CN107739371A - A kind of Tetrahydrocarbazolesand small molecular organic compounds and its purposes in antibacterials are prepared and preparation method thereof - Google Patents

A kind of Tetrahydrocarbazolesand small molecular organic compounds and its purposes in antibacterials are prepared and preparation method thereof Download PDF

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CN107739371A
CN107739371A CN201710819964.2A CN201710819964A CN107739371A CN 107739371 A CN107739371 A CN 107739371A CN 201710819964 A CN201710819964 A CN 201710819964A CN 107739371 A CN107739371 A CN 107739371A
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amino
bases
bromo
carbazoles
tetrahydrochysenes
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CN107739371B (en
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陈益华
杨财广
苏立强
李家慧
赵秋华
吴海刚
刘明耀
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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Shanghai Institute of Materia Medica of CAS
East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses a kind of Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically acceptable salt and pharmaceutical composition as shown in structure formula (I), and its purposes in antibacterials are prepared, micromolecular compound of the present invention can effectively suppress gram-positive bacteria, simultaneously to the clinically staphylococcus aureus of more refractory multidrug resistance and Gram-negative bacteria as having good inhibition, available for preparing efficient bacterial-infection resisting medicine.The invention also discloses the preparation method containing the compound.

Description

A kind of Tetrahydrocarbazolesand small molecular organic compounds and its in antibacterials are prepared Purposes and preparation method thereof
Technical field
The present invention relates to a series of Tetrahydrocarbazolesand micromolecular compounds and the like, and such compound or contain this Purposes of the pharmaceutical composition of class compound in the medicine for preparing anti-various bacteria infection.The invention further relates to such compound Preparation method.
Background technology
Bacterial drug resistance (Bacterial Resistance) is also known as the resistance to the action of a drug, means what bacterium acted on for antibacterials Tolerance, once producing, the Chemotherapy of medicine is just decreased obviously drug resistance1.It is generally divided into intrinsic resistance and acquired resistance to Medicine (being the main reason for causing bacterial drug resistance), it includes：The amplification of drug resistant gene and transfection, the mutation of target spot, bacterium are thin The osmosis of after birth change or the increase of drug efflux and reduce the intake of antibiotic, to being repaiied into bacterium intracellular antibiotic Decorations or zymetology inactivation, additionally the overexpression including target spot or administration deficiency, other target spots competitions and cause the suppression of target spot Rate reduces2, find that some virulence factors such as Protein A of bacterium surface can be helped by immunologic research in recent years It is realized immunologic escape and produces drug resistance3.The drug resistance of bacterium exists always as a kind of defense mechanism of pathogen, simultaneously Growed in intensity under the induction of antibiotic.
Before first antibiotic enters clinic, the presence of drug-fast bacteria is just had found4.What is had found causes human body The drug-fast bacteria of infection has a lot5, such as：Third generation cephalosporin for the last treatment means of gonorrhoea has also lost treatment now Effect, infection caused by gonococcus is caused not treat6；The oral fluoquinolone for being used to treat urinary tract infections caused by Escherichia coli Also generate drug resistance now；The case that carbapenem antibiotic for enterobacterial infection treatment also has drug resistance is reported Road comes out, staphylococcus aureus, clostridium difficile additionally including resistance to oxygenation XiLin, salmonella, Chlamydia, tuberculosis bar Bacterium.WHO in 2014 a research report shows that sprawling of the bacterial drug resistance in the whole world causes its treatment to become increasingly to choose War property, it is estimated that if the mankind can not effectively develop the antibiotic of new type, to the year two thousand fifty by the annual institute of resistant infections Caused by death toll be up to 10,000,000 people, caused by global economy loss be up to 1,000,000,000,000 dollars7。
Research and development new antibiotic is the most important measure for solving the propagation of drug-fast bacteria worldwide, but unfortunately In the research in past 50 years, the antibiotic of only 5 new types is developed, Linezolid, Daptomycin, Retapamulin, Feldamycin, shellfish reach quinoline, but this five new drugs can only target gram-positive bacteria, thus explore new drug target and The antibiotic for developing new type is very urgent in solving antibiotics resistance sex chromosome mosaicism8。
For current drug-fast bacteria infection situation more come sternness further, the antibiotic with stylish type and mechanism of action is developed In downward trend year by year, therefore the antibiotic for developing new structurally and functionally mechanism is significant9。
Tetrahydrocarbazolesand small molecular organic compounds and the like have many bioactivity, such as antitumor work With10, antivirus action11,12, kinase inhibitory activity etc., it is less in the report of antibiosis.
The content of the invention
Research of the invention based on early stage, it was found that a kind of Tetrahydrocarbazolesand small molecular organic compounds, they have latent Antibacterial activity, by combining correlative study achievement, devise the novel tetrahydro carbazole micromolecular of a class formation and organise Compound, and the structure activity study of system has been carried out to it, cell experiment finds that this kind of compound has to the bacterium of multidrug resistance There is obvious inhibitory action, the bacterium of the multidrug resistance includes gram-positive bacteria (such as staphylococcus aureus Newman bacterium Strain), and the staphylococcus aureus (NRS-1, NRS-70, NRS-100, NRS-108, NRS-271) of multidrug resistance, gram-negative Property bacterium (such as Escherichia coli (AB1157, DH5a), pseudomonas aeruginosa PA01) be respectively provided with obvious inhibitory action, below it is main right Present invention does a detailed description.
First purpose of the present invention is to provide a kind of novel tetrahydro carbazole micromolecular with antibacterial activity of structure Inhibitor.
The present invention has synthesized a kind of Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically acceptable salt, and it is by following Structure formula (I) represents：
Wherein,
N is 0,1,2,3,4.
X is NH, NHCO, CONH.
Y is NH, O, C=O, CH2, pyrimidine radicals.
R1For hydrogen, halogen, alkyl, alkoxy, carboxyl, cyano group, haloalkyl, halogenated alkoxy.
R2For methyl；Phenyl, halogenophenyl, alkoxyl phenyl；Furyl；Morpholinyl；Cyclohexyl；Alkylamino radical pyrimidine radicals； Hydroxyl, alkane hydroxyl；A-amino acid, Boc- a-amino acids, Cbz- a-amino acids, a-amino acid methyl esters；Furanylcarbonyl；Halo-furan Acyl group, thienyl, halogenated thiophene acyl group, pyrrole radicals, pyrroles's acyl group, imidazole radicals, imidazoyl.
Preferably,
N is 0,1,2,3,4.
X is NH, NHCO, CONH.
Y is NH, O, C=O, CH2, pyrimidine radicals.
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy.
R2For methyl；Phenyl, halogenophenyl, C1-10Alkoxyl phenyl；Furyl；Morpholinyl；Cyclohexyl；C1-3Alkylamino radical is phonetic Piperidinyl；Hydroxyl, C1-3Alkane hydroxyl；A-amino acid, Boc- a-amino acids, Cbz- a-amino acids, a-amino acid methyl esters；Furanylcarbonyl； Halo-furan acyl group, thienyl, halogenated thiophene acyl group, pyrrole radicals, pyrroles's acyl group, imidazole radicals, imidazoyl.
It is further preferred that
N is 0,1,2,3,4.
X is NH, NHCO, CONH.
Y is NH, O, C=O, CH2, pyrimidine radicals.
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, C1-6Alkylamidoalkyl, C1-6Alkenyl acyl Amido, C6-8Aryl amido group, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy.
R2For C1-3Alkyl；Phenyl, halogenophenyl, C1-3Alkoxyl phenyl；Furyl；C1-4Alkylamino radical pyrimidine radicals；Hydroxyl, C1-3Alkane hydroxyl；A-amino acid, Boc- a-amino acids, Cbz- a-amino acids, a-amino acid methyl esters；Furanylcarbonyl；Halo-furan acyl Base, thienyl, halogenated thiophene acyl group, pyrrole radicals, pyrroles's acyl group, imidazole radicals, imidazoyl.
It is further preferred that
N is 0,1,2,3,4.
X is NH, NHCO, CONH.
Y is NH, O, C=O, CH2, pyrimidine radicals.
R1For hydrogen, fluorine, chlorine, bromine, methyl, methoxyl group, carboxyl, cyano group, trifluoromethoxy.
R2For methyl, propyl group, isobutyl amine pyrimidine radicals, phenyl, difluorophenyl, hydroxyl, ethoxy, hydroxypropyl, alanine Methyl esters, proline methyl ester, thiophene or furans.
In the present invention, the a-amino acid include glycine, alanine, serine, cysteine, threonine, leucine, Isoleucine, methionine, phenylalanine, tryptophan, tyrosine, histidine, aspartic acid, glutamic acid, lysine, smart ammonia Acid, proline, valine.
In the present invention, the Boc- a-amino acids include Boc- glycine, Boc- alanine, Boc- serines, Boc- half Cystine, Boc- threonines, Boc- leucines, Boc- isoleucines, Boc- methionines, Boc- phenylalanines, Boc- color ammonia Acid, Boc- tyrosine, Boc- histidines, Boc- aspartic acids, Boc- glutamic acid, Boc- lysines, Boc- arginine, Boc- dried meat Propylhomoserin, Boc- valines.
In the present invention, the Cbz- a-amino acids include glycine, Cbz- alanine, Cbz- serines, the Guang ammonia of Cbz- half Acid, Cbz- threonines, Cbz- leucines, Cbz- isoleucines, Cbz- methionines, Cbz- phenylalanines, Cbz- tryptophans, Cbz- tyrosine, Cbz- histidines, Cbz- aspartic acids, Cbz- glutamic acid, Cbz- lysines, Cbz- arginine, Cbz- dried meat ammonia Acid, Cbz- valines.
In the present invention, described structure formula (I), as X=NH, it is represented by following structural formula (II)：
Wherein,
N=0,1,2,3,4.
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, C1-6Alkylamidoalkyl,C1-6Eneamide Base, C6-8Aryl amido group, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy.
Y is O, NH, C=O, CH2、C1-2Alkylol.
R2For methyl；Phenyl；Halogenophenyl；C1-3Alkoxyl phenyl；Furyl；Morpholinyl；Cyclohexyl；C1-4Alkylamino radical is phonetic Piperidinyl；Hydroxyl, C1-3Alkane hydroxyl；A-amino acid, Boc-- a-amino acids, Cbz- a-amino acids, a-amino acid methyl esters；Furans acyl Base, halo-furan acyl group；Thienyl, thiophene acyl group, halogenated thiophene acyl group.
In the present invention, in described structure formula (I), work as X=NH, Y=NH, R2For 2- isobutyl amine pyrimidine radicals when, its by Following structural formula (III) represents：
Wherein,
N is 0,1,2,3,4；
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy.
Preferably, n 1,2,3,4.
R1For H, halogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy, carboxyl, cyano group.
In the present invention, in the structure formula (I), work as n=0, X=NH, Y is pyrimidine radicals, R2For isobutyl amine when, it is by following Structure formula (IV) represents：
Wherein,
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, cyano group, C1-3Haloalkyl, C1-3Halo Alkoxy.
In the present invention, in the structure formula (I), work as R2For phenyl or halogenophenyl or alkoxyl phenyl when, it is under State the expression of structure formula (V)：
Wherein,
N is 0,1,2,3,4.
X is NH, NHCO, CONH.
Y is CH2、NH。
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, C1-6Alkylamidoalkyl, C1-6Alkenyl acyl Amido, C6-8Aryl amido group, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy.
R3For H or halogen or C1-3Alkoxy.
Second object of the present invention is to provide any foregoing Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically may be used The salt of receiving, the acid-addition salts that including but not limited to described Tetrahydrocarbazolesand small molecular organic compounds are formed with following acid： Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, salicylic acid, citric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, lactic acid, acetone Acid, maleic acid, butanedioic acid etc..
Heretofore described Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically acceptable salt, radiation can be used Property, fluorophor or biotin labeling.
