CN101475571B - Beta-carbolines cell cycle protein related kinase 2 inhibitor and use thereof - Google Patents

Beta-carbolines cell cycle protein related kinase 2 inhibitor and use thereof Download PDF

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CN101475571B
CN101475571B CN2009100283014A CN200910028301A CN101475571B CN 101475571 B CN101475571 B CN 101475571B CN 2009100283014 A CN2009100283014 A CN 2009100283014A CN 200910028301 A CN200910028301 A CN 200910028301A CN 101475571 B CN101475571 B CN 101475571B
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lin
carbamyl
amino
sulfonyl
methoxyl group
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CN101475571A (en
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陆涛
林国武
陈亚东
王越
张陆勇
孙倪悦
郝兰虎
朱雍
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention relates to the field of pharmacochemistry, in particular to beta-carboline alkaloids (I), and methods for preparing the same, pharmaceutical compositions containing the same and the pharmaceutical uses of the same, especially the use of the compounds as cyclin-dependent kinase 2 inhibitors.

Description

Beta-carbolines cell cycle protein related kinase 2 enzyme 2 inhibitor and uses thereof
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to β-Ka Lin analog derivative, their preparation method, the medicinal compositions that contains these compounds and their medical use, particularly as the purposes of cell cycle protein dependent kinase 2 inhibitor.
Background technology
Cell cycle is the primary process of cell activities, under the normal circumstances, enters physiological statuss such as propagation, differentiation, aging and death in the transition of cell phase when the cycle.If cell cycle regulating is unusual, cell will enter pathological state, as cell transformation, canceration.At present, in the human cell, found 13 kinds of cell cycle protein dependent kinases (CDKs), when they are distributed in each of cell cycle mutually in, combine back performance regulating effect with cyclin (cyclin).Find that in the research of cell cycle the cell cycle is regulated by multiple regulatory factor, be divided into positive (pungency) conditioning agent and negative (inhibition) conditioning agent according to the effect difference.The pungency conditioning agent comprises cyclin (cyclins) and cell cycle protein dependent kinase (CDKs), and the agent of SC periodic adjustment is cell cycle protein dependent kinase inhibitor (CKIs).Wherein CDKs is the key link of cell cycle regulating, and cyclins and CKIs regulate the process of cell cycle in conjunction with CDKs by competitiveness.The generation development of its excessive activation or expression and tumour has confidential relation, suppresses the activity of CDKs, can suppress growth of tumor.
Generally believe that CDK2, CDK4 among the CDKs and CDK6 and tumour have substantial connection, often have overexpression, as mammary cancer, the esophageal carcinoma and primary hepatocarcinoma etc. in tumour cell.Though CDKs all in whole cell cycle progression have irreplaceable effect, but because CDK2 crosses G1/S phase checkpoint the cell cycle, it is the crucial regulatory factor that starts S phase dna replication dna, also be the prerequisite of moving the G2 phase, therefore optionally the CDK2 inhibitor is the main direction of current CDKs inhibitor research.
Present research mainly concentrates on the research and development of selectivity CDK2 micromolecular inhibitor, and the inhibitor of existing many types is in clinical preceding or clinical experimental stage.
Summary of the invention
The present invention is studying on the basis that has CDK2 micromolecular inhibitor optionally in a large number, to suppress active natural product banisterine (parent nucleus is the β-Ka Lin ring) be lead compound to have CDK2, crystal structure model according to CDK2, utilize area of computer aided medicinal design means to build the structure activity relationship model and the medicine virtual screening model of CDK2 inhibitor, having designed and synthesized a series of on this basis is the compound of the brand new of parent nucleus with the β-Ka Lin ring, pharmacological testing shows that compound of the present invention has excellent CDK2 and suppresses active.
Compound general formula I of the present invention is as follows:
Figure G2009100283014D00021
R wherein 1Expression hydrogen, carbamyl, methylol, aminomethyl or ethanoyl;
R 2Expression hydrogen, C 1-C 6Alkoxyl group, C 3-C 10Substituted cycloalkyl oxygen base, C 3-C 10The substituted cycloalkyl methoxyl group, wherein substituting group is selected from: hydrogen, methyl, ethyl, hydroxyl, trifluoromethyl, halogen, methoxy or ethoxy;
R 3, R 4, R 6Or R 7Represent hydrogen, halogen, hydroxyl, nitro, amino, C independently of one another 1-C 6Alkyl, C 1-C 6Alkoxyl group, itrile group or carboxyl;
R 5Expression-SO 2NR 9R 10, R wherein 9Or R 10Represent hydrogen, C independently of one another 1-C 6Alkyl ,-(CH 2) nOCH 3N=1～4 ,-(CH 2) nNHCH 3N=1～4, C 1-C 6Hydroxyalkyl, C 3-C 10Cycloalkyl, substituted-phenyl, substituted benzene methyl, substituted benzene ethyl, substituted heterocyclic radical, wherein substituting group is selected from: hydrogen, methyl, ethyl, trifluoromethyl, halogen, hydroxyl, methoxyl group, oxyethyl group, nitro, amino, itrile group or carboxyl; Heterocyclic radical is selected from: pyrroles, furans, thiophene, pyrazoles, thiazole, imidazoles, oxazole, pyridine, pyrimidine, pyrazine or pyridazine;
R 5Expression-SO also 2R 11, R wherein 11Expression 1-pyrrolidyl, piperidino, 4-hydroxy piperidine-1-base, 4-methyl isophthalic acid-piperazinyl, 1-morpholinyl or 4-(2-hydroxyethyl) piperazine-1-base;
R 8Expression hydrogen or C 1-C 6Alkyl.
R 1Preferred expression hydrogen, carbamyl or methylol.
R 2Preferred expression hydrogen, C 1-C 6Alkoxyl group, C 3-C 10The substituted cycloalkyl methoxyl group, wherein substituting group is selected from: hydrogen, methyl, ethyl, hydroxyl, methoxy or ethoxy.
R 3, R 4, R 6Or R 7Preferably represent hydrogen, C independently of one another 1-C 6Alkyl or C 1-C 6Alkoxyl group.
R 8Preferred expression hydrogen.
