CN104211631A - Indoles compound, preparation method thereof, pharmaceutical composition and application thereof - Google Patents

Indoles compound, preparation method thereof, pharmaceutical composition and application thereof Download PDF

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CN104211631A
CN104211631A CN201310211442.6A CN201310211442A CN104211631A CN 104211631 A CN104211631 A CN 104211631A CN 201310211442 A CN201310211442 A CN 201310211442A CN 104211631 A CN104211631 A CN 104211631A
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straight
branched
halogen
replace
replaced
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柳红
谢欣
赵飞
李静
栗增
陈颖
孙海丰
周宇
蒋华良
陈凯先
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Shanghai Institute of Materia Medica of CAS
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    • 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
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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

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  • Urology & Nephrology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to an indoles compound, a preparation method, a pharmaceutical composition and an application thereof. The indoles compound has a structure shown in a general formula(I), can be used for treating disease related to alpha1-adrenocepter, and especially for treating urinary system diseases such as prostatoplasia, urinary retention and bladder outlet obstruction.

Description

One class Benzazole compounds, its preparation method, pharmaceutical composition and application
Technical field
The present invention relates to pharmaceutical chemistry and chemotherapy field.Particularly, the present invention relates to the Benzazole compounds shown in a class general formula (Ι), its preparation method, pharmaceutical composition and at preparation treatment and α 1application in the urinary systems such as the disease that-adrenoceptor is relevant, especially benign prostatic hyperplasia, uroschesis, bladder outlet obstruction (BOO).
Background technology
Benign prostatic hyperplasia (benign prostatic hyperplasia, BPH) be the common physiology pathology of middle-aging male, along with inevitable aging population, the sickness rate of benign prostatic hyperplasia is compared and is greatly improved than before, has become one of modal senile disease of China's middle-aging male.Data demonstration, hyperplasia of prostate sickness rate before 40 years old is very low, and more than 50 years old, in the male sex, approximately has half to suffer from benign prostatic hyperplasia, and within 80 years old, person nearly 90% suffers from this disease.Benign prostatic hyperplasia is the optimum adenomatous hyperplasia of prostate-urethra peripheral region cell, the carrying out property enlargement of body of gland can make prostate ankylo-urethria, cause bladder urine flow out block, initial clinical manifestation is lower urinary tract systemic symptom (LUTS), finally can develop into uroschesis, bladder infection, vesical calculus and renal failure, even entail dangers to patient's life.Therefore, hyperplasia of prostate, as one of common disease of home and abroad middle-aging male, has greatly reduced patient's quality of life.
The pathogenesis more complicated of benign prostatic hyperplasia, with plurality of enzymes and receptor related.At present, the medicine that is used for the treatment of clinically BPH mainly contains: α 1-adrenoceptor antagonists, 5α-reductase inhibitor, natural product preparation etc.Two large medicine 5α-reductase inhibitor and the alpha-receptor antagonists for the treatment of BPH are to treat for prostate volume and level and smooth these two factors of muscular tension of causing hyperplasia of prostate symptom respectively; And in theory, the existence of hyperplasia relies on this two important factors just: statics factor and kinetic factor, the two acting in conjunction affects lesion degree.Wherein α 1-adrenoceptor antagonists energy rapid recovery symptom, but such medicine that can not significantly dwindle prostatic volume and early development often has serious untoward reaction.5α-reductase inhibitor can dwindle prostate volume, fundamentally relief of symptoms, but poor and onset is slower to small volume BPH effect.
Adrenoceptor (adrenergic receptors, ARs) is divided into alpha-receptor and beta-receptor, and these two acceptors are subdivided into again some receptor subtypes.Alpha-2-adrenoceptor belongs to 7 cross-film G-protein linked receptors (GPCRs) family, is distributed widely in various organs, tissue and the cell of body.Alpha-2-adrenoceptor (α-ARs) point α 1, α 2two types.Research shows, in prostatic matrix components and glandular tube epithelium, mainly has α 1receptor.Molecular cloning method has separated and has determined α 1A, α 1Band α 1Dthree kinds of α 1the hypotype of-acceptor, wherein α 1A-ARs accounts for total α in human body prostate gland and urinary tract system 170% of-ARs.At reproduction, urinary system, α 1A-acceptor is mainly distributed in prostate gland, urethra and trigone of urinary bladder, vas deferens, α 1B-acceptor is distributed in blood vessel, α 1D-acceptor is distributed in detrusor urinae of bladder and ureter unstriated muscle.
Under BPH pathologic condition, α 1-ARs density obviously increases.In addition, along with the variation α at age 1the characteristic distributions of-ARs hypotype is also different, and the dependency of this age and distribution, to understanding and treatment benign prostatic hyperplasia and lower urinary tract systemic symptom, is developed α 1-adrenoceptor antagonists is significant.The kinetic factor of BPH depends on the contraction of matrix unstriated muscle, and this contraction is by α 1-beta-2-adrenoreceptor mediated sympathetic stimulation causes.α 1the stimulation of-ARs can cause the contraction of prostate smooth musculature cells, causes the closed of urethra pressure to strengthen, and causes that urine stream blocks and irritation sign of bladder.Research discovery, the urethra pressure of Patients with Prostatic Hyperplasia 40% is from α 1the adjusting of-ARs.Ligand binding experiment shows, α 1the signal transduction pathway of-ARs mediation smooth muscle contraction is to make downstream produce second messenger-InsP3 and DG by a series of phospho-esterase c activation process, causes endogenous C a 2+thereby release regulatory gene express.
For α 1the distribution situation of-adrenoceptor hypotype and the understanding of function contribute to people to determine the treatment target spot of benign prostatic hyperplasia.α 1A-adrenoceptor is the desirable target spot for the treatment of, its blocking-up has been proved to be to the contraction frequency that can effectively reduce prostate smooth musculature cells, improves the emptying of bladder simultaneously.To α 1Bthe blocking-up of-adrenoceptor can cause to relax the VSM, phlebarteriectasia, and the symptoms such as Peripheral resistance minimizing, may cause side effect at some patient, such as dizziness and ypotension.α 1Dthe intensity of activation of-adrenoceptor causes the hyperactivity hyperkinesia of detrusor, can reduce the generation of emptying symptom to its retardance, and this has obtained confirmation in animal experiment.α in theory 1Aand α 1Dthe combined depressant of-adrenoceptor is to control the very effective medicine of benign prostatic hyperplasia.Reduce prostate smooth musculature cells contraction frequency and suppress two functions of detrusor function imbalance because it comprises, can avoid again in addition α 1Bthe caused cardiovascular side effect of-adrenoceptor retardance.
The alpha receptor blocking agent that can effectively slow down benign prostate hyperplasia shape that the first-generation is exploited is Phenoxybenzamine (Phenox ybenzamine).Phenoxybenzamine belongs to the irreversible non-selective α of β-halo alkanes 1/ α 2receptor blocking agent, can block the α acceptor in prostate gland, makes body of prostate fibrous tissue lax, is used for the treatment of clinically the misnicturition that on-mechanical urethral obstruction that prostate gland causes causes.In Phenoxybenzamine structure, contain β-chlorethamin structure, it in vivo easily and other enzymes react, therefore Side effect is more.And as non-selective alpha receptor blocking agent, it is at retardance α 1when acceptor, block presynaptic α 2acceptor, so just impels the release of norepinephrine, thereby can cause the increase of heart rate and myocardial contraction, causes untoward reaction.
Non-selective α 1/ α 2the application of receptor blocking agent is limited by its multiple side effect, comprising: faint, and postural hypotension, reflex tachycardia, arrhythmia etc., these side effects are mainly derived from α 2the blocking-up of acceptor.In order to reduce these side effects, for α 1acceptor has the s-generation α of highly selective 1-adrenoceptor antagonists arise at the historic moment (as: Prazosin, terazosin, Doxazosin, alfuzosin).α 1-adrenoceptor can be alleviated the prostate gland that caused by sympathetic nerve and the contraction of urethral smooth muscle, and driven terms of mechanics alleviates the symptom of urethral obstruction.These medicines have reduced the side effect causing because of vasodilation in effectively alleviating lower urinary tract symptom.Azoles piperazine class medicine all has the structure parent nucleus of quinazoline, is the common drug of current lower urinary tract symptom (LUTS) for the treatment of clinically BPH and cause.
But due to α 1extensive distribution and the important physiological function of-adrenoceptor, used α 1-adrenoceptor antagonists often there will be postural hypotension, dizziness, the side effect such as unable.We show in nearest research, and shown in general formula (I), Benzazole compounds has good α 1A-adrenoceptor antagonistic activity, can develop and become optionally α 1A-adrenoceptor antagonists, thus side effect reduced, provide useful help to the treatment of benign prostatic hyperplasia.
The invention provides a class Benzazole compounds, its preparation method, pharmaceutical composition and the application in urinary systems such as preparation treatment disease, the especially benign prostatic hyperplasia relevant to α 1-adrenoceptor, uroschesis, bladder outlet obstruction (BOO) thereof.
Summary of the invention
One aspect of the present invention be to provide by general formula (I) represent Benzazole compounds, with and pharmacy acceptable salt, crystalline hydrate, solvate or their mixture.
It is the preparation method of compound shown in general formula (II) that another aspect of the present invention is to provide an intermediate preparing general formula (I) compound.
Another aspect of the present invention is to provide that to prepare another required intermediate of general formula (I) compound be the preparation method of compound shown in general formula (III).
Another aspect of the present invention is to provide a kind of pharmaceutical composition, and this pharmaceutical composition comprises one or more in compound, its pharmacy acceptable salt, crystalline hydrate and the solvate described in the general formula (I) for the treatment of significant quantity; And one or more pharmaceutically acceptable carriers.
Another aspect of the present invention be to provide the described compound of general formula (I) with and pharmacy acceptable salt, crystalline hydrate, solvate or their mixture at preparation treatment and α 1application in the medicine of the disease that-adrenoceptor is relevant.
Another aspect of the present invention is to provide the disease that treatment is relevant to α 1-adrenoceptor, especially the method for the urinary system such as benign prostatic hyperplasia, uroschesis, bladder outlet obstruction (BOO), comprises one or more in general formula (I) described compound, its pharmacy acceptable salt, crystalline hydrate and solvate of being selected to the object drug treatment significant quantity of this treatment of needs.
According to an aspect of the present invention, provide the Benzazole compounds shown in general formula (I) below, its pharmacy acceptable salt, crystalline hydrate or solvate.
Wherein: R 1, R 2, R 3, R 4, R 5represent the substituting group on phenyl ring, be selected from independently of one another hydrogen, halogen, amino, carboxyl, cyano group, nitro, hydroxyl, the alkyl of the C1-C6 straight or branched not replacing or replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the alkoxyl group of the C1-C6 straight or branched not replacing or replaced by C3-C6 cycloalkyl or halogen, the thiazolinyl of the C2-C12 straight or branched not replacing or replaced by halogen, the alkynyl of the C2-C12 straight or branched not replacing or replaced by halogen, the C3-C6 cycloalkyl that does not replace or replaced by halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by halogen, do not replace or replace C1-C6 straight or branched alkyl carbonyl oxy by halogen, do not replace or replace C1-C6 straight or branched alkyl-carbonyl by halogen, the C1-C6 straight or branched carbalkoxy that does not replace or replaced by halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the benzyloxy that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the carbobenzoxy-(Cbz) that the alkoxyl group of the alkyl of C1-C6 straight or branched and C1-C6 straight or branched replaces, preferably be selected from independently of one another hydrogen, halogen, amino, hydroxyl, not replacement or the alkyl by the thiazolinyl of C2-C4 straight or branched or the C1-C6 straight or branched of 1-3 halogen replacement, do not replace or by the alkoxyl group of the C1-C6 straight or branched of C3-C6 cycloalkyl or the replacement of 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by 1-3 halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the benzyloxy that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, the alkoxyl group of the alkyl of the C1-C6 straight or branched that is more preferably hydrogen, halogen independently of one another, do not replace or replaced by vinyl or 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by C3-C6 cycloalkyl or 1-3 halogen, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement and not replacement or the C3-C6 cycloalkyloxy by 1-3 halogen replacement, most preferably be selected from independently of one another hydrogen, fluorine, chlorine, bromine, methyl, ethyl, allyl group, methoxyl group, oxyethyl group, ring propoxy-, ring the third methoxyl group, tert.-butoxy, neopentyl oxygen, trifluoromethoxy and 2,2,2-trifluoro ethoxy,
Or R 1, R 2, R 3, R 4, R 5in adjacent two substituting groups can form and contain 1～3 heteroatomic 5-6 unit heterocycle that is selected from N, O and S together with carbon atom coupled on phenyl ring; Be preferably formed and contain 1～2 first heterocycle of heteroatomic 5-6 that is selected from O and S; More preferably forming dioxane penta encircles;
N=0,1 or 2, preferably n=1;
R 6be selected from hydrogen, do not replace or the C1-C6 straight or branched alkyl-carbonyl that replaced by halogen and the benzoyl that do not replace or replaced by the alkoxyl group of the alkyl of halogen, C1-C6 straight or branched, C1-C6 straight or branched; The C1-C4 straight or branched alkyl-carbonyl that is preferably selected from the alkyl of hydrogen, C1-C4 straight or branched and does not replace or replaced by 1-3 halogen; More preferably be selected from hydrogen, methyl, ethanoyl and trifluoroacetyl group;
R 7be selected from the alkyl of hydrogen, C1-C6 straight or branched and the alkoxyl group of C1-C6 straight or branched; Be preferably selected from the alkyl of hydrogen and C1-C4 straight or branched; More preferably be selected from hydrogen and methyl;
* represent chiral carbon.
The Benzazole compounds that general formula of the present invention (I) represents can be its R type isomer, S type isomer and racemic modification, is preferably R type isomer.
In preferred embodiments,
R 1be selected from hydrogen, halogen, amino, carboxyl, cyano group, nitro, hydroxyl, the alkyl of the C1-C6 straight or branched not replacing or replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the alkoxyl group of the C1-C6 straight or branched not replacing or replaced by C3-C6 cycloalkyl or halogen, the thiazolinyl of the C2-C12 straight or branched not replacing or replaced by halogen, the alkynyl of the C2-C12 straight or branched not replacing or replaced by halogen, the C3-C6 cycloalkyl that does not replace or replaced by halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by halogen, the C1-C6 straight or branched alkyl carbonyl oxy that does not replace or replaced by halogen, the C1-C6 straight or branched alkyl-carbonyl that does not replace or replaced by halogen, the C1-C6 straight or branched carbalkoxy that does not replace or replaced by halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the benzyloxy that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the carbobenzoxy-(Cbz) that the alkoxyl group of C1-C6 straight or branched replaces, be preferably selected from hydrogen, not replacement or the alkyl by the thiazolinyl of C2-C4 straight or branched or the C1-C6 straight or branched of 1-3 halogen replacement, do not replace or by the alkoxyl group of the C1-C6 straight or branched of C3-C6 cycloalkyl or the replacement of 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by 1-3 halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the benzyloxy that the alkoxyl group of C1-C6 straight or branched replaces, the alkoxyl group of the alkyl of the C1-C6 straight or branched that is more preferably selected from hydrogen, does not replace or is replaced by vinyl or 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by C3-C6 cycloalkyl or 1-3 halogen, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement and not replacement or the C3-C6 cycloalkyloxy by 1-3 halogen replacement, most preferably be selected from methyl, ethyl, allyl group, methoxyl group, oxyethyl group, ring propoxy-, ring the third methoxyl group, tert.-butoxy, neopentyl oxygen, trifluoromethoxy and 2,2,2-trifluoro ethoxy.
R 2the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by thiazolinyl or the halogen of C2-C6 straight or branched; The alkyl of the C1-C4 straight or branched that is preferably selected from hydrogen, halogen and do not replace or replaced by thiazolinyl or the halogen of C2-C4 straight or branched; The alkyl of the C1-C4 straight or branched that is more preferably selected from hydrogen, fluorine, chlorine, bromine and do not replace or replaced by 1-3 halogen; Most preferably be selected from hydrogen, fluorine, chlorine, bromine, methyl and ethyl;
R 3the thiazolinyl of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the C2-C12 straight or branched that does not replace or replaced by 1-3 halogen; The alkyl of the C1-C4 straight or branched that is preferably selected from hydrogen, halogen and do not replace or replaced by thiazolinyl or the halogen of C2-C4 straight or branched; More preferably be selected from hydrogen, fluorine, chlorine, bromine and do not replace or by the alkyl of the C1-C4 straight or branched of vinyl or 1-3 halogen replacement; Most preferably be selected from hydrogen, methyl, ethyl, allyl group, fluorine, chlorine and bromine;
R 4the thiazolinyl of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by thiazolinyl or the halogen of C2-C6 straight or branched and the C2-C12 straight or branched that does not replace or replaced by 1-3 halogen; The alkyl of the C1-C4 straight or branched that is preferably selected from hydrogen, halogen and do not replace or replaced by thiazolinyl or the halogen of C2-C4 straight or branched; More preferably be selected from hydrogen, do not replace or by alkyl, fluorine, chlorine and the bromine of the C1-C4 straight or branched of vinyl or the replacement of 1-3 halogen; More preferably be selected from hydrogen, methyl, ethyl, allyl group, fluorine, chlorine and bromine;
Or R 3and R 4can form and contain 1～3 heteroatomic 5～6 yuan of heterocycle that are selected from O and S together with the coupled carbon atom on phenyl ring; Be preferably formed and contain 1～2 first heterocycle of heteroatomic 5-6 that is selected from O and S; More preferably forming dioxane penta encircles;
R 5be selected from hydrogen, halogen, amino, carboxyl, cyano group, nitro, hydroxyl, the alkyl of the C1-C6 straight or branched not replacing or replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the alkoxyl group of the C1-C6 straight or branched not replacing or replaced by C3-C6 cycloalkyl or halogen, the thiazolinyl of the C2-C12 straight or branched not replacing or replaced by halogen, the alkynyl of the C2-C12 straight or branched not replacing or replaced by halogen, the C3-C6 cycloalkyl that does not replace or replaced by halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by halogen, the C1-C6 straight or branched alkyl carbonyl oxy that does not replace or replaced by halogen, the C1-C6 straight or branched carbonyl that does not replace or replaced by halogen, the C1-C6 straight or branched carbalkoxy that does not replace or replaced by halogen, do not replace or by halogen, the phenoxy group that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, do not replace or by halogen, the benzyloxy that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, do not replace or by halogen, the carbobenzoxy-(Cbz) that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, be preferably selected from not replacement or the alkyl by the thiazolinyl of C2-C4 straight or branched or the C1-C6 straight or branched of 1-3 halogen replacement, do not replace or by the alkoxyl group of the C1-C6 straight or branched of C3-C6 cycloalkyl or the replacement of 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by 1-3 halogen, do not replace or by halogen, the phenoxy group that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, do not replace or by halogen, the benzyloxy that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, more preferably be selected from the alkyl of the C1-C6 straight or branched not replacing or replaced by vinyl or 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by C3-C6 cycloalkyl or 1-3 halogen alkoxyl group, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement and not replacement or the C3-C6 cycloalkyloxy by 1-3 halogen replacement, most preferably be selected from methyl, ethyl, allyl group, methoxyl group, oxyethyl group, ring propoxy-, ring the third methoxyl group, tert.-butoxy, neopentyl oxygen, trifluoromethoxy and 2,2,2-trifluoro ethoxy.
R 6be selected from hydrogen, do not replace or the C1-C6 straight or branched alkyl-carbonyl that replaced by halogen and the benzoyl that do not replace or replaced by the alkoxyl group of the alkyl of halogen, C1-C6 straight or branched, C1-C6 straight or branched; The C1-C4 straight or branched alkyl-carbonyl that is preferably selected from hydrogen and does not replace or replaced by 1-3 halogen; Be preferably selected from hydrogen, ethanoyl and trifluoroacetyl group;
R 7be selected from the alkyl of hydrogen, C1-C6 straight or branched and the alkoxyl group of C1-C6 straight or branched; Be preferably selected from the alkyl of hydrogen and C1-C4 straight or branched; More preferably be selected from hydrogen and methyl; Most preferably be hydrogen;
N=0,1 or 2, preferably n=1.