Heretofore described Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically acceptable salt, specifically include with Lower compound：
N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- isobutyl group -2,4- di-amino-pyrimidines,
The bromo- N- of 6- (3- phenyl propyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
The bromo- N- of 6- (4- (4- fluorophenyls) butyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
2- amino-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) acetamide,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) thiophene-2-carboxamide derivatives,
Methyl (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propiono) methyl lactamine,
N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 7-) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 8-) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((6- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- two Aminopyrimidine,
N4- (3- ((7- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- two Aminopyrimidine,
N4- (3- ((8- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- two Aminopyrimidine,
N4- (3- ((the fluoro- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((the chloro- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((6- methyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminos Yl pyrimidines,
N4- (3- ((2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- di-amino-pyrimidines,
N4- (3- ((6- trifluoromethyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- Di-amino-pyrimidine,
N4- (3- ((6- methyl formate -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- Di-amino-pyrimidine,
N4- (3- ((6- carboxyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminos Yl pyrimidines,
N4- (2- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) ethyl)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (4- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) normal-butyl)-N2- isobutyl group -2,4- diaminos Yl pyrimidines,
N4- (2- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) ethyl)-N2- isobutyl group -2, 4- di-amino-pyrimidines,
N4- (3- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2, 4- di-amino-pyrimidines,
N4- (4- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) normal-butyl)-N2- isobutyl group- 2,4- di-amino-pyrimidines,
N4- (6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases)-N2- isobutyl group -2,4- di-amino-pyrimidines,
6- trifluoromethoxies-N- (3- is to fluorobenzene propyl group) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- cyano group-N- (3- is to fluorobenzene propyl group) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (4- benzene butyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (2- methoxybenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (furans -2- methylene) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (2- morpholines ethyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N, N- diethylformamide)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N- cyclopropylmethylamides)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N- phenyl formamides)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N, N- diallyl formamide)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- (4- fluorophenyls) -1,2- ethylenediamines,
3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group -1- alcohol,
2- (2- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) ethyoxyl) ethyl -1- alcohol,
2- ((6- cyano group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) ethyl -1- alcohol,
2- (N-Boc- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) acetyl Amine,
2- amino-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) acetamide,
(2R) -2- (N-Boc- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) Propionamide,
(2R) -2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) propionamide,
(2S) -2- ((3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) carbamoyl) pyrroles Alkane -1- t-butyl formates,
(2S) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- (4- hydroxy phenyls) propionamide,
(2S) -2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- (4- hydroxyls Base phenyl) propionamide,
(2S, 3R) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) third Base) -3- hydroxybutyrate amides,
(2R) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- (1H- imidazoles -5- bases) propionamide,
(2R)-2- amino-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) propionamide,
Benzyl ((2S)-1-((3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) amino)-3- hydroxyls Base -1- oxo-butanes -2- bases) t-butyl carbamate,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) benzamide,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) -2- phenyl acetamides,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) -3- hydrocinnamamides,
The bromo- N- of 5- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) thiophene-2-carboxamide derivatives,
N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) thiophene-2-carboxamide derivatives,
The chloro- N- of 5- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) thiophene-2-carboxamide derivatives,
The bromo- N- of 5- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) furans-2- formamides,
The bromo- N- of 6- (4- phenyl butyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
6- bromo- N- (to chlorobenzene ethyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
The chloro- N- of 6- (4- phenyl butyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
(3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propiono) glycine ethyl ester,
(3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propiono) methyl lactamine,
3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propionos-L-PROLINE methyl esters.
Third object of the present invention is to provide a kind of pharmaceutical composition, and described pharmaceutical composition contains above-mentioned tetrahydro carbazole Micromolecular organic compound or its hydrate or pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.Described Pharmaceutical composition is configured to injectable fluid, aerosol, emulsifiable paste, gel, pill, capsule, syrup or transdermal patch.
Fourth object of the present invention is to provide above-mentioned Tetrahydrocarbazolesand small molecular organic compounds or its hydrate or medicine The application of acceptable salt or pharmaceutical composition in antibacterials are prepared on.The antibacterials are used to suppress gram sun Property bacterium and Gram-negative bacteria growth, breeding, invasion and attack to bacterial strain and caused infection are effective.Wherein, the gram Positive bacteria includes：Staphylococcus aureus, enterococcus, streptococcus pneumonia, tubercle bacillus, and their own Multidrug resistant bacteria； The Gram-negative bacteria includes：Escherichia coli, Shigella, acinetobacter calcoaceticus, campylobacter, typhoid bacillus, gonococcus, verdigris Pseudomonad, and their own Multidrug resistant bacteria.Preferably, the Gram-negative bacteria is Escherichia coli AB1157, DH5a, Pseudomonas aeruginosa PA01；The gram-positive bacteria is staphylococcus aureus Newman bacterial strains；The Multidrug resistant bacteria is NRS-1、NRS-70、NRS-100、NRS-108、NRS-271。
Antibacterials of the present invention can be used alone or are used in combination with other medicines.
Present invention also offers described Tetrahydrocarbazolesand small molecular organic compounds or its hydrate or can pharmaceutically connect The preparation method for the salt received, hydrazinobenzene hydrochloride salt and 1,2- cyclohexanedione of the methods described to substitute pass through Fei Sheer Yin for raw material Diindyl synthetic method obtains 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone, or with the aniline of substituted base and the bromo- 2- oxygen-cyclohexanone of 3- Ethyl formate cyclization forms 6-R bases -2,3,4,9- tetrahydrochysene -1H- carbazole -1- Ethyl formates, is then obtained by further derivative The tetrahydro carbazole small molecular organic compounds or its hydrate or its pharmaceutically acceptable salt.
In the present invention, the Tetrahydrocarbazolesand small molecular organic compounds or its hydrate or pharmaceutically acceptable salt can It is prepared by following three kinds of methods.
The preparation of Tetrahydrocarbazolesand small molecular organic compounds is enumerated：
1. the present invention is implemented by the step of reaction equation (a)：
Wherein, substituted hydrazinobenzene hydrochloride salt 1 and 1,2- cyclohexanedione obtain compound 2 by Fei Sheer indole synthesis, Compound 2 is stretched out chain length by reduction amination, and obtaining described tetrahydro carbazole micromolecular through subsequent derivation organises Compound or its hydrate or pharmaceutically acceptable salt 1；
2. the present invention is implemented by the step of reaction equation (b)：
Wherein, substituted aniline 4 forms compound 6, the water of compound 6 with the bromo- 2- oxygen of 3--cyclization of cyclohexanone Ethyl formate 5 Solution sloughs ethyl and forms carboxyl, then by a series of derivatives, obtain described Tetrahydrocarbazolesand small molecular organic compounds or its Hydrate or pharmaceutically acceptable salt 7.
3. the present invention is implemented by the step of reaction equation (c)：
Wherein, substituted hydrazinobenzene hydrochloride salt 1 and 1,2- cyclohexanedione obtain compound 2 by Fei Sheer indole synthesis, Compound 2 obtains compound 8 with sloughing benzyl under benzylamine reduction amination, Pd/C hydrogen atmospheres, and compound 8 is by further derivative Obtain described Tetrahydrocarbazolesand small molecular organic compounds or its hydrate or pharmaceutically acceptable salt 9.
The beneficial effects of the present invention are by molecular hybridization, using tetrahydro carbazole structure as basic framework, with reference to two The dominance structure of aminopyrimidine has synthesized a series of Tetrahydrocarbazolesand small molecular organic compounds, and the compound is for gram Negative bacterium such as Escherichia coli AB1157, DH5a, pseudomonas aeruginosa PA01 and gram-positive bacteria such as staphylococcus aureus There is obvious antibacterial to live by Newman bacterial strains and its Multidrug resistant bacteria NRS-1, NRS-70, NRS-100, NRS-108, NRS-271 Property.
Embodiment
With reference to specific examples below, the present invention is described in further detail, and of the invention protects content not limit to With following examples.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and excellent Point is all included in the present invention, and using appended claims as protection domain.Implement the present invention process, condition, Reagent, test method etc., it is the universal knowledege and common knowledge of this area in addition to the following content specially referred to, this hair It is bright that content is not particularly limited.
1H-NMR Bruker500 type Instrument measurings, MS VG ZAB-HS or VG-7070 type Instrument measurings, in addition to indicating It is ESI methods；All solvents all have passed through re-distillation using preceding, and used anhydrous solvent is according to standard method Dry and obtain.In addition to explanation, all reactions are all to be reacted under N2 protections and monitor tracking reaction process with TLC, are post-processed Cheng Junxu washes by saturated common salt, anhydrous sodium sulfate drying.The purifying of product is in addition to explanation, generally using silica gel (200- 300 mesh) column chromatography, it is that Haiyang Chemical Plant, Qingdao or Yantai edge win silica gel to use silica gel to include 200-300 mesh and GF254 Company produces.
Embodiment 1：The preparation of each compound
Embodiment 1-1：N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group- The synthesis of 2,4- di-amino-pyrimidines (SLQ001)
4- bromobenzenes hydrazine hydrochloride (10mmol, 2235mg) is dissolved in 25mL methanol into stirring is completely dissolved it, by 1, 2- cyclohexanediones (20mmol, 2243mg) are dissolved in 40mL glacial acetic acid, 13mL dense HCl are added with being stirred at 60 DEG C, by 4- The methanol solution of bromobenzene hydrazine hydrochloride is slowly dropped into wherein with constant pressure funnel, keeps reacting at 60 DEG C overnight, TLC monitorings are anti- After answering completely, solvent evaporated, dissolved with EA (20mL), with saturation NaHCO3PH to 8-9 is adjusted, then adds EA (2 × 20mL) Extraction merging organic phase, is washed with saturated common salt, uses anhydrous Na2SO4Dry, be evaporated under reduced pressure and remove solvent, with methanol and dichloromethane Alkane is recrystallized to give the tetrahydrochysene -1H- carbazole -1- ketone (1.48g, yield 56%) of intermediate 6- bromo- 2,3,4,9-.
Tetrahydrochysene -1H- carbazole -1- the ketone (4.0mmol, 1056mg) of 6- bromo- 2,3,4,9- is added in 15mL toluene, then Add N-Boc-1,3- propane diamine (8.0mmol, 1.4mL) and catalytic amount p-methyl benzenesulfonic acid, bonus point hydrophone and 140 DEG C are next time 16h is flowed, removing solvent is stayed in steaming of then pressurizeing, and adds 20mL methanol, NaBH is added portionwise at room temperature4(20mmol, 757mg), so After flow back 4h, TLC monitoring reactions are complete, gone out reaction with a small amount of water quenching, distillation under pressure removal solvent, with EA, H2O systems extract, With saturated common salt water washing, anhydrous Na is used2SO4Dry, column chromatography obtains intermediate N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- clicks of 6- Azoles -1- bases)-N3- Boc-1,3- propane diamine (1.237g, yield 73%).
By N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3- Boc-1,3- propane diamine (1.237g, 2.93mmol) it is dissolved in the anhydrous DCM of 20mL, 4.6mol/L THF HCl solution 25mL is added under ice-water bath, reaction overnight, subtracts Pressure is distilled off organic solvent and obtains intermediate N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3- 1,3- propane diamine Hydrochloride (1076mg, yield 93%).
By intermediate N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3- 1,3- propane diamine hydrochloride (339mg, 0.93mmol) it is dissolved in 2,4- dichloro pyrimidines (210mg) in 8mL ethanol, reaction and TLC, which are monitored, at room temperature reacts complete, adds Enter a small amount of water quenching to go out reaction, be evaporated under reduced pressure and remove solvent, with EA (3 × 20mL) and H2O (20mL) is extracted, and is washed with saturated common salt Wash, use anhydrous Na2SO4Dry, column chromatography obtains intermediate N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3-(2- Chlorine pyrimidine-4-yl) -1,3,-propane diamine (249mg, yield 61%).
By intermediate N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3- (2- chlorine pyrimidine-4-yl) -1,3,-the third Diamines (249mg, 0.57mmol) is dissolved in 10mL n-butanol, adds isobutyl amine (0.57mL), DIEA (0.28mL), and nitrogen is protected 120 DEG C of reaction 12h of shield, are evaporated under reduced pressure and remove solvent, direct column chromatography for separation obtains end-product N4- (3- ((the bromo- 2,3,4,9- of 6- Tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- di-amino-pyrimidine (217mg, yield 81%).1H NMR (500MHz, DMSO) δ 10.85 (s, 1H), 7.60 (s, 1H), 7.52 (d, J=1.5Hz, 1H), 7.27 (d, J=8.5Hz, 1H), 7.12 (dd, J=8.5,2.0Hz, 1H), 6.85 (s, 1H), 6.35 (s, 1H), 5.68 (d, J=5.5Hz, 1H), 3.91 (s, 1H), 2.98 (t, J=6.5Hz, 2H), 2.79-2.62 (m, 2H), 2.57 (s, 2H), 2.04-1.89 (m, 3H), 1.82-1.63 (m, 5H), 1.25-1.20 (m, 2H), 0.83 (d, J=7.0Hz, 6H)
Embodiment 1-2：N4- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- isobutyl group -2,4- di-amino-pyrimidines Synthesis
With raw material para-bromophenyl-hydrazine hydrochloride and 1,2- cyclohexanediones by Fei Sheer indole synthesis by the side in embodiment 1-1 Method obtains the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- ketone of 6-.
