H, COCH ₂CH₃),2.32(s,3H,PhCH ₃), 1.22 (t, J=7.08Hz, 3H, CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.32,151.55,143.85,140.43,137.08,130.11, 129.43,127.34,126.36,124.27,122.71,121.93,120.78,119.00,112.02,109.07,102.06, 66.16,61.00,21.40,14.51.

ESI-MS(C23H22N2O5S):m/z 437.1193(M-H+)；ESI-HRMS(C23H22N2O5S): m/z 437.11767(M-H+).

Embodiment 4, ethyl 2- ((1- (4- acetylaminobenzene sulfonamides base) -9H- carbazole -3- bases) oxo) acetic acid esters (MI-4) synthesis

First to fourth step

Be the same as Example 3

5th step

Intermediate compound I M4 obtained by previous step is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride is added portionwise (322.5mg,1.38mmol).Mixture is stirred overnight at room temperature.Solvent pyridine is steamed with membrane pump, crude product silicagel column color Spectrum separation (petroleum ether/acetone=1:1) white solid (103.9mg) is obtained, yield is 21.6%.

¹H NMR(400MHz,DMSO-d₆):δ10.73(s,1H,carbazoleNH),10.26(s,1H, NHCOCH₃), 9.93(s,1H,NHSO₂), 8.02 (d, J=7.76Hz, 1H, ArH), 7.70 (m, 4H, ArH), 7.54 (d, J=8.12Hz, 1H,ArH),7.49(s,1H,ArH),7.37(t,1H,ArH),7.12(t,1H,ArH), 6.68(s,1H,ArH),4.71(s, 2H,OCH₂), CO 4.17 (q, J=7.08Hz, 2H, COCH ₂CH₃),2.04(s, 3H,NHCOCH ₃), 1.22 (t, J=7.08Hz, 3H,CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.45,169.34,151.55,143.70,140.44,133.34, 129.53,128.56,126.35,124.26,122.71,121.95,120.77,118.98,118.90,112.02,109.25, 102.06,66.15,60.99,24.56,14.51.

ESI-MS(C₂₄H₂₃N₃O₆S):m/z 480.1262(M-H⁺)；ESI-HRMS(C₂₄H₂₃N₃O₆S):m/z 480.12348(M-H⁺).

The synthesis of embodiment 5,2- ((1- (4- p-methylphenyl sulphonylamines base) -9H- carbazole -3- bases) oxo) acetic acid (MI-5)

Sodium hydroxide (20mg, 0.5mmol) is dissolved in 1mL water, MI-3 (76.5mg, 0.17mmol) tetrahydrochysene is added drop-wise to In furans (1mL) solution.Mixture was stirred at room temperature after 1.5 hours to be diluted with 20mL ethyl acetate, molten with saturated sodium bicarbonate Liquid is extracted three times, each 20mL.Merge aqueous phase, pH is gradually adjusted with 2M dilute hydrochloric acid solutions to pH=1 so that white solid is slow It is precipitated out.Use Buchner funnel suction filtration, filter white solid in infrared lower drying, be weighed as 58.0mg, yield is 81%.

¹H NMR(400MHz,DMSO-d₆):δ12.96(br s,1H,COOH),10.75(s,1H, carbazoleNH), 10.02(br s,1H,NHSO₂), 8.02 (d, J=7.80Hz, 1H, ArH), 7.70 (d, J=7.92 Hz, 2H, ArH), 7.54 (d, J=8.12Hz, 1H, ArH), 7.47 (s, 1H, ArH), 7.37 (t, 1H, ArH), 7.33 (d, J=8.08Hz, 2H, ArH), 7.11(t,1H,ArH),6.70(s,1H,ArH),4.61(s,2H,CH₂),2.32 (s,3H,CH₃).

¹³C NMR(100MHz,DMSO-d₆):δ170.84,151.74,143.86,140.42,137.10,130.12, 129.30,127.36,126.31,124.24,121.96,120.76,118.97,112.00,109.07,101.75,65.94, 21.41.

ESI-HRMS(C₂₁H₁₈N₂O₅S):m/z 409.08637(M-H⁺).

Embodiment 6,2- ((1- (4- acetylaminobenzene sulfonamides base) -9H- carbazole -3- bases) oxo) acetic acid (MI-6) Synthesis

Sodium hydroxide (15.2mg, 0.4mmol) is dissolved in 1mL water, MI-4 (48.3mg, 0.1mmol) tetrahydrochysene is added drop-wise to In furans (1mL) solution.Mixture was stirred at room temperature after 1 hour to be diluted with 20mL ethyl acetate, uses saturated sodium bicarbonate solution Extraction three times, each 20mL.Merge aqueous phase, pH is gradually adjusted with 2M dilute hydrochloric acid solutions to pH=1 so that white solid slowly sinks Shallow lake comes out.Use Buchner funnel suction filtration, filter white solid in infrared lower drying, be weighed as 20.7mg, yield is 45.5%.

¹H NMR(400MHz,DMSO-d₆):δ12.95(s,1H,COOH),10.71(s,1H, carbazoleNH), 10.25(s,1H,NHCOCH₃),9.94(s,1H,SO₂), NH 8.02 (d, J=6.68Hz, 1H, ArH), 7.71 (d, J= 7.60Hz, 4H, ArH), 7.53 (d, J=7.88Hz, 1H, ArH), 7.46 (s, 1H, ArH), 7.36 (t, 1H, ArH), 7.11 (t,1H,ArH),6.71(s,1H,ArH),4.62(s,2H,OCH₂),2.04(s,3H, COCH₃).

¹³C NMR(100MHz,DMSO-d₆):δ170.79,169.45,151.74,143.69,140.42,133.40, 129.33,128.57,126.29,124.22,122.74,122.00,120.75,118.96,111.99,109.23,101.69, 65.93,24.56.

ESI-HRMS(C₂₂H₁₉N₃O₆S):m/z 452.09218(M-H⁺).

The conjunction of embodiment 7,2- ((1- (4- p-methylphenyl sulphonylamines base) -9H- carbazole -3- bases) oxo) acetamide (MI-7) Into

MI-3 (440mg, 1mmol) is dissolved in 18mL concentrated ammonia liquors, mixture is stirred at room temperature 3 hours, and solid is completely dissolved, Solution is in light yellow.Deammoniation is removed after the completion of reaction with concentrated solvent, solid is weighed as 389.9mg, yield in infrared lower drying For 94.9%.

¹H NMR(400MHz,DMSO-d₆):δ10.74(s,1H,carbazole NH),10.00(s,1H, SO₂NH), 8.01 (d, J=7.76Hz, 1H, ArH), 7.71 (d, J=8.08Hz, 2H, ArH), 7.54 (d, J=8.08Hz, 1H, ArH), 7.49 (d, J=1.64Hz, 1H, ArH), 7.41-7.31 (m, 4H, ArH), 7.12 (t, 1H, ArH), 6.84 (d, J= 1.84Hz,1H,ArH),4.39(s,2H,CH₂),2.30(s,3H,PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ170.57,151.74,143.87,140.37,137.05,130.12, 129.19,127.39,126.33,124.19,122.72,122.02,120.70,119.03,112.02,109.09,101.85, 68.20,21.41.

ESI-HRMS(C₂₁H₁₉N₃O₄S):m/z 408.10235(M-H⁺).

Embodiment 8, N- (3- ((1H- tetrazole -5- bases) methoxyl group) -9H- carbazole -1- bases) -4- p-methylphenyl sulphonylamines (MI-8) synthesis

Under argon gas protective condition, MI-7 (271.8mg, 0.66mmol), sodium azide (651.6mg, 9.96 mmol), Silicon tetrachloride (0.38mL, 3.32mmol) is heated to 80 degrees Celsius of 14 hours of reaction in anhydrous acetonitrile (6mL).React Room temperature is cooled to after, with 50mL methanol dilution reaction solutions, inorganic salts are filtered out.After filtrate concentration (first is separated with silica gel column chromatography Alcohol/dichloromethane=1:30-1:20) white solid 179.2mg, is obtained, yield is 62.1%.

¹H NMR(400MHz,DMSO-d₆):δ10.79(s,1H,carbazole NH),10.05(s,1H, SO₂NH), 8.04 (d, J=7.80Hz, 1H, ArH), 7.68 (d, 3H, ArH), 7.56 (d, J=8.16Hz, 1H, ArH), 7.38 (t, 1H, ), ArH 7.31 (d, J=8.08Hz, 2H, ArH), 7.14 (t, 1H, ArH), 6.83 (d, J=2.00Hz, 1H, ArH), 5.46 (s,2H,CH₂),2.30(s,3H,PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ151.31,143.91,140.39,136.96,130.14,129.41, 127.32,126.47,124.25,122.69,122.10,120.77,119.13,112.09,109.20,102.31,60.87, 21.41.

