CN104003988A - CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor - Google Patents
CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor Download PDFInfo
- Publication number
- CN104003988A CN104003988A CN201410252248.7A CN201410252248A CN104003988A CN 104003988 A CN104003988 A CN 104003988A CN 201410252248 A CN201410252248 A CN 201410252248A CN 104003988 A CN104003988 A CN 104003988A
- Authority
- CN
- China
- Prior art keywords
- carboline
- amino
- piperidines
- formamido group
- arh
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention relates to novel compounds based on 3-amino-beta-carboline, and a preparation method and medical application of the compounds, and in particular relates to an application of the compounds in serving as a CDK2 (cyclin-dependent kinase 2) kinase inhibitor. The novel compound compositions can be independently used or combined with at least one other medicament for treating protein kinase regulated diseases, such as cancers.
Description
Invention field
The present invention relates to a class based on 3-amino-beta--carboline new compound, their preparation method and their medical use, particularly as the purposes of CDK2 kinase inhibitor.This new compound composition can be used alone or be used for the treatment of at least one the other medicines coupling that is subject to the disorders such as cancers that protein kinase regulates.
Background technology
Malignant tumour is one of major disease of serious threat human life, antitumor drug plays an important role in the clinical treatment of tumour, in recent years, along with the development of Protocols in Molecular Biology and on cellular and molecular level the further understanding to Tumorigenesis, new drug development is just from traditional cell toxicity medicament towards the new type antineoplastic medicine development for a plurality of link targets tumor development mechanism.Cell cycle regulating is not normal closely related with generation human diseases.A key character of tumour cell is exactly cell cycle disorder, and the overactivity of cyclin dependent kinase (cyclin-dependent kinases, CDKs) is to cause a disorderly major reason.
CDKs is the important serine/threonine protein kitase of a class, itself does not have activity, must with cyclin (cyclins) in conjunction with after could produce activity, can catalytic substrate phosphorylation, drive the cell cycle each time phase process, sequentially complete DNA and synthesize and mitotic division, cause growth and the propagation of cell.Meanwhile, CDKs also can suppress cell cycle progression with CDKs supressor (CDI) in conjunction with performance down regulation, stops cell fission.CDKs Major Members has 11 kinds of CDK1～CDK11, and cyclins has nine kinds of A～I.Wherein, Cyclin D is combined with CDK4 and CDK6, mainly in the G1 phase, works; CDK2/cyclin E makes cell enter the S phase from the G1 after date phase, is the initial prerequisite of DNA replication dna, and plays an important role in whole reproduction process; And CDK1/cyclin B can impel the G2 phase to enter mitotic division.Also have other several CDK hypotypes, comprise CDK7, CDK8, CDK9, although directly do not affect the cell cycle, transcribing of cell cycle regulatory factor and genes involved plays an important role.
It is reported, surpass the variation that has Rb protein kinase path in 90% human tumor cell.These variations change relevant with expression imbalance with the expression level of CDK2, CDK4, CDK6, cyclin D, Rb albumen and p16 gene family etc.Research discovery in recent years, at most normal cell, in the cycle, CDK2, CDK4 and CDK6 are optional, and in tumour cell, knock out the growth that these kinase whose genes have affected tumour cell greatly.Because CDKs plays a crucial role in the Proliferation and apoptosis of regulate tumor cell, by optionally suppressing the activity of CDKs in tumor tissues, can play a positive role to the treatment of the neoplasm diseases such as tumour, so the screening of CDKs micromolecular inhibitor and research have been become to one of hot fields of oncotherapy and development of new chemotherapeutics.Over the past two years, CDKs inhibitor had been obtained breakthrough progress in clinical study.CDK1/2/5/9 inhibitor-the MK-7965 (dinaciclib) of Merk company is at the white blood for chronic lymphocytic. in the research of sick (CLL), enter the III phase clinical.Meanwhile, Pfizer company to announce that its CDK4/6 inhibitor-PD-0332991 also enters the III phase in the research that is used for the treatment of mammary cancer clinical.These datas show, CDKs inhibitor is an antitumor target very with researching value.
Summary of the invention
The present invention is by the crystal structure model of research CDK2 protein kinase, take and there is CDK2 to suppress active natural product banisterine (parent nucleus is β-carboline ring) be lead compound, a series of compounds of take the brand new that β-carboline ring is parent nucleus have been designed and synthesized, pharmacological tests shows: compound of the present invention has good CDK2 kinase inhibiting activity, two kinds of tumor cell lines of test are had to stronger inhibition active, the inhibition rate of tumor cell of part of compounds is better than the CDK2 inhibitor AT-7519 having reported at present.
Technical scheme of the present invention is as follows:
The compound of general formula (I) or its pharmacy acceptable salt:
R wherein
1, R
2, R
5, R
6or R
7represent independently of one another hydrogen, alkyl;
R
3represent hydrogen, halogen, alkyl, cycloalkyl, aryl or Het;
R
4expression-NHCOR
9, R wherein
9represent alkyl, cycloalkyl, haloalkyl, aryl or Het;
R
8represent N-ethanoyl-4-piperidyl, N-methylsulfonyl-4-piperidyl or-CH
2ar;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for thering is the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom;
Aryl is the carbocyclic ring that is selected from phenyl, naphthyl, acenaphthenyl or tetralyl, it is optionally replaced by 1,2 or 3 substituting group separately, and each substituting group is independently selected from hydrogen, alkyl, cyano group, halogen, nitro, haloalkyl, hydroxyl, sulfydryl, alkoxyl group, alkylthio, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or Het;
Het is the monocyclic heterocycles that is selected from piperidyl, pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; Or be selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, benzofuryl, benzothienyl, 2,3-dihydrobenzo [1,4] bicyclic heterocycle of dioxine base or benzo [1,3] dioxa cyclopentenyl; Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituting group, and each substituting group is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxyl group;
Halogen is the substituting group that is selected from fluorine, chlorine, bromine or iodine;
Haloalkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom, or for thering is the cyclic saturated hydrocarbon base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Wherein one or more carbon atoms are replaced by one or more halogen atoms.
Another preferred version of the present invention is:
R wherein
1, R
2, R
5, R
6or R
7represent independently of one another hydrogen, alkyl;
R
3represent hydrogen, halogen, alkyl, heteroaryl;
R
4expression-NHCOR
9, R wherein
9represent alkyl, haloalkyl, cycloalkyl, aryl or Het;
R
8represent N-ethanoyl-4-piperidyl, N-methylsulfonyl-4-piperidyl or-CH
2ar;
Another preferred version of the present invention is:
R wherein
1, R
2, R
5, R
6or R
7represent independently of one another hydrogen;
R
3represent hydrogen, bromine, ethyl, thienyl, furyl;
R
4expression-NHCOR
9, R wherein
9represent trifluoromethyl, cyclopropyl, phenyl, substituted-phenyl, heteroaryl or binary heteroaryl; R
8represent N-ethanoyl-4-piperidyl, N-methylsulfonyl-4-piperidyl or-CH
2ar;
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, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.The acid salt that comprises in addition mineral alkali, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
The compound of general formula I is following structural compounds preferably:
3-(N-ethanoyl-4-piperidines is amino)-6-(2-thiazolyl formamido group)-β-carboline (I-9-1)
3-(N-ethanoyl-4-piperidines is amino)-6-phenyl formamido group-β-carboline (I-9-2)
3-(N-ethanoyl-4-piperidines is amino)-6-(4-methyl-phenyl formamido group)-β-carboline (I-9-3)
3-(N-ethanoyl-4-piperidines is amino)-6-cyclopropyl formamido group-β-carboline (I-9-4)
3-(N-ethanoyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3,4-bis-)-β-carboline (I-9-5)
3-(N-ethanoyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-9-6)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-methyl-phenyl formamido group)-β-carboline (I-9-7)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-nitro-phenyl formamido group)-β-carboline (I-9-8)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-9-9)
3-(N-ethanoyl-4-piperidines is amino)-6-(the bromo-phenyl formamido group of 3-)-β-carboline (I-9-10)
3-(N-ethanoyl-4-piperidines is amino)-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-9-11)
3-(N-ethanoyl-4-piperidines is amino)-6-(the bromo-3-trifluoromethyl-phenyl of 4-formamido group)-β-carboline (I-9-12)
3-(N-ethanoyl-4-piperidines is amino)-6-(2-pyrazinyl formamido group)-β-carboline (I-9-13)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-indazolyl formamido group)-β-carboline (I-9-14)
3-(N-ethanoyl-4-piperidines is amino)-6-trifluoroacetamido-β-carboline (I-9-15)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-12-1)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3,4-bis-)-β-carboline (I-12-2)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-12-3)
3-(N-methylsulfonyl-4-piperidines is amino)-6-cyclopropyl formamido group-β-carboline (I-12-4)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the bromo-phenyl formamido group of 3-)-β-carboline (I-12-5)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-methyl-phenyl formamido group)-β-carboline (I-12-6)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-12-7)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-nitro-phenyl formamido group)-β-carboline (I-12-8)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(2-pyrazinyl formamido group)-β-carboline (I-12-9)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the bromo-3-trifluoromethyl-phenyl of 4-formamido group)-β-carboline (I-12-10)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-indazolyl formamido group)-β-carboline (I-12-11)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(4-methyl-phenyl formamido group)-β-carboline (I-12-12)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(2-thiazolyl formamido group)-β-carboline (I-12-13)
3-(N-methylsulfonyl-4-piperidines is amino)-6-trifluoroacetamido-β-carboline (I-12-14)
3-benzyl amino-6-cyclopropyl formamido group-β-carboline (I-15-1)
3-benzyl amino-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-15-2)
3-benzyl amino-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-15-3)
3-benzyl amino-6-(2-thiazolyl formamido group)-β-carboline (I-15-4)
3-benzyl amino-6-(2-pyrazinyl formamido group)-β-carboline (I-15-5)
3-benzyl amino-6-(3-indazolyl formamido group)-β-carboline (I-15-6)
3-benzyl amino-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-15-7)
3-benzyl amino-6-(3-nitro-phenyl formamido group)-β-carboline (I-15-8)
3-benzyl amino-6-(3-methyl-phenyl formamido group)-β-carboline (I-15-9)
3-(N-ethanoyl-4-piperidines is amino) the bromo-6-of-5-encircles the third formamido group-β-carboline (I-17)
3-(N-ethanoyl-4-piperidines is amino)-5-(3-furyl)-6-cyclopropyl formamido group-β-carboline (I-18-1)
3-(N-ethanoyl-4-piperidines is amino)-5-(3-thienyl)-6-cyclopropyl formamido group-β-carboline (I-18-2)
3-(N-ethanoyl-4-piperidines is amino)-5-(3-ethyl)-6-cyclopropyl formamido group-β-carboline (I-18-3)
Part of compounds preparation method of the present invention is as follows:
Method one:
Method two:
Method three:
Method four:
The compounds of this invention can prepare by above-mentioned or similar above-mentioned preparation method, according to the difference of substituent difference and substituting group position, selects corresponding raw material.