According to the present invention, pharmacy acceptable salt comprises the acid salt that compound of Formula I and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetate, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.The acid salt that comprises mineral alkali in addition, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
The preferred following structural compounds of the compound of general formula I:
3-cyclohexyl methoxyl group-β-Ka Lin (code name 1-8, down together)
1-carbamyl-3-cyclohexyl methoxyl group-β-Ka Lin (I-9-a)
1-methylol-3-cyclohexyl methoxyl group-β-Ka Lin (I-9-b)
1-carbamyl-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-11-a)
1-methylol-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-11-b)
3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-10-1)
1-carbamyl-3-cyclohexyl methoxyl group-6-methylamino-alkylsulfonyl-β-Ka Lin (I-11-a-1)
1-carbamyl-3-cyclohexyl methoxyl group-6-phenylsulfamoyl-β-Ka Lin (I-11-a-2)
1-carbamyl-3-cyclohexyl methoxyl group-6-hexamethylene amino-sulfonyl-β-Ka Lin (I-11-a-3)
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin (I-11-a-4)
1-carbamyl-3-cyclohexyl methoxyl group-6-(1-morpholinyl) alkylsulfonyl-β-Ka Lin (I-11-a-5)
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-methylpiperazine-1-yl) alkylsulfonyl-β-Ka Lin (I-11-a-6)
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-methoxy ethyl) amino-sulfonyl-β-Ka Lin (I-11-a-7)
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-methylamino-ethyl) amino-sulfonyl-β-Ka Lin (I-11-a-8)
1-carbamyl-3-cyclohexyl methoxyl group-6-(6-picoline-2-yl) amino-sulfonyl-β-Ka Lin (I-11-a-9)
1-carbamyl-3-cyclohexyl methoxyl group-6-(pyridine-2-yl) amino-sulfonyl-β-Ka Lin (I-11-a-10)
1-carbamyl-3-cyclohexyl methoxyl group-6-[4-(2-hydroxyethyl) piperazine-1-yl) alkylsulfonyl-β-Ka Lin (I-11-a-11)
1-carbamyl-3-cyclohexyl methoxyl group-6-[3-(1-morpholinyl) propyl group) amino-sulfonyl-β-Ka Lin (I-11-a-12)
1-carbamyl-3-cyclohexyl methoxyl group-6-dimethylamino alkylsulfonyl-β-Ka Lin (I-11-a-13)
1-carbamyl-3-cyclohexyl methoxyl group-6-(piperidino) alkylsulfonyl-β-Ka Lin (I-11-a-14)
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-nitrophenyl) amino-sulfonyl-β-Ka Lin (I-11-a-15)
1-carbamyl-3-cyclohexyl methoxyl group-6-(p-methylphenyl) amino-sulfonyl-β-Ka Lin (I-11-a-16)
1-carbamyl-3-cyclohexyl methoxyl group-6-(styroyl) amino-sulfonyl-β-Ka Lin (I-11-a-17)
1-carbamyl-3-cyclohexyl methoxyl group-6-(pyrazole-3-yl) amino-sulfonyl-β-Ka Lin (I-11-a-18)
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-hydroxy piperidine-1-yl) alkylsulfonyl-β-Ka Lin (I-11-a-19)
1-carbamyl-3-cyclohexyl methoxyl group-6-(thiazol-2-yl) amino-sulfonyl-β-Ka Lin (I-11-a-20)
1-carbamyl-β-Ka Lin (I-15)
1-carbamyl-6-amino-sulfonyl-β-Ka Lin (I-17-1)
1-carbamyl-6-methylamino-alkylsulfonyl-β-Ka Lin (I-17-2)
1-carbamyl-6-hexamethylene amino-sulfonyl-β-Ka Lin (I-17-3)
1-carbamyl-6-(6-picoline-2-yl) amino-sulfonyl-β-Ka Lin (I-17-4)
1-carbamyl-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin (I-17-5)
1-carbamyl-6-dimethylamino alkylsulfonyl-β-Ka Lin (I-17-6)
1-carbamyl-6-phenylsulfamoyl-β-Ka Lin (I-17-7)
1-carbamyl-6-(p-methylphenyl) amino-sulfonyl-β-Ka Lin (I-17-8)
1-carbamyl-6-(m-nitro base) amino-sulfonyl-β-Ka Lin (I-17-9)
3-isobutoxy-β-Ka Lin (I-8-A)
1-carbamyl-3-isobutoxy-β-Ka Lin (I-9-A)
1-carbamyl-3-isobutoxy-6-amino-sulfonyl-β-Ka Lin (I-11-A)
1-carbamyl-3-isobutoxy-6-phenylsulfamoyl-β-Ka Lin (I-11-A-1)
1-carbamyl-3-isobutoxy-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin (I-11-A-2)
1-carbamyl-3-isobutoxy-6-(diethylamino alkylsulfonyl)-β-Ka Lin (I-11-A-3)
1-carbamyl-3-isobutoxy-6-(styroyl) amino-sulfonyl-β-Ka Lin (I-11-A-4)
1-carbamyl-3-isobutoxy-6-(2-hydroxypropyl) amino-sulfonyl-β-Ka Lin (I-11-A-5)
Part of compounds preparation method of the present invention is as follows:
Method one
Figure G2009100283014D00051
Method two
Figure G2009100283014D00052
Method three
Figure G2009100283014D00053
Figure G2009100283014D00061
Method four
Figure G2009100283014D00062
The compounds of this invention can prepare with above-mentioned or similar above-mentioned preparation method, selects for use corresponding raw material to get final product according to the different of substituent difference and substituting group position.
The pharmacology test result shows, the compound of general formula I and pharmacy acceptable salt thereof all have in various degree restraining effect to cell in vitro cyclin-dependent kinase 2, therefore, compound of Formula I and pharmacy acceptable salt thereof can be used for the treatment of the clinical disease relevant with telomerase inhibitor.Described and cell cycle protein dependent kinase 2 inhibitor diseases associated can be melanoma, liver cancer, kidney, acute, leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma.
Be part pharmacology test and result below:
[material]
Instrument TECAN Safire 2Plate reading (the Switzerland Supreme Being agree company)
Black wall black matrix 384 orifice plates (U.S. corning company)
Dull and stereotyped shaking table (the bright laboratory apparatus in Jiangsu Province factory)
Reagent C DK-2/clyclin A (American I nvitrogen)
Z '-LYTE kit 12peptide (American I nvitrogen)
DMSO (U.S. Sigma)
[method]
1. getting 133 μ l, 5 * damping fluid joins and obtains 500 μ l, 1.33 * kinase buffer liquid in the 367 μ l water.
2. getting 0.2 μ l CDK-2/clyclin A and 0.8 μ l substrate joins and obtains 200 μ l kinases/substrate mixture in 199ul 1.33 * kinase buffer liquid.
3. getting 6 μ l 10mM ATP adds and obtains 150 μ l, 4 * ATP liquid in 144 μ l, 1.33 * kinase buffer liquid.
4. get in 1.33 * kinase buffer liquid that 0.2 μ l phosphorylated peptide joins 49.8 μ l and obtain 50 μ l phosphorylated peptide liquid.
5. get 2 μ l 10 -2The M mother liquor joins and obtains 500 μ l, 4 * test compounds liquid in the 498 μ l water.
6. according to the form below application of sample:
Figure G2009100283014D00071
With oscillator plate with the sample mixing, room temperature is placed 1h.
8. get 0.1 μ l developing solution and join in the 100 μ l water, get developing solution.Every hole adds 5 μ l, and oscillator plate is with the sample mixing, and room temperature is placed 1h.
9. every hole adds 5 μ l stop buffers, and oscillator plate is with the sample mixing.
10. use TECAN Safire 2Plate reading, the setting excitation wavelength is 400nm, detects emission wavelength 445nm and 520nm fluorescent value respectively, and calculates inhibiting rate by following formula.
Suppress percentage=100 * (1-test group phosphorylation rate/control group phosphorylation rate)
[result]
The compound code name Final concentration mol/L Inhibiting rate % The compound code name Final concentration mol/L Inhibiting rate %
I-9-a 1×10 -5 39.2 I-11-a-17 1×10 -5 36.5
I-9-b 1×10 -5 22.7 I-11-a-18 1×10 -5 46.5
I-11-a 1×10 -5 51.8 I-11-a-19 1×10 -5 39.9
I-11-b 1×10 -5 42.1 I-15 1×10 -5 44.8
I-10-1 1×10 -5 32.6 I-17-1 1×10 -5 87.2
I-11-a-1 1×10 -5 53.6 I-17-3 1×10 -5 54.7
I-11-a-2 1×10 -5 47.2 I-17-6 1×10 -5 49.6
I-11-a-4 1×10 -5 68.9 I-17-9 1×10 -5 55.1
I-11-a-6 1×10 -5 50.2 I-8-A 1×10 -5 18.1
I-11-a-7 1×10 -5 63.4 I-11-A 1×10 -5 36.4
I-11-a-8 1×10 -5 66.8 I-11-A-1 1×10 -5 30.4
I-11-a-10 1×10 -5 45.6 I-11-A-4 1×10 -5 27.8
I-11-a-11 1×10 -5 59.7 Cross bud alkali 1×10 -5 93.5
(the compound code name is corresponding to the compound code name of front in the table)
The pharmacology test result shows, The compounds of this invention has cell cycle protein dependent kinase 2 and suppresses active, can be used for preventing or clinical disease that treatment is relevant with telomerase inhibitor, these diseases can be: melanoma, liver cancer, kidney, acute, leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma etc.