ESI-MS(C₂₁H₁₈N₆O₃S):m/z 433.28(M-H⁺)；ESI-HRMS(C₂₁H₁₈N₆O₃S):m/z 434.11556 (M⁺)473.08103(M+K⁺).

Embodiment 9, N- (3- ((5- amino -1,3,4- oxadiazole -2- bases) methoxyl group) -9H- carbazole -1- bases) -4- are to first The synthesis of base benzsulfamide (MI-9)

First step intermediate compound I M5 synthesis

MI-3 (943.4,2.15mmol) and hydrazine hydrate (1.05mL, 50wt%) are flowed back in absolute ethyl alcohol (13mL) One day, solid gradually dissolved, solution clarification.Reaction is cooled to room temperature after terminating, and the solid of precipitation is filtered out, with a small amount of Ethanol washing and then infrared lower drying.White solid 758.2mg is obtained, yield is 83.0%.

¹H NMR(400MHz,DMSO-d₆):δ10.73(s,1H,carbazole NH),10.01(s,1H, SO₂NH), 9.39(s,1H,CONHNH₂), 8.01 (d, J=7.72Hz, 1H, ArH), 7.71 (d, J=7.96Hz, 2H, ArH), 7.54 (d, J=8.12Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7.37 (t, 1H, ArH), 7.33 (d, J=7.92Hz, 2H, ArH), 7.12(t,1H,ArH),6.84(s,1H,ArH),4.45(s,2H,CH₂),4.36(s,2H, CONHNH ₂),2.31(s,3H, PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ167.17,151.81,143.86,140.35,137.07,130.13, 129.15,127.38,126.32,124.14,122.73,122.02,120.70,119.01,112.03,109.22,101.61, 67.72,21.41.

Second step

Intermediate compound I M5 (422.1mg, 1mmol) obtained in the previous step and cyanogen bromide (121.0mg, 1.2mmol) are existed Flowed back 3 hours in 10mL ethanol.(acetone/dichloromethane=1 is separated after concentrated solvent with silica gel column chromatography:4-1:2), obtain white Color solid 102mg, yield is 22.8%.

¹H NMR(400MHz,DMSO-d₆):δ10.79(s,1H,carbazole NH),10.02(s,1H, SO₂NH), 8.02 (d, J=7.20Hz, 1H, ArH), 7.68 (t, 3H, ArH), 7.55 (d, J=7.64Hz, 1H, ArH), 7.38 (t, 1H, ), ArH 7.32 (d, J=7.08Hz, 2H, ArH), 7.20 (s, 2H, NH₂),7.14(t,1H, ArH),6.74(s,1H,ArH), 5.11(s,2H,CH₂),2.30(s,3H,PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ164.90,155.93,151.26,143.90,140.41,136.95, 130.14,129.51,127.37,126.45,124.26,122.69,122.05,120.74,119.11,112.08,109.34, 102.54,61.17,21.41.

ESI-HRMS(C₂₂H₁₉N₅O₄S):m/z 450.12305(M+H⁺)472.10488(M+Na⁺)488.07883 (M+K⁺).

Embodiment 10,4- methyl-N- (3- ((3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) methoxyl group) -9H- carbazole -1- bases) The synthesis of benzsulfamide (MI-10)

First step intermediate compound I M6 synthesis

Lithium hydroxide (338.6mg, 8mmol) is added dropwise into IM3 (1.255g, 4mmol) tetrahydrofuran solution (12mL) The aqueous solution (12mL), 4.5 hours are stirred at room temperature after completion of dropping.Reaction solution is dilute with 80mL ethyl acetate after the completion of reaction Release, three times (each 80mL) is extracted with saturated sodium bicarbonate solution.Merge aqueous phase, slowly adjusted with 10% watery hydrochloric acid pH to 1, the yellow solid Buchner funnel suction filtration of precipitation, a small amount of water washing, then infrared lower drying.1.14g is weighed as, yield is 99.8%.

¹H NMR(400MHz,DMSO-d₆):δ13.11(br s,1H,COOH),11.97(s,1H,NH),8.37 (s,1H, ), ArH 8.24 (d, J=7.68Hz, 1H, ArH), 7.85 (s, 1H, ArH), 7.71 (d, J=8.04Hz, 1H, ArH), 7.51 (t,1H,ArH),7.27(t,1H,ArH),4.89(s,2H,CH ₂COOH).

¹³C NMR(100MHz,DMSO-d₆):δ170.65,150.84,141.93,131.37,129.31,128.24, 128.05,121.82,121.48,120.68,115.95,113.04,108.46,66.35.

Second step intermediate compound I M7 synthesis

By intermediate compound I M6 (167.0mg, 0.58mmol), HOBt (95.7mg, 0.7mmol) and EDCI (129.6 mg, Half an hour first 0.67mmol) is stirred at room temperature in anhydrous acetonitrile (2mL).Acetyl amidoxime (57.3 mg, 0.61mmol) is then added dropwise Acetonitrile solution (1.5mL), then mixture heat 90 degrees celsius flow through night next time.Concentrated solvent, solid silica gel Pillar layer separation (petrol ether/ethyl acetate=3:1) mg of orange solids 101.8 is obtained, yield is 53.8%.

¹H NMR(400MHz,DMSO-d₆):δ 12.04 (s, 1H, NH), 8.49 (d, J=1.68Hz, 1H, ArH), 8.24 (d, J=7.80Hz, 1H, ArH), 8.01 (d, J=1.68Hz, 1H, ArH), 7.72 (d, J=8.16 Hz, 1H, ArH), 7.52 (t,1H,ArH),7.28(t,1H,ArH),5.70(s,2H,OCH₂),2.38(s,3H, CH₃).

¹³C NMR(100MHz,CDCl₃):δ174.09,167.61,150.33,140.60,131.25,130.04, 128.23,128.20,121.76,121.09,120.79,115.47,111.72,108.31,62.55,11.56.

3rd step

Intermediate compound I M7 (153.7mg, 0.474mmol) is dissolved in the mixed liquor (1 of methanol and dichloromethane:1,30 mL), Be slowly added dropwise under nitrogen protective condition with half an hour sodium dithionite (1.03g, 5.688mmol) and potassium carbonate (814.0mg, The aqueous solution (4mL) 5.688mmol).Two hours are stirred at room temperature after completion of dropping, inorganic salts are then filtered out, filtrate concentrates it After be directly used in next step.

Reduzate is dissolved in pyridine (10mL), paratoluensulfonyl chloride (128.8mg, 0.65mmol) is slowly added to.Mixing Thing is stirred overnight at room temperature.Pyridine is evaporated off with membrane pump, crude product separates (petroleum ether/acetone=3 through silica gel column chromatography:1) obtain white Color solid 29.2mg, yield is 13.7%.

¹H NMR(400MHz,DMSO-d₆):δ10.79(s,1H,carbazoleNH),10.02(s,1H, NHSO₂), 8.02 (d, J=7.76Hz, 1H, ArH), 7.67 (d, J=8.12Hz, 2H, ArH), 7.65 (s, 1H, ArH), 7.55 (d, J= 8.24Hz, 1H, ArH), 7.38 (t, 1H, ArH), 7.32 (d, J=7.96Hz, 2H, ArH), 7.13 (t, 1H, ArH), 6.75 (s,1H,ArH),5.42(s,2H,CH₂),2.36(s,3H,oxadiazoleCH ₃), 2.31(s,3H,PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ175.59,167.51,151.20,143.90,140.45,136.99, 130.12,129.67,127.34,126.49,124.27,122.67,122.09,120.78,119.13,112.09,109.21, 102.48,62.19,21.41,11.55.

ESI-MS(C₂₃H₂₀N₄O₄S):m/z 447.1143(M-H⁺)；ESI-HRMS(C₂₃H₂₀N₄O₄S):m/z 447.11215(M-H⁺).