Pharmacology test result shows, it is active that the compound of general formula I and pharmacy acceptable salt thereof have good inhibition to CDK2, and therefore, compound of Formula I and pharmacy acceptable salt thereof can be used for the treatment of the clinical disease relevant with CDK2.The described disease relevant with CDK2 can be melanoma, liver cancer, kidney, kemia, 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.
Part pharmacology test and result below:
(1) CDK2 of target compound suppresses determination of activity
FRET (fluorescence resonance energy transfer) for compound (FRET) method of synthesized is measured the inhibition of CDK2/A active, and with positive control drug comparison, filter out active compound preferably.CDK2/A is by purifying or directly buy test kit and obtain.
Concrete grammar: CDK2/A is used after being diluted to suitable concn with kinase dilution liquid.In kinase reaction mixture, contain CDK2/A, peptide substrate, HEPES (pH7.5), BRIJ-35, MgCl
2and EDTA.CDK2phospho-peptide substrate, as 100% phosphorylation contrast, does not add ATP as 0% phosphorylation contrast.Under room temperature, react after 1h, in reaction system, add the appropriate Development Reagent A diluting.Under room temperature, continue reaction 1h, add Stop Reagent stopped reaction.Excitation wavelength 400nm, detect wavelength is the fluorescence intensity of 445nm (coumarin) and 520nm (tluorescein) simultaneously.Press formula and calculate test-compound inhibiting rate.
(2) anti tumor activity in vitro of target compound is measured
With mtt assay, measure breast carcinoma cell strain MDA231, stomach cancer cell line MGC803, stomach cancer cell line BSG823, leukemia cell line K562, breast carcinoma cell strain MCF7, resistance breast carcinoma cell strain MCF7, Leukemic cell strains NB4, hepatoma cell strain HEPG2, umbilical vein vascular endothelial cell strain HUVEC, lung cancer cell line A549, colon cancer cell line HCT116, maxicell lung cancer cell line H460, liver cancer cell SMMC7721, the restraining effect of the tumor cell lines such as lung carcinoma cell H1299.
Mtt assay utilizes the existence desaturase relevant to NADP in viable cell plastosome can make ectogenic MTT be reduced into the bluish voilet crystallisate (Formazan) of insoluble, and is deposited in cell, and dead cell is without this function.Use again the purple crystal thing in dimethyl sulfoxide (DMSO) (DMSO) or three liquid (10%SDS-5% isopropylcarbinol-0.01mol/L HCL) dissolved cell, with enzyme-linked immunosorbent assay instrument, at 570nm wavelength place, measure its its amount of viable cell of OD value indirect reaction.
Concrete grammar: the tumour cell that will test in cell log vegetative period is inoculated in 96 well culture plates by certain cell concentration, adds sieved sample (can directly add after suspension cell fishplate bar) after cultivating 24h, cell is at 37 ℃, 5%CO
2under condition, continue to cultivate after 48 hours, add MTT to continue to cultivate 4 hours, dissolving crystallized with DMSO, under microplate reader, detect.
3), following table is external CDK2 kinase activity and the cancer cell in vitro active testing result of part of compounds:
(in table, compound code name is corresponding to compound code name above)
Pharmacology test result shows, the compounds of this invention has good CDK2 and suppresses active, and it is active to have good antitumor cell, can be used for prevention or the treatment clinical disease relevant with CDK2 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 methyl-silicone oil, and thermometer is not proofreaied and correct; Nicolet Impact410 type determination of infrared spectroscopy for IR spectrum, KBr compressing tablet;
1for HNMR, JEOL FX90Q type fourier transform NMR instrument, BRUKER ACF-300 type nuclear magnetic resonance analyser and BRUKER AM-500 type nuclear magnetic resonance analyser complete (mark in TMS); MS measures with Nicolet2000 type Fourier transform mass spectrometer and MAT-212 type mass spectrograph; CEM Discover single mold microwave instrument for microwave reaction.
Embodiment 1
1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (I-1)
In 250mL three-necked bottle, add tryptophane 10.2g (50mmol), sodium hydrate solid 2.05g (55mmol) and water 100mL, being stirred to solid all dissolves, under room temperature, add formalin 6mL (mmol), this reaction solution is prior to stirring at room 3hr, then reflux 3hr, TLC detects the raw material (methyl alcohol: chloroform=1: 1) that disappears.Reaction solution is poured in frozen water (100mL), with glacial acetic acid, regulated pH to 5, have a large amount of white solids to separate out, cooling, suction filtration, filter cake washes with water, obtain light color white solid (I-1) 9.0g, yield 83.0%, mp:308-310 ℃ [document mp:309-310 ℃].
Embodiment 2
1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid, ethyl ester (I-2)
In 250mL three-necked bottle, add (I-1) 4g (4.6mmol) and dehydrated alcohol 100mL, slowly drip thionyl chloride 5mL under 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, with sodium hydroxide, regulate reaction solution pH to 8-9,4 times (30mL * 4) of ethyl acetate extraction, united extraction liquid is washed once (40mL * 1) with saturated sodium-chloride, removes solvent under reduced pressure and obtains faint yellow solid, by re-crystallizing in ethyl acetate, obtains white solid (I-2) 3.5g, yield 77.8%, mp:319-321 ℃ [document mp:319-321 ℃].
Embodiment 3
β-carboline-3-carboxylic acid, ethyl ester (I-3)
In the mono-neck bottle of 250ml, add crude product I-21g (4.1mmol) and DMF150mL, under ice bath, add KMnO4 solid 1g (6.6mmol), finish 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-3) 0.85g by re-crystallizing in ethyl acetate, yield 86.7%, mp:230-231 ℃ [document mp:231-232 ℃].
Embodiment 4
6-nitro-β-carboline-3-carboxylic acid, ethyl ester (I-4)
In the mono-neck bottle of 250mL, add 60mL nitrosonitric acid, be cooled to-10 ℃, add (I-3) 10g (0.035mmol) solid under stirring in batches, under cold condition, react 2hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 1).Thin up, separates out a large amount of solids, suction filtration, and a small amount of water washing of filter cake, and dry, obtain yellow solid (I-4) 9.4g, yield 89.2%, product, without purifying, is directly cast single step reaction.
Embodiment 5
6-nitro-β-carboline-3-carbonyl hydrazide (I-5)
In 250mL three-necked bottle, add (I-4) 6g (0.025mol), hydrazine hydrate (30mL) and methyl alcohol (100mL), reflux 6hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 1).Naturally cooling is separated out a large amount of solids, suction filtration, and a small amount of washing with alcohol for filter cake, obtains yellow solid (I-5) 4.86g, yield 86.0%, product, without being further purified, is directly cast single step reaction.