Embodiment
Fusing point is measured with b shape melting point tube, and medium is a methyl-silicone oil, and thermometer is not proofreaied and correct; IR spectrum Nicolet Impact 410 type determination of infrared spectroscopy, the KBr compressing tablet; 1HNMR finishes (mark in the TMS) with JEOL FX90Q type fourier transform NMR instrument, BRUKERACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser; MS measures with Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph.
Embodiment 1
1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid (I-1)
In the single neck bottle of 250mL, add L-tryptophane 10.2g (50mmol), sodium hydrate solid 2.05g (55mmol) and water 100mL, being stirred to solid all dissolves, add formalin (6mL) under the room temperature, this reaction solution is prior to stirring at room 3hr, reflux 3hr then, TLC detect the raw material (methyl alcohol: chloroform=1: 1) that disappears.Reaction solution is poured in the frozen water (100mL), regulated pH to 6, have a large amount of white solids to separate out with glacial acetic acid, cooling, suction filtration, filter cake washes with water, recrystallizing methanol gets pale solid I-19.0g, yield 83.0%, mp:308-310 ℃ [document mp:309-310 ℃].
Embodiment 2
1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid, ethyl ester (I-2)
Add I-14g (4.6mmol) and dehydrated alcohol 100mL in the 250mL three-necked bottle, slowly drip thionyl chloride (5mL) under the room temperature, finish reflux 2hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 4).Remove ethanol under reduced pressure, add the about 100mL of frozen water, regulate pH to 8-9 with sodium hydroxide solution, ethyl acetate extraction 3 times (30mL * 3), united extraction liquid water and saturated sodium-chloride is respectively respectively washed once (40mL * 1), removes solvent under reduced pressure and obtains faint yellow solid, and re-crystallizing in ethyl acetate obtains white solid I-23.5g, yield 77.8%, mp:319-321 ℃ [document mp:319-321 ℃].
Embodiment 3
β-Ka Lin-3-carboxylic acid, ethyl ester (I-3)
In the single neck bottle of 250mL, add crude product I-21g (4.1mmol) and DMF (150mL), under ice-water bath, add KMnO in batches 4Solid 1g (6.6mmol) finishes stirring at room 24hr.Suction filtration, filter cake is washed (30mL * 2) twice with DMF, removes solvent under reduced pressure, and residuum obtains white solid I-30.85g with re-crystallizing in ethyl acetate, yield 86.7%, mp:230-231 ℃ [document mp:231-232 ℃].
Embodiment 4
β-Ka Lin-3-carbonyl hydrazide (I-4)
Add I-36g (0.025mol), hydrazine hydrate (30mL) and methyl alcohol (100mL) in the 250mL three-necked bottle, reflux 6hr, TLC detect raw material disappearance (methyl alcohol: chloroform=1: 1).Naturally cooling is separated out a large amount of solids, and a spot of washing with alcohol of suction filtration, filter cake obtains yellow solid (I-4) 4.86g, and yield 86.0%, product need not to be further purified, and directly cast single step reaction.Mp:287-290 ℃ [document mp:288-290 ℃].
Embodiment 5
3-amino-beta--carboline (1-6)
Add I-46g (0.027mol), concentrated hydrochloric acid (5mL) and water (120mL) in the 250mL three-necked bottle, vigorous stirring makes it dissolving, cools to 0 ℃, slowly drips NaNO 21.9g (0.028mol) frozen water solution (20mL) drips complete insulation reaction 30min, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2), obtain clear soln I-5.Reaction solution slowly heated up to be made it to reflux, and emits a large amount of gases, and backflow 1hr, TLC detect the raw material (methyl alcohol: chloroform=1: 2) that disappears.Naturally cooling is regulated pH to 8-9 with dense NaOH, separates out a large amount of solids, leaves standstill, and suction filtration obtains xanchromatic solid (I-6) 4.04g, and yield 83.1%, product need not to be further purified, and directly cast single step reaction.Mp:289-291 ℃ [document mp:289-291 ℃].
Embodiment 6
3-chloro-β-Ka Lin (I-7)
Add 1-61g (5.4mmol) and concentrated hydrochloric acid (15mL) in the 150mL three-necked bottle, vigorous stirring makes it dissolving, cools to-5 ℃, adds NaNO in batches 20.56g (8.1mmol), add insulation reaction 2hr, TLC detects raw material disappearance (ethyl acetate: sherwood oil=1: 1).Reaction solution slowly is warmed up to 50 ℃, emit a large amount of gases, regulate pH to 8-9 with dense NaOH, chloroform extraction 3 times (20mL * 3), united extraction liquid water and saturated sodium-chloride are respectively respectively washed once (20mL * 1), remove solvent under reduced pressure and obtain yellow oil, crude product is through column chromatography (developping agent: chloroform: methyl alcohol=20: 1) get sample 0.59g, yield 53.6%, mp:278-281 ℃, MS[M+H] +203.0.
1H-NMR[300MHz，DMSO-d 6]：δ7.5(1H，d，ArH)；δ7.6(1H，m，ArH)；δ8.1(1H，d，ArH)；δ8.5(1H，d，ArH)；δ8.9(1H，s，ArH)；δ11.77(1H，s，indole)。
Embodiment 7
3-cyclohexyl methoxyl group-β-Ka Lin (1-8)
In the 100mL three-necked bottle, add 1-7200mg (0.99mmol), hexahydrobenzyl alcohol (35mL), an amount of DABCO (triethylene diamine) 25mg (0.2mmol) and NaH (excessive), reflux 24hr, TLC detect raw material disappearance (ethyl acetate: sherwood oil=1: 2).Remove solvent under reduced pressure, residuum adds entry (100mL), with ethyl acetate extraction 3 times (30mL * 3), united extraction liquid water and saturated sodium-chloride is respectively respectively washed once (30mL * 1), remove solvent under reduced pressure and obtain faint yellow oily thing, crude product is through column chromatography (ethyl acetate: sherwood oil=1: 10) get sample 125mg, yield 45.1%, mp:167-169 ℃, MS[M+H] +281.4.
1H-NMR[300MHz，DMSO-d 6]：δ0.8-1.9(11H，m，-CH 2-×5，-CH-)；δ4.1(2H，d，-CH 2-)；δ7.1(1H，m，ArH)；δ7.4-7.5(3H，m，ArH)；58.1(1H，d，ArH)；δ8.4(1H，s，ArH)；δ11.2(1H，s，indole)。
Embodiment 8
1-carbamyl-3-cyclohexyl methoxyl group-β-Ka Lin (I-9-a)
Add I-8200mg (0.71mmol), methane amide (50mL) and the vitriol oil (0.2mL) in the 150mL three-necked bottle, ice-water bath cools to 10 ℃, drips H simultaneously 2O 2(5mL) with saturated copperas solution (10mL), insulation reaction 0.5hr, TLC detect raw material disappearance (ethyl acetate: sherwood oil=1: 2).Reaction solution is poured in the trash ice of 150mL, regulate pH to 8-9 with saturated aqueous sodium carbonate, ethyl acetate extraction 3 times (40mL * 3), united extraction liquid water and saturated sodium-chloride is respectively respectively washed once (40mL * 1), remove solvent under reduced pressure and obtain faint yellow oily thing, crude product is through column chromatography (developping agent: ethyl acetate: sherwood oil=1: 5) get sample 138mg, yield 60.0%, mp:216-218 ℃, MS[M+H] +324.1.