Embodiment 11, N- (4- (N- (3- ((3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) methoxyl group) -9H- carbazole -1- bases) Amino-sulfonyl) phenyl) acetamide (MI-11) synthesis

Intermediate compound I M7 (165.4mg, 0.5mmol) is dissolved in the mixed liquor (1 of methanol and dichloromethane:1,20mL), nitrogen Sodium dithionite (1.06g, 6mmol) and potassium carbonate (828.3 mg, 6mmol) is slowly added dropwise under the conditions of gas shielded with half an hour The aqueous solution (4mL).Two hours, subsequent concentrated solvent, crude product 50mL water and 30mL dichloros are stirred at room temperature after completion of dropping Methane point liquid, aqueous phase is extracted twice with dichloromethane again, each 30mL.Merge and anhydrous sodium sulfate drying is used after organic phase, it is organic Next step is directly used in after mutually concentrating.

Reduzate is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride (199mg, 0.85 mmol) is slowly added to. Mixture is stirred overnight at room temperature.Pyridine is evaporated off with membrane pump, crude product separates (petroleum ether/acetone=3 through silica gel column chromatography:2) To white solid 78.3mg, yield is 31.2%.

¹H NMR(400MHz,DMSO-d₆):δ10.78(s,1H,carbazole NH),10.26(s,1H, NHCOCH₃), 9.97(s,1H,SO₂), NH 8.03 (d, J=7.68Hz, 1H, ArH), 7.73-7.65 (m, 5H, ArH), 7.55 (d, J= 8.04Hz, 1H, ArH), 7.38 (t, J=7.48Hz, 1H, ArH), 7.13 (t, J=7.20Hz, 1H, ArH), 6.77 (s, 1H, ArH),5.44(s,2H,CH₂),2.37(s,3H,oxadiazoleCH₃),2.04(s,3H, NHCOCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ175.60,169.45,167.51,151.21,143.73,140.46, 133.28,129.75,128.57,126.47,124.26,122.68,122.12,120.79,119.11,118.92,112.08, 109.37,102.54,62.23,24.56,11.54.

ESI-HRMS(C₂₄H₂₁N₅O₅S):m/z 490.11906(M-H⁺).

Embodiment 12,4- methyl-N- (3- ((5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) methoxyl group) -9H- carbazole -1- bases) The synthesis of benzsulfamide (MI-12)

First step intermediate compound I M8 synthesis

By IM6 (561.7mg, 1.96mmol), acethydrazide (291.4mg, 4mmol), HOBt (400.6mg, 3mmol) and EDCI (565.4mg, 3mmol) is dissolved in 8mL DMF.Mixture is stirred at room temperature 12 hours, and 40mL water is added dropwise after the completion of reaction and causes Product is separated out.Buchner funnel suction filtration is used, rear infrared drying is washed with a small amount in filter cake.Obtain red solid 502mg, yield 74.7%.It is directly used in next step.

Second step intermediate compound I M9 synthesis

IM8 (173.2mg, 0.5mmol) is dissolved in POCl3 (2mL), reaction is carried out under the conditions of tube sealing, is heated to 100 degrees Celsius are reacted 1 hour.Room temperature is then cooled to, concentrated solvent adds saturated sodium bicarbonate solution and adjusts pH to be alkalescence, with Extracted afterwards with dichloromethane (50mL x 2).Crude product silica gel column chromatography after organic phase anhydrous sodium sulfate drying, concentrated solvent Separate (petrol ether/ethyl acetate=3:1) yellow solid 107.9mg is obtained, yield is 65.8%.

¹H NMR(400MHz,DMSO-d₆):δ 12.02 (s, 1H, NH), 8.47 (s, 1H, ArH), 8.23 (d, J= 7.76Hz, 1H, ArH), 8.02 (s, 1H, ArH), 7.72 (d, J=8.08Hz, 1H, ArH), 7.52 (t, 1H, ArH), 7.28 (t,1H,ArH),5.57(s,2H,CH₂),2.55(s,3H,CH₃).

¹³C NMR(100MHz,DMSO-d₆):δ165.30,162.78,150.18,141.98,131.40,129.69, 128.33,128.19,121.78,121.46,120.80,116.53,113.11,108.95,61.49,10.97.

3rd step

Previous step product IM9 (91.2mg, 0.28mmol) is dissolved in methanol (25mL), add palladium carbon (10%, 32.8mg).Mixture is stirred overnight at room temperature in hydrogenation instrument (40psi).Palladium carbon is filtered out, is directly used in after filtrate concentration next Step.

Reduzate is dissolved in pyridine (5mL), p-methyl benzene sulfonic chloride (79.8mg, 0.39mmol) is added portionwise.Mixing Thing is stirred overnight at room temperature.Solvent pyridine is steamed with membrane pump, crude product separates (petroleum ether/acetone=2 with silica gel column chromatography:1- 1:1) white solid (34.6mg) is obtained, yield is 27.4%.

¹H NMR(400MHz,DMSO-d₆):δ10.77(s,1H,carbazoleNH),10.13(s,1H, NHSO₂), 8.02 (d, J=7.52Hz, 1H, ArH), 7.68 (d, J=7.52Hz, 2H, ArH), 7.62 (s, 1H, ArH), 7.55 (d, J= 7.96Hz, 1H, ArH), 7.37 (t, 1H, ArH), 7.31 (d, J=7.52Hz, 2H, ArH), 7.13 (t, 1H, ArH), 6.77 (s,1H,ArH),5.30(s,2H,CH₂),2.53(s,3H,oxadiazoleCH ₃), 2.30(s,3H,PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ165.13,163.08,151.31,143.56,140.39,137.55, 130.03,129.74,127.30,126.33,124.05,123.12,122.76,120.70,119.02,112.07,108.98, 101.97,61.14,21.38,10.96.

ESI-HRMS(C₂₃H₂₀N₄O₄S):m/z 447.11215(M-H⁺).

Embodiment 13, N- (4- (N- (3- ((5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) methoxyl group) -9H- carbazole -1- bases) Amino-sulfonyl) phenyl) acetamide (MI-13) synthesis

Intermediate compound I M9 (228mg, 0.7mmol) is dissolved in methanol (25mL), palladium carbon (10%, 44.4mg) is added.Mixing Thing is stirred overnight at room temperature in hydrogenation instrument (40psi).Palladium carbon is filtered out, next step is directly used in after filtrate concentration.

Reduzate is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride (273.2mg, 1.17 is added portionwise mmol).Mixture is stirred overnight at room temperature.Solvent pyridine is steamed with membrane pump, crude product separated with silica gel column chromatography (petroleum ether/ Acetone=3:2-1:1) white solid (182mg) is obtained, yield is 52.7%.

¹H NMR(400MHz,DMSO-d₆):δ10.78(s,1H,carbazole NH),10.26(s,1H, NHCOCH₃), 9.97(s,1H,SO₂), NH 8.03 (d, J=7.84Hz, 1H, ArH), 7.73-7.67 (m, 5H, ArH), 7.55 (d, J= 8.20Hz, 1H, ArH), 7.38 (td, 1H, ArH), 7.14 (td, 1H, ArH), 6.75 (d, J=2.32Hz, 1H, ArH), 5.31 (s,2H,CH₂),2.53(s,3H,oxadiazoleCH₃),2.04(s,3H, NHCOCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.46,165.15,163.04,151.21,143.71,140.45, 133.28,129.75,128.58,126.46,124.26,122.69,122.10,120.76,119.12,118.94,112.08, 109.54,102.75,61.21,24.56,10.95.

ESI-HRMS(C₂₄H₂₁N₅O₅S):m/z 492.13362(M+H⁺)530.09093(M+K⁺).

Embodiment 14, N- (3- (N- (3- ((5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) methoxyl group) -9H- carbazole -1- bases) Amino-sulfonyl) phenyl) acetamide (MI-14) synthesis

Intermediate compound I M9 (149.6mg, 0.46mmol) is dissolved in methanol (20mL), palladium carbon (10%, 24.4 mg) is added.It is mixed Compound is stirred overnight at room temperature in hydrogenation instrument (40psi).Palladium carbon is filtered out, next step is directly used in after filtrate concentration.

Reduzate is dissolved in pyridine (5mL), 3- acetamidobenzenesulfonyl chlorides (170mg, 0.73 mmol) are added portionwise. Mixture is stirred overnight at room temperature.Solvent pyridine is steamed with membrane pump, crude product separated with silica gel column chromatography (petroleum ether/acetone= 3:2-1:1) white solid (122.5mg) is obtained, yield is 54.0%.