Tetrahydrochysene -1H- carbazole -1- the ketone (266mg) of 6- bromo- 2,3,4,9- is dissolved in 10mL toluene, addition benzylamine (216mg, 0.2mL), Catalyzed by p-Toluenesulfonic Acid amount, bonus point hydrophone react 16h at 140 DEG C, are then evaporated under reduced pressure and remove solvent, add 10mL methanol dissolves, and then adds NaBH4A small amount of water quenching is added after (191mg) back flow reaction 4h, TLC monitoring reaction completely to go out instead Should, it is evaporated under reduced pressure and removes solvent, post-processes to obtain intermediate 6- bromo- 2,3,4,9,-tetrahydrochysene -1H- carbazoles -1- according to standard operation Benzylamine (280mg, yield 78%).
By intermediate 6- bromo- 2,3,4,9,-tetrahydrochysene -1H- carbazole -1- benzylamines (280mg) are dissolved in 15mL ethanol, change N2Three It is secondary, 10% Pd/C (dry agent) of catalytic amount is added, changes N2Three times, H is then changed2Three times, reaction is stayed overnight at room temperature, filter-press Steaming stays removing solvent to obtain the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- amine (197mg) of intermediate 6-.
Thereafter successively with the reaction method of 2,4- dichloro pyrimidines and isobutyl amine as described in embodiment 1-1, production is finally given Thing N4- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- isobutyl group -2,4- di-amino-pyrimidines (35mg).1H NMR (500MHz, DMSO) δ 11.94 (s, 1H), 7.73 (s, 1H), 7.44 (d, J=8.0Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.07 (dd, J=7.9,7.2Hz, 1H), 6.98 (dd, J=7.5,7.4Hz, 1H), 6.07 (s, 1H), 5.42 (s, 1H), 3.21 (m, 2H), 2.79-2.60 (m, 2H), 2.08 (s, 1H), 1.97-1.78 (m, 4H), 1.35-1.11 (m, 1H), 0.92 (d, J= 6.0Hz,6H).
Embodiment 1-3：The synthesis of the bromo- N- of 6- (3- phenyl propyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides
By 2- cyclohexanone Ethyl formate (12mmol, 2042mg) 4mL ether dissolution, bromine is added at 0 DEG C (0.61mL) reacts 90min, is raised to room temperature reaction afterwards, question response is complete, and reaction solution is poured into the Na of the cold saturations of 30mL2CO3 Middle stirring neutralizes, and is extracted with EA, merges organic phase, is washed with saturated common salt, use anhydrous Na2SO4Dry, it is molten to be evaporated under reduced pressure removing Agent, obtain 2- bromo- 6- (carbethoxyl group) cyclohexanone (3.675g).
With 2- bromo- 6- (carbethoxyl group) cyclohexanone (3.675g) for solvent, para-bromoaniline (6.344g), N are added2Protection Reacted 3 hours at 150 DEG C, after TLC monitoring reactions completely, reactant is dissolved with DCM, first extracted with watery hydrochloric acid (1.0N) and EA Take, remove excessive para-bromoaniline, then with EA and saturation NaHCO3System extracts, and merges organic phase and is washed with saturated common salt Wash, use anhydrous Na2SO4Dry, be evaporated under reduced pressure and remove solvent, silica gel column chromatography obtains the tetrahydrochysene -1H- of intermediate 6- bromo- 2,3,4,9- Carbazole -1- Ethyl formates (591mg, yield 12%).
Tetrahydrochysene -1H- carbazole -1- the Ethyl formates (591mg) of intermediate 6- bromo- 2,3,4,9- are dissolved in 12mL ethanol, added Enter NaOH (366mg) water (4mL) solution, react at room temperature, TLC monitoring reactions are complete, are evaporated under reduced pressure and remove organic solvent, so Watery hydrochloric acid (1.0N) regulation PH to 2 or so is added afterwards, is extracted with EA, is merged organic phase saturated common salt water washing, use is anhydrous Na2SO4Dry, be evaporated under reduced pressure and remove solvent, obtain the tetrahydrochysene -1H- carbazole -1- formic acid of crude intermediate 6- bromo- 2,3,4,9- (398mg)。
By the tetrahydrochysene -1H- carbazole -1- formic acid (151mg, 0.5mmol) of 6- bromo- 2,3,4,9- and EDCHCl (117mg), HOBt (83mg), DMF (5mL) react 0.5h under ice bath, then add 3- phenylpropylamines (83mg), react at room temperature 6h, TLC prisons It is complete to survey reaction, extracts organic phase with EA (3 × 20mL) and water (40mL), merges organic phase saturated common salt water washing, with nothing Water Na2SO4Dry, be evaporated under reduced pressure and remove solvent, silica gel column chromatography obtains the bromo- N- of product 6- (3- phenyl propyls) -2,3,4,9- tetra- Hydrogen -1H- carbazole -1- formamides (110mg, yield 52%).1H NMR(500MHz,DMSO)δ10.76(s,1H),7.91(s, 1H), 7.53 (d, J=1.9Hz, 1H), 7.31-7.15 (m, 6H), 7.12 (dd, J=8.5,2.0Hz, 1H), 3.69 (t, J= 6.3Hz,1H),3.22–3.02(m,2H),2.64–2.55(m,4H),2.07–2.00(m,1H),1.99–1.91(m,2H), 1.80–1.65(m,3H).
Embodiment 1-4：The synthesis of the bromo- N- of 6- (4- (4- fluorophenyls) butyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine
By the tetrahydrochysene -1H- carbazole -1- ketone (66mg, 0.25mmol) of 6- bromo- 2,3,4,9- and 4- p-fluorophenyls butylamine (84mg, 0.5mmol) dissolved with 5mL toluene, add the p-methyl benzenesulfonic acid (0.1eq) of catalytic amount, bonus point hydrophone flows back at 140 DEG C Solvent is evaporated after 16h, TLC monitoring reaction completely, is then dissolved with 10mL methanol, adds sodium borohydride (5.0eq, 48mg) And the 4h that flowed back at 80 DEG C, after monitoring reaction completely, gone out reaction with a small amount of water quenching, be evaporated under reduced pressure removing organic solvent, then With EA and H2O systems extract organic phase, merge organic phase saturated common salt water washing, use anhydrous Na2SO4Dry, vacuum distillation removes Solvent is removed, silica gel column chromatography obtains the tetrahydrochysene -1H- carbazole -1- amine of the bromo- N- of product 6- (4- (4- fluorophenyls) butyl) -2,3,4,9- (94mg, yield 52%).1H NMR (500MHz, DMSO) δ 10.84 (s, 1H), 7.50 (d, J=1.8Hz, 1H), 7.25 (d, J =8.6Hz, 1H), 7.23-7.19 (m, 2H), 7.10 (dd, J=4.2,2.0Hz, 1H), 7.09-7.05 (m, 2H), 4.08- 3.68(m,1H),2.69–2.62(m,1H),2.61–2.52(m,6H),2.01–1.93(m,2H),1.69–1.63(m,2H), 1.63–1.57(m,2H),1.50–1.38(m,2H).
Embodiment 1-5：2- (N-Boc- amino)-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) Propyl group) acetamide (SLQ005) preparation
The bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- ketone of 6- and N-Boc-1,3- propane diamine reduction aminations are obtained into N1-(6- Bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazole -1- bases)-N3- Boc-1,3- propane diamine, amino protecting group Boc groups are then sloughed, are obtained To intermediate N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3- 1,3- propane diamine hydrochloride, take N-Boc- glycine (1.0eq, 73mg), EDCHCl (96mg), HOBt (68mg) protect with nitrogen under ice-water bath in 3mL DMF, react 10min, Then N is added1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N3- 1,3- propane diamine hydrochloride (198mg) and DIEA (3.0eq), and with reacting 6h at room temperature, after TLC monitoring reactions completely, handled by standard, silica gel column chromatography obtains product 2- (N-Boc- amino)-N- (3-((tetrahydrochysene-1H- carbazole-1- bases of 6- bromo- 2,3,4,9-) amino) propyl group) acetamide (167mg, production Rate 63%).1H NMR (500MHz, DMSO) δ 10.84 (s, 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.28 (d, J= 8.2Hz, 1H), 7.17-7.05 (m, 1H), 6.93 (d, J=5.1Hz, 1H), 3.97-3.78 (m, 1H), 3.49 (d, J= 5.8Hz,2H),3.20–3.08(m,2H),2.87–2.54(m,5H),2.06–1.99(m,1H),1.97–1.91(m,1H), 1.79–1.65(m,2H),1.64–1.52(m,2H),1.34(s,9H).
Embodiment 1-6：The preparation of N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) thiophene-2-carboxamide derivatives
Debenzylation after the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- ketone of 6- and benzylamine reduction amination is obtained into 6- bromo- 2,3,4, 9- tetrahydrochysene -1H- carbazole -1- amine (85mg) is dissolved in 5mL DCM, the protection of ice-water bath nitrogen plus lower addition thiophene -2- formyls Chlorine (68 μ L), DIEA (0.2mL), react at room temperature 6h after solvent evaporated, extract and column chromatography obtain product N- (6- bromo- 2,3,4, 9- tetrahydrochysene -1H- carbazole -1- bases) thiophene-2-carboxamide derivatives (94mg, yield 78%)1H NMR(500MHz,DMSO)δ10.78(s, 1H), 8.83 (d, J=8.2Hz, 1H), 7.88-7.87 (m, 1H), 7.77-7.72 (m, 1H), 7.40 (d, J=7.8Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.12 (dd, J=4.9,3.8Hz, 1H), 7.03 (dd, J=11.1,4.0Hz, 1H), 5.35- 5.24(m,1H),2.72–2.59(m,2H),2.08–2.00(m,2H),1.91–1.78(m,2H).
Embodiment 1-7：(3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propiono) glycine ethyl ester (SLQ007) preparation
The bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- amine (190mg) of 6- and potassium carbonate (294mg) are dissolved in 3mL dry DMFs In, nitrogen protection, add 3- methyl bromide cs (0.24mL) and reacted at 40 DEG C, obtain intermediate 3- ((6- bromo- 2,3,4,9- Tetrahydrochysene -1H- carbazole -1- bases) amino) methyl propionate (143mg)；Then hydrolysis obtains 3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- of 6- Carbazole -1- bases) amino) propionic acid (71mg), then by its with glycine ethyl ester hydrochloride (35mg) in EDCHCl (48mg), HOBt Reaction obtains product (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) under the conditions of (34mg), 3mL dry DMFs Propiono) glycine ethyl ester (77mg, yield 87%), 1H NMR (500MHz, DMSO) δ 10.57 (s, 1H), 8.44 (s, 1H), 7.36 (d, J=7.7Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.01 (dd, J=7.0,7.0Hz, 1H), 6.92 (dd, J= 7.0,7.0Hz, 1H), 3.87 (t, J=8.1Hz, 3H), 3.63 (s, 3H), 3.40 (s, 1H), 3.31-3.18 (m, 1H), 2.97- 2.79 (m, 2H), 2.66-2.55 (m, 2H), 2.35 (t, J=6.7Hz, 2H), 1.99 (t, J=10.9Hz, 2H), 1.73 (t, J =11.5Hz, 2H)
The synthesis of SLQ008-040 tetrahydrocarbazole compounds shown in embodiment 1-8 to 1-40
Embodiment 2：Inhibition test of the compounds of this invention to a variety of bacterium
(1) inhibitory action of growth and breeding of the compounds of this invention to gram-positive bacteria and Gram-negative bacteria
The compounds of this invention is to different strains (such as staphylococcus aureus Newman and the meningitidis strains of multidrug resistance NRS-1, NRS-70, NRS-100, NRS-108, NRS-271, Escherichia coli AB1157 etc.) growth and breeding all have it is obvious Inhibitory action.
Experimentation：The compounds of this invention is dissolved with DMSO, mother liquid concentration 10mg/mL, is stored at -20 DEG C, is tested Shi Shouxian provokes bacterial strain monoclonal shake overnight after OD600 be diluted to 0.01 and continue to shake 5-8h, bacterium solution is then diluted to OD0.6 After diluting 400 times again afterwards, equal proportion is added in the nutrient solution containing the compounds of this invention, the growth shape of 37 DEG C of growth 16h observation bacterium Condition.