1H-NMR[500MHz，DMSO-d 6]：δ1.0-1.9(11H，m，-CH 2-×5，-CH-)；δ4.1(2H，d，-CH 2-)；δ7.1(1H，t，ArH)；δ7.5(1H，t，ArH)；δ7.6(2H，d，-CONH 2)；δ7.7(1H，t，ArH)；δ8.0(1H，s，ArH)；δ8.2(1H，d，ArH)；δ11.2(1H，s，indole)。
Embodiment 9
1-methylol-3-cyclohexyl methoxyl group-β-Ka Lin (I-9-b)
Add I-8200mg (0.71mmol), methyl alcohol (60mL) and the vitriol oil (0.2mL) in the 150mL three-necked bottle, ice-water bath cools to 10 ℃, drips H simultaneously 2O 2(5mL) with saturated copperas solution (10mL), insulation reaction 0.5hr, TLC detect raw material disappearance (ethyl acetate: sherwood oil=1: 2).Reaction solution is poured in the trash ice of 150mL, regulate pH to 8-9 with saturated aqueous sodium carbonate, ethyl acetate extraction 3 times (40mL * 3), united extraction liquid water and saturated sodium-chloride is respectively respectively washed once (40mL * 1), remove solvent under reduced pressure and obtain faint yellow oily thing, crude product is through column chromatography (developping agent: ethyl acetate: sherwood oil=1: 3) get sample 105mg, yield 56.1%, mp:128-130 ℃, MS[M+H] +311.2.
1H-NMR[500MHz，DMSO-d 6]：δ1.06-1.85(11H，m，-CH 2-×5，-CH-)；δ4.0(2H，d，-CH 2-)；δ4.8(2H，d，-CH 2OH)；δ5.4(1H，t，-OH)；δ7.1(1H，t，ArH)；δ7.3(1H，s，ArH)；δ7.4(1H，t，ArH)；δ7.5(1H，d，ArH)；δ8.1(1H，d，ArH)；δ10.9(1H，s，indole)。
Embodiment 10
1-carbamyl-3-cyclohexyl methoxyl group-6-chlorosulfonyl-β-Ka Lin (I-10-a)
Add chlorsulfonic acid (2mL) in the single neck bottle of the 10mL that drying tube is housed, cryosel is bathed and is cooled to about-5 ℃, adds III-6-a 150mg (0.48mmol) fast, and insulation reaction 10min, TLC detect raw material disappearance (ethyl acetate: sherwood oil=2: 1).Reaction solution is poured in the frozen water of 100mL, separated out a large amount of solids immediately, suction filtration obtains flaxen solid I-10-a, and product need not to be further purified, and directly casts single step reaction.
Embodiment 11
1-carbamyl-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-11-a)
In the 150mL three-necked bottle, add crude product I-10-a 100mg and strong aqua (50mL), stir 2hr at 40 ℃, TLC detects raw material disappearance (ethyl acetate: sherwood oil=2: 1), reaction solution is regulated pH value to 7.5 with glacial acetic acid, ethyl acetate extraction 3 times (25mL * 3), united extraction liquid water and saturated sodium-chloride is respectively respectively washed once (25mL * 1), remove solvent under reduced pressure and obtain faint yellow oily thing, crude product is through column chromatography (developping agent: ethyl acetate: sherwood oil=1: 1) get sample 78mg, yield 62.9%, mp:297-299 ℃, MS[M+H] +403.6.
1H-NMR[500MHz，DMSO-d 6]：δ1.06-1.98(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ7.2(2H，s，-SO 2NH 2)；δ7.7-7.8(2H，d，-CONH 2)；δ7.89(1H，s，ArH)；δ7.97(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.64(1H，s，indole)。
Embodiment 12
1-methylol-3-cyclohexyl methoxyl group-6-chlorosulfonyl-β-Ka Lin (I-10-b)
The preparation method is similar to (I-10-a).
Embodiment 13
1-methylol-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-11-b)
The preparation method is similar to (I-11-a), gets sample 56mg, yield 29.8%.mp：158-160℃，MS[M+H] +390.2。
1H-NMR[500MHz，DMSO-d 6]：δ1.06-1.85(11H，m，-CH 2-×5，-CH-)；δ4.0(2H，d，-CH 2-)；δ4.8(2H，d，-CH 2OH)；δ5.5(1H，t，-OH)；δ7.1(2H，s，-SO 2NH 2)；δ7.6(1H，d，ArH)；δ7.9(1H，d，ArH)；δ8.6(1H，s，ArH)；δ11.38(1H，s，indole)。
Embodiment 14
3-cyclohexyl methoxyl group-6-chlorosulfonyl-β-Ka Lin (I-9-1)
The preparation method is similar to (I-10-a).
Embodiment 15
3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-10-1)
The preparation method is similar to (I-11-a), gets sample 141mg, yield 55.0%.mp：298-300℃，MS[M+H] +360.3。
1H-NMR[500MHz，DMSO-d 6]：δ1.06-1.98(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ7.2(2H，s，-SO 2NH 2)；δ7.6(2H，d，ArH)；δ7.9(1H，m，ArH)；δ8.5(1H，s，ArH)；δ8.6(1H，s，ArH)；δ11.66(1H，s，indole)。
Embodiment 16
1-carbamyl-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-11-a)
Can I-10-1 be raw material also, the preparation method be similar to (I-9-a), gets sample 58mg, yield 67.3%.
Embodiment 17
1-methylol-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin (I-11-b)
Can I-10-1 be raw material also, the preparation method be similar to (I-9-b), gets sample 101mg, yield 62.3%.