¹H NMR(400MHz,DMSO-d₆):δ10.80(s,1H,carbazole NH),10.23(s,1H, NHCOCH₃), 10.18(s,1H,SO₂NH), 8.27 (s, 1H, ArH), 8.04 (d, J=7.84Hz, 1H, ArH), 7.70-7.67 (m, 2H, ), ArH 7.56 (d, J=8.16Hz, 1H, ArH), 7.45 (d, J=4.80Hz, 2H, ArH), 7.39 (t, 1H, ArH), 7.14 (t, 1H, ArH), 6.74 (d, J=2.04Hz, 1H, ArH), 5.31 (s, 2H, CH₂), 2.53(s,3H,oxadiazoleCH₃), 2.04(s,3H,NHCOCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.29,165.17,163.02,151.20,140.47,140.36, 140.32,130.10,129.88,126.50,124.30,123.28,122.66,121.82,121.63,120.78,119.13, 117.36,112.09,109.74,102.87,61.15,24.47,10.96.

ESI-HRMS(C₂₄H₂₁N₅O₅S):m/z 490.11906(M-H⁺).

Embodiment 15, N- (4- (N- (6- ((5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) methoxyl group) -2,3,4,9- tetrahydrochysenes - 1H- carbazole -8- bases) amino-sulfonyl) phenyl) and acetamide (MI-15) synthesis

First step intermediate compound I M10 synthesis

To IM2 (1.99g, 6.25mmol) tetrahydrofuran solution (20mL) in be added dropwise lithium hydroxide (570mg, 2 hours are stirred at room temperature after the aqueous solution (20mL) 12.5mmol), completion of dropping.Reaction solution 100mL second after the completion of reaction Acetoacetic ester is diluted, and three times (each 100mL) is extracted with saturated sodium bicarbonate solution.Merge aqueous phase, it is slow with 10% watery hydrochloric acid Adjust pH to 1, the yellow solid Buchner funnel suction filtration of precipitation, a small amount of water washing, then infrared lower drying.It is weighed as 1.527g, yield is 84.1%.

¹H NMR(400MHz,DMSO-d₆):δ 13.05 (s, 1H, COOH), 11.39 (s, 1H, NH), 7.53 (d, J= 2.12Hz, 1H, ArH), 7.47 (d, J=2.04Hz, 1H, ArH), 4.79 (s, 2H, OCH ₂COOH),2.76 (t,2H,1-CH ₂), 2.62(t,2H,4-CH ₂),1.81(m,4H,2,3-CH ₂CH ₂).

Second step intermediate compound I M11 synthesis

By IM10 (1.1623g, 4mmol), acethydrazide (611.8mg, 8mmol), HOBt (822.3mg, 6 mmol) and EDCI (1.15g, 3mmol) is dissolved in 16mL DMF.Mixture is stirred at room temperature 7.5 hours, and 160mL water is added dropwise after the completion of reaction to be made Product is obtained to separate out.Buchner funnel suction filtration is used, rear infrared drying is washed with a small amount in filter cake.Obtain red solid 1.316g, yield 94.9%.It is directly used in next step.

3rd step intermediate compound I M12 synthesis

IM11 (703.2mg, 2mmol) is dissolved in POCl3 (10mL), reaction is carried out under the conditions of tube sealing, is heated to 100 degrees Celsius are reacted 4 hours.Room temperature is then cooled to, concentrated solvent adds 2M sodium hydroxide solutions and adjusts pH to be alkalescence, then Dissolved (150mL) with ethyl acetate.Organic phase is first washed twice with 100mL 0.5M sodium hydroxide solutions, then uses anhydrous slufuric acid Sodium is dried, and crude product separates (petrol ether/ethyl acetate=3 with silica gel column chromatography after concentrated solvent:1) yellow solid is obtained, completely Conversion.

¹H NMR(400MHz,DMSO-d₆):δ 11.44 (s, 1H, NH), 7.67 (d, J=1.88Hz, 1H, ArH), 7.60 (d, J=1.64Hz, 1H, ArH), 5.46 (s, 2H, OCH ₂COOH),2.76(t,2H,1-CH ₂), 2.62(t,2H,4-CH ₂), 2.53(s,3H,CH₃)1.81(m,4H,2,3-CH ₂CH ₂).

¹³C NMR(100MHz,DMSO-d₆):δ165.24,162.91,150.04,140.54,132.63,131.46, 125.17,112.92,110.34,105.19,61.32,23.41,22.98,22.92,20.72,10.95.

4th step

Intermediate compound I M12 (656.4mg, 2mmol) is dissolved in the mixed liquor (1 of methanol and dichloromethane:1,50mL), nitrogen Sodium dithionite (2.165g, 12mmol) and potassium carbonate (1.79 g, 12mmol) is slowly added dropwise under protective condition with half an hour The aqueous solution (7mL).Two hours, subsequent concentrated solvent, crude product 50mL water and 50mL dichloros are stirred at room temperature after completion of dropping Methane point liquid, aqueous phase is extracted twice with dichloromethane again, each 50mL.Merge and anhydrous sodium sulfate drying is used after organic phase, it is organic Next step is directly used in after mutually concentrating.

Reduzate is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride (645mg, 2.76 mmol) is slowly added to. Mixture is stirred overnight at room temperature.Pyridine is evaporated off with membrane pump, crude product separates (petroleum ether/acetone=1 through silica gel column chromatography:1-1: 2) white solid 190mg is obtained, yield is 19.2%.

¹H NMR(400MHz,DMSO-d₆):δ10.29(s,1H,carbazole NH),10.19(s,1H, NHCOCH₃), 9.72(s,1H,SO₂NH), 7.69 (t, 4H, ArH), 6.77 (d, J=1.88Hz, 1H, ArH), 6.49 (d, J=2.00Hz, 1H,ArH),5.19(s,2H,OCH₂),2.66(t,2H,1-CH ₂),2.52(m,5H, 4-CH ₂&oxadiazoleCH ₃),2.05 (s,3H,NHCOCH ₃),1.77(m,4H,2,3-CH ₂CH ₂).

¹³C NMR(100MHz,DMSO-d₆):δ169.46,165.06,163.24,151.23,143.63,136.15, 133.41,128.94,128.51,124.77,121.93,118.92,109.44,103.56,99.04,60.97,24.57, 23.28,23.21,23.16,21.06,10.93.

ESI-HRMS(C₂₄H₂₅N₅O₅S):m/z 494.15036(M-H⁺).

Embodiment 16, ethyl 2- ((1- (4- Methyl benzenesulfonyls amido) -9H- carbazole -3- bases) is thio) acetic acid esters (MI-16) Synthesis

First step intermediate compound I M13 synthesis

The concentrated hydrochloric acid suspension (50mL) of amino metanitrophenol (4.6192g, 30mmol) will be stirred at room temperature half Hour is until black suspension solid gradually becomes white.- 10 degrees Celsius then are cooled to, nitrous is slowly added dropwise into suspension The aqueous solution (3.5mL) of sour sodium (2.4897g, 36mmol) carries out diazo-reaction.Stannous chloride is slowly added dropwise after 1 hour The concentrated hydrochloric acid solution (10mL) of (13.6g, 60mmol).Completion of dropping mixture is stirred half an hour at -10 degrees Celsius, is then risen Continue to stir 3 hours to room temperature.

Said mixture is diluted with 50mL ethanol, cyclohexanone (3.4mL, 33mmol) is then slowly added dropwise, is heated to 90 and takes the photograph The backflow of family name's degree is stayed overnight.Room temperature is cooled to, the black solid of precipitation is washed with a small amount, subsequent infrared drying is weighed as 2.34g, Yield is 38.1%.

¹H NMR(400MHz,DMSO-d₆):δ11.19(s,1H,NH),9.44(s,1H,OH),7.43(s,1H, ArH), 7.22(s,1H,ArH),2.74(t,2H,1-CH₂),2.58(t,2H,4-CH₂),1.80(m,4H,2, 3-CH₂).

¹³C NMR(100MHz,DMSO-d₆):δ149.91,139.70,132.79,131.49,124.07,112.58, 109.62,104.86,23.40,23.07,23.00,20.69.

Second step intermediate compound I M14 synthesis

Intermediate compound I M13 (116.6mg, 0.5mmol) is suspended in 5mL dichloromethane, 2,6- are added dropwise under condition of ice bath Lutidines (192uL, 1.65mmol), then be slowly added dropwise with 5 minutes trifluoromethanesulfanhydride anhydride (138uL, 1.1mmol).Mixed liquor is stirred overnight at room temperature, then uses 20mL dchloromethanes, organic phase is washed with 20mL 2N watery hydrochloric acid Three times, 20mL saturated common salts are washed once, anhydrous sodium sulfate drying.Concentrated solvent obtains yellow solid (conversion completely).