Embodiment 6
3-amino-6-nitro-β-carboline (I-6)
In 250mL three-necked bottle, add (I-5) 6g (0.027mol), concentrated hydrochloric acid (5mL) and water (120mL), vigorous stirring makes it to dissolve, and cools to 0 ℃, slowly drips NaNO
21.9g (0.028mol) frozen water solution (20mL), drips complete insulation reaction 30min, and TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2), obtain clear soln.Reaction solution is slowly heated up and makes it to reflux, emit a large amount of gas, backflow 1hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Naturally cooling, regulates pH to 8-9 with dense NaOH, separates out a large amount of solids, and standing, suction filtration, obtains yellow solid (I-6) 4.04g, yield 83.1%, and product, without being further purified, is directly cast single step reaction.
Embodiment 7
3-(N-ethanoyl-4-piperidines is amino)-6-nitro-β-carboline (I-7)
In single neck bottle of 100mL, add (I-6) 2g (8.8mmol), N-ethanoyl-4-piperidone 2g (17.6mmol), trifluoroacetic acid 2.2mL and DMF (40mL), stir, add NaBH (AcO)
34g (20mmol), room temperature reaction 12hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Add water, with dense NaOH, regulate pH to 8-9, separate out solid, ethyl alcohol recrystallization, obtains 1.8g orange/yellow solid (I-7), yield 58.1%.
Embodiment 8
3-(N-ethanoyl-4-piperidines is amino)-6-amino-beta--carboline (I-8)
In the mono-neck bottle of 100mL, add (I-7) 2g (5.6mmol), 10% palladium carbon 0.2g and 40mL methyl alcohol, stir, add sodium borohydride 0.7g (16.8mmol) in batches, room temperature reaction 6hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Reaction solution suction filtration, filtrate is spin-dried for, and obtains light yellow solid (I-8) 1.7g, and yield is 94.1%, and product, without being further purified, is directly cast single step reaction.
Embodiment 9
3-(N-ethanoyl-4-piperidines is amino)-6-(2-thiazolyl formamido group)-β-carboline (I-9-1)
In the eggplant-shape bottle of 50mL, add thiazole-2-formic acid 60mg (0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 62mg (0.5mmol), I-hydroxybenzotriazole (HOBT) 59mg (0.3mmol) and dry DMF 10mL.After stirring 10min, slowly add (I-8) 100mg (0.31mmol), room temperature reaction, spends the night.In reaction solution, add 40mL water, 3 times (40mL * 3) of ethyl acetate extraction, merge organic layer and use the water washing of 40mL saturated common salt once, and anhydrous sodium sulfate drying, spends the night, suction filtration, and concentrated filtrate obtains yellow solid.Crude product is through column chromatography (developping agent: methyl alcohol: chloroform=1: 30), obtain product (I-9-1) 72mg, yield 53.5%.MS[M-H]
-433.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.4(1H，s，indole)，10.9(1H，s，-CONH-)，8.8(1H，s，ArH)，8.4(1H，s，ArH)，8.1(2H，m，ArH)，7.9(1H,d，J＝8.9Hz，ArH)，7.7(1H，s，ArH)，7.5(1H，d，J＝8.9Hz，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2).
Embodiment 10
3-(N-ethanoyl-4-piperidines is amino)-6-phenyl formamido group-β-carboline (I-9-2)
In the eggplant-shape bottle of 50mL, add phenylformic acid 56mg (0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 62mg (0.5mmol), I-hydroxybenzotriazole (HOBT) 59mg (0.3mmol) and dry DMF 10mL.After stirring 10min, slowly add (I-8) 100mg (0.31mmol), room temperature reaction, spends the night.Preparation method is similar to (I-9-1), obtains product (I-9-2) 69mg, yield 52.1%.MS[M+H]
+428.3。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.6(1H，s，indole)，10.3(1H，s，-CONH-)，8.7(1H，s，ArH)，8.6(1H，s，ArH)，8.0(1H，m，ArH)，7.7(2H,m，ArH)，7.5(2H，m，ArH)，7.2(2H，m，ArH)，7.1(1H，s，ArH)，5.9(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.1(3H，s，-OCCH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 11
3-(N-ethanoyl-4-piperidines is amino)-6-(4-methyl-phenyl formamido group)-β-carboline (I-9-3)
Preparation method is similar to (I-9-1), obtains product (I-9-3) 74mg, yield 57.3%.MS[M+H]
+442.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.2(1H，s，-CONH-)，8.5(1H，s，ArH)，8.3(1H，s，ArH)，7.9(2H，d，J＝7.8Hz，ArH)，7.7(1H，d，J＝8.5Hz，ArH)，7.3(3H，m，ArH)，7.1(1H，s，ArH)，5.8(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.4(3H，s，-ArCH
3)，2.1(3H，s，-OCCH
3)，1.6(4H，m，-CH
2-×2).
Embodiment 12
3-(N-ethanoyl-4-piperidines is amino)-6-cyclopropyl formamido group-β-carboline (I-9-4)
Preparation method is similar to (I-9-1), obtains product (I-9-4) 64mg, yield 62.3%.MS[M+H]
+392.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.7(1H，s，indole)，10.1(1H，s，-CONH-)，8.3(1H，s，ArH)，8.3(1H，s，ArH)，7.5(1H，d，J＝5.4Hz，ArH)，7.3(1H，d，J＝5.4Hz，ArH)，7.0(1H，s，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2)，1.3(1H，m，-CH-)，1.2(4H，m，-CH
2-×2).
Embodiment 13
3-(N-ethanoyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3,4-bis-)-β-carboline (I-9-5)
Preparation method is similar to (I-9-1), obtains product (I-9-5) 83mg, yield 69.5%.MS[M+H]
+496.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.7(1H，s，indole)，10.1(1H，s，-CONH-)，8.3(1H，s，ArH)，8.3(1H，s，ArH)，7.5(1H，d，J＝5.4Hz，ArH)，7.3(1H，d，J＝5.4Hz，ArH)，7.0(1H，s，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2).
Embodiment 14
3-(N-ethanoyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-9-6)
Preparation method is similar to (I-9-1), obtains product (I-9-6) 63mg, yield 67.3%.MS[M+H]
+462.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.3(1H，s，indole)，10.4(1H，s，-CONH-)，8.6(1H，s，ArH)，8.3(1H，s，ArH)，8.1(1H，s，ArH)，7.9(1H，d，J＝4.5Hz，ArH)，7.8(1H，d，J＝5.1Hz，ArH)，7.7(1H，d，J＝4.8Hz，ArH)，7.6(2H，m，ArH)，7.4(1H，s，ArH)，5.9(1H，s，NH)，4.0(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2).
Embodiment 15
3-(N-ethanoyl-4-piperidines is amino)-6-(3-methyl-phenyl formamido group)-β-carboline (I-9-7)
Preparation method is similar to (I-9-1), obtains product (I-9-7) 54mg, yield 56.9%.MS[M+H]
+442.3。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.3(1H，s，indole)，10.3(1H，s，-CONH-)，8.7(1H，s，?ArH)，8.4(1H，s，ArH)，7.8(3H，m，ArH)，7.6(1H，s，ArH)，7.5(1H，m，ArH)，7.0-7.1(2H，m，ArH)，5.9(1H，s，NH)，4.0(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.4(3H，s，-ArCH
3)，2.0(3H，s，-OCCH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 16
3-(N-ethanoyl-4-piperidines is amino)-6-(3-nitro-phenyl formamido group)-β-carboline (I-9-8)
Preparation method is similar to (I-9-1), obtains product (I-9-8) 80mg, yield 71.9%.MS[M+H]
+473.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.6(1H，s，-CONH-)，8.8(1H，s，ArH)，8.5(3H，m，ArH)，8.4(1H，s，ArH)，7.9(1H，m，ArH)，7.7(1H，m，ArH)，7.4(1H，d，J＝8.7Hz，ArH)，7.1(1H，s，ArH)，5.9(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 17
3-(N-ethanoyl-4-piperidines is amino)-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-9-9)
Preparation method is similar to (I-9-1), obtains product (I-9-9) 72mg, yield 63.9%.MS[M+H]
+471.3。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.0(1H，s，indole)，10.2(1H，s，-CONH-)，8.6(1H，s，ArH)，8.4(1H，m，ArH)，7.7(1H，m，ArH)，7.5(1H，d，J＝8.7Hz，ArH)，7.3(3H，m，ArH)，7.0(1H，d，J＝8.7Hz，ArH)，6.4(1H，s，ArH)，5.9(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，3.2(6H，s，-NCH
3×2)，2.9(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2).
Embodiment 18
3-(N-ethanoyl-4-piperidines is amino)-6-(the bromo-phenyl formamido group of 3-)-β-carboline (I-9-10)
Preparation method is similar to (I-9-1), obtains product (I-9-10) 58mg, yield 65.7%.MS[M+H]
+506.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.4(1H，s，-CONH-)，8.5(1H，s，ArH)，8.4(1H，s，ArH)，8.2(1H，s，ArH)，8.0(1H，d，J＝7.5Hz，ArH)，7.8(1H，d，J＝7.8Hz，ArH)，7.7(1H，d，J＝7.8Hz，ArH)，7.5(1H，m，ArH)，7.4(1H，m，ArH)，7.2(1H，s，ArH)，5.9(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，3.0(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.2(4H，m，-CH
2-×2).