Embodiment 18
1-carbamyl-3-cyclohexyl methoxyl group-6-methylamino-alkylsulfonyl-β-Ka Lin (I-11-a-1)
The preparation method is similar to (I-11-a), gets sample 50mg, yield 45.3%.mp：299-301℃，MS[M+H] +417.1。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ2.4(3H，d，-CH 3)；δ4.1(2H，d，-CH 2-)；δ7.2(1H，s，-SO 2NH-)；δ7.8(2H，d，CONH 2)；δ7.9(1H，s，ArH)；δ7.97(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.6(1H，s，ArH)；δ11.7(1H，s，indole)。
Embodiment 19
1-carbamyl-3-cyclohexyl methoxyl group-6-phenylsulfamoyl-β-Ka Lin (I-11-a-2)
The preparation method is similar to (I-11-a), gets sample 120mg, yield 55.7%.mp：317-319℃，MS[M+H] +479.7。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ6.9-7.1(5H，m，ArH)；δ7.3(1H，s，-SO 2NH-)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.78(1H，s，indole)。
Embodiment 20
1-carbamyl-3-cyclohexyl methoxyl group-6-hexamethylene amino-sulfonyl-β-Ka Lin (I-11-a-3)
The preparation method is similar to (I-11-a), gets sample 99mg, yield 52.0%.mp：310-312℃，MS[M+H] +485.8。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(21H，m，-CH 2-×10，-CH-)；δ3.1(1H，m，-CHN-)；δ4.2(2H，d，-CH 2O-)；δ7.2(1H，s，-SO 2NH-)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.78(1H，s，indole)。
Embodiment 21
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin (I-11-a-4)
The preparation method is similar to (I-11-a), gets sample 80mg, yield 49.0%.mp：290-292℃，MS[M+H] +447.6。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ3.4-3.5(4H，m，-CH 2-×2)；δ4.2(2H，d，-CH 2-)；δ4.9(1H，t，-OH)；δ7.2(1H，s，-SO 2NH-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.64(1H，s，indo1e)。
Embodiment 22
1-carbamyl-3-cyclohexyl methoxyl group-6-(1-morpholinyl) alkylsulfonyl-β-Ka Lin (I-11-a-5)
The preparation method is similar to (I-11-a), gets sample 60mg, yield 47.0%.mp：316-318℃，MS[M+H] +474.1。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ2.4(4H，m，-CH 2O-×2)；δ3.2(4H，m，-CH 2N-×2)；δ4.2(2H，d，-CH 2-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.64(1H，s，indole)。
Embodiment 23
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-methylpiperazine-1-yl) alkylsulfonyl-β-Ka Lin (I-11-a-6)
The preparation method is similar to (I-11-a), gets sample 67mg, yield 44.3%.mp：315-317℃，MS[M+H] +487.0。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ2.3(3H，s，-CH 3)；δ2.5(4H，m，-CH 2N-×2)；δ3.1(4H，m，-CH 2NS-×2)；δ4.2(2H，d，-CH 2-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.67(1H，s，indole)。
Embodiment 24
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-methoxy ethyl) amino-sulfonyl-β-Ka Lin (I-11-a-7)
The preparation method is similar to (I-11-a), gets sample 87mg, yield 52.1%.mp：308-310℃，MS[M+H] +462.0。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ3.4(3H，s，-OCH 3)；δ3.6-3.7(4H，m，-CH 2×2)；δ4.2(2H，d，-CH 2-)；δ7.2(1H，s，-SO 2NH-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.7(1H，s，indole)。
Embodiment 25
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-methylamino-ethyl) amino-sulfonyl-β-Ka Lin (I-11-a-8)
The preparation method is similar to (I-11-a), gets sample 90mg, yield 55.3%.mp：307-309℃，MS[M+H] +462.0。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ2.5(1H，s，-NH-)；δ2.9-3.1(4H，m，-CH 2×2)；δ3.3(3H，s，-NCH 3)；δ4.2(2H，d，-CH 2-)；δ7.1(1H，s，-SO 2NH-)；δ7.6(2H，d，-CONH 2)；δ7.7(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.45(1H，s，indole)。
Embodiment 26
1-carbamyl-3-cyclohexyl methoxyl group-6-(6-picoline-2-yl) amino-sulfonyl-β-Ka Lin (I-11-a-9)
The preparation method is similar to (I-11-a), gets sample 60mg, yield 50.0%.mp：335-337℃，MS[M+H] +494.8。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ3.0(3H，s，-CH 3)；δ4.2(2H，d，-CH 2-)；δ6.6-7.0(3H，m，ArH)；δ7.2(1H，s，-SO 2NH-)；δ7.6(2H，d，-CONH 2)；δ7.7(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.56(1H，s，indole)。
Embodiment 27
1-carbamyl-3-cyclohexyl methoxyl group-6-(pyridine-2-yl) amino-sulfonyl-β-Ka Lin (I-11-a-10)
The preparation method is similar to (I-11-a), gets sample 70mg, yield 60.5%.mp：330-332℃，MS[M+H] +481.0。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ6.6-7.0(4H，m，ArH)；δ7.2(1H，s，-SO 2NH-)；δ7.6(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.64(1H，s，indole)。
Embodiment 28
1-carbamyl-3-cyclohexyl methoxyl group-6-[4-(2-hydroxyethyl) piperazine-1-yl) alkylsulfonyl-β-Ka Lin (I-11-a-11)
The preparation method is similar to (I-11-a), gets sample 75mg, yield 65.5%.mp：320-322℃，MS[M+H] +517.0。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ2.4(4H，m，-NCH 2-×2)；δ2.5(2H，m，-CH 2-)；δ2.9(4H，m，-NCH 2-×2)；δ3.3(2H，m，-CH 2-)；δ4.2(2H，d，-CH 2-)；δ4.3(H，d，-OH)；δ7.6(1H，s，-SO 2NH-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.77(1H，s，indole)。
Embodiment 29
1-carbamyl-3-cyclohexyl methoxyl group-6-[3-(1-morpholinyl) propyl group) amino-sulfonyl-β-Ka Lin (I-11-a-12)
The preparation method is similar to (I-11-a), gets sample 80mg, yield 63.5%.mp：355-357℃，MS[M+H] +517.0。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(13H，m，-CH 2-×6，-CH-)；δ2.1(6H，m，-NCH 2-×3)；δ2.8(2H，m，-NCH 2-)；δ3.2(4H，m，-OCH 2-×2)；δ4.2(2H，d，-CH 2-)；δ7.4(1H，s，-SO 2NH-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.69(1H，s，indole)。
Embodiment 30
1-carbamyl-3-cyclohexyl methoxyl group-6-dimethylamino alkylsulfonyl-β-Ka Lin (I-11-a-13)
The preparation method is similar to (I-11-a), gets sample 50mg, yield 43.5%.mp：312-314℃，MS[M+H] +431.4。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ3.3(6H，s，-CH 3×2)；δ4.2(2H，d，-CH 2-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.67(1H，s，indole)。
Embodiment 31
1-carbamyl-3-cyclohexyl methoxyl group-6-(piperidino) alkylsulfonyl-β-Ka Lin (I-11-a-14)
The preparation method is similar to (I-11-a), gets sample 42mg, yield 41.0%.mp：329-331℃，MS[M+H] +471.5。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(17H，m，-CH 2-×8，-CH-)；δ3.0(4H，s，-CH 2N×2)；δ4.2(2H，d，-CH 2-)；δ7.7(2H，d，-CONH 2)；δ7.8(1H，s，ArH)；δ7.9(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.74(1H，s，indole)。
Embodiment 32
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-nitrophenyl) amino-sulfonyl-β-Ka Lin (I-11-a-15)
The preparation method is similar to (I-11-a), gets sample 80mg, yield 80.7%.mp：323-325℃，MS[M+H] +524.7。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ6.8-7.0(4H，m，ArH)；δ7.4(1H，s，-SO 2NH-)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.72(1H，s，indole)。
Embodiment 33
1-carbamyl-3-cyclohexyl methoxyl group-6-(p-methylphenyl) amino-sulfonyl-β-Ka Lin (I-11-a-16)
The preparation method is similar to (I-11-a), gets sample 90mg, yield 70.0%.mp：325-327℃，MS[M+H] +494.1。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ3.0(3H，s，-CH 3)；δ4.2(2H，d，-CH 2-)；δ6.8-7.1(4H，m，ArH)；δ7.4(1H，s，-SO 2NH-)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.74(1H，s，indole)。
Embodiment 34
1-carbamyl-3-cyclohexyl methoxyl group-6-(styroyl) amino-sulfonyl-β-Ka Lin (I-11-a-17)
The preparation method is similar to (I-11-a), gets sample 65mg, yield 54.7%.mp：337-339℃，MS[M+H] +507.9。
1H-NMR[500MHz, DMSO-d 6]: δ 1.0-2.0 (11H, m ,-CH 2-* 5 ,-CH-); δ 2.6 (2H, m ,-CH 2-); δ 3.3 (2H, ,-CH 2-); δ 4.2 (2H, d ,-CH 2-); δ 6.9-7.1 (5H, m, ArH); δ 7.3 (1H, s ,-SO 2NH-); δ 7.8 (2H, d ,-CONH 2); δ 7.9 (1H, s, ArH); δ 8.0 (1H, d, ArH); δ 8.1 (1H, s, ArH); δ 8.7 (1H, s, ArH); δ 11.56 (1H, s, indole).
