CN1671386A - Substituted anilinic piperidines as MCH selective antagonists - Google Patents

Substituted anilinic piperidines as MCH selective antagonists Download PDF

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Publication number
CN1671386A
CN1671386A CNA028172124A CN02817212A CN1671386A CN 1671386 A CN1671386 A CN 1671386A CN A028172124 A CNA028172124 A CN A028172124A CN 02817212 A CN02817212 A CN 02817212A CN 1671386 A CN1671386 A CN 1671386A
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chemical compound
phenyl
branched
straight
alkyl
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M·R·马扎巴迪
J·维策尔
J·E·德莱安
Y·蒋
K·陆
B·拉古
C·－A·陈
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H Lundbeck AS
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H Lundbeck AS
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Abstract

This invention is directed to compounds which are selective antagonists for melanin concentrating hormone-1 (MCH1) receptors. The invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.

Description

Substituted anilinic piperidines as the MCH selective antagonist
Background of invention
The application is the part continuation application of United States Patent (USP) series number of submitting on January 9th, 2,002 10/042582 and the United States Patent (USP) series number of submitting to July 5 calendar year 2001 09/899794, and both contents are attached among the application by reference at this.
In this application, the various open source literatures of quoting indicate its author and time in bracket.In the ending of application, can find that in the front of sequence list and claim the whole of these lists of references quote.The disclosure of these description is attached to herein at this by reference with their integral body, so that more fully set forth the present situation in field involved in the present invention.It is a kind of cyclic peptide (Kawauchi etc., 1983) of initial separation from salmon (bony fish) hypophysis that melanin is assembled hormone (MCH).In the fish body, this 17 seed amino acid peptide causes that melanin assembles and suppress the release of ACTH in melanocyte, works as the functional antagonist of α-MSH.Mammal MCH (19 aminoacid) is stored between rat, mice and the people in a large number, present 100% amino acid identity, but its physiological function is not very clear.It is reported MCH participate in comprising diet, water balance, energy metabolism, general awakening/attention state, memory and cognitive function and mental sickness various processes (to summarizing, referring to Baker, 1991; Baker, 1994; Nahon, 1994; Knigge etc., 1996).Reported its effect in diet or body weight adjusting by up-to-date Nature publication (Qu etc., 1996), confirmed and ob/+ -Mice is compared, and MCH is overexpression in the hypothalamus of ob/ob mice, and fasting has further increased the MCH mRNA level of fat and normal mouse during the fasting.In the time of in being expelled to tricorn, MCH also stimulates the diet (Rossi etc., 1997) of normal rat.It is reported behavior effect (Miller etc., 1993 of the also functional antagonism α-MSH of MCH; Gonzalea etc., 1996; Sanchez etc., 1997); In addition, also showing to increase the POMCmRNA level, and reduces MCH precursor preproMCH (ppMCH) mRNA level (Presse etc., 1992).Therefore, MCH can be as the integration neuropeptide (Baker, 1991 that participate in stress and regulate diet and sexual activity; Knigge etc., 1996).
Although people be sure of the biological agent of MCH and mediate by specific receptor, the not fine as yet description of the binding site of MCH.It is reported, contain the tritium part ([ 3H]-MCH) meninges is presented the specificity combination, but can not be used for saturation analysis, thereby can not measure affinity and can not measure B Max(Drozdz and Eberle, 1995).Tyrosine causes the part biological activity unexpectedly to reduce (referring to Drozdz and Eberle, 1995) at 13 radioiodination.Otherwise, MCH analog [Phe 13, Tyr 19The radioiodination of]-MCH is successful (Drozdz etc., 1995); Part retains biological activity and to various kinds of cell system comprises that mouse black-in lymphoma (B16-F1, G4F and G4F-7), PC12 and COS cell present the specificity combination.In the G4F-7 cell, K D=0.118nM and B Max=～1100 sites/cell.Importantly, this is in conjunction with not suppressed by α-MSH but by the faint inhibition of rat ANF (Ki=116nM is to natural MCH12nM) (Drozdz etc., 1995).Recently, reported and transformed keratinocyte (Burgaud etc., 1997) and melanoma cells (Drozdz etc., 1998) the specificity MCH combination in, wherein photo-crosslinking research prompting receptor is for having the daltonian memebrane protein of apparent molecular weight 45-50K, and the molecular weight ranges of the receptor of they and GPCR superfamily is suitable.Also not about the report of the autoradiography research of the MCH receptor mapping of adopting this part.
The adjusting of the location of MCH peptide and biological activity prompting MCH receptor active can be used for multiple therapeutic use.The effect of MCH in diet is the best features of its potential clinical application.MCH expresses (Grillon etc., 1997) in participating in the hypothalamus outside in the thirsty and hungry brain zone of adjusting; Orexin (orexin) A and B (they all are the medicines that effectively whets the appetite) have shown to have the location closely similar with MCH (Sakurai etc., 1998) in the hypothalamus outside recently.After the fasting 24 hours, the MCH mRNA level in the rat body in this brain zone increases (Herve and Fellman, 1997); Behind the insulin injection, amount and the dyeing brightness of observing MCH immunoreation perikaryon and fiber significantly increase, and MCH mRNA level significantly increases (Bahjaoui-Bouhaddi etc., 1994) simultaneously.What conform to the ability of MCH stimulation in rats diet is to observe MCH mRNA level forward in the hypothalamus of fat ob/ob mice to regulate (Qu etc., 1996), and in rat hypothalamus, reduce with leptin (leptin) treatment, its food intake and weight increase also reduce (Sahu etc., 1998).As if MCH use functional antagonist as black cortex color (melanocortin) system work (Ludwig etc., 1998) at it to food intake among the HPA (hypothalamus hypophysis/kidney axle) and hormone secretion.These data are pointed out endogenous MCH the effect in regulating the energy balance and stress together, and provide exploitation to be used for the treatment of the principle of the specific compound that acts on the MCH receptor of obesity and disease that stress be relevant.
In the research of all kinds so far, the neuron of most of MCH groups of cells occupies metastable location in those zones of their existing hypothalamus outsides and subthalamus, can be the part of some what is called " tractus pyramidalis outward " motor circuit.These comprise relate to thalamus and cerebral cortex, hypothalamus zone, cross-join, black substance with subthalamus nuclear and in centrencephalic a large amount of stricture of vagina shapes and from pallidum approach (Bittencourt etc., 1992).In their location, the MCH cell can provide expresses active bridge of hypothalamus internal organs or mechanism, follows suitable and collaborative locomotor activity.It can have some and is considered to participate in for example value of this MCH system in parkinson disease and the hungtington's chorea (the wherein known tractus pyramidalis outer ring that relates to) of dyskinetic disorder clinically.
People's genetic linkage research has made the hMCH site be positioned chromosome 12 sites (12q23-24) and variant chromosome hMCH5 site (5q12-13) (Pedeutour etc., 1994).Site 12 q23-24 exists (Auburger etc., 1992 jointly with the site of wherein having drawn the cerebellar ataxia (SCA2) of II type autosomal dominant; Twells etc., 1992).This disease comprises neurodegenerative disease, comprises olivopontocerebellar atrophy.In addition, the gene of darier's disease has been plotted as site 12 q23-24 (Craddock etc., 1993).Darier's disease is characterized in that unusual I type keratinocyte adheres to and mental sickness in some family.According to neural function of the MCH of rat and human brain and neuroanatomy pattern, the MCH gene can be represented the good candidate of SCA2 or darier's disease.It is the drawn gene mapping of disease with high social influence interestingly.Really, adopt genetic linkage analysis, the genophore of the spinal muscular atrophy of chronic or acute form has been designated as chromosome 5q12-13 (Melki etc., 1990; Westbrook etc., 1992).In addition, the main schizophrenia site of a series of independently evidence support is in 5q11.2-13.3 (Sherrington, 1988; Bassett, 1988; Gilliam, 1989).More than research prompting MCH can work in neurodegenerative disease and emotionally disturbed.
Other therapeutic use by the MCH chemical compound that observable effect prompting is relevant with MCH in other biosystem.For example, MCH can regulate male and reproductive function female rats.Find MCH transcript and MCH peptide in the test of adult rat sexual cell, this prompting MCH can participate in stem cell and upgrade and/or early stage spermatocytal differentiation.MCH is injected directly into the sexual activity (Gonzalez etc., 1996) that medial preoptic nucleus zone (MPOA) or ventromedial nucleus (VMN) can stimulate female rats.In the ovariectomized rat body contacted with estradiol, MCH stimulates interstitialcellstimulating hormone (ICSH) (LH) to discharge, and anti-MCH antiserum suppresses LH release (Gonzalez etc., 1997).The zona incerta that had before contained a large amount of MCH cytons has been accredited as the control band (Mackenzie etc., 1984) of preceding ovulation surgery.The MCH analog also is useful in the treatment epilepsy.In PTZ tic model, twitch induce before the injection MCH neuron that stops tic activity on rat and the Cavia porcellus, prompting to contain MCH can participate in experiencing the nerve circulation (Knigge and Wagner, 1997) of the inductive tic of PTZ.Having observed MCH influences the behavior dependency of cognitive function.MCH treatment promotes that passivity is avoided the disappearance (McBride etc., 1994) of replying in the rat body, improved the probability that the MCH receptor antagonist helps memory storage and/or reservation.The fine and close innovation of the periaqueductal (PAG) by the MCH-positive fiber supports MCH in the adjusting of pain or the possible effect in participating in.Finally, MCH can participate in the adjusting of fluid picked-up.In the sheep body of Consciousness ICV perfusion MCH be created in increase blood volume reply middle diuresis, urinate sharp sodium and urine potassium changes (Parkes, 1996).With the anatomical data that the MCH in the fluid regulation zone of report brain exists, it can be an important peptide that participates in the maincenter control of mammalian body inner fluid homeostasis that the result indicates MCH.
Evaluation (Chambers etc., 1999 of G-G-protein linked receptor to MCH are disclosed recently; Saito etc., 1999).These research groups are identified endogenic ligand (Lakaye etc., 1998) into the lonely G-G-protein linked receptor of people SLC-1 to MCH.The rat congener of this receptor (now being called MCH-1) it is reported and is positioned the rat brain zone relevant with dietary behavior (for example carrying on the back inboard and ventromedial hypothalamus).The report of up-to-date phenotype about the MCH-1 knock-out mice has strengthened related between the diet effect of MCH-1 and MCH.Two groups are independent displaying (Marsh etc., 2002; Chen etc., 2002) but MCH-1 acceptor gene (MCH-1 knocks out) causes the animal polyphagia thin and reduced the body weight relevant with wild type littermates intravital directed destruction of mice.Losing weight increases owing to metabolism.Every group of obesity that confirms MCH-1 knock-out mice antagonism diet induced presents the similar body weight of keeping with the regular cycle of littermates usually.
At last, synthetic MCH-1 receptor antagonist agent molecule has been described in the literature.Bednarrek etc. (2002) have reported high-affinity peptide antagonists synthetic of MCH-1.In addition, Takekawa etc. have described the micromolecule antagonist (Takekawa etc., 2002) of MCH-1.This chemical compound T-226296 to the MCH-1 receptor present high-affinity (to rat and people MCH-1 for～5-9nM), and shown and suppress to use the inductive food intake of MCH by Intraventricular.The strategy of these data acknowledgements MCH-1 receptor antagonist treatment of obesity.
In addition, in we self research, we have tested the MCH1 antagonist on several animal models, these models as predictive compound to the effectiveness of human body be know (Borowsky etc. are in the publication; Undisclosed data).It is useful in treatment of obesity, depression, anxiety neurosis and urinary disorders that these experiments indicate the MCH1 antagonist.
As adopting in the present invention, term " antagonist " refers to that chemical compound is incorporated into the chemical compound of receptor and the receptor active of minimizing in the presence of agonist.Under the situation of G-G-protein linked receptor, adopt any suitable second messenger system can measure activation, but the second messenger system coupling in cell or in-house receptor, wherein receptor is expressed.Some of the second messenger system of knowing is specific, but does not mean that the example of restriction is adenyl cyclase, intracellular Ca2+ metabolism, ion channel activation, guanylate cyclase and the hydrolysis of phosphoric acid mannitol.Otherwise term " agonist " refers to the chemical compound of comparing and being incorporated into receptor and increasing receptor active with the receptor active under any agonist does not exist.
In one embodiment of the invention, the selective binding of comparing with other clone's G-G-protein linked receptor is assembled noval chemical compound synthetic of hormone 1 (MCH1) receptor in clone's human melanin, and as the activation of the inhibition clone receptor in vitro tests, measured be disclosed.Adopt various cultured cells to be, each cell line is with the transfection of monospecific polyclonal receptor and only use the monospecific polyclonal expression of receptor, and the extracorporeal receptor of describing hereinafter is in conjunction with test.
In addition, chemical compound of the present invention also can be used for the treatment of abnormal symptom, for example eating disorder, property/reproductive disease, depression, anxiety neurosis, depression and anxiety, inattentive tic, hypertension, cerebral ischemia, congestive heart failure, sleep disordered or wherein the MCH1 receptor antagonist can be effective any symptom.In addition, chemical compound of the present invention can be used to reduce patient's body weight.In addition, chemical compound of the present invention can be used for the treatment of urinary disorders.
Summary of the invention
The invention provides chemical compound with following structure:
Figure A0281721200191
R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CH 3,-CF 3,-COR 2,-CO 2R 2, phenyl, phenoxy group or straight or branched C 1-C 7Alkyl; R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl; R wherein 3Be aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl; Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 3,-CO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Wherein X is O or NH; With
Wherein n is the integer (comprising 0 and 5) of 0-5.
In one embodiment, R 1For the optional aryl that is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, COR 2,-CO 2R 2, straight or branched C 1-C 7Alkyl; R wherein 3Be phenyl; Wherein A is H; With
Wherein X is O.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
In one embodiment, chemical compound has following structure:
Figure A0281721200202
In one embodiment, R 1Be hydrogen, straight or branched C 1-C 7Alkyl; And R wherein 3Be aryl.
In one embodiment, R 2Be isopropyl; And A is a hydrogen.
In one embodiment, described chemical compound has following structure:
Figure A0281721200203
In one embodiment, described chemical compound has following structure:
The present invention also provides the chemical compound with following structure:
Figure A0281721200205
R wherein 1For by optional aryl or the heteroaryl that replaces of one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-OCH 3, phenoxy group, condensed Pentamethylene. base, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; R wherein 2Be straight or branched C 1-C 4Alkyl or cyclopropyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; With
Wherein n is the integer (comprising 1 and 5) of 1-5.
In one embodiment, R 1For by the optional aryl that replaces of one or more following groups :-F ,-Cl ,-Br ,-I or straight or branched C 1-C 4Alkyl; With
Wherein A is H.
In one embodiment, R 2Be isopropyl; With
Wherein n is 2.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
Figure A0281721200213
In one embodiment, R 1Be thienyl; And wherein A is H.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
The invention provides chemical compound with following structure:
Figure A0281721200222
Wherein W is
Figure A0281721200223
Or
Figure A0281721200224
Each R wherein 1Independent is hydrogen, methyl or ethyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl; R wherein 3Be hydrogen, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl;
Wherein each A independently be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 3,-CO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
Wherein X is O, NR 3, CO or can not exist;
And wherein Y is hydrogen, aryl or heteroaryl, and wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl.
In one embodiment, W is
And wherein X is O or can exist.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, W is
In one embodiment, A be-H ,-F ,-Cl ,-Br.
In one embodiment, R 2Be isopropyl; And A is a hydrogen.
In one embodiment, described chemical compound has following structure:
Figure A0281721200234
The invention provides chemical compound with following structure:
Wherein W is
Or
R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-OCH 3,-CO 2CH 3,-CF 3, phenyl, straight or branched C 1-C 7Alkyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 1,-CO 2R 1, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl or phenyl;
Wherein each B independently be-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-COR 1,-CO 2R 1,-OCH 3,-OCF 3,-CF 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl or aryl, phenoxy group or benzyloxy, wherein aryl, phenoxy group or benzyloxy are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 1,-CO 2R 1,-OCH 3,-OCF 3,-CF 3Or straight or branched C 1-C 3Alkyl.
In one embodiment, W is
In one embodiment, R 1For hydrogen or by the optional phenyl that replaces of one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
The invention provides chemical compound with following structure:
Figure A0281721200251
R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-CF 3,-OCH 3, straight or branched C 1-C 3Alkyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R wherein 3For-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CF 3,-OCH 3Perhaps straight or branched C 1-C 3Alkyl, a fluoroalkyl or Polyfluoroalkyl, or with the indole partial C 6And C 7Condensed phenyl ring;
R wherein 4For hydrogen or the optional aryl that is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CF 3, straight or branched C 1-C 3Alkyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; With
Wherein n is the integer (comprising 2 and 4) of 2-4.
In one embodiment, R 3For-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-OCF 3Or-OCH 3With
R wherein 4For hydrogen or by the optional phenyl that replaces of one or more following groups :-F ,-Cl or-CF 3
In one embodiment, R 1For hydrogen or by the optional phenyl that replaces of one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-CF 3,-OCH 3Perhaps straight or branched C 1-C 3Alkyl;
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
Figure A0281721200262
In one embodiment, described chemical compound has following structure:
Figure A0281721200263
The invention provides chemical compound with following structure:
Figure A0281721200264
Each R wherein 1Independent is hydrogen or CH 3
R wherein 2Be straight or branched C 1-C 4Alkyl or cyclopropyl;
R wherein 3Be benzyl or phenyl, wherein benzyl or phenyl are optional is replaced by methylene-dioxy or one or more following group :-F or-Cl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
Wherein X is (CH 2) 2, COCH 2Or CONH.
In one embodiment, R 3Be phenyl by the optional replacement of one or more-F; With
Wherein A is a hydrogen.
In one embodiment, X is CONH.
In one embodiment, R 2Be methyl.
In one embodiment, described chemical compound has following structure:
Figure A0281721200271
In one embodiment, described chemical compound has following structure:
Wherein each Y independently be hydrogen or-F.
In one embodiment, described chemical compound has following structure:
Figure A0281721200273
In one embodiment, described chemical compound has following structure:
In one embodiment, R 3For by methylene-dioxy or one or more-F or-the optional benzyl that replaces of Cl.
In one embodiment, described chemical compound has following structure:
Wherein each Y independently be hydrogen or-F.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound is the chemical compound of enantiomeric pure.
In one embodiment, described chemical compound is the chemical compound of diastereisomericallypure pure.
In one embodiment, described chemical compound is the chemical compound of the pure and mild diastereisomericallypure pure of enantiomer isomer.
The present invention also provides the The compounds of this invention that comprises therapeutic dose and the Pharmaceutical composition of pharmaceutically acceptable carrier.
In one embodiment, the consumption of described chemical compound is the about 500mg of about 0.01mg-.
In one embodiment, the consumption of described chemical compound is the about 60mg of about 0.1mg-.
In one embodiment, the consumption of described chemical compound is the about 20mg of about 1mg-.
In one embodiment, described Pharmaceutical composition is made up of liquid-carrier and described compositions is a solution.
In one embodiment, described Pharmaceutical composition is made up of solid carrier and described compositions is a tablet.
In one embodiment, described Pharmaceutical composition is made up of gel carrier and described compositions is a suppository.
The present invention also provides a kind of method for preparing Pharmaceutical composition, and it comprises that the of the present invention any chemical compound with the treatment effective dose mixes with pharmaceutically acceptable carrier.
The present invention also provides a kind of treatment to suffer from the patient's who is selected from following disease method: depression, anxiety neurosis, urinary incontinence (urge incontinence) or obesity, this method comprises the The compounds of this invention that gives described patient treatment effective dose.
In one embodiment, described treatment effective dose is between the about 1000mg of about 0.03-every day.
In one embodiment, described treatment effective dose is between the about 300mg of about 0.30-every day.
In one embodiment, described treatment effective dose is between the about 100mg of about 1.0-every day.
In one embodiment, described disease is a depression.
In one embodiment, described disease is an anxiety neurosis.
In one embodiment, described disease is an obesity.
In one embodiment, described disease is a urinary incontinence.
The invention provides the method that alleviates weight in patients, this method comprises and gives the The compounds of this invention that the patient effectively alleviates the amount of weight in patients.
The invention provides treatment and suffer from patient's the method for depression, this method comprises each chemical compound of the claim of the present invention of the amount that gives the depression that the patient effectively treats the patient.
The invention provides treatment and suffer from patient's the method for anxiety neurosis, this method comprises the The compounds of this invention of the amount that gives the anxiety neurosis that the patient effectively treats the patient.
The invention provides the method that alleviates the urinary incontinence that the patient causes owing to the bladder hyperkinesia, this method comprises the The compounds of this invention of the amount that gives the urinary incontinence that the patient effectively alleviates the patient.
The invention provides the method for controlling obesity disease in the slimming patient of needs, this method comprises and gives the The compounds of this invention that the patient effectively alleviates the amount of weight in patients.
The present invention is for providing the method for controlling obesity disease through the patient who loses weight, this method comprises that giving the patient effectively keeps the The compounds of this invention that it has the amount of the amount of losing weight now.
The invention provides treatment patient's bladder hyperactive method, this method comprises the of the present invention any chemical compound that gives the hyperactive amount of bladder that the patient effectively treats the patient.
The invention provides the method for treatment patient disease, wherein patient's symptom can be by alleviating with the MCH1 antagonist for treating, and wherein the MCH1 antagonist is a chemical compound of the present invention.
The invention provides the method for the symptom that alleviates patient disease, this method comprises the MCH1 antagonist of the amount that gives the effective mitigation symptoms of patient, and wherein the MCH1 antagonist is a chemical compound of the present invention.
Detailed Description Of The Invention
The invention provides chemical compound or its pharmaceutically acceptable salt with following structure:
Figure A0281721200301
Or
Figure A0281721200311
Wherein each V independently is phthalimide, aryl, phenoxy group or heteroaryl, and wherein aryl, phenoxy group or heteroaryl are optional is replaced by one or more following groups: F; Cl; Br; I; COR 5CO 2R 5-OCOR 5-CON (R 5) 2-N (R 5) COR 5CN;-NO 2-N (R 5) 2-OR 5-SR 5(CH 2) qOR 5(CH 2) qR 5(CH 2) qSR 5Straight or branched C 1-C 7Alkyl, a fluoroalkyl, Polyfluoroalkyl, aminoalkyl or amido alkyl; Straight or branched C 2-C 7Thiazolinyl, C 2-C 7Alkynyl; Aryl; Phenoxy group; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
Wherein each W independently is aryl or heteroaryl, and wherein aryl or heteroaryl are optional is replaced by one or more following groups: F; Cl; Br; I; COR 3-OCOR 3CO 2R 3-CON (R 3) 2-N (R 3) COR 3CN;-NO 2-N (R 3) 2-OR 3-SR 3(CH 2) qOR 3(CH 2) qSR 3Straight or branched C 1-C 7Alkyl, a fluoroalkyl, Polyfluoroalkyl, aminoalkyl or amido alkyl; Straight or branched C 2-C 7Thiazolinyl, C 2-C 7Alkynyl; Aryl; Phenoxy group; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
Wherein X be hydrogen or-OR 3, prerequisite is to be-OR as X 3The time, with the V of X geminal can not be phthalimide;
Wherein Y be hydrogen ,=O (ketonic oxygen), OR 3, OV, COV ,=NNHV ,=NNR 5, NZR 5, NZV, NCONV (urea), NCONR 5, NR 3, carbazole, indole or phthalimide;
Wherein each R independently is-H;-F; Straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl;-N (R 3) 2-NO 2-CN;-CO 2R 3-OCOR 3-OR 3Or-N (R 3) COR 3-CON (R 3) 2
Each R wherein 3Independently be-H; Straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
Each R wherein 5For-H;-NO 2-N 3-CN; Straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;-N (R 3) 2-OR 3-(CH 2) pOR 3-COR 3-CO 2R 3-OCOR 3-CON (R 3) 2-N (R 3) COR 3Aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups: F; Cl; Br; I; COR 6CO 2R 3-OCOR 3-CON (R 3) 2-N (R 3) COR 3CN;-NO 2-N (R 3) 2-OR 6-SR 6(CH 2) qOR 6(CH 2) qSR 6Straight or branched C 1-C 7Alkyl, a fluoroalkyl, Polyfluoroalkyl, aminoalkyl or amido alkyl; Straight or branched C 2-C 7Thiazolinyl, C 2-C 7Alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
R wherein 6For-H; Straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;-N (R 3) 2-OR 3-(CH 2) pOR 3-COR 3-CO 2R 3-OCOR 3-CON (R 3) 2-N (R 3) COR 3Optional by one or more F; Cl; Br; I; COR 3CO 2R 3-OCOR 3-CON (R 3) 2-N (R 3) COR 3, CN;-NO 2-N (R 3) 2-OR 3-SR 3(CH 2) qOR 3(CH 2) qSR 3The aryl, benzyl or the heteroaryl that replace; Straight or branched C 1-C 7Alkyl, a fluoroalkyl, Polyfluoroalkyl, aminoalkyl or amido alkyl; Aryl; Benzyl; Straight or branched C 2-C 7Thiazolinyl, C 2-C 7Alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
Wherein Z is CO, SO 2Or SO 2NR 6
Wherein each m independently is the integer of 0-3 (comprising 0 and 3);
Wherein each n independently is the integer of 0-5 (comprising 0 and 5);
Wherein each p independently is the integer of 0-7 (comprising 0 and 7); With
Wherein q is the integer (comprising 0 and 3) of 0-3.
Term " cycloalkyl " is used for comprising C when of the present invention 3-C 7Cycloalkyl moiety, it can be replaced by one or more following groups: F; CN;-NO 2Straight or branched C 1-C 7Alkyl, straight or branched C 1-C 7One fluoroalkyl, straight or branched C 1-C 7Polyfluoroalkyl, straight or branched C 2-C 7Thiazolinyl, straight or branched C 2-C 7Alkynyl; C 3-C 7Cycloalkyl, C 3-C 7One fluorine cycloalkyl, C 3-C 7The polyfluoro cycloalkyl, C 5-C 7Cycloalkenyl group ,-N (R 3) 2-OR 3-NCOR 3-COR 3-CO 2R 3-CON (R 3) 2Or (CH 2) p-O-(CH 3) m-CH 2
In the present invention, term " cycloalkenyl group " comprises C 5-C 7The cycloalkenyl group part, it can be replaced by one or more following groups :-F;-Cl;-Br ,-I; CN;-NO 2Straight or branched C 1-C 7Alkyl, straight or branched C 1-C 7One fluoroalkyl, straight or branched C 1-C 7Polyfluoroalkyl, straight or branched C 2-C 7Thiazolinyl, straight or branched C 2-C 7Alkynyl; C 3-C 7Cycloalkyl, C 3-C 7One fluorine cycloalkyl, C 3-C 7The polyfluoro cycloalkyl, C 5-C 7Cycloalkenyl group ,-N (R 3) 2-OR 3-NCOR 3-COR 3-CO 2R 3-CON (R 3) 2Or (CH 2) p-O-(CH 3) m-CH 3
Be used for when of the present invention, term " heteroaryl " is used to comprise 5 and 6 yuan of unsaturated rings, and it can contain one or more oxygen, sulfur or nitrogen-atoms.The example of heteroaryl includes, but is not limited to furyl, thienyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl and triazine radical.
In addition, term " heteroaryl " is used to comprise condensed bicyclo-system, and it can contain one or more hetero atoms such as oxygen, sulfur and nitrogen.The example of this type of heteroaryl includes, but is not limited to indolizine base, indyl, isoindolyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl, purine radicals, benzoxazolyl, benzoisoxazole base, benzo [b] thiazolyl, imidazo [2,1-b] thiazolyl, cinnolinyl, quinazolyl, quinoxalinyl, 1,8-phthalazinyl, pteridyl, quinolyl, isoquinolyl, phthalimido and 2,1, the 3-benzothiazolyl.
Term " heteroaryl " also comprises above-named those chemical parts, and it can be replaced by one or more following groups :-F;-Cl;-Br;-I; CN;-NO 2Straight or branched C 1-C 7Alkyl, straight or branched C 1-C 7One fluoroalkyl, straight or branched C 1-C 7Polyfluoroalkyl, straight or branched C 2-C 7Thiazolinyl, straight or branched C 2-C 7Alkynyl; C 3-C 7Cycloalkyl, C 3-C 7One fluorine cycloalkyl, C 3-C 7Polyfluoro cycloalkyl, C 5-C 7Cycloalkenyl group ,-N (R 3) 2-OR 3-NCOR 3-COR 3-CO 2R 3CON (R 3) 2Or (CH 2) p-O-(CH 3) m-CH 3-
In another embodiment of the invention described above, described chemical compound has following structure:
In another embodiment of the invention, R 6Be straight or branched C 1-C 7Alkyl; C 3-C 7Cycloalkyl;-N (R 3) 2-OR 3-(CH 2) pOR 3Optional aryl, benzyl or the heteroaryl that is replaced by one or more following groups: F; Cl; Br; I;-OR 3-(CH 2) qOR 3Perhaps straight or branched C 1-C 7Alkyl.
In one embodiment of the invention, described chemical compound has following structure:
Or
In another embodiment of the invention, at least one V is the optional phenyl that is replaced by one or more following groups: F; Cl; Br;-OR 3(CH 2) qOR 3Straight or branched C 1-C 7Alkyl; C 1-C 7Polyfluoroalkyl; Or phenoxy group.
In one embodiment of the invention, described chemical compound is:
In one embodiment, described chemical compound is:
Figure A0281721200352
In one embodiment, described chemical compound is:
Figure A0281721200353
In another embodiment of the invention, described chemical compound has following structure:
Figure A0281721200354
Or
In another embodiment of the invention, at least one V is the optional phenyl that is replaced by one or more following groups: F; Cl; Br;-OR 3(CH 2) qOR 3Straight or branched C 1-C 7Alkyl; C 1-C 7Polyfluoroalkyl; Or phenoxy group.
In another embodiment of the invention, described chemical compound is
Figure A0281721200361
In one embodiment, described chemical compound is
In another embodiment of the invention, described chemical compound has following structure:
Or
In another embodiment of the invention, at least one V is the optional phenyl that is replaced by one or more following groups: F; Cl; Br;-OR 3-COR 3(CH 2) qOR 3Straight or branched C 1-C 7Alkyl; C 1-C 7Polyfluoroalkyl; Aryl or phenoxy group.
In another embodiment of the invention, described chemical compound is
In one embodiment, described chemical compound is
In one embodiment, described chemical compound is
Figure A0281721200372
In one embodiment, described chemical compound is
Figure A0281721200373
In one embodiment, described chemical compound is
In one embodiment, described chemical compound is
In one embodiment of the invention, described chemical compound has following structure:
Figure A0281721200382
Or
In another embodiment of the invention, at least one V is the optional phenyl that is replaced by one or more following groups: F; Cl; Br;-OR 3(CH 2) qOR 3Straight or branched C 1-C 7Alkyl; C 1-C 7Polyfluoroalkyl; Or phenoxy group.
In another embodiment of the invention, described chemical compound is
Figure A0281721200384
In one embodiment, show structure under described chemical compound has:
Figure A0281721200385
In one embodiment, show structure under described chemical compound has:
Figure A0281721200391
In one embodiment, show structure under described chemical compound has:
In one embodiment, show structure under described chemical compound has:
In one embodiment, show structure under described chemical compound has:
Figure A0281721200394
In one embodiment of the invention, described chemical compound has following structure:
In one embodiment, show structure under described chemical compound has:
Figure A0281721200401
In one embodiment, show structure under described chemical compound has:
Figure A0281721200402
In another embodiment of the invention, Y is a hydrogen, and V is a phthalimide.
In another embodiment of the invention, R 6Be straight or branched C 1-C 7Alkyl; C 3-C 7Cycloalkyl;-N (R 3) 2-OR 3-(CH 2) pOR 3Optional aryl, benzyl or the heteroaryl that is replaced by one or more following groups: F; Cl; Br; I;-OR 3-(CH 2) qOR 3Perhaps straight or branched C 1-C 7Alkyl.
In another embodiment of the invention, described chemical compound is:
In one embodiment of the invention, described chemical compound has following structure:
In one embodiment of the invention, at least one V is optional phenyl or the heteroaryl that is replaced by one or more following groups: F; Cl; Br; I; R 5-OR 5(CH 2) qOR 5(CH 2) qR 5Straight or branched C 1-C 7Alkyl; C 1-C 7One fluoroalkyl or Polyfluoroalkyl; Or phenoxy group.
In one embodiment of the invention, described chemical compound has following structure:
In one embodiment of the invention, described chemical compound has following structure:
Figure A0281721200412
In one embodiment of the invention, V is the optional phenyl that is replaced by one or more following groups: F; Cl; Br;-OR 5(CH 2) qOR 5(CH 2) qR 5Straight or branched C 1-C 7Alkyl; C 1-C 7One fluoroalkyl or C 1-C 7Polyfluoroalkyl; Or phenoxy group.
In one embodiment, described chemical compound has following structure:
Figure A0281721200413
In one embodiment, described chemical compound has following structure:
Figure A0281721200414
In one embodiment, described chemical compound has following structure:
Figure A0281721200415
In one embodiment, described chemical compound has following structure:
Figure A0281721200421
In one embodiment, described chemical compound has following structure:
In an embodiment of described chemical compound, R 5Be straight or branched C 1-C 7Alkyl; C 3-C 7Cycloalkyl;-N (R 6) 2-OR 6-(CH 2) qOR 6-CH (R 6) 2-(CH 2) qR 6Perhaps aryl, benzyl or heteroaryl, wherein said aryl, benzyl or heteroaryl are optional to be replaced by one or more following groups: F; Cl; I; R 6-N (R 6) 2-OR 6(CH 2) qOR 6(CH 2) qR 6Perhaps straight or branched C 1-C 7Alkyl.
In one embodiment, described chemical compound has following structure:
Figure A0281721200423
In one embodiment, described chemical compound has following structure:
Figure A0281721200424
In an embodiment of described chemical compound, X is a hydrogen, and Y is by the optional carbazole that replaces of one or more following groups: F; Cl; Br; R 5-OR 5(CH 2) qOR 5(CH 2) qR 5Straight or branched C 1-C 7Alkyl; Or C 1-C 7One fluoroalkyl or Polyfluoroalkyl; Or phenoxy group.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
Figure A0281721200432
In an embodiment of described chemical compound, Y is a hydrogen, and V is can be by the optional indole that replaces of one or more following groups: F; Cl; Br; R 5-CO 2R 5-OR 5(CH 2) qOR 5-(CH 2) qR 5Straight or branched C 1-C 7Alkyl; C 1-C 7One fluoroalkyl or Polyfluoroalkyl; Or at 1,2,3,4,5,6 or 7 phenoxy groups on being.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
Figure A0281721200435
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
Figure A0281721200446
In one embodiment, described chemical compound has following structure:
Figure A0281721200451
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
Figure A0281721200453
In one embodiment, described chemical compound has following structure:
Figure A0281721200454
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
The invention provides chemical compound or its pharmaceutically acceptable salt with following structure:
Figure A0281721200462
Or
Wherein each X independently is O or S;
Wherein q is 1 or 2;
Each R wherein 2Independent is H;-(CH 2) tXR 3-(CH 2) tC (X) N (R 3) 2-(CH 2) tCO 2R 3-CO 2R 3By-N (R 3) 2,-CON (R 3) 2Or-N (R 3) C (O) R 3The optional straight or branched C that replaces 1-C 7Alkyl; Straight or branched C 2-C 7Thiazolinyl, or alkynyl; Or C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
Wherein each t independently is the integer of 1-4 (comprising 1 and 4);
Each R wherein 3Independent is H; Straight or branched C 1-C 7Alkyl; Straight or branched C 2-C 7Thiazolinyl, or alkynyl; Or C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
R wherein 4The C that replaces for aryl, heteroaryl, by one or two aryl 1-C 7Alkyl or the C that replaces by one or two heteroaryl 1-C 7Alkyl, wherein said aryl or heteroaryl can be replaced by one or more following groups: F, Cl, Br, I ,-CN ,-NO 2,-N (R 3) 2,-COR 3,-(CH 2) nXR 3-(CH 2) nC (X) NR 3-(CH 2) nN (R 3) C (X) R 3-(CH 2) nCO 2R 3-(CH 2) nOCOR 3Straight or branched C 1-C 7Alkyl; One fluoroalkyl or Polyfluoroalkyl or straight or branched C 2-C 7Aminoalkyl, alkenyl or alkynyl or C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
Wherein each n independently is the integer of 0-7 (comprising 0 and 7);
R wherein 5Be H; Aryl, the C that replaces by aryl 1-C 7Alkyl, heteroaryl or the C that replaces by heteroaryl 1-C 7Alkyl, wherein said aryl or heteroaryl can be replaced by one or more following groups: F, Cl, Br, I ,-CN ,-NO 2,-N (R 3) 2,-COR 3,-(CH 2) nXH 3-(CH 2) nC (X) NR 3-(CH 2) nCO 2R 3Straight or branched C 1-C 7Alkyl; One fluoroalkyl, Polyfluoroalkyl or amido alkyl, perhaps straight or branched C 2-C 7Aminoalkyl, alkenyl or alkynyl, or C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
R wherein 5With a R on adjacent carbon atom 2Can form aryl, heteroaryl, 2 together, 3-dihydroindene or tetrahydro naphthyl, C 3-C 7Cycloalkyl or Heterocyclylalkyl, one of them or two hetero atoms can be O, N or S;
R wherein 1For
Figure A0281721200471
Or
Figure A0281721200472
Wherein each V independently is aryl, phenoxy group or heteroaryl, and wherein aryl, phenoxy group or heteroaryl are optional is replaced by one or more following groups: F; Cl; Br; I; COR 5CO 2R 5-OCOR 5-CON (R 5) 2-N (R 5) COR 5CN;-NO 2-N (R 5) 2-OR 5-SR 5(CH 2) qOR 5(CH 2) qSR 5By-CON (R 5) 2,-N (R 5) C (O) R 3Or N (R 3) 2The optional straight or branched C that replaces 1-C 7Alkyl, straight or branched one fluoroalkyl or Polyfluoroalkyl, straight or branched C 2-C 7Thiazolinyl, C 2-C 7Alkynyl; Phenoxy group; Or C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
Each R wherein 6Independent is H; (CH 2) tXR 3(CH 2) tC (X) NR 3(CH 2) tN (R 3) C (X) R 3(CH 2) tCO 2R 3(CH 2) tOCOR 3By-CON (R 3) 2Or-NC (O) R 3The optional straight or branched C that replaces 1-C 7Alkyl; By-N (R 3) 2The straight or branched C that replaces 2-C 7Alkyl, straight or branched C 2-C 7Alkenyl or alkynyl; Or C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
Each R wherein 7Independent is H; F; Cl; Br; I;-COR 3-CO 2R 3-(CH 2) nXR 3,-(CH 2) nN (R 3) C (O) R 3-(CH 2) nC (X) N (R 3) 2-(CH 2) nCO 2R 3-CN;-NO 2-N (R 3) 2Straight or branched C 1-C 7Alkyl, hydroxy alkyl, aminoalkyl, amido alkyl, alkoxyalkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or C 5-C 7Cycloalkenyl group, wherein said alkyl, aminoalkyl, amido alkyl, hydroxy alkyl, alkoxyalkyl, thiazolinyl, alkynyl, cycloalkyl or cycloalkenyl group can be replaced by one or more aryl or heteroaryl, and wherein said aryl or heteroaryl can be replaced by one or more following groups: F, Cl, Br, I ,-(CH 2) nXR 3,-COR 3,-(CH 2) nC (X) N (R 3) 2,-(CH 2) nCO 2R 3,-CN ,-NO 2,-(CH 2) nN (R 3) C (O) R 3,-N (R 3) 2,-SO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl, or C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or C 5-C 7Cycloalkenyl group; Aryl or heteroaryl, wherein said aryl or heteroaryl can be replaced by one or more following groups: F, Cl, Br, I ,-(CH 2) nXR 3,-COR 3,-(CH 2) nC (X) N (R 3) 2,-(CH 2) nCO 2R 3,-(CH 2) nN (R 3) C (O) R 3,-CN ,-NO 2,-N (R 3) 2,-SO 2R 3, straight or branched C 1-C 7Alkyl, straight or branched C 1-C 7One fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl; Perhaps C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or C 5-C 7Cycloalkenyl group;
Wherein B is CO, SO 2Or SO 2NR 6
R wherein 8Be H; Straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; Straight or branched C 2-C 7Alkenyl or alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;-N (R 3) 2-NR 3C (O) R 3-OR 3-(CH 2) pOR 3-COR 3-CO 2R 3-OCOR 3-CON (R 3) 2By optional aryl or the heteroaryl that replaces of one or more following groups: F; Cl; Br; I;-COR 3-CO 2R 3-OCOR 3-NR 3C (O) R 3-CON (R 3) 2-CN;-NO 2-N (R 3) 2-OR 3-SR 3(CH 2) qOR 3(CH 2) qSR 3By-CON (R 3) 2-NR 3C (O) R 3Or N (R 3) 2The optional straight or branched C that replaces 1-C 7Alkyl; Straight or branched one fluoroalkyl, Polyfluoroalkyl; Straight or branched C 2-C 7Thiazolinyl, C 2-C 7Alkynyl; C 3-C 7Cycloalkyl, a fluorine cycloalkyl, polyfluoro cycloalkyl or cycloalkenyl group;
Wherein each m independently is the integer of 0-3 (comprising 0 and 3);
Wherein z is
Figure A0281721200491
Figure A0281721200501
Or
Or C 2-C 7Thiazolinyl, wherein said C 2-C 7Thiazolinyl can be unsubstituted or by one or more R 9Group replaces;
Each R wherein 9Independent is H; F; Cl; Br; I;-(CH 2) mXR 3-(CH 2) mC (X) NR 3-(CH 2) mCO 2R 3Straight or branched C 1-C 7Alkyl, a fluoroalkyl, Polyfluoroalkyl, aminoalkyl or amido alkyl; Straight or branched C 2-C 7Alkenyl or alkynyl, or C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
R wherein 10For-H; (CH 2) tXR 3(CH 2) tC (X) NR 3(CH 2) tCO 2R 3Straight or branched C 1-C 7Alkyl; Amido alkyl; A straight chain or an aminoalkyl, C 2-C 7Alkenyl or alkynyl; Perhaps C 3-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group;
Wherein Y is S, O or NR 10
Wherein each p independently is the integer of 1-7 (comprising 1 and 7).
In another embodiment of the invention, described chemical compound has following structure:
Figure A0281721200503
Or
Figure A0281721200504
In another embodiment of the invention, described chemical compound has following structure:
Figure A0281721200511
Or
In another embodiment of the invention, described chemical compound has following structure:
In one embodiment of the invention, Z is:
Figure A0281721200514
In one embodiment of the invention, Z is:
Figure A0281721200515
In another embodiment of the invention, described chemical compound has following structure:
Figure A0281721200521
In another embodiment of the invention, described chemical compound has following structure:
Figure A0281721200522
The invention provides chemical compound with following structure:
R wherein 1Be H; Straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl, aryl or heteroaryl, wherein said aryl or heteroaryl are optional to be replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CH 3-,-CF 3,-COCH 3,-CO 2R 2, phenyl, phenoxy group or straight or branched C 1-C 7Alkyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R wherein 3Be aryl or heteroaryl, wherein said aryl or heteroaryl are optional to be replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 3,-CO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
Wherein X independently is O or NH;
Wherein n is the integer (comprising 0 and 5) of 0-5.
In one embodiment, R 1For optional by the aryl of one or more following groups replacements :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-COCH 3,-CO 2R 2, straight or branched C 1-C 7Alkyl;
R wherein 3Be phenyl;
Wherein A is H;
Wherein X is O.
In one embodiment, R 2Be isopropyl.
In a preferred embodiment, X is NH, R 1Be alkyl, n is 1 or 2.
In a most preferred embodiment, X is O, R 1Be 3-acetylphenyl, R 2Be isopropyl, R 3Be phenyl, n is 1.
In one embodiment, described chemical compound has following structure:
Figure A0281721200531
In one embodiment, described chemical compound has following structure:
In one embodiment, R 1Be hydrogen, straight or branched C 1-C 7Alkyl; And R wherein 3Be aryl.
In one embodiment, R 2Be isopropyl; And A is a hydrogen.
In one embodiment, described chemical compound has following structure:
In one embodiment, described chemical compound has following structure:
The present invention also provides the chemical compound with following structure:
R wherein 1For optional by the aryl or the heteroaryl of one or more following groups replacements :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-OCH 3, phenoxy group, fused rings pentyl, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
R wherein 2Be straight or branched C 1-C 4Alkyl or cyclopropyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; And
Wherein n is the 1-5 integer of (comprising 1 and 5).
At an embodiment, R 1For optional by the aryl of one or more following groups replacements :-F ,-Cl ,-Br ,-I or straight or branched C 1-C 4Alkyl; And
Wherein A is H.
In one embodiment, R 2Be isopropyl; And wherein
N is 2.
In a preferred embodiment, n is 2 and R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
Figure A0281721200543
In one embodiment, described chemical compound has following structure:
Figure A0281721200551
In one embodiment, described chemical compound has following structure:
In one embodiment, R 1Be thienyl, and wherein A is H.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has following structure:
Figure A0281721200553
The invention provides a kind of chemical compound with following formula structure:
Wherein:
W is
Figure A0281721200555
Or
Each R wherein 1Independent is hydrogen, methyl or ethyl;
R 2Be straight or branched C 3-C 4Alkyl, or
R 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R 3Be hydrogen, aryl or heteroaryl, wherein said aryl or heteroaryl optional by one or more-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl replaces;
Each A independently is-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 3,-CO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
X is O, NR 3, CO or can not exist; And
Y is hydrogen, aryl or heteroaryl, wherein said aryl or heteroaryl optional by one or more-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl replaces.
In one embodiment, W is
Figure A0281721200561
And X is O or can exist.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has the structure of following formula:
Figure A0281721200562
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, W is
In one embodiment, A be-H ,-F ,-Cl ,-Br.
In one embodiment, R 2Be isopropyl; And A is a hydrogen.
In one embodiment, described chemical compound has the structure of following formula:
Figure A0281721200571
The invention provides a kind of chemical compound with following formula structure:
Wherein:
W is
Figure A0281721200573
Or
Figure A0281721200574
Each R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl optional by one or more-F ,-Cl ,-Br ,-CN ,-NO 2,-OCH 3,-CO 2CH 3, CF 3, phenyl, straight or branched C 1-C 7Alkyl replaces;
R 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
A is-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 1,-CO 2R 1, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl or phenyl;
Each B independently is-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-COR 1,-CO 2R 1,-OCH 3,-OCF 3, CF 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl, Polyfluoroalkyl or aryl, phenoxy group or benzyloxy, wherein said aryl, phenoxy group or benzyloxy optional by one or more-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 1,-CO 2R 1,-OCH 3,-OCF 3, CF 3Perhaps straight or branched C 1-C 3Alkyl replaces.
In one embodiment, W is
In one embodiment, R 1For hydrogen or optional by one or more-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7The phenyl that alkyl replaces.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, described chemical compound has the structure of following formula:
The invention provides a kind of chemical compound with following formula structure:
Wherein:
R 1Be hydrogen, straight or branched C 1-C 7Alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl optional by one or more-F ,-Cl ,-Br ,-CN ,-NO 2,-CF 3,-OCH 3, straight or branched C 1-C 3Alkyl replaces;
R 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R 3For-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CF 3,-OCH 3, straight or branched C 1-C 3Alkyl, a fluoroalkyl, Polyfluoroalkyl or with the indole partial C 6And C 7Condensed phenyl ring;
R 4For hydrogen or optional by one or more-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CF 3, straight or branched C 1-C 3The aryl that alkyl replaces;
A is-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; And
N is the integer of 2 to 4 (comprising 2 and 4).
In one embodiment, R 3For-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-OCF 3Or-OCH 3And
R 4For hydrogen or optional by one or more-F ,-Cl or-CF 3The phenyl that replaces.
In one embodiment, R 1For hydrogen or optional by one or more-F ,-Cl ,-Br ,-CN ,-NO 2,-CF 3,-OCH 3Or straight or branched C 1-C 3The phenyl that alkyl replaces.
In one embodiment, R 2Be isopropyl.
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, described chemical compound has the structure of following formula:
Figure A0281721200592
In one embodiment, described chemical compound has the structure of following formula:
Figure A0281721200593
The invention provides a kind of chemical compound with following formula structure:
Wherein:
Each R 1Independent is hydrogen or CH 3
R 2Be straight or branched C 1-C 4Alkyl or cyclopropyl;
R 3Be benzyl or phenyl, wherein said benzyl or phenyl optional by methylene-dioxy or one or more-F or-Cl replaces;
A is-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
X is (CH 2) 2, COCH 2Or CONH.
In one embodiment, R 3Be the optional phenyl that is replaced by one or more-F; And
A is a hydrogen.
In one embodiment, X is CONH.
In one embodiment, R 2Be methyl.
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, described chemical compound has the structure of following formula:
Figure A0281721200602
Wherein each Y independently be hydrogen or-F.
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, R 3For optional by methylene-dioxy or one or more-F or-benzyl that Cl replaces.
In one embodiment, described chemical compound has the structure of following formula:
Figure A0281721200613
Wherein each Y independently be hydrogen or-F.
In one embodiment, described chemical compound has the structure of following formula:
In one embodiment, described chemical compound is the chemical compound of enantiomeric pure.
In one embodiment, described chemical compound is the chemical compound of diastereisomericallypure pure.
In one embodiment, described chemical compound is the chemical compound of the pure and mild diastereisomericallypure pure of enantiomer.
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition comprises the The compounds of this invention and the pharmaceutically acceptable carrier of therapeutic dose.
In one embodiment, the amount of described chemical compound is that about 0.01mg is to about 500mg.
In one embodiment, the amount of described chemical compound is that about 0.1mg is to about 60mg.
In one embodiment, the amount of described chemical compound is that about 1mg is to about 20mg.
In one embodiment, to contain liquid carrier and described compositions be solution to described pharmaceutical composition.
In one embodiment, described pharmaceutical composition contains solid-state carrier and described compositions is a tablet.
In one embodiment, to contain the carrier and the described compositions of gel state be suppository to described pharmaceutical composition.
The present invention also provides a kind of method of pharmaceutical compositions, and this method comprises that any chemical compound of the present invention with the treatment effective dose mixes with pharmaceutically acceptable carrier.
The present invention also provides a kind of treatment to suffer from the patient's who is selected from following disease method: depression, anxiety neurosis, urinary incontinence or obesity, this method comprises the The compounds of this invention that gives described patient treatment effective dose.
In one embodiment, described treatment effective dose is that every day about 0.03 is to about 1000mg.
In one embodiment, described treatment effective dose is that every day about 0.30 is to about 300mg.
In one embodiment, described treatment effective dose is that every day about 1.0 is to about 100mg.
In one embodiment, described disease is a depression.
In one embodiment, described disease is an anxiety neurosis.
In one embodiment, described disease is an obesity.
In one embodiment, described disease is a urinary incontinence.
The invention provides the method that alleviates weight in patients, this method comprises and gives the The compounds of this invention that the patient effectively alleviates the amount of its body weight.
The invention provides treatment and suffer from patient's the method for depression, this method comprises the present invention's any chemical compound required for protection that gives the amount that the patient effectively treats its depression.
The invention provides treatment and suffer from patient's the method for anxiety neurosis, this method comprises and gives the The compounds of this invention that the patient effectively treats the amount of its anxiety neurosis.
The invention provides the method that alleviates the urinary incontinence that the patient causes owing to the bladder hyperkinesia, this method comprises the The compounds of this invention of the amount that gives the urinary incontinence that the patient effectively alleviates the patient.
The invention provides in the slimming patient of needs the method for controlling obesity disease, this method comprises and gives the The compounds of this invention that the patient effectively alleviates the amount of its body weight.
The present invention is for providing the method for controlling obesity disease through the patient who loses weight, this method comprises that giving the patient effectively keeps the The compounds of this invention that it has the amount of the amount of losing weight now.
The invention provides treatment patient's bladder hyperactive method, this method comprises and gives any chemical compound of the present invention that the patient effectively treats the hyperactive amount of its bladder.
The invention provides the method for treatment patient disease, wherein patient's symptom can be by alleviating with the MCH1 antagonist for treating, and wherein the MCH1 antagonist is a chemical compound of the present invention.
The invention provides the method that alleviates the disease of patient symptom, this method comprises the MCH1 antagonist of the amount that gives the effective mitigation symptoms of patient, and wherein the MCH1 antagonist is a chemical compound of the present invention.
The term of Shi Yonging " heteroaryl " comprises 5 and 6 yuan of unsaturated rings in the present invention, and described ring can contain one or more oxygen, sulfur or nitrogen-atoms.The example of heteroaryl includes but not limited to carbazole, furyl, thienyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazole base, triazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl and triazine radical.
In addition, used term " heteroaryl " comprises and can contain one or more heteroatomic condensed-bicyclic systems as oxygen, sulfur and nitrogen.The example of this heteroaryl includes but not limited to indolizine base, indyl, isoindolyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl, purine radicals, benzoxazolyl, benzoisoxazole base, benzo [b] thiazolyl, imidazo [2,1-b] thiazolyl, cinnolines base, quinazolyl, quinoxalinyl, 1,8-phthalazinyl, pteridyl, quinolyl, isoquinolyl, phthaloyl imino and 2,1, the 3-benzothiazolyl.
Term " heteroaryl " also comprise the above-mentioned chemical group that can be replaced by following one or more groups :-F ,-Cl ,-Br ,-I, CN ,-NO 2, straight or branched C 1-C 7Alkyl, straight or branched C 1-C 7One fluoroalkyl, straight or branched C 1-C 7Polyfluoroalkyl, straight or branched C 2-C 7Thiazolinyl, straight or branched C 2-C 7Alkynyl, C 3-C 7Cycloalkyl, C 3-C 7One fluorine cycloalkyl, C 3-C 7Polyfluoro cycloalkyl, C 5-C 7Cycloalkenyl group.
Term " heteroaryl " also comprises the above-mentioned N-oxide that contains the chemical group of at least one nitrogen-atoms.
In the present invention, term " aryl " is a phenyl or naphthyl.
The invention provides any various pure stereoisomers of describing chemical compound.These stereoisomers can comprise enantiomer, diastereomer or E or Z alkene or imine isomer.The present invention also provides stereoisomer mixture, comprises racemic mixture, non-enantiomer mixture or E/Z isomer mixture.Stereoisomer (N ó gr á di, the M. that can synthesize pure state; Stereoselective Synthesis,(1987) VCH Edit or Ebel, H. and Asymmetri Synthesis, Volumes 3 B 5, (1983) Academic Press, EditorMorrison J.), maybe can adopt the whole bag of tricks such as crystallization and chromatographic technique to split (Jaques, J.; Collet, A.; Wilen, S.; Enantiomer, Racemates, and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis, vol.2,1983, AcademicPress, Editor Morrison, J).
In addition, The compounds of this invention can enantiomer, the form of diastereomer, isomers exists, and perhaps can have two or more these chemical compounds and forms racemic mixture or non-enantiomer mixture.
Preferred The compounds of this invention purity is 80%, more preferably 90% and most preferably 95%.The pharmaceutically acceptable salt and the complex of all chemical compounds described herein include in the present invention.The bronsted lowry acids and bases bronsted lowry for preparing these salt includes but not limited to the various bronsted lowry acids and bases bronsted lowries that this description is listed.Acid includes but not limited to following mineral acid: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid and boric acid.Acid also includes but not limited to following organic acid: acetic acid, malic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic, lactic acid and mandelic acid.Alkali includes but not limited to ammonia, methylamine, ethamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, aminoethyle alcohol, morpholine, piperazine and guanidine.The present invention also provides the hydrate and the polymorph of all chemical compounds described herein.
The present invention also comprises the prodrug of the chemical compound that it provided.Usually, these prodrugs are the functional derivative of The compounds of this invention, change into required chemical compound in vivo easily.Therefore, in the present invention, term " administration " should comprise the disclosed especially chemical compound of employing or adopt not disclosed especially chemical compound, but can be converted into the compounds for treating various diseases of specific compound after delivering medicine to the patient in its body.The conventional method of selecting and preparing suitable prodrug derivant is described in for example Design of Prodrugs, H.Bundgaard, and Elsevier edits, and 1985.
The present invention also comprises the metabolite of The compounds of this invention.Metabolite comprises introduces the active substance that produces behind the biological environment with The compounds of this invention.
The present invention also provides and has comprised the The compounds of this invention for the treatment of effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.In one embodiment, the amount of described chemical compound is that about 0.01mg is to about 800mg.In another embodiment, the amount of described chemical compound is that about 0.01mg is to about 500mg.And in another embodiment, the amount of described chemical compound is that about 0.1mg is to about 250mg.In another embodiment, the amount of described chemical compound is that about 0.1mg is to about 60mg.And in another embodiment, the amount of described chemical compound is that about 1mg is to about 20mg.In one embodiment, described carrier is that liquid and described compositions are solution.In another embodiment, described carrier is that solid and described compositions are tablet.In one embodiment, described carrier is that gel and described compositions are capsule, suppository or ointment.In another embodiment, described chemical compound can be formulated as pharmaceutically acceptable transdermal patch.Also in another embodiment, can give the patient with described chemical compound by spraying or the mode that sucks.
The present invention also provides a kind of pharmaceutical composition, and described pharmaceutical composition makes by the The compounds of this invention and the pharmaceutically acceptable carrier of mixing treatment effective dose.
The invention provides a kind of method of pharmaceutical compositions, described method comprises the The compounds of this invention and the pharmaceutically acceptable carrier of mixing treatment effective dose.
Solid carrier can comprise that one or more also can be used as the material of following reagent: interior source carrier (endogenous carriers is as nutrient carrier or micronutrient carrier), correctives, lubricant, solubilizer, suspending agent, filler, fluidizer, compression aid, binding agent or tablet disintegrant.These materials also can be coating material.For powder, carrier is a dispersed solids in small, broken bits, is mixed together with active ingredient dispersed in small, broken bits.For tablet, the carrier of the compression performance that having of active component and appropriate amount is essential is mixed together, and is compressed into required shape and size.Preferred powder and tablet contain 99% active component at most.Suitable solid carrier includes but not limited to for example calcium phosphate, magnesium stearate, Pulvis Talci, sugar, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidone/, low melt wax and ion exchange resin.
Liquid-carrier is used to prepare solution, suspending agent, Emulsion, syrup, elixir and spray composite.Can or be suspended in the active component dissolving as in water, organic solvent or both mixed liquors or the pharmaceutically acceptable liquid-carriers such as pharmaceutically acceptable oil or fat.Liquid-carrier can contain other suitable medicated premix, as solubilizer, Emulsion, buffer agent, antiseptic, sweeting agent, correctives, suspending agent, thickening agent, coloring agent, viscosity modifier, stabilizing agent or transmissive modulation agent.The example that is suitable for the liquid-carrier of oral and parenteral comprises that (part contains above-mentioned additive to water, as cellulose derivative, preferably carboxymethyl cellulose sodium solution), alcohol (comprise monohydric alcohol and polyhydric alcohol, as dihydroxylic alcohols) and their derivant, also have oil (as fractionated Oleum Cocois and Oleum Arachidis hypogaeae semen).For parenteral, carrier can be grease, as ethyl oleate or isopropyl myristate.Sterile liquid carrier can be used for the sterile liquid form compositions that parenteral is used.The liquid-carrier that is used for spray composite can be halogenated hydrocarbon or other pharmaceutically acceptable appropriate excipients.
The composition of liquid medicine of sterile solution or form of suspension can be used for as in intramuscular, the sheath, epidural, intraperitoneal or subcutaneous injection.Sterile solution also can be used for intravenous administration.Described chemical compound can be made into aseptic solid composite, when administration, and available sterilized water, saline or dissolving of other suitable sterile injectable medium or suspension.Carrier contains necessary and inert binding agent, suspending agent, lubricant, correctives, sweeting agent, antiseptic, dyestuff and coating.Described chemical compound can sterile solution or the form oral administration of suspension, and it contains other solute or suspending agent (as containing the saline of q.s or glucose to make isosmotic solution), bile salt, arabic gum, gelatin, dehydrated sorbitol mono-fatty acid ester, Tween 80 (oleate of the copolymer of Sorbitol and dehydrate thereof and oxirane) etc.