Embodiment 19
3-(N-acetyl 4-piperidines is amino)-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-9-11)
Preparation method is similar to (I-9-1), obtains product (I-9-11) 54mg, yield 59.4%.MS[M+H]
+446.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.3(1H，s，-CONH-)，8.5(1H，s，ArH)，8.4(1H，s，ArH)，7.8(3H，m，ArH)，7.6(1H，m，ArH)，7.4(2H，m，ArH)，7.1(1H，s，ArH)，?5.9(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，2.7(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.2(4H，m，-CH
2-×2).
Embodiment 20
3-(N-ethanoyl-4-piperidines is amino)-6-(the bromo-3-trifluoromethyl-phenyl of 4-formamido group)-β-carboline (I-9-12)
Preparation method is similar to (I-9-1), obtains product (I-9-12) 73mg, yield 62.7%.MS[M+H]
+574.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.2(1H，s，indole)，10.6(1H，s，-CONH-)，8.6(1H，s，ArH)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，8.2(1H，d，J＝7.8Hz，ArH)，8.1(1H，d，J＝7.8Hz，ArH)，7.8(1H，m，ArH)，7.5(1H，m，ArH)，7.4(1H，s，ArH)，5.9(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.2(4H，m，-CH
2-×2).
Embodiment 21
3-(N-ethanoyl-4-piperidines is amino)-6-(2-pyrazinyl formamido group)-β-carboline (I-9-13)
Preparation method is similar to (I-9-1), obtains product (I-9-13) 49mg, yield 52.1%.MS[M+H]
+430.4。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.3(1H，s，indole)，10.9(1H，s，-CONH-)，9.3(1H，d，J＝1.2Hz，ArH)，8.9(1H，d，J＝2.4Hz，ArH)，8.8(2H，m，ArH)，8.4(1H，s，ArH)，8.0(1H，d，J＝8.7Hz，ArH)，7.6(1H，m，ArH)，7.1(1H，s，ArH)，5.9(1H，s，NH)，4.0(4H，m，-NCH
2-×2)，3.1(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.3(4H，m，-CH
2-×2).
Embodiment 22
3-(N-ethanoyl-4-piperidines is amino)-6-(3-indazolyl formamido group)-β-carboline (I-9-14)
Preparation method is similar to (I-9-1), obtains product (I-9-14) 76mg, yield 68.4%.MS[M+H]
+468.3。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.8(1H，s，1H-indazole)，11.3(1H，s，indole)，10.5(1H，s，-CONH-)，8.8(1H，s，ArH)，8.4(1H，s，ArH)，8.3(1H，d，J＝5.1Hz，ArH)，8.0(1H，d，J＝9.0Hz，ArH)，7.7(1H，d，J＝9.0Hz，ArH)，7.5(3H，m，ArH)，7.2(1H，s，ArH)，5.9(1H，s，NH)，4.0(4H，m，-NCH
2-×2)，3.1(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.2(4H，m，-CH
2-×2).
Embodiment 23
3-(N-ethanoyl-4-piperidines is amino)-6-trifluoroacetamido-β-carboline (I-9-15)
Preparation method is similar to (I-9-1), obtains product (I-9-14) 51mg, yield 48.9%.MS[M+H]
+420.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.4(1H，s，indole)，11.3(1H，s，-CONH-)，8.6(1H，s，ArH)，8.4(1H，s，ArH)，7.7(1H，d，J＝9.1Hz，ArH)，7.5-7.6(2H，m，ArH)，5.9(1H，s，NH)，3.9(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.1(3H，s，-OCCH
3)，1.3(4H，m，-CH
2-×2).
Embodiment 24
3-(N-methylsulfonyl base-4-piperidines is amino)-6-nitro-β-carboline (I-10)
In single neck bottle of 100mL, add (I-6) 2g (8.8mmol), N-methylsulfonyl-4-piperidone 2g (17.6mmol), trifluoroacetic acid 2.2mL and DMF (40mL); stir; add NaBH (AcO) 34g (20mmol); room temperature reaction 12hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Add water, with dense NaOH, regulate pH to 8-9, separate out solid, ethyl alcohol recrystallization, obtains 1.5g orange/yellow solid (I-10), yield 54.3%.
Embodiment 25
3-(N-methylsulfonyl-4-piperidines is amino)-6-amino-beta--carboline (I-11)
In the mono-neck bottle of 100mL, add (I-10) 2g (5.6mmol), 10% palladium carbon 0.2g and 40mL methyl alcohol, stir, add sodium borohydride 0.7g (16.8mmol) in batches, room temperature reaction 6hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Reaction solution suction filtration, filtrate is spin-dried for, and obtains light yellow solid (I-11) 1.8g, and yield is 94.3%, and product, without being further purified, is directly cast single step reaction.
Embodiment 26
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-12-1)
In the eggplant-shape bottle of 50mL, add m-chlorobenzoic acid 65mg (0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 62mg (0.5mmol), I-hydroxybenzotriazole (HOBT) 59mg (0.3mmol) and dry DMF 10mL.After stirring 10min, slowly add (1-11) 100mg (0.31mmol), room temperature reaction, spends the night.In reaction solution, add 40mL water, 3 times (40mL * 3) of ethyl acetate extraction, merge organic layer and use the water washing of 40mL saturated common salt once, and anhydrous sodium sulfate drying, spends the night, suction filtration, and concentrated filtrate obtains yellow solid.Crude product is through column chromatography (developping agent: methyl alcohol: chloroform=1: 30), obtain product (I-12-1) 89mg, yield 57.8%.MS[M+H]
+498.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.4(1H，s，-CONH-)，8.5(1H，s，ArH)，8.4(1H,s，ArH)，8.1(1H,s，ArH)，8.0(1H，d，J＝7.2Hz，ArH)，7.7(2H，m，ArH)，7.6(1H，d，J＝7.2Hz，ArH)，7.4(1H，m，ArH)，7.1(1H,s，ArH)，5.9(1H，s，NH)，3.5(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.8(3H，s，-SO
2CH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 27
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3,4-bis-)-β-carboline (I-12-2)
Preparation method is similar to (I-12-1), obtains product (I-12-2) 78mg, yield 58.9%.MS[M+H]
+532.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.2(1H，s，indole)，10.5(1H，s，-CONH-)，8.6(1H，s，?ArH)，8.4(1H，s，ArH)，8.3(1H，d，J＝2.0Hz，ArH)，8.0(1H，m，ArH)，7.8-7.9(2H，m，ArH)，7.5(1H，d，J＝8.5Hz，ArH)，7.4(1H，s，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 28
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-12-3)
Preparation method is similar to (I-12-1), obtains product (I-12-3) 67mg, yield 61.5%.MS[M+H]
+482.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.3(1H，s，-CONH-)，8.5(1H，s，ArH)，8.4(1H，s，ArH)，7.7-7.9(3H，m，ArH)，7.6(1H，m，ArH)，7.4-7.5(2H，m，ArH)，7.1(1H，s，ArH)，6.0(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.8(3H，s，-SO
2CH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 29
3-(N-methylsulfonyl-4-piperidines is amino)-6-cyclopropyl formamido group-β-carboline (I-12-4)
Preparation method is similar to (I-12-1), obtains product (I-12-4) 64mg, yield 58.4%.MS[M+H]
+428.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.0(1H，s，indole)，10.2(1H，s，-CONH-)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，7.5(1H，m，ArH)，7.4(1H，d，J＝8.7Hz，ArH)，7.2(1H，s，ArH)，6.1(1H，s，NH)，3.6(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.8(1H，m，-CH-)，1.5(4H，m，-CH
2-×2)，1.1-1.2(4H，m，-CH
2-×2).
Embodiment 30
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the bromo-phenyl formamido group of 3-)-β-carboline (I-12-5)
Preparation method is similar to (I-12-1), obtains product (I-12-5) 73mg, yield 64.7%.MS[M+H]
+542.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.4(1H，s，indole)，10.5(1H，s，-CONH-)，8.7(1H，s，ArH)，8.4(1H，s，ArH)，8.2(1H，s，ArH)，8.0(1H，d，J＝7.7Hz，ArH)，7.8-7.9(2H，m，ArH)，7.7(1H，s，ArH)，7.5-7.6(2H，m，ArH)，5.7(1H，s，NH)，3.6(4H，m，-NCH
2-×2)，3.0(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.6(4H，m，-CH
2-×2).
Embodiment 31
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-methyl-phenyl formamido group)-β-carboline (I-12-6)
Preparation method is similar to (I-12-1), obtains product (I-12-6) 64mg, yield 63.8%.MS[M+H]
+478.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.2(1H，s，-CONH-)，8.5(1H，s，ArH)，8.3(1H，s，ArH)，7.7(3H，m，ArH)，7.4(3H，m，ArH)，7.1(1H，s，ArH)，6.0(1H，s，NH)，3.5(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.8(3H，s，-SO
2CH
3)，2.4(3H，s，-ArCH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 32
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-12-7)
Preparation method is similar to (I-12-1), obtains product (I-12-7) 72mg, yield 62.2%.MS[M+H]
+507.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.3(1H，s，indole)，10.2(1H，s，-CONH-)，8.7(1H，s，ArH)，8.4(1H，m，ArH)，7.8(1H，d，J＝9.3Hz，ArH)，7.5(2H，m，ArH)，7.3(3H，m，ArH)，6.9(1H，s，ArH)，5.8(1H，s，NH)，3.6(4H，m，-NCH
2-×2)，3.0(6H，s，-NCH
3×2)，2.9(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.6(4H，m，-CH
2-×2).