¹H NMR(400MHz,DMSO-d₆):δ11.93(s,1H,NH),7.98(s,2H,ArH),2.80(t,2H, 1- CH₂),2.66(t,2H,4-CH₂),1.82(m,4H,2,3-CH₂).

¹³C NMR(100MHz,DMSO-d₆):δ142.41,140.63,132.47,131.23,127.63,118.78 (q, ), J=320Hz 118.10,111.63,110.00,23.42,22.77,22.71,20.55.

3rd step intermediate compound I M15 synthesis

By intermediate compound I M14 (0.5mmol) obtained by previous step and DDQ heated overnight at reflux in 5mL toluene, then cooling To room temperature.Reaction solution is diluted with 50mL ethyl acetate, and 5 times are washed with 50mL saturated sodium bicarbonate solutions until aqueous phase is colourless, is had Machine mutually uses anhydrous sodium sulfate drying.Concentrated solvent, gained crude product separates (dichloromethane/petroleum ether=1 through silica gel column chromatography: 3) yellow solid 126.5mg, is obtained, yield is 77.5%.

¹H NMR(400MHz,DMSO-d₆):δ12.46(s,1H,NH),8.89(s,1H,ArH),8.37(s,2H, ArH), 7.78(d,1H,ArH),7.59(t,1H,ArH),7.35(t,1H,ArH).

¹³C NMR(100MHz,DMSO-d₆):δ142.16,140.37,132.47,131.24,129.04,128.47, (121.93,121.65,121.57,121.45,118.81 q, J=320Hz), 114.87,113.47.

19F NMR(376MHz,DMSO-d6):δ-72.41.

4th step intermediate compound I M16 synthesis

Under conditions of argon gas protection by Pd2 (dba) 3 (2311.4mg, 0.25mmol) and Xantphos (292.4mg, 0.5mmol) it is pre-mixed 1 hour in anhydrous dioxane.Intermediate compound I M15 (360mg, 1mmol) is added then to reaction tube, Argon gas is irrigated after vacuumizing again, in triplicate.Then DIPEA (0.35mL) and ethyl thioglycolate are added with syringe (0.11mL), is heated to 100 degrees Celsius and reacts 20 hours.Reaction uses 50mL ethyl acetate dilute reaction solutions after terminating, and filters out and urges After agent three times, anhydrous sodium sulfate drying are washed with 50mL 2N watery hydrochloric acid.After concentrated solvent (acetic acid is separated with silica gel column chromatography Ethyl ester/petroleum ether=1:20-1:10) yellow solid 250.0mg, is obtained, yield is 75.6%.

¹H NMR(400MHz,DMSO-d₆):δ12.25(s,1H,carbazoleNH),8.76(s,1H,ArH), 8.35 (s, 1H, ArH), 8.27 (d, J=7.76Hz, 1H, ArH), 7.75 (d, J=8.12Hz, 1H, ArH), 7.54 (t, 1H, ArH), 7.32 (t, 1H, ArH), 4.07 (q, J=7.12Hz, 2H, CH ₂CH₃),3.93(s,2H,SCH ₂), 1.10 (t, J=7.08Hz, 3H,CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.75,141.58,132.83,131.95,131.59,128.42, 128.30,124.83,123.72,121.48,121.42,113.22,61.35,37.72,14.38.

5th step

Intermediate compound I M16 (250mg, 0.75mmol) is dissolved in the mixed liquor (1 of methanol and dichloromethane:1,50 mL), nitrogen Be slowly added dropwise under the conditions of gas shielded with half an hour sodium dithionite (816.4mg, 4.64mmol) and potassium carbonate (650.6mg, The aqueous solution (7mL) 4.67mmol).Two hours, subsequent concentrated solvent, crude product 50mL water are stirred at room temperature after completion of dropping With 50mL dichloromethane point liquid, aqueous phase is extracted twice with dichloromethane again, each 50mL.Anhydrous slufuric acid is used after merging organic phase Sodium is dried, and next step is directly used in after organic phase concentration.

Reduzate is dissolved in pyridine (5mL), p-methyl benzene sulfonic chloride (239.1mg, 1.25mmol) is slowly added to.It is mixed Compound is stirred overnight at room temperature.Pyridine is evaporated off with membrane pump, crude product separates (petroleum ether/acetone=3 through silica gel column chromatography:1) obtain White solid 219.8mg, yield is 63.9%.

¹H NMR(400MHz,DMSO-d₆):δ11.10(s,1H,carbazoleNH),9.94(s,1H,SO₂NH), 8.09 (d, J=8.20Hz, 1H, ArH), 8.07 (s, 1H, ArH), 7.64 (d, J=7.96Hz, 2H, ArH), 7.59 (d, J= 8.12Hz, 1H, ArH), 7.42 (t, 1H, ArH), 7.33 (d, J=7.84Hz, 2H, ArH), 7.18 (t, 1H, ArH), 7.00 (s, 1H, ArH), 4.03 (q, J=7.08Hz, 2H, CH ₂CH₃),3.58(s,2H,SCH₂),2.33(s, 3H,PhCH ₃),1.09 (t, J=7.12Hz, 3H, CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.69,143.84,140.31,136.85,134.70,130.03, 127.45,126.81,124.97,124.29,123.03,122.52,122.18,121.76,120.87,119.78,112.17, 61.15,38.56,21.40,14.40.

ESI-HRMS(C₂₃H₂₂N₂O₄S₂):m/z 453.09482(M-H⁺).

Embodiment 17, ethyl 2- ((1- (4- P-acetamido benzene sulfonyls amido) -9H- carbazole -3- bases) is thio) acetic acid esters (MI-17) synthesis

Reduzate is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride (301.2mg, 1.275 is slowly added to mmol).Mixture is stirred overnight at room temperature.Be evaporated off pyridine with membrane pump, crude product separate through silica gel column chromatography (petroleum ether/acetone= 2:1-3:2) white solid 186mg is obtained, yield is 49.4%.

¹H NMR(400MHz,DMSO-d₆):δ11.09(s,1H,carbazoleNH),10.26(s,1H, NHCOCH₃), 9.89(s,1H,SO₂), NH 8.09 (d, J=8.08Hz, 1H, ArH), 8.07 (s, 1H, ArH), 7.69 (t, 4H, ArH), 7.59 (d, J=8.08Hz, 1H, ArH), 7.42 (t, 1H, ArH), 7.18 (t, 1H, ArH), 7.03 (s, 1H, ArH), 4.02 (q, J= 7.04Hz,2H,CH ₂CH₃),3.59(s,2H,SCH₂),2.05(s,3H, NHCOCH ₃), 1.07 (t, J=7.04Hz, CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.72,169.43,143.73,140.30,134.75,133.16, 128.63,126.80,124.96,124.43,122.98,122.57,122.19,121.80,120.86,119.77,118.86, 112.16,61.13,38.58,24.57,14.39.

ESI-HRMS(C₂₄H₂₃N₃O₅S₂):m/z 496.10064(M-H⁺).

The synthesis of embodiment 18,2- ((1- (4- Methyl benzenesulfonyls amido) -9H- carbazole -3- bases) is thio) acetic acid (MI-18)

The aqueous solution of 1N sodium hydroxides is added dropwise into MI-16 (89.5mg, 0.2mmol) tetrahydrofuran solution (1mL) 0.5 hour is stirred at room temperature after (1mL), completion of dropping.Reaction solution is diluted with 20mL ethyl acetate after the completion of reaction, uses saturation Sodium bicarbonate solution extracts three times (each 20mL).Merge aqueous phase, slowly adjust pH to 1 with 10% watery hydrochloric acid, precipitation it is white Color solid Buchner funnel suction filtration, a small amount of water washing, then infrared lower drying.74.2mg is weighed as, yield is 88.4%.

¹H NMR(400MHz,DMSO-d₆):δ12.51(s,1H,COOH),11.10(s,1H, carbazoleNH), 10.03(s,1H,SO₂NH), 8.08 (d, J=7.96Hz, 1H, ArH), 8.05 (s, 1H, ArH), 7.65 (d, J=7.96Hz, 2H, ArH), 7.58 (d, J=7.96Hz, 1H, ArH), 7.41 (t, 1H, ArH), 7.32 (d, J=7.96Hz, 2H, ArH), 7.18(t,1H,ArH),7.01(s,1H,ArH),3.55(s,2H,SCH₂),2.32(s, 3H,PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ171.06,143.85,140.29,136.82,134.46,130.04, 127.47,126.76,124.96,123.80,123.75,122.18,121.79,121.72,120.87,119.70,112.14, 38.85,21.42.

ESI-HRMS(C₂₁H₁₈N₂O₄S₂):m/z 425.06352(M-H⁺).