By compareing discovery with positive compound (vancomycin and kanamycins), the compounds of this invention is for gram sun Property bacterium：Staphylococcus aureus Newman bacterial strains, Gram-negative bacteria：Escherichia coli AB1157, DH5a bacterial strain, P. aeruginosa Bacterium PA01 bacterial strains have obvious inhibitory action.Table one is the inhibitory activity of part the compounds of this invention four kinds of bacterial strains to more than, From table one, compound SLQ001-002, SLQ008-009, SL012-016, SLQ020-026, SLQ051, SLQ053 and SLQ057 has obvious bacteriostatic activity.
The compounds of this invention of table one to staphylococcus aureus, Escherichia coli, pseudomonas aeruginosa bacteriostatic experiment result
(2) the compounds of this invention is to multidrug resistance bacteria growing and the inhibitory action of breeding
The compounds of this invention for staphylococcus aureus NRS-1, NRS-70 of multidrug resistance, NRS-100, NRS-108, NRS-271 bacterial strains are respectively provided with obvious bacteriostatic activity.
Experimentation：Compound is dissolved with DMSO, mother liquid concentration 10mg/mL, is stored at -20 DEG C, during experiment first Bacterial strain monoclonal is provoked to OD600 after shaking overnight to be diluted to 0.01 and continue to shake 5-8h, is then diluted to bacterium solution after OD 0.6 again After 400 times of dilution, equal proportion is added in the nutrient solution containing compound, 37 DEG C of upgrowth situations for growing 16h, 40h or so observation bacterium.
By compareing discovery, staphylococcus aureus NRS- of the compounds of this invention for multidrug resistance with positive compound 1st, NRS-70, NRS-100, NRS-108, NRS-271 bacterial strain have obvious inhibitory action, and partial results are shown in Table shown in two, from It can be found that compound SLQ001-002, SLQ008-009, SLQ014, SLQ023, SLQ025, SLQ051, SLQ053 in table two There is obvious bacteriostatic activity with SLQ057.
Bacteriostatic experiment result of the compounds of this invention of table two for the staphylococcus aureus of multidrug resistance
Example 1 below -8 provides the compounds of this invention SLQ008-058 preparation method and product detection knot to 1-58 Fruit.
Embodiment 1-8：N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 7-) amino) propyl group)-N2- isobutyl group- The preparation of 2,4- di-amino-pyrimidines (SLQ008)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as a bromophenyl-hydrazine hydrochloric acid Salt, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, the tetrahydrochysene -1H- carbazole -1- ketone of 7- bromo- 2,3,4,9- is obtained, then Using similar operating procedure, most product SLQ008, yield are obtained through column chromatography afterwards：74%,1H NMR(500MHz,DMSO)δ 11.34 (s, 1H), 7.64 (s, 1H), 7.58 (d, J=1.3Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 7.14 (dd, J= 8.4,1.6Hz,1H),5.81(s,1H),4.42(s,1H),3.06–2.94(m,5H),2.73–2.56(m,3H),2.08–1.88 (m, 6H), 1.86-1.71 (m, 3H), 1.24 (m, 1H), 0.85 (d, J=6.7Hz, 6H)
Embodiment 1-9：N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 8-) amino) propyl group)-N2- isobutyl group- The preparation of 2,4- di-amino-pyrimidines (SLQ009)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as bromophenyl hydrazonium salt acid Salt, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, the tetrahydrochysene -1H- carbazole -1- ketone of 8- bromo- 2,3,4,9- is obtained, then Using similar operating procedure, most product SLQ009, yield are obtained through column chromatography afterwards：79%,1H NMR(500MHz,CDCl3)δ 10.67 (s, 1H), 8.74-8.54 (m, 1H), 7.77-7.60 (m, 1H), 7.35 (d, J=7.8Hz, 1H), 7.29 (d, J= 7.6Hz,1H),6.94–6.87(m,1H),6.06(d,1H),4.63(s,1H),3.56–3.40(m,2H),3.23–3.08(m, 2H),3.07–2.94(m,2H),2.75–2.61(m,2H),2.33–2.21(m,3H),2.15–2.08(m,2H),2.03–1.96 (m, 1H), 1.91-1.71 (m, 3H), 1.65-1.56 (m, 1H), 0.91 (d, J=6.0Hz, 6H)
Embodiment 1-10：N4- (3- ((6- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- different The preparation of butyl -2,4- di-amino-pyrimidines (SLQ010)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to methoxybenzene hydrazonium salt Hydrochlorate, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, obtain 6- methoxyl groups -2,3,4,9- tetrahydrochysene -1H- carbazoles -1- Ketone, then using similar operating procedure, most obtain product SLQ010, yield through column chromatography afterwards：61%,1H NMR(500MHz, CDCl3) δ 10.31 (s, 1H), 8.73 (s, 1H), 7.64 (d, J=5.6Hz, 1H), 6.95-6.61 (m, 2H), 6.14 (d, J= 5.5Hz,1H),5.05–4.81(m,1H),4.67(s,1H),3.81(s,2H),3.71–3.60(m,1H),3.56–3.39(m, 2H),3.26–3.08(m,2H),3.05–2.88(m,2H),2.77–2.60(m,2H),2.36–2.19(m,3H),1.89–1.76 (m, 2H), 1.66-1.57 (m, 1H), 1.28 (s, 3H), 0.91 (d, J=3.8Hz, 6H)
Embodiment 1-11：N4- (3- ((7- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- different The preparation of butyl -2,4- di-amino-pyrimidines (SLQ011)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as meta-methoxy phenylhydrazine salt Hydrochlorate, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, obtain 7- methoxyl groups -2,3,4,9- tetrahydrochysene -1H- carbazoles -1- Ketone, then using similar operating procedure, most obtain product SLQ011, yield through column chromatography afterwards：54%,1H NMR(500MHz, CDCl3) δ 10.57 (s, 1H), 8.46 (s, 1H), 7.87-7.58 (m, 1H), 7.43-7.31 (m, 1H), 6.69 (d, J= 4.9Hz, 1H), 5.93 (d, J=6.3Hz, 1H), 3.56-3.46 (m, 2H), 3.43-3.27 (m, 3H), 3.25-3.16 (m, 2H), 2.35-2.22 (m, 1H), 2.04 (d, J=1.3Hz, 2H), 1.95-1.71 (m, 4H), 1.67-1.54 (m, 1H), 1.29- 1.27 (m, 1H), 1.24 (s, 3H), 0.96 (d, J=6.7Hz, 6H)
Embodiment 1-12：N4- (3- ((8- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- different The preparation of butyl -2,4- di-amino-pyrimidines (SLQ012)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as O-methoxy phenylhydrazine salt Hydrochlorate, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, obtain 8- methoxyl groups -2,3,4,9- tetrahydrochysene -1H- carbazoles -1- Ketone, then using similar operating procedure, most obtain product SLQ012, yield through column chromatography afterwards：56%,1H NMR(500MHz, DMSO) δ 11.07 (s, 1H), 7.67 (m, 1H), 7.07 (d, J=7.9Hz, 1H), 6.98-6.92 (m, 1H), 6.72 (d, J= 7.6Hz, 1H), 6.03 (d, J=6.3Hz, 1H), 3.91 (s, 2H), 3.46 (m, 2H), 3.16 (m, 2H), 3.08 (m, 2H), 2.71–2.61(m,2H),2.20–2.11(m,2H),2.04(m,4H),1.82(m,2H),1.41–1.32(m,1H),0.89(d, J=6.7Hz, 6H)
Embodiment 1-13：N4- (3- ((the fluoro- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl The preparation of base -2,4- di-amino-pyrimidines (SLQ013)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to fluorine phenylhydrazine hydrochloric acid Salt, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, the tetrahydrochysene -1H- carbazole -1- ketone of 6- fluoro- 2,3,4,9- is obtained, then Using similar operating procedure, most product SLQ013, yield are obtained through column chromatography afterwards：62%,1H NMR(500MHz,DMSO)δ 11.44 (s, 1H), 7.75-7.54 (m, 2H), 7.38 (dd, J=8.7,4.4Hz, 1H), 7.28-7.22 (m, 1H), 7.02- 6.94 (m, 1H), 5.98 (s, 1H), 4.22 (t, J=6.5Hz, 1H), 3.14-2.96 (m, 4H), 2.71-2.56 (m, 2H), 2.23–2.10(m,2H),2.05–1.92(m,4H),1.87–1.72(m,3H),1.67–1.60(m,1H),1.41–1.33(m, 1H), 0.87 (d, J=6.7Hz, 6H)
Embodiment 1-14：N4- (3- ((the chloro- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl The preparation of base -2,4- di-amino-pyrimidines (SLQ014)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to chlorophenyl hydrazine hydrochloric acid Salt, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, the tetrahydrochysene -1H- carbazole -1- ketone of 6- chloro- 2,3,4,9- is obtained, then Using similar operating procedure, most product SLQ014, yield are obtained through column chromatography afterwards：71%,1H NMR(500MHz,DMSO)δ 10.85 (s, 1H), 7.59 (s, 1H), 7.37 (d, J=1.7Hz, 1H), 7.30 (d, J=8.5Hz, 1H), 7.00 (dd, J= 8.5,1.9Hz, 1H), 6.94-6.74 (m, 1H), 6.49-6.21 (m, 1H), 5.67 (d, J=3.5Hz, 1H), 3.86 (s, 1H), 2.97 (t, J=6.2Hz, 2H), 2.79-2.59 (m, 3H), 2.58-2.53 (m, 2H), 2.05-1.88 (m, 3H), 1.81-1.73 (m, 1H), 1.73-1.61 (m, 4H), 1.25-1.22 (m, 1H), 0.81 (d, J=6.2Hz, 6H)
Embodiment 1-15：N4- (3- ((6- methyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl The preparation of base -2,4- di-amino-pyrimidines (SLQ015)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to procarbazine hydrochloric acid Salt, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, obtain 6- methyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone, so Similar operating procedure is used afterwards, most obtains product SLQ015, yield through column chromatography afterwards：55%, 1H NMR (500MHz, CDCl3) δ 10.31 (s, 1H), 8.73 (s, 1H), 7.64 (d, J=5.6Hz, 1H), 6.95-6.61 (m, 2H), 6.14 (d, J= 5.5Hz,1H),5.05–4.81(m,1H),4.67(s,1H),3.81(s,2H),3.71–3.60(m,1H),3.56–3.39(m, 2H),3.26–3.08(m,2H),3.05–2.88(m,2H),2.77–2.60(m,2H),2.36–2.19(m,3H),1.89–1.76 (m, 2H), 1.66-1.57 (m, 1H), 1.28 (s, 3H), 0.91 (d, J=3.8Hz, 6H)
Embodiment 1-16：N4- (3- ((2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- The preparation of di-amino-pyrimidine (SLQ016)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as hydrazinobenzene hydrochloride salt, with 1,2- cyclohexanedione obtains 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone, then using similar by Fei Sheer indole synthesis Operating procedure, most obtain product SLQ016, yield through column chromatography afterwards：73%,1H NMR(500MHz,DMSO)δ11.29(s, 1H), 8.39 (d, J=1.5Hz, 1H), 7.66 (d, J=1.2Hz, 1H), 7.48 (d, J=7.8Hz, 1H), 7.37 (d, J= 8.1Hz,1H),7.17–7.11(m,1H),7.05–6.99(m,1H),5.91(s,1H),4.56(s,1H),3.62–3.38(m, 2H),3.14–3.01(m,4H),2.75–2.58(m,2H),2.22–1.93(m,5H),1.87–1.74(m,2H),1.27–1.21 (m, 1H), 0.87 (d, J=6.7Hz, 6H)