Embodiment 35
1-carbamyl-3-cyclohexyl methoxyl group-6-(pyrazole-3-yl) amino-sulfonyl-β-Ka Lin (I-11-a-18)
The preparation method is similar to (I-11-a), gets sample 50mg, yield 50.0%.mp：312-314℃，MS[M+H] +469.6。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ6.3(1H，d，ArH)；δ7.5(1H，d，ArH)；δ7.3(1H，s，-SO 2NH-)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.56(1H，s，indole)；δ12.6(1H，s，-NH-)。
Embodiment 36
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-hydroxy piperidine-1-yl) alkylsulfonyl-β-Ka Lin (I-11-a-19)
The preparation method is similar to (I-11-a), gets sample 78mg, yield 62.0%.mp：354-356℃，MS[M+H] +487.8。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(15H，m，-CH 2-×7，-CH-)；δ2.8(4H，m，-CH 2N×2)；δ3.0(1H，m，-CH-)；δ4.2(2H，d，-CH 2-)；δ4.8(1H，t，-OH)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.76(1H，s，indole)。
Embodiment 37
1-carbamyl-3-cyclohexyl methoxyl group-6-(thiazol-2-yl) amino-sulfonyl-β-Ka Lin (I-11-a-20)
The preparation method is similar to (I-11-a), gets sample 45mg, yield 32.0%.mp：322-324℃，MS[M+H] +485.6。
1H-NMR[500MHz，DMSO-d 6]：δ1.0-2.0(11H，m，-CH 2-×5，-CH-)；δ4.2(2H，d，-CH 2-)；δ6.0-7.0(3H，m，ArH)；δ7.3(1H，s，-SO 2NH-)；δ7.8(2H，d，-CONH 2)；δ7.9(1H，s，ArH)；δ8.0(1H，d，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.66(1H，s，indole)。
Embodiment 38
1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-1-carboxylic acid (I-12)
In the 1000mL three-necked bottle, add tryptamines 20g (125mmol) and 275mL water, stirring down, adding an amount of concentrated hydrochloric acid to solid dissolves, drip acetaldehyde aqueous acid [98% oxoethanoic acid (28.13mL under the room temperature simultaneously, 494mmol) among the water-soluble 100mL] and 6.5% KOH solution, reacting liquid pH value is remained on about 4.Dropwise back stirring at room 5hr, have a large amount of solids to separate out, suction filtration, the filter cake washing gets light brown solid I-12 25.45g, yield 94.7%, mp:209-210 ℃ [document mp:210-211 ℃].
Embodiment 39
1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-1-carboxylate methyl ester hydrochloride (I-13)
Add 1,2,3 in the 1000mL three-necked bottle, 4-tetrahydrochysene-β-Ka Lin-1-carboxylic acid I-12 25g (116mmol) and absolute methyl alcohol 580mL slowly drip thionyl chloride 23mL (315mmol) under the stirring at room.Be warming up to backflow after dropwising, back flow reaction 6h.Cool off reaction solution to room temperature, the pressure reducing and steaming solvent, the gained solid gets yellow solid I-13 29.5g, yield 95.4%, mp.212-213 ℃ [document mp:212-214 ℃] with methyl alcohol-re-crystallizing in ethyl acetate.
Embodiment 40
The preparation of β-Ka Lin-1-carboxylate methyl ester (I-14)
With 1,2,3,4-tetrahydrochysene-β-Ka Lin-1-carboxylate methyl ester hydrochloride I-13 27g (101.39mmol), sedimentation sulphur 7.63g (237.26mmol), 2,2,6,6-tetramethyl piperidine TEMP 16.2g (114.95mmol) and dimethylbenzene 600ml place the single neck bottle of 1000mL, are heated to backflow, back flow reaction 8hr, reaction solution is cooled to room temperature, suction filtration, filtrate decompression boils off solvent, the gained crude product is dissolved among the acetone 500mL, after stirring 2hr, the filtering insolubles, filtrate decompression boils off solvent, gained solid ethyl acetate-sherwood oil (V: V=1: 1) recrystallization, get yellow solid I-14 20g, yield 87.2%, mp.165-167 ℃ [document mp:165-166 ℃].
Embodiment 41
The preparation of 1-amine formyl-β-Ka Lin (I-15)
β-Ka Lin-1-carboxylate methyl ester I-14 20g (88.5mmol) and ammoniacal liquor 320mL (8.17mol) add in the single neck bottle of 500mL stirring reaction 24hr under the room temperature.The reaction solution suction filtration, filter cake washing twice, oven dry gets light yellow solid I-15 18.45g, yield 98.8%, mp.226-228 ℃ [document mp:228-228.5 ℃].
Embodiment 42
The preparation of 1-amine formyl-3-chlorosulfonyl-β-Ka Lin (I-16)
Chlorsulfonic acid 2mL (30.1mmol) is placed the single neck bottle of 25mL; add 1-amine formyl-β-Ka Lin I-15 250mg (1.18mmol) under the ice-water bath in batches; add stirring reaction 2hr under the room temperature of back; slowly pour into reaction solution in the ice; there are a large amount of yellow solids to separate out, suction filtration, twice of filter cake washing; gained solid I-16 crude product is not purified, directly drops into next step.
Embodiment 43
The preparation of 1-carbamyl-6-amino-sulfonyl-β-Ka Lin (I-17-1)
The I-16 250mg that in the single neck bottle of 25mL reaction is obtained is scattered in the 2mL water, adds ammoniacal liquor and dissolves until solid, the reaction solution clarification, be heated to 50 ℃ of reaction 2hr, the cooling reaction solution is regulated pH to 6 with dilute hydrochloric acid, has a large amount of solids to separate out, suction filtration, filter cake washing back water recrystallization gets white needles solid I-17-1 140mg, yield 48.47%, mp:217-219 ℃, MS[M+H] +291.3.
1HNMR[DMSO-d 6]δ7.28(2H，s，-SO 2NH 2)；7.83(1H，s，ArH)；8.02(2H，m，-CONH 2)；8.32(1H，s，ArH)；8.50(2H，q，ArH)；8.79(1H，s，ArH)；12.05(1H，s，indole)。
Embodiment 44
The preparation of 1-carbamyl-6-methylamino-alkylsulfonyl-β-Ka Lin (I-17-2)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol); the same I-17-1 of preparation method, the gained crude product through column chromatography for separation [ethyl acetate: sherwood oil (V: V)=1: 1] light yellow solid I-17-2150mg, yield 43.78%; mp:198-200 ℃, MS[M+H] +305.4.
1HNMR[DMSO-d 6]δ2.42(3H，s，-CH 3)；7.33(1H，q，-SO 2NH-)；7.81(1H，s，ArH)，7.96(2H，s，-CONH 2)；8.31(1H，s，ArH)；8.48(1H，d，ArH)；8.55(1H，d，ArH)；8.77(1H，s，ArH)；12.09(1H，s，indole)。
Embodiment 45
The preparation of 1-carbamyl-6-hexamethylene amino-sulfonyl-β-Ka Lin (I-17-3)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol), the same I-17-1 of preparation method, the gained crude product is through column chromatography for separation [ethyl acetate: sherwood oil (V: V)=1; 1] gets white solid I-17-3200mg, yield 48.74%, mp:176-177 ℃, MS[M+H] +373.4.
1HNMR[DMSO-d 6]δ1.54(10H，m，cyclohexane-H)；2.96(s，1H，cyclohexanel-H)；7.57(d，1H，-SO 2NH-)；7.84(1H，s，ArH)；7.98(2H，q，-CONH 2)；8.34(1H，s，ArH)；8.48(1H，d，ArH)；8.53(1H，d，ArH)；8.79(1H，s，ArH)；12.10(1H，s，indole)。
Embodiment 46
The preparation of 1-carbamyl-6-(6-picoline-2-yl) amino-sulfonyl-β-Ka Lin (I-17-4)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol), 6-methyl-2-Fampridine 108mg (1mmol), Na 2CO 3211mg (1.99mmol), the same I-17-1 of preparation method, the gained crude product gets white solid I-17-4186mg, yield 44.36%, mp:200-202 ℃, MS[M+H with second alcohol and water recrystallization] +382.4.