Described chemical compound can also liquid or solid composition forms oral administration.Be suitable for liquid preparations for oral administration and comprise solid form, as pill, capsule, granule, tablet and powder, and liquid form, as solution, syrup, elixir and suspension liquor.The form that can be used for parenteral comprises sterile solution, emulsion and suspension.
The optimal dose of administration can be definite by those skilled in the art, and different according to intensity, administering mode and the advancing of disease situation of the concrete chemical compound that uses, preparation.In addition, regulate dosage according to patient's age, body weight, sex, diet situation and the administration time of concrete treatment.
In this application, " treatment effective dose " be meant when the patient of the disease of chemical compound being suffered from available described compounds for treating, anyly alleviates, alleviates or the amount of the chemical compound of the described disease that disappears.In this application, " patient " is vertebrates, mammal or people.
The invention provides a kind of treatment and suffer from the patient's of abnormal symptom method, wherein said abnormal symptom can alleviate by reducing the MCH1 receptor active, described method comprises and gives the patient a certain amount of The compounds of this invention, and described chemical compound is the MCH1 receptor antagonist of the abnormal symptom that can effectively treat described patient.
At each independently in the embodiment, described is that steroid or pituitary hormone are regulated disorder unusually, epinephrine discharges disorderly, gastroenteropathy, cardiovascular disease, the electrolyte balance disease, hypertension, diabetes, respiratory disorder, asthma, the reproductive function obstacle, immune disease, endocrinopathy, flesh and skeletal diseases, neuroendocrine disorder, cognitive disorders, dysmnesia such as presenile dementia, sensation is regulated and conductive obstruction, motor coordination sexual disorders, the sensation dysintegration, the motion dysintegration, dopaminergic functional disorder such as parkinson, the sensation conductive obstruction, olfactory disorder, the sympathetic innervation disorder, affective disorder such as depression and anxiety neurosis, stress be diseases related, the fluid balance obstacle, epileptics, pain, psychotic behavior such as schizophrenia, the morphine tolerance, the opiophagy, migraine or dysuria such as urinary incontinence.
Below illustrate the purposes of The compounds of this invention to depression and anxiety neurosis.Below given depression and anxiety neurosis be defined in Diagnostic and Statistical Manual ofMental Disorders (the 4th edition, DSM-IV; American Psychiatric Association, 1994a) or Diagnostic and Statistical Manual of Mental Disorders (the 3rd edition, revised edition, DSM-III-R; American Psychiatric Association, 1987) list in.Other can be referring to this list of references about the information of these diseases, and following other listed document, and all these documents are attached to herein by reference.
Depression comprise major depression and dispiritment (American PsychiatricAssociation, 1994a or American Psychiatric Association, 1994b).The principal character of major depression is no manic or hypomania history to occur once or the outbreak of once above major depression.The major depression outbreak shows as obvious and long-term depression or dysphoric mental state; usually to daily routines forfeiture interest (at least 2 weeks; almost every day is like this); should comprise at least 4 kinds in the symptom in following 8: appetite changes, sleep change, psychokinesia or dull mind, can't concentrate daily routines forfeiture interest or hyposexuality, fatigue, compunction or sense of uselessness, bradykinesia or spirit; and thought (Medical Economics Company, 2002) with suicidal tendency or suicide.Dispiritment is one type a depression, do not reach the standard of major depression outbreak, but the persistent period is longer than major depression, does not have manic excited performance.
Thinking that The compounds of this invention can effectively be treated by following test is diagnosed as the symptom of suffering from patients with depression: the Clinical Global Impression (CGI) of Hamilton (Hamilton) depression scale (HDRS), Hamilton depressive mood project (depressed mood item), disease seriousness.Think that also The compounds of this invention can effectively improve measured some factor of these tests, as HDRS subfactor scores, comprise depressive mood item, the sleep disorder factor and the anxiety factor, and CGI disease seriousness scale.Think that also The compounds of this invention will effectively suppress the recurrence of major depression outbreak.
Anxiety neurosis comprises in terror, has or does not have psychentonia disease after terrified historical agoraphobia, special phobia, social phobia, obsessive-compulsive disorder, the wound, serious psychentonia disease and extensive anxiety neurosis.Thinking that The compounds of this invention can effectively be treated is diagnosed as any disease of patient of suffering from all these diseases.
(mandatory idea) stiffly appears in being characterized as idea that certain oneself forces, pondering over of obsessive-compulsive disorder, impulsion or association etc. repeatedly, and/or repeat the patient also recognize for too much or irrational, deliberate, purposive behaviour (compelling sex behavior) (AmericanPsychiatric Association, 1994a).Mandatory idea and behavior cause serious worries, lose time or have seriously disturbed social communication or cause.
Thinking that The compounds of this invention can effectively be treated by suitable test is diagnosed as the symptom of suffering from the obsessive-compulsive disorder patient, and wherein said test includes but not limited to: the global OCD scale of Mental Health (NIMH GOCS), CGI disease seriousness scale that mandatory idea of YaleBrown and behavior rating scale (YBOCS) (Goodman 1989) (being applicable to the adult), association of country formulate.Think that also The compounds of this invention can effectively improve some measured factor of these tests, as reducing the several points in the YBOCS overall score.Think that also The compounds of this invention can effectively prevent obsessive idea and behavior palindromia.
Paranoid fears is characterised in that unexpected terrified of frequent generation, follow worried conflict to take place once more, the omen or the result of conflict produced worry, and/or obviously change conflict-related behavior (American Psychiatric Association, 1994a).Panic attack is defined as intensive fear of unexpected generation or discomfort, wherein produces suddenly following symptom four kinds (or more kinds of), and reached the peak in 10 minutes: (1) cardiopalmus, the uncomfortable in chest or fast quickening of the heart; (2) perspire; (3) tremble or rock; (4) breathe hard or sensation that gas is not come thoroughly; The sensation of (5) suffocating; (6) chest pain or discomfort; (7) regurgitation or stomachache; (8) dizziness, uneasiness, lighthead or faintness; (9) derealization (untrue sensation) or depersonalization (oneself becomes estranged); Frightened or out of hand; (11) extremely sense frequently; (12) shiver with cold or hot flush.Paranoid fears may or can not be followed agoraphobia, or does not have obvious cause or produce frightened in spite of oneself away from public situation the time.
Thinking that The compounds of this invention can effectively be treated according to the frequency of panic attack or by CGI-disease seriousness scale is diagnosed as the symptom of suffering from terrified patient.Think that also The compounds of this invention can effectively improve some measured factor of these tests, as reduce the frequency of panic attack or make it disappearance, improving CGI-disease seriousness scale or obtaining CGI-Global improvement achievement is 1 (greatly improvement), 2 (big improvement) or 3 (improvement is arranged slightly).Think that also The compounds of this invention will effectively suppress the recurrence of paranoid fears.
Social anxiety disorder (being also referred to as social phobia) be characterized as to one or more people must contact with unfamiliar people or by social sight that other people monitored or performance sight produce obvious and obstinate fear (American Psychiatric Association, 1994a).Place oneself in the midst of the almost constant real estate green coke of frightened sight consider, may reach the degree of panic attack.Avoid frightened sight, or continue anxiety or misery consumingly.To avoidance, anxiety or the painful serious normal life of individual, work or the study or the social activity disturbed of frightened sight, perhaps to this fear of patient and deep painful.Slight anxiety or timidly do not need spiritual pharmacological treatment usually.
Thinking that The compounds of this invention can effectively be treated by following test is diagnosed as the symptom of suffering from the social anxiety disorder patient: Liebowitz social anxiety disorder scale (LSAS), CGI-disease seriousness scale, Hamilton Manifest Anxiety Scale (HAM-A), Hamilton depression scale (HAM-D), social and the performance evaluation scale of DSM-IV V axle, the invalidity assessment of II axle (ICD-10) World Health Organization (WHO), table 2 (DAS-2), Sheehan hinders useless scale, Schneier hinders useless scale, World Health Organization (WHO) quality of life-100 (WHOQO-100) or at Bobes, other test of describing in 1998, these test descriptions are attached to herein by reference.Thinking that also The compounds of this invention can effectively improve some measured factor of these tests, is 1 (greatly improving), 2 (big improvement) or 3 (improvement is arranged slightly) as baseline or the acquisition CGI-Global improvement achievement that changes Liebowitz social anxiety disorder scale (LSAS).Think that also The compounds of this invention will effectively suppress the recurrence of social phobia.
Extensive anxiety neurosis be characterized as overanxiexty and worry (expectation uneasily), at least 6 months persistent period, that the patient feels is restive (American Psychiatric Association, 1994a).Extensive anxiety neurosis must be attended by 3 kinds in the symptom in following 6: uneasy or feel impassioned or dysphoria, fatiguability, be difficult to concentrate on or remember bad, irritability, muscular tone, insomnia.The diagnostic criteria of this symptom has more detailed description in DSM-IV, the document be attached to herein by reference (American Psychiatric Association, 1994a).
Thinking that The compounds of this invention can effectively be treated according to the described diagnostic criteria of DSM-IV is diagnosed as the symptom of suffering from extensive anxiety patient.Think that also The compounds of this invention can effectively alleviate the symptom of this disease, as excessive worry and anxiety, to be difficult to control worried, uneasy or feel impassioned or dysphoria, fatiguability, be difficult to concentrate on or remember bad, irritability, muscular tone, insomnia.Think that also The compounds of this invention will effectively suppress the recurrence of extensive anxiety neurosis.
Psychentonia disease (PTSD) is as DSM-III-R/IV definition (AmericanPsychiatric Association after the wound, 1987, American Psychiatric Association, 1994a), must experience traumatic event, these incidents are actual or threaten death or seriously injured, or threaten the complete of I or other people health, and intensive fear, helpless or frightened.The symptom of experience after the traumatic event comprise uncontrollably recall repeatedly, " flash back ", the traumatogenic incident of nightmare, intensive psychic pain and occur this incident mentally repeatedly; Avoid to recall the sight of traumatic event, can't recall the details of incident, and/or show as to large-scale activity reduce interest, become estranged with other people, numb to spirit such as emotion constraints; Automatically the symptom of awakening (autonomic arousal) comprises hypervigilance, exaggerative startle reaction, insomnia, spirit can't be concentrated and irritability or angry.PTSD diagnosis requires symptom to have at least one month, and they cause significant clinically painful or the activity in social, work or other field brought inconvenience.
Thinking that The compounds of this invention can effectively be treated by following test is diagnosed as the symptom of suffering from PTSD patient: injury event scale (the Patient-rated Impact ofEvent Scale (IES) that clinical administration PTSD scale part 2 (Clinician-Administered PTSDScale Part 2 (CAPS)), patient estimate, Medical Economics Company, 2002,2752 pages).Think that also The compounds of this invention can effectively improve the achievement in CAPS, IES, CGI-disease seriousness or the CGI-Global retrofit testing.Think that also The compounds of this invention will effectively suppress the recurrence of PTSD.
An embodiment preferred of the present invention provides a kind of method for the treatment of or controlling following disease: depression, anxiety neurosis, eating disorder/body weight imbalance and dysuria.The example of depression comprises major depression or dispiritment.The example of anxiety neurosis comprises in terror, has or does not have psychentonia disease after terrified historical agoraphobia, special phobia, social phobia, obsessive-compulsive disorder, the wound, serious psychentonia disease or extensive anxiety neurosis.The example of eating disorder/body weight imbalance has obesity, weightening finish, bulimia nerovsa, bulimia nervosa or anorexia nervosa.The example of dysuria includes but not limited to urinary incontinence, bladder hyperkinesia, urge incontinence, frequent micturition, urgent micturition, nocturia or the enuresis.Bladder activity transition or urgent micturition may or can not be attended by benign prostatic hyperplasia.
The invention provides a kind of method of the patient's of improvement dietary behavior, described method comprises and gives the The compounds of this invention that the patient effectively reduces the amount of its food consumption.The present invention also provides a kind of method of the patient's of treatment eating disorder, and described method comprises and gives the The compounds of this invention that the patient effectively treats the amount of its eating disorder.In one embodiment of the invention, described eating disorder is obesity, bulimia nerovsa, bulimia nervosa or anorexia nervosa.
The present invention also provides a kind of method that reduces weight in patients, and described method comprises and gives the The compounds of this invention that the patient effectively reduces the weight of its body.The present invention also provides the method for the slimming patient of needs being carried out obesity control, and this method comprises and gives the The compounds of this invention that the patient effectively alleviates the amount of weight in patients.The present invention also provides the method for the patient through fat-reducing being carried out obesity control, and this method comprises that giving the patient effectively keeps it to have the The compounds of this invention of the amount of the amount of losing weight now.
The invention provides treatment and suffer from patient's the method for depression, this method comprises the The compounds of this invention of the amount that gives the depression that the patient effectively treats the patient.The invention provides treatment and suffer from patient's the method for anxiety neurosis, this method comprises the The compounds of this invention of the amount that gives the anxiety neurosis that the patient effectively treats the patient.The invention provides treatment and suffer from patient's the method for depression and anxiety neurosis, this method comprises the The compounds of this invention of the amount that gives depression that the patient effectively treats the patient and anxiety neurosis.The invention provides treatment and suffer from patient's the method for major depression, this method comprises the The compounds of this invention of the amount that gives the major depression that the patient effectively treats the patient.The invention provides treatment and suffer from low spirits patient's method, this method comprises and gives the The compounds of this invention that the patient effectively treats patient's in low spirits amount.The invention provides treatment and suffer from patient's the method for mandatory idea and behavior disorders, this method comprises the The compounds of this invention of the amount that gives mandatory idea that the patient effectively treats the patient and behavior disorders.The invention provides treatment and suffer from patient's the method for paranoid fears (being with or without agoraphobia), this method comprises the The compounds of this invention of the amount that gives the paranoid fears that the patient effectively treats the patient.The invention provides treatment and suffer from patient's the method for social anxiety disorder, this method comprises the The compounds of this invention of the amount that gives the social anxiety disorder that the patient effectively treats the patient.The invention provides treatment and suffer from patient's the method for extensive anxiety neurosis, this method comprises the The compounds of this invention of the amount that gives the extensive anxiety neurosis that the patient effectively treats the patient.The invention provides treatment and suffer from the method for the patient of psychentonia obstacle after the wound, this method comprises the The compounds of this invention that gives the amount of psychentonia obstacle after the wound that the patient effectively treats the patient.
Thinking that The compounds of this invention can effectively be treated by test below one or more is diagnosed as the symptom of suffering from the obesity patient, and comprise losing weight and the maintenance amount of losing weight: Body Mass Index increases, waistline increases (index of fat in the abdomen), double energy X-ray absorptiometric analysis (DEXA) and trunk fat weight.Think that also The compounds of this invention can effectively improve some measured factor of these tests.
Think that The compounds of this invention can effectively treat the controlled micturition obstacle, described patient suffers from urgent micturition or mixes urinary incontinence (based on urgent micturition), shows as weekly unnecessary outbreak for several times, and every day is unnecessary urinates that voided volume is few for several times and at every turn.Think that also The compounds of this invention can effectively improve some measured factor of these tests.
The present invention also provides treatment to suffer from the patient's of following disease method: the cognitive disorder of bipolar disorder I or II obstacle, schizoaffective disorder, band depressive mood, personality disorder, insomnia, hypersomnia, Gelineau's syndrome, 24 hours rhythm sleep disorder, nightmare, night terror or somnambulisms.
The invention provides a kind of patient's of treatment the hyperactive method of bladder, wherein the bladder hyperkinesia has the symptom of urge incontinence, urgent micturition and/or frequent micturition, and described method comprises the The compounds of this invention that gives the hyperactive amount of bladder that the patient effectively treats the patient.The invention provides a kind of method that alleviates the hyperactive patient's of bladder urge incontinence, described method comprises the The compounds of this invention of the amount that gives the urge incontinence that the patient effectively treats the patient.The invention provides a kind of method that alleviates the hyperactive patient's of bladder urgent micturition, described method comprises the The compounds of this invention of the amount that gives the urgent micturition that the patient effectively treats the patient.In addition, the invention provides a kind of method that alleviates the hyperactive patient's of bladder frequent micturition, described method comprises the The compounds of this invention of the amount that gives the frequent micturition that the patient effectively treats the patient.
The method that the present invention also provides a kind of treatment to suffer from the patient of dysuria, described method comprise the The compounds of this invention of the amount that gives the dysuria that the patient effectively treats the patient.In some embodiments, described dysuria is urinary incontinence, bladder hyperkinesia, urge incontinence, frequent micturition, urgent micturition, nocturia or the enuresis.
The invention provides the method for disease symptoms that a kind of patient of alleviating takes a disease, described method comprises and gives the MCH1 antagonist that the patient effectively alleviates described symptom that wherein said MCH1 antagonist is any chemical compound of the present invention.
In one embodiment of the invention, described patient is vertebrates, mammal, people or Canis animals.In another embodiment, described chemical compound oral administration.And in another embodiment, described chemical compound gives with food.
Can understand the present invention better from preferred embodiment to the detailed description of experiment, the invention provides a kind of method for the treatment of following disease: depression, anxiety neurosis, eating disorder/body weight imbalance and dysuria.The example of eating disorder/body weight imbalance has obesity, bulimia nerovsa or bulimia nervosa.The example of dysuria includes but not limited to urinary incontinence, bladder hyperkinesia, urge incontinence, frequent micturition, urgent micturition, nocturia or the enuresis.Bladder activity transition or urgent micturition may or can not be attended by benign prostatic hyperplasia.
The invention provides the method for a kind of patient's of change dietary behavior, described method comprises and gives the The compounds of this invention that the patient effectively reduces the amount of its food consumption.
The invention provides the method for a kind of patient's of treatment eating disorder, described method comprises and gives the The compounds of this invention that the patient effectively reduces the amount of its food consumption.In one embodiment of the invention, described eating disorder is bulimia nerovsa, obesity or bulimia nervosa.In one embodiment of the invention, described patient is vertebrates, mammal, people or Canis animals.In another embodiment, described chemical compound gives with food.
The present invention also provides a kind of method that alleviates weight in patients, and this method comprises the The compounds of this invention of the amount that gives effective its body weight of patient.
The invention provides treatment and suffer from patient's the method for depression, this method comprises the The compounds of this invention of the amount that gives the depression that the patient effectively treats the patient.The invention provides treatment and suffer from patient's the method for anxiety neurosis, this method comprises the The compounds of this invention of the amount that gives the anxiety neurosis that the patient effectively treats the patient.The invention provides treatment and suffer from patient's the method for depression and anxiety neurosis, this method comprises the The compounds of this invention of the amount that gives depression that the patient effectively treats the patient and anxiety neurosis.
The present invention also provides a kind of treatment to suffer from the patient's of following disease method: major depression, in low spirits, bipolar disorder I or II obstacle, schizoaffective disorder, the cognitive disorder of band depressive mood, personality disorder, insomnia, hypersomnia, Gelineau's syndrome, 24 hours rhythm sleep disorder, nightmare, night terror, somnambulism, obsessive-compulsive disorder, there be or do not have the terrified of agoraphobia, psychentonia disease after the wound, social phobia and extensive anxiety neurosis.
The method that the present invention also provides a kind of treatment to suffer from the patient of dysuria, described method comprise the The compounds of this invention of the amount that gives the dysuria that the patient effectively treats the patient.In some embodiments, described dysuria is urinary incontinence, bladder hyperkinesia, urge incontinence, frequent micturition, urgent micturition, nocturia or the enuresis.
Can understand the present invention from preferred embodiment better to the detailed description of experiment.But those skilled in the art can understand the concrete grammar and the result that are discussed well and illustrate of the present invention, will make more fully limiting in additional claims to the present invention.
Experimental section
I. The synthetic method that is used for embodiment
Universal method:
Institute respond (except that parallel synthetic reaction) all in argon gas atmosphere, carry out, through syringe and intubate reactant (pure or in appropriate solvent) is transferred in the reaction vessel.Parallel synthetic reaction is then used J-KEM heating shaker, and (Saint Louis MO), carries out in phial (not having inert atmosphere).Anhydrous solvent does not add purification and directly uses available from Aldrich Chemical Company.The naming program name of the example use ACD that in this patent, uses (2.51 editions, Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, canada).Unless otherwise stated, otherwise 1H spectrum 300 and 400MHz note down (adopting QE Plus and Br ü ker respectively), be interior mark with tetramethylsilane.S=is unimodal; D=is bimodal; The t=triplet; The q=quartet; P=quintet, sextet, nine heavy peaks; The br=broad peak; The m=multiplet.Elementary analysis is by Robertson Microlit Laboratories, and Inc. tests.Unless otherwise stated, otherwise use low resolution electron spray (ESMS) to obtain mass spectrum, report MH +Data.Thin layer chromatography (TLC) is scribbling silica gel 60 F in advance 254Carry out on the glass plate of (0.25mm, EM Separations Tech.).(2mm carries out on glass plate Analtech) the preparation thin layer chromatography scribbling silica gel G F in advance.Rapid column chromatography carries out on Merck silica gel 60 (230-400 order).Fusing point (mp) adopts the open type capillary tube to test on the Mel-Temp device, and data are not proofreaied and correct.
Piperidines side chain intermediate
The 4-{[(trifluoromethyl) sulfonyl] the oxygen base }-1,2,3, the 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester
Under 0 ℃, n-BuLi (17.6mL, 44.2mmol, the hexane solution of 2.5M) is added diisopropylamine, and (96.2mL in anhydrous THF (40mL) solution 44.2mmol), and stirred 20 minutes.Reactant mixture is cooled to-78 ℃, (Aldrich Chemical Company, THF 40.0mmol) (40mL) solution stirred 30 minutes toward wherein being added dropwise to 4-oxo-1-piperidine acid tert-butyl ester.In the gained reactant mixture, be added dropwise to Tf 2NPh (42.0mmol, THF 15.0g) (40mL) solution, and under 0 ℃, stir and spend the night.With the reactant mixture vacuum concentration, be dissolved in hexane once more: in the ethyl acetate (9: 1),, and use hexane: the described alumina packing pipe of ethyl acetate (9: 1) washing by the alumina packing pipe.The extract that merges concentrated obtain the required product of 16.5g, be mingled with some raw material Tf in the product 2NPh.
1H?NMR(400MHz，400MHz，CDCl 3)δ5.77(s，1H)，4.05(dm，2H，J＝3.0Hz)，3.63(t，2H，J＝5.7Hz)，2.45(m，2H)，1.47(s，9H)。
4-[3-(amino) phenyl]-1,2,3, the 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester
With 2M aqueous sodium carbonate (4.2mL), 4-{[(trifluoromethyl) sulfonyl] the oxygen base }-1; 2; 3; 6-tetrahydrochysene-1-pyridine carboxylic acid the tert-butyl ester (0.500g; 1.51mmol), 3-aminophenyl boric acid Hemisulphate (0.393g; 2.11mmol), lithium chloride (0.191g; 4.50mmol) and four (triphenylphosphines) close palladium (O) (0.080g, the 0.075mmol) heating 3 hours in inert atmosphere (be recommended in when beginning to the described mixture degassing to prevent to form triphenylphosphine oxide), under reflux temperature of the mixture in dimethoxy-ethane (5mL).Isolate the organic layer of refrigerative reactant mixture, water layer washs (3X) with ethyl acetate.The dry organic extract liquid that merges, vacuum concentration.Crude product obtains the required product of 0.330g, productive rate 81% through chromatography purification (silica gel, hexane: ethyl acetate: dichloromethane (6: 1: 1) is an eluent, adds 1% 2-aminopropane. to avoid the hydrolysis of BOC group).
1HNMR(400MHz，CDCl 3)δ7.12(t，1H，J＝7.60Hz)，6.78(d，1H，J＝8.4Hz)，6.69(t，1H，J＝2.0Hz)，6.59(dd，1H，J＝2.2，8.0Hz)，6.01(m，1H)，4.10-4.01(d，2H，J＝2.4Hz)，3.61(t，2H，J＝5.6Hz)，2.52-2.46(m，2H)，1.49(s，9H)；ESMS?m/e：275.2(M+H) +。
To C 16H 24N 2O 2Value of calculation: C, 70.04; H, 8.08; N, 10.21;
Measured value: C, 69.78; H, 7.80; N, 9.92.
4-[3-(amino) phenyl]-the 1-piperidine acid tert-butyl ester
Under the room temperature, adopt the balloon method, with 3.10g 4-(3-aminophenyl)-1,2,3,6-tetrahydropyridine-1-t-butyl formate (11.3mmol) and the mixture hydrogenation of 1.0g 10%Pd/C in 200mL ethanol 2 days.Filter reaction mixture is also used washing with alcohol.With the alcohol extraction liquid vacuum concentration that merges, residue is chromatography (dichloromethane: methanol=95: 5 adds 1% 2-aminopropane. to avoid the hydrolysis of BOC group) on silica gel, obtains the required product of 2.63g (84%).
1H?NMR(400MHz，CDCl 3)δ7.10(t，1H，J＝7.60Hz)，6.62(d，1H，J＝8.4Hz)，6.60-6.59(m，2H)，4.27-4.18(m，2H)，3.62-3.58(m，2H)，2.80-2.72(m，2H)，2.62-2.59(m，1H)，1.89-1.52(m，4H)，1.49(s，9H)；ESMS?m/e：277.2(M+H) +。
4-[3-(acetyl-amino) phenyl]-1,2,3, the 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester
With saturated aqueous sodium carbonate (25mL), 4-{[(trifluoromethyl) sulfonyl] the oxygen base }-1; 2; 3, the 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester (20mmol), 3-acetyl amino phenyl ylboronic acid (30mmol) and four (triphenylphosphines) close palladium (O) (1.15g) and the mixture of dimethoxy-ethane (40mL) heated overnight under reflux temperature.Isolate organic layer, and water layer is washed (3X) with ethyl acetate through refrigerative reactant mixture.Dry and the vacuum concentration with the organic extract liquid that merges.Crude product obtains required product through chromatography purification.
1H NMR (CDCl 3) δ 8.11 (br s, 1H), 7.57 (br s, 1H), 7.41 (br d, 1H, J=7.8Hz), 7.25 (tangible t, 1H, J=7.8Hz), 7.08 (br d, 1H, J=7.8Hz), 5.99 (br s, 1H), 4.03 (br m, 2H, J=2.7Hz), 3.59 (t, 2H, J=5.7Hz), 2.46 (m, 2H), 2.16 (s, 3H), 1.49 (s, 9H).
N1-[3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals) phenyl] acetamide
4M HCl De diox (10mL) solution is added 4-[3-(acetyl-amino) phenyl]-1,2,3, in dichloromethane (30mL) solution of 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester (8.25mmol).Stir described reactant mixture under the room temperature and spend the night, vacuum concentration obtains the required product (2.1g) into hydrochlorate.
1H?NMR(CDCl 3)δ7.41-7.00(m，4H)，6.10(br，1H)，3.55(m，2H)，3.16(t，2H，J＝5.7Hz)，2.44(m，2H)，2.19(s，3H)。
N-(3-bromopropyl) t-butyl carbamate
In the presence of alkali, in dichloromethane by 3-propantheline bromide hydrobromide and BOC 2O prepares titled reference compound (9.89mmol).
1H NMR (CDCl 3) δ 5.07 (br, 1H), 3.31 (t, 2H, J=6.6Hz), 3.12 (tangible br q, 2H, J=6.0Hz), 1.92 (p, 2H, J=6.6Hz), 1.30 (s, 9H).
N-(3-{4-[3-(acetylamino) phenyl]-1,2,3,6-tetrahydrochysene-1-pyridine radicals } propyl group) t-butyl carbamate
With N1-[3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals) phenyl] acetamide hydrochloride (8.24mmol), N-(3-bromopropyl) t-butyl carbamate and the solution of potassium carbonate (33mmol) in no Shui diox (30mL) heated overnight under reflux temperature.The solids removed by filtration thing with solution for vacuum concentration, with the product chromatography purification, obtains required product (110mg).
1H NMR (CDCl 3) δ 7.65 (s, 1H), 6.98 (s, 1H), 7.45 (d, 1H, J=7.8Hz), 7.16 (tangible t, 1H, J=7.8Hz), 7.10 (d, 1H, J=7.8Hz), 6.02 (s, 1H), 5.23 (b, 1H), 3.40 (b, 2H), 3.30-1.80 (m, 10H), 2.18 (s, 3H), 1.45 (s, 9H).
N1-{3-[1-(3-aminopropyl)-1,2,3,6-tetrahydrochysene-4-pyridine radicals] phenyl } acetamide
With TFA: dichloromethane (1: 1, solution 5mL) add N-(3-{4-[3-(acetylamino) phenyl]-1,2,3,6-tetrahydrochysene-1-pyridine radicals } propyl group) in dichloromethane (5mL) solution of t-butyl carbamate.Stirred gained solution 1-3 days under the room temperature, add saturated sodium bicarbonate until pH＞6.Isolate organic layer, vacuum drying obtains required product (45mg).
1H NMR (CDCl 3) δ 7.68 (br, 1H), 7.35 (dm, 1H, J=7.8Hz), 7.25 (tangible t, 1H, J=7.8Hz), 7.15 (dm, 1H, J=7.8Hz), 6.12 (m, 1H), 3.22 (m, 2H), 3.03 (t, 2H, J=7.3Hz), 2.78 (t, 2H, J=5.5Hz), and 2.70-2.50 (m, 4H), 2.10 (s, 3H), 1.87 (p, 2H, J=7.3Hz).
4-[3-(acetylamino) phenyl]-the 1-piperidine acid tert-butyl ester:
Under the room temperature with 4-[3-(acetylamino) phenyl]-1,2,3, EtOH (10mL) the solution hydrogenation (balloon technology) of 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester (710mg) and 5%Pd/C (100mg) is spent the night.Reactant mixture by Celite 545 filter beds and Celite filter bed, is used washing with alcohol.The alcohol extraction liquid that merges is concentrated and chromatography purification, obtain required product (660mg).
1H?NMR(CDCl 3)δ7.80(s，1H)，7.41-7.20(m，3H)，6.94(d，1.H，J＝7.5Hz)，4.21(m，2H)，2.75(m，2H)，2.62(m，1H)，2.16(s，3H)，1.78(m，2H)，1.56(m，2H)，1.48(s，9H)。
N1-[3-(4-piperidyl) phenyl] acetamide:
With hydrogen chloride De dioxane solution (4N 5mL) adds 4-[3-(acetylamino) phenyl]-anhydrous methylene chloride (15mL) solution of 1-piperidine acid tert-butyl ester (660mg) in.Spend the night and vacuum concentration stirring under the reactant mixture room temperature, obtain required product (550mg)
mp?102-104℃； 1H?NMR(CDCl 3)δ2.02(d，J＝13.2Hz，2H)，2.11-2.45(m，5H)，2.67-2.77(m，1H)，3.00-3.10(m，2H)，3.51(d，J＝10.5Hz，2H)，6.94(d，J＝7.5Hz，1H)，7.20-7.46(m，3H)，7.60(s，1H)；
To C 13H 19N 2The value of calculation of OCl+0.86 dichloromethane: C, 50.78; H, 6.37; N, 8.55;
Measured value: C, 50.80; H, 7.55; N, 7.01.
N-(3-{4-[3-(acetylamino) phenyl] piperidino } propyl group) t-butyl carbamate:
With N1-[3-(4-piperidyl) phenyl] acetamide (550mg, 0.210mmol), N-(3-bromopropyl) t-butyl carbamate (550mg, 0.230mmol), K 2CO 3(1.10g, 0.890mmol), the solution in diisopropylethylamine (1.50mL) and a small amount of KI crystal Zai diox (20mL) heated 2 days under reflux temperature.Remove by filter sedimentary salt, vacuum concentration and, obtain required product (340mg) the crude product chromatography purification.
1H?NMR(CDCl 3)δ8.15(s，1H)，7.47-7.44(m，2H)，7.22(t，1H，J＝7.8Hz)，6.94(d，1H，J＝7.8Hz)，5.53(b，1H)，3.23(b，6H)，2.80-1.60(m，9H)，2.20(s，3H)，1.45(s，9H)。
N1-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide
TFA (1.0mL) is added in anhydrous methylene chloride (10mL) solution of N-(3-{4-[3-(acetylamino) phenyl] piperidino } propyl group) t-butyl carbamate (340mg) and at room temperature stirred 5 hours.In the gained reactant mixture, add 10% potassium hydroxide aqueous solution,, remove dichloromethane with final vacuum up to pH＞6.Freezing and lyophilization obtains solids with water layer, uses methanol extraction.Removing desolvates obtains required product (120mg), is grease.
1H NMR (CDCl 3) δ 7.23-7.16 (tangible t, 1H, J=7.5Hz), 6.95-6.92 (m, 1H), 3.03-2.99 (m, 2H), 2.77-2.73 (t, 2H, J=6.6Hz), 2.50-1.60 (m, 10H), 2.13 (s, 3H).
4-(3-nitrobenzophenone)-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
According to synthetic 4-[3-(amino) phenyl]-1; 2; 3; the method of 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester; by 2M aqueous sodium carbonate (2.2mL), 4-{[(trifluoromethyl) sulfonyl] the oxygen base }-1; 2; 3; 6-tetrahydrochysene-1-pyridine-t-butyl formate (0.500g; 1.51mmol), 3-nitrobenzophenone boric acid (0.353g; 2.11mmol), lithium chloride (0.191g, 4.50mmol) and four (triphenylphosphines) close palladium (O) (0.080g, 0.075mmol) mixture in dimethoxy-ethane (5mL) obtain the required product of 0.380g.
1H?NMR(400MHz，CDCl 3)δ8.23(s，1H)，8.11(d，1H，J＝8.0Hz)，7.69(d，1H，J＝8.0Hz)，7.51(t，1H，J＝8.0Hz)，6.20(m，1H)，4.17-4.08(m，2H)，3.67(t，2H，J＝5.6Hz)，2.61-2.52(m，2H)，1.50(s，9H)；?ESMS?m/e：249.1(M+H-C 4H 8) +。
1,2,3,6-tetrahydrochysene-4-(3-nitrobenzophenone) pyridine
Under 0 ℃, toward the 5.00g (16.0mmol) 1,2,3 that is stirring, 6-tetrahydrochysene-4-(3-nitrobenzophenone) pyridine-1-t-butyl formate fed the hydrogen chloride gas bubbling 10 minutes at 100ml 1 in the solution in the 4-diox.Make reactant mixture be warming up to room temperature, continue to use hydrogen chloride gas bubbling 1 hour.Solvent removed in vacuo is dissolved in residue in the 50mL water, and adds the neutralization of KOH granule.Aqueous solution is with 3 * 80mL dichloromethane extraction.With the organic extract liquid drying (magnesium sulfate) that merges, filter and vacuum concentration.Residue is through column chromatography purification (silica gel, 9: 1 dichloromethane: methanol+1% 2-aminopropane .), obtain the required product of 2.85g (yield 87.5%).
1H NMR (400MHz, CDCl 3) δ 8.24 (s, 1H), 8.09 (d, 1H, J=8.4Hz), 7.71 (d, 1H, J=8.0Hz), 7.49 (t, 1H, J=8.0Hz), 6.35-6.25 (m, 1H), 3.58 (tangible q, 2H, J=3.0Hz), 3.14 (t, 2H, J=5.6Hz), 2.54-2.46 (m, 2H).
3-(4-(3-nitrobenzophenone)-3,6-dihydro-1 (2H)-pyridine radicals) the propyl carbamic acid tert-butyl ester
With 2.80g (14.0mmol) 1,2,3,6-tetrahydrochysene-4-(3-nitrobenzophenone) pyridine, 3.60g (15.0mmol) N-(3-bromopropyl) t-butyl carbamate, 11.6g (84.0mmol) potassium carbonate, 14.6mL (84.0mmol) diisopropylethylamine and 0.78g (2.00mmol) tetrabutylammonium iodide are at 250mL 1, and the mixture in the 4-diox heated 14 hours under reflux temperature.Filter reaction mixture and dried filtrate (magnesium sulfate), vacuum concentration, residue is through column chromatography purification (silica gel, 9: 1, dichloromethane: methanol+1% 2-aminopropane .) obtain the required product of 4.35g (yield 85.7%).
1HNMR (400MHz, CDCl 3) δ 8.24 (t, 1H, J=1.9Hz), 8.09 (dd, 1H, J=1.9,8.0Hz), 7.70 (tangible d, 1H, J=8.0Hz), 7.49 (t, 1H, J=8.0Hz), 6.23 (m, 1H), and 3.29-3.18 (m, 4H), 2.75 (t, 2H, J=5.6Hz), 2.64-2.54 (m, 4H), 1.82-1.70 (m, 2H), 1.44 (s, 9H); ESMS m/e:362.2 (M+H) +
3-(4-(3-nitrobenzophenone)-3,6-dihydro-1 (2H)-pyridine radicals)-1-propylamine
Under 0 ℃, at 100ml 1, fed the hydrogen chloride gas bubbling 10 minutes in the solution in the 4-diox toward 4.35 (12.0mmol) 3-(4-(3-nitrobenzophenone)-3,6-dihydro-1 (2H)-pyridine radicals) the propyl carbamic acid tert-butyl ester that is stirring.Make reactant mixture be warming up to room temperature and continued bubbling 1 hour.Solvent removed in vacuo is dissolved in residue in the 50mL water, adds the neutralization of KOH granule.Aqueous solution is with 3 * 80mL dichloromethane extraction, with organic extract liquid drying (magnesium sulfate), filtration and the vacuum concentration that merges.Residue is through column chromatography purification (silica gel, 9: 1 dichloromethane: methanol+1% 2-aminopropane .) obtain the required product of 3.05g (yield 97.0%).
1H?NMR(400MHz，CDCl 3)δ8.24(t，1H，J＝1.8Hz)，8.09(dd，1H，J＝1.8，8.2Hz)，7.69(dd，1H，J＝1.8，8.2Hz)，7.48(t，1H，J＝8.2Hz)，6.24(m，1H)，3.21(d，2H，J＝3.6Hz)，2.84(t，2H，J＝6.6Hz)，2.75(t，2H，J＝5.8Hz)，2.64-2.54(m，4H)，1.76(m，2H)；ESMS?m/e：262.2(M+H) +；
To C 14H 19N 3O 2(0.06 CHCl 3) value of calculation: C, 62.90; H, 7.16; N, 15.65;
Measured value: C, 63.20; H, 7.16; N, 15.65.
(4S)-and 3-[({3-[4-(3-aminophenyl)-piperidino] propyl group } amino) carbonyl]-4-(3, the 4-difluorophenyl)-6-(methoxy)-2-oxo-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid methyl ester
Under the room temperature, with 3.02g (6.33mmol) (6S)-6-(3, the 4-difluorophenyl)-4-(methoxy)-2-oxo-3,6-dihydro-1,5 (2H)-pyrimidine dioctyl phthalate 5-methyl ester 1-(4-nitrobenzophenone) esters, 1.50g (5.80mmol) 3-(4-(3-nitrobenzophenone)-3,6-dihydro-1 (2H)-pyridine radicals)-1-propylamine, 7.94g (75.5mmol) potassium carbonate and the 1.00mL methanol mixture in 200mL dichloromethane (argon gas atmosphere) stirred 1 hour.Reactant mixture is filtered and vacuum concentration.With residue be dissolved in the 100mL ethyl acetate and with 5% aqueous sodium hydroxide washes wash (3 * 50mL), with organic layer drying (magnesium sulfate) and vacuum concentration.Residue is dissolved in the dehydrated alcohol that 100mL contains 0.50g10%Pd/C, and reactant mixture was stirred 24 hours under hydrogen air bag air feed.Reactant mixture is filtered by Celite 545 posts, use washing with alcohol, filtrate drying (magnesium sulfate) and vacuum concentration.Through column chromatography purification residue (silica gel, 9.5: 0.5, dichloromethane: methanol+1% 2-aminopropane .) obtain the required product of 1.65g (yield 52.0%).
1H?NMR(400MHz，CDCl 3)δ7.80(s，1H)，7.22-7.02(m，2H)，6.95(t，J＝8.70Hz，1H)，6.63-6.44(m，4H)，4.56(Abq，2H)，3.62(s，3H)，3.33(s，3H)，3.32-3.20(m，4H)，2.96(br?s，2H)，2.33(t，J＝7.50Hz，2H)，2.11-1.94(m，3H)，1.81-1.64(m，4H)；ESMS?m/e：572.3(M+H) +；
4-[3-(isobutyryl amino) phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
Toward 4.00g (16.0mmol) 4-(3-aminophenyl)-3, slowly add 1.90mL (19.0mmol) isobutyryl chloride in 6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester and the solution of 5.60mL (32.0mmol) diisopropylethylamine in the 100mL dichloromethane.Reactant mixture was at room temperature stirred 2 hours, wash with water, dry (magnesium sulfate) and vacuum concentration.Residue is through column chromatography purification (silica gel, 50: 46: 3: 1 hexane: dichloromethane: methanol: 2-aminopropane .), obtain the required product of 2.90g (yield 52.0%).
1HNMR (400MHz, CDCl 3) δ 7.69 (s, 1H), 7.34 (d, 1H, J=7.8Hz), 7.27 (t, 1H, J=7.8Hz), 7.11 (d, 1H, J=7.8Hz), 6.04 (s, 1H), 4.05 (s, 2H), 3.62 (tangible t, 2H, J=4.9Hz), 2.51 (m, 3H), 1.49 (s, 9H), 1.25 (d, 6H, J=7.4Hz); ESMS m/e:345.5 (M+H) +
To C 20H 28N 2O 3+ 0.175CHCl 3Value of calculation: C, 66.33; H, 7.77; N, 7.67;
Measured value: C, 66.20; H, 7.41; N, 7.88.
4-[3-(isobutyryl amino) phenyl]-the 1-piperidine acid tert-butyl ester
With 2.90g (8.40mmol) 4-[3-(isobutyryl amino) phenyl]-3, the mixture of Pd/C in 100mL ethanol of 6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester and 0.80g 10% yield stirred 24 hours under hydrogen air bag air feed.Reactant mixture is filtered by Celite 545 posts, with filtrate drying (magnesium sulfate) and vacuum concentration.Residue is through column chromatography purification (silica gel, 9.5: 0.5, dichloromethane: methanol+1% 2-aminopropane .), obtain the required product of 2.40g (yield 84.0%).
1H?NMR(400MHz，CDCl 3)δ7.49-7.44(m，2H)，7.24(t，1H，J＝7.6Hz)，6.93(d，1H，J＝7.6Hz)，4.20-4.10(m，2H)，2.86-2.45(m，4H)，1.86-1.75(m，4H)，1.48(s，9H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e：345.2(M+H) +；
To C 20H 30N 2O 3+ 0.3H 2The value of calculation of O: C, 68.27; H, 8.77; N, 7.96;
Measured value: C, 68.25; H, 8.54; N, 7.84.
2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide.
Under 0 ℃, toward 2.20 (6.50mmol) 4-[3-(isobutyryl amino) phenyl that is stirring]-the 1-piperidine acid tert-butyl ester is at 100mL 1, and feeding hydrogen chloride gas bubbling is 10 minutes in the solution in the 4-diox.Reactant mixture is warming up to room temperature and continued to feed HCl gas bubbling 1 hour.Solvent removed in vacuo is dissolved in residue in the 50mL water, adds the neutralization of KOH granule.Aqueous solution is with 3 * 80mL dichloromethane extraction, with organic extract liquid drying (magnesium sulfate), filtration and the vacuum concentration that merges.Residue is through column chromatography purification (silica gel, 9: 1 dichloromethane: methanol+1% 2-aminopropane .), obtain the required product of 0.700g (yield 46.0%).
1H NMR (400MHz, CDCl 3) δ 7.47 (s, 1H), 7.40 (d, 1H, J=7.8Hz), 7.24 (t, 1H, J=7.8Hz), 7.00 (d, 1H, J=7.8Hz), 3.23-3.14 (m, 5H), 2.82-2.57 (m, 4H), 1.20 (d, 6H, J=6.8Hz); ESMS m/e:247.2 (M+H) +The gained hydrochlorate is carried out combustion analysis.
To C 15H 22N 2O+HCl+0.15 CHCl 3Value of calculation: C, 60.51; H, 7.76; N, 9.32;
Measured value: C, 60.57; H, 7.83; N, 8.88.
3-(4-piperidyl) aniline
4M HCl De diox (25mL) solution is added 4-[3-(amino) phenyl]-(2.60g is in dichloromethane 9.00mmol) (250mL) solution for the 1-piperidine acid tert-butyl ester.Reactant mixture at room temperature stirred spend the night, vacuum concentration and residue water-soluble (50mL).Mixture is neutralized with the KOH granule, and (3 * 50mL) extract with dichloromethane.With the organic extract liquid drying (magnesium sulfate) that merges, concentrated and chromatography purification, obtain required product (1.03g).
1H?NMR(400MHz，CDCl 3)δ7.01(t，1H，J＝7.6Hz)，6.62-6.54(m，3H)，3.16(br?d，2H，J＝10.3Hz)，2.75(dt，2H，J＝2.7，12.3Hz)，2.56(tt，1H，J＝3.6，12.3Hz)，1.81(br?d，2H，J＝12.3Hz)，1.65(dq，2H，J＝4.0，12.3Hz)；ESMS?m/e：177.2(M+H) +。
4-(4-nitrobenzophenone)-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
The 4-{[(trifluoromethyl of packing in the 25-mL round-bottomed flask that is equipped with condenser) sulfonyl] the oxygen base }-3,6-dihydro-1 (2H) the pyridine carboxylic acid tert-butyl ester (1.0g), 4-nitrobenzophenone boric acid (0.71g), sodium carbonate (0.430mL 2M solution), lithium chloride (0.382g), four (triphenylphosphines) close palladium (O) (0.173g) and glycol dimethyl ether (10mL).With argon purge reactant mixture 3 times, reacting by heating mixture to 100 ℃ continues 3 hours subsequently.After being chilled to room temperature, reactant mixture with dichloromethane (30mL) and water (30mL) dilution, is isolated organic layer.The water layer dichloromethane extraction (3 * 20mL), the organic extract liquid that merges is washed with saturated ammonium chloride (20mL) and saline (20mL), with dried over mgso and concentrating under reduced pressure.Residue is through chromatography purification (6: the 1=hexane: ethyl acetate, 1%NH 3), obtain product (0.55g, 59.9%), be yellow oil.Described chemical compound is at room temperature unstable, should in time use after the preparation.
1H NMR (400MHz, CDCl 3) δ 8.20 (d, 2H, J=8.6Hz), 7.51 (d, 2H, J=8.6Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (tangible t, 2H, J=5.5Hz), 2.55 (m, 2H), 1.49 (s, 9H).
4-(4-nitrobenzophenone)-1,2,3, the 6-tetrahydropyridine
According to preparation 2-methyl-N-[3-(4-piperidyl) phenyl] method like the Propionamides, under the room temperature, use hydrogen chloride gas and 4-(4-nitrobenzophenone)-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester (130mg) De diox (5.0mL) formulations prepared from solutions 4-(4-nitrobenzophenone)-1,2,3, the 6-tetrahydropyridine.With the reactant mixture vacuum concentration, obtain crude product (69.8mg), this product is not purified to be directly used in next reactions steps.
The oxazolidone intermediate:
Amino-(3, the 4-difluorophenyl)-acetonitrile
Under the room temperature, in the round-bottomed flask 3, the 4-difluorobenzaldehyde (fed the ammonia bubbling 2 hours among the 25.0g, MeOH solution (500mL) 0.176mol).Flask is chilled to 0 ℃ subsequently, slowly adds the cyaniding trimethyl silyl.Stirred reaction mixture 2 hours, TLC the analysis showed that and reacted completely (Rf=0.35,3: 2 hexanes/EtOAc) this moment.Solvent removed in vacuo, residue obtains required product through silica gel rapid column chromatography purification, and product is not purified to be directly used in the next step.
Amino-(3, the 4-difluorophenyl)-methyl acetate
Under the room temperature, toward well-beaten amino-(3, the 4-difluorophenyl)-acetonitrile (22.0g, 0.130mol) MeOH (200mL) solution of adding HCl in the solution.The yellow solution of gained was at room temperature stirred 10 hours, and heating is 1.5 hours under reflux temperature.After the cooling, solvent removed in vacuo is in gained yellow solid water-soluble (200mL).With 20%NaOH solution aqueous solution is carefully alkalized to pH9 subsequently.(3 * 100mL) extract water layer with dichloromethane.Isolate organic layer and with dried over sodium sulfate, filtration and solvent removed in vacuo, obtain required product, product is not purified to be directly used in the next step.
2-amino-2-(3, the 4-difluorophenyl)-ethanol
Under 0 ℃, toward the well-beaten LiAlH that is loaded in the 3 neck round-bottomed flasks (being equipped with condenser and Dropping funnel) 4(4.7g is added dropwise to amino-(3, the 4-difluorophenyl)-methyl acetate (10.0g, THF 0.05mol) (100mL) solution in THF 0.125mol) (120mL) suspension.The brown-green suspension of gained was heated 2 hours under reflux temperature.Reactant mixture is chilled to 0 ℃, uses 5mL water, 5mL 3N NaOH and the quencher carefully of 15mL water subsequently successively.The suspension of gained is filtered through the cellular glass funnel.On filter cake, add 100mL Et 2O, and suspension heated 20 minutes under reflux temperature.Filtering suspension liquid and with the filtrate that merges with dried over mgso, filter and solvent removed in vacuo.Obtain the melicera 2-amino-2-of yellow glass (3, the 4-difluorophenyl)-ethanol product, be directly used in the next step without being further purified.
[1-(3, the 4-difluorophenyl)-2-hydroxyl-ethyl]-t-butyl carbamate
Under 0 ℃, toward 2-amino-2-(3,4 difluorophenyl)-ethanol (8.6g, disposable adding Bis(tert-butoxycarbonyl)oxide (11.4g in chloroform 49.7mmol) (150mL) solution, 52.0mmol) chloroform (50mL) solution, the solution that stirs gained under the room temperature spends the night.Solvent removed in vacuo, residue obtains [1-(3, the 4-difluorophenyl)-2-hydroxyl-ethyl]-carbamic acid-tert-butyl ester through purification by silica gel column chromatography (2: 1 hexane-EtOAc then are EtOAc), is white solid thing (10.0g, 74% yield).
(+)-4-(3, the 4-difluorophenyl)-oxazolidines-2-ketone
Under the room temperature, (add [1-(3, the 5-difluorophenyl)-2-hydroxyl-ethyl]-t-butyl carbamate (5.0g, THF 18.3mmol) (20mL) solution among the 1.1g, THF suspension (40mL) 45.8mmol) toward well-beaten NaH by Dropping funnel.Stir the suspension 3h of gained, then careful with the quencher of 10mL water.With biphase mixture 100mL Et 2The salt water washing is used in the O extraction, filters and solvent removed in vacuo.With the gumminess residue that obtains thus through purification by silica gel column chromatography (R f=0.15,3: 2 hexanes: EtOAc), obtain 4-(3, the 5-difluorophenyl)-oxazolidines-2-ketone, be white flakes solids (2.8g, yield 77%).
M.P.81-83℃； 1H?NMR(300MHz，CDCl 3)δ7.23-7.03(m，3H)，-6.08.(brs，1H)，4.94(dd，J＝6.6Hz，J＝8.7Hz，1H)，4.73(t，J＝8.7Hz，1H)，4.13(dd，J＝6.6Hz，J＝8.7Hz，1H)。
Adopt HPLC (with the separating obtained enantiomer of Chiralcel OD (20 * 250mm) posts are eluent system with 80% hexane/20% isopropyl alcohol, speed 12.0mL/min (U.V.254nm)).The retention time of two kinds of isomers is respectively 16.19min and 20.08min.
(4S)-and 4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester
In the argon gas atmosphere, (0.14g 5.30mmol) is added dropwise to (+)-4-(3, the 4-difluorophenyl)-oxazolidines-2-ketone (0.88g, THF solution 4.42mmol) (adding through Dropping funnel) in the suspension in the anhydrous THF of 20mL toward NaH.The suspension of gained was at room temperature stirred 30 minutes.With after intubate is added to another with described hanging drop chloro-carbonic acid 4-nitro phenyl ester is housed (1.11g is 5.30mmol) in the round-bottomed flask of the solution in 25mL THF ,-78 ℃ of down coolings 15 minutes.Continue to stir 2h, remove subsequently and desolvate, residue with 1: 1 hexanes/ch, is followed dichloromethane (R through purification by silica gel column chromatography f=0.4, dichloromethane) be eluent, obtain required product, be white solid thing (1.55g, 86% yield).
Equally, according to the method described above, in first step, adopt 3 respectively, 5-difluorobenzaldehyde or 3,4, the 5-trifluro benzaldehyde replaces 3, the 4-difluorobenzaldehyde, obtain 4-(3, the 5-difluorophenyl)-2-oxo-oxazolidines-3-formic acid-4-nitro-phenyl ester and 4-(3,4, the 5-trifluorophenyl)-2-oxo-oxazolidines-3-formic acid-4-nitro-phenyl ester.Adopt HPLC (with Chiralcel OD post (as described in the previous embodiment)) Chai Fen oxazolidone enantiomer.Carbamic acid 4-nitro phenyl ester is made by chloro-carbonic acid 4-nitro phenyl ester.
(4S)-and 4-(3, the 5-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester
According to the method for synthetic 4-(3, the 4-difluorophenyl)-2-oxo-oxazolidines-3-formic acid-4-nitro-phenyl ester, by 3, the 5-difluorobenzaldehyde obtains required product.
1H?NMR(400MHz，CDCl 3)δ8.26(d，2H，J＝9.3Hz)，7.33-6.81(m，5H)，5.41(dd，1H，J＝4.1，8.7Hz)，4.81(t，1H，J＝9.3Hz)，4.33(dd，1H，J＝4.1，9.3Hz)；
To C 16H 10F 2N 2O 6The value of calculation of+0.2EtOAc: C, 52.84; H, 3.06; N, 7.34;
Measured value: C, 53.26; H, 2.83; N, 7.73
(4S)-and 2-oxo-4-(3,4, the 5-trifluorophenyl)-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester
According to the method for synthetic 4-(3, the 4-difluorophenyl)-2-oxo-oxazolidines-3-formic acid-4-nitro-phenyl ester, by 3,4, the 5-trifluro benzaldehyde obtains required product.
1H NMR (400MHz, CDCl 3) δ 8.27 (d, 2H, J=9.0Hz), 7.31 (d, 2H, J=9.0Hz), 7.11-7.02 (m, 2H), 5.37 (dd, 1H, J=4.1,9.0Hz), 4.81 (tangible t, 1H, J=9.0Hz), 4.33 (dd, 1H, J=4.1,9.0Hz);
To C 16H 9F 3N 2O 6Value of calculation: C, 50.27; H, 2.37; N, 7.33;
Measured value: C, 50.56; H, 2.50; N, 7.49.
1-(3, the 4-difluorophenyl)-2-methyl-2-hydroxyl propylamine
Under 0 ℃, (10.5g added methyl-magnesium-bromide (3M, 87mL, diethyl ether solution 261mmol) in absolute ether 52.19mmol) (200mL) solution toward well-beaten 2-amino-2-(3, the 4-difluorophenyl) methyl acetate with 10 minutes.0 ℃ of following stirred reaction mixture 2.5h is warming up to room temperature simultaneously.After 12 hours, carefully reactant mixture is poured in the mixture of ice (300g) and saturated aqueous ammonium chloride (50g).Isolate the ether layer, the more extracted with diethyl ether (4 * 200mL) of water layer.With the extract that merges with dried over mgso and evaporating solvent.Crude product is through purification by silica gel column chromatography, methanol solution (1000: 20: 10,1000: 40: 20,1000: 80: 40) with chloroform/methanol/2M ammonia is an eluent, obtain oily product (6.5g, yield 62%), product is directly used in the next step without being further purified.
4-(3, the 4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidines
With 1-(3, the 4-difluorophenyl)-2-methyl-2-hydroxyl propylamine (3.00g, 14.9mmol) and carbonyl dimidazoles (2.418g, 14.9mmol) mixture in dichloromethane (150mL) heated 36 hours under reflux temperature, evaporating solvent.Residue is eluent through purification by silica gel column chromatography with chloroform/ethyl acetate (9: 1), obtains thickness oily product (1.80g, productive rate 50%), and this product solidifies when placing.Product is not purified to be directly used in the next step.
4-(3, the 4-difluorophenyl)-5,5-dimethyl-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester
Under 0 ℃, toward the sodium hydride that is stirring (60% suspension in the paraffin, 203mg, 1.4 equivalent) add 4-(3, the 4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine (870mg in the suspension in THF (20mL), 3.622mmol) THF (5mL) solution, then stirred 30 minutes.-78 ℃ down and in the argon gas atmosphere, with this suspension add chloro-carbonic acid 4-nitro phenyl ester (950mg in THF 4.71mmol) (20mL) solution, continues to stir 2 hours, slowly is warming up to room temperature, after 4 hours, evaporating solvent.Residue is mixed with dichloromethane (150mL), and the washing of usefulness 0.05N sodium hydroxide (3 * 10mL), dry (sodium sulfate).Evaporating solvent and with residue through purification by silica gel column chromatography, be eluent with chloroform/ethyl acetate (9: 1), obtain white powder product (860mg, yield 59%).
1H?NMR(400MHz，CDCl 3)δ8.24(d，2H，J＝9Hz)，7.29-6.97(m，5H)，5.04(s，1H)，1.09(s，6H)；
To C 18H 14F 2N 2O 6+ 0.2%H 2The value of calculation of O: C, 54.61; H, 3.76; N, 7.08;
Measured value: C, 54.89; H, 3.59; N, 7.41.
(3, the 4-difluorophenyl)-N-(diphenyl methylene) methylamine
Toward 3, and 4-difluoro benzene methanamine (9.8g, 69mmol) and benzophenone (13.0g, 71.0mmol) BF of adding catalytic amount in the solution in toluene (200mL) 3OEt 2, gained solution was heated 12 hours under reflux temperature.The vacuum concentration reactant mixture obtains grease (21g,＞95%), and product is through the NMR analysis and characterization, not purifiedly is used for next step reaction. 1HNMR(CDCl 3)δ4.57(s，2H)，7.80-6.80(m，13H)。
1-(3, the 4-difluorophenyl)-1-[(diphenyl methylene) amino] propan-2-ol
(21g, (1.7M 60ml), stirs 0.5h with the solution of gained down at-78 ℃ to be added dropwise to tert-butyl lithium in 250mL anhydrous THF solution 69mmol) toward diphenyl methylene-(3,4-two fluoro-benzyls)-amine.(10ml, 100mL THF solution 180mmol), and gained solution stirred 2 hours down at-78 ℃ stirred 1 hour down at 25 ℃ to add acetaldehyde in the described solution.Add saline quencher reactant mixture.Reactant mixture is used the dilution of 500mL ether and used the salt water washing.With dried over sodium sulfate organic layer and vacuum concentration, obtain grease, product is directly used in the next step without being further purified. 1H NMR (CDCl 3) δ 1.04 (d, 3H), 2.77 (wide singlet, 1H), 4.08 (m, 1H), 4.15 (d, 1H), 7.80-6.80 (m, 13H).
1-amino-1-(3,4-two fluoro-phenyl)-propan-2-ol
The solution and the MeONH of the crude product that obtains with 200mL MeOH dilution said method 2(10g, solution 120mmol) also stirred 12 hours HCl.The vacuum concentration reactant mixture obtains the oily residue, once more this residue is dissolved among the 200mL EtOAc, uses the salt water washing.The vacuum concentration organic layer obtains oily mixture, with this mixture through column chromatography purification [5%NH 3The chloroform soln of (the MeOH solution of 2.0M)], obtain the non-enantiomer mixture of required product (with 3,4-difluoro benzene methanamine calculates for 8.8g, yield 68%).