Embodiment 1-17：N4- (3- ((6- trifluoromethyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- The preparation of isobutyl group -2,4- di-amino-pyrimidines (SLQ017)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to trifluoromethyl phenyl hydrazine Hydrochloride, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, obtain 6- trifluoromethyls -2,3,4,9- tetrahydrochysene -1H- clicks Azoles -1- ketone, then using similar operating procedure, most obtain product SLQ017, yield through column chromatography afterwards：69%,1H NMR (500MHz, DMSO) δ 11.76 (s, 1H), 8.53 (s, 1H), 7.89 (d, J=8.5Hz, 1H), 7.66 (d, J=3.0Hz, 1H), 7.58 (d, J=8.5Hz, 1H), 7.43 (dd, J=8.6,1.2Hz, 1H), 5.94 (s, 1H), 4.56 (s, 1H), 3.56-3.41 (m,2H),3.18–2.97(m,4H),2.82–2.66(m,2H),2.20–2.02(m,3H),2.01–1.93(m,2H),1.87– 1.75 (m, 2H), 1.25-1.21 (m, 2H), 0.86 (d, J=6.7Hz, 6H)
Embodiment 1-18：N4- (3- ((6- methyl formate -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- The preparation of isobutyl group -2,4- di-amino-pyrimidines (SLQ018)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to methyl formate phenylhydrazine Hydrochloride, then using similar operating procedure, product SLQ018, yield are obtained through column chromatography：63%,1H NMR(500MHz, DMSO) δ 11.24 (s, 1H), 8.08 (s, 1H), 7.88-7.77 (m, 1H), 7.73-7.63 (m, 1H), 7.60 (d, J=7.3Hz, 1H), 7.45-7.35 (m, 1H), 5.69 (d, J=5.2Hz, 1H), 4.04 (s, 1H), 3.89-3.78 (m, 3H), 3.05-2.91 (m,2H),2.87–2.71(m,2H),2.69–2.58(m,2H),1.98–1.84(m,4H),1.81–1.66(m,4H),1.32– 1.18 (m, 3H), 0.81 (d, J=6.1Hz, 6H)
Embodiment 1-19：N4- (3- ((6- carboxyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl The preparation of base -2,4- di-amino-pyrimidines (SLQ019)
Using the method similar to prepare compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as to methyl formate phenylhydrazine Hydrochloride, with 1,2- cyclohexanediones by Fei Sheer indole synthesis, obtain 6- methyl formates -2,3,4,9- tetrahydrochysene -1H- clicks Azoles -1- ketone, then using similar operating procedure, obtains N4- (3- ((6- methyl formate -2,3,4,9- tetrahydrochysene -1H- carbazoles -1- Base) amino) propyl group)-N2- isobutyl group -2,4- di-amino-pyrimidine, then hydrolyzes and obtains product SLQ019, yield through column chromatography： 61%,1H NMR (500MHz, DMSO) δ 12.40 (s, 1H), 11.76 (s, 1H), 8.82 (d, J=11.3Hz, 1H), 8.16 (s, 1H), 8.11-7.91 (m, 1H), 7.76 (dd, J=8.6,1.6Hz, 1H), 7.68 (d, J=4.1Hz, 1H), 7.44 (d, J= 8.5Hz, 1H), 6.02 (d, J=2.0Hz, 1H), 4.59 (s, 1H), 3.59-3.41 (m, 2H), 3.23-2.95 (m, 4H), 2.81–2.61(m,2H),2.26–2.08(m,2H),2.07–1.95(m,2H),1.89–1.69(m,2H),1.25–1.21(m, 2H), 0.88 (d, J=6.7Hz, 6H)
Embodiment 1-20：N4- (2- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) ethyl)-N2- isobutyl The preparation of base -2,4- di-amino-pyrimidines (SLQ020)
Using the method similar to prepare compound SLQ001, by N-Boc-1,3- propane diamine is replaced as N-Boc-1,2- second Then diamines uses similar operating procedure, most obtain product SLQ020, yield through column chromatography afterwards：68%,1H NMR (500MHz, DMSO) δ 10.87 (s, 1H), 7.61 (s, 1H), 7.51 (d, J=1.5Hz, 1H), 7.28 (dd, J=15.2, 8.6Hz, 1H), 7.11 (dd, J=8.5,1.8Hz, 1H), 6.78 (s, 1H), 6.35 (s, 1H), 5.70 (d, J=5.7Hz, 1H), 3.89 (s, 1H), 3.45-3.35 (m, 2H), 3.00 (t, J=6.4Hz, 2H), 2.85-2.71 (m, 2H), 2.55 (m, 2H), 2.07-1.92 (m, 2H), 1.85-1.74 (m, 1H), 1.73-1.64 (m, 2H), 1.25 (m, 1H), 0.83 (d, J=6.7Hz, 6H).
Embodiment 1-21：N4- (4- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) normal-butyl)-N2- isobutyl The preparation of base -2,4- di-amino-pyrimidines (SLQ021)
Using the method similar to compound SLQ001, by N-Boc-1,3- propane diamine is replaced as N-Boc-1,4- fourths two Amine, the tetrahydrochysene -1H- carbazole -1- ketone of 6- bromo- 2,3,4,9- and N-Boc-1,4- butanediamine reduction amination, subsequent preparation process with SLQ001 preparation method is similar, and product SLQ021, yield are obtained through column chromatography：72%,1H NMR(500MHz,DMSO)δ 11.37 (s, 1H), 7.63 (m, 2H), 7.34 (d, J=8.6Hz, 1H), 7.21 (dd, J=8.6,1.8Hz, 1H), 5.77 (d, J =6.0Hz, 1H), 4.39 (s, 1H), 3.47-3.33 (m, 1H), 3.28 (s, 2H), 3.12-2.88 (m, 4H), 2.73-2.56 (m, 3H), 2.16-2.06 (m, 1H), 2.04-1.95 (m, 2H), 1.85-1.74 (m, 2H), 1.67 (m, 2H), 1.59 (d, J= 6.4Hz, 2H), 1.27-1.21 (m, 1H), 0.85 (d, J=6.7Hz, 6H)
Embodiment 1-22：N4- (2- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) ethyl) - N2The preparation of-isobutyl group -2,4- di-amino-pyrimidines (SLQ022)
Using the method similar to compound SLQ020, para-bromophenyl-hydrazine hydrochloride is replaced as to trifluomethoxybenzene hydrazonium salt Hydrochlorate, 6- trifluoromethoxies -2,3 are obtained by Fei Sheer indole synthesis with 1,2- cyclohexanediones, 4,9- tetrahydrochysene -1H- carbazoles - 1- ketone, subsequent method is similar, and product SLQ022, yield are obtained through column chromatography：61%,1H NMR(500MHz,DMSO)δ11.10 (s, 1H), 7.64 (d, J=2.4Hz, 1H), 7.45-7.36 (m, 1H), 7.34 (s, 1H), 7.01 (d, J=8.6Hz, 1H), 5.80 (d, J=5.9Hz, 1H), 4.09 (s, 1H), 3.50-3.35 (m, 2H), 3.03 (t, J=5.6Hz, 2H), 2.94-2.77 (m,2H),2.63–2.57(m,2H),2.09–2.01(m,1H),1.91(s,1H),1.82–1.69(m,3H),1.37–1.19 (m, 3H), 0.84 (d, J=6.5Hz, 6H)
Embodiment 1-23：N4- (3- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group) - N2The preparation of-isobutyl group -2,4- di-amino-pyrimidines (SLQ023)
Using the method similar to compound SLQ001, para-bromophenyl-hydrazine hydrochloride is replaced as trifluomethoxybenzene hydrazonium salt acid Salt, it obtains 6- trifluoromethoxies -2,3 with 1,2- cyclohexanediones by Fei Sheer indole synthesis, and 4,9- tetrahydrochysene -1H- carbazoles - 1- ketone, subsequent method is similar, and product SLQ023, yield are obtained through column chromatography：63%,1H NMR(500MHz,DMSO)δ11.02 (s, 1H), 7.61 (s, 1H), 7.39 (d, J=8.5Hz, 1H), 7.33 (s, 1H), 7.00 (d, J=9.0Hz, 1H), 5.70 (d, J =5.5Hz, 1H), 4.03 (s, 2H), 2.98 (t, J=6.5Hz, 2H), 2.76 (m, 2H), 2.65-2.56 (m, 3H), 1.91 (s, 3H),1.83–1.64(m,4H),1.25(m,4H),0.88–0.74(m,6H).
Embodiment 1-24：N4- (4- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) positive fourth Base)-N2The preparation of-isobutyl group -2,4- di-amino-pyrimidines (SLQ024)
Using the method similar to compound SLQ021, para-bromophenyl-hydrazine hydrochloride is replaced as to trifluomethoxybenzene hydrazonium salt Hydrochlorate, and compound 1,2- cyclohexanediones obtain intermediate 6- trifluoromethoxies -2,3 by Fei Sheer indole synthesis, and 4,9- Tetrahydrochysene -1H- carbazole -1- ketone, subsequent preparation process is similar to SLQ021 preparation method, and product SLQ024 is obtained through column chromatography, Yield：68%,1H NMR(500MHz,DMSO)δ11.74(s,1H),9.03(s,1H),8.24(s,1H),7.68(s,1H), 7.47 (d, J=8.8Hz, 2H), 7.11 (d, J=9.1Hz, 1H), 6.08 (d, J=6.3Hz, 1H), 4.61 (t, J=5.3Hz, 1H), 3.39 (s, 3H), 3.17 (s, 2H), 3.05 (t, J=7.6Hz, 2H), 2.74-2.61 (m, 2H), 2.23-2.00 (m, 3H), 1.89-1.75 (m, 4H), 1.65 (s, 2H), 0.90 (d, J=6.7Hz, 6H)
Embodiment 1-25：N4- (6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases)-N2- isobutyl group -2,4- The preparation of di-amino-pyrimidine (SLQ025)
Using the method similar to compound SLQ002, para-bromophenyl-hydrazine hydrochloride is replaced as to trifluomethoxybenzene hydrazonium salt Hydrochlorate, and compound 1,2- cyclohexanediones obtain 6- trifluoromethoxies -2,3 by Fei Sheer indole synthesis, and 4,9- tetrahydrochysenes - 1H- carbazole -1- ketone, subsequent preparation method is similar to compound SLQ002 method, and product SLQ025 is obtained through column chromatography, production Rate：42%,1H NMR (500MHz, DMSO) δ 12.26 (s, 1H), 7.77 (d, J=6.0Hz, 1H), 7.47-7.32 (m, 2H), 7.04 (d, J=8.5Hz, 1H), 6.09 (d, J=6.0Hz, 1H), 5.43 (d, J=5.5Hz, 1H), 3.30-3.10 (m, 2H), 3.10–3.01(m,1H),2.78–2.59(m,2H),2.09(s,1H),1.94(s,2H),1.90–1.78(m,2H),1.25– 1.14 (m, 1H), 0.90 (d, J=5.0Hz, 6H)
Embodiment 1-26：6- trifluoromethoxies-N- (3- is to fluorobenzene propyl group) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ026) preparation
It is similar to compound SLQ004 preparation method, para-bromophenyl-hydrazine hydrochloride and 4- are replaced as to three to fluorobenzene butylamine Fluorine methoxyphenyl hydrazine hydrochloride and 3- will pass through expense to Fenfluramine to trifluoromethoxy hydrazinobenzene hydrochloride salt and 1,2- cyclohexanedione She Er indole synthesis obtain 6- trifluoromethoxies -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone, then with 3- to Fenfluramine also Former amination obtains product SLQ026, yield：85%,1H NMR (500MHz, DMSO) δ 10.92 (s, 1H), 7.38 (d, J= 8.7Hz, 1H), 7.30 (s, 1H), 7.24 (dd, J=8.2,5.8Hz, 2H), 7.12-7.04 (m, 2H), 6.97 (d, J= 8.5Hz,1H),3.94–3.83(m,1H),2.78–2.53(m,7H),2.08–1.92(m,2H),1.81–1.62(m,4H).
Embodiment 1-27：6- cyano group-N- (3- is to fluorobenzene propyl group) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ027) Preparation
It is similar to compound SLQ026 preparation method, trifluoromethoxy hydrazinobenzene hydrochloride salt will be replaced as to cyanophenylhydrazine Hydrochloride, 6- cyano group -2,3 will be obtained by Fei Sheer indole synthesis to cyanophenylhydrazine hydrochloride and 1,2- cyclohexanedione, 4, 9- tetrahydrochysene -1H- carbazole -1- ketone, then obtains product SLQ027, yield with 3- to Fenfluramine reduction amination：51%,1H NMR (500MHz, DMSO) δ 11.28 (s, 1H), 7.89 (d, J=0.9Hz, 1H), 7.45 (d, J=8.4Hz, 1H), 7.36 (dd, J= 8.4,1.6Hz,1H),7.27–7.21(m,2H),7.11–7.04(m,2H),3.85(s,1H),3.36(s,1H),2.72–2.63 (m,3H),2.62–2.53(m,3H),2.03–1.92(m,2H),1.78–1.62(m,4H).