Embodiment 33
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-nitro-phenyl formamido group)-β-carboline (I-12-8)
Preparation method is similar to (I-12-1), obtains product (I-12-8) 57mg, yield 57.2%.MS[M+H]
+509.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.5(1H，s，indole)，10.8(1H，s，-CONH-)，8.9(1H，s，ArH)，8.8(1H，s，ArH)，8.5(2H，m，ArH)，8.4(1H，s，ArH)，7.8-7.9(2H，m，ArH)，7.7(1H，s，ArH)，7.6(1H，s，ArH)，5.7(1H，s，NH)，3.6(4H，m，-NCH
2-×2)，3.1(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.6(4H，m，-CH
2-×2).
Embodiment 34
3-(N-methylsulfonyl-4-piperidines is amino)-6-(2-pyrazinyl formamido group)-β-carboline (I-12-9)
Preparation method is similar to (I-12-1), obtains product (I-12-9) 65mg, yield 63.4%.MS[M+H]
+466.4。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.9(1H，s，indole)，10.7(1H，s，-CONH-)，9.3(1H，sArH)，8.9(1H，d，J＝2.4Hz，ArH)，8.8(1H，m，ArH)，8.6(1H，s，ArH)，8.4(1H，s，ArH)，7.8-7-9(1H，dd，J＝1.9Hz，ArH)，7.4(1H，d，J＝8.7Hz，ArH)，7.1(1H，s?ArH)，5.9(1H，s，NH)，3.6(4H，m，?-NCH
2-×2)，3.0(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 35
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the bromo-3-trifluoromethyl-phenyl of 4-formamido group)-β-carboline (I-12-10)
Preparation method is similar to (I-12-1), obtains product (I-12-10) 73mg, yield 69.7%.MS[M+H]
+610.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.3(1H，s，indole)，10.5(1H，s，-CONH-)，8.6(1H，s，ArH)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，8.2(1H，d，J＝7.7Hz，ArH)，8.1(1H，d，J＝7.7Hz，ArH)，7.8(1H，m，ArH)，7.5(1H，m，ArH)，7.3(1H，s，ArH)，5.8(1H，s，NH)，3.6(4H，m，-NCH
2-×2)，3.0(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.6(4H，m，-CH
2-×2).
Embodiment 36
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-indazolyl formamido group)-β-carboline (I-12-11)
Preparation method is similar to (I-12-1), obtains product (I-12-11) 58mg, yield 52.6%.MS[M+H]
+504.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.9(1H，s，1H-indazole)，11.3(1H，s，indole)，10.3(1H，s，-CONH-)，8.9(1H，s，ArH)，8.4(1H，s，ArH)，8.2(1H，d，J＝5.4Hz，ArH)，8.1(1H，d，J＝9.0Hz，ArH)，7.8(1H，d，J＝9.0Hz，ArH)，7.5(3H，m，ArH)，7.2(1H，s，ArH)，6.0(1H，s，NH)，3.5(4H，m，-NCH
2-×2)，3.0(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 37
3-(N-methylsulfonyl-4-piperidines is amino)-6-(4-methyl-phenyl formamido group)-β-carboline (I-12-12)
Preparation method is similar to (I-12-1), obtains product (I-12-12) 59mg, yield 57.4%.MS[M+H]
+478.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.3(1H，s，-CONH-)，8.6(1H，s，ArH)，8.4(1H，s，ArH)，7.9(2H，d，J＝7.8Hz，ArH)，7.7(1H，d，J＝8.5Hz，ArH)，7.2(3H，m，ArH)，7.1(1H，s，ArH)，5.9(1H，s，NH)，3.5(4H，m，-NCH
2-×2)，3.0(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，2.2(3H，s，-ArCH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 38
3-(N-methylsulfonyl-4-piperidines is amino)-6-(2-thiazolyl formamido group)-β-carboline (I-12-13)
Preparation method is similar to (I-12-1), obtains product (I-12-13) 76mg, yield 65.8%.MS[M+H]
+471.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.5(1H，s，indole)，10.9(1H，s，-CONH-)，8.7(1H，s，ArH)，8.4(1H，s，ArH)，8.2(2H，m，ArH)，7.9(1H,d，J＝8.9Hz，ArH)，7.7(1H，s，ArH)，7.5(1H，d，J＝8.9Hz，ArH)，5.7(1H，s，NH)，3.6(4H，m，-NCH
2-×2)，3.0(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.4(4H，m，-CH
2-×2).
Embodiment 39
3-(N-methylsulfonyl-4-piperidines is amino)-6-trifluoroacetamido-β-carboline (I-12-14)
Preparation method is similar to (I-12-1), obtains product (I-12-14) 71mg, yield 64.1%.MS[M+H]
+456.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.2(1H，s，indole)，11.0(1H，s，-CONH-)，8.4(1H,s，ArH)，8.3(1H,s，ArH)，7.6(1H，d，J＝8.7Hz，ArH)，7.4(1H，d，J＝8.7Hz，ArH)，7.1(1H,s，ArH)，5.9(1H，s，NH)，4.1(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.9(3H，s，-SO
2CH
3)，1.5(4H，m，-CH
2-×2).
Embodiment 40
3-benzyl amino-6-nitro-β-carboline (I-12-15)
In single neck bottle of 100mL, add (I-6) 2g (8.8mmol), phenyl aldehyde 1.9g (17.6mmol), trifluoroacetic acid 2.2mL and DMF (40mL), stir, add NaBH (AcO)
34g (20mmol), room temperature reaction 12hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Add water, with dense NaOH, regulate pH to 8-9, separate out solid, ethyl alcohol recrystallization, obtains 1.4g yellow solid (I-13), yield 54.3%.
Embodiment 41
3-benzyl amino-6-amino-beta--carboline (I-14)
In the mono-neck bottle of 100mL, add (I-13) 2g (5.6mmol), 10% palladium carbon 0.2g and 40mL methyl alcohol, stir, add sodium borohydride 0.7g (16.8mmol) in batches, room temperature reaction 6hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Reaction solution suction filtration, filtrate is spin-dried for, and obtains light yellow solid (I-14) 1.8g, and yield is 93.5%, and product, without being further purified, is directly cast single step reaction.
Embodiment 42
3-benzyl amino-6-cyclopropyl formamido group-β-carboline (I-15-1)
In the eggplant-shape bottle of 50mL, add cyclopropanecarboxylic acid 40mg (0.46mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 62mg (0.5mmol), I-hydroxybenzotriazole (HOBT) 59mg (0.3mmol) and dry DMF 10mL.After stirring 10min, slowly add (I-14) 100mg (0.31mmol), room temperature reaction, spends the night.In reaction solution, add 40mL water, 3 times (40mL * 3) of ethyl acetate extraction, merge organic layer and use the water washing of 40mL saturated common salt once, and anhydrous sodium sulfate drying, spends the night, suction filtration, and concentrated filtrate obtains yellow solid.Crude product is through column chromatography (developping agent: methyl alcohol: chloroform=1: 30), obtain product (I-15-1) 66mg, yield 59.8%.MS[M+H]
+367.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.7(1H，s，indole)，10.1(1H，s，-CONH-)，8.3(1H，s，ArH)，8.2(1H，s，ArH)，7.5(1H，d，J＝8.7Hz，ArH)，7.2-7.4(5H，m,ArH)，7.2(1H，d，J＝7.0Hz，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(2H，m，-NCH
2Ar)，1.7(1H，m，-CH-)，0.8(4H，m，-CH
2-×2).
Embodiment 43
3-benzyl amino-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-15-2)
Preparation method is similar to (I-15-1), obtains product (I-15-2) 58mg, yield 66.5%.MS[M+H]
+427.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.3(1H，s，-CONH-)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，8.0(1H，s，ArH)，7.9(1H，d，J＝9.0Hz，ArH)，7.7(1H，d，J＝9.0Hz，ArH)，7.6(1H，d，J＝9.0Hz，ArH)，7.5-7.6(1H，d，J＝6.0Hz，ArH)，7.3-7.4(5H，m，ArH)，7.2(1H，s，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(4H，m，-NCH
2Ar).
Embodiment 44
3-benzyl amino-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-15-3)
Preparation method is similar to (I-15-1), obtains product (I-15-3) 73mg, yield 69.7%.MS[M+H]
+436.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.1(1H，s，-CONH-)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，8.0(1H，s，ArH)，7.9(1H，d，J＝9.0Hz，ArH)，7.7(1H，d，J＝9.0Hz，ArH)，7.6(1H，d，J＝9.0Hz，ArH)，7.5-7.6(1H，d，J＝6.0Hz，ArH)，7.3-7.4(5H，m，ArH)，7.2(1H，s，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(4H，m，-NCH
2Ar).