1H NMR (CDCl 3) (mixture of～4: 1 diastereomer) δ 1.02 (d, J=6.0Hz, 3H), 1.04 (d, J=6.3Hz, 3H), 2.10 (br, 6H), 3.56-3.69 (m, 2H), 3.88-3.92 (m, 2H), 7.02-7.17 (m, 6H).
[1-(3, the 4-difluorophenyl)-2-hydroxyl-propyl group]-t-butyl carbamate
Under 0 ℃, toward 1-amino-1-(3, the 4-difluorophenyl)-propan-2-ol (13.1g, disposable adding Bis(tert-butoxycarbonyl)oxide (19.3g, CHCl 87.6mmol) in chloroform 70.1mmol) (150mL) solution 3(50mL) solution at room temperature stirs the solution of gained and to spend the night.Solvent removed in vacuo, residue obtains buttery [1-(3, the 4-the difluorophenyl)-2-hydroxyl-propyl group]-carbamic acid-tert-butyl ester of thickness (18.4g, yield 91%) through purification by silica gel column chromatography (2: 1 hexane-EtOAc then are EtOAc). 1H NMR (CDCl 3) (mixture of～4: 1 diastereomer) δ 1.05 (d, J=6.6Hz, 3H), 1.25 (d, J=6.0Hz, 3H), 1.41 (br, 20H), 3.92-4.19 (br, 2H), 4.45-4.60 (m, 2H), 5.41-5.49 (br, 2H), 7.02-7.17 (m, 6H).
4-(3, the 4-difluorophenyl)-5-methyl-oxazolidines-2-ketone
Under the room temperature, toward [1-(3, the 4-difluorophenyl)-2-hydroxyl-propyl group]-carbamic acid-tert-butyl ester of fully stirring (0.43g, add in THF 1.5mmol) (20mL) solution 95%NaH (0.09g, 3.8mmol).When reacting with fairly large carrying out (＞5g), use 1.0 equivalent KH and 1.5 equivalent NaH as alkali.The suspension of gained was stirred 3 hours down in about 35 ℃ (tepidariums), careful subsequently with the ice quencher.Biphase mixture with 100mL EtOAc extraction, is used the salt water washing, use dried over sodium sulfate, filter and solvent removed in vacuo.Separate two kinds of diastereomers (first kind of isomer: 0.16g, R through silica gel column chromatography f=0.6,3: 1 hexane-EtOAc; Second kind of isomer: 0.18g, R f=0.5,3: 1 hexanes-EtOAc).First kind of diastereomer of NOE test shows contains the methyl and the aryl of anti-configuration, and these two kinds of groups are cis-configuration in second kind of diastereomer.Trans diastereomer 1H NMR wave spectrum is as follows:
1H?NMR(CDCl 3)δ1.49(d，J＝6.0Hz，3H)，4.37(dq，J＝6.0Hz，J＝7.2Hz，1H)，4.45(d，J＝7.2Hz，1H)，6.63(br?s，1H)，7.08-7.28(m，3H)。
The cis diastereomer 1H NMR wave spectrum is as follows:
1H?NMR(CDCl 3)δ0.96(d，J＝6.6Hz，3H)，4.91(d，J＝8.1Hz，1H)，4.99(dq，J＝6.6Hz，J＝8.1Hz，1H)，6.63(br?s，1H)，?7.08-7.28(m，3H)。
4-(3, the 4-difluorophenyl)-5-methyl-2-oxo-oxazolidines-3-formic acid-4-nitro-phenyl ester
Under argon gas atmosphere reaches-78 ℃, through the past 4-(3, the 4-difluorophenyl) of syringe-5-methyl-oxazolidines-2-ketone (0.97g, hexane (3.06mmol, 4.9mmol) solution of dropping n-BuLi in THF 4.55mmol) (60mL) solution.The yellow solution of gained was stirred 40 minutes down at-78 ℃.Use 15 minutes subsequently, this solution is dropped to another through intubate the chloro-carbonic acid 4-nitro phenyl ester that is chilled to-78 ℃ is housed (1.03g is in the round-bottomed flask of THF 5.1mmol) (60mL) solution.After 5 minutes, flask is shifted out from cryostat, continue to stir 1 hour.Adding is iced the quencher reactant mixture and is extracted with EtOAc.Also use the dried over sodium sulfate organic layer with salt water washing organic extract liquid.Filter the back and remove and desolvate, residue is through purification by silica gel column chromatography, is eluent with 1: 1 hexanes/ch and dichloromethane successively, obtains required product.
Respectively p-nitrophenyl oxygen base carbonyl derivative is carried out 1H NMR analyzes, to demarcate the relative configuration of cis and transisomer.For transisomer, between the proton of the proton of C-5 methyl and C-4 methyl, observe NOE.But do not observe NOE between the proton of the C-4 of this isomer and C-5 position, therefore specifying this isomer is trans three-dimensional chemical isomer.For cis-isomer, do not observe the NOE between the proton of the proton of C-5 methyl and C-4 methyl.But observe the NOE between the proton of C-4 and C-5 position, so we are labeled as the cis three-dimensional chemical isomer with this isomer.The ortho position coupling constant of the C-4 proton of cis and transisomer is respectively J=7.8Hz and J=5.1Hz, and therefore the data consistent that this is also reported with Lei Si De oxazolidone helps labelling spatial chemistry (Dondoni, A.; Perrone, D.; Semola, T.Synthesis 1995,181).
Adopt HPLC, and usefulness Chiralcel OD post (20 * 250mm), be eluent system (12mL/min) with 80% hexane/20% isopropyl alcohol/0.1% diethylamine, (U.V.254nm) separates each enantiomer in the described diastereomer under the isocratic elution condition.
Absolute configuration for the asymmetric center (stereogenic centers) of Biao Ji oxazolidine ring has designed a kind of new route of synthesis, wherein adopts the enantiomeric pure matrix derived from chiral source (chiral pool).Method according to Martin etc. changes into its pyrrolidine amide (Martin, R. with commodity (S)-(+)-methyl lactate; Pascual, O.; Romea, P.; Rovira, R.; Urpi, F.; Vilarrasa, J.Tetrahedron Lett.1997,38,1633).After the hydroxyl protection of (2S)-1-oxo-1-(1-pyrrolidinyl)-2-propanol is the TBDMS group; with 3; 4-difluorophenyl lithium is handled the tert-butyl group (dimethyl) silicyl (1S)-1-methyl-2-oxo-2-(1-pyrrolidinyl) ethylether; obtain unique product (the 2S)-2-{[tert-butyl group (dimethyl) silicyl] the oxygen base }-1-(3; the 4-difluorophenyl)-1-acetone; subsequently this product is converted into (2S)-2-{[tert-butyl group (dimethyl) silicyl] the oxygen base }-1-(3, the 4-difluorophenyl)-1-acetone oxime.Use LiAlH 4Reduction (2S)-2-{[tert-butyl group (dimethyl) silicyl] the oxygen base }-1-(3, the 4-difluorophenyl)-1-acetone oxime, N-acidylate and induce cyclisation with alkali, De is Dao the oxazolidone diastereomer, and product separates through rapid column chromatography.The enantiomeric purity of these isomers analyze to determine through chirality HPLC, and with they 1The spectral data of HNMR wave spectrum and racemic isomer relatively comes its relative configuration of labelling.The absolute configuration of the C-5 of De oxazolidone is for (S) because above-mentioned lactic acid is derived, and the C-4 center of anti-configuration chemical compound also has (S) configuration, therefore the absolute configuration of the asymmetric center of described cis-configuration chemical compound correspondingly be labeled as (4R, 5S).
(4S, 5R)-4-(3, the 4-difluorophenyl)-5-methyl-2-oxo-1,3-oxazolidine-3-formic acid 4-nitrobenzophenone ester
1H NMR (400MHz, CDCl 3) δ 8.25 (d, 2H, J=8.8Hz), 7.30-6.99 (m, 5H), 5.35 (d, 1H, J=7.7Hz), 5.07 (tangible quintet, 1H), 1.17 (d, 3H, J=6.5Hz);
To C 17H 12F 2N 2O 6+ 0.5H 2The value of calculation of O: C, 52.72; H, 3.38; N, 7.23;
Measured value: C, 53.09; H, 3.19; N, 7.50.
(+)-2-amino-3-(3, the 4-difluoro)-phenyl-third-1-alcohol
Under 0 ℃, with (+)-3, (1.0g is 5.0mmol) with a small amount of LiAlH that is stirring that repeatedly adds for 4-difluorophenyl alanine 4(0.480g is in THF 12.5mmol) (30mL) suspension.Grey suspension with gained heated 2 hours under reflux temperature subsequently.Reactant mixture is cooled to 0 ℃, subsequently water (0.5mL), 3N NaOH (0.5mL) and water (1.50mL) quencher successively carefully.The suspension of gained is filtered through the cellular glass funnel.On filter cake, add ether (50mL), the gained suspension was heated 20 minutes under reflux temperature.Filtering suspension liquid also merges with aforementioned filtrate.With the Organic substance dried over mgso that merges, filter and solvent removed in vacuo, obtain 2-amino-3-(3, the 4-difluoro)-phenyl-third-1-alcohol, be white solid thing (0.500g, 100%).Product is directly used in the next step without being further purified.
(+)-[1-(3, the 4-difluorobenzyl)-2-hydroxyl-ethyl]-carbamic acid-tert-butyl ester
Under 0 ℃, with Bis(tert-butoxycarbonyl)oxide (0.640g, 2.90mmol) chloroform (10mL) the disposable adding of solution (+)-2-amino-3-(3, the 4-difluoro)-phenyl-third-1-alcohol (0.500g, 2.62mmol) chloroform (20mL) solution in, the solution of gained at room temperature stirred spends the night.Solvent removed in vacuo, residue obtains (+)-[1-(3, the 4-difluorobenzyl)-2-hydroxyl-ethyl]-carbamic acid-tert-butyl ester through chromatography purification (2: 1 hexane-EtOAc then are EtOAc), is white solid thing (0.640g, 99%).
(+)-4-(3,4-two fluoro-benzyls)-oxazolidine-2-ketone
Under the room temperature, through Dropping funnel with (+)-[1-(3, the 4-difluorobenzyl)-2-hydroxyl-ethyl]-(1.00g, THF 4.00mmol) (10mL) solution add the 95%NaH that is stirring, and (0.12g is in THF 5.0mmol) (20mL) suspension for carbamic acid-tert-butyl ester.The suspension of gained is stirred 3h, careful subsequently water (10mL) quencher.Biphase mixture is with ether (50mL) extraction, with salt water washing, filtration and solvent removed in vacuo.The plastic cement shape residue of gained is through column chromatography purification (Rf=0.25,3: 2 hexanes-EtOAc), obtain the required product (0.320g, 76%) of white solid.
(+)-4-(3,4-two fluoro-benzyls)-oxazolidine-2-ketone-3-formic acid-4-nitro-phenyl ester
Under argon gas atmosphere, (0.210g, THF 1.0mmol) (10mL) drips of solution adds the NaH that is stirring, and (30.0mg is in anhydrous THF (10mL) suspension 1.30mmol) with (+)-4-(3,4-two fluoro-benzyls)-oxazolidine-2-ketone through Dropping funnel.With the suspension of gained stirring at room 30 minutes.Under-78 ℃, (0.300g is in THF 1.50mmol) (20mL) solution with 15 minutes this suspension to be dropped to chloro-carbonic acid 4-nitro phenyl ester through intubate subsequently.Continue to stir 2 hours, remove subsequently and desolvate, (1: 1 hexanes/ch then is dichloromethane through column chromatography purification with residue; R f=0.4, dichloromethane), obtain the required product (0.350g, 82%) of yellow solid shape.
According to above-mentioned similar approach, to use fluorophenylalanine is replaced (+)-3,4-difluorophenyl alanine obtains 4-(4-luorobenzyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester.4-(4-luorobenzyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester
1H?NMR(400MHz，CDCl 3)δ8.32(d，2H，J＝9.3Hz)，7.42(d，2H，J＝8.9Hz)，7.24-6.99(m，4H)，4.69-4.59(m，1H)，4.35(t，1H，J＝8.6Hz)，4.23(dd，1H，J＝2.7，9.3Hz)，3.37(da，1H，J＝3.8，13.6Hz)，2.94(dd，1H，J＝9.3，13.6Hz)；
To C 17H 13FN 2O 6Value of calculation: C, 56.67; H, 3.64; N, 7.77;
Measured value: C, 56.94; H, 3.76; N, 7.71.
2-[6-(4-phenyl-piperidino) hexyl]-1H-iso-indoles-1,3 (2H)-diketone
Under the room temperature, pack in the 500mL round-bottomed flask 4-Phenylpiperidine hydrochlorate (5g, 25mmol), N-(6-bromine hexyl) phthalimide (15.5g, 50mmol), N, the N-diisopropylethylamine (21.8ml, 125mmol), (0.2g) is with diox (250ml) for tetrabutylammonium iodide.100 ℃ of following stirred reaction mixtures 72 hours.Solvent removed in vacuo, crude product is through flash chromatography purification (98: the 2=chloroform: the methanol solution of 2N ammonia), obtain the required product of 7.67g (yield 77%).
1H NMR (400MHz, CDCl 3) δ 7.78-7.79 (m, 2H), 7.74-7.65 (m, 2H), 7.32-7.14 (m, 5H), 3.69 (t, 2H, J=7.35Hz), 3.06 (d, 2H, J=11.0Hz), 2.49 (quintet, 1H, J=7.6Hz), 2.36 (t, 2H, J=7.6Hz), 2.02 (t, 2H, J=12.5Hz), 1.82 (br s, 4H), 1.69 (t, 2H, J=6.3Hz), 1.54 (br s, 2H), 1.37 (br s, 4H); ESMS m/e:391.3 (M+H) +
To C 25H 30N 2O 2+ H 2The value of calculation of O: C, 76.19; H, 7.77; N, 7.11;
Measured value: C, 76.14; H, 7.38; N, 7.13.
4-[4-(3-aminophenyl)-piperidino that method I. preparation replaces]-universal method of 1-(phenyl)-1-butanone
The phenyl butyl chloride that 4-(3-aminophenyl) piperidines (2.0mmol), 2.4mmol are suitably replaced (as 4-chloro-4 '-the positive butyrophenone of phenoxy group, 4-chloro-3 ', 4 '-dimethyl n butyrophenone, 4-chloro-4 '-the positive butyrophenone of chlorine, the positive butyrophenone of γ-chlorine, 4-chloro-3 ', 4 '-the positive butyrophenone of dimethoxy), 3.0mmol potassium carbonate and the mixture of 10mg 18-hat-6 in 5mL toluene be 110 ℃ of heating 2.5 days down.Concentrated reaction mixture and through silica gel column chromatography purification (dichloromethane solution of 5% methanol) obtains required compound.
4-[4-(3-aminophenyl)-piperidino]-1-(4-Phenoxyphenyl)-1-butanone
Using method I obtains required product (305mg); ESMS m/e:415.4 (M+H) +
4-[4-(3-aminophenyl)-piperidino]-1-(3, the 4-3,5-dimethylphenyl)-1-butanone
Using method I obtains required product (320mg); ESMS m/e:351.3 (M+H) +
4-[4-(3-aminophenyl)-piperidino]-1-(4-chlorphenyl)-1-butanone
Using method I obtains required product (500mg).
To C 21H 25ClN 2O+0.3H 2The value of calculation of O: C, 69.62; H, 7.12; N, 7.73;
Measured value: C, 69.63; H, 7.34; N, 7.60.
ESMS?m/e：357.3(M+H) +。
4-[4-(3-aminophenyl)-piperidino]-1-phenyl-1-butanone
Using method I obtains required product (250mg).
To C 21H 26N 2O+0.2H 2The value of calculation of O: C, 77.36; H, 8.16; N, 8.59;
Measured value: C, 77.55; H, 8.12; N, 8.75.
ESMS?m/e：323.3(M+H) +。
4-[4-(3-aminophenyl)-piperidino]-1-(2, the 4-Dimethoxyphenyl)-1-butanone
Using method I obtains required product (330mg).
To C 23H 30N 2O 3+ 0.5H 2The value of calculation of O: C, 70.56; H, 7.98; N, 7.16;
Measured value: C, 70.69; H, 7.87; N, 6.99.
ESMS?m/e：383.3(M+H) +。
4-[4-(3-aminophenyl)-piperidino that method II. acidylate or sulfonylation replace]-universal method of 1-(4-phenyl)-1-butanone
4-[4-(3-aminophenyl)-piperidino that 1 equivalent is replaced]-1-(4-phenyl)-1-butanone, 1.5 equivalent acyl chlorides or sulfonic acid chloride and the mixture of 5 equivalent diisopropylethylamine in dichloromethane at room temperature stirred 2 days.Reactant mixture is coated on the preparation TLC plate, and use dichloromethane: methanol (15: 1, contain 1% 2-aminopropane .) eluting obtains required product.
The 4-N-that method III. preparation replaces (3-{1-[4-(phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl] universal method of acetamide
With N-[3-(4-piperidyl) phenyl] (mixture (0.5 to 1.0M) in about 5-10%) Zai diox heated 16 hours under reflux temperature for acetamide (1.0 equivalent) and the aryl positive butyrophenone of chloro (2.0 equivalent), potassium carbonate (5.0 equivalent), diisopropylethylamine (3.0 equivalent) and the tetrabutylammonium iodide that replace.Filter reaction mixture and vacuum concentration.Crude product obtains required product through preparation of silica gel TLC chromatography (chloroform: methanol contains 0.5% 2-aminopropane .).
Embodiment 1
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(CDCl 3)δ7.75(s，1H)，7.71(d，1H，J＝7.6Hz)，7.45(d，2H，J＝7.2Hz)，7.35(s，1H)，7.26-7.22(m，2H)，6.93(d，1H，J＝7.6Hz)，3.24-3.21(m，2H)，3.04(t，2H，J＝7.0Hz)，2.67-2.63(m，2H)，2.59-2.48(m，1H)，2.32(s，6H)，2.30-2.27(m，2H)，2.18(s，3H)，2.14-2.06(m，2H)，2.00-1.80(m，4H)；ESMSm/e：393.3(M+H) +。
Embodiment 2
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.0500g, 0.200mmol), 4-chloro-3 ', 4 '-dimethyl n butyrophenone (0.100g, 0.480mmol), potassium carbonate (0.080g, 0.600mmol) and NaI (0.090g, 0.600mmol) mixture in 5mL DMF heated 18 hours under reflux temperature.Filter reaction mixture is poured filtrate in the 5mL water into, with ethyl acetate washing (3 * 5mL).The dry organic extract liquid (magnesium sulfate) that merges, vacuum concentration and through preparation TLC purification (silica gel, 9.5: the 0.5=dichloromethane: methanol+1% 2-aminopropane .), obtain the required product of 0.067g (yield 80.0%).
1H?NMR(400MHz，CDCl 3)δ7.72(d，1H，J＝8.0Hz)，7.44(s，1H)，7.38(d，1H，J＝8.0Hz)，7.23-7.20(m，2H)，7.16(s，1H)，6.95(d，1H，J＝6.8Hz)，3.13-3.11(m，2H)，3.02(t，2H，J＝7.0Hz)，2.56-2.40(m，4H)，2.32(s，6H)，2.17-2.15(m，2H)，2.04-1.78(m，6H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：421.3(M+H) +。
Embodiment 3
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclohexane carboxamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.80-6.81(m，7H)，3.41-3.00(m，4H)，2.95-2.41(m，4H)，2.32(s，6H)，2.22-1.05(m，18H)；ESMS?m/e：461.4(M+H) +。
Embodiment 4
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-phenyl-acetamides
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.85-7.65(m，2H)，7.45-6.92(m，10H)，3.76(s，2H)，3.10-2.90(m，4H)，2.50-2.35(m，3H)，2.32(s，6H)，2.10-1.85(m，4H)，1.80-1.60(m，4H)；ESMS?m/e：469.4(M+H) +。
Embodiment 5
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-(3-methoxyphenyl) acetamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.76-7.65(m，2H)，7.38-7.12(m，6H)，6.95-6.80(m，3H)，3.82(s，3H)，3.70(s，2H)，3.10-2.90(m，4H)，2.50-2.38(m，3H)，2.32(s，6H)，2.10-1.85(m，4H)，1.80-1.60(m，4H)；ESMS?m/e：499.4(M+H) +。
Embodiment 6
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-methoxyl group acetamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.80-7.75(m，2H)，7.50-7.38(m，2H)，7.34-6.90(m，3H)，4.00(s，2H)，3.51(s，3H)，3.30-2.95(m，4H)，2.70-2.50(m，3H)，2.32(s，6H)，2.15-1.80(m，8H)；ESMS?m/e：423.3(M+H) +。
Embodiment 7
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) Methanesulfomide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.82-7.10(m，7H)，3.41(s，3H)，3.40-2.85(m，4H)，2.82-2.35(m，5H)，2.32(s，6H)，2.22-1.80(m，6H)；ESMSm/e：429.3(M+H) +。
Embodiment 8
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) ethyl sulfonamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.75(s，1H)，7.71(d，1H，J＝7.6Hz)，7.30-7.09(m，4H)，7.02(d，1H，J＝7.2Hz)，3.36-3.05(m，6H)，2.77-2.52(m，3H)，2.32(s，6H)，2.15-1.82(m，8H)，1.37(t，3H，J＝7.4Hz)；ESMS?m/e：443.3(M+H) +
Embodiment 9
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.92(d，2H，J＝8.8Hz)，7.55-7.40(m，3H)，7.35(s，1H)，7.22(t，1H，J＝8.0Hz)，6.92(d，1H，J＝8.0Hz)，3.30-3.27(m，2H)，3.09(t，2H，J＝7.0Hz)，2.76-2.39(m，5H)，2.20(s，3H)，2.17-1.85(m，6H)；ESMS?m/e：399.3(M+H) +。
Embodiment 10
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.93?(d，2H，J＝8.6Hz)，7.45?(d，2H，J＝8.6Hz)，7.39(d，1H，J＝7.2Hz)，7.32(s，1H)，7.24(t，1H，J＝7.8Hz)，6.94(d，1H，J＝8.4Hz)，3.21-3.18(m，2H)，3.05(t，2H，J＝7.0Hz)，2.64-2.51(m，4H)，2.28-1.86(m，8H)，1.26(d，6H，J＝6.8Hz)；?ESMS?m/e：427.3(M+H) +。
Embodiment 11
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-cyclohexane carboxamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.93(d，2H，J＝8.4Hz)，7.55-7.19(m，5H)，6.93(d，1H，J＝7.6Hz)，3.25-3.00(m，4H)，2.65-2.45(m，4H)，2.30-1.50(m，18H)；ESMS?m/e：467.3(M+H) +。
Embodiment 12
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-phenyl-acetamides
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.92(d，2H，J＝8.4Hz)，7.46-7.26(m，9H)，7.20(t，1H，J＝7.6Hz)，6.92(d，1H，J＝7.6Hz)，3.75(s，2H)，3.15-3.13(m，2H)，3.03(t，2H，J＝7.0Hz)，2.64-2.46(m，3H)，2.22-1.60(m，8H)；ESMS?m/e：475.3(M+H) +。
Embodiment 13
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-(3-methoxyphenyl) acetamide
Using method II obtains required product.
1HNMR(400MHz，CDCl 3)δ7.92(d，2H，J＝8.4Hz)，7.44(d，2H，J＝8.4Hz)7.38(s，1H)，7.35-7.25(m，3H)，7.19(t，1H，J＝7.8Hz)，6.94-6.86(m，3H)，3.81(s，3H)，3.72(s，2H)，3.12-3.09(m，2H)，3.02(t，2H，J＝6.8Hz)，2.57-2.44(m，3H)，2.20-1.60(m，8H)；ESMS?m/e；505.3(M+H) +。
Embodiment 14
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-methoxyl group acetamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.93(d，2H，J＝8.4Hz)，7.50-7.25(m，5H)，6.98(d，1H，J＝7.8Hz)，4.01(s，2H)，3.57(s，3H)，3.30-3.15(m，2H)，3.06(t，2H，J＝6.8Hz)，2.70-2.50(m，3H)，2.35-1.80(m，8H)；ESMS?m/e：429.3(M+H) +。
Embodiment 15
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) Methanesulfomide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.95-6.96(m，8H)，3.48(s，3H)，3.28-2.90(m，6H)，2.80-2.57(m，3H)，2.38-1.86(m，6H)；ESMS?m/e：435.2(M+H) +。
Embodiment 16
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) ethyl sulfonamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.93(d，2H，J＝8.2Hz)，7.45(d，2H，J＝8.2Hz)，7.30-7.08(m，3H)，6.99(d，1H，J＝7.6Hz)，3.26-3.02(m，6H)，2.69-2.45(m，3H)，2.32-1.75(m，8H)，1.36(t，3H，J＝7.4Hz)；ESMS?m/e：449.3(M+H) +。
Embodiment 17
N-{3-[1-(4-oxo-phenyl butyl)-4-piperidyl] phenyl } acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ8.10-6.80(m，9H)，3.40-2.95(m，4H)，2.85-2.20(m，3H)，2.19(s，3H)，2.15-1.70(m，8H)；ESMS?m/e：365.3(M+H) +。
Embodiment 18
2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide.
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.99(d，2H，J＝7.4Hz)，7.57(t，1H，J＝7.4Hz)，7.48(t，2H，J＝7.4Hz)，7.45-7.20(m，2H)，7.24(t，1H，J＝8.0Hz)，6.94(d，1H，8.0Hz)，3.24-3.21(m，2H)，3.09(t，2H，J＝7.0Hz)，2.57-2.25(m，4H)，2.31-1.84(m，8H)，1.26(d，6H，J＝7.2Hz)；ESMS?m/e：393.3(M+H) +。
Embodiment 19
N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl }-the 2-phenyl-acetamides
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.98(d，2H，J＝7.6Hz)，7.65-7.15(m，11H)，6.92(d，2H，J＝7.2Hz)，3.74(s，2H)，3.20-2.95(m，4H)，2.65-2.40(m，3H)，2.25-1.70(m，8H)；?ESMS?m/e：441.3(M+H) +。
Embodiment 20
2-(3-methoxyphenyl)-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } acetamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.98(d，2H，J＝7.6Hz)，7.56(t，1H，J＝7.62Hz)，7.46(t，2H，J＝7.6Hz)，7.40(s，1H)，7.37-7.26(m，2H)，7.19(t，1H，J＝7.8Hz)，6.94-6.86(m，3H)，3.81(s，3H)，3.71(s，3H)，3.12-3.03(m，4H)，2.57-2.44(m，3H)，2.16-1.77(m，8H)；ESMS?m/e：471.3(M+H) +。
Embodiment 21
N-(3-{1-[4-(2, the 4-Dimethoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.82(d，1H，J＝8.8Hz)，7.54(d，1H，J＝7.6Hz)，7.33(s，1H)，7.22(t，1H，J＝7.6Hz)，6.93(d，1H，J＝7.6Hz)，6.53(d，1H，J＝8.8Hz)，6.46(s，1H)，3.90(s，3H)，3.86(s，3H)，3.48-3.27(m，2H)，3.05(t，2H，J＝6.8Hz)，2.90-2.68(m，2H)，2.65-2.38(m，3H)，2.25(s，3H)，2.18-1.80(m，6H)；ESMS?m/e：425.3(M+H) +。
Embodiment 22
N-(3-{1-[4-(2, the 4-Dimethoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.98(d，1H，J＝8.6Hz)，7.41-7.37(m，2H)，7.24(t，1H，J＝7.8Hz)，6.96(d，1H，J＝7.8Hz)，6.54(d，1H，J＝8.6Hz)，6.46(s，1H)，3.89(s，3H)，3.86(s，3H)，3.11-3.08(m，2H)，2.98(t，2H，J＝7.2Hz)，2.53-2.46(m，4H)，2.13-1.79(m，8H)，1.25(d，6H，J＝6.8Hz)；?ESMS?m/e：453.3(M+H) +。
Embodiment 23
N-(3-{1-[4-(2, the 4-Dimethoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-phenyl-acetamides
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.85(m，12H)，3.89(s，3H)，3.86(s，3H)，3.74(s，2H)，3.22-2.90(m，4H)，2.64-2.40(m，3H)，2.25-1.70(m，8H)；ESMS?m/e：501.3(M+H) +。
Embodiment 24
N-(3-{1-[4-(2, the 4-Dimethoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-(3-methoxyphenyl) acetamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.82(d，1H，J＝8.8Hz)，7.48-7.15(m，5H)，6.95-6.80(m，3H)，6.58-6.45(m，2H)，3.89(s，3H)，3.86(s，3H)，3.81(s，3H)，3.72(s，2H)，3.25-2.95(m，4H)，2.65-2.40(m，3H)，2.30-1.95(m，4H)，1.93-1.72(m，4H)；ESMS?m/e：531.3(M+H) +。
Embodiment 25
N-(3-{1-[4-oxo-4-(4-Phenoxyphenyl) butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ8.15-6.75(m，13H)，3.30-2.80(m，4H)，2.75-2.10(m，5H)，2.03(s，3H)，2.00-1.60(m，6H)；?ESMS?m/e：457.3(M+H) +。
Embodiment 26
2-methyl-N-(3-{1-[4-oxo-4-(4-Phenoxyphenyl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.96(d，2H，J＝8.8Hz)，7.43-7.15(m，6H)，7.10-6.93(m，5H)，3.42-2.95(m，4H)，2.80-2.45(m，4H)，2.20-1.80(m，8H)，1.14(d，6H，J＝6.8Hz)；ESMS?m/e：485.4(M+H) +。
Embodiment 27
2-(3-methoxyphenyl)-N-(3-{1-[4-oxo-4-(4-Phenoxyphenyl) butyl]-the 4-piperidyl } phenyl) acetamide
Using method II obtains required product.
1HNMR(400MHz，CDCl 3)δ7.97(d，2H，J＝8.8Hz)，7.41-7.18(m，7H)，7.08-6.99(m，5H)，6.94-6.87(m，3H)，3.82(s，3H)，3.70(s，2H)，3.10-2.95(m，4H)，2.55-2.40(m，3H)，2.15-1.95(m，4H)，1.81-1.70(m，4H)；ESMS?m/e：563.4(M+H) +。
Embodiment 28
N1-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-N, N-dimethyl methyl amide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.93(d，2H，J＝8.8Hz)，7.44(d，2H，J＝8.8Hz)，7.27(s，1H)，7.25-7.10(m，2H)，6.94(d，1H，J＝7.6Hz)，3.30-3.10(m，2H)，3.04(t，2H，J＝6.8Hz)，2.83(s，6H)，2.68-2.45(m，3H)，2.30-1.75(m，8H)；ESMS?m/e：464.3(M+H) +。
Embodiment 29
N-(3-{1-[4-oxo-4-(2-thienyl) butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.90-6.78(m，7H)，3.22-2.88(m，4H)，2.69-2.25(m，5H)，2.02(s，3H)，2.00-1.64(m，6H)；ESMS?m/e：371.2(M+H) +。
Embodiment 30
N-(3-{1-[4-(4-isopropyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ8.00-6.78(m，8H)，3.15-2.98(m，4H)，2.77-2.15(m，4H)，2.03(s，3H)，2.00-1.62(m，8H)，0.927(d，6H，J＝6.0Hz)；ESMS?m/e：407.3(M+H) +。
Embodiment 31
N-(3-{1-[4-(4-aminomethyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.90-6.80(m，8H)，3.10-2.45(m，7H)，2.32(S，3H)，2.02(s，3H)，2.01-1.68(m，8H)；ESMS?m/e：379.3(M+H) +。
Embodiment 32
N-(3-{1-[4-(4-bromophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) acetamide
Using method III obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.90-6.80(m，8H)，3.30-3.05(m，4H)，2：70-2.45(m，3H)，2.05(s，3H)，1.98-1.65(m，8H)；ESMS?m/e：444.0(M+H) +。
Embodiment 33
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-third sulfonamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.75(s，1H)，7.71(d，1H，J＝7.6Hz)，7.27-7.00(m，5H)，3.32-3.24(m，3H)，3.10-3.02(m，2H)，2.78-2.50(m，3H)，2.32(s，6H)，2.19-1.84(m，8H)，1.39(d，6H，J＝6.8Hz)；ESMS?m/e：457.4(M+H) +。
Embodiment 34
N-(3-{1-[4-oxo-4-(4-Phenoxyphenyl) butyl]-the 4-piperidyl } phenyl)-2-third sulfonamide
Using method II obtains required product.
1H?NMR(400MHz，CDCl 3)δ7.97(d，2H，J＝7.6Hz)，7.44(t，2H，J＝7.6Hz)，7.27-7.00(m，9H)，3.35-2.96(m，5H)，2.69-2.45(m，3H)，2.14-1.79(m，8H)，1.39(d，6H，J＝6.8Hz)；ESMS?m/e：521.4(M+H) +。
Embodiment 35
N-(3-{1-[3-(4-chlorphenyl)-3-methoxy-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 3-methoxyl group-3-(rubigan)-n-propyl chloride (27.4mg, 0.125mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.125mmol), the mixture in the tetrabutylammonium iodide Zai diox (2.0mL) of diisopropylethylamine (0.50mL) and catalytic amount stirred 72 hours down at 90 ℃.Reactant mixture is concentrated into only surplus a little volume, with preparation TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery N-of thickness (3-{1-[3-(4-chlorphenyl)-3-methoxy-propyl]-the 4-piperidyl phenyl)-2-methyl propanamide (39.5mg, yield 73.8%).
1H NMR δ 7.48 (s, 1H), 7.34-7.3 (m, 2H), 7.25 (m, 4H), 6.96 (d, 1H, J=7.4Hz), 4.20 (tangible dd, 1H, J=5.9,7.6Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1Hz), 2.99 (d, 1H, J=10.1Hz), 2.49 (h, 4H, J=6.6Hz), 2.20-2.10 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1Hz); ESMS m/e:429.4 (M+H) +
Embodiment 36
N-(3-{1-[6-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Synthetic method and 2-[6-(4-phenyl-piperidino) hexyl]-1H-iso-indoles-1, the preparation method of 3 (2H)-diketone is identical, (3-{1-[6-(1 to obtain N-, 3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) hexyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (506mg, yield 56%).
1H NMR (400MHz, CDCl 3) δ 7.86-7.80 (m, 2H), 7.73-7.68 (m, 2H), 7.44 (s, 1H), 7.37 (d, 1H, J=8.3Hz), 7.22 (t, 1H, J=7.7Hz), 6.96 (d, 1H, J=7.7Hz), 3.69 (t, 2H, J=7.2Hz), 3.01 (tangible d, 2H, J=11.3Hz), and 2.58-2.40 (m, 2H), 2.33 (m, 2H) 1.98 (dt, 2H, J=3.2,11.3Hz), 1.84-1.64 (m, 4H), 1.51 (q, 2H, J=7.1Hz), 1.43-1.30 (m, 6H), 1.24 (d, 6H, J=6.8Hz); ESMSm/e:476.4 (M+H) +
Embodiment 37
N-{3-[1-(3-methoxyl group-3-phenyl propyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
With 3-methoxyl group-3-phenyl-n-propyl chloride (23.1mg, 0.126mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.126mmol), the mixture in the tetrabutylammonium iodide Zai diox (2.0mL) of diisopropylethylamine (0.50mL) and catalytic amount stirred 72 hours down at 90 ℃.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery N-{3-[1-of thickness (3-methoxyl group-3-phenyl propyl)-4-piperidyl] phenyl }-2-methyl propanamide (45.4mg, yield 91.2%).
1H NMR (400MHz, CDCl 3) δ 7.45 (S, 1H), 7.34-7.25 (m, 5H), 7.25 (m, 2H), 6.96 (d, 1H, J=7.4Hz), 4.20 (tangible dd, 1H, J=5.9,7.6Hz), 3.2 (s, 3H), 3.04 (d, 1H, J=10.1Hz), 2.99 (d, 1H, J=10.Hz), 2.49 (tangible sept, part is covered, 4H, J=6.6Hz), 2.3-2.1 (m, 4H), 1.82 (m, 4H), 1.25 (d, 6H, J=7.1Hz); ESMS m/e:395.4 (M+H) +
Embodiment 38
N-(3-{1-[4-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Synthetic method and 2-[6-(4-phenyl-piperidino) hexyl]-1H-iso-indoles-1, the preparation method of 3 (2H)-diketone is identical, (3-{1-[4-(1 to obtain N-, 3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) butyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (664mg, yield 74%).
1H NMR (400MHz, CDCl 3) δ 7.87-7.78 (m, 2H), 7.76-7.64 (m, 2H), 7.47 (s, 1H), 7.39 (d, 1H, J=7.6Hz), 7.21 (t, 1H, J=8.1Hz), 6.94 (d, 1H, J=7.6Hz), 3.72 (t, 2H, J=6.8Hz), 3.37-3.22 (m, 2H), 3.0 (tangible d, 2H, J=10.7Hz), 2.75 (q, 2H, J=7.0Hz), 2.64-2.33 (m, 4H), 1.99 (dt, 2H, J=2.6,11.7Hz), 1.86-1.65 (m, 2H), 1.63-1.50 (m, 2H), 1.23and 1,21 (two d, 6H, J=5.5Hz); ESMS m/e:448.4 (M+H) +
To C 27H 34N 3ClO 3+ 0.4H 2The value of calculation of O: C, 66.02; H, 7.14; N, 8.55;
Measured value: C, 66.07; H, 6.78; N, 8.65.
Embodiment 39
N-(3-{1-[4-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Synthetic method and 2-[6-(4-phenyl-piperidino) hexyl]-1H-iso-indoles-1, the preparation method of 3 (2H)-diketone is identical, (3-{1-[5-(1 to obtain N-, 3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide (614mg, yield 64%).
1H NMR (400MHz, CDCl 3) δ 7.87-7.8 (m, 2H), 7.76-7.68 (m, 2H), 7.48 (s, 1H), 7.41 (d, 1H, J=7.6Hz), 7.21 (t, 1H, J=7.6Hz), 6.95 (d, 1H, J=7.6Hz), 3.69 (t, 2H, J=7.2Hz), 3.39-3.28 (m, 2H), 3.02 (tangible d, 2H, J=11.6Hz), 2.78 (q, 2H, J=7.2Hz), and 2.64-2.52 (m, 1H), 2.52-2.40 (m, 1H), 2.40-2.31 (m, 2H), 2.01 (dt, 2H, J=3.7,11.1Hz), 1.85-1.64 (m, 2H), 1.58 (q, 2H, J=7.6Hz), 1.45-1.32 (m, 2H), 1.23 (d, 6H, J=6.9Hz), ESMS m/e:462.4 (M+H) +
To C 28H 36N 3ClO 3Value of calculation: C, 67.52; H, 7.29; N, 8.44;
Measured value: C, 67.04; H, 7.06; N, 8.38.
Embodiment 40
2-methyl-N-{3-[1-(4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide.
With 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.100mmol), 4-phenyl-1-chlorobutane (21.1mg, 0.125mmol), the mixture in the tetrabutylammonium iodide Zai diox (2.0mL) of diisopropylethylamine (0.50mL) and catalytic amount heated 3 days under reflux temperature.Reactant mixture concentrated and with preparing TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery product 2-of thickness methyl-N-{3-[1-(4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. (9.50mg, yield 25.1%).
1H NMR δ 7.37 (s, 1H), 7.29 (tangible d, 1H, J=7.9Hz), 7.18 (m, 3H), 7.11 (m, 3H), 6.90 (tangible d, 1H, J=7.9Hz), 3.02 (d, 2H, J=6.8Hz), (2.41 part is covered for m, 4H), 2.01 (m, 2H), 1.78 (m, 4H), 1.57 (m, 4H), 1.18 (d, 6H, J=7.7Hz); ESMS m/e:379.4 (M+H) +
Embodiment 41
N-(3-{1-[3-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Synthetic method and 2-[6-(4-phenyl-piperidino) hexyl]-1H-iso-indoles-1, the preparation method of 3 (2H)-diketone is identical, (3-{1-[3-(1 to obtain N-, 3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) propyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide (810mg, yield 93%).
1H NMR (400MHz, CDCl 3) δ 7.87-7.82 (m, 2H), 7.73-7.68 (m, 2H), 7.57 (s, 1H), 7.36 (d, 1H, J=8.5Hz), 7.18 (t, 1H, J=7.7Hz), 6.79 (d, 1H, J=7.1Hz), 3.78 (t, 2H, J=6.8Hz), 3.06 (quintet, 2H, J=6Hz), 2.95 (tangible d, 2H, J=12.2Hz), 2.58-2.31 (m, 4H), 1.96-1.83 (m, 2H), 1.70 (tangible d, 2H, J=12.1Hz), 1.52 (dt, 2H, J=3.5,12.5Hz), 1.03 (d, 6H, J=6.5Hz); ESMS m/e:434.4 (M+H) +
Embodiment 42
N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With (S)-(-)-3-chloro-1-phenyl-1-propanol (0.426g, 2.50mmol, 99%ee), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.565g, 2.00mmol), (1.29g, 10.0mmol) the mixture of the tetrabutylammonium iodide of, diox (5.0mL) and catalytic amount stirred 72 hours down at 90 ℃ diisopropylethylamine.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (306mg, yield 39.3%).
1H NMR (400MHz, CDCl 3) δ 7.46 (S, 1H), 7.42 (d, 4H, J=8.1Hz), 7.35 (m, 1H), 7.30 (d, 1H, J=8.0Hz), 7.23 (t, 1H, J=8.1Hz), 7.12 (s, 1H), 6.96 (tangible dd, 1H, J=8.0Hz), 5.0 (tangible dd, 1H, J=4.4,8.3Hz), 3.18 (tangible dd, 2H, J=2.5,12.5Hz), 2.74 (m, 2H), 2.50 (m, 2H), 2.3-2.1 (m, 6H), 1.8 (m, 2H), 1.25 (d, 6H, J=7.1Hz); ESMS m/e:389.2 (M+H) +
Embodiment 43
N-(3-{1-[3-methoxyl group-3-(4-aminomethyl phenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 3-methoxyl group-3-(p-methylphenyl)-n-propyl chloride (24.9mg, 0.126mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.126mmol), the mixture in the tetrabutylammonium iodide Zai diox (2.0mL) of diisopropylethylamine (0.50mL) and catalytic amount stirred 72 hours down at 90 ℃.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (10.9mg, yield 21.2%).
1H NMR (400MHz, CDCl 3) δ 7.44 (s, 1H), 7.38 (m, 1H), 7.3-7.1 (m, 5H), 6.96 (d, 1H, J=7.4Hz), 4.18 (tangible dd, 1H, J=5.6,7.9Hz), 3.24 (d, 1H, J=8.2Hz), 3.2 (s, 3H), 3.11 (m, 2H, J=10.1Hz), 2.49 (m, 4H), 2.35 (s, 3H), 2.3-2.1 (m, 3H), 1.92 (d, 4H), 1.25 (d, 6H, J=7.1Hz); ESMSm/e:409.4 (M+H) +
Embodiment 44
N-{3-[1-(3-isopropoxy-3-phenyl propyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
With 3-isopropyl-3 '-phenyl-n-propyl chloride (26.6mg, 0.126mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.126mmol), the mixture in the tetrabutylammonium iodide Zai diox (2.0mL) of diisopropylethylamine (0.50mL) and catalytic amount stirred 72 hours down at 90 ℃.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (14.1mg, yield 26.5%).
1H NMR (400MHz, CDCl 3) δ 7.46 (s, 1H), 7.43-7.37 (m, 2H), 7.33 (m, 3H), 7.23 (m, 2H), 6.95 (d, 1H, J=8.4Hz), 4.46 (tangible dd, 1H, J=5.0,8.3Hz), 3.49 (tangible sept, 1H, J=7.1Hz), 3.10 (s, 2H), 2.70 (m, 2H), 2.52 (tangible sept, part is covered, 4H, J=6.6Hz), 2.30-2.10 (m, 2H), 1.90-1.80 (d, 4H), 1.25 (d, 6H, J=7.1Hz), 1.15 (d, 3H, J=6.4Hz), 1.08 (d, 3H, J=6.4Hz); ESMS m/e:423.4 (M+H) +
Embodiment 45
N-(3-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 4, two (the 4-fluorophenyl)-1-chlorobutane (39.0mg of 4-, 0.126mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.126mmol), the mixture in the tetrabutylammonium iodide Zai diox (2.0mL) of diisopropylethylamine (0.50mL) and catalytic amount stirred 72 hours down at 90 ℃.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (15.9mg, yield 25.2%).
1H NMR (400MHz, CDCl 3) δ 8.02 (s, 1H), 7.41 (s, 1H), 7.3-7.15 (m, 4H), 7.10 (m, 3H), 6.89 (tangible t, 5H), 3.81 (t, 1H, J=7.8Hz), 3.30 (s, 1H), 2.91 (d, 1H, J=12.5Hz), 2.80 (m, 1H), 2.40 (m, 2H), 2.31 (t, 1H, J=8.0Hz), 1.93 (tangible q, 3H, J=8.0Hz), 1.72 (m, 3H), 1.40 (m, 2H), 1.20 (m, 2H), 1.15 (d, 6H, J=8.1Hz); ESMS m/e:491.4 (M+H) +
Embodiment 46
N-{3-[1-(3-methoxy-benzyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.100mmol), 3-methoxy-benzyl chlorine (19.6mg, 0.125mmol), the tetrabutylammonium iodide of diisopropylethylamine (0.50mL) and catalytic amount is with the mixture of diox (2.0mL).With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the required product (10.2mg, yield 27.9%) of yellow solid shape.
1H NMR (400MHz, CDCl 3) δ 7.46 (s, 1H), 7.35 (tangible d, 1H, J=8.3Hz), 7.27-7.21 (m, 2H), 6.95 (tangible t, 3H, J=6.9Hz), 6.82 (tangible dd, 1H, J=2.4,8.3Hz), 3.84 (m, 3H), 3.56 (s, 2H), 3.05 (d, 2H, J=10.5Hz), 2.51 (tangible sept, part is covered, 4H, J=7.2Hz), 2.13 (tangible t, 2H, J=9.7Hz), 1.88 (m, 2H), 1.25 (d, 6H, J=6.7Hz); ESMS m/e:367.3 (M+H) +
Embodiment 47
N-(3-{1-[3, two (trifluoromethyl) benzyls of 5-]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (28.3mg, 0.100mmol), 3, two (trifluoromethyl) benzyl bromide a-bromotoluenes of 5-(38.4mg, 0.125mmol), the tetrabutylammonium iodide of diisopropylethylamine (0.50mL), catalytic amount is with the mixture of diox (2.0mL).With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (12.2mg, yield 25.8%).
1H NMR (400MHz, CDCl 3) δ 7.83 (s, 2H), 7.77 (s, 1H), 7.53 (s, 1H), 7.30-7.21 (m, 2H), 7.16 (s, 1H), 6.98 (tangible d, 1H, J=7.6Hz), 3.62 (s, 2H), 2.94 (d, 2H, J=9.4Hz), 2.51 (tangible sept, part is covered, 2H, J=6.6Hz), 2.14 (m, 2H), 1.82 (m, 4H), 1.25 (d, 6H, J=6.6Hz); ESMS m/e:473.2 (M+H) +
Embodiment 48
N-(3-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Method A
4-{[(1R)-and 3-chloro-1-phenyl propyl] the oxygen base }-1, the 2-dimethoxy benzene
With 3,4-syringol (4.07g, 26.4mmol), (S)-(-)-3-chloro-phenyl-1-propanol (4.50g, 26.4mmol, 99%ee, Aldrich Chemical Co.), triphenylphosphine (6.92g, 26.4mmol) and the diethylazodicarboxylate (4.59g, 26.4mmol) mixture in THF (110mL) at room temperature stirred 24 hours.The vacuum concentration reactant mixture.At this moment, can the pentane extract that merge be concentrated with residue with pentane washing (* 3), and chromatography (silica gel is eluent with hexane-ethyl acetate at 8: 1), it is (consistent with the universal method of describing in the following document: Srebnik, M. to obtain required product; Ramachandran, P.V.; Brown, H.C.J.Org.Chem.1988,53,2916-2920).This method is used in small-scale reaction, can only obtain 40% productive rate.
Perhaps, for extensive (26.4mmol) preparation, crude product is ground in a spot of dichloromethane, and leach the triphenyl phosphine oxide that is precipitated out.Concentrated filtrate obtains the crude product chromatography the required product (7.30g, yield 88.9%) of thickness yellow oily.
1H NMR (400MHz, CDCl 3) δ 7.39-7.32 (m, 4H), 7.20 (m, 1H), 6.64 (d, 1H, J=8.7Hz), 6.51 (d, 1H, J=2.7Hz), 6.30 (dd, 1H, J=2.7,8.7Hz), 5.27 (tangible dd, 1H, J=4.5,8.7Hz), 3.79 (s, 3H), 3.77 (s, 3H), 3.61 (m, 1H), 2.45 (m, 1H), 2.20 (m, 1H), 1.80 (s, 1H); ESMSm/e:307.11 (M+H) +
N-(3-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With potassium carbonate (321mg, 2.32mmol), sodium iodide (522mg, 3.48mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (570mg, 2.32mmol) and 4-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-1,2-dimethoxy benzene (712mg, 2.32mmol) mixture in DMF (5.0mL) stirred 3 hours down at 100 ℃, this moment, the TLC test shows reacted completely.Reactant mixture is poured in the water (50mL), and with water layer dichloromethane extraction (3 * 30mL).With the organic extract liquid salt water washing (30mL) that merges, with dried over mgso and concentrating under reduced pressure.Crude product is with preparing TLC plate layer chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery product of thickness (970mg, 90.1%).
Method B
Under the room temperature, triphenylphosphine (9.80mg packs in the round-bottomed flask of 25mL, 0.0375mmol), diethylazodicarboxylate (5.22mg, 0.0300mmol), N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 3, the 4-syringol (7.70mg, 0.050mmol) and THF (1.0mL).Reactant mixture is at room temperature stirred spend the night (16 hours).Removal of solvent under reduced pressure, residue is through preparation TLC plate layer chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.4mg, yield 34.1%).
1HNMR (400MHz, CDCl 3) δ 7.46 (s, 1H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 6.97 (d, 1H, J=7.8Hz), 6.64 (d, 1H, J=9.1Hz), 6.51 (d, 1H, J=2.6Hz), 6.29 (d, 1H, J=2.6,9.1Hz), 5.20 (tangible dd, 1H, J=4.4,8.5Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.23 (m, 2H), 2.77 (m, 2H), 2.5 (m, 2H), 2.3-2.1 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9Hz); ESMS m/e:517.4 (M+H) +
Embodiment 49
2-methyl-N-(3-{1-[(3S)-3-phenoxy group-3-phenyl propyl-4-piperidyl] phenyl } propionic acid amide.
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), phenol (4.70mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.7mg, yield 23.6%).
1H NMR δ 7.46 (s, 2H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (tangible d, 1H, J=7.4Hz), 6.89 (tangible tt, 1H, J=0.8,7.6Hz), 6.84 (tangible dt, 1H, J=0.8,8.0Hz), 5.20 (tangible dd, 1H, J=4.4,8.5Hz), 3.35 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.9Hz); ESMSm/e:457.4 (M+H) +
Embodiment 50
N-(3-{1-[(3S)-3-(4-methoxyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 4-methylphenol (6.20mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.2mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.6mg, yield 37.9%).
1H NMR (400MHz, CDCl 3) δ 7.38-7.14 (m, 8H), 6.90 (tangible d, 1H, J=7.7Hz), and 6.72-6.46 (m, 4H), 5.09 (tangible dd, 1H, J=4.8,8.1Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.37-1.72 (m, 8H), 1.25 (d, 6H, J=7.4Hz); ESMS m/e:487.4 (M+H) +
Embodiment 51
N-(3-{1-[(3S)-3-(3-chlorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 3-chlorophenol (6.40mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.9mg, yield 40.0%).
1H NMR (400MHz, CDCl 3) δ 7.39 (s, 1H), 7.35-7.10 (m, 7H), 7.02 (t, 1H, J=8.0Hz), 6.90 (d, 1H, J=7.6Hz), 6.84-6.75 (m, 2H), 6.65 (m, 1H), 5.09 (tangible dd, 1H, J=4.99,8.1Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.50 (m, 2H), 2.30-1.70 (m, 8H), 1.18 (d, 6H, J=6.8Hz); ESMS m/e:491.4 (M+H) +
Embodiment 52
N-(3-{1-[(3S)-3-(4-chlorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 4-chlorophenol (6.40mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (3.3mg, yield 26.9%).
1H NMR δ 7.36 (s, 1H), 7.35-7.22 (m, 7H), 7.12 (m, 2H), 6.97 (tangible d, 1H, J=7.2Hz), 6.77 (m, 2H), 5.23 (m, 1H), 3.18 (m, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:491.4 (M+H) +
Embodiment 53
2-methyl-N-[3-(1-{ (3S)-3-phenyl-3-[4-(trifluoromethyl) phenoxy group] propyl group }-the 4-piperidyl } phenyl) propionic acid amide.
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 4-trifloro methyl phenol (8.100mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (5.10mg, yield 38.9%).
1H NMR δ 8.06 (s, 1H), 7.49 (s, 1H), 7.44 (tangible d, 2H, J=.6Hz), 7.38-7.30 (m, 4H), 7.30-7.20 (m, 3H), 6.96 (tangible d, 1H, J=7.6Hz), 6.91 (tangible d, 2H, J=8.6Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H), 2.53 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:525.4 (M+H) +
Embodiment 54
N-(3-{1-[(3R)-3-(2,5-two fluorophenoxies)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 2,5-difluorophenol (6.50mg, 0.050mmol), triphenyl phasphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (3.60mg, yield 29.3%).
1H?NMRδ7.46(s，1H)，7.40-7.32(m，4H)，7.31-7.20(m，2H)，7.17(s，1H)，7.01-6.92(m，2H)，6.65-6.42(m，2H)，5.27(m，1H)，3.13(m，2H)，2.64(m，2H)，2.51(m，2H)，2.28-1.80(m，8H)，1.25(d，6H，J＝7.1Hz)；ESMS?m/e：493.4(M+H) +。
Embodiment 55
N-(3-{1-[(3R)-3-(3, the 4-dichlorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 3,4-chlorophenesic acid (8.20mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (5.20mg, yield 39.7%).
1H?NMR(CDCl 3)δ7.70-7.63(m，2H)，7.55(m，1H)，7.47-7.43(m，3H)，7.40-7.19(m，3H)，7.00-6.50(m，2H)，6.69(dd，1H，J＝2.2，8.8Hz)，5.25(m，1H)，3.20(m，2H)，2.70(m，2H)，2.53(m，2H)，2.40-2.20(m，4H)，2.10-1.80(m，4H)，1.25(d，6H，J＝7.1Hz)；?ESMS?m/e：525.4(M+H) +。
Embodiment 56
2-methyl-N-(3-{1-[(3R)-3-phenoxy group-3-phenyl propyl]-the 4-piperidyl } phenyl) propionic acid amide.
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), phenol (4.70mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.0mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.10mg, yield 36.0%).
1H?NMR(400MHz，CDCl 3)δ7.45(s，1H)，7.40-7.15(m，10H)，6.97(d，1H，J＝7.6Hz)，6.88-6.82(m，2H)，5.26(m，1H)，3.18(m，2H)，2.75(m，2H)，2.53(m，2H)，2.40-2.10(m，4H)，2.10-1.80(m，4H)，1.25(d，6H，J＝6.9Hz)；ESMS?m/e：457.4(M+H) +。
Embodiment 57
N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Method A
Under the room temperature, (R)-(+)-3-chloro-1-phenyl-1-propanol (0.545g packs in the round-bottomed flask of 25mL, 3.19mmol, 99%ee, Aldrich Chemical Co.), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.748g, 3.04mmol), potassium carbonate (0.420g, 3.04mmol) and sodium iodide (0.684g, 4.56mmol) and DMF (6.0mL).Stirring is after 3 hours down at 100 ℃, and the TLC test shows reacts completely.Reactant mixture is poured in the water (50mL), and (3 * 20mL) extract water layer with dichloromethane.The organic extract liquid that merges is washed with saline (20mL), with dried over sodium sulfate and concentrating under reduced pressure.Residue obtains the required product (1.09g, yield 94.3%) of light yellow solid shape through flash chromatography purification (1: the 1=hexane: ethyl acetate, and 1% 2-aminopropane .).
1H NMR (400MHz, CDCl 3) δ 8.10 (s, 1H), 7.46-7.35 (m, 6H), 7.27 (m, 2H), 6.98 (tangible d, 1H, J=7.6Hz), 5.02 (tangible dd, 1H, J=4.4,8.1Hz), 3.18 (tangible dd, 2H, J=2.5,12.5Hz), 2.74 (m, 2H), 2.50 (m, 2H), and 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.1Hz); ESMS m/e:381.2 (M+H) +
The diethyl ether solution (1.2 equivalent) that adds excessive a little 1N HCl in the dichloromethane solution of described free alkali makes hydrochlorate.Removal of solvent under reduced pressure, residue washs with ether, drying under reduced pressure.
To C 24H 32N 2O 2+ HCl+0.8H 2The value of calculation of O: C, 66.82; H, 8.08; N, 6.49; Cl, 8.22;
Measured value: C, 66.90; H, 7.78; N, 6.63; Cl, 8.52.
Method B
Under the room temperature, (R)-(+)-3-chloro-1-phenyl-1-propanol (0.426g packs in the round-bottomed flask of 25mL, 2.50mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.565g, 2.00mmol), diisopropylethylamine (1.29g, 10.0mmol the) tetrabutylammonium iodide of, diox (5.0mL) and catalytic amount.After stirring 72 hours under 90 ℃, reactant mixture is poured in the water (50mL) into water layer dichloromethane extraction (3 * 20mL).The organic extract liquid that merges is washed with saline (20mL), with dried over sodium sulfate and concentrating under reduced pressure.Residue is through preparing TLC plate purification (1: 5: 100=2-aminopropane.: methanol: ethyl acetate), obtain the required product (0.260g, yield 34.2%) of light yellow solid shape.
Embodiment 58
N-(3-{1-[(3S)-3-(4-cyano group-phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 4-cyanophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.70mg, yield 71.3%).
1H NMR (400MHz, CDCl 3) δ 7.54 (m, 2H), 7.48 (d, 2H, J=8.4Hz), 7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.97 (tangible d, 1H, J=8.4Hz), 6.92 (tangible d, 2H, J=8.4Hz), 5.36 (tangible dd, 1H, J=3.9,7.6Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (tangible sept, part is covered, 2H, J=7.6Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:482.2 (M+H) +
Embodiment 59
N-(3-{1-[(3S)-3-(4-fluorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 4-fluorophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.20mg, yield 64.7%).
1H NMR (400MHz, CDCl 3) δ 7.40 (m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (tangible d, 1H, J=7.7Hz), 6.87 (m, 1H), 6.76 (m, 1H), 5.26 (tangible dd, 1H, J=4.0,8.1Hz), 3.09 (m, 2H), 2.66 (m, 2H), 2.51 (m, 2H), 2.3-2.1 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, overlapping); ESMS m/e:475.2 (M+H) +
Embodiment 60
N-(3-{1-[(3S)-3-(4-bromine phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 4-bromophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (0.70mg, yield 9.6%).
1H NMR (400MHz, CDCl 3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (tangible d, 1H, J=8.5Hz), 6.73 (tangible d, 2H, J=8.5Hz), 5.22 (tangible dd, 1H, J=4.9,7.8Hz), 3.15 (m, 2H), 2.65 (m, 2H), 2.51 (tangible sept, part is covered, 2H, J=7.6Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:535.1 (M+H) +
Embodiment 61
N-(3-{1-[(3S)-3-(3-methoxyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 3-methoxyphenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (3.1mg, yield 46.6%).