Embodiment 1-28：The system of 6- methyl-N- (4- benzene butyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ028) It is standby
It is similar to compound SLQ004 preparation method, para-bromophenyl-hydrazine hydrochloride and 4- are replaced as to first to fluorobenzene butylamine Base hydrazinobenzene hydrochloride salt and 4- phenyl -1- butylamine, will be closed to hydrazinobenzoic acid hydrochloride and 1,2- cyclohexanediones by Fei Sheer indoles 6- methyl -2,3 is obtained into method, 4,9- tetrahydrochysene -1H- carbazole -1- ketone, then obtains product with 4- phenyl -1- butylamine reduction aminations SLQ028, yield：37%,1H NMR(300MHz,CDCl3) δ 8.23 (s, 1H), 7.30 (dd, J=10.3,4.5Hz, 2H), 7.26–7.23(m,1H),7.23–7.11(m,4H),6.99–6.92(m,1H),3.97–3.85(m,1H),2.89–2.77(m, 1H),2.71–2.63(m,4H),2.63–2.59(m,1H),2.44(s,3H),2.28–2.14(m,1H),2.08–1.95(m, 1H),1.83–1.65(m,4H),1.63–1.48(m,4H).
Embodiment 1-29：6- methyl-N- (2- methoxybenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ029) Prepare
It is similar to compound SLQ028 preparation method, 4- phenyl -1- butylamine is replaced as 2- methoxybenzylamines, yield： 53%,1H NMR(300MHz,CDCl3)δ8.62(s,1H),7.46–7.16(m,4H),7.06–6.83(m,3H),3.92–3.78 (m, 4H), 2.91-2.68 (m, 2H), 2.53 (d, J=5.0Hz, 1H), 2.46 (s, 3H), 2.34-2.17 (m, 1H), 2.12- 1.93(m,2H),1.89–1.73(m,1H),1.41–1.25(m,2H).
Embodiment 1-30：6- methyl-N- (furans -2- methylene) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ030) Preparation
It is similar to compound SLQ028 preparation method, 4- phenyl -1- butylamine is replaced as 2- furylamines, yield： 59%,1H NMR(300MHz,CDCl3) δ 8.18 (s, 1H), 7.44-7.36 (m, 1H), 7.25 (s, 1H), 7.18 (d, J= 8.2Hz, 1H), 6.96 (dd, J=8.0,1.1Hz, 1H), 6.38-6.29 (m, 1H), 6.27-6.21 (m, 1H), 4.06-3.92 (m,2H),3.90(s,1H),2.73–2.63(m,2H),2.43(s,3H),2.27–2.13(m,2H),2.09–1.96(m,1H), 1.88–1.69(m,2H).
Embodiment 1-31：6- methyl-N- (2- morpholines ethyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ031) Prepare
It is similar to compound SLQ028 preparation method, 4- phenyl -1- butylamine is replaced as N- (2- aminoethyls) morpholine, produced Rate 77%,1H NMR(300MHz,CDCl3) δ 9.09 (s, 1H), 7.30-7.16 (m, 2H), 6.96 (dd, J=5.8,3.4Hz, 1H),4.10–4.00(m,1H),3.81–3.64(m,4H),3.04–2.91(m,1H),2.86–2.74(m,1H),2.73–2.59 (m,3H),2.58–2.37(m,7H),2.27–2.08(m,3H),2.02(s,1H),1.87–1.62(m,2H).
Embodiment 1-32：6- (N, N- diethylformamide)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazoles -1- The preparation of amine (SLQ032)
According to embodiment 1-1, para-bromophenyl-hydrazine hydrochloride is replaced as to obtain intermediate 6- to methyl formate hydrazinobenzene hydrochloride salt Methyl formate -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone；It is condensed to form intermediate 6- (N, N- bis- with N, TMSDEA N diethylamine after hydrolysis Ethyl-formamide) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone；SLQ032 is being obtained with 4-Fluorobenzylamine reduction amination afterwards, is being produced Rate：31%,1H NMR(300MHz,CDCl3) δ 8.59 (s, 1H), 7.49 (s, 1H), 7.39 (dd, J=8.4,5.6Hz, 2H), 7.23 (d, J=8.3Hz, 1H), 7.12 (dd, J=8.3,1.5Hz, 1H), 7.07-6.92 (m, 2H), 4.06-3.90 (m, 2H), 3.85 (d, J=13.0Hz, 1H), 3.42 (s, 4H), 2.71-2.52 (m, 2H), 2.37-2.23 (m, 1H), 1.38-1.02 (m, 10H).
Embodiment 1-33：6- (N- cyclopropylmethylamides)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ033) preparation
Similar to compound SLQ032 preparation method, by N, TMSDEA N diethylamine is replaced as n-propylamine, yield：46%,1H NMR(300MHz,CDCl3) δ 8.51 (s, 1H), 7.94 (s, 1H), 7.53 (dd, J=8.4,1.3Hz, 1H), 7.38 (dd, J= 8.3,5.6Hz, 2H), 7.29 (d, J=8.7Hz, 1H), 7.09-6.97 (m, 2H), 6.16 (s, 1H), 3.98 (d, J= 12.8Hz, 2H), 3.84 (d, J=12.8Hz, 1H), 3.45 (dd, J=13.3,6.9Hz 2H), 2.79-2.63 (m, 2H), 2.40-2.25 (m, 1H), 1.70-1.62 (m, 6H), 1.00 (t, J=7.4Hz, 3H)
Embodiment 1-34：6- (N- phenyl formamides)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine (SLQ034) preparation
Similar to compound SLQ032 preparation method, by N, TMSDEA N diethylamine is replaced as aniline, yield：29%,1H NMR (300MHz, DMSO) δ 10.05 (s, 1H), 7.97 (d, J=6.8Hz, 2H), 7.82 (s, 1H), 7.57-7.44 (m, 6H), 7.35 (dd, J=8.7,2.1Hz, 1H), 7.29 (s, 1H), 7.18-7.09 (m, 2H), 3.95-3.77 (m, 3H), 2.65-2.53 (m, 3H),2.12–1.99(m,2H),1.75–1.63(m,2H).
Embodiment 1-35：6- (N, N- diallyl formamide)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazoles - The preparation of 1- amine (SLQ035)
Similar to compound SLQ032 preparation method, by N, TMSDEA N diethylamine is replaced as N, N- diallylamines, yield： 51%,1H NMR(300MHz,CDCl3)δ8.56(s,1H),7.61(s,1H),7.45–7.35(m,2H),7.31–7.18(m, 2H),7.11–6.97(m,2H),5.84(s,2H),5.29–5.13(m,4H),4.13–3.75(m,6H),2.72–2.65(m, 1H),2.44–2.20(m,1H),1.90–1.61(m,4H),1.41–1.12(m,2H).
Embodiment 1-36：N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- (4- fluorophenyls) -1,2- second two The preparation of amine (SLQ036)
It is similar to compound SLQ004 preparation method, 4- is replaced as N- p-fluorophenyls -1,2- second two to fluorobenzene butylamine Amine, para-bromophenyl-hydrazine hydrochloride and 1,2- cyclohexanedione are obtained into 6- bromo- 2 by Fei Sheer indole synthesis, 3,4,9- tetrahydrochysenes- 1H- carbazole -1- ketone, then obtain product SLQ036, yield with N- p-fluorophenyl -1,2- ethylenediamine reduction aminations：81%,1H NMR (500MHz, DMSO) δ 10.92 (s, 1H), 7.52 (s, 1H), 7.27 (d, J=8.5Hz, 1H), 7.12 (d, J=8.4Hz, 1H), 6.98-6.82 (m, 2H), 6.59 (dd, J=8.5,4.3Hz, 2H), 5.48 (s, 1H), 4.03-3.74 (m, 1H), 3.17- 3.01(m,2H),2.92–2.74(m,2H),2.64–2.53(m,2H),2.07–1.93(m,2H),1.74–1.60(m,2H), 1.24(s,1H).
Embodiment 1-37：3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group -1- alcohol (SLQ037) Preparation
It is similar to compound SLQ004 synthetic method, 4- is replaced as to 3- amino -1- propyl alcohol to fluorobenzene butylamine, will be to bromobenzene Hydrazine hydrochloride and 1,2- cyclohexanedione obtain the tetrahydrochysene -1H- carbazole -1- ketone of 6- bromo- 2,3,4,9- by Fei Sheer indole synthesis, Then product SLQ037, yield are obtained with 3- amino -1- propyl alcohol reduction aminations：89%,1H NMR(500MHz,DMSO)δ10.84 (s, 1H), 7.51 (d, J=1.3Hz, 1H), 7.26 (d, J=8.5Hz, 1H), 7.11 (dd, J=8.5,1.7Hz, 1H), 3.90- 3.77 (m, 1H), 3.52-3.42 (m, 2H), 3.17 (d, J=5.0Hz, 1H), 2.78-2.60 (m, 2H), 2.58-2.52 (m, 2H),2.03–1.90(m,3H),1.72–1.65(m,2H),1.64–1.56(m,2H).
Embodiment 1-38：2- (2- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) ethyoxyl) ethyl -1- The preparation of alcohol (SLQ038)
It is similar to compound SLQ004 preparation method, 4- is replaced as diglycolamine to fluorobenzene butylamine, by para-bromophenyl-hydrazine Hydrochloride and 1,2- cyclohexanedione obtain the tetrahydrochysene -1H- carbazole -1- ketone of 6- bromo- 2,3,4,9- by Fei Sheer indole synthesis, so Afterwards product SLQ038, yield are obtained with diglycolamine reduction amination：84%,1H NMR(500MHz,DMSO)δ10.85(s,1H), 7.52 (d, J=1.4Hz, 1H), 7.27 (d, J=8.5Hz, 1H), 7.12 (dd, J=8.5,1.6Hz, 1H), 4.64 (s, 1H), 4.08–3.82(m,1H),3.67–3.48(m,4H),3.47–3.38(m,2H),2.90–2.69(m,2H),2.62–2.54(m, 2H),2.04–1.90(m,2H),1.79–1.60(m,2H),1.28–1.20(m,1H).
Embodiment 1-39：2- ((6- cyano group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) ethyl -1- alcohol (SLQ039) preparation
It is similar to compound SLQ004 preparation method, para-bromophenyl-hydrazine hydrochloride and 4- are replaced as to cyanogen to fluorobenzene butylamine Base hydrazinobenzene hydrochloride salt and monoethanolamine, 6- is obtained by Fei Sheer indole synthesis to cyanophenylhydrazine hydrochloride and 1,2- cyclohexanedione Cyano group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone, then obtains product SLQ039, yield with monoethanolamine reduction amination：75%,1H NMR (500MHz, DMSO) δ 11.34 (s, 1H), 7.90 (s, 1H), 7.45 (d, J=8.3Hz, 1H), 7.37 (d, J= 8.3Hz,1H),4.52(s,1H),3.94(s,1H),3.61–3.44(m,2H),3.20–3.12(m,1H),2.85–2.67(m, 2H),2.67–2.57(m,2H),2.07–1.91(m,2H),1.83–1.61(m,2H).
Embodiment 1-40：2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) second The preparation of acid amides (SLQ040)
It is similar to compound SLQ005 preparation method, SLQ005 is taken off into Boc and obtains SLQ040, yield：58%,1H NMR (500MHz, DMSO) δ 10.86 (s, 1H), 8.03 (s, 1H), 7.51 (s, 1H), 7.28 (d, J=8.5Hz, 1H), 7.11 (dd, J =8.5,1.3Hz, 1H), 3.88-3.81 (m, 1H), 3.32 (s, 2H), 3.25-3.14 (m, 4H), 2.74-2.63 (m, 1H), 2.59–2.53(m,2H),2.02–1.94(m,2H),1.72–1.63(m,2H),1.62–1.55(m,2H),1.25–1.22(m, 2H).