In the present invention, described pharmacy acceptable salt comprises the non-toxic salt forming with mineral acid or organic acid reaction, described mineral acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid without limitation, and described organic acid is selected from propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid and aspartic acid without limitation.
In the present invention, halogen is fluorine, chlorine, bromine, iodine.
In the preferred embodiment of the present invention, the compound of general formula of the present invention (I) is preferably following particular compound:
Compound of the present invention has chiral centre, can be R type isomer, S type isomer and racemic modification, is preferably R type isomer.
The invention provides the preparation method of the compound of a kind of general formula (I) expression.First the compound of preparing general formula (I) expression needs preparation following two intermediates, i.e. intermediate (II) and intermediate (III).Raw materials used and the reagent of the present invention if no special instructions, is business and buys.
Reaction scheme one: the preparation of intermediate (II)
Reaction scheme one comprises following reactions steps:
Step 1a: compound 1a and methyl bromoacetate carry out nucleophilic substitution reaction, obtains compound 1b; Wherein, described nucleophilic substitution reaction can carry out under alkali exists, and described alkali can be for example salt of wormwood, cesium carbonate, potassiumphosphate, sodium hydroxide or potassium hydroxide, preferably salt of wormwood; Reaction solvent can be for example acetone, acetonitrile, tetrahydrofuran (THF) or DMF, is preferably acetone;
Step 1b: compound 1b and N, O-dimethyl oxammonium hydrochloride carries out amine transesterification reaction, obtains compound 1c; Described amine transesterification reaction can be carried out under the catalyzer of for example trimethyl aluminium exists, and reaction solvent can be for example anhydrous methylene chloride;
Step 1c: compound 1c carries out reduction reaction, obtains compound 1d; Wherein, described reduction reaction can be used the reductive agent of for example Lithium Aluminium Hydride to carry out; Reaction solvent can be for example anhydrous tetrahydro furan.
Reaction scheme two: the preparation of intermediate (III):
Reaction scheme two comprises following reactions steps:
Step 3a: the bromo-1-ethanol of compound 3a and 2-or the bromo-1-propyl alcohol of 3-or the bromo-n-butyl alcohol of 4-carry out nucleophilic substitution reaction, obtain compound 3b; Wherein, described nucleophilic substitution reaction can be under alkali exists the 12-20 hour that reflux, described alkali can be for example salt of wormwood; Reaction solvent can be for example acetonitrile;
Step 3b: compound 3b and acylating reagent carry out acylation reaction, obtains compound 3c; Wherein, described acylation reaction can be carried out under alkali exists, described acylating reagent can be for example acyl chlorides, for example, replaced by the alkoxyl group of the alkyl of halogen, C1-C6 straight or branched, C1-C6 straight or branched or unsubstituted Benzoyl chloride or do not replace or by 1-3 halogen replacement C1-C6 straight or branched alkyl acyl chloride; Described alkali can be for example triethylamine; Reaction solvent can be for example anhydrous methylene chloride;
Step 3c: compound 3c and DMF carry out formylation reaction, obtains compound 3d; Wherein, described formylation reaction can carry out under the catalyzer of for example phosphorus oxychloride exists, and reaction solvent can be for example anhydrous 1,2-ethylene dichloride;
Step 3d: compound 3d and nitroethane carry out condensation reaction, obtains compound 3e; Wherein, described condensation reaction can be carried out under the existence of the catalyzer of for example ammonium acetate; Reaction solvent can be for example the mixed solvent of acetic acid and nitroethane;
Step 3e: compound 3e carries out reduction reaction, obtains compound 3f; Wherein, described reduction reaction can be used the reductive agent of for example sodium borohydride; Reaction solvent can be for example the mixed solvent of methylene dichloride and methyl alcohol;
Step 3f: compound 3f and DMF carry out formylation reaction, obtains compound 2a; Wherein, described formylation reaction can carry out under the catalyzer of for example phosphorus oxychloride exists, and reaction solvent can be for example DMF;
Step 2a: compound 2a carries out oxidizing reaction, obtains compound 2b; Wherein, described oxidizing reaction can be used for example 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone oxygenant of (being called for short DDQ); Reaction solvent can be for example ethyl acetate, methylene dichloride or Isosorbide-5-Nitrae-dioxane;
Step 2b: compound 2b and oxammonium hydrochloride carry out condensation reaction, obtains compound 2c; Wherein, described condensation reaction can be carried out under alkali and dewatering agent existence, and described alkali can be for example pyridine; Described dewatering agent can be for example aceticanhydride; Described solvent can be for example anhydrous tetrahydro furan;
Step 2c: compound 2c carries out reduction reaction, obtains compound 2d; Wherein, described reduction reaction can be used for example reductive agent of 10% Palladium carbon; Reaction solvent can be for example the mixed solvent of methyl alcohol, tetrahydrofuran (THF) or methyl alcohol and tetrahydrofuran (THF);
Step 2d: compound 2d is split to obtain to compound 2e and compound 2f; Resolving agent can be for example L-(+)-tartrate or L-(-)-tartrate; Reaction solvent can be for example acetone.
Reaction scheme three: the preparation of compound shown in general formula (I) (n is 0,1,2, is preferably 1)
Step 4a: intermediate (II) and intermediate (III) carry out reductive amination process, obtain compound 4a; Wherein, for example acetic acid sodium borohydride of the former amination of described reduction or sodium cyanoborohydride carry out under existing, and reaction solvent is for example 1,2-ethylene dichloride;
Step 4b: the compound 4a reaction that is hydrolyzed, obtains compound 4b; Wherein, described hydrolysis for example can be carried out under alkali exists, and described alkali can be for example potassium hydroxide, sodium hydroxide or lithium hydroxide; Reaction solvent can be for example the mixed solvent of water and methyl alcohol;
Step 4c: the compound 4b reaction that is hydrolyzed, obtains compound 4c; Wherein, described hydrolysis reaction can carry out under the catalyzer of for example alkali and hydrogen peroxide exists, and described alkali can be for example sodium hydroxide; Reaction solvent can be for example methyl-sulphoxide; Or
Step 4d: compound 4a and cylite carry out nucleophilic substitution reaction, obtains compound 4d; Wherein, described nucleophilic substitution reaction for example can carry out under alkali exists, and described alkali can be for example salt of wormwood; Reaction solvent can be for example acetone;
Step 4e: the compound 4d reaction that is hydrolyzed, obtains compound 4e; Wherein, described hydrolysis reaction for example can carry out under alkali exists, and described alkali can be for example potassium hydroxide, sodium hydroxide or lithium hydroxide; Reaction solvent can be for example the mixed solvent of water and methyl alcohol;
Step 4f: the compound 4e reaction that is hydrolyzed, obtains compound 4f; Wherein, described hydrolysis reaction can carry out under the catalyzer of for example alkali and hydrogen peroxide exists, and described alkali can be for example sodium hydroxide; Reaction solvent can be for example methyl-sulphoxide;
Step 4g: compound 4f and acylating reagent carry out acylation reaction, obtains compound 4g; Wherein, described acylation reaction can be carried out under alkali exists, described acylating reagent can be for example acyl chlorides, for example, replaced by the alkoxyl group of the alkyl of halogen, C1-C6 straight or branched, C1-C6 straight or branched or unsubstituted Benzoyl chloride, do not replace or by 1-3 halogen replacement C1-C6 straight or branched alkyl acyl chloride; Described alkali can be for example triethylamine; Reaction solvent can be for example anhydrous methylene chloride;
Step 4h: compound 4g carries out hydrogenation debenzylation reaction, obtains compound 4h; Wherein, described hydrogenation debenzylation reaction can use for example reductive agent of 10% Palladium carbon; Reaction solvent can be for example the mixed solvent of methyl alcohol, tetrahydrofuran (THF) or methyl alcohol and tetrahydrofuran (THF).
In reaction scheme one, two and three, except R 6be not beyond hydrogen, R 1～R 7definition identical with aforementioned definitions.
In addition, the inventor found through experiments general formula (I) compound and has excellent α 1-adrenoceptor antagonistic activity and selectivity, therefore compound of the present invention can be used for preparation and α 1the experimental model instrument medicine that-adrenoceptor is relevant or for the preparation for the treatment of and prevention and α 1the medicine of the urinary systems such as-adrenoceptor relative disease, especially benign prostatic hyperplasia, uroschesis, bladder outlet obstruction (BOO).
The present invention also provides a kind of pharmaceutical composition, and it contains general formula (I) compound for the treatment of significant quantity, or its pharmacy acceptable salt, crystalline hydrate and solvate, and contains one or more pharmaceutically acceptable carriers.Its pharmacy acceptable salt comprises the non-toxic salt forming with mineral acid or organic acid reaction, described mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid, and described organic acid comprises propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, aspartic acid.This medicinal compositions can also further comprise the conventional additives such as odorant agent, flavouring agent.
Pharmaceutical composition provided by the present invention preferably contain weight ratio be 1-99% be selected from general formula (I) compound, one or more in its pharmacy acceptable salt, crystalline hydrate and solvate are as activeconstituents, preferably, described activeconstituents accounts for the 65%-99% of pharmaceutical composition gross weight, and rest part is pharmaceutically acceptable carrier and/or conventional additives.
Compound provided by the present invention and pharmaceutical composition can be various ways, as tablet, capsule, pulvis, syrup, solution shape, suspension and aerosol etc., and may reside in the carrier of suitable solid or liquid or diluent and the suitable disinfector for injecting or instiling.
The various formulations of pharmaceutical composition of the present invention can be according to conventional preparation method's preparation of pharmaceutical field.In the unit metering of its pharmaceutical formulation, can comprise 0.05-200mg, preferably 0.1mg-100mg be selected from one or more in its pharmacy acceptable salt of general formula (I) compound, crystalline hydrate and solvate.
Compound of the present invention and pharmaceutical composition can, to the clinical use of Mammals, comprise humans and animals, can pass through the administration of mouth, nose, skin, lung or gi tract etc.Most preferred route of administration is oral.
Therefore, the present invention also provides a kind for the treatment of the disease relevant to α 1-adrenoceptor, especially the method for the urinary system such as benign prostatic hyperplasia, uroschesis, bladder outlet obstruction (BOO), comprise to the object drug treatment significant quantity of this treatment of needs be selected from the described compound of general formula (I) with and pharmacy acceptable salt, crystalline hydrate and solvate in one or more.
Embodiment
In following embodiment, will further illustrate the present invention.These embodiment are only for the present invention is described, but do not limit the present invention in any way.
The starting raw material of using in the present invention, without special instruction, is business and buys.
Embodiment 1:1-(3-hydroxypropyl)-5-[(2R)-2-[2,6-dimethyl-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC371801) is (as shown in reaction formula 1 and reaction formula 2, first prepare its corresponding two intermediates, then prepare (DC471801) with reaction scheme three shown in reaction formula 3
Reaction formula 1:
1.1:1-(3-hydroxypropyl)-indoline
By 50g(31.5ml) indoline is dissolved in 600ml acetonitrile, adds the bromo-1-propyl alcohol of 3-47.5ml, adds salt of wormwood 120g, backflow 12h, after question response liquid cooling but, suction filtration, column chromatography purification obtains oily matter 64g, yield 86%. 1H?NMR(d-DMSO,400MHz):δ7.95-8.06(2H,m),7.55(1H,dd),7.28(1H,dd),4.40-4.50(2H,m),3.48-3.60(2H,m),3.3-3.4(2H,m),2.98-2.93(2H,m),2.36-2.50(2H,m).ESI-MS?m/z:178[M+H] +.
1.2:1-(3-benzoyloxy propyl group)-indoline
Previous step gained 1-(3-hydroxypropyl)-indoline 64g is dissolved in 600ml anhydrous methylene chloride, add triethylamine 56ml, under ice bath agitation condition, slowly drip Benzoyl chloride 43ml, finish reaction 10h, then add three times (100ml × 3) of water extraction, organic layer concentrates to obtain lavender oily matter 96.8g, productive rate 96%. 1H?NMR(CDCl 3,400MHz):δ7.95-8.08(m,2H),7.56-7.66(m,1H),7.31-7.50(m,6H),4.4-4.5(m,2H),3.79-4.0(m,2H),3.5-3.6(m,2H),3.31-3.40(m,2H),2.38-2.5(m,2H).ESI-MS?m/z:282[M+H] +.
1.3:1-(3-benzoyloxy propyl group)-5-formyl radical-indoline
By 40ml N, dinethylformamide is dissolved in 500ml anhydrous 1, in 2-ethylene dichloride, under nitrogen protection and ice bath agitation condition, slowly drip 64ml phosphorus oxychloride, finish reaction 1h, then drip wherein anhydrous 1 of previous step gained 1-(3-benzoyloxy propyl group)-indoline (96.8g), 2-dichloroethane solution (300ml), finish, be transferred to 80 DEG C of oil bath reaction 2h, after completion of the reaction, be cooled to room temperature, concentrate and remove most of solvent, the phosphorus oxychloride of the cancellation remnants that slowly add water, then be extracted with ethyl acetate (300ml × 3), merge organic layer, dry, column chromatography purification obtains yellow solid 86g, yield 82%. 1H?NMR(CDCl 3,400MHz):δ9.8(s,1H),8.0-8.12(m,2H),7.42-7.63(m,5H),6.4(d,1H,J=8Hz),4.45(t,2H,J=6.2Hz),3.57-3.66(m,2H),3.36-3.45(m,2H),3.05(t,2H,J=8.5Hz),2.01-2.2(m,2H).ESI-MS?m/z:310[M+H] +.
1.4:1-(3-benzoyloxy propyl group)-5-(2-nitro propenyl)-indoline
Previous step gained 1-(3-benzoyloxy propyl group)-5-formyl radical-indoline 86g is dissolved in 250ml nitroethane; add ammonium acetate 42g; add acetic acid 120ml; after back flow reaction 4h; then reaction solution is concentrated, then add 600ml ethyl acetate, three times (300ml × 3) of water extraction; organic layer drying, concentrated gained resistates obtain red granules shape solid product 70g, productive rate 71% with Virahol recrystallization. 1H?NMR(CDCl 3,400MHz):δ8.05-8.1(m,3H),7.55-7.65(m,1H),7.42-7.5(m,2H),7.2-7.3(m,2H),6.40(d,1H,J=8.4Hz),4.41-4.49(m,2H),3.5-3.6(m,2H),3.3-3.4(m,2H),3.0-3.1(m,2H),2.48(S,3H),2.0-2.1(m,2H).ESI-MS?m/z:367[M+H] +.
1.5:1-(3-benzoyloxy propyl group)-5-(2-nitro propyl group)-indoline
Previous step gained 1-(3-benzoyloxy propyl group)-5-(2-nitro propenyl)-indoline 70g is dissolved in the mixed solvent of 300ml methylene dichloride and 600ml methyl alcohol, under ice bath agitation condition, slowly add wherein sodium borohydride in batches, until reaction solution is by the redness clear (approximately needing to add sodium borohydride 75g) that becomes colorless, TLC detection reaction, after completion of the reaction, reaction solution is concentrated to go out most of methyl alcohol, then add wherein 600ml ethyl acetate, add wherein again saturated aqueous ammonium chloride, produce a large amount of white solids, suction filtration, filtrate water is washed (200ml × 3) three times, merge organic layer, dry, column chromatography purification obtains faint yellow oily matter 64.3g, yield 91%. 1H?NMR(CDCl 3,400MHz):δ8.0-8.1(m,1H),7.56-7.64(m,1H),7.4-7.5(m,2H),6.85(s,1H),6.83(d,1H,J=8.0Hz),6.39(d,1H,J=8.0Hz),6.53-6.51(m,1H),4.65-4.75(m,1H),4.4-4.5(m,2H),3.3-3.4(m,2H),3.15-3.28(m,3H),2.8-3.0(m,3H),2.0-2.1(m,2H),1.50(d,3H,J=6.6Hz).ESI-MS?m/z:369[M+H] +.
1.6:1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoline
Under nitrogen protection and ice bath agitation condition, 40ml phosphorus oxychloride is slowly added drop-wise to 120ml N, in dinethylformamide, finish reaction 1h, then drip wherein the N of previous step gained 1-(3-benzoyloxy propyl group)-5-(2-nitro propyl group)-indoline (64.3g), dinethylformamide solution (200ml), finish, be transferred to 80 DEG C of oil bath reaction 2h, after completion of the reaction, be cooled to room temperature, concentrate and remove most of solvent, the phosphorus oxychloride of the cancellation remnants that slowly add water, then be extracted with ethyl acetate (500ml × 3), merge organic layer, dry, column chromatography purification obtains yellow solid 60g, yield 86%. 1H?NMR(CDCl 3,400MHz):δ9.94(s,1H),8.0-8.1(m,2H),7.5-7.6(m,1H)7.4-7.5(m,2H),7.22(s,1H),6.93(brs,1H),4.65-4.76(m,1H),4.4-4.5(m,2H),3.6-3.7(m,4H),3.20(dd,1H,J=7.7,14.2Hz),3.0-3.1(m,2H),2.93(dd,1H,J=6.4,14.2Hz),2.1-2.2(m,2H),1.54(d,3H,J=6.6Hz).ESI-MS?m/z:397[M+H] +.
1.7:1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoline 60g is dissolved in 500ml ethyl acetate; add 2; 3-bis-chloro-5; 6-dicyano-1; 4-benzoquinones 52g; finish reaction 12h, add saturated sodium bicarbonate and wash (300ml × 3) 3 times, organic layer concentrates to obtain faint yellow oily matter 53.7g productive rate 90%. 1H?NMR(CDCl 3,400MHz):δ10.04(s,1H),8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.18(d,J=3.2Hz,1H),6.52(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.45(dd,J=14.2,7.7Hz,1H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.58(d,J=6.6Hz,3H).ESI-MS?m/z:395[M+H] +.
1.8:1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-nitro propyl group)-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoles 53.7g is dissolved in 450ml anhydrous tetrahydro furan; add oxammonium hydrochloride 12g; add again pyridine 50ml; in 50 DEG C of reaction 12h; then add aceticanhydride 52ml in batches; be warming up to back flow reaction 8h; reaction solution is concentrated; add 500ml ethyl acetate; wash three times (200ml × 3); the concentrated yellow solid that to obtain of organic layer, obtains yellow solid product 47g, yield 87% by recrystallizing methanol. 1H?NMR(CDCl 3,400MHz):δ8.0-8.1(m,2H),7.5-7.6(m,1H),7.4-7.5(m,2H),7.16(d,J=3.2Hz,1H),6.93(brs,1H),6.89(brs,1H),6.54(d,J=3.2Hz,1H),4.6-4.7(m,1H),4.4-4.5(m,2H),3.7-3.81(m,2H),3.12(dd,1H,J=7.8,14.2Hz),2.86(dd,1H,J=6.2,14.2Hz),2.1-2.2(m,2H),1.54(d,3H,J=6.7Hz).ESI-MS?m/z:392[M+H] +.
1.9:1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-nitro propyl group)-indoles (47g) is dissolved in the mixed solvent of 400ml methyl alcohol and 400ml tetrahydrofuran (THF), add 10% Palladium carbon 4.7g, under a normal atmosphere hydrogen, reduce, reaction 48h, suction filtration after completion of the reaction, filtrate concentrates to obtain product 41.2g, yield 94%. 1H?NMR(CDCl 3,400MHz):δ8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.15(d,J=3.2Hz,1H),6.52(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.45-3.52(m,3H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.05(d,J=6.6Hz,3H).ESI-MS?m/z:362[M+H] +.
1.10:1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles 5g is dissolved in acetone 30ml, under agitation condition, add wherein 1.2gL-(+)-aqueous tartaric acid solution (1.2gL-(+)-tartrate is dissolved in 30ml water), finish and stir 12h, separate out a large amount of solids, suction filtration obtains L-(+)-tartrate 2.0g of target product.Gained solid is dissolved in 80ml water, adds saturated sodium carbonate solution to adjust pH to 10, add 2 times (100 × 2) of ethyl acetate extraction, merge organic layer, dry, concentrate to obtain faint yellow oily solid 1.8g, productive rate 35%. 1H?NMR(CDCl 3,400MHz):δ8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.18(d,J=3.2Hz,1H),6.50(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.46-3.54(m,3H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.05(d,J=6.6Hz,3H).ESI-MS?m/z:362[M+H] +.