1H NMR (400MHz, CDCl 3) δ 7.47 (d, 1H, J=6.7Hz), 7.42 (s, 1H), 7.3-7.20 (m, 3H), 7.20 (m, 3H), 7.07 (t, 1H, J=8.4Hz), 6.97 (tangible d, 1H, J=6.7Hz), 6.40 (m, 3H), 5.27 (tangible dd, 1H, J=5.3,8.0Hz), 3.74 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (significantly sept is partly covered, 1H, J=6.5Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.9Hz); ESMS m/e:487.3 (M+H) +
Embodiment 62
N-(3-{1-[(3S)-3-(4-cyano group-2-methoxyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-methoxyl group-4-cyanophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (5.50mg, yield 76.5%).
1H NMR (400MHz, CDCl 3) δ 7.51 (s, 1H), 7.38 (s, 1H), 7.37 (d, 2H, J=2.4Hz), 7.20 (m, 4H), 7.10 (d, 1H, J=2.4Hz), 7.08 (s, 1H), 6.99 (tangible d, 1H, J=8.3Hz), 6.76 (tangible d, 1H, J=8.3Hz), 5.43 (tangible dd, 1H, J=5.1,8.0Hz), 3.91 (s, 3H), 3.34 (m, 2H), 2.63 (m, 2H), 2.63 (s, 1H), 2.53 (tangible sept, part is covered 1H, J=7.7Hz), and 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.28 (d, 6H, J=6.8Hz); ESMS m/e:512.2 (M+H) +
Embodiment 63
N-(3-{1-[(3S)-3-(5-acetyl group-2-methoxyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg; 0.0137mmol), 2-methoxyl group-5-acetyl phenol (100mg), triphenylphosphine (30.0mg; 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (1.60mg, yield 22.2%).
1H NMR (400MHz, CDCl 3) δ 7.52 (d, 2H, J=2.4Hz), 7.3-7.2 (m, 5H), 7.20 (m, 3H), 6.97 (tangible d, 1H, J=6.7Hz), 6.69 (tangible d, 1H, J=8.0Hz), 5.47 (tangible dd, 1H, J=4.3,7.8Hz), 3.95 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (tangible sept, part is covered, 1H, J=7.6Hz), 2.50 (s, 3H), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:529.6 (M+H) +
Embodiment 64
N-(3-{1-[(3R)-3-(2-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.2mg; 0.0137mmol), 2-acetyl phenol (100mg), triphenylphosphine (30.0mg; 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (1.70mg, yield 24.9%).
1H NMR (400MHz, CDCl 3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (tangible d, 1H), 5.49 (tangible dd, 1H, J=4.3,8.0Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.71 (s, 3H), 2.60 (s, 1H), 2.53 (significantly sept is partly covered, 1H, J=7.6Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.9Hz); ESMS m/e:498.8 (M +).
Embodiment 65
N-[3-(1-{ (3R)-3-[2-fluoro-5-(trifluoromethyl) phenoxy group]-the 3-phenyl propyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-fluoro-5-trifloro methyl phenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.50mg, yield 33.7%).
1HNMR (400MHz, CDCl 3) δ 8.07 (s, 1H), 7.67 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H), 7.30-7.10 (m, 6H), 7.14 (d, 1H, J=7.4Hz), 6.97 (tangible d, 1H, J=7.7Hz), 5.37 (tangible dd, 1H, J=5.0,8.5Hz), 3.4 (m, 2H), 2.8 (m, 2H), 2.6 (s, 1H), 2.53 (significantly sept is partly covered, 1H, J=7.4Hz), 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.1Hz, overlapping); ESMS m/e:542.6 (M +), 543.54 (M+H) +
Embodiment 66
N-[3-(1-{ (3S)-3-[2-fluoro-5-(trifluoromethyl) phenoxy group]-the 3-phenyl propyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-fluoro-5-trifloro methyl phenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (3.00mg, yield 40.4%).
1H NMR (400MHz, CDCl 3) δ 8.06 (s, 1H), 7.67 (m, 2H), 7.55 (m, 2H), 7.50-7.40 (m, 3H), 7.30-7.10 (m, 3H), 7.17 (d, 1H, J=8.9Hz), 7.07 (tangible d, 1H, J=6.7Hz), 6.97 (tangible d, 1H, J=7.8Hz), 5.37 (tangible dd, 1H, J=4.2,8.1Hz), 3.37 (m, 2H), 2.93 (m, 2H), 2.63 (s, 1H), 2.50 (tangible sept, part is covered 1H, J=7.9Hz), and 2.30-2.10 (m, 6H), 1.85 (m, 2H), 1.25 (d, 6H, J=6.9Hz); ESMS m/e:542.7 (M+H) +
Embodiment 67
N-(3-{1-[(3S)-3-(2,5-two fluorophenoxies)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2,5-difluorophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.70mg, yield 40.1%).
1H NMR (400MHz, CDCl 3) δ 7.46 (s, 1H), 7.40-7.30 (m, 4H), 7.20 (m, 2H), 7.17 (s, 1H), 6.97 (m, 2H), 6.58 (m, 1H), 6.51 (m, 1H), 5.27 (tangible dd, 1H, J=5.1,8.2Hz), 3.13 (tangible d, J=9.7Hz, 2H), 2.64 (m, 2H), 2.51 (m, 2H), 2.34 (significantly sept is partly covered, J=7.1Hz, 1H), 2.17 (m, 3H), 1.90-1.80 (m, 4H), 1.25 (d, 6H, J=7.1Hz); ESMS m/e:493.1 (M+H) +
Embodiment 68
N-(3-{1-[(3R)-3-(3-chlorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 3-fluorophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.4mg, yield 35.8%).
1H NMR (400MHz, CDCl 3) δ 7.30 (m, 2H), 7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.90 (tangible d, 1H, J=7.7Hz), 6.71 (tangible d, 1H, J=2.9Hz), 6.69 (tangible t, 1H, J=2.9Hz), 6.67 (tangible t, 1H, J=2.9Hz), 6.65 (tangible d, 1H, J=2.9Hz), 5.09 (tangible dd, 1H, J=4.8,8.1Hz), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (tangible sept, part is covered 2H, J=7.1Hz), and 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, overlapping); ESMS m/e:491.1 (M+H) +
Embodiment 69
(1S)-1-naphthoic acid 3-{4-[3-(isobutylamino) phenyl]-piperidino }-the 1-phenyl propyl) ester
Under the room temperature, N-(the 3-{1-[(3S)-3-hydroxyl-3-phenyl propyl of packing in the round-bottomed flask of 25mL]-the 4-piperidyl } phenyl)-the 2-methyl propanamide (5.20mg, 0.0137mmol), 1-naphthoyl chloride (100mg), the mixture of diisopropylethylamine (0.30mL) in THF (0.50mL).Stir after 16 hours, under the room temperature the reactant mixture concentrating under reduced pressure.Residue is with preparing TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.70mg, yield 71.3%).
1H NMR (400MHz, CDCl 3) δ 8.90 (d, 1H, J=8.9Hz), 8.28 (tangible dd, 1H, J=1.5,7.2Hz), 8.03 (d, 1H, J=8.7Hz), 7.88 (dm, 2H, J=8.7Hz), 7.60-7.48 (m, 7H), 7.40-7.32 (m, 3H), 7.25 (m, 1H), 6.90 (tangible d, 1H, J=7.4Hz), 6.18 (tangible dd, 1H, J=5.7,7.8Hz), 3.42 (m, 2H), 2.84 (m, 2H), 2.53 (m, 2H), 2.44 (tangible sept, part is covered 4H, J=7.5Hz), and 2.30-2.10 (m, 2H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:535.6 (M+H) +
Embodiment 70
N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-acetophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (1.50mg, yield 22.0%).
1H NMR (400MHz, CDCl 3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (tangible d, 1H), 5.49 (tangible dd, 1H, J=4.3,8.0Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.75 (s, 3H), 2.53 (tangible sept, part is covered, 2H, J=7.6Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.9Hz); ESMS m/e:498.81 (M+), 499.6 (M+H) +
Embodiment 71
N-(3-{1-[(3S)-3-(2-fluorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-fluorophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (3.5mg, yield 53.9%).
1H NMR (400MHz, CDCl 3) δ 8.07 (s, 1H), 7.65 (m, 1H), 7.41 (s, 1H), 7.40-7.10 (m, 5H), 7.05 (m, 2H), 6.97 (tangible d, 1H, J=8.7Hz), 6.86 (m, 2H), 6.79 (tangible dt, 1H, J=2.4,7.9Hz), 5.31 (tangible dd, 1H, J=4.5,8.0Hz), 3.39 (m, 2H), 2.97 (m, 2H), 2.53 (significantly sept is partly covered, 2H, J=7.5Hz), 2.3-2.1 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.7Hz); ESMS m/e:475.7 (M+H) +
Embodiment 72
(4S)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 5-difluorophenyl)-2-oxo-1,3-oxazolidine-3-Methanamide
Method: under the room temperature, in the phial of 20mL, add N1-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide (15mg, 0.054mmol), (4S)-4-(3, the 5-difluorophenyl)-2-oxo-oxazolidine-3-formic acid-4-nitro phenyl ester (39.3mg, 1.08mmol, 2 equivalents) and dichloromethane and 0.6% methanol (3mL).After at room temperature stirring 3 hours, filter reaction mixture and through preparation silica gel tlc purification (19: the 1=chloroform: methanol), obtain required product (18.3mg, yield 68%).
1H?NMR(400MHz，CDCl 3)δ8.09(brs，1H)，7.40(d，1H，J＝8.0Hz)，7.36-7.28(m，2H)，7.24(t，1H，J＝8.0Hz)，6.99(d，1H，J＝8.0Hz)，6.86-6.82(m，2H)，5.41(dd，1H，J＝4.1，9.0Hz)，4.72(t，1H，J＝9.0Hz)，4.22(dd，1H，J＝3.9，9.1Hz)，3.42-3.29(m，2H)；3.02(d，2H?J＝11.1Hz)，2.52-2.38(m，3H)，2.16(s，3H)，2.08-1.98(m，2H)，1.86-1.70(m，6H)；ESMS?m/e：501.2(M+H) +；
To C 26H 30F 2N 4O 4+ 0.5H 2The value of calculation of O: C, 60.64; H, 6.18; N, 10.88;
Measured value: C, 60.67; H, 5.79; N, 10.86.
Embodiment 73
Synthetic method and synthetic (4S)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 5-difluorophenyl)-2-oxo-1, the method of 3-oxazolidine-3-Methanamide is identical, obtain (4S)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino propyl group)-2-oxo-4-(3,4, the 5-trifluorophenyl)-1,3-oxazolidine-3-Methanamide (18.8mg, yield 67%).
1H?NMR(400MHz，CDCl 3)δ8.09(br?s，1H)，7.41-7.20(m，3H)，7.02-6.91(m，3H)，5.37(dd，1H，J＝3.8，8.9Hz)，4.71(t，1H，J＝9Hz)，4.21(dd，1H，J＝4，9.3Hz)，3.43-3.27(m，2H)，3.02(d，2H，J＝11.0Hz)，2.53-2.37(m，3H)，2.16(s，3H)，2.08-1.97(m，2H)，1.85-1.69(m，6H)；ESMSm/e：519.2(M+H) +；
To C 26H 29F 3N 4O 4+ 0.5H 2The value of calculation of O: C, 59.20; H, 5.73; N, 10.62;
Measured value: C, 59.40; H, 5.35; N, 10.65.
Embodiment 74
Synthetic method and synthetic (4S)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 5-difluorophenyl)-2-oxo-1, the method of 3-oxazolidine-3-Methanamide is identical, obtain N-(3-{4-[3-(acetylamino) phenyl]-piperidino propyl group)-4-(3, the 4-difluorophenyl)-5,5-dimethyl-2-oxo-1,3-oxazolidine-3-Methanamide (19.6mg, yield 68%).
1H?NMR(400MHz，CDCl 3)δ8.18(t，1H，J＝5.9Hz)，7.41(d，1H，J＝8.8Hz)，7.33(s，1H)，7.27-7.14(m，2H)，7.02-6.88(m，3H)，5.04(s，1H)，3.34(qm，2H，J＝6.3Hz)，3.02(dm，2H，J＝10.9Hz)，2.53-2.38(m，3H)，2.16(s，3H)，2.07-1.96(m，2H)，1.87-1.69(m，6H)，1.62(s，3H)，1.02(s，3H)；ESMS?m/e：529.3(M+H) +；
To C 28H 34F 2N 4O 4Value of calculation: C, 63.62; H, 6.48; N, 10.60;
Measured value: C, 63.15; H, 6.27; N, 10.48.
Embodiment 75
Synthetic method and synthetic (4S)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 5-difluorophenyl)-2-oxo-1, the method of 3-oxazolidine-3-Methanamide is identical, obtain (4S, 5R)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 4-difluorophenyl)-and 5-methyl-2-oxo-1,3-oxazolidine-3-Methanamide (20.5mg, yield 74%).
1H?NMR(400MHz，CDCl 3)δ8.14(t，1H，J＝5.5Hz)，7.40(d，1H，J＝7.8Hz)，7.37-6.89(m，6H)，5.35(d，1H，J＝7.5Hz)，5.02-4.93(m，1H)，3.41-3.25(m，2H)，3.02(d，2H，J＝10.8Hz)，2.53-2.37(m，3H)，2.16(s，3H)，2.07(m，2H)，1.89-1.68(m，6H)，1.04(d，3H，J＝6.4Hz)；ESMSm/e：515.3(M+H) +；
To C 27H 32F 2N 4O 4+ 0.5H 2The value of calculation of O: C, 61.94; H, 6.35; N, 10.70;
Measured value: C, 61.90; H, 6.13; N, 10.64.
Embodiment 76
Synthetic method and synthetic (4S)-N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 5-difluorophenyl)-2-oxo-1, the method of 3-oxazolidine-3-Methanamide is identical, obtain N-(3-{4-[3-(acetylamino) phenyl]-piperidino propyl group)-4-(4-luorobenzyl)-2-oxo-1,3-oxazolidine-3-Methanamide (17.4mg, yield 65%).
1H?NMR(400MHz，CDCl 3)δ8.08(t，1H，J＝5.6Hz)，7.4(d，1H，J＝7.2Hz)，7.34(s，1H)，7.28-7.14(m，3H)，7.05-6.95(m，3H)，4.69-4.60(m，1H)，4.26(t，1H，J＝8.8Hz)，4.15(dd，1H，J＝3.2，9Hz)，3.43(q，2H，J＝6.2Hz)，3.3(dm?1H，J＝13.6Hz)，3.04(dm，2H，J＝11Hz)，2.87(dd，1H，J＝9.3，14.4Hz)，2.53-2.42(m，3H)，2.16(s，3H)，2.09-1.99(m，2H)，1.87-1.65(m，6H)；ESMS?m/e：497.3(M+H) +；
To C 27H 33FN 4O 4+ 0.5H 2The value of calculation of O: C, 64.14; H, 6.78; N, 11.08;
Measured value: C, 64.26; H, 6.39; N, 11.12.
Embodiment 77
2-methyl-N-(3-{1-[(3R)-3-(2-nitro-phenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl) propionic acid amide.
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-nitrophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.37mg, yield 34.5%).
1H NMR (400MHz, CDCl 3) δ 7.84 (d, 1H), 7.90 (m, 1H), 7.45 (m, 1H), 7.30-7.20 (m, 5H), 7.20 (m, 2H), 6.98 (m, 2H), 6.89 (tangible d, 1H, J=7.7Hz), 5.62 (tangible dd, 1H, J=4.1,8.9Hz), 3.10 (m, 2H), 2.60 (m, 2H), 2.53 (m, 2H), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, overlapping); ESMS m/e:502.3 (M+H) +
Embodiment 78
N-(3-{1-[(3S)-3-([1,1 '-biphenyl]-4-base oxygen base)-the 3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-phenylphenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (3.00mg, yield 41.2%).
1H NMR (400MHz, CDCl 3) δ 8.06 (s, 1H), 7.48 (m, 2H), 7.40-7.30 (m, 8H), 7.30-7.25 (m, 4H), 6.97 (tangible d, 1H, J=7.6Hz), 6.91 (tangible d, 2H, J=8.7Hz), 5.34 (tangible dd, 1H, J=4.4,8.0Hz), 3.40 (m, 2H), 2.98 (m, 2H), 2.53 (tangible sept, part is covered, 1H, J=8.1Hz), 2.44 (m, 1H), 2.30-2.10 (m, 6H), 1.93 (d, 2H), 1.26 (d, 6H, J=6.9Hz); ESMS m/e:533.4 (M+H) +
Embodiment 79
2-methyl-N-(3-{1-[(3R)-3-(3-nitro-phenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-propionic acid amide.
With N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 3-nitrophenol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.80mg, yield 40.8%).
1H NMR (400MHz, CDCl 3) δ 7.76 (dm, 1H), 7.71 (t, 1H, J=1.8Hz), 7.50-7.40 (m, 2H), and 7.40-7.25 (m, 7H), 7.17 (tangible dd, 1H, J=2.4,8.2), 6.97 (tangible d, 1H, J=7.7Hz), 5.45 (tangible dd, 1H, J=5.0,8.1Hz), 3.45 (m, 2H), 2.89 (m, 2H), 2.53 (significantly sept is partly covered, 2H, J=8.3Hz), 2.30-2.10 (m, 6H), 1.92 (m, 2H), 1.25 (d, 6H, J=6.8Hz); ESMS m/e:502.3 (M+H) +
Embodiment 80
N-(3-{1-[(3S)-3-(2-ethoxy phenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 2-thanatol (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (1.16mg, yield 15.5%).
1H NMR (400MHz, CDCl 3) δ 8.06 (s, 1H), 7.52 (s, 1H), 7.40-7.33 (m, 4H), 7.30-7.20 (m, 3H), 6.97 (tangible d, 1H, J=7.7Hz), 6.88 (m, 2H), 6.68 (m, 2H), 5.21 (m, 1H), 4.11 (q, 2H, J=7.3Hz), 3.37 (m, 2H), 2.71 (m, 2H), 2.53 (tangible sept, part is covered, 2H, J=7.6Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.49 (t, 3H, J=7.3Hz), 1.25 (d, 6H, J=6.8.Hz); ESMS m/e:501.4 (M+H) +
Embodiment 81
2-methyl-N-(3-{1-[(3S)-3-(1-naphthoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-propionic acid amide.
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (5.20mg, 0.0137mmol), 1-naphthols (100mg), triphenylphosphine (30.0mg, 0.115mmol) and the diethylazodicarboxylate (7.42mg, 0.0426mmol) mixture in THF (0.50mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.30mg, yield 66.2%).
1H NMR (400MHz, CDCl 3) δ 8.06 (s, 1H), 7.72 (d, 1H, J=8.5Hz), 7.59 (d, 1H, J=8.5Hz), 7.5 (m, 2H), 7.45-7.30 (m, 6H), 7.25 (m, 3H), 7.17 (tangible dd, 1H, J=2.6,9.0Hz), 7.01 (tangible d, 1H, J=2.6Hz), 6.97 (tangible d, 1H, J=7.9Hz), 5.46 (tangible dd, 1H, J=4.5,8.1Hz), 3.12 (m, 2H), 2.61 (m, 2H), 2.53 (significantly sept is partly covered, 2H, J=7.9Hz), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.3Hz, overlapping); ESMS m/e:507.2 (M+H) +
Embodiment 82
N-(3-{1-[(3S)-3-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Step 1
2-[(1S)-3-chloro-1-phenyl propyl]-1H-iso-indoles-1,3 (2H)-diketone
According at Srebnik, M.; Ramachandran, P.V.; Brown, H.C.J.Org.Chem.1988,53, the method of describing among the 2916-2920, with phthalimide (0.147g, 1.0mmol), (R)-(+)-3-chloro-phenyl-1-propanol (0.171g, 1.0mmol), triphenylphosphine (0.262g, 1.0mmol) and the diethylazodicarboxylate (0.174g, 1.0mmol) mixture in THF (5.0mL) at room temperature stirred 24 hours.With the reactant mixture vacuum concentration.Residue concentrates the pentane extract that merges and chromatography (silica gel, hexane-ethyl acetate are eluent at 8: 1) with pentane washing (* 3), obtains the required product (0.121g, yield 50.2%) of yellow solid shape.
1H NMR (400MHz, CDCl 3) δ 7.82 (tangible dd, 2H, J=2.9Hz), 7.70 (tangible dd, 2H, J=2.9Hz), 7.56 (m, 2H), 7.39-7.27 (m, 3H), 5.64 (tangible dd, 1H, J=7.0,9.2Hz), 3.57 (m, 2H), 3.05 (m, 1H), 2.82 (tangible sept, 1H, J=7.0Hz); ESMS m/e:300.13 (M+H) +
Step 2
N-(3-{1-[(3S)-3-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With potassium carbonate (29.2mg, 0.211mmol), sodium iodide (47.5mg, 0.317mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (51.8mg, 0.211mmol) and 2-[(1S)-3-chloro-1-phenyl propyl]-1H-iso-indoles-1,3 (2H)-diketone (63.1mg, 0.211mmol) mixture in DMF (5.0mL) stirred 3 hours down at 100 ℃, this moment, the TLC test shows reacted completely.Reactant mixture is poured in the water (50mL), and with water layer dichloromethane extraction (3 * 30mL).With the organic extract liquid salt water washing (30mL) that merges, with dried over mgso and concentrating under reduced pressure.Crude product is with preparing TLC plate layer chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (74.1mg, 77.1%).
1H NMR (400MHz, CDCl 3) δ 7.83 (tangible dd, 2H, J=2.9Hz), 7.69 (tangible dd, 2H, J=2.9Hz), 7.56 (tangible dt, 3H, J=2.9,7.3Hz), 7.33 (m, 4H), 7.21 (t, 1H, J=7.8Hz), 7.09 (s, 1H), 6.81 (tangible d, 1H, J=7.8Hz), 5.49 (tangible dd, 1H, J=5.5,9.5Hz), 2.98 (d, 1H, J=9.5Hz), 2.87 (m, 2H), 2.50 (tangible sept, 1H, J=6.7Hz), 2.40-2.35 (m, 4H), 1.94 (m, 2H), 1.70-1.50 (m, 4H), 1.25 (d, 6H, J=7.9Hz); ESMS m/e:510.37 (M+H) +
Embodiment 83
2-methyl-N-(3-{1-[(3S)-3-(4-phenoxy group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl) propionic acid amide.
Step 1
4-{[(1S)-and 3-chloro-1-phenyl propyl] the oxygen base }-(4-phenoxy group) benzene
With 4-phenoxy phenyl (1.86g, 10.0mmol), (R)-(-)-3-chloro-phenyl-1-propanol (1.70g, 10.0mmol), triphenylphosphine (2.62g, 10.0mmol) and the diethylazodicarboxylate (1.57mL, 10.0mmol) mixture in THF (5.0mL) at room temperature stirred 24 hours.With the reactant mixture vacuum concentration.Residue concentrates the pentane extract that merges and chromatography (silica gel, hexane-ethyl acetate are eluent at 97: 3) with pentane washing (* 3), obtains the buttery required product of thickness (2.51g, yield 75.7%), and product solidifies when placing.
1H NMR (400MHz, CDCl 3) δ 7.4-7.23 (m, 7H), 7.03 (tangible t, 1H, J=7.3Hz), 6.91 (tangible dm, 2H, J=7.8Hz), 6.93 (tangible q, 4H, J=7.8Hz), 5.31 (tangible dd, 1H, J=4.5,8.6Hz), 3.82 (m, 1H), 3.62 (tangible quintet, 1H, J=5.6Hz), 2.47 (m, 1H), 2.20 (m, 1H).
Step 2
2-methyl-N-(3-{1-[(3S)-3-(4-phenoxy group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl) propionic acid amide.
With 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (65.5mg, 0.266mmol), 4-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base-(4-phenoxy group) benzene (0.100mg, 0.296mmol), potassium carbonate (40.9mg, 0.296mmol) and sodium iodide (67.0mg, 0.444mmol) mixture in DMF (1.0mL) stirred 3 hours down at 100 ℃.Reactant mixture is poured in the water (50mL), and with water layer dichloromethane extraction (3 * 30mL).With the organic extract liquid salt water washing (30mL) that merges, with dried over mgso and concentrating under reduced pressure.Crude product is with preparing TLC plate layer chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (0.109g, 74.6%).
1HNMR (400MHz, CDCl 3) δ 7.48 (s, 1H), 7.40-7.30 (m, 4H), 7.20-7.10 (m, 6H), 7.09 (s, 1H), 6.99 (tangible d, 1H, J=7.8Hz), 6.98 (tangible t, 1H, J=7.8Hz), 6.93 (tangible d, 2H, J=8.4Hz), 6.84 (m, 2H), 5.20 (tangible dd, 1H, J=4.4,8.5Hz), 3.03 (m, 2H), 2.51 (m, 4H), 2.24 (tangible sept, 1H, J=7.8Hz), 2.20-2.10 (m, 3H), 1.90 (m, 4H), 1.25 (d, 6H, J=7.9Hz); ESMS m/e:549.41 (M+H) +
To C 36H 40N 2O 3Value of calculation: C, 78.80; H, 7.35; N, 5.11;
Measured value: C, 78.58; H, 7.48; N, 5.09.
Embodiment 84
N-(4-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Step 1
1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-4-(4-nitrobenzophenone)-1,2,3, the 6-tetrahydropyridine
With potassium carbonate (24.0mg, 0.174mmol), sodium iodide (39.0mg, 0.260mmol), 4-(4-nitrobenzophenone)-1,2,3,6-tetrahydropyridine (35.4mg, 0.174mmol) and 4-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-1, the 2-dimethoxy benzene (53.4mg, 0.174mmol) mixture in DMF (0.5mL) stirred 3 hours down at 100 ℃, and this moment, the TLC test shows reacted completely.Reactant mixture is poured in the water (5.0mL), and with water layer dichloromethane extraction (3 * 30mL).With the organic extract liquid salt water washing (30mL) that merges, with dried over mgso and concentrating under reduced pressure.Crude product is with preparing TLC plate layer chromatography purification [1: the 1=hexane: ethyl acetate, 1%NH 3], obtain the product (63.1mg, 76.6%) of yellow oily.
Product is not purified to be directly used in the next step.
Step 2
4-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } aniline
Under the room temperature, 1-[(3R packs in the 25mL round-bottomed flask that is connected with the hydrogen air bag)-3-(3,4-dimethoxy phenoxy group)-the 3-phenyl propyl]-4-(4-nitrobenzophenone)-1,2,3, and the 6-tetrahydropyridine (63.0mg, 0.133mmol), palladium on carbon (5.0mol-equivalent %, 0.00665mmol, 7.04mg) and ethanol (2.0mL).After 1 hour, the pipe of reactant mixture through being filled with Celite 545 filtered and concentrating under reduced pressure.Not purified being directly used in the next step of crude product (54.1mg, 89.4%).
Step 3
N-(4-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Under the room temperature, with 4-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-the 3-phenyl propyl]-the 4-piperidyl } aniline (5.31mg, 0.0119mmol), isobutyryl chloride (2.08mg, 0.019mmol), N, (8.40mg, 0.0650mmol) mixture in dichloromethane (1.0mL) stirred 24 hours the N-diisopropylethylamine.Concentrated reaction mixture is also used preparation TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery product of thickness (3.5mg, yield 56.5%).
1H NMR (400MHz, CDCl 3) δ 7.38 (d, 1H, J=8.6Hz), 7.30-7.20 (m, 4H), 7.20 (m, 1H), 7.11 (d, 2H, J=8.6Hz), 7.04 (s, 1H), 6.57 (d, 1H, J=8.3Hz), 6.44 (d, 1H, J=2.6Hz), 6.22 (dd, 1H, J=2.6,8.3Hz), 5.09 (tangible dd, 1H, J=4.4,8.1Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.08 (m, 2H), 2.57 (m, 2H), 2.43 (tangible sept, part is covered 2H, J=6.8Hz), and 2.30-2.10 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9Hz); ESNS m/e:517.3 (M+H) +
Embodiment 85
N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Under the room temperature, in the 25mL round-bottomed flask, add triphenylphosphine (9.80mg, 0.0375mmol), diethylazodicarboxylate (5.22mg, 0.0300mmol), N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide (9.53mg, 0.0250mmol), 3-hydroxy acetophenone (100mg) and THF (1.0mL).Reactant mixture is at room temperature stirred spend the night (16 hours).Removal of solvent under reduced pressure, residue is with preparing TLC plate layer chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.73mg, yield 39.9%).
1H NMR (CDCl 3) δ 7.70-7.64 (m, 2H), 7.54 (m, 2H), 7.49-7.44 (m, 6H), 7.25 (m, 1H), 7.05 (d, 1H, J=8.3Hz), 6.96 (tangible d, 1H, J=7.7Hz), 5.34 (tangible dd, 1H, J=4.8,8.2Hz), 3.15 (m, 2H), 2.67 (m, 2H), 2.52 (s, 3H), 2.53 (significantly sept is partly covered, 2H, J=7.6Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, J=6.9Hz); ESMS m/e:499.4 (M+H) +
Synthesizing of option A .4-(3-aminophenyl)-1-piperidine acid tert-butyl ester
A. n-BuLi, diisopropylamine, THF, PhN (Tf) 2,-78 are ℃ to room temperature, 81%
B.3-aminophenyl boric acid Hemisulphate, LiCl, four (triphenylphosphine) close palladium (O), sodium carbonate, DME-H 2O, backflow, 81%
C.10%Pd/C, ethanol, H 2, room temperature, balloon method, 84%
The universal method of option b 1. synthetic MCH antagonisies
Figure A0281721201421
The universal method of option b 2. synthetic MCH antagonisies
Figure A0281721201422
The instantiation of the synthetic MCH antagonist of scheme C1.
The instantiation of the synthetic MCH antagonist of scheme C2.
The instantiation of the synthetic MCH antagonist of scheme D1.
Figure A0281721201441
The instantiation of the synthetic MCH antagonist of scheme D2.
The universal method of the synthetic MCH antagonist of scheme E.
A. diox, diisopropylethylamine, Bu 4Nl, backflow or DMF, KI, sodium carbonate, 90-100 ℃ or toluene, 110 ℃, 18-hat-6
B. diisopropylethylamine, dichloromethane
X＝S(＝O)、C
R 1=aryl, substituted aryl or heterocycle
R 2=aliphatic group or aryl
The universal method of the synthetic MCH antagonist of scheme F.
As R=(CH 2) nCHOH-Ar, then,
Figure A0281721201453
The universal method of the synthetic MCH antagonist of scheme G.
The method of scheme H. He Cheng oxazolidone
A.NH 3, then be TMS-CN;
The methanol solution of b.HCl (room temperature is to refluxing);
C.LAH, THF, backflow;
D. (BOC) 2O, chloroform;
e.NaH、THF
F.Chiralcel OD post
G.NaH, p-nitrophenyl chloroformate ester, THF;
H. amine is as N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide
Ar=3,4-difluorophenyl, 3,5-difluorophenyl or 3,4,5-trifluorophenyl
Method I: the synthetic method that replaces the De oxazolidone together with dialkyl group
A. methyl-magnesium-bromide, THF; B.N, N-carbonyl dimidazoles, DCM; C.NaH, THF, p-nitrophenyl chloroformate ester; D. amine is as N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide
Synthetic and the chiral separation of scheme J: oxazolidone
A (a) tert-butyl lithium, THF, RCHO; (b) CH 3ONH 2HCl, MeOH, more than two the step total recovery 50-68%; (c) Boc 2O, CHCl 3,＞90%; (d) NaH, THF, 76-92%; (e) through the column chromatography for separation diastereomer with separate enantiomer through chirality HPLC, 10-16%; (f) n-BuLi, THF, chloro-carbonic acid 4-nitro phenyl ester ,～75%; (g) THF,＞80%, amine, as N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl acetamide
Scheme K: by aminoacid He Cheng oxazolidone
A.LAH, THF; (b) (BOC) 2O, CHCl 3C.NaH, THF; D. p-nitrophenyl chloroformate ester, NaH, THF; H. amine, N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide
The Ar=aryl, as 4-fluorophenyl or 3, the 4-difluorophenyl
Scheme L: use lactic acid derivative to measure the absolute stereo chemical structure of Er substituted oxazolidinone
Figure A0281721201491
A. pyrrolidine, methanol, heating; B. tert-butyldimethylsilyl chloride; C.LAH, ether, backflow; D. (BOC) 2O, chloroform; E.NaH, THF; H. silica gel column chromatography
Detailed content is referring to Lagu, B.; Wetzel, J.M.; Forray, C.; Patane, M.A.; Bock, M.G. " Determination of the Relative and Absolute Stereochemistryof a Potent α 1 A Selective Adrenoceptor Antagonist " Bioorg.Med.Chem.Lett.2000.10.2705.
Scheme M
Example
Figure A0281721201501
n＝2，R1＝H，R2＝Ph，R3＝H
n＝5，R1＝H，R2＝H，R3＝5-OMe
n＝1，R1＝H，R2＝Ph，R3＝H
n＝4，R1＝H，R2＝H，R3＝5-OMe
Scheme N
Figure A0281721201502
Example
Figure A0281721201503
R1＝6-Cl，R2＝H
R1=H, R2=4 '-tolyl
Scheme P
Figure A0281721201504
Example
Scheme O
R1＝H，R2＝4′-Me
Scheme Q
Example
Figure A0281721201514
Scheme R
Figure A0281721201515
Example
Figure A0281721201521
Experimental section
Used following abbreviation: HOAc, acetic acid; DMF, N, dinethylformamide; EtOAc, ethyl acetate; MeOH, methanol; NMP, 1-Methyl-2-Pyrrolidone; TEA, triethylamine; THF, oxolane; Unless otherwise stated, otherwise all solvent ratios are volume ratio.
1-(4-aminomethyl phenyl)-1H-indole
With 1-H-indole (58.5mg, 0.500mmol), 1-(iodine)-4-methylbenzene (0.218g, 1.00mmol), copper powder (32.0mg, 0.500mmol) and potassium carbonate (0.138g, 1.00mmol) mixture in 1-Methyl-2-Pyrrolidone (1mL) heats 12h in 150 ℃, argon gas atmosphere.Mixture water (6mL) dilution with gained.Water layer dichloromethane extraction (3 * 10mL).The organic extract liquid that merges is with saline (10mL) washing, with dried over mgso and vacuum concentration.Residue uses EtOAc/ hexane (1: 4) eluting through preparation TLC purification, obtains required product (82mg, 79%).
1H?NMR(400MHz，CDCl 3)δ7.67(d，1H，J＝7.7Hz)，7.52(d，1H，J＝7.4Hz)，7.38(d，2H，J＝8.4Hz)，7.34-7.29(m，3H)，7.21(t，1H，J＝7.0Hz)，7.15(t，1H，J＝7.0Hz)，6.66(d，1H，3.3Hz)，2.43(s，3H)；ESMS?m/e：208.0(M+H) +。
Embodiment 86
N-(3-{1-[(6-chloro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.369g, 1.50mmol) and 37% weight formalin (30.0mg, 1.50mmol) solution in 1mL HOAc ∶ diox (1: 4) adds 6-chloro-1-H-indole (0.152g, 1.00mmol) in, reactant mixture is at room temperature stirred 12h.Mixture water (10mL) dilution of gained.(3 * 100mL) extract water layer with dichloromethane.The organic extract liquid that merges is used dried over mgso with saline (10mL) washing, and vacuum concentration.Residue uses 5%NH through preparation of silica gel TLC purification 3(2.0M methanol solution) solution in dichloromethane, eluting obtain required product (79mg, 42%).
1H?NMR(400MHz，CDCl 3)δ9.14(s，1H)，8.04(s，1H)，7.52(t，2H，J＝8.1Hz)，7.35(d，2H，J＝13.3Hz)，7.18(t，1H，J＝7.9Hz)，7.09(dd，1H，J＝1.9，8.5Hz)，6.85(d，1H，J＝7.4Hz)，5.18(s，1H)，4.01(s，2H)，2.55(septet，1H，J＝6.8Hz)，2.48-2.34(m，3H)，2.08-1.95(m，4H)，1.78(d，2H，J＝12.8Hz)，1.22(d，6H，J＝6.8Hz)；ESMSm/e：410.1(M+H) +。
Embodiment 87
2-methyl-N-[3-(1-{[1-(4-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to synthetic N-(3-{1-[(6-chloro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, by 1-(4-aminomethyl phenyl)-1H-indole (0.207g, 1.00mmol) obtain 2-methyl-N-[3-(1-{[1-(4-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide. (0.441g, 78%).
1H?NMR(400MHz，CDCl 3)δ7.90(s，1H)，7.73(d，1H，J＝7.2Hz)，7.58-7.51(m，2H)，7.43-7.36(m，3H)，7.35-7.29(m，3H)，7.26-7.15(m，3H)，6.89(d，1H，J＝7.7Hz)，4.07(s，2H)，3.36(d，2H，J＝11.6Hz)，2.59-2.39(m，6H)，2.55(sept，1H，J＝6.7Hz)，2.10-1.98(m，2H)，1.83(d，2H，J＝12.9Hz)，1.23(d，6H，J＝6.9Hz)；ESMS?m/e：466.2(M+H) +。
2-[(1S)-3-chloro-1-phenyl propyl]-1H-iso-indoles-1,3 (2H)-diketone
With triphenylphosphine (5.25g, 20.0mmol) and diethylazodicarboxylate (3.58g, 20.0mmol) add (1R)-3-chloro-1-phenyl-1-propanol (3.42g, 20.0mmol) and phthalimide (2.94g is in THF 20.0mmol) (100mL) solution.Under the room temperature reactant mixture is stirred 4h.Removal of solvent under reduced pressure, residue grind (3 * 50mL) in pentane.The pentane partial vacuum that merges is concentrated, and crude product uses EtOAc/ hexane (3: 97) eluting through the silica gel column chromatography purification, obtains required product (4.40g, 74%).
1H?NMR(400MHz，CDCl 3)δ7.82(d，1H，J＝5.7Hz)，7.81(d，1H，J＝5.5Hz)，7.70(d，1H，J＝5.4Hz)，7.69(d，1H，J＝5.8Hz)，7.55(d，2H，J＝7.2Hz)，7.38-7.28(m，3H)，5.64(dd，1H，J＝6.8，9.2Hz)，3.56(t，2H，J＝6.4Hz)，3.11-3.02.(m，1H)，2.85-2.75(m，1H)；ESMS?m/e：300.1(M+H) +。
N-(3-{1-[(3S)-3-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 2-[(1 S)-3-chloro-1-phenyl propyl]-1H-iso-indoles-1,3 (2H)-diketone (4.50g, 15.0mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (4.26g, 15.0mmol), potassium carbonate (4.16g, 30.0mmol) and NaI (3.40g, 20.0mmol) mixture in DMF (40mL) stirred 12 hours down at 90 ℃.With reactant mixture water (50mL) dilution, (3 * 50mL) extractions are with the organic extract liquid that merges saline (50mL) washing, with dried over mgso and concentrating under reduced pressure with dichloromethane.Residue uses 5% NH through the silica gel column chromatography purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product (5.10g, 74%).
1H?NMR(400MHz，CDCl 3)δ7.83(d，1H，J＝5.5Hz)，7.82(d，1H，J＝5.5Hz)，7.71(d，1H，J＝5.5Hz)，7.70(d，1H，J＝5.4Hz)，7.56(d，2H，J＝7.1Hz)，7.35-7.27(m，5H)，7.22(t，1H，J＝7.5Hz)，7.09(s，1H)，6.81(d，1H，J＝7.8Hz)，5.49(dd，1H，J＝5.5，9.6Hz)，2.97(d，1H，J＝10.1Hz)，2.92-2.82(m，2H)，2.44(sept，1H，J＝6.7Hz)，2.40-2.29(m，3H)，2.00-1.83(m，2H)，1.79-1.39(m，5H)，1.26(d，6H，J＝6.9Hz)；ESMS?m/e：510.4(M+H) +。
N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With N-(3-{1-[(3S)-3-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl)-the 3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide (4.60g, 9.06mmol) and hydrazine (3.62g, 72.4mmol) the mixture backflow 12h in ethanol (150mL).The white precipitate of gained is filtered and vacuum concentrated filtrate.Residue with dichloromethane/EtOAc (1: 1,3 * 50mL) washings and will merge the machine eluate vacuum concentration arranged, obtain required product (2.90g, 95%).
1H?NMR(400MHz，CDCl 3)δ7.45(s，1H)，7.39-7.30(m，6H)，7.29-7.19(m，2H)，6.95(d，1H，J＝7.2)，4.01(t，1H，J＝6.8Hz)，3.04(t，2H，J＝10.6Hz)，2.62-2.30(m，6H)，2.05-1.70(m，8H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e：380.4(M+H) +。
Embodiment 88
2-methyl-N-(3-{1-[(3S)-3-phenyl-3-(propionamido) propyl group]-the 4-piperidyl) phenyl) propionic acid amide.
According to synthetic N-(3-{1-[(3S)-3-(acetylamino)-3-phenyl propyl]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, by N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (11.0mg, 0.0280mmol) and propionyl chloride (3.80mg, 0.0420mmol) obtain 2-methyl-N-(3-{1-[(3S)-3-phenyl-3-(propionamido) propyl group]-the 4-piperidyl) phenyl) propionic acid amide. (12mg, yield 97%).
1H?NMR(400MHz，CDCl 3)δ8.05(s，1H)，7.59(s，1H)，7.40-7.20(m，7H)，6.96(s，1H)，5.19-5.12(m，1H)，3.18(d，1H，J＝12.0Hz)，2.99(d，1H，J＝10.4Hz)，2.93-2.86(m，1H)，2.61-2.40(m，3H)，2.38-2.23(m，3H)，2.19-1.75(m，8H)，1.25(d，6H，J＝6.9Hz)，1.22-1.08(m，3H)；ESMS?m/e：436.4(M+H) +。
Embodiment 89
N-(3-{1-[(3S)-3-{[(4-fluorophenyl) acetyl group] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
With N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (11.0mg, 0.0280mmol) and (4-fluorophenyl) chloroacetic chloride (7.20mg, 0.0420mmol) mixture in THF (5mL) at room temperature stirred 4 hours.Removal of solvent under reduced pressure, residue be through preparation TLC purification, and with hexane: ethyl acetate (2: 1) eluting obtains required product (13mg, yield 90%).
1H?NMR(400MHz，CDCl 3)δ7.89(d，1H，J＝8.4Hz)，7.59(s，1H)，7.31-6.93(m，13H)，5.13(q，1H，J＝6.0Hz)，3.56(s，2H)，3.07(d，1H，J＝11.7Hz)，2.91(d，1H，J＝11.0Hz)，2.62-2.42(m，2H)，2.40-2.30(m，1H)，2.12-1.54(m，9H)，1.24(d，6H，J＝6.7Hz)；ESMS?m/e：515.3(M+H) +。
Embodiment 90
N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 1,1-diphenyl hydrazonium salt hydrochlorate (10.3mg, 0.0470mmol), 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl propionic acid amide. (14.7mg, 0.0362mmol), ZnCl 2(14.85mg, 0.109mmol) and the mixture of HOAc (0.5mL) 80 ℃ of down heating 4 hours.With gained crude mixture water (10mL) dilution, water layer is with the saturated potassium carbonate neutralization and with dichloromethane extraction (3 * 20mL).With the organic layer vacuum concentration that merges, residue uses 5% NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane, obtain product N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide (4.1mg, 37%).
1H?NMR(400MHz，CDCl 3)δ7.71-7.65(m，1H)，7.42(d，1H，J＝7.4Hz)，7.39(s，1H)，7.36-7.15(m，15H)，6.94(d，1H，J＝7.8Hz)，3.12(d，2H，J＝11.2Hz)，2.90(t，2H，J＝7.8Hz)，2.59-2.45(m，3H)，2.19-1.91(m，7H)，1.82(d，2H，J＝13.5Hz)，1.24(d，6H，J＝6.9Hz)；?ESMS?m/e：555.3(M+H) +。
Embodiment 91
N-(3-{1-[3-(5-methoxyl group-2-phenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl) phenyl)-the 2-methyl propanamide
(3-{1-[3-(1 according to synthetic N-, 2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, by 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide. (15.6mg, 38.2mmol) and 1-(4-methoxyphenyl) hydrazonium salt hydrochlorate (8.00mg, 0.0458mmol) obtain N-(3-{1-[3-(5-methoxyl group-2-phenyl-1H-indol-3-yl) propyl group]-4-piperidyl) phenyl)-2-methyl propanamide (3.9mg, yield 20%).
1H?NMR(400MHz，CDCl 3)δ8.06(s，1H)，7.55.(d，2H，J＝7.4Hz)，7.43-7.39(m，3H)，7.38-7.35(m，2H)，7.27-7.19(m，3H)，7.08(d，1H，J＝7.4Hz)，6.94(d，1H，J＝7.6Hz)，6.87(dd，1H，J＝4.0，6.6Hz)，3.88(s，3H)，3.80-3.69(m，1H)，2.99(d，2H，J＝11.7Hz)，2.89(t，2H，J＝7.3)，2.55-2.39(m，4H)，2.02-1.88(m，3H)，1.82-1.68.(m，4H)，1.24(d，6H，J＝6.9Hz)；ESMS?m/e：510.3(M+H) +。
Embodiment 92
N-(3-{1-[4-(5-methoxyl group-2-phenyl-1H-indol-3-yl) butyl]-the 4-piperidyl) phenyl)-the 2-methyl propanamide
(3-{1-[3-(1 according to synthetic N-, 2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, by 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. (14.3mg, 0.0339mmol) and 1-(4-methoxyphenyl) hydrazonium salt hydrochlorate (7.10mg, 0.0407mmol) obtain N-(3-{1-[4-(5-methoxyl group-2-phenyl-1H-indol-3-yl) butyl]-4-piperidyl) phenyl)-2-methyl propanamide (5.8mg, yield 33%).
1H?NMR(400MHz，CDCl 3)δ7.95(d，2H，J＝7.8Hz)，7.61-7.15(m，11H)，6.97(d，1H，J＝7.0Hz)，3.88(s，3H)，3.09(d，2H，J＝11.3Hz)，2.99(t，2H，J＝7.0Hz)，2.55-2.35(m，4H)，2.12-1.70(m，6H)，1.68-1.52(m，2H)，1.48-1.34(m，2H)，1.25(d，6H，J＝6.7Hz)；ESMS?m/e：524.3(M+H) +。
Embodiment 93
2-methyl-N-(3-{1-[(1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl) phenyl) propionic acid amide.
(3-{1-[3-(1 according to synthetic N-, 2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, by N-{3-[1-(3,3-dimethoxy propyl group)-and the 4-piperidyl] phenyl }-2-methyl propanamide (15.2mg, 0.0436mmol) and 1,1-diphenyl hydrazonium salt hydrochlorate (11.6mg 0.0524mmol) obtains 2-methyl-N-(3-{1-[(1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl) phenyl) propionic acid amide. (11mg, yield 56%).
1H?NMR(400MHz，CDCl 3)δ7.79(d，1H，J＝7.8Hz)，7.57(d，1H，J＝7.7Hz)，7.54-7.47(m，4H)，7.43-7.32(m，4H)，7.25-7.16(m，4H)，6.95(d，1H，J＝7.8Hz)，3.87(s，2H)，2.53-2.47(m，2H)，2.21(dt，2H，J＝3.0，10.5Hz)，2.12-1.77(m，6H)，1.24(d，6H，J＝6.9Hz)；?ESMS?m/e：451.3(M+H) +。
Embodiment 94
2-methyl-N-(3-{1-[(4E)-4-phenyl-4-(2-pyridine radicals hydrazono-) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
(3-{1-[3-(1 according to synthetic N-, 2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, by 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. (8.70mg, 0.0223mmol) and 2-hydrazino pyridine (2.92mg, 0.0268mmol) obtain 2-methyl-N-(3-{1-[(4E)-4-phenyl-4-(2-pyridine radicals hydrazono-) butyl]-the 4-piperidyl } phenyl) propionic acid amide. (2.5mg, yield 24%).
1H?NMR(400MHz，CDCl 3)δ7.97(d，1H，J＝8.6Hz)，7.85(d，1H，J＝7.3Hz)，7.64-7.27(m，9H)，7.09(d，1H，J＝8.0Hz)，6.97(d，1H，J＝8.4Hz)，6.73(q，1H，J＝6.6Hz)，3.52-3.48(m，2H)，3.20-3.10(m，2H)，2.85-1.75(m，13H)，1.26(d，6H，J＝6.8Hz)；ESMS?m/e：484.4(M+H) +。
Embodiment 95
N-(3-{1-[3-(5-methoxyl group-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
(3-{1-[3-(1 according to synthetic N-, 2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-method of 2-methyl propanamide, (3-{1-[4-(1 by N-, 3-dioxolane-2-yl) butyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (23.5mg, 0.0628mmol) and 1-(4-methoxyphenyl) hydrazonium salt hydrochlorate (13.2mg, 0.0774mmol) obtain N-(3-{1-[3-(5-methoxyl group-1H-indol-3-yl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide (11mg, yield 42%).
1HNMR(400MHz，CDCl 3)δ7.86(s，1H)，7.45(s，1H)，7.32(d，1H，J＝8.4Hz)，7.28-7.21(m，2H)，7.10(s，1H)，7.05(d，1H，J＝2.3Hz)，7.00-6.91(m，2H)，6.85(dd，1H，J＝2.7，9.0Hz)，3.87(s，3H)，3.06(d，2H，J＝11.6Hz)，2.75(t，2H，J＝7.2Hz)，2.55-2.42(m，4H)，2.08-1.90(m，4H)，1.88-1.74(m，4H)，1.25(d，6H，J＝6.9Hz)；ESMS?m/e：434.2(M+H) +。
4-[3-(propionamido) phenyl]-the 1-piperidine acid tert-butyl ester
With propionyl chloride (5.53g, 0.0597mol) be added dropwise to 4-(3-aminophenyl)-1-piperidine acid tert-butyl ester (15.0g, 0.0543mol) and TEA (16.5g 0.163mol) in the solution in THF (200mL), at room temperature stirred mixture 3 hours.Add entry (50mL) in described reactant mixture, (wash the organic extract liquid that merges, with dried over sodium sulfate and concentrating under reduced pressure with saline (50mL) by 3 * 100mL) extractions with dichloromethane for water layer.Residue uses hexane/ethyl acetate (10: 1) eluting through the silica gel column chromatography purification, obtains product (18.8g, 99%).
1H?NMR(400MHz，CDCl 3)δ7.48(s，1H)，7.34-7.21(m，3H)，6.93(d，1H，J＝7.4Hz)，2.77(t，2H，J＝11.5Hz)，2.68-2.58(m，1H)，2.38(q，2H，J＝7.6Hz)，1.87-1.67(m，4H)，1.67-1.54(m，2H)，1.48(s，9H)，1.25(t，3H，J＝7.5Hz)；ESMS?m/e：333.4(M+H) +。
N-[3-(4-piperidyl) phenyl] propionic acid amide.
Under 5 ℃, toward 4-[3-(propionamido) phenyl that is stirring]-(18.8g 0.0543mmol) fed the hydrogen chloride gas bubbling 2 hours in the solution in the Zai diox (100mL) to the 1-piperidine acid tert-butyl ester.Solvent removed in vacuo in residue water-soluble (100mL), adds the neutralization of 10% potassium hydroxide aqueous solution.Water layer with the mixed liquor extraction of chloroform/isopropyl alcohol (3: 1) (3 * 200mL), the organic layer that merges with saline (100mL) washing, use dried over sodium sulfate, filter also vacuum concentration.Residue uses 5% NH through purification by silica gel column chromatography 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product (12.6g, 99%).
1H?NMR(400MHz，CDCl 3)δ7.44(s，1H)，7.32(d，1H，J＝7.2Hz)，7.28-7.21(m，1H)，7.09(s，1H)，6.97(d，1H，J＝7.6Hz)，3.18(d，2H，J＝12.6Hz)，2.73(dt，2H，J＝2.2，11.2Hz)，2.65-2.57(m，1H)，2.38(q，2H，J＝7.4Hz)，1.83(d，2H，J＝12.1Hz)，1.70-1.61(m，3H)，1.25(t，3H，J＝7.5Hz)；ESMS?m/e：233.1(M+H) +。
The 4-{3-[(cyclopropyl carbonyl) amino] phenyl }-the 1-piperidine acid tert-butyl ester
According to synthetic 4-[3-(propionamido) phenyl]-method of 1-piperidine acid tert-butyl ester, by 4-(3-aminophenyl)-1-piperidine acid tert-butyl ester (16.47g, 0.0596mol) and cyclopropanecarbonyl chloride (6.27g, 0.0597mol), obtain the 4-{3-[(cyclopropyl carbonyl) amino] phenyl }-1-piperidine acid tert-butyl ester (18.1g, yield 100%).
1H?NMR(400MHz，CDCl 3)δ7.55-7.46(m，2H)，7.29-7.21(m，2H)，6.96-6.89(m，1H)，2.79(t，2H，J＝12.1Hz)，2.68-2.58(m，1H)，1.84(d，2H，J＝12.6Hz)，1.83-1.76(m，4H)，1.48(s，9H)，1.19-1.12(m，1H)，1.09-1.05(m，2H)，0.89-0.75(m，2H)；ESMS?m/e：345.5(M+H) +。
N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide
According to synthetic N-[3-(4-piperidyl) phenyl] method of propionic acid amide., by the 4-{3-[(cyclopropyl carbonyl) amino] phenyl }-1-piperidine acid tert-butyl ester (18.9g, 0.0543mol) obtain N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide (13.2g, yield 100%).
1H?NMR(400MHz，CDCl 3)δ7.46(s，1H)，7.36-7.22(m，3H)，7.23(d，1H，J＝6.9Hz)，3.17(d，2H，J＝11.9Hz)，2.72(dt，2H，J＝2.6，12.2Hz)，2.65-2.55(m，1H)，1.82(d，2H，J＝13.9Hz)，1.63(dt，3H，J＝4.1，12.5Hz)，1.53-1.45(m，1H)，1.11-1.06(m，2H)，0.87-0.81(m，2H)；ESMS?m/e：245.03(M+H) +。
1-(6-chlorine hexyl)-1H-indole
Under 0 ℃, (0.249g is 10.0mmol) with interior 1-H-indole (0.585g, DMF 5.00mmol) (2mL) solution of adding of the mixture of DMF (5mL) toward NaH.Reactant mixture was stirred 30 minutes, and be warming up to room temperature.(0.998g 5.00mmol), stirs the gained reactant mixture and spends the night to drip 1-bromo-6-chlorohexane by syringe subsequently.Described reactant mixture is diluted with ethyl acetate (30mL), wash with water (3 * 10mL), use dried over mgso, vacuum concentration, chromatography purification uses hexane/ethyl acetate (97.5: 2.5) eluting, obtains required product (0.900g, 76%).
1H?NMR(CDCl 3)δ7.76-7.54(m，1H)，7.47-6.96(m，4H)，6.60-6.34(m，1H)，4.13(t，2H，J＝6.8Hz)，3.50(t，2H，J＝5.6Hz)，1.98-1.79(m，2H)，1.79-1.64(m，2H)，1.54-1.17(m，4H)。
1-(5-chlorine amyl group)-1H-indole
According to the method for synthetic 1-(6-chlorine hexyl)-1H-indole, (0.585g, 5.00mmol) (0.928g 5.00mmol) obtains required product (0.890g, yield 80%) with 1-bromo-5-chloropentane by the 1-H-indole.
1H?NMR(CDCl 3)δ7.76-7.51(m，1H)，7.44-6.96(m，4H)，6.60-6.38(m，1H)，4.11(t，2H，J＝6.8Hz)，3.47(t，2H，J＝6.4Hz)，1.97-1.79(m，2H)，1.79-1.61(m，2H)，1.58-1.32(m，2H)。
Embodiment 96
N-(3-{1-[6-(1H-indole-1-yl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Merge 1-(6-chlorine hexyl)-1H-indole (23.6mg, 0.100mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (24.6mg, 0.100mmol), potassium carbonate (27.6mg, 0.200mmol), NaI (22.5mg, 0.150mmol) and DMF (1.00mL), and under 100 ℃, stir and spend the night.Reactant mixture is cooled to room temperature, and crude product uses 5% NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains the required product of yellow solid shape (40mg, 90%).
1H?NMR(400MHz，CDCl 3)δ8.08-6.52(m，11H)，4.17(t，2H，J＝7.2Hz)，3.26(d，2H，J＝11.6Hz)，2.74-2.52(m，4H)，2.44-2.28(m，2H)，2.20-2.02(m，2H)，1.98-1.82(m，4H)，1.78-1.62(m，2H)，1.43-1.28(m，4H)，1.28(d，6H，J＝6.8Hz)；ESMS?m/e：446.5(M+H) +。
Embodiment 97
N-(3-{1-[5-(1H-indole-1-yl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
As above method is prepared, use 1-(5-chlorine amyl group)-1H-indole (22.2mg, 0.100mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (24.6mg, 0.100mmol), potassium carbonate (27.6mg, 0.200mmol), NaI (23.0mg, 0.150mmol) and DMF (1.00mL), obtain the required product (36mg, 81%) of yellow oily.
1H?NMR(400MHz，CDCl 3)δ8.08-6.52(m，11H)，4.19(t，2H，J?＝?7.2Hz)，3.26-3.10(m，2H)，2.71-2.55(m，2H)，2.55-2.42(m，2H)，2.35-2.12(m，2H)，2.12-1.80(m，6H)，1.80-1.57(m，2H)，1.51-1.34(m，2H)，1.31(d，6H，J＝6.8Hz)；ESMS?m/e：432.2(M+H) +。
Embodiment 98
N-(4-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to synthetic N-(3-{1-[4-(4-chlorophenoxy) benzyl]-the 4-piperidyl phenyl)-method of 2-methyl propanamide (embodiment 108), (3-{1-[3-(1 by N-, 2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide, 9-ethyl-9H-carbazole-3-formaldehyde (22.3mg, 0.100mmol) and 2-methyl-N-[4-(4-piperidyl) phenyl] propionic acid amide. (24.6mg, 0.100mmol) obtain N-(4-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (20mg, 44%), is white crystalline solid.
1HNMR(400MHz，CDCl 3)δ8.21-7.09(m，12H)，4.38(q，2H，J＝7.2Hz)，3.81(s，2H)，3.25-3.03(m，2H)，2.60-2.38(m，2H)，2.31-2.09(m，2H)，1.98-1.69(m，4H)，1.44(t，3H，J＝7.2Hz)，1.23(d，6H，J＝6.8Hz)；ESMS?m/e：454.3(M+H) +。
Embodiment 99
N-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to synthetic N-(3-{1-[4-(4-chlorophenoxy) benzyl]-the 4-piperidyl phenyl)-method of 2-methyl propanamide (embodiment 108), by N-(4-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-2-methyl propanamide, 9-ethyl-9H-carbazole-3-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. obtains N-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (37mg, 95%).
1H?NMR(400MHz，CDCl 3)δ8.24-6.29(m，12H)，4.37(q，2H，J＝7.2Hz)，3.82(s，2H)，3.23-3.06(m，2H)，2.65-2.38(m，2H)，2.31-2.11(m，2H)，2.01-1.73(m，4H)，1.43(t，3H，J＝7.2Hz)，1.25(d，6H，J＝4.0Hz)；?ESMS?m/e：454.3(M+H) +。
Embodiment 100
N-[3-(1-{[1-(4-methoxyphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
Method according to synthetic 1-(4-aminomethyl phenyl)-1H-indole, by N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-2-methyl propanamide (37.5mg, 0.100mmol) and 1-iodo-4-methoxybenzene (46.8mg 0.200mmol) obtains required product (27mg, 56%).
1H?NMR(400MHz，CDCl 3)δ7.70-6.58(m，14H)，3.88(s，3H)，3.67(s，2H)，3.14-3.01(m，2H)，2.57-2.41(m，2H)，2.25-2.01(m，2H)，1.93-1.69(m，4H)，1.24(d，6H，J＝7.2Hz)；ESMSm/e：482.2(M+H) +。
Embodiment 101
N-[3-(1-{[1-(4-fluorophenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
Method according to synthetic 1-(4-aminomethyl phenyl)-1H-indole, by N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-2-methyl propanamide (37.5mg, 0.100mmol) and 1-fluoro-4-iodobenzene (44.4mg 0.200mmol) obtains required product (21mg, 45%).