Embodiment 1-41：(2R) -2- (N-Boc- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) Amino) propyl group) propionamide (SLQ041) preparation
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as N-Boc-D- alanine, yield： 61%,1H NMR (500MHz, DMSO) δ 10.85 (s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.29 (d, J=8.2Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 6.85 (d, J=5.9Hz, 1H), 3.99-3.77 (m, 2H), 3.25-3.06 (m, 2H), 2.79–2.54(m,4H),2.07–1.92(m,2H),1.85–1.66(m,2H),1.65–1.52(m,2H),1.37(s,9H), 1.25 (d, J=11.6Hz, 2H), 1.14 (d, J=6.7Hz, 3H)
Embodiment 1-42：(2R) -2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) third Base) propionamide (SLQ042) preparation
It is similar to compound SLQ041 preparation method, SLQ041 is taken off into Boc and obtains SLQ042, yield：58%,1H NMR (500MHz, DMSO) δ 11.65 (s, 1H), 8.80 (d, J=6.1Hz, 1H), 7.65 (d, J=1.5Hz, 1H), 7.35 (d, J= 8.6Hz, 1H), 7.22 (dd, J=8.6,1.8Hz, 1H), 4.52 (s, 2H), 3.88-3.75 (m, 1H), 3.29-3.13 (m, 2H), 3.11-2.92 (m, 2H), 2.79-2.57 (m, 2H), 2.16 (m, 2H), 2.07-2.00 (m, 1H), 1.90 (d, J= 9.2Hz, 2H), 1.81-1.71 (m, 1H), 1.37-1.28 (m, 2H), 1.24 (d, J=11.9Hz, 3H)
Embodiment 1-43：(2S) -2- ((3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) amino Formoxyl) pyrrolidines -1- t-butyl formates (SLQ043) preparation
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as Cbz-L- proline and obtained SLQ043, yield：49%,1H NMR(500MHz,DMSO)δ10.85(s,1H),7.97(s,1H),7.53(s,1H),7.41– 7.18 (m, 6H), 7.13 (d, J=7.8Hz, 1H), 5.16-4.88 (m, 2H), 4.20-4.08 (m, 1H), 3.86 (s, 1H), 3.55-3.34 (m, 2H), 3.26-3.03 (m, 2H), 2.62-2.54 (m, 2H), 2.26 (t, J=6.6Hz, 1H), 2.15-1.92 (m, 3H), 1.76 (d, J=6.4Hz, 4H), 1.71-1.44 (m, 4H), 1.25 (d, J=11.5Hz, 1H)
Embodiment 1-44：(2S) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) ammonia Base) propyl group) -3- (4- hydroxy phenyls) propionamides (SLQ044) preparation
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as Cbz-L- tyrosine and obtained SLQ044, yield：26%,1H NMR(500MHz,DMSO)δ10.83(s,1H),9.17(s,1H),8.03–7.85(m,1H), 7.51 (d, J=13.2Hz, 1H), 7.41 (d, J=7.9Hz, 1H), 7.35-7.26 (m, 3H), 7.26-7.16 (m, 2H), 7.12 (d, J=8.6Hz, 1H), 7.02 (dd, J=8.0,3.5Hz, 2H), 6.68-6.56 (m, 2H), 5.03-4.85 (m, 2H), 4.14–4.06(m,1H),3.23–3.09(m,2H),2.86–2.76(m,1H),2.75–2.54(m,6H),2.04–1.92(m, 2H),1.69(s,2H),1.59(s,2H),1.24(s,2H).
Embodiment 1-45：(2S) -2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) third Base) -3- (4- hydroxy phenyls) propionamides (SLQ045) preparation
It is similar to compound SLQ044 preparation method, SLQ044 is taken off into Cbz and protects to obtain SLQ045, yield：18%,1H NMR (500MHz, DMSO) δ 10.78 (s, 1H), 9.26 (s, 1H), 8.41 (s, 1H), 7.44 (d, J=7.8Hz, 1H), 7.37 (d, J=8.1Hz, 1H), 7.12-7.07 (m, 1H), 7.05-6.97 (m, 3H), 6.73-6.64 (m, 2H), 4.26 (s, 1H), 3.78 (t, J=6.9Hz, 1H), 3.26-3.04 (m, 3H), 2.99-2.57 (m, 7H), 2.16-2.02 (m, 2H), 1.87-1.67 (m, 3H), 1.25 (d, J=11.5Hz, 1H)
Embodiment 1-46：(2S, 3R) -2- (Cbz- amino)-N- (3- ((bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- of 6- Base) amino) propyl group) and -3- hydroxybutyrate amides (SLQ046) preparation
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as Cbz-L- threonines and obtained SLQ046, yield：41%,1H NMR(500MHz,DMSO)δ11.36(s,1H),9.28(s,1H),9.06(s,1H),8.13 (s, 1H), 7.68 (s, 1H), 7.32-7.28 (m, 2H), 7.25 (d, J=8.2Hz, 2H), 7.05-6.98 (m, 1H), 5.13- 4.89(m,3H),4.81(d,1H),4.52(d,1H),3.99–3.79(m,2H),3.04(s,3H),2.73–2.56(m,4H), 1.89-1.71 (m, 4H), 1.24-1.22 (m, 2H), 1.03 (d, J=5.4Hz, 3H)
Embodiment 1-47：(2R) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) ammonia Base) propyl group) -3- (1H- imidazoles -5- bases) propionamide (SLQ047) preparation
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as Cbz-D- histidines, yield： 35%,1H NMR(500MHz,DMSO)δ11.44(s,1H),8.21(s,1H),7.81(s,1H),7.68(s,1H),7.57(s, 1H), 7.41-7.33 (m, 3H), 7.31 (d, J=7.3Hz, 3H), 7.27-7.14 (m, 2H), 6.89 (s, 1H), 5.08-4.89 (m,2H),4.52(s,1H),4.21(s,1H),3.26–3.10(m,3H),3.09–2.91(m,3H),2.85–2.77(m,1H), 2.73–2.58(m,3H),2.07–1.96(m,2H),1.89–1.75(m,3H).
Embodiment 1-48：The preparation of N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) benzamide (SLQ048)
It is similar with compound SLQ006 preparation method, thiophene -2- formyl chlorides are replaced as chlorobenzoyl chloride, obtained through column chromatography To product SLQ048, yield：39%,1H NMR(500MHz,CDCl3) δ 8.85 (s, 1H), 7.78 (s, 1H), 7.77 (dd, J= 1.6Hz, 1H), 7.54-7.49 (m, 2H), 7.43 (dd, J=10.5,4.7Hz, 2H), 7.32 (d, J=8.1Hz, 1H), 7.19- 7.14(m,1H),7.11–7.06(m,1H),2.85–2.68(m,2H),2.38–2.23(m,1H),2.02–1.94(m,3H), 1.76–1.62(m,1H).
Embodiment 1-49：The system of N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) -2- phenyl acetamides (SLQ049) It is standby
It is similar to preparing for compound SLQ006, thiophene -2- formyl chlorides are replaced as phenyllacetyl chloride, produced through column chromatography Thing SLQ049, yield：57%,1H NMR (500MHz, DMSO) δ 10.75 (s, 1H), 8.57 (s, 1H), 7.39 (d, J= 7.7Hz, 1H), 7.30 (d, J=5.3Hz, 4H), 7.26-7.19 (m, 1H), 7.08-7.01 (m, 1H), 6.99-6.92 (m, 1H),5.07–4.99(m,1H),3.54–3.40(m,2H),2.73–2.54(m,2H),1.96–1.84(m,2H),1.83–1.68 (m,2H).
Embodiment 1-50：The system of N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) -3- hydrocinnamamides (SLQ050) It is standby
It is similar to compound SLQ006 preparation method, thiophene -2- formyl chlorides are replaced as 3- phenylpropionyl chlorides, through post layer Analysis obtains product SLQ050, yield：78%,1H NMR(500MHz,DMSO)δ10.63(s,1H),8.30(s,1H),7.38(d, J=7.8Hz, 1H), 7.30-7.27 (m, 2H), 7.23 (d, J=6.9Hz, 2H), 7.18 (dd, J=10.1,4.3Hz, 1H), 7.06–7.01(m,1H),6.97–6.91(m,1H),5.11–5.02(m,1H),2.93–2.81(m,2H),2.68–2.54(m, 2H),2.47–2.39(m,2H),1.95–1.81(m,2H),1.79–1.64(m,2H).
Embodiment 1-51：The bromo- N- of 5- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) thiophene - The preparation of 2- formamides (SLQ051)
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as 5- bromothiophene -2- formic acid, other Operate similar, product SLQ051, yield are obtained through column chromatography：54%,1H NMR(500MHz,DMSO)δ10.83(s,1H), 8.60 (s, 1H), 7.54 (d, J=3.0Hz, 1H), 7.51 (s, 1H), 7.31-7.22 (m, 2H), 7.11 (d, J=8.5Hz, 1H), 4.17-4.03 (m, 1H), 3.85 (s, 1H), 3.18 (d, J=4.8Hz, 1H), 2.82-2.60 (m, 3H), 2.59-2.54 (m,2H),2.03–1.91(m,2H),1.78–1.61(m,4H).
Embodiment 1-52：N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) thiophene -2- first The preparation of acid amides (SLQ052)
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as thiophene -2-carboxylic acid, other operations It is similar, obtain product SLQ052, yield through column chromatography：51%,1H NMR(500MHz,DMSO)δ10.99(s,1H),8.59(s, 2H), 7.74 (d, J=5.2Hz, 1H), 7.58 (s, 1H), 7.32 (d, J=8.5Hz, 1H), 7.17 (d, J=6.2Hz, 1H), 7.14–7.06(m,1H),4.16–4.06(m,1H),3.21–3.09(m,2H),3.03–2.72(m,2H),2.68–2.55(m, 2H),2.04–1.93(m,2H),1.88–1.40(m,4H),1.24(s,1H).
Embodiment 1-53：The chloro- N- of 5- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) thiophene - The preparation of 2- formamides (SLQ053)
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as 5- chlorothiophene -2- formic acid, other Operate similar, product SLQ053, yield are obtained through column chromatography：57%,1H NMR(500MHz,DMSO)δ10.84(s,1H), 8.61 (s, 1H), 7.59 (d, J=4.1Hz, 1H), 7.52 (d, J=1.8Hz, 1H), 7.27 (d, J=8.5Hz, 1H), 7.15 (d, J=4.0Hz, 1H), 7.11 (dd, J=8.5,1.9Hz, 1H), 3.86 (s, 1H), 3.38-3.33 (m, 1H), 3.31-3.26 (m, 1H), 3.17 (d, J=5.2Hz, 1H), 2.77-2.60 (m, 2H), 2.59-2.54 (m, 2H), 2.03-1.91 (m, 2H), 1.76–1.59(m,4H).
Embodiment 1-54：The bromo- N- of 5- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) furans - The preparation of 2- formamides (SLQ054)
It is similar to compound SLQ005 preparation method, N-Boc- glycine is replaced as 5- bromine furans -2- formic acid, other Operate similar, product SLQ054, yield are obtained through column chromatography：52%,1H NMR(500MHz,DMSO)δ11.52(s,1H), 8.78-8.57 (m, 1H), 7.68 (d, J=1.5Hz, 1H), 7.37 (d, J=8.6Hz, 1H), 7.26 (dd, J=8.6,1.8Hz, 1H), 7.18 (d, J=3.5Hz, 1H), 6.76 (d, J=3.5Hz, 1H), 4.60 (s, 1H), 3.41-3.35 (m, 1H), 3.33- 3.28(m,1H),3.17–3.03(m,2H),2.77–2.57(m,2H),2.23–2.00(m,4H),2.00–1.90(m,2H), 1.86–1.75(m,1H).
Embodiment 1-55：6- bromo- N- (to chlorobenzene ethyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides (SLQ055) Preparation
It is similar to compound SLQ003 preparation method, 3- phenylpropylamines are replaced as to chlorophenethylamine, yield：33%,1H NMR (500MHz, DMSO) δ 10.74 (s, 1H), 7.89 (s, 1H), 7.53 (d, J=1.6Hz, 1H), 7.33 (d, J= 8.3Hz, 2H), 7.24 (dd, J=8.3,6.7Hz, 3H), 7.13 (dd, J=8.5,1.8Hz, 1H), 3.65 (t, J=5.9Hz, 1H), 3.48-3.35 (m, 1H), 3.30-3.19 (m, 1H), 2.79-2.73 (m, 2H), 2.59 (t, J=5.8Hz, 2H), 1.98- 1.83(m,3H),1.73–1.62(m,1H).
Embodiment 1-56：The bromo- N- of 6- (4- phenyl butyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides (SLQ056) Preparation
It is similar to preparing for compound SLQ003,3- phenylpropylamines are replaced as 4- phenyibutylamines, by 6- bromo- 2,3,4, 9- tetrahydrochysene -1H- carbazole -1- carboxylic acids are condensed to yield product SLQ056, yield with 4- phenyibutylamines in the presence of condensing agent： 57%,1H NMR (500MHz, DMSO) δ 10.77 (s, 1H), 7.85 (s, 1H), 7.53 (d, J=1.9Hz, 1H), 7.30-7.22 (m, 3H), 7.21-7.14 (m, 3H), 7.14-7.10 (m, 1H), 3.66 (t, J=5.9Hz, 1H), 3.24-3.14 (m, 1H), 3.12–3.01(m,1H),2.63–2.54(m,4H),2.05–1.87(m,3H),1.74–1.63(m,1H),1.62–1.52(m, 2H),1.51–1.41(m,2H).