Embodiment 19,2- ((1- (4- P-acetamido benzene sulfonyls amido) -9H- carbazole -3- bases) is thio) acetic acid (MI-19) Synthesis

The aqueous solution of 1N sodium hydroxides is added dropwise into MI-17 (84.7mg, 0.15mmol) tetrahydrofuran solution (1mL) 0.5 hour is stirred at room temperature after (1mL), completion of dropping.Reaction solution is diluted with 20mL ethyl acetate after the completion of reaction, uses saturation Sodium bicarbonate solution extracts three times (each 20mL).Merge aqueous phase, slowly adjust pH to 1 with 10% watery hydrochloric acid, precipitation it is white Color solid Buchner funnel suction filtration, a small amount of water washing, then infrared lower drying.65.8mg is weighed as, yield is 82.3%.

¹H NMR(400MHz,DMSO-d₆):δ12.23(br s,1H,COOH),11.09(s,1H, carbazoleNH), 10.26(s,1H,NHCOCH₃),9.97(br s,1H,SO₂), NH 8.08 (d, J=8.00Hz, 1H, ArH), 8.05 (s, 1H, ), ArH 7.69 (s, 4H, ArH), 7.58 (d, J=7.92Hz, 1H, ArH), 7.41 (t, 1H, ArH), 7.17 (t, 1H, ArH), 7.03(s,1H,ArH),3.56(s,2H,ArH),2.05(s,3H,ArH).

¹³C NMR(100MHz,DMSO-d₆):δ171.11,169.45,143.70,140.28,134.47,133.20, 128.66,126.74,124.95,123.84,123.80,122.18,121.83,121.66,120.87,119.69,118.90, 112.13,38.92,24.57.

ESI-HRMS(C₂₂H₁₉N₃O₅S₂):m/z 468.06934(M-H⁺).

Embodiment 20, ethyl 2- ((1- (4- Methyl benzenesulfonyls amido) -9H- carbazole -3- bases) sulfonyl) acetic acid esters (MI- 20) synthesis

MI-16 (100.3mg, 0.22mmol) is dissolved in 4mL acetone, be then added dropwise 4mL oxone (700.4 mg, Aqueous solution 1.1mmol).Mixed liquor is stirred overnight at room temperature, and is then diluted with 4mL water, filters to obtain white solid, washes, and dries It is dry.Solid purifies (petroleum ether/acetone=3 with silica gel column chromatography:1) mg of white solid 52.7 is obtained, yield is 49.3%.

¹H NMR(400MHz,DMSO-d₆):δ11.66(s,1H,carbazole NH),10.17(s,1H, SO₂NH), 8.55 (d, J=1.52Hz, 1H, ArH), 8.26 (d, J=7.84Hz, 1H, ArH), 7.68 (d, J=8.20Hz, 1H, ArH), 7.64 (d, J=8.28Hz, 2H, ArH), 7.52 (td, 1H, ArH), 7.37 (d, J=1.64 Hz, 1H, ArH), 7.34 (d, J= 8.00Hz,2H,ArH),7.29(td,1H,ArH),4.35(s,2H,SO₂CH₂), 3.98 (q, J=7.12Hz, 2H, CH ₂CH₃), 2.32(s,3H,PhCH ₃), 0.97 (t, J=7.12Hz, 3H, CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ162.96,144.09,140.79,137.98,136.45,130.10, 129.07,127.73,127.52,124.15,122.53,121.60,121.37,120.81,119.85,119.39,112.67, 61.85,61.32,21.40,14.09.

ESI-HRMS(C₂₃H₂₂N₂O₆S₂):m/z 485.08465(M-H⁺).

The conjunction of embodiment 21,2- ((1- (4- Methyl benzenesulfonyls amido) -9H- carbazole -3- bases) sulfonyl) acetic acid (MI-21) Into

The water-soluble of 1N sodium hydroxides is added dropwise into MI-20 (114.5mg, 0.235mmol) tetrahydrofuran solution (1mL) 0.5 hour is stirred at room temperature after liquid (1mL), completion of dropping.Reaction solution is diluted with 20mL ethyl acetate after the completion of reaction, with full Three times (each 20mL) is extracted with sodium bicarbonate solution.Merge aqueous phase, pH to 1 is slowly adjusted with 10% watery hydrochloric acid, precipitation White solid Buchner funnel suction filtration, a small amount of water washing, then infrared lower drying.94.6mg is weighed as, yield is 87.7%.

¹H NMR(400MHz,DMSO-d₆):δ11.78(s,1H,carbazole NH),10.37(s,1H, SO₂NH), 8.54 (s, 1H, ArH), 8.22 (d, J=7.80Hz, 1H, ArH), 7.65-7.63 (m, 3H, ArH), 7.48 (t, 1H, ArH), 7.43 (d, J=1.64Hz, 1H, ArH), 7.30-7.24 (m, 3H, ArH), 4.19 (s, 2H, SO₂CH₂),2.29(s,3H, PhCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ164.58,143.97,140.78,137.81,136.56,130.04, 129.82,127.58,127.52,123.99,122.56,121.66,121.29,120.64,119.57,119.40,112.60, 62.00,21.39.

ESI-HRMS(C₂₁H₁₈N₂O₆S₂):m/z 457.05335(M-H⁺).

Embodiment 22, ethyl 2- ((1- (4- P-acetamido benzene sulfonyls amido) -9H- carbazole -3- bases) sulfonyl) acetic acid esters (MI-22) synthesis

MI-17 (90mg, 0.18mmol) is dissolved in 4mL acetone, 4mL oxone (558.8mg, 0.9mmol) are then added dropwise The aqueous solution.Mixed liquor is stirred overnight at room temperature, and is then diluted with 4mL water, filters to obtain white solid, washes, drying.Solid is used Silica gel column chromatography purifies (dichloromethane/acetone=5:1-3:1) white solid 43.3mg is obtained, yield is 45.2%.

¹H NMR(400MHz,DMSO-d₆):δ11.67(s,1H,carbazole NH),10.30(s,1H, NHCOCH₃), 10.14(s,1H,SO₂NH), 8.56 (s, 1H, ArH), 8.27 (d, J=7.80Hz, 1H, ArH), 7.72-7.67 (m, 5H, ), ArH 7.52 (t, J=7.72Hz, ArH), 7.38 (s, 1H, ArH), 7.28 (t, J=7.36 Hz, ArH), 4.38 (s, 2H, SO₂CH ₂), 3.97 (q, J=7.12Hz, 2H, CH ₂CH₃),2.05(s,3H, NHCOCH ₃), 0.96 (t, J=7.08Hz, 3H, CH₂CH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.47,162.97,143.88,140.79,138.07,132.66, 129.01,128.74,127.72,124.13,122.52,121.61,121.37,120.79,119.89,119.56,118.88, 112.67,61.84,61.34,24.57,14.07.

ESI-HRMS(C₂₄H₂₃N₃O₇S₂):m/z 528.09047(M-H⁺).

Embodiment 23, N- (4- (N- (3- (((3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) methyl) is thio) -9H- carbazoles -1- Base) amino-sulfonyl) phenyl) and acetamide (MI-23) synthesis

First step intermediate compound I M18 synthesis

Lithium hydroxide (180.2mg, 4mmol) is added dropwise into IM17 (645mg, 2mmol) tetrahydrofuran solution (6mL) The aqueous solution (6mL), 1 hour is stirred at room temperature after completion of dropping.Reaction solution is diluted with 50mL ethyl acetate after the completion of reaction, Three times (each 40mL) is extracted with saturated sodium bicarbonate solution.Merge aqueous phase, pH to 1 is slowly adjusted with 10% watery hydrochloric acid, analyse The yellow solid gone out Buchner funnel suction filtration, a small amount of water washing, then infrared lower drying.580.4mg is weighed as, yield is 98.3%.

¹H NMR(400MHz,DMSO-d₆):δ 12.81 (br s, 1H, COOH), 12.21 (s, 1H, NH), 8.73 (d, J= 1.32Hz, 1H, ArH), 8.33 (d, J=1.64Hz, 1H, ArH), 8.25 (d, J=7.80Hz, 1H, ArH), 7.74 (d, J= 8.12Hz,1H,ArH),7.53(td,1H,ArH),7.30(td,1H,ArH),3.88(s,2H, CH₂).

¹³C NMR(100MHz,DMSO-d₆):δ171.10,141.56,132.65,131.97,130.91,128.39, 128.24,124.50,124.16,121.46,121.41,121.33,113.18,38.03.