1H?NMR(400MHz，CDCl 3)δ7.71-6.60(m，14H)，3.69(s，2H)，3.19-2.99(m，2H)，2.62-2.41(m，2H)，2.22-2.07(m，2H)，1.94-1.70(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e：470.2(M+H) +。
Embodiment 102
4-[5-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-1H-indole-1-yl] essence of Niobe
Method according to synthetic 1-(4-aminomethyl phenyl)-1H-indole, by N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-2-methyl propanamide (37.5mg, 0.100mmol) and 4-iodo-benzoic acid methyl ester (52.4mg 0.200mmol) obtains required product (11mg, 22%).
1H?NMR(400MHz，CDCl 3)δ8.31-6.64(m，14H)，3.96(s，3H)，3.67(s，2H)，3.16-2.96(m，2H)，2.57-2.41(m，2H)，2.18-2.02(m，2H)，1.91-1.73(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMSm/e：510.2(M+H) +。
Embodiment 103
2-methyl-N-[3-(1-{[1-(3-aminomethyl phenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
Method according to synthetic 1-(4-aminomethyl phenyl)-1H-indole, by N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-2-methyl propanamide (37.5mg, 0.100mmol) and 1-iodo-3-methylbenzene (43.6mg 0.200mmol) obtains required product (28mg, 60%).
1H?NMR(400MHz，CDCl 3)δ7.68-6.60(m，14H)，3.66(s，2H)，3.16-2.96(m，2H)，2.59-2.44(m，2H)，2.44(s，3H)，2.18-2.01(m，2H)，1.91-1.68(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMSm/e：466.2(M+H) +。
Embodiment 104
N-{3-[1-(3-{[(4-chloro-3-nitrobenzophenone) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
With N-{3-[1-(2-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide (10.0mg, 0.0350mmol), 4-chloro-3-nitrobenzene sulfonyl chloride (9.90mg, 0.0380mmol) and TEA (7.00mg, 0.0700mmol) mixture in THF (2mL) at room temperature stirred 12 hours.Crude product obtains required product (16mg, 86%) through preparation TLC (methylene chloride/2-aminopropane .=19: 1: 0.2) purification.
1HNMR(400MHz，CDCl 3)δ8.45-8.38(m，1H)，8.02(d，1H，J＝8.4Hz)，7.72(d，1H，J＝8.8Hz)，7.48-7.40(m，3H)，7.29-7.24(m，2H)，6.96(d，1H，J＝7.5Hz)，3.17-3.09(m，4H)，2.63-2.48(m，4H)，2.15(t，2H，J＝11.8Hz)，1.96-1.72(m，6H)，1.25(d，6H，J＝6.9Hz)；ESMS?m/e：523.2(M+H) +。
Embodiment 105
N-[3-(1-{5-[4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-yl] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
With 3-(5-bromine amyl group)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone (38.0mg, 0.110mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (26.0mg, 0.100mmol), NaI (23.0mg, 0.1 50mmol) and potassium carbonate (14.0mg, 0.100mmol) mixture in DMF (2mL) is 50 ℃ of down heating 1 hour.Crude product obtains required product (21mg, 41%) through preparation TLC (methylene chloride/2-aminopropane .=19: 1: 0.2) purification.
1H?NMR(400MHz，CDCl 3)δ7.49(s，1H)，7.39-7.32(m，2H)，7.26-7.20(m，2H)，7.18-7.11(m，1H)，7.10-7.03(m，1H)，6.96(d，1H，J＝7.6Hz)，4.80-4.73(m，1H)，4.62(t，1H，J＝7.9Hz)，4.09-4.04(m，1H)，3.51-3.42(m，1H)，3.03(d，2H，J＝11.7Hz)，2.82-2.72(m，1H)，2.51-2.42(m，2H)，2.32(t，2H，J＝7.9Hz)，2.11(s，1H)，2.03-1.97(m，2H)，1.85-1.70(m，4H)，1.49(m，4H)，1.31-1.27(m，1H)，1.24(d，6H，J＝6.9Hz)；ESMS?m/e：514.4(M+H) +。
Embodiment 106
3-(2, the 6-Dichlorobenzene base)-N-(5-{4-[3-(isobutyryl amino) phenyl]-piperidino } amyl group]-5-methyl-4-Isoxazolecarboxamidederivatives
With 3-(2; the 6-Dichlorobenzene base)-4-formoxyl-5-isoxazole formyl chloride (69.0mg; 0.250mmol), N-{3-[1-(5-amino amyl group)-4-piperidyl] phenyl-2-ethyl propionic acid amide. (44.0mg; 0.150mmol), (30.0mg, 0.300mmol) mixture in THF (2mL) at room temperature stirred 12 hours TEA.Crude product obtains required product (52mg, 67%) through preparation TLC (methylene chloride/2-aminopropane .=19: 1: 0.2) purification.
1H?NMR(400MHz，CDCl 3)δ7.52-7.49(m，2H)，7.49-7.41(m，2H)，7.39-7.31(m，2H)，7.29-7.21(m，2H)，6.92(d，1H，J＝7.6Hz)，3.25-3.11(m，5H)，2.81-2.74(m，4H)，2.58-2.44(m，4H)，2.30-2.19(m，2H)，1.93-1.78(m，4H)，1.56-1.44(m，2H)，1.31-1.28(m，2H)，1.24(d，6H，J＝6.6Hz)；ESMS?m/e：585.2(M+H) +。
Embodiment 107
N-[3-(1-{2-[(diphenyl acetyl group) amino] ethyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
With N-{3-[1-(2-amino-ethyl)-4-piperidyl] phenyl }-2-methyl propanamide (20.0mg, 0.0700mmol), diphenyl-acetyl chloride (23.0mg, 0.110mmol) and TEA (20.0mg, 0.140mmol) mixture in THF (2mL) stirs down at 23 ℃ and spends the night.Crude product obtains required product (8.0mg, 47%) through preparation TLC (methylene chloride/2-aminopropane .=19: 1: 0.2) purification.
1H?NMR(400MHz，CDCl 3)δ7.53(s，1H)，7.37-7.20(m，13H)，6.97-6.92(m，1H)，6.67(s，1H)，4.98(s，1H)，3.43(q，2H，J＝5.9Hz)，2.90(d，2H，J＝11.6Hz)，2.57-2.42(m，4H)，2.11(t，2H，J＝10.4Hz)，1.75(d，2H，J＝12.4Hz)，1.70-1.58(m，2H)，1.25(d，6H，J＝6.7Hz)；ESMS?m/e：484.2(M+H) +。
Embodiment 108
N-(3-{1-[4-(4-chlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 4-(4-chlorophenoxy) benzaldehyde (0.119g, 0.510mmol) and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.126g, 0.510mmol) 1, mix in the 2-dichloroethanes (5mL), use sodium triacetoxy borohydride (0.424g subsequently, 2.00mmol) and HOAc (0.03mL, 0.5mmol) processing.Mixture at room temperature stirred spend the night.With saturated sodium bicarbonate aqueous solution neutralization reaction mixture, water layer dichloromethane extraction (3 * 10mL).With the organic layer salt water washing that merges, use dried over mgso, vacuum concentration through preparation TLC purification, uses 5% NH 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product (53mg, 23%).
1H?NMR(400MHz，CDCl 3)δ7.50(s，1H)，7.34-7.19(m，7H)，6.98-6.87(m，5H)，3.50(s，2H)，2.98(d，2H，J＝11.8Hz)，2.58-2.44(m，2H)，2.10-1.98(m，2H)，1.83-1.76(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e：463.2(M+H) +。
Embodiment 109
N-{3-[1-(2,5-dimethyl-1-[3-(trifluoromethyl) phenyl]-1H-pyrroles-3-yl } methyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
The method of describing according to embodiment 108 prepares, with 2, and 5-dimethyl-1-[3-(trifluoromethyl) phenyl]-(0.136g 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde to 1H-pyrroles-3-formaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.69-7.56(m，2H)，7.53-7.32(m，4H)，7.28-7.18(m，2H)，6.99(s，1H)，5.98(s，1H)，3.43(s，2H)，3.16-3.06(m，2H)，2.57-2.42(m，2H)，2.07-1.95(m，8H)，1.89-1.76(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e：498.2(M+H) +。
Embodiment 110
N-(3-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to the method preparation that embodiment 108 describes, (0.119g 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde with 4-(3,4-two fluorophenoxies) benzaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.52(s，1H)，7.32(d，2H，J＝8.4Hz)，7.28-7.21(m，2H)，7.14-7.06(m，2H)，6.98-6.94(m，3H)，6.86-6.79(m，1H)，6.76-6.69(m，1H)，3.51(s，2H)，2.99(d，2H，J＝11.7Hz)，2.55-2.44(m，2H)，2.12-2.02(m，2H)，1.86-1.74(m，4H)，1.25(d，6H，J＝7.0Hz)；ESMS?m/e：465.2(M+H) +。
Embodiment 111
N-(3-{1-[(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to the method preparation that embodiment 108 describes, (0.113g 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde with 5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-formaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.62-7.19(m，9H)，6.97(s，1H)，3.43(s，2H)，3.08-2.98(m，2H)，2.58-2.43(m，2H)，2.39-2.32(m，3H)，2.18-1.71(m，6H)，1.24(d，6H，J＝6.9Hz)；?ESMS?m/e：451.2(M+H) +。
Embodiment 112
N-(3-{1-[4-(3, the 4-dichlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to the method preparation that embodiment 108 describes, (0.136g 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde with 4-(3,4-two fluorophenoxies) benzaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.53(s，1H)，7.36-7.18(m，6H)，7.08(d，1H，J＝1.8Hz)，6.96(d，3H，J＝6.8Hz)，6.84(dd，1H，J＝2.8，8.9Hz)，3.51(s，2H)，2.99(d，2H，J＝11.5Hz)，2.55-2.42(m，2H)，2.12-2.02(m，2H)，1.84-1.73(m，4H)，1.24(d，6H，J＝7.0Hz)；ESMS?m/e：497.1(M+H) +。
Embodiment 113
2-methyl-N-(3-{1-[(2-phenyl-1H-imidazol-4 yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to the method preparation that embodiment 108 describes, (88.0mg 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde with 2-phenyl-1H-imidazoles-4-formaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.92(d，2H，J＝7.4Hz)，7.65-7.31(m，6H)，7.28-7.18(m，2H)，7.12-7.05(m，1H)，6.95-6.88(m，1H)，3.69(s，2H)，3.17-3.05(m，2H)，2.62-2.45(m，2H)，2.28-2.18(m，2H)，1.88-1.70(m，4H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：403.2(M+H) +。
Embodiment 114
N-(3-{1-[4-(diphenyl amino) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to the method preparation that embodiment 108 describes, (0.139g 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde with 4-(diphenyl amino) benzaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.49(s，1H)，7.39-6.92(m，18H)，3.49(s，2H)，3.02-2.99(m，2H)，2.59-2.43(m，2H)，2.15-2.03(m，2H)，1.92-1.76(m，4H)，1.23(d，6H，J＝6.8Hz)；ESMS?m/e：504.2(M+H) +。
Embodiment 115
N-[3-(1-{[4-bromo-1-(4-benzyl chloride base)-1H-pyrazoles-5-yl] methyl }-the 4-piperidines) phenyl]-the 2-methyl propanamide
According to the method preparation that embodiment 108 describes, (0.153g 0.510mmol) replaces 4-(4-chlorophenoxy) benzaldehyde with 4-bromo-1-(4-benzyl chloride base)-1H-pyrazoles-5-formaldehyde.
1H?NMR(400MHz，CDCl 3)δ7.41(s，1H)，7.36(d，1H，J＝8.8Hz)，7.34-7.30(m，3H)，7.29-7.26(m，1H)，7.22(t，1H，J＝7.8Hz)，7.16(d，2H，J＝8.6Hz)，6.95(d，1H，J＝7.5Hz)，5.24(s，2H)，3.61(s，2H)，3.09(d，2H，J＝11.9Hz)，2.55-2.42(m，2H)，2.19(dt，2H，J＝4.4，11.4Hz)，1.89-1.76(m，4H)，1.24(d，6H，J＝6.7Hz)；ESMS?m/e：529.1(M+H) +。
1-(3-{[(1R)-3-chloro-phenyl propyl] the oxygen base } phenyl) ethyl ketone
With azodiformate (5.37g, 0.0310mol) add triphenylphosphine (8.09g, 0.0308mol), (4.20g is 0.031mol) and in the solution of 1-(3-hydroxy phenyl) ethyl ketone in THF (150mL) for 1S-3-chloro-1-phenyl-1-propanol.The gained reactant mixture was stirred 4 days down at 23 ℃.Removal of solvent under reduced pressure, residue ether/hexane (1: 2, grind in 3 * 100mL).The organic liquor that merges is concentrated to vacuum, and crude product uses ethyl acetate/hexane (1: 14) eluting through chromatography purification, obtains required product (6.55g, 74%).
1H?NMR(400MHz，CDCl 3)δ7.48-7.31(m，6H)，7.26(t，2H，J＝8.2Hz)，7.04(d，1H，J＝8.1Hz)，5.44(dd，1H，J＝4.4，8.1Hz)，3.83-3.74(m，1H)，3.63-3.56(m，1H)，2.51(s，3H)，2.51-2.45(m，1H)，2.29-2.17(m，1H)；ESMS?m/e：289.0(M+H) +。
Embodiment 116
N-(3-{1-[(3R)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 1-(3-{[(1R)-3-chloro-phenyl propyl] the oxygen base } phenyl) ethyl ketone (58.5mg, 0.200mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (56.8mg, 0.200mmol), NaI (34.0mg, 0.200mmol) and potassium carbonate (55.5mg, 0.400mmol) mixture in DMF (1mL) stirred 3 hours down at 100 ℃.Removal of solvent under reduced pressure, residue are used 5% NH through the silica gel column chromatography purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product (98mg, 98%).
1H?NMR(400MHz，CDCl 3)δ8.01(s，1H)，7.49-7.21(m，11H)，7.09-7.03(m，1H)，6.96(d，1H，J＝7.9Hz)，5.32(dd，1H，J＝5.0，7.9Hz)，3.08-2.98(m，2H)，2.57-2.43(m，6H)，2.11-1.72(m，9H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：499.4(M+H) +。
Method:
Method A (reference example 48)
N-(3-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Figure A0281721201711
The A method
4-{[(1R)-and 3-chloro-1-phenyl propyl] the oxygen base }-1, the 2-dimethoxy benzene
With 3,4-syringol (4.07g, 26.4mmol), (S)-(-)-3-chloro-phenyl-1-propanol (4.50g, 26.4mmol, 99%ee, Aldrich Chemical Co.), triphenylphosphine (6.92g, 26.4mmol) and the diethylazodicarboxylate (4.59g, 26.4mmol) mixture in THF (110mL) at room temperature stirred 24 hours.The vacuum concentration reactant mixture.At this moment, residue can be washed with pentane, the pentane extract that merges is concentrated, and chromatography (is eluent with hexane-ethyl acetate at 8: 1), it is (consistent with the universal method of describing in the following document: Srebnik, M. to obtain required product; Ramachandran, P.V.; Brown, H.C.J.Org.Chem.1988,53,2916-2920).This method is used in small-scale reaction, can only obtain 40% productive rate.
Perhaps,, crude product is ground in a spot of dichloromethane, and leach the triphenylphosphine oxide that is precipitated out for mass preparation (26.4mmol).Concentrated filtrate obtains the crude product chromatography the required product (7.30g, yield 88.9%) of thickness yellow oily.
1H NMR (400MHz, CDCl 3) δ 7.39-7.32 (m, 4H), 7.20 (m, 1H), 6.64 (d, 1H, J=8.7Hz), 6.51 (d, 1H, J=2.7Hz), 6.30 (dd, 1H, J=2.7,8.7Hz), 5.27. (tangible dd, 1H, J=4.5,8.7Hz), 3.79 (s, 3H), 3.77 (s, 3H), 3.61 (m, 1H), 2.45 (m, 1H), 2.20 (m, 1H), 1.80 (s, 1H); ESMSm/e:307.1 (M+H) +
N-(3-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With potassium carbonate (321mg, 2.32mmol), sodium iodide (522mg, 3.48mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (570mg, 2.32mmol) and 4-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base }-1,2-dimethoxy benzene (712mg, 2.32mmol) mixture in DMF (5.00mL) stirred 3 hours down at 100 ℃, this moment, the TLC test shows reacted completely.Reactant mixture is poured in the water (50mL), and with water layer dichloromethane extraction (3 * 30mL).With the organic extract liquid salt water washing (30mL) that merges, with dried over mgso and concentrating under reduced pressure.Crude product is with preparing TLC chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery product of thickness (970mg, 90.1%).
The B method
Under the room temperature, triphenylphosphine (9.80mg packs in the round-bottomed flask of 25mL, 0.0375mmol), diethylazodicarboxylate (5.22mg, 0.0300mmol), N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), 3, the 4-syringol (7.70mg, 0.0500mmol) and THF (1.00mL).Reactant mixture is at room temperature stirred spend the night (16 hours).Removal of solvent under reduced pressure, residue is through preparation TLC plate layer chromatography purification [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (4.40mg, yield 34.1%).
1H NMR (400MHz, CDCl 3) δ 7.46 (s, 1H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 6.97 (d, 1H, J=7.8Hz), 6.64 (d, 1H, J=9.1Hz), 6.51 (d, 1H, J=2.6Hz), 6.29 (d, 1H, J=2.6,9.1Hz), 5.20 (tangible dd, 1H, J=4.4,8.5Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.23 (m, 2H), 2.77 (m, 2H), 2.5 (m, 2H), 2.3-2.1 (m, 6H), 1.80 (m, 2H), 1.25 (d, 6H, J=7.9Hz); ESMS m/e:517.4 (M+H) +
Method B (reference example 49)
2-methyl-N-(3-{1-[(3S)-3-phenoxy group-3-phenyl propyl-4-piperidyl] phenyl } propionic acid amide.
With N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (9.53mg, 0.0250mmol), phenol (4.70mg, 0.050mmol), triphenylphosphine (9.80mg, 0.0375mmol) and the diethylazodicarboxylate (5.22mg, 0.0300mmol) mixture in THF (1.00mL) at room temperature stirred 3 days.With preparation of silica gel TLC plate layer chromatography [2.5%NH 3The chloroformic solution of (methanol solution of 2.0M)], obtain the buttery required product of thickness (2.70mg, yield 23.6%).
1H NMR δ 7.46 (s, 2H), 7.40-7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (tangible d, 1H, J=7.4Hz), 6.89 (tangible tt, 1H, J=0.8,7.6Hz), 6.84 (tangible dt, 1H, J=0.8,8.0Hz), 5.20 (tangible dd, 1H, J=4.4,8.5Hz), 3.35 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H), 2.30-2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.9Hz); ESMS m/e:457.4 (M+H) +
Method C
Scheme O
Figure A0281721201741
R 1＝H，R 2＝4′-Me
1-(4-aminomethyl phenyl)-1H-indole
With 1-H-indole (58.5mg, 0.500mmol), 1-(iodine)-4-methylbenzene (0.218g, 1.00mmol), copper powder (32.0mg, 0.500mmol) and potassium carbonate (0.138g, 1.00mmol) mixture in 1-Methyl-2-Pyrrolidone (1.00mL) heats 12h in 150 ℃, argon gas atmosphere.Mixture water (6mL) dilution with gained.Water layer dichloromethane extraction (3 * 10mL).The organic extract liquid that merges is with saline (10mL) washing, with dried over mgso and vacuum concentration.Residue uses EtOAc/ hexane (1: 4) eluting through preparation TLC purification, obtains required product (82.0mg, 79.0%).
1H?NMR(400MHz，CDCl 3)δ7.67(d，1H，J＝7.7Hz)，7.52(d，1H，J＝7.4Hz)，7.38(d，2H，J＝8.4Hz)，7.34-7.29(m，3H)，7.21(t，1H，J＝7.0Hz)，7.15(t，1H，J＝7.0Hz)，6.66(d，1H，J＝3.3Hz)，2.43(s，3H)；ESMS?m/e：208.0(M+H) +。
Method D (reference example 86)
Scheme N
Figure A0281721201742
Example
Figure A0281721201751
R 1＝6-Cl，R 2＝H
R 1=H, R 2=4 '-tolyl
N-(3-{1-[(6-chloro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.369g, 1.50mmol) and 37% weight formalin (30.0mg, 1.50mmol) solution in 1mL HOAc ∶ diox (1: 4) adds 6-chloro-1-H-indole (0.152g, 1.00mmol) in, reactant mixture is at room temperature stirred 12h.Mixture water (10mL) dilution of gained.(3 * 100mL) extract water layer with dichloromethane.The organic extract liquid that merges is used dried over mgso with saline (10mL) washing, and vacuum concentration.Residue uses 5%NH through preparation TLC plate purification 3(2.0M methanol solution) solution in dichloromethane, eluting obtain required product (79.0mg, 42.0%).
1H?NMR(400MHz，CDCl 3)δ9.14(s，1H)，8.04(s，1H)，7.52(t，2H，J＝8.1Hz)，7.35(d，2H，J＝13.3Hz)，7.18(t，1H，J＝7.9Hz)，7.09(dd，1H，J＝1.9，8.5Hz)，6.85(d，1H，J＝7.4Hz)，5.18(s，1H)，4.01(s，2H)，2.55(septet，1H，J＝6.8Hz)，2.48-2.34(m，3H)，2.08-1.95(m，4H)，1.78(d，2H，J＝12.8Hz)，1.22(d，6H，J＝6.8Hz)，ESMS?m/e：410.1(M+H) +。
Method E (reference example 90)
Scheme M
Figure A0281721201752
Example
Figure A0281721201761
n＝2，R 1＝H，R 2＝Ph，R 3＝H
n＝5，R 1＝H，R 2＝H，R 3＝5-OM
n＝1，R 1＝H，R 2＝Ph，R 3＝H
n＝4，R 1＝H，R 2＝H，R 3＝5-OM
N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 1,1-diphenyl hydrazonium salt hydrochlorate (10.3mg, 0.0470mmol), 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl propionic acid amide. (14.7mg, 0.0362mmol), ZnCl 2(14.8mg, 0.109mmol) and the mixture of HOAc (0.500mL) 80 ℃ of down heating 4 hours.With gained crude mixture water (10mL) dilution, water layer is with the saturated potassium carbonate neutralization and with dichloromethane extraction (3 * 20mL).With the organic layer vacuum concentration that merges, residue uses 5% NH through preparation TLC plate purification 3(2.0M methanol solution) eluant solution in dichloromethane, obtain product N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide (4.10g, 37.0%).
1H?NMR(400MHz，CDCl 3)δ7.71-7.65(m，1H)，7.42(d，1H，J＝7.4Hz)，7.39(s，1H)，7.36-7.15(m，15H)，6.94(d，1H，J＝7.8Hz)，3.12(d，2H，J＝11.2Hz)，2.90(t，2H，J＝7.8Hz)，2.59-2.45(m，3H)，2.19-1.91(m，7H)，1.82(d，2H，J＝13.5Hz)，1.24(d，6H，J＝6.9Hz)；ESMS?m/e：555.3(M+H) +。
Method F (reference example 108)
Scheme R
Example
N-(3-{1-[4-(4-chlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Under the room temperature, with 4-(4-chlorophenoxy) benzaldehyde (0.119g, 0.510mmol) and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (0.126g, 0.510mmol) 1, solution in the 2-dichloroethanes (5.00mL) sodium triacetoxy borohydride (0.424g, 2.00mmol) and acetic acid (0.0300mL, 0.500mmol) processing.Mixture at room temperature stirred spend the night.With saturated sodium bicarbonate aqueous solution (10mL) neutralization reaction mixture, water layer dichloromethane extraction (3 * 10mL).With the organic layer salt water washing that merges, use dried over mgso, vacuum concentration through preparation TLC plate purification, uses 5% NH 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product (53.0mg, 23.0%).
1H?NMR(400MHz，CDCl 3)δ7.50(s，1H)，7.34-7.19(m，7H)，6.98-6.87(m，5H)，3.50(s，2H)，2.98(d，2H，J＝11.8Hz)，2.58-2.44(m，2H)，2.10-1.98(m，2H)，1.83-1.76(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e463.2(M+H) +。
Method G (reference example 116)
Scheme F
Figure A0281721201772
N-(3-{1-[(3R)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 1-(3-{[(1R)-3-chloro-1-phenyl propyl] the oxygen base } phenyl) ethyl ketone (58.5mg, 0.200mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (56.8mg, 0.200mmol), NaI (34.0mg, 0.200mmol) and potassium carbonate (55.5mg, 0.400mmol) mixture in DMF (1.00mL) stirred 3 hours down at 100 ℃.Removal of solvent under reduced pressure, residue are used 5% NH through the silica gel column chromatography purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product (98.0mg, 98.0%).
1H?NMR(400MHz，CDCl 3)δ8.01(s，1H)，7.49-7.21(m，11H)，7.09-7.03(m，1H)，6.96(d，1H，J＝7.9Hz)，5.32(dd，1H，J＝5.0，7.9Hz)，3.08-2.98(m，2H)，2.57-2.43(m，6H)，2.11-1.72(m，9H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：499.4(M+H) +。
Scheme S
Figure A0281721201781
Method H
2-methyl-N-(3-{1-[3-(1-Methyl-1H-indole-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
With N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide (100mg, 0.270mmol), 1-methyl isophthalic acid-phenyl hydrazine (106mg, 0.870mmol), ZnCl 2(119mg, 0.870mmol) and the mixture of HOAc (1.00mL) at 80 ℃ of following heating 12h.With crude mixture water (20mL) dilution of gained, (3 * 20mL) extract water layer with unsaturated carbonate potassium solution (10mL) neutralization and with dichloromethane.The organic layer that vacuum concentration merges and with residue through preparation TLC purification, use 3%NH 3(2.0M methanol solution) eluant solution in dichloromethane, obtain required product 2-methyl-N-(3-{1-[3-(1-Methyl-1H-indole-3-yl) propyl group]-the 4-piperidyl phenyl) propionic acid amide. (20.7mg, 18.7%).
1H?NMR(400MHz，CDCl 3)δ7.60(d，1H，J＝8.1Hz)，7.45(s，1H)，7.35(d，1H，J＝7.4Hz)，7.26-7.24(m，4H)，7.09(t，1H，J＝7.3Hz)，6.97(d，1H，J＝7.3Hz)，6.86(s，1H)，3.75(s，3H)，3.11(d，2H，J＝11.6Hz)，2.79(t，2H，J＝7.3Hz)，2.51-2.50(m，4H)，2.12-1.81(m，8H)，1.25(d，6H，J＝7.1Hz)；
To C 27H 35N 3O+0.225CHCl 3Value of calculation: C, 73.57; H, 7.99; N, 9.45;
Measured value: C, 73.93; H, 7.90; N, 9.23;
ESMS?m/e：418.2(M+H) +。
Method I
Scheme T
7-(2-fluorophenyl)-1H-indole
Under argon gas atmosphere, with 2-fluorophenyl boric acid (83.4mg, 0.600mmol), 7-bromo-1H-indole (98.0mg, 0.500mmol), LiCl (42.0mg, 1.00mmol), Na 2CO 3(2.0M, 0.100mL), Pd (PPh 3) 4(115mg, 0.100mmol) and the mixture of DME (2.00mL) 75 ℃ of down heating 12 hours.With crude mixture water (40mL) dilution of gained, water layer CH 2Cl 2(3 * 20mL) extractions.The organic layer that merges is washed with saline (30mL), use dried over sodium sulfate, filter and vacuum concentration.Residue uses hexane: EtOAc (8: 1) eluting through preparation TLC purification, obtains required product 7-(2-fluorophenyl)-1H-indole (108mg, 100%).
1H?NMR(400MHz，CDCl 3)8.21(br?s，1H)，7.71(dm，1H，J＝7.3)，7.55(dt，1H，J＝7.3，1.6Hz)，7.39(m，1H)，7.30-7.19(m，5H)，6.62(dd，1H，J＝2.1-3.3Hz)；ESMS?m/e：211.9(M+H) +。
Method J
Scheme U
Figure A0281721201801
5-(4-methylphenoxy)-1H-indole
With 5-bromo-1H-indole (98.0mg, 0.500mmol), paracresol (108mg, 1.00mmol), Cu (32.0mg, 0.500mmol), potassium carbonate (138mg, 1.00mL) and the mixture of DMF (1.00mL) at 160 ℃ of following heating 12h.Crude mixture water (40mL) dilution, (3 * 20mL) extractions of water layer dichloromethane with gained.The organic layer that merges is washed with saline (30mL), use dried over sodium sulfate, filter and vacuum concentration.Residue uses hexane: EtOAc (4: 1) eluting through preparation TLC purification, obtains required product 5-(4-methylphenoxy)-1H-indole (57.5mg, 51.5%): ESMS m/e:224.0 (M+H) +
Method K
Option A N
Figure A0281721201812
N-(3-{1-[7-(2-fluorophenyl)-7-oxo heptyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
7-chloro-1-oxo-1-(2-fluorophenyl) heptane (2.42g packs in the 50-mL round-bottomed flask, 10.0mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (2.46g, 10.0mmol), potassium carbonate (2.76g, 20.0mmol) and NaI (2.25g, 15.0mmol) solution in DMF (25.0mL).Mixture was stirred 10 minutes down at 25 ℃, heated 12 hours down at 100 ℃ subsequently, be cooled to 25 ℃, with EtOAc (100mL) dilution.(4 * 50mL) washings, water layer extracts with EtOAc (100mL) the reactant mixture water.Organic layer is used dried over mgso with saline (50mL) washing, vacuum concentration, and crude product is through chromatography purification (EtOAc: MeOH=97: 3), obtain required product (3.70g, 82.0%).
Method L
Option A N
N-(3-{1-[7-(2-fluorophenyl)-7-hydroxyl heptyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
Toward be equipped with N-(3-1-[7-(2-fluorophenyl)-7-oxo heptyl]-the 4-piperidyl phenyl)-the 50-mL round-bottomed flask (0 ℃, the ice bath cooling) of 2-methyl propanamide (5.0mmol) and methanol (20mL) in adding NaBH 4(7.5mmol).The gained reactant mixture is warming up to 25 ℃ and stirred 2 hours.TLC (EtOAc: MeOH=95: 5) monitoring reaction.When needing, in reactant mixture, add 5.0mmol NaBH again 4And with reaction mixture refluxed 1 hour.Water (5.0mL) quencher reactant, and dilute with EtOAc (10mL).Isolate organic layer, with saturated sodium bicarbonate solution (10mL) washing, through dried over mgso and vacuum concentration.Crude product is through chromatography purification (EtOAc: MeOH=97: 3), obtain required product (90%).
Method M
Option A
Step 1: when independently reacting, amine or aniline (1.00 equivalent), diisopropylethylamine or TEA (2.00 equivalent) and the solution of electrophilic reagent (1.50eq) in dichloromethane were stirred 24 hours down at 23 ℃.Solvent removed in vacuo and with crude product chromatography purification (silica gel) obtains end product.
The 4-{3-[(4-chlorobutyryl) amino] phenyl }-the 1-piperidine acid tert-butyl ester
Obtain topic according to option A and state product (3.32g, 87.4%)
1H?NMR(400MHz，CDCl 3)δ7.55(s，1H)，7.47(s，1H)，7.37(m，1H)，7.28(m，1H)，6.97(d，1H，J＝7.6Hz)，3.89(t，1H，J＝6.4Hz)，3.74(m，2H)，2.79-2.75(m，4H)，2.64(m，2H)，1.88-1.77(m，4H)，1.60-1.59(m，4H)，1.48(s，9H)。
Figure A0281721201833
Step B:
4-[3-(2-OXo-1-pyrrolidine base) phenyl]-the 1-piperidine acid tert-butyl ester
Under 25 ℃, toward 4-[3-(2-OXo-1-pyrrolidine base) phenyl]-(0.429g 16.9mmol) fed the hydrogen chloride gas bubbling 1 hour in De diox (100mL) solution to the 1-piperidine acid tert-butyl ester.With 10%KOH solution (100mL) alkalization, water layer was with 3: 1 chloroform: (3 * 150mL) extract isopropyl alcohol with the crude mixture of gained.The organic layer that merges is washed with saline (100mL), use dried over sodium sulfate, filter and vacuum concentration.Residue uses 20%NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product 4-[3-(2-OXo-1-pyrrolidine base) phenyl]-1-piperidine acid tert-butyl ester (245mg, 78.7%)
1H?NMR(400MHz，CDCl 3)δ7.52(t，1H，J＝1.8Hz)，7.41(ddd，1H，J＝8.1，2.3，0.9Hz)，7.30(t，1H，J＝7.9Hz)，7.02(d，1H，J＝7.9Hz)，3.86(t，2H，J＝7.3Hz)，3.21(dt，2H，J＝11.9，2.9Hz)，2.76(dt，2H，J＝12.1，2.4Hz)，2.65(tt，1H，J＝11.9，3.5Hz)，2.61(t，2H，J＝8.3Hz)，2.22(br?s，1H)，2.16(qt，2H，J＝7.5Hz)，1.85(d，2H，J＝12.4Hz)，1.67(dq，2H，J＝12.5，4.0Hz)。
Figure A0281721201841
4-(4-aminophenyl)-1-piperidine acid tert-butyl ester
Available from Arch Chemical Company, NJ.
2-methyl-N-[4-(4-piperidyl) phenyl] propionic acid amide.
Under 0 ℃, toward 4-(4-aminophenyl)-1-piperidine acid tert-butyl ester (8.20g, 29.7mmol) and triethylamine (8.4mL, 60mmol) slow 2-methyl-prop acyl chlorides (3.84g, THF 36.0mmol) (50mL) solution of adding in the solution of anhydrous THF (100mL).Subsequently reactant mixture is warming up to room temperature and stirred 2 hours.After the solvent removed in vacuo, with the crude product recrystallization purifying (hexane/THF), obtain required amide: 4-[4-(isobutyryl amino) phenyl]-the 1-piperidine acid tert-butyl ester, be white solid thing (8.60g, 84%).Under the room temperature, with 4-[4-(isobutyryl amino) phenyl]-the 1-piperidine acid tert-butyl ester is dissolved in CH 2Cl 2(50mL), add TFA (13.68g, 120mmol, 5 equivalents) by syringe.Stirred reaction mixture 3 or 4 hours add 5 equivalent TFA again, the gained mixture are stirred 2 or 3 hours again.Then (aqueous solution, 2M) quaternization solution is to pH＞14 by adding KOH.With solution CH 2Cl 2Extraction (8 * 200mL).With the organic layer drying that merges, removal of solvent under reduced pressure obtains unhindered amina: 2-methyl-N-[4-(4-piperidyl) phenyl with potassium carbonate] propionic acid amide., be brown solid thing (5.99g, 98%).
1H?NMR(400MHz，CDCl 3)δ7.55-7.35(m，2H)，7.35-6.9(m，3H)，3.26-2.98(m，2H)，2.84-2.64(m，2H)，2.64-2.53(m，1H)，2.53-2.32(m，1H)，1.90-1.68(m，2H)，1.68-1.36(m，3H)，1.22(d，6H，J＝6.0Hz)；ESMSm/e：247.1(M+H) +。
N-[4-(4-piperidyl) phenyl] propionic acid amide.
According to preparing 2-methyl-N-[4-(4-piperidyl) phenyl] method of propionic acid amide., use 4-(4-aminophenyl)-1-piperidine acid tert-butyl ester and propionyl chloride to make titled reference compound.ESMS?m/e：233.1(M+H) +。
N-[4-(4-piperidyl) phenyl] butyramide
According to preparing 2-methyl-N-[4-(4-piperidyl) phenyl] method of propionic acid amide., use 4-(4-aminophenyl)-1-piperidine acid tert-butyl ester and butyl chloride to make titled reference compound.ESMS?m/e：247.2(M+H) +。
N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide
According to preparing 2-methyl-N-[4-(4-piperidyl) phenyl] method of propionic acid amide., use 4-(3-aminophenyl)-1-piperidine acid tert-butyl ester and cyclopropanecarbonyl chloride to make titled reference compound.
To C 15H 20N 2O+0.15CH 2Cl 2Value of calculation: C, 70.8; H, 7.87; 11N, 10.9;
Measured value: C, 70.9; H, 7.68; N, 11.1.
ESMS?m/e：245.0(M+H) +。
N-[3-(4-piperidyl) phenyl] propionic acid amide.
According to preparing 2-methyl-N-[4-(4-piperidyl) phenyl] method of propionic acid amide., use 4-(3-aminophenyl)-1-piperidine acid tert-butyl ester and propionyl chloride to make titled reference compound.
To C 14H 20N 2The value of calculation of O: C, 72.2; H, 8.63; N, 12.1;
Measured value: C, 72.4; H, 8.68; N, 12.1.
ESMS?m/e：233.1。
Method N
Option A V
Structure library in polypropylene RobbinsShi 46 orifice plates " Reactor Blocks ".When initial incubation, each Kong Jun pack into the PS-TBD resin (available from Argonaut Technologies, 0.280mmol, 2.50 equivalents, 200mg) and piperidines (0.120mmol, acetonitrile 1.10eq) (0.500mL) solution stirred 1 hour.Acetonitrile (0.500mL) solution and the acetonitrile (1.00mL) that add benzyl iodide or benzyl bromide a-bromotoluene (0.110mmol, 1.00 equivalents) successively in each hole are so that cumulative volume is 2.00mL.Under the room temperature, in the Robbins rotary oven, mixture was rotated 16 hours.(0.430mmol 4.00eq), and at room temperature reacted 12 hours again for ArgonautTechnologies, 250mg to add the AP-isocyanate resin subsequently in each hole.Mixture is filtered, and vacuum concentrated filtrate obtains required product.Product characterizes through LC-MS.
Method O
In Robbins 48 orifice plates " Reactor Blocks ", use various pure and mild PS-TSC1 resins with the alkylation of piperidines material.
Scheme W
Figure A0281721201871
In polypropylene RobbinsShi " Reactor Blocks " 46 orifice plates, construct the library.PS-TSCl resin (100mg, 1.00eq is available from Argonaut Technologies) is placed each hole of described " Reactor Blocks " 46 orifice plates.In each hole, add the solution of a kind of alcohol (1.50mmol) in 3.00mL dichloromethane and pyridine (1: 1).The gained mixture was stirred 5 hours, resin is used CH successively 2Cl 2(3 * 4mL), DMF (5 * 4.0mL), DMF/ water (3: 1,5 * 4.0mL), THF (3 * 4.0mL), CH 2Cl 2(3 * 4.0mL), acetonitrile (2 * 4.0mL) washing and drying under reduced pressure.(0.0750mmol, 0.500eq) and N, (19.0mg, 0.150mmol, acetonitrile 1.00eq) (3.00mL) solution add and are equipped with in the hole of described deutero-resin the N-diisopropylethylamine, make the gained mixture 70 ℃ of reactions 16 hours down with a kind of amine.At last, with the AP-isocyanate resin (120mg, 0.150mmol, 1.00eq) and THF (2.00mL) add in the reaction vessel, and at room temperature reacted again 3 hours.Be filtered in the RobbinsShi receiver sheet described solution and vacuum concentration, obtain required tertiary amine, adopt LC-MS that product is analyzed.
Method P
Option A B
Figure A0281721201872
N-{3-[1-(3-{[(4-fluoroanilino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
With N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide (26.4mg, 0.0870mol), (11.9mg, 0.0870mmol) solution in THF (1.00mL) stirred 12 hours down at 25 ℃ 1-fluoro-4-isocyanato-benzene.With crude mixture water (10mL) dilution of gained, water layer CH 2Cl 2Extraction (3 * 20mL).With the organic layer vacuum concentration that merges, residue uses 2.5%NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product N-{3-[1-(3-{[(4-fluoroanilino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-2-methyl propanamide (4.18mg, 10.9%).
1H?NMR(400MHz，CDCl 3)7.45(q，2H，J＝4.7Hz)，7.23-7.21(m，4H)，7.05(t，4H，J＝7.8Hz)，6.75(m，1H)，4.05(m，1H)，3.19(s，1H)，2.71(m，1H)，2.53(m，1H)，2.26-2.21(m，3H)，1.80-1.60(m，9H)，1.25(d，6H，J＝6.4Hz)；ESMS?m/e：439.4(M+H) +。
Method Q 1
Option A T
Figure A0281721201881
When independent reaction, with described amine (1.0eq), electrophilic reagent (1.5eq), diisopropylethylamine (2.0eq) at CH 2Cl 2In mixture stirred 1 day.Solvent removed in vacuo and with the crude product chromatography purification obtains final product.
2-methyl-N-{3-[1-(3-{[(4-aminomethyl phenyl) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
With 4-Methyl benzenesulfonyl chlorine (16.6mg, 0.0870mmol), N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl-2-methyl propanamide (26.4mg, 0.0870mmol), (10.0mg, 0.174mmol) solution in THF (1.00mL) stirred 12 hours down at 25 ℃ TEA.With crude mixture water (20mL) dilution of gained, water layer dichloromethane extraction (2 * 20mL).With the organic layer vacuum concentration that merges, residue uses 2.5%NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product 2-methyl-N-{3-[1-(3-{[(4-aminomethyl phenyl) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl } propionic acid amide. (17.3mg, 43.6%).
1H?NMR(400MHz，CDCl 3)δ8.19(s，1H)，7.53(s，1H)，7.41(s，1H)，7.32-7.21(m，4H)，7.16(s，1H)，6.97(d，1H，J＝7.9Hz)，3.44(t，2H，J＝6.3Hz)，3.15(d，2H，J＝9.8Hz)，2.62-2.45(m，4H)，2.15(m，3H)，2.05(s，3H)，1.95-1.71(m，5H)，1.26(d，6H，J＝6.6Hz)；ESMS?m/e：458.2(M+H) +。
Method Q 2
Synthesize collection and method for releasing with purification piperidines library
Use Amberlyst 15 exchanger resins (Aldrich) of following method activation available from market:
1. the gained resin was swayed in methanol 24 hours.
2. on the porous funnel, filter and with the described resin of methanol wash.
3. use 2N NH 3MeOH solution in and resin (check pH value)-swayed 1 hour.
With described through neutral resin with the MeOH solution acidify (check pH value) of 3M HCl-swayed 1 hour.
5. on a porous funnel, collect described resin and wash with MeOH.
6. vacuum drying resin and preservation.
Synthetic (acidylate of amine)
At polypropylene Robbins " Reactor Blocks ", construct the library in 46 orifice plates.(acyl chlorides, sulfonic acid chloride 1.5eq) (2.0mL) solution in the presence of react at the THF/DCM of triethylamine (2.0eq) and spend the night at 3: 1, obtain 40 groups of chemical compound/plates to make 5 histamine (0.10mmol) and 8 groups of electrophilic reagents on each plate.The consumption situation of raw material amine in each reaction of the tight monitoring of TLC, this involves the purification that adopts acid Amberlyst 15 resins to carry out subsequently.After the full consumption of raw material amine, collect required product, then use following method to discharge.
The purification of piperidines product
(0.90g Aldrich) adds in each hole, in the RobbinsShi rotary oven described plate is rotated 2 hours, to collect required end-product from reactant mixture with activated Amberlyst 15 ion exchange resin.Filter solvents is also washed (x3) with resin with methanol and dichloromethane or with each solvent wash (each 10 minutes).After last the filtration, add the methanol solution (every hole adds 2mL) of 2N ammonia in the resin, then described " reaction blocks " rotated 2 hours to discharge required chemical compound from described resin.Filter out final compound to RobbinsShi " Receiving Blocks ", remove and desolvate, the gained chemical compound is through the LC-MS Analysis and Identification.
Method R
Scheme Z
Figure A0281721201901
X＝F，Cl，Br，I
[(3-chloropropyl) sulfenyl] benzene
With benzenethiol (0.550g, 5.00mmol), 1-bromo-3-chloropropane (106mg, 5.50mmol), TEA (1.01g, 10.0mmol) and the mixture of THF (10.0mL) stirred 12 hours down at 25 ℃.Crude mixture water (40mL) dilution, water layer CH with gained 2Cl 2Extraction (3 * 30mL).The organic layer that vacuum concentration merges, residue uses hexane: EtOAc (10: 1) eluting through preparation TLC purification, obtains required product [(3-chloropropyl) sulfenyl] benzene (1.05g, 100%).
Option A A
Figure A0281721201911
X＝F，Cl，8r，I
Method S
3-chloropropyl 4-fluorophenyl sulfoxide
(77.5mg, dichloromethane solution 0.380mmol) (2.00mL) is cooled to 0 ℃ with 3-chloropropyl 4-fluorophenyl thioether.Add in this solution m-CPBA (78.7mg, 0.460mmol).Reactant mixture was stirred 30 minutes down at 0 ℃, stirred 4 hours down at 23 ℃ subsequently.The crude mixture of gained is diluted with 10% aqueous sodium persulfate solution (10mL), water layer dichloromethane extraction (2 * 15mL).The organic layer that merges is used dried over sodium sulfate with salt water washing (10mL), filters and vacuum concentration.Residue uses 2.5%NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product 3-chloropropyl 4-fluorophenyl sulfoxide (47.8mg, 57.0%).
Method T
Option A D
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-N, 2-dimethyl propylene amide
(3-{1-[4-(3 with N-, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (15.0mg, 0.0357mmol), MeI (5.07mg, 0.0357mmol), NaOtBu (6.86mg, 0.0714mmol) and the mixture of THF (1.00mL) stirred 5 hours down at 25 ℃.With crude mixture water (10mL) dilution of gained, water layer dichloromethane extraction (3 * 20mL).With the organic layer vacuum concentration that merges, residue uses 4.0% NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane, obtain required product N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl phenyl)-N, 2-dimethyl propylene amide (13.8mg, 89.1%).
1H?NMR(400MHz，CDCl 3)7.76(s，1H)，7.72(dd，1H，J＝1.8，7.7.Hz)，7.33(t，1H，J＝8.8Hz)，7.22(d，1H，J＝7.8Hz)，7.18(d，1H，J＝8.8Hz)，7.01(m，2H)，3.24(s，3H)，3.10(d，1H，J＝10.6Hz)，3.00(t，1H，J＝7.6Hz)，2.49-2.44(m，4H)，2.33(s，6H)，2.112.10(m，2H)，1.99(m，1H)，1.79-1.77(m，4H)，1.26(t，2H，J＝7.6Hz)，1.02(d，6H，J＝7.6Hz)；ESMS?m/e：435.2(M+H) +。
Method U
Option A K
Figure A0281721201921
X＝F，Cl，?Br，I
1-[3-(3-chlorine propoxyl group) phenyl] ethyl ketone
Under 0 ℃, toward NaH (50.5mg, add in DMF 2.00mmol) (1.00mL) suspension 1-(3-hydroxy phenyl) ethyl ketone (136mg, 1.00mmol).Reactant mixture was at room temperature stirred 1 hour.In this mixture, add 1-bromo-3-chloropropane (188mg, DMF 1.20mmol) (0.500mL) solution.The gained reactant mixture was at room temperature stirred 5 hours.With crude mixture water (20mL) dilution of gained, water layer dichloromethane extraction (3 * 20mL).The organic layer that merges is washed with saline (20mL),, filter and vacuum concentration through dried over sodium sulfate, residue is through preparation TLC purification, use hexane: ethyl acetate (4: 1) eluting obtains required product 1-[3-(3-chlorine propoxyl group) phenyl] ethyl ketone (235mg, 55.2%).
1H?NMR(400MHz，CDCl 3)δ7.7(d，1H，J＝6.6Hz)，7.52(s，1H)，7.25(t，1H，J＝6.6Hz)，7.01(m，1H)，4.11(t，2H，J＝7.9Hz)，3.69(t，2H，J＝7.9Hz)，2.61(s，3H)，1.95-1.92(m，2H)。
Method V
Option A E
1-[(2,2-dimethyl propylene acyl group) the oxygen base]-4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-1,2,3, the 6-tetrahydropyridine
Under argon gas atmosphere, room temperature, toward be equipped with hypoboric acid two (pinacol ester) (bis (pinacolato) diboron) (422mg, 1.66mmol), potassium acetate (444mg, 4.53mmol) and PdCl 2Dppf (37.0mg, 3.00mol%), dppf (25.0mg, trifluoromethanesulfonic acid 1-[(2 packs in 50mL round-bottomed flask 3.00mol%); 2-dimethyl propylene acyl group) oxygen base]-1,2,3; 6-tetrahydrochysene-4-pyridyl ester (500mg, 1.51mmol) 1, the solution in the 4-diox (10.0mL).With the gained mixture 80 ℃ of following heated overnight, be cooled to room temperature after, mixture is filtered and washs described Celite (3 * 20mL) with ethyl acetate through Celite.Vacuum concentrated filtrate.The gained residue is dissolved in the ethyl acetate, and magnesium sulfate is used in water and salt water washing successively, filtration drying and vacuum concentration.Crude product is through flash chromatography purification (1: the 9=ethyl acetate: hexane), obtain 1-[(2,2-dimethyl propylene acyl group) oxygen base]-4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-1,2,3,6-tetrahydropyridine (355mg, 76.0%).
Method W
Option A F
Figure A0281721201941
4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
Under argon gas atmosphere, room temperature, toward 1-[(2,2-dimethyl propylene acyl group are housed) the oxygen base]-4-(4,4,5; 5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-1,2; 3, the 6-tetrahydropyridine (500mg, 1.62mmol), potassium carbonate (670mg, 4.86mmol) and PdCl 2N-(3-bromo-4-aminomethyl phenyl)-2-methyl propanamide (415mg, 1.62mmol) solution in DMF (10.0mL) of packing in the 50mL round-bottomed flask of dppf (155mg).With gained mixture heated overnight under 80 ℃ and argon gas atmosphere.After being cooled to room temperature, mixture is washed described Celite (3 * 20mL) through the Celite filtration and with ethyl acetate.With filtrate water successively (20mL) and saline (20mL) washing, use dried over mgso, filter and vacuum concentration.Crude product through the flash chromatography purification (20% ethyl acetate: hexane), obtain 4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester (360mg, 62.0%).
Option A G
Figure A0281721201951
Method X
4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-the 1-piperidine acid tert-butyl ester
Use hydrogen air bag air supply method, at room temperature with 4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-3, (335mg's 6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester 0.93mmol) spends the night with the solution hydrogenation of 10% palladium on carbon (35.0mg) in ethanol (20.0mL).Reactant mixture is filtered through Celite, with washing with alcohol (3 * 10mL).The extract vacuum concentration that merges is obtained 4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-1-piperidine acid tert-butyl ester (335mg, 100%).
Method Y
Option A H
Figure A0281721201952
2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide.
Under the room temperature, toward 4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-(335mg adds TFA (10.0mL) in dichloromethane 0.930mmol) (10.0mL) solution to the 1-piperidine acid tert-butyl ester.Reactant mixture was stirred 2 hours, subsequently vacuum concentration.Residue is dissolved in 20mL chloroform/isopropyl alcohol (3: 1), alkalizes with 5% potassium hydroxide (10mL) solution.(3: 1,3 * 10mL) extracted water layer with chloroform/isopropyl alcohol.With the organic extract liquid salt water washing that merges, through dried over mgso, filter and vacuum concentration, obtain 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. (190mg, 78.0%).
Method Z
Option A I
Figure A0281721201961
N-(3-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
With 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. (49.0mg, 0.190mmol), 1-[4-chloro-1-(4-fluorophenyl) butyl]-4-fluorobenzene (58.0mg, 0.210mmol), NaI (42.0mg, 0.280mmol) and potassium carbonate (52.0mg, DMF 0.380mmol) (10.0mL) solution is 95 ℃ of following heated overnight.Extract (3 * 20mL) with described mixture water (20mL) dilution and with water layer with EtOAc.With the organic layer salt water washing that merges, through dried over mgso and vacuum concentration.Crude product is through flash chromatography purification [5% NH 3(2.0M methanol solution) eluant solution in dichloromethane], obtain N-(3-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl-the 4-aminomethyl phenyl)-2-methyl propanamide (37.0mg, 38.0%).
Method AA
Option A J
N-(3-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
Under the room temperature, toward 4-(3,4-two fluorophenoxies) benzaldehyde (41.0mg, 0.170mmol) and 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. (45.0mg, 0.170mmol) 1, add in the solution in the 2-dichloroethanes (5.00mL) sodium triacetoxy borohydride (110mg, 0.520mmol) and AcOH (10.0 μ L, 0.170mmol).The stirring of gained mixture is spent the night.Reactant mixture is also used dichloromethane extraction (3 * 10mL) with saturated sodium bicarbonate solution (10mL) quencher.With the organic layer salt water washing that merges, through dried over mgso and vacuum concentration.Crude product uses 5% NH through preparation TLC purification 3(2.0M methanol solution) eluant solution in dichloromethane, obtain required product N-(3-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl-the 4-aminomethyl phenyl)-2-methyl propanamide (44.0mg, 54.0%).
Method AC
Option A T: use PS-carbodiimide resin synthesizing amide
Figure A0281721201981
(1.34mmol/g) at DCM: (10: 1,3.00mL) mixture in swayed 30 minutes DMF for 2.00eq, 80.0mg with carboxylic acid (0.0800mmo1) and PS-carbodiimide resin.In described reactant mixture, add amine (0.0540mmol), the mixture of gained was at room temperature swayed 12 hours.Filter reaction mixture is with the resin washed with dichloromethane.The organic extract liquid that merges is concentrated into a little volume, is applied on the preparation TLC plate NH with 6% 3(2.0M methanol solution) eluant solution in dichloromethane obtains required product.
Method AD
Scheme X
Figure A0281721201982
N-(3-bromopropyl) t-butyl carbamate
In the dichloromethane solution of alkali, by 3-propantheline bromide hydrobromide and BOC 2O makes topic and states product.
1H NMR (300MHz) δ 5.07 (br, 1H), 3.31 (t, 2H, J=6.6Hz), 3.12 (tangible br q, 2H, J=6.0Hz), 1.92 (p, 2H, J=6.6Hz), 1.30 (s, 9H).
Step 1.
Under the room temperature, (add N-(tert-butoxycarbonyl)-3-bromine propylamine (21.2mmol) and potassium carbonate (38.7mmol) in 19.3mmol) De diox (20.0mL) solution, the gained mixture was heated 24 hours under reflux temperature toward piperidines.Reactant mixture is chilled to room temperature, and vacuum concentration also distributes between chloroform (40mL) and water (5mL).Organic layer salt water washing through dried over sodium sulfate, is filtered and vacuum concentration.Crude product through column chromatography purification (ethyl acetate: methanol 9: 1), obtain the required product of colorless oil: 3-{4-[3-(acetylamino) phenyl]-piperidino the propyl carbamic acid tert-butyl ester: ESMS m/e:376.2[M+H] +
Step 2.
Under 0-5 ℃, hydrogen chloride gas is fed the amine (in 12.1mmol) De diox (5.00mL) solution bubbling 10-20 minute of Boc-protection.The solution of gained was stirred 1 hour down at 0-5 ℃, concentrate, extract with 10%KOH solution (10mL) neutralization and with dichloromethane (25mL).With organic extract liquid salt water washing, through dried over sodium sulfate and vacuum concentration.With the crude product chromatography, obtain required product N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide: ESMS m/e:276.1[M+H] +
Method AE
Scheme Y
Figure A0281721202001
Step 1
With piperidines (1.00eq, 0.0226mmol), N-(bromine alkyl) phthalimide (1.50eq, 0.0338mmol), Bu 4(5.00eq, 0.113mmol) the mixture in the Zai diox (200mL) heated 24 hours down at 99 ℃ for NI (200mg) and diisopropylethylamine.Adopt TLC to analyze (95: 5 dichloromethane: monitoring reaction methanol).In each reactant mixture, add 0.0113mmol suitable brominated alkyl phthalic imide again when needing, continue heating 48 hours again.Reactant mixture is chilled to room temperature, filters out ammonium salt, removal of solvent under reduced pressure.With the crude product chromatography, obtain required product.
ESMS?m/e：420.2??????????????????????????????????ESMS?m/e：434.4
[M+H] +??????????????????????????????????????????[M+H] +
Figure A0281721202013
ESMS?m/e：448.4??????????????????????????????????ESMS?m/e：462.4
[M+H] +??????????????????????????????????????????[M+H] +
Figure A0281721202015
ESMS?m/e：476.4
[M+H] +
Step 2
By the amine of the phthalimide of gained protection ethanol (0.5-1.0M) solution with excessive hydrazonium salt hydrochlorate (10eq) was heated 4 hours down at 90 ℃, phthalimide is carried out deprotection.With TLC monitoring reaction mixture until reacting completely.After reacting completely, mixture is cooled to room temperature, leaches insoluble by-product, solvent removed in vacuo through Celite.Crude product obtains required product through chromatography purification (methylene chloride-methanol-2-aminopropane .).
Figure A0281721202022
ESMS?m/e：290.2[M+H] +????????????????????????????ESMS?m/e：304.1[M+H] +
Figure A0281721202023
Figure A0281721202024
ESMS?m/e：318.2[M+H] +????????????????????????????ESMS?m/e：332.2[M+H] +
Figure A0281721202025
ESMS?m/e：346.3[M+H] +
Method AF
Figure A0281721202026
Scheme H
Figure A0281721202031
(4R)-4-(3, the 4-difluorophenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-oxo-1,3-oxazolidine-3-Methanamide
According to the synthetic titled reference compound of scheme H and method AF: in-78 ℃, argon gas atmosphere, toward (4R)-4-(3, the 4-difluorophenyl)-1, (this chemical compound and analog are according to J.Med.Chem 2000 for 3-oxazolidine-2-ketone, 43,2775 method preparation) (0.300mol adds LDA (2.0M THF solution in THF 60.0mg) (5.00mL) solution, 0.390mmol, 0.200mL).-78 ℃ of down reactions after 30 minutes, under-78 ℃, adding chloro-carbonic acid 4-nitro phenyl ester (0.330mmol, THF 51.2mg) (0.500mL) solution in the described mixture.After 30 minutes, reactant mixture is diluted water layer dichloromethane extraction (3 * 10mL) with saturated sodium carbonate solution (5.0mL)-78 ℃ of stirrings.The organic layer that merges is washed with saline (10mL), with dried over sodium sulfate and vacuum concentration.Residue is through preparation TLC plate purification (10: 1 hexanes: ethyl acetate) obtain (4R)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester (51.5mg, 54.0%).
(4R)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester (169mg, 0.465mmol), N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl-2-methyl propanamide (141mg, 0.465mmol), potassium carbonate (0.193g, 1.39mmol), dichloromethane (10mL) and methanol (0.1mL) mixes in flask.The gained mixture at room temperature stirred spend the night, solvent removed in vacuo, residue is through chromatography purification [2.5% NH 3(2.0M methanol solution) eluant solution in dichloromethane], obtain required product (26.1mg, 10.6%).
1H?NMR(400MHz，CDCl 3)δ8.08(t，1H，J＝5.5Hz)，7.45(S，2H)，7.38(d，1H，J＝8.6Hz)，7.24-7.12(m，3H)，7.06(m，1H)，6.97(d，1H，J＝8.6Hz)，5.40(dd，1H，J＝3.9-8.8Hz)，4.71(t，1H，J＝8.8Hz)，4.23(dd，1H，J＝4.4，9.1Hz)，3.32(qt，2H，J＝6.1Hz)，2.99(d，2H，J＝11.0Hz)，2.49(qt，2H，J＝7.0Hz)，2.41(t，2H，J＝7.0Hz)，1.99-1.97(m，2H)，1.82-1.68(m，6H)，1.23(d，6H，J＝7.3Hz)；
To C 28H 34F 2N 4O 4The value of calculation of+HCl+0.185 chloroform: C, 57.6; H, 6.04; N, 9.54;
Measured value: C, 58.5; H, 6.08; N, 9.47;
ESMS?m/e：529.1(M+H) +。
Method AG
Option A R:
Figure A0281721202041
Step 1
Keto ester (10mmol), Meldrum acid (10mmol), aldehyde (10mmol) and the solution of ammonium acetate (11mmol) in HOAc (10mL) were heated 18 hours under reflux temperature.Cooled reactant mixture is poured in the ice (100g).The grease that collecting precipitation goes out, drying under reduced pressure.The analog of benzyl ester protection solidifies in the mixture with ether/hexane grinds.