Embodiment 1-57：(3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propiono) methyl lactamine (SLQ057) preparation
It is similar to compound SLQ007 preparation method, glycine ethyl ester hydrochloride is replaced as alanine methyl ester hydrochloride Obtain SLQ057, yield：57%,1H NMR (500MHz, DMSO) δ 10.56 (s, 1H), 8.41 (s, 1H), 7.36 (d, J= 7.8Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.07-6.97 (m, 1H), 6.97-6.88 (m, 1H), 4.33-4.23 (m, 1H), 3.87 (s, 1H), 3.61 (d, J=2.5Hz, 3H), 2.96-2.86 (m, 1H), 2.86-2.77 (m, 1H), 2.66-2.57 (m, 2H), 2.33 (t, J=6.8Hz, 2H), 2.04-1.92 (m, 2H), 1.78-1.64 (m, 2H), 1.30-1.24 (m, 3H)
Embodiment 1-58：3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propiono-L-PROLINE first The preparation of ester (SLQ058)
It is similar to compound SLQ007 preparation method, glycine ethyl ester hydrochloride is replaced as L-PROLINE methyl esters, passed through Series reaction is crossed, product SLQ058, yield are obtained after column chromatography：62%,1H NMR(500MHz,DMSO)δ11.08(s, 1H), 7.47 (d, J=7.8Hz, 1H), 7.37 (d, J=8.1Hz, 1H), 7.16-7.10 (m, 1H), 7.04-6.98 (m, 1H), 4.49(s,1H),4.39–4.24(m,1H),3.61(s,3H),3.58–3.47(m,2H),3.25–3.12(m,2H),2.86– 2.78(m,2H),2.75–2.58(m,2H),2.25–2.11(m,2H),2.08–1.97(m,2H),1.96–1.90(m,2H), 1.89–1.79(m,2H).
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The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, this Art personnel it is conceivable that change and advantage be all included in the present invention, and using appended claims as protect Protect scope.

Claims (11)

1. a kind of tetrahydrocarbazole compound or pharmaceutically acceptable salt, it is characterised in that it is by following structural formula (I) table Show：
Wherein,
N is 0,1,2,3,4；
X is NH, NHCO, CONH；
Y is NH, O, C=O, CH2, pyrimidine radicals；
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy；
R2For methyl；Phenyl, halogenophenyl, C1-10Alkoxyl phenyl；Furyl；Morpholinyl；Cyclohexyl；C1-3Alkanamine yl pyrimidines Base；Hydroxyl, C1-3Alkane hydroxyl；A-amino acid, Boc- a-amino acids, Cbz- a-amino acids, a-amino acid methyl esters；Furanylcarbonyl；Halogen For furanylcarbonyl, thienyl, halogenated thiophene acyl group, pyrrole radicals, pyrroles's acyl group, imidazole radicals, imidazoyl.
2. tetrahydrocarbazole compound according to claim 1 or pharmaceutically acceptable salt, it is characterised in that work as X= NH, it is represented by following structural formula (II)：
Wherein,
N=0,1,2,3,4；
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, C1-6Alkylamidoalkyl,C1-6Eneamide base, C6-8Aryl amido group, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy；
Y is O, NH, C=O, CH2、C1-2Alkylol；
R2For methyl；Phenyl；Halogenophenyl；C1-3Alkoxyl phenyl；Furyl；Morpholinyl；Cyclohexyl；C1-4Alkylamino radical pyrimidine radicals； Hydroxyl, C1-3Alkane hydroxyl；A-amino acid, Boc-- a-amino acids, Cbz- a-amino acids, a-amino acid methyl esters；Furanylcarbonyl, halo Furanylcarbonyl；Thienyl, thiophene acyl group, halogenated thiophene acyl group.
3. tetrahydrocarbazole compound according to claim 1 or pharmaceutically acceptable salt, it is characterised in that work as X= NH, Y=NH, R2For 2- isobutyl amine pyrimidines when, it is characterised in that its by following structural formula (III) represent：
Wherein,
N is 0,1,2,3,4；
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy.
4. tetrahydrocarbazole compound according to claim 1 or pharmaceutically acceptable salt, it is characterised in that work as n= 0, X=NH, Y are pyrimidine radicals, R2For isobutyl amine when, it is characterised in that its by following structural formula (IV) represent：
Wherein,
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, cyano group, C1-3Haloalkyl, C1-3Haloalkoxy Base.
5. tetrahydrocarbazole compound according to claim 1 or pharmaceutically acceptable salt, it is characterised in that work as R2For When phenyl or halogenophenyl or alkoxyl phenyl, it is characterised in that it is represented by following structural formula (V)：
Wherein,
N is 0,1,2,3,4；
X is NH, NHCO, CONH；
Y is CH2、NH；
R1For hydrogen, halogen, C1-3Alkyl, C1-3Alkoxy, carboxyl, C1-3Carbalkoxy, C1-6Alkylamidoalkyl, C1-6Eneamide base, C6-8Aryl amido group, cyano group, C1-3Haloalkyl, C1-3Halogenated alkoxy；
R3For H or halogen or C1-3Alkoxy.
6. Tetrahydrocarbazolesand small molecular organic compounds according to claim 1 or pharmaceutically acceptable salt, its feature It is, including following compound：
N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- isobutyl group -2,4- di-amino-pyrimidines,
The bromo- N- of 6- (3- phenyl propyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
The bromo- N- of 6- (4- (4- fluorophenyls) butyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
2- amino-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) acetamide,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) thiophene-2-carboxamide derivatives,
Methyl (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propiono) methyl lactamine,
N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 7-) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 8-) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (3- ((6- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((7- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((8- methoxyl group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminourea Pyrimidine,
N4- (3- ((the fluoro- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (3- ((the chloro- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (3- ((6- methyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (3- ((2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- di-amino-pyrimidines,
N4- (3- ((6- trifluoromethyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminos Yl pyrimidines,
N4- (3- ((6- methyl formate -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- diaminos Yl pyrimidines,
N4- (3- ((6- carboxyl -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (2- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) ethyl)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (4- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) normal-butyl)-N2- isobutyl group -2,4- Diaminopyrimidines Pyridine,
N4- (2- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) ethyl)-N2- isobutyl group -2,4- two Aminopyrimidine,
N4- (3- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) propyl group)-N2- isobutyl group -2,4- two Aminopyrimidine,
N4- (4- ((6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) normal-butyl)-N2- isobutyl group -2,4- Di-amino-pyrimidine,
N4- (6- trifluoromethoxy -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases)-N2- isobutyl group -2,4- di-amino-pyrimidines,
6- trifluoromethoxies-N- (3- is to fluorobenzene propyl group) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- cyano group-N- (3- is to fluorobenzene propyl group) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (4- benzene butyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (2- methoxybenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (furans -2- methylene) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- methyl-N- (2- morpholines ethyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N, N- diethylformamide)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N- cyclopropylmethylamides)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N- phenyl formamides)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
6- (N, N- diallyl formamide)-N- (4- luorobenzyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- amine,
N1- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-)-N2- (4- fluorophenyls) -1,2- ethylenediamines,
3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group -1- alcohol,
2- (2- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) ethyoxyl) ethyl -1- alcohol,
2- ((6- cyano group -2,3,4,9- tetrahydrochysene -1H- carbazole -1- bases) amino) ethyl -1- alcohol,
2- (N-Boc- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) acetamide,
2- amino-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) acetamide,
(2R) -2- (N-Boc- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) propionyl Amine,
(2R) -2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) propionamide,
(2S) -2- ((3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) carbamoyl) pyrrolidines - 1- t-butyl formates,
(2S) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- (4- Hydroxy phenyl) propionamide,
(2S) -2- amino-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- (4- hydroxy benzenes Base) propionamide,
(2S, 3R) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- Hydroxybutyrate amide,
(2R) -2- (Cbz- amino)-N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) -3- (1H- Imidazoles -5- bases) propionamide,
(2R)-2- amino-N- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) propionamide,
Benzyl ((2S)-1-((3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) amino)-3- hydroxyls- 1- oxo-butanes -2- bases) t-butyl carbamate,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) benzamide,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) -2- phenyl acetamides,
N- (the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) -3- hydrocinnamamides,
The bromo- N- of 5- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) thiophene-2-carboxamide derivatives,
N- (3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propyl group) thiophene-2-carboxamide derivatives,
The chloro- N- of 5- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) thiophene-2-carboxamide derivatives,
The bromo- N- of 5- (3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propyl group) furans-2- formamides,
The bromo- N- of 6- (4- phenyl butyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
6- bromo- N- (to chlorobenzene ethyl) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
The chloro- N- of 6- (4- phenyl butyls) -2,3,4,9- tetrahydrochysene -1H- carbazole -1- formamides,
(3- ((the bromo- 2,3,4,9- tetrahydrochysenes -1H- carbazoles -1- bases of 6-) amino) propiono) glycine ethyl ester,
(3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propiono) methyl lactamine,
3-((the bromo- 2,3,4,9- tetrahydrochysenes-1H- carbazoles-1- bases of 6-) amino) propionos-L-PROLINE methyl esters.
7. a kind of pharmaceutical composition, it is characterised in that it contains small point of Tetrahydrocarbazolesand described in any one of claim 1-5 Sub- organic compound or pharmaceutically acceptable salt, and pharmaceutically acceptable carrier.
8. the Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically acceptable according to any one of claim 1-5 Application of the pharmaceutical composition in antibacterials are prepared described in salt or claim 7.
9. the Tetrahydrocarbazolesand small molecular organic compounds or pharmaceutically acceptable according to any one of claim 1-5 Purposes of the pharmaceutical composition in the medicine of bacterial-infection resisting is prepared described in salt or claim 7, it is characterised in that described Bacterium includes gram-positive bacteria and Gram-negative bacteria, and the gram-positive bacteria includes：Staphylococcus aureus, intestines ball Bacterium, streptococcus pneumonia, tubercle bacillus and their own drug-fast bacteria；Gram-negative bacteria includes：Escherichia coli, P. aeruginosa Bacterium, Shigella, acinetobacter calcoaceticus, campylobacter, typhoid bacillus, gonococcus.
10. a kind of Tetrahydrocarbazolesand small molecular organic compounds according to any one of claim 1-5 pharmaceutically may be used The preparation method of the salt of receiving, it is characterised in that methods described with the hydrazinobenzene hydrochloride salt and 1,2- cyclohexanedione that substitute for raw material, 2,3,4,9- tetrahydrochysene -1H- carbazole -1- ketone are obtained by Fei Sheer indole synthesis, or it is bromo- with the aniline of substituted base and 3- 2- oxygen-cyclohexanone Ethyl formate cyclization forms 6-R bases -2,3,4,9- tetrahydrochysene -1H- carbazole -1- Ethyl formates, then by entering one Step derivative obtains the tetrahydro carbazole small molecular organic compounds or its hydrate or its pharmaceutically acceptable salt.
11. preparation method according to claim 10, it is characterised in that methods described includes：
Method one：
As shown in reaction equation (a)：
Wherein, substituted hydrazinobenzene hydrochloride salt 1 and 1,2- cyclohexanedione obtain compound 2, chemical combination by Fei Sheer indole synthesis Thing 2 is stretched out chain length by reduction amination, and described Tetrahydrocarbazolesand small molecular organic compounds are obtained through subsequent derivation Or its hydrate or pharmaceutically acceptable salt；
Method two：As shown in reaction equation (b)：
Wherein, substituted aniline 4 forms compound 6 with the bromo- 2- oxygen of 3--cyclization of cyclohexanone Ethyl formate 5, and the hydrolysis of compound 6 is de- Go ethyl to form carboxyl, then by a series of derivatives, obtain described Tetrahydrocarbazolesand small molecular organic compounds or its hydration Thing or pharmaceutically acceptable salt；
Method three：As shown in reaction equation (c)：
Wherein, substituted hydrazinobenzene hydrochloride salt 1 and 1,2- cyclohexanedione obtain compound 2, chemical combination by Fei Sheer indole synthesis Benzyl is sloughed under thing 2 and benzylamine reduction amination, Pd/C hydrogen atmospheres and obtains compound 8, compound 8 is by further derivative To described Tetrahydrocarbazolesand small molecular organic compounds or its hydrate or pharmaceutically acceptable salt.
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