Second step intermediate compound I M19 synthesis

By intermediate compound I M18 (530.2mg, 1.75mmol), HOBt (367.4mg, 2.63mmol) and EDCI (527.8mg, Half an hour first 2.63mmol) is stirred at room temperature in anhydrous acetonitrile (6mL).Acetyl amidoxime (259.3mg, 3.5mmol) is then added dropwise Acetonitrile solution (4mL), then mixture heat 90 degrees celsius flow through night next time.Concentrated solvent, solid silicagel column Chromatographic isolation (petrol ether/ethyl acetate=3:1) orange solids 455.1mg is obtained, yield is 76.2%.

¹H NMR(400MHz,DMSO-d₆):δ12.28(s,1H,carbazole NH),8.74(s,1H,ArH), 8.30 (s, 1H, ArH), 8.25 (d, J=7.64Hz, 1H, ArH), 7.75 (d, J=8.00Hz, 1H, ArH), 7.54 (t, J= 7.24Hz, 1H, ArH), 7.32 (t, J=7.32Hz, 1H, ArH), 4.60 (s, 2H, SCH₂),2.25(s,3H, oxadiazoleCH₃).

¹³C NMR(100MHz,DMSO-d₆):δ176.95,167.54,141.55,133.05,132.27,131.93, 128.48,128.36,125.65,122.24,121.50,121.47,121.42,113.25,30.01,11.50.

3rd step

Intermediate compound I M19 (340.36mg, 1mmol) is dissolved in the mixed liquor (1 of methanol and dichloromethane:1,50 mL), nitrogen Be slowly added dropwise under the conditions of gas shielded with half an hour sodium dithionite (1.08g, 6.18mmol) and potassium carbonate (868mg, The aqueous solution (8mL) 6.23mmol).Two hours, subsequent concentrated solvent, crude product 50mL water are stirred at room temperature after completion of dropping With 50mL dichloromethane point liquid, aqueous phase is extracted twice with dichloromethane again, each 50mL.Anhydrous slufuric acid is used after merging organic phase Sodium is dried, and next step is directly used in after organic phase concentration.

Reduzate is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride (397mg, 1.7 mmol) is slowly added to.It is mixed Compound is stirred overnight at room temperature.Pyridine is evaporated off with membrane pump, crude product separates (petroleum ether/acetone=3 through silica gel column chromatography:2-1:1) White solid 174.4mg is obtained, yield is 34.4%.

¹H NMR(400MHz,DMSO-d₆):δ11.14(s,1H,carbazole NH),10.25(s,1H, NHCOCH₃), 9.89(s,1H,SO₂), NH 8.08 (d, J=7.88Hz, 1H, ArH), 8.07 (d, J=1.44Hz, 1H, ArH), 7.70-7.65 (m, 4H, ArH), 7.59 (d, J=8.16Hz, 1H, ArH), 7.42 (td, 1H, ArH), 7.19 (td, 1H, ArH), 7.02 (d, J =1.60Hz, 1H, ArH), 4.27 (s, 2H, SCH₂),2.27(s,3H, oxadiazoleCH₃),2.04(s,3H,NHCOCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ177.03,169.43,167.47,143.73,140.30,135.08, 133.08,128.64,126.91,125.02,123.32,122.17,121.87,121.76,120.92,119.87,118.85, 112.19,30.94,24.56,11.55.

ESI-HRMS(C₂₄H₂₁N₅O₄S₂):m/z 506.09622(M-H⁺).

Embodiment 24, N- (4- (N- (3- (((3- methyl isophthalic acids, 2,4- oxadiazole -5- bases) methyl) sulfonyl) -9H- carbazoles - 1- yls) amino-sulfonyl) phenyl) and acetamide (MI-24) synthesis

MI-23 (82.8mg, 0.16mmol) is dissolved in 4mL acetone, be then added dropwise 4mL oxone (985.6mg, Aqueous solution 1.6mmol).Mixed liquor is stirred overnight at room temperature, and is then diluted with 8mL water, filters to obtain white solid, washes, and dries It is dry.Solid purifies (petroleum ether/acetone=3 with silica gel column chromatography:1-1:1) white solid 43.3mg is obtained, yield is 50.2%.

¹H NMR(400MHz,DMSO-d₆):δ11.67(s,1H,carbazole NH),10.28(s,1H, NHCOCH₃), 10.11(s,1H,SO₂NH), 8.53 (s, 1H, ArH), 8.26 (d, J=7.72Hz, 1H, ArH), 7.70-7.65 (m, 5H, ArH),7.53(t,1H,ArH),7.33(s,1H,ArH),7.29(t,1H,ArH),5.15(s, 2H,SO₂CH ₂),2.29(s, 3H,oxadiazoleCH₃),2.03(s,3H,NHCOCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.62,169.47,167.94,143.90,140.80,138.23, 132.68,128.70,128.14,127.84,124.30,122.50,121.72,121.41,120.90,119.94,119.52, 118.87,112.70,53.63,24.56,11.50.

ESI-HRMS(C₂₄H₂₁N₅O₆S₂):m/z 538.08605(M-H⁺).

Embodiment 25, N- (4- (N- (3- (((5- methyl isophthalic acids, 3,4- oxadiazole -2- bases) methyl) is thio) -9H- carbazoles -1- Base) amino-sulfonyl) phenyl) and acetamide (MI-25) synthesis

First step intermediate compound I M20 synthesis

IM18 (305.4mg, 1mmol) and acethydrazide (125.9mg, 1.5mmol) are dissolved in POCl3 (8 mL).Mixing Liquid reacts under 100 degrees celsius to be stayed overnight.Concentrated solvent, crude product is through the isolated yellow solid of silica gel column chromatography 168.2mg, yield is 48.9%.

¹H NMR(400MHz,DMSO-d₆):δ12.29(s,1H,carbazole NH),8.74(s,1H,ArH), 8.30 (s, 1H, ArH), 8.26 (d, J=7.80Hz, 1H, ArH), 7.75 (d, J=7.80Hz, 1H, ArH), 7.54 (t, J= 7.80Hz, 1H, ArH), 7.32 (t, J=7.80Hz, 1H, ArH), 4.53 (s, 2H, SCH₂),2.44(s,3H, oxadiazoleCH₃).

¹³C NMR(100MHz,DMSO-d₆):δ164.70,164.13,141.54,133.05,132.54,131.92, 128.47,128.35,125.82,122.21,121.49,121.45,113.25,29.32,10.88.

Second step

Intermediate compound I M20 (173.4mg, 0.5mmol) is dissolved in the mixed liquor (1 of methanol and dichloromethane:1,28 mL), nitrogen Be slowly added dropwise under the conditions of gas shielded with half an hour sodium dithionite (544mg, 3.1mmol) and potassium carbonate (432.3mg, The aqueous solution (3mL) 3.1mmol).Be stirred at room temperature two hours after completion of dropping, subsequent concentrated solvent, crude product with 30mL water and 30mL dichloromethane point liquid, aqueous phase is extracted twice with dichloromethane again, each 30mL.Anhydrous sodium sulfate is used after merging organic phase Dry, next step is directly used in after organic phase concentration.

Reduzate is dissolved in pyridine (5mL), N-acetylsulfanilyl chloride (206.4mg, 0.85 is slowly added to mmol).Mixture is stirred overnight at room temperature.Be evaporated off pyridine with membrane pump, crude product separate through silica gel column chromatography (petroleum ether/acetone= 3:2-1:1) white solid 94.6mg is obtained, yield is 36.6%.

¹H NMR(400MHz,DMSO-d₆):δ11.14(s,1H,carbazole NH),10.27(s,1H, NHCOCH₃), 9.89(s,1H,SO₂), NH 8.08 (d, J=7.80Hz, 1H, ArH), 8.04 (d, J=1.00Hz, 1H, ArH), 7.67 (q, J =6.64Hz, 4H, ArH), 7.58 (d, J=8.12Hz, 1H, ArH), 7.42 (t, J=7.48Hz, 1H, ArH), 7.18 (t, J =7.40Hz, 1H, ArH), 6.99 (d, J=1.32Hz, 1H, ArH), 4.19 (s, 2H, SCH₂),2.43(s,3H, oxadiazoleCH₃),2.03(s,3H,NHCOCH ₃).

¹³C NMR(100MHz,DMSO-d₆):δ169.44,164.55,164.21,143.70,140.28,135.10, 133.06,128.68,126.88,125.40,125.01,123.69,122.18,121.81,121.58,120.93,119.85, 118.85,112.18,30.27,24.56,10.88.