1HNMR[DMSO-d 6]δ2.28(3H，s，-CH 3)；6.63(1H，s，ArH)；7.05(1H，s，ArH)；7.56(1H，t，ArH)，7.89(2H，t，-CONH 2)；8.04(H，d，ArH)；8.31(1H，s，ArH)；8.46(1H，d，ArH)；8.54(1H，d，ArH)，8.90(1H，s，ArH)；12.03(1H，s，indole)。
Embodiment 47
The preparation of 1-carbamyl-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin (I-17-5)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol), thanomin 61mg (1mmol), Na 2CO 3211mg (1.99mmol), the same I-17-1 of preparation method, the gained crude product gets white solid I-17-5173mg with ethyl alcohol recrystallization, yield 44.77%, mp:172-175 ℃, MS[M+H] +335.3.
1HNMR[DMSO-d 6]δ2.79(2H，q，-CH 2OH)；4.01(2H，q，-NHCH 2)；4.66(1H，s，-OH)，7.50(1H，t，-SO 2NH-)；7.85(1H，s，ArH)；7.96(2H，s，-CONH 2)；8.34(1H，s，ArH)；8.49(2H，q，ArH)，8.79(1H，s，ArH)；12.11(1H，s，indole)。
Embodiment 48
The preparation of 1-carbamyl-6-dimethylamino alkylsulfonyl-β-Ka Lin (I-17-6)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol), dimethylamine hydrochloride 82mg (1.01mmol) and Na 2CO 3211mg (1.99mmol), the same I-17-1 of preparation method gets light brown solid I-17-6150mg, yield 42.07%, mp:187-188 ℃, MS[M+H] +319.9.
1HNMR[DMSO-d 6]δ2.63(6H，s，-(CH 3) 2)；7.93(2H，m，-CONH 2)；8.49(1H，d，ArH)；8.61(1H，d，ArH)；8.81(1H，s，ArH)；12.17(1H，s，indole)。
Embodiment 49
The preparation of 1-carbamyl-6-phenylsulfamoyl-β-Ka Lin (I-17-7)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol); the preparation method is with the same I-17-1 of preparation method; the gained crude product through column chromatography for separation [ethyl acetate: sherwood oil (V: V)=1: 1] light brown solid I-17-7190mg; yield 46.99%; mp:195-197 ℃, MS[M+H] +367.0.
1HNMR[DMSO-d 6]δ6.97(1H，m，ArH)；7.12(4H，m，ArH)；7.80(1H，d，ArH)；7.90(2H，m，-CONH 2)；8.3(1H，d，ArH)；8.47(2H，q，ArH)；8.77(1H，s，ArH)；10.20(1H，s，-SO 2NH-)；12.08(1H，s，indole)。
Embodiment 50
The preparation of 1-carbamyl-6-(p-methylphenyl) amino-sulfonyl-β-Ka Lin (I-17-8)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol) is to amino toluene 107mg (1.0mmol), Na 2CO 3211mg (1.99mmol), the same I-17-1 of preparation method, the gained crude product gets white needles solid I-17-8195mg, yield 46.61%, mp:154-156 ℃, MS[M+H with first alcohol and water recrystallization] +381.5.
1HNMR[DMSO-d 6]δ2.12(3H，s，-CH 3)；7.02(4H，m，ArH)；8.34(1H，s，ArH)；8，49(2H，q，ArH)；8.76(1H，s，ArH)；10.09(1H，s，-SO 2NH-)；12.11(1H，s，indole)。
Embodiment 51
The preparation of 1-carbamyl-6-(m-nitro base) amino-sulfonyl-β-Ka Lin (I-17-9)
1-amine formyl-3-chlorosulfonyl-β-Ka Lin I-16250mg (1.18mmol), m-nitro ammonia 138mg (1mmol), Na 2CO 3211mg (1.99mmol), the same I-17-1 of preparation method, the gained crude product gets 200mg with tetrahydrofuran (THF) and water recrystallization, yield 44.52%, mp:189-191 ℃, MS[M+H] +412.5.
1HNMR[DMSO-d 6]δ7.15(4H，m，ArH)；7.81(1H，d，ArH)；7.90(2H，m，-CONH 2)；8.29(1H，d，ArH)；8.49(2H，q，ArH)；8.78(1H，s，ArH)；10.21(1H，s，-SO 2NH-)；12.08(1H，s，indole)。
Embodiment 52
3-isobutoxy-β-Ka Lin (I-8-A)
In the 500mL three-necked bottle, add I-61g (5.5mmol), dry isobutanol (250mL) and an amount of glacial acetic acid, add Isopentyl nitrite (10mL) when cooling to-20 ℃, reaction solution is at low temperature (20 ℃) vigorous stirring 10min, slowly drip the dry isobutanol solution (100mL) of the inferior ketone of potassium sulfocyanate and thiocyanic acid, drip complete insulation reaction 4hr, the room temperature vigorous stirring detects raw material disappearance (ethyl acetate: sherwood oil=2: 1) up to TLC then.Suction filtration removes solvent under reduced pressure and obtains oily matter, adds 0.5mol/LNa 2CO 3Solution (150mL) makes reacting liquid pH value at 8-9, ethyl acetate extraction 3 times (40mL * 3), united extraction liquid water and saturated sodium-chloride is respectively respectively washed once (40mL * 1), remove solvent under reduced pressure and obtain faint yellow oily thing, crude product is through column chromatography (developping agent: ethyl acetate: sherwood oil=1: 10) get sample 0.3g, yield 23.1%.mp：151-153℃，MS[M+H] +241.4。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(6H，d，-CH 3-×2)；δ2.0(1H，m-CH-)；δ4.2(2H，d，-OCH 2-)；δ7.2(1H，m，ArH)；δ7.6(2H，m，ArH)；δ8.0(1H，s，ArH)；δ8.3(1H，d，ArH)；δ8.6(1H，s，ArH)；δ11.76(1H，s，indole)。
Embodiment 53
1-carbamyl-3-isobutoxy-β-Ka Lin (I-9-A)
The preparation method is similar to (I-9-a), gets sample 45mg, yield 46.3%.mp：200-202℃，MS[M+H] +284.3。
1H-NMR[300MHz，DMSO-d 6]：δ0.9(6H，d，-CH 3-×2)；δ2.1(1H，m-CH-)；δ4.2(2H，d，-OCH 2-)；δ7.1(1H，t，ArH)；δ7.5(1H，t，ArH)；δ7.6(1H，m，ArH)；δ7.7(2H，m，-CONH 2)；δ8.0(1H，s，ArH)；δ8.2(1H，d，ArH)；δ11.23(1H，s，indole)。
Embodiment 54
1-carbamyl-3-isobutoxy-6-chlorosulfonyl-β-Ka Lin (I-10-A)
The preparation method is similar to (I-10-a).