Figure A0281721202051
Figure A0281721202052
1.05g，29.0％?????????????523mg，15.0％
1MORALES，A.；OCHOA，E.；SUAREZ，M.；VERDECIA，Y.；
GONZALEZ，L.；MARTIN，N.；QUINTEIRO，M.；SEOANE、C.；
SOTO，J.L.；J.Heterocycl.Chem.[JHTCAD]1996，33(1)，103-107。
Step 2
At room temperature, adopt the mixture hydrogenation in methanol of balloon method with benzyl ester and 10%Pd/C.Until reacting completely, (3 * 10mL) wash reactant mixture with methanol through Celite 545 filtrations and with the Celite filter cake with the TLC monitoring.Methanol extraction liquid vacuum concentration with merging obtains required carboxylic acid, and product is not purified to be directly used in the next step.
4-(2,4 difluorobenzene base)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-pyridine carboxylic acid
According to method AG and the synthetic titled reference compound of option A R.
1H?NMR(CDCl 3，400MHz)δ7.82(s，1H)，7.00-6.72(m，3H)，4.51(d，1H，J＝8.4Hz)，2.90(dd，1H，J＝8.4，16.3Hz)，2.68(d，1H，J＝16.3Hz)，2.46(s，3H)。
Figure A0281721202061
4-(3, the 4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-pyridine carboxylic acid
According to method AG and the synthetic titled reference compound of option A R.
1H?NMR(CDCl 3，300MHz)δ7.40-6.80(m，4H)，4.23(d，1H，J＝7.5avg.Hz)，2.93(dd，1H，J＝16.8，7.5avg.Hz)，2.68(d，1H，J＝16.5avg.Hz)，2.45(s，3H)。
Method AH
Figure A0281721202062
1-(6-chlorine hexyl)-1H-indole
Under 0 ℃, (0.249g 10.0mmol) adds 1-H-indole (0.585g, DMF 5.00mmol) (2.00mL) solution in the mixture in DMF (5.00mL) toward NaH.0 ℃ of following stirred reaction mixture 30 minutes is warming up to room temperature.In reactant mixture, drip 1-bromo-6-chlorohexane (0.998g through syringe, 5.00mmol), the reactant mixture stirring is spent the night, with EtOAc (30mL) dilution, successively water (3 * 10mL) and saline (10mL) wash, use dried over mgso, vacuum concentration and through chromatography purification, use hexane: EtOAc (97.5: 2.5) eluting, obtain required product (0.900g, 76.0%).
1H?NMR(400MHz，CDCl 3)δ7.76-7.54(m，1H)，7.47-6.96(m，4H)，6.60-6.34(m，1H)，4.13(t，2H，J＝6.8Hz)，3.50(t，2H，J＝5.6Hz)，1.98-1.79(m，2H)，1.79-1.64(m，2H)，1.54-1.17(m，4H)。
N-(3-{1-[6-(1H-indole-1-yl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
With 1-(6-chlorine hexyl)-1H-indole (23.6mg, 0.100mmol), 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (24.6mg, 0.100mmol), potassium carbonate (27.6mg, 0.200mmol), NaI (22.5mg, 0.150mmol) and the mixture of DMF (1.00mL) 100 ℃ of down heating 12 hours.Reaction mixture is to room temperature, and crude product is through preparation TLC purification, the NH with 5% 3(2.0M methanol solution) eluant solution in dichloromethane obtains the required product (40mg, 90%) of yellow solid shape.
1H?NMR(400MHz，CDCl 3)δ8.08-6.52(m，11H)，4.17(t，2H，J＝7.2Hz)，3.26(d，2H，J＝11.6Hz)，2.74-2.52(m，4H)，2.44-2.28(m，2H)，2.20-2.02(m，2H)，1.98-1.82(m，4H)，1.78-1.62(m，2H)，1.43-1.28(m，4H)，1.28(d，6H，J＝6.8Hz)；?ESMS?m/e：446.5(M+H) +。
Method AI
Option A U: use PS-SO 2Cl resins uncle-piperidines
Figure A0281721202071
On polypropylene RobbinsShi " Reactor Blocks " 48 orifice plates, make up the chemical compound group.In each hole of described " Reactor Blocks " 48 orifice plates, add PS-TSC1 resin (100mg, 1.00eq is available from Argonaut Technologies).Add 2-10 equivalent alcohol in each hole at dichloromethane: pyridine (1: 1, the 3.00mL) solution in.The gained mixture was at room temperature stirred 5 hours.Resin use successively dichloromethane (3 * 4.00mL), DMF (5 * 4.00mL), DMF/H 2O (3: 1,5 * 4.00mL), THF (3 * 4.00mL), dichloromethane (3 * 4.00mL), acetonitrile (2 * 4.00mL) washings, drying under reduced pressure subsequently.In the hole that the derivatization resin is housed, add amine (0.0750mmol, 0.500eq) and N, N-diisopropylethylamine (19.0mg, 0.150mmol, 1.00eq) solution in acetonitrile (3.00mL), the gained mixture was reacted 16 hours in 70 ℃ Robbins rotary oven.After the cooling, add in each reaction vessel the AP-isocyanate resin (120mg, 0.150mmol, 1.00eq) and THF (2.00mL) also at room temperature reacted again 3 hours.Described solution is filtered to Robbin _In the collecting board, vacuum concentration obtains required tertiary amine (identifying through LC-MS).
Method AJ
Option A V: use piperidines to prepare uncle-piperidines
Figure A0281721202081
At polypropylene Robbins _Construction compound group in 48 orifice plates " Reactor Blocks ".In initial incubation period, the PS-TBD resin of packing in each hole (available from ArgonautTechnologies, 200mg, 0.280mmol, 2.50eq) and piperidines (0.120mmol, (0.500mL) solution of acetonitrile 1.10eq) also stirred 1 hour.Add in each hole benzyl iodide or benzyl bromide a-bromotoluene (0.110mmol, acetonitrile 1.00eq) (0.500mL) solution then replenish acetonitrile (1.00mL) and make that cumulative volume is 2mL, with mixture in the Robbins rotary oven, at room temperature rotated 16 hours.Add in each hole subsequently the AP-isocyanate resin (ArgonautTechnologies, 250mg (0.430mmol, 4.00eq), reaction 12 hours under room temperature again.Obtain required product (identifying) with the mixture filtration and with the filtrate vacuum concentration through LC-MS.
Option A X
Embodiment 117
N-(3-{1-[3-(4-bromophenyl)-3-oxopropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 1-(4-bromophenyl)-3-chloro-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：457.1(M+H) +。
Embodiment 118
N-(3-{1-[3-(4-chlorphenyl)-3-oxopropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 3-chloro-1-(4-chlorphenyl)-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.1(M+H) +。
Embodiment 119
N-(3-{1-[3-(4-methoxyphenyl)-3-oxopropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 3-chloro-1-(4-methoxyphenyl)-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409.2(M+H) +。
Embodiment 120
N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-oxopropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 3-chloro-1-(2,3-dihydro-1H-indenes-5-yl)-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：419.2(M+H) +
Embodiment 121
2-methyl-N-{3-[1-(3-oxo-3-phenyl propyl)-4-piperidyl] phenyl } propionic acid amide..
According to method K (KI) and scheme E (potassium carbonate), using 3-chloro-1-phenyl-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：379.2(M+H) +。
Embodiment 122
2-methyl-N-(3-{1-[3-(4-aminomethyl phenyl)-3-oxopropyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K (KI) and scheme E (potassium carbonate), using 3-chloro-1-(4-aminomethyl phenyl)-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：393.2(M+H) +。
Embodiment 123
N-(3-{1-[3-(4-fluorophenyl)-3-oxopropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 3-chloro-1-(4-fluorophenyl)-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：397.2(M+H) +。
Embodiment 124
N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-oxopropyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：415.1(M+H) +。
Embodiment 125
N-(3-{1-[3-(4-chlorphenyl)-3-(3,4-two fluorophenoxies) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：526.8(M+H) +。
Embodiment 126
N-(3-{1-[3-(4-chlorphenyl)-3-(2-methylphenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and orthoresol prepare titled reference compound.
ESMS?m/e：505.4(M+H) +。
Embodiment 127
N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-oxopropyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：399.2(M+H) +。
Embodiment 128
N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[3-(4-methoxyphenyl)-3-oxopropyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：411.2(M+H) +。
Embodiment 129
N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-oxopropyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：459.1(M+H) +。
Embodiment 130
N-(3-{1-[3-(4-chlorphenyl)-3-(4-methoxyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyphenol prepare titled reference compound.
ESMS?m/e：520.8(M+H) +。
Embodiment 131
N-(3-{1-[3-(4-chlorophenoxy)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-chlorophenol prepare titled reference compound.
ESMS?m/e：509.1(M+H) +。
Embodiment 132
N-(3-{1-[3-(4-fluorophenyl)-3-(2,3,4,5,6-phenyl-pentafluoride oxygen base) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2,3,4,5, the 6-Pentafluorophenol prepares titled reference compound.
ESMS?m/e：564.7(M+H) +。
Embodiment 133
N-(3-{1-[3-(4-bromophenyl)-3-(2-methylphenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-methylphenol prepare titled reference compound.
ESMS?m/e：548.8(M+H) +。
Embodiment 134
N-(3-{1-[3-(3,4-two fluorophenoxies)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3, the 4-difluorophenol prepares titled reference compound.
ESMS?m/e：511.1(M+H) +。
Embodiment 135
N-(3-{1-[3-(4-bromine phenoxy group)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-bromophenol prepare titled reference compound.
ESMS?m/e：553.0(M+H) +。
Embodiment 136
N-(3-{1-[3-(3, the 4-dichlorophenoxy)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3, the 4-chlorophenesic acid prepares titled reference compound.
ESMS?m/e：542.7(M+H) +。
Embodiment 137
N-[3-(1-{3-(4-fluorophenyl)-3-[4-(trifluoromethyl) phenoxy group] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethyl) phenol prepares titled reference compound.
ESMS?m/e：543.1(M+H) +。
Embodiment 138
N-(3-{1-[3-(3-bromine phenoxy group)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-bromophenol prepare titled reference compound.
ESMS?m/e：552.7(M+H) +。
Embodiment 139
N-(3-{1-[3-(4-fluorophenoxy)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-fluorophenol prepare titled reference compound.
ESMS?m/e：493.2(M+H) +。
Embodiment 140
N-(3-{1-[3-(3-fluorophenoxy)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-fluorophenol prepare titled reference compound.
ESMS?m/e：492.9(M+H) +。
Embodiment 141
N-(3-{1-[3-(2, the 6-dichlorophenoxy)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2, the 6-chlorophenesic acid prepares titled reference compound.
ESMS?m/e：543.0(M+H) +。
Embodiment 142
N-(3-{1-[3-(2,5-two fluorophenoxies)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2, the 5-difluorophenol prepares titled reference compound.
ESMS?m/e：511.5(M+H) +。
Embodiment 143
N-(3-{1-[3-(3-chlorophenoxy)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-chlorophenol prepare titled reference compound.
ESMS?m/e：509.1(M+H) +。
Embodiment 144
N-(3-{1-[3-(4-bromophenyl)-3-(3-methylphenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-methylphenol prepare titled reference compound.
ESMS?m/e：549.1(M+H) +。
Embodiment 145
N-(3-{1-[3-([1,1 '-biphenyl]-4-base oxygen base)-3-(4-bromophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-phenylphenol prepare titled reference compound.
ESMS?m/e：611.2(M+H) +。
Embodiment 146
N-(3-{1-[3-(2,4 difluorobenzene oxygen base)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2,4 difluorobenzene phenol prepares titled reference compound.
ESMS?m/e：511.1(M+H) +。
Embodiment 147
N-(3-{1-[3-(4-bromophenyl)-3-(3-methoxyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-methoxyphenol prepare titled reference compound.
ESMS?m/e：564.6(M+H) +。
Embodiment 148
4-(1-(4-bromophenyl)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propoxyl group) essence of Niobe
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methyl hydroxybenzoate prepare titled reference compound.
ESMS?m/e：593.0(M+H) +。
Embodiment 149
N-(3-{1-[3-(4-bromophenyl)-3-(4-phenoxy group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-phenoxy phenyl prepare titled reference compound.
ESMS?m/e：626.6(M+H) +。
Embodiment 150
N-(3-{1-[3-(4-bromophenyl)-3-(2-chloro-4-methylphenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-chloro-4-methylphenol prepare titled reference compound.
ESMS?m/e：583.0(M+H) +。
Embodiment 151
N-(3-{1-[3-(4-bromophenyl)-3-phenoxy propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and phenol prepares titled reference compound.
ESMS?m/e：535.0(M+H) +。
Embodiment 152
N-[3-(1-{3-(4-bromophenyl)-3-[4-(trifluoromethyl) phenoxy group] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethyl) phenol prepares titled reference compound.
ESMS?m/e：603.1(M+H) +。
Embodiment 153
N-(3-{1-[3-(2-acetyl group phenoxy group)-3-(4-bromophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-acetyl phenol prepare titled reference compound.
ESMS?m/e：576.6(M+H) +。
Embodiment 154
N-(3-{1-[3-(3-acetyl group phenoxy group)-3-(4-bromophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-acetyl phenol prepare titled reference compound.
ESMS?m/e：576.9(M+H) +。
Embodiment 155
N-(3-{1-[3-(3-acetyl group phenoxy group)-3-(2,3-dihydro-1H-indenes-5-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-acetyl phenol prepare titled reference compound.
ESMS?m/e：539.2(M+H) +。
Embodiment 156
N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-phenoxy propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and phenol prepares titled reference compound.
ESMS?m/e：497.2(M+H) +。
Embodiment 157
N-(3-{1-[3-(2-acetyl group phenoxy group)-3-(2,3-dihydro-1H-indenes-5-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-acetyl phenol prepare titled reference compound.
ESMS?m/e：539.1(M+H) +。
Embodiment 158
N-(3-{1-[3-(4-bromine phenoxy group)-3-(4-bromophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-bromophenol prepare titled reference compound.
ESMS?m/e：612.7(M+H) +。
Embodiment 159
N-(3-{1-[3-(4-bromophenyl)-3-(4-chlorophenoxy)]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-chlorophenol prepare titled reference compound.
ESMS?m/e：568.7(M+H) +。
Embodiment 160
N-(3-{1-[3-(4-bromophenyl)-3-(4-fluorophenoxy)]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-fluorophenol prepare titled reference compound.
ESMS?m/e：552.8(M+H) +。
Embodiment 161
N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-(4-methoxyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-methoxyphenol prepare titled reference compound.
ESMS?m/e：527.3(M+H) +。
Embodiment 162
N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-(4-fluorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-fluorophenol prepare titled reference compound.
ESMS?m/e：515.2(M+H) +。
Embodiment 163
N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-oxopropyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：421.2(M+H) +。
Embodiment 164
N-[3-(1-{3-(2,3-dihydro-1H-indenes-5-yl)-3-[4-(trifluoromethyl) phenoxy group] propyl group }-the 4-piperidyl) phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-trifloro methyl phenol prepare titled reference compound.
ESMS?m/e：565.0(M+H) +。
Embodiment 165
N-(3-{1-[3-(4-bromine phenoxy group)-3-(2,3-dihydro-1H-indenes-5-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-bromophenol prepare titled reference compound.
ESMS?m/e：577.4(M+H) +。
Embodiment 166
N-(3-{1-[3-(3-acetyl group phenoxy group)-3-(4-chlorphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-acetyl phenol prepare titled reference compound.
ESMS?m/e：533.1(M+H) +。
Embodiment 167
N-(3-{1-[3-(4-methoxyl group phenoxy group)-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyphenol prepare titled reference compound.
ESMS?m/e：517.4(M+H) +。
Embodiment 168
N-(3-{1-[3-(4-chlorophenoxy)-3-(2,3-dihydro-1H-indenes-5-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(2,3-dihydro-1H-indenes-5-yl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-chlorophenol prepare titled reference compound.
ESMS?m/e：531.1(M+H) +。
Embodiment 169
N-(3-{1-[3-(2-acetyl group phenoxy group)-3-(4-chlorphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-acetyl phenol prepare titled reference compound.
ESMS?m/e：533.4(M+H) +。
Embodiment 170
N-(3-{1-[3-(4-bromophenyl)-3-(4-methoxyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyphenol prepare titled reference compound.
ESMS?m/e：565.0(M+H) +。
Embodiment 171
N-(3-{1-[3-(4-bromine phenoxy group)-3-(4-chlorphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-bromophenol prepare titled reference compound.
ESMS?m/e：568.8(M+H) +。
Embodiment 172
N-(3-{1-[3-(4-chlorophenoxy)-3-(4-chlorphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-chlorophenol prepare titled reference compound.
ESMS?m/e：525.0(M+H) +。
Embodiment 173
N-(3-{1-[3-(4-methoxyphenyl)-3-phenoxy propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenol prepares titled reference compound.
ESMS?m/e：487.4(M+H) +。
Embodiment 174
N-(3-{1-[3-(4-fluorophenyl)-3-phenoxy propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and phenol prepares titled reference compound.
ESMS?m/e：475.6(M+H) +。
Embodiment 175
N-(3-{1-[3-(2-acetyl group phenoxy group)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-acetyl phenol prepare titled reference compound.
ESMS?m/e：517.1(M+H) +。
Embodiment 176
N-(3-{1-[3-(3-acetyl group phenoxy group)-3-(4-fluorophenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-acetyl phenol prepare titled reference compound.
ESMS?m/e：516.9(M+H) +。
Embodiment 177
N-(3-{1-[3-(4-fluorophenyl)-3-(4-methoxyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-methoxyphenol prepare titled reference compound.
ESMS?m/e：505.2(M+H) +。
Embodiment 178
N-(3-{1-[3-(4-chlorophenoxy)-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-chlorophenol prepare titled reference compound.
ESMS?m/e：521.5(M+H) +。
Embodiment 179
N-(3-{1-[3-(3-acetyl group phenoxy group)-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 3-acetyl phenol prepare titled reference compound.
ESMS?m/e：529.0(M+H) +。
Embodiment 180
N-(3-{1-[3-(4-chlorphenyl)-3-phenoxy propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and phenol prepares titled reference compound.
ESMS?m/e：490.9(M+H) +。
Embodiment 181
N-(3-{1-[3-(4-bromine phenoxy group)-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-bromophenol prepare titled reference compound.
ESMS?m/e：564.9(M+H) +。
Embodiment 182
N-[3-(1-{3-(4-methoxyphenyl)-3-[4-trifluoromethyl) phenoxy group] propyl group }-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-trifloro methyl phenol prepare titled reference compound.
ESMS?m/e：555.1(M+H) +。
Embodiment 183
N-(3-{1-[3-(4-chlorphenyl)-3-(4-fluorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-fluorophenol prepare titled reference compound.
ESMS?m/e：509.1(M+H) +。
Embodiment 184
N-(3-{1-[3-(4-fluorophenoxy)-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-fluorophenol prepare titled reference compound.
ESMS?m/e：505.5(M+H) +。
Embodiment 185
N-(3-{1-[3-(2-acetyl group phenoxy group)-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-hydroxyl-3-(4-methoxyphenyl) propyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 2-acetyl phenol prepare titled reference compound.
ESMS?m/e：529.2(M+H) +。
Embodiment 186
N-[3-(1-{3-(4-chlorphenyl)-3-[4-(trifluoromethyl) phenoxy group] propyl group }-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use N-(3-{1-[3-(4-chlorphenyl)-3-hydroxypropyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-trifloro methyl phenol prepare titled reference compound.
ESMS?m/e：559.1(M+H) +。
Embodiment 187
N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
According to method G and option A I, use 1-(3-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base } phenyl) ethyl ketone and 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：513.0(M+H) +。
2-(isopentyl oxygen base)-1-naphthaldehyde
With 2-hydroxyl-1-naphthaldehyde (1.72g, 10.0mmol) and THF (50mL) in flask, mix.Add successively NaH (312mg, 13mmol) and 1-bromo-3-methybutane (1.20mL, 10.0mmol).Solution at room temperature stirred spend the night, solvent removed in vacuo is with residue chromatography purification (5-10% ethyl acetate/hexane).
1H?NMR(400MHz，CDCl 3)δ10.9(s，1H)，9.28(dd，1H，J＝0.7Hz，8.6Hz)，8.02(d，1H，J＝9.1Hz)，7.75(d，1H，J＝8.1Hz)，7.63-7.59(m，1H)，7.43-7.39(m，1H)，7.27(d，1H，J＝9.2Hz)，4.25(t，2H，J＝6.5Hz)，1.98-1.84(m，1H)，1.80-1.75(m，2H)，0.99(d，6H，J＝6.6Hz)；ESMS?m/e：242.8(M+H) +。
Embodiment 188
N-[3-(1-{[2-(isopentyl oxygen base)-1-naphthyl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method F and scheme R, using 2-(isopentyl oxygen base)-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.3(M+H) +。
2-propoxyl group-1-naphthaldehyde
According to the method for preparing 2-(isopentyl oxygen base)-1-naphthaldehyde, use 2-hydroxyl-1-naphthaldehyde and 1-N-Propyl Bromide to prepare titled reference compound.
Embodiment 189
2-methyl-N-(3-{1-[(2-propoxyl group-1-naphthyl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 2-propoxyl group-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：445.2(M+H) +。
4-{[(1-formoxyl-2-naphthyl) oxygen base] methyl } benzonitrile
According to the method for preparing 2-(isopentyl oxygen base)-1-naphthaldehyde, use 2-hydroxyl-1-naphthaldehyde and 4-(bromomethyl) benzonitrile to prepare titled reference compound.
Embodiment 190
N-{3-[1-(2-[(4-cyano group benzyl) the oxygen base]-the 1-naphthyl } methyl)-the 4-piperidyl] phenyl)-the 2-methyl propanamide
According to method F and scheme R, use 4-{[(1-formoxyl-2-naphthyl) the oxygen base] methyl } benzonitrile and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：518.2(M+H) +。
[(1-formoxyl-2-naphthyl) oxygen base] acetonitrile
According to the method for preparing 2-(isopentyl oxygen base)-1-naphthaldehyde, use 2-hydroxyl-1-naphthaldehyde and bromoacetonitrile to prepare titled reference compound.
Embodiment 191
N-[3-(1-{[2-(cyano group methoxyl group)-1-naphthyl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method F and scheme R, using [(1-formoxyl-2-naphthyl) oxygen base] acetonitrile and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：442.2(M+H) +。
2-[(3-benzyl chloride base) oxygen base]-the 1-naphthaldehyde
According to the method for preparing 2-(isopentyl oxygen base)-1-naphthaldehyde, use 2-hydroxyl-1-naphthaldehyde and 1-(bromomethyl)-3-chlorobenzene to prepare titled reference compound.
Embodiment 192
N-{3-[1-(2-[(3-benzyl chloride base) the oxygen base]-the 1-naphthyl } methyl)-the 4-piperidyl] phenyl)-the 2-methyl propanamide
According to method F and scheme R, use 2-[(3-benzyl chloride base) the oxygen base]-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：527.2(M+H) +。
Embodiment 193
N-(3-{1-[4-(4-chlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(4-chlorophenoxy) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.50(s，1H)，7.34-7.19(m，7H)，6.98-6.87(m，5H)，3.50(s，2H)，2.98(d，2H，J＝11.8Hz)，2.58-2.44(m，2H)，2.10-1.98(m，2H)，1.83-1.76(m，4H)，1.24(d，6H，J＝6.8Hz)；ESMS?m/e：463.2(M+H) +。
Embodiment 194
N-(3-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(3,4-two fluorophenoxies) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：465.2(M+H) +。
4-(isopentyl oxygen base)-1-naphthaldehyde
According to the method for preparing 2-(isopentyl oxygen base)-1-naphthaldehyde, use the method for 4-hydroxyl-1-naphthaldehyde and 1-bromo-3-methybutane to prepare titled reference compound.
Embodiment 195
N-[3-(1-{[4-(isopentyl oxygen base)-1-naphthyl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method F and scheme R, using 4-(isopentyl oxygen base)-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.3(M+H) +。
Embodiment 196
N-(3-{1-[4-(4-methoxyl group phenoxy group) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(4-methoxyl group phenoxy group) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：459.2(M+H) +。
4-propoxyl group-1-naphthaldehyde
According to the method for preparing 2-(isopentyl oxygen base)-1-naphthaldehyde, use 4-hydroxyl-1-naphthaldehyde and 1-N-Propyl Bromide to prepare titled reference compound.
Embodiment 197
2-methyl-N-(3-{1-[(4-propoxyl group-1-naphthyl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-propoxyl group-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：445.2(M+H) +。
Embodiment 198
N-(3-{1-[4-(3, the 4-dichlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(3, the 4-dichlorophenoxy) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：497.1(M+H) +。
Embodiment 199
N-(3-{1-[4-(diphenyl amino) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(diphenyl amino) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：504.2(M+H) +。
Embodiment 200
N-(3-{1-(2,5-dimethyl-1-[3-(trifluoromethyl) phenyl]-1H-pyrroles-3-yl } methyl)-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, use 2,5-dimethyl-1-[3-(trifluoromethyl) phenyl]-1H-pyrroles-3-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：498.2(M+H) +。
Embodiment 201
2-methyl-N-(3-{1-[1-(2-phenyl-1,3-thiazoles-4-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 1-(2-phenyl-1,3-thiazoles-4-yl) ethyl ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：434.2(M+H) +。
Embodiment 202
N-(3-{1-[(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：451.2(M+H) +。
Embodiment 203
2-methyl-N-(3-{1-[(2-phenyl-1H-imidazol-4 yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 2-phenyl-1H-imidazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：403.2(M+H) +。
Embodiment 204
N-[3-(1-{[4-bromo-1-(4-benzyl chloride base)-1H-pyrazoles-5-yl] methyl }-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-bromo-1-(4-benzyl chloride base)-1H-pyrazoles-5-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：529.1(M+H) +。
Embodiment 205
2-methyl-N-(3-{1-[(3-phenoxy benzyl)-4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, using 3-phenoxy benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.2(M+H) +。
Embodiment 206
N-(3-{1-[3-(3, the 4-dichlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(3, the 4-dichlorophenoxy) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：497.15(M+H) +。
Embodiment 207
N-(3-{1-[3-(3, the 5-dichlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(3, the 5-dichlorophenoxy) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：497.2(M+H) +。
Embodiment 208
2-methyl-N-(3-{1-[3-(4-methylphenoxy) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 3-(4-methylphenoxy) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：443.2(M+H) +。
Embodiment 209
2-methyl-N-[3-(1-{3-[3-(trifluoromethyl) phenoxy group] benzyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method F and scheme R, use 3-[3-(trifluoromethyl) phenoxy group] benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：497.2(M+H) +。
Embodiment 210
N-(3-{1-[3-(4-chlorophenoxy) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(4-chlorophenoxy) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：463.2(M+H) +。
Embodiment 211
N-(3-{1-[3-(dimethylamino) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(dimethylamino) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：380.2(M+H) +。
Embodiment 212
N-(3-{1-[3-(4-methoxyl group phenoxy group) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(4-methoxyl group phenoxy group) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：459.2(M+H) +。
Embodiment 213
N-(3-{1-[3-(4-tert-butyl group phenoxy group) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(4-tert-butyl group phenoxy group) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：485.3(M+H) +。
Embodiment 214
2-methyl-N-(3-{1-[3-nitro-4-(piperidino) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 3-nitro-4-(piperidino) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：465.2(M+H) +。
Embodiment 215
N-(3-{1-[(3,4-thioxene be [2,3-b] thiophene-2-yl also) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, use 3, the 4-thioxene is [2,3-b] thiophene-2-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl also] propionic acid amide. prepares titled reference compound.
ESMS?m/e：427.1(M+H) +。
Embodiment 216
2-methyl-N-{3-[1-(3-[4-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, use 3-[4-(trifluoromethyl) phenyl]-1H-pyrazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：471.1(M+H) +。
Embodiment 217
2-methyl-N-(3-{1-[4-(1H-1,2,4-triazol-1-yl) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-(1H-1,2,4-triazol-1-yl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：404.1(M+H) +。
Embodiment 218
2-methyl-N-(3-{1-[(5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 5-methyl isophthalic acid-phenyl-1H-pyrazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：417.1(M+H) +。
Embodiment 219
2-methyl-N-(3-{1-[4-(4-morpholinyl)-3-nitrobenzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-(4-morpholinyl)-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：467.1(M+H) +。
Embodiment 220
N-{3-[1-(5[2-chloro-4-(trifluoromethyl) phenyl]-the 2-furyl } methyl)-the 4-piperidyl } phenyl]-the 2-methyl propanamide
According to method F and scheme R, use 5-[2-chloro-4-(trifluoromethyl) phenyl]-2-furfural and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：505.0(M+H) +。
Embodiment 221
4-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-2,5-dimethyl-1-phenyl-1H-pyrroles-3-Ethyl formate
According to method F and scheme R, using 4-formoxyl-2,5-dimethyl-1-phenyl-1H-pyrroles-3-Ethyl formate and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：502.2(M+H) +。
Embodiment 222
5-(4-chlorphenyl)-2-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-the 3-ethyl furoate
According to method F and scheme R, using 5-(4-chlorphenyl)-2-formoxyl-3-ethyl furoate and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：509.0(M+H) +。
Embodiment 223
N-{3-[1-(2,3-dihydro-1,4-benzo dioxine-6-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 2,3-dihydro-1,4-benzo dioxine-6-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：395.1(M+H) +。
Embodiment 224
2-methyl-N-(3-{1-[(6-phenoxy group-3-pyridine radicals) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 6-phenoxy group nicotine aldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：430.1(M+H) +。
Embodiment 225
2-methyl-N-[3-(1-{[5-(2-pyridine radicals)-2-thienyl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method F and scheme R, using 5-(2-pyridine radicals)-2 thiophene carboxaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：420.1(M+H) +。
Embodiment 226
2-methyl-N-{3-[1-(5-[1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-the 2-thienyl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, use 5-[1-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-2 thiophene carboxaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：491.0(M+H) +。
Embodiment 227
2-methyl-N-[3-(1-{[1-(phenyl sulfonyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method F and scheme R, using 1-(phenyl sulfonyl)-1H-indole-3-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：516.1(M+H) +。
Embodiment 228
N-(3-{1-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-yl) methyl]-the 4-piperidyl } phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 h-pyrazole-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：447.2(M+H) +。
Embodiment 229
N-(3-{1-[4-(the 4-tert-butyl group-1,3-thiazoles-2-yl) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(the 4-tert-butyl group-1,3-thiazoles-2-yl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
Embodiment 230
N-{3-[1-(2,3-dihydro-1-benzofuran-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 2,3-dihydro-1-benzofuran-5-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：379.1(M+H) +。
Embodiment 231
2-methyl-N-(3-{1-[(4-methyl-2-phenyl-5-pyrimidine radicals) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-methyl-2-phenyl-5-pyrimidine formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.2(M+H) +。
Embodiment 232
N-{3-[1-(2,1,3-diazosulfide-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 2,1,3-diazosulfide-5-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：395.1(M+H) +。
Embodiment 233
2-methyl-N-(3-{1-[(5-phenyl-2-thienyl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 5-phenyl-2 thiophene carboxaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：419.1(M+H) +。
Embodiment 234
N-{3-[1-(3,4-dihydro-2H-1,5-benzo two oxa-English in heptan (benzodioxepin)-7-ylmethyls)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 3,4-dihydro-2H-1,5-benzo two oxa-English in heptan-7-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409.2(M+H) +。
Embodiment 235
2-methyl-N-[3-(1-{ (3-(2-thienyl)-1H-pyrazoles-4-yl) methyl }-the 4-piperidyl) phenyl) propionic acid amide.
According to method F and scheme R, using 3-(2-thienyl)-1H-pyrazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409.1(M+H) +。
Embodiment 236
N-{3-[1-([1,1 '-the bithiophene base]-the 4-ylmethyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, use 2,2 '-bithiophene-5-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.0(M+H) +。
Embodiment 237
N-(3-{1-[(2,2-dimethyl-3,4-dihydro-2H-.alpha.-5:6-benzopyran-6-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 2,2-dimethyl-6-benzodihydropyran formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：421.2(M+H) +。
Embodiment 238
2-methyl-N-{3-[1-(5-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-the 2-thienyl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, use 5-[1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-2 thiophene carboxaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：491.1(M+H) +。
Embodiment 239
2-methyl-N-(3-{1-[(2-phenyl-1,3-thiazoles-4-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 2-phenyl-1,3-thiazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：420.0(M+H) +。
Embodiment 240
2-methyl-N-(3-{1-[(3-phenoxy group-2-thienyl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 3-phenoxy group-2 thiophene carboxaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：435.0(M+H) +。
Embodiment 241
N-{3-[1-(the 2-[(4-chlorphenyl) sulfenyl]-the 3-thienyl } methyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, use the 2-[(4-chlorphenyl) sulfenyl]-3-thiophenecarboxaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：485.0(M+H) +。
Embodiment 242
N-[3-(1-{[1-(4-chlorphenyl)-1H-pyrroles-2-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method F and scheme R, using 1-(4-chlorphenyl)-1H-pyrrole-2-aldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：436.0(M+H) +。
Embodiment 243
2-methyl-N-{3-[1-(5-[2-(trifluoromethoxy) phenyl]-the 2-furyl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, use 5-[2-(trifluoromethoxy) phenyl]-2-furfural and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：487.1(M+H) +。
Embodiment 244
2-methyl-N-(3-{1-[2-(4-morpholinyl) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 2-(4-morpholinyl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：422.2(M+H) +。
Embodiment 245
N-[3-(1-{[3-(4-methoxyphenyl)-1H-pyrazoles-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method F and scheme R, using 3-(4-methoxyphenyl)-1H-pyrazoles-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：433.1(M+H) +。
Embodiment 246
2-methyl-N-(3-{1-[4-(1H-pyrazol-1-yl) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-(1H-pyrazol-1-yl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：402.8(M+H) +。
Embodiment 247
2-methyl-N-{3-[1-(4-quinoline methyl)-4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, using 4-quinoline aldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：388.1(M+H) +。
Embodiment 248
2-methyl-N-(3-{1-[4-(4-morpholinyl) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-(4-morpholinyl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：422.5(M+H) +。
Embodiment 249
2-methyl-N-(3-{1-[4-(2-thienyl) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-(2-thienyl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：419.1(M+H) +。
Embodiment 250
2-methyl-N-(3-{1-[(2-methyl-5-phenyl-furyl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 2-methyl-5-phenyl-furfural and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：417.2(M+H) +。
Embodiment 251
N-(3-{1-[3-(cyclopentyloxy)-methoxy-benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 3-(cyclopentyloxy)-4-methoxybenzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：451.1(M+H) +。
Embodiment 252
2-methyl-N-(3-{1-(5-[4-(trifluoromethoxy) phenyl]-the 2-furyl } methyl)-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, use 5-[4-(trifluoromethoxy) phenyl]-2-furfural and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：487.1(M+H) +。
Embodiment 253
N-{3-[1-(1-benzothiophene-2-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 1-benzothiophene-2-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：393.2(M+H) +。
Embodiment 254
2-methyl-N-{3-[1-(5-[3-(trifluoromethoxy) phenyl]-the 2-furyl } methyl)-the 4-piperidyl } phenyl] propionic acid amide.
According to method F and scheme R, use 5-[3-(trifluoromethoxy) phenyl]-2-furfural and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：487.2(M+H) +。
Embodiment 255
2-methyl-N-{3-[1-(2-quinoline methyl)-4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, using 2-quinoline aldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：388.1(M+H) +。
Embodiment 256
N-(3-{1-[4-(1H-imidazoles-1-yl) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(1H-imidazoles-1-yl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：403.2(M+H) +。
Embodiment 257
N-{3-[1-(9H-fluorenes-2-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 9H-fluorenes-2-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.1(M+H) +。
Embodiment 258
3-[5-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-the 2-furyl]-the 2-thiophenecarboxylate
According to method F and scheme R, using 3-(5-formoxyl-2-furyl)-2-thiophenecarboxylate and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：467.1(M+H) +。
Embodiment 259
2-methyl-N-{3-[1-(4-phenoxy benzyl)-4-piperidyl] phenyl } propionic acid amide.
According to method F and scheme R, using 4-phenoxy benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.2(M+H) +。
Embodiment 260
N-{3-[1-([1,1 '-xenyl]-the 4-ylmethyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using [1,1 '-xenyl]-4-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.2(M+H) +。
Embodiment 261
N-(3-{1-[4-(dibutylamino) benzyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R, using 4-(dibutylamino) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：464.6(M+H) +。
Embodiment 262
2-methyl-N-[3-(1-{4-[(4-aminomethyl phenyl) sulfenyl]-the 3-nitrobenzyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method F and scheme R, use the 4-[(4-aminomethyl phenyl) sulfenyl]-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：504.2(M+H) +。
Embodiment 263
2-methyl-N-(3-{1-[4-(1,2,3-thiadiazoles-4-yl) benzyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R, using 4-(1,2,3-thiadiazoles-4-yl) benzaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：421.1(M+H) +。
1-(3-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base } phenyl) ethyl ketone
With (1R)-3-chloro-1-phenyl-1-propanol (1.000g, 5.86mmol), 1-(3-hydroxy phenyl) ethyl ketone (0.797g, 5.86mmol), triphenylphosphine (1.54g, 5.86mmol) and diethylazodicarboxylate (1.53g, 8.79mmol) in flask, mix, immediately with the flask argon purge.Add THF (20mL), mixture is stirred in argon gas atmosphere spend the night.Vacuum is removed THF, and crude product is dissolved in 50mL dichloromethane/water (1: 1), isolates organic layer, uses dried over mgso.After the solvent removed in vacuo, residue with 10% ethyl acetate/hexane eluting, obtains required product (900mg, 76.0%) through the flash chromatography purification.
1H?NMR(400MHz，CDCl 3)δ7.49-7.46(m，2H)，7.40-7.26(m，6H)，7.07-7.04(m，1H)，5.46-5.43(dd，1H，J＝4.4Hz，8.8Hz)，3.84-3.78(m，1H)，3.64-3.59(m，1H)，2.52(s，3H)，2.51-2.46(m，1H)，2.29-2.22(m，1H).
4-(3,4-two fluorophenoxies) benzaldehyde
With the 4-fluorobenzaldehyde (5.32mL, 49.6mmol), 3, the 4-difluorophenol (7.10g, 54.6mmol) and potassium carbonate (8.31g 60.1mmol) mixes in flask, immediately with the flask argon purge.Add DMF (50.0mL), mixture was heated 6 hours under reflux temperature in argon gas atmosphere.After being chilled to room temperature, add ethyl acetate (100mL) and water (100mL), isolate ethyl acetate layer, wash (2 * 100mL) with water.With the organic layer salt water washing that merges, use dried over mgso.Solvent removed in vacuo obtains required product (11.4g, 98.0%).
1H?NMR(400MHz，CDCl 3)δ9.95(s，1H)，7.88(dd，2H，J＝0.8Hz，8.8Hz)，7.24-7.17(m，1H)，7.07(d，2H，J＝8.8Hz)，6.97-6.92(m，1H)，6.86-6.82(m，1H)，ESMS?m/e；235.0(M+H) +.
4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
Add in the flask hypoboric acid two (pinacol ester) (422mg, 1.66mmol), potassium acetate (444mg, 4.53mmol), PdCl 2Dppf (37.0mg, 3.00mol%), dppf (25.0mg, 3.00mol%), with the flask argon purge.Add the 4-{[(trifluoromethyl) sulfonyl] the oxygen base-1,2,3, the 6-tetrahydrochysene-1-pyridine carboxylic acid tert-butyl ester (500mg, 1.51mmol) 1,4-diox (10.0mL) solution stirs mixture down at 80 ℃ and to spend the night.Mixture filters through Celite, with filtrate vacuum evaporation.The gained residue is dissolved in the ethyl acetate, successively water and salt water washing.The organic layer dried over mgso is filtered and vacuum concentration.Crude product obtains 4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester (355mg, 76.0%) through flash chromatography purification (10% ethyl acetate/hexane).
1H?NMR(400MHz，CDCl 3)δ6.44(br?s，1H)，3.93(br?s，2H)，3.42(br?s，2H)，2.21(br?s，2H)，1.45(s，9H)，1.25(s，12M)；ESMSm/e：310.4(M+H) +.
N-(6-bromo-2-pyridine radicals)-2-methyl propanamide
According to method Q1, use 2-methyl-prop acyl chlorides and 6-bromo-2-pyridine amine to prepare titled reference compound.
ESMS?m/e：242.8(M+H) +。
4-[6-(isobutyryl amino)-2-pyridine]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
According to method W and option A F, use N-(6-bromo-2-pyridine radicals)-2-methyl propanamide and 4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：245.8(M-100) +。
2-methyl-N-[6-(4-piperidyl)-2-pyridine] propionic acid amide.
According to method X and Y, option A G and AH use 4-[6-(isobutyryl amino)-2-pyridine radicals respectively]-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：248.1(M+H) +。
Embodiment 264
N-(6-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl }-the 2-pyridine radicals)-the 2-methyl propanamide
According to method G and option A I, using 4-chloro-1-(3, the 4-3,5-dimethylphenyl)-1-butanone and 2-methyl-N-[6-(4-piperidyl)-2-pyridine radicals] propionic acid amide. prepares titled reference compound.
ESMS?m/e：492.1(M+H) +。
Embodiment 265
N-(6-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl }-the 2-pyridine radicals)-the 2-methyl propanamide
According to method G and option A I, use 1-[4-chloro-1-(4-fluorophenyl) butyl]-4-fluorobenzene and 2-methyl-N-[6-(4-piperidyl)-2-pyridine radicals] propionic acid amide. prepares titled reference compound.
ESMS?m/e：492.2(M+H) +。
Embodiment 266
N-(6-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl }-the 2-pyridine radicals)-the 2-methyl propanamide
According to method AA and option A J, using 4-(3,4-two fluorophenoxies) benzaldehyde and 2-methyl-N-[6-(4-piperidyl)-2-pyridine radicals] propionic acid amide. prepares titled reference compound.
ESMS?m/e：466.0(M+H) +。
N-(3-bromo-4-aminomethyl phenyl)-2-methyl propanamide
According to method Q1, use 2-methyl-prop acyl chlorides and 3-bromo-2-aminotoluene to prepare titled reference compound.
ESMS?m/e：255.9(M+H) +。
4-[5-(isobutyryl amino)-2-aminomethyl phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
According to method W and option A F, use N-(3-bromo-4-aminomethyl phenyl)-2-methyl propanamide and 4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：259.1(M-100) +。
2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide.
According to method X and Y, option A G and AH use 4-[5-(isobutyryl amino)-2-aminomethyl phenyl respectively]-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：261.0(M+H) +。
Embodiment 267
N-(3-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
According to method AA and option A J, using 4-(3,4-two fluorophenoxies) benzaldehyde and 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：479.1(M+H) +。
N-(5-bromo-2-aminomethyl phenyl)-2-methyl propanamide
According to method Q1, use 2-methyl-prop acyl chlorides and 5-bromo-2-aminotoluene to prepare titled reference compound.
ESMS?m/e：255.9(M+H) +。
4-[3-(isobutyryl amino)-2-aminomethyl phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
According to method W and option A F, use N-(5-bromo-2-aminomethyl phenyl)-2-methyl propanamide and 4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：259.1(M-100) +。
2-methyl-N-[2-methyl-5-(4-piperidyl) phenyl] propionic acid amide.
According to method X and Y, option A G and AH use 4-[3-(isobutyryl amino)-4-aminomethyl phenyl respectively]-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：261.0(M+H) +。
Embodiment 268
N-(5-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl }-the 2-aminomethyl phenyl)-the 2-methyl propanamide
According to method AA and option A J, using 9-ethyl-9H-carbazole-3-formaldehyde and 2-methyl-N-[2-methyl-5-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：468.1(M+H) +。
Embodiment 269
N-(5-{1-[4-(3,4-two fluorophenoxies) benzyl]-the 4-piperidyl }-the 2-aminomethyl phenyl)-the 2-methyl propanamide
According to method AA and option A J, using 4-(3,4-two fluorophenoxies) benzaldehyde and 2-methyl-N-[2-methyl-5-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：479.2(M+H) +。
Embodiment 270
N-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
According to method AA and option A J, using 9-ethyl-9H-carbazole-3-formaldehyde and 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：468.1(M+H) +。
Embodiment 271
2-methyl-N-[2-methyl-5-(4-piperidyl) phenyl] propionic acid amide.
According to method G and option A I, use 1-[4-chloro-1-(4-fluorophenyl) butyl]-4-fluorobenzene and 2-methyl-N-[2-methyl-5-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：505.1(M+H) +。
Embodiment 272
N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
According to method G and option A I, use 1-(3-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base } phenyl) ethyl ketone and 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：513.0(M+H) +。
Embodiment 273
N-(5-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl }-the 2-aminomethyl phenyl)-the 2-methyl propanamide
According to method G and option A I, use 1-(3-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base } phenyl) ethyl ketone and 2-methyl-N-[2-methyl-5-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：512.9(M+H) +。
N-(2-iodophenyl)-2-methyl propanamide
According to method Q1, use 2-methyl-prop acyl chlorides and 2-Iodoaniline to prepare titled reference compound.
ESMS?m/e：289.9(M+H) +。
4-[2-(isobutyryl amino) phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
According to method W and option A F, use N-(2-iodophenyl)-2-methyl propanamide and 4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：245.1(M-100) +。
2-methyl-N-[2-(4-piperidyl) phenyl] propionic acid amide.
According to method X and Y, option A G and AH use 4-[2-(isobutyryl amino) phenyl respectively]-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：247.1(M+H) +。
Embodiment 274
N-(2-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method AA and option A J, using 9-ethyl-9H-carbazole-3-formaldehyde and 2-methyl-N-[2-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：454.1(M+H) +。
Embodiment 275
N-(3-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl }-the 4-aminomethyl phenyl)-the 2-methyl propanamide
According to method G and option A I, use 1-[4-chloro-1-(4-fluorophenyl) butyl]-4-fluorobenzene and 2-methyl-N-[4-methyl-3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：505.0(M+H) +。
Embodiment 276
N-(2-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option A I, use 1-[4-chloro-1-(4-fluorophenyl) butyl]-4-fluorobenzene and 2-methyl-N-[2-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：490.9(M+H) +。
N-[2-bromo-4-(trifluoromethoxy) phenyl]-the 2-methyl propanamide
According to method Q1, use 2-methyl-prop acyl chlorides and 2-bromo-4-(trifluoromethoxy) aniline to prepare titled reference compound.
ESMS?m/e：325.9(M+H) +。
4-[2-(isobutyryl amino)-5-(trifluoromethoxy) phenyl]-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester
According to method W and option A F, use N-[2-bromo-4-(trifluoromethoxy) phenyl]-2-methyl propanamide and 4-(4,4,5,5-tetramethyl-1,3,2-two oxa-bora Pentamethylene .-2-yls)-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：329.0(M-100) +。
2-methyl-N-[2-(4-piperidyl)-4-(trifluoromethoxy) phenyl] propionic acid amide.
According to method X and Y, option A G and AH use 4-[2-(isobutyryl amino)-5-(trifluoromethoxy) phenyl respectively]-3,6-dihydro-1 (2H)-pyridine carboxylic acid tert-butyl ester prepares titled reference compound.
ESMS?m/e：330.9(M+H) +。
Embodiment 277
N-[2-{1-[4, two (4-fluorophenyl) butyl of 4-]-the 4-piperidyl }-4-(trifluoromethoxy) phenyl]-the 2-methyl propanamide
According to method G and option A I, use 1-[4-chloro-1-(4-fluorophenyl) butyl]-4-fluorobenzene and 2-methyl-N-[2-(4-piperidyl)-4-(trifluoromethoxy) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：574.8(M+H) +。
N-{3-[1-(4-hydroxybutyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method G and option b 1, using 4-chloro-1-butanols and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：319.3(M+H) +。
N-{3-[1-(5-hydroxyl amyl group)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method G and option b 1, using 5-chloro-1-amylalcohol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：333.3(M+H) +。
N-{3-[1-(6-hydroxyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method G and option b 1, using 6-chloro-1-hexanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：347.3(M+H) +。
N-{3-[1-(3-hydroxypropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method G and option b 1, using trimethylene chlorohydrin and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：305.3(M+H) +。
N-(3-{1-[(2S)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using (1S)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：367.2(M+H) +。
N-(3-{1-[(2R)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using (1R)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：367.2(M+H) +。
N-(3-{1-[(2S)-3-hydroxy-2-methyl propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using (2R)-3-chloro-2-methyl isophthalic acid-propanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：319.2(M+H) +。
N-(3-{1-[(2R)-3-hydroxy-2-methyl propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using (2S)-3-chloro-2-methyl isophthalic acid-propanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：319.2(M+H) +。
Embodiment 278
N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, using (1R)-3-chloro-1-phenyl-1-propanol and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：379.2(M+H) +。
Embodiment 279
N-{3-[1-(4-hydroxy-4-phenyl butyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method L and option A N step 1, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. prepares titled reference compound.
To C 25H 34N 2O 2+ 0.08CHCl 3Value of calculation: C, 74.5; H, 8.50; N, 6.93;
Measured value: C, 74.5; H, 8.63; N, 6.81;
ESMS?m/e：395.2(M+H) +。
Embodiment 280
N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method L and option A N, step 1 is used 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide. prepares titled reference compound.
To C 26H 36N 2O 2+ 0.25CHCl 3Value of calculation: C, 71.9; H, 8.33; N, 6.39;
Measured value: C, 71.3; H, 8.96; N, 6.86;
ESMS?m/e：409.2(M+H) +。
Embodiment 281
N-{3-[1-(6-hydroxyl-6-phenyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method L and option A N, step 1 is used 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. prepares titled reference compound.
To C 27H 38N 2O 2+ 0.1CHCl 3Value of calculation: C, 75.5; H, 8.93; N, 6.50;
Measured value: C, 75.3; H, 8.52; N, 6.00;
ESMS?m/e：423.2(M+H) +。
Embodiment 282
N-{3-[1-(7-hydroxyl-7-phenyl heptyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method L and option A N, step 1 is used 2-methyl-N-{3-[1-(7-oxo-7-phenyl heptyl)-4-piperidyl] phenyl } propionic acid amide. prepares titled reference compound.
To C 28H 40N 2O 2+ 0.1CHCl 3Value of calculation: C, 75.8; H, 9.10; N, 6.29;
Measured value: C, 75.1; H, 9.24; N, 6.51;
ESMS?m/e：437.1(M+H) +。
Embodiment 283
N-(3-{1-[4-(4-fluorophenyl)-4-hydroxybutyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, step 1, use N-(3-{1-[4-(4-fluorophenyl)-4-oxo butyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：413.1(M+H) +。
Embodiment 284
3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole carboxylic acid 4-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-butyloxy phenyl
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxy-4-phenyl butyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.56(m，1H)，7.47(m，2H)，7.44-7.39(m，3H)，7.25(m，2H)，7.09(s，1H)，7.03(m，2H)，6.95(m，1H)，6.83(m，1H)，5.75(t，1H，J＝7.1Hz)，3.03(t，2H，J＝7.2Hz)，2.93(m，2H)，2.78(s，3H)，2.48(m，3H)，2.25(m，2H)，1.48(m，3H)，1.77(m，2H)，1.54(m，2H)，1.25(d，6H，J＝7.3Hz)；ESMSm/e：647.7(M+H) +.
Embodiment 285
(4-fluorophenyl) acetic acid 4-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-butyloxy phenyl
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxy-4-phenyl butyl)-4-piperidyl] phenyl }-2-methyl propanamide and (4-fluorophenyl) chloroacetic chloride prepare titled reference compound.
1HNMR(400MHz，CDCl 3)δ7.45(s，1H)，7.34-7.19(m，8H)，7.11(m，1H)，6.98(m，3H)，5.75(t，1H，J＝6.8Hz)，3.61(s，2H)，2.92(d，2H，J＝8.1Hz)，2.48(m，2H)，2.31(m，2H)，1.99-1.84(m，4H)，1.84-1.67(m，5H)，1.55-1.35(m，2H)，1.25(d，6H，J＝6.9Hz)；ESMS?m/e：531.1(M+H) +.
Embodiment 286
(4-fluorophenyl) acetic acid 3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(3-hydroxypropyl)-4-piperidyl] phenyl }-2-methyl propanamide and (4-fluorophenyl) chloroacetic chloride prepare titled reference compound.
ESMS?m/e：441.3(M+H) +。
Embodiment 287
3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid 3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl diester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(3-hydroxypropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：542.2(M+H) +。
Embodiment 288
3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole carboxylic acid 3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl diester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(3-hydroxypropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：558.2(M+H) +。
Embodiment 289
3-(2-chlorphenyl)-5-methyl-4-isoxazole carboxylic acid 3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl diester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(3-hydroxypropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chlorphenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：524.2(M+H) +。
Embodiment 290
3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole carboxylic acid (1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-1-phenyl propyl ester
According to method Q1 and scheme C2 (TEA), use N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：633.6(M+H) +。
Embodiment 291
3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid 4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxybutyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
To C 30H 35ClFN 3O 4+ CH 2Cl 2Value of calculation: C, 63.3; H, 6.23; N, 7.33;
Measured value: C, 63.0; H, 6.39; N, 7.03;
ESMS?m/e：556.2(M+H) +。
Embodiment 292
3-(2-chlorphenyl)-5-methyl-4-isoxazole carboxylic acid (4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxybutyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chlorphenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：538.2(M+H) +。
Embodiment 293
5-methyl-3-phenyl-4-isoxazole carboxylic acid (3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(3-hydroxypropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-methyl-3-phenyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：490.3(M+H) +。
Embodiment 294
3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole carboxylic acid [4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl] ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxybutyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：572.2(M+H) +。
Embodiment 295
3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole carboxylic acid (4-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl butyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxy-4-phenyl butyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
To C 36H 39ClFN 3O 4+ 0.54CHCl 3Value of calculation: C, 63.0; H, 5.72; N, 6.03;
Measured value: C, 63.0; H, 5.54; N, 6.05;
ESMS?m/e：632.2(M+H) +。
Embodiment 296
5-methyl-3-phenyl-4-isoxazole carboxylic acid (4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxybutyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-methyl-3-phenyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：504.3(M+H) +。
Embodiment 297
3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole carboxylic acid [6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl] ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(6-hydroxyl hexyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：600.0(M+H) +。
Embodiment 298
5-methyl-3-phenyl-4-isoxazole carboxylic acid (6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(6-hydroxyl hexyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-methyl-3-phenyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：532.1(M+H) +。
Embodiment 299
(4-fluorophenyl) acetic acid (4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxybutyl)-4-piperidyl] phenyl }-2-methyl propanamide and (4-fluorophenyl) chloroacetic chloride prepare titled reference compound.
ESMS?m/e：455.3(M+H) +。
Embodiment 300
3-(2-chlorphenyl)-5-methyl-4-isoxazole carboxylic acid (4-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl butyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxy-4-phenyl butyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chlorphenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：614.2(M+H) +。
Embodiment 301
5-methyl-3-phenyl-4-isoxazole carboxylic acid (4-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl butyl) ester
According to method Q1 and scheme C2 (TEA), use N-{3-[1-(4-hydroxy-4-phenyl butyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-methyl-3-phenyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：580.0(M+H) +。
Embodiment 302
(4-fluorophenyl) acetic acid [(1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl] ester
According to method Q1 and scheme C2 (TEA), use N-(3-{1-[(3S)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and (4-fluorophenyl) chloroacetic chloride prepare titled reference compound.
To C 32H 37FN 2O 3+ 0.07CHCl 3Value of calculation: C, 73.4; H, 7.12; N, 5.34;
Measured value: C, 73.4; H, 6.96; N, 5.14;
ESMS?m/e：517.1(M+H) +。
Embodiment 303
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) Benzoylamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and Benzenecarbonyl chloride. prepare titled reference compound.
To C 31H 37N 3O 2+ 0.55CHCl 3Value of calculation: C, 69.0; H, 6.89; N, 7.65;
Measured value: C, 69.7; H, 6.73; N, 6.03;
ESMS?m/e：484.4(M+H) +。
Embodiment 304
N-[3-(1-{ (3S)-3-[(diphenyl acetyl group) amino]-the 3-phenyl propyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and diphenyl-acetyl chloride prepare titled reference compound.
ESMS?m/e：574.3(M+H) +。
Embodiment 305
3-chloro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) Benzoylamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3-chlorobenzoyl chloride prepare titled reference compound.
ESMS?m/e：518.3(M+H) +。
Embodiment 306
3,5-two chloro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) Benzoylamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3, the 5-dichlorobenzoyl chloride prepares titled reference compound.
ESMS?m/e：552.3(M+H) +。
Embodiment 307
2-(ethyl sulfenyl)-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) nicotiamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2-(ethyl sulfenyl) nicotinoyl chlorine prepare titled reference compound.
ESMS?m/e：545.3(M+H) +。
Embodiment 308
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) [1,1 '-xenyl]-the 4-Methanamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and [1,1 '-xenyl]-4-formyl chloride prepare titled reference compound.
ESMS?m/e：560.3(M+H) +。
Embodiment 309
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 2-ascorbyl palmitate
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2-pyridine formyl chloride prepare titled reference compound.
ESMS?m/e：484.6(M+H) +。
Embodiment 310
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 2-methoxy benzamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2-methoxy benzoyl chloride prepare titled reference compound.
ESMS?m/e：514.1(M+H) +。
Embodiment 311
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 1-naphthalenecarboxamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1-naphthoyl chloride prepare titled reference compound.
ESMS?m/e：533.7(M+H) +。
Embodiment 312
2,4-two fluoro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) Benzoylamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2,4 difluorobenzene formyl chloride prepare titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 313
3-(2-chloro-6-fluorophenyl)-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：617.2(M+H) +。
Embodiment 314
3-chloro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 2-thenoyl amine
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3-chloro-2-thiophene chloride prepare titled reference compound.
ESMS?m/e：524.2(M+H) +。
Embodiment 315
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-2-phenoxy group nicotiamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2-phenoxy group nicotinoyl chlorine prepare titled reference compound.
ESMS?m/e：577.3(M+H) +。
Embodiment 316
1-(4-chlorphenyl)-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-3-propyl group-1H-pyrazole-4-carboxamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1-(4-chlorphenyl)-3-propyl group-1H-pyrazoles-4-formyl chloride prepare titled reference compound.
ESMS?m/e：626.3(M+H) +。
Embodiment 317
(4-chloro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-Methanamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 4-chloro-1,3-dimethyl-1H-pyrazolo [3,4-b] pyridine-5-formyl chloride prepares titled reference compound.
ESMS?m/e：587.3(M+H) +。
Embodiment 318
5-(3, the 5-dichlorophenoxy)-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-1H-pyrroles-2-Methanamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 5-(3, the 5-dichlorophenoxy)-1H-pyrroles-2-formyl chloride prepare titled reference compound.
ESMS?m/e：634.2(M+H) +。
Embodiment 319
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) nicotiamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and nicotinoyl chlorine prepare titled reference compound.
ESMS?m/e：485.3(M+H) +。
Embodiment 320
3,4-two fluoro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) Benzoylamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3, the 4-difluoro benzoyl chloride prepares titled reference compound.
ESMS?m/e：520.3(M+H) +。
Embodiment 321
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-1-phenyl-3-propyl group-1H-pyrazole-4-carboxamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1-phenyl-3-propyl group-1H-pyrazoles-4-formyl chloride prepare titled reference compound.
ESMS?m/e：592.2(M+H) +。
Embodiment 322
4-(dimethylamino)-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl) Benzoylamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 4-(dimethylamino) Benzenecarbonyl chloride. prepare titled reference compound.
ESMS?m/e：527.3(M+H) +。
Embodiment 323
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 2-thenoyl amine
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 2-thiophene chloride prepare titled reference compound.