1.11:1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2S)-2-aminopropyl]-indoles
Step 1.9 gained 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles 5g is dissolved in acetone 30ml, under agitation condition, add wherein 1.2gL-(-)-aqueous tartaric acid solution (1.2gL-(-)-tartrate is dissolved in 30ml water), finish and stir 12h, separate out a large amount of solids, suction filtration obtains L-(-)-tartrate 2.0g of target product.Gained solid is dissolved in 80ml water, adds saturated sodium carbonate solution to adjust pH to 10, add 2 times (100 × 2) of ethyl acetate extraction, merge organic layer, dry, concentrate to obtain faint yellow oily solid 1.7g, productive rate 35%. 1H?NMR(CDCl 3,400MHz):δ8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.08(d,J=3.2Hz,1H),6.42(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.43-3.50(m,3H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.05(d,J=6.6Hz,3H).ESI-MS?m/z:362[M+H] +.
Reaction formula 2:
1.12:2,6-dimethyl phenoxyacetic acid methyl esters
2,6-xylenol (4g) is dissolved in acetone, adds methyl bromoacetate 3.68ml, add salt of wormwood 9.12g, reflux 12 hours, suction filtration, concentrates to obtain faint yellow oily matter 6.2g, yield 97%. 1H?NMR(CDCl 3,400MHz):δ7.2-7.0(m,3H),4.68(s,2H),3.8(s,3H)2.2(s,6H).ESI-MS?m/z:195[M+H] +.
1.13:N-methyl-N-methoxyl group-2,6-dimethyl benzene acetamide oxide
By 6.2g N, O-dimethyl oxammonium hydrochloride is scattered in 200ml anhydrous methylene chloride, under nitrogen protection and ice bath agitation condition; drip wherein the toluene solution (2mol/L) of 16ml trimethyl aluminium; finish reaction 1h, then drip previous step gained 2, the anhydrous methylene chloride solution (50ml) of 6-dimethyl phenoxyacetic acid methyl esters; finish; reaction 3h, reaction solution washes (150ml × 3) with water three times, and organic layer is dry; concentrate to obtain faint yellow oily matter 7.0g, yield 98%. 1H?NMR(CDCl 3,400MHz):δ7.2(s,1H),7.16-7.08(m,2H),4.70(s,2H),4.0(s,3H),3.7(s,3H),2.2(s,6H).ESI-MS?m/z:224[M+H] +.
1.14:2,6-dimethyl benzene oxygen acetaldehyde
By previous step gained N-methyl-N-methoxyl group-2,6-dimethyl benzene acetamide oxide (7.0g) is dissolved in anhydrous tetrahydro furan, at-78 DEG C, slowly add wherein Lithium Aluminium Hydride 1.2g in batches, finish reaction 3h, dropwise the add water Lithium Aluminium Hydride of cancellation remnants of reaction solution, suction filtration, filtrate is dry, concentrates to obtain white solid 4.6g, productive rate 89%. 1H?NMR(CDCl 3,400MHz):δ10.05(s,1H),7.16-7.1(m,3H),4.70(s,2H),2.23(s,6H).ESI-MS?m/z:163[M-H] +.
Reaction formula 3:
1.15:1-(3-benzoyloxy propyl group)-5-[(2R)-2-[2,4-dimethyl-phenoxy group] ethylamino-] propyl group]-7-cyano group-indoles
1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2R that step 1.10 is made)-2-aminopropyl]-indoles 150mg is dissolved in 1, in 2-ethylene dichloride, add 2,6-dimethyl benzene oxygen acetaldehyde 100mg, add acetic acid sodium borohydride 125mg, reaction 12h, column chromatography purification obtains faint yellow oily matter 178mg, yield 83%.ESI-MS?m/z:510[M+H] +.
1.16:1-(3-hydroxypropyl)-5-[(2R)-2-[2,6-dimethyl-phenoxy group] ethylamino-] propyl group]-7-cyano group-indoles
Previous step gained compound (178mg) is dissolved in methyl alcohol, adds 525 μ l aqueous sodium hydroxide solutions (concentration is 1mol/L), react 6 hours, concentrated, add 20ml ethyl acetate and 20ml water stratification, organic layer is dry, concentrate to obtain faint yellow oily matter 130mg, yield 90%.ESI-MS?m/z:406[M+H] +.
1.17:1-(3-hydroxypropyl)-5-[(2R)-2-[2,6-dimethyl-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471801)
Previous step gained compound (130mg) is dissolved in methyl-sulphoxide, add 5mol/L aqueous sodium hydroxide solution 110 μ l, add 30% aqueous hydrogen peroxide solution 65 μ l, after reaction 12h, add water 20ml, be extracted with ethyl acetate three times (20ml × 3), merge organic layer, column chromatography purification obtains faint yellow oily matter 129mg, yield 96%. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.16(s,1H),7.10(d,J=3.2Hz,1H),6.96(s,1H),6.92-6.87(m,3H),6.87-6.80(m,1H),6.49(d,J=3.2Hz,1H),4.38(m,2H),3.88(m,2H),3.29(t,J=8.4Hz,2H),3.17-2.94(m,3H),2.83-2.70(m,1H),2.64-2.53(m,1H),2.15(s,6H),1.67(m,2H),1.11(d,J=6.0Hz,3H).ESI-MS?m/z:424[M+H] +.
Embodiment 2:1-(3-hydroxypropyl)-5-[(2R)-2-[2,4,6-trimethylammonium-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471802)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2，4，6-trimethyl phenol and makes. 1H?NMR(400MHz,CDCl 3)：δ7.44(s,1H),7.14(d,J=3.2Hz,1H),7.02(s,1H),6.97(s,1H),6.87(d,J=7.6Hz,1H),6.80(d,J=7.6Hz,1H),6.72(s,1H),6.44(d,J=3.2Hz,1H),3.88-3.76(m,2H),3.68(t,J=5.6Hz,2H),3.14(t,J=6.8Hz,2H),3.05(m,1H),3.00-2.92(t,J=6.8Hz,2H),2.69(dd,J=13.5,6.7Hz,1H),2.58(dd,J=13.5,6.5Hz,1H),2.19(s,3H),2.16(s,3H),2.11(s,3H),1.79-1.70(m,2H),1.09(d,J=6.3Hz,3H).ESI-MSm/z:438[M+H] +.
Embodiment 3:1-(3-hydroxypropyl)-5-[(2R)-2-[2,3,6-trimethylammonium-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471803)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2,3,6-TMP and makes. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.12(d,J=3.2Hz,1H),7.02(s,1H),7.01-6.98(m,1H),6.78(s,2H),6.70(s,1H),6.52(d,J=3.2Hz,1H),3.90-3.80(m,2H),3.68(t,J=5.6Hz,2H),3.14(t,J=6.8Hz,2H),3.07-3.02(m,1H),2.92-2.96(m,2H),2.71(dd,J=13.5,6.7Hz,1H),2.63-2.56(m,1H),2.20(s,3H),2.16(s,6H),1.79-1.69(m,2H),1.10(d,J=6.3Hz,3H).ESI-MS?m/z:438[M+H] +.
Embodiment 4:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[5-ethyl-2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471804)
Press the preparation method of embodiment 1, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 5-ethyl-2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde makes, 5-ethyl-2-(2,2,2-trifluoro ethoxy) being prepared as follows shown in reaction formula 4 of-benzene oxygen acetaldehyde. 1H?NMR(400MHz,CDCl 3)：δ7.45(s,1H),7.13(d,J=3.2Hz,1H),6.98(s,2H),6.86(d,J=8.0Hz,1H),6.71(m,2H),6.62(s,1H),6.55(d,J=3.2Hz,1H),4.31-4.18(m,2H),4.10(t,J=7.52Hz,2H),3.68(t,J=5.5Hz,2H),3.13(m,2H),3.08-2.87(m,3H),2.69(dd,J=13.5,6.3Hz,1H),2.62-2.46(m,3H),1.82-1.67(m,2H),1.20-1.14(t,J=7.7Hz,3H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:522[M+H] +.
Reaction formula 4:5-ethyl-2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde syntheti c route
4.1:5-ethyl-2-(2,2,2-trifluoro ethoxy)-methyl-phenoxide
2-methoxyl group-4-ethyl-phenol 2.5g is dissolved in to N, in dinethylformamide, add 2,2,2-trifluoroethyl p-toluenesulfonic esters 4.2g, add salt of wormwood 7.0g, in 100 DEG C of reaction 12h, add 200ml water and the layering of 200ml ethyl acetate, organic layer washes (200ml × 3) with water 3 times, merge organic layer, column chromatography purification obtains faint yellow oily matter 2.5g, yield 65%. 1H?NMR(400MHz,CDCl 3)：δ6.85(d,J=2.2Hz,1H),6.8(d,J=2.5Hz,1H),6.74(m,1H),4.31-4.18(m,2H),3.8(s,3H),2.6(q,J=6.8Hz,2H),1.25(t,J=6.8Hz,3H).ESI-MS?m/z:235[M+H] +.
4.2:5-ethyl-2-(2,2,2-trifluoro ethoxy)-phenol
By previous step gained 5-ethyl-2-(2; 2; 2-trifluoro ethoxy)-methyl-phenoxide 2.5g is dissolved in anhydrous methylene chloride, under-20 DEG C and nitrogen protection, slowly drips wherein boron tribromide 2.0ml; finish reaction 2h; then to the boron tribromide of the cancellation remnants that dropwise add water in reaction solution, add 200ml ethyl acetate and 200ml water stratification, organic layer is dry concentrated; obtain faint yellow oily matter 2.35g, yield 100%. 1H?NMR(400MHz,CDCl 3)：δ6.80(d,J=2.2Hz,1H),6.78(d,J=2.5Hz,1H),6.72(m,1H),4.28-4.18(m,2H),2.8(q,J=6.8Hz,2H),1.25(t,J=6.8Hz,3H).ESI-MS?m/z:221[M+H] +.
4.3:5-ethyl-2-(2,2,2-trifluoro ethoxy)-methyl phenoxyacetate
Previous step gained 5-ethyl-2-(2,2,2-trifluoro ethoxy)-phenol 2.35g is dissolved in acetone, adds methyl bromoacetate 1.2ml, add salt of wormwood 3.0g, reflux 12 hours, suction filtration, concentrates to obtain faint yellow oily matter 3.1g, yield 99%. 1HNMR(400MHz,CDCl 3)：δ6.80(d,J=2.2Hz,1H),6.78(d,J=2.5Hz,1H),6.72(m,1H),4.8(s,2H),4.28-4.18(m,2H),3.7(s,3H),2.8(q,J=6.8Hz,2H),1.25(t,J=6.8Hz,3H).ESI-MS?m/z:293[M+H] +.
4.4:N-methyl-N-methoxyl group-5-ethyl-2-(2,2,2-trifluoro ethoxy)-phenoxy acetamide
By 2.2g N; O-dimethyl oxammonium hydrochloride is scattered in 150ml anhydrous methylene chloride; under nitrogen protection and ice bath agitation condition; drip wherein the toluene solution (2mol/L) of 8.2ml trimethyl aluminium; finish reaction 1h; then drip previous step gained 5-ethyl-2-(2; 2; 2-trifluoro ethoxy) the anhydrous methylene chloride solution (30ml) of-methyl phenoxyacetate, finish reaction 3h; reaction solution washes (150ml × 3) with water three times; organic layer is dry, concentrates to obtain faint yellow oily matter 3.5g, yield 99%. 1H?NMR(400MHz,CDCl 3)：δ6.83(d,J=2.2Hz,1H),6.80(d,J=2.5Hz,1H),6.74(m,1H),4.78(s,2H),4.22-4.14(m,2H),3.8(s,3H),3.6(s,3H),2.77(q,J=6.6Hz,2H),1.26(t,J=6.6Hz,3H).ESI-MS?m/z:322[M+H] +.
4.5:5-ethyl-2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde
By previous step gained N-methyl-N-methoxyl group-5-ethyl-2-(2,2,2-trifluoro ethoxy)-phenoxy acetamide (3.5g) is dissolved in anhydrous tetrahydro furan, slowly adds wherein Lithium Aluminium Hydride 414mg at-78 DEG C in batches, finish, reaction 3h, the reaction solution Lithium Aluminium Hydride that cancellation participates in that dropwise adds water, suction filtration, filtrate is dry, concentrate to obtain white solid 2.57g, productive rate 91%. 1HNMR(400MHz,CDCl 3:δ10.2(s,1H),6.83-6.78(m,2H),6.70(m,1H),4.82(s,2H),4.24-4.16(m,2H),2.75(q,J=6.6Hz,2H),1.22(t,J=6.6Hz,3H).ESI-MS?m/z:261[M-H] +.
Embodiment 5:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-ethyl-2-oxyethyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471805)
Press the preparation method of embodiment 1, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 2-oxyethyl group-4-ethyl-benzene oxygen acetaldehyde and makes, being prepared as follows shown in reaction formula 5 of 2-oxyethyl group-4-ethyl-benzene oxygen acetaldehyde. 1H?NMR(400MHz,CDCl 3)：δ7.42(s,1H),7.18(d,J=3.2Hz,1H),6.98(s,2H),6.88(d,J=8.0Hz,1H),6.71(m,2H),6.62(s,1H),6.56(d,J=3.2Hz,1H),4.10(t,J=7.52Hz,2H),3.8(q,J=6.8Hz,2H)，3.68(t,J=5.5Hz,2H),3.13(m,2H),3.08-2.87(m,3H),2.69(dd,J=13.5,6.3Hz,1H),2.62-2.46(m,3H),1.82-1.67(m,2H),1.20-1.14(m,6H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:468[M+H] +.
The preparation of reaction formula 5:2-oxyethyl group-4-ethyl-benzene oxygen acetaldehyde
5.1:2-methoxyl group-4-ethyl-methyl phenoxyacetate
2-methoxyl group-4-ethyl-phenol 2.5g is dissolved in acetone, adds methyl bromoacetate 1.68ml, add salt of wormwood 4.54g, reflux 12 hours, suction filtration, concentrates to obtain faint yellow oily matter 3.5g, yield 95%. 1HNMR(400MHz,CDCl 3):δ6.83(d,J=7.8Hz,1H),6.80(s,1H),6.72(d,J=7.8Hz,1H),4.82(s,2H),3.7(s,3H),3.58(s,3H),2.65(q,J=7.2Hz,2H),1.2(t,J=7.2Hz,3H).ESI-MS?m/z:225[M+H] +.
5.2:N-methyl-N-methoxyl group-2-methoxyl group-4-ethyl-phenoxy acetamide
By 3.1g N; O-dimethyl oxammonium hydrochloride is scattered in 150ml anhydrous methylene chloride; under nitrogen protection and ice bath agitation condition; drip wherein the toluene solution (2mol/L) of 11.5ml trimethyl aluminium; finish reaction 1h; then drip the anhydrous methylene chloride solution (30ml) of previous step gained 2-methoxyl group-4-ethyl-methyl phenoxyacetate (3.5g); finish; reaction 3h; reaction solution washes (150ml × 3) with water three times; organic layer is dry, concentrates to obtain faint yellow oily matter 3.6g, yield 91%. 1HNMR(400MHz,CDCl 3):δ6.83-6.80(m,2H),6.74(d,J=7.5Hz,1H),4.83(s,2H),3.83(s,3H),3.72(s,3H),3.56(s,3H),2.64(q,J=7.2Hz,2H),1.22(t,J=7.2Hz,3H).ESI-MS?m/z:254[M+H] +.
5.3:N-methyl-N-methoxyl group-2-hydroxyl-4-ethyl-phenoxy acetamide
Previous step gained N-methyl-N-methoxyl group-2-methoxyl group-4-ethyl-phenoxy acetamide 3.6g is dissolved in anhydrous methylene chloride; under-20 DEG C and nitrogen protection; slowly drip wherein boron tribromide 2.1ml; finish reaction 2h; then to the boron tribromide of the cancellation remnants that dropwise add water in reaction solution, add 200ml ethyl acetate and 200ml water stratification, organic layer is dry concentrated; obtain faint yellow oily matter 3.3g, yield 97%. 1HNMR(400MHz,CDCl 3):δ6.85-6.79(m,2H),6.68(d,J=7.2Hz,1H),4.81(s,2H),3.70(s,3H),3.52(s,3H),2.65(q,J=7.82Hz,2H),1.26(t,J=7.2Hz,3H).ESI-MSm/z:240[M+H] +.
5.4:N-methyl-N-methoxyl group-2-oxyethyl group-4-ethyl-phenoxy acetamide
Previous step gained N-methyl-N-methoxyl group-2-hydroxyl-4-ethyl-phenoxy acetamide 3.3g is dissolved in to N, in dinethylformamide, add iodoethane 1.2ml, cesium carbonate 9.0g, in 100 DEG C of reaction 12h, then in reaction solution, add respectively 200ml ethyl acetate and 200ml water, layering, 2 times (150ml × 2) of organic layer washing, are dried and concentrate, column chromatography obtains faint yellow oily matter 3.3g, yield 89%. 1HNMR(400MHz,CDCl 3):δ6.83(d,J=7.8Hz,1H),6.80(s,1H),6.72(d,J=7.8Hz,1H),4.81(s,2H),3.8(q,J=7.5Hz,2H),3.70(s,3H),3.52(s,3H),2.65(q,J=7.82Hz,2H),1.26(t,J=7.2Hz,3H),1.21(t,J=7.5Hz,3H).ESI-MS?m/z:268[M+H] +.
5.5:2-oxyethyl group-4-ethyl-benzene oxygen acetaldehyde
Previous step gained N-methyl-N-methoxyl group-2-oxyethyl group-4-ethyl-phenoxy acetamide 3.3g is dissolved in anhydrous tetrahydro furan, at-78 DEG C, slowly add wherein Lithium Aluminium Hydride 470mg in batches, finish, reaction 3h, the reaction solution Lithium Aluminium Hydride that cancellation participates in that dropwise adds water, suction filtration, filtrate is dry, concentrate to obtain white solid 2.0g, productive rate 90%. 1HNMR(400MHz,CDCl 3):δ10.1(s,1H),6.82-6.76(m,2H),6.65(d,J=7.3Hz,1H),4.78(s,2H),3.68(q,J=7.4Hz,2H),2.65(q,J=7.4Hz,2H),1.28(t,J=7.3Hz,3H),1.23(t,J=7.3Hz,3H).ESI-MS?m/z:207[M-H] +.
Embodiment 6:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-ethyl-2-methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471806)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2-methoxyl group-4-ethyl-phenol and makes. 1H?NMR(400MHz,CDCl 3)：δ7.43(s,1H),7.13(d,J=3.2Hz,1H),7.07(d,J=5.6Hz,1H),6.98(s,1H),6.76(d,J=7.8Hz,1H),6.71-6.65(m,2H),6.55(d,J=17.6Hz,1H),6.55(d,J=3.2Hz,1H),4.14-4.00(m,2H),3.76(s,3H),3.69(t,J=4.6Hz,2H),3.15(t,J=6.7Hz,2H),3.10-2.88(m,3H),2.70(dd,J=13.6,6.5Hz,1H),2.62-2.50(m,3H),1.76(dd,J=11.9,5.9Hz,2H),1.19(t,J=7.6Hz,3H),1.07(d,J=6.3Hz,3H).ESI-MS?m/z:454[M+H] +.
Embodiment 7:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-ethyl-2-encircles propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471807)
Press the preparation method of embodiment 5, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.16(d,J=3.2Hz,1H),7.06(d,J=5.6Hz,1H),6.98(s,1H),6.74(d,J=7.8Hz,1H),6.70-6.63(m,2H),6.54(d,J=17.6Hz,1H),6.46(d,J=3.2Hz,1H),4.14-4.00(m,2H),3.70(t,J=4.6Hz,2H),3.68(m,1H),3.40-3.35(m,2H),3.16(t,J=6.7Hz,2H),3.10-2.90(m,3H),2.70(dd,J=13.6,6.5Hz,1H),2.62-2.50(m,4H),1.76(dd,J=11.9,5.9Hz,2H),1.19(t,J=7.6Hz,3H),1.1(d,J=6.3Hz,3H),0.73(m,1H),0.56(m,2H).ESI-MS?m/z:454[M+H] +.