ESI-HRMS(C₂₄H₂₁N₅O₄S₂):m/z 506.09622(M-H⁺).

The inhibitory action of embodiment 26, compound to disactivation MEK1

HTRF (homogeneous time-resolved fluorescence are used in inhibitory activity test experiments Assay) technology combines two kinds of technologies of FRET (FRET) and time-resolved fluorescence (TRF).The technology is Make use of the Eu elements with cave-shaped structure chela and label as a donor (Donor), be based on Eu cryptates Donor and acceptor (the second fluorescent marker) between FRET (FRET).In FRET In experiment, the life-span of acceptor emission fluorescence is equal to the life-span of the transmitting fluorescence of donor.Because the Eu fluorescence decay cycle compared with Long, so the meeting inducing receptor of the donor containing Eu launches fluorescence for a long time, the fluorescence that acceptor is produced after exciting just can continue longer Time, such passage time, which differentiates, can just distinguish the fluorescence of those itself short-life scatterings, so be carried on the back from short life fluorescence FRET signals are just easily discriminated out in scape.

When due to bio-molecular interaction causes two fluorophors close when, caught when exciting by cryptate The portion of energy release obtained, launch wavelength is 615nm；Another part energy transfer is on acceptor (acceptor), launch wavelength For 665nm.Only the FRET as caused by donor (donor) is produced 665nm transmitting light.So, work as bio-molecular interaction When, there are two exciting lights 615nm and 665nm；When in the absence of interaction, only mono- exciting light of 615nm.Experimental principle As shown in Figure 1.

If compound has inhibitory action to npMEK1, npMEK1 phosphorylation can be suppressed, combined accordingly with MEK1 Anti- phosphorus antibody reduce, therefore the MAb Anti GST-XL665 excited signal also can reduce accordingly.By detecting 668nm Signal and 620nm signal ratio, evaluate compound to npMEK1 inhibitory action.

Concrete operation step is divided into two steps, is kinase reaction step and detection reactions steps, kinase reaction step respectively The step of being BRAF phosphorylation MEK1, add by kinase reaction buffer solution 50mM pH=7.0HEPES buffer, 10mM The compound of MgCl2,1mM DTT, 0.5mM Orthovanadate, 0.01%BSA dilution, 0.48ng/uL active BRAF (09-122) (Carna), 40nM inactive MEK1GST tagged- (07-141-10) (Carna), 100 μM ATP, is reacted at room temperature 2 hours；Second step is detection reactions steps, adds cisbio company antibody MAb Anti-phospho MEK1/2-K (61P17KAE) and MAb Anti GST-XL665 (61GSTXLA), reaction uses ELIASA after 3 hours FlexStation 3 (Molecular Devices) detects signal, and inhibiting rate computational methods are as follows：

Data are handled using mapping software GraphPad Prism 6.Experiment is repeated 3 times.Part of compounds is lived Property result is as shown in the table.

The inhibitory activity of table 1, the compounds of this invention to disactivation MEK1

The preferred embodiments of the present invention are the foregoing is only, are merely illustrative for the purpose of the present invention, and it is non-limiting 's；Those of ordinary skill in the art understand, many can be carried out to it in the spirit and scope that the claims in the present invention are limited Change, modification, or even equivalent change, but fall within protection scope of the present invention.

Claims

1. compound and its pharmaceutically acceptable salt with MEK1 inhibitory activity, it is characterised in that the structure of the compound Shown in formula I：

Wherein, A rings are phenyl or cyclohexene；

R is hydrogen atom；

R₁For hydrogen or halogen；

R₂For p-methylphenyl, acetparaminosalol phenyl or m-acetamino phenyl；

R₃For hydrogen or hydroxyl；

X is oxygen, sulphur or SO₂；

N is 1；

R₄For carboxyl ,-COOR₇,-CONH₂, 1,2,4- oxadiazole, 1,3,4- oxadiazole, tetrazole or 5- amino -1,3,4- Evil bis- Azoles；

R₇Selected from C_1-3Alkyl.

2. compound as claimed in claim 1 and its pharmaceutically acceptable salt, it is characterised in that described halogen be fluorine, Chlorine, bromine or iodine.

3. the method for the compound and its pharmaceutically acceptable salt described in preparation claim 1, it is characterised in that described Formulas I A rings are phenyl, R in structure₃For the preparation method of the compound of hydroxyl, comprise the following steps：

1) diazo-reaction generation diazol occurs under the conditions of natrium nitrosum and concentrated hydrochloric acid for substituted aniline, then in stannous chloride Under the conditions of be reduced to the compound of Formula II structure；

2) in trifluoroacetic acid as the condition of solvent with hydroresorcinol Fischer indoles cyclizations occur for Formula II structural compounds Reaction, obtains the compound of formula III structure；

3) chlorination occurs under conditions of copper chloride and lithium chloride for the compound of formula III structure, then in lithium chloride and carbon The compound that elimination reaction obtains formula IV structure occurs under conditions of sour lithium；

4) chemical combination that chlorination obtains Formula V structure occurs under conditions of N- chlorosuccinimides for the compound of formula IV structure Thing；

6) compound and sulfonamide of Formula IV structure are generated under conditions of titanium tetrachloride and triethylamine using microwave heating response The compound of Formula VII structure；

7) compound of Formula VII structure then obtains A rings in Formulas I structure with nucleopilic reagent generation substitution reaction with sodium hydrosulfite reduction For phenyl ring, R₃For the compound of hydroxyl；

Wherein, R is hydrogen atom；

R₁For hydrogen or halogen；

R₂For p-methylphenyl, acetparaminosalol phenyl or m-acetamino phenyl；

X is oxygen or sulphur；

N is 1；

R₇Selected from C_1-3Alkyl.

4. the method for the compound and its pharmaceutically acceptable salt described in preparation claim 1, it is characterised in that described Formulas I R in structure₁, R₃For hydrogen atom, X is the preparation method of the compound of oxygen atom, is comprised the following steps：

1) amino metanitrophenol occurs under the conditions of potassium carbonate the compound that alkylated reaction obtains Formula VIII structure；

2) compound of Formula VIII structure obtains corresponding hydrazinobenzene hydrochloride salt after diazotising reduction reaction, then and cyclohexanone Occurs the compound that Fischer indoles ring closure reactions obtain Formula IX structure；

3) compound that aromatization obtains Formula X structure occurs under conditions of DDQ for the compound of Formula IX structure, saves this step Rapid then A rings are cyclohexene ring；

4) compound of Formula X structure obtains corresponding amino-compound through catalytic hydrogenation, with obtaining Formulas I structure after sulfonic acid chloride reaction Middle R₃For hydrogen atom, X is the compound of oxygen atom；

Wherein, A rings are phenyl or cyclohexene；

R is hydrogen atom；

R₂For p-methylphenyl, acetparaminosalol phenyl or m-acetamino phenyl；

X is oxygen；

N is 1；

R₇Selected from C_1-3Alkyl.

5. the method for the compound and its pharmaceutically acceptable salt described in preparation claim 1, it is characterised in that described Formulas I R in structure₁, R₃For hydrogen atom, X is the preparation method of the compound of sulphur atom or sulfone, is comprised the following steps：

1) corresponding hydrazinobenzene hydrochloride salt is obtained after diazotising reduction reaction to amino metanitrophenol, then sent out with cyclohexanone Raw Fischer indoles ring closure reactions obtain the compound of Formula X I structures；

3) compound that aromatization obtains Formula X III structures occurs under conditions of DDQ for the compound of Formula X II structures, saves Then A rings are cyclohexene ring to this step；

4) compound of Formula X III structures is in Pd₂(dba)₃Coupling reaction occurs under catalysis with XantPhos systems and obtains Formula X IV The compound of structure；

5) nitro is reduced to amino by the compound of Formula X IV structures using sodium hydrosulfite, is then passed through acylation reaction and is obtained Formula X V knots R in the compound of structure, as Formulas I structure₃For hydrogen atom, X is the compound of sulphur atom；

If 6) X is sulfone, the oxidized reaction of compound of Formula X V structure can obtain R in Formulas I structure₃For hydrogen atom, X is the chemical combination of sulfone Thing；

Wherein, A rings are phenyl or cyclohexene；

R is hydrogen atom；

R₂For p-methylphenyl, acetparaminosalol phenyl or m-acetamino phenyl；

N is 1；

R₇Selected from C_1-3Alkyl.

6. the application of compound and its pharmaceutically acceptable salt in mek inhibitor is prepared described in claim 1 or 2.