ESMS?m/e：490.2(M+H) +。
Embodiment 324
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-5-nitro-2-furoamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 5-nitro-2 furoyl chloride prepare titled reference compound.
ESMS?m/e：519.2(M+H) +。
Embodiment 325
N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-5-methyl-3-phenyl-4-Isoxazolecarboxamidederivatives
According to method Q1 and option A C, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-methyl-3-phenyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：489.1(M+H) +。
Embodiment 326
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 2-furoamide
According to method Q1 and option A C, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 2 furoyl chloride prepare titled reference compound.
ESMS?m/e：474.2(M+H) +。
Embodiment 327
N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-1-(4-nitrobenzophenone)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide
According to method Q1 and option A C, use N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1-(4-nitrobenzophenone)-5-(trifluoromethyl)-1H-pyrazoles-4-formyl chloride prepare titled reference compound.
ESMS?m/e：663.2(M+H) +。
Embodiment 328
3-(2-chloro-6-fluorophenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q1 and option A C, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：541.2(M+H) +。
Embodiment 329
N-[3-(1-{3-[(diphenyl acetyl group) amino] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method Q1 and option A C, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and diphenyl-acetyl chloride prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.51(s，1H)，7..33-7.21(m，13H)，6.94(m，2H)，4.88(s，1H)，3.39(t，2H，J＝5.6Hz)，2.93(d，2H，J＝11.3Hz)，2.52-2.36(m，4H)，1.97(t，2H，J＝11.3Hz)，1.83-1.58(m，6H)，1.24(d，6H，J＝7.6Hz)；
Embodiment 330
N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-1-benzothiophene-3-Methanamide
According to method Q1 and option A C, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 1-benzothiophene-3-formyl chloride prepare titled reference compound.
ESMS?m/e：464.2(M+H) +。
Embodiment 331
3-(2-chlorphenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q1 and option A C, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.50(d，1H，J＝2.3Hz)，7.48(s，1H)，7.4(m，1H)，7.39(s，1H)，7.37(m，2H)，7.24(t，1H，J＝7.2Hz)，6.92(d，1H，J＝7.9Hz)，6.06(s，1H)，3.31(q，2H，J＝6.4Hz)，2.94(d，2H，J＝10.8Hz)，2.79(s，3H)，2.53(q，1H，J＝6.1)，2.47(tt，1H，J＝4.2，11.4Hz)，2.29(t，2H，J＝7.2Hz)，1.99(t，2H，J＝11.4Hz)，1.81(m，2H)，1.69(dt，2H，J＝2.4，11.6)，1.59(q，2H，J＝6.6Hz)，1.24(d，6H，J＝6.5Hz)；ESMS?m/e：557.0(M+H) +.
1-[3-(3-chlorine propoxyl group) phenyl] ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-3-chloropropane to prepare titled reference compound.
1-(3-chlorine propoxyl group)-2-fluorobenzene
According to method U and option A K, use 2-fluorophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-chloro-3-(3-chlorine propoxyl group) benzene
According to method U and option A K, use 3-chlorophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-chloro-4-(3-chlorine propoxyl group) benzene
According to method U and option A K, use 4-chlorophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-(3-chlorine propoxyl group)-3-fluorobenzene
According to method U and option A K, use 3-fluorophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-(3-chlorine propoxyl group)-4-fluorobenzene
According to method U and option A K, use 4-fluorophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-chloro-2-(3-chlorine propoxyl group) benzene
According to method U and option A K, use 2-chlorophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
4-(3-chlorine propoxyl group)-1, the 2-dimethyl benzene
According to method U and option A K, use 3,4-xylenol and 1-bromo-3-chloropropane prepare titled reference compound.
1-bromo-2-(3-chlorine propoxyl group) benzene
According to method U and option A K, use 2-bromophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-bromo-3-(3-chlorine propoxyl group) benzene
According to method U and option A K, use 3-bromophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-bromo-4-(3-chlorine propoxyl group) benzene
According to method U and option A K, use 4-bromophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-(3-chlorine propoxyl group)-4-methylbenzene
According to method U and option A K, use paracresol and 1-bromo-3-chloropropane to prepare titled reference compound.
4-bromophenyl (2R)-3-chloro-2-methyl-propyl ether
According to method U and option A K, use 4-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base }-2,4, the 5-trifluoro-benzene
According to method U and option A K, use 2,4,5-trifluoromethyl phenol and (2S)-1-bromo-3-chloro-2-methylpropane prepares titled reference compound.
1-chloro-3-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base } benzene
According to method U and option A K, use 3-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base }-the 4-fluorobenzene
According to method U and option A K, use 4-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base }-the 3-fluorobenzene
According to method U and option A K, use 3-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-chloro-2-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base } benzene
According to method U and option A K, use 2-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base }-the 2-fluorobenzene
According to method U and option A K, use 2-fluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-chloro-4-{[(2R)-and 3-chloro-2-methyl-propyl] the oxygen base } benzene
According to method U and option A K, use 4-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
3-bromophenyl (2R)-3-chloro-2-methyl-propyl ether
According to method U and option A K, use 3-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
2-bromophenyl (2R)-3-chloro-2-methyl-propyl ether
According to method U and option A K, use 2-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2S)-and 3-chloro-2-methyl-propyl] the oxygen base }-the 3-fluorobenzene
According to method U and option A K, use 3-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2S)-and 3-chloro-2-methyl-propyl] the oxygen base }-the 4-fluorobenzene
According to method U and option A K, use 4-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-{[(2S)-and 3-chloro-2-methyl-propyl] the oxygen base }-the 2-fluorobenzene
According to method U and option A K, use 2-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-chloro-2-{[(2S)-and 3-chloro-2-methyl-propyl] the oxygen base } benzene
According to method U and option A K, use 2-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-chloro-4-{[(2S)-and 3-chloro-2-methyl-propyl] the oxygen base } benzene
According to method U and option A K, use 4-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
4-bromophenyl (2S)-3-chloro-2-methyl-propyl ether
According to method U and option A K, use 4-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
3-bromophenyl (2S)-3-chloro-2-methyl-propyl ether
According to method U and option A K, use 3-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
2-bromophenyl (2S)-3-chloro-2-methyl-propyl ether
According to method U and option A K, use 2-bromophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-chloro-3-{[(2S)-and 3-chloro-2-methyl-propyl] the oxygen base } benzene
According to method U and option A K, use 3-chlorophenol and (2R)-1-bromo-3-chloro-2-methylpropane to prepare titled reference compound.
1-[3-(4-chlorine butoxy) phenyl] ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-4-chlorobutane to prepare titled reference compound.
1-[3-(4-chlorine butoxy) phenyl] ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-4-chlorobutane to prepare titled reference compound.
1-(4-chlorine butoxy)-3-methoxybenzene
According to method U and option A K, use 3-methoxyphenol and 1-bromo-4-chlorobutane to prepare titled reference compound.
1-(4-chlorine butoxy)-4-methoxybenzene
According to method U and option A K, use 4-methoxyphenol and 1-bromo-4-chlorobutane to prepare titled reference compound.
1-(4-chlorine butoxy)-2-methoxybenzene
According to method U and option A K, use 2-methoxyphenol and 1-bromo-4-chlorobutane to prepare titled reference compound.
4-(4-chlorine butoxy)-1,2-dimethylbenzene
According to method U and option A K, use 3,4-xylenol and 1-bromo-4-chlorobutane prepare titled reference compound.
1-{3-[(5-chlorine amyl group) oxygen base] phenyl } ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-5-chloropentane to prepare titled reference compound.
1-{3-[(5-chlorine amyl group) oxygen base] phenyl } ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-5-chloropentane to prepare titled reference compound.
1-{3-[(6-chlorine hexyl) oxygen base] phenyl } ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-6-chlorohexane to prepare titled reference compound.
1-{3-[(6-chlorine hexyl) oxygen base] phenyl } ethyl ketone
According to method U and option A K, use 1-(3-hydroxy phenyl) ethyl ketone and 1-bromo-6-chlorohexane to prepare titled reference compound.
Embodiment 333
N-(3-{1-[(2S)-2-(3-acetyl group phenoxy group)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 1-(3-hydroxy phenyl) ethyl ketone and N-(3-{1-[(2R)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：485.0(M+H) +。
Embodiment 334
N-(3-{1-[(2S)-2-(2-acetyl group phenoxy group)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 1-(2-hydroxy phenyl) ethyl ketone and N-(3-{1-[(2R)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：485.2(M+H) +。
Embodiment 335
N-(3-{1-[(2S)-2-(3-chlorophenoxy)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 3-chlorophenol and N-(3-{1-[(2R)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：477.1(M+H) +。
Embodiment 336
N-(3-{1-[(2S)-2-(3,4-dimethoxy phenoxy group)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 3,4-syringol and N-(3-{1-[(2R)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：503.2(M+H) +。
Embodiment 337
N-(3-{1-[(2R)-2-(4-fluorophenoxy)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 4-fluorophenol and N-(3-{1-[(2S)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：461.2(M+H) +。
Embodiment 338
N-(3-{1-[(2R)-2-(3-methoxyl group phenoxy group)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 3-methoxyphenol and N-(3-{1-[(2S)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：472.9(M+H) +。
Embodiment 339
N-(3-{1-[(2R)-2-(3-chlorophenoxy)-2-phenethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option b 1, use 3-chlorophenol and N-(3-{1-[(2S)-2-hydroxyl-2-phenylethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：478.5(M+H) +。
N-{3-[1-(3,3-dimethoxy propyl group)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method G and option b 1, using 3-bromo-1,1-dimethoxy propane and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：349.2(M+H) +。
Embodiment 340
N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method B and option b 1, use 1-(3-hydroxy phenyl) ethyl ketone and N-(3-{1-[(3R)-3-hydroxyl-3-phenyl propyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：497.1(M+H) +。
Embodiment 341
N-(3-{1-[3-(3-acetyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-[3-(3-chlorine propoxyl group) phenyl] ethyl ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：423.2(M+H) +。
Embodiment 342
N-(3-{1-[3-(3-acetyl group phenoxy group) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, use 1-[3-(3-chlorine propoxyl group) phenyl] ethyl ketone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：421.2(M+H) +。
Embodiment 343
N-(3-{1-[3-(2-fluorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-(3-chlorine propoxyl group)-2-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：399.2(M+H) +。
Embodiment 344
N-(3-{1-[3-(3-chlorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-chloro-3-(3-chlorine propoxyl group) benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：415.2(M+H) +。
Embodiment 345
N-(3-{1-[3-(4-chlorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-chloro-4-(3-chlorine propoxyl group) benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.71(dd，1H，J＝3.2，5.7Hz)，7.53(dd，1H，J＝3.2，5.7Hz)，7.50(m，1H)，7.31(m，1H)，7.24-7.20(m，2H)，6.94(d，1H，J＝7.9Hz)，6.85-6.82(m，2H)，4.00(t，2H，J＝6.1Hz)，3.07(d，2H，J＝10.9Hz)，2.55(m，3H)，2.50(sept，1H，J＝6.2Hz)，2.08(dt，2H，J＝3.1，10.9Hz)，2.00(m，2H)，1.83(m，3H)，1.69(qt，1H，J＝6.2Hz)，1.24(d，6H，J＝6.8Hz)；
To C 24H 31ClN 2O 2The value of calculation of+HCl: C, 63.8; H, 7.09; N, 6.21;
Measured value: C, 63.3; H, 7.04; N, 6.27;
ESMS?m/e：415.2(M+H) +。
Embodiment 346
N-(3-{1-[3-(3-fluorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-(3-chlorine propoxyl group)-3-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：399.2(M+H) +。
Embodiment 347
N-(3-{1-[3-(4-fluorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-(3-chlorine propoxyl group)-4-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：399.2(M+H) +。
Embodiment 348
N-(3-{1-[3-(2-chlorophenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-chloro-2-(3-chlorine propoxyl group) benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：415.2(M+H) +。
Embodiment 349
N-(3-{1-[3-(3, the 4-dimethyl phenoxy) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 4-(3-chlorine propoxyl group)-1,2-dimethyl benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409.2(M+H) +。
Embodiment 350
N-(3-{1-[3-(2-bromine phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-bromo-2-(3-chlorine propoxyl group) benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.53(dd，1H，J＝1.6，7.9Hz)，7.48(s，1H)，7.32(m，1H)，7.28-7.22(m，3H)，7.17(s，1H)，6.98(d，1H，J＝7.7Hz)，6.93(dd，1H，J＝1.4，8.4Hz)，6.82(dt，1H，J＝7.6，1.4Hz)，4.11(t，2H，J＝6.3Hz)，3.07(d，2H，J＝11.3Hz)，2.61(t，2H，J＝6.9Hz)，2.50(m，3H)，2.07(m，1H)，1.8-1.75(m，5H)，1.25(d，6H，J＝6.7Hz)；
To C 24H 31BrN 2O 2HCl+0.2CHCl 3Value of calculation: C, 55.9; H, 6.24; N, 5.39;
Measured value: C, 55.8; H, 6.23; N, 5.47;
ESMS?m/e：459.1(M+H) +。
Embodiment 351
N-(3-{1-[3-(3-bromine phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-bromo-3-(3-chlorine propoxyl group) benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：459.1(M+H) +。
Embodiment 352
N-(3-{1-[3-(4-bromine phenoxy group) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-bromo-4-(3-chlorine propoxyl group) benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.51(s，1H)，7.37(d，2H，J＝7.6Hz)，7.26(m，3H)，6.97(d，1H，J＝7.7Hz)，6.79(d，2H，J＝7.7Hz)，4.01(t，2H，J＝5.6Hz)，3.08(d，2H，J＝9.4Hz)，2.53(m，4H)，2.05(m，4H)，1.84(m，4H)，1.24(d，6H，J＝5.9Hz)；
To C 24H 31BrN 2O 2HCl+0.34CHCl 3Value of calculation: C, 54.5; H, 6.08; N, 5.22;
Measured value: C, 54.5; H, 6.22; N, 5.22;
ESMS?m/e：459.1(M+H) +。
Embodiment 353
N-(3-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-N, 2-dimethyl propylene amide
According to method T and option A D, use N-(3-{1-[(3R)-3-(3,4-dimethoxy phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and methyl iodide prepare titled reference compound.
ESMS?m/e：531.2(M+H) +。
Embodiment 354
N-(3-{1-[(3R)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-N, 2-dimethyl propylene amide
According to method T and option A D, use N-(3-{1-[(3R)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and methyl iodide prepare titled reference compound.
ESMS?m/e：513.2(M+H) +。
Embodiment 355
N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-N, 2-dimethyl propylene amide
According to method T and option A D, use N-(3-{1-[(3S)-3-(3-acetyl group phenoxy group)-3-phenyl propyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and methyl iodide prepare titled reference compound.
ESMS?m/e：513.2(M+H) +。
Embodiment 356
N-(3-{1-[(2S)-3-(4-bromine phenoxy group)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 4-bromophenyl (2R)-3-chloro-2-methyl-propyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.0(M+H) +。
Embodiment 357
2-methyl-N-(3-{1-[(2S)-2-methyl-3-(2,4,5-trifluoromethoxy phenoxy base) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, use 1-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base }-2,4,5-trifluoro-benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：449.2(M+H) +。
Embodiment 358
N-(3-{1-[(2S)-3-(3-chlorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-chloro-3-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.2(M+H) +。
Embodiment 359
N-(3-{1-[(2S)-3-(4-fluorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base }-4-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.2(M+H) +。
Embodiment 360
N-(3-{1-[(2S)-3-(3-fluorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base }-3-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.2(M+H) +。
Embodiment 361
N-(3-{1-[(2S)-3-(2-chlorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-chloro-2-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.1(M+H) +。
Embodiment 362
N-(3-{1-[(2S)-3-(2-fluorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base }-2-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.2(M+H) +。
Embodiment 363
N-(3-{1-[(2S)-3-(4-chlorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-chloro-4-{[(2R)-3-chloro-2-methyl-propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.2(M+H) +。
Embodiment 364
N-(3-{1-[(2S)-3-(3-bromine phenoxy group)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 3-bromophenyl (2R)-3-chloro-2-methyl-propyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：474.0(M+H) +。
Embodiment 365
N-(3-{1-[(2S)-3-(2-bromine phenoxy group)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 2-bromophenyl (2R)-3-chloro-2-methyl-propyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.0(M+H) +。
Embodiment 366
N-(3-{1-[(2R)-3-(3-fluorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{[(2S)-3-chloro-2-methyl-propyl] the oxygen base }-3-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.2(M+H) +。
Embodiment 367
N-(3-{1-[(2R)-3-(4-fluorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{[(2S)-3-chloro-2-methyl-propyl] the oxygen base }-4-fluorobenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.8(M+H) +。
Embodiment 368
N-(3-{1-[(2R)-3-(2-chlorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-chloro-2-{[(2S)-3-chloro-2-methyl-propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.1(M+H) +。
Embodiment 369
N-(3-{1-[(2R)-3-(4-chlorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-chloro-4-{[(2S)-3-chloro-2-methyl-propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.1(M+H) +。
Embodiment 370
N-(3-{1-[(2R)-3-(4-bromine phenoxy group)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 4-bromophenyl (2S)-3-chloro-2-methyl-propyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.0(M+H) +。
Embodiment 371
N-(3-{1-[(2R)-3-(3-bromine phenoxy group)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 3-bromophenyl (2S)-3-chloro-2-methyl-propyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.0(M+H) +。
Embodiment 372
N-(3-{1-[(2R)-3-(2-bromine phenoxy group)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 2-bromophenyl (2S)-3-chloro-2-methyl-propyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：473.0(M+H) +。
Embodiment 373
N-(3-{1-[(2R)-3-(3-chlorophenoxy)-2-methyl-propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-chloro-3-{[(2S)-3-chloro-2-methyl-propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：429.1(M+H) +。
Embodiment 374
N-(3-{1-[3-(5,5-dimethyl-1,3-dioxane-2-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 2-(3-bromopropyl)-5,5-dimethyl-1,3-dioxane and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：403.2(M+H) +。
Embodiment 375
N-(3-{1-[4-(3-acetyl group phenoxy group) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-[3-(4-chlorine butoxy) phenyl] ethyl ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：437.2(M+H) +。
Embodiment 376
N-(3-{1-[4-(3-methoxyl group phenoxy group) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-(4-chlorine butoxy)-3-methoxybenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 377
N-(3-{1-[4-(4-methoxyl group phenoxy group) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-(4-chlorine butoxy)-4-methoxybenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 378
N-(3-{1-[4-(2-methoxyl group phenoxy group) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 1-(4-chlorine butoxy)-2-methoxybenzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 379
N-(3-{1-[4-(3, the 4-dimethyl phenoxy) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 4-(4-chlorine butoxy)-1,2-dimethyl benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：423.2(M+H) +。
Embodiment 380
N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, using 2-(4-chlorobutyl)-1,3-dioxolane and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：375.2(M+H) +。
Embodiment 381
N-(3-{1-[5-(3-acetyl group phenoxy group) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{3-[(5-chlorine amyl group) the oxygen base] phenyl } ethyl ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：451.3(M+H) +。
Embodiment 382
N-(3-{1-[5-(3-acetyl group phenoxy group) amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, use 1-{3-[(5-chlorine amyl group) the oxygen base] phenyl } ethyl ketone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：449.2(M+H) +。
Embodiment 383
N-(3-{1-[6-(3-acetyl group phenoxy group) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method G and option b 1, use 1-{3-[(6-chlorine hexyl) the oxygen base] phenyl } ethyl ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：465.3(M+H) +。
Embodiment 384
N-(3-{1-[6-(3-acetyl group phenoxy group) hexyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, use 1-{3-[(6-chlorine hexyl) the oxygen base] phenyl } ethyl ketone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：463.3(M+H) +。
Embodiment 385
N-(3-{1-[4-(4-chlorophenoxy)-4-(4-chlorphenyl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method B and option A N, use 4-chlorophenol and N-(3-{1-[4-(4-chlorphenyl)-4-hydroxybutyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：562.9(M+23) +。
Embodiment 386
2-methyl-N-(3-{1-[2-(1-methyl-2-phenyl-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：480.3(M+H) +。
Embodiment 387
2-methyl-N-(3-{1-[2-(2-phenyl-1H-benzo [G] indol-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(1-naphthyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：516.4(M+H) +。
Embodiment 388
2-methyl-N-(3-{1-[3-(2-phenyl-1H-benzo [G] indol-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(1-naphthyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：530.2(M+H) +。
Embodiment 389
2-methyl-N-[3-(1-{3-[2-phenyl-5-(trifluoromethoxy)-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide. and 1-[4-(trifluoromethoxy) phenyl] the hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：564.2(M+H) +。
Embodiment 390
2-methyl-N-[3-(1-{4-[2-phenyl-5-(trifluoromethoxy)-1H-indol-3-yl] butyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1-[4-(trifluoromethoxy) phenyl] the hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：578.2(M+H) +。
Embodiment 391
2-methyl-N-(3-{1-[3-(1-methyl-2-phenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide. and 1-methyl isophthalic acid-phenyl hydrazine prepare titled reference compound.
ESMS?m/e：495.3(M+H) +。
Embodiment 392
N-(3-{1-[4-(1,2-diphenyl-1H-indol-3-yl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1,1-diphenyl hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：570.3(M+H) +。
Embodiment 393
2-methyl-N-[3-(1-{5-[2-phenyl-5-(trifluoromethoxy)-1H-indol-3-yl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(7-oxo-7-phenyl heptyl)-4-piperidyl] phenyl } propionic acid amide. and 1-[4-(trifluoromethoxy) phenyl] the hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：592.3(M+H) +。
Embodiment 394
N-(3-{1-[5-(1,2-diphenyl-1H-indol-3-yl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-{3-[1-(7-oxo-7-phenyl heptyl)-4-piperidyl] phenyl } propionic acid amide. and 1,1-diphenyl hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：584.3(M+H) +。
Embodiment 395
2-methyl-N-(3-{1-[5-(1-methyl-2-phenyl-1H-indol-3-yl) amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(7-oxo-7-phenyl heptyl)-4-piperidyl] phenyl } propionic acid amide. and 1-methyl isophthalic acid-phenyl hydrazine prepare titled reference compound.
ESMS?m/e：522.3(M+H) +。
Embodiment 396
2-methyl-N-(3-{1-[4-(2-phenyl-1H-benzo [G] indol-3-yl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(1-naphthyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：544.3(M+H) +。
Embodiment 397
2-methyl-N-(3-{1-[4-(1-methyl-2-phenyl-1H-indol-3-yl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1-methyl isophthalic acid-phenyl hydrazine prepare titled reference compound.
ESMS?m/e：508.3(M+H) +。
Embodiment 398
2-methyl-N-(3-{1-[5-(2-phenyl-1H-benzo [G] indol-3-yl) amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(7-oxo-7-phenyl heptyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(1-naphthyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：558.2(M+H) +。
Embodiment 399
2-methyl-N-(3-{1-[2-(5-methyl-2-phenyl-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(4-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：480.2(M+H) +。
Embodiment 400
N-(3-{1-[2-(7-methoxyl group-2-phenyl-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(2-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：496.2(M+H) +。
Embodiment 401
2-methyl-N-(3-{1-[2-(7-methyl-2-phenyl-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：480.2(M+H) +。
Embodiment 402
N-(3-{1-[3-(7-methoxyl group-2-phenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl) propionic acid amide. and 1-(2-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：510.2(M+H) +。
Embodiment 403
2-methyl-N-(3-{1-[4-(7-methyl-2-phenyl-1H-indol-3-yl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：508.3(M+H) +。
Embodiment 404
N-(3-{1-[2-(5-methoxyl group-2-phenyl-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-{3-[1-(4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(4-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：496.2(M+H) +。
Embodiment 405
2-methyl-N-(3-{1-[3-(5-methyl-2-phenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(4-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：494.3(M+H) +。
Embodiment 406
N-(3-{1-[4-(7-methoxyl group-2-phenyl-1H-indol-3-yl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(2-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：524.3(M+H) +。
Embodiment 407
2-methyl-N-(3-{1-[3-(1-phenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl } phenyl }-2-methyl propanamide and 1,1-diphenyl hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：480.2(M+H) +。
Embodiment 408
2-methyl-N-(3-{1-[2-(1-phenyl-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl } phenyl }-2-methyl propanamide and 1,1-diphenyl hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 409
2-methyl-N-(3-{1-[2-(7-Methyl-1H-indole-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：404.2(M+H) +。
Embodiment 410
2-methyl-N-(3-{1-[2-(1-Methyl-1H-indole-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl phenyl-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：404.2(M+H) +。
Embodiment 411
2-methyl-N-(3-{1-[2-(5-Methyl-1H-indole-3-yl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(4-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：404.2(M+H) +。
Embodiment 412
2-methyl-N-[3-(1-{2-[5-(trifluoromethoxy)-1H-indol-3-yl] ethyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl phenyl-2-methyl propanamide and 1-[4-(trifluoromethoxy) phenyl] the hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：474.2(M+H) +。
Embodiment 413
N-(3-{1-[3-(1H-benzo [G] indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method H and scheme S, use N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(1-naphthyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：454.2(M+H) +。
Embodiment 414
2-methyl-N-(3-{1-[3-(1-Methyl-1H-indole-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
Be prepared according to method H and scheme S.(3-{1-[4-(1 with N-, 3-dioxolane-2-yl) butyl]-the 4-piperidyl } phenyl)-2-methyl propanamide (100mg, 0.270mmol), 1-methyl isophthalic acid-phenylhydrazine (106mg, 0.870mmol), zinc dichloride (119mg, 0.870mmol) and acetic acid (1.00mL) 80 ℃ of down heating 12 hours.With gained crude mixture water (20mL) dilution, (3 * 20mL) extract water layer with unsaturated carbonate potassium solution (10mL) neutralization and with dichloromethane.With the organic layer vacuum concentration that merges, residue is through preparation TLC purification, with 3%NH 3(methanol solution of 2.0M) eluant solution in dichloromethane, obtain required product 2-methyl-N-(3-{1-[3-(1-Methyl-1H-indole-3-yl) propyl group]-the 4-piperidyl phenyl) propionic acid amide..
1H?NMR(400MHz，CDCl 3)δ7.60(d，1H，J＝8.1Hz)，7.45(s，1H)，7.35(d，1H，J＝7.4Hz)，7.25(m，4H)，7.09(t，1H，J＝7.3Hz)，6.97(d，1H，J＝7.3Hz)，6.86(s，1H)，3.75(s，3H)，3.11(d，2H，J＝11.6Hz)，2.79(t，2H，J＝7.3Hz)，2.51(m，4H)，2.12-1.81(m，8H)，1.25(d，6H，J＝7.1Hz)；
To C 27H 35N 3O+0.225CHCl 3Value of calculation: C, 73.57; H, 7.99; N, 9.45;
Measured value: C, 73.93; H, 7.90; N, 9.23;
ESMS?m/e：418.2(M+H) +。
Embodiment 415
2-methyl-N-(3-{1-[3-(5-Methyl-1H-indole-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(4-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：418.2(M+H) +。
Embodiment 416
2-methyl-N-[3-(1-{3-[5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method H and scheme S, use N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl phenyl-2-methyl propanamide and 1-[4-(trifluoromethoxy) phenyl] the hydrazonium salt hydrochlorate prepares titled reference compound.
ESMS?m/e：488.2(M+H) +。
Embodiment 417
2-methyl-N-(3-{1-[3-(7-Methyl-1H-indole-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method H and scheme S, use N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：418.2(M+H) +。
Embodiment 418
N-(3-{1-[3-(7-methoxyl group-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method H and scheme S, use N-(3-{1-[4-(1,3-dioxolane-2-yl) butyl]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(2-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：434.0(M+H) +。
Embodiment 419
N-(3-{1-[2-(7-methoxyl group-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(2-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：420.2(M+H) +。
Embodiment 420
N-(3-{1-[2-(5-methoxyl group-1H-indol-3-yl) ethyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method H and scheme S, use N-(3-{1-[3-(1,3-dioxolane-2-yl) propyl group]-the 4-piperidyl phenyl-2-methyl propanamide and 1-(4-methoxyphenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：420.2(M+H) +。
Embodiment 421
2-methyl-N-(3-{1-[4-(5-methyl-2-phenyl-1H-indol-3-yl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and scheme M, use 2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide. and 1-(4-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：508.3(M+H) +。
Embodiment 422
2-methyl-N-[4-(1-{[1-(4-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[4-(4-piperidyl) phenyl] propionic acid amide. and 1-(4-aminomethyl phenyl)-1H-indole prepare titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 423
N-[4-(1-{[1-(4-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] butyramide
According to method D and scheme N, using N-[4-(4-piperidyl) phenyl] butyramide and 1-(4-aminomethyl phenyl)-1H-indole prepare titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 424
N-[3-(1-{[2-(2-aminophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 2-(1H-indole-2-yl) aniline prepares titled reference compound.
ESMS?m/e：467.2(M+H) +。
Embodiment 425
3-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-the 1H-indole-2-ethyl formate
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1H-indole-2-ethyl formate prepare titled reference compound.
ESMS?m/e：448.2(M+H) +。
Embodiment 426
2-methyl-N-(3-{1-[(1-Methyl-1H-indole-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 2-Methyl-1H-indole prepare titled reference compound.
ESMS?m/e：390.2(M+H) +。
Embodiment 427
N-(3-{1-[(5-methoxyl group-2-Methyl-1H-indole-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5-methoxyl group-2-Methyl-1H-indole prepare titled reference compound.
ESMS?m/e：420.2(M+H) +。
Embodiment 428
2-methyl-N-(3-{1-[(1-methyl-2-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-methyl-2-phenyl-1H-indole prepare titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 429
2-methyl-N-(3-{1-[(5-nitro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5-nitro-1H-indole prepare titled reference compound.
ESMS?m/e：421.1M+H) +。
Embodiment 430
2-methyl-N-(3-{1-[(2-Methyl-1H-indole-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 2-Methyl-1H-indole prepare titled reference compound.
ESMS?m/e：390.2M+H) +。
Embodiment 431
N-(3-{1-[(4-bromo-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 4-bromo-1H-indole prepare titled reference compound.
ESMS?m/e：455.0(M+H) +。
Embodiment 432
N-[3-(1-{[2-(4-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 2-(4-fluorophenyl)-1H-indole prepare titled reference compound.
ESMS?m/e：470.0(M+H) +。
Embodiment 433
N-(3-{1-[(1,2-diphenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, use 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1,2-diphenyl-1H-indole prepares titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 434
N-[3-(1-{[2-(4-chlorphenyl)-1-ethyl-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 2-(4-chlorphenyl)-1-ethyl-1H-indole prepare titled reference compound.
ESMS?m/e：514.1(M+H) +。
Embodiment 435
N-(3-{1-[(5-chloro-2-Methyl-1H-indole-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5-chloro-2-Methyl-1H-indole prepare titled reference compound.
ESMS?m/e：424.1(M+H) +。
Embodiment 436
N-(3-{1-[(5-cyano-1 H-indol--3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1H-indole-5-formonitrile HCN prepare titled reference compound.
ESMS?m/e：401.1(M+H) +。
Embodiment 437
2-methyl-N-(3-{1-[(5-methyl-2-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5-methyl-2-phenyl-1H-indole prepare titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 438
2-methyl-N-[3-(1-{[1-(4-nitrobenzophenone)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-(4-nitrobenzophenone)-1H-indole prepare titled reference compound.
ESMS?m/e：497.2(M+H) +。
Embodiment 439
N-[3-(1-{[1-(2-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-(2-fluorophenyl)-1H-indole prepare titled reference compound.
ESMS?m/e：470.1(M+H) +。
Embodiment 440
N-(3-{1-[(5,6-dimethoxy-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, use 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5,6-dimethoxy-1H-indole prepares titled reference compound.
ESMS?m/e：436.2(M+H) +。
Embodiment 441
2-methyl-N-[3-(1-{[1-(3-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-(3-aminomethyl phenyl)-1H-indole prepare titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 442
2-methyl-N-{3-[1-(1-[3-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method D and scheme N, use 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-[3-(trifluoromethyl) phenyl]-the 1H-indole prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 443
N-[3-(1-{[1-(4-methoxyphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5-methoxyl group-2-phenyl-1H-indole prepare titled reference compound.
ESMS?m/e：482.2(M+H) +。
Embodiment 445
2-methyl-N-(3-{1-[(5-Methyl-1H-indole-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 5-Methyl-1H-indole prepare titled reference compound.
ESMS?m/e：390.2(M+H) +。
Embodiment 446
N-[3-(1-{[1-(2-nitrobenzophenone)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(2-nitrobenzophenone)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：497.2(M+H) +。
Embodiment 447
N-[3-(1-{[1-(2-methoxyphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(2-methoxyphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：482.2(M+H) +。
Embodiment 448
2-methyl-N-{3-[1-(1-[2-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method D and scheme N, use 1-[2-(trifluoromethyl) phenyl]-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 449
N-(3-{1-[(5-methoxyl group-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 1H-indole-5-ylmethyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：406.2(M+H) +。
Embodiment 450
N-[3-(1-{[1-(4-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(4-fluorophenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：470.2(M+H) +。
Embodiment 451
N-[3-(1-{[1-(3-methoxyphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(3-methoxyphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：482.2(M+H) +。
Embodiment 452
2-methyl-N-[3-(1-{[1-(2-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 1-(2-aminomethyl phenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 453
3-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-5-methoxyl group-1H-indole-2-ethyl formate
According to method D and scheme N, using 5-methoxyl group-1H-indole-2-ethyl formate and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：478.2(M+H) +。
Embodiment 454
N-(3-{1-[(5-fluoro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 5-fluoro-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：394.2(M+H) +。
1-phenyl-1H-indole
According to method C and scheme O, use 1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：193.9(M+H) +。
1-(4-chlorphenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-chloro-4-iodobenzene to prepare titled reference compound.
ESMS?m/e：227.9(M+H) +。
1-(3-chlorphenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-chloro-3-iodobenzene to prepare titled reference compound.
ESMS?m/e：227.9(M+H) +。
1-(2-chlorphenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-chloro-2-iodobenzene to prepare titled reference compound.
ESMS?m/e：227.9(M+H) +。
1-[2-(trifluoromethyl) phenyl]-the 1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-2-(trifluoromethyl) benzene to prepare titled reference compound.
ESMS?m/e：262.0(M+H) +。
4-(1H-indole-1-yl) benzonitrile
According to method C and scheme O, use 1H-indole and 4-iodo-benzonitrile to prepare titled reference compound.
ESMS?m/e：219.0(M+H) +。
1-(4-nitrobenzophenone)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-4-Nitrobenzol to prepare titled reference compound.
ESMS?m/e：238.2(M+H) +。
1-(2-nitrobenzophenone)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-2-Nitrobenzol to prepare titled reference compound.
ESMS?m/e：238.2(M+H) +。
Embodiment 455
N-[3-(1-{[1-(4-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 1-(4-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：472.1(M+H) +。
Embodiment 456
N-[3-(1-{[1-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 1-(3-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：472.1(M+H) +。
Embodiment 457
N-[3-(1-{[1-(2-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 1-(2-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：484.1(M+H) +。
Embodiment 458
N-[3-(1-{[1-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(3-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：486.1(M+H) +。
Embodiment 459
N-[3-(1-{[1-(4-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(4-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 460
N-[3-(1-{[1-(2-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 1-(2-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 461
N-[3-(1-{[1-(2-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 1-(2-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：472.1(M+H) +。
Embodiment 462
N-[3-(1-{[1-(4-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 1-(4-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：484.1(M+H) +。
Embodiment 463
N-[3-(1-{[1-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 1-(3-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：484.1(M+H) +。
Embodiment 464
N-(3-{1-[(1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 1-phenyl-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：438.2(M+H) +。
Embodiment 465
N-(3-{1-[(1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method D and scheme N, using 1-phenyl-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：450.2(M+H) +。
6-chloro-1-(4-nitrobenzophenone)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-4-Nitrobenzol to prepare titled reference compound.
ESMS?m/e：272.6(M+H) +。
6-chloro-1-(2, the 3-Dichlorobenzene base)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1,2-two chloro-3-iodobenzenes prepare titled reference compound.
ESMS?m/e：296.5(M+H) +。
6-chloro-1-(3-aminomethyl phenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-3-methylbenzene to prepare titled reference compound.
ESMS?m/e：241.9(M+H) +。
6-chloro-1-(2-aminomethyl phenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-2-methylbenzene to prepare titled reference compound.
ESMS?m/e：241.9(M+H) +。
2-(6-chloro-1H-indole-1-yl) phenyl methyl ether
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-2-methoxybenzene to prepare titled reference compound.
ESMS?m/e：257.9(M+H) +。
6-chloro-1-[3-(trifluoromethyl) phenyl]-the 1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-3-(trifluoromethyl) benzene to prepare titled reference compound.
ESMS?m/e：295.6(M+H) +。
6-chloro-1-(2-fluorophenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-fluoro-2-iodobenzene to prepare titled reference compound.
ESMS?m/e：245.9(M+H) +。
6-chloro-1-(3-chlorphenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-chloro-3-iodobenzene to prepare titled reference compound.
ESMS?m/e：261.9(M+H) +。
6-chloro-1-(4-chlorphenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-chloro-4-iodobenzene to prepare titled reference compound.
ESMS?m/e：262.9(M+H) +。
6-chloro-1-(2-chlorphenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-chloro-2-iodobenzene to prepare titled reference compound.
ESMS?m/e：262.9(M+H) +。
3-(6-chloro-1H-indole-1-yl) phenyl methyl ether
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-3-methoxybenzene to prepare titled reference compound.
ESMS?m/e：257.9(M+H) +。
6-chloro-1-[4-(trifluoromethyl) phenyl]-the 1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-4-(trifluoromethyl) benzene to prepare titled reference compound.
ESMS?m/e：295.6(M+H) +。
6-chloro-1-(4-aminomethyl phenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-iodo-4-methylbenzene to prepare titled reference compound.
ESMS?m/e：241.9(M+H) +。
6-chloro-1-(4-fluorophenyl)-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and 1-fluoro-4-iodobenzene to prepare titled reference compound.
ESMS?m/e：245.9(M+H) +。
Embodiment 466
N-[3-(1-{[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 6-chloro-1-(4-fluorophenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：502.1(M+H) +。
Embodiment 467
N-[3-(1-{[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 6-chloro-1-(4-fluorophenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：490.1(M+H) +。
Embodiment 468
N-(3-{1-[(6-fluoro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 6-fluoro-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：380.1(M+H) +。
Embodiment 469
N-(3-{1-[(6-fluoro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method D and scheme N, using 6-fluoro-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：392.1(M+H) +。
Embodiment 470
N-(3-{1-[(6-fluoro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 6-fluoro-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：394.1(M+H) +。
Embodiment 471
N-[3-(1-{[6-chloro-1-(4-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(4-fluorophenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：504.1(M+H) +。
Embodiment 472
N-[3-(1-{[6-chloro-1-(2-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 6-chloro-1-(2-fluorophenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409.1(M+H) +。
Embodiment 473
N-[3-(1-{[6-chloro-1-(2-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 6-chloro-1-(2-fluorophenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：502.1(M+H) +。
Embodiment 474
N-[3-(1-{[6-chloro-1-(2-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(2-fluorophenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：504.1(M+H) +。
Embodiment 475
N-[3-(1-{[6-chloro-1-(4-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 6-chloro-1-(4-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：506.1(M+H) +。
Embodiment 476
N-[3-(1-{[6-chloro-1-(4-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 6-chloro-1-(4-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：518.1(M+H) +。
Embodiment 477
N-[3-(1-{[6-chloro-1-(4-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(4-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：520.1(M+H) +。
Embodiment 478
N-[3-(1-{[6-chloro-1-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 6-chloro-1-(3-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：506.1(M+H) +。
Embodiment 479
N-[3-(1-{[6-chloro-1-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method D and scheme N, using 6-chloro-1-(3-chlorphenyl)-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.72(d，1H，J＝8.4Hz)，7.68(s，1H)，7.49(m，2H)，7.44(d，2H，J＝7.9Hz)，7.49-7.25(m，4H)，7.21(d，1H，J＝7.9Hz)，7.17(d，1H，J＝7.9Hz)，6.93(d，1H，J＝7.9Hz)，3.79(s，2H)，3.13(d，2H，J＝9.4Hz)，2.48(sept，1H，J＝7.5Hz)，2.16(m，2H)，1.80(m，4H)，1.51(s，1H)，1.06(m，2H)，0.806(m，2H)；
To C 30H 29Cl 2N 3O+HCl+1.4H 2The value of calculation of O: C, 62.11; H, 5.70; N, 7.24;
Measured value: C, 62.19; H, 6.21; N, 7.06;
ESMS?m/e：519.2(M+H) +。
Embodiment 480
N-[3-(1-{[6-chloro-1-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(3-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：520.1(M+H) +。
Embodiment 481
N-(3-{1-[(5-fluoro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method D and scheme N, using 5-fluoro-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：392.1(M+H) +。
Embodiment 482
N-[3-(1-{[6-chloro-1-(2-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(2-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 483
N-[3-(1-{[6-chloro-1-(3-methoxyphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 3-(6-chloro-1H-indole-1-yl) phenyl methyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：516.2(M+H) +。
Embodiment 484
N-[3-(1-{[6-chloro-1-(2-methoxyphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 2-(6-chloro-1H-indole-1-yl) phenyl methyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：516.2(M+H) +。
Embodiment 485
N-[3-(1-{[6-chloro-1-(2, the 3-Dichlorobenzene base)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(2, the 3-Dichlorobenzene base)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：555.1(M+H) +。
Embodiment 486
N-[3-(1-{[6-chloro-1-(4-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(4-aminomethyl phenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：500.2(M+H) +。
Embodiment 487
N-{3-[1-(6-chloro-1-[3-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } methyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method D and scheme N, use 6-chloro-1-[3-(trifluoromethyl) phenyl]-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：554.2(M+H) +。
Embodiment 488
N-{3-[1-(6-chloro-1-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } methyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method D and scheme N, use 6-chloro-1-[4-(trifluoromethyl) phenyl]-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：554.2(M+H) +。
Embodiment 489
N-[3-(1-{[6-chloro-1-(2-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(2-aminomethyl phenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：500.2(M+H) +。
Embodiment 490
N-[3-(1-{[6-chloro-1-(3-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-(3-aminomethyl phenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：500.2(M+H) +。
Embodiment 491
N-(3-{1-[(7-chloro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method D and scheme N, using 7-chloro-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：408.1(M+H) +。
Embodiment 492
N-(3-{1-[(7-chloro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 7-chloro-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：410.1(M+H) +。
Embodiment 493
N-(3-{1-[(4-fluoro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 4-fluoro-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：380.2(M+H) +。
Embodiment 494
N-(3-{1-[(7-chloro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 7-chloro-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：396.1(M+H) +。
Embodiment 495
2-methyl-N-(3-{1-[(6-Methyl-1H-indole-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 6-Methyl-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：390.2(M+H) +。
Embodiment 496
N-[3-(1-{[6-(benzyloxy)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-(benzyloxy)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：482.2(M+H) +。
Embodiment 497
N-(3-{1-[(6-methoxyl group-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 1H-indole-6-ylmethyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：406.2(M+H) +。
Embodiment 498
3-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-1H-indole-6-methyl formate
According to method D and scheme N, using 1H-indole-6-methyl formate and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：434.2(M+H) +。
Embodiment 499
2-methyl-N-[3-(1-{[6-(trifluoromethyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 6-(trifluoromethyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ8.11(s，1H)，7.66(s，1H)，7.63(s，2H)，7.44(d，1H，J＝8.4Hz)，7.39(s，2H)，7.32(d，1H，J＝8.4Hz)，7.16(t，1H，J＝8.4Hz)，6.84(d，1H，J＝8.4Hz)，4.06(s，2H)，3.27(d，2H，J＝11.6Hz)，2.56(sept，1H，J＝6.8Hz)，2.37(m，3H)，1.93(m，2H)，1.75(m，2H)，1.22(d，6H，J＝6.8Hz)，
To C 25H 28F 3N 3The value of calculation of O+2HCl+0.5EtOAc: C, 57.8; H, 6.11; N, 7.50;
Measured value: C, 56.5; H, 6.46; N, 7.77;
ESMS?m/e：444.2(M+H) +。
1-(2-pyridine radicals)-1H-indole
According to method C and scheme O, use 2-iodo pyridine and 1H-indole to prepare titled reference compound.
ESMS?m/e：195.0(M+H) +。
1-(3-pyridine radicals)-1H-indole
According to method C and scheme O, use 3-iodo pyridine and 1H-indole to prepare titled reference compound.
ESMS?m/e：195.0(M+H) +。
Embodiment 500
2-methyl-N-[3-(1-{[1-(3-pyridine radicals)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 1-(3-pyridine radicals)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 501
2-methyl-N-[3-(1-{[1-(2-pyridine radicals)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 1-(2-pyridine radicals)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 502
N-(3-{1-[(6-fluoro-1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 6-fluoro-1-phenyl-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：470.2(M+H) +。
Embodiment 503
N-(3-{1-[(6-chloro-1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 6-chloro-1-phenyl-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
7-methyl isophthalic acid-phenyl-1H-indole
According to method C and scheme O, use 7-Methyl-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：208.1(M+H) +。
1-phenyl-1H-indole-6-methyl formate
According to method C and scheme O, use 1H-indole-6-methyl formate and iodobenzene to prepare titled reference compound.
ESMS?m/e：252.0(M+H) +。
6-methyl isophthalic acid-phenyl-1H-indole
According to method C and scheme O, use 6-Methyl-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：208.0(M+H) +。
7-chloro-1-phenyl-1H-indole
According to method C and scheme O, use 7-chloro-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：228.0(M+H) +。
6-nitro-1-phenyl-1H-indole
According to method C and scheme O, use 6-nitro-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：238.2(M+H) +。
6-methoxyl group-1-phenyl-1H-indole
According to method C and scheme O, use 1H-indole-6-ylmethyl ether and iodobenzene to prepare titled reference compound.
ESMS?m/e：224.0(M+H) +。Benzyl 1-phenyl-1H-indole-6-base ether
According to method C and scheme O, use 6-(benzyloxy)-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：300.0(M+H) +。
1-phenyl-1H-indole-6-base trifluoromethyl ethers
According to method C and scheme O, use 6-(trifluoromethoxy)-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：278.0(M+H) +
7-methoxyl group-1-phenyl-1H-indole
According to method C and scheme O, use 1H-indole-7-ylmethyl ether and iodobenzene to prepare titled reference compound.
ESMS?m/e：224.0(M+H) +。
1-phenyl-6-(trifluoromethyl)-1H-indole
According to method C and scheme O, use 6-(trifluoromethyl)-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：262.0(M+H) +。
1-(4-pyridine radicals)-1H-indole
According to method C and scheme O, use 1H-indole and 4-iodo pyridine to prepare titled reference compound.
ESMS?m/e：195(M+H) +。
Embodiment 504
N-[3-(1-{[6-(benzyloxy)-1-phenyl-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using benzyl 1-phenyl-1H-indole-6-base ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：558.0(M+H) +。
Embodiment 505
2-methyl-N-(3-{1-[(6-methyl isophthalic acid-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 6-methyl isophthalic acid-phenyl-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.66(s，1H)，7.64(d，1H，J＝7.8Hz)，7.51(d，1H，J＝3.9Hz)，7.50(m，3H)，7.4(m，2H)，7.36-7.32(m，2H)，7.31(s，1H)，7.19(t，1H，J＝7.8Hz)，7.04(d，1H，J＝7.8Hz)，6.91(d，1H，J＝7.8Hz)，3.94(s，2H)，3.25(d，2H，J＝9.2Hz)，2.52(sept，1H，J＝6.4Hz)，2.46(s，3H)，2.28(dt，2H，J＝11.8，2.6Hz)，1.89(dq，2H，J＝2.9Hz)，1.80(m，3H)，1.22(d，6H，J＝6.9Hz)；
To C 31H 35N 3The value of calculation of O+HCl+0.6EtOAc: C, 72.2; H, 7.41; N, 7.57;
Measured value: C, 71.0; H, 7.40; N, 7.66;
ESMS?m/e：466(M+H) +。
Embodiment 506
3-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-1-phenyl-1H-indole-6-methyl formate
According to method D and scheme N, using 1-phenyl-1H-indole-6-methyl formate and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：510.0(M+H) +。
Embodiment 507
2-methyl-N-(3-{1-[(6-nitro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 6-nitro-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：421.0(M+H) +。
Embodiment 508
2-methyl-N-[3-(1-{[1-phenyl-6-(trifluoromethyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl } propionic acid amide.
According to method D and scheme N, using 1-phenyl-6-(trifluoromethyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：520.0(M+H) +。
Embodiment 509
2-methyl-N-(3-{1-[(7-methyl isophthalic acid-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 7-methyl isophthalic acid-phenyl-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：466.0(M+H) +。
Embodiment 510
N-(3-{1-[(7-methoxyl group-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 1H-indole-7-ylmethyl ether and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：406.0(M+H) +。
Embodiment 511
N-(3-{1-[(7-methoxyl group-1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 7-methoxyl group-1-phenyl-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：482.0(M+H) +。
Embodiment 512
N-(3-{1-[(7-chloro-1-phenyl-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, use 7-chloro-1-phenyl-1H-indole and 2-methyl-[3-(4-piperidyl) phenyl] propionic acid amide. to prepare titled reference compound.
ESMS?m/e：488.6(M+H) +。
Embodiment 513
2-methyl-N-(3-{1-[(7-nitro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 7-nitro-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：421.1(M+H) +。
Embodiment 514
N-(3-{1-[(7-nitro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method D and scheme N, using 7-nitro-1H-indole and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：419.5(M+H) +。
Embodiment 515
N-(3-{1-[(7-nitro-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method D and scheme N, using 7-nitro-1H-indole and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：407.3(M+H) +。
7-(2-fluorophenyl)-1H-indole
According to method I and scheme T, use 7-bromo-1H-indole and 2-fluorophenyl boric acid to prepare titled reference compound.
ESMS?m/e：211.9(M+H) +
Embodiment 516
N-[3-(1-{[7-(2-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
Be prepared according to method D and scheme N.With 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. (23.3mg, 0.0948mmol) and the formalin (11.4mg of 37% weight, 0.142mmol) solution in 1.00mL HOAc ∶ diox (1: 4) adds 7-(2-fluorophenyl)-1H-indole (20.0mg, 0.0948mmol) in, the gained reactant mixture was at room temperature stirred 12 hours.Gained reactant mixture water (10mL) is diluted.Water layer dichloromethane extraction (3 * 10mL).The organic extract liquid that merges is washed with saline (10mL), through dried over mgso and vacuum concentration.Residue is through preparation of silica gel TLC purification, with 4%NH 3(methanol solution of 2.0M) eluant solution in dichloromethane obtains required product (56.1mg, 100%).
1HNMR(400MHz，CDCl 3)δ8.58(s，1H)，7.73(dd，1H，J＝2.8，6.3Hz)，7.69(s，1H)，7.53(dt，1H，J＝1.8，7.6Hz)，7.44(d，1H，J＝8.1Hz)，7.38(m，2H)，7.32(s，1H)，7.27-7.21(m，4H)，7.17(t，1H，J＝7.6Hz)，6.88(d，1H，J＝7.6Hz)，3.92(s，2H)，3.20(d，1H，J＝11.6Hz)，2.51(qt，1H，J＝6.7Hz)，2.42(m，1H)，2.25(dt，2H，J＝2.2，11.6Hz)，1.89-1.72(m，5H)，1.22(d，6H，J＝7.3Hz)；ESMS?m/e：470.1(M+H) +.
7-(4-ethylphenyl)-1H-indole
According to method I and scheme T, use 7-bromo-1H-indole and 4-ethylphenyl boric acid to prepare titled reference compound.
ESMS?m/e：222.0(M+H) +。
7-(2-naphthyl)-1H-indole
According to method I and scheme T, use 7-bromo-1H-indole and 2-naphthalene boronic acids to prepare titled reference compound.
ESMS?m/e：244.0(M+H) +。
7-(3-chlorphenyl)-1H-indole
According to method I and scheme T, use 7-bromo-1H-indole and 3-chlorophenylboronic acid to prepare titled reference compound.
ESMS?m/e：227.9(M+H) +。
6-(2-fluorophenyl)-1H-indole
According to method I and scheme T, use 6-bromo-1H-indole and 2-fluorophenyl boric acid to prepare titled reference compound.
ESMS?m/e：211.9(M+H) +。
7-(3-nitrobenzophenone)-1H-indole
According to method I and scheme T, use 7-bromo-1H-indole and 3-nitrobenzophenone boric acid to prepare titled reference compound.
ESMS?m/e：238.9(M+H) +。
1-[4-(1H-indole-7-yl) phenyl] ethyl ketone
According to method I and scheme T, use 7-bromo-1H-indole and 4-acetylbenzene ylboronic acid to prepare titled reference compound.
ESMS?m/e：235.2(M+H) +。
6-(2-aminomethyl phenyl)-1H-indole
According to method I and scheme T, use 6-bromo-1H-indole and 2-aminomethyl phenyl boric acid to prepare titled reference compound.
ESMS?m/e：207.9(M+H) +。
6-(3-chlorphenyl)-1H-indole
According to method I and scheme T, use 6-bromo-1H-indole and 3-chlorophenylboronic acid to prepare titled reference compound.
ESMS?m/e：227.9(M+H) +。
1-[4-(1H-indole-6-yl) phenyl] ethyl ketone
According to method I and scheme T, use 6-bromo-1H-indole and 4-acetylbenzene ylboronic acid to prepare titled reference compound.
ESMS?m/e：235.8(M+H) +。
7-(2-aminomethyl phenyl)-1H-indole
According to method I and scheme T, use 7-bromo-1H-indole and 2-aminomethyl phenyl boric acid to prepare titled reference compound.
ESMS?m/e：208(M+H) +。
6-(4-ethylphenyl)-1H-indole
According to method I and scheme T, use 6-bromo-1H-indole and 4-ethylphenyl boric acid to prepare titled reference compound.
ESMS?m/e：221.9(M+H) +。
Embodiment 517
2-methyl-N-[3-(1-{[7-(2-naphthyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 7-(2-naphthyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：502.2(M+H) +。
Embodiment 518
N-[3-(1-{[7-(4-ethylphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 7-(4-ethylphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：480.2(M+H) +。
Embodiment 519
2-methyl-N-[3-(1-{[6-(2-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 6-(2-aminomethyl phenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ8.2(s，1H)，7.53(m，4H)，7.41(d，1H，J＝8.4Hz)，7.34(m，2H)，7.27-7.12(m，5H)，6.81(d，1H，J＝8.4Hz)，4.09(s，2H)，3.32(d，2H，J＝11.4Hz)，2.57(q，2H，J＝7.6Hz)，2.43(m，3H)，2.08(s，3H)，1.98(m，1H)，1.75(m，2H)，1.22(d，6H，J＝6.3Hz)；
To C 31H 35N 3O+CHCl 3The value of calculation of+DMF: C, 57.0; H, 6.09; N, 8.06;
Measured value: C, 56.5; H, 5.94; N, 7.76;
ESMS?m/e：466.2(M+H) +。
Embodiment 520
N-[3-(1-{[7-(3-chlorphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 7-(3-chlorphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：486.1(M+H) +。
Embodiment 521
2-methyl-N-[3-(1-{[7-(3-nitrobenzophenone)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 7-(3-nitrobenzophenone)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：497.0(M+H) +。
Embodiment 522
N-[3-(1-{[7-(4-acetylphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, use 1-[4-(1H-indole-7-yl) phenyl] ethyl ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：493.6(M+H) +。
Embodiment 523
N-[3-(1-{[6-(4-ethylphenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-(4-ethylphenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：480.1(M+H) +。
Embodiment 524
2-methyl-N-[3-(1-{[7-(2-aminomethyl phenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 7-(2-aminomethyl phenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：466.1(M+H) +。
Embodiment 525
N-[3-(1-{[6-(2-fluorophenyl)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method D and scheme N, using 6-(2-fluorophenyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：470.2(M+H) +。
5-(4-methylphenoxy)-1H-indole
According to method J and scheme U, use 5-bromo-1H-indole and paracresol to prepare titled reference compound.
ESMS?m/e：224.0(M+H) +。
Embodiment 526
N-(3-{1-[(5-bromo-1H-indol-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method D and scheme N, using 5-bromo-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：454.0(M+H) +。
1-(4-pyridine radicals)-6-(trifluoromethyl)-1H-indole
According to method C and scheme O, use 6-(trifluoromethyl)-1H-indole and 4-iodo pyridine to prepare titled reference compound.
ESMS?m/e：262.9(M+H) +。
Embodiment 527
2-methyl-N-[3-(1-{[5-(4-methylphenoxy)-1H-indol-3-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method D and scheme N, using 5-(4-methylphenoxy)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：481.9(M+H) +。
1-(4-aminomethyl phenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-4-methylbenzene to prepare titled reference compound.
ESMS?m/e：208.0(M+H) +。
1-(3-aminomethyl phenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-3-methylbenzene to prepare titled reference compound.
ESMS?m/e：208.0(M+H) +。
1-[3-(trifluoromethyl) phenyl]-the 1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-3-(trifluoromethyl) benzene to prepare titled reference compound.
ESMS?m/e：262.0(M+H) +。
1-(4-methoxyphenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-3-methoxybenzene to prepare titled reference compound.
ESMS?m/e：224.0(M+H) +。
1-(2-methoxyphenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-2-methoxybenzene to prepare titled reference compound.
ESMS?m/e：224.0(M+H) +。
1-(3-methoxyphenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-3-methoxybenzene to prepare titled reference compound.
ESMS?m/e：224.0(M+H) +。
1-(2-aminomethyl phenyl)-1H-indole
According to method C and scheme O, use 1H-indole and 1-iodo-2-methylbenzene to prepare titled reference compound.
ESMS?m/e：208.0(M+H) +。
6-fluoro-1-phenyl-1H-indole
According to method C and scheme O, use 6-fluoro-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：212.0(M+H) +。
6-chloro-1-phenyl-1H-indole
According to method C and scheme O, use 6-chloro-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：228.0(M+H) +。
7-chloro-1-phenyl-1H-indole
According to method C and scheme O, use 7-chloro-1H-indole and iodobenzene to prepare titled reference compound.
ESMS?m/e：228.0(M+H) +。
6-(2-fluorophenyl)-1H-indole
According to method I and scheme T, use 6-bromo-1H-indole and 2-fluorophenyl boric acid to prepare titled reference compound.
ESMS?m/e：211.9(M+H) +。
Embodiment 528
2-methyl-N-{3-[1-(7-oxo-7-phenyl heptyl)-4-piperidyl] phenyl } propionic acid amide.
According to method K and option b 1, using 7-chloro-1-phenyl-1-heptanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：435.1(M+H) +。
Embodiment 529
2-methyl-N-{3-[1-(6-oxo-6-phenyl hexyl)-4-piperidyl] phenyl } propionic acid amide.
According to method K and option b 1, using 6-chloro-1-phenyl-1-hexanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
To C 27H 36N 2O 2+ 0.1CHCl 3Value of calculation: C, 75.3; H, 8.39; N, 6.46;
Measured value: C, 75.4; H, 7.89; N, 6.18;
ESMS?m/e：421.1(M+H) +。
Embodiment 530
2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidyl] phenyl } propionic acid amide.