Embodiment 45
3-benzyl amino-6-(2-thiazolyl formamido group)-β-carboline (I-15-4)
Preparation method is similar to (I-15-1), obtains product (I-15-4) 63mg, yield 59.4%.MS[M+H]
+400.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.7(1H，s，-CONH-)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，8.1(2H，m，ArH)，7.8(1H，d，J＝6.0Hz，ArH)，7.4(3H，m，ArH)，7.3(2H，m，ArH)，7.2(1H，d，J＝9.0Hz，ArH)，7.0(1H，s，ArH)，6.5(1H，s，NH)，4.5(2H，m，-NCH
2Ar).
Embodiment 46
3-benzyl amino-6-(2-pyrazinyl formamido group)-β-carboline (I-15-5)
Preparation method is similar to (I-15-1), obtains product (I-15-5) 58mg, yield 52.3%.MS[M+H]
+395.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.7(1H，s，-CONH-)，9.3(1H，s，ArH)，8.9(1H，d，J＝3.0Hz，ArH)，8.8(1H，s，ArH)，8.5(1H，s，ArH)，8.3(1H，s，ArH)，7.8(1H，d，J＝9.0Hz，ArH)，7.3-7.4(5H，m，ArH)，7.2(1H，d，J＝9.0Hz，ArH)，7.0(1H，s，ArH)，6.5(1H，s，NH)，4.5(2H，m，-NCH
2Ar).
Embodiment 47
3-benzyl amino-6-(3-indazolyl formamido group)-β-carboline (I-15-6)
Preparation method is similar to (I-15-1), obtains product (I-15-6) 72mg, yield 69.3%.MS[M+H]
+433.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：13.7(1H，s，1H-indazole)，10.8(1H，s，indole)，10.3(1H，s，-CONH-)，8.5(1H，s，ArH)，8.3(1H，s，ArH)，8.2(1H，d，J＝6.0Hz，ArH)，7.8(1H，m，ArH)，7.6(1H，d，J＝6.0Hz，ArH)，7.3-7.4(7H，m，ArH)，7.2(1H，m，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(2H，m，-NCH
2Ar).
Embodiment 48
3-benzyl amino-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-15-7)
Preparation method is similar to (I-15-1), obtains product (I-15-7) 65mg, yield 62.7%.MS[M+H]
+411.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.3(1H，s，-CONH-)，8.4(1H，s，ArH)，8.3(1H，s，ArH)，7.9(1H，s，ArH)，7.8(1H，d，J＝9.0Hz，ArH)，7.7(1H，d，J＝9.0Hz，ArH)，7.6(1H，d，J＝9.0Hz，ArH)，7.5(1H，d，J＝6.0Hz，ArH)，7.3-7.4(5H，m，ArH)，7.2(1H，s，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(2H，m，-NCH
2Ar).
Embodiment 49
3-benzyl amino-6-(3-nitro-phenyl formamido group)-β-carboline (I-15-8)
Preparation method is similar to (I-15-1), obtains product (I-15-8) 55mg, yield 49.7%.MS[M+H]
+438.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：11.5(1H，s，indole)，10.8(1H，s，-CONH-)，
8.7(1H，s，ArH)，8.6(1H，s，ArH)，7.5(1H，s，ArH)，7.4(1H,m，ArH)，7.3(1H，d，J＝9.0Hz，ArH)，7.2(1H，d，J＝9.0Hz，ArH)，7.1-7.2(7H，m，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(2H，m，-NCH
2Ar).
Embodiment 50
3-benzyl amino-6-(3-methyl-phenyl formamido group)-β-carboline (I-15-9)
Preparation method is similar to (I-15-1), obtains product (I-15-9) 55mg, yield 49.7%.MS[M+H]
+407.4。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.3(1H，s，-CONH-)，8.4(1H，s，ArH)，8.2(1H，s，ArH)，8.1(1H，s，ArH)，8.0(1H，d，J＝9.0Hz，ArH)，7.8(1H，d，J＝9.0Hz，ArH)，7.6(1H，d，J＝9.0Hz，ArH)，7.5(1H，d，J＝6.0Hz，ArH)，7.3-7.4(5H，m，ArH)，7.1(1H，s，ArH)，7.0(1H，s，ArH)，6.4(1H，s，NH)，4.5(2H，m，-NCH
2Ar)，2.3(3H，s，-ArCH
3).
Embodiment 51
3-(N-ethanoyl-4-piperidines is amino) the bromo-6-amino-beta--carboline of-5-(I-16)
In single neck bottle of 100mL, add (I-8) 1g (3mmol) and dimethyl sulfoxide (DMSO) 30mL, stirring at room, drips 30mL hydrogen bromide solution, reaction 24hr, and TLC detects raw material disappearance (methyl alcohol: chloroform=1: 2).Reaction solution thin up, regulates PH to 9 with dense NaOH, separates out solid, suction filtration, and solid is dried, and obtains product (I-16) 0.8g, and yield is 66.7%.Product, without purifying, is directly thrown next step.
Embodiment 52
3-(N-ethanoyl-4-piperidines is amino) the bromo-6-of-5-encircles the third formamido group-β-carboline (I-17)
In the eggplant-shape bottle of 50mL, add cyclopropanecarboxylic acid 0.2g (2.3mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) 0.4g (3mmol), I-hydroxybenzotriazole (HOBT) 0.4g (2mmol) and dry DMF 40mL.After stirring 10min, slowly add (I-16) 0.8g (2mmol), room temperature reaction, spends the night, and TLC detects raw material disappearance (methyl alcohol: chloroform=1: 10).In reaction solution, add 40mL water, 3 times (40mL * 3) of ethyl acetate extraction, merge organic layer and use the water washing of 40mL saturated common salt once, anhydrous sodium sulfate drying, spends the night, suction filtration, concentrated filtrate obtains yellow solid, obtains product (I-17) 0.6g, yield 61.8%.MS[M+H]
+469.3。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.5(1H，s，-CONH-)，8.7(1H，s，ArH)，7.1(1H，s，ArH)，7.0(1H，s，ArH)，6.9(1H，m，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，?2.8(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2)，1.3(1H，m，-CH-)，1.2(4H，m，-CH
2-×2).
Embodiment 53
3-(N-ethanoyl-4-piperidines is amino)-5-(3-furyl)-6-cyclopropyl formamido group-β-carboline (I-18-1)
Mixed solvent (the dioxane: water=10: 1) that adds (I-17) 100mg (0.21mmol) and 20mL dioxane and water in the three-necked bottle of 100mL; under nitrogen protection condition; add 3-furans boric acid 36mg (0.3mmol), tetra-triphenylphosphine palladium 13mg (0.01mmol) and three water potassiumphosphate 170mg (0.63mmol); reaction solution backflow 12hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 10).Be spin-dried for solvent, crude product is through column chromatography (developping agent: methyl alcohol: chloroform=1: 30), obtain product (I-18-1) 76mg, yield 69.8%.MS[M+H]
+458.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.2(1H，s，-CONH-)，8.4(1H，s，ArH)，7.5(1H，d，J＝5.4Hz，ArH)，7.4(1H，m，ArH)，7.3(1H，d，J＝5.4Hz，ArH)，7.2(1H，s，ArH)，7.0(1H，s，ArH)，6.4(1H，m，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.0(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2)，1.3(1H，m，-CH-)，1.2(4H，m，-CH
2-×2).
Embodiment 54
3-(N-acetyl 4-piperidines is amino)-5-(3-thienyl)-6-cyclopropyl formamido group-β-carboline (I-18-2)
Mixed solvent (the dioxane: water=10: 1) that adds (I-17) 120mg (0.26mmol) and 20mL dioxane and water in the three-necked bottle of 100mL; under nitrogen protection condition; add 3-thiophene trifluoro boron potassium 72mg (0.37mmol), tetra-triphenylphosphine palladium 13mg (0.01mmol) and three water potassiumphosphate 210mg (0.78mmol); reaction solution backflow 12hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 10).Be spin-dried for solvent, crude product is through column chromatography (developping agent: methyl alcohol: chloroform=1: 30), obtain product (I-18-2) 80mg, yield 65.1%.MS[M+H]
+474.2。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.8(1H，s，indole)，10.2(1H，s，-CONH-)，8.0(1H，m，ArH)，7.5(1H，d，J＝5.4Hz，ArH)，7.4(1H，m，ArH)，7.3(1H，d，J＝5.4Hz，ArH)，7.2(1H，s，ArH)，7.0(1H，s，ArH)，6.9(1H，m，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.9(1H，m，-NCH-)，2.1(3H，s，-OCCH
3)，1.4(4H，m，-CH
2-×2)，1.4(1H，m，-CH-)，1.2(4H，m，-CH
2-×2).