Embodiment 8:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-ethyl-2-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471808)
Press the preparation method of embodiment 5, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,CDCl 3)：δ7.50(d,J=1.3Hz,1H),7.14(d,J=1.4Hz,1H),7.13(d,J=3.2Hz,1H),6.94-6.83(m,2H),6.65(s,1H),6.61(d,J=8.5Hz,1H),6.46(s,1H),6.42(d,J=3.2Hz,1H),4.14-4.00(m,2H),3.69(t,J=4.6Hz,2H),3.56(m,2H),3.18(t,J=6.7Hz,2H),3.10-2.92(m,3H),2.70(dd,J=13.6,6.5Hz,1H),2.62-2.50(m,3H),1.76(dd,J=11.9,5.9Hz,2H),1.19(t,J=7.6Hz,3H),1.09(d,J=6.3Hz,3H),0.83(m,2H),0.38(m,1H),0.35(m,2H).ESI-MS?m/z:494[M+H] +.
Embodiment 9:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-ethyl-2-tert.-butoxy-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471809)
Press the preparation method of embodiment 5, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,CDCl 3)：δ7.44(d,J=1.3Hz,1H),7.10(d,J=1.3Hz,1H),7.08(d,J=3.2Hz,1H),6.93-6.82(m,2H),6.62(s,1H),6.62(d,J=8.5Hz,1H),6.38(s,1H),6.36(d,J=3.2Hz,1H),4.14-4.00(m,2H),3.68(t,J=4.6Hz,2H),3.15(t,J=6.7Hz,2H),3.10-2.90(m,3H),2.70(dd,J=13.6,6.5Hz,1H),2.62-2.51(m,3H),1.76(dd,J=11.9,5.9Hz,2H),1.45(s,9H),1.19(t,J=7.6Hz,3H),1.08(d,J=6.3Hz,3H).ESI-MS?m/z:496[M+H] +.
Embodiment 10:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-ethyl-2-neopentyl oxygen-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471810)
Press the preparation method of embodiment 5, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1HNMR(400MHz,CDCl 3)：δ7.48(d,J=1.3Hz,1H),7.15(d,J=1.3Hz,1H),7.10(d,J=3.2Hz,1H),6.99-6.87(m,2H),6.62(s,1H),6.60(d,J=8.5Hz,1H),6.49(s,1H),6.45(d,J=3.2Hz,1H),4.14-4.00(m,2H),3.69(t,J=4.6Hz,2H),3.52(s,2H),3.15(t,J=6.7Hz,2H),3.10-2.88(m,3H),2.70(dd,J=13.6,6.5Hz,1H),2.62-2.50(m,3H),1.76(dd,J=11.9,5.9Hz,2H),1.19(t,J=7.6Hz,3H),1.07(d,J=6.3Hz,3H),0.85(s,9H).ESI-MS?m/z:510[M+H] +.
Embodiment 11:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471811)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-and make. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.12(d,J=3.2Hz,1H),7.05-6.99(m,3H),6.96(s,1H),6.87-6.82(m,1H),6.69(s,1H),6.50(d,J=3.2Hz,1H),4.34-4.24(m,2H),4.12-4.00(m,2H),3.72(t,J=5.6Hz,2H),3.16(t,J=7.0Hz,2H),3.10-2.94(m,3H),2.67(dd,J=13.6,6.6Hz,1H),2.53(dd,J=13.6,6.7Hz,1H),1.84-1.73(m,2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:573[M+H] +.
Embodiment 12:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-oxyethyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471812)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-and make. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.12(d,J=3.2Hz,1H),7.08-6.99(m,3H),6.98(s,1H),6.87-6.84(m,1H),6.69(s,1H),6.53(d,J=3.2Hz,1H),4.12-4.00(m,2H),3.78(q,J=7.0Hz,2H),3.75(t,J=5.6Hz,2H),3.16(t,J=7.0Hz,2H),3.12-2.94(m,3H),2.67(dd,J=13.6,6.6Hz,1H),2.55(dd,J=13.4,6.8Hz,1H),1.84-1.75(m,2H),1.2(t,3H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:518:520=1:1[M+H] +.
Embodiment 13:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-methoxyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471813)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with the bromo-phenol of 2-methoxyl group-4-and makes.1H?NMR(400MHz,CDCl3):δ7.49(d,J=1.3Hz,1H),7.13(d,J=1.3Hz,1H),7.09(d,J=3.2Hz,1H),6.95-6.89(m,2H),6.65(s,1H),6.60(d,J=8.5Hz,1H),6.49(s,1H),6.46(d,J=3.2Hz,1H),4.33(t,J=7.1Hz,2H),4.06-3.90(m,2H),3.63(s,3H),3.52-3.43(m,2H),3.06-2.88(m,3H),2.81-2.70(m,2H),2.01-1.88(m,2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:504:506=1:1[M+H] +.
Embodiment 14:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-ring of-2-[2-[4-propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471814)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.15(d,J=3.2Hz,1H),7.05-6.98(m,3H),6.97(s,1H),6.87-6.84(m,1H),6.71(s,1H),6.56(d,J=3.2Hz,1H),4.12-4.02(m,2H),3.74(t,J=5.6Hz,2H),3.69(m,1H),3.16(t,J=7.0Hz,2H),3.14-2.95(m,4H),2.68(dd,J=13.4,6.5Hz,1H),2.55(dd,J=13.6,7.1Hz,1H),1.84-1.76(m,2H),1.06(d,J=6.2Hz,3H),0.75(m,1H),0.58(m,2H).ESI-MSm/z:530:532=1:1[M+H] +.
Embodiment 15:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-of-2-[2-[4-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471815)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,CDCl 3)：δ7.44(s,1H),7.12(d,J=3.2Hz,1H),7.03-6.87(m,3H),6.95(s,1H),6.87-6.83(m,1H),6.66(s,1H),6.53(d,J=3.2Hz,1H),4.13-4.04(m,2H),3.74(t,J=5.7Hz,2H),3.55(m,2H),3.18(t,J=7.2Hz,2H),3.13-2.94(m,3H),2.69(dd,J=13.4,6.8Hz,1H),2.55(dd,J=13.8,6.8Hz,1H),1.84-1.76(m,2H),1.07(d,J=6.4Hz,3H),0.82(m,2H),0.36(m,1H),0.34(m,2H).ESI-MS?m/z:544:546=1:1[M+H] +.
Embodiment 16:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-tert.-butoxy-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471816)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,CDCl 3)：δ7.42(s,1H),7.12(d,J=3.2Hz,1H),7.08-6.95(m,3H),6.94(s,1H),6.87-6.82(m,1H),6.69(s,1H),6.48(d,J=3.2Hz,1H),4.12-4.04(m,2H),3.75(t,J=5.6Hz,2H),3.16(t,J=7.5Hz,2H),3.11-2.95(m,3H),2.67(dd,J=13.6,6.7Hz,1H),2.53(dd,J=13.3,6.8Hz,1H),1.84-1.73(m,2H),1.46(s,9H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:546:548=1:1[M+H] +.
Embodiment 17:1-(3-hydroxypropyl)-5-[(2R) the bromo-2-neopentyl oxygen-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471817)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1H?NMR(400MHz,CDCl 3)：δ7.49(s,1H),7.12(d,J=3.2Hz1H),7.06-6.97(m,3H),6.94(s,1H),6.87-6.83(m,1H),6.65(s,1H),6.51(d,J=3.2Hz,1H),4.12-4.01(m,2H),3.75(t,J=5.6Hz,2H),3.54(s,2H),3.15(t,J=7.3Hz,2H),3.12-2.93(m,3H),2.68(dd,J=13.4,6.7Hz,1H),2.54(dd,J=13.2,6.8Hz,1H),1.84-1.75(m,2H),1.1(d,J=6.4Hz,3H),0.86(s,9H).ESI-MSm/z:560:562=1:1[M+H] +.
Embodiment 18:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-of-2-[2-[4-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471818)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-and make. 1H?NMR(400MHz,CDCl 3)：δ7.52(s,1H),7.10(d,J=3.2Hz,1H),7.04-6.87(m,2H),6.87-6.78(m,1H),6.75-6.64(m,3H),6.44(d,J=3.2Hz,1H),4.38-4.28(m,2H),4.13-4.00(m,2H),3.71(t,J=5.6Hz,2H),3.17(t,J=6.9Hz,2H),3.07-3.02(m,1H),2.99-2.94(m,2H),2.70(dd,J=13.6,6.6Hz,1H),2.54(dd,J=13.6,6.8Hz,1H),1.83-1.74(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:512[M+H] +.
Embodiment 19:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-oxyethyl group-phenoxy group of-2-[2-[5-] ethylamino-] propyl group]-indoles-7-methane amide (DC471819)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-and make. 1H?NMR(400MHz,CDCl 3)：δ7.50(s,1H),7.12(d,J=3.2Hz,1H),7.05-6.89(m,2H),6.88-6.75(m,1H),6.78-6.66(m,3H),6.56(d,J=3.2Hz,1H),4.14-4.02(m,2H),3.76(q,J=7.1Hz,2H),3.70(t,J=5.8Hz,2H),3.18(t,J=6.7Hz,2H),3.09-3.02(m,1H),2.99-2.93(m,2H),2.71(dd,J=13.5,6.7Hz,1H),2.56(dd,J=13.6,6.6Hz,1H),1.83-1.77(m,2H),1.22(t,3H),1.08(d,J=6.3Hz,3H).ESI-MS?m/z:458[M+H] +.
Embodiment 20:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-methoxyl group-phenoxy group of-2-[2-[5-] ethylamino-] propyl group]-indoles-7-methane amide (DC471820)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with the fluoro-phenol of 2-methoxyl group-5-and makes.1H?NMR(400MHz,CDCl3):δ7.52-7.44(m,1H),7.13(d,J=1.4Hz,1H),7.07(t,J=3.6Hz,1H),6.79-6.66(m,2H),6.63-6.51(m,3H),6.45(d,J=3.2Hz,1H),4.38-4.25(m,2H),4.05-3.90(m,2H),3.60(s,3H),3.47(t,J=5.8Hz,2H),3.05-2.94(m,3H),2.79-2.70(m,2H),2.00-1.86(m,2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:444[M+H]+.
Embodiment 21:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-ring of-2-[2-[5-propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471821)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.10(d,J=3.2Hz,1H),7.07-6.89(m,2H),6.86-6.77(m,1H),6.74-6.68(m,3H),6.49(d,J=3.2Hz,1H),4.15-4.04(m,2H),3.72(t,J=5.8Hz,2H),3.69(m,1H),3.15(t,J=6.8Hz,2H),3.07-3.05(m,2H),2.98-2.91(m,2H),2.70(dd,J=13.8,6.5Hz,1H),2.54(dd,J=13.8,6.6Hz,1H),1.83-1.76(m,2H),1.09(d,J=6.2Hz,3H),0.78(m,1H),0.59(m,2H).ESI-MS?m/z:470[M+H] +.
Embodiment 22:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-of-2-[2-[5-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471822)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.13(d,J=3.2Hz,1H),7.06-6.85(m,2H),6.88-6.76(m,1H),6.74-6.63(m,3H),6.54(d,J=3.2Hz,1H),4.15-4.03(m,2H),3.74(t,J=5.8Hz,2H),3.61(m,2H),3.16(t,J=6.6Hz,2H),3.07-3.04(m,1H),2.99-2.92(m,2H),2.73(dd,J=13.8,6.7Hz,1H),2.54(dd,J=13.8,6.8Hz,1H),1.83-1.74(m,2H),1.09(d,J=6.2Hz,3H),0.84(m,2H),0.36(m,1H),0.35(m,2H).ESI-MS?m/z:484[M+H] +.
Embodiment 23:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-tert.-butoxy-phenoxy group of-2-[2-[5-] ethylamino-] propyl group]-indoles-7-methane amide (DC471823)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,CDCl 3)：δ7.49(s,1H),7.12(d,J=3.2Hz,1H),7.02-6.86(m,2H),6.84-6.77(m,1H),6.78-6.63(m,3H),6.55(d,J=3.2Hz,1H),4.13-4.05(m,2H),3.73(t,J=5.4Hz,2H),3.15(t,J=6.9Hz,2H),3.08-3.02(m,1H),2.99-2.94(m,2H),2.73(dd,J=13.8,6.6Hz,1H),2.54(dd,J=13.6,6.8Hz,1H),1.83-1.76(m,2H),1.48(s,9H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:486[M+H] +.
Embodiment 24:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-neopentyl oxygen-phenoxy group of-2-[2-[5-] ethylamino-] propyl group]-indoles-7-methane amide (DC471824)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1H?NMR(400MHz,CDCl 3)：δ7.44(s,1H),7.12(d,J=3.2Hz,1H),7.04-6.85(m,2H),6.84-6.76(m,1H),6.75-6.65(m,3H),6.47(d,J=3.2Hz,1H),4.13-4.06(m,2H),3.75(t,J=5.6Hz,2H),3.59(s,2H),3.19(t,J=6.8Hz,2H),3.1-3.02(m,1H),2.99-2.92(m,2H),2.75(dd,J=13.7,6.5Hz,1H),2.54(dd,J=13.4,6.9Hz,1H),1.83-1.76(m,2H),1.08(d,J=6.2Hz,3H),0.85(s,9H).ESI-MS?m/z:500[M+H] +.
Embodiment 25:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471825)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-and make. 1H?NMR(400MHz,CDCl 3)：δ7.94(s,1H),7.52(s,1H),7.40(d,J=1.2Hz,1H),7.31(d,J=3.0Hz,1H),7.02(d,J=1.2Hz,1H),6.93-6.85(m,2H),6.63(td,J=8.6,3.2Hz,1H),6.42(dd,J=7.8,3.1Hz,1H),4.38-4.27(m,2H),4.15-4.10(m,2H),3.73(t,J=5.5Hz,2H),3.16(t,J=6.8Hz,2H),3.05-3.01(m,1H),2.99-2.91(m,2H),2.70(dd,J=13.6,6.8Hz,1H),2.52(dd,J=13.8,6.6Hz,1H),1.83-1.73(m,2H),1.08(d,J=6.2Hz,3H).ESI-MSm/z:512[M+H] +.
Embodiment 26:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-oxyethyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471826)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-and make. 1H?NMR(400MHz,CDCl 3)：δ7.96(s,1H),7.53(s,1H),7.42(d,J=1.2Hz,1H),7.30(d,J=3.3Hz,1H),7.03(d,J=1.2Hz,1H),6.93-6.82(m,2H),6.64(m,1H),6.40(dd,J=7.8,3.1Hz,1H),3.56(q,J=7.4Hz,2H),3.72(t,J=5.6Hz,2H),3.18(t,J=6.8Hz,2H),3.11-3.04(m,1H),2.98-2.94(m,4H),2.75(dd,J=13.8,6.6Hz,1H),2.58(dd,J=13.6,6.8Hz,1H),1.83-1.79(m,2H),1.25(t,3H),1.09(d,J=6.3Hz,3H).ESI-MS?m/z:458[M+H] +.
Embodiment 27:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-methoxyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471827)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with the fluoro-phenol of 2-methoxyl group-4-and makes.1H?NMR(400MHz,DMSO)：δ7.96(s,1H),7.53(s,1H),7.42(d,J=1.2Hz,1H),7.30(d,J=3.1Hz,1H),7.03(d,J=1.2Hz,1H),6.93-6.82(m,2H),6.64(td,J=8.6,3.0Hz,1H),6.40(dd,J=7.8,3.1Hz,1H),4.32(t,J=6.9Hz,2H),4.00-3.91(m,2H),3.70(s,3H),3.25(t,J=6.2Hz,2H),2.99-2.89(m,3H),2.88-2.81(m,1H),2.53(dd,J=11.3,5.6Hz,1H),1.77(m,2H),0.96(dd,J=14.6,6.4Hz,3H).ESI-MS?m/z:444[M+H]+.
Embodiment 28:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-ring of-2-[2-[4-propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471828)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,CDCl 3)：δ7.92(s,1H),7.50(s,1H),7.38(d,J=1.2Hz,1H),7.33(d,J=3.0Hz,1H),7.01(d,J=1.2Hz,1H),6.96-6.84(m,2H),6.63(m,1H),6.43(dd,J=7.8,3.1Hz,1H),4.12-3.98(m,2H),3.67(m,1H),3.68(t,J=8.6Hz,2H),3.15(t,J=6.6Hz,2H),3.07-2.99(m,2H),2.98-2.87(m,2H),2.68(dd,J=13.7,6.6Hz,1H),2.51(dd,J=13.8,6.5Hz,1H),1.84-1.68(m,2H),1.07(d,J=6.2Hz,3H),0.76(m,1H),0.60(m,2H).ESI-MS?m/z:470[M+H] +.
Embodiment 29:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-of-2-[2-[4-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471829)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,CDCl 3)：δ7.90(s,1H),7.55(s,1H),7.36(d,J=1.3Hz,1H),7.31(d,J=3.1Hz,1H),7.03(m,1H),6.94-6.85(m,2H),6.68(m,1H),6.44(m,1H),4.09-3.96(m,2H),3.67(t,J=8.5Hz,2H),3.64(t,J=7.4Hz,2H),3.14(t,J=6.8Hz,2H),3.03-2.98(m,1H),2.99-2.88(m,2H),2.66(dd,J=13.6,6.5Hz,1H),2.51(dd,J=13.6,6.7Hz,1H),1.81-1.68(m,2H),1.05(d,J=6.2Hz,3H),0.85(m,2H),0.37(m,1H),0.33(m,2H).ESI-MS?m/z:484[M+H] +.
Embodiment 30:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-tert.-butoxy-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471830)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,CDCl 3)：δ7.92(s,1H),7.50(s,1H),7.44(d,J=1.2Hz,1H),7.31(d,J=3.1Hz,1H),7.03(d,J=1.3Hz,1H),6.93-6.82(m,2H),6.64(td,J=8.6,3.0Hz,1H),6.43(m,1H),4.09-3.95(m,2H),3.67(t,J=8.8Hz,2H),3.16(t,J=6.7Hz,2H),3.03-2.98(m,1H),2.99-2.88(m,2H),2.66(dd,J=13.6,6.5Hz,1H),2.51(dd,J=13.6,6.7Hz,1H),1.81-1.68(m,2H),1.44(s,9H),1.07(d,J=6.4Hz,3H).ESI-MS?m/z:486[M+H] +.
Embodiment 31:1-(3-hydroxypropyl)-5-[(2R) the fluoro-2-neopentyl oxygen-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471831)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1H?NMR(400MHz,CDCl 3)：δ7.90(s,1H),7.50(s,1H),7.44(m,1H),7.31(d,J=3.1Hz,1H),7.05(d,J=1.2Hz,1H),6.94-6.82(m,2H),6.64(m,1H),6.40(dd,J=7.8,3.1Hz,1H),4.09-3.98(m,2H),3.67(t,J=8.2Hz,2H),3.61(s,2H),3.14(t,J=6.8Hz,2H),3.03-2.98(m,1H),2.99-2.88(m,2H),2.66(dd,J=13.4,6.5Hz,1H),2.51(dd,J=13.6,6.7Hz,1H),1.81-1.68(m,2H),1.05(d,J=6.2Hz,3H),0.86(s,9H).ESI-MS?m/z:500[M+H] +.
Embodiment 32:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[5-methyl-2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471832)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to 2-methoxyl group-4-methyl-phenol and make. 1H?NMR(400MHz,CDCl3):δ7.49(d,J=1.3Hz,1H),7.12(d,J=1.3Hz,1H),7.07(d,J=3.2Hz,1H),6.82(d,J=8.6Hz,1H),6.68-6.63(m,2H),6.58(d,J=2.9Hz,2H),6.45(d,J=3.2Hz,1H),4.36-4.27(m,2H),4.19-3.97(m,4H),3.47(t,J=5.7Hz,2H),3.07-2.99(m,2H),2.99-2.91(m,1H),2.81-2.75(m,1H),2.73-2.68(m,1H),2.25(s,3H),1.99-1.89(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:508[M+H] +.