Embodiment 55
1-carbamyl-3-isobutoxy-6-amino-sulfonyl-β-Ka Lin (I-11-A)
The preparation method is similar to (I-11-a), gets sample 85mg, yield 62.3%.mp：281-283℃，MS[M+H] +363.4。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(6H，d，-CH 3-×2)；δ2.2(1H，m-CH-)；δ4.2(2H，d，-OCH 2-)；δ7.2(2H，s，-SO 2NH 2)；δ7.8(2H，m，-CONH 2)；δ7.92(1H，m，ArH)；δ7.96(1H，m，ArH)；δ8.0(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.67(1H，s，indole)。
Embodiment 56
1-carbamyl-3-isobutoxy-6-phenylsulfamoyl-β-Ka Lin (I-11-A-1)
The preparation method is similar to (I-11-a), gets sample 120mg, yield 64.3%.mp：301-303℃，MS[M+H] +439.8。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(6H，d，-CH 3-×2)；δ2.0(1H，m-CH-)；δ4.2(2H，d，-OCH 2-)；δ6.9(1H，m，ArH)；δ7.1-7.2(4H，m，ArH)；δ7.8(2H，m，-CONH 2)；δ7.9(2H，m，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ10.2(1H，s，-SO 2NH-)；δ11.73(1H，s，indole)。
Embodiment 57
1-carbamyl-3-isobutoxy-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin (I-11-A-2)
The preparation method is similar to (I-11-a), gets sample 65mg, yield 64.3%.mp：286-288℃，MS[M+H] +407.5。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(6H，d，-CH 3-×2)；δ2.0(1H，m-CH-)；δ3.4-3.5(4H，m，-CH 2-×2)；δ4.2(2H，d，-OCH 2-)；δ4.8(1H，t，-OH)；δ7.7(1H，s，-SO 2NH-)；δ7.8(2H，m，-CONH 2)；δ7.9(2H，m，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.73(1H，s，indole)。
Embodiment 58
1-carbamyl-3-isobutoxy-6-(diethylin alkylsulfonyl)-β-Ka Lin (I-11-A-3)
The preparation method is similar to (I-11-a), gets sample 50mg, yield 66.0%.mp：293-295℃，MS[M+H] +420.0。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(12H，m，-CH 3-×4)；δ2.0(1H，m-CH-)；δ3.2(4H，m，-CH 2N-×2)；δ4.2(2H，d，-OCH 2-)；δ7.6(1H，s，ArH)；δ7.8(2H，m，-CONH 2)；δ8.0(2H，m，ArH)；δ8.7(1H，s，ArH)；δ11.74(1H，s，indole)。
Embodiment 59
1-carbamyl-3-isobutoxy-6-(styroyl) amino-sulfonyl-β-Ka Lin (I-11-A-4)
The preparation method is similar to (I-11-a), gets sample 70mg, yield 65.0%.mp：311-313℃，MS[M+H] +467.8。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(6H，m，-CH 3-×2)；δ2.1(1H，m-CH-)；δ2.8(2H，m-CH 2-)；δ3.0(2H，m-CH 2-)；δ4.2(2H，d，-OCH 2-)；δ7.1-7.2(4H，m，ArH)；δ7.3(1H，m，ArH)；δ7.7(2H，m，-CONH 2)；δ7.8(1H，s，-SO 2NH-)；δ8.0(2H，m，ArH)；δ8.7(1H，s，ArH)；δ11.7(1H，s，indole)。
Embodiment 60
1-carbamyl-3-isobutoxy-6-(2-hydroxypropyl) amino-sulfonyl-β-Ka Lin (I-11-A-5)
The preparation method is similar to (I-11-a), gets sample 50mg, yield 44.03%.mp：287-289℃，MS[M+H] +421.6。
1H-NMR[300MHz，DMSO-d 6]：δ1.0(9H，m，-CH 3-×3)；δ2.0(1H，m-CH-)；δ2.5(1H，m-CH-)；δ3.4(2H，m，-CH 2-)；δ4.2(2H，d，-OCH 2-)；δ4.8(1H，t，-OH)；δ7.7(1H，s，-SO 2NH-)；δ7.8(2H，m，-CONH 2)；δ7.9(2H，m，ArH)；δ8.1(1H，s，ArH)；δ8.7(1H，s，ArH)；δ11.75(1H，s，indole)。

Claims (8)

1. the compound of general formula (I) or its pharmacy acceptable salt:
R wherein 1Expression carbamyl, methylol;
R 2Expression hydrogen, C 1-C 6Alkoxyl group, C 3-C 10Cycloalkyl oxy, C 3-C 10The cycloalkyl methoxyl group;
R 3, R 4, R 6Or R 7Represent hydrogen independently of one another;
R 5Expression-SO 2NR 9R 10, R wherein 9Or R 10Represent hydrogen, C independently of one another 1-C 6Alkyl ,-(CH 2) nOCH 3N=1～4 ,-(CH 2) nNHCH 3N=1～4, C 1-C 6Hydroxyalkyl, C 3-C 10Cycloalkyl, substituted-phenyl, substituted benzene methyl, substituted benzene ethyl, substituted heterocyclic radical, wherein substituting group is selected from: hydrogen, methyl, ethyl, trifluoromethyl, halogen, hydroxyl, methoxyl group, oxyethyl group, nitro, amino, itrile group or carboxyl; Heterocyclic radical is selected from: pyrryl, furan are fed base, thienyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl;
R 5Expression-SO also 2R 11, R wherein 11Expression 1-pyrrolidyl, piperidino, 4-hydroxy piperidine-1-base, 4-methyl isophthalic acid-piperazinyl, 1-morpholinyl or 4-(2-hydroxyethyl) piperazine-1-base;
R 8Expression hydrogen or C 1-C 6Alkyl.
2. the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt, wherein R 2Expression hydrogen, C 1-C 6Alkoxyl group, C 3-C 10The cycloalkyl methoxyl group.
3. the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt, wherein R 8Expression hydrogen.
4. following compound or its pharmacy acceptable salt:
1-carbamyl-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin
1-methylol-3-cyclohexyl methoxyl group-6-amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-methylamino-alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-phenylsulfamoyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-hexamethylene amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(1-morpholinyl) alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-methylpiperazine-1-yl) alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-methoxy ethyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(2-methylamino-ethyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(6-picoline-2-yl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(pyridine-2-yl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-[4-(2-hydroxyethyl) piperazine-1-yl) alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-[3-(1-morpholinyl) propyl group) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-dimethylamino alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(piperidino) alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-nitrophenyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(p-methylphenyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(styroyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(pyrazole-3-yl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(4-hydroxy piperidine-1-yl) alkylsulfonyl-β-Ka Lin
1-carbamyl-3-cyclohexyl methoxyl group-6-(thiazol-2-yl) amino-sulfonyl-β-Ka Lin
1-carbamyl-6-amino-sulfonyl-β-Ka Lin
1-carbamyl-6-methylamino-alkylsulfonyl-β-Ka Lin
1-carbamyl-6-hexamethylene amino-sulfonyl-β-Ka Lin
1-carbamyl-6-(6-picoline-2-yl) amino-sulfonyl-β-Ka Lin
1-carbamyl-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-6-dimethylamino alkylsulfonyl-β-Ka Lin
1-carbamyl-6-phenylsulfamoyl-β-Ka Lin
1-carbamyl-6-(p-methylphenyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-6-(m-nitro base) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-isobutoxy-6-amino-sulfonyl-β-Ka Lin
1-carbamyl-3-isobutoxy-6-phenylsulfamoyl-β-Ka Lin
1-carbamyl-3-isobutoxy-6-(2-hydroxyethyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-isobutoxy-6-(diethylamino alkylsulfonyl)-β-Ka Lin
1-carbamyl-3-isobutoxy-6-(styroyl) amino-sulfonyl-β-Ka Lin
1-carbamyl-3-isobutoxy-6-(2-hydroxypropyl) amino-sulfonyl-β-Ka Lin.
5. the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt, wherein pharmacy acceptable salt comprises the acid salt that general formula (I) compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid, naphthene sulfonic acid, citric acid, tartrate, lactic acid, pyruvic acid, acetate, toxilic acid or Phenylsulfonic acid, succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid or tussol.
6. pharmaceutical composition wherein contains general formula (I) compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier of claim 1.
7. the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt are used for preventing or the purposes of the medicine of treatment and cell cycle protein dependent kinase 2 inhibitor diseases associated in preparation.
8. the purposes of claim 7 is melanoma, liver cancer, kidney, acute leukemia, nonsmall-cell lung cancer, prostate cancer, thyroid carcinoma, skin carcinoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, mammary cancer, myelodysplastic syndrome, the esophageal carcinoma, gastrointestinal cancer or mesothelioma with cell cycle protein dependent kinase 2 inhibitor diseases associated wherein.
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