According to method K and option b 1, using 5-chloro-1-phenyl-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：407.1(M+H) +。
Embodiment 531
N-(3-{1-[4-(4-methoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(4-methoxyphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409.2(M+H) +。
Embodiment 532
N-(3-{1-[4-(4-chlorphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(4-chlorphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：413.1(M+H) +。
Embodiment 533
N-(3-{1-[4-(4-bromophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 1-(4-bromophenyl)-4-chloro-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：457.1(M+H) +。
Embodiment 534
N-(3-{1-[4-(4-tert-butyl-phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 1-(4-tert-butyl-phenyl)-4-chloro-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：435.2(M+H) +。
Embodiment 535
N-(3-{1-[4-(4-fluorophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(4-fluorophenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：397.2(M+H) +。
Embodiment 536
N-(3-{1-[4-oxo-4-(4-Phenoxyphenyl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(4-Phenoxyphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：471.2(M+H) +。
Embodiment 537
N-(3-{1-[4-(4-isopropyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 4-chloro-1-(4-isopropyl phenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：433.2(M+H) +。
Embodiment 538
N-(3-{1-[4-(4-methoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 4-chloro-1-(4-methoxyphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：421.2(M+H) +。
Embodiment 539
N-(3-{1-[4-oxo-4-(4-methoxyphenyl) butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 4-chloro-1-(4-Phenoxyphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：483.2(M+H) +。
Embodiment 540
N-(3-{1-[4-(4-isopropyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(4-isopropyl phenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：421.3(M+H) +。
Embodiment 541
N-(3-{1-[4-(4-tert-butyl-phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 1-(4-tert-butyl-phenyl)-4-chloro-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：447.2(M+H) +。
Embodiment 542
N-(3-{1-[4-(4-aminomethyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(4-aminomethyl phenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：393.2(M+H) +。
Embodiment 543
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 4-chloro-1-(3, the 4-3,5-dimethylphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：407.2(M+H) +。
Embodiment 544
N-(3-{1-[4-(4-bromophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 1-(4-bromophenyl)-4-chloro-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：469.1(M+H) +。
Embodiment 545
N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(4-fluorophenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：411.2(M+H) +。
Embodiment 546
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 4-chloro-1-(3, the 4-3,5-dimethylphenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：419.2(M+H) +。
Embodiment 547
N-(3-{1-[4-(4-aminomethyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 4-chloro-1-(4-aminomethyl phenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：405.2(M+H) +。
Embodiment 548
N-(3-{1-[4-(4-fluorophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 4-chloro-1-(4-fluorophenyl)-1-butanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：409.2(M+H) +。
Embodiment 549
N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：423.2(M+H) +。
Embodiment 550
N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and option b 1, use 5-chloro-1-[4-(trifluoromethyl) phenyl]-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：461.2(M+H) +。
Embodiment 551
N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(4-fluorophenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：423.2(M+H) +。
Embodiment 552
N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(3-nitrobenzophenone)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：438.2(M+H) +。
Embodiment 553
N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(3-nitrobenzophenone)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：450.2(M+H) +。
Embodiment 554
N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(2-fluorophenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：411.2(M+H) +。
Embodiment 555
N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(3-fluorophenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：411.2(M+H) +。
Embodiment 556
N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(4-nitrobenzophenone)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：438.1(M+H) +。
Embodiment 557
N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(4-nitrobenzophenone)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：450.1(M+H) +。
Embodiment 558
N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(4-chlorphenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：439.1(M+H) +。
Embodiment 559
N-[3-(1-{5-oxo-5-[2-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and option b 1, use 5-chloro-1-[2-(trifluoromethyl) phenyl]-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：461.2(M+H) +。
Embodiment 560
N-[3-(1-{5-oxo-5-[2-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method K and option b 1, use 5-chloro-1-[2-(trifluoromethyl) phenyl]-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：473.2(M+H) +。
Embodiment 561
N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(4-chlorphenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：427.1(M+H) +。
Embodiment 562
N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(3-chlorphenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：427.1(M+H) +。
Embodiment 563
N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(2-fluorophenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：423.1(M+H) +。
Embodiment 564
N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(3-chlorphenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：439.1(M+H) +。
Embodiment 565
N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method K and option b 1, use 5-chloro-1-[4-(trifluoromethyl) phenyl]-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：473.2(M+H) +。
Embodiment 566
N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1, using 5-chloro-1-(2-chlorphenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：427.1(M+H) +。
Embodiment 567
N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method K and option b 1, using 5-chloro-1-(2-chlorphenyl)-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：439.1(M+H) +。
Embodiment 568
N-[3-(1-(5-oxo-5-[3-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] cyclopropane carboxamide
According to method K and option b 1, use 5-chloro-1-[3-(trifluoromethyl) phenyl]-1-pentanone and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：473.2(M+H) +。
Embodiment 569
N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-N, 2-dimethyl propylene amide
According to method T and option A D, use N-(3-{1-[4-(3, the 4-3,5-dimethylphenyl)-4-oxo butyl]-the 4-piperidyl phenyl)-2-methyl propanamide and methyl iodide prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.76(s，1H)，7.72(dd，1H，J＝1.8，7.7Hz)，7.33(t，1H，J＝8.8Hz)，7.22(d，1H，J＝7.8Hz)，7.18(d，1H，J＝8.8Hz)，7.01(m，2H)，3.24(s，3H)，3.10(d，1H，J＝10.6Hz)，3.00(t，1H，J＝7.6Hz)，2.49(m，4H)，2.33(s，6H)，2.11(m，3H)，1.99(m，1H)，1.79(m，4H)，1.26(t，2H，J＝7.6Hz)，1.02(d，6H，J＝7.6Hz)，ESMS?m/e：435.2(M+H) +.
Embodiment 570
2-methyl-N-{3-[1-(1-methyl-4-oxo-4-phenyl butyl)-4-piperidyl] phenyl } propionic acid amide.
According to method K and option b 1, using 4-chloro-1-phenyl-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：407.2(M+H) +。
Embodiment 571
N-[3-(1-{5-oxo-5-[3-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and option b 1, use 5-chloro-1-[3-(trifluoromethyl) phenyl]-1-pentanone and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：461.2(M+H) +。
3-(5-chlorine valeryl)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone
According to method AF and scheme H, use 4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone and 5-chlorine valeric chloride prepare titled reference compound.
3-(5-chlorine amyl group)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone
According to method G and scheme C1, use 4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone and 1-bromo-5-chloropentane prepare titled reference compound.
Embodiment 572
N-[3-(1-{5-[(4R)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-yl]-5-oxo amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method G and option b 1, using (4R)-3-(5-chlorine valeryl)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 573
(4R)-4-(3, the 4-difluorophenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-oxo-1,3-oxazolidine-3-Methanamide
According to method AF and scheme H, use (4R)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ8.08(t，1H，J＝5.5Hz)，7.45(S，2H)，7.38(d，1H，J＝8.6Hz)，7.24-7.12(m，3H)，7.06(m，1H)，6.97(d，1H，J＝8.6Hz)，5.40(dd，1H，J＝3.9，8.8Hz)，4.71(t，1H，J＝8.8Hz)，4.23(dd，1H，J＝4.4，9.1Hz)，3.32(qt，2H，J＝6.1Hz)，2.99(d，2H，J＝11.0Hz)，2.49(qt，2H，J＝7.0Hz)，2.41(t，2H，J＝7.0Hz)，1.99(m，2H)，1.82-1.68(m，6H)，1.23(d，6H，J＝7.3Hz)；ESMS?m/e：529.1(M+H) +.
(4S)-and 3-(5-chlorine amyl group)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone
According to method G and scheme Cl, use (4S)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone and 1-bromo-5-chloropentane prepare titled reference compound.
Embodiment 574
N-[3-(1-{5-[(4S)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-yl] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method G and option b 1, using (4S)-3-(5-chlorine amyl group)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.48(s，1H)，7.32(d，1H，J＝8.6Hz)，7.26-7.21(m，2H)，7.20-7.12(m，2H)，7.06(m，1H)，6.97(d，1H，J＝6.96Hz)，4.76(dd，1H，J＝6.3，8.3Hz)，4.62(t，1H，J＝9.0Hz)，4.06(dd，1H，J＝6.4，8.7Hz)，3.46(m，1H)，3.0(d，2H，J＝9.0Hz)，2.77(q，1H，J＝6.8Hz)，2.50(q，2H，J＝6.8Hz)，2.31(t，2H，J＝6.8Hz)，2.01(m，4H)，1.81(m，4H)，1.48(m，4H)，1.26(d，6H，J＝7.3Hz)；
To C 28H 37F 2N 3O 3+ HCl+0.25CHCl 3Value of calculation: C, 60.6; H, 6.65; N, 7.25;
Measured value: C, 60.7; H, 6.91; N, 7.05;
ESMS?m/e：514.2(M+H) +。
Embodiment 575
N-[3-(1-{5-[(4S)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-yl]-5-oxo amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method G and option b 1, using (4S)-3-(5-chlorine valeryl)-4-(3, the 4-difluorophenyl)-1,3-oxazolidine-2-ketone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：528.1(M+H) +。
Embodiment 576
(4S)-4-(3, the 4-difluorophenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-oxo-1,3-oxazolidine-3-Methanamide
According to method AF and scheme H, use (4S)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：529.1(M+H) +。
Embodiment 577
(4S)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-oxo-4-(3,4, the 5-trifluorophenyl)-1,3-oxazolidine-3-Methanamide
According to method AF and scheme H, use (4S)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：547.1(M+H) +。
Embodiment 578
(4S)-4-(3, the 5-difluorophenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-oxo-1,3-oxazolidine-3-Methanamide
According to method AF and scheme H, use (4S)-4-(3, the 4-difluorophenyl)-2-oxo-1,3-oxazolidine-3-formic acid 4-nitro phenyl ester and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：529.2(M+H) +。
Embodiment 579
N-(3-{1-[3-(phenyl sulfenyl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(3-chloropropyl) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：382.9(M+H) +
Embodiment 580
N-(3-{1-[3-(phenyl sulfenyl) propyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, using [(3-chloropropyl) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：395.1(M+H) +
Embodiment 581
2-methyl-N-(3-{1-[3-(phenyl sulfenyl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(3-chloropropyl) sulfenyl] benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1HNMR(400MHz，CDCl 3)δ7.63(s，1H)，7.48(s，1H)，7.33(m，3H)，7.27(t，2H，J＝7.5Hz)，7.20(t，1H，J＝7.9Hz)，7.15(tt，1H，J＝7.2，1.4Hz)，6.95(d，1H，J＝7.6Hz)，2.97(t，4H，J＝7.3Hz)，2.46(m，4H)，1.99(dt，2H，J＝11.4，3.0Hz)，1.84(qt，2H，J＝7.3Hz)，1.77(m，4H)，1.21(d，6H，J＝6.8Hz)；ESMS?m/e：396.8(M+H) +.
Embodiment 582
N-(3-{1-[6-(phenyl sulfenyl) hexyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, using [(6-chlorine hexyl) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：437.4(M+H) +。
Embodiment 583
N-(3-{1-[4-(phenyl sulfenyl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(4-chlorobutyl) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：396.8(M+H) +。
Embodiment 584
N-(3-{1-[4-(phenyl sulfenyl) butyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, using [(4-chlorobutyl) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：409.5(M+H) +。
Embodiment 585
2-methyl-N-(3-{1-[4-(phenyl sulfenyl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(4-chlorobutyl) sulfenyl] benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：410.6(M+H) +。
Embodiment 586
2-methyl-N-(3-{1-[5-(phenyl sulfenyl) amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(5-chlorine amyl group) sulfenyl] benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.1(M+H) +。
Embodiment 587
N-(3-{1-[5-(phenyl sulfenyl) amyl group]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method G and option b 1, using [(5-chlorine amyl group) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：423.1(M+H) +。
[(6-chlorine hexyl) sulfenyl] benzene
According to method R and scheme Z, use phenylmercaptan. and 1-bromo-4-chlorohexane to prepare titled reference compound.
[(4-chlorobutyl) sulfenyl] benzene
According to method R and scheme Z, use phenylmercaptan. and 1-bromo-4-chlorobutane to prepare titled reference compound.
Embodiment 588
N-(3-{1-[6-(phenyl sulfenyl) hexyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(6-chlorine hexyl) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.4(M+H) +。
[(5-chlorine amyl group) sulfenyl] benzene
According to method R and scheme Z, use phenylmercaptan. and 1-bromo-5-chloropentane to prepare titled reference compound.
[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use phenylmercaptan. and 1-bromo-3-chloropropane to prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.37-7.34(m，2H)，7.32-7.26(m，2H)，7.19(tt，1H，J＝1.4，7.3Hz)，3.67(t，2H，J＝6.6Hz)，3.08(t，2H，J＝6.6Hz)，2.06(qt，2H，J＝6.6Hz).
Embodiment 589
N-(3-{1-[5-(phenyl sulfenyl) amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method G and option b 1, using [(5-chlorine amyl group) sulfenyl] benzene and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：411.1(M+H) +。
3-chloropropyl 4-fluorophenyl thioether
According to method R and scheme Z, use 4-fluorobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-bromo-2-[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use 2-bromobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
3-chloropropyl 4-fluorophenyl sulfoxide
According to method S and option A A, use 3-chloropropyl 4-fluorophenyl thioether and 1 normal m-CPBA to prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.65-7.62(m，2H)，7.28-7.21(m，2H)，3.65(m，2H)，2.94(m，2H)，2.28(m，1H)，2.06(m，1H)；ESMS?m/e：220.9(M+H) +.
3-chloropropyl 3-fluorophenyl thioether
According to method R and scheme Z, use 3-fluorobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
3-chloropropyl 2-fluorophenyl thioether
According to method R and scheme Z, use 2-fluorobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-bromo-2-[(3-chloropropyl) sulfinyl] benzene
According to method S and option A A, use 1-bromo-2-[(3-chloropropyl) sulfenyl] benzene and 1eqm-CPBA prepare titled reference compound.
ESMS?m/e：282.8(M+H) +
1-chloro-2-[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use 2-chlorobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-chloro-3-[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use 3-chlorobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-chloro-4-[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use 4-chlorobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-bromo-3-[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use 3-bromobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
1-bromo-4-[(3-chloropropyl) sulfenyl] benzene
According to method R and scheme Z, use 4-bromobenzene thiophenol and 1-bromo-3-chloropropane to prepare titled reference compound.
3-chloropropyl 3,4-3,5-dimethylphenyl thioether
According to method R and scheme Z, use 3,4-thiophenol dimethyl benzene and 1-bromo-3-chloropropane prepare titled reference compound.
Embodiment 590
N-[3-(1-{3-[(4-fluorophenyl) sulfinyl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method G and option b 1, using 3-chloropropyl 4-fluorophenyl sulfoxide and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.64(m，2H)，7.53(s，1H)，7.24(m，5H)，6.94(d，1H，J＝7.7Hz)，2.89(m，4H)，2.45(m，4H)，1.99(m，3H)，1.77(m，5H)，1.24(d，6H，J＝6.8Hz)；
To C 24H 31FN 2O 2The value of calculation of S+0.6EtOAc: C, 65.5; H, 7.45; N, 5.79;
Measured value: C, 65.4; H, 7.30; N, 5.73;
ESMS?m/e：431.1(M+H) +。
Embodiment 591
N-[3-(1-{3-[(2-bromophenyl) sulfinyl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method G and option b 1, use 1-bromo-2-[(3-chloropropyl) sulfinyl] benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
C 24H 31BrN 2O 2S+0.3CHCl 3：ESMS?m/e：491.0(M+H) +。
Embodiment 592
N-{3-[1-((3S)-3-{[(3,4-difluorophenyl) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 and option A C, use 3,4-difluorophenyl sulfonic acid chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：556.2(M+H) +。
Embodiment 593
3-chloro-N-((1S)-3-{4-[3-(isobutyryl amino) phenyl]-piperidino }-the 1-phenyl propyl)-the 2-thenoyl amine
According to method Q1 and option A C, use 3-chloro-2-thiophene chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：524.2(M+H) +。
Embodiment 594
N-(3-{1-[(3S)-3-({ [5-(dimethylamino)-1-naphthyl] sulfonyl } amino)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method Q1 and option A C, use 5-(dimethylamino)-1-naphthalene sulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：613.3(M+H) +。
Embodiment 595
2-methyl-N-{3-[1-((3S)-3-{[(4-aminomethyl phenyl) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method Q1 and option A C, use 4-Methyl benzenesulfonyl chlorine and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：534.2(M+H) +。
Embodiment 596
N-{3-[1-((3S)-3-{[(3,5-two chloro-2-hydroxy phenyls) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 and option A C, use 3,5-two chloro-2-hydroxy benzenes sulfonic acid chlorides and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：605.4(M+H) +。
Embodiment 597
2-methyl-N-[3-(1-{ (3S)-3-[(methyl sulphonyl) amino]-the 3-phenyl propyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method Q1 and option A C, use mesyl chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：458.6(M+H) +。
Embodiment 598
N-{3-[1-((3S)-3-{[(4-fluorophenyl) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 and option A C, use 4-fluorobenzene sulfonic acid chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：538.1(M+H) +
Embodiment 599
N-{3-[1-((3S)-3-{[(4-tert-butyl-phenyl) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 and option A C, use 4-tert-butyl benzene sulfonic acid chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：576.2(M+H) +。
Embodiment 600
N-{3-[1-((3S)-3-{[(2,5-Dichlorobenzene base) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 and option A C, use 2,5--two chloro phenylsulfonyl chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：588.0(M+H) +。
Embodiment 601
2-methyl-N-[3-(1-{ (3S)-3-phenyl-3-[(sulfonyl propyl base) amino] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method Q1 and option A C, use 1-third sulfonic acid chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 602
N-{3-[1-((3S)-3-{[(3,5-dimethyl-4-isoxazolyl) sulfonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 and option A C, use 3,5-dimethyl-4-isoxazole sulfonic acid chloride and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.53(s，2H)，7.3-7.1(m，5H)，7.05(t，2H，J＝6.5Hz)，6.81(d，1H，J＝7.1Hz)，4.65(dd，1H，J＝6.3，2.2Hz)，3.11(t，2H，J＝7.2Hz)，2.4(m，4H)，2.2(s，3H)，2.05(m，2H)，2.01(s，3H)，2.0-1.8(m，7H)，1.21(d，6H，J＝7.1Hz)；ESMS?m/e：539.5(M+H) +.
Embodiment 603
3-{[(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group) amino] sulfonyl }-the 2-thiophenecarboxylate
According to method Q1 and option A C, use 3-(chlorosulfonyl)-2-thiophenecarboxylate and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
To C 24H 33N 3O 5The value of calculation of SHCl: C, 6.00; H, 5.30; N, 7.72;
Measured value: C, 52.9; H, 6.04; N, 7.59;
ESMS?m/e：508.2(M+H) +。
Embodiment 604
2-methyl-N-{3-[1-((3S)-3-{[(4-phenoxy group phenylamino) carbonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method P and option A B, use 1-isocyanato--4-phenoxy group benzene and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：591.3(M+H) +。
1H?NMR(400MHz，CDCl 3)δ7.53(s，2H)，7.3-7.1(m，5H)，7.05(t，2H，J＝6.5Hz)，6.81(d，1H，J＝7.1Hz)，4.65(dd，1H，J＝6.3，2.2Hz)，3.11(t，2H，J＝7.2Hz)，2.4(m，4H)，2.2(s，3H)，2.05(m，2H)，2.01(s，3H)，2.0-1.8(m，7H)，1.21(d，6H，J＝7.1Hz)，ESMS?m/e：539.5(M+H) +.
Embodiment 605
N-[3-(1-{ (3S)-3-[(phenylamino carbonyl) amino]-the 3-phenyl propyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method P and option A B, use isocyanato-benzene and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：499.2(M+H) +。
Embodiment 606
N-{3-[1-((3S)-3-{[(tert-butyl group amino) thiocarbonyl (carbothioyl)] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 2-isothiocyanato-2-methylpropane and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：495.1(M+H) +。
Embodiment 607
N-{3-[1-((3S)-3-{[(2-fluoroanilino) carbonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 1-fluoro-2-isocyanato-benzene and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：517.0(M+H) +。
Embodiment 608
2-methyl-N-[3-(1-{ (3S)-3-phenyl-3-[(2-toluidino thiocarbonyl) amino] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method P and option A B, use 1-isothiocyanato-2-methylbenzene and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：529.1(M+H) +。
Embodiment 609
N-{3-[1-((3S)-3-{[(benzylamino) carbonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
1H?NMR(400MHz，CDCl 3)δ8.44(s，1H)，7.67(d，1H，J＝7.9Hz)，7.31-7.13(m，13H)，6.38(s，1H)，6.80(d，1H，J＝7.9Hz)，5.54(m，1H)，4.81(m，1H)，4.41(dd，1H，J＝14.8，6.2Hz)，4.29(dd，1H，J＝14.9，5.4Hz)，2.99(d，1H，J＝11.2Hz)，2.87(d，1H，J＝11.2Hz)，2.67(q，1H，J＝6.2Hz)，2.3(m，3H)，2.0-1.5(m，7H)，1.23(d，6H，J＝6.7Hz)；ESMS?m/e：513.2(M+H) +.
Embodiment 610
2-methyl-N-{3-[1-((3S)-3-{[(2-Nitrobenzol amino) carbonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method P and option A B, use 1-isocyanato--2-Nitrobenzol and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：543.6(M+H) +。
Embodiment 611
N-{3-[1-((3S)-3-{[(3,4-dichloro-benzenes amino) carbonyl] amino }-the 3-phenyl propyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 1,2-two-chloro-4-isocyanato-benzene and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：567.1(M+H) +。
Embodiment 612
2-methyl-N-(3-{1-[(3S)-3-({ [2-(methyl sulfenyl) phenylamino] carbonyl } amino)-3-phenyl propyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method P and option A B, use 1-isocyanato--2-(methyl sulfenyl) benzene and N-(3-{1-[(3S)-3-amino-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：545.0(M+H) +。
Embodiment 613
N-{3-[1-(3-{[(4-fluoroanilino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 1-fluoro-4-isocyanato-benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.45(q，2H，J＝4.7Hz)，7.23(m，4H)，7.05(t，4H，J＝7.8Hz)，6.75(m，1H)，4.05(m，1H)，3.19(s，1H)，2.71(m，1H)，2.53(m，1H)，2.25(m，3H)，1.8(m，9H)，1.25(d，6H，J＝6.4Hz)；ESMS?m/e：441.1(M+H) +.
Embodiment 614
N-{3-[1-(3-{[(3,4-dichloro-benzenes amino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 1,2-two chloro-4-isocyanato-benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：493.2(M+H) +。
Embodiment 615
2-methyl-N-[3-(1-{3-[(2-toluidino thiocarbonyl) amino] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method P and option A B, use 1-isothiocyanato-2-methylbenzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 616
N-{3-[1-(3-{[(benzylamino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use (isocyanato-methyl) benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：437.2(M+H) +。
Embodiment 617
N-{3-[1-(3-{[(4-phenetidino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 1-ethyoxyl-4-isocyanato-benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：467.2(M+H) +。
Embodiment 618
N-[3-(1-{3-[(phenylamino carbonyl) amino] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method P and option A B, use isocyanato-benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：422.9(M+H) +。
Embodiment 619
2-methyl-N-(3-{1-[3-({ [2-(methyl sulfenyl) phenylamino] carbonyl } amino) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method P and option A B, use 1-isocyanato--2-(methyl sulfenyl) benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：469.1(M+H) +。
Embodiment 620
N-{3-[1-(3-{[(tert-butyl group amino) thiocarbonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method P and option A B, use 2-isothiocyanato-2-methylpropane and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：419.0(M+H) +。
Embodiment 621
2-methyl-N-{3-[1-(3-{[(4-phenoxy group phenylamino) carbonyl] amino } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method P and option A B, use 1-isocyanato--4-phenoxy group benzene and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：515.5(M+H) +。
Embodiment 622
N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(2,4 difluorobenzene base)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-ascorbyl palmitate
According to method AC and option A M, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide and 4-(2,4 difluorobenzene base)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-pyridine carboxylic acid prepares titled reference compound.
ESMS?m/e：525.2(M+H) +。
Embodiment 623
N-(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group)-4-(3, the 4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-ascorbyl palmitate
According to method AC and option A M, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl } acetamide and 4-(3, the 4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-pyridine carboxylic acid prepares titled reference compound.
ESMS?m/e：525.2(M+H) +。
Embodiment 624
N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } ethyl)-1-(4-nitrobenzophenone)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 1-(4-nitrobenzophenone)-5-(trifluoromethyl)-1H-pyrazoles-4-formyl chloride prepare titled reference compound.
ESMS?m/e：629.2(M+H) +。
Embodiment 625
N-[3-(1-{6-[(diphenyl acetyl group) amino] hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and diphenyl-acetyl chloride prepare titled reference compound.
ESMS?m/e：540.3(M+H) +。
Embodiment 626
5-(3, the 5-dichlorophenoxy)-N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl)-the 2-furoamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 5-(3, the 5-dichlorophenoxy)-2-furoyl chloride prepare titled reference compound.
ESMS?m/e：600.2(M+H) +。
Embodiment 627
N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl)-2-phenoxy group nicotiamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 2-phenoxy group nicotinoyl chlorine prepare titled reference compound.
ESMS?m/e：543.3(M+H) +。
Embodiment 628
N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl)-the 2-naphthalenecarboxamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 2-naphthoyl chloride prepare titled reference compound.
ESMS?m/e：500.3(M+H) +。
Embodiment 629
1-benzyl-3-the tert-butyl group-N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl)-1H-pyrazoles-5-Methanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 1-benzyl-3-tert-butyl group-1H-pyrazoles-5-formyl chloride prepare titled reference compound.
ESMS?m/e：586.3(M+H) +。
Embodiment 630
3-chloro-N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl)-4-(isopropyl sulfonyl)-2-thenoyl amine
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 3-chloro-4-(isopropyl sulfonyl)-2-thiophene chloride prepare titled reference compound.
ESMS?m/e：596.2(M+H) +。
Embodiment 631
N-[3-(1-{6-[(phenylamino carbonyl) amino] hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and phenyl isocyanate prepare titled reference compound.
ESMS?m/e：465.2(M+H) +。
Embodiment 632
N-{3-[1-(6-{[(2,4-dichloro-benzenes amino) carbonyl] amino } hexyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 2,4-dichloro-benzenes isocyanates prepares titled reference compound.
ESMS?m/e：533.2(M+H) +。
Embodiment 633
N-(6-{4-[3-(isobutyryl amino) phenyl]-piperidino } hexyl)-1-phenyl-5-propyl group-1H-pyrazole-4-carboxamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 1-phenyl-5-propyl group-1H-pyrazoles-4-formyl chloride prepare titled reference compound.
ESMS?m/e：558.3(M+H) +。
Embodiment 634
2-methyl-N-{3-[1-(6-{[(1-naphthyl amino) carbonyl] amino } hexyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 1-naphthyl isocyanates prepare titled reference compound.
ESMS?m/e：515.3(M+H) +。
Embodiment 635
N-{3-[1-(6-{[([1,1 '-biphenyl]-the 4-base is amino) carbonyl] amino } hexyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 4-biphenyl isocyanates prepare titled reference compound.
ESMS?m/e：541.3(M+H) +。
Embodiment 636
2-methyl-N-{3-[1-(6-{[(2-naphthyl amino) carbonyl] amino } hexyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-2-methyl propanamide and 2-naphthyl isocyanates prepare titled reference compound.
ESMS?m/e：515.3(M+H) +。
Embodiment 637
N-{3-[1-(3-{[(3,4-Dimethoxyphenyl) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3,4-dimethoxy benzene sulfonyl chloride prepares titled reference compound.
ESMS?m/e：504.2(M+H) +。
Embodiment 638
N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-5-methyl-3-phenyl-4-Isoxazolecarboxamidederivatives
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-methyl-3-phenyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：489.3(M+H) +。
Embodiment 639
N-{3-[1-(3-{[(4-fluorophenyl) acetyl group] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and (4-fluorophenyl) chloroacetic chloride prepare titled reference compound.
ESMS?m/e：440.3(M+H) +。
Embodiment 640
N-{3-[1-(3-{[(4-chloro-3-nitrobenzophenone) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 4-chloro-3-nitrobenzene sulfonyl chloride prepare titled reference compound.
ESMS?m/e：523.1(M+H) +。
Embodiment 641
2-(4-chlorophenoxy)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group) nicotiamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 2-(4-chlorophenoxy) nicotinoyl chlorine prepare titled reference compound.
ESMS?m/e：535.2(M+H) +。
Embodiment 642
5-(3, the 5-dichlorophenoxy)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-the 2-furoamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-(3, the 5-dichlorophenoxy)-2-furoyl chloride prepare titled reference compound.
ESMS?m/e：558.2(M+H) +。
Embodiment 643
N-{3-[1-(3-{[(2-fluorophenyl) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 2-fluorobenzene sulfonic acid chloride prepare titled reference compound.
ESMS?m/e：462.2(M+H) +。
Embodiment 644
N-{3-[1-(3-{[(3,5-dimethyl-4-isoxazolyl) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 3,5-dimethyl-4-isoxazole sulfonic acid chloride prepares titled reference compound.
ESMS?m/e：463.2(M+H) +。
Embodiment 645
N-{3-[1-(3-{[(4-tert-butyl-phenyl) sulfonyl] amino } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-2-methyl propanamide and 4-tert-butyl benzene sulfonic acid chloride prepare titled reference compound.
ESMS?m/e：500.3(M+H) +。
Embodiment 646
N-{3-[1-(the amino hexyl of 6-)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method AE and scheme Y, use N-(3-{1-[6-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) hexyl]-the 4-piperidyl phenyl)-2-methyl propanamide and hydrazine hydrate prepare titled reference compound.
ESMS?m/e：346.2(M+H) +。
Embodiment 647
N-{3-[1-(2-{[([1,1 '-biphenyl]-the 4-base is amino) carbonyl] amino } ethyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(2-amino-ethyl)-4-piperidyl] phenyl }-2-methyl propanamide and 4-biphenyl isocyanates prepare titled reference compound.
ESMS?m/e：485.2(M+H) +。
Embodiment 648
5-(3, the 5-dichlorophenoxy)-N-(2-{4-[3-(isobutyryl amino) phenyl]-piperidino } ethyl)-the 3-furoamide
According to method Q1 (THF) and option A T, use N-{3-[1-(2-amino-ethyl)-4-piperidyl] phenyl }-2-methyl propanamide and 5-(3, the 5-dichlorophenoxy)-3-furoyl chloride prepare titled reference compound.
ESMS?m/e：544.1(M+H) +。
Embodiment 649
N-[3-(1-{2-[(diphenyl acetyl group) amino] ethyl }-the 4-piperidyl) phenyl }-the 2-methyl propanamide
According to method Q1 (THF) and option A T, use N-{3-[1-(2-amino-ethyl)-4-piperidyl] phenyl }-2-methyl propanamide and diphenyl-acetyl chloride prepare titled reference compound.
ESMS?m/e：484.2(M+H) +。
Embodiment 650
N-(2-{4-[3-(isobutyryl amino) phenyl]-piperidino } ethyl)-the 2-naphthalenecarboxamide
According to method Q1 (THF) and option A T, use N-{3-[1-(2-amino-ethyl)-4-piperidyl] phenyl }-2-methyl propanamide and 2-naphthoyl chloride prepare titled reference compound.
ESMS?m/e：444.2(M+H) +。
Embodiment 651
3-(2,6-Dichlorobenzene base-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：571.2(M+H) +。
Embodiment 652
3-(2, the 6-Dichlorobenzene base)-N-(5-{4-[3-(isobutyryl amino) phenyl]-piperidino } amyl group)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q1 (THF) and option A T, use N-{3-[1-(the amino amyl group of 5-)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2, the 6-Dichlorobenzene base)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：585.2(M+H) +。
Embodiment 653
N-[3-(1-{4-[(diphenyl acetyl group) amino] butyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and diphenyl-acetyl chloride prepare titled reference compound.
ESMS?m/e：512.0(M+H) +。
Embodiment 654
N-[3-(1-{5-[(diphenyl acetyl group) amino] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino amyl group of 5-)-4-piperidyl] phenyl }-2-methyl propanamide and diphenyl-acetyl chloride prepare titled reference compound.
ESMS?m/e：526.0(M+H) +。
Embodiment 655
3,5-two chloro-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) Benzoylamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 3, the 5-dichlorobenzoyl chloride prepares titled reference compound.
ESMS?m/e：490.0(M+H) +。
Embodiment 656
5-(3, the 5-dichlorophenoxy)-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl)-the 2-furoamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 5-(3, the 5-dichlorophenoxy)-2-furoyl chloride prepare titled reference compound.
ESMS?m/e：572.0(M+H) +。
Embodiment 657
3-chloro-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) Benzoylamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 3-chlorobenzoyl chloride prepare titled reference compound.
ESMS?m/e：456.0(M+H) +。
Embodiment 658
3,4-two fluoro-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) Benzoylamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 3, the 4-difluoro benzoyl chloride prepares titled reference compound.
ESMS?m/e：458.0(M+H) +。
Embodiment 659
N-{3-[1-(4-{[(3,5-dichloro-benzenes amino) carbonyl] amino } butyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-(3-{1-[4-(formamido group) butyl]-the 4-piperidyl } phenyl)-2-methyl propanamide and 3, the 5-difluorophenyl isocyanate prepares titled reference compound.
ESMS?m/e：505.0(M+H) +。
Embodiment 660
N-{3-[1-(4-{[([1,1 '-biphenyl]-the 4-base is amino) carbonyl] amino } butyl)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 4-biphenyl isocyanate prepare titled reference compound.
ESMS?m/e：513.0(M+H) +。
Embodiment 661
2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1 (potassium carbonate), using 5-chloro-1-(4-nitrobenzophenone)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：452.2(M+H) +。
Embodiment 662
N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 5-chloro-1-(4-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 663
2-methyl-N-[3-(1-{5-oxo-5-[2-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and option b 1 (potassium carbonate), use 5-chloro-1-[2-(trifluoromethyl) phenyl]-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：475.2(M+H) +。
Embodiment 664
N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(3-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：485.1(M+H) +。
Embodiment 665
2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K and option b 1 (potassium carbonate), using 5-chloro-1-(3-nitrobenzophenone)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：452.2(M+H) +。
Embodiment 666
N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(3-chlorphenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.1(M+H) +。
Embodiment 667
N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(4-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：485.1(M+H) +。
Embodiment 668
N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(2-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：533.0(M+H) +。
Embodiment 669
N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(3-fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 670
2-methyl-N-[3-(1-{5-oxo-5-[3-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and option b 1 (potassium carbonate), use 1-[3-(trifluoromethyl) phenyl]-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：475.2(M+H) +。
Embodiment 671
N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(2-fluorophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 672
N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(3-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：533.0(M+H) +。
Embodiment 673
N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(2-chlorphenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.1(M+H) +。
Embodiment 674
2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and option b 1 (potassium carbonate), use 1-[4-(trifluoromethyl) phenyl]-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：475.2(M+H) +。
Embodiment 675
N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(4-chlorphenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.1(M+H) +。
Embodiment 676
N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(4-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：533(M+H) +。
Embodiment 677
N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and option b 1 (potassium carbonate), using 1-(2-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：485.1(M+H) +。
Embodiment 678
2-(4-chlorophenoxy)-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl) nicotiamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 2-(4-chlorophenoxy) nicotinoyl chlorine prepare titled reference compound.
ESMS?m/e：549.0(M+H) +。
Embodiment 679
N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl)-3,4-dimethoxy Benzoylamide
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 3, the 4-dimethoxy-benzoyl chloride prepares titled reference compound.
ESMS?m/e：482.0(M+H) +。
Embodiment 680
3-(2-chlorphenyl)-N-(4-{4-[3-(isobutyryl amino) phenyl]-piperidino } butyl)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino butyl of 4-)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chlorphenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：537.0(M+H) +。
Embodiment 681
3-(2-chlorphenyl)-N-(5-{4-[3-(isobutyryl amino) phenyl]-piperidino } amyl group)-5-methyl-4-Isoxazolecarboxamidederivatives
According to method Q2 (THF/DCM, 1: 3) and option A T, use N-{3-[1-(the amino amyl group of 5-)-4-piperidyl] phenyl }-2-methyl propanamide and 3-(2-chlorphenyl)-5-methyl-4-isoxazole formyl chloride prepare titled reference compound.
ESMS?m/e：551.0(M+H) +。
Embodiment 682
2-methyl-N-{3-[1-(3-{1-methyl-2-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：562.2(M+H) +。
Embodiment 683
2-methyl-N-{3-[1-(3-{1-methyl-2-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 4-(tetrafluoro methoxyl group) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：632.2(M+H) +。
Embodiment 684
2-methyl-N-{3-[1-(3-{2-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and phenylhydrazine prepare titled reference compound.
ESMS?m/e：548.2(M+H) +。
Embodiment 685
2-methyl-N-{3-[1-(3-{1-phenyl-2-[4-(trifluoromethyl) phenyl]-1 H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：624.2(M+H) +。
Embodiment 686
2-methyl-N-{3-[1-(3-{2-[4-(trifluoromethyl) phenyl]-1H-benzo [G] indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 1-naphthyl hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：598.2(M+H) +。
Embodiment 687
2-methyl-N-{3-[1-(3-{7-methyl-2-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：562.2(M+H) +。
Embodiment 688
2-methyl-N-{3-[1-(3-{5-methyl-2-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：562.2(M+H) +。
Embodiment 689
N-{3-[1-(3-{5-methoxyl group-2-[4-(trifluoromethyl) phenyl]-the 1H-indol-3-yl } propyl group)-the 4-piperidyl] phenyl }-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：578.2(M+H) +。
Embodiment 690
N-[3-(1-{3-[2-(3-fluorophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo-amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 691
N-[3-(1-{3-[2-(4-chlorphenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 692
N-[3-(1-{3-[2-(4-fluorophenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 693
N-[3-(1-{3-[2-(2-fluorophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：498.2(M+H) +。
Embodiment 694
N-[3-(1-{3-[2-(3-fluorophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：582.2(M+H) +。
Embodiment 695
N-[3-(1-{3-[2-(2-fluorophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：582.2(M+H) +。
Embodiment 696
N-[3-(1-{3-[2-(4-fluorophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：548.2(M+H) +。
Embodiment 697
N-[3-(1-(3-[2-(2-fluorophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：547.7(M+H) +。
Embodiment 698
N-[3-(1-{3-[2-(2-fluorophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methyl-hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 699
N-[3-(1-{3-[2-(3-fluorophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：548.2(M+H) +。
Embodiment 700
N-[3-(1-{3-[2-(4-fluorophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 701
N-[3-(1-{3-[2-(3-fluorophenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 702
N-[3-(1-{3-[2-(3-fluorophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：574.2(M+H) +。
Embodiment 703
N-[3-(1-{3-[2-(4-chlorphenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group } the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：598.2(M+H) +。
Embodiment 704
N-[3-(1-{3-[2-(3-fluorophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：498.2(M+H) +。
Embodiment 705
N-[3-(1-{3-[2-(3-fluorophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 706
N-[3-(1-{3-[2-(3-fluorophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 707
N-[3-(1-{3-[2-(4-chlorphenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：564.2(M+H) +。
Embodiment 708
N-[3-(1-{3-[2-(4-chlorphenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：514.2(M+H) +。
Embodiment 709
N-[3-(1-{3-[2-(2-fluorophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 710
N-[3-(1-{3-[2-(2-fluorophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-methylbenzene) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 711
N-[3-(1-{3-[2-(2-fluorophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：574.2(M+H) +。
Embodiment 712
N-[3-(1-{3-[2-(2-fluorophenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 713
N-[3-(1-{3-[2-(4-chlorphenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：544.2(M+H) +。
Embodiment 714
N-[3-(1-{3-[2-(4-fluorophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：548.2(M+H) +。
Embodiment 715
N-[3-(1-{3-[2-(4-fluorophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：582.9(M+H) +。
Embodiment 716
N-[3-(1-{3-[2-(4-fluorophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 717
N-[3-(1-{3-[2-(4-fluorophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：498.2(M+H) +。
Embodiment 718
N-[3-(1-{3-[2-(4-fluorophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：512.2(M+H) +。
Embodiment 719
N-[3-(1-{3-[2-(4-chlorphenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 720
N-[3-(1-{3-[2-(4-chlorphenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 721
N-[3-(1-{3-[2-(4-chlorphenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：590.2(M+H) +。
Embodiment 722
N-[3-(1-{3-[2-(3-chlorphenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：528.1(M+H) +。
Embodiment 723
N-[3-(1-{3-[2-(3-chlorphenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：598.2(M+H) +。
Embodiment 724
N-[3-(1-{3-[2-(3-chlorphenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 725
N-[3-(1-{3-[2-(3-chlorphenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：590.3(M+H) +。
Embodiment 726
N-[3-(1-{3-[2-(3-chlorphenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：544.3(M+H) +。
Embodiment 727
N-[3-(1-{3-[2-(3-chlorphenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：528.2(M+H) +
Embodiment 728
N-[3-(1-{3-[2-(3-chlorphenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：564.2(M+H) +。
Embodiment 729
N-[3-(1-{3-[2-(3-chlorphenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：514.2(M+H) +。
Embodiment 730
N-[3-(1-{3-[2-(2-chlorphenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：514.2(M+H) +。
Embodiment 731
N-[3-(1-{3-[2-(2-chlorphenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：598.2(M+H) +。
Embodiment 732
N-[3-(1-{3-[2-(2-chlorphenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：564.2(M+H) +。
Embodiment 733
N-[3-(1-{3-[2-(2-chlorphenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：528.2(M+H) +
Embodiment 734
N-[3-(1-{3-[2-(2-chlorphenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：590.2(M+H) +。
Embodiment 735
N-[3-(1-{3-[2-(2-chlorphenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 736
N-[3-(1-{3-[2-(2-chlorphenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：528.2(M+H) +。
Embodiment 737
N-[3-(1-{3-[2-(3-iodophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：606.2(M+H) +。
Embodiment 738
N-[3-(1-{3-[2-(3-iodophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：620.2(M+H) +。
Embodiment 739
N-[3-(1-{3-[2-(3-iodophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：682.2(M+H) +。
Embodiment 740
N-[3-(1-{3-[2-(3-iodophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：656.2(M+H) +。
Embodiment 741
N-[3-(1-{3-[2-(3-iodophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：690.2(M+H) +。
Embodiment 742
N-[3-(1-{3-[2-(3-iodophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：620.2(M+H) +。
Embodiment 743
N-[3-(1-{3-[2-(3-iodophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：620.2(M+H) +。
Embodiment 744
N-[3-(1-{3-[2-(4-iodophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：690.1(M+H) +。
Embodiment 745
N-[3-(1-{3-[2-(4-iodophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：620.1(M+H) +。
Embodiment 746
N-[3-(1-{3-[2-(4-iodophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：620.1(M+H) +。
Embodiment 747
N-[3-(1-{3-[2-(4-iodophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：682.1(M+H) +。
Embodiment 748
N-[3-(1-{3-[2-(4-iodophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：620.1(M+H) +。
Embodiment 749
N-[3-(1-{3-[2-(4-iodophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：656.1(M+H) +。
Embodiment 750
N-[3-(1-{3-[2-(4-iodophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：606.1(M+H) +。
Embodiment 751
N-[3-(1-{3-[2-(3-bromophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：642.0(M+H) +。
Embodiment 752
N-[3-(1-{3-[2-(4-bromophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：608.0(M+H) +。
Embodiment 753
N-[3-(1-{3-[2-(4-bromophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：572(M+H) +。
Embodiment 754
N-[3-(1-{3-[2-(4-bromophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：642(M+H) +。
Embodiment 755
N-[3-(1-{3-[2-(3-bromophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：608.0(M+H) +。
Embodiment 756
N-[3-(1-{3-[2-(4-bromophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：558.1(M+H) +
Embodiment 757
N-[3-(1-{3-[2-(3-bromophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：634.0(M+H) +。
Embodiment 758
N-[3-(1-{3-[2-(3-bromophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：572.0(M+H) +。
Embodiment 759
N-[3-(1-{3-[2-(4-bromophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：572.0(M+H) +。
Embodiment 760
N-[3-(1-{3-[2-(4-bromophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：634.0(M+H) +。
Embodiment 761
N-[3-(1-{3-[2-(4-bromophenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：588.1(M+H) +。
Embodiment 762
N-[3-(1-{3-[2-(3-bromophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：572(M+H) +。
Embodiment 763
N-[3-(1-{3-[2-(3-bromophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：572(M+H) +。
Embodiment 764
N-[3-(1-{3-[2-(4-bromophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(4-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：572.0(M+H) +。
Embodiment 765
N-[3-(1-{3-[2-(3-bromophenyl)-5-methoxyl group-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(3-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：588.0(M+H) +。
Embodiment 766
2-methyl-N-[3-(1-{3-[2-(3-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and phenylhydrazine prepare titled reference compound.
ESMS?m/e：525.2(M+H) +。
Embodiment 767
2-methyl-N-[3-(1-{3-[2-(3-nitrobenzophenone)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：575.1(M+H) +。
Embodiment 768
2-methyl-N-[3-(1-{3-[2-(3-nitrobenzophenone)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：609.1(M+H) +。
Embodiment 769
2-methyl-N-[3-(1-{3-[5-methyl-2-(3-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：539.2(M+H) +。
Embodiment 770
N-[3-(1-{3-[5-methoxyl group-2-(3-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：555.2(M+H) +。
Embodiment 771
2-methyl-N-[3-(1-{3-[2-(3-nitrobenzophenone)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide. and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：601.1(M+H) +。
Embodiment 772
2-methyl-N-[3-(1-{3-[1-methyl-2-(3-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：539.2(M+H) +。
Embodiment 773
2-methyl-N-[3-(1-{3-[7-methyl-2-(3-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(3-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：539.2(M+H) +。
Embodiment 774
N-[3-(1-{3-[5-methoxyl group-2-(4-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 4-methoxyl group hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：555.6(M+H) +。
Embodiment 775
N-[3-(1-{3-[2-(2-bromophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：557.9(M+H) +。
Embodiment 776
2-methyl-N-[3-(1-{3-[5-methyl-2-(4-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：539.1(M+H) +。
Embodiment 777
2-methyl-N-[3-(1-{3-[2-(4-nitrobenzophenone)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：574.7(M+H) +。
Embodiment 778
2-methyl-N-(3-{1-[(5E)-5-(4-nitrobenzophenone)-5-(phenyl hydrazono-) amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method E and option A X, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and phenylhydrazine prepare titled reference compound.
ESMS?m/e：542.4(M+H) +。
Embodiment 779
2-methyl-N-[3-(1-{3-[7-methyl-2-(4-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：538.8(M+H) +。
Embodiment 780
2-methyl-N-{3-(1-((5E)-5-(4-nitrobenzophenone)-5-{[4-(trifluoromethoxy) phenyl] hydrazono-} amyl group)-the 4-piperidyl) phenyl } propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：626.2(M+H) +。
Embodiment 781
N-[3-(1-{3-[2-(2-bromophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：608.0(M+H) +。
Embodiment 782
N-[3-(1-{3-[2-(2-bromophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：641.9(M+H) +。
Embodiment 783
N-[3-(1-{3-[2-(2-bromophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：572.0(M+H) +。
Embodiment 784
N-[3-(1-{3-[2-(2-bromophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：634(M+H) +。
Embodiment 785
N-[3-(1-{3-[2-(2-bromophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：572.0(M+H) +。
Embodiment 786
N-[3-(1-{3-[2-(2-iodophenyl)-5-(trifluoromethoxy)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-(trifluoromethoxy) hydrazinobenzene hydrochloride salt prepare titled reference compound.
ESMS?m/e：690.0(M+H) +。
Embodiment 787
N-[3-(1-{3-[2-(2-iodophenyl)-5-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 4-procarbazine hydrochlorate prepare titled reference compound.
ESMS?m/e：620.2(M+H) +。
Embodiment 788
2-methyl-N-[3-(1-{3-[1-methyl-2-(4-nitrobenzophenone)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl phenyl) propionic acid amide. and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：539.6(M+H) +。
Embodiment 789
2-methyl-N-[3-(1-{3-[2-(4-nitrobenzophenone)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method E and scheme M, use 2-methyl-N-(3-{1-[5-(4-nitrobenzophenone)-5-oxo amyl group]-the 4-piperidyl } phenyl) propionic acid amide. and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：601.6(M+H) +。
Embodiment 790
N-[3-(1-{3-[2-(2-iodophenyl)-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and phenylhydrazine prepare titled reference compound.
ESMS?m/e：606.1(M+H) +。
Embodiment 791
N-[3-(1-{3-[2-(2-iodophenyl)-1H-benzo [G] indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-naphthylhydrazine hydrochlorate prepare titled reference compound.
ESMS?m/e：656.1(M+H) +。
Embodiment 792
N-[3-(1-{3-[2-(2-iodophenyl)-1-phenyl-1H-indol-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-2-methyl propanamide and 1,1-hydrazo-benzene hydrochlorate prepares titled reference compound.
ESMS?m/e：682.1(M+H) +。
Embodiment 793
N-[3-(1-{3-[2-(2-iodophenyl)-7-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-iodophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate prepare titled reference compound.
ESMS?m/e：619.6(M+H) +。
Embodiment 794
N-[3-(1-{3-[2-(2-bromophenyl)-1-Methyl-1H-indole-3-yl] propyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method E and scheme M, use N-(3-{1-[5-(2-bromophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-2-methyl propanamide and 1-methyl isophthalic acid-phenylhydrazine prepare titled reference compound.
ESMS?m/e：572(M+H) +。
Embodiment 795
4-(3, the 4-difluorophenyl)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-ascorbyl palmitate
According to method AC and option A M, use 4-(3, the 4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-pyridine carboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：553.0(M+H) +。
Embodiment 796
4-(2,4 difluorobenzene base)-N-(3-{4-[3-(isobutyryl amino) phenyl]-piperidino } propyl group)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-ascorbyl palmitate
According to method AC and option A M, use 4-(2,4 difluorobenzene base)-2-methyl-6-oxo-1,4,5,6-tetrahydrochysene-3-pyridine carboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：553.0(M+H) +。
Embodiment 797
N-(3-{1-[4-(4-methoxyphenyl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method O and scheme W, using 4-(4-methoxyphenyl)-1-butanols and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：409(M+H) +。
Embodiment 798
N-(4-{1-[3-(1,2-diphenyl-1H-indol-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method O and scheme W, using 3-(1,2-diphenyl-1H-indol-3-yl)-1-propanol and N-[4-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：542.0(M+H) +。
Embodiment 799
N-{4-[1-(3, the 3-diphenyl propyl)-4-piperidyl] phenyl } propionic acid amide.
According to method O and scheme W, using 3,3-diphenyl-1-propanol and N-[4-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：427.0(M+H) +。
Embodiment 800
2-methyl-N-(3-{1-[4-(4-nitrobenzophenone) butyl]-the 4-piperidyl } phenyl)
According to method O and scheme W, using 4-(4-nitrobenzophenone)-1-butanols and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：424.2(M+H) +。
Embodiment 801
2-methyl-N-(3-{1-[2-(1-naphthyl) ethyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method O and scheme W, using 2-(1-naphthyl) ethanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：401.2(M+H) +。
Embodiment 802
N-{3-[1-(3, the 3-diphenyl propyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method O and scheme W, using 3,3-diphenyl-1-propanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.2(M+H) +。
Embodiment 803
N-(3-{1-[3-(3, the 4-Dimethoxyphenyl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method O and scheme W, using 3-(3, the 4-Dimethoxyphenyl)-1-propanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 804
2-methyl-N-{3-[1-(3-phenyl propyl)-4-piperidyl] phenyl } propionic acid amide.
According to method O and scheme W, using 3-phenyl-1-propanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：365.2(M+H) +。
Embodiment 805
2-methyl-N-(3-{1-[3-(4-pyridine radicals) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method O and scheme W, using 3-(4-pyridine radicals)-1-propanol and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：366.2(M+H) +。
Embodiment 806
N-{3-[1-(4-tert-butyl group benzyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method AJ and option A V, using 1-bromomethyl-4-tert-butyl benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：393.0(M+H) +。
Embodiment 807
N-{3-[1-(4-benzoyl benzyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method AJ and option A V, using [4-(bromomethyl) phenyl] (phenyl) ketone (methanone) and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.0(M+H) +。
1,2-two-chloro-4-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base } benzene
According to method A, use 3,4-chlorophenesic acid and (1R)-3-chloro-1-phenyl-1-propanol prepares titled reference compound.
Embodiment 808
N-(3-{1-[(3S)-3-(3, the 4-dichlorophenoxy)-3-phenyl propyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A, use 1,2-two chloro-4-{[(1S)-3-chloro-1-phenyl propyl] the oxygen base } benzene and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：525.3(M+H) +
Embodiment 809
N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[6-(2-fluorophenyl)-6-oxo-hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：441.3(M+H) +。
Embodiment 810
N-[3-(1-{5-hydroxyl-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method L and option A N, use 2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：477.2(M+H) +。
Embodiment 811
N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：427.2(M+H) +。
Embodiment 812
N-(3-{1-[7-(2-fluorophenyl)-7-hydroxyl heptyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[7-(2-fluorophenyl)-7-oxo heptyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：455.2(M+H) +。
Embodiment 813
N-(3-{1-[6-(3-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[6-(3-fluorophenyl)-6-oxo-hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：441.2(M+H) +。
Embodiment 814
N-(3-{1-[5-(2-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：427.2(M+H) +。
Embodiment 815
N-(3-{1-[5-(3-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：427.2(M+H) +。
Embodiment 816
N-(3-{1-[5-(3-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：443.1(M+H) +。
Embodiment 817
N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[6-(4-fluorophenyl)-6-oxo-hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：441.2(M+H) +。
Embodiment 818
N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[6-(4-chlorphenyl)-6-oxo-hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：456.9(M+H) +。
Embodiment 819
N-(3-{1-[5-(4-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method L and option A N, use N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：443.0(M+H) +。
Embodiment 820
N-(4-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl) butyramide
According to method F and scheme R (not adopting HOAc), using 9-ethyl-9H-carbazole-3-formaldehyde and N-[4-(4-piperidyl) phenyl] butyramide prepares titled reference compound.
ESMS?m/e：454.2(M+H) +。
Embodiment 821
N-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R (not adopting HOAc), using 9-ethyl-9H-carbazole-3-formaldehyde and N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：440.5(M+H) +。
Embodiment 822
N-(3-{1-[(1,9-dimethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method F and scheme R (not adopting HOAc), using 1,9-dimethyl-9H-carbazole-3-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ8.05-6.77(m，10H)，5.20-5.12(m，1H)，4.04(s，3H)，3.93(s，2H)，3.34-3.24(m，2H)，2.79(s，3H)，2.56-2.38(m，2H)，2.38-2.26(m，2H)，2.08-1.88(m，2H)，1.82-1.70(m，2H)，1.16(d，6H，J＝6.8Hz)；ESMS.m/e：454.2(M+H) +.
Embodiment 823
N-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl) cyclopropane carboxamide
According to method F and scheme R (not adopting HOAc), using 9-ethyl-9H-carbazole-3-formaldehyde and N-[3-(4-piperidyl) phenyl] cyclopropane carboxamide prepares titled reference compound.
ESMS?m/e：452.6(M+H) +。
Embodiment 824
1-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-2-Pyrrolidone
Be prepared according to scheme R and method F.With sodium triacetoxy borohydride (63.6mg, 0.300mmol) and acetic acid (5.70 μ L, 0.100mmol) processing 1-(9-ethyl-9H-carbazole-3-yl) ethyl ketone (22.3mg, 0.100mmol) and 1-[3-(4-piperidyl) phenyl]-2-Pyrrolidone (27.2mg, 0.100mmol) 1, the solution in the 2-dichloroethanes (1.00mL).The mixture of gained at room temperature stirred spend the night.Described reactant mixture is handled with saturated sodium bicarbonate aqueous solution (10mL).The water layer dichloromethane extraction (3 * 10mL), the organic layer that merges is washed with saline (10mL), with dried over mgso and vacuum concentration.Residue is through preparation TLC purification, the NH with 5% 3(methanol solution of 2.0M) eluant solution in dichloromethane obtains required product 1-(3-{1-[(9-ethyl-9H-carbazole-3-yl) methyl]-the 4-piperidyl } phenyl)-2-Pyrrolidone (4.60mg, 9.43%).
1H?NMR(400MHz，CDCl 3)δ8.04(d，1H，J＝7.4Hz)，7.99(s，1H)，7.43-7.28(m，5H)，6.96(d，1H，J＝7.4Hz)，4.31(q，2H，J＝6.8Hz)，3.77(t，2H，J＝7.3Hz)，3.70(s，2H)，3.06(d，2H，J＝10.6Hz)，2.56-2.42(m，3H)，2.07(m，4H)，1.77(m，4H)，1.36(m，3H)；ESMS?m/e：452.5(M+H) +.
N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R (not adopting HOAc), using 1H-indole-5-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：376.2(M+H) +。
1-(4-chlorobutyl)-1H-indole
According to method AH and scheme P, use 1H-indole and 1-bromo-4-chlorobutane to prepare titled reference compound.
1NMR(400MHz，CDCl 3)δ7.72-7.02(m，5H)，6.49(d，1H，J＝2.8Hz)，4.13(t，2H，J＝6.8Hz)，3.48(t，2H，J＝6.8Hz)，2.06-1.92(m，2H)，1.80-1.70(m，2H).
1-(3-chloropropyl)-1H-indole
According to method AH and scheme P, use 1H-indole and 1-bromo-3-chloropropane to prepare titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.70-7.04(m，5H)，6.50(d，1H，J＝2.8Hz)，4.31(t，2H，J＝6.8Hz)，3.42(t，2H，J＝6.4Hz)，2.28-2.20(m，2H).
Embodiment 825
N-(4-{1-[5-(1H-indole-1-yl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method AH and scheme P, using 1-(5-chlorine amyl group)-1H-indole and 2-methyl-N-[4-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：432.3(M+H) +。
Embodiment 826
N-(4-{1-[5-(1H-indole-1-yl) amyl group]-the 4-piperidyl } phenyl) butyramide
According to method AH and scheme P, using 1-(5-chlorine amyl group)-1H-indole and N-[4-(4-piperidyl) phenyl] butyramide prepares titled reference compound.
ESMS?m/e：432.3(M+H) +。
Embodiment 827
N-(4-{1-[5-(1H-indole-1-yl) amyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method AH and scheme P, using 1-(5-chlorine amyl group)-1H-indole and N-[4-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：418.2(M+H) +。
Embodiment 828
N-(4-{1-[6-(1H-indole-1-yl) hexyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method AH and scheme P, using 1-(6-chlorine hexyl)-1H-indole and N-[4-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：432.3(M+H) +。
Embodiment 829
2-methyl-N-(3-{1-[(1-Methyl-1H-indole-2-yl) methyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method F and scheme R (not adopting HOAc), using 1-Methyl-1H-indole-2-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：390.3(M+H) +。
Embodiment 830
N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R (not adopting HOAc), using 1H-indole-4-methanal and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：376.2(M+H) +。
Embodiment 831
N-(4-{1-[6-(1H-indole-1-yl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method AH and scheme P, using 1-(6-chlorine hexyl)-1H-indole and 2-methyl-N-[4-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：446.3(M+H) +。
Embodiment 832
N-{3-[1-(1H-indole-7-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R (not adopting HOAc), using 1H-indole-7-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：376.2(M+H) +。
Embodiment 833
N-[3-(1-{[1-(4-methoxyphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-4-methoxybenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：482.0(M+H) +。
Embodiment 834
4-[4-(4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-1H-indole-1-yl] essence of Niobe
According to method C and scheme Q1 (adopting CuBr replaced C u), use 4-iodo-benzoic acid methyl ester and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：510.3(M+H) +。
Embodiment 835
2-methyl-N-[3-(1-{[1-(3-aminomethyl phenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-methylbenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：466.3(M+H) +。
Embodiment 836
N-[3-(1-{[1-(4-fluorophenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-fluoro-4-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1HNMR(400MHz，CDCl 3)δ7.66-6.92(m，12H)，6.65(d，1H，J＝3.2Hz)，3.69(s，2H)，3.15-3.02(m，2H)，2.58-2.40(m，2H)，2.20-2.04(m，2H)，1.94-1.76(m，4H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：470.6(M+H) +.
Embodiment 837
N-(3-{1-[4-(1H-indole-1-yl) butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method AