CN1960973A - 1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake - Google Patents

1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake Download PDF

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CN1960973A
CN1960973A CN 200580017378 CN200580017378A CN1960973A CN 1960973 A CN1960973 A CN 1960973A CN 200580017378 CN200580017378 CN 200580017378 CN 200580017378 A CN200580017378 A CN 200580017378A CN 1960973 A CN1960973 A CN 1960973A
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propane
alcohol
methylamino
indoles
phenyl
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C·Y·基姆
P·E·马哈伊
E·J·特里布斯基
张普文
E·A·特雷芬克
C·C·麦库马斯
M·A·马雷拉
R·D·科格伦
G·D·赫弗伦
S·T·科恩
A·T·乌
J·P·萨巴图奇
叶飞
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Wyeth LLC
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Abstract

The present invention is directed to phenylaminopropanol derivatives of formula (I): or a pharmaceutically acceptable salt thereof; wherein: the dotted line between Y and Z represents an optional double bond; the dotted line between the two R4 groups represents an optional heterocyclic ring of 4 to 6 ring atoms that may be formed between the two R4 groups, together with the nitrogen through which they are attached; Y is N, CR6, or C=O; Z is N, CR7, CR5, or C(R5)2; R2 is aryl substituted with 0-3 R1 or heteroaryl substituted with 0-3 R1; R3 is H or C1-C4 alkyl; n is an integer form 0 to 4; x is an integer from 1 to 2; and the other substituents are defined in the claims; compositions containing these derivatives, and methods of their use for the prevention and treatment of conditions ameliorated by monoamine reuptake including, inter alia, vasomotor symptoms (VMS), sexual dysfunction, gastrointestinal and genitourinary disorders, chronic fatigue syndrome, fibromylagia syndrome, nervous system disorders, and combinations thereof, particularly those conditions selected form the group consisting of major depressive disorder, vasomotor symptoms, stress and urge urinary incontinence, fibromyalgia, pain, diabetic neuropathy, and combinations thereof.

Description

The adjusting control agent of active as norepinephrine (NE) and thrombotonin (5-HT) in monoamine reuptake is to treat 1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-the yl)-1-phenyl-propane-2-alcohol derivate and the related compound of vasomotor symptoms (VMS)
The cross reference of related application
The application requires the right of priority of the U. S. application No.____ of submission on March 28th, 2005, this U. S. application requires the U. S. application No.60/557 of submission on March 30th, 2004 again, the U. S. application No.60/569 that on May 11st, 651 and 2004 submitted to, 863 rights and interests, their complete disclosure is quoted at this as a reference.
Technical field
The present invention relates to the phenyl amino propanol derivative, the composition that contains these derivatives is used to prevent and treat the using method of the illness of improving because of monoamine reuptake with them, described illness especially comprises vasomotor symptoms (VMS), sexual dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, myofiber pain (fibromylagia) syndrome, nervous system disorders and combination thereof particularly are selected from down those illnesss of organizing: major depression, vasomotor symptoms, the tonus and the impulsion property urinary incontinence, myofiber pain, pain, diabetic neuropathy and their combination.
Background technology
Vasomotor symptoms (VMS) is called as upsurge and night sweat, is the modal symptom relevant with menopause, sees 60% to 80% all postmenopausal women, the menopause no matter natural menopause is still performed the operation-brought out.VMS may be the adaptation reaction of central nervous system for declining sex steroid.So far, be hormonotherapy to the most effective therapy of VMS, comprise oestrogenic hormon and/or some progesterone.Hormonotherapy is very effective for alleviating VMS, but they are not suitable for all women.What obtained fully realizing is that VMS is that the fluctuation of do as one likes steroid levels causes, and all may be destructive in masculinity and femininity and disabling property.Upsurge can last up to 30 minutes, and its frequency repeatedly took place not wait from all several times to every day.The patient is when the experience upsurge, and sensation heating suddenly is diffused into chest and back from face rapidly, spreads all over all the other positions of health then.It is usually with a large amount of sweatings that happen suddenly.Sometimes may several times take place in one hour, and often occur in night.The upsurge and the burst sweating that occur in night can cause the sleep disappearance.Viewed psychology and mood symptom, for example nervousness, fatigue, excitement, insomnia, depression, the loss of memory, headache, anxiety, nervousness maybe can not be concentrated, be regarded as by (people such as Kramer due to the sleep disappearance after upsurge and the night sweat, people such as In:Murphy, 3rd Int ' l Symposium on Recent Advances in Urological Cancer Diagnosisand Treatment-Proceedings, Paris, FRA: SCI:3-7 (1992)).
Upsurge is possibility even more serious in accepting the women of breast cancer treatment, this has following some reasons: 1) a lot of breast cancer survivors are given tamoxifen, its the most general side effect is a upsurge, 2) women who much accepts breast cancer treatment experiences the premature menopause that chemotherapy causes, 3) women with breast cancer medical history generally is rejected estrin treatment, may recur (people such as Loprinzi, Lancet because worry breast cancer, 2000,356 (9247): 2059-2063).
The male sex also experiences upsurge behind the disconnected medicine of steroid hormone (male sex hormone).This is (people such as Katovich, Proceedings of the Society forExperimental Biology ﹠amp under the male sex hormone decline situation relevant with the age; Medicine, 1990,193 (2): (people such as Berendsen, European Journal ofPharmacology, 2001,419 (1): 47-54) all the more so 129-35) and under the extreme case of the hormone absence relevant with prostate cancer therapy.Nearly these patients of 1/3rd will experiences lasting and frequent symptom, and its severity is enough to cause significantly do not accommodate inconvenience.
These symptoms cutter reason really are still unknown, but generally be considered to represent the disorder (people such as Kronenberg of the normal homeostasis mechanism of control thermoregulation and vasomotor activity, " Thermoregulatory Physiology of Menopausal Hot Flashes:A Review; " Can.J.Physiol.Pharmacol., 1987,65:1312-1324).
A kind of like this fact of estrin treatment (for example controversies in hormone replacement in the elderly) relief of symptoms has been established getting in touch between these symptoms and the estrogen deficiency.For example, the menopause stage in the life is relevant with above-mentioned other acute symptom widely, and these symptoms generally are the oestrogenic hormon responsivenesss.
Someone points out, and oestrogenic hormon may stimulate activity (the J.Pharmacology ﹠amp of norepinephrine (NE) and/or thrombotonin (5-HT) system; Experimental Therapeutics, 1986,236 (3) 646-652).Suppose oestrogenic hormon regulation and control NE and 5-HT level, in hypothalamic heat-regulating centers, provide homeostasis.Keep normal skin temperature via brain stem/spinal cord and suprarenal gland to the descending pathway participation of skin from hypothalamus.Known NE and 5-HT reuptake inhibitor act on CNS and peripheral nervous system (PNS).The physiopathology of VMS is subjected to the mediation of maincenter and periphery mechanism, thus the interaction possible explanation between CNS and the PNS effect of dual function SRI/NRI in treatment thermoregulation dysfunction.In fact, physiology aspect and CNS/PNS involving in VMS, can explain that the dosage aspect being used for the treatment of depressed behavior compares lower recommended doses treatment VMS (people such as Loprinzi, Lancet, 2000,356:2059-2063; People such as Stearns, JAMA, 2003,289:2827-2834).CNS/PNS in the VMS physiopathology interaction and the data that in the document, presented be used to support that with the norepinephrine system be the claim that target can be treated VMS.
Although VMS is the most common with hormonotherapy treatment (oral, transdermal or via implant), but some patient can not tolerate estrin treatment (Berendsen, Maturitas, 2000,36 (3): 155-164, people such as Fink, Nature, 1996,383 (6598): 306).In addition, Hormone Replacement Therapy is not recommended the women or the male sex who suffers from or face hormone-sensitive cancer risk (for example breast cancer or prostate cancer) usually.Thereby non-hormonotherapy (for example fluoxetine, paroxetine [SRI] and clonidine) is in the clinical evaluation.WO 9944601 discloses by giving the method that fluoxetine reduces women's upsurge.After deliberation other selection of upsurge treatment, comprise steroid, alpha-adrenergic agonist and beta-Blocking agent, and obtain in various degree success (people such as Waldinger, Maturitas, 2000,36 (3): 165-168).
Someone has reported α 2-adrenergic receptor has effect (people such as Freedman, Fertility ﹠amp in the thermoregulation dysfunction; Sterility, 2000,74 (1): 20-3).These acceptors are positioned at presynaptic and postsynaptic, the inhibition effect in mediation maincenter and the peripheral nervous system.Adrenergic α 2Acceptor has four kinds of different hypotypes, i.e. α 2A, α 2B, α 2CAnd α 2D(people such as Mackinnon, TIPS, 1994,15:119; French, Pharmacol.Ther., 1995,68:175).Someone has reported non-selective α 2-adrenoceptor antagonist Yohimbine brings out flush, α 2-3 adrenergic receptor agonists clonidine alleviates Yohimbine effect (people such as Katovich, Proceedings of the Society forExperimental Biology ﹠amp; Medicine, 1990,193 (2): 129-35, people such as Freedman, Fertility ﹠amp; Sterility, 2000,74 (1): 20-3).Clonidine has been used for the treatment of upsurge.But, adopt the treatment of this class with a large amount of unwanted side effects, described side effect is as described herein and knownly in association area cause by alleviating the necessary high dosage of upsurge like that.
Because the interaction between thermotaxic complicated diversity and CNS and the PNS in keeping the thermoregulation homeostasis can be developed multiple therapy and means and be come at vasomotor symptoms.The present invention concentrates on the new compound that relates to these and other important use and contains these compound compositions.
Summary of the invention
The present invention relates to the phenyl amino propanol derivative, contain the composition of these derivatives and they are used to prevent and treat the using method of the illness of improving because of monoamine reuptake, described illness especially comprises vasomotor symptoms (VMS), sexual dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combination thereof, particularly is selected from down those illnesss of group: major depression, vasomotor symptoms, tonus and the impulsion urinary incontinence, myofiber pain, pain, diabetic neuropathy and their combination.
In one embodiment, the present invention relates to formula I compound:
Figure A20058001737800321
Or its pharmacy acceptable salt;
Wherein:
Dotted line between Y and the Z is represented optional double bond;
Two R 4Dotted line between the group is represented the optional heterocycle of 4 to 6 annular atomses, and this heterocycle can be with nitrogen that they connected at two R 4Constitute between the group;
Y is N, CR 6Or C=O;
Z is N, NR 7, CR 5Or C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl, perhaps two R 4Group constitutes the heterocycle of 4 to 6 annular atomses with the nitrogen that they connected, and one of them carbon can be alternatively by N, O, S or SO 2Replace, and wherein carboatomic ring atom or other N atom can be alternatively by C arbitrarily 1-C 4Alkyl, F or CF 3Replace;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
In other embodiments, the present invention relates to composition, it comprises:
A. at least a formula I compound; With
B. at least a pharmaceutically acceptable carrier.
In another embodiment, the present invention relates to the method for the illness that in the curee who needs is arranged treatment or prevention improve because of monoamine reuptake, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.The illness of improving because of monoamine reuptake comprises those that are selected from down group: vasomotor symptoms, sexual dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combination thereof particularly are selected from down those illnesss of organizing: major depression, vasomotor symptoms, tonus and the impulsion urinary incontinence, myofiber pain, pain, diabetic neuropathy and their combination.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for vasomotor symptoms, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for dysthymia disorders, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.
In other embodiments, the present invention relates to treatment or preventative handicapped method in the curee who needs is arranged, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In further embodiment, the present invention relates to the method for in the curee who needs is arranged treatment or prevent irritation, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for stomach and intestine or urogenital obstacle, particularly stress or the impulsion property urinary incontinence, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for chronic fatigue syndrome, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for fibromyalgia syndrome, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.
Brief description of drawings
From the accompanying drawing of following detailed description and formation the application part, can understand the present invention more fully.
Fig. 1 is the thermotaxic effect of oestrogenic hormon to norepinephrine/thrombotonin mediation.
Fig. 2 is norepinephrine and thrombotonin and their acceptor (5-HT separately 2 α, α 1With α 2-adrenergic receptor) interactional graphic representation.
Detailed description of the invention
The present invention relates to the phenyl amino propanol derivative, contain the using method that the composition of these derivatives and they are used for the illness that prevention and treatment improve because of monoamine reuptake, described illness especially comprises vasomotor symptoms (VMS), sex dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combination thereof, particularly is selected from those illnesss of lower group: PD, vasomotor symptoms, tonicity and the impulsion urinary incontinence, fibromyalgia, pain, diabetic neuropathy and their combination.
Following definition is for the term and the abbreviation that fully understand in this manual.
Used as this paper and claims, singulative " ", " a kind of " and " being somebody's turn to do " comprise plural appellation, context have in addition obvious indication except. Thereby for example, comprise multiple this class antagonist for the appellation of " a kind of antagonist ", be appellation to one or more compounds and its equivalent well known by persons skilled in the art for the appellation of " a kind of compound ", etc.
Abbreviation in the specification is as follows corresponding to unit, technology, character or compound: " min " expression minute, " h " expression hour, " μ L " represents microlitre, " mL " represents milliliter, " mM " expression volume millimolar concentration, and " M " represents molarity, " mmole " expression mM, " cm " expression centimetre, " SEM " represents standard error of mean, " IU " represents international unit. " Δ ℃ " and " Δ ED50Value " represent to cause observed illness or effect to alleviate 50% dosage (50% average maximum terminal point).
" norepinephrine transporter " is abbreviated as NET. " people's norepinephrine transporter " is abbreviated as hNET. " thrombocytin transport protein " is abbreviated as SERT. " human serum element transport protein " is abbreviated as hSERT. " norepinephrine reuptake inhibitor " is abbreviated as NRI. " selective norepinephrine reuptake inhibitor " is abbreviated as SNRI. " thrombocytin reuptake inhibitor " is abbreviated as SRI. " selective serotonin reuptake inhibitor " is abbreviated as SSRI. " norepinephrine " is abbreviated as NE. " thrombocytin " is abbreviated as 5-HT. " subcutaneous " is abbreviated as sc. " in the peritonaeum " is abbreviated as ip. " oral " is abbreviated as po.
In context disclosed herein, should adopt multiple term. Noun used herein " treatment " comprises preventative (for example preventive), healing property or retentivity are disposed, and that verb used herein " treatment " also comprises is preventative, healing property and retentivity disposal.
Term used herein " effective dose " is illustrated on the dosage and with regard to essential time phase, effectively reaches about the prevention of vasomotor symptoms, depression, sex dysfunction or pain or the amount for the treatment of results needed. Definite, about vasomotor symptoms, the composition of " effective dose " expression compound or compound will increase noradrenaline levels in suffering from the curee of vasomotor symptoms, with in the amount of the shortage of degree compensation steroids utilizability partially or completely. Changing hormonal readiness will affect the amount of compound required for the present invention. For example, because hormonal readiness is higher, may need before the menopause than the lower level compound of climacteric.
Should be appreciated that, the effective dose of component of the present invention will be different because of the patient, this specific compound that not only is allowed a choice, component or composition, the approach of administration and each component (separately or with the combination of one or more composition of medicine) cause the ability of required response in individuality, and following factor arranged, the morbid state of the illness that for example will alleviate or seriousness, individual hormonal readiness, age, sex, body weight, the residing state of patient, the seriousness of the illness for the treatment of with particular patient, parallel drug therapy or special diet, with the other factors that those skilled in the art will recognize that, suitable dosage finally depends on the attending doctor. By regulating dosage regimen, can provide the treatment response of improvement. Effective dose also is such, and wherein any toxicity of each component or ill-effect are not as good as the treatment beneficial effect.
Preferably, the dosage of the compounds of this invention with the time so that the upsurge number of times is compared with the upsurge number of times before the treatment beginning is reduced. Compare with the upsurge seriousness before the treatment beginning, this class treatment also can be of value to reduce any still in overall seriousness or the intensity distribution of the upsurge of experience. About depression, sex dysfunction and pain, the dosage of the compounds of this invention and time so that symptom or illness prevented, alleviated or eliminated.
For example, with regard to the patient, formula I compound or its pharmaceutically acceptable salt be about 0.1mg/ days to about 500mg/ days dosage preferably, every natural gift give once or twice, more preferably about 1mg/ days to about 200mg/ days, most preferably be about 1mg/ days to 100mg/ days, administration time is enough to reduce and/or basically eliminates the number of times of upsurge and/or symptom or the illness of seriousness or depression, sex dysfunction or pain.
Term " component ", " composition of compound ", " compound ", " medicine ", " pharmacological component ", " active component " or " medicine " are used interchangeably in this article, represent a kind of compound or multiple compounds or composition entity, when it induces required pharmacology and/or physiological effect by part and/or general action to curee (human or animal) administration the time.
Term " component ", " medicine ", " pharmacological component ", " active component " or " medicine " are used interchangeably in this article, represent a kind of compound or multiple compounds or composition entity, when it induces required pharmacology and/or physiological effect by part and/or general action to biological (human or animal) administration the time.
The ability of the functional character of term " regulating and controlling effect " expression enhancer or inhibitor biologically active or process, for example receptors bind or signaling activity. This class humidification or inhibitory action may be decided according to the generation of particular event, for example activation of signal transduction path, and/or may only show in the particular cell types. Adjusting control agent is intended to comprise any compound, for example antibody, little molecule, peptide, oligopeptides, polypeptide or protein, preferred little molecule or peptide.
Term used herein " inhibitor " represents any inhibition, forbids, stops or reduces given activity, for example the reagent of thrombocytin reuptake activity or norepinephrine reuptake activity.
Term " inhibitor " is intended to comprise any compound, for example antibody, little molecule, peptide, oligopeptides, polypeptide or protein, preferred little molecule or peptide, they to mammal, preferred human norepinephrine reuptake or thrombocytin reuptake and norepinephrine reuptake performance part, fully, competition and/or depression effect, thereby reduce or retardance, preferably reduce some or all biological effects of endogenous norepinephrine reuptake or thrombocytin reuptake and norepinephrine reuptake.
In the present invention, formula I compound can be made into the pharmaceutically acceptable salt form. Term used herein " pharmaceutically acceptable salt " expression comprises inorganic salts and organic salt from the salt of pharmaceutically acceptable avirulence acid preparation. The avirulence acid that is fit to comprises inorganic and organic acid, such as acetic acid, benzene sulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, glactaric acid, nitric acid, pounce on acid (pamoic acid), pantothenic acid, phosphoric acid, butanedioic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid etc. Particularly preferably be hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, most preferably hydrochloride.
" giving " used herein expression directly gives compound of the present invention or composition, perhaps gives pro-drug, derivative or analog, and it will generate reactive compound or the material of equivalent in vivo.
The animal of term " curee " or " patient " available composition of the present invention of expression and/or method treatment comprises the mankind. Term " curee " is intended to represent male and female sex, specifically note a kind of sex except. Correspondingly, term " patient " comprises any mammal that may benefit from treatment or the prevention of vasomotor symptoms, depression, sex dysfunction or pain, people for example, especially this mammal is female, before it is in menopause, after climacteric or the menopause. In addition, the term patient comprises jenny, this comprises the people, and in the mankind, not only comprise the aged women who has passed through menopause, but also comprise and experience uterectomy or be prevented from producing estrogenic women for some other reasons, for example experience long-term corticosteroid administration, suffered from those of cushing's syndrome or hypogenitalism. But, term " patient " is not limited to the women.
Term " premature menopause " or " people is menopause " express possibility and occur in the ovarian failure of 40 years old unknown cause in the past. This may be with smoking, live in high height above sea level place or malnutritive physique is relevant. The people may be by due to the process of oophorectomy, chemotherapy, pelvis radiation or the blood supply of any weakening ovary for menopause.
Before term " before the menopause " the expression menopause, term " climacteric " represented between climacteric, after term " after the menopause " the expression menopause. The excision of " oophorectomy " expression one or both sides ovary, and can be according to people such as Merchenthaler, Maturitas, 1998,30 (3): 307-316 implements.
A kind of like this consequence of " side effect " expression is not to use a kind of composition or means for this reason, and this consequence is the ill-effect that is produced by medicine, especially for and its administration of unprovoked and ill-effect that benefited tissue or tract produce. In the situation of for example independent high dose NRI or NRI/SRI compound, term " side effect " can represent this class illness, such as vomit, feel sick, sweating and the flush (people such as Janowsky, Journal of Clinical Psychiatry, 1984,45 (10 Pt 2): 3-9).
Optional substituted, the saturated straight chain of " alkyl " used herein expression, side chain or cyclic hydrocarbon, it has about 1 to about 20 carbon atoms (with the in this article scope of carbon atom and all combinations and the sub-portfolio of given number), preferably have about 1 to about 8 carbon atoms, more preferably have about 1 to about 4 carbon atoms (this paper is referred to as " low alkyl group "). Alkyl includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, cyclopenta, isopentyl, neopentyl, n-hexyl, isohesyl, cyclohexyl, ring octyl group, adamantyl, 3-methyl amyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.
" perfluoroalkyl " used herein represents as defined above alkyl, and the hydrogen that wherein directly is connected with carbon atom is replaced by fluoro fully.
" thiazolinyl " used herein expression has the alkyl of at least two carbon atoms of one or more pair of key, and wherein alkyl is as herein defined. Thiazolinyl can be optional substituted.
" alkynyl " used herein expression has the alkyl of at least two carbon atoms of one or more 3 keys, and wherein alkyl is as herein defined. Alkynyl can be optional substituted.
" aryl " used herein expression optional substituted, single-, two-, three-or other polycyclic aromatic ring system, it has about 5 to about 50 carbon atoms (with the in this article scope of carbon atom and all combinations and the sub-portfolio of given number), preferably has about 6 to about 10 carbon. Limiting examples for example comprises phenyl, naphthyl, anthryl and phenanthryl.
" heteroaryl " used herein expression optional substituted, single-, two-, three-or other polycyclic aromatic ring system, its comprise at least one, preferred 1 to about 4 heteroatomic ring members that are selected from sulphur, oxygen and nitrogen. Heteroaryl for example can have about 3 to about 50 carbon atoms (with the in this article scope of carbon atom and all combinations and the sub-portfolio of given number), preferably has about 4 to about 10 carbon. The limiting examples of heteroaryl for example comprises pyrrole radicals, furyl, pyridine radicals, 1,2,4-thiadiazolyl group, pyrimidine radicals, thienyl (thienyl), isothiazolyl, imidazole radicals, tetrazole radical, pyrazinyl, pyrimidine radicals, quinolyl, isoquinolyl, thienyl (thiophenyl), benzothienyl, isobenzofuran-base, pyrazolyl, indyl, purine radicals, carbazyl, benzimidazolyl and different  azoles base.
The heterocycle of 5-to 7-unit's monocycle that " heterocycle " used herein expression is stable or bicyclic heterocycles or 7-to 10-unit two rings, it be saturated, part is unsaturated or unsaturated (aromatics), and contain carbon atom and 1 to 4 and independently be selected from the hetero atom of N, O and S, and comprise wherein arbitrarily any bicyclic groups that as defined above heterocycle and phenyl ring condense. Nitrogen and sulfur heteroatom can be oxidized alternatively. Heterocycle can be connected with side group at any hetero atom of rock-steady structure or carbon atom of causing. Heterocycle described herein can be substituted at carbon or nitrogen-atoms, if the gained compound is stable. If concrete note is arranged, assorted ring nitrogen can be quaternized alternatively. Preferably, if the S in the heterocycle and O total atom number surpass one, then these hetero atoms are not adjacent to each other. Preferably, the S in the heterocycle and O total atom number are no more than one. The example of heterocycle includes but not limited to the 1H-indazole, the 2-Pyrrolidone base, 2H, 6H-1,5,2-dithiazine base, the 2H-pyrrole radicals, the 3H-indyl, the 4-piperidone base, the 4aH-carbazole, 4H-quinolizine base, 6H-1,2,5-thiadiazine base, acridinyl, the azocine base, benzimidazolyl, benzofuranyl, benzothiopyran derivative base (benzothiofurayl), benzothienyl, the benzoxazol base, benzothiazolyl, the BTA base, the benzo tetrazole radical, benzisoxa  azoles base, the benzisothiazole base, the benzimidazole ketone group, carbazyl, the 4H-carbazyl, α-, β-or the B-carboline base, chromanyl, benzopyranyl, the cinnolines base, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran also [2,3-b] oxolane, furyl, the furazan base, imidazolidinyl, imidazolinyl, imidazole radicals, the 1H-indazolyl, indolenyl, indolinyl, the indolizine base, indyl, isobenzofuran-base, the isochroman base, iso indazolyl, iso-dihydro-indole-group, isoindolyl, isoquinolyl, isothiazolyl, different  azoles base, morpholinyl, the naphthyridines base, the octahydro isoquinolyl, the  di azoly, 1,2,3- di azoly, 1,2,4- di azoly, 1,2,5- di azoly, 1,3,4- di azoly, the  oxazolidinyl,  azoles base, the  oxazolidinyl, pyrimidine radicals, phenanthridinyl, the phenanthroline base, fen  piperazine base, phenazinyl, phenothiazinyl, phenoxathiinyl, fen  piperazine base, phthalazinyl (phthalazinyl), piperazinyl, piperidyl, pteridyl, piperidone base, the 4-piperidone base, pteridyl, purine radicals, pyranose, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido  azoles, the pyrimido imidazoles, the pyrido thiazole, pyridine radicals (pyridinyl), pyridine radicals (pyridyl), pyrimidine radicals, pyrrolidinyl, pyrrolinyl, pyrrole radicals, quinazolyl, quinolyl, 4H-quinolizine base, quinoxalinyl, quininuclidinyl, the carboline base, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thianthrene group, thiazolyl, thienyl (thienyl), the thieno thiazolyl, thieno  azoles base, the Thienoimidazole base, thienyl (thiophenyl), triazine radical, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3,4-triazolyl, xanthyl. Preferred heterocycle includes but not limited to pyridine radicals, furyl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, indyl, benzimidazolyl, 1H-indazolyl,  oxazolidinyl, BTA base, benzisoxa  azoles base, hydroxyindole base, benzoxazol quinoline base or isatin base. Also comprise the fused rings and the spiro-compound that for example contain above-mentioned heterocycle.
" alkoxyl " used herein expression radicals R-O-, wherein R is alkyl as herein defined.
" aryloxy group " used herein expression radicals R-O-, wherein R is aryl as herein defined.
" heteroaryloxy " used herein expression radicals R-O-, wherein R is heteroaryl as herein defined.
" alkanoyloxy " used herein expression radicals R-C (=O)-and O-, wherein R is the alkyl of 1 to 5 carbon atom.
" alkyl sulfoxide " used herein expression-S (=O)-R, wherein R is alkyl as defined above.
" alkyl sulfone " used herein expression-S (=O)2-R, wherein R is alkyl as defined above.
" alkyl sulfonamide " used herein expression-NR-S (=O) 2-R, wherein each R is alkyl as defined above independently, perhaps the NR part also can be NH.
" phenyl-sulfamide " used herein expression-NR-S (=O) 2-phenyl, wherein R is H or alkyl as defined above.
" heteroaryl methoxyl group " used herein expression-OCH 2-R, wherein R is a heteroaryl as defined above.
" alkyl amido " used herein expression-NR-C (=O)-R, wherein each R is alkyl as defined above independently, perhaps the NR part also can be NH.
" phenyl amido " used herein expression-NR-C (=O)-phenyl, wherein R is H or alkyl as defined above.
" halogeno-group " used herein expression chlorine, bromine, fluorine and iodine.
In one embodiment, the present invention relates to formula I compound:
Or its pharmacy acceptable salt;
Wherein:
Dotted line between Y and the Z is represented optional double bond;
Two R 4Dotted line between the group is represented the optional heterocycle of 4 to 6 annular atomses, and this heterocycle can be with nitrogen that they connected at two R 4Constitute between the group;
Y is N, CR 6Or C=O;
Z is N, NR 7, CR 5Or C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl, perhaps two R 4Group constitutes the heterocycle of 4 to 6 annular atomses with the nitrogen that they connected, and one of them carbon can be alternatively by N, O, S or SO 2Replace, and wherein carboatomic ring atom or other N atom can be alternatively by C arbitrarily 1-C 4Alkyl, F or CF 3Replace;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
And the dotted line in the ring A condensed ring is represented optional double bond between Y and the Z.Two R 4Dotted line between the group is represented the optional heterocycle of 4 to 6 annular atomses, and this heterocycle can be with nitrogen that they connected at two R 4Constitute between the group.
In some preferred embodiment of formula I compound, Y is N.In some other embodiment preferred, Y is CR 6, preferred CH.In some other embodiment preferred, Y is C=O.
In some preferred embodiment, Z is N.In some preferred embodiment of formula I compound, Z is NR 7In other preferred embodiment, Z is CR at some 5In other preferred embodiment, Z is C (R at some 5) 2In some even preferred embodiment, Z is CH, C (CH 3) or C (CN).
In some preferred embodiment of formula I compound, R 1Be alkyl independently when occurring at every turn, preferred C 1-C 4Alkyl, more preferably methyl.In some other embodiment preferred, R 1Be alkoxyl group independently when occurring at every turn.In some other preferred embodiment of compound, R 1Be halogeno-group independently when occurring at every turn, preferred F or Cl in some other embodiment preferred, R 1Be CF independently when occurring at every turn 3In some other embodiment preferred, R 1Be OCF independently when occurring at every turn 3In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The benzyloxy that replaces.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The aryloxy that replaces.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The aryl that replaces.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The heteroaryl that replaces.In some other embodiment preferred, R 1Be hydroxyl independently when occurring at every turn.In some other embodiment preferred, R 1Be alkanoyloxy independently when occurring at every turn.In some other embodiment preferred, R 1Be methylene-dioxy independently when occurring at every turn.In some other embodiment preferred, R 1Be nitro independently when occurring at every turn.In some other embodiment preferred, R 1Be nitrile independently when occurring at every turn.In some other embodiment preferred, R 1Be thiazolinyl independently when occurring at every turn.In some other embodiment preferred, R 1Be alkynyl independently when occurring at every turn.In some other embodiment preferred, R 1Be alkyl sulfoxide independently when occurring at every turn.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The phenyl sulfoxide that replaces.In some other embodiment preferred, R 1Be the alkyl sulfone independently when occurring at every turn.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The phenylsulfone that replaces.In some other embodiment preferred, R 1Be alkyl sulfonamide independently when occurring at every turn.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The phenyl-sulfamide that replaces.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The heteroaryloxy that replaces.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The heteroaryl methoxyl group that replaces.In some other embodiment preferred, R 1Be alkyl amido independently when occurring at every turn.In some other embodiment preferred, R 1When occurring at every turn independently by 0-3 R 1The phenyl amido that replaces.
In some preferred embodiment of formula I compound, R 2By 0-3 R 1The aryl that replaces does not preferably have R 1Replace.In certain preferred aspects, R 2By 0-3 R 1The naphthyl that replaces does not preferably have R 1Replace.In certain preferred aspects, R 2By 0-3 R 1The heteroaryl that replaces does not preferably have R 1Replace.
In some preferred embodiment of formula I compound, R 3Be H.In some other embodiment preferred, R 3Be C 1-C 4Alkyl, preferred C 1Alkyl.
In some preferred embodiment of formula I compound, R 4Be H independently when occurring at every turn.In certain preferred aspects, R 4Be C independently when occurring at every turn 1-C 4Alkyl, preferred C 1-C 3Alkyl, more preferably methyl, ethyl, sec.-propyl.In some preferred embodiment of formula I compound, R 4Be benzyl independently when occurring at every turn.In certain preferred aspects, R 4Be the heteroaryl methyl independently when occurring at every turn.In certain preferred aspects, R 4Be suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl independently when occurring at every turn.
In some preferred embodiment of formula I compound, two R 4Group constitutes the heterocycle of 4 to 6 annular atomses with the nitrogen that they connected, and one of them carbon can be alternatively by N, O, S or SO 2Replace, and wherein any carboatomic ring atom or other N atom can be alternatively by C 1-C 4Alkyl, F or CF 3Replace.In some preferred embodiment, two R 4Group with the nitrogen that they connected constitute pyridine, piperidines, piperazine, by methyl substituted piperazine or morpholine ring.
In some preferred embodiment of formula I compound, R 5Be H independently when occurring at every turn.In some preferred embodiment of compound, R 5Be C independently when occurring at every turn 1-C 4Alkyl, preferable methyl.In some preferred embodiment of compound, R 5When occurring at every turn independently by 0-3 R 1The aryl that replaces, preferred phenyl, tolyl or xylyl.In certain preferred aspects, R 5Be cyano group independently when occurring at every turn.
In some preferred embodiment of formula I compound, when there being two R 5The time, they constitute the carbocyclic ring of 3-7 carbon, preferred cyclopentyl or cyclohexyl.
In some preferred embodiment of formula I compound, R 6Be H independently when occurring at every turn.In some preferred embodiment of compound, R 6Be C independently when occurring at every turn 1-C 4Alkyl, preferable methyl.In certain preferred aspects, R 6Be cyano group independently when occurring at every turn.
In some preferred embodiment of formula I compound, R 7Be H independently when occurring at every turn.In some preferred embodiment of compound, R 7Be C independently when occurring at every turn 1-C 6Alkyl, preferred C 1-C 4Alkyl, more preferably methyl.In some preferred embodiment of compound, R 7Be C independently when occurring at every turn 3-C 6Cycloalkyl, preferred cyclopentyl or cyclohexyl.In some preferred embodiment of compound, R 5When occurring at every turn independently by 0-3 R 1The aryl that replaces, preferred phenyl, tolyl or xylyl.
In some preferred embodiment of formula I compound, R 8Be H independently when occurring at every turn.In some preferred embodiment of compound, R 8Be C independently when occurring at every turn 1-C 4Alkyl, preferable methyl.
In some preferred embodiment of formula I compound, R 9Be H independently when occurring at every turn.In some preferred embodiment of compound, R 9Be C independently when occurring at every turn 1-C 4Alkyl, preferable methyl.
In some preferred embodiment of formula I compound, R 10Be H independently when occurring at every turn.In some preferred embodiment of compound, R 10Be C independently when occurring at every turn 1-C 4Alkyl, preferable methyl.In some preferred embodiment of formula I compound, R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together, especially pyrrolidyl, pyrryl, piperidyl, pyridyl, azepan base and azepine  base.
In some preferred embodiment of formula I compound, n is 0 to 3 integer.More preferably, n is 0 to 2 integer.And then more preferably, n is 0 to 1 integer.More preferably, n is 0.
In some preferred embodiment of formula I compound, x is 1 to 2 integer.More preferably, x is 1.
In some preferred embodiment of formula I compound, 1-2 carbon atom among the ring A can be replaced by N alternatively.In some preferred embodiment of compound, a carbon atom among the ring A can be replaced by N alternatively.In certain preferred aspects, there is not carbon atom to be replaced among the ring A by N.
In some preferred embodiment of formula I compound,
Y is N, CR 6Or C=O;
Z is N, NR 7, CR 5Or C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H;
R 4Be H or C independently when occurring at every turn 1-C 4Alkyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H;
R 9Be H;
R 10Be H;
N is 0 to 4 integer;
X is 1; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
In some preferred embodiment of formula I compound,
Y is CR 6
Z is CR 5
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
In some preferred embodiment of formula I compound,
Y is CR 6
Z is C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
In some preferred embodiment of formula I compound,
Y is C=O;
Z is C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
In some preferred embodiment of formula I compound,
Y is C=O;
Z is NR 7
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they can constitute C 3-C 7Carbocyclic ring;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
Preferred formula I compound comprises:
1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-morpholine-4-base-1-phenyl-propane-2-alcohol;
3-(dimethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
3-(ethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(sec.-propyl amino)-1-phenyl-propane-2-alcohol;
3-(benzylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
The 3-[(cyclohexyl methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
The 3-[(cyclohexyl methyl) amino]-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-(sec.-propyl amino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(ethylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-1-phenyl-3-piperazine-1-base propane-2-alcohol;
1-(1H-indoles-1-yl)-1-phenyl-3-[(pyridin-4-yl methyl) amino] propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-1-phenyl-3-piperidines-1-base propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
3-(ethylamino)-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
3-amino-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-[ethyl (methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-1-alcohol;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 1H-indole-3-formonitrile;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(4-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(2-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol;
1-(3-bromophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
3-[2-hydroxyl-1-(1H-indoles-1-yl)-3-(methylamino) propyl group] cyanobenzene;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(4-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(2-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(4-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(3-aminomethyl phenyl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-morpholine-4-base propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(propyl group amino) propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(4-aminomethyl phenyl) propane-2-alcohol;
1-(2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(2-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(1H-indoles-1-yl)-1-(3-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-(2-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-1-phenyl-propane-2-alcohol;
1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-2-alcohol;
1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-(3-fluorophenyl)-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(6-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(7-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl) propane-2-alcohol;
3-(methylamino)-1-(4-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(5-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(3-ethyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indoles-1-yl) propane-2-alcohol;
7-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
7-fluoro-1-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol;
2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-(tetramethyleneimine-2-yl) ethanol;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
7 '-fluoro-1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5 '-bromo-1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-[3-(3, the 4-dichlorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(5-chloro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
[3-(5-chloro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
1-(7-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
[3-(5-fluoro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
1-(4-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(4-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(5-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-4-formonitrile HCN;
1-(6-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-5-formonitrile HCN;
1-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1H-indoles-4-formonitrile HCN;
1-(6-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(6-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
3-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
1-(7-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3, the 4-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(4-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(6-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(4-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(6-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
4-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) butane-2-alcohol;
1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(4-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
1-[3-(4-tert-butyl-phenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(3-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(2-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(7-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(4-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(4-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(6-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(the 3-tertiary butyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-2-methyl-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(1H-indoles-1-yl)-1-(methylamino)-3-phenyl butane-2-alcohol;
The 1-tertiary butyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-bromo-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
6-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
4-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-cyclobutyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-cyclopentyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
3-[3-(ethylamino)-2-hydroxyl-1-phenyl propyl]-5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-5-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[2-hydroxyl-3-(methylamino)-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-[3-(2, the 3-difluorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-[3-(2-chloro-phenyl-)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
With its pharmacy acceptable salt, particularly its hydrochloride and dihydrochloride.
Particularly preferred formula I compound comprises:
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-morpholine-4-base-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(dimethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(ethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(sec.-propyl amino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(benzylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-the 3-[(cyclohexyl methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-the 3-[(cyclohexyl methyl) amino]-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(sec.-propyl amino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(ethylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-piperazine-1-base propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-[(pyridin-4-yl methyl) amino] propane-2-alcohol;
(1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-1-phenyl-3-piperidines-1-base propane-2-alcohol;
(1RS, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-amino-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(ethylamino)-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-amino-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-[ethyl (methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2RS)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-1-alcohol;
1-[(1RS, 2SR)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 1H-indole-3-formonitrile;
(1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-chloro-phenyl-)-1-(H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-1-(2-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1SR, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol;
(1S, 2R)-1-(3-bromophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
3-[(1S, 2R)-2-hydroxyl-1-(1H-indoles-1-yl)-3-(methylamino) propyl group] cyanobenzene;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(4-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(2-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(3-aminomethyl phenyl) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
(1S, 2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-morpholine-4-base propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(propyl group amino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(4-aminomethyl phenyl) propane-2-alcohol;
(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(2-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-1-(3-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
(1SR, 2RS)-1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
(1RS, 2SR)-3-(methylamino)-1-(2-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(methylamino)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(5-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(3-fluorophenyl)-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(6-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-ethyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indoles-1-yl) propane-2-alcohol;
7-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
7-fluoro-1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
(1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
(1S, 2R)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol;
(1R, 2S)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
(1S, 2R)-3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
7 '-fluoro-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5 '-bromo-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-[3-(3, the 4-dichlorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S*, 2R*)-3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-amino-1-(5-chloro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
[(2R, 3S)-3-(5-chloro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
(1S, 2R)-1-(7-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
[(2R, 3S)-3-(5-fluoro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
(1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-4-formonitrile HCN;
(1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-5-formonitrile HCN;
1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1H-indoles-4-formonitrile HCN;
(1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(7-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
(1S, 2S)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 4-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(4-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(6-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(6-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-4-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) butane-2-alcohol;
(1S, 2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(4-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-[3-(4-tert-butyl-phenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
(1S, 2R)-3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-amino-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(4-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(the 3-tertiary butyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-2-methyl-3-(methylamino)-1-phenyl-propane-2-alcohol;
(2R, 3S)-3-(1H-indoles-1-yl)-1-(methylamino)-3-phenyl butane-2-alcohol;
The 1-tertiary butyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-bromo-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
6-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
4-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-cyclobutyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-cyclopentyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
3-[(1S, 2R)-3-(ethylamino)-2-hydroxyl-1-phenyl propyl]-5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-5-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
(1S, 2R)-1-[3-(2, the 3-difluorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-[3-(2-chloro-phenyl-)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
With its pharmacy acceptable salt, particularly its hydrochloride and dihydrochloride.
Some The compounds of this invention may contain chiral centre, and this compounds may exist with the form of steric isomer (being enantiomorph).The present invention includes all these class steric isomers and its any mixture, this comprises racemic mixture.The racemic mixture of steric isomer and pure basically steric isomer are all within the scope of the invention.Term used herein " pure basically " expression for other possible steric isomer, exist at least about 90 moles of %, more preferably at least about 95 moles of %, most preferably at least about the required steric isomer of 98 moles of %.Preferred enantiomorph can separate from racemic mixture by any method well known by persons skilled in the art, this method comprises high performance liquid chromatography (HPLC), and by generating chirality salt and, perhaps preparing by methods described herein with its Crystallization Separation.For example referring to people such as Jacques, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, people such as S.H., Tetrahedron, 33:2725 (1977); Eliel, E.L.Stereochemistry of Carbon Compounds, (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and OpticalResolutions, p.268 (E.L.Eliel, Ed., University of Notre Dame Press, NotreDame, IN 1972).
The present invention includes the prodrug of formula I compound." prodrug " used herein expression can be by the compound that is converted into formula I compound in metabolic way (for example hydrolysis) body.Various prodrug form are known in the art, for example as being discussed in following document: Bundgaard, (editor), Design of Prodrugs, Elsevier (1985); People such as Widder (editor), Methods inEnzymology, vol.4, Academic Press (1985); People such as Krogsgaard-Larsen, (editor). " Design and Application of Prodrugs, " Textbook of Drug Design andDevelopment, Chapter 5,113-191 (1991), people such as Bundgaard, Journal of DrugDeliver Reviews, 1992,8:1-38, Bundgaard, J.of Pharmaceutical Sciences, 1988,77:285 and following pages; With Higuchi and Stella (editor) Prodrugs as NovelDrug Delivery Systems, American Chemical Society (1975).
And then, formula I compound can with solvation form not exist and with pharmaceutically acceptable solvent for example the solvation form of water, ethanol etc. exist.Generally speaking, for the purpose of the present invention, the solvation form is regarded as being equivalent to not solvation form.
The compounds of this invention can be prepared according to multiple mode well known to those skilled in the art.These compounds for example can synthesize by following method or its modification that the technician understanded.All relevant and disclosed processes with the present invention can be implemented with any scale, and this comprises milligram, gram, many grams, kilogram, many kilograms or industrial technical scale.
Such just as will be readily understood, blocking group can be contained in existing functional group during building-up process.Blocking group is known such chemical functional group itself, and they can optionally be connected in the functional group and from this functional group and remove, for example hydroxyl and carboxyl.These groups are present in the compound and are inertia to give this class functional group for the chemical reaction condition that compound was exposed.The present invention can adopt any in the various blocking groups.Can be according to the blocking group that the present invention can adopt referring to Greene, T.W.and Wuts, P.G.M., Protective Groups inOrganic Synthesis 2d.Ed., Wiley ﹠amp; Sons, 1991.
The compounds of this invention is fit to be prepared according to following general remark and specific embodiment.Used variable is defined suc as formula I, but except annotated in addition.Being used in reagent in the The compounds of this invention preparation can be commercial or can be prepared by the described standard technology of document.According to the present invention, formula I compound is produced by following reaction scheme (scheme I-IV).
The compounds of this invention contains chiral centre, and various stereoisomeric forms in any ratio are provided, for example mixture of enantiomers and optically active isomer.Each optically active isomer can be directly by asymmetric and/or stereospecificity is synthetic is prepared, perhaps by conventional chiral separation separating optical isomers from mixture of enantiomers.
The compounds of this invention is fit to be prepared according to following general remark and specific embodiment.Used variable is defined suc as formula I, but except annotated in addition.Being used in reagent in the The compounds of this invention preparation can be commercial or can be prepared by the described standard technology of document.According to the present invention, formula I compound is produced by following reaction scheme (scheme I-IV).
The compounds of this invention contains chiral centre, and various stereoisomeric forms in any ratio are provided, for example mixture of enantiomers and optically active isomer.Each optically active isomer can be directly by asymmetric and/or stereospecificity is synthetic is prepared, perhaps by conventional chiral separation separating optical isomers from mixture of enantiomers.
According to the present invention, formula I compound is produced by following reaction scheme (scheme I to IV).Depend on required diastereomer, can be via two kinds of different route of synthesis (A and B, scheme I and II) preparation compound.Synthesis type I-a compound if desired then can be by formula 4 compounds according to being prepared as follows them: primary alconol is selectively converted to leavings group, uses required amine with its displacement (approach A, scheme I) again.This transformation can adopt any method and any method that is usually used in amine displacement uncle leavings group that is usually used in primary alconol to the selective conversion of leavings group.According to the preferred embodiments of the invention, the glycol of formula 4 is handled with the pyridine solution of Tosyl chloride, and the tosylate of production 5 is handled with the alcohol excess amine aqueous solution again, be converted into formula I-a compound, condition be in the sealing test tube under room temperature or be heated to about 40 ℃ to about 80 ℃.Utilize any ordinary method formula I-a compound can be converted into pharmacy acceptable salt.
Scheme I
Wherein: A, Y, Z, R 1, n, R 2, R 4, R 8, R 9, R 10Be as previously described, R 3=C 1-C 4Low alkyl group, P=blocking group, preferred trimethyl silyl, t-butyldimethylsilyl, p-nitrophenyl formyl radical, and OTs=tosic acid ester group or any conventional leavings group.
Production I-aa compound if desired then can be by formula 4 compounds according to being prepared as follows: selective protection primary alconol, alkylation secondary alcohol and primary alconol gone protection then.This transformation can adopt the pure blocking group of any routine, and can adopt any method that is used for the selective protection of primary alconol.According to the preferred embodiments of the invention, this reacts under the low temperature in methylene dichloride with trimethylsilyl chloride with as the triethylamine of alkali and carries out production 6 compounds.Can realize the alkylation of secondary alcohol via any conventional alkylation that the secondary alcohol of bibliographical information arranged.According to the preferred embodiments of the invention, use sodium hydride to make formula 6 compounds and alkylogen reaction as alkali, production 8 compounds, it can go protection and production 9 compounds via any de-protected method of primary alconol that is usually used in.According to the preferred embodiments of the invention, formula 8 compounds are handled production 9 compounds with the dichloromethane solution of diluted hydrochloric acid aqueous solution or trifluoroacetic acid.Can carry out the conversion of the primary alconol in formula 9 compounds as preamble about as described in formula I-a compound synthetic, synthetic with perfect I-aa compound.Can utilize any ordinary method that formula I-aa compound is converted into pharmacy acceptable salt.
Select as an alternative, can be directly by formula 5 compound formulas 10 compounds.This transformation can adopt any in the presence of tosyl group the method with hydroxy alkylated.According to the preferred embodiments of the invention, in hindered base for example 2,6-di-t-butyl-4-picoline exists down, with formula 5 compounds with the trifluoromethanesulfonic acid alkyl ester for example the trifluoromethanesulfonic acid methyl esters handle.This reaction can be carried out under room temperature, perhaps is heated to about 40 ℃ and carries out to about 80 ℃ situation.Can as described in formula I-a compound synthetic, formula 10 compounds be converted into formula I-aa compound as preamble.Can utilize any ordinary method that formula I-aa compound is converted into pharmacy acceptable salt.
Generate Compound I-b if desired, also can via approach B (scheme II) by formula 4 compound they.This approach relates to the conversion to leavings group of the selective protection of primary alconol and secondary alcohol subsequently.This transformation can adopt any method and any method that is usually used in secondary alcohol is converted into leavings group that is usually used in the selective protection of primary alconol.According to the preferred embodiments of the invention, (preferably be lower than about 0 ℃) at low temperatures, formula 4 compounds are handled production 11 compounds with the pyridine solution of paranitrobenzoyl chloride.Use triethylamine as alkali, via with the reaction of the dichloromethane solution of methylsulfonyl chloride, formula 11 compounds can be converted into the secondary methanesulfonates of formula 12.This reaction is preferably being carried out under the temperature between-15 ℃ and about 10 ℃ approximately.The protection of going of primary alconol allows to pass through S in formula 12 compounds N2 reactions generate uncle's epoxide, cause the counter-rotating at three-dimensional center.This transformation can adopt any de-protected method of primary alconol and any method that is usually used in generating epoxy group(ing) on the α leavings group of being usually used in.According to the preferred embodiments of the invention, formula 12 compounds are handled in organic solvent with the alkali aqueous solution that is fit to, preferably in two  alkane, handle with aqueous NaOH.The epoxide of gained formula 13 can be used the ground open loop of amine regioselectivity, generates the amino alcohol of required formula I-b.This transformation can adopt any regioselectivity open-loop method that is usually used in uncle's epoxide.According to the preferred embodiments of the invention, in sealed flask, with formula 13 compounds with the alcohol excess amine aqueous solution under the room temperature or be heated to about 40 ℃ and handle to about 90 ℃ situation.Can utilize ordinary method that formula I-b compound is converted into pharmacy acceptable salt.
Scheme II
Figure A20058001737800731
Wherein: A, Y, Z, R 1, n, R 2, R 4, R 8, R 10Be as previously described, R 9Be H, PNB=p-nitrophenyl formyl radical or any GPF (General Protection False group, and OMs=methylsulfonic acid ester group or any conventional leavings group.
Production I-bb compound if desired, can by formula I-b compound via the alkylation of the protection of amine, secondary alcohol and amine go the protection preparation they (scheme III).This transformation can adopt any protection of amine, the alkylation of secondary alcohol and de-protected method of amine of being usually used in.According to the preferred embodiments of the invention, formula I-b compound is handled with the boc acid anhydrides, boc=tertbutyloxycarbonyl wherein, production 14 compounds, it can use sodium hydride as alkali alkylogen alkylation, production 15 compounds.Use the dichloromethane solution of acid, preferred trifluoroacetic acid to realize going protection, production I-bb compound, this compound can utilize ordinary method to be converted into pharmacy acceptable salt.
Scheme III
Wherein: A, Y, Z, R 1, n, R 2, R 4, R 8, R 10Be as previously described, R 9Be H, R 3=C 1-C 3Low alkyl group, P=blocking group, preferred tertiary butoxy carbonyl.
The zone of formula 17 epoxide that suitably replace with formula 16 compounds of suitable replacement (epoxidation via the allylic alcohol of suitable replacement generates)-with solid-selective opening, production 4 compounds (scheme IV).This transformation can adopt any zone that is usually used in epoxide-with the method for solid-selective opening.According to the preferred embodiments of the invention, with formula 16 compound alkali, for example sodium hydride, sodium tert-butoxide, potassium hydroxide, potassium tert.-butoxide or potassium hydroxide treatment are handled with formula 17 epoxide then.Formula 17 epoxide can be used Lewis acid, and for example pre-treatment such as titanium isopropylate, boron trifluoride is to guarantee zone-selective opening.React on to go through under the room temperature and carried out in about 2 hours to about 72 hours.Select as an alternative, formula 16 compounds, for example indoline and formula 17 epoxide of suitable nucleophilicity can be heated production 4 compounds at about 50 ℃ to about 170 ℃ temperature.
Utilize the described method of document, can carry out the epoxidation of trans-allylic alcohol with racemize or asymmetric mode.According to the preferred embodiments of the invention, carry out racemation epoxyization with peracetic acid or metachloroperbenzoic acid.The single enantiomer of production I compound can carry out the asymmetric Epoxidation of allylic alcohol with t-butyl hydroperoxide or cumene hydroperoxide in the presence of suitable tartrate, titanium isopropylate (IV) and molecular sieve if desired.This method is sophisticated literature method (for example people such as K.B.Sharpless, J.Org.Chem.1986,51,3710).Formula 16 compounds and initial allylic alcohol are commercially available or make by sophisticated literature method.
Scheme IV
Wherein: A, Y, Z, R 1, n, R 8, R 9, R 10And R 2Be as previously described.
In other embodiments, the present invention relates to pharmaceutical composition, it comprises:
A. at least a formula I compound or its pharmacy acceptable salt; With
B. at least a pharmaceutically acceptable carrier.
Generally speaking, based on the gross weight of pharmaceutical composition, formula I compound or its pharmacy acceptable salt will exist to the level of about 90 weight % with about 0.1 weight %.Preferably, based on the gross weight of pharmaceutical composition, formula I compound or its pharmacy acceptable salt will exist with the level at least about 1 weight %.More preferably, based on the gross weight of pharmaceutical composition, formula I compound or its pharmacy acceptable salt will exist with the level at least about 5 weight %.And then more preferably, based on the gross weight of pharmaceutical composition, norepinephrine reuptake inhibitor or its pharmacy acceptable salt will exist with the level at least about 10 weight %.And then more preferably, based on the gross weight of pharmaceutical composition, formula I compound or its pharmacy acceptable salt will exist with the level at least about 25 weight %.
This based composition is according to acceptable pharmacy prepared, and for example following document is described: Remington ' s Pharmaceutical Sciences, 17th edition, editor Alfonoso R.Gennaro, Mack Publishing Company, Easton, PA (1985).Pharmaceutically acceptable carrier be with preparation in other composition compatible and biologically acceptable those.
The compounds of this invention can be with the oral or administered parenterally separately or with the form of conventional medicine carrier combinations.The available solid carrier can comprise that one or more also can serve as the material of correctives, lubricant, solubilizing agent, suspension agent, weighting agent, glidant (glidant), compression aids, tackiness agent or tablet disintegrant or encapsulating material, they.In pulvis, carrier is a solid in small, broken bits, and it and activeconstituents in small, broken bits mix.In tablet, activeconstituents and the carrier with necessary compressing tablet character by the mixed that is fit to, are pressed into required shape and size.Pulvis and tablet preferably contain 99% activeconstituents at the most.The solid carrier that is fit to for example comprises calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Liquid vehicle can be used to prepare solution, suspension, emulsion, syrup and elixir.Activeconstituents of the present invention can be dissolved or suspended in the pharmaceutically acceptable liquid vehicle, for example water, organic solvent, the two mixture or pharmaceutically acceptable oil or fat.Liquid vehicle can contain other medicated premix that is fit to, for example solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, correctives, suspension agent, thickening material, pigment, viscosity modifier, stablizer or Osmolyte regulator.The example that is suitable for the liquid vehicle of oral and administered parenterally comprises that water (particularly contains above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol, for example glycol) and derivative and oil (for example fractionated coconut oil and peanut oil).With regard to administered parenterally, carrier also can be oily ester, for example ethyl oleate and Isopropyl myristate.Sterile liquid carrier is used in the sterile liquid form composition of administered parenterally.
Composition of liquid medicine is aseptic solution or suspension, for example can be by intramuscular, intraperitoneal or subcutaneous injection administration.Sterile solution also can be by intravenous administration.Oral administration can be a liquid or solid composition mode.
Preferably, pharmaceutical composition is a presented in unit dosage form, for example tablet, capsule, pulvis, solution, suspendible liquor, emulsion agent, granule or suppository.In this class form, composition is subdivided into the dosage unit that contains an amount of activeconstituents; Presented in unit dosage form can be the band packaged composition, for example pockaged powder, bottle, ampoule, pre-filled syringe or contain the anther sac of liquid.Presented in unit dosage form for example can be capsule or a tablet itself, perhaps can be the packaged form of an amount of any this based composition.
In another embodiment of the invention, can be used for compound of the present invention can be with one or more other medicines activeconstituentss to the Mammals administration, for example with those compositions that are used for the treatment of any other medical conditions that is present in this Mammals.The example of this class active constituents of medicine comprises pain relief agents, anti-angiogenic agent, antineoplastic agent, antidiabetic, anti-infection agent or stomach and intestine agent or their combination.
One or more other medicines activeconstituentss can (for example separate simultaneously, perhaps together in pharmaceutical composition) and/or administration successively simultaneously by treatment significant quantity and one or more The compounds of this invention.
The administration for treatment therapeutic illness described herein or obstacle of two or more therapeutical agents or compound represented in term " conjoint therapy ", for example is treatment upsurge, sweating, thermoregulation dependency illness or obstacle or other.This class administration comprises the therapeutical agent with every type of parallel mode use.In both cases, treatment system will provide drug regimen to treat the beneficial effect of illness described herein or obstacle.
The approach of administration can be any approach, effectively formula I active compound or its pharmacy acceptable salt are delivered to suitable or required site of action, for example via oral, nose, lung, transdermal (for example passive or iontophoretic delivery) or parenteral (for example in rectum, bank, subcutaneous, intravenously, the urethra, in intramuscular, the nose, ophthalmic solution or ointment).In addition, the administration of formula I compound or its pharmacy acceptable salt and other activeconstituents can be walk abreast or simultaneously.
Believe described the present invention in the treatment of conditions of improving because of monoamine reuptake, alleviate, inhibition and/or prevention area present substantive breakthroughs, described illness especially comprises vasomotor symptoms (VMS), sexual dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combination thereof, particularly is selected from down those illnesss of group: major depression, vasomotor symptoms, tonus and the impulsion urinary incontinence, myofiber pain, pain, diabetic neuropathy and their combination.
Therefore, in one embodiment, the present invention relates to the method for the illness that in the curee who needs is arranged treatment or prevention improve because of monoamine reuptake, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.The illness of improving because of monoamine reuptake comprises those that are selected from down group: vasomotor symptoms, sexual dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and combination thereof particularly are selected from down those illnesss of organizing: major depression, vasomotor symptoms, tonus and the impulsion urinary incontinence, myofiber pain, pain, diabetic neuropathy and their combination.
" vasomotor symptoms ", " vasomotion can not symptom " and " vasomotion disorder " include but not limited to upsurge (flush), insomnia, sleep disordered, mood disorder, excitement, excessively perspiration, night sweat, fatigue etc., are especially caused by the thermoregulation obstacle.
Term " upsurge " is art-recognized term, and the paroxysmal disorder of expression organism temperature is made up of the flush of burst usually, common perspiration with the curee.
Term " sexual dysfunction " includes but not limited to the illness that relates to sexual desire and/or arouse.
" stomach and intestine and urogenital obstacle " used herein comprises irritable bowel syndrome, symptomatic GERD, the supersensitivity esophagus, non-ucler dyspepsia, non-heart source property chest pain, biliary dyskinesia, the choledochal sphincter dysfunction, incontinence (impulsion property incontinence just, the tonus incontinence, true sexual tension incontinence and mixed type incontinence) (comprise the nonautonomy discharging of stool and urine, with the oozing or spilling of stool and urine, this may include but not limited to the control of pathological change sphincter muscle owing to one or more reasons, the cognitive function forfeiture, bladder excessive expands, hyperreflexia and/or nonautonomy urethra are lax, weak with bladder or the unusual relevant muscle of neurological), interstitial cystitis (irritable bladder) and chronic pelvic pain (include but not limited to vulvodynia, prostatodynia and rectalgia).
" chronic fatigue syndrome " used herein is to be the illness of feature to be selected from following physiology symptom (CFS): weak, myalgia, excessively sleep, discomfort, heating, throat pain, lymphoglandula tenderness, remember and/or concentrate go down, insomnia, somnopathy, localization's tenderness, dispersivity pain and fatigue and their combination.
" fibromyalgia syndrome " used herein (FMS) comprises and FMS and other somatoform disorder (somatoform disorder) comprises the FMS relevant with following illness: depression, health disease (somatization disorder), conversive disorder, painful obstacle, hypochondriasis, drive the body deformability sexual dysfunction, do not break up health form disease (undifferentiated somatoform disorder) and somatic form NOS.FMS and other somatoform disorder are with being selected from following physiology symptom: pain perception of the height perception of generalization sensory stimuli, the pain perception of allodynia form unusual (innocuousness stimulation pain), hyperpathia form unusual (having pain to stimulate susceptibility to increase) and their combination.
" nervous system disorders " used herein comprises that assuetude disturbance (comprises by alcohol, those that nicotine and other psychoactive drug substance cause) and withdrawal syndrome, study relevant and mental disorder (comprising Alzheimer) with the age, anorexia nervosa, bulimia nervosa, with or do not have a distractibility obstacle of hyperactivity obstacle, the two-phase mental disorder, pain, the cycloophrenia obstacle, dysthymia disorders (comprises major depression, refractory depression, the teenager is depressed and slight depressed), dysthymia sexual dysfunction, generalized-anxiety disorder (GAD), fat (just alleviating fat or overweight patient's body weight), obsessional idea and behavior disorder and relevant obstacles, the provocative obstacle of antagonism, panic disorder, post-traumatic stress disorder, through preceding irritated sexual dysfunction (just premenstrual syndrome and corpus luteum irritated sexual dysfunction in late period), psychotic disorders (comprises schizophrenia, Schizoaffective and schizophrenia-like disorder), seasonal affective disorder, somnopathy (for example the paroxysmal sleep and the enuresis), social phobia (comprising social anxiety disorder), the selective serotonin reuptake suppresses (SSRI) " fatigue " syndrome and (that is to say, after the gratifying response of starting stage, the patient can not keep gratifying SSRI therapy response).
" pain " used herein comprises acute pain and chronic pain, and it can be central pain, periphery pain or their combination.This term comprises a lot of dissimilar pain, include but not limited to neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain, inflammatory pain and their combination, for example low back pain, atypical chest pain, headache (for example bunch headache), migraine, bleb neurodynia, phantom limb pain, pelvic pain, the muscular fascia face ache, abdominal pain, cervical pain, central pain, tooth pain, opium tolerance pain, visceral pain, operation pain, bone injury pain, produce pain with farrowing interval, pain caused by burning, postpartum pain, angina pain, neuropathic pain (for example peripheral neurophaty and diabetic neuropathy), postoperative pain and with the get involved pain of (comorbid) of nervous system disorders described herein.
A kind of like this central of term used herein " acute pain " expression or periphery pain, it is intensive, localization, sharp-pointed or stinging, and/or attribute blunt, pain, disperse or that burn, and time of origin is short.
Term used herein " chronic pain " a kind of like this central of expression or periphery pain, it is intensive, localization, sharp-pointed or stinging, and/or attribute blunt, pain, disperse or that burn, and time of origin long (just persistence and/or generation repeatedly regularly) comprises neuropathic pain and cancer pain for the purpose of the present invention.Chronic pain comprises neuropathic pain, hyperpathia and/or allodynia.
Term used herein " neuropathic pain " expression changes the chronic pain that is caused by periphery or central nervous system injury or pathologic.The example that relates to the pathologic change of neuropathic pain comprises long-term periphery or axoneuron sensitization, relates to the maincenter sensitization of neural system inhibition and/or expression power function damage and the abnormal interaction between parasympathetic and the sympathetic nervous system.Clinical disease all may be relevant with neuropathic pain or be constituted its basis widely, for example comprise diabetes, pain after the amputation wound is (by the nerve injury that damage caused that causes periphery and/or maincenter sensitization, phantom limb pain for example), low back pain, cancer, chemical damage, toxin, other capital operation, oppress the peripheral nerve injury that causes by traumatic damage, postherpetic neuralgia, trigeminal neuralgia, waist or Cervical radiculopathy, myofiber pain, glossopharyngeal neuralgia, reflectivity associability malnutrition, accidental pain, thalamic syndrome, nerve root avulsion, reflectivity associability malnutrition or thoracotomy postoperative pain, auxotrophy, perhaps virus or infectation of bacteria, for example zoster or human immunodeficiency virus (HIV) and their combination.In the definition of neuropathic pain, also comprise the illness that is secondary to following illness: transitivity infiltration, adiposis dolorosa, the central pain illness of burning, relate to the thalamus illness and their combination.
The pain that term used herein " hyperpathia " expression wherein exists typical destructive stimulus susceptibility to increase.
The typical non-destructive stimulus susceptibility of term used herein " allodynia " expression increases.
Term used herein " visceral pain " expression is relevant with internal's disease or by the pain that it caused, for example ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn disease, rheumatosis (arthrodynia), tumour, gastritis, pancreatitis, organ infection, biliary tract obstacle and their combination.
The pain that term used herein " the distinctive pain of women " expression is relevant with women's illness can be acute and/or chronic pain.This group pain only comprises or is mainly those that the women runs into, comprises the pain relevant with following factors: menstruation, ovulation, gestation or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, ovarian follicle or rupture of corpus luteum cyst, the pelvis internal organ stimulate, hysteromyoma, endometriosis (adenomyosis), endometriosis (endometriosis), infect and inflammation, pelvic organs's ischemic, block, intra-abdominal adhesions, the dissection distortion of pelvis internal organ, ovarian abscess, the pelvic support forfeiture, tumour, pelvis congested or the pain of non-gynaecology reason and their combination.
In one embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for vasomotor symptoms, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
When low or oestrogenic hormon did not exist when estrogen level, the normal level between NE and the 5-HT changed, and the change of this neurotransmitter levels may cause the variation of heat-regulating centers susceptibility.The chemical level that changes can be translated as hotness and response in heat-regulating centers, hypothalamus can activate descending autonomous approach, causes via the heat dissipation (upsurge) of vasorelaxation and sweating (Fig. 1).Therefore, estrogen deficiency may cause the norepinephrine activity change.
The nerve ending place of synthetic norepinephrine in hypothalamus and brain stem is released in the brain stem perikaryon.In hypothalamus, NE regulates the neuronic activity that is present in the heat-regulating centers.In brain stem, NE arranges serotonergic neurone (5-HT), via adrenergic α 1With adrenergic α 2Postsynaptic receptor plays a role, and stimulates the activity of serotonergic systems.In response, the 5-HT neurone is also regulated and control the activity and the neuronic feedback of NE of heat-regulating centers.Via this feedback relationship, via 5-HT 2aThe 5-HT that acceptor plays a role suppresses the neuronic activity of NE.The NE translocator (NET) that norepinephrine in the synaptic cleft also is positioned in the NE neurone absorbs.Translocator makes NE recirculation, makes it can be used for repeatedly neurotransmission (Fig. 2).
The present invention provides treatment to vasomotor symptoms by the active method of having recovered to reduce of norepinephrine.Can raise in the hypothalamus or norepinephrine activity in the brain stem by following manner: (i) activity of retardance NE translocator, (ii) with antagonist retardance presynaptic adrenergic α 2The activity of acceptor is perhaps (iii) used 5-HT 2a5-HT is to the neuronic activity of NE in the antagonist retardance.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for dysthymia disorders, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In other embodiments, the present invention relates to treatment or preventative handicapped method in the curee who needs is arranged, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for stomach and intestine or urogenital obstacle, particularly tonus incontinence or the impulsion property urinary incontinence, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for chronic fatigue syndrome, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In another embodiment, the present invention relates in the curee who needs is arranged, treat or prevent the method for fibromyalgia syndrome, comprise giving the formula I compound of significant quantity or the step of its pharmacy acceptable salt described curee.
In further embodiment, the present invention relates to the method for in the curee who needs is arranged treatment or prevent irritation, comprise giving at least a formula I compound of significant quantity or the step of its pharmacy acceptable salt to described curee.
Pain for example can be acute pain (short-term) or chronic pain (taking place repeatedly regularly or persistence).Pain also can be central or periphery.
May be acute or chronic and can comprise inflammatory pain, musculoskeletal pain, bone pain, lumbus sacrum pain, neck according to the example of the pain of the inventive method treatment or go up back pain, visceral pain, body pain, neuropathic pain, cancer pain, by damage or perform the operation pain caused (pain of for example burning or tooth pain) or have a headache (for example migraine or tension headache) or the combination of these pain.Those skilled in the art will recognize that these pain may overlap each other.For example, pain caused by inflammation also may be internal organ or muscle skeleton attribute.
In a preferred embodiment of the invention, in Mammals, can be used for compound of the present invention, with the treatment chronic pain, for example: for example with periphery or central nervous system injury or the relevant neuropathic pain of pathological change; Cancer pain; For example with peritonaeum, pelvis and/or perineal region or the relevant visceral pain of pancreatitis; For example with lower back portion or last back, backbone, myofiber pain, temporomandibular joint (TMJ) or the relevant musculoskeletal pain of myofasical pain syndrome; The bone pain of for example relevant for example osteoarthritis, rheumatoid arthritis or spinal stenosis with bone or joint degeneration obstacle; Headache, for example migraine or tonus pain; Perhaps with for example infect HIV, sicklemia, autoimmunization obstacle, multiple sclerosis or inflammation for example osteoarthritis or the relevant pain of rheumatoid arthritis.
In a more preferred embodiment, can be used for compounds in treating chronic pain of the present invention according to the methods described herein use, this pain is neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain or inflammatory pain or their combination.Inflammatory pain may be relevant with multiple medical conditions, for example with osteoarthritis, rheumatoid arthritis, operation or damage relevant.Neuropathic pain may be relevant with following illness: diabetic neuropathy for example, peripheral neurophaty, postherpetic neuralgia, trigeminal neuralgia, waist or uterine neck radiculopathy, myofiber pain, glossopharyngeal neuralgia, reflectivity associability malnutrition, accidental pain, thalamic syndrome, nerve root avulsion, perhaps by the nerve injury that damage caused that causes periphery and/or maincenter sensitization (for example phantom limb pain), reflectivity associability malnutrition or thoracotomy postoperative pain, cancer, chemical damage, toxin, auxotrophy, perhaps virus or infectation of bacteria (for example zoster or HIV), perhaps their combination.The using method of The compounds of this invention comprises that further wherein neuropathic pain is to be secondary to following treatment of conditions: transitivity infiltration, adiposis dolorosa, burn or relate to the central pain illness of thalamus illness.
Just as mentioned previously, the inventive method can be used for the treatment of the pain of body and/or internal organ attribute.For example, can comprise according to the body pain of the inventive method treatment with surgery, dental operation, burn or traumatic body injury during experienced structural or pain that soft tissue injury is relevant.Can comprise relevant according to the example of the visceral pain of the inventive method treatment or by the pain that it caused, for example ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn disease, rheumatosis (arthrodynia), tumour, gastritis, pancreatitis, organ infection or biliary tract obstacle or their combination with internal's disease.Those skilled in the art will recognize that, according to the pain of the inventive method treatment also may relate to hyperpathia, allodynia or this two.In addition, chronic pain may with or do not have periphery or a maincenter sensitization.
Can be used for compound of the present invention and also can be used for the treatment of the acute and/or chronic pain relevant with women's illness, these pain also can be called as the distinctive pain of women.This group pain only comprises or is mainly those that the women runs into, comprises the pain relevant with following factors: menstruation, ovulation, gestation or childbirth, miscarriage, ectopic pregnancy, retrograde menstruation, ovarian follicle or rupture of corpus luteum cyst, the stimulation of pelvis internal organ, hysteromyoma, endometriosis (adenomyosis), endometriosis (endometriosis), infection and inflammation, pelvic organs's ischemic, block, the pain of dissection distortion, ovarian abscess, pelvic support forfeiture, tumour, pelvis hyperemia or the non-gynaecology reason of intra-abdominal adhesions, pelvis internal organ.
In the following example, further limit the present invention, wherein all umbers and per-cent all by weight, temperature is degree centigrade, but have in addition regulation except.The preferred embodiments of the invention have been shown although should be appreciated that these embodiment, only for illustrating.From above-mentioned discussion and these embodiment, those skilled in the art can determine essential feature of the present invention, under the prerequisite that does not deviate from its spirit and scope, can make variations and modifications to invention, to adapt to various application and condition.
Embodiment
Embodiment 1:(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol dihydrochloride
Step 1: (2.34g, 20mmol) (1.12g, mixture 20mmol) is in stirring 30 minutes under nitrogen atmosphere under the room temperature with the solid potassium hydroxide of pulverizing with indoles.(3.0g, the 20mmol) solution in dimethyl sulfoxide (DMSO) (1mL) stir mixture 2 hours down at 70 ℃, until there not being the epoxide residue to add trans-3-phenyl glycidyl then.With the mixture cooling, between water and methylene dichloride, distribute then.Separate organic layer, wash several times with water,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 10%, 20%, 30% ethyl acetate/hexane), and (2RS, 3RS)-3-indoles-1-base-3-phenyl-propane-1, the 2-glycol is oil to obtain 1.92g (36%). 1HNMR(DMSO)：δ3.27(m，2H，CH 2OH)，δ4.45(m，1H，CHOH)，δ4.80(t，1H，CH 2OH)，δ5.20(d，1H，CHOH)，δ5.60(d，1H，CHPh)；MS(ESI)m/z 268([M+H] +).
Step 2: will (2RS, 3RS)-3-indoles-1-base-3-phenyl-propane-1, (1.83g, 6.8mmol) (1.31g, 6.8mmol) solution in anhydrous pyridine (10mL) is in stirring 15 hours under nitrogen atmosphere under the room temperature with Tosyl chloride for the 2-glycol.With mixture water (10mL) dilution, in ice/water-bath,, be pH=3 until solution, and use dichloromethane extraction then with the cancellation of 2N aqueous hydrochloric acid.Organic layer is washed with water once more,, filter, concentrate through anhydrous sodium sulfate drying.Resistates is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 10%, 25% EtOAc/ hexane), and (2RS 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-phenyl propyl ester, is white solid to obtain 1.98g (69%). 1HNMR(DMSO)：δ3.70and δ3.85(dd and dd，2H，CH 2OTs)，δ4.80(m，1H，CHOH)，δ5.52(d，1H，CHPh)，δ5.82(d，1H，CHOH)；MS(ESI)m/z 422([M+H] +).
Step 3: with (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-phenyl propyl ester (0.185g, 0.4mmol), 1-methylpiperazine (0.05mL, 0.4mmol) (0.07g, 0.44mmol) mixture in acetonitrile (10mL) stirred 24 hours under nitrogen atmosphere under refluxing with salt of wormwood.After the cooling, mixture is filtered, concentrated filtrate, via Biotage chromatography purification (5% ethanol/methylene), obtain (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol, be white solid.Free alkali being dissolved in small amount of ethanol, handling with the ethereal solution of 1N hydrochloric acid, is pH=3 until solution, handles with ether then.Add a small amount of hexane then and make the product crystallization, obtain title compound, (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol dihydrochloride, be pale solid.MS m/z 350 ([M+H] +); HRMS: calculated value C 22H 27N 3O+ H+, 350.22269; Measured value (ESI, [M+H]+), 350.2228.
Embodiment 2:(1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol dihydrochloride
By 5-fluoro indole and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 1 step 1 that (2RS, 3RS)-3-(5-fluoro-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 286([M+H] +)。
By (2RS, 3RS)-3-(5-fluoro-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-fluoro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 440([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-fluoro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol dihydrochloride.
MS m/z 368 ([M+H] +); HRMS: calculated value C 22H 26FN 3O+ H+, 368.21327; Measured value (ESI, [M+H]+), 368.213.
Embodiment 3:(1RS, 2SR)-1-(1H-indoles-1-yl)-3-morpholine-4-base-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800852
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3) and morpholine, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ESI) m/z 337 ([M+H] +); HRMS: calculated value C 21H 24N 2O 2+ H+, 337.19105; Measured value (ESI, [M+H]+), 337.1909.
Embodiment 4:(1RS, 2SR)-3-(dimethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800861
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3) and dimethylamine hydrochloride, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-3-(dimethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ES) m/z 295.2 ([M+H] +); HRMS: calculated value C 19H 22N 2O+ H+, 295.18049; Measured value (ESI, [M+H]+), 295.1829.
Embodiment 5:(1RS, 2SR)-3-(ethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
According to the mode that is similar to embodiment 1 step 3, will (2RS, 3RS)-(embodiment 1 for toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-phenyl propyl ester, step 3,0.42g 1.0mmol) (2N methanol solution, solution 5mL) stirred 15 hours in sealed flask, under room temperature with ethamine.After the saturated sodium bicarbonate aqueous solution dilution, mixture is extracted with methylene dichloride/aqueous isopropanol (3/1).Extraction liquid is washed with water,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying.Crude product obtains oil via Biotage chromatography purification (FlasH40i, silicon-dioxide, methylene dichloride, 5% ethanol/methylene), is the free alkali of expection product.Free alkali being dissolved in small amount of ethanol, handling with the ethereal solution of 1N hydrochloric acid, is pH=3 until solution, handles with ether then.Add amount of ethyl acetate then and make the product crystallization, (1RS 2SR)-3-(ethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, is pale brown look solid to obtain title compound.MS (ES) m/z 295.2 ([M+H] +); HRMS: calculated value C 19H 22N 2O+H+, 295.18049; Measured value (ESI, [M+H]+), 295.1797.
Embodiment 6:(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(sec.-propyl amino)-1-phenyl-propane-2-alcohol hydrochloride
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3) and Isopropylamine, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(sec.-propyl amino)-1-phenyl-propane-2-alcohol hydrochloride.MS (ES) m/z 309.2 ([M+H] +); HRMS: calculated value C 20H 24N 2O+ H+, 309.19614; Measured value (ESI, [M+H]+), 309.1971.
Embodiment 7:(1RS, 2SR)-3-(benzylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3) and benzylamine, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-3-(benzylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ES) m/z 357.2 ([M+H] +); HRMS: calculated value C 24H 24N 2O+ H+, 357.19614; Measured value (ESI, [M+H]+), 357.1962.
Embodiment 8:(1RS, 2SR)-the 3-[(cyclohexyl methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800873
Prepare (1RS according to the mode that is similar to embodiment 1 step 3,2SR)-and the 3-[(cyclohexyl methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, by (2RS, 3RS)-(embodiment 1, step 3) and cyclohexyl methyl amine for toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-phenyl propyl ester.
MS (ES) m/z 363.3 ([M+H] +); HRMS: calculated value C 24H 30N 2O+ H+, 363.24309; Measured value (ESI, [M+H]+), 363.2421.
Embodiment 9:(1RS, 2SR)-the 3-[(cyclohexyl methyl) amino]-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By 3-skatole and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 1 step 1 that (2RS, 3RS)-3-(3-skatole-1-yl)-3-phenyl-propane-1, the 2-glycol is yellow solid.MS(ESI)m/z 282([M+H] +)。
By (2RS, 3RS)-3-(3-methyl-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2RS, 3RS)-toluene-4-sulfonic acid 3-(3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 436([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and cyclohexyl methyl amine, prepare (1RS, 2SR)-3-[(cyclohexyl methyl) amino according to the mode that is similar to embodiment 1 step 3]-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ES) m/z 377.3 ([M+H] +); HRMS: calculated value C 25H 32N 2O+ H+, 377.25874; Measured value (ESI, [M+H]+), 377.2577.
Embodiment 10:(1RS, 2SR)-3-(sec.-propyl amino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By (2RS, 3RS)-(3-methyl-indoles-1-yl)-(embodiment 12 for 2-hydroxyl-3-phenyl-propyl diester for toluene-4-sulfonic acid 3-, step 2) and Isopropylamine, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-3-(sec.-propyl amino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 323.2 ([M+H] +); HRMS: calculated value C 21H 26N 2O+ H+, 323.21179; Measured value (ESI, [M+H]+), 323.2135.
Embodiment 11:(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800891
By (2RS, 3RS) toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-yl)-(embodiment 1 for 3-phenyl-propyl diester, step 3) and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.
MS(ESI)m/z 281([M+H] +)；
HRMS: calculated value C 18H 20N 2O+ H+, 281.16484; Measured value (ESI, [M+H]+), 281.166.
Embodiment 12:(1RS, 2SR)-3-(ethylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800892
By (2RS, 3RS)-(3-methyl-indoles-1-base-(embodiment 12 for 2-hydroxyl-3-phenyl-propyl diester for toluene-4-sulfonic acid 3-, step 2) and ethamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1RS, 2SR)-3-(ethylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 309 ([M+H] +); HRMS: calculated value C 20H 24N 2O+ H+, 309.19614; Measured value (ESI, [M+H]+), 309.198.
Embodiment 13:(1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-piperazine-1-base propane-2-alcohol dihydrochloride
Figure A20058001737800893
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3,0.211g, 0.5mmol) and the 1-piperazinecarboxylic acid tert-butyl ester (0.19g, 1.0mmol), according to the mode that is similar to embodiment 1 step 3 prepare (2SR, 3RS)-4-(2-hydroxyl-3-indoles-1-base-3-phenyl-propyl group)-piperazine-1-t-butyl formate.Product is dissolved in ether (3mL), uses 4N hydrochloric acid in two  alkane (0.75mL, 3.0mmol) solution-treated in.Then reaction mixture was stirred under room temperature 15 hours, filter thick solid product, recrystallization from the ethanol that contains a small amount of ether obtains title compound (1RS, 2SR)-and 1-(1H-indoles-1-yl)-1-phenyl-3-piperazine-1-base propane-2-alcohol dihydrochloride, be pale brown look solid.MS(ESI)m/z 336
([M+H] +); HRMS: calculated value C 21H 25N 3O+ H+, 336.20704; Measured value (ESI, [M+H]+), 336.2085.
Embodiment 14:(1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-[(pyridin-4-yl methyl) amino] propane-2-alcohol hydrochloride
Figure A20058001737800901
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3) and pyridin-4-yl-methylamine, prepare (1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-[(pyridin-4-yl methyl) amino according to the mode that is similar to embodiment 1 step 3] propane-2-alcohol hydrochloride.
MS(ESI)m/z 358([M+H] +)；
HRMS: calculated value C 23H 23N 3O+H+, 358.19139; Measured value (ESI, [M+H]+), 358.1928.
Embodiment 15:(1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-1-phenyl-3-piperidines-1-base propane-2-alcohol hydrochloride
By 5-chloro-indole and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 1 step 1 that (2RS, 3RS)-3-(5-chloro-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 302([M+H] +)。
By (2RS, 3RS)-3-(5-chloro-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-chloro-indoles-1-base-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 456([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-chloro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and piperidines, according to the mode that is similar to embodiment 1 step 3 prepare (1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-1-phenyl-3-piperidines-1-base propane-2-alcohol hydrochloride.
MS m/z 369 ([M+H] +); HRMS: calculated value C 22H 25ClN 2O+ H+, 369.17282; Measured value (ESI, [M+H]+), 369.1725.
Embodiment 16:(1RS, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800911
Step 2: under-10 ℃, to (2RS, 3RS)-3-indoles-1-base-3-phenyl-propane-1, (embodiment 1, step 1,1.83g for the 2-glycol, 6.9mmol) anhydrous pyridine (25mL) solution in drip paranitrobenzoyl chloride (1.3g, 6.9mmol) solution in the 1mL pyridine.Stir after 30 minutes, reaction mixture is cooled off with ice bath, water and the cancellation of 2N aqueous hydrochloric acid are pH=3 until solution, use ethyl acetate extraction.Extraction liquid is washed with water,, concentrate through anhydrous sodium sulfate drying, quantitatively obtain (2RS, 3RS)-4-nitro-phenylformic acid 2-hydroxyl-3-indoles-1-base-3-phenyl propyl ester, be yellow solid.MS(ESI)m/z 417([M+H] +)。
Step 3: under 0-5 ℃, under agitation to (2RS, 3RS)-4-nitro-phenylformic acid 2-hydroxyl-3-indoles-1-base-3-phenyl propyl ester and triethylamine (1.4mL, 10.5mmol) drip in the solution in methylene dichloride (20mL) methylsulfonyl chloride (0.59mL, 7.6mmol).Stir after 30 minutes, mixture with 1N aqueous hydrochloric acid, 5% sodium bicarbonate aqueous solution and water washing, through anhydrous sodium sulfate drying, is filtered, concentrate, obtain light yellow fine hair shape solid.Make crude product recrystallization from the methylene dichloride that contains a small amount of ether, obtain (2RS, 3RS)-4-nitro-phenylformic acid 3-indoles-1-base-2-mesyloxy-3-phenyl propyl ester, be yellow solid.MS(ESI)m/z 495([M+H] +)。
Step 4: will (2RS, 3RS)-solution and the 2N aqueous sodium hydroxide solution (15mL) of 4-nitro-phenylformic acid 3-indoles-1-base-2-mesyloxy-3-phenyl propyl ester in two  alkane solution (30mL) stirred 4 hours under room temperature.With the mixture dilute with water, use ethyl acetate extraction.Extraction liquid with 5% aqueous sodium carbonate and water washing, through anhydrous sodium sulfate drying, is filtered, concentrate, obtain (1RS, 2SR)-1-(Oxyranyle-phenyl-methyl)-1H-indoles, be oil.MS(ESI)m/z 250([M+H] +)。
Step 5: under room temperature under agitation will (1RS, 2SR)-1-(Oxyranyle-phenyl-methyl)-the 1H-indoles handled 15 hours with 5mL methylamine (2N methanol solution).Concentrated reaction mixture makes crude product recrystallization from methylene dichloride in a vacuum.The free alkali of expection product being dissolved in a small amount of methylene dichloride, handling with the ethereal solution of 1N hydrochloric acid, is pH=3 until solution.Add other ether then and make the solid product recrystallization, obtain (1RS, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be the sundown solid.
MS m/z 281 ([M+H] +); HRMS: calculated value C 18H 20N 2O+ H+, 281.16484; Measured value (ESI, [M+H]+), 281.1654.
Embodiment 17:(1RS, 2SR)-3-amino-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800921
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-(embodiment 1 for 3-phenyl propyl ester, step 3,0.42g, 1.0mmol) solution in small amount of methanol and excessive 30% ammonium hydroxide aqueous solution, according to the mode that is similar to embodiment 5 prepare (1RS, 2SR)-3-amino-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.Crude product is dissolved in normal hexane, filters, obtain white solid, be free alkali.The free alkali of product being dissolved in small amount of ethanol, handling with the ethereal solution of 1N hydrochloric acid, is pH=3 until solution, handles with ether then.Add amount of ethyl acetate then and make the product crystallization, obtain title compound, be pale brown look solid.
MS (ESI) m/z 267 ([M+H] +); HRMS: calculated value C 17H 18N 2O+ H+, 267.14919; Measured value (ESI, [M+H]+), 267.1493.
Embodiment 18:(1RS, 2SR)-3-(ethylamino)-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800931
By (2RS, 3RS)-(5-fluoro-indoles-1-base-(embodiment 2 for 2-hydroxyl-3-phenyl-propyl diester for toluene-4-sulfonic acid 3-, step 2) and ethamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1RS, 2SR)-3-(ethylamino)-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ES) m/z313.2 ([M+H] +); HRMS: calculated value C 19H 21FN 2O+ H+, 313.17107; Measured value (ESI, [M+H]+), 313.1706.
Embodiment 19:(1RS, 2SR)-3-amino-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By (2RS, 3RS) (5-fluoro-indoles-1-base-(embodiment 2 for 2-hydroxyl-3-phenyl-propyl diester for toluene-4-sulfonic acid 3-, step 2) and 30% ammonium hydroxide aqueous solution, prepare (1RS according to the mode that is similar to embodiment 17,2SR)-and 3-amino-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.
MS (ES) m/z 285.2 ([M+H] +); HRMS: calculated value C 17H 17FN 2O+ H+, 285.13977; Measured value (ESI, [M+H]+), 285.1403.
Embodiment 20:(1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
(2RS by gained, 3RS)-(5-fluoro-indoles-1-base-(embodiment 2 for 2-hydroxyl-3-phenyl-propyl diester for toluene-4-sulfonic acid 3-, step 2) and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ESI) m/z 299 ([M+H] +); HRMS: calculated value C 18H 19FN 2O+ H+, 299.15542; Measured value (ESI, [M+H]+), 299.1564.
Embodiment 21:(1RS, 2SR)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800941
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(3-methyl-indoles-1)-Ji-(embodiment 10 for 2-hydroxyl-3-phenyl-propyl diester, step 2) and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1RS, 2SR)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.
MS (ESI) m/z295 ([M+H] +); HRMS: calculated value C 19H 22N 2O+ H+, 295.18049; Measured value (ESI, [M+H]+), 295.1816.
Embodiment 22:(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By indoles and [(2S, 3S)-3-phenyl ethylene oxide-2-yl] methyl alcohol, prepare according to the mode that is similar to embodiment 1 step 1 that (2R, 3R)-3-indoles-1-base-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 286([M+H] +)。
By (2R, 3R)-3 indoles-1-base-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2R, 3R)-toluene-4-sulfonic acid 3-indoles-1-base-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 440([M+H] +)。
By (2R, 3R) toluene-4-sulfonic acid 3-indoles-1-base-2-hydroxyl-3-phenyl-propyl diester and methylamine (2N methanol solution), prepare according to the mode that is similar to embodiment 5 that (1R 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, is white solid.CD/MeOH=(+); E/e=99.9%, this measures according to chirality HPLC.MS (ESI) m/z 281 ([M+H] +); HRMS: calculated value C 18H 20N 2O+ H+, 281.16484; Measured value (ESI, [M+H]+), 281.1649.
Embodiment 23:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800951
With racemic (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol (embodiment 11) is dissolved in methyl alcohol.With the gained injection of solution to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use Chiralcel OJ-H 5 μ, 250mm * 4.6mm ID post, flow velocity 2.0mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).
The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel OJ-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: the 20%MeOH that contains 1% diethylamine
Flow velocity: 50mL/min
Top hole pressure: 100 crust
Detector: UV is in 218nm
Separate (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol, be slower retention time peak, it has chirality and detects (-) rotation of (CD) and the e/e=99.4% that measures according to chirality HPLC.The isolating free alkali of institute being concentrated in a vacuum, be dissolved in small amount of ethanol, handle with the ethereal solution of 1N hydrochloric acid, is pH=3 until solution, handles with ether then.Add amount of ethyl acetate then and make the product crystallization, obtain title compound, be the white solid of hydrochloride.
MS (ESI) m/z 281 ([M+H] +); HRMS: calculated value C18H20N2O+H+, 281.16484; Measured value (ESI, [M+H]+), 281.1646.
Embodiment 24:(1RS, 2SR)-3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800961
By (2RS, 3RS)-(3-methyl-indoles-1-yl)-(embodiment 9 for 2-hydroxyl-3-phenyl-propyl diester for toluene-4-sulfonic acid 3-, step 2) and 30% aqueous solution of ammonium hydroxide, prepare (1RS according to the mode that is similar to embodiment 17,2SR)-and 3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be pale brown look solid.MS(ES)
M/z 281.1 ([M+H] +); HRMS: calculated value C 18H 20N 2O+ H+, 281.16484; Measured value (ESI, [M+H]+), 281.1645.
Embodiment 25:(1RS, 2SR)-3-[ethyl (methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By (1RS, 2SR)-3-(methylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol (embodiment 11) and ethamine (2N methanol solution), prepare (1RS according to the mode that is similar to embodiment 5,2SR)-3-[ethyl (methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be pale brown look solid.
MS (ES) m/z 309.0 ([M+H] +); HRMS: calculated value C 20H 24N 2O+ H+, 309.19614; Measured value (ESI, [M+H]+), 309.1955.
Embodiment 26:(1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 5-chloro-indole and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 1 step 1 that (2RS, 3RS)-3-(5-chloro-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 302([M+H] +)。
By (2RS, 3RS)-3-(5-chloro-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-chloro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 456([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-chloro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 steps 3 prepare (1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 315 ([M+H] +); HRMS: calculated value C 18H 19ClN 2O+ H+, 315.12587; Measured value (ESI, [M+H]+), 315.1258.
Embodiment 27:(1RS, 2RS)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-1-alcohol hydrochloride
By (2RS, 3RS)-and 3-(5-chloro-indoles-1-yl)-3-phenyl-propane-1, (embodiment 1, step 1) for the 2-glycol, according to the mode that is similar to embodiment 16 steps 2 prepare (2RS, 3RS)-4-nitro-phenylformic acid 3-(5-chloro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 451([M+H] +)。
By (2RS, 3RS)-4-nitro-phenylformic acid 3-(5-chloro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, according to the mode that is similar to embodiment 16 steps 3 prepare (2RS, 3RS)-4-nitro-phenylformic acid 3-(5-chloro-indoles-1-yl)-2-mesyloxy-3-phenyl propyl ester.MS(ESI)m/z 529([M+H] +)。
By (2RS, 3RS)-4-nitro-phenylformic acid 3-(5-chloro-indoles-1-yl)-2-mesyloxy-3-phenyl propyl ester, according to the mode that is similar to embodiment 16 steps 4 prepare (1RS, 2SR)-5-chloro-1-(Oxyranyle-phenyl-methyl)-1H-indoles.MS(ESI)m/z 284([M+H] +)。
Prepare according to the mode that is similar to embodiment 16 steps 5 that (1RS 2RS)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, is pale brown look solid.
MS (ESI) m/z 315 ([M+H] +); HRMS: calculated value C 18H 19ClN 2O+ H+, 315.12587; Measured value (ESI, [M+H]+), 315.1276.
Embodiment 28:1-[(1RS, 2SR)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indole-3-formonitrile hydrochloride
Figure A20058001737800981
By 3-cyanoindole and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 1 step 1 that (2RS, 3RS)-3-(3-cyano group-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 293([M+H] +)。
By (2RS, 3RS)-3-(3-cyano group-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2RS, 3RS)-toluene-4-sulfonic acid 3-(3-cyano group-indoles-1-base-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 447([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(3-cyano group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, prepare (1RS according to the mode that is similar to embodiment 1 step 3,2SR)-and 1-(3-cyano-1 H-indol--1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.
MS (ESI) m/z 306 ([M+H] +); HRMS: calculated value C 19H 19N 3O+ H+, 306.16009; Measured value (ESI, [M+H]+), 306.1614.
Embodiment 29:(1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
With racemic (1RS, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol (embodiment 16) is dissolved in methyl alcohol.With the gained injection of solution to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use Chiralcel OJ-H 5 μ, 250mm * 4.6mm ID post, flow velocity 2.0mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).
The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel OJ-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: the 20%MeOH that contains 1% ethyl sulfonic acid
Flow velocity: 50mL/min
Top hole pressure: 100 crust
The UV of detector: 220nm
Separate that (1R 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol, is retention time peak faster, and it has chirality and detects (+) rotation of (CD) and the e/e=99.9% that measures according to chirality HPLC.
Mode according to being similar to embodiment 23 obtains title compound, is the white solid of hydrochloride.MS(ESI)m/z 306([M+H] +)；
HRMS: calculated value C18H20N2O+H+, 281.16484; Measured value (ESI, [M+H]+), 281.1654.
Embodiment 30:(1S, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737800991
According to the mode that is similar to embodiment 29, separate (1S, 2S)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol, be slower retention time peak, it has chirality and detects (-) rotation of (CD) and the e/e=99.9% that measures according to chirality HPLC.
Mode according to being similar to embodiment 23 obtains title compound, is the white solid of hydrochloride.
MS (ESI) m/z 306 ([M+H] +); HRMS: calculated value C18H20N2O+H+, 281.16484; Measured value (ESI, [M+H]+), 281.1655.
Embodiment 31:(1S, 2R)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By the 3-skatole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares according to the mode that is similar to embodiment 1 step 1 that (2S, 3S)-3-(3-methyl-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil for methyl alcohol.MS(ESI)m/z 282([M+H] +)。
By (2S, 3S)-3-(3-methyl-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 436([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl group and methylamine (2N methanol solution), prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.[ ] D 25/ MeOH=+116; CD/MeOH=(-); MS (ESI) m/z 295 ([M+H] +); HRMS: calculated value C 19H 22N 2O+ H+, 295.18049; Measured value (ESI, [M+H]+), 295.1816.
Embodiment 32:(1RS, 2SR)-1-(2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol dihydrochloride
Figure A20058001737801002
With 3, (2.027g, 15.00mmol) (2.883g, mixture 15.00mmol) stirred 12 hours down at 135 ℃ 4-dihydro-2H-benzo [1,4]  piperazine with trans-3-ethyl phenylglycidate.After the cooling, with viscous liquid via Biotage Horizon purifying (FLASH 40 M, silicon-dioxide, 10%, 20%, the 30%EtOAc/ hexane) and recrystallization (slight warm chloroform/hexane/-20 ℃), obtain 4.261g (87%) (2RS, 3RS)-3-(2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 2-hydroxyl-3-phenylpropionic acid ethyl ester, be white solid.MS(ESI)m/z 328.0([M+H] +)。
Will (2RS, 3RS)-3-(2,3-dihydro-4H-1,4-benzoxazine-4-yl)-2-hydroxyl-3-phenylpropionic acid ethyl ester (283mg, 0.864mmol) with the mixture of the ethanolic soln (5mL, 33%) of methylamine under 70 ℃, in the sealing test tube, stirred 5 hours.After the cooling, under reduced pressure remove all volatile matters.With the gained yellow solid via Biotage Horizon purifying (FLASH 12 S, silicon-dioxide, 20%, 35%, the 50%EtOAc/ hexane), obtain 235mg (87%) (2RS, 3RS)-3-(2,3-dihydro-4H-1,4 benzoxazines-4-yl)-2-hydroxy-n-methyl-3-Phenylpropionamide, be white solid.MS(ESI)m/z 311.0([M-H]-)。
With (2RS, 3RS)-3-(2,3-dihydro-4H-1,4-benzoxazine-4-yl)-2-hydroxy-n-methyl-3-Phenylpropionamide (216mg, 0.692mmol) solution in anhydrous tetrahydro furan (3mL) under nitrogen atmosphere with borine solution (1.0M tetrahydrofuran solution, 3.50mL, 3.50mmol) dropwise handle, gained solution was stirred 2 hours down at 70 ℃.In ice bath, after the cooling, reaction mixture is handled with 2N aqueous hydrochloric acid (1mL), the gained mixture was heated 30 minutes down at 50 ℃.Under reduced pressure remove tetrahydrofuran (THF), with water-based resistates water-soluble (5mL), with ether (10mL) washing.Water layer transfers to alkalescence with solid carbonic acid potassium, with ethyl acetate extraction (2 * 10mL).With the organic extract liquid salt water washing that merges, dry (sodium sulfate) under reduced pressure concentrates, obtain 202mg (98%) (1RS, 2SR)-1-(2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-(methylamino)-1-phenyl-propane-2-alcohol, be colourless oil.This oil is dissolved in ethanol (1mL), handles with hydrochloric acid soln (0.5mL, 4M 1,4-two  alkane solution).Under reduced pressure remove all volatile matters once more.Make gained white solid recrystallization (slight warm ethanol/ether/-20 ℃), obtain 105mg (41%) (1RS, 2SR)-1-(2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-(methylamino)-1-phenyl-propane-2-alcohol dihydrochloride, be white solid.MS(ESI)m/z299.0([M+H] +)；
HRMS: calculated value C 18H 22N 2O 2+ H+, 299.17540; Measured value (ESI, [M+H]+), 299.1755.
Embodiment 33:(1S, 2R)-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801011
Step 1: under 23 ℃, ((20mL 100mmol) dropwise handles tetrahydrofuran (THF) 100mmol) (600mL) suspension with the ethoxycarbonylmethyl group diethyl phosphonate for 60% mineral oil dispersion, 4.0g with sodium hydride.After 1 hour, and adding 3-chlorobenzaldehyde (9.3mL, 82mmol).After other 1 hour, will react water (20mL) cancellation, and under vacuum, concentrate and remove tetrahydrofuran (THF).Resistates is dissolved in ethyl acetate (300mL), water (5 * 300mL) and salt solution (1 * 300mL) washing, dry (sal epsom) concentrates under vacuum, (18g quantitatively), is the clarification light yellow oil to obtain (2E)-3-(3-chloro-phenyl-)-ethyl propenoate.MS(ESI)m/z 210([M+H] +)。
Step 2: with (2E)-3-(3-chloro-phenyl-)-ethyl propenoate (17.6g 82mmol) is dissolved in anhydrous methylene chloride (300mL), is cooled to-78 ℃, go through 20 minutes with diisobutyl aluminium hydride solution (1.0M hexane solution, 250mL 250mmol) handle.Amount to after 1.5 hours, under-78 ℃, will react, be warming up to 23 ℃, handle with saturated soluble tartrate sodium water solution (300mL) with methyl alcohol (75mL) cancellation.Water phase separated is with dichloromethane extraction (2 * 300mL).With the extraction liquid that merges with the saturated sodium tartrate aqueous solution (450mL) washing, dry (sodium sulfate), concentrated under vacuum, obtain muddy xanchromatic oil (14.6g), with its preadsorption to silica gel (25g).Handle (silicon-dioxide 250g, 10%, 20% ethyl acetate/hexane) through flash column chromatography, obtain (2E)-3-(3-chloro-phenyl-) third-2-alkene-1-alcohol (12.4g, 90%), for clarifying colourless oil.MS(ESI)m/z 151([M+H-H 2O] +)。
Step 3: by (2E)-3-(3-chloro-phenyl-) third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare [(2R, 3R)-3-(3-chloro-phenyl-) oxyethane-2-yl] methyl alcohol.MS(ESI)m/z 167([M+H-H 2O] +)。
Step 4 (method A): by the 1H-indoles and [(2R, 3R)-3-(3-chloro-phenyl-) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(3-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1, the 2-glycol.MS(ES)m/z 302([M+H] +)。
Step 4a (method B): in the flask of sealing, will [(2R, 3R)-3-(3-chloro-phenyl-) oxyethane-2-yl] methyl alcohol (4.8g, 26mmol) and indoline (d 1.063, and 2.9mL 26mmol) heats down only at 135 ℃.1.5 after hour, make refrigerative mixture preadsorption to silica gel (25g).Handle (silicon-dioxide 375g, 20%, 40%, 80% ethyl acetate/hexane) through flash column chromatography, obtain (2S, 3S)-3-(3-chloro-phenyl-)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1,2-glycol (5.8g, 73%) is white solid.MS(ES)m/z 304([M+H] +)。
Step 4b (method B): under 0 ℃, with (2S, 3S)-3-(3-chloro-phenyl-)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, and the 2-glycol (5.8g, 19mmol) solution in about 1: 1 (v/v) toluene-methylene dichloride (200mL) is with 2,3-two chloro-5,6-dicyano-1,4-benzoquinones (4.4g, 19mmol) solution-treated in toluene (100mL).After 30 minutes, with mixture with ethyl acetate (1L) dilution, with 5% aqueous sodium carbonate (4 * 1L), water (1L) and salt solution (1L) washs, dry (sal epsom), under vacuum, concentrate, obtain dark-coloured oil (5.4g), with its preadsorption to silica gel (15g).Handle (silicon-dioxide 235g, 20%, 40% ethyl acetate/hexane) through flash column chromatography, obtain (2S, 3S)-3-(3-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1,2-glycol (4.7g, 82%) is muddy xanchromatic oil.MS(ES)m/z 302([M+H] +)。
Step 5: by (2S, 3S)-3-(3-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester.MS(ES)m/z 456([M+H] +)。
Step 6: will (2S, 3S)-(0.60g, 1.2mmol) (2.0M, 3mL 6mmol) handle toluene-4-sulfonic acid 3-(3-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester, and solution was stirred 18 hours down at 23 ℃ with the methanol solution of methylamine.At this moment, under vacuum, concentrate this solution, be dissolved in ether (50mL).Organic solution is washed with 1N aqueous sodium hydroxide solution (50mL), water (50mL) and salt solution (50mL), dry (sodium sulfate), under vacuum, concentrate, obtain orange foam (0.30g), through reversed-phase HPLC purifying (90: 10 water-acetonitriles to 50: 50 water-acetonitrile, contain 0.1% trifluoroacetic acid, flow velocity 20mL/min).The enriched product fraction is to remove acetonitrile under vacuum, and the aqueous solution alkalizes with the 2N ammonium hydroxide aqueous solution.Gained emulsus suspension is extracted with ethyl acetate (200mL), organic phase water (200mL) and salt solution (100mL) washing, dry (sodium sulfate) concentrates under vacuum.Resistates is dissolved in dehydrated alcohol (4mL), and with 1 of 4M hydrochloric acid, 4-two  alkane solution (1.3eq) are handled, and stir 10 minutes.Solution is concentrated under vacuum, be dissolved in dehydrated alcohol (3mL) then, place down at 23 ℃ and spend the night.Vacuum filtration, obtain (1S, 2R)-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride (62mg, 5%, 3 step), be the white crystalline solid.The HRMS calculated value
C 18H 19ClN 2O+H +, 315.12587; Measured value (ESI) 315.1267 ([M+H] +).
Embodiment 34:(1S, 2R)-1-(4-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801041
By ethoxycarbonylmethyl group diethyl phosphonate and 4-chlorobenzaldehyde, prepare (2E)-3-(4-chloro-phenyl-)-ethyl propenoate according to the mode that is similar to embodiment 33 steps 1.MS(ESI)m/z 210([M+H] +)。
By (2E)-3-(4-chloro-phenyl-)-ethyl propenoate, prepare (2E)-3-(4-chloro-phenyl-) third-2-alkene-1-alcohol according to the mode that is similar to embodiment 33 steps 2.MS(ESI)m/z 151([M+H-H 2O] +)。
By (2E)-3-(4-chloro-phenyl-) third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare [(2R, 3R)-3-(4-chloro-phenyl-) oxyethane-2-yl] methyl alcohol.
MS(ESI)m/z 167([M+H-H 2O] +)；[□□ D+41(c 0.0121g/mL，DMSO)；99.2％ee.
By the 1H-indoles and [(2R, 3R)-3-(4-chloro-phenyl-) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(4-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1, the 2-glycol.MS(ES)m/z 302([M+H] +)。
By (2S, 3S)-3-(4-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(4-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester.MS(ES)m/z 456([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(4-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 prepare (1S, 2R)-1-(4-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride.HRMS: calculated value C 18H 19ClN 2O+H +, 315.12587; Measured value (ESI) 315.124 ([M+H] +).
Embodiment 35:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride
Figure A20058001737801042
By ethoxycarbonylmethyl group diethyl phosphonate and 3-(trifluoromethoxy) phenyl aldehyde, prepare (2E)-3-(3-trifluoromethoxy-phenyl)-ethyl propenoate according to the mode that is similar to embodiment 33 steps 1.MS(ES)m/z 261([M+H] +)。
By (2E)-3-(3-trifluoromethoxy-phenyl)-ethyl propenoate, prepare (2E)-3-[3-(trifluoromethoxy) phenyl according to the mode that is similar to embodiment 33 steps 2] third-2-alkene-1-alcohol.MS(ES)m/z 201([M+H-H 2O] +)。
By (2E)-3-[3-(trifluoromethoxy) phenyl] third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare (2R, 3R)-3-[3-(trifluoromethoxy) phenyl] oxyethane-2-yl methyl alcohol.MS(ES)m/z 217([M+H-H 2O] +)；[α] D 25＝+30(c＝0.0118g/mL，DMSO)；84.4％ee。
By 1H-indoles and { (2R, 3R)-and 3-[3-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol, prepare (2S, 35)-3-(1H-indoles-1-yl)-3-[3-(trifluoromethoxy) phenyl according to the mode that is similar to embodiment 117 steps 5] propane-1, the 2-glycol.MS(ES)m/z 352([M+H] +)。
By (2S, 3S)-and 3-(1H-indoles-1-yl)-3-[3-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(3-trifluoromethoxy-phenyl)-propyl diester.MS(ES)m/z 506([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(3-trifluoromethoxy-phenyl)-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 prepare (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride.MS(ES)m/z 365([M+H] +)。
Embodiment 36:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride
Step 1:, prepare (2E)-3-(2 trifluoromethoxies-phenyl)-ethyl propenoate according to the mode that is similar to embodiment 33 steps 1 by ethoxycarbonylmethyl group diethyl phosphonate and 2-(trifluoromethoxy) phenyl aldehyde.(ES)m/z 261([M+H] +)。
Step 2:, prepare (2E)-3-[2-(trifluoromethoxy) phenyl according to the mode that is similar to embodiment 33 steps 2 by (2E)-3-(2 trifluoromethoxies-phenyl)-ethyl propenoate] third-2-alkene-1-alcohol.MS(ES)m/z 201([M+H-H 2O] +)。
Step 3: under 23 ℃, with (2E)-3-[2-(trifluoromethoxy) phenyl] (3.9g, 18mmol) (77%, 8.0g 36mmol) handles the solution in methylene dichloride (90mL) third-2-alkene-1-alcohol with metachloroperbenzoic acid.After 5 hours, will react with 1N aqueous sodium hydroxide solution (200mL) cancellation, vigorous stirring is separated each phase simultaneously.Water extracted with diethyl ether (2 * 100mL).The organic phase that merges is washed with water (3 * 100mL), dry (sodium sulfate) concentrates under vacuum, obtains clarifying colourless oil (3.8g), with its preadsorption to silica gel (6g).Handle (silicon-dioxide 60g, 10%, 20% ethyl acetate/hexane) through flash column chromatography, obtain (2RS, 3RS)-3-[2-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol (2.4g, 57%), be white solid.MS(ES)m/z 217([M+H-H 2O] +)。
Will (2RS, 3RS)-3-[2-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol is dissolved in methyl alcohol.With the gained injection of solution to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use Chiralcel AS-H 5 μ, 250mm * 4.6mm ID post, flow velocity 2.0mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel AS-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: 5%IPA/95%CO 2
Flow velocity: 35mL/min
Top hole pressure: 100 crust
The UV of detector: 220nm
Separate (2R, 3R)-3-[2-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol, be peak 1.MS(ES)m/z 217([M+H-H 2O] +)；[α] D 25＝+19.4(c＝0.0102g/mL，DMSO)；＞99.9％ee。
Separate (2S, 3S)-3-[2-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol, be peak 2.MS(ES)m/z 217([M+H-H 2O] +)；[α] D 25＝-15.7(c＝0.0125g/mL，DMSO)；95.8％ee。
Step 4: by 1H-indoles and { (2R, 3R)-and 3-[2-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(1H-indoles-1-yl)-3-[2-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, but replace potassium hydride KH with sodium tert-butoxide.MS(ES)m/z 352([M+H] +)。
Step 5: by (2S, 3S)-and 3-(1H-indoles-1-yl)-3-[2-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(2-trifluoromethoxy-phenyl)-propyl diester.MS(ES)m/z 506([M+H] +)。
Step 6: by (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(2-trifluoromethoxy-phenyl)-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 prepare (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride.MS(ES)m/z 365([M+H] +)。
Embodiment 37:(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride
By 1H-indoles and { (2S, 3S)-and 3-[2-(trifluoromethoxy) phenyl] oxyethane-2-yl } (embodiment 36 for methyl alcohol, step 3), prepare (2R according to the mode that is similar to embodiment 117 steps 5,3R)-and 3-(1H-indoles-1-yl)-3-[2-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, but replace potassium hydride KH with sodium tert-butoxide.MS(ES)m/z 352([M+H] +)。
By (2R, 3R)-and 3-(1H-indoles-1-yl)-3-[2-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2R, 3R)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(2-trifluoromethoxy-phenyl)-propyl diester.MS(ES)m/z 506([M+H] +)。
By (2R, 3R)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(2-trifluoromethoxy-phenyl)-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 prepare (1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride.MS(ES)m/z 365([M+H] +)。
Embodiment 38:(1S, 2R)-1-(2-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
By ethoxycarbonylmethyl group diethyl phosphonate and 2-chlorobenzaldehyde, prepare (2E)-3-(2-chloro-phenyl-)-ethyl propenoate according to the mode that is similar to embodiment 33 steps 1.MS(ESI)m/z 210([M+H] +)。
By (2E)-3-(2-chloro-phenyl-)-ethyl propenoate, prepare (2E)-3-(2-chloro-phenyl-) third-2-alkene-1-alcohol according to the mode that is similar to embodiment 33 steps 2.MS(ESI)m/z 151([M+H-H 2O] +)。
By (2E)-3-(2-chloro-phenyl-) third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 36 steps 3 prepare [(2RS, 3RS)-3-(2-chloro-phenyl-) oxyethane-2-yl] methyl alcohol.
Will [(2RS, 3RS)-3-(2-chloro-phenyl-) oxyethane-2-yl] methyl alcohol is dissolved in methyl alcohol.With gained injection of solution (50mg/ injection) to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use Chiralcel AD-H 5 μ, 250mm * 4.6mm ID post, flow velocity 2.0mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel AD-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: 20%MeOH/80%CO 2
Flow velocity: 50mL/min
Top hole pressure: 100 crust
The UV of detector: 220nm
Separate [(2S, 3S)-3-(2-chloro-phenyl-) oxyethane-2-yl] methyl alcohol, be peak 1.MS(ES)m/z167([M+H-H 2O] +)；[α] D 25＝+2.6(c＝0.0153g/mL，DMSO)；＞99.8％ee。
Separate [(2R, 3R)-3-(2-chloro-phenyl-) oxyethane-2-yl] methyl alcohol, be peak 2.MS(ES)m/z167([M+H-H 2O] +)；[α] D 25＝-2.5(c＝0.0139g/mL，DMSO)；＞99.8％ee。
By 1H-indoles and [(2R, 3R)-3-(2-chloro-phenyl-) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(2-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1, the 2-glycol, but replace potassium hydride KH with sodium tert-butoxide.MS(ES)m/z 302([M+H] +)。
By (2S, 3S)-3-(2-chloro-phenyl-)-3-(1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(2-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester.MS(ES)m/z 456([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(2-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 prepare (1S, 2R)-1-(2-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 315([M+H] +)。
Embodiment 39:(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride
Figure A20058001737801091
Step 1:, prepare (2E)-3-(4-trifluoromethoxy-phenyl)-ethyl propenoate according to the mode that is similar to embodiment 33 steps 1 by ethoxycarbonylmethyl group diethyl phosphonate and 4-(trifluoromethoxy) phenyl aldehyde.(ES)m/z 261([M+H] +)。
Step 2:, prepare (2E)-3-[4-(trifluoromethoxy) phenyl according to the mode that is similar to embodiment 33 steps 2 by (2E)-3-(4-trifluoromethoxy-phenyl)-ethyl propenoate] third-2-alkene-1-alcohol.MS(ES)m/z 201([M+H-H 2O] +)。
Step 3: by (2E)-3-[4-(trifluoromethoxy) phenyl] third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 36 steps 3 prepare (2RS, 3RS)-3-[4-(trifluoromethoxy) phenyl] oxyethane-2-yl methyl alcohol.MS(ES)m/z 217([M+H-H 2O] +)。
Step 4: by indoline and { (2RS, 3RS)-and 3-[4-(trifluoromethoxy) phenyl] oxyethane-2-yl } methyl alcohol, according to the mode that is similar to embodiment 33 step 4a (method B) preparation (2RS, 3RS)-3-(2,3-dihydro-1H-indoles-1-yl)-and 3-[4-(trifluoromethoxy) phenyl] propane-1, the 2-glycol.MS(ES)m/z 354([M+H] +)。
Step 5: by (2RS, 3RS)-3-(2,3-dihydro-1H-indoles-1-yl)-and 3-[4-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 33 step 4b (method B) preparation (2RS, 3RS)-and 3-(1H-indoles-1-yl)-3-[4-(trifluoromethoxy) phenyl] propane-1, the 2-glycol.MS(ES)m/z 352([M+H] +)。
Step 6: by (2RS, 3RS)-and 3-(1H-indoles-1-yl)-3-[4-(trifluoromethoxy) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(4-trifluoromethoxy-phenyl)-propyl diester.MS(ES)m/z 506([M+H] +)。
Step 7: by (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-indoles-1-base-3-(4-trifluoromethoxy-phenyl)-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 (method B) preparation (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride.MS(ES)m/z 365([M+H] +)。
Embodiment 40:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride
Step 1: will (1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] (embodiment 39, and step 7) is dissolved in methyl alcohol for propane-2-alcohol hydrochloride.With gained injection of solution (35mg/ injection) to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use Chiralcel AD-H 5 μ, 250mm * 4.6mm ID post, flow velocity 2.0mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).
The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel AD-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: 20%MeOH w/1.0%DEA/75%CO 2
Flow velocity: 50mL/min
Top hole pressure: 100 crust
The UV of detector: 220nm
After according to embodiment 33 steps 6 free alkali being neutralized and being converted into hydrochloride, separate (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride, be peak 1.MS(ES)m/z 365([M+H] +)；98.4％ee。
Embodiment 41:(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol hydrochloride
Figure A20058001737801111
After according to embodiment 33 steps 6 free alkali being neutralized and being converted into hydrochloride, separate (1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] (embodiment 40, and step 1) is peak 2 for propane-2-alcohol hydrochloride.MS(ES)m/z 365([M+H] +)；＞99.9％ee。
Embodiment 42:(1S, 2R)-4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol hydrochloride
Step 1: with (2S, 3S)-(embodiment 33, step 5,1.9g for toluene-4-sulfonic acid 3-(3-chloro-phenyl-)-2-hydroxyl-3-indoles-1-base-propyl diester, 4.2mmol) (0.23g, 4.7mmol) mixture in anhydrous dimethyl sulphoxide (20mL) is 100 ℃ of heating (microwave) down with sodium cyanide.After 15 minutes, refrigerative solution is dissolved in ethyl acetate (200mL), wash with water (3 * 200mL), dry (sodium sulfate) concentrates under vacuum, obtains pale brown look foam (1.3g), with its preadsorption to silica gel (3g).Handle (silicon-dioxide 30g, 10%, 20%, 40% ethyl acetate/hexane) through flash column chromatography, obtain (3R, 4S)-4-(3-chloro-phenyl-)-3-hydroxyl-4-indoles-1-base-butyronitrile (1.2g, 92%), be pale brown look foam.MS(ES)m/z311([M+H] +)。
Step 2: under 23 ℃, will (3R, 4S)-(1.2g, 3.9mmol) (1.0M, 20mL 20mmol) handle the solution in anhydrous tetrahydro furan (20mL) 4-(3-chloro-phenyl-)-3-hydroxyl-4-indoles-1-base-butyronitrile with diboron hexahydride-tetrahydrofuran solution.After 16 hours, will react under 23 ℃ with methyl alcohol (7mL) cancellation, concentrated solution under vacuum obtains the canescence foam, and it is distributed between ether (200mL) and 1N aqueous sodium hydroxide solution (200mL).Separate organic phase, wash with salt solution (200mL), dry (sodium sulfate) concentrates under vacuum, obtains yellow foam (1.2g), via Biotage chromatography purification [AnaLogix silica column, 2 * 40g series, the ethanol/methylene that methylene dichloride to 5% ammonia is saturated], obtain (1S, 2R)-4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol (0.43g, 36%).As described in embodiment 33 steps 6, free alkali is converted into its hydrochloride, obtain (1S, 2R)-4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol hydrochloride (0.47g, 34%), be foam.MS(ES)m/z 315([M+H] +)。
Embodiment 43:(1S, 2R)-1-(3-bromophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801121
Step 1:, prepare (2E)-3-(3-bromophenyl)-ethyl propenoate according to the mode that is similar to embodiment 33 steps 1 by ethoxycarbonylmethyl group diethyl phosphonate and 3-bromobenzaldehyde.MS(ES)m/z 255([M+H] +)。
Step 2:, prepare (2E)-3-(3-bromophenyl) third-2-alkene-1-alcohol according to the mode that is similar to embodiment 33 steps 2 by (2E)-3-(3-bromophenyl)-ethyl propenoate.MS(ES)m/z 195([M+H-H 2O] +)。
Step 3: by (2E)-3-(3-bromophenyl) third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare [(2R, 3R)-3-(3-bromophenyl) oxyethane-2-yl] methyl alcohol.MS(ES)m/z 211([M+H-H 2O] +)；95％ee。
Step 4: by indoline and [(2R, 3R)-3-(3-bromophenyl) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 33 step 4a (method B) preparation (2S, 3S)-3-(3-bromophenyl)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol.MS(ES)m/z 348([M+H] +)。
Step 5: by (2S, 3S)-3-(3-bromophenyl)-3-(2,3-dihydro-1H indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 33 step 4b (method B) preparation (2S, 3S)-3-(3-bromophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol.MS(ES)m/z 346([M+H] +)。
Step 6: by (2S, 3S)-3-(3-bromophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-bromophenyl)-2-hydroxyl-3-indoles-1-base-propyl diester.MS(ES)m/z 500([M+H] +)。
Step 7: by (2S, 3S)-toluene-4-sulfonic acid 3-(3-bromophenyl)-2-hydroxyl-3-indoles-1-base-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 33 steps 6 prepare (1S, 2R)-1-(3-bromophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 359([M+H] +)。
Embodiment 44:3-[(1S, 2R)-2-hydroxyl-1-(1H-indoles-1-yl)-3-(methylamino) propyl group] the cyanobenzene hydrochloride
In the flask of sealing, with (2S, 3S)-3-(3-bromophenyl)-(1H-indoles-1-yl) propane-1, (embodiment 43 for the 2-glycol, step 5,1.4g, 4.0mmol), zinc cyanide (II) (4.7g, 40mmol) (0.46g, 0.40mmol) mixture in degassing 1-Methyl-2-Pyrrolidone (25mL) is 150 ℃ of heating down with four (triphenyl phosphine) palladium (0).3.5 after hour, refrigerative brown mixture with ethyl acetate (250mL) dilution, is passed through diatomite filtration.With filtrate water (5 * 250mL) and salt solution (1 * 250mL) washing, dry (sodium sulfate) concentrates under vacuum, obtains amber oil (1.6g), with its preadsorption to silica gel (6g).Handle (silicon-dioxide 70g, 30%, 60% ethyl acetate/hexane) through flash column chromatography, obtain 3-[(1S, 2S)-2,3-dihydroxyl-1-(1H-indoles-1-yl) propyl group] cyanobenzene (1.0g, 83%), be weak yellow foam.MS(ES)m/z 293([M+H] +)。
By 3-[(1S, 2S)-2,3-dihydroxyl-1-(1H-indoles-1-yl) propyl group] cyanobenzene, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-cyano group-phenyl)-2-hydroxyl-3-indoles-1-base-propyl diester.MS(ES)m/z 447([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-cyano group-phenyl)-2-hydroxyl-3-indoles-1-base-propyl diester and methylamine (2N methanol solution), prepare 3-[(1S according to the mode that is similar to embodiment 33 steps 6,2R)-2-hydroxyl-1-(1H-indoles-1-yl)-3-(methylamino) propyl group] the cyanobenzene hydrochloride.MS(ESI)m/z 306([M+H] +)。
Embodiment 45:(1SR, 2RS)-3-(methylamino)-1-(4-methyl-3,4-dihydro-quinoxaline-1 (2H)-yl)-1-phenyl-propane-2-alcohol hydrochloride
Step 1: by styryl carbinol, prepare the 3-phenyl glycidyl, be white solid according to the mode that is similar to embodiment 53 steps 3.MS(ES)m/z 151.1([M+H] +)。
Step 2: by the 1-methyl isophthalic acid, 2,3,4-tetrahydroquinoxaline (Cavagnol, J.C.; Wiselogle, F.Y.J.Am.Chem.Soc.1947,69,795-799) and the 3-phenyl glycidyl, according to the mode that is similar to embodiment 47 steps 4 prepare (2SR, 3SR)-3-(4-methyl-3,4-dihydro-quinoxaline-1 (2H)-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.
MS (ES) m/z 299.0 ([M+H] +); HRMS: calculated value C 18H 22N 2O 2+ H +, 299.1760;
Measured value (ESI, [M+H] +), 299.1739.
Step 3: by (2SR, 3SR)-3-(4-methyl-3,4-dihydro-quinoxaline-1 (2H)-yl)-3-phenyl-propane-1, the 2-glycol, prepare (1SR according to the mode that is similar to embodiment 47 steps 6,2RS)-(4-methyl 3,4-dihydro-quinoxaline-1 (2H)-yl)-1-phenyl-propane-2-alcohol hydrochloride is white powder to 3-(methylamino)-1-.
MS(ES)m/z 312.0([M+H] +)；
HRMS: calculated value C 19H 25N 3O+H +, 312.2076; Measured value (ESI, [M+H] +), 312.2065.
Embodiment 46:(1SR, 2RS)-3-(methylamino)-1-phenyl-1-[4-(2,2, the 2-trifluoroethyl)-3,4-dihydro-quinoxaline-1 (2H)-yl] propane-2-alcohol hydrochloride
Figure A20058001737801151
Use the trifluoroacetic acid solution of sodium borohydride, obtain compound 1-(2,2, the 2-trifluoroethyl)-1,2,3, the 4-tetrahydroquinoxaline, for the quinoxaline reduction reaction becomes 1,2,3, white powder by product (Bugle, the R.C. of 4-tetrahydroquinoxaline; Osteryoung, R.A.J.Org.Chem.1979,44,1719-1720).MS(ES)m/z 217.1([M+H] +)。
By 1-(2,2, the 2-trifluoroethyl)-1,2,3, (embodiment 45 for 4-tetrahydroquinoxaline and 3-phenyl glycidyl, step 1), according to the mode that is similar to embodiment 47 steps 4 prepare (2SR, 3SR)-(4-(2,2 for 3-, the 2-trifluoroethyl)-3,4-dihydro-quinoxaline-1 (2H)-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.
By (2SR, 3SR)-3-(4-(2,2,2 trifluoroethyl)-3,4-dihydro-quinoxaline-1 (2H)-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 6 prepare (1SR, 2RS)-3-(methylamino)-1-phenyl-1-[4-(2,2, the 2-trifluoroethyl)-3,4-dihydro-quinoxaline-1 (2H)-yl] propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z 380.0 ([M+H] +); HRMS: calculated value C 20H 24F 3N 3O+H +, 380.1950; Measured value (ESI, [M+H] +), 380.1934.
Embodiment 47:(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Step 1: to trans-3-fluoro cinnamic acid (50g, 300mmol) Yu in the mixture of methyl iodide (300mL) in acetone (1L) add cesium carbonate (147g in batches, 450mmol 1.5equiv.), heats mixture 1.5 hours down at 65 ℃ in the reaction vessel of sealing.After being cooled to room temperature, reaction mixture with ethyl acetate (1L) dilution, is filtered by silicagel pad, concentrates, obtain 47.33g (87%) trans-3-fluoro cinnamic acid methyl esters, be colourless oil.MS(ES)m/z 180.0(M+)。
Step 2: under-78 ℃ under nitrogen atmosphere, via addition funnel to trans-3-fluoro cinnamic acid methyl esters (69.61g, 386mmol) drip in the solution in anhydrous methylene chloride (1L) diisobutyl aluminium hydride (clean, 172mL, 965mmol, 2.5equiv.).After adding finishes, make reaction mixture be warming up to-30 ℃, stirred other 1 hour, use methyl alcohol (150mL) cancellation then.After being warming up to room temperature, reaction mixture is handled with saturated soluble tartrate sodium water solution (300mL), stirred 30 minutes.Organic layer is successively used 1N aqueous hydrochloric acid, saturated sodium bicarbonate aqueous solution, salt water washing, dry (anhydrous sodium sulphate).Thick oil through the silica gel chromatography purifying (the 0-50% ethyl acetate: hexane), obtain 53.07g (90%) trans-3-fluorine styryl carbinol, be colourless oil.MS(ES)m/z 152.1(M+)。
Step 3: under nitrogen atmosphere, D-tartrate diisopropyl ester (11.55g packs in the process 3-neck 2-L round-bottomed flask of oven drying of addition funnel that two process oven dryings are housed and diaphragm of rubber, 49.3mmol, 0.30equiv.), 4  activated molecular sieve (40g) and the anhydrous methylene chloride (800mL) pulverized.After being cooled to-25 ℃, via syringe in reaction mixture, slowly add titanium isopropylate (9.6mL, 33mmol, 0.20equiv.).Stir after 10 minutes, via addition funnel with moderate speed add anhydrous t-butyl hydroperoxide (5.5M decane solution, 75.0mL, 413mmol, 2.5equiv.).The gained mixture was stirred 30 minutes down at-25 ℃.(holding temperature is at-25 ℃ simultaneously for 25.0g, the 164mmol) solution in anhydrous methylene chloride (50mL) to drip trans-3-fluorine styryl carbinol via addition funnel.After the adding, reaction mixture was stirred 1 hour down at-25 ℃, stirred other 3 hours down at-20 ℃.After reacting completely, and the slow adding saturated refrigerative aqueous sodium hydroxide solutions of sodium-chlor under-20 ℃ (30%, 20mL).After adding ether (150mL), remove cooling bath, make mixture be warming up to～5 ℃, stirred 1 hour.Adding sal epsom (anhydrous, 50g), mixture was stirred 20 minutes, filter by silicagel pad then, with ether (300mL) washing.Concentrated filtrate uses methylbenzene azeotropic to remove the excessive hydrogen tert-butyl peroxide.Remaining oil through silica gel purification (the 0-30% ethyl acetate: hexane), obtain 24.80g (90%) [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol, be the colourless oil of viscosity.Ee per-cent:＞96.5%.MS(ESI)m/z 169.1([M+H] +)。
Step 4: in the reaction bottle of sealing, with indoline (1.42g, 11.89mmol) with [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (2.0g, mixture 11.89mmol) is 125 ℃ of down heating 5 hours for methyl alcohol.After the cooling, crude product is dissolved in ethyl acetate, be adsorbed onto on the Fluorocil, through Biotage chromatography purification (FlasH40i, silicon-dioxide, the 0-55%EtOAc/ hexane), obtain 2.55g (75%) (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is colourless oil.MS(ESI)m/z 288.1([M+H] +)。
Step 5: with (2S, 3S)-and 3-(2,3-dihydro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1,2-glycol (2.00g, 6.96mmol) (20.0g, 230mmol) mixture in methylene dichloride (30mL) stirred 3 hours down at 20 ℃ with activated manganese dioxide.Mixture with ethyl acetate (15mL) dilution, is filtered by silicagel pad, concentrate.Crude product is through Biotage chromatography purification (FlasH40i, silicon-dioxide, 0-70%EtOAc/ hexane), and (2S, 3S)-3-(3-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol is colourless oil to obtain 1.40g (71%).MS (ESI) m/z286.0 ([M+H] +) .HRMS: calculated value C 17H 16FNO 2+ H +, 286.1238; Measured value (ESI, [M+H] +), 286.1239.
Step 6: under nitrogen atmosphere, to (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol (452mg, 1.586mmol) add in the solution in methylene dichloride (3mL) triethylamine (1.1mL, 7.93mmol).Mixture is cooled to 0 ℃, add in batches Tosyl chloride (423mg, 2.22mmol).Reaction mixture was stirred 1 hour down at 0 ℃, store down at 0 ℃ and spend the night.The ethanol solution of adding methylamine (40mmol), with the reaction mixture sealing, spend the night, and is warming up to room temperature simultaneously for 8M, 5mL by stirring.Under reduced pressure remove all volatile matters.Oily resistates is dissolved in methylene dichloride (20mL), and with wet chemical (5mL) washing, dry (anhydrous sodium sulphate) concentrates.Through Biotage chromatography purification (FlasH12i, silicon-dioxide, 0-15%MeOH/ methylene dichloride/0.5% triethylamine), obtain (1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol, it is dissolved in methylene dichloride (5mL), with ethereal solution (1.9mL, 1.9mmol) processing of 1M hydrochloric acid.In gained solution, add hexane, generate, collect this powder until the adularescent powder, use hexane wash, dry in a vacuum, obtain 209mg (44%) (1S, 2R)-and 1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z 299.0 ([M+H] +); HRMS: calculated value C 18H 19FN 2O+H +, 299.1554; Measured value (ESI, [M+H] +), 299.1553.
Embodiment 48:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 3-methylbenzene are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[3-aminomethyl phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[3-aminomethyl phenyl]-H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(2-chloro-phenyl-)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluoro-phenyl)-3-[3-(3-aminomethyl phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride.MS (ESI) m/z 389.2; HRMS: calculated value C25H25FN2O+H+, 389.20237; Measured value (ESI, [M+H]+), 389.2005.
Embodiment 49:(1S, 2R)-1-(4-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801182
Step 1: by trans-4-fluorine styryl carbinol (Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N.J.Am.Chem.Soc., 2001,123,9525-9534), according to the mode that is similar to embodiment 47 steps 3 prepare [(2R, 3R)-3-(4-fluorophenyl) oxyethane-2-yl] methyl alcohol, be white solid.Ee per-cent:＞97%.MS(ES)m/z 167.0([M-H]-)。
Step 2: by 3-skatole and [(2R, 3R)-3-(4-fluorophenyl) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(4-fluorophenyl)-3-(3-Methyl-1H-indole-1-yl) propane-1, the 2-glycol is the colourless oil of viscosity.
MS (ES) m/z 300.1 ([M+H] +); HRMS: calculated value C 18H 18FNO 2+ H +, 300.1400; Measured value (ESI, [M+H] +), 300.1406.
Step 3: by (2S, 3S)-3-(4-fluorophenyl)-3-(3-Methyl-1H-indole-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(4-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride, be white powder.
MS (ESI) m/z 313.1 ([M+H] +); HRMS: calculated value C 19H 21FN 2O+H +, 313.1711; Measured value (ESI, [M+H] +), 313.1727.
Embodiment 50:(1S, 2R)-1-(2-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
By trans-2-fluoro cinnamic acid, prepare trans-2-fluoro cinnamic acid methyl esters according to the mode that is similar to embodiment 47 steps 1, be white solid.MSm/z 180.9([M+H] +)。
By trans-2-fluoro cinnamic acid methyl esters, prepare trans-2-fluorine styryl carbinol according to the mode that is similar to embodiment 47 steps 2, be colourless oil.
MS (ESI) m/z 152.0[M] +HRMS: calculated value C 9H 9FO, 152.0637; Measured value (ESI, [M] +), 152.0640.
By trans-2-fluorine styryl carbinol, according to the mode that is similar to embodiment 47 steps 3 prepare [(2R, 3R)-3-(2-fluorophenyl) oxyethane-2-yl] methyl alcohol, be white solid.MS m/z 169.0([M+H] +)。
By indoles and [(2R, 3R)-3-(2-fluorophenyl) oxyethane-2-yl] methyl alcohol, prepare according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(2-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 286.2 ([M+H] +); HRMS: calculated value C 17H 16FNO 2+ H +, 286.1238; Measured value (ESI, [M+H] +), 286.1231.
By (2S, 3S)-and 3-(2-fluorophenyl)-3-(3-methyl-H-indoles-1-yl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(2-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 299.1 ([M+H] +); HRMS: calculated value C 18H 19FN 2O+H +, 299.1554; Measured value (ESI, [M+H] +), 299.1557.
Embodiment 51:(1S, 2R)-1-(4-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
(embodiment 49 for methyl alcohol with [3-(4-fluorophenyl) oxyethane-2-yl] by indoles, step 1), according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(4-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol is the colourless oil of viscosity.
MS (ES) m/z 286.1 ([M+H] +); HRMS: calculated value C 17H 16FNO 2+ H +, 286.1238; Measured value (ESI, [M+H] +), 286.1230.
By (2S, 3S)-and 3-(4-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(4-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS(ES)m/z 299.1([M+H] +)。
Embodiment 52:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(3-aminomethyl phenyl) propane-2-alcohol hydrochloride
Figure A20058001737801202
By trans-3-tolyl acrylic acid, prepare trans-3-tolyl acrylic acid methyl esters according to the mode that is similar to embodiment 47 steps 1.
By trans-3-tolyl acrylic acid methyl esters, prepare trans-3-methyl styryl carbinol according to the mode that is similar to embodiment 47 steps 2, be colourless oil.
By trans-3-methyl styryl carbinol, according to the mode that is similar to embodiment 47 steps 3 prepare [(2R, 3R)-3-(3-aminomethyl phenyl) oxyethane-2-yl] methyl alcohol, be colourless oil.
HRMS: calculated value C 10H 12O 2+ H +, 165.0916; Measured value (ESI, [M+H] +), 165.0926.
By indoles and [(2R, 3R)-3-(3-aminomethyl phenyl) oxyethane-2-yl] methyl alcohol, prepare according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(1H-indoles-1-yl)-3-(3-aminomethyl phenyl) propane-1, the 2-glycol is the viscosity colourless liquid.MS (ES) m/z 282.1 ([M+H] +); HRMS: calculated value C 18H 19NO 2+ H +, 282.1494; Measured value (ESI, [M+H] +), 282.1488.
By (2S, 3S)-and 3-(1H-indoles-1-yl)-3-(3-aminomethyl phenyl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-(3-aminomethyl phenyl) propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z 295.3 ([M+H] +); HRMS: calculated value C 19H 20N 2O+ H +, 295.1805; Measured value (ESI, [M+H] +), 295.1799.
Embodiment 53:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol hydrochloride
Figure A20058001737801211
Step 1:, prepare trans-2-tolyl acrylic acid methyl esters according to the mode that is similar to embodiment 47 steps 1 by trans-2-tolyl acrylic acid.
Step 2: by trans-2-tolyl acrylic acid methyl esters, prepare trans-2-methyl styryl carbinol, be colourless oil according to the mode that is similar to embodiment 47 steps 2.MS(ES)m/z 146.9([M-H]-)。
Step 3: to trans-2-methyl styryl carbinol (1.50g, 10.14mmol) add in the solution in methylene dichloride (30mL) yellow soda ash (1.50g, 14.19mmol).Mixture is cooled to 10 ℃, via addition funnel drip peracetic acid (32wt%, 2.56mL, 12.16mmol).Reaction mixture was stirred 3 hours, be warming up to room temperature simultaneously, slowly use the saturated sodium sulfite aqueous solution (15mL) cancellation.Add more methylene dichloride (30mL), the extraction mixture.With organic layer salt water washing, dry (anhydrous sodium sulphate) concentrates.The oil resistates obtains 920mg (55%) 3-(2-aminomethyl phenyl) Racemic glycidol through silica gel chromatography purifying (10-30%EtOAc/ hexane), is colourless oil.
HRMS: calculated value C 10H 12O 2+ H +, 165.0916; Measured value (ESI, [M+H] +), 165.0936.
Step 4:, prepare according to the mode that is similar to embodiment 117 steps 5 that (2SR, 3SR)-3-(1H-indoles-1-yl)-3-(2-aminomethyl phenyl) propane-1, the 2-glycol is the viscosity colourless liquid by indoles and 3-(2-aminomethyl phenyl) Racemic glycidol.MS(ES)m/z 282.2([M+H] +)；
HRMS: calculated value C 18H 19NO 2+ H +, 282.1494; Measured value (ESI, [M+H] +), 282.1499.
Step 5: by (2SR, 3SR)-and 3-(1H-indoles-1-yl)-3-(2-aminomethyl phenyl) propane-1, the 2-glycol prepares (1SR according to the mode that is similar to embodiment 47 steps 6,2RS)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol, be oil.
Step 6: with racemic (1SR, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol is dissolved in ethanol (20mg/mL).Gained solution piled up be expelled on the supercritical fluid chromatograph, increment is 1mL.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use ChiralcelOJ-H 5 μ, 250mm L * 4.6mm ID post, flow velocity 1.2mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).
The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel OJ-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: the 15%MeOH/85%CO that contains 1.0%DEA 2
Flow velocity: 50mL/min
Top hole pressure: 100 crust
The UV of detector: 220nm
Step 7: by (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol, prepare (1S according to the mode that is similar to embodiment 144 steps 2,2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol hydrochloride, be white solid, be separated into the peak 1 (step 6) of chiral separation.Chiral purity: 100%.MS (ESI) m/z 295.3 ([M+H] +); HRMS: calculated value C 19H 22N 2O+H +, 295.1805; Measured value (ESI, [M+H] +), 295.1795.
Embodiment 54:(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol hydrochloride
Figure A20058001737801231
By (1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol, prepare (1R according to the mode that is similar to embodiment 53 steps 7,2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol hydrochloride, be white solid, (embodiment 53, step 6) to be separated into the peak 2 of chiral separation.Chiral purity: 100%.MS (ESI) m/z 295.3 ([M+H] +); HRMS: calculated value C 19H 22N 2O+H +, 295.1805; Measured value (ESI, [M+H] +), 295.1805.
Embodiment 55:(1S, 2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801232
Step 1: by (2S, 3S)-3-(3-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, (embodiment 47 for the 2-glycol, step 5), prepare 4-toluene sulfonic acide (2S according to the mode that is similar to embodiment 1 step 2,3S)-and 3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl) propyl diester, be ivory white solid.
HRMS: calculated value C 24H 22FN 2O 4S+H +, 440.1326; Measured value (ESI, [M+H] +), 440.1345.
Step 2: with the 4-toluene sulfonic acide (2S, 3S)-(200mg, (2.0M 10mL), stirred 12 hours in the reaction vessel of sealing 3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl) propyl diester 0.456mmol) to be dissolved in the methanol solution of ethamine.Under reduced pressure remove all volatile matters, liquid residue is dissolved in methylene dichloride (15mL), use the saturated potassium carbonate solution washing, dry (anhydrous sodium sulphate) concentrates.Liquid residue is through Biotage chromatography purification (FIasH12i, silicon-dioxide, 0-15%MeOH/ methylene dichloride/0.5% triethylamine), obtain (1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(ethylamino) propane-2-alcohol, use it for and prepare according to the mode that is similar to embodiment 144 steps 2 that (1S 2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol hydrochloride, is white powder.Yield: 99mg (70%).MS (ES) m/z 313.1 ([M+H] +); HRMS: calculated value C 19H 21FN 2O+H +, 313.1716; Measured value (ESI, [M+H] +), 313.1716.
Embodiment 56:(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-morpholine-4-base propane-2-alcohol hydrochloride
Figure A20058001737801241
By morpholine and 4-toluene sulfonic acide (2S, 3S)-(embodiment 55 for propyl diester for 3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl), step 1), prepare (1S according to the mode that is similar to embodiment 55 steps 2,2R)-and 1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-morpholine-4-base propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z355.1 ([M+H] +); HRMS: calculated value C 21H 23FN 2O 2+ H +, 355.1816; Measured value (ESI, [M+H] +), 355.1822.
Embodiment 57:(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(propyl group amino) propane-2-alcohol hydrochloride
By propylamine and 4-toluene sulfonic acide (2S, 3S)-(embodiment 55 for propyl diester for 3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl), step 1), prepare (1S according to the mode that is similar to embodiment 55 steps 2,2R)-and 1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(propyl group amino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 327.1 ([M+H] +); HRMS: calculated value C 20H 23FN 2O+H +, 327.1867; Measured value (ESI, [M+H] +), 327.1873.
Embodiment 58:(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl) propane-2-alcohol dihydrochloride
Figure A20058001737801243
By 1-methylpiperazine and 4-toluene sulfonic acide (2S, 3S)-(embodiment 55 for propyl diester for 3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl), step 1), prepare (1S according to the mode that is similar to embodiment 55 steps 2,2R)-and 1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl) propane-2-alcohol dihydrochloride, be white powder.MS (ES) m/z 368.1 ([M+H] +); HRMS: calculated value C 22H 26FN 3O+H +, 368.2133; Measured value (ESI, [M+H] +), 368.2138.
Embodiment 59:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(4-aminomethyl phenyl) propane-2-alcohol hydrochloride
Figure A20058001737801251
By trans-4-methyl styryl carbinol (Takeuchi, R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N.J.Am.Chem.Soc., 2001,123,9525-9534), according to the mode that is similar to embodiment 47 steps 3 prepare [(2R, 3R)-3-(4-aminomethyl phenyl) oxyethane-2-yl] methyl alcohol, be colourless oil.MS (ES) m/z 165.1 ([M+H] +); HRMS: calculated value C 10H 12O 2+ H +, 165.0916; Measured value (ESI, [M+H] +), 165.0937.
By indoles and [(2R, 3R)-3-(4-aminomethyl phenyl) oxyethane-2-yl] methyl alcohol, prepare according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(1H-indoles-1-yl)-3-(4-aminomethyl phenyl) propane-1, the 2-glycol is the viscosity colourless liquid.MS (ES) m/z 282.1 ([M+H] +); HRMS: calculated value C 18H 19NO 2+ H +, 282.1494; Measured value (ESI, [M+H] +), 282.1492.
By (2S, 3S)-and 3-(1H-indoles-1-yl)-3-(4-aminomethyl phenyl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-(4-aminomethyl phenyl) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 295.1 ([M+H] +); HRMS: calculated value C 19H 22N 2O+H +, 295.1805; Measured value (ESI, [M+H] +), 295.1810.
Embodiment 60:(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, (embodiment 47 for the 2-glycol, step 4), according to the mode that is similar to embodiment 47 steps 6 prepare (1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-and 1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white solid.
MS (ES) m/z 301.1 ([M+H] +); HRMS: calculated value C 18H 21FN 2O+H +, 301.1711; Measured value (ESI, [M+H] +), 301.1716.
Embodiment 61:(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801261
By indoline and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 270.2 ([M+H] +); HRMS: calculated value C 17H 20NO 2+ H +, 270.1494; Measured value (ESI, [M+H] +), 270.1493.
By (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 6 prepare (1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-and 3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ES)m/z 283.1([M+H] +)；
HRMS: calculated value C 18H 21N 2O+H +, 283.1805; Measured value (ESI, [M+H] +), 283.1810.
Embodiment 63:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801262
By 2-methyl indoline and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the colourless oil of viscosity.
MS (ES) m/z 302.1 ([M+H] +); HRMS: calculated value C 18H 20FNO 2+ H +, 302.1551; Measured value (ESI, [M+H] +), 302.1556.
By (2S, 3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z315.0 ([M+H] +); HRMS: calculated value C 19H 23FN 2O+H +, 315.1867; Measured value (ESI, [M+H] +), 315.1850.
Embodiment 64:(1S, 2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Step 1: with 7-fluoro-3,3-dimethyl oxindole (embodiment 99, step 5, and 2.24g, 12.5mmol) mixture in toluene (15mL) heats down at 80 ℃ under nitrogen atmosphere.Via addition funnel drip two (2-methoxyethoxy) sodium aluminates (vitride) of dihydro (the 65wt% toluene solution, 6mL, 19.3mmol).Gained solution was stirred other 1.5 hours down at 80 ℃, in ice bath, cool off then.(1N, 15mL), cancellation is reacted slowly to add aqueous sodium hydroxide solution.Add entry (15mL), reaction mixture extracts with ethyl acetate (20mL).With organic layer salt water washing, dry (anhydrous sodium sulphate) filters by silicagel pad, under reduced pressure concentrates, and obtains 1.68g (82%) 7-fluoro-3, and 3-dimethyl indoline is colourless oil.MS (ES) m/z 166.1 ([M+H] +); HRMS: calculated value C 10H 12FN+H +, 166.1032; Measured value (ESI, [M+H] +), 166.1040.
Step 2: by 7-fluoro-3,3-dimethyl indoline and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 334.1 ([M+H] +); HRMS: calculated value C 19H 21F 2NO 2+ H +, 334.1613; Measured value (ESI, [M+H] +), 334.1616.
Step 3: by (2S, 3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 347 ([M+H] +); HRMS: calculated value C 20H 24F 2N 2O+H +, 347.1929; Measured value (ESI, [M+H] +), 347.1935.
Embodiment 65:(1S, 2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801281
By 7-fluoro-3, (embodiment 64 for 3-dimethyl indoline, step 1) and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z316.1 ([M+H] +); HRMS: calculated value C 19H 22FNO 2+ H +, 316.1707; Measured value (ESI, [M+H] +), 316.1690.
By (2S, 3S)-3-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.
HRMS: calculated value C 20H 25FN 2O+H +, 329.2029; Measured value (ESI, [M+H] +), 329.2041.
Embodiment 66:(1S, 2R)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801282
By 7-methyl indoline (Gribble, G.W.; Hoffman, J.H.Synthesis 1977,12,859-860) and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.MS(ES)m/z 284.2([M+H] +)；
HRMS: calculated value C 18H 21NO 2+ H +, 284.1651; Measured value (ESI, [M+H] +), 284.1650.
By (2S, 3S)-3-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 297.0 ([M+H] +); HRMS: calculated value C 19H 24N 2O+H +, 297.1961; Measured value (ESI, [M+H] +), 297.1957.
Embodiment 67:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride
By 7-methyl indoline (Gribble, G.W.; Hoffman, J.H.Synthesis 1977,12,859-860) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3-fluorophenyl)-3-(7-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 302.1 ([M+H] +); HRMS: calculated value C 18H 20FNO 2+ H +, 302.1551; Measured value (ESI, [M+H] +), 302.1551.
By (2S, 3S)-3-(3-fluorophenyl)-3-(7-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride, be white solid.
MS (ES) m/z 315.0 ([M+H] +); HRMS: calculated value C 19H 23FN 2O+H +, 315.1873; Measured value (ESI, [M+H] +), 315.1862.
Embodiment 68:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride
By 5-methyl indoline and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(3-fluorophenyl)-3-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the colourless oil of viscosity.
MS(ES)m/z 302.1([M+H] +)；
HRMS: calculated value C 18H 20FNO 2, 302.1551; Measured value (ESI, [M+H] +), 302.1551.
By (2S, 3S)-3-(3-fluorophenyl)-3-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride, be white solid.
MS (ES) m/z 315.0 ([M+H] +); HRMS: calculated value C 19H 23FN 2O+H +, 315.1873; Measured value (ESI, [M+H] +), 315.1896.
Embodiment 69:(1S, 2R)-1-(1H-indoles-1-yl)-1-(3-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 3-methoxybenzaldehyde and ethoxycarbonylmethyl group diethyl phosphonate, prepare (2E)-3-(3-p-methoxy-phenyl) ethyl propenoate according to the mode that is similar to embodiment 33 steps 1.
1H NMR (DMSO): 1.26 (t, 3H, OCH 2CH 3), 3.79 (s, 3H, OCH 3), 4.19 (q, 2H, OCH 2CH 3), 6.66 (d, 1H, CH=CHC (O)), 6.99 (m, 1H, CH=CH (CO)), 7.31 (m, 3H, ArH) and 7.62 (d, 1H, ArH).
By (2E)-3-(3-p-methoxy-phenyl) ethyl propenoate, prepare (2E)-3-(3-p-methoxy-phenyl) third-2-alkene-1-alcohol according to the mode that is similar to embodiment 33 steps 2.MS(ES)m/z 147.2([M+H-H 2O] +)。
By (2E)-3-(3-p-methoxy-phenyl) third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare [(2R, 3R)-3-(3-p-methoxy-phenyl) oxyethane-2-yl] methyl alcohol.MS(ES)m/z222([M+H+CH 3CN] +)；93.2％ee。
By the 1H-indoles and [(2R, 3R)-3-(3-p-methoxy-phenyl) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(1H-indoles-1-yl)-3-(3-p-methoxy-phenyl) propane-1, the 2-glycol.MS(ES)m/z 298.2([M+H] +)。
By (2S, 3S)-3-(1H-indoles-1-yl)-3-(3-p-methoxy-phenyl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-(1H-indoles-1-yl)-3-(3-p-methoxy-phenyl)-propyl diester.MS(ES)m/z 452.2([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-(1H-indoles-1-yl)-3-(3-p-methoxy-phenyl)-propyl diester, according to the mode that is similar to embodiment 33 steps 6 prepare (1S, 2R)-1-(1H-indoles-1-yl)-1-(3-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 311.3([M+H] +)；
HRMS: calculated value C 19H 22N 2O 2+ H +, 311.17540; Measured value (ESI, [M+H] +), 311.1758.
Embodiment 70:(1SR, 2RS)-1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801311
(2.11g, 10.1mmol) (1.14mL, mixture 10.1mmol) are heated to 135 ℃ and reach 16 hours in the sealing test tube with indoline with trans-3-(4-p-methoxy-phenyl) glycidic acid methyl esters.The refrigerative reaction mixture directly passes through purified by flash chromatography (silicon-dioxide, 20%, 30% ethyl acetate/hexane) then, obtain 2.94g (89%) (2SR, 3SR)-and 3-(2,3-dihydro-1H-indoles-1-yl)-2-hydroxyl-3-(4-p-methoxy-phenyl) methyl propionate, be yellow solid.MS (ES) m/z 328.2 ([M+H] +); HRMS: calculated value C 19H 21NO 4+ H +, 328.15434; Measured value (ESI, [M+H] +), 328.1536.
In under 0 ℃ under nitrogen atmosphere, go through 5 fens clockwise (2SR, 3SR)-3-(2,3-dihydro-1H-indoles-1-yl)-2-hydroxyl-3-(4-p-methoxy-phenyl) methyl propionate (2.63g, 8.0mmol) add 2,3-two chloro-5,6-dicyano-1 in the solution in dry toluene (50mL), 4-benzoquinones (1.87g, 8.2mmol) solution in dry toluene (50mL).Reaction mixture was stirred 1.5 hours to room temperature at 0 ℃, add 7%w/v aqueous sodium carbonate (100mL) cancellation then.With gained two-phase mixture vigorous stirring 5 minutes, between ethyl acetate (300mL) and 7%w/v aqueous sodium carbonate (250mL), distribute then.Separate organic phase, with the 7%w/v aqueous sodium carbonate (3 * 250mL), water (250mL) and saturated brine (250mL) washing, through anhydrous magnesium sulfate drying, filter, under reduced pressure concentrated, obtain the lavender solid.Through purified by flash chromatography (silicon-dioxide, 20%, 30% ethyl acetate/hexane), (2SR 3SR)-2-hydroxyl-3-(1H-indoles-1-yl)-3-(4-p-methoxy-phenyl) methyl propionate, is the butteriness solid to obtain 2.5g (96%).MS (ES) m/z 326.3 ([M+H] +); HRMS: calculated value C 19H 19NO 4+ H +, 326.13869; Measured value (ESI, [M+H] +), 326.1378.
Will (2SR, 3SR)-(2.43g, 7.5mmol) (the 33%wt. ethanol solution, 40mL) solution in is heated to 75 ℃ in sealing in the test tube and reaches 1 hour 2-hydroxyl-3-(1H-indoles-1-yl)-3-(4-p-methoxy-phenyl) methyl propionate at methylamine solution.Under reduced pressure concentrate the refrigerative reaction mixture then, obtain yellow syrup thing.Crystallization purifying from 80% chloroform/hexane (50mL), (2SR 3SR)-2-hydroxyl-3-(1H-indoles-1-yl)-3-(4-p-methoxy-phenyl)-N-methyl propanamide, is the white crystalline solid to obtain 1.93g (80%).MS (ES) m/z 323.2 ([M-H] -); HRMS: calculated value C 19H 20N 2O 3+ H +, 325.15467; Measured value (ESI, [M+H] +), 325.1562.
In under the room temperature under nitrogen atmosphere, to (2SR, 3SR)-2-hydroxyl-3-(1H-indoles-1-yl)-3-(4-p-methoxy-phenyl)-N-methyl propanamide (900mg, 2.8mmol) drip borine-tetrahydrofuran (THF) title complex (1.0M tetrahydrofuran solution in the solution in anhydrous tetrahydro furan (50mL), 13.9mL, 13.9mmol), mixture heating up is reached 3 hours to refluxing.Reaction mixture is cooled to 50 ℃ then, adds methyl alcohol (20mL), mixture was stirred 1 hour down at 50 ℃.Under reduced pressure concentrate the refrigerative reaction mixture then, obtain white solid.Through purified by flash chromatography (silicon-dioxide, 15% ethanol/methylene), (1SR 2RS)-1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol, is yellow syrup thing to obtain 272mg (32%).Product is dissolved in dehydrated alcohol (4mL), add hydrogen chloride solution (4M 1,4-two  alkane solution, 0.28mL 1.12mmol), with solution stirring 10 minutes, under reduced pressure concentrates then, obtains white foam.Under-35 ℃ from 1: 1: 1v/v dehydrated alcohol: ether: crystallization the hexane (12mL), obtain 81.3mg (8%) (1SR, 2RS)-and 1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be the water absorbability white solid.MS (ES) m/z 311.3 ([M+H] +); HRMS: calculated value C 19H 22N 2O 2+ H +, 311.17540; Measured value (ESI, [M+H] +), 311.176.
Embodiment 71:(1RS, 2SR)-3-(methylamino)-1-(2-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Step 1: with sodium hydride (60% mineral oil dispersion, 0.40g, 10mmol) with the mixture of the trimethyl carbinol (5mL) under nitrogen atmosphere, stirring 15 minutes under the room temperature.(1.31g, the 10mmol) solution in methylene dichloride (2mL) stirred mixture other 30 minutes under room temperature to add 2 methyl indole then.(3.55mL, 12mmol) (1.5g, the 10mmol) premixed solution in methylene dichloride (2mL) stirred reaction mixture 15 hours under room temperature, do not have the epoxide residue until measuring according to TLC with trans-3-phenyl glycidyl to add titanium isopropylate.Mixture is filtered by Celite pad, under agitation go through 30 minutes then filtrate usefulness 2N aqueous hydrochloric acid (50mL) processing.Separate organic layer, water layer dichloromethane extraction several times.Combining extraction liquid washes with water, through anhydrous sodium sulfate drying, filters, and concentrates in a vacuum.Crude product is via Biotage Horizon purifying (Flash 40M, silicon-dioxide, gradient: 10% ethyl acetate/hexane to 65% ethyl acetate/hexane), obtain (2RS, 3RS)-and 3-(2-methyl-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is white solid.MS(ESI)m/z 282([M+H] +)。
By (2RS, 3RS)-3-(2-methyl-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares according to the mode that is similar to embodiment 1 step 2 that (2RS 3RS)-toluene-4-sulfonic acid 3-(2-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, is oil.MS(ESI)m/z 436([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(2-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine (2N methanol solution), prepare (1RS according to the mode that is similar to embodiment 5,2SR)-and 3-(methylamino)-1-(2-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be pale brown look solid.MS(ES)m/z 295.0；
HRMS: calculated value C19H22N2O+H+, 295.18049; Measured value (ESI, [M+H] +), 295.1818.
Embodiment 72:(1RS, 2SR)-1-(1H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By benzoglyoxaline and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 17 steps 1 that (2RS, 3RS)-3-(1H-benzoglyoxaline-1-yl)-3-phenyl-propane-1, the 2-glycol is the oily solid.MS(ESI)m/z 269([M+H] +)。
By (2RS, 3RS)-1-(1H-benzoglyoxaline-1-yl)-3-phenyl-propane-1, the 2-glycol prepares according to the mode that is similar to embodiment 1 step 2 that (2RS 3RS)-toluene-4-sulfonic acid 3-benzoglyoxaline-1-base-2-hydroxyl-3-phenyl-propyl diester, is white solid.MS(ESI)m/z 423([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-benzoglyoxaline-1-base-2-hydroxyl-3-phenyl-propyl diester and methylamine (2N methanol solution), prepare (1RS according to the mode that is similar to embodiment 5,2SR)-and 1-(1H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z282.1; HRMS: calculated value C17H19N3O+H+, 282.16009; Measured value (ESI, [M+H] +), 282.1617.
Embodiment 73:(1RS, 2SR)-3-(methylamino)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801341
By 2 tolimidazoles and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 17 steps 1 that (2RS, 3RS)-3-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-3-phenyl-propane-1, the 2-glycol is yellow solid.MS(ESI)m/z 283([M+H] +)。
By (2RS, 3RS)-and 3-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2RS according to the mode that is similar to embodiment 1 step 2,3RS)-and toluene-4-sulfonic acid 2-hydroxyl-3-(2-methyl-benzoglyoxaline-1-yl)-3-phenyl propyl ester, be white solid.MS(ESI)m/z 437([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-(2-methyl-benzoglyoxaline-1-yl)-3-phenyl propyl ester and methylamine, prepare (1RS according to the mode that is similar to embodiment 5,2SR)-and 1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 296.1; SHRMS: calculated value C18H21N3O+H+, 296.17574; Measured value (ESI, [M+H] +), 296.1752.
Embodiment 74:(1RS, 2SR)-1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801342
By 4-methoxyl group indoles and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 17 steps 1 that (2RS, 3RS)-3-(4-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 298([M+H] +)。
By (2RS, 3RS)-and 3-(4-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2RS according to the mode that is similar to embodiment 1 step 2,3RS)-and toluene-4-sulfonic acid 2-hydroxyl-3-(4-methoxyl group-indoles-1-yl)-3-phenyl propyl ester, be white solid.MS(ESI)m/z 452([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 2-hydroxyl-3-(4-methoxyl group-indoles-1-yl)-3-phenyl propyl ester and methylamine, prepare (1RS according to the mode that is similar to embodiment 5,2SR)-and 3-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z311; HRMS: calculated value C19H22N2O2+H+, 311.17540; Measured value (ESI, [M+H] +), 311.1772
Embodiment 75:(1S, 2R)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801351
By the 5-fluoro indole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares according to the mode that is similar to embodiment 17 steps 1 that (2S, 3S)-3-(5-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil for methyl alcohol.MS(ESI)m/z 286([M+H] +)。
By (2S, 3S)-3-(5-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares according to the mode that is similar to embodiment 1 step 2 that (2S 3S)-toluene-4-sulfonic acid 3-(5-fluoro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, is oil.MS(ESI)m/z 438([M+H] +)。
By (2S, 3S) toluene-4-sulfonic acid 3-(5-fluoro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare according to the mode that is similar to embodiment 5 that (1S 2R)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, is white solid.MS (ES) m/z 299.1; HRMS: calculated value C18H19FN2O+H+, 299.15542; Measured value (ESI, [M+H] +), 299.1556.
Embodiment 76:(1S, 2R)-1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801352
By 5-methoxyl group indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 17 steps 1,3S)-and 3-(5-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 298([M+H] +)。
By (2S, 3S)-and 3-(5-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(5-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 452([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(5-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 311.1; HRMS: calculated value C19H22N2O2+H+, 311.17540; Measured value (ESI, [M+H] +), 311.1745.
Embodiment 77:(1S, 2R)-1-(7-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801361
By 7-methoxyl group indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 17 steps 1,3S)-and 3-(7-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 298([M+H] +)。
By (2S, 3S)-and 3-(7-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(7-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 452([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(7-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(7-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 311.1; HRMS: calculated value C19H22N2O2+H+, 311.17540; Measured value (ESI, [M+H] +), 311.1753.
Embodiment 78:(1S, 2R)-1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801362
By 4-methoxyl group indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 17 steps 1,3S)-and 3-(4-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 298([M+H] +)。
By (2S, 3S)-and 3-(4-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(4-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 452([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(4-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ESI) m/z 311; HRMS: calculated value C19H22N2O2+H+, 311.17540; Measured value (ESI, [M+H] +), 311.175.
Embodiment 79:(1S, 2R)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 6-methoxyl group indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 17 steps 1,3S)-and 3-(6-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 298([M+H] +)。
By (2S, 3S)-and 3-(6-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(6-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 452([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(6-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ESI) m/z 311; HRMS: calculated value C19H22N2O2+H+, 311.17540; Measured value (ESI, [M+H] +), 311.1757.
Embodiment 80:(1RS, 2SR)-1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801381
By 5-methoxyl group indoles and trans-3-phenyl glycidyl, prepare according to the mode that is similar to embodiment 17 steps 1 that (2RS, 3RS)-3-(5-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 298([M+H] +)。
By (2RS, 3RS)-and 3-(5-methoxyl group-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (2RS according to the mode that is similar to embodiment 1 step 2,3RS)-and toluene-4-sulfonic acid 3-(5-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 452([M+H] +)。
By (2RS, 3RS)-toluene-4-sulfonic acid 3-(5-methoxyl group-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1RS according to the mode that is similar to embodiment 5,2SR)-and 1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ESI) m/z 311; HRMS: calculated value C19H22N2O2+H+, 311.17540; Measured value (ESI, [M+H] +), 311.1756.
Embodiment 81:(1S, 2R)-1-(3-fluorophenyl)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methyl-amino) propane-2-alcohol hydrochloride
By 6-methoxyl group indoles and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, step 3) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 17 steps 1,3S)-and 3-(6-methoxyl group-1H-indoles-1-yl)-3-(3-fluorophenyl)-propane-1, the 2-glycol is oil.MS(ESI)m/z 316([M+H] +)。
By (2S, 3S)-and 3-(6-methoxyl group-1H-indoles-1-yl)-3-(3-fluorophenyl)-propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(6-methoxyl group-indoles-1-yl)-2-hydroxyl-3-(3-fluorophenyl)-propyl diester, be oil.MS(ESI)m/z 470([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(6-methoxyl group-indoles-1-yl)-2-hydroxyl-3-(3-fluorophenyl)-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(3-fluorophenyl)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 329.2; HRMS: calculated value C19H21FN2O2+H+, 329.16598; Measured value (ESI, [M+H] +), 329.1663.
Embodiment 82:(1S, 2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-2-alcohol
Figure A20058001737801391
By the 7-azaindole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, according to the mode that is similar to embodiment 17 steps 1 prepare (2S, 3S)-3-phenyl-3-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-1, the 2-glycol is white solid.MS (ES) m/z 269.2; HRMS: calculated value C16H16N2O2+H+, 269.12845; Measured value (ESI, [M+H] +), 269.13.
By (2S, 3S)-3-phenyl-3-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 2-hydroxyl-3-phenyl-3-pyrrolo-[2,3-b] pyridine-1-base-propyl diester, be oil.MS(ESI)m/z 423([M+H] +)。
By (2S, 3S) toluene-4-sulfonic acid 2-hydroxyl-3-phenyl-3-pyrrolo-[2,3-b] pyridine-1-base-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-2-alcohol, be white solid.MS (ES) m/z 282.3; HRMS: calculated value C17H19N3O+H+, 282.16009; Measured value (ESI, [M+H] +), 282.16.
Embodiment 83:(1S, 2R)-1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801392
By 5-chlorine indoline and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 322.1 ([M+H] +); HRMS: calculated value C 17H 17ClFNO 2+ H +, 322.1005; Measured value (ESI, [M+H] +), 322.1005.