Embodiment 55
3-(N-ethanoyl-4-piperidines is amino)-5-(3-ethyl)-6-cyclopropyl formamido group-β-carboline (I-18-3)
Mixed solvent (the dioxane: water=10: 1) that adds (I-17) 100mg (0.21mmol) and 20mL dioxane and water in the three-necked bottle of 100mL; under nitrogen protection condition; add ethyl-boron dihydroxide 23mg (0.3mmol), tetra-triphenylphosphine palladium 13mg (0.01mmol) and three water potassiumphosphate 170mg (0.63mmol); reaction solution backflow 12hr, TLC detects raw material disappearance (methyl alcohol: chloroform=1: 10).Be spin-dried for solvent, crude product is through column chromatography (developping agent: methyl alcohol: chloroform=1: 30), obtain product (I-18-3) 76mg, yield 43.4%.MS[M+H]
+419.1。
1H-NMR(300MHz，DMSO-d
6)δ(ppm)：10.7(1H，s，indole)，10.3(1H，s，-CONH-)，8.5(1H，s，ArH)，7.2(1H，s，ArH)，7.0(1H，s，ArH)，6.5(1H，m，ArH)，5.8(1H，s，NH)，3.8(4H，m，-NCH
2-×2)，2.8(1H，m，-NCH-)，2.5(2H，m，-CH
2CH
3)，2.0(3H，s，-OCCH
3)，1.6(3H，m，-CH
2CH
3)，1.4(4H，m，-CH
2-×2)，1.3(1H，m，-CH-)，1.2(4H，m，-CH
2-×2)。
Claims (11)
1. the compound of general formula (I) or its pharmacy acceptable salt:
R wherein
1, R
2, R
5, R
6or R
7represent independently of one another hydrogen, alkyl;
R
3represent hydrogen, halogen, alkyl, cycloalkyl, aryl or Het;
R
4expression-NHCOR
9, R wherein
9represent alkyl, cycloalkyl, haloalkyl, aryl or Het;
R
8represent N-ethanoyl-4-piperidyl, N-methylsulfonyl-4-piperidyl or-CH
2ar;
Alkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Or for thering is the cyclic saturated hydrocarbon base of 3-6 carbon atom; Or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom;
Aryl is the carbocyclic ring that is selected from phenyl, naphthyl, acenaphthenyl or tetralyl, it is optionally replaced by 1,2 or 3 substituting group separately, and each substituting group is independently selected from hydrogen, alkyl, cyano group, halogen, nitro, haloalkyl, hydroxyl, sulfydryl, alkoxyl group, alkylthio, alkoxyalkyl, aralkyl, alkyl diaryl, aryl or Het;
Het is the monocyclic heterocycles that is selected from piperidyl, pyrryl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; Or be selected from quinolyl, quinoxalinyl, indyl, benzimidazolyl-, benzoxazolyl, benzoisoxazole base, benzothiazolyl, benzisothiazole base, benzofuryl, benzothienyl, 2,3-dihydrobenzo [1,4] bicyclic heterocycle of dioxine base or benzo [1,3] dioxa cyclopentenyl; Each monocycle or bicyclic heterocycle are optionally replaced by 1,2 or 3 substituting group, and each substituting group is independently selected from halogen, haloalkyl, hydroxyl, alkyl or alkoxyl group;
Halogen is the substituting group that is selected from fluorine, chlorine, bromine or iodine;
Haloalkyl is the straight or branched saturated hydrocarbyl with 1-6 carbon atom, or for thering is the cyclic saturated hydrocarbon base of 3-6 carbon atom, or for connecting the cyclic saturated hydrocarbon base with 3-6 carbon atom of the straight or branched saturated hydrocarbyl with 1-6 carbon atom; Wherein one or more carbon atoms are replaced by one or more halogen atoms.
2. according to the general formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein R
1, R
2, R
5, R
6or R
7represent independently of one another hydrogen.
3. according to the general formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein R
3represent hydrogen, halogen, alkyl, cycloalkyl, aryl or heteroaryl.
4. according to the general formula of claim 3 (I) compound or its pharmacy acceptable salt, wherein R
3represent hydrogen, bromine, ethyl, furans or thiophene.
5. according to the general formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein R
4expression-NHCOR
9, R wherein
9represent alkyl, cycloalkyl, haloalkyl, aryl or Het.
6. according to the general formula of claim 5 (I) compound or its pharmacy acceptable salt, wherein R
4expression-NHCOR
9, R wherein
9represent trifluoromethyl, cyclopropyl, phenyl, substituted-phenyl, heteroaryl or binary heteroaryl.
7. according to the general formula of claim 1 (I) compound or its pharmacy acceptable salt, wherein R
8represent N-ethanoyl-4-piperidyl, N-methylsulfonyl-4-piperidyl or-CH
2ar.
8. according to the general formula of claim 1 (I) compound or its pharmacy acceptable salt, be wherein following arbitrary compound or its pharmacy acceptable salt:
3-(N-ethanoyl-4-piperidines is amino)-6-(2-thiazolyl formamido group)-β-carboline (I-9-1)
3-(N-ethanoyl-4-piperidines is amino)-6-phenyl formamido group-β-carboline (I-9-2)
3-(N-ethanoyl-4-piperidines is amino)-6-(4-methyl-phenyl formamido group)-β-carboline (I-9-3)
3-(N-ethanoyl-4-piperidines is amino)-6-cyclopropyl formamido group-β-carboline (I-9-4)
3-(N-ethanoyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3,4-bis-)-β-carboline (I-9-5)
3-(N-ethanoyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-9-6)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-methyl-phenyl formamido group)-β-carboline (I-9-7)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-nitro-phenyl formamido group)-β-carboline (I-9-8)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-9-9)
3-(N-ethanoyl-4-piperidines is amino)-6-(the bromo-phenyl formamido group of 3-)-β-carboline (I-9-10)
3-(N-ethanoyl-4-piperidines is amino)-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-9-11)
3-(N-ethanoyl-4-piperidines is amino)-6-(the bromo-3-trifluoromethyl-phenyl of 4-formamido group)-β-carboline (I-9-12)
3-(N-ethanoyl-4-piperidines is amino)-6-(2-pyrazinyl formamido group)-β-carboline (I-9-13)
3-(N-ethanoyl-4-piperidines is amino)-6-(3-indazolyl formamido group)-β-carboline (I-9-14)
3-(N-ethanoyl-4-piperidines is amino)-6-trifluoroacetamido-β-carboline (I-9-15)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-12-1)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the chloro-phenyl formamido group of 3,4-bis-)-β-carboline (I-12-2)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-12-3)
3-(N-methylsulfonyl-4-piperidines is amino)-6-cyclopropyl formamido group-β-carboline (I-12-4)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the bromo-phenyl formamido group of 3-)-β-carboline (I-12-5)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-methyl-phenyl formamido group)-β-carboline (I-12-6)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-12-7)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-nitro-phenyl formamido group)-β-carboline (I-12-8)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(2-pyrazinyl formamido group)-β-carboline (I-12-9)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(the bromo-3-trifluoromethyl-phenyl of 4-formamido group)-β-carboline (I-12-10)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(3-indazolyl formamido group)-β-carboline (I-12-11)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(4-methyl-phenyl formamido group)-β-carboline (I-12-12)
3-(N-methylsulfonyl-4-piperidines is amino)-6-(2-thiazolyl formamido group)-β-carboline (I-12-13)
3-(N-methylsulfonyl-4-piperidines is amino)-6-trifluoroacetamido-β-carboline (I-12-14)
3-benzyl amino-6-cyclopropyl formamido group-β-carboline (I-15-1)
3-benzyl amino-6-(the chloro-phenyl formamido group of 3-)-β-carboline (I-15-2)
3-benzyl amino-6-(3-N, N-dimethylamino-phenyl formamido group)-β-carboline (I-15-3)
3-benzyl amino-6-(2-thiazolyl formamido group)-β-carboline (I-15-4)
3-benzyl amino-6-(2-pyrazinyl formamido group)-β-carboline (I-15-5)
3-benzyl amino-6-(3-indazolyl formamido group)-β-carboline (I-15-6)
3-benzyl amino-6-(the fluoro-phenyl formamido group of 3-)-β-carboline (I-15-7)
3-benzyl amino-6-(3-nitro-phenyl formamido group)-β-carboline (I-15-8)
3-benzyl amino-6-(3-methyl-phenyl formamido group)-β-carboline (I-15-9)
3-(N-ethanoyl-4-piperidines is amino) the bromo-6-of-5-encircles the third formamido group-β-carboline (I-17)
3-(N-ethanoyl-4-piperidines is amino)-5-(3-furyl)-6-cyclopropyl formamido group-β-carboline (I-18-1)
3-(N-ethanoyl-4-piperidines is amino)-5-(3-thienyl)-6-cyclopropyl formamido group-β-carboline (I-18-2)
3-(N-ethanoyl-4-piperidines is amino)-5-(3-ethyl)-6-cyclopropyl formamido group-β-carboline (I-18-3).
9. according to the general formula of claim 1 (I) compound or its pharmacy acceptable salt, 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, acetic acid, toxilic acid or succsinic acid, fumaric acid, Whitfield's ointment, phenylacetic acid, tussol.The acid salt that comprises in addition mineral alkali, as: basic metal positively charged ion, alkaline earth metal cation, ammonium cation salt contained.