Embodiment 33:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-oxyethyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471833)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-methyl-phenol and make. 1H?NMR(400MHz,CDCl 3)：δ7.49(s,1H),7.16(d,J=3.2Hz,1H),7.01(s,1H),6.96(s,1H),6.80(d,J=8.2Hz,1H),6.79(s,1H),6.72(s,1H),6.69-6.63(m,1H),6.50(d,J=3.2Hz,1H),4.11-4.02(m,2H),3.84(s,3H),3.65(t,J=5.8Hz,2H),3.60(q,J=7.6Hz,2H),3.15(t,J=6.9Hz,3H),3.08-2.90(m,2H),2.65(dd,J=13.8,6.5Hz,1H),2.46(dd,J=13.8,6.6Hz,1H),1.80-1.73(m,2H),1.23(t,3H),1.06(d,J=6.2Hz,3H).ESI-MSm/z:454[M+H] +.
Embodiment 34:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471834)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2-methoxyl group-4-methyl-phenol and makes. 1H?NMR(400MHz,MeOD)：δ7.49(d,J=1.3Hz,1H),7.18(d,J=3.2Hz,1H),7.09(m,1H),6.90-6.83(m,2H),6.74(d,J=8.0Hz,1H),6.52(d,J=3.2Hz,1H),4.25-4.10(m,2H),3.84(s,3H),3.65(t,J=6.3Hz,2H),3.42-3.36(m,1H),3.33-3.28(m,2H),3.25(t,J=7.6Hz,2H),3.04-2.93(m,1H),2.65(dd,J=13.3,8.5Hz,1H),2.31(s,3H),1.86-1.76(m,2H),1.24(d,J=6.4Hz,3H).ESI-MS?m/z:440[M+H] +.
Embodiment 35:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-encircles propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471835)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-methyl-phenol, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,MeOD)：δ7.48(d,J=1.3Hz,1H),7.16(d,J=3.2Hz,1H),7.11(d,J=6.5Hz,1H),6.89-6.83(m,2H),6.76(d,J=8.2Hz,1H),6.51(d,J=3.2Hz,1H),4.25-4.13(m,2H),3.84(s,3H),3.69(m,1H),3.68(t,J=6.3Hz,2H),3.42-3.37(m,2H),3.33-3.28(m,2H),3.25(t,J=7.8Hz,2H),3.07-2.99(m,1H),2.68(dd,J=13.5,8.6Hz,1H),1.86-1.78(m,2H),1.25(d,J=6.4Hz,3H),0.77(m,1H),0.62(m,2H).ESI-MS?m/z:466[M+H] +.
Embodiment 36:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471836)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-methyl-phenol, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,MeOD)：δ7.46(d,J=1.3Hz,1H),7.18(d,J=3.2Hz,1H),7.09(d,J=6.5Hz,1H),6.90-6.83(m,2H),6.74(d,J=8.0Hz,1H),6.52(d,J=3.2Hz,1H),4.25-4.10(m,2H),3.65(t,J=6.3Hz,2H),3.58(t,J=7.4Hz,2H),3.42-3.36(m,4H),3.33-3.28(m,2H),3.25(t,J=7.6Hz,2H),3.04-2.93(m,1H),2.65(dd,J=13.3,8.5Hz,1H),1.86-1.76(m,2H),1.24(d,J=6.4Hz,3H),0.86(m,2H),0.38(m,1H),0.36(m,2H).ESI-MS?m/z:480[M+H] +.
Embodiment 37:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-tert.-butoxy-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471837)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-methyl-phenol, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,MeOD)：δ7.44(d,J=1.3Hz,1H),7.18(d,J=3.2Hz,1H),7.10(d,J=6.5Hz,2H),6.91-6.87(m,1H),6.76(d,J=8.3Hz,1H),6.50(d,J=3.2Hz,1H),4.26-4.13(m,2H),3.85(s,3H),3.67(t,J=6.7Hz,2H),3.42-3.38(m,1H),3.34-3.26(m,2H),3.25(t,J=7.7Hz,2H),3.05-2.96(m,1H),2.66(dd,J=13.5,8.5Hz,1H),1.86-1.77(m,2H),1.46(s,9H),1.22(d,J=6.4Hz,3H).ESI-MS?m/z:482[M+H] +.
Embodiment 38:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-methyl-2-neopentyl oxygen-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471838)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-methyl-phenol, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1H?NMR(400MHz,MeOD)：δ7.45(d,J=1.3Hz,1H),7.12(d,J=3.2Hz,1H),7.08(d,J=6.4Hz,1H),6.92-6.86(m,2H),6.73(d,J=8.1Hz,1H),6.49(d,J=3.2Hz,1H),4.23-4.10(m,2H),3.85(s,3H),3.62(t,J=6.5Hz,2H),3.64(s,2H),3.42-3.37(m,1H),3.35-3.29(m,2H),3.23(t,J=7.6Hz,2H),3.06-2.94(m,1H),2.66(dd,J=13.4,8.6Hz,1H),1.88-1.75(m,2H),1.25(d,J=6.4Hz,3H),0.88(s,9H).ESI-MS?m/z:496[M+H] +.
Embodiment 39:1-(3-hydroxypropyl)-5-[(2R) the chloro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471839)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-and make. 1H?NMR(400MHz,CDCl3):δ7.47(t,J=3.8Hz,1H),7.10(t,J=4.7Hz,1H),7.07(d,J=3.2Hz,1H),6.87-6.80(m,3H),6.63(d,J=18.6Hz,2H),6.45(d,J=3.1Hz,1H),4.37-4.24(m,2H),4.20-4.06(m,2H),4.06-3.90(m,2H),3.47(t,J=5.7Hz,2H),3.03-2.92(m,3H),2.81-2.75(m,1H),2.69(dd,J=13.6,6.5Hz,1H),1.99-1.86(m,2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:528:530=3:1[M+H] +.
Embodiment 40:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-chloro-2-ethoxy-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471840)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-and make. 1H?NMR(400MHz,CDCl 3)：δ7.44(t,J=3.8Hz,1H),7.12(s,1H),7.07(d,J=3.2Hz,1H),6.87-6.82(m,3H),6.65(d,J=18.6Hz,2H),6.44(d,J=3.1Hz,1H),4.12-3.98(m,2H),3.70(t,J=5.4Hz,2H),3.62(q,J=7.6Hz,2H),3.21-3.12(m,2H),3.09-3.10(m,1H),3.05-2.89(m,2H),2.69-2.64(m,1H),2.52(dd,J=13.5,6.8Hz,1H),1.83-1.73(m,2H),1.25(t,3H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:474:476=3:1[M+H] +.
Embodiment 41:1-(3-hydroxypropyl)-5-[(2R) the chloro-2-methoxyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC341841)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with the chloro-phenol of 2-methoxyl group-4-and makes.1H?NMR(400MHz,CDCl3):δ7.46(s,1H),7.11(s,1H),7.05(d,J=3.1Hz,1H),6.84(s,1H),6.79-6.73(m,3H),6.63(d,J=9.1Hz,1H),6.43(d,J=3.1Hz,1H),4.29(t,J=7.1Hz,2H),4.04-3.89(m,2H),3.61(s,3H),3.43(t,J=5.8Hz,2H),3.02-2.93(m,2H),2.93-2.84(m,1H),2.79-2.63(m,2H),1.89(dq,J=12.1,6.1Hz,2H),1.04(t,J=10.6Hz,3H).ESI-MS?m/z:460:462=3:1[M+H] +.
Embodiment 42:1-(3-hydroxypropyl)-5-[(2R) the chloro-2-ring of-2-[2-[4-propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471842)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.10(s,1H),7.08(d,J=3.1Hz,1H),6.85(s,1H),6.81-6.76(m,3H),6.60(d,J=9.1Hz,1H),6.44(d,J=3.1Hz,1H),4.08-3.98(m,2H),3.65(m,1H),3.68(t,J=5.5Hz,2H),3.16(t,J=7.0Hz,2H),3.05-2.99(m,1H),2.98-2.89(m,3H),2.64(dd,J=13.8,6.5Hz,1H),2.51(dd,J=13.3,6.5Hz,1H),1.82-1.74(m,2H),1.04(d,J=6.2Hz,3H),0.79(m,1H),0.64(m,2H).ESI-MS?m/z:486:488=3:1[M+H] +.
Embodiment 43:1-(3-hydroxypropyl)-5-[(2R) the chloro-2-of-2-[2-[4-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471843)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.13(s,1H),7.06(d,J=3.1Hz,1H),6.83(s,1H),6.79-6.72(m,3H),6.66(d,J=9.1Hz,1H),6.44(d,J=3.1Hz,1H),4.10-3.95(m,2H),3.68(t,J=5.8Hz,2H),3.66(t,J=7.4Hz,2H),3.14(t,J=6.9Hz,2H),3.02-2.98(m,1H),2.96-2.88(m,2H),2.64(dd,J=13.5,6.5Hz,1H),2.50(dd,J=13.5,6.6Hz,1H),1.80-1.71(m,2H),1.04(d,J=6.2Hz,3H),0.85(m,2H),0.39(m,1H),0.37(m,2H).ESI-MS?m/z:500:502=3:1[M+H] +.
Embodiment 44:1-(3-hydroxypropyl)-5-[(2R) the chloro-2-tert.-butoxy-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471844)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,CDCl 3)：δ7.43(s,1H),7.08(s,1H),7.03(d,J=3.1Hz,1H),6.82(s,1H),6.78-6.72(m,3H),6.65(d,J=9.1Hz,1H),6.41(d,J=3.1Hz,1H),4.09-3.95(m,2H),3.68(t,J=5.8Hz,2H),3.16(t,J=6.6Hz,2H),3.08-2.99(m,1H),2.97-2.89(m,2H),2.63(dd,J=13.4,6.6Hz,1H),2.52(dd,J=13.8,6.4Hz,1H),1.82-1.71(m,2H),1.44(s,9H),1.05(d,J=6.2Hz,3H).ESI-MS?m/z:502:504=3:1[M+H] +.
Embodiment 45:1-(3-hydroxypropyl)-5-[(2R) the chloro-2-neopentyl oxygen-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471845)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1H?NMR(400MHz,CDCl 3)：δ7.49(s,1H),7.15(s,1H),7.08(d,J=3.1Hz,1H),6.82(s,1H),6.78-6.73(m,3H),6.54(d,J=9.1Hz,1H),6.41(d,J=3.1Hz,1H),4.09-3.99(m,2H),3.65(t,J=5.5Hz,2H),3.65(s,2H),3.16(t,J=6.7Hz,2H),3.04-2.99(m,1H),2.96-2.89(m,2H),2.66(dd,J=13.3,6.2Hz,1H),2.52(dd,J=13.6,6.8Hz,1H),1.82-1.71(m,2H),1.06(d,J=6.2Hz,3H),0.86(s,9H).ESI-MS?m/z:516:518=3:1[M+H] +.
Embodiment 46:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[5-allyl group-2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471846)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to 2-methoxyl group-4-allyl group-phenol and make. 1H?NMR(400MHz,CDCl 3)：δ1H?NMR(400MHz,CDCl3):δ7.48(s,1H),7.19-7.12(m,1H),7.09(d,J=3.2Hz,1H),6.88(d,J=5.4Hz,1H),6.82-6.73(m,1H),6.70(dd,J=8.4,6.1Hz,1H),6.65(m,1H),6.49-6.37(m,2H),6.15-6.03(m,1H),5.99-5.83(m,1H),5.09-5.02(m,1H),4.31-4.23(m,2H),4.16-4.05(m,2H),3.75(t,J=5.6Hz,2H),3.45-3.29(m,1H),3.26-3.17(m,1H),3.08-2.89(m,2H),2.72(dd,J=13.4,6.6Hz,1H),2.58(dd,J=14.1,6.3Hz,1H),1.86-1.69(m,2H),1.22(t,3H),1.10(d,J=6.1Hz,3H).ESI-MSm/z:534[M+H] +.
Embodiment 47:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-allyl group-2-oxyethyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471847)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-allyl group-phenol and make. 1H?NMR(400MHz,CDCl 3)：δ1H?NMR(400MHz,CDCl3):δ7.49(s,1H),7.19-7.12(m,1H),7.09(d,J=3.2Hz,1H),6.86(d,J=5.3Hz,1H),6.83-6.75(m,1H),6.71(dd,J=8.4,6.1Hz,1H),6.68(dd,J=4.2,2.4Hz,1H),6.49-6.36(m,2H),6.14-6.01(m,1H),5.98-5.85(m,1H),5.09-5.01(m,1H),4.16-4.01(m,2H),3.73(t,J=5.8Hz,2H),3.60(q,J=7.6Hz,2H),3.43-3.29(m,3H),3.24-3.14(m,2H),3.06-2.89(m,2H),2.72(dd,J=13.6,6.8Hz,1H),2.59(dd,J=14.1,6.3Hz,1H),1.84-1.69(m,2H),1.24(t,3H),1.11(d,J=6.1Hz,3H).ESI-MS?m/z:480[M+H] +.
Embodiment 48:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-allyl group-2-methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC371848)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2-methoxyl group-4-allyl group-phenol and makes.1H?NMR(400MHz,CDCl3):δ7.44(s,1H),7.19-7.12(m,1H),7.1(d,J=3.2Hz,1H),6.89(m,1H),6.83-6.74(m,1H),6.66(dd,J=8.4,6.1Hz,1H),6.63(dd,J=4.2,2.4Hz,1H),6.45-6.34(m,2H),6.16-6.00(m,1H),5.96-5.83(m,1H),5.07-5.02(m,1H),4.34(t,J=7.0Hz,2H),4.09-3.99(m,2H),3.65(s,3H),3.46(t,J=5.7Hz,2H),3.34-3.26(m,1H),3.15-3.02(m,2H),3.02-2.92(m,1H),2.89-2.72(m,2H),2.00-1.90(m,2H),1.86-1.82(m,1H),1.13(d,J=6.2Hz,3H).ESI-MS?m/z:466[M+H] +.
Embodiment 49:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-allyl group-2-encircles propoxy--phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471849)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-allyl group-phenol, the iodoethane in step 5.4 is replaced with to cyclopropane bromide and make. 1H?NMR(400MHz,CDCl 3):δ 1H?NMR(400MHz,CDCl 3)：δ1H?NMR(400MHz,CDCl3):δ7.46(s,1H),7.17-7.10(m,1H),7.05(d,J=3.2Hz,1H),6.85(d,J=5.4Hz,1H),6.82-6.72(m,1H),6.65(dd,J=8.4,6.1Hz,1H),6.62(dd,J=4.2,2.4Hz,1H),6.48-6.39(m,2H),6.13-6.03(m,1H),5.97-5.84(m,1H),5.06-4.98(m,1H),4.18-4.04(m,2H),3.72(t,J=5.6Hz,2H),3.66(m,1H)3.44-3.29(m,1H),3.23-3.13(m,5H),3.06-2.88(m,2H),2.72(dd,J=13.6,6.8Hz,1H),2.59(dd,J=14.2,6.2Hz,1H),1.83-1.68(m,2H),1.09(d,J=6.1Hz,3H),0.78(m,1H),0.66(m,2H).ESI-MS?m/z:492[M+H] +.
Embodiment 50:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-allyl group-2-encircles the third methoxyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471850)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-allyl group-phenol, the iodoethane in step 5.4 is replaced with to brooethyl cyclopropane and make. 1H?NMR(400MHz,CDCl 3)：1H?NMR(400MHz,CDCl3):δ7.47(s,1H),7.18-7.13(m,1H),7.08(d,J=3.2Hz,1H),6.87(d,J=5.4Hz,1H),6.83-6.74(m,1H),6.69(dd,J=8.4,6.1Hz,1H),6.64(dd,J=4.2,2.4Hz,1H),6.49-6.38(m,2H),6.14-6.01(m,1H),5.98-5.85(m,1H),5.09-5.01(m,1H),4.19-4.03(m,2H),3.74(t,J=5.6Hz,2H),3.68(t,J=7.6Hz,2H),3.43-3.28(m,1H),3.24-3.13(m,2H),3.05-2.89(m,4H),2.72(dd,J=13.3,6.8Hz,1H),2.56(dd,J=14.2,6.5Hz,1H),1.84-1.69(m,2H),1.10(d,J=6.1Hz,3H),0.85(m,2H),0.38(m,1H),0.37(m,2H).ESI-MSm/z:506[M+H] +.
Embodiment 51:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-allyl group-2-tert.-butoxy-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471851)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-allyl group-phenol, the iodoethane in step 5.4 is replaced with to tert-bromo butane and make. 1H?NMR(400MHz,CDCl 3)：1H?NMR(400MHz,CDCl3):δ7.44(s,1H),7.19-7.13(m,1H),7.10(d,J=3.2Hz,1H),6.88(d,J=5.4Hz,1H),6.85-6.76(m,1H),6.70(dd,J=8.4,6.1Hz,1H),6.65(dd,J=4.2,2.4Hz,1H),6.52-6.38(m,2H),6.14-6.03(m,1H),5.96-5.82(m,1H),5.10-5.01(m,1H),4.22-4.09(m,2H),3.75(t,J=5.8Hz,2H),3.46-3.29(m,1H),3.22-3.15(m,2H),3.04-2.88(m,2H),2.73(m,3H),2.56(dd,J=14.0,6.5Hz,1H),1.82-1.69(m,2H),1.46(s,9H),1.10(d,J=6.1Hz,3H).ESI-MS?m/z:508[M+H] +.
Embodiment 52:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[4-allyl group-2-neopentyl oxygen-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471852)
Press the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-4-allyl group-phenol, the iodoethane in step 5.4 is replaced with to 1-bromo-2,2-dimethylpropane makes. 1H?NMR(400MHz,CDCl 3)：1H?NMR(400MHz,CDCl3):δ7.47(s,1H),7.18-7.13(m,1H),7.08(d,J=3.2Hz,1H),6.87(d,J=5.4Hz,1H),6.83-6.74(m,1H),6.69(dd,J=8.4,6.1Hz,1H),6.64(dd,J=4.2,2.4Hz,1H),6.49-6.38(m,2H),6.14-6.01(m,1H),5.98-5.85(m,1H),5.09-5.01(m,1H),4.15-4.03(m,2H),3.74(t,J=5.4Hz,2H),3.68(s,2H),3.43-3.27(m,1H),3.23-3.14(m,2H),3.06-2.89(m,4H),2.72(dd,J=13.5,6.7Hz,1H),2.59(dd,J=14.1,6.3Hz,1H),1.83-1.69(m,2H),1.10(d,J=6.1Hz,3H),0.87(s,9H).ESI-MS?m/z:522[M+H] +.
Embodiment 53:1-(3-hydroxypropyl)-5-[(2R) the fluoro-phenoxy group of the bromo-4-of-2-[2-] ethylamino-] propyl group]-indoles-7-methane amide (DC471853)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with the fluoro-phenol of the bromo-4-of 2-and makes. 1H?NMR(400MHz,CDCl 3)：δ7.44(m,1H),7.17(s,1H),7.13(d,J=3.2Hz,1H),7.00(s,1H),6.99-6.88(m,2H),6.78(dd,J=9.1,4.8Hz,2H),6.50(d,J=3.2Hz,1H),4.09-4.03(m,1H),4.03-3.95(m,1H),3.40-3.32(m,2H),3.18-3.10(m,2H),2.98-2.90(m,2H),2.66-2.51(m,3H),1.81-1.71(m,2H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:492:494=1:1[M+H] +.
Embodiment 54:1-(3-hydroxypropyl)-5-[(2R)-2-[2-ethyl-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471854)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2-ethyl-phenol and makes. 1H?NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.16(s,1H),7.15(d,J=3.2Hz,1H),6.96(s,1H),6.92-6.89(m,2H),6.87-6.80(m,1H),6.52(d,J=3.2Hz,1H),4.38(m,2H),3.88(m,2H),3.29(t,J=8.4Hz,2H),3.17-2.94(m,2H),2.87(t,J=7.9Hz,2H),2.83-2.70(m,1H),2.65(q,J=7.3Hz,2H)2.64-2.53(m,1H),1.67(m,2H),1.11(d,J=6.0Hz,3H),1.08(t,J=7.3,3H).ESI-MS?m/z:424[M+H] +.
Embodiment 55:1-(3-hydroxypropyl)-5-[(2R)-2-[2-n-propyl-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471855)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with 2-n-propyl-phenol and makes. 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.18(s,1H),7.18(d,J=3.2Hz,1H),6.96(s,1H),6.92-6.88(m,3H),6.87-6.80(m,1H),6.55(d,J=3.2Hz,1H),4.38(m,2H),3.88(m,2H),3.29(t,J=8.4Hz,2H),3.17-2.94(m,2H),2.87(t,J=7.9Hz,2H),2.83-2.70(m,1H),2.65(t,J=7.0Hz,2H),2.64-2.53(m,1H),1.67(m,2H),1.6(m,2H),1.11(d,J=6.0Hz,3H),0.91(t,J=6.6Hz,3H).ESI-MS?m/z:438[M+H] +.
Embodiment 56:1-(2-hydroxyethyl)-5-[(2R) the fluoro-2-of-2-[2-[4-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471856)
Press the preparation method of embodiment 1, bromo-3-in step 1.1 1-propyl alcohol is replaced with to the bromo-1-ethanol of 2-, and by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 4-, 2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2,2 of 4-, 2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4,2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-and make 2,2,2. 1H?NMR(400MHz,CDCl 3)：δ7.49(s,1H),7.16(d,J=3.2Hz,1H),7.13(s,1H),7.06-6.85(m,1H),6.89-6.76(m,1H),6.77-6.63(m,3H),6.51(d,J=3.2Hz,1H),4.35-4.29(m,2H),4.13-4.04(m,2H),3.74(t,J=5.8Hz,2H),3.2(t,J=6.6Hz,2H),3.08-3.02(m,1H),2.98-2.93(m,2H),2.73(dd,J=13.6,6.6Hz,1H),2.55(dd,J=13.4,6.6Hz,1H),1.07(d,J=6.4Hz,3H).ESI-MS?m/z:498[M+H] +.
Embodiment 57:1-(4-hydroxybutyl)-5-[(2R) the fluoro-2-of-2-[2-[4-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471857)
Press the preparation method of embodiment 1, bromo-3-in step 1.1 1-propyl alcohol is replaced with to the bromo-n-butyl alcohol of 4-, and by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 4-, 2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2,2 of 4-, 2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4,2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-and make 2,2,2. 1H?NMR(400MHz,CDCl 3)：δ7.49(s,1H),7.16(d,J=3.2Hz,1H),7.14(s,1H),7.06-6.86(m,1H),6.89-6.78(m,1H),6.78-6.65(m,3H),6.53(d,J=3.2Hz,1H),4.40-4.29(m,2H),4.13-4.04(m,2H),3.75(t,J=5.6Hz,2H),3.15(t,J=6.6Hz,2H),3.09-3.02(m,1H),2.96-2.92(m,2H),2.74(dd,J=13.2,6.8Hz,1H),2.55(dd,J=13.7,6.5Hz,1H),1.88-1.73(m,4H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:526[M+H] +.
Embodiment 58:1-(2-hydroxyethyl)-5-[(2R) the fluoro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471858)
Press the preparation method of embodiment 1, bromo-3-in step 1.1 1-propyl alcohol is replaced with to the bromo-1-ethanol of 2-, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-of 5-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2 of 5-, 2,2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-and make.2,2,2 1H?NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.15(d,J=3.2Hz,1H),7.13(s,1H),7.10(s,1H),7.0-6.87(m,1H),6.88(s,1H),6.79-6.66(m,2H),6.47(d,J=3.2Hz,1H),4.39-4.25(m,2H),4.17-4.12(m,2H),3.72(t,J=5.6Hz,2H),3.17(t,J=6.4Hz,2H),3.06-3.01(m,1H),2.98-2.90(m,2H),2.72(dd,J=13.4,6.6Hz,1H),2.50(dd,J=13.8,6.7Hz,1H),1.07(d,J=6.3Hz,3H).ESI-MS?m/z:498[M+H] +.
Embodiment 59:1-(4-hydroxybutyl)-5-[(2R) the fluoro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471859)
Press the preparation method of embodiment 1, bromo-3-in step 1.1 1-propyl alcohol is replaced with to the bromo-n-butyl alcohol of 4-, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-of 5-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2 of 5-, 2,2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-and make.2,2,2 1H?NMR(400MHz,CDCl 3)：δ7.48(s,1H),7.18(d,J=3.2Hz,1H),7.13(s,1H),7.06(s,1H),7.03-6.89(m,1H),6.84(s,1H),6.76-6.67(m,2H),6.50(d,J=3.2Hz,1H),4.35-4.24(m,2H),4.16-4.11(m,2H),3.75(t,J=5.5Hz,2H),3.18(t,J=6.9Hz,2H),3.07-3.01(m,1H),2.99-2.90(m,2H),2.72(dd,J=13.3,6.9Hz,1H),2.55(dd,J=13.4,6.7Hz,1H),1.86-1.70(m,4H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:526[M+H] +.
The fluoro-2-of embodiment 60:1-(3-hydroxypropyl)-5-[2-[2-[4-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471860)
Press the preparation method of embodiment 1, by 1-in step 1.15 (3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles replaces with 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles, by 2 in step 1.15, 6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 4-, 2, 2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2 of 4-, 2, 2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4, 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-to be made.2,2,2 1H?NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.16(d,J=3.2Hz,1H),7.04-6.87(m,2H),6.87-6.78(m,1H),6.75-6.64(m,3H),6.52(d,J=3.2Hz,1H),4.38-4.28(m,2H),4.13-4.00(m,2H),3.71(t,J=5.6Hz,2H),3.17(t,J=6.9Hz,2H),3.07-3.02(m,1H),2.99-2.93(m,2H),2.70(dd,J=7.5,6.6Hz,1H),2.54(dd,J=7.5,6.8Hz,1H),1.83-1.74(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:512[M+H] +.
Embodiment 61:1-(3-hydroxypropyl)-5-[(2S) the fluoro-2-of-2-[2-[4-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471861)
Press the preparation method of embodiment 1, by 1-in step 1.15 (3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles replaces with 1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2S)-2-aminopropyl]-indoles, by 2 in step 1.15, 6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 4-, 2, 2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2 of 4-, 2, 2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4, 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-to be made.2,2,2 1H?NMR(400MHz,CDCl 3)：δ7.43(s,1H),7.15(d,J=3.2Hz,1H),7.04-6.87(m,2H),6.87-6.78(m,1H),6.75-6.64(m,3H),6.53(d,J=3.2Hz,1H),4.38-4.28(m,2H),4.13-4.00(m,2H),3.71(t,J=5.6Hz,2H),3.17(t,J=6.9Hz,2H),3.07-3.02(m,1H),2.99-2.93(m,2H),2.70(dd,J=13.6,6.6Hz,1H),2.54(dd,J=13.6,6.8Hz,1H),1.83-1.74(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:512[M+H] +.
The fluoro-2-of embodiment 62:1-(3-hydroxypropyl)-5-[2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471862)
Press the preparation method of embodiment 1, by 1-in step 1.15 (3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles replaces with 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles, by 2 in step 1.15, 6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 5-, 2, 2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2 of 5-, 2, 2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4, 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-to be made.2,2,2 1H?NMR(400MHz,CDCl 3)：δ7.15(s,1H),7.16(d,J=3.2Hz,1H),7.08(s,1H),7.0-6.88(m,1H),6.85(s,1H),6.78-6.69(m,3H),6.54(d,J=3.2Hz,1H),4.38-4.27(m,2H),4.15-4.10(m,2H),3.73(t,J=5.5Hz,2H),3.16(t,J=6.8Hz,2H),3.05-3.01(m,1H),2.99-2.91(m,2H),2.70(dd,J=7.2,6.8Hz,1H),2.52(dd,J=7.2,6.6Hz,1H),1.83-1.73(m,2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:512[M+H] +.
Embodiment 63:1-(3-hydroxypropyl)-5-[(2S) the fluoro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471863)
Press the preparation method of embodiment 1, by 1-in step 1.15 (3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles replaces with 1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2S)-2-aminopropyl]-indoles, by 2 in step 1.15, 6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 5-, 2, 2-trifluoro ethoxy)-benzene oxygen acetaldehyde, the fluoro-2-(2 of 5-, 2, 2-trifluoro ethoxy)-preparation method that benzene oxygen acetaldehyde is pressed embodiment 4, 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-to be made.2,2,2 1H?NMR(400MHz,CDCl 3)：δ7.45(s,1H),7.15(d,J=3.2Hz,1H),7.08(s,1H),7.0-6.88(m,1H),6.85(s,1H),6.78-6.69(m,3H),6.48(d,J=3.2Hz,1H),4.38-4.27(m,2H),4.15-4.10(m,2H),3.73(t,J=5.5Hz,2H),3.16(t,J=6.8Hz,2H),3.05-3.01(m,1H),2.99-2.91(m,2H),2.70(dd,J=13.6,6.8Hz,1H),2.52(dd,J=13.8,6.6Hz,1H),1.83-1.73(m,2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:512[M+H] +.
Embodiment 64:1-(3-hydroxypropyl)-5-[(2R)-2-[3,4-methylenedioxy group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471864)
Press the preparation method of embodiment 1, by 2 in step 1.12,6-xylenol replaces with sesamol and makes. 1HNMR(400MHz,CDCl 3)：δ7.46(s,1H),7.15(d,J=3.2Hz,1H),7.00(s,1H),6.86(s,1H),6.65(d,J=8.5Hz,1H),6.56(s,1H),6.56(d,J=3.2Hz,1H),6.38(d,J=2.5Hz,1H),6.23(dd,J=8.5,2.5Hz,1H),5.90-5.84(m,2H),4.01-3.89(m,2H),3.71(t,J=5.6Hz,2H),3.17(t,J=6.8Hz,2H),3.00-2.85(m,3H),2.64(dd,J=13.5,6.9Hz,1H),2.55(dd,J=13.6,6.5Hz,1H),1.83-1.73(m,2H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:440[M+H] +.
Embodiment 65:1-(3-hydroxypropyl)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471865)
Press the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to 2-methoxyphenol and make. 1H?NMR(400MHz,CDCl 3):δ7.49(d,J=1.3Hz,1H),7.13(d,J=1.3Hz,1H),7.07(d,J=3.2Hz,1H),7.01-6.84(m,3H),6.81(dd,J=8.0,1.4Hz,1H),6.60(d,J=4.5Hz,2H),6.45(d,J=3.2Hz,1H),4.31(t,J=7.3Hz,2H),4.23-4.11(m,2H),4.11-3.97(m,2H),3.46(t,J=5.8Hz,2H),3.06-2.91(m,3H),2.75(m,2H),1.99-1.88(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:494[M+H] +.
Embodiment 66:1-(3-acetoxyl group propyl group)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471866)
Prepare 1-(3-acetoxyl group propyl group)-5-[(2R according to as above reaction formula)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide, concrete steps are as follows:
66.1:1-(3-hydroxypropyl)-indoline
By 50g(31.5ml) indoline is dissolved in 600ml acetonitrile, adds the bromo-1-propyl alcohol of 3-47.5ml, adds salt of wormwood 120g, backflow 12h, after question response liquid cooling but, suction filtration, column chromatography purification obtains oily matter 64g, yield 86%. 1H?NMR(d-DMSO,400MHz):δ7.95-8.06(2H,m),7.55(1H,dd),7.28(1H,dd),4.40-4.50(2H,m),3.48-3.60(2H,m),3.3-3.4(2H,m),2.98-2.93(2H,m),2.36-2.50(2H,m).ESI-MS?m/z:178[M+H] +.
66.2:1-(3-benzoyloxy propyl group)-indoline
Previous step gained 1-(3-hydroxypropyl)-indoline 64g is dissolved in 600ml anhydrous methylene chloride, add triethylamine 56ml, under ice bath agitation condition, slowly drip Benzoyl chloride 43ml, finish reaction 10h, then add three times (100ml × 3) of water extraction, organic layer concentrates to obtain lavender oily matter 96.8g, productive rate 96%. 1H?NMR(CDCl 3,400MHz):δ7.95-8.08(m,2H),7.56-7.66(m,1H),7.31-7.50(m,6H),4.4-4.5(m,2H),3.79-4.0(m,2H),3.5-3.6(m,2H),3.31-3.40(m,2H),2.38-2.5(m,2H).ESI-MS?m/z:282[M+H] +.
66.3:1-(3-benzoyloxy propyl group)-5-formyl radical-indoline
By 40ml N, dinethylformamide is dissolved in 500ml anhydrous 1, in 2-ethylene dichloride, under nitrogen protection and ice bath agitation condition, slowly drip 64ml phosphorus oxychloride, finish reaction 1h, then drip wherein anhydrous 1 of previous step gained 1-(3-benzoyloxy propyl group)-indoline (96.8g), 2-dichloroethane solution (300ml), finish, be transferred to 80 DEG C of oil bath reaction 2h, after completion of the reaction, be cooled to room temperature, concentrate and remove most of solvent, the phosphorus oxychloride of the cancellation remnants that slowly add water, then be extracted with ethyl acetate (300ml × 3), merge organic layer, dry, column chromatography purification obtains yellow solid 86g, yield 82%. 1H?NMR(CDCl 3,400MHz):δ9.8(s,1H),8.0-8.12(m,2H),7.42-7.63(m,5H),6.4(d,1H,J=8Hz),4.45(t,2H,J=6.2Hz),3.57-3.66(m,2H),3.36-3.45(m,2H),3.05(t,2H,J=8.5Hz),2.01-2.2(m,2H).ESI-MS?m/z:310[M+H] +.
66.4:1-(3-benzoyloxy propyl group)-5-(2-nitro propenyl)-indoline
Previous step gained 1-(3-benzoyloxy propyl group)-5-formyl radical-indoline 86g is dissolved in 250ml nitroethane; add ammonium acetate 42g; add acetic acid 120ml; after back flow reaction 4h; then reaction solution is concentrated, then add 600ml ethyl acetate, three times (300ml × 3) of water extraction; organic layer drying, concentrated gained resistates obtain red granules shape solid product 70g, productive rate 71% with Virahol recrystallization. 1H?NMR(CDCl 3,400MHz):δ8.05-8.1(m,3H),7.55-7.65(m,1H),7.42-7.5(m,2H),7.2-7.3(m,2H),6.40(d,1H,J=8.4Hz),4.41-4.49(m,2H),3.5-3.6(m,2H),3.3-3.4(m,2H),3.0-3.1(m,2H),2.48(S,3H),2.0-2.1(m,2H).ESI-MS?m/z:367[M+H] +.
66.5:1-(3-benzoyloxy propyl group)-5-(2-nitro propyl group)-indoline
Previous step gained 1-(3-benzoyloxy propyl group)-5-(2-nitro propenyl)-indoline 70g is dissolved in the mixed solvent of 300ml methylene dichloride and 600ml methyl alcohol, under ice bath agitation condition, slowly add wherein sodium borohydride in batches, until reaction solution is by the redness clear (approximately needing to add sodium borohydride 75g) that becomes colorless, TLC detection reaction, after completion of the reaction, reaction solution is concentrated to go out most of methyl alcohol, then add wherein 600ml ethyl acetate, add wherein again saturated aqueous ammonium chloride, produce a large amount of white solids, suction filtration, filtrate water is washed (200ml × 3) three times, merge organic layer, dry, column chromatography purification obtains faint yellow oily matter 64.3g, yield 91%. 1H?NMR(CDCl 3,400MHz):δ8.0-8.1(m,1H),7.56-7.64(m,1H),7.4-7.5(m,2H),6.85(s,1H),6.83(d,1H,J=8.0Hz),6.39(d,1H,J=8.0Hz),6.53-6.51(m,1H),4.65-4.75(m,1H),4.4-4.5(m,2H),3.3-3.4(m,2H),3.15-3.28(m,3H),2.8-3.0(m,3H),2.0-2.1(m,2H),1.50(d,3H,J=6.6Hz).ESI-MS?m/z:369[M+H] +.
66.6:1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoline
Under nitrogen protection and ice bath agitation condition, 40ml phosphorus oxychloride is slowly added drop-wise to 120ml N, in dinethylformamide, finish reaction 1h, then drip wherein the N of previous step gained 1-(3-benzoyloxy propyl group)-5-(2-nitro propyl group)-indoline (64.3g), dinethylformamide solution (200ml), finish, be transferred to 80 DEG C of oil bath reaction 2h, after completion of the reaction, be cooled to room temperature, concentrate and remove most of solvent, the phosphorus oxychloride of the cancellation remnants that slowly add water, then be extracted with ethyl acetate (500ml × 3), merge organic layer, dry, column chromatography purification obtains yellow solid 60g, yield 86%. 1H?NMR(CDCl 3,400MHz):δ9.94(s,1H),8.0-8.1(m,2H),7.5-7.6(m,1H)7.4-7.5(m,2H),7.22(s,1H),6.93(brs,1H),4.65-4.76(m,1H),4.4-4.5(m,2H),3.6-3.7(m,4H),3.20(dd,1H,J=7.7,14.2Hz),3.0-3.1(m,2H),2.93(dd,1H,J=6.4,14.2Hz),2.1-2.2(m,2H),1.54(d,3H,J=6.6Hz).ESI-MS?m/z:397[M+H] +.
66.7:1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoline 60g is dissolved in 500ml ethyl acetate; add 2; 3-bis-chloro-5; 6-dicyano-1; 4-benzoquinones 52g; finish reaction 12h, add saturated sodium bicarbonate and wash (300ml × 3) 3 times, organic layer concentrates to obtain faint yellow oily matter 53.7g productive rate 90%. 1H?NMR(CDCl 3,400MHz):δ10.04(s,1H),8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.18(d,J=3.2Hz,1H),6.52(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.45(dd,J=14.2,7.7Hz,1H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.58(d,J=6.6Hz,3H).ESI-MS?m/z:395[M+H] +.
66.8:1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-nitro propyl group)-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-formyl radical-5-(2-nitro propyl group)-indoles 53.7g is dissolved in 450ml anhydrous tetrahydro furan; add oxammonium hydrochloride 12g; add again pyridine 50ml; in 50 DEG C of reaction 12h; then add aceticanhydride 52ml in batches; be warming up to back flow reaction 8h; reaction solution is concentrated; add 500ml ethyl acetate; wash three times (200ml × 3); the concentrated yellow solid that to obtain of organic layer, obtains yellow solid product 47g, yield 87% by recrystallizing methanol. 1H?NMR(CDCl 3,400MHz):δ8.0-8.1(m,2H),7.5-7.6(m,1H),7.4-7.5(m,2H),7.16(d,J=3.2Hz,1H),6.93(brs,1H),6.89(brs,1H),6.54(d,J=3.2Hz,1H),4.6-4.7(m,1H),4.4-4.5(m,2H),3.7-3.81(m,2H),3.12(dd,1H,J=7.8,14.2Hz),2.86(dd,1H,J=6.2,14.2Hz),2.1-2.2(m,2H),1.54(d,3H,J=6.7Hz).ESI-MS?m/z:392[M+H] +.
66.9:1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-nitro propyl group)-indoles (47g) is dissolved in the mixed solvent of 400ml methyl alcohol and 400ml tetrahydrofuran (THF), add 10% Palladium carbon 4.7g, under a normal atmosphere hydrogen, reduce, reaction 48h, suction filtration after completion of the reaction, reaction solution suction filtration, filtrate concentrates to obtain product 41.2g, yield 94%. 1H?NMR(CDCl 3,400MHz):δ8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.15(d,J=3.2Hz,1H),6.52(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.45-3.52(m,3H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.05(d,J=6.6Hz,3H).ESI-MS?m/z:362[M+H] +.
66.10:1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles
Previous step gained 1-(3-benzoyloxy propyl group)-7-cyano group-5-(2-aminopropyl)-indoles 5g is dissolved in acetone 30ml, under agitation condition, add wherein 1.2gL-(+)-aqueous tartaric acid solution (1.2gL-(+)-tartrate is dissolved in 30ml water), finish and stir 12h, separate out a large amount of solids, suction filtration obtains L-(+)-tartrate 2.0g of target product.Gained solid is dissolved in 80ml water, adds saturated sodium carbonate solution to adjust pH to 10, add 2 times (100 × 2) of ethyl acetate extraction, merge organic layer, dry, concentrate to obtain faint yellow oily solid 1.8g, productive rate 35%. 1H?NMR(CDCl 3,400MHz):δ8.02(d,2H),7.67(d,J=1.3Hz,1H),7.57(t,J=7.4Hz,1H),7.49-7.40(m,3H),7.18(d,J=3.2Hz,1H),6.50(d,J=3.2Hz,1H),4.89-4.76(m,3H),4.24(t,J=6.1Hz,2H),3.46-3.54(m,3H),3.16(dd,J=14.2,6.5Hz,1H),2.24-2.11(m,2H),1.05(d,J=6.6Hz,3H).ESI-MS?m/z:362[M+H] +.
66.11:1-(3-benzoyloxy propyl group)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-7-cyano group-indoles
By previous step gained 1-(3-benzoyloxy propyl group)-7-cyano group-5-[(2R)-2-aminopropyl]-indoles 400mg is dissolved in 20ml1, in 2-ethylene dichloride, add 2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde 363mg, add acetic acid sodium borohydride 375mg, reaction 12h, column chromatography obtains faint yellow oily product 480mg, productive rate 75%.ESI-MS?m/z:580[M+H] +.
66.12:1-(3-benzoyloxy propyl group)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-7-cyano group-indoles
By previous step gained 1-(3-benzoyloxy propyl group)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-7-cyano group-indoles 480mg is dissolved in 15ml acetone, add cylite 156mg, add again salt of wormwood 230mg, backflow 12h, column chromatography obtains white solid 500mg, productive rate 90%.ESI-MS?m/z:670[M+H] +.
66.13:1-(3-hydroxypropyl)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-7-cyano group-indoles
By previous step gained 1-(3-benzoyloxy propyl group)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-7-cyano group-indoles 500mg is dissolved in 10ml methyl alcohol, add 2mol/L NaOH aqueous solution 1ml, reaction 4h, concentrating under reduced pressure is removed most of methyl alcohol, in resistates, add 30ml ethyl acetate, add again 20ml water, extraction, dry faint yellow oily matter 420mg, the productive rate 99% of concentrating to obtain of organic layer.ESI-MS?m/z:566[M+H] +.
66.14:1-(3-hydroxypropyl)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-indoles-7-methane amide
By previous step gained 1-(3-hydroxypropyl)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-7-cyano group-indoles 420mg is dissolved in 5ml methyl-sulphoxide, then add wherein 5mol/L aqueous sodium hydroxide solution 500 μ l, add 30% aqueous hydrogen peroxide solution 300 μ l, after reaction 12h, add water 20ml, be extracted with ethyl acetate three times (20ml × 3), merge organic layer, column chromatography purification obtains faint yellow oily matter 400mg, yield 92%.ESI-MS?m/z:584[M+H] +.
66.15:1-(3-acetoxyl group propyl group)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-indoles-7-methane amide
By previous step gained 1-(3-hydroxypropyl)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-indoles-7-methane amide 400mg is dissolved in 25ml anhydrous methylene chloride, add triethylamine 145 μ l, then add Acetyl Chloride 98Min. 54 μ l, reaction 10h, in reaction solution, add 20ml methylene dichloride, washing (20ml × 3), organic layer concentrates to obtain faint yellow oily matter 410mg, productive rate 96%.ESI-MS?m/z:626[M+H] +.
66.16.1-(3-acetoxyl group propyl group)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide
By previous step gained 1-(3-acetoxyl group propyl group)-5-[(2R)-N-benzyl-N-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethyl-amino] propyl group]-indoles-7-methane amide 410mg is dissolved in 20ml methyl alcohol, add 10% Palladium carbon 100mg, under a normal atmosphere hydrogen, reduce, reaction 24h, after completion of the reaction suction filtration, filtrate concentrates to obtain product 330mg, yield 94%. 1H?NMR(400MHz,CDCl 3):δ7.52(d,J=1.3Hz,1H),7.16(d,J=1.5Hz,1H),7.05(d,J=3.4Hz,1H),7.04-6.85(m,3H),6.82(dd,J=8.2,1.4Hz,1H),6.63(d,J=4.6Hz,2H),6.45-6.40(m,1H),4.33(t,J=7.5Hz,2H),4.24-4.13(m,2H),4.11-3.95(m,2H),3.48(t,J=5.6Hz,2H),3.06-2.93(m,3H),2.74(m,2H),2.21(s,3H),1.99-1.86(m,2H),1.08(d,J=6.3Hz,3H).ESI-MS?m/z:536[M+H] +.
Embodiment 67:1-(3-trifluoroacetyl oxygen base propyl group)-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471867)
Press the preparation method of embodiment 66, Acetyl Chloride 98Min. in step 66.15 is replaced with to trifluoroacetyl chloride. 1H?NMR(400MHz,CDCl 3):δ7.454(d,J=1.3Hz,1H),7.16(d,J=1.3Hz,1H),7.09(d,J=3.0Hz,1H),7.05-6.85(m,3H),6.82(dd,J=8.3,1.4Hz,1H),6.63(d,J=4.6Hz,2H),6.47(d,J=3.3Hz,1H),4.34(t,J=7.4Hz,2H),4.25-4.11(m,2H),4.10-3.95(m,2H),3.48(t,J=5.8Hz,2H),3.14-2.99(m,3H),2.82(m,2H),2.03-1.97(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:590[M+H] +.
Embodiment 68:1-(3-acetoxyl group propyl group)-2-methyl-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471868)
Press the preparation method of embodiment 66, the indoline in step 66.1 is replaced with to 2-methyl-indoline. 1HNMR(400MHz,CDCl 3):δ7.49(d,J=1.3Hz,1H),7.14(d,J=1.4Hz,1H),7.08(d,J=3.4Hz,1H),7.06-6.84(m,2H),6.83(dd,J=8.3,1.4Hz,1H),6.65(d,J=4.5Hz,2H),6.46-6.42(m,1H),4.34(t,J=7.5Hz,2H),4.24-4.10(m,2H),4.13-3.96(m,2H),3.49(t,J=5.8Hz,2H),3.09-2.95(m,3H),2.76(m,2H),2.22(s,3H),2.17(s,3H),2.05-1.90(m,2H),1.06(d,J=6.5Hz,3H).ESI-MS?m/z:550[M+H] +.
Embodiment 69:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[5-ethyl-2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471869)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 5-ethyl-2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (preparation method of 5-ethyl-2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde is with embodiment 4). 1H?NMR(400MHz,CDCl 3)：δ7.44(s,1H),7.12(d,J=3.4Hz,1H),6.95(s,2H),6.83(d,J=8.1Hz,1H),6.70(m,1H),6.65(s,1H),6.53(d,J=3.1Hz,1H),4.30-4.15(m,2H),4.12(t,J=7.5Hz,2H),3.66(t,J=5.6Hz,2H),3.14(m,2H),3.06-2.89(m,3H),2.71(dd,J=13.3,6.4Hz,1H),2.63-2.44(m,3H),2.20(s,3H),1.81-1.68(m,2H),1.22-1.15(t,J=7.7Hz,3.2H),1.08(d,J=6.2Hz,3H).ESI-MS?m/z:536[M+H] +.
Embodiment 70:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[4-ethyl-2-oxyethyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471870)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 2-oxyethyl group-4-ethyl-benzene oxygen acetaldehyde (preparation method of 2-oxyethyl group-4-ethyl-benzene oxygen acetaldehyde is with embodiment 5). 1H?NMR(400MHz,CDCl 3)：δ7.45(s,1H),7.17(d,J=3.2Hz,1H),6.96(s,1H),6.85(d,J=8.1Hz,1H),6.74(m,2H),6.63(s,1H),6.57(d,J=3.1Hz,1H),4.12(t,J=7.52Hz,2H),3.83(q,J=6.7Hz,2H)，3.69(t,J=5.6Hz,2H),3.15(m,2H),3.12-2.90(m,3H),2.66(dd,J=13.4,6.5Hz,1H),2.64-2.44(m,3H),2.19(s,3H),1.80-1.69(m,2H),1.21-1.13(m,6H),1.05(d,J=6.2Hz,3H).ESI-MS?m/z:482[M+H] +.
Embodiment 71:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the bromo-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471871)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the bromo-2-(2 of 5-, 2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (the bromo-2-(2,2 of 5-, 2-trifluoro ethoxy) preparation method of-benzene oxygen acetaldehyde is with embodiment 4, and 2-methoxyl group-4-ethyl-phenol in 4.1 is replaced with to the bromo-phenol of 2-methoxyl group-4-). 1H?NMR(400MHz,CDCl 3)：δ7.46(s,1H),7.13(d,J=3.0Hz,1H),7.08-6.98(m,2H),6.94(s,1H),6.86-6.83(m,1H),6.66(s,1H),6.52(d,J=3.3Hz,1H),4.34-4.25(m,2H),4.12-4.02(m,2H),3.74(t,J=5.7Hz,2H),3.15(t,J=7.1Hz,2H),3.11-2.96(m,3H),2.68(dd,J=13.7,6.8Hz,1H),2.55(dd,J=13.4,6.8Hz,1H),2.19(s,3H),1.83-1.75(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:586:588=1:1[M+H] +.
Embodiment 72:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the bromo-2-oxyethyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471872)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the bromo-2-oxyethyl group-benzene of 4-oxygen acetaldehyde (preparation method of the bromo-2-oxyethyl group-benzene of 4-oxygen acetaldehyde, with embodiment 5, replaces with the bromo-phenol of 2-methoxyl group-4-by the 2-methoxyl group-4-ethyl-phenol in step 5.1 and makes). 1H?NMR(400MHz,CDCl 3)：δ7.44(s,1H),7.11(d,J=3.2Hz,1H),7.05-6.94(m,2H),6.97(s,1H),6.90-6.85(m,1H),6.62(s,1H),6.55(d,J=3.5Hz,1H),4.13-4.04(m,2H),3.79(q,J=7.1Hz,2H),3.73(t,J=5.8Hz,2H),3.17(t,J=7.3Hz,2H),3.14-2.98(m,3H),2.66(dd,J=13.5,6.6Hz,1H),2.54(dd,J=13.6,6.8Hz,1H),2.21(s,3H),1.84-1.78(m,2H),1.21(t,3H),1.04(d,J=6.2Hz,3H).ESI-MS?m/z:532:534=1:1[M+H] +.
Embodiment 73:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the fluoro-2-of-2-[2-[4-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471873)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 4-, 2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (the fluoro-2-(2,2 of 4-, 2-trifluoro ethoxy) preparation method of-benzene oxygen acetaldehyde is with embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-5-and make). 1H?NMR(400MHz,CDCl 3)：δ7.50(s,1H),7.12(d,J=3.0Hz,1H),7.05-6.89(m,1H),6.86-6.79(m,1H),6.73-6.63(m,3H),6.43(d,J=3.3Hz,1H),4.39-4.26(m,2H),4.15-4.04(m,2H),3.70(t,J=5.5Hz,2H),3.16(t,J=6.8Hz,2H),3.08-3.02(m,1H),2.99-2.92(m,2H),2.72(dd,J=13.5,6.8Hz,1H),2.53(dd,J=13.6,6.8Hz,1H),2.22(s,3H),1.83-1.75(m,2H),1.08(d,J=6.3Hz,3H).ESI-MS?m/z:526[M+H] +.
Embodiment 74:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the fluoro-2-oxyethyl group-phenoxy group of-2-[2-[5-] ethylamino-] propyl group]-indoles-7-methane amide (DC471874)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-oxyethyl group-benzene of 5-oxygen acetaldehyde (preparation method of the fluoro-2-oxyethyl group-benzene of 5-oxygen acetaldehyde, with embodiment 5, replaces with the fluoro-phenol of 2-methoxyl group-5-by the 2-methoxyl group-4-ethyl-phenol in step 5.1 and makes). 1H?NMR(400MHz,CDCl 3)：δ7.51(s,1H),7.13(d,J=3.1Hz,1H),7.08-6.88(m,2H),6.89-6.74(m,1H),6.74-6.62(m,2H),6.58(d,J=3.1Hz,1H),4.15-4.01(m,2H),3.77(q,J=7.2Hz,2H),3.72(t,J=5.8Hz,2H),3.15(t,J=6.8Hz,2H),3.11-3.03(m,1H),2.99-2.91(m,2H),2.73(dd,J=13.6,6.7Hz,1H),2.55(dd,J=13.6,6.6Hz,1H),2.16(s,3H),1.85-1.75(m,2H),1.23(t,3H),1.07(d,J=6.3Hz,3H).ESI-MS?m/z:472[M+H] +.
Embodiment 75:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the fluoro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471875)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-(2 of 5-, 2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (the fluoro-2-(2,2 of 5-, 2-trifluoro ethoxy) preparation method of-benzene oxygen acetaldehyde is with embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the fluoro-phenol of 2-methoxyl group-4-and make). 1H?NMR(400MHz,CDCl 3)：δ7.96(s,1H),7.53(s,1H),7.41(d,J=1.4Hz,1H),7.32(d,J=3.0Hz,1H),7.03(d,J=1.2Hz,1H),6.94-6.83(m,1H),6.65(td,J=8.5,3.2Hz,1H),6.43(dd,J=7.9,3.2Hz,1H),4.37-4.26(m,2H),4.16-4.10(m,2H),3.74(t,J=5.6Hz,2H),3.18(t,J=6.7Hz,2H),3.08-3.01(m,1H),2.99-2.90(m,2H),2.72(dd,J=13.7,6.8Hz,1H),2.54(dd,J=13.8,6.8Hz,1H),2.13(s,3H),1.85-1.75(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:526[M+H] +.
Embodiment 76:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the fluoro-2-oxyethyl group-phenoxy group of-2-[2-[4-] ethylamino-] propyl group]-indoles-7-methane amide (DC471876)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the fluoro-2-oxyethyl group-benzene of 4-oxygen acetaldehyde (preparation method of the fluoro-2-oxyethyl group-benzene of 4-oxygen acetaldehyde, with embodiment 5, replaces with the fluoro-phenol of 2-methoxyl group-4-by the 2-methoxyl group-4-ethyl-phenol in step 5.1 and makes). 1H?NMR(400MHz,CDCl 3)：δ7.94(s,1H),7.53(s,1H),7.44(d,J=1.3Hz,1H),7.33(d,J=3.3Hz,1H),7.13(d,J=1.2Hz,1H),6.96-6.87(m,1H),6.66(m,1H),6.43(dd,J=7.9,3.3Hz,1H),3.58(q,J=7.4Hz,2H),3.74(t,J=5.8Hz,2H),3.18(t,J=6.9Hz,2H),3.13-3.04(m,1H),2.98-2.92(m,4H),2.76(dd,J=13.8,6.6Hz,1H),2.59(dd,J=13.6,6.8Hz,1H),2.19(s,3H),1.83-1.78(m,2H),1.26(t,3H),1.05(d,J=6.3Hz,3H).ESI-MSm/z:472[M+H] +.
Embodiment 77:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[5-methyl-2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471877)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 5-methyl-2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (5-methyl-2-(2,2,2-trifluoro ethoxy) preparation method of-benzene oxygen acetaldehyde is with embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to 2-methoxyl group-4-methyl-phenol and make). 1H?NMR(400MHz,CDCl3):δ7.55(d,J=1.3Hz,1H),7.16(d,J=1.2Hz,1H),7.08(d,J=3.4Hz,1H),6.86(d,J=8.8Hz,1H),6.69-6.65(m,2H),6.57(d,J=2.9Hz,1H),6.47(d,J=3.1Hz,1H),4.38-4.25(m,2H),4.21-3.99(m,4H),3.48(t,J=5.9Hz,2H),3.12-2.99(m,2H),2.96-2.90(m,1H),2.85-2.79(m,1H),2.73-2.69(m,1H),2.23(s,3H),2.13(s,3H),1.99-1.88(m,2H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:522[M+H] +.
Embodiment 78:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[4-methyl-2-oxyethyl group-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471878)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 4-methyl-2-oxyethyl group-benzene oxygen acetaldehyde (preparation method of 4-methyl-2-oxyethyl group-benzene oxygen acetaldehyde, with embodiment 5, replaces with 2-methoxyl group-4-methyl-phenol by the 2-methoxyl group-4-ethyl-phenol in step 5.1 and makes). 1H?NMR(400MHz,CDCl 3)：δ7.52(s,1H),7.18(d,J=3.2Hz,1H),7.09(s,1H),6.98(s,1H),6.84(d,J=8.3Hz,1H),6.82(s,1H),6.72-6.62(m,1H),6.53(d,J=3.0Hz,1H),4.15-4.02(m,2H),3.86(s,3H),3.67(t,J=5.8Hz,2H),3.63(q,J=7.6Hz,2H),3.16(t,J=7.0Hz,3H),3.12-2.93(m,2H),2.68(dd,J=13.7,6.4Hz,1H),2.48(dd,J=13.8,6.6Hz,1H),2.21(s,3H),1.82-1.75(m,2H),1.25(t,3H),1.09(d,J=6.2Hz,3H).ESI-MSm/z:468[M+H] +.
Embodiment 79:1-(3-hydroxypropyl)-2-methyl-5-[(2R) the chloro-2-of-2-[2-[5-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471879)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with the chloro-2-(2 of 5-, 2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (the chloro-2-(2,2 of 5-, 2-trifluoro ethoxy) preparation method of-benzene oxygen acetaldehyde is with embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to the chloro-phenol of 2-methoxyl group-4-and make). 1H?NMR(400MHz,CDCl3):δ7.55(t,J=3.8Hz,1H),7.13(t,J=4.7Hz,1H),7.08(d,J=3.2Hz,1H),6.89-6.81(m,2H),6.64(d,J=8.5Hz,2H),6.47(d,J=3.3Hz,1H),4.39-4.25(m,2H),4.26-4.06(m,2H),4.04-3.94(m,2H),3.45(t,J=5.8Hz,2H),3.08-2.93(m,3H),2.86-2.78(m,1H),2.66(dd,J=13.7,6.5Hz,1H),2.20(s,3H),1.98-1.87(m,2H),1.09(d,J=6.2Hz,3H).ESI-MS?m/z:542:544=3:1[M+H] +.
Embodiment 80:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[4-chloro-2-ethoxy-phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471880)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 4-chloro-2-ethoxy-benzene oxygen acetaldehyde (preparation method of 4-chloro-2-ethoxy-benzene oxygen acetaldehyde, with embodiment 5, replaces with the chloro-phenol of 2-methoxyl group-4-by the 2-methoxyl group-4-ethyl-phenol in step 5.1 and makes). 1H?NMR(400MHz,CDCl 3)：δ7.48(t,J=3.8Hz,1H),7.14(s,1H),7.08(d,J=3.3Hz,1H),6.88-6.83(m,2H),6.67(d,J=8.5Hz,2H),6.47(d,J=3.2Hz,1H),4.14-3.98(m,2H),3.73(t,J=5.6Hz,2H),3.63(q,J=7.8Hz,2H),3.26-3.15(m,2H),3.12-3.09(m,1H),3.07-2.89(m,2H),2.68-2.62(m,1H),2.55(dd,J=13.5,6.8Hz,1H),2.13(s,3H),1.85-1.73(m,2H),1.26(t,3H),1.06(d,J=6.2Hz,3H).ESI-MS?m/z:488:490=3:1[M+H] +.
Embodiment 81:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471881)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with that 2-(2,2,2-trifluoro ethoxy)-benzene oxygen acetaldehyde (wherein, 2-(2,2,2-trifluoro ethoxy) preparation method of-benzene oxygen acetaldehyde is:, according to the preparation method of embodiment 4, the 2-methoxyl group-4-ethyl-phenol in step 4.1 is replaced with to 2-methoxyl group-phenol and make). 1H?NMR(400MHz,CDCl 3):δ7.48(d,J=1.3Hz,1H),7.11(d,J=1.3Hz,1H),7.06(d,J=3.3Hz,1H),7.03-6.85(m,2H),6.85(dd,J=8.1,1.4Hz,1H),6.62(d,J=4.5Hz,2H),6.46(d,J=3.2Hz,1H),4.32(t,J=7.4Hz,2H),4.25-4.12(m,2H),4.11-3.94(m,2H),3.48(t,J=5.7Hz,2H),3.08-2.90(m,3H),2.76(m,2H),2.14(s,3H),1.99-1.88(m,2H),1.07(d,J=6.2Hz,3H).ESI-MS?m/z:508[M+H] +.
Embodiment 82:1-(3-hydroxypropyl)-2-methyl-5-[(2R)-2-[2-[2-(oxyethyl group) phenoxy group] ethylamino-] propyl group]-indoles-7-methane amide (DC471882)
Press the preparation method of embodiment 1, indoline in step 1.1 is replaced with to 2-methyl-indoline, by 2 in step 1.15,6-dimethyl benzene oxygen acetaldehyde replaces with 2-oxyethyl group-benzene oxygen acetaldehyde (wherein, the preparation method of 2-oxyethyl group-benzene oxygen acetaldehyde is: according to the preparation method of embodiment 5, the 2-methoxyl group-4-ethyl-phenol in step 5.1 is replaced with to 2-methoxyl group-phenol and make). 1H?NMR(400MHz,CDCl 3)：δ7.93(s,1H),7.56(s,1H),7.48(d,J=1.5Hz,1H),7.39-7.32(m,1H),7.14(d,J=1.4Hz,1H),6.99-6.87(m,2H),6.64(m,1H),6.44(dd,J=7.8,3.5Hz,1H),3.59(q,J=7.5Hz,2H),3.73(t,J=5.9Hz,2H),3.17(t,J=6.8Hz,2H),3.15-3.04(m,1H),2.99-2.92(m,4H),2.76(dd,J=13.6,6.6Hz,1H),2.59(dd,J=13.6,6.8Hz,1H),2.18(s,3H),1.86-1.79(m,2H),1.25(t,3H),1.06(d,J=6.3Hz,3H).ESI-MS?m/z:[M+H] +.
Embodiment 83: the test of activity of cell biology
Experimental technique:
By stably express α 1A-adrenoceptor (α 1A-AR) and G Protein G α 16hEK293 cell be inoculated in 96 hole flat boards, cultivate after 24 hours, remove substratum, every hole adds 40 μ L containing Hank balanced salt solution (the Hank balanced salt solution: comprise 5.4mM KCl, 0.3mM Na of 2 μ M Fluo-4AM 2hPO 4, 0.4mM KH 2pO 4, 4.2mM NaHCO 3, 1.3mM CaCl 2, 0.5mM MgCl 2, 0.6mM MgSO 4, 137mM NaCl, 5.6mM D-Glucose and 250 μ M sulfinpyrazones, pH7.4) in incubator, hatch 45 minutes.Dyestuff is abandoned in suction, adds 50 μ L containing testing compound or 1%DMSO(negative control) HBSS, incubated at room 10 minutes, then uses Flex Station3 microwell plate detector reading.Detector is point at the appointed time, can be automatically by 25 μ L agonist phyenlephrinium (Phenylephrine, final concentration 30nM) join in reaction system, simultaneously with the optical excitation of 485nm and detect intracellular calcium concentration in 525nm wave band and change the variation of the dye fluorescence intensity causing.
Data analysis:
After different pharmaceutical is hatched, cell is to α 1Athe reactivity of-AR agonist phyenlephrinium (Phenylephrine) is calculated by following formula:
Reactivity %=(D-B)/(S-B) * 100%;
Wherein D is with after drug incubation to be measured, the calcium current signal peak that phyenlephrinium evokes; B is after 10 μ M positive control drug Tamsulosins (Tamsulosin) are hatched, the calcium current signal peak that phyenlephrinium evokes; After the negative contrast of S 1%DMSO is hatched, the calcium current signal peak that phyenlephrinium evokes.
The reactivity of same medicine various dose is done nonlinear regression analysis with GraphPad Prism software, obtains dose response curve and records IC 50value.Data are explained with mean+SD, are three independent experiment results, and each experiment is three multiple holes.
Acquired results sees the following form:
Compound IC 50（nM） Compound IC 50（nM）
DC471801 12.30 DC471829 0.45
DC471802 15.62 DC471832 2.01
DC471803 10.85 DC471834 0.43
DC471804 6.83 DC471845 2.13
DC471808 4.62 DC471848 12.46
DC471809 10.22 DC471853 13.02
DC471813 2.50 DC471854 12.21
DC471817 3.61 DC471855 2.13
DC471820 0.21 DC471865 0.34
DC471822 0.18 DC471829 0.45
DC471827 1.70 DC471832 2.01
As can be seen from the table, compound of the present invention is α 1Athe high reactivity antagonist of-AR, the IC of all compounds 50lower than the level of 20nM, the IC of 6 compounds 50lower than 1nM.This compounds has good anti-benign prostatic hyperplasia application prospect, thereby the good commercial value of tool.

Claims (10)

1. the Benzazole compounds that general formula (I) represents, its pharmacy acceptable salt, crystalline hydrate, solvate or their mixture,
Wherein,
R 1, R 2, R 3, R 4, R 5represent the substituting group on phenyl ring, be selected from independently of one another hydrogen, halogen, amino, carboxyl, cyano group, nitro, hydroxyl, the alkyl of the C1-C6 straight or branched not replacing or replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the alkoxyl group of the C1-C6 straight or branched not replacing or replaced by C3-C6 cycloalkyl or halogen, the thiazolinyl of the C2-C12 straight or branched not replacing or replaced by halogen, the alkynyl of the C2-C12 straight or branched not replacing or replaced by halogen, the C3-C6 cycloalkyl that does not replace or replaced by halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by halogen, do not replace or replace C1-C6 straight or branched alkyl carbonyl oxy by halogen, do not replace or replace C1-C6 straight or branched alkyl-carbonyl by halogen, the C1-C6 straight or branched carbalkoxy that does not replace or replaced by halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the benzyloxy that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the carbobenzoxy-(Cbz) that the alkoxyl group of the alkyl of C1-C6 straight or branched and C1-C6 straight or branched replaces, preferably be selected from independently of one another hydrogen, halogen, amino, hydroxyl, not replacement or the alkyl by the thiazolinyl of C2-C4 straight or branched or the C1-C6 straight or branched of 1-3 halogen replacement, do not replace or by the alkoxyl group of the C1-C6 straight or branched of C3-C6 cycloalkyl or the replacement of 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by 1-3 halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the benzyloxy that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, the alkoxyl group of the alkyl of the C1-C6 straight or branched that is more preferably hydrogen, halogen independently of one another, do not replace or replaced by vinyl or 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by C3-C6 cycloalkyl or 1-3 halogen, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement and not replacement or the C3-C6 cycloalkyloxy by 1-3 halogen replacement, most preferably be selected from independently of one another hydrogen, fluorine, chlorine, bromine, methyl, ethyl, allyl group, methoxyl group, oxyethyl group, ring propoxy-, ring the third methoxyl group, tert.-butoxy, neopentyl oxygen, trifluoromethoxy and 2,2,2-trifluoro ethoxy,
Or R 1, R 2, R 3, R 4, R 5in adjacent two substituting groups can form and contain 1～3 heteroatomic 5-6 unit heterocycle that is selected from N, O and S together with carbon atom coupled on phenyl ring; Be preferably formed and contain 1～2 first heterocycle of heteroatomic 5-6 that is selected from O and S; More preferably forming dioxane penta encircles;
N=0,1 or 2, preferably n=1;
R 6be selected from hydrogen, do not replace or the C1-C6 straight or branched alkyl-carbonyl that replaced by halogen and the benzoyl that do not replace or replaced by the alkoxyl group of the alkyl of halogen, C1-C6 straight or branched, C1-C6 straight or branched; The C1-C4 straight or branched alkyl-carbonyl that is preferably selected from the alkyl of hydrogen, C1-C4 straight or branched and does not replace or replaced by 1-3 halogen; More preferably be selected from hydrogen, methyl, ethanoyl and trifluoroacetyl group;
R 7be selected from the alkyl of hydrogen, C1-C6 straight or branched and the alkoxyl group of C1-C6 straight or branched; Be preferably selected from the alkyl of hydrogen and C1-C4 straight or branched; More preferably be selected from hydrogen and methyl;
* represent chiral carbon.
2. Benzazole compounds according to claim 1, its pharmacy acceptable salt, crystalline hydrate, solvate or their mixture, wherein,
R 1be selected from hydrogen, halogen, amino, carboxyl, cyano group, nitro, hydroxyl, the alkyl of the C1-C6 straight or branched not replacing or replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the alkoxyl group of the C1-C6 straight or branched not replacing or replaced by C3-C6 cycloalkyl or halogen, the thiazolinyl of the C2-C12 straight or branched not replacing or replaced by halogen, the alkynyl of the C2-C12 straight or branched not replacing or replaced by halogen, the C3-C6 cycloalkyl that does not replace or replaced by halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by halogen, the C1-C6 straight or branched alkyl carbonyl oxy that does not replace or replaced by halogen, the C1-C6 straight or branched alkyl-carbonyl that does not replace or replaced by halogen, the C1-C6 straight or branched carbalkoxy that does not replace or replaced by halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the benzyloxy that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the carbobenzoxy-(Cbz) that the alkoxyl group of C1-C6 straight or branched replaces, be preferably selected from hydrogen, not replacement or the alkyl by the thiazolinyl of C2-C4 straight or branched or the C1-C6 straight or branched of 1-3 halogen replacement, do not replace or by the alkoxyl group of the C1-C6 straight or branched of C3-C6 cycloalkyl or the replacement of 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by 1-3 halogen, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the phenoxy group that the alkoxyl group of C1-C6 straight or branched replaces, do not replace or by halogen, the alkyl of C1-C6 straight or branched, the benzyloxy that the alkoxyl group of C1-C6 straight or branched replaces, the alkoxyl group of the alkyl of the C1-C6 straight or branched that is more preferably selected from hydrogen, does not replace or is replaced by vinyl or 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by C3-C6 cycloalkyl or 1-3 halogen, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement and not replacement or the C3-C6 cycloalkyloxy by 1-3 halogen replacement, most preferably be selected from methyl, ethyl, allyl group, methoxyl group, oxyethyl group, ring propoxy-, ring the third methoxyl group, tert.-butoxy, neopentyl oxygen, trifluoromethoxy and 2,2,2-trifluoro ethoxy.
R 2the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by thiazolinyl or the halogen of C2-C6 straight or branched; The alkyl of the C1-C4 straight or branched that is preferably selected from hydrogen, halogen and do not replace or replaced by thiazolinyl or the halogen of C2-C4 straight or branched; The alkyl of the C1-C4 straight or branched that is more preferably selected from hydrogen, fluorine, chlorine, bromine and do not replace or replaced by 1-3 halogen; Most preferably be selected from hydrogen, fluorine, chlorine, bromine, methyl and ethyl;
R 3the thiazolinyl of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the C2-C12 straight or branched that does not replace or replaced by 1-3 halogen; The alkyl of the C1-C4 straight or branched that is preferably selected from hydrogen, halogen and do not replace or replaced by thiazolinyl or the halogen of C2-C4 straight or branched; More preferably be selected from hydrogen, fluorine, chlorine, bromine and do not replace or by the alkyl of the C1-C4 straight or branched of vinyl or 1-3 halogen replacement; Most preferably be selected from hydrogen, methyl, ethyl, allyl group, fluorine, chlorine and bromine;
R 4the thiazolinyl of the alkyl of the C1-C6 straight or branched that is selected from hydrogen, halogen, does not replace or is replaced by thiazolinyl or the halogen of C2-C6 straight or branched and the C2-C12 straight or branched that does not replace or replaced by 1-3 halogen; The alkyl of the C1-C4 straight or branched that is preferably selected from hydrogen, halogen and do not replace or replaced by thiazolinyl or the halogen of C2-C4 straight or branched; More preferably be selected from hydrogen, do not replace or by alkyl, fluorine, chlorine and the bromine of the C1-C4 straight or branched of vinyl or the replacement of 1-3 halogen; More preferably be selected from hydrogen, methyl, ethyl, allyl group, fluorine, chlorine and bromine;
Or R 3and R 4can form and contain 1～3 heteroatomic 5～6 yuan of heterocycle that are selected from O and S together with the coupled carbon atom on phenyl ring; Be preferably formed and contain 1～2 first heterocycle of heteroatomic 5-6 that is selected from O and S; More preferably forming dioxane penta encircles;
R 5be selected from hydrogen, halogen, amino, carboxyl, cyano group, nitro, hydroxyl, the alkyl of the C1-C6 straight or branched not replacing or replaced by thiazolinyl or the halogen of C2-C6 straight or branched, the alkoxyl group of the C1-C6 straight or branched not replacing or replaced by C3-C6 cycloalkyl or halogen, the thiazolinyl of the C2-C12 straight or branched not replacing or replaced by halogen, the alkynyl of the C2-C12 straight or branched not replacing or replaced by halogen, the C3-C6 cycloalkyl that does not replace or replaced by halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by halogen, the C1-C6 straight or branched alkyl carbonyl oxy that does not replace or replaced by halogen, the C1-C6 straight or branched carbonyl that does not replace or replaced by halogen, the C1-C6 straight or branched carbalkoxy that does not replace or replaced by halogen, do not replace or by halogen, the phenoxy group that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, do not replace or by halogen, the benzyloxy that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, do not replace or by halogen, the carbobenzoxy-(Cbz) that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, be preferably selected from not replacement or the alkyl by the thiazolinyl of C2-C4 straight or branched or the C1-C6 straight or branched of 1-3 halogen replacement, do not replace or by the alkoxyl group of the C1-C6 straight or branched of C3-C6 cycloalkyl or the replacement of 1-3 halogen, the C3-C6 cycloalkyl that does not replace or replaced by 1-3 halogen, the C3-C6 cycloalkyloxy that does not replace or replaced by 1-3 halogen, do not replace or by halogen, the phenoxy group that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, do not replace or by halogen, the benzyloxy that the alkoxyl group of the alkyl of C1-C6 straight or branched or C1-C6 straight or branched replaces, more preferably be selected from the alkyl of the C1-C6 straight or branched not replacing or replaced by vinyl or 1-3 halogen, the C1-C6 straight or branched that do not replace or replaced by C3-C6 cycloalkyl or 1-3 halogen alkoxyl group, do not replace or by the C3-C6 cycloalkyl of 1-3 halogen replacement, not replacement or the C3-C6 cycloalkyloxy by 1-3 halogen replacement, most preferably be selected from methyl, ethyl, allyl group, methoxyl group, oxyethyl group, ring propoxy-, ring the third methoxyl group, tert.-butoxy, neopentyl oxygen, trifluoromethoxy and 2,2,2-trifluoro ethoxy.
R 6be selected from hydrogen, do not replace or the C1-C6 straight or branched alkyl-carbonyl that replaced by halogen and the benzoyl that do not replace or replaced by the alkoxyl group of the alkyl of halogen, C1-C6 straight or branched, C1-C6 straight or branched; The C1-C4 straight or branched alkyl-carbonyl that is preferably selected from hydrogen and does not replace or replaced by 1-3 halogen; Be preferably selected from hydrogen, ethanoyl and trifluoroacetyl group;
R 7be selected from the alkyl of hydrogen, C1-C6 straight or branched and the alkoxyl group of C1-C6 straight or branched; Be preferably selected from the alkyl of hydrogen and C1-C4 straight or branched; More preferably be selected from hydrogen and methyl; Most preferably be hydrogen;
N=0,1 or 2, preferably n=1.
3. Benzazole compounds according to claim 1 and 2, its pharmacy acceptable salt, crystalline hydrate, solvate or their mixture, wherein, described Benzazole compounds is selected from:
4. according to the Benzazole compounds described in any one in claim 1-3, its pharmacy acceptable salt, crystalline hydrate, solvate or their mixture, wherein, Benzazole compounds is R type isomer, S type isomer or racemic modification, is preferably R type isomer.
5. according to the Benzazole compounds described in any one in claim 1-4, its pharmacy acceptable salt, crystalline hydrate, solvate or their mixture, wherein, described pharmacy acceptable salt is selected from the non-toxic salt forming with mineral acid or organic acid reaction, preferably, described mineral acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, amidosulfonic acid and phosphoric acid, and described organic acid is selected from propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid and aspartic acid.
6. prepare according to a method for the Benzazole compounds described in claim 1-5, as shown in reaction scheme three, described method comprises:
Reaction scheme three
Step 4a: intermediate (II) and intermediate (III) carry out reductive amination process, obtain compound 4a;
Step 4b: the compound 4a reaction that is hydrolyzed, obtains compound 4b;
Step 4c: the compound 4b reaction that is hydrolyzed, obtains compound 4c; Or
Step 4d: compound 4a and cylite carry out nucleophilic substitution reaction, obtains compound 4d;
Step 4e: the compound 4d reaction that is hydrolyzed, obtains compound 4e;
Step 4f: the compound 4e reaction that is hydrolyzed, obtains compound 4f;
Step 4g: compound 4f and acylating reagent carry out acylation reaction, obtains compound 4g;
Step 4h: compound 4g carries out hydrogenation debenzylation reaction, obtains compound 4h;
Wherein, except R 6be not beyond hydrogen, R 1～R 7the definition in requiring of definition and respective right identical.
7. preparation method according to claim 6, wherein, the preparation method of described intermediate (II), as shown in reaction scheme one, comprising:
Reaction scheme one
Step 1a: compound 1a and methyl bromoacetate carry out nucleophilic substitution reaction, obtains compound 1b;
Step 1b: compound 1b and N, O-dimethyl oxammonium hydrochloride carries out amine transesterification reaction, obtains compound 1c;
Step 1c: compound 1c carries out reduction reaction, obtains compound 1d;
The preparation method of described intermediate (III), as shown in reaction scheme two, comprising:
Reaction scheme two
Step 3a: the bromo-1-ethanol of compound 3a and 2-or the bromo-1-propyl alcohol of 3-or the bromo-n-butyl alcohol of 4-carry out nucleophilic substitution reaction, obtain compound 3b;
Step 3b: compound 3b and acylating reagent carry out acylation reaction, obtains compound 3c;
Step 3c: compound 3c and DMF carry out formylation reaction, obtains compound 3d;
Step 3d: compound 3d and nitroethane carry out condensation reaction, obtains compound 3e;
Step 3e: compound 3e carries out reduction reaction, obtains compound 3f;
Step 3f: compound 3f and DMF carry out formylation reaction, obtains compound 2a;
Step 2a: compound 2a carries out oxidizing reaction, obtains compound 2b;
Step 2b: compound 2b and oxammonium hydrochloride carry out condensation reaction, obtains compound 2c;
Step 2c: compound 2c carries out reduction reaction, obtains compound 2d;
Step 2d: compound 2d is split to obtain to compound 2e and compound 2f;
Wherein, R 1～R 7definition identical with the definition in claim 6.
8. a pharmaceutical composition, the Benzazole compounds described in any one in claim 1-5 that is selected from that it comprises treatment significant quantity, with one or more in its pharmacy acceptable salt, crystalline hydrate and solvate, and contain one or more pharmaceutically acceptable carriers.
9. the Benzazole compounds described in any one in claim 1-5, or its pharmacy acceptable salt, crystalline hydrate and the solvate purposes in the medicine of preparing the disease that treatment is relevant to α 1-adrenoceptor.
10. purposes according to claim 9, the described disease relevant to α 1-adrenoceptor is selected from urinary system, is selected from especially benign prostatic hyperplasia, uroschesis and bladder outlet obstruction (BOO).
CN201310211442.6A 2013-05-30 2013-05-30 Indoles compound, preparation method thereof, pharmaceutical composition and application thereof Pending CN104211631A (en)

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