By (2S, 3S)-3-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z335.1 ([M+H] +); HRMS: calculated value C 18H 20ClFN 2O+H +, 335.1326; Measured value (ESI, [M+H] +), 335.1349.
Embodiment 84:(1S, 2R)-3-methylamino-1-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol dihydrochloride
By 7-chloro-1H-pyrrolo-[2,3-c] pyridine (Zhang, people such as Z., J.Org.Chem.2002,67,2345-2347) and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), according to the mode that is similar to embodiment 17 steps 1 prepare (2S, 3S)-3-(7-chloro-1H-pyrrolo-[2,3-c] pyridine-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ES)m/z 303([M+H] +)。
By (2S, 3S)-3-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 457([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-1-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-3-methylamino-1-phenyl-propane-2-alcohol, be white solid.MS(ES)m/z316.1([M+H] +)。
Step 4: will (1S, 2R)-(0.12g 0.38mmol) is dissolved in ethanol (20mL) to 1-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-3-methylamino-1-phenyl-propane-2-alcohol, handles with 10% palladium on carbon.Reaction mixture placed on the Parr vibrator assigned 15 hours at 50psi hydrogen.Reaction mixture is filtered by Celite pad, in a vacuum concentrated filtrate.Crude product via Biotage Horizon purifying (Flash 25S, silicon-dioxide, gradient: 0.9% ammonium hydroxide in 10% methyl alcohol-methylene dichloride 30% to 100% solution/methylene dichloride), obtain white solid, be the free alkali of expection product.Free alkali being dissolved in small amount of ethanol, handling with the ethereal solution of 1N hydrochloric acid, is pH=3 until solution, handles with ether then.Add amount of ethyl acetate then and make the product crystallization, (1S 2R)-3-methylamino-1-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl)-propane-2-alcohol dihydrochloride, is white solid to obtain title compound.MS(ES)m/z 282.1。
Embodiment 85:(1S, 2R)-1-(5-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methyl-amino) propane-2-alcohol hydrochloride
Figure A20058001737801411
By the 5-fluoro indole and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, step 3) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 17 steps 1,3S)-and 3-(5-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl)-propane-1, the 2-glycol is oil.MS(ESI)m/z 304([M+H] +)。
By (2S, 3S)-and 3-(5-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl)-propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(5-fluoro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, be oil.MS(ESI)m/z 458([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(5-fluoro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-and 1-(5-fluoro-1H-indol-3-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be the sundown solid.MS (ES) m/z 317.2; HRMS: calculated value C18H18F2N2O+H+, 317.14599; Measured value (ESI, [M+H] +), 317.1472.
Embodiment 86:(1S, 2R)-3-methylamino-1-(3-fluorophenyl)-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol dihydrochloride
By 7-chloro-1H-pyrrolo-[2,3-c] pyridine (Zhang, people such as Z., J.Org.Chem.2002,67,2345-2347) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 17 steps 1 prepare (2S, 3S)-3-(7-chlorine pyrrolo-[2,3-c] pyridine-1-yl)-3-(3-fluorophenyl)-propane-1, the 2-glycol is oil.MS(ESI)m/z 321([M+H] +)。
By (2S, 3S)-3-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-3-(3-fluorophenyl)-propane-1, the 2-glycol, prepare (2S according to the mode that is similar to embodiment 1 step 2,3S)-and toluene-4-sulfonic acid 3-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-2-hydroxyl-3-(3-fluorophenyl)-propyl diester, be oil.MS(ESI)m/z 475([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-2-hydroxyl-3-(3-fluorophenyl)-propyl diester and methylamine, prepare (1S according to the mode that is similar to embodiment 5,2R)-1-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-3-methylamino-1-(3-fluorophenyl)-propane-2-alcohol, be white solid.MS(ESI)m/z 334([M+H] +)。
By (1S, 2R)-1-(7-chloro-pyrrolo-[2,3-c] pyridine-1-yl)-3-methylamino-1-(3-fluorophenyl)-propane-2-alcohol, prepare (1S according to the mode that is similar to embodiment 84 steps 4,2R)-3-methylamino-1-(3-fluorophenyl)-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl)-propane-2-alcohol dihydrochloride, be white solid.MS(ESI)m/z 282.1([M+H] +)。
Embodiment 87:(1S, 2R)-1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801421
By 5-chlorine indoline and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.
MS (ES) m/z 304.1 ([M+H] +); HRMS: calculated value C 17H 18ClNO 2+ H +, 304.1099; Measured value (ESI, [M+H] +), 304.1081.
By (2S, 3S)-3-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z317.1 ([M+H] +); HRMS: calculated value C 18H 21ClN 2O+H +, 317.1421; Measured value (ESI, [M+H] +), 317.1431.
Embodiment 88:(1S, 2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-1-(3, the 5-difluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801431
Step 1: by 6-chloro-2H-1,4-benzoxazine-3 (4H)-ketone prepares 6-chloro-3 according to the mode that is similar to embodiment 165 steps 1,4-dihydro-2H-1, and the 4-benzoxazine is yellow solid.MS (ES) m/z170.0 ([M+H] +); HRMS: calculated value C 8H 8ClNO+H +, 170.0367; Measured value (ESI, [M+H] +), 170.0365.
Step 2: by 6-chloro-3,4-dihydro-2H-1,4-benzoxazine and [(2R, 3R)-3-(3, the 5-difluorophenyl) oxyethane-2-yl] (embodiment 157, and step 3) prepares (2S according to the mode that is similar to embodiment 47 steps 4 for methyl alcohol, 3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(3, the 5-difluorophenyl) propane-1, the 2-glycol is the little yellow liquid of viscosity.MS (ES) m/z 356.1 ([M+H] +); HRMS: calculated value C 17H 16ClF 2NO 3+ H +, 356.0860; Measured value (ESI, [M+H] +), 356.0869.
Step 3: by (2S, 3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(3, the 5-difluorophenyl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 6 prepare (1S, 2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 1-(3, the 5-difluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 369.1 ([M+H] +); HRMS: calculated value C 18H 19ClF 2N 2O 2+ H +, 369.1176; Measured value (ESI, [M+H] +), 369.1178.
Embodiment 89:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-2-alcohol hydrochloride
By 2-methyl-2H-1,4-benzoxazine-3 (4H)-ketone (Wheeler, K.W.J.Med.Pharm.Chem.1962,5,1378-1383), prepare 2-methyl-3 according to the mode that is similar to embodiment 165 steps 1,4-dihydro-2H-1, the 4-benzoxazine is the oil of brown.MS(ES)m/z 149.9([M+H] +)。
By 2-methyl-3,4-dihydro-2H-1, the 4-benzoxazine and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, step 3) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-1, the 2-glycol is the viscosity brown liquid.MS (ES) m/z 318.2 ([M+H] +); HRMS: calculated value C 18H 20FNO 3+ H +, 318.1500; Measured value (ESI, [M+H] +), 318.1513.
By (2S, 3S)-3-(3-fluorophenyl)-3-(2-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 331.0 ([M+H] +); HRMS: calculated value C 19H 23FN 2O 2+ H +, 331.1816; Measured value (ESI, [M+H] +), 331.1804.
Embodiment 90:(1S, 2R)-3-(methylamino)-1-(6-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By 6-skatole and 2R, 3R-(+)-3-phenyl glycidyl prepares according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(6-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 282([M+H] +)。
By (2S, 3S)-3-(6-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(6-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 436([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(6-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl group and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-3-(methylamino)-1-(6-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 295 ([M+H] +); HRMS: calculated value C19H22N2O+H+, 295.18049; Measured value (ESI-FT/MS, [M+H] 1+), 295.1809.
Embodiment 91:(1S, 2R)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By 7-skatole and 2R, 3R-(+)-3-phenyl glycidyl prepares according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(7-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 282([M+H]+] +)。
By (2S, 3S)-3-(7-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(7-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 436([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(7-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 295 ([M+H] +); HRMS: calculated value C19H22N2O+H+, 295.18049; Measured value (ESI-FT/MS, [M+H] 1+), 295.1809.
Embodiment 92:((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801451
By the 5-skatole and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol is (referring to embodiment 47, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(5-Methyl-1H-indole-1-yl) propane-1, the 2-glycol is oil.MS(ESI)m/z 300([M+H] +)。
By (2S, 3S)-3-(3-fluorophenyl)-3-(5-Methyl-1H-indole-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(5-methyl-indoles-1-yl)-2-hydroxyl-propyl diester.MS(ESI)m/z 454([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(5-methyl-indoles-1-yl)-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare ((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride.MS (ESI) m/z 311; ([M+H] +); HRMS: calculated value C19H21FN2O+H+, 313.17107; Measured value (ESI-FTMS, [M+H] 1+), 313.17163.
Embodiment 93:((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801461
By 7 skatoles and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol is (referring to embodiment 47, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(7-Methyl-1H-indole-1-yl) propane-1, the 2-glycol is oil.MS(ESI)m/z 300([M+H] +)。
By (2S, 3S)-3-(3-fluorophenyl)-3-(7-Methyl-1H-indole-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(7-methyl-indoles-1-yl)-2-hydroxyl-propyl group.MS(ESI)m/z 454([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(7-methyl-indoles-1-yl)-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare ((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride.MS (ESI) m/z 311; ([M+H] +); HRMS: calculated value C19H21FN2O+H+, 313.17107; Measured value (ESI-FTMS, [M+H] 1+), 313.17141.
Embodiment 94:(1S, 2R)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801462
By 4-skatole (Raucher, Stanley; Koolpe, Gary A.J.Org.Chem.1983,48 (12), 2066-9) and 2R, 3R-(+)-3-phenyl glycidyl prepares (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(4-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 282([M+H] +)。
By (2S, 3S)-3-(4-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(4-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 436([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(4-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 295 ([M+H] +); HRMS: calculated value C19H22N2O+H+, 295.18049; Measured value (ESI-FT/MS, [M+H] 1+), 295.1811.
Embodiment 95:(1S, 2R)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801471
By 5-skatole and 2R, 3R-(+)-3-phenyl glycidyl prepares according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(5-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 282([M+H] +)。
By (2S, 3S)-3-(5-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(5-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 436([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(5-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl group and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride.MS (ESI) m/z 295 ([M+H] +); HRMS: calculated value C19H22N2O+H+, 295.18049; Measured value (ESI-FT/MS, [M+H] 1+), 295.1812.
Embodiment 96:((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride
By 4-skatole (Raucher, Stanley; Koolpe, Gary A.J.Org.Chem.1983,48 (12), 2066-9) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol is (referring to embodiment 47, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(4-Methyl-1H-indole-1-yl) propane-1, the 2-glycol is oil.MS(ESI)m/z 300([M+H] +)。
By (2S, 3S)-3-(3-fluorophenyl)-3-(4-Methyl-1H-indole-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(4-methyl-indoles-1-yl)-2-hydroxyl-propyl diester.MS(ESI)m/z 454([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(4-methyl-indoles-1-yl)-2 hydroxyls-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare ((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride.MS (ESI) m/z 311; ([M+H] +); HRMS: calculated value C19H21FN2O+H+, 313.17107; Measured value (ESI-FT/MS, [M+H] 1+), 313.171.
Embodiment 97:((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-ethyl-1H-indoles-1-yl) propane-2-alcohol hydrochloride
By 3-ethylindole (Ainsworth, D.P.; Suschitzky, Hans J.ChemSoc.[Section] C:Organic 1967, (4), 315-19) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol is (referring to embodiment 47, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(3-ethyl-1H-indoles-1-yl) propane-1, the 2-glycol is oil.MS(ESI)m/z 314([M+H] +)。
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-ethyl-1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(3-ethyl-indoles-1-yl)-2-hydroxyl-propyl diester.MS(ESI)m/z 468([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(3-ethyl-indoles-1-yl)-2-hydroxy-propyl ester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare ((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-ethyl-1H-indoles-1-yl) propane-2-alcohol hydrochloride.
MS(ESI)m/z 327([M+H] +)；
HRMS: calculated value C20H23FN2O+H+, 327.18672; Measured value (ESI, [M+H]+), 327.1871.
Embodiment 98:((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indoles-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801491
By 3-Phenylindole (Cacchi, Sandro; Fabrizi, Giancarlo; Marinelli, Fabio; Moro, Leonardo; Pace, Paola Synlett 1997, (12), 1363-1366) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol is (referring to embodiment 47, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(3-phenyl-1H-indoles-1-yl) propane-1, the 2-glycol is oil.MS(ESI)m/z 362([M+H] +)。
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-phenyl-H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(3-phenyl-indole-1-yl)-2-hydroxyl-propyl diester.MS(ESI)m/z 516([M+H] +)。
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(3-phenyl-indole-1-yl)-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare ((1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indoles-1-yl) propane-2-alcohol hydrochloride.MS (ESI) m/z 375 ([M+H] +); HRMS: calculated value C24H23FN2O+H+, 375.18672; Measured value (ESI, [M+H]+), 375.1886.
Embodiment 99:7-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Step 1: (65g, 422mmol) mixture in glacial acetic acid (250mL) stirs down at 80 ℃ with sodium perborate tetrahydrate.In mixture, slowly add 2,6-difluoroaniline (11.0g, 85mmol) solution in glacial acetic acid (50mL).Holding temperature reaches 1 hour between 80-90 ℃.The refrigerative reaction mixture is poured in the water, used twice of extracted with diethyl ether.The organic layer that merges is washed with dilute sodium bicarbonate solution, through anhydrous magnesium sulfate drying, evaporation.Resistates is via Biotage chromatography purification (FlasH90i, silicon-dioxide, 10%THF/ hexane), and the product hexane wash obtains 2,6-difluoro nitrobenzene (7.0g) (52%).MS(ESI)m/z 160([M+H] +)。
Step 2: to 2, the 6-difluoro nitrobenzene (5.0g, 31.44mmol) at anhydrous N, add in the solution in the dinethylformamide (50mL) salt of wormwood (4.41g, 32mmol) and dimethyl malonate (3.6mL, 31.44mmol).Reaction mixture is heated to 65 ℃, stirred 24 hours.After being cooled to room temperature, mixture is neutralized with diluted hydrochloric acid aqueous solution, use extracted with diethyl ether.The ether layer through anhydrous magnesium sulfate drying, is concentrated in a vacuum.Crystallization from 5% ethyl acetate/hexane obtains 4.6g (54%) 2-(6-fluoro-2-nitro-phenyl)-dimethyl malonate.MS(ESI)m/z 272[M+H] +)。
Step 3: (12g 44mmol) heated 4 hours under refluxing in 6N aqueous hydrochloric acid (200mL) with 2-(6-fluoro-2-nitro-phenyl)-dimethyl malonate.With the mixture cooling,, use extracted with diethyl ether with the dilution of 250mL water.The ether layer through anhydrous magnesium sulfate drying, is concentrated in a vacuum.Crystallization from 5% ethyl acetate/hexane obtains 7.6g (6-fluoro-2-nitro-phenyl)-acetate (54%).MS(ESI)m/z200([M+H] +)。
Step 4: (9.6g is 48mmol) with the hydrogenation 24 hours under 50psi of the mixture of 10% palladium on carbon (1.3g) in acetate (100mL) with (6-fluoro-2-nitro-phenyl)-acetate.Remove catalyzer by diatomite filtration, evaporating solvent.Then resistates is dissolved in ethanol (100mL), adds tosic acid pyridine  salt (50mg), mixture was heated 1 hour under refluxing.With the mixture cooling, pour in the water, use ethyl acetate extraction, through anhydrous magnesium sulfate drying.Filter solvents concentrates in a vacuum.Solid is developed with 5% ethyl acetate/hexane, obtained 6.0g (83%) 7-fluoro-1, the 3-dihydro-indol-2-one.MS(ESI)m/z 152([M+H] +)。
Step 5: with 7-fluoro-1, the 3-dihydro-indol-2-one (7.3g, 48mmol) and lithium chloride (6.67g 158mmol) is dissolved in tetrahydrofuran (THF) (200mL).Solution is cooled to-78 ℃, go through slowly added in 15 minutes n-Butyl Lithium (40mL, 100mmol).At-78 ℃ after following 20 minutes, (6mL 96mmol), makes mixture be warming up to room temperature to add methyl-iodide.After 24 hours, mixture is poured in the water, used ethyl acetate extraction.Organic layer through anhydrous magnesium sulfate drying, is concentrated in a vacuum.Crude product obtains 4.1g (48%) 7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one via Biotage chromatography purification (Flash40i, silicon-dioxide, 10% 20% ethyl acetate/hexane then).MS(ESI)m/z 180([M+H] +)。
Step 6: with sodium hydride (244mg, 6.1mmol, 60% mineral oil dispersion) and 7-fluoro-3,3-dimethyl-1, (1.1g, 6.1mmol) at anhydrous N, the mixture in the dinethylformamide (3.5mL) stirred under room temperature 20 minutes 3-dihydro-2H-indol-2-one.Add [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol (embodiment 117, step 4, and 460mg 3.0mmol), is heated to 60 ℃ with mixture under nitrogen atmosphere.After 20 minutes, add other [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol (230mg), add in addition after 30 minutes [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol (230mg).With TLC (1: 1 hexane: ethyl acetate) to the disappearance of the initial property of reaction monitoring epoxide.Reaction mixture is poured in the 2N aqueous hydrochloric acid, diluted with ethyl acetate.Separate each layer, organic layer water and salt water washing.Organic layer through anhydrous sodium sulfate drying, is filtered, concentrate in a vacuum, obtain the 1.8g crude product, be xanchromatic oil.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 6: 1 to 1: 1 hexanes: ethyl acetate), obtain 450mg (23%) 1-((1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one is xanchromatic oil.MS(ESI)m/z 330[(M+H) +]。
Step 7: with 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-7-fluoro-3,3-dimethyl-1, (870mg, 2.6mmol) solution in anhydrous pyridine (7.5mL) is cooled to 0 ℃ to 3-dihydro-2H-indol-2-one.(524mg 2.75mmol) with 4-Dimethylamino pyridine (50mg), makes reaction be warming up to room temperature, and stirring is spent the night to add Tosyl chloride.Reaction mixture is poured in the ice-cold 2N aqueous hydrochloric acid, used ethyl acetate extraction.Organic layer water and salt water washing.Organic layer through anhydrous sodium sulfate drying, is filtered, concentrate in a vacuum, obtain the oil of 1.2g viscosity.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 16% 20% ethyl acetate/hexane then), obtain 200mg (22%) 1-[(1S, 2S)-3-chloro-2-hydroxyl-1-phenyl propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 348[(M+H) +]。
Step 8: with 1-[(1S, 2S)-3-chloro-2-hydroxyl-1-phenyl propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (300mg, 0.86mmol), the solution of sodium iodide (10mg) and methylamine (8M ethanolic soln) is heated to 60 ℃ and reaches 1 hour.Reaction mixture is cooled to room temperature, concentrates in a vacuum, preadsorption is to diatomite.Crude product obtains the 187mg free alkali via Biotage chromatography purification (5%, 8% and 10% contains the ethanol/methylene of ammonia for FlasH40i, silicon-dioxide).Free alkali is dissolved in a small amount of methylene dichloride, handles,, handle with ether then until pH=3 with the ethereal solution of 1M hydrochloric acid.Add a small amount of hexane and make the product crystallization, obtain title compound 7-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride is white solid.MS (ESI) m/z 343 ([M+H] +); HRMS: calculated value C20H23FN2O2+H +, 343.18163; Measured value (ESI, [M+H] +), 343.1804.
Embodiment 100:1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Figure A20058001737801521
Step 1: by 3,3-dimethyl-1,3-dihydro-indol-2-one (A.Kende, Synth.Comm.1:12 (1982)) and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 1-[(1S according to the mode that is similar to embodiment 99 steps 6,2S)-2,3-dihydroxyl-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 311([M+H] +)。
Step 2: by 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one prepares 1-[(1S according to the mode that is similar to embodiment 99 steps 7,2S)-3-chloro-2-hydroxyl-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 330([M+H] +)。
Step 3: by 1-[(1S, 2S)-and 3-chloro-2-hydroxyl-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one, prepare 1-[(1S according to the mode that is similar to embodiment 99 steps 8,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.MS (ESI) m/z 325 ([M+H) +], HRMS: calculated value C20H24N2O2+H +, 325.19105; Measured value (ESI-FTMS, [M+H] 1 +), 325.19093.
Embodiment 101:7-fluoro-1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Figure A20058001737801522
Step 1: with 7-fluoro-3,3-dimethyl-1, (embodiment 99, step 5,1.0g for 3-dihydro-2H-indol-2-one; 5.58mmol) (1.0g, 11.16mmol) mixture in anhydrous methylene chloride (15mL) is in stirring 20 minutes under nitrogen atmosphere under the room temperature with sodium tert-butoxide.With titanium isopropylate (2.0mL, 6.70mmol) join [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol (embodiment 47, step 3,844mg 5.02mmol) in the solution in anhydrous methylene chloride (6mL), stirred under room temperature 20 minutes.In the tert butoxide mixture, drip the epoxide title complex, stirred 4 days.Reaction mixture is poured in the 2N aqueous hydrochloric acid, diluted with ethyl acetate.Separate each layer, organic layer water and salt water washing.Organic layer through anhydrous sodium sulfate drying, is filtered, concentrate in a vacuum, obtain the 2.0g crude product.Crude product is via Isco chromatography purification (RediSep, silicon-dioxide, gradient: the hexane solution of 0% to 100% ethyl acetate), obtain 600mg (31%) (2S, 3S)-and 7-fluoro-1-[1-(3-fluoro-phenyl)-2,3-dihydroxyl-propyl group]-3,3-dimethyl-1, the 3-dihydro-indol-2-one is oil.MS(ESI)m/z348([M+H] +)。
Step 2: by (2S, 3S)-7-fluoro-1-[1-(3-fluoro-phenyl)-2,3-dihydroxyl-propyl group]-3,3-dimethyl-1, the 3-dihydro-indol-2-one, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-3-(3-fluorophenyl)-2-hydroxyl-propyl diester.MS(ESI)m/z 502([M+H] +)。
Step 3: by (2S, 3S)-toluene-4-sulfonic acid 3-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-3-(3-fluorophenyl)-2-hydroxyl-propyl diester, prepare 7-fluoro-1-[(1S according to the mode that is similar to embodiment 5,2R)-and 1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.MS (ESI) m/z 360 ([M+H] +), HRMS: calculated value C20H22F2N2O2+H +, 361.17221; Measured value (ESI, [M+H] +), 361.1719.
Embodiment 102:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol hydrochloride
Figure A20058001737801531
Step 1: (2.42mL 30.6mmol) is dissolved in tetrahydrofuran (THF) (50mL), is cooled to-78 ℃, and (9.2mL 18.4mmol) handles, and is warming up to 25 ℃ then with n-Butyl Lithium with thiophene.Mixture was stirred 30 minutes, be cooled to-78 ℃ then, drip 2,3-O-isopropylidene-D-Glycerose (Schmid, C.R.; Bryant, J.D.; Dowlatzedah, M.; Phillips, J.L.; Prather, D.E.; Schantz, R.D.; Sear, N.L.; Vianco, C.S.J.Org.Chem.1991,56,4056) (2.00g, 15.3mmol) solution in tetrahydrofuran (THF) (15.3mL).Continue to stir 20 minutes, be warming up to 0 ℃ then, use the saturated aqueous ammonium chloride cancellation.Mixture is diluted water and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 10% acetone/hexane), obtain product 1.6g (51%), be (R)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl alcohol with (S)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] 2: 1 mixtures of (2-thienyl) methyl alcohol, be oil.
HRMS: calculated value C 16H 18N 2OS+H+, 287.12126; Measured value (ESI, [M+H]+), 287.1204.
Step 2: with (R)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl alcohol with (S)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl alcohol (1.5g, 7.0mmol) mixture be dissolved in tetrahydrofuran (THF) (28mL), add sodium carbide (2.1g, 7.7mmol; 18wt% dimethylbenzene/light mineral oil slurries), mixture was stirred 2 hours.Add Tosyl chloride (1.46g 7.7mmol), continues to stir 2 hours, add then indoline (2.5g 21mmol), adds 2 afterwards again, the 6-lutidine (0.81mL, 7.0mmol).After 72 hours, with mixture saturated aqueous ammonium chloride cancellation, with the ethyl acetate dilution, water and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 1-10% ethyl acetate), obtain the 590mg product, it is dissolved in two  alkane (10mL) immediately, with DDQ (552mg, 2.4mmol) handle, stirred 30 minutes.Mixture is diluted with ethyl acetate, with saturated sodium bicarbonate, water and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 1-20% ethyl acetate), obtain 355mg 1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl]-the 1H-indoles.
HRMS: calculated value C 18H 19NO 2S+H+, 314.12092; Measured value (ESI-FTMS, [M+H] 1+), 314.12111.
Step 3: with 1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl]-the 1H-indoles (350mg 1.12mmol) is dissolved in methyl alcohol (20mL), add Phenylsulfonic acid (17mg, 0.11mmol).Mixture was stirred 6 hours, then with the ethyl acetate dilution, with saturated sodium bicarbonate aqueous solution, water and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via flash column chromatography purifying (silicon-dioxide, 5% methyl alcohol/chloroform), obtain 260mg (82%) (2S, 3S)-3-(1H-indoles-1-yl)-3-thiophene-2-base propane-1, the 2-glycol.
HRMS: calculated value C 15H 15NO 2S+H+, 274.08963; Measured value (ESI, [M+H]+), 274.0892.
Step 4: will (2S, 3S)-3-(1H-indoles-1-yl)-3-thiophene-2-base propane-1, (250mg 0.91mmol) is dissolved in pyridine (3mL) to the 2-glycol, and (216mg 1.13mmol), stirs mixture 2 hours to add Tosyl chloride.Mixture is diluted water, the copper/saturated copper sulphate aqueous solution and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.(gradient: the hexane solution of 0%-100% ethyl acetate), obtain the 360mg product, it is dissolved in methylamine immediately, and (the 8M ethanolic soln 15mL), stirred 16 hours crude product for Redisep, silicon-dioxide via the Isco chromatography purification.Enriched mixture in a vacuum, via flash column chromatography purifying (silicon-dioxide, gradient: the 2%-10% chloroformic solution of the saturated methyl alcohol of ammonia), obtain 180mg (1S, 2R)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol, be colourless oil.Free alkali is dissolved in ether (5mL), handles with the ethereal solution (0.63mL, 0.63mmol, 1 equivalent) of 1N hydrochloric acid.Collect white precipitate, dry under vacuum, obtain 193mg (60%) (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol hydrochloride.
HRMS: calculated value C 16H 18N 2OS+H+, 287.12126; Measured value (ESI, [M+H]+), 287.1204
Embodiment 103:(1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol hydrochloride
Step 1: (2.42mL 30.6mmol) is dissolved in tetrahydrofuran (THF) (50mL), is cooled to-78 ℃, and (9.2mL 18.4mmol) handles, and is warming up to 25 ℃ then with n-Butyl Lithium with thiophene.Mixture was stirred 30 minutes, be cooled to-78 ℃ then, drip 2,3-O-isopropylidene-D-Glycerose (Schmid, C.R.; Bryant, J.D.; Dowlatzedah, M.; Phillips, J.L.; Prather, D.E.; Schantz, R.D.; Sear, N.L.; Vianco, C.S.J.Org.Chem.1991,56,4056) (2.00g, 15.3mmol) solution in tetrahydrofuran (THF) (15.3mL).Continue to stir 20 minutes, be warming up to 0 ℃ then, use the saturated aqueous ammonium chloride cancellation.Mixture is diluted water and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 10% acetone/hexane), obtain product 1.6g (51%), be (R)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl alcohol with (S)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] 2: 1 mixtures of (2-thienyl) methyl alcohol, be oil.
HRMS: calculated value C 16H18N 2OS+H+, 287.12126; Measured value (ESI, [M+H]+), 287.1204.
Step 2: with (R)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl alcohol with (S)-[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl alcohol (1.5g, 7.0mmol) mixture be dissolved in tetrahydrofuran (THF) (28mL), add sodium carbide (2.1g, 7.7mmol; 18wt% dimethylbenzene/light mineral oil slurries), mixture was stirred 2 hours.Add Tosyl chloride (1.46g 7.7mmol), continues to stir 2 hours, add then indoline (2.5g 21mmol), adds 2 afterwards, the 6-lutidine (0.81mL, 7.0mmol).After 72 hours, with mixture saturated aqueous ammonium chloride cancellation, with the ethyl acetate dilution, water and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 1-10% ethyl acetate), obtain the 590mg product, it is dissolved in two  alkane (10mL) immediately, with DDQ (552mg, 2.4mmol) handle, stirred 30 minutes.Mixture is diluted with ethyl acetate, with saturated sodium bicarbonate aqueous solution, water and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 1-20% ethyl acetate), obtain 160mg 1-[(R)-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl]-the 1H-indoles.HRMS: calculated value C 18H 19NO 2S+H+, 314.12092; Measured value (ESI-FTMS, [M+H] 1+), 314.12089.
Step 3: with 1-[(S)-[(4S)-2,2-dimethyl-1,3-dioxolane-4-yl] (2-thienyl) methyl]-the 1H-indoles (160mg 0.51mmol) is dissolved in methyl alcohol (10mL), add Phenylsulfonic acid (10mg, 0.06mmol).Mixture was stirred 16 hours, then with the ethyl acetate dilution, with saturated sodium bicarbonate aqueous solution, water and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via flash column chromatography purifying (silicon-dioxide, 5% methyl alcohol/chloroform), and (2S, 3R)-3-(1H-indoles-1-yl)-3-thiophene-2-base propane-1, the 2-glycol directly carries out next step with it to obtain 102mg (74%).
Step 4: will (2S, 3R)-3-(1H-indoles-1-yl)-3-thiophene-2-base propane-1, the 2-glycol (102mg, 0.37mmol] be dissolved in pyridine (1.5mL), (88mg 0.46mmol), stirs mixture 16 hours to add Tosyl chloride.Mixture is diluted water, the copper/saturated copper sulphate aqueous solution and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.(gradient: the hexane solution of 0%-100% ethyl acetate), obtain the 140mg product, it is dissolved in methylamine immediately, and (the 8M ethanolic soln 15mL), stirred 3 hours crude product for Redisep, silicon-dioxide via the Isco chromatography purification.Enriched mixture in a vacuum, via flash column chromatography purifying (silicon-dioxide, gradient: the 2%-10% chloroformic solution of the saturated methyl alcohol of ammonia), obtain 65mg (71%) (1R, 2R)-and 1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol, be colourless oil.Free alkali is dissolved in ether (5mL), handles with the ethereal solution (0.23mL, 0.23mmol, 1 equivalent) of 1N hydrochloric acid.Collect white precipitate, dry under vacuum, obtain (1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol hydrochloride.
HRMS: calculated value C 16H 18N 2OS+H+, 287.12126; Measured value (ESI, [M+H]+), 287.1209
Embodiment 104:1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride
Figure A20058001737801571
Step 1: with spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone (Fensome, A.; Miller, L.L.; Ullrich, J.W.; Bender, R.H.W.; Zhang, P.; Wrobel, J.E.; Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M.PCT Int.PCT Int.Appl.2000,127pp.WO 2000066556) (0.82g, 4.1mmol) being dissolved in N, dinethylformamide (1mL) adds sodium hydride (168mg, 4.4mmol, 60%wt mineral oil suspension), the gained mixture was stirred 15 minutes.Mixture is warming up to 75 ℃, divide four parts of addings trans-the 3-phenyl glycidyl (306mg, 2.04mmol).Continue to stir 2 hours, with the reaction mixture cooling, use the saturated aqueous ammonium chloride cancellation then.Mixture is diluted water and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 20% to 100% ethyl acetate), obtain 290mg (41%) 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone is oil.HPLC purity 100%, 210-370nm, 9.4min.; Xterra RP18,3.5 μ, 150 * 4.6mm post, 1.2mL/ minute, 85/15-5/95 (Ammon.Form.Buff.Ph=3.5/ACN+MeOH) reached 10 minutes, kept 4 minutes.
Step 2: with 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone (and 250mg 0.71mmol) is dissolved in pyridine (2.5mL), add Tosyl chloride (169mg, 0.89mmol).To react and stir 5 hours, then reaction mixture be diluted with ethyl acetate, water, the copper/saturated copper sulphate aqueous solution, 2N aqueous hydrochloric acid and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.(the 8M ethanolic soln 15mL), stirred 16 hours immediately crude product to be dissolved in methylamine.Enriched mixture in a vacuum, via flash column chromatography purifying (silicon-dioxide, the chloroformic solution of the methyl alcohol that 5% usefulness ammonia is saturated), obtain 85mg (32%) 1 '-[(1S, 2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [ring-hexane-1,3 '-indoles]-2 ' (1 ' H)-ketone is colourless oil.Free alkali is dissolved in ether (5mL), handles with the ethereal solution (0.23mL, 0.23mmol, 1 equivalent) of 1N hydrochloric acid.Collect white precipitate, dry under vacuum, obtain 193mg (60%) 1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [ring-hexane-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride.HRMS: calculated value C 23H 28N 2O 2+ H+, 365.22235; Measured value ([M+H]+), 365.2226;
Embodiment 105:(1S, 2R)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] the ethylate hydrochlorate
Figure A20058001737801581
Step 1: under 0 ℃, (6.8g 15mmol) adds sodium hydride (0.57g, 15mmol, 60%wt mineral oil suspension) in the suspension in tetrahydrofuran (THF) (50mL), mixture was stirred 1 hour to 3-luorobenzyl triphenyl bromination .Add (S)-2-formyl radical-tetramethyleneimine-1-t-butyl formate (Cook, G.R.; Stille, J.R.Tetrahedron, 1994,50 (14), 4105) (2.5g, the 12.5mmol) solution in tetrahydrofuran (THF) (10mL) stir mixture 1 hour, are warming up to 25 ℃ then, use the saturated aqueous ammonium chloride cancellation.Mixture is diluted water and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, 10% ethyl acetate/hexane), obtain 2.18g (60%) (2S)-2-[(E)-2-(3-fluorophenyl) vinyl] tetramethyleneimine-1-t-butyl formate, be colourless oil, place post crystallization.HRMS: calculated value C 17H 22FNO 2+ H+, 292.17073; Measured value (ESI, M+H), 292.1713.
Step 2: with (2S)-2-[(E)-2-(3-fluorophenyl) vinyl] (400mg 1.37mmol) is dissolved in methylene dichloride (50mL) to tetramethyleneimine-1-t-butyl formate.Add saturated sodium bicarbonate aqueous solution (50mL), add afterwards acetone (10mL) and 4-butyl ammonium hydrogen sulfate (46mg, 0.14mmol).Under vigorous stirring, go through 2 hours branches and add Oxone (8.4g, 13.7mmol) (per 15 minutes 1.05g) for 8 parts.Mixture was stirred other 16 hours, dilute with methylene dichloride then.Separate organic layer, water and saturated brine washing through anhydrous magnesium sulfate drying, are filtered, and concentrate in a vacuum.Crude product obtains the 240mg product via Isco chromatography purification (Redisep, silicon-dioxide, 20% ethyl acetate/hexane), and (0.14g 1.2mmol) merges, and is heated to 90 ℃ and reaches 16 hours with indoline immediately with it.With the mixture cooling, thick orange oil is through Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 0% to 25% ethyl acetate), obtain the 130mg product, it is dissolved in methylene dichloride (20mL) immediately.(0.86g 10mmol), stirs mixture 5 hours, with the methylene dichloride dilution, filters by Celite pad then, concentrates to add Manganse Dioxide.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 0% to 50% ethyl acetate), obtain 50mg (S)-2-[2-(R)-(3-fluoro-phenyl)-1-hydroxyl-2-indoles-1-base-ethyl]-(S)-tetramethyleneimine-1-t-butyl formate.
Step 3: with (S)-2-[2-(R)-(3-fluoro-phenyl)-1-hydroxyl-2-indoles-1-base-ethyl]-(S)-tetramethyleneimine-1-t-butyl formate (50mg 0.12mmol) is dissolved in methyl alcohol (1mL), and the ethereal solution of adding 1N hydrochloric acid (0.96mL, 0.96mmol).After 6 hours, enriched mixture is via flash column chromatography purifying (silicon-dioxide, the chloroformic solution of the methyl alcohol that 10% usefulness ammonia is saturated), obtain 6mg (15%) (1S, 2R)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol.Free alkali is dissolved in ether (2mL), handles with the ethereal solution (0.02mL, 0.02mmol, 1 equivalent) of 1N hydrochloric acid.Collect white precipitate, dry under vacuum, obtain 4mg (1S, 2R)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] the ethylate hydrochlorate.
HRMS: calculated value C 20H 21FN 2O+ H+, 325.17107; Measured value (ESI, [M+H]+), 325.1712
Embodiment 106:(1R, 2S)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] the ethylate hydrochlorate
Figure A20058001737801601
Step 1: under 0 ℃, (6.8g 15mmol) adds sodium hydride (0.57g, 15mmol, 60%wt mineral oil suspension) in the solution in tetrahydrofuran (THF) (50mL), mixture was stirred under room temperature 1 hour to 3-luorobenzyl triphenyl bromination .(2.5g, the 12.5mmol) solution in tetrahydrofuran (THF) (10mL) stir mixture 1 hour, are warming up to 25 ℃ then, use the saturated aqueous ammonium chloride cancellation to add (S)-2-formyl radical-tetramethyleneimine-1-t-butyl formate.Mixture is diluted water and saturated brine washing with ethyl acetate.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, 10% ethyl acetate/hexane), obtain 2.18g (60%) (2S)-2-[(E)-2-(3-fluorophenyl) vinyl] tetramethyleneimine-1-t-butyl formate, be colourless oil, place post crystallization.
HRMS: calculated value C 17H 22FNO 2+ H+, 292.17073; Measured value (ESI, M+H), 292.1713.
Step 2: with (2S)-2-[(E)-2-(3-fluorophenyl) vinyl] (400mg 1.37mmol) is dissolved in methylene dichloride (50mL) to tetramethyleneimine-1-t-butyl formate.Add saturated sodium bicarbonate aqueous solution (50mL), add afterwards acetone (10mL) and 4-butyl ammonium hydrogen sulfate (46mg, 0.14mmol).Under vigorous stirring, go through 2 hours branches and add Oxone (8.4g, 13.7mmol) (per 15 minutes 1.05g) for 8 parts.Mixture was stirred other 16 hours, dilute with methylene dichloride then.Separate organic layer, water and saturated brine washing through anhydrous magnesium sulfate drying, are filtered, and concentrate in a vacuum.Crude product obtains the 240mg product via Isco chromatography purification (Redisep, silicon-dioxide, 20% ethyl acetate/hexane), and (0.14g 1.2mmol) merges, and is heated to 90 ℃ and reaches 16 hours with indoline immediately with it.With the mixture cooling, thick orange oil is through Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 0% to 25% ethyl acetate), obtain the 130mg product, it is dissolved in methylene dichloride (20mL) immediately.(0.86g 10mmol), stirs mixture 5 hours, with the methylene dichloride dilution, filters by Celite pad then, concentrates to add Manganse Dioxide.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 0% to 50% ethyl acetate), obtain 50mg (R)-2-[2-(S)-(3-fluoro-phenyl)-1-hydroxyl-2-indoles-1-base-ethyl]-(S)-tetramethyleneimine-1-t-butyl formate.
Step 3: with (R)-2-[2-(S)-(3-fluoro-phenyl)-1-hydroxyl-2-indoles-1-base-ethyl]-(S)-tetramethyleneimine-1-t-butyl formate (50mg 0.12mmol) is dissolved in methyl alcohol (1mL), and the ethereal solution of adding 1N hydrochloric acid (1.0mL, 1.0mmol).After 16 hours, enriched mixture is via flash column chromatography purifying (silicon-dioxide, the chloroformic solution of the methyl alcohol that 10% usefulness ammonia is saturated), obtain 19mg (50%) (1R, 2S)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol.Free alkali is dissolved in ether (2mL), handles with the ethereal solution (0.06mL, 0.06mmol, 1 equivalent) of 1N hydrochloric acid.Collect white precipitate, dry under vacuum, obtain 17mg (1R, 2S)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] the ethylate hydrochlorate.
HRMS: calculated value C 20H 21FN 2O+H+, 325.325.17107; Measured value (ESI, [M+H]+), 325.1711
Embodiment 107:1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride
Figure A20058001737801611
Step 1: by spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone (Fensome, A.; Miller, L.L.; Ullrich, J.W.; Bender, R.H.W.; Zhang, P.; Wrobel, J.E.; Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M.PCT Int.PCT Int.Appl.2000,127pp.WO 2000066556) and trans-3-phenyl glycidyl, according to the mode that is similar to embodiment 104 steps 1 prepare 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone.HPLC purity 100%, 210-370nm, 8.4min.; Xterra RP18,3.5 μ, 150 * 4.6mm post, 1.2mL/ minute, 85/15-5/95 (Ammon.Form.Buff.Ph=3.5/ACN+MeOH) reached 10 minutes, kept 4min.
Step 2: by 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell-[tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone, according to the mode that is similar to embodiment 104 steps 2 prepare 1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride.
HRMS: calculated value C 21H 24N 2O 2+ H+, 337.19105; Measured value (ESI, [M+H]+), 337.1917
Embodiment 108:1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell-[pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride
Figure A20058001737801621
Step 1: by spiral shell [pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone (Fensome, A.; Miller, L.L.; Ullrich, J.W.; Bender, R.H.W.; Zhang, P.; Wrobel, J.E.; Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M.PCT Int.PCT Int.Appl.2000,127pp.WO 2000066556) and trans-3-phenyl glycidyl, according to the mode that is similar to embodiment 104 steps 1 prepare 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell [pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone.
HRMS: calculated value C 21H 23NO 3+ H+, 338.17507; Measured value (ESI, [M+H]+), 338.1769
Step 2: by 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell-[pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone, according to the mode that is similar to embodiment 104 steps 2 prepare 1 '-[(1S, 2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell-[pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride.
HRMS: calculated value C 22H 26N 2O 2+ H+, 351.20670; Measured value (ESI, [M+H]+), 351.2061
Embodiment 109:1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell-[cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride
Step 1: by spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone (Roberston, D.W.; Krushinski, J.H.; Pollock, G.D.; Wilson, H.; Kauffman, R.F.; Hayes, J.S.J.Med.Chem.1987,30,824) and trans-3-phenyl glycidyl, according to the mode that is similar to embodiment 104 steps 1 prepare 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone.HPLC purity 89.1%, 210-370nm, 7.7min.; Xterra RP18,3.5 μ, 150 * 4.6mm post, 1.2mL/ minute, 85/15-5/95 (Ammon.Form.Buff.Ph=3.5/ACN+MeOH) reached 10 minutes, kept 4min.
Step 2: by 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone, according to the mode that is similar to embodiment 104 steps 2 prepare 1 '-[(1S, 2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell-[cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride.
HRMS: calculated value C 20H 22N 2O 2+ H+, 323.17540; Measured value (ESI, [M+H]+), 323.1744
Embodiment 110:5-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Figure A20058001737801631
Step 1: with 5-fluoro-1, the 3-dihydro-indol-2-one (2.0g, 13.2mmol) and lithium chloride (1.39g 33.0mmol) is dissolved in tetrahydrofuran (THF) (40mL), is cooled to 0 ℃.(10.6mL 26.4mmol), stirs mixture 20 minutes to drip n-Butyl Lithium.(1.63mL 26.4mmol), continues to stir 2 hours down at 0 ℃, is warming up to 25 ℃ then slowly to add methyl-iodide.After 16 hours, with saturated aqueous ammonium chloride cancellation reaction.Mixture is diluted water and saturated brine washing with ether.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product via the Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 10% to 50% ethyl acetate), obtain 1.18g (50%) 5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one is white crystal.HPLC purity 100%, 210-370nm, 7.1min.; Xterra RP18,3.5 μ, 150 * 4.6mm post, 1.2mL/ minute, 85/15-5/95 (Ammon.Form.Buff.Ph=3.5/ACN+MeOH) reached 10 minutes, kept 4min.
Step 2: by 5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and trans-3-phenyl glycidyl, prepare 1-[(1S according to the mode that is similar to embodiment 104 steps 1,2S)-2,3-dihydroxyl-1-phenyl propyl]-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
HRMS: calculated value C 19H 20FNO 3+ H+, 330.15000; Measured value (ESI, [M+H]+), 330.1495
Step 3: by 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one prepares 5-fluoro-1-[(1S according to the mode that is similar to embodiment 104 steps 2,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.HPLC purity 100%, 210-370nm, 7.2min.; Xterra RP18,3.5 μ, 150 * 4.6mm post, 1.2mL/ minute, 85/15-5/95 (Ammon.Form.Buff.Ph=3.5/ACN+MeOH) reached 10 minutes, kept 4min.
HRMS: calculated value C 20H 23FN 2O 2+ H+, 343.18163; Measured value (ESI, [M+H]+), 343.184
Embodiment 111:(1S, 2R)-3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801641
Step 1: will (2S, 3S)-3-(3-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol (embodiment 47, step 5) (0.6g 2.1mmol) is dissolved in pyridine (5mL), and the adding Tosyl chloride (0.44g, 2.3mmol).Mixture was stirred 3 hours, and reaction mixture with the ethyl acetate dilution, washes with water then, afterwards with the copper/saturated copper sulphate aqueous solution, 2N aqueous hydrochloric acid and saturated brine washing.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.(the 8M ethanolic soln 25mL), stirred 16 hours immediately crude product to be dissolved in methylamine.Enriched mixture in a vacuum, via flash column chromatography purifying (silicon-dioxide, the chloroformic solution of the methyl alcohol that 5% usefulness ammonia is saturated), obtain (1S, 2R)-and 3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol, be colourless oil.Free alkali is dissolved in ether (5mL), handles with the ethereal solution (1 equivalent) of 1N hydrochloric acid.Collect white precipitate, dry under vacuum, obtain 80mg (12%) (1S, 2R)-3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol hydrochloride.
HRMS: calculated value C 20H 21FN 2O+H+, 325.17107; Measured value (ESI, [M+H]+), 325.1728.
Embodiment 112:7 '-fluoro-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride
Figure A20058001737801651
Step 1: with 7-fluoro-1, the 3-dihydro-indol-2-one (embodiment 99, step 4) (1.16g, 7.68mmol) and lithium chloride (0.81g 19.2mmol) is dissolved in tetrahydrofuran (THF) (50mL), is cooled to 0 ℃.(6.14mL 15.4mmol), stirs mixture 15 minutes to drip n-Butyl Lithium.(1.05mL 7.7mmol), continues to stir 2 hours down at 0 ℃, is warming up to 25 ℃ then slowly to add pentamethylene bromide.After 16 hours, with saturated aqueous ammonium chloride cancellation reaction.Mixture is diluted water and saturated brine washing with ether.Separate organic layer,, filter, concentrate in a vacuum through anhydrous magnesium sulfate drying.Crude product is via Isco chromatography purification (Redisep, silicon-dioxide, gradient: the hexane solution of 5% to 40% ethyl acetate), obtain 0.90g (54%) 7 '-fluorine spiral shell-[hexanaphthene-1,3 ' indoles]-2 ' (1 ' H)-ketone.HPLC purity 95.9%, 210-370nm, 19.2min.; Xterra MSC18,5 μ, 150 * 3.0mm post, 0.5mL/ minute, the 95/5-5/95 (H of 0.1% formic acid 2O/MeOH solution) reach 20 minutes, keep 3min.
Step 2: by 7 '-fluorine spiral shell-[hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone and trans-3-phenyl glycidyl, according to the mode that is similar to embodiment 104 steps 1 prepare 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-7 '-the fluorine spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone.
HRMS: calculated value C22H24FNO3+H+, 370.18130; Measured value (ESI, [M+H]+), 370.1798
Step 3: by 1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-7 '-fluorine spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone, according to the mode that is similar to embodiment 104 steps 2 prepare 7 '-fluoro-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride.
HRMS: calculated value C 23H 27FN 2O 2+ H+, 383.21293; Measured value (ESI, [M+H]+), 383.2109
Embodiment 113:5 '-bromo-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride
Figure A20058001737801661
Step 1: by 5 '-the bromine spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone (Fensome, A.; Miller, L.L.; Ullrich, J.W.; Bender, R.H.W.; Zhang, P.; Wrobel, J.E.; Zhi, L.; Jones, T.K.; Marschke, K.B.; Tegley, C.M.PCT Int.PCT Int.Appl.2000,127pp.WO 2000066556) and trans-3-phenyl glycidyl, according to the mode that is similar to embodiment 104 steps 1 prepare 5 '-bromo-1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone.
HRMS: calculated value C22H24BrNO3+H+, 430.10123; Measured value (ESI, [M+H]+), 430.1006
Step 2: by 5 '-bromo-1 '-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone, according to the mode that is similar to embodiment 104 steps 2 prepare 5 '-bromo-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-keto hydrochloride.
HRMS: calculated value C23H27BrN2O2+H+, 443.13286; Measured value (ESI, [M+H]+), 443.1333.
Embodiment 114:(1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride
Step 1: to (2S, 3S)-3-indoles-1-base-3-(3-fluorophenyl)-propane-1, (embodiment 47 for the 2-glycol, step 5,1.34g is 4.56mmol) at N, the solid potassium hydroxide that adding is pulverized in the solution in the dinethylformamide (20mL) (0.76g, 13.68mmol).With mixture under nitrogen atmosphere, stirring 15 minutes under the room temperature, disposable then adding iodine (1.21g, 4.72mmol).Mixture was stirred under room temperature 30 minutes, pour into then in 100mL 5% sodium thiosulfate solution.With solution ethyl acetate extraction 3 times, the extraction liquid that merges is washed with water 3 times.Organic layer through anhydrous sodium sulfate drying, is filtered, concentrate in a vacuum.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 40% ethyl acetate/hexane), and (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, the 2-glycol is dun oil to obtain 0.91g (48%).MS(ES)m/z 411.9。
Step 2: with (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1,2-glycol (0.25g, 0.61mmol), the 2-fluorobenzene is for boric acid (0.12g, 0.85mmol) and potassiumphosphate (0.39g, 1.83mmol) at N, the mixture in the dinethylformamide (10mL) outgased 5 minutes with nitrogen, [1,4-pair-(diphenyl phosphine) butane] palladium chloride (II) that adds catalytic amount (0.02g) then.Solution is heated to 90 ℃ reaches 3 hours, cooling is poured in the 100mL water then.With aqueous mixture ethyl acetate extraction 3 times, then the extraction liquid that merges is washed with water 2 times.By silica gel plug filtration drying ethyl acetate, concentrate then.Resistates is through Biotage chromatography purification (FlasH40i, silicon-dioxide, 40% ethyl acetate/hexane), obtain 0.14g (2S, 3S)-3-(3-fluorophenyl)-3-{3-[2-fluorophenyl]-1H-indoles-1-yl propane-1, the 2-glycol, be oil, it need not to be further purified and promptly can be used for next step.
Step 3: by (2S, 3S)-3-(3-fluorophenyl)-3-{3-[2-fluorophenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(2-fluorophenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
Step 4: by (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluoro-phenyl)-3-[3-(2-fluorophenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 393.1。
Embodiment 115:(1S, 2R)-1-[3-(3, the 4-dichlorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 3, the 4-dichlorobenzene is for boric acid, according to the mode that is similar to embodiment 114 steps 2 prepare (2S, 3S)-3-(3, the 4-dichlorophenyl)-the 3-{3-[2-fluorophenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-[3-(3,4-two chloro-phenyl)-indoles-1-yl]-3-(3-fluoro-phenyl) propane-1, the 2-glycol, prepare (2S according to the mode that is similar to embodiment 1 step 2,3S)-toluene-4-sulfonic acid 3-[3-(3,4-two chloro-phenyl)-indoles-1-yl]-3-(3-fluorophenyl)-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-[3-(3,4-two chloro-phenyl)-indoles-1-yl]-3-(3-fluoro-phenyl)-2-hydroxyl-propyl diester and methylamine (2N methanol solution), prepare (1S according to the mode that is similar to embodiment 5,2R)-1-[3-(3, the 4-dichlorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 443.0。
Embodiment 116:(1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 3-fluorobenzene are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[3-fluorophenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[3-fluorophenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(3-fluorophenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluoro-phenyl)-3-[3-(3-fluorophenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride.MS(ESI)m/z 393。
Embodiment 117:(1S, 2R)-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801691
Step 1: to 4-fluoro-phenyl amine (9g, 81mmol), add Sodium Nitrite (6.3g, 89.1mmol) solution in water-soluble (7.8mL) in the mixture of concentrated hydrochloric acid (20.4mL) and water (35.1mL).In independent flask, (14.4g, 89.1mmol) (5.1g, 89.1mmol) handle, and adds above-mentioned solution with potassium hydroxide down by solution in water (7.5mL) and ice at 0 ℃ for the solution in ethanol (63.6mL) with the 2-ethyl ethylacetoacetate.The pH to 5-6 of conditioned reaction will be reflected at 0 ℃ and stir 3 hours down, be stored in refrigerator overnight then.To react then with ethyl acetate (100mL) extraction, organic layer is used anhydrous magnesium sulfate drying with saturated brine solution (100mL) washing.Remove most of solvent in a vacuum, under 78 ℃, be added drop-wise to then in the ethanolic soln (70mL) of 14.5% hydrochloric acid.Continue heating 2 hours.Remove in a vacuum and desolvate, resistates is handled with methylene dichloride (300mL) and water (100mL).Organic layer with saturated sodium-chloride (200mL) washing, through dried over sodium sulfate, is concentrated in a vacuum.Purifying (silica gel, 25% ethyl acetate/hexane) on short washing column obtains 5-fluoro-3-Methyl-1H-indole-2-ethyl formate, is white solid.MS(ES)m/z 220.0
Step 2: with 5-fluoro-3-Methyl-1H-indole-2-ethyl formate (8.3g, 37.5mmol) and potassium hydroxide (6.3g, 112.5mmol) heating 1 hour under refluxing in the mixture of ethanol (20mL) and water (15mL).Under reduced pressure reduce volume to 10mL, use 3N aqueous hydrochloric acid regulator solution to acid pH.Filtration gained precipitation, water (100mL) washing, dried overnight in 80 ℃ of vacuum obtains 5-fluoro-3-Methyl-1H-indole-2-formic acid, is white solid.MS(ES)m/z 192.0
Step 3: with 5-fluoro-3-Methyl-1H-indole-2-formic acid (8.49g, 43.9mmol) and the copper metal (0.35g 5.5mmol) reaches 3 hours being heated to reflux in distillatory quinoline (22mL).Leach copper powder, regulate filtrate to pH 3 with the 6N aqueous hydrochloric acid down at 0 ℃.Solution is extracted with ether (200mL), and organic layer, concentrates through dried over mgso in a vacuum with saturated sodium-chloride (200mL) washing, obtains 5-fluoro-3-Methyl-1H-indole, is brown solid.MS (ES)m/z 150.0。
Step 4: under-10 ℃ under nitrogen atmosphere, to D-tartrate diisopropyl ester (6mL, 28mmol) add in the solution in methylene dichloride (800mL) 4A molecular sieve (15g), titanium isopropylate (5.9mL, 20mmol) and styryl carbinol (27g, 200mmol).Make mixture-10 ℃ of following slakings 40 minutes, be cooled to-20 ℃ then, (TBHP ,～450mmol) isooctane solution is handled with t-butyl hydroperoxide in mode dropwise.At-30 to-15 ℃ after following 18 hours, reaction mixture is handled with 30% aqueous sodium hydroxide solution (5mL) and ether (100mL).Remove cooling bath, make mixture be warming up to-10 ℃.Adding sal epsom (anhydrous, 15g), mixture was stirred 20 minutes.Behind the solid settlement, solution is filtered by silicagel pad, with ether (50mL) washing.Concentrated filtrate adds toluene in a vacuum, removes unreacted TBHP with azeotropic.Resistates use then the silicagel column purifying (hexane: ethyl acetate 3/1), make purified product crystallization from hexane/ethyl acetate, obtain [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol, for white crystal (18g, 60%, 98.2%ee).MS(ESI)m/z 151。
Step 5: (2.91g, 19.5mmol) (2.8g, 35.1mmol) mixture in methylene dichloride (40mL) is in stirring 10 minutes under nitrogen atmosphere under the room temperature with 50% mineral oil dispersion of potassium hydride KH with 5-fluoro-3-Methyl-1H-indole.Add then [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (2.0g, 13.0mmol) (4.3mL, the 14.3mmol) solution in methylene dichloride (10mL) stirred mixture 12 hours methyl alcohol under room temperature with titanium isopropylate.Epoxide distributes mixture after disappearing between 1N aqueous hydrochloric acid (50mL) and ethyl acetate (50mL).Separate organic layer,,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying with saturated sodium bicarbonate (50mL) washing.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 60% ethyl acetate/hexane), obtain (2S, 3S)-3-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol.MS(ESI)m/z 300
Step 6: with (2S, 3S)-3-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, (1.03g, 3.4mmol) (0.78g, 4.1mmol) solution in anhydrous pyridine (11mL) is in stirring 12 hours under nitrogen atmosphere under the room temperature with Tosyl chloride for the 2-glycol.Reaction mixture is poured in the 1N aqueous hydrochloric acid (50mL), with ethyl acetate (50mL) extraction.Organic layer through anhydrous sodium sulfate drying, is filtered, concentrate, obtain (2S, 3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.Product need not to be further purified and promptly can be used for next step.(1.6g, (8.6mL 17mmol), stirs reaction mixture 12 hours 3.4mmol) to add the methanol solution of 2N methylamine in the solution in methyl alcohol (10mL) to toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.After reacting completely, reaction mixture is distributed between saturated sodium bicarbonate (50mL) and ethyl acetate (50mL).Separate organic layer,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 20%MeOH/ methylene dichloride), obtain (1S, 2R)-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol, be clarifying oil.Free alkali is dissolved in small amount of ethanol, handles, stirred 1 hour with the ethereal solution of 2N hydrochloric acid.Remove ethanol in a vacuum, clarifying oil is developed with ether/methylene dichloride, obtain (1S, 2R)-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ESI)m/z 313
Embodiment 118:(1SR, 2RS)-3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
To (2S, 3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester (embodiment 117 step 6 intermediates, 0.15g .33mmol) add dense ammonium hydroxide (20mL) in the solution in methyl alcohol (10mL), reaction mixture was stirred 12 hours.After reacting completely, reaction mixture is distributed between water (25mL) and ethyl acetate (25mL).Separate organic layer,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying.Crude product is via Biotage chromatography purification (FlasH40i, silicon-dioxide, 25%MeOH/ methylene dichloride), obtain (1SR, 2RS)-3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol, be clarifying oil.Free alkali is dissolved in small amount of ethanol, and two  alkane solution-treated with 4N hydrochloric acid stirred 1 hour.Remove ethanol in a vacuum, clarifying oil is developed with ether/methylene dichloride, obtain (1SR, 2RS)-3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ES)m/z 299.0
Embodiment 119:(1S, 2R)-1-(5-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801712
By 4-chloro-phenyl amine, prepare 5-chloro-3-Methyl-1H-indole-2-ethyl formate according to the mode that is similar to embodiment 117 steps 1.MS(ES)m/z 235.9
By 5-chloro-3-Methyl-1H-indole-2-ethyl formate, prepare 5-chloro-3-Methyl-1H-indole-2-formic acid according to the mode that is similar to embodiment 117 steps 2.MS(ESI)m/z 208
By 5-chloro-3-Methyl-1H-indole-2-formic acid, prepare 5-chloro-3-Methyl-1H-indole according to the mode that is similar to embodiment 117 steps 3.MS(ESI)m/z 166。
By 5-chloro-3-Methyl-1H-indole and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares (2S according to the mode that is similar to embodiment 117 steps 5 for methyl alcohol, 3S)-and 3-(5-chloro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol.MS(ES)m/z 316.0
By (2S, 3S)-3-(5-chloro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(5-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.MS(ES)m/z 329.0
Embodiment 120:(1S, 2R)-3-amino-1-(5-chloro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By (2S, 3S)-and 3-(5-chloro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, (embodiment 119, step 4) for the 2-glycol, according to the mode that is similar to embodiment 118 prepare (1S, 2R)-3-amino-1-(5-chloro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol.MS(ES)m/z 315.1。
Embodiment 121:[(2R, 3S)-3-(5-chloro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine
With (2S, 3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester (embodiment 119 step 6 intermediates, 0.52g, 1.1mmol), trifluoromethanesulfonic acid methyl esters (0.6mL, 5.5mmol) with 2, (1.1g, mixture 5.5mmol) heated 2 hours in methylene dichloride (20mL) under refluxing 6-di-t-butyl-4-methyl-pyridine.Reaction mixture is distributed between ethyl acetate (25mL) and 1N aqueous hydrochloric acid (25mL).Separate organic layer,,, concentrate in a vacuum through anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution (25mL) washing.Crude product is via flash column chromatography purifying (silicon-dioxide, the hexane solution of 20% ethyl acetate), obtain (2S, 3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indoles-1-yl)-2-methoxyl group-3-phenyl propyl ester.To toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indoles-1-yl)-2-methoxyl group-3-phenyl propyl ester (0.13g, 0.27mmol) add the methanol solution (1.4mL of 2N methylamine in the solution in methyl alcohol (10mL), 2.7mmol), will be reflected in the sealing test tube and heat 12 hours.After reacting completely, reaction mixture is distributed between saturated sodium bicarbonate aqueous solution (25mL) and methylene dichloride (25mL).Separate organic layer, remove in a vacuum.Resistates is dissolved in ether (25mL), with 1N aqueous hydrochloric acid (25mL) washing.Water layer alkalizes to pH 8 with saturated sodium bicarbonate aqueous solution (50mL).Product with ether (25mL) extraction, through anhydrous sodium sulfate drying, is concentrated in a vacuum.Free alkali is dissolved in small amount of ethanol, and two  alkane solution-treated with 4N hydrochloric acid stirred 1 hour.Remove ethanol in a vacuum, obtain [(2R, 3S)-3-(5-chloro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine, be xanchromatic oil.MS(ESI)m/z 343。
Embodiment 122:(1S, 2R)-1-(7-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 2-chloro-phenyl amine, prepare 7-chloro-3-Methyl-1H-indole-2-ethyl formate according to the mode that is similar to embodiment 117 steps 1.MS(ESI)m/z 238[0616]。
By 7-chloro-3-Methyl-1H-indole-2-ethyl formate, prepare 7-chloro-3-Methyl-1H-indole-2-formic acid according to the mode that is similar to embodiment 117 steps 2.MS(ES)m/z 208.0。
By 7-chloro-3-Methyl-1H-indole-2-formic acid, prepare 7-chloro-3-Methyl-1H-indole according to the mode that is similar to embodiment 117 steps 3.
By 7-chloro-3-Methyl-1H-indole and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares (2S according to the mode that is similar to embodiment 117 steps 5 for methyl alcohol, 3S)-and 3-(7-chloro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol.MS(ESI)m/z 316；MS(ESI)m/z314。
By (2S, 3S)-3-(7-chloro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(7-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.MS(ESI)m/z 329。
Embodiment 123:[(2R, 3S)-3-(5-fluoro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine hydrochloride
Figure A20058001737801741
By (2S, 3S)-toluene-4-sulfonic acid 3-(5-fluoro-3-methyl-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester (embodiment 117 step 6 intermediates), according to the mode that is similar to embodiment 121 prepare [(2R, 3S)-3-(5-fluoro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine hydrochloride.MS(ESI)m/z 327。
Embodiment 124:(1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801742
By 4-bromo-1H-indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol (embodiment 117, step 4), according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(4-bromo-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol.MS(ESI)m/z 346。
By (2S, 3S)-3-(4-bromo-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.MS(ESI)m/z 359。
Embodiment 125:(1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801751
By 4-bromo-1H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol (embodiment 47 step 3), according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(4-bromo-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol.MS(ESI)m/z 364。
By (2S, 3S)-3-(4-bromo-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ESI)m/z 377。
Embodiment 126:(1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 5-bromo-1H-indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol (embodiment 117, step 4), according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(5-bromo-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol.MS(ESI)m/z 346。
By (2S, 3S)-3-(5-bromo-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.MS(ESI)m/z 359。
Embodiment 127:(1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801753
By 5-bromo-1H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol (embodiment 47 step 3), according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(5-bromo-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol.MS(ESI)m/z 364。
By (2S, 3S)-3-(5-bromo-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ESI)m/z 377。
Embodiment 128:1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-4-formonitrile HCN hydrochloride
By 1H-indoles-4-formonitrile HCN and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares 1-(2,3-dihydroxyl-1-phenyl-propyl group)-1H-indoles-4-formonitrile HCN according to the mode that is similar to embodiment 117 steps 5 for methyl alcohol.
By 1-(2,3-dihydroxyl-1-phenyl-propyl group)-1H-indoles-4-formonitrile HCN, prepare 1-[(1S according to the mode that is similar to embodiment 117 steps 6,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-4-formonitrile HCN hydrochloride.MS(ESI)m/z 306。
Embodiment 129:(1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 6-bromo-1H-indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares 3-(6-bromo-indoles-1-yl)-3-phenyl-propane-1,2-glycol according to the mode that is similar to embodiment 117 steps 5 for methyl alcohol.
By 3-(6-bromo-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.MS(ESI)m/z 359。
Embodiment 130:1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-5-formonitrile HCN hydrochloride
Figure A20058001737801771
By 1H-indoles-5-formonitrile HCN and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] methyl alcohol (embodiment 117, and step 4) prepares 1-[(1S according to the mode that is similar to embodiment 117 steps 5,2S)-2,3-dihydroxyl-1-phenyl propyl]-1H-indoles-5-formonitrile HCN.MS(ESI)m/z 293。
By 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-1H-indoles-5-formonitrile HCN, prepare 1-[(1S according to the mode that is similar to embodiment 117 steps 6,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-5-formonitrile HCN hydrochloride.MS(ES)m/z 306.1。
Embodiment 131:1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1H-indoles-4-formonitrile HCN hydrochloride
Figure A20058001737801772
By 1H-indoles-4-formonitrile HCN and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3) prepares 1-[1-(3-fluoro-phenyl)-2,3-dihydroxyl-propyl group according to the mode that is similar to embodiment 117 steps 5]-1H-indoles-4-formonitrile HCN.
By 1-[1-(3-fluoro-phenyl)-2,3-dihydroxyl-propyl group]-1H-indoles-4-formonitrile HCN, prepare 1-[(1S according to the mode that is similar to embodiment 117 steps 6,2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1H-indoles-4-formonitrile HCN hydrochloride.MS(ES)m/z 324.2。
Embodiment 132:(1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 6-bromo-1H-indoles and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 step 3) prepare 3-(6-bromo-indoles-1-yl)-3-(3-fluoro-phenyl)-propane-1,2-glycol according to the mode that is similar to embodiment 117 steps 5 to methyl alcohol.
By 3-(6-bromo-indoles-1-yl)-3-(3-fluoro-phenyl)-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 377.1。
Embodiment 133:(1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 6-fluoro-1H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] methyl alcohol (embodiment 47 step 3), according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-3-(6-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol.MS(ESI)m/z 304。
By (2S, 3S)-3-(6-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 317.1。
Embodiment 134:(1S, 2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol hydrochloride
Figure A20058001737801782
By the 1H-indoles and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, and step 3) prepares 3-(3-fluoro-phenyl)-3-indoles-1-base-propane-1,2-glycol according to the mode that is similar to embodiment 117 steps 5 for methyl alcohol.
By 3-(3-fluoro-phenyl)-3-indoles-1-base-propane-1,2-two pure and mild tosic acid and dense ammonium hydroxide subsequently, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol hydrochloride.MS(ES)m/z 285.2。
Embodiment 135:(1S, 2R)-1-(7-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801791
By 7-bromo-1H-indoles and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 step 3) prepare 3-(7-bromo-indoles-1-yl)-3-(3-fluoro-phenyl)-propane-1,2-glycol according to the mode that is similar to embodiment 117 steps 5 to methyl alcohol.
By 3-(7-bromo-indoles-1-yl)-3-(3-fluoro-phenyl)-propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(7-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 377。
Embodiment 136:(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol hydrochloride
By 3-(3-trifluoromethyl-phenyl)-vinylformic acid, prepare styracin according to the mode that is similar to embodiment 47 steps 1 ,-(trifluoromethyl)-, methyl ester.MS(ES)m/z 231.1。
By-(trifluoromethyl)-methyl cinnamate, prepare (2E)-3-[3-(trifluoromethyl) phenyl according to the mode that is similar to embodiment 47 steps 2] third-2-alkene-1-alcohol.MS(ES)m/z 185.1。
By (2E)-3-[3-(trifluoromethyl) phenyl] third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 47 steps 3 prepare (2R, 3R)-3-[3-(trifluoromethyl) phenyl] oxyethane-2-yl methyl alcohol.MS(ES)m/z 217.3。
By indoline and { (2R, 3R)-3-[3-(trifluoromethyl) phenyl] oxyethane-2-yl methyl alcohol, according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-and 3-[3-(trifluoromethyl) phenyl] propane-1, the 2-glycol.MS(ESI)m/z 338。
By (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-[3-(trifluoromethyl) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 5 prepare (2S, 3S)-3-(1H-indoles-1-yl)-3-[3-(trifluoromethyl) phenyl] propane-1, the 2-glycol.MS(ESI)m/z 336。
By (2S, 3S)-and 3-(1H-indoles-1-yl)-3-[3-(trifluoromethyl) phenyl] propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol hydrochloride.MS(ES)m/z 349.1。
Embodiment 137:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol hydrochloride
By 1 ', 2 '-the dihydro spiral shell [hexanaphthene-1,3 '-indoles] (Kucerovy, A.; Hathaway, J.S.; Mattner, P.G.; Repic, O.Synth.Commun.1992,22,729-733) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3-fluorophenyl)-3-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-1, the 2-glycol is white solid.
MS (ES) m/z 356.2 ([M+H] +); HRMS: calculated value C 22H 26FNO 2+ H +, 356.2020; Measured value (ESI, [M+H] +), 356.2031.
By (2S, 3S)-3-(3-fluorophenyl)-3-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol hydrochloride is white powder.
MS (ES) m/z 369.2 ([M+H] +); HRMS: calculated value C 23H 29FN 2O+H +, 369.2337; Measured value (ESI, [M+H] +), 369.2332.
Embodiment 138:(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol hydrochloride
By (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-and 3-[3-(trifluoromethyl) phenyl] propane-1, (embodiment 136 for the 2-glycol, step 4), according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol.MS(ES)m/z 351.1。
Embodiment 139:(1S, 2S)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801811
By 3-(3-fluoro-phenyl)-3-indoles-1-base-propane-1, (embodiment 134 for the 2-glycol, step 1), according to the mode that is similar to embodiment 16 steps 2 prepare the 4-nitrobenzoic acid (2S, 3S)-3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl) propyl diester.MS(ES)m/z 435.0。
By 4-nitrobenzoic acid (2S, 3S)-and 3-(3-fluorophenyl)-2-hydroxyl-3-(1H-indoles-1-yl) propyl diester, prepare 4-nitro-phenylformic acid 3-(3-fluoro-phenyl)-3-indoles-1-base-2-mesyloxy-propyl diester according to the mode that is similar to embodiment 16 steps 3.
By 4-nitro-phenylformic acid 3-(3-fluoro-phenyl)-3-indoles-1-base-2-mesyloxy-propyl diester, prepare 1-{ (S)-(3-fluorophenyl) [(2R)-oxyethane-2-yl] methyl according to the mode that is similar to embodiment 16 steps 4 }-the 1H-indoles.MS(ESI)m/z 338。
By 1-{ (S)-(3-fluorophenyl) [(2R)-oxyethane-2-yl] methyl)-the 1H-indoles, according to the mode that is similar to embodiment 16 steps 5 prepare (1S, 2S)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ESI)m/z 299。
Embodiment 140:(1S, 2R)-1-(3, the 4-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
By 3-(3,4-two fluoro-phenyl)-vinylformic acid, prepare (E)-3 according to the mode that is similar to embodiment 47 steps 1,4-two fluoro-methyl cinnamates.MS(ES)m/z 199.1
By (E)-3,4-two fluoro-methyl cinnamates prepare (2E)-3-(3, the 4-difluorophenyl) third-2-alkene-1-alcohol according to the mode that is similar to embodiment 47 steps 2.MS(ES)m/z 153.1。
By (2E)-3-(3, the 4-difluorophenyl) third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 47 steps 3 prepare [(2R, 3R)-3-(3, the 4-difluorophenyl) oxyethane-2-yl] methyl alcohol.MS(ES)m/z185.1。
By indoline and [(2R, 3R)-3-(3, the 4-difluorophenyl) oxyethane-2-yl] methyl alcohol, according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3, the 4-difluorophenyl)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol.MS(ES)m/z 306.1。
By (2S, 3S)-3-(3, the 4-difluorophenyl)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 47 steps 5,3S)-and 3-(3, the 4-difluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol.MS(ESI)m/z 304。
By (2S, 3S)-3-(3, the 4-difluorophenyl)-3-(H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 117 steps 6 prepare (1S, 2R)-1-(3, the 4-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride.MS(ES)m/z 317.1。
Embodiment 141:(1RS, 2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 6-chloro-3,4-dihydro-2H-1, (embodiment 88 for the 4-benzoxazine, step 1) and trans-3-ethyl phenylglycidate, according to the mode that is similar to embodiment 33 steps 1 prepare (2RS, 3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 2-hydroxyl-3-phenylpropionic acid ethyl ester, be the viscosity yellow liquid.MS (ESI) m/z 362.0 ([M+H] +); HRMS: calculated value C 19H 20ClNO 4+ H +, 362.1154; Measured value (ESI, [M+H] +), 362.1150.
By (2RS, 3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-2-hydroxyl-3-phenylpropionic acid ethyl ester, according to the mode that is similar to embodiment 33 steps 2 prepare (2RS, 3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 2-hydroxy-n-methyl-3-Phenylpropionamide, be the white needles thing.
MS (ESI) m/z 344.9 ([M-H] -); HRMS: calculated value C 18H 19ClN 2O 3+ H +, 347.1157; Measured value (ESI, [M+H] +), 347.1150.
By (2RS, 3RS)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-2-hydroxy-n-methyl-3-Phenylpropionamide, according to the mode that is similar to embodiment 33 steps 3 prepare (1RS, 2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ESI) m/z 333.1 ([M+H] +); HRMS: calculated value C 18H 21ClN 2O 2+ H +, 333.1370; Measured value (ESI, [M+H] +), 333.1381.
Embodiment 142:(1RS, 2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-1-phenyl-propane-2-alcohol hydrochloride
By 6-methyl-2H-1,4-benzoxazine-3 (4H)-ketone prepares 6-methyl-3 according to the mode that is similar to embodiment 165 steps 1,4-dihydro-2H-1, and the 4-benzoxazine is xanchromatic oil.
MS (ES) m/z 150.0 ([M+H] +); HRMS: calculated value C 9H 11NO+H +, 150.0919; Measured value (ESI, [M+H] +), 150.0924.
By 6-methyl-3,4-dihydro-2H-1,4-benzoxazine and trans-3-ethyl phenylglycidate, prepare (2RS according to the mode that is similar to embodiment 33 steps 1,3RS)-2-hydroxyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-phenylpropionic acid ethyl ester, be the viscosity yellow liquid.
MS (ESI) m/z 342.0 ([M+H] +); HRMS: calculated value C 20H 23NO 4+ H +, 342.1700; Measured value (ESI, [M+H] +), 342.1683.
By (2RS, 3RS)-2-hydroxyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-phenylpropionic acid ethyl ester, according to the mode that is similar to embodiment 33 steps 2 prepare (2RS, 3RS)-2-hydroxy-n-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and the 3-Phenylpropionamide, be white powder.
MS (ESI) m/z 325.0 ([M-H] -); HRMS: calculated value C 19H 22N 2O 3+ H +, 327.1703; Measured value (ESI, [M+H] +), 327.1703.
By (2RS, 3RS)-2-hydroxy-n-methyl-3-(6-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-the 3-Phenylpropionamide, according to the mode that is similar to embodiment 33 steps 3 prepare (1RS, 2SR)-3-(methylamino)-1-(6-methyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ESI) m/z 313.0 ([M+H] +); HRMS: calculated value C 19H 24N 2O 2+ H +, 313.1911; Measured value (ESI, [M+H] +), 313.1908.
Embodiment 143:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride
By 3-skatole and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(3-fluorophenyl)-3-(3-Methyl-1H-indole-1-yl) propane-1, the 2-glycol is the little yellow oil of viscosity.MS (ES) m/z 300.0 ([M+H] +); HRMS: calculated value C 18H 18FNO 2+ H +, 300.1400; Measured value (ESI, [M+H] +), 300.1400.
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-Methyl-1H-indole-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol hydrochloride, be white solid.MS (ES) m/z 313.0 ([M+H] +); HRMS: calculated value C 19H 21FN 2O+H +, 313.1711; Measured value (ESI, [M+H] +), 313.1713.
Embodiment 144:(1S, 2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Step 1: with racemic (1RS, 2SR)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol (embodiment 141) is dissolved in methyl alcohol.With the gained injection of solution to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.Under identical supercritical fluid chromatography condition, measure the enantiomeric purity of every kind of enantiomorph, wherein use ChiralcelAD-H 5 μ, 250mm * 4.6mm ID post, flow velocity 2.0mL/ minute, utilize analysis mode supercritical fluid chromatography (Berger Instruments, Inc.Newark, DE USA).
The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: Chiralcel AD-H; 5 μ; 250mm L * 20mm ID (Chiral Technologies, Inc, Exton, PA, USA)
Column temperature: 35 ℃
SFC properties-correcting agent: the 40%MeOH that contains 0.5%DEA
Flow velocity: 50mL/min
Top hole pressure: 100 crust
The UV of detector: 266nm
Step 2: will be isolating as 1 at peak (1S, 2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol (58mg, 0.17mmol) (1M, 0.2mL 0.2mmol) handle with the hydrochloric acid ethereal solution for solution in methylene dichloride (3mL).Add hexane to gained solution, generate until the adularescent powder, and collect this powder, use hexane wash, dry in a vacuum, obtain 62mg (45%) (1S, 2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride.Chiral purity:＞99.9%.MS (ESI) m/z 333.0 ([M+H] +); HRMS: calculated value C 18H 21ClN 2O 2+ H +, 333.1370; Measured value (ESI, [M+H] +), 333.1372.
Embodiment 145:(1R, 2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801851
By (1R, 2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol, according to the mode that is similar to embodiment 144 steps 2 prepare (1R, 2S)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, it is that (embodiment 144, and 2 at the peak of step 1) is isolating as chiral separation.Chiral purity:＞99.9%.MS (ESI) m/z 333.0 ([M+H] +); HRMS: calculated value C 18H 21ClN 2O 2+ H +, 333.1370; Measured value (ESI, [M+H] +), 333.1374.
Embodiment 146:(1S, 2R)-1-(4-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801861
By the 4-chloro-indole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(4-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the little yellow oil of viscosity.MS(ES)m/z 300.0([M-H]-)。
By (2S, 3S)-and 3-(4-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(4-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z315.0 ([M+H] +); HRMS: calculated value C 18H 19ClN 2O+H +, 315.1259; Measured value (ESI, [M+H] +), 315.1255.
Embodiment 147:(1S, 2R)-1-(6-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801862
By the 6-chloro-indole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(6-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 302.0 ([M+H] +); HRMS: calculated value C 17H 16ClNO 2+ H +, 302.0948; Measured value (ESI, [M+H] +), 302.0946.
By (2S, 3S)-and 3-(6-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(6-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z315.0 ([M+H] +); HRMS: calculated value C 18H 19ClN 2O+H +, 315.1259; Measured value (ESI, [M+H] +), 315.1263.
Embodiment 148:(1S, 2R)-1-(7-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801863
By the 7-chloro-indole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(7-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 302.0 ([M+H] +); HRMS: calculated value C 17H 16ClNO 2+ H +, 302.0948; Measured value (ESI, [M+H] +), 302.0949.
By (2S, 3S)-and 3-(7-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(7-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z315.0 ([M+H] +); HRMS: calculated value C 18H 19ClN 2O+H +, 315.1259; Measured value (ESI, [M+H] +), 315.1269.
Embodiment 149:(1S, 2R)-1-(7-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 7-chloro-indole and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(7-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 320.0 ([M+H] +); HRMS: calculated value C 17H 15ClFNO 2+ H +, 320.0848; Measured value (ESI, [M+H] +), 320.0858.
By (2S, 3S)-3-(7-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(7-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z333.0 ([M+H] +); HRMS: calculated value C 18H 18ClFN 2O+H +, 333.1170; Measured value (ESI, [M+H] +), 333.1189.
Embodiment 150:(1S, 2R)-1-(4-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801872
By 4-chloro-indole and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(4-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 320.0 ([M+H] +); HRMS: calculated value C 17H 15ClFNO 2+ H +, 320.0848; Measured value (ESI, [M+H] +), 320.0856.
By (2S, 3S)-3-(4-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(4-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z333.2 ([M+H] +); HRMS: calculated value C 18H 18ClFN 2O+H +, 333.1170; Measured value (ESI, [M+H] +), 333.1156.
Embodiment 151:(1S, 2R)-1-(6-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801881
By 6-chloro-indole and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(6-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 320.0 ([M+H] +); HRMS: calculated value C 17H 15ClFNO 2+ H +, 320.0848; Measured value (ESI, [M+H] +), 320.0855.
By (2S, 3S)-3-(6-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(6-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z333.2 ([M+H] +); HRMS: calculated value C 18H 18ClFN 2O+H +, 333.1170; Measured value (ESI, [M+H] +), 333.1174.
Embodiment 152:(1S, 2R)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801882
By the 5-chloro-indole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(5-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 302.2 ([M+H] +); HRMS: calculated value C 17H 16ClNO 2+ H +, 302.0948; Measured value (ESI, [M+H] +), 302.0956.
By (2S, 3S)-and 3-(5-chloro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z315.1 ([M+H] +); HRMS: calculated value C 18H 19ClN 2O+H +, 315.1259; Measured value (ESI, [M+H] +), 315.1247.
Embodiment 153:(1S, 2R)-1-(5-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 5-chloro-indole and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(5-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is the colourless oil of viscosity.MS (ES) m/z 320.1 ([M+H] +); HRMS: calculated value C 17H 15ClFNO 2+ H +, 320.0848; Measured value (ESI, [M+H] +), 320.0854.
By (2S, 3S)-3-(5-chloro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(5-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 333.1 ([M+H] +); HRMS: calculated value C 18H 18ClFN 2O+H +, 333.1170; Measured value (ESI, [M+H] +), 333.1154.
Embodiment 154:(1S, 2R)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 3-isopropyl indole (Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L.S.J.Org.Chem.1980,45,2709-2710) and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-sec.-propyl-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the little yellow oil of viscosity.HRMS: calculated value C 20H 23NO 2+ H +, 310.1802; Measured value (ESI, [M+H] +), 310.1793.
By (2S, 3S)-and 3-(3-sec.-propyl-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 323.3 ([M+H] +); HRMS: calculated value C 21H 26N 2O+H +, 323.2118; Measured value (ESI, [M+H] +), 323.2117.
Embodiment 155:(1S, 2R)-1-(3-fluorophenyl)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
By 3-isopropyl indole (Odle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L.S.J.Org.Chem.1980,45,2709-2710) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, step 3) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(3-sec.-propyl-1H-indoles-1-yl) propane-1, the 2-glycol is the little yellow oil of viscosity.MS (ES) m/z 326.2 ([M-H] -); HRMS: calculated value C 20H 22FNO 2+ H +, 328.1707; Measured value (ESI, [M+H] +), 328.1709.
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-sec.-propyl-1H-indoles-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-fluorophenyl)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 341.3 ([M+H] +); HRMS: calculated value C 21H 25FN 2O+H +, 341.2024; Measured value (ESI, [M+H] +), 341.2025.
Embodiment 156:(1S, 2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 6-chloro-3,4-dihydro-2H-1, (embodiment 88, step 1) and [(2R for the 4-benzoxazine, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol is the little yellow liquid of viscosity.MS (ES) m/z 335.8 ([M-H] -); HRMS: calculated value C 20H 22FNO 2+ H +, 338.0959; Measured value (ESI, [M+H] +), 338.0959.
By (2S, 3S)-3-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(6-chloro-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 351.0 ([M+H] +); HRMS: calculated value C 18H 20ClFN 2O 2+ H +, 351.1276; Measured value (ESI, [M+H] +), 351.1276.
Embodiment 157:(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Step 1: by trans-3, the 5-cinnamic acid difluoride prepares transly-3 according to the mode that is similar to embodiment 47 steps 1, and 5-cinnamic acid difluoride methyl esters is white solid.MS (ESI) m/z 198.0; HRMS: calculated value C 10H 8F 2O 2, 198.0492; Measured value (ESI, [M] +), 198.0489.
Step 2: by trans-3,5-cinnamic acid difluoride methyl esters prepares transly-3 according to the mode that is similar to embodiment 47 steps 2, and 5-difluoro styryl carbinol is colourless oil.
Step 3: by trans-3,5-difluoro styryl carbinol, according to the mode that is similar to embodiment 47 steps 3 prepare [(2R, 3R)-3-(3, the 5-difluorophenyl) oxyethane-2-yl] methyl alcohol, be colourless liquid.Ee per-cent: 97.9%.ME (ES) m/z 186.0HRMS: calculated value C 9H 8F 2O 2, 186.0492; Measured value (ESI, [M] +), 186.0501.
Step 4: by indoline and [(2R, 3R)-3-(3, the 5-difluorophenyl) oxyethane-2-yl] methyl alcohol, prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(3, the 5-difluorophenyl)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the little yellow oil of viscosity.MS (ES) m/z 306.2 ([M+H] +); HRMS: calculated value C 17H 17F 2NO 2+ H +, 306.1300; Measured value (ESI, [M+H] +), 306.1299.
Step 5: by (2S, 3S)-3-(3, the 5-difluorophenyl)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol prepares (2S according to the mode that is similar to embodiment 47 steps 5,3S)-3-(3, the 5-difluorophenyl)-and 3-(1H-indoles-1-yl) propane-1, the 2-glycol is the little yellow oil of viscosity.
MS (ES) m/z 304.0 ([M+H] +); HRMS: calculated value C 17H 15F 2NO 2+ H +, 304.1144; Measured value (ESI, [M+H] +), 304.1146.
Step 6: by (2S, 3S)-3-(3, the 5-difluorophenyl)-3-(1H-indoles-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3, the 5-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 317.0 ([M+H] +); HRMS: calculated value C 18H 18F 2N 2O+H +, 317.1465; Measured value (ESI, [M+H] +), 317.1465.
Embodiment 158:(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3, the 5-difluorophenyl)-3-(2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3, the 5-difluorophenyl)-and 1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol, be white powder.MS (ES) m/z 319.0 ([M+H] +); HRMS: calculated value C 18H 20F 2N 2O+H +, 319.1622; Measured value (ESI, [M+H] +), 319.1622.
Embodiment 159:(1S, 2R)-4-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) butane-2-alcohol hydrochloride
Figure A20058001737801922
By (2S, 3S)-and 3-(3-fluorophenyl)-3-(1H-indoles-1-yl) propane-1, (embodiment 47, step 4) for the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-2-hydroxyl-3-indoles-1-base-propyl diester.MS(ES)m/z 440([M+H] +)。
Embodiment 160:(1S, 2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801923
By 3,3-dimethyl indoline (Kucerovy, A.; Hathaway, J.S.; Mattner, P.G.; Repic, O.Synth.Commun.1992,22,729-733) with [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol is the viscosity brown liquid.MS (ES) m/z 316.0 ([M+H] +); HRMS: calculated value C 19H 22FNO 2+ H +, 316.1713; Measured value (ESI, [M+H] +), 316.1713.
By (2S, 3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS(ES)m/z 329.0([M+H] +)。
Embodiment 161:(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801931
By 3,3-dimethyl indoline (Kucerovy, A.; Hathaway, J.S.; Mattner, P.G.; Repic, O.Synth.Commun.1992,22,729-733) and [(2R, 3R)-3-(3, the 5-difluorophenyl) oxyethane-2-yl] (embodiment 157 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3, the 5-difluorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the viscosity brown liquid.MS (ES) m/z 334.0 ([M+H] +); HRMS: calculated value C 19H 21F 2NO 2+ H +, 334.1619; Measured value (ESI, [M+H] +), 334.1619.
By (2S, 3S)-and 3-(3, the 5-difluorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 6 prepare (1S, 2R)-1-(3, the 5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 347.0 ([M+H] +); HRMS: calculated value C 20H 24F 2N 2O+H +, 347.1929; Measured value (ESI, [M+H] +), 347.1929.
Embodiment 162:(1S, 2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 3,3-dimethyl indoline (Kucerovy, A.; Hathaway, J.S.; Mattner, P.G.; Repic, O.Synth.Commun.1992,22,729-733) with [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-phenyl-propane-1, the 2-glycol is the viscosity brown liquid.MS (ES) m/z 298.0 ([M+H] +); HRMS: calculated value C 19H 23NO 2+ H +, 298.1807; Measured value (ESI, [M+H] +), 298.1807.
By (2S, 3S)-3-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-and 3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z 311.0 ([M+H] +); HRMS: calculated value C 20H 26N 2O+H +, 311.2118; Measured value (ESI, [M+H] +), 311.2107.
Embodiment 163:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride
By 3-methyl indoline (Gribble, G.W.; Hoffman, J.H.Synthesis 1977,12,859-860) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3-fluorophenyl)-3-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the little yellow liquid of viscosity.MS (ES) m/z301.8 ([M+H] +); HRMS: calculated value C 18H 20FNO 2+ H +, 302.1551; Measured value (ESI, [M+H] +), 302.1539.
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-and 1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z 315.2 ([M+H] +); HRMS: calculated value C 19H 23FN 2O+H +, 315.1873; Measured value (ESI, [M+H] +), 315.1881.
Embodiment 164:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol hydrochloride
Figure A20058001737801951
By 1 ', 2 '-the dihydro spiral shell [pentamethylene-1,3 '-indoles] (Kucerovy, A.; Hathaway, J.S.; Mattner, P.G.; Repic, O.Synth.Commun.1992,22,729-733) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3-fluorophenyl)-3-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-1, the 2-glycol is the little yellow liquid of viscosity.MS(ES)m/z 342.2([M+H] +)。
By (2S, 3S)-3-(3-fluorophenyl)-3-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol hydrochloride is white powder.
MS (ES) m/z 355.0 ([M+H] +); HRMS: calculated value C 22H 27FN 2O+H +, 355.2180; Measured value (ESI, [M+H] +), 355.2178.
Embodiment 165:(1S, 2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801952
Step 1: under nitrogen atmosphere, via syringe to 2,2-dimethyl-2H-1,4-benzoxazine-3 (4H)-ketone (Caliendo, G.; Perissutti, E.; Santagada, V.; Fiorino, F.; Severino, B.; Bianca, R.) (2.658g, 15.0mmol) slowly add in the solution in tetrahydrofuran (THF) (10mL) borine solution (the 1.0M tetrahydrofuran solution, 22.5mL, 22.5mmol).The gained mixture was stirred under room temperature 10 minutes, stirred 1 hour down at 70 ℃ then.After the cooling, reaction mixture slowly cancellation of methyl alcohol (3mL).Under reduced pressure remove all volatile matters.In liquid residue, add 1N aqueous hydrochloric acid (10mL), mixture is warming up to 50 ℃ reaches 10 minutes.After the cooling, reaction mixture is transferred to alkalescence with saturated sodium bicarbonate solution (15mL), with ethyl acetate (25mL) extraction.With organic layer water, salt water washing, dry (anhydrous sodium sulphate) filters by silicagel pad, under reduced pressure concentrates, and obtains 2.310g (94%) 2,2-dimethyl-3,4-dihydro-2H-1, and the 4-benzoxazine is the oil of brown.MS(ES)m/z164.0([M+H] +)。
Step 2: by 2,2-dimethyl-3,4-dihydro-2H-1,4-benzoxazine and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, and step 3) prepares (2S according to the mode that is similar to embodiment 47 steps 4 for methyl alcohol, 3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is white solid.MS (ES) m/z 332.2 ([M+H] +); HRMS: calculated value C 19H 22FNO 3+ H +, 332.1657; Measured value (ESI, [M+H] +), 332.1648.
Step 3: by (2S, 3S)-and 3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 6 prepare (1S, 2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS(ES)m/z 345.2([M+H] +)；
HRMS: calculated value C 20H 25FN 2O 2+ H +, 345.1978; Measured value (ESI, [M+H] +), 345.1981.
Embodiment 166:(1S, 2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737801961
By 2,2-dimethyl-3,4-dihydro-2H-1, the 4-benzoxazine (embodiment 165, step 1) and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-and 3-phenyl-propane-1, the 2-glycol is white solid.MS(ES)m/z 314.1([M+H] +)。
By (2S, 3S)-and 3-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-phenyl-propane-1, the 2-glycol, according to the mode that is similar to embodiment 47 steps 6 prepare (1S, 2R)-1-(2,2-dimethyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 327.2 ([M+H] +); HRMS: calculated value C 20H 26N 2O 2+ H +, 327.2073; Measured value (ESI, [M+H] +), 327.2082.
Embodiment 167:(1S, 2R)-1-(2,3-dihydro-4H-1,4-benzothiazine-4-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801971
By 3,4-dihydro-2H-1,4-benzothiazine (El-Subbagh, H.I.; Abadi, A.H.; Al-Khawad, I.E.; Al-Rashood, K.A.Arch.Pharm.1999,332,19-24) with [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(2,3-dihydro-4H-1,4-benzothiazine-4-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol is the little yellow liquid of viscosity.MS (ES) m/z320.1 ([M+H] +); HRMS: calculated value C 17H 18FNO 2S+H +, 320.1115; Measured value (ESI, [M+H] +), 320.1113.
By (2S, 3S)-3-(2,3-dihydro-4H-1,4-benzothiazine-4-yl)-and 3-(3-fluorophenyl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(2,3-dihydro-4H-1,4-benzothiazine-4-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.MS(ES)m/z 333.1([M+H] +)；
HRMS: calculated value C 18H 21FN 2OS+H +, 333.1431; Measured value (ESI, [M+H] +), 333.1420.
Embodiment 168:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-2-alcohol hydrochloride
Figure A20058001737801972
By 2-phenyl-3,4-dihydro-2H-1,4-benzoxazine (Olagbemiro, T.O.; Nyakutse, C.A.; Lajide, L.; Agho, M.O.; Chukwu, C.E.Bull.Soc.Chim.Belg.1987,96,473-480) with [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(3-fluorophenyl)-3-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-1, the 2-glycol is white solid.MS (ES) m/z 380.0 ([M+H] +); HRMS: calculated value C 23H 22FNO 3+ H +, 380.1662; Measured value (ESI, [M+H] +), 380.1661.
By (2S, 3S)-3-(3-fluorophenyl)-3-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 393.2 ([M+H] +); HRMS: calculated value C 24H 25FN 2O 2+ H +, 393.1978; Measured value (ESI, [M+H] +), 393.1986.
Embodiment 169:(1S, 2R)-1-(3-fluorophenyl)-1-[3-(4-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 4-anisole are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[4-p-methoxy-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[4-p-methoxy-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4-p-methoxy-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4 p-methoxy-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-1-[3-(4-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride.MS(ESI)m/z 405。
Embodiment 170:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride
Figure A20058001737801991
By (2S, 3S)-and 3-(3-fluorophenyl)-3-{3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 4-methylbenzene are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[4-aminomethyl phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-(the 3-[4-aminomethyl phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4-aminomethyl phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4-aminomethyl phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride.MS(ESI)m/z 389.2。
Embodiment 171:(1S, 2R)-1-[3-(4-tert-butyl-phenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737801992
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 4-tert-butyl-phenyl are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[4-tert-butyl-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[4-tert-butyl-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4-tert-butyl-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4-tert-butyl-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-[3-(4-tert-butyl-phenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS (ESI) m/z 430.9; HRMS: calculated value C28H31FN2O+H+, 431.24932; Measured value (ESI, [M+H]+), 431.2516.
Embodiment 172:(1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 3-anisole are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[3-p-methoxy-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[3-p-methoxy-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(3-p-methoxy-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(3-p-methoxy-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride.MS (ESI) m/z405.1; HRMS: calculated value C25H25FN2O2+H+, 405.19728; Measured value (ESI, [M+H]+), 405.196.
Embodiment 173:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 4-(trifluoromethyl) benzene is for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(4-(trifluoromethyl) phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluoro-phenyl)-3-[3-(4-(trifluoromethyl) phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl propane-2-alcohol hydrochloride.MS(ESI)m/z 443.1。
Embodiment 174:(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737802012
By 6-fluorine indoline and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 47 steps 4,3S)-3-(3, the 5-difluorophenyl)-3-(6-fluoro-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol is the little yellow liquid of viscosity.MS(ES)m/z 324.1([M+H] +)；
HRMS: calculated value C 17H 16F 3NO 2+ H +, 324.1211; Measured value (ESI, [M+H] +), 324.1226.
By (2S, 3S)-3-(3, the 5-difluorophenyl)-3-(6-fluoro-2,3-dihydro-1H-indoles-1-yl) propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 47 steps 6,2R)-1-(3, the 5-difluorophenyl)-and 1-(6-fluoro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol hydrochloride, be white powder.
MS (ES) m/z 337.3 ([M+H] +); HRMS: calculated value C 18H 19F 3N 2O+H +, 337.1522; Measured value (ESI, [M+H] +), 337.1505.
Embodiment 175:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 2-(trifluoromethyl) are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-2-hydroxyl-3-[3-(2-(trifluoromethyl) phenyl)-indoles-1-yl]-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-2-hydroxyl-3-[3-(2-(trifluoromethyl) phenyl)-indoles-1-yl]-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl propane-2-alcohol hydrochloride.MS (ESI) m/z 443.1; HRMS: calculated value C25H22F4N2O+H+, 443.17410; Measured value (ESI, [M+H]+), 443.172.
Embodiment 176:(1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737802022
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 2-anisole are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[2-p-methoxy-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[2-p-methoxy-phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(2-p-methoxy-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(2-p-methoxy-phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol hydrochloride.MS (ESI) m/z 405.1; HRMS: calculated value C25H25FN2O2+H+, 405.19728; Measured value (ESI, [M+H]+), 405.1984.
Embodiment 177:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol hydrochloride
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 3-(trifluoromethyl) benzene is for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(3-(trifluoromethyl) phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(3-(trifluoromethyl) phenyl)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl propane-2-alcohol hydrochloride.MS (ESI) m/z 443.1; HRMS: calculated value C25H22F4N2O+H+, 443.17410; Measured value (ESI, [M+H]+), 443.1764.
Embodiment 178:(1S, 2R)-3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737802041
By the 3-skatole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares according to the mode that is similar to embodiment 117 steps 5 that (2S, 3S)-3-(3-skatole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil for methyl alcohol.MS(ESI)m/z 282([M+H] +)。
By (2S, 3S)-3-(3-methyl-indoles-1-yl)-3-phenyl-propane-1,2-two pure and mild tosic acid and dense ammonium hydroxide subsequently, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride, be pale solid.MS(ESI)m/z 281。
Embodiment 179:(1S, 2R)-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By the 2-fluoroaniline, prepare 7-fluoro-3-Methyl-1H-indole-2-ethyl formate according to the mode that is similar to embodiment 117 steps 1, be little brown solid.MS(ESI)m/z 221。
By 7-fluoro-3-Methyl-1H-indole-2-ethyl formate, prepare 7-fluoro-3-Methyl-1H-indole-2-formic acid according to the mode that is similar to embodiment 117 steps 2, be green solid.MS(ESI)m/z 192。
By 7-fluoro-3-Methyl-1H-indole-2-formic acid, prepare 7-fluoro-3-Methyl-1H-indole according to the mode that is similar to embodiment 117 steps 3, be white solid.MS(ESI)m/z 150。
By 7-fluoro-3-Methyl-1H-indole and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ESI)m/z 300。
By (2S, 3S)-3-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ES)m/z 313.1。
Embodiment 180:(1S, 2R)-3-amino-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride
By (2S, 3S)-3-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-phenyl-propane-1, (embodiment 179 for the 2-glycol, step 4) and tosic acid and ammonium hydroxide subsequently, prepare 3-amino-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol hydrochloride according to the mode that is similar to embodiment 117 steps 6, be white solid.MS(ES)m/z 299.0。
Embodiment 181:(1S, 2R)-1-(7-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 7-fluoro-1H-indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(7-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ES)m/z 286.1。
By (2S, 3S)-and 3-(7-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(7-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be pink solid.MS(ESI)m/z 299。
Embodiment 182:(1S, 2R)-1-(4-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 4-fluoro-1H-indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(4-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is oil.MS(ES)m/z 286.1。
By (2S, 3S)-and 3-(4-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(4-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ESI)m/z 299。
Embodiment 183:(1S, 2R)-1-(7-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
By 7-fluoro-1H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(7-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is the oil of brown.MS(ESI)m/z 304。
By (2S, 3S)-3-(7-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(7-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be the micro mist red solid.MS(ESI)m/z 317。
Embodiment 184:(1S, 2R)-1-(4-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737802062
By 4-fluoro-1H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-3-(4-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol is the oil of brown.MS(ESI)m/z 304。
By (2S, 3S)-3-(4-fluoro-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(4-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride, be white solid.MS(ESI)m/z 317。
Embodiment 185:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride
Figure A20058001737802071
By 5-Trifluoromethyl-1 H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(3-fluorophenyl)-3-(5-Trifluoromethyl-1 H-indoles-1-yl)-propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-(5-Trifluoromethyl-1 H-indoles-1-yl)-propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride, be pale solid.MS(ESI)m/z 367。
Embodiment 186:(1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
Figure A20058001737802072
By 6-fluoro-1H-indoles and [(2R, 3R)-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) for methyl alcohol, prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-(6-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol is the oil of brown.MS(ES)m/z 286.1。
By (2S, 3S)-and 3-(6-fluoro-1H-indoles-1-yl)-3-phenyl-propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(6-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ESI)m/z 299。
Embodiment 187:(1S, 2R)-3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride
By 6-Trifluoromethyl-1 H-indoles and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-phenyl-3-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-1, the 2-glycol is the oil of brown.MS(ES)m/z336。
By (2S, 3S)-and 3-phenyl-3-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride, be white solid.MS(ESI)m/z 349。
Embodiment 188:(1S, 2R)-3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride
Figure A20058001737802082
By 5-Trifluoromethyl-1 H-indoles and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare (2S according to the mode that is similar to embodiment 117 steps 5,3S)-and 3-phenyl-3-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-1, the 2-glycol is the oil of brown.MS(ES)m/z336。
By (2S, 3S)-and 3-phenyl-3-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol hydrochloride, be pale solid.MS(ESI)m/z 349.2。
Embodiment 189:(1S, 2R)-1-(the 3-tertiary butyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol
Step 1: at room temperature under nitrogen atmosphere, to indoles (5g, 42.7mmol), trifluoromethanesulfonic acid zinc (9.3g, 25.6mmol) with tetrabutylammonium iodide (7.9g, 21.4mmol) add in the mixture in dry toluene (120mL) diisopropylethylamine (8.2mL, 47mmol).To react on and stir under the room temperature after 15 minutes, (2.5mL 21.7mmol) handles reaction mixture with tert.-butyl bromide.Reaction soln in stirring 3 hours under nitrogen atmosphere under the room temperature, is poured in the saturated aqueous ammonium chloride (150mL) then.Separate organic layer, water layer ethyl acetate extraction (3 * 50mL).The organic layer that merges through dried over mgso, is concentrated, and resistates obtains the 3-tertiary butyl-1H-indoles via flash column chromatography purifying (silicon-dioxide, the hexane solution of 10% ethyl acetate), is white solid.MS(ES)m/z 174.2。
By the 3-tertiary butyl-1H-indoles and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47, and step 3) prepares (2S according to the mode that is similar to embodiment 117 steps 5 for methyl alcohol, 3S)-and 3-(the 3-tertiary butyl-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol.
By (2S, 3S)-3-(the 3-tertiary butyl-1H-indoles-1-yl)-3-(3-fluorophenyl) propane-1, the 2-glycol, prepare (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(the 3-tertiary butyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol, be clarifying oil.MS(ESI)m/z 355.3。
Embodiment 190:(1S, 2R)-1-(1H-indoles-1-yl)-2-methyl-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride
By 2-methyl-3-phenyl third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare [(2R, 3R)-2-methyl-3-phenyl ethylene oxide-2-yl] methyl alcohol, be white crystal.MS(ES)m/z147.1。
By [(2R, 3R)-2-methyl-3-phenyl ethylene oxide-2-yl] methyl alcohol (embodiment 117, step 4) and indoles, according to the mode that is similar to embodiment 117 steps 5 prepare (2S, 3S)-2-methyl-3-phenyl-[1H-indoles-1-yl] propane-1, the 2-glycol.
By (2S, 3S)-and 2-methyl-3-phenyl-[1H-indoles-1-yl] propane-1, the 2-glycol prepares (1S according to the mode that is similar to embodiment 117 steps 6,2R)-and 1-(1H-indoles-1-yl)-2-methyl-3-(methylamino)-1-phenyl-propane-2-alcohol hydrochloride, be white solid.MS(ES)m/z 295.0。
Embodiment 191:(2R, 3S)-3-(1H-indoles-1-yl)-1-(methylamino)-3-phenyl butane-2-alcohol hydrochloride
By 3-methyl-3-phenyl third-2-alkene-1-alcohol, according to the mode that is similar to embodiment 117 steps 4 prepare [(2R, 3R)-3-methyl-3-phenyl ethylene oxide-2-yl] methyl alcohol, be white crystal.MS(ES)m/z147.1。
By [(2R, 3R)-3-methyl-3-phenyl ethylene oxide-2-yl] (embodiment 117, step 4) and indoline for methyl alcohol, according to the mode that is similar to embodiment 47 steps 4 prepare (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-phenyl butane-1, the 2-glycol is brown solid.MS(ES)m/z 284.1。
By (2S, 3S)-3-(2,3-dihydro-1H-indoles-1-yl)-3-phenyl butane-1, the 2-glycol prepares according to the mode that is similar to embodiment 47 steps 5 that (2S, 3S)-3-(1H-indoles-1-yl)-3-phenyl butane-1, the 2-glycol is pale solid.MS(ESI)m/z 282。
By (2S, 3S)-3-(1H-indoles-1-yl)-3-phenyl butane-1, the 2-glycol prepares according to the mode that is similar to embodiment 117 steps 6 that (2R 3S)-3-(1H-indoles-1-yl)-1-(methylamino)-3-phenyl butane-2-alcohol hydrochloride, is white solid.MS(ES)m/z 295.1。
The embodiment 192:1-tertiary butyl-3-(2-hydroxy-3-methyl amino-1-phenyl-propyl group)-1,3-dihydro-benzimidazolyl-2 radicals-keto hydrochloride
Step 1: under room temperature, to 1-fluoro-2-nitro-benzene (1g, 7.1mmol) add in the solution in dimethyl formamide (15mL) TERTIARY BUTYL AMINE (0.82mL, 7.81mmol), with reaction mixture under nitrogen atmosphere, stirring 12 hours under the room temperature.After reacting completely, reaction mixture is poured in the saturated sodium-chloride water solution (50mL), with ethyl acetate (50mL) extraction.Organic layer through anhydrous sodium sulfate drying, is concentrated in a vacuum, and resistates obtains the tertiary butyl-(2-nitrophenyl)-amine via flash column chromatography purifying (silicon-dioxide, the hexane solution of 1% ethyl acetate), is orange oil.MS(ES)m/z 195.2
Step 2: with mode dropwise to the tertiary butyl-(2-nitrophenyl)-amine (1.27g, 6.5mmol), (0.49g 13.1mmol) adds methyl alcohol (10mL) in the solution in tetrahydrofuran (THF) (20mL) to 5% palladium on carbon (0.5g) with sodium borohydride.After reacting completely, filter, filtrate is poured in the saturated aqueous ammonium chloride (50mL), with ethyl acetate (50mL) extraction by Celite pad.Organic layer through anhydrous magnesium sulfate drying, is concentrated in a vacuum, obtain the N-tertiary butyl-benzene-1, the 2-diamines, it need not to be further purified and promptly can be used for next step.With the N-tertiary butyl-benzene-1, (1.1g, 6.7mmol) (1.63g, 10mmol) solution in anhydrous tetrahydro furan (50mL) stirred 12 hours under room temperature the 2-diamines with carbonyl dimidazoles.After reacting completely, reaction mixture is poured in the 1N aqueous hydrochloric acid (50mL), with ethyl acetate (50mL) extraction.Organic layer through anhydrous sodium sulfate drying, is concentrated in a vacuum.Crude product obtains the 1-tertiary butyl-1 via flash column chromatography purifying (silicon-dioxide, the hexane solution of 50% ethyl acetate), and 3-dihydro-benzimidazolyl-2 radicals-ketone is pale solid.MS(ES)m/z 191.1。
Step 3: with the 1-tertiary butyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone (0.66g, 3.5mmol) (3.8mmol) mixture in anhydrous dimethyl formamide (4mL) is in stirring 10 minutes under nitrogen atmosphere under the room temperature for 60% mineral oil dispersion, 0.15g with sodium hydride.Add 20 minutes [(2R of slaking then, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4,1.07g, 7.1mmol) and titanium isopropylate (2.14mL, 7.1mmol) solution in dimethyl formamide (4mL), with mixture under nitrogen atmosphere, stirring 12 hours under the room temperature.Epoxide distributes mixture after disappearing between 1N aqueous hydrochloric acid (50mL) and ethyl acetate (50mL).Separate organic layer,,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying with saturated sodium bicarbonate (50mL) washing.Resistates obtains the 1-tertiary butyl-3-[(1S via silicagel column purifying (hexane solution of 60% ethyl acetate), 2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is oil.MS(ES)m/z 341.2。
Step 4: with the 1-tertiary butyl-3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone (0.55g, 1.6mmol) (0.37g, 1.9mmol) solution in anhydrous pyridine (5mL) is in stirring 12 hours under nitrogen atmosphere under the room temperature with Tosyl chloride.Reaction mixture is poured in the cold 1N aqueous hydrochloric acid (50mL), with ethyl acetate (50mL) extraction.Organic layer through anhydrous sodium sulfate drying, is filtered, concentrate, obtain (2S, 3S)-toluene-4-sulfonic acid 3-(the 3-tertiary butyl-2-oxo-2,3-dihydro-benzoglyoxaline-1-yl)-2-hydroxyl-3-phenyl-propyl diester.To (2S, 3S)-toluene-4-sulfonic acid 3-(the 3-tertiary butyl-2-oxo-2,3-dihydro-benzoglyoxaline-1-yl)-2-hydroxyl-3-phenyl-propyl diester (0.8g, 1.6mmol) add the methanol solution (4mL of 2N methylamine in the solution in methyl alcohol (10mL), 8mmol), in the test tube of sealing, reaction mixture was stirred 12 hours under room temperature.After reacting completely, reaction mixture is distributed between saturated sodium bicarbonate aqueous solution (50mL) and ethyl acetate (50mL).Separate organic layer,, filter, concentrate in a vacuum through anhydrous sodium sulfate drying.Resistates obtains the 1-tertiary butyl-3-[(1S via flash column chromatography purifying (silicon-dioxide, the dichloromethane solution of 20%MeOH), 2R)-2-hydroxy-3-methyl amino-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is clarifying oil.Free alkali is dissolved in small amount of ethanol, handles, stirred 1 hour with the ethereal solution of 2N hydrochloric acid.Remove ethanol in a vacuum, clarifying oil with ether/methylene dichloride development, is obtained the 1-tertiary butyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.
HRMS: calculated value C 21H 27N 3O 2+ H+, 354.21760; Measured value (ESI, [M+H] +), 354.2179.
Embodiment 193:1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
Figure A20058001737802121
By 1-fluoro-2-nitro-benzene and propyl group amine, prepare 2-nitro-N propyl aniline according to the mode that is similar to embodiment 192 steps 1.MS(ES)m/z 181.1。
By 2-nitro-N propyl aniline, prepare 1-propyl group-1 according to the mode that is similar to embodiment 192 steps 2,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.MS(ES)m/z 177.1。
By 1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 1-propyl group-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.
By 1-propyl group-3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.HRMS: calculated value C 20H 25N 3O 2+ H+, 340.20195; Measured value (ESI, [M+H] +), 340.2007
Embodiment 194:5-bromo-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Step 1: by 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one (WO 00/66166) and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares 5-bromo-1-[(2S according to the mode that is similar to embodiment 99 steps 6 for methyl alcohol, 3S)-2,3-dihydroxyl-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 391([M+H] +)。
Step 2: by (5-bromo-1-[(2S, 3S)-2,3-dihydroxyl-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one), according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 545([M+H] +)。
Step 3: by (2S, 3S)-toluene-4-sulfonic acid 3-(5-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, prepare 5-bromo-1-[(1S according to the mode that is similar to embodiment 5,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.MS m/z 404 ([M+H] +), HRMS: calculated value C20H23BrN2O2+H +, 403.10156; Measured value (ESI, [M+H] +), 403.0998.
Embodiment 195:6-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Step 1: by 2,5-difluoro nitrobenzene and dimethyl malonate prepare (4-fluoro-2-nitrophenyl) dimethyl malonate according to the mode that is similar to embodiment 99 steps 2.MS(ESI)m/z 272([M+H] +)。
Step 2:, prepare (4-fluoro-2-nitrophenyl) acetate according to the mode that is similar to embodiment 99 steps 3 by (4-fluoro-2-nitrophenyl) dimethyl malonate.MS(ESI)m/z 200([M+H] +)。
Step 3:, prepare 6-fluoro-1 according to the mode that is similar to embodiment 99 steps 4,3-dihydro-2H-indol-2-one by (4-fluoro-2-nitrophenyl) acetate.MS(ESI)m/z 152([M+H] +)。
Step 4: by 6-fluoro-1,3-dihydro-2H indol-2-one prepares 6-fluoro-3 according to the mode that is similar to embodiment 99 steps 5,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 180([M+H] +)。
Step 5: by 6-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares (2S according to the mode that is similar to embodiment 99 steps 6 for methyl alcohol, 3S)-1-(2,3-dihydroxyl-1-phenyl-propyl group)-and 6-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one.MS(ESI)m/z 330([M+H] +)。
Step 6: by (2S, 3S)-1-(2,3-dihydroxyl-1-phenyl-propyl group)-6-fluoro-3,3-dimethyl-1, the 3-dihydro-indol-2-one, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 484([M+H] +)。
Step 7: will (2S, 3S)-(367mg is 0.76mmol) with methylamine (20mL for toluene-4-sulfonic acid 3-(6-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester; The 8M ethanolic soln) solution stirred 16 hours in the sealing test tube.Concentrated solution obtains the 250mg crude product in a vacuum.Crude product obtains the impure required product of 77mg via Biotage chromatography purification (5%, 8% and 10% contains the ethanol/methylene of ammonia for FlasH40i, silicon-dioxide).At last via reversed-phase HPLC purifying (X-terra MS C 1819 * 150mm uses the 60% methanol geometric ratio mixture that contains 0.05% ammonium hydroxide, and flow velocity 20mL/ minute, 250nm), obtain the required product of 35mg, be free alkali.Free alkali is handled with the ethereal solution of 1M hydrochloric acid, is pH=3 until solution, handles with ether then.Add a small amount of hexane and make the product crystallization, obtain title compound 6-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.
MS (ESI) m/z 343 ([M+H] +); HRMS: calculated value C20H23FN2O2+H +, 343.18163; Measured value (ESI, [M+H] +), 343.18.
Embodiment 196:4-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Figure A20058001737802151
Step 1: by 2,3-two fluoro-phenyl amine and sodium perborate tetrahydrate mixture prepare 1 according to the mode that is similar to embodiment 99 steps 1,2-two fluoro-3-nitro-benzene.MS(ESI)m/z 160([M+H] +)。
Step 2: by 1,2-two fluoro-3-nitro-benzene prepare (2-fluoro-6-nitrophenyl) dimethyl malonate according to the mode that is similar to embodiment 99 steps 2.MS(ESI)m/z 272.0576。
Step 3:, prepare (2-fluoro-6-nitrophenyl) acetate according to the mode that is similar to embodiment 99 steps 3 by (2-fluoro-6-nitrophenyl) dimethyl malonate.MS(ESI)m/z 200([M+H] +)。
Step 4:, prepare 4-fluoro-1 according to the mode that is similar to embodiment 99 steps 4,3-dihydro-2H-indol-2-one by (2-fluoro-6-nitrophenyl) acetate.MS(ESI)m/z 152([M+H] +)。
Step 5: by 4-fluoro-1,3-dihydro-2H indol-2-one prepares 4-fluoro-3 according to the mode that is similar to embodiment 99 steps 5,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 180([M+H] +)。
Step 6: by 4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117, and step 4) prepares 1-[(2S according to the mode that is similar to embodiment 99 steps 6 for methyl alcohol, 3S)-2,3-dihydroxyl-1-phenyl propyl]-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.MS(ESI)m/z 330([M+H] +)。
Step 7: by 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-4-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester.MS(ESI)m/z 484([M+H] +)。
Step 8: by (2S, 3S)-toluene-4-sulfonic acid 3-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-2-hydroxyl-3-phenyl-propyl diester, prepare 4-fluoro-1-[(1S according to the mode that is similar to embodiment 195 steps 7,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.
HRMS: calculated value C20H23FN2O2+H +, 343.18163; Measured value (ESI, [M+H] +), 343.1807.
Embodiment 197:1-cyclobutyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
Figure A20058001737802161
By 1-fluoro-2-nitro-benzene and cyclobutyl amine, prepare N-cyclobutyl-2-N-methyl-p-nitroaniline according to the mode that is similar to embodiment 192 steps 1.MS(ES)m/z 193。
By N-cyclobutyl-2-N-methyl-p-nitroaniline, prepare 1-cyclobutyl-1 according to the mode that is similar to embodiment 192 steps 2,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.MS(ES)m/z 189。
By 1-cyclobutyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 1-cyclobutyl-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.MS(ES)m/z 339.2。
By 1-cyclobutyl-3-[(1S, 2R)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-cyclobutyl-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS(ES)m/z 352.2
HRMS: calculated value C 21H 25N 3O 2+ H+, 352.20195; Measured value (ESI, [M+H] +), 352.207
Embodiment 198:5-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1,4-two fluoro-2-nitro-benzene and propyl group amine prepare (4-fluoro-2-nitro-phenyl) propyl group-amine according to the mode that is similar to embodiment 192 steps 1.
By (4-fluoro-2-nitro-phenyl)-propyl group amine, prepare 5-fluoro-1-propyl group-1,3-dihydro-benzimidazolyl-2 radicals-ketone according to the mode that is similar to embodiment 192 steps 1 and 2.MS(ES)m/z 195.2。
By 5-fluoro-1-propyl group-1,3-dihydro-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 5-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.
By 5-fluoro-3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 5-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS (ES) m/z 358.2; HRMS: calculated value C 20H 24FN 3O 2+ H+, 358.19253; Measured value (ESI, [M+H] +), 358.1895
Embodiment 199:1-ethyl-3-[1-(3-fluoro-phenyl)-2-hydroxy-3-methyl amino-propyl group]-1,3-dihydro-benzimidazolyl-2 radicals-keto hydrochloride
Figure A20058001737802172
Step 1: to the methanol solution of ethamine (2.0M, 150mL, add in 300mmol) 1-fluoro-2-oil of mirbane (8mL, 75.7mmol).Reaction mixture is placed the container of sealing, be heated to 55C and reach 15 hours.Remove in a vacuum and desolvate, resistates is dissolved in ethyl acetate (200mL), with saturated sodium bicarbonate aqueous solution (80mL) washing, through anhydrous sodium sulphate (50g) drying.Except that after desolvating, (12.5g 75mmol), is the oil of brown to obtain ethyl-(2-nitro-phenyl) amine.MS(ES)m/z 167.1。
Step 2: (12.5g, (5.8g is 153mmol) with 5% palladium on carbon (150mg) 75mmol) to add sodium borohydride in the solution in anhydrous tetrahydro furan (150mL) to ethyl-(2-nitro-phenyl)-amine.Then under nitrogen atmosphere, adding methyl alcohol (25mL) under the room temperature in mode dropwise.After the adding, with reaction mixture stir about 30 minutes under room temperature, until reacting completely.Then by the Celite pad filter reaction mixture.Filtrate with ethyl acetate (200mL) dilution, is washed with saturated aqueous ammonium chloride (80mL), through the S-WAT drying, concentrate in a vacuum, obtain thick N-ethyl-benzene-1,2-diamines (8.4g, 62mmol), it need not to be further purified and promptly can be used for next step.
Step 3: to thick N-ethyl-benzene-1, the 2-diamines (8.4g, 62mmol) add 1,1 in the solution in anhydrous tetrahydro furan (200mL) '-carbonyl dimidazoles (10g, 62mmol).Mixture in stirring 12 hours under the room temperature, is added ethyl acetate (250mL) under nitrogen atmosphere, add cold 3N aqueous hydrochloric acid (200mL) afterwards.Separate organic layer, through dried over sodium sulfate, concentrate in a vacuum, obtain 1-ethyl-1,3-dihydrobenzo imidazoles-2-ketone is white solid (8.5g, three step yields 69%).MS(ES)m/z 163.2。
Step 4: by 1-ethyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), prepare 1-ethyl-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.
Step 5: by 1-ethyl-3-[(1S, 2S)-2,3-dihydroxyl-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-ethyl-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-and 1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS(ES)m/z 344.2。
Embodiment 200:1-ethyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1-ethyl-1, (embodiment 199 for 3-dihydro-benzimidazolyl-2 radicals-ketone, step 2) and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4) prepares 1-ethyl-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.
By 1-ethyl-3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-ethyl-3-[(1S according to the mode that is similar to embodiment 192 steps 4 and 5,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS(ES)m/z 326.2
HRMS: calculated value C 19H 23N 3O 2+ H+, 326.18630; Measured value (ESI, [M+H] +), 326.1845.
Embodiment 201:4-fluoro-3-(2-hydroxy-3-methyl amino-1-phenyl-propyl group)-1-sec.-propyl-1,3-dihydro-benzimidazolyl-2 radicals-keto hydrochloride
By 1,3-two fluoro-2-nitro-benzene and Isopropylamines prepare (3-fluoro-2-nitro-phenyl) sec.-propyl-amine according to the mode that is similar to embodiment 192 steps 1.
By (3-fluoro-2-nitro-phenyl)-isopropylamine, prepare 4-fluoro-1-sec.-propyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone according to the mode that is similar to embodiment 192 steps 2.MS(ES)m/z 195.2。
By 4-fluoro-1-sec.-propyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 4-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.
By 4-fluoro-3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl-propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 4-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS (ES)m/z 358.4。
Embodiment 202:1-cyclopentyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1-fluoro-2-nitro-benzene and cyclopentyl amine, prepare N-cyclopentyl-2-N-methyl-p-nitroaniline according to the mode that is similar to embodiment 192 steps 1.MS(ESI)m/z 207。
By N-cyclopentyl-2-N-methyl-p-nitroaniline, prepare 1-cyclopentyl-1 according to the mode that is similar to embodiment 192 steps 2,3-dihydro-benzimidazolyl-2 radicals-ketone.MS(ESI)m/z 203。
By 1-cyclopentyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 1-cyclopentyl-3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is white solid.MS(ES)m/z 352.9。
By 1-cyclopentyl-3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-cyclopentyl-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS(ESI)m/z 366。
Embodiment 203:1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1-fluoro-2-nitro-benzene and isopropylamine, prepare N-sec.-propyl-2-N-methyl-p-nitroaniline according to the mode that is similar to embodiment 192 steps 1.MS(ES)m/z 181.2。
By N-sec.-propyl-2-N-methyl-p-nitroaniline, prepare 1-sec.-propyl-1 according to the mode that is similar to embodiment 192 steps 2,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.MS(ES)m/z 176.9。
By 1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 1-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is white solid.
By 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS (ES) m/z MS (ES) m/z 340.3; HRMS: calculated value C 20H 25N 3O 2+ H+, 340.20195; Measured value (ESI, [M+H] +), 340.2012.
Embodiment 204:3-[(1S, 2R)-3-(ethylamino)-2-hydroxyl-1-phenyl propyl]-5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1,4-two fluoro-2-nitro-benzene and isopropylamine prepare 4-fluoro-N-sec.-propyl-2-N-methyl-p-nitroaniline according to the mode that is similar to embodiment 192 steps 1.MS(ES)m/z 199.1。
By 4-fluoro-N-sec.-propyl-2-N-methyl-p-nitroaniline, prepare 5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone according to the mode that is similar to embodiment 192 steps 2.MS(ES)m/z 195.1。
By 5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 5-fluoro-1-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is white solid.
By 5-fluoro-1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and tosic acid and ethylamine subsequently, prepare 3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-3-(ethylamino)-2-hydroxyl-1-phenyl propyl]-5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS(ESI)m/z 372.21；
HRMS: calculated value C 21H 26FN 3O 2+ H+, 372.20818; Measured value (ESI, [M+H] +), 372.2099.
Embodiment 205:1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
Figure A20058001737802221
By the 1-methyl isophthalic acid, 3-dihydro-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 1-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone is white solid.
By 1-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.
MS (ES) m/z 312.3; HRMS: calculated value C 18H 21N 3O 2+ H+, 312.17065; Measured value (ESI, [M+H] +), 312.17.
Embodiment 206:1-ethyl-5-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1,4-two fluoro-2-N-methyl-p-nitroaniline and ethylamines prepare ethyl-(4-fluoro-2-nitrophenyl)-amine according to the mode that is similar to embodiment 199 steps 1.
By ethyl-(4-fluoro-2-nitro-phenyl)-amine, prepare N-ethyl-4-fluorobenzene-1,2-diamines according to the mode that is similar to embodiment 199 steps 2.
By N-ethyl-4-fluoro-benzene-1,2 diamines, prepare 1-ethyl-5-fluoro-1 according to the mode that is similar to embodiment 199 steps 3,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.MS(ES)m/z 181.2。
By 1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl propyl]-1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is white solid.MS(ES)m/z 331.1。
By 3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-1-ethyl-5-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-ethyl-5-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS (ES) m/z 344.2; HRMS: calculated value C 19H 22FN 3O 2+ H+, 344.17688; Measured value (ESI, [M+H] +), 344.175.
Embodiment 207:1-ethyl-4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
Figure A20058001737802231
By 1,3-two fluoro-2-N-methyl-p-nitroaniline and ethylamines prepare ethyl-(3-fluoro-2-nitrophenyl)-amine according to the mode that is similar to embodiment 199 steps 1.
By ethyl-(3-fluoro-2-nitro-phenyl)-amine, prepare N-ethyl-3-fluorobenzene-1,2-diamines according to the mode that is similar to embodiment 199 steps 2.
By N-ethyl-3-fluoro-benzene-1,2 diamines, prepare 1-ethyl-4-fluoro-1 according to the mode that is similar to embodiment 199 steps 3,3-dihydro-2H-benzimidazolyl-2 radicals-ketone.MS(ES)m/z 181.2。
By 1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone and [(2R, 3R)-and 3-phenyl ethylene oxide-2-yl] (embodiment 117 for methyl alcohol, step 4), prepare 3-[(1S according to the mode that is similar to embodiment 192 steps 3,2S)-2,3-dihydroxyl-1-phenyl propyl]-1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is white solid.MS(ES)m/z 331.1。
By 3-[(1S, 2S)-2,3-dihydroxyl-1-phenyl propyl]-1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-ethyl-4-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-and 2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS (ES) m/z 344.2; HRMS: calculated value C 19H 22FN 3O 2+ H+, 344.17688; Measured value (ESI, [M+H] +), 344.1768.
Embodiment 208:4-fluoro-3-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino)-propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 4-fluoro-1-sec.-propyl-1, (embodiment 201 for 3-dihydro-benzimidazolyl-2 radicals-ketone, step 2) and [(2R, 3R)-and 3-(3-fluorophenyl)-oxyethane-2-yl] (embodiment 47, and step 3) prepares 4-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 3 for methyl alcohol, 2S)-1-(3-fluoro-phenyl)-2,3-dihydroxyl-propyl group]-1-sec.-propyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone is oil.
By 4-fluoro-3-[(1S, 2S)-1-(3-fluorophenyl)-2,3-dihydroxyl-propyl group]-1-sec.-propyl-1,3-dihydro-benzimidazolyl-2 radicals-ketone, prepare 4-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino)-propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS (ES)m/z 376.2。
Embodiment 209:1-ethyl-4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride
By 1-ethyl-4-fluoro-1, (embodiment 207 for 3-dihydro-2H-benzimidazolyl-2 radicals-ketone, step 2) and [(2R, 3R)-and 3-(3-fluorophenyl)-oxyethane-2-yl] (embodiment 47, and step 3) prepares 3-[(1S according to the mode that is similar to embodiment 192 steps 3 for methyl alcohol, 2S)-2,3-dihydroxyl-1-(3-fluorophenyl)-propyl group]-1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone is clarifying oil.MS(ES)m/z349.1。
By 3-[(1S, 2S)-2,3-dihydroxyl-1-(3-fluorophenyl)-propyl group]-1-ethyl-4-fluoro-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, prepare 1-ethyl-4-fluoro-3-[(1S according to the mode that is similar to embodiment 192 steps 4,2R)-and 2-hydroxyl-3-(methylamino)-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-keto hydrochloride is white solid.MS(ES)m/z 362.1。
Embodiment 210:1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride
Step 1: by 3,3-dimethyl-1,3-dihydro-indol-2-one (A.Kende, Synth.Comm.1:12 (1982)) and [(2R, 3R)-3-(3-fluorophenyl) oxyethane-2-yl] (embodiment 47 for methyl alcohol, step 3), according to the mode that is similar to embodiment 101 steps 1 prepare (2S, 3S)-1-[1-(3-fluoro-phenyl)-2,3-dihydroxyl-propyl group]-3,3-dimethyl-1, the 3-dihydro-indol-2-one.MS(ESI)m/z 330([M+H] +)。
Step 2: by (2S, 3S)-1-[1-(3-fluoro-phenyl)-2,3 dihydroxyl-propyl group]-3,3-dimethyl-1, the 3-dihydro-indol-2-one, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-3-(3-fluoro-phenyl)-2 hydroxyls-propyl diester.MS(ESI)m/z 484([M+H] +)。
Step 3: by (2S, 3S)-toluene-4-sulfonic acid 3-(3,3-dimethyl-2-oxo-2,3-dihydro-indoles-1-yl)-3-(3-fluoro-phenyl)-2-hydroxyl-propyl diester, prepare 1-[(1S according to the mode that is similar to embodiment 5,2R)-and 1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one hydrochloride.MS(ESI)m/z 343([M+H] +)。
Embodiment 211:(1S, 2R)-1-[3-(2, the 3-difluorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737802252
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 2,3-two fluorobenzene are for boric acid, according to the mode that is similar to embodiment 114 steps 2 prepare (2S, 3S)-(3-fluorophenyl)-[3-(2 for 3-, the 3-difluorophenyl)-and 1H-indoles-1-yl] propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-[3-(2, the 3-difluorophenyl)-and 1H-indoles-1-yl] propane-1, the 2-glycol, prepare (2S according to the mode that is similar to embodiment 1 step 2,3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(2, the 3-difluorophenyl)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-(2, the 3-difluorophenyl)-indoles-1-yl]-2-hydroxyl-propyl diester, prepare (1S according to the mode that is similar to embodiment 5,2R)-1-[3-(2, the 3-difluorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol.MS (ES) m/z 411.1; HRMS: calculated value C24H21F3N2O+H+, 411.16787; Measured value (ESI, [M+H]+), 411.1675.
Embodiment 212:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl] propane-2-alcohol hydrochloride
Figure A20058001737802261
Step 1: will (1S, 2R)-non-enantiomer mixture (embodiment 168) of 1-(3-fluorophenyl)-3-(methylamino)-1-(2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl) propane-2-alcohol is dissolved in methyl alcohol.With the gained injection of solution to supercritical fluid chromatograph.The enantiomorph that utilizes following conditional capture baseline to split.
The SFC instrument: (DE 19702 for Berger Instruments, Inc.Newark for Berger MultiGram Prep SFC.
Post: ethylpyridine; 250mm L * 20mm ID (Princeton Chromatography Inc.)
Column temperature: 35 ℃
SFC properties-correcting agent: 15%MeOH and 85%CO 2
Flow velocity: 50mL/min
Top hole pressure: 100 crust
The UV of detector: 220nm
Step 2: make as peak 1 isolating (1S according to the mode that is similar to embodiment 144 steps 2,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl] propane-2-alcohol generation hydrochloride, obtain (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2R)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl] propane-2-alcohol hydrochloride, be white powder.MS (ES) m/z 393.2 ([M+H] +); HRMS: calculated value C 24H 25FN 2O 2+ H +, 393.1973; Measured value (ESI, [M+H] +), 393.1992.
Embodiment 213:(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl] propane-2-alcohol hydrochloride
By (1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl] propane-2-alcohol, prepare (1S according to the mode that is similar to embodiment 212,2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[(2S)-2-phenyl-2,3-dihydro-4H-1,4-benzoxazine-4-yl] propane-2-alcohol hydrochloride, be white powder, it is to separate as diastereomer that (embodiment 212, and 2 at the peak of step 1) is isolating.MS (ES) m/z 393.2 ([M+H] +); HRMS: calculated value C 24H 25FN 2O 2+ H +, 393.1973; Measured value (ESI, [M+H] +), 393.1982.
Embodiment 214:(1S, 2R)-1-[3-(2-chloro-phenyl-)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride
Figure A20058001737802272
By (2S, 3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indoles-1-yl) propane-1, (embodiment 114 for the 2-glycol, step 1) and 2-chlorobenzene are for boric acid, prepare (2S according to the mode that is similar to embodiment 114 steps 2,3S)-3-(3-fluorophenyl)-3-{3-[2-chloro-phenyl-]-1H-indoles-1-yl } propane-1, the 2-glycol.
By (2S, 3S)-3-(3-fluorophenyl)-3-(the 3-[2-chloro-phenyl-]-1H-indoles-1-yl) propane-1, the 2-glycol, according to the mode that is similar to embodiment 1 step 2 prepare (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluorophenyl)-3-[3-(2-chloro-phenyl-)-indoles-1-yl]-2-hydroxyl-propyl diester.
By (2S, 3S)-toluene-4-sulfonic acid 3-(3-fluoro-phenyl)-3-[3-(2-chloro-phenyl-)-indoles-1-yl]-2-hydroxyl-propyl diester and methylamine (2N methanol solution), according to the mode that is similar to embodiment 5 prepare (1S, 2R)-1-[3-(2-chloro-phenyl-)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol hydrochloride.MS (ESI) m/z 409.1; HRMS: calculated value C24H22ClFN2O+H+, 409.14774; Measured value (ESI, [M+H]+), 409.146.
Clone, cultivation reagent and test
Contain high glucose DMEM (Gibco, Cat.No.11995), 10%FBS (dialysis, hot deactivation, US Bio-Technologies, Lot FBD1129HI) and 500 μ g/mL G418 (Gibco in growth substrate Cat.No.10131), cultivates the MDCK-Net6 cell (Pacholczyk of personnel selection hNET stable transfection, T., R.D.Blakely, and S.G.Amara, Nature, 1991,350 (6316): p.350-4).According to 300,000/T75 flask plating cell, cell divides weekly twice.Jar cell system (people's placental villi film cancer) buys (Cat.No.HTB-144) from ATCC.Contain RPMI 1640 (Gibco, Cat.No.72400), 10%FBS (Irvine, Cat.No.3000), 1% Sodium.alpha.-ketopropionate (Gibco, culturing cell Cat.No.1136) and in the growth substrate of 0.25% glucose.According to 250,000 cells/T75 flask plating cell, divide weekly twice.For all tests, with the cell plating the aseptic flat board in Wallac 96-hole (PerkinElmer, Cat.No.3983498) in.
Norepinephrine (NE) picked-up test
The 1st day, with cell according to 3,000 cells/well platings in growth substrate, support in the cell incubator (37 ℃, 5%CO 2).The 2nd day, growth substrate is contained test damping fluid (the 25mM HEPES of 0.2mg/mL xitix and 10 μ M Pargylines with 200 μ L; 120mM NaCl; 5mMKCl; 2.5mM CaCl 21.2mM MgSO 42mg/ml glucose (7.4,37 ℃ of pH)) replace.Before adding compound, make the flat board that contains cell and 200 μ L test damping fluid 37 ℃ of following balances 10 minutes.The stock solution (10mM) of preparation Desipramine is delivered to the aperture that contains cell in triplicate in DMSO, makes that final test concentration is 1 μ M.Be used to from the non-specific NE picked-up of the data definition of these apertures (minimum NE picked-up).In DMSO, prepare test compound (10mM), according to test specification (1 to 10,000nM) be diluted in the test damping fluid in.Directly add 25 μ L test damping fluid (maximum NE picked-up) or test compound to the triplicate aperture that in 200 μ L test damping fluid, contains cell.Make test in the damping fluid cell and test compound 37 ℃ of following incubations 20 minutes.In order to cause NE picked-up, to every hole send be diluted in the test damping fluid [ 3H] the 25 μ L aliquots containigs of NE (finally measuring concentration 120nM), with dull and stereotyped incubation 5 minutes (37 ℃).Decantation supernatant liquor termination reaction from flat board.The flat board that will contain cell is with 200 μ L test damping fluid washed twice (37 ℃), to remove the free radioligand.With the flat board reversing, control was done 2 minutes then, reversing again then, air-dry again 10 minutes.Cytolysis in 25 μ L 0.25N NaOH solution (4 ℃), is placed on the oscillating table thermal agitation 5 minutes.After the cytolysis, add the liquid flicker of 75 μ L cocktail (scintillation cocktail), flat board is sealed with the film band to every hole.Flat board is put back to oscillating table, and minimum 10 minutes of thermal agitation is to guarantee the abundant distribution of the organic solution and the aqueous solution.Counting is dull and stereotyped in Wallac Microbeta counter (PerkinElmer), collects original cpm data.
Thrombotonin (5-HT) picked-up is measured
Bibliographical information before utilizing improves the method for using jar cell system to measure the functional reuptake of 5-HT (people such as Prasad, Placenta, 1996.17 (4): 201-7).The 1st day, with cell according to 15,000 cells/well platings in the 96 hole flat boards that contain growth substrate (RPMI 1640 that contains 10%FBS), support in the cell incubator (37 ℃, 5%CO 2).The 2nd day, with Staurosporine (40nM) irritation cell, to increase the expression [17] of 5-HT translocator.The 3rd day, before measuring, from the cell incubator, took out cell in 2 hours, support under room temperature, make growth substrate and environmental oxygen concentration balance.Subsequently, test damping fluid (the 25mM HEPES that growth substrate is contained 0.2mg/mL xitix and 10 μ M Pargylines with 200 μ L; 120mM NaCl; 5mM KCl; 2.5mM CaCl 21.2mMMgSO 42mg/ml glucose (7.4,37 ℃ of pH)) replace.In DMSO, prepare the stock solution (10mM) of paroxetine (AHR-4389-1), be delivered to the aperture that contains cell in triplicate, make that final test concentration is 1 μ M.Be used to from the non-specific 5-HT picked-up of the data definition of these apertures (minimum 5-HT picked-up).In DMSO, prepare test compound (10mM), according to test specification (1 to 1,000nM) be diluted in the test damping fluid in.Directly add 25 μ L test damping fluid (maximum 5-HT picked-up) or test compound to the triplicate aperture that in 200 μ L test damping fluid, contains cell.Make cell and test compound incubation 10 minutes (37 ℃).For initiation reaction, to every hole send be diluted in test in the damping fluid [ 3H] 25 μ L aliquots containigs of hydroxyl color amine creatinine sulfate, make that final to measure concentration be 15nM.Make cell and reaction mixture 37 ℃ of following incubations 5 minutes.Decantation test damping fluid stops 5-HT picked-up reaction.Cell is tested damping fluid washed twice (37 ℃) with 200 μ L, to remove the free radioligand.With the flat board reversing, control was done 2 minutes then, reversing again then, air-dry again 10 minutes.Subsequently, cytolysis in 25 μ L 0.25N NaOH solution (4 ℃), is placed on the oscillating table thermal agitation 5 minutes then.After the cytolysis, add the liquid flicker of 75 μ L cocktail, flat board with the sealing of film band, is placed to reach minimum 10 minutes on the oscillating table again to every hole.Counting is dull and stereotyped in Wallac Microbeta counter (PerkinElmer), collects original cpm data.
Evaluation of result
For each experiment, the cpm Value Data that will collect from Wallac Microbeta counter flows down the Microsoft Excel statistics application program that is loaded onto.Utilization is carried out EC by the conversion bilateral logic dosage responder that Wyeth BiometricsDepartment writes 50The calculating of value.Statistics program adopts from the average cpm value of the aperture of represent maximum combined or picked-up (test damping fluid) with from represent the minimum combination or absorbing the average cpm value of the aperture of (1 μ M Desipramine (hNET) or 1 μ M paroxetine (hSERT)).Finish EC with logarithmically calibrated scale 50The estimation of value, maximum combine with minimum or the picked-up value between mate lines.Based on minimum and maximum combination or picked-up value, making each data point normalization is average percent, generates all pictorial data representaton forms.By compiling from the raw data of each experiment and analyze the data of being compiled, the EC that will be reported from experiment repeatedly 50Value is calculated as once experiment.The result is reported in the following table 1.
Table 1
Embodiment Suppress %@1 μ M (hNET)
1 4.6
2 66.5(@10μM)
3 17.6
4 24.5
5 58.1
6 13.1
7 25.6
8 53.4
9 79.2(@10μM)
10 70.5(@10μM)
11 94.5
12 70.6
13 34.3
14 24.4
15 8.5
16 96.8
17 71.0
18 11.3
19 31.6
20 85.0
21 97.5
22 83.8
23 89.7
24 57.2
25 37.5
26 54.0
27 75.4
Embodiment Suppress %@1 μ M (hNET)
28 30.1
29 89.5
30 79.7
31 98.9
33 99.4
34 78.4
35 94.3
36 82.3
37 21.4
38 71.9
39 57.4
40 57.6
41 32.4
42 95.7
43 99
44 98.2
47 99.9
48 96.6
49 101.2
50 91.8
51 87.0
52 94.3
53 57.4
54 68.6
55 61.1
56 12.3
57 17.5
58 26.5
59 93.2
60 100
Embodiment Suppress %@1 μ M (hNET)
61 99.8
62 99.7
63 91.9
64 99.9
65 100
66 86.6
67 90.9
68 99.6
69 87.5
70 77.7
71 44.9
72 24
73 21.8
74 67
75 88.4
76 75.2
77 77.3
78 70.9
79 66
80 83.5
81 58.0
82 53.9
83 99.5
84 40.9
85 97.4
86 52.7
87 99.7
90 73.1
91 90.8
92 85.8
Embodiment Suppress %@1 μ M (hNET)
93 96.3
94 94.9
95 97.6
96 98.2
97 99.6
98 99.1
99 98.1
100 94.2
101 98.6
102 95.3
103 86.1
104 99.4
105 92.6
106 85.8
107 96.6
108 98.7
109 94.7
110 86.4
111 42.7
112 100.3
113 99.7
114 100
115 23.9
116 97.3
117 95.3
118 67.9
119 96.3
120 68.6
121 21.2
122 97.4
Embodiment Suppress %@1 μ M (hNET)
123 65
124 91.5
125 94.3
126 92.9
127 95.7
128 45.6
129 71.8
130 76
131 63.1
132 93
133 96.4
134 68.5
135 99.5
136 97
137 99.1
138 97.9
139 94.9
140 96.7
143 96.8
146 97.1
147 91.7
148 97.8
149 100.4
150 98.3
151 94.3
152 96.2
153 97.4
154 96.1
155 98.9
157 99.6
Embodiment Suppress %@1 μ M (hNET)
158 99.6
159 93.8
160 99.3
161 99.4
162 99.2
163 99.7
164 98.6
169 72
170 96.4
171 98.3
172 88
173 67.5
174 99.1
175 99.6
176 100
177 29.9
178 69.2
179 99.8
180 70.4
181 96.9
182 97.1
183 100.5
184 99.7
185 80.8
186 96.6
187 52
188 71.6
189 99.3
190 53.7
191 63.9
Embodiment Suppress %@1 μ M (hNET)
192 54.6
193 98.4
194 79
195 91
196 94.6
197 97
198 97.7
199 99.1
200 97.9
201 98.8
202 92.7
203 98.9
204 47.4
205 82.9
206 96.9
207 98.3
208 99.8
209 99.3
210 96.3
211 99.8
214 99.9
When scope used herein is represented physical properties, for example molecular weight or chemical property, for example chemical formula, be intended to comprise described scope specific embodiments all combinations and sub-portfolio wherein.
The disclosure of every part of patent, patent application and publication that this paper quotes or describes is introduced in this as a reference in full.
Those skilled in the art will figure out, and can change in a large number and revise for the preferred embodiments of the invention, and this class changes and revises and can make under the situation that does not deviate from spirit of the present invention.Therefore, appended claims is contained all these class equivalent variations that fall in true spirit of the present invention and the scope.

Claims (54)

1, formula I compound:
Figure A2005800173780002C1
Or its pharmacy acceptable salt;
Wherein:
Dotted line between Y and the Z is represented optional double bond;
Two R 4Dotted line between the group is represented the optional heterocycle of 4 to 6 annular atomses, and this heterocycle can be with nitrogen that they connected at two R 4Constitute between the group;
Y is N, CR 6Or C=O;
Z is N, NR 7, CR 5Or C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl, perhaps two R 4Group constitutes the heterocycle of 4 to 6 annular atomses with the nitrogen that they connected, and one of them carbon can be alternatively by N, O, S or SO 2Replace, and wherein carboatomic ring atom or other N atom can be alternatively by C arbitrarily 1-C 4Alkyl, F or CF 3Replace;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
2, according to the compound of claim 1, wherein: Y is CR 5
3, according to the compound of claim 2, wherein: Y is CH.
4, the compound any according to claim 1 to 3, wherein: X is CR 5
5, the compound any according to claim 1 to 4, wherein: R 1It is halogeno-group.
6, according to the compound of claim 5, wherein: R 1It is fluorine or chlorine.
7, the compound any according to claim 1 to 6, wherein: R 2By 0-3 R 1The aryl that replaces.
8, according to the compound of claim 6, wherein: R 2It is phenyl.
9, the compound any according to claim 1 to 8, wherein: R 3Be H or C 1Alkyl.
10, the compound any according to claim 1 to 9, wherein: R 4Be H or C 1-C 4Alkyl.
11, according to the compound of claim 10, wherein: R 4Be H, methyl, ethyl or sec.-propyl.
12, the compound any according to claim 1 to 9, wherein: two R 4Group with the nitrogen that they connected constitute pyridine, piperidines, piperazine, by methyl substituted piperazine or morpholine ring.
13, the compound any according to claim 1 to 12, wherein: R 5Be H, C independently when occurring at every turn 1Alkyl or cyano group.
14, the compound any according to claim 1 to 13, wherein: R 6Be H, methyl, ethyl or cyano group.
15, the compound any according to claim 1 to 14, wherein: R 7Be H, methyl, ethyl, sec.-propyl, cyclopentyl, cyclohexyl, phenyl, tolyl or xylyl.
16, the compound any according to claim 1 to 15, wherein: R 8Be H, methyl or ethyl.
17, the compound any according to claim 1 to 16, wherein: R 9Be H, methyl or ethyl.
18, the compound any according to claim 1 to 17, wherein: R 10Be H or methyl.
19, the compound any according to claim 1 to 18, wherein: n is 0 or 1.
20, the compound any according to claim 1 to 19, wherein: x is 1.
21, according to the compound of claim 1, wherein:
Y is N, CR 6Or C=O;
Z is N, NR 7, CR 5Or C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H;
R 4Be H or C independently when occurring at every turn 1-C 4Alkyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H;
R 9Be H;
R 10Be H;
N is 0 to 4 integer;
X is 1; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
22, according to the compound of claim 1, wherein:
Y is CR 6
Z is CR 5
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
23, according to the compound of claim 1, wherein:
Y is CR 6
Z is C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
24, according to the compound of claim 1, wherein:
Y is C=O;
Z is C (R 5) 2
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they constitute the carbocyclic ring of 3-7 carbon;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
25, according to the compound of claim 1, wherein:
Y is C=O;
Z is NR 7
R 1Be alkyl, alkoxyl group, halogeno-group, CF independently when occurring at every turn 3, OCF 3, by 0-3 R 11The alkoxy aryl that replaces, by 0-3 R 11The aryloxy that replaces, by 0-3 R 11The aryl that replaces, by 0-3 R 11The heteroaryl that replaces, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, by 0-3 R 11The phenyl sulfoxide that replaces, alkyl sulfone, by 0-3 R 11The phenylsulfone that replaces, alkyl sulfonamide, by 0-3 R 11The phenyl-sulfamide that replaces, by 0-3 R 11The heteroaryloxy that replaces, by 0-3 R 11The heteroaryl methoxyl group that replaces, alkyl amido or by 0-3 R 11The aryl amido that replaces; Perhaps two adjacent R 1Also represent methylene-dioxy;
R 2By 0-3 R 1The aryl that replaces or by 0-3 R 1The heteroaryl that replaces;
R 3Be H or C 1-C 4Alkyl;
R 4Be H, C independently when occurring at every turn 1-C 4Alkyl, arylalkyl, heteroaryl methyl, suberyl methyl, cyclohexyl methyl, cyclopentyl-methyl or cyclobutylmethyl;
R 5Be H, C independently when occurring at every turn 1-C 4Alkyl, by 0-3 R 1The aryl or the cyano group that replace; Perhaps when there being two R 5During group, they can constitute C 3-C 7Carbocyclic ring;
R 6Be H, C 1-C 4Alkyl or cyano group;
R 7Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl or by 0-3 R 1The aryl that replaces;
R 8Be H or C 1-C 4Alkyl;
R 9Be H or C 1-C 4Alkyl;
R 10Be H or C independently when occurring at every turn 1-C 4Alkyl; Perhaps R 10And R 4With R 4The nitrogen that is connected constitutes the azo-cycle that contains that contains 3-6 carbon atom together;
N is 0 to 4 integer;
X is 1 to 2 integer; And
R 11Be alkyl, alkoxyl group, halogeno-group, CF 3, OCF 3, hydroxyl, alkanoyloxy, nitro, nitrile, thiazolinyl, alkynyl, alkyl sulfoxide, alkyl sulfone, alkyl sulfonamide or alkyl amido; Perhaps two adjacent R 11Also represent methylene-dioxy;
1-3 the carbon atom that wherein encircles among the A can be replaced by N alternatively.
26, according to the compound of claim 1, wherein said compound is:
1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-morpholine-4-base-1-phenyl-propane-2-alcohol;
3-(dimethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
3-(ethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(sec.-propyl amino)-1-phenyl-propane-2-alcohol;
3-(benzylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
The 3-[(cyclohexyl methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
The 3-[(cyclohexyl methyl) amino]-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-(sec.-propyl amino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(ethylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-1-phenyl-3-piperazine-1-base propane-2-alcohol;
1-(1H-indoles-1-yl)-1-phenyl-3-[(pyridin-4-yl methyl) amino] propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-1-phenyl-3-piperidines-1-base propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
3-(ethylamino)-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
3-amino-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-[ethyl (methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-1-alcohol;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 1H-indole-3-formonitrile;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(4-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(2-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol;
1-(3-bromophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
3-[2-hydroxyl-1-(1H-indoles-1-yl)-3-(methylamino) propyl group] cyanobenzene;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(4-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(2-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(4-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(3-aminomethyl phenyl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-morpholine-4-base propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(propyl group amino) propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(4-aminomethyl phenyl) propane-2-alcohol;
1-(2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(2-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(1H-indoles-1-yl)-1-(3-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-(2-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(1H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-1-phenyl-propane-2-alcohol;
1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-2-alcohol;
1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
1-(5-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
3-(methylamino)-1-(3-fluorophenyl)-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(6-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(7-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl) propane-2-alcohol;
3-(methylamino)-1-(4-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-(5-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(3-ethyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indoles-1-yl) propane-2-alcohol;
7-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
7-fluoro-1-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol;
2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-(tetramethyleneimine-2-yl) ethanol;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
L '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
7 '-fluoro-1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5 '-bromo-1 '-[2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-[3-(3, the 4-dichlorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(5-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(5-chloro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
[3-(5-chloro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
1-(7-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
[3-(5-fluoro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
1-(4-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(4-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(5-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-4-formonitrile HCN;
1-(6-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-5-formonitrile HCN;
1-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1H-indoles-4-formonitrile HCN;
1-(6-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(6-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
3-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
1-(7-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3, the 4-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
1-(4-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(6-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(4-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(6-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(5-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
4-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) butane-2-alcohol;
1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(4-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
1-[3-(4-tert-butyl-phenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(3-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
1-(3, the 5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
1-(3-fluorophenyl)-1-[3-(2-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-amino-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
1-(7-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(4-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-(7-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(4-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(6-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
1-(the 3-tertiary butyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-(1H-indoles-1-yl)-2-methyl-3-(methylamino)-1-phenyl-propane-2-alcohol;
3-(1H-indoles-1-yl)-1-(methylamino)-3-phenyl butane-2-alcohol;
The 1-tertiary butyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-bromo-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
6-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
4-fluoro-1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-cyclobutyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-cyclopentyl-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
3-[3-(ethylamino)-2-hydroxyl-1-phenyl propyl]-5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-5-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[2-hydroxyl-3-(methylamino)-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-[3-(2, the 3-difluorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-[3-(2-chloro-phenyl-)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol; Perhaps its pharmacy acceptable salt.
27, according to the compound of claim 1, wherein said compound is:
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-morpholine-4-base-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(dimethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(ethylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(sec.-propyl amino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(benzylamino)-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-the 3-[(cyclohexyl methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-the 3-[(cyclohexyl methyl) amino]-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(sec.-propyl amino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(ethylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-piperazine-1-base propane-2-alcohol;
(1RS, 2SR)-1-(1H-indoles-1-yl)-1-phenyl-3-[(pyridin-4-yl methyl) amino] propane-2-alcohol;
(1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-1-phenyl-3-piperidines-1-base propane-2-alcohol;
(1RS, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-amino-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(ethylamino)-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-amino-1-(5-fluoro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-[ethyl (methyl) amino]-1-(1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2RS)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-1-alcohol;
1-[(1RS, 2SR)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 1H-indole-3-formonitrile;
(1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-chloro-phenyl-)-1-(H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[2-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-1-(2-chloro-phenyl-)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1SR, 2RS)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[4-(trifluoromethoxy) phenyl] propane-2-alcohol;
(1S, 2R)-4-amino-1-(3-chloro-phenyl-)-1-(1H-indoles-1-yl) butane-2-alcohol;
(1S, 2R)-1-(3-bromophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
3-[(1S, 2R)-2-hydroxyl-1-(1H-indoles-1-yl)-3-(methylamino) propyl group] cyanobenzene;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(3-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(4-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(2-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(3-aminomethyl phenyl) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
(1R, 2S)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-aminomethyl phenyl) propane-2-alcohol;
(1S, 2R)-3-(ethylamino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-morpholine-4-base propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(propyl group amino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(4-methylpiperazine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(4-aminomethyl phenyl) propane-2-alcohol;
(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(2-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(2-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(7-methyl-2,3-dihydro-1H-indoles-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-methyl-2,3-dihydro-H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-1-(3-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
(1SR, 2RS)-1-(1H-indoles-1-yl)-1-(4-p-methoxy-phenyl)-3-(methylamino) propane-2-alcohol;
(1RS, 2SR)-3-(methylamino)-1-(2-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(1H-benzoglyoxaline-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-3-(methylamino)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(4-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1RS, 2SR)-1-(5-methoxyl group-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(6-methoxyl group-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-b] pyridine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(5-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(3-fluorophenyl)-1-(1H-pyrrolo-[2,3-c] pyridine-1-yl) propane-2-alcohol;
(1S, 2R)-1-(5-chloro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(6-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(7-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-(5-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(4-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-ethyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-phenyl-1H-indoles-1-yl) propane-2-alcohol;
7-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
7-fluoro-1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
(1R, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-(2-thienyl) propane-2-alcohol;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
(1S, 2R)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol;
(1R, 2S)-2-(3-fluorophenyl)-2-(1H-indoles-1-yl)-1-[(2S)-tetramethyleneimine-2-yl] ethanol;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [tetramethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [pentamethylene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [cyclopropane-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
(1S, 2R)-3-(cyclopropyl amino)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
7 '-fluoro-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
5 '-bromo-1 '-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl] spiral shell [hexanaphthene-1,3 '-indoles]-2 ' (1 ' H)-ketone;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-[3-(3, the 4-dichlorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-fluorophenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S *, 2R *)-3-amino-1-(5-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-amino-1-(5-chloro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
[(2R, 3S)-3-(5-chloro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
(1S, 2R)-1-(7-chloro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
[(2R, 3S)-3-(5-fluoro-3-Methyl-1H-indole-1-yl)-2-methoxyl group-3-phenyl propyl] methylamine;
(1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(4-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-4-formonitrile HCN;
(1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1H-indoles-5-formonitrile HCN;
1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1H-indoles-4-formonitrile HCN;
(1S, 2R)-1-(6-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-3-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(7-bromo-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [hexanaphthene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
(1S, 2R)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-[3-(trifluoromethyl) phenyl] propane-2-alcohol;
(1S, 2S)-1-(3-fluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 4-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-Methyl-1H-indole-1-yl) propane-2-alcohol;
(1S, 2R)-1-(4-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(6-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(6-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(5-chloro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(5-chloro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-(3-sec.-propyl-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-4-amino-1-(3-fluorophenyl)-1-(1H-indoles-1-yl) butane-2-alcohol;
(1S, 2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3,3-dimethyl-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-(3-methyl-2,3-dihydro-1H-indoles-1-yl) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-spiral shell [pentamethylene-1,3 '-indoles]-1 ' (2 ' H)-Ji propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(4-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[3-(4-aminomethyl phenyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-[3-(4-tert-butyl-phenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(3-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[4-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
(1S, 2R)-1-(3, the 5-difluorophenyl)-1-(6-fluoro-2,3-dihydro-1H-indoles-1-yl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[2-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-1-[3-(2-p-methoxy-phenyl)-1H-indoles-1-yl]-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-{3-[3-(trifluoromethyl) phenyl]-1H-indoles-1-yl } propane-2-alcohol;
(1S, 2R)-3-amino-1-(3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-amino-1-(7-fluoro-3-Methyl-1H-indole-1-yl)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(4-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-1-(7-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(4-fluoro-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(3-fluorophenyl)-3-(methylamino)-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(6-fluoro-1H-indoles-1-yl)-3-(methylamino)-1-phenyl-propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-[6-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-3-(methylamino)-1-phenyl-1-[5-(trifluoromethyl)-1H-indoles-1-yl] propane-2-alcohol;
(1S, 2R)-1-(the 3-tertiary butyl-1H-indoles-1-yl)-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-(1H-indoles-1-yl)-2-methyl-3-(methylamino)-1-phenyl-propane-2-alcohol;
(2R, 3S)-3-(1H-indoles-1-yl)-1-(methylamino)-3-phenyl butane-2-alcohol;
The 1-tertiary butyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-bromo-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
6-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
4-fluoro-1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
1-cyclobutyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
5-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-propyl group-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-cyclopentyl-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-3-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
3-[(1S, 2R)-3-(ethylamino)-2-hydroxyl-1-phenyl propyl]-5-fluoro-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-the 3-methyl isophthalic acid, 3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-5-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-phenyl propyl]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
4-fluoro-3-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-1-sec.-propyl-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-ethyl-4-fluoro-3-[(1S, 2R)-2-hydroxyl-3-(methylamino)-1-(3-fluorophenyl)-propyl group]-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone;
1-[(1S, 2R)-1-(3-fluorophenyl)-2-hydroxyl-3-(methylamino) propyl group]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one;
(1S, 2R)-1-[3-(2, the 3-difluorophenyl)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol;
(1S, 2R)-1-[3-(2-chloro-phenyl-)-1H-indoles-1-yl]-1-(3-fluorophenyl)-3-(methylamino) propane-2-alcohol; Perhaps
Its pharmacy acceptable salt.
28, composition comprises:
A. at least a compound any according to claim 1 to 27; With
B. at least a pharmaceutically acceptable carrier.
29, the method for the illness that treatment or prevention improve because of monoamine reuptake in the curee who needs is arranged, comprise to described curee give significant quantity according to any one compound of claim 1 to 27 or its pharmacy acceptable salt or according to the step of the composition of claim 28.
30, according to the method for claim 29, the wherein said illness of improving because of monoamine reuptake is selected from vasomotor symptoms, sexual dysfunction, stomach and intestine and urogenital obstacle, chronic fatigue syndrome, fibromyalgia syndrome, nervous system disorders and their combination.
31, according to the method for claim 30, the wherein said illness of improving because of monoamine reuptake is selected from major depression, vasomotor symptoms, tonus and the impulsion urinary incontinence, myofiber pain, pain, diabetic neuropathy and their combination.
32, the treatment or the method for preventing at least a vasomotor symptoms in the curee who needs is arranged, comprise to described curee give significant quantity according to any one compound of claim 1 to 27 or its pharmacy acceptable salt or according to the step of the composition of claim 28.
33, according to the method for claim 32, wherein said vasomotor symptoms is a upsurge.
34, according to the method for claim 33, wherein said curee is the people.
35, according to the method for claim 34, wherein said people is the women.
36, according to the method for claim 35, before wherein said women is in menopause.
37, according to the method for claim 35, wherein said women is in climacteric.
38, according to the method for claim 35, after wherein said women is in menopause.
39, according to the method for claim 34, wherein said people is the male sex.
40, according to the method for claim 39, the wherein said male sex is natural, chemical or operation andropausal.
41, treatment or prevent the method for at least a dysthymia disorders in the curee who needs is arranged, comprise to described curee give significant quantity according to any one compound of claim 1 to 27 or its pharmacy acceptable salt or according to the step of the composition of claim 28.
42, according to the method for claim 41, wherein said dysthymia disorders is major depression, anxiety, sleep disordered or social phobia.
43, according to the method for claim 42, wherein said curee is the people.
44, treatment or prevent the method for at least a sexual dysfunction in the curee who needs is arranged, comprise to described curee give significant quantity according to any one compound of claim 1 to 27 or its pharmacy acceptable salt or according to the step of the composition of claim 28.
45, according to the method for claim 44, wherein said sexual dysfunction is that sexual desire is correlated with or arouses relevant.
46, according to the method for claim 45, wherein said curee is the people.
47, the method for treatment or prevent irritation in the curee who needs is arranged, comprise to described curee give significant quantity according to any one compound of claim 1 to 27 or its pharmacy acceptable salt or according to the step of the composition of claim 28.
48, according to the method for claim 47, wherein said pain is acute central pain, acute periphery pain or their combination.
49, according to the method for claim 47, wherein said pain is chronic central pain, chronic periphery pain or their combination.
50, according to the method for claim 47, wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bone pain, cancer pain, inflammatory pain or their combination.
51, according to the method for claim 50, wherein said neuropathic pain is relevant with following illness: diabetes, pain after the amputation wound, low back pain, cancer, chemical damage, toxin, capital operation, oppress the peripheral nerve injury that causes by traumatic damage, postherpetic neuralgia, trigeminal neuralgia, waist or Cervical radiculopathy, myofiber pain, glossopharyngeal neuralgia, reflectivity associability malnutrition, accidental pain, thalamic syndrome, nerve root avulsion, reflectivity associability malnutrition or thoracotomy postoperative pain, auxotrophy, virus infection, infectation of bacteria, transitivity soaks into, adiposis dolorosa, burn, relate to the central pain illness of thalamus illness and their combination.
52, according to the method for claim 50, wherein said visceral pain is relevant with following illness: ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn disease, rheumatosis (arthrodynia), tumour, gastritis, pancreatitis, organ infection, biliary tract obstacle and their combination.
53, according to the method for claim 47, wherein said pain is the distinctive pain of women.
54, according to the method for claim 47, wherein said curee is the people.
CN 200580017378 2004-03-30 2005-03-29 1-(1h-indol-1-yl)-3-(4-methylpiperazin-1-yl)-1-phenyl propan-2-ol derivatives and related compounds as modulators of the norepinephrine(NE) and the serotonine(5-HT) activity and the monoamine reuptake Pending CN1960973A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012097744A1 (en) * 2011-01-20 2012-07-26 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
CN104619693A (en) * 2012-07-17 2015-05-13 葛兰素史克知识产权第二有限公司 Indolecarbonitriles as selective androgen receptor modulators

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012097744A1 (en) * 2011-01-20 2012-07-26 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
CN103384661A (en) * 2011-01-20 2013-11-06 默沙东公司 Mineralocorticoid receptor antagonists
US8933113B2 (en) 2011-01-20 2015-01-13 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
AU2012208837B2 (en) * 2011-01-20 2016-07-28 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
US9403807B2 (en) 2011-01-20 2016-08-02 Merck Sharp & Dohme Corp. Mineralocorticoid receptor antagonists
CN104619693A (en) * 2012-07-17 2015-05-13 葛兰素史克知识产权第二有限公司 Indolecarbonitriles as selective androgen receptor modulators
CN104619693B (en) * 2012-07-17 2019-08-13 葛兰素史克知识产权第二有限公司 The alternatively indoles nitrile of property androgen receptor modifier

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