10. the purposes in the medicine for the preparation of prevention or the treatment disease relevant with CDK2 kinase inhibitor according to the compound of the general formula of claim 1 (I) or its pharmacy acceptable salt.
11. according to the purposes of claim 10, and the described disease relevant with CDK2 can be melanoma, liver cancer, kidney, kemia, 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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410252248.7A CN104003988A (en) | 2014-06-05 | 2014-06-05 | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410252248.7A CN104003988A (en) | 2014-06-05 | 2014-06-05 | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104003988A true CN104003988A (en) | 2014-08-27 |
Family
ID=51364921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410252248.7A Pending CN104003988A (en) | 2014-06-05 | 2014-06-05 | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104003988A (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432235A (en) * | 2016-10-19 | 2017-02-22 | 南通大学 | Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof |
| CN106588918A (en) * | 2016-12-08 | 2017-04-26 | 广东省测试分析研究所（中国广州分析测试中心） | Preparation method and application of 3-amino-beta-carboline |
| CN108727370A (en) * | 2018-05-25 | 2018-11-02 | 华东师范大学 | The tetrahydro-beta-carboline micromolecular organic compound and its derivative and medical usage of a kind of hydroxyl substitution |
| CN111333639A (en) * | 2020-04-20 | 2020-06-26 | 四川大学 | Carboline derivative/analogue, preparation method and application thereof |
| WO2020223558A1 (en) * | 2019-05-01 | 2020-11-05 | Incyte Corporation | Tricyclic amine compounds as cdk2 inhibitors |
| WO2021072232A1 (en) * | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
| US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
| US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
| US11427567B2 (en) | 2019-08-14 | 2022-08-30 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors |
| US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
| US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
| US11485734B2 (en) | 2018-10-02 | 2022-11-01 | Northwestern University | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C) |
| US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
| US11976073B2 (en) | 2022-12-09 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475571A (en) * | 2009-01-21 | 2009-07-08 | 中国药科大学 | Beta-carbolines cell cycle protein related kinase 2 inhibitor and use thereof |
| CN102068430A (en) * | 2011-01-11 | 2011-05-25 | 中国药科大学 | 1,6-disubstituted-beta-carboline cyclin-dependent kinase 2/Raf kinase dual inhibitor and application thereof |
-
2014
- 2014-06-05 CN CN201410252248.7A patent/CN104003988A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101475571A (en) * | 2009-01-21 | 2009-07-08 | 中国药科大学 | Beta-carbolines cell cycle protein related kinase 2 inhibitor and use thereof |
| CN102068430A (en) * | 2011-01-11 | 2011-05-25 | 中国药科大学 | 1,6-disubstituted-beta-carboline cyclin-dependent kinase 2/Raf kinase dual inhibitor and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| KILIAN HUBER ETAL: "7,8-Dichloro-1-oxo-β-carbolines as a Versatile Scaffold for the Development of Potent and Selective Kinase Inhibitors with Unusual Binding Modes", 《J.MED.CHEM.》 * |
| REIKO IKEDA ETAL: "Structure–activity relationship in the antitumor activity of 6-, 8- or 6,8-substituted 3-benzylamino-b-carboline derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| YUE WANG ETAL: "Synthesis and Structure of the β-Carboline Derivatives and Their Binding Intensity with Cyclin-Dependent Kinase 2", 《CHEM. PHARM. BULL.》 * |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432235B (en) * | 2016-10-19 | 2018-02-02 | 南通大学 | Target CDK and DNA β carboline derivatives and preparation method thereof and medical usage |
| CN106432235A (en) * | 2016-10-19 | 2017-02-22 | 南通大学 | Beta-carboline derivative targeted to CDK and DNA and preparation method and medical application thereof |
| CN106588918A (en) * | 2016-12-08 | 2017-04-26 | 广东省测试分析研究所（中国广州分析测试中心） | Preparation method and application of 3-amino-beta-carboline |
| CN108727370A (en) * | 2018-05-25 | 2018-11-02 | 华东师范大学 | The tetrahydro-beta-carboline micromolecular organic compound and its derivative and medical usage of a kind of hydroxyl substitution |
| US11485734B2 (en) | 2018-10-02 | 2022-11-01 | Northwestern University | Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C) |
| US11866432B2 (en) | 2018-10-11 | 2024-01-09 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
| US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
| US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
| US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
| US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
| US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
| US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
| WO2020223558A1 (en) * | 2019-05-01 | 2020-11-05 | Incyte Corporation | Tricyclic amine compounds as cdk2 inhibitors |
| US11427567B2 (en) | 2019-08-14 | 2022-08-30 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors |
| WO2021072232A1 (en) * | 2019-10-11 | 2021-04-15 | Incyte Corporation | Bicyclic amines as cdk2 inhibitors |
| CN115298177A (en) * | 2019-10-11 | 2022-11-04 | 因赛特公司 | Bicyclic amines as CDK2 inhibitors |
| US11851426B2 (en) | 2019-10-11 | 2023-12-26 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
| CN111333639A (en) * | 2020-04-20 | 2020-06-26 | 四川大学 | Carboline derivative/analogue, preparation method and application thereof |
| US11976073B2 (en) | 2022-12-09 | 2024-05-07 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104003988A (en) | CDK2 (cyclin-dependent kinase 2) kinase inhibitor based on 3-amino-beta-carboline and derivatives thereof, as well as preparation method and application of CDK2 kinase inhibitor | |
| Gaber et al. | Design, synthesis and anticancer evaluation of 1H-pyrazolo [3, 4-d] pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers | |
| Aneja et al. | Design and development of Isatin-triazole hydrazones as potential inhibitors of microtubule affinity-regulating kinase 4 for the therapeutic management of cell proliferation and metastasis | |
| CN103012428A (en) | 4-(five-membered heterocycle pyrimidin/substituted pyridine) amino-1H-3-pyrazolecarboxamide CDK (cyclin dependent kinase)/Aurora dual inhibitor and application thereof | |
| Jalili-Baleh et al. | New racemic annulated pyrazolo [1, 2-b] phthalazines as tacrine-like AChE inhibitors with potential use in Alzheimer's disease | |
| CN105315285B (en) | 2,4 2 substitution 7H pyrrolo-es [2,3 d] pyrimidine derivatives, its preparation method and purposes pharmaceutically | |
| CN101475571B (en) | Beta-carbolines cell cycle protein related kinase 2 inhibitor and use thereof | |
| Hou et al. | Design, synthesis and biological evaluation of novel 7-amino-[1, 2, 4] triazolo [4, 3-f] pteridinone, and 7-aminotetrazolo [1, 5-f] pteridinone derivative as potent antitumor agents | |
| CN107245073B (en) | 4- (aromatic heterocycle substituted) amino-1H-3-pyrazolecarboxamide FLT3 inhibitor and application thereof | |
| EP3287463A1 (en) | Condensed-ring pyrimidylamino derivative, preparation method therefor, and intermediate, pharmaceutical composition and applications thereof | |
| WO2015120800A1 (en) | Nitrogen heterocyclic compound, preparation method therefor and use thereof | |
| Zhou et al. | Design, synthesis and pharmacological evaluation of 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents | |
| KR20180066985A (en) | Thienopyrimidine derivative and use thereof | |
| CN110156803A (en) | Dioxanes and quinolines and the preparation method and application thereof | |
| Chand et al. | Synthesis, Antiproliferative, and c‐Src Kinase Inhibitory Activities of 4‐Oxo‐4H‐1‐benzopyran Derivatives | |
| WO2020125759A1 (en) | Compound as wnt signal pathway inhibitor and medical use thereof | |
| Ayman et al. | Development of novel pyrazole, imidazo [1, 2-b] pyrazole, and pyrazolo [1, 5-a] pyrimidine derivatives as a new class of COX-2 inhibitors with immunomodulatory potential | |
| Sztanke et al. | Synthesis, structure elucidation and identification of antiproliferative activities of a novel class of thiophene bioisosteres bearing the privileged 7, 8-dihydroimidazo [2, 1-c][1, 2, 4] triazin-4 (6H)-one scaffold | |
| Hao et al. | Development of 2, 4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy | |
| Toan et al. | Quinoline-pyrimidine hybrid compounds from 3-acetyl-4-hydroxy-1-methylquinolin-2 (1H)-one: Study on synthesis, cytotoxicity, ADMET and molecular docking | |
| CA2983040C (en) | Heterocyclic-imidazole compounds, pharmaceutical compositions thereof, preparation method therefor and use thereof | |
| CN102068430A (en) | 1,6-disubstituted-beta-carboline cyclin-dependent kinase 2/Raf kinase dual inhibitor and application thereof | |
| CN105541825A (en) | Preparation method of triazole derivatives and application of triazole derivatives as drugs | |
| CN102127074A (en) | 6-sulfamyl substituted-beta-carboline-1-ketone cell cycle protein dependent kinase 2 inhibitor and application thereof | |
| Liu et al. | Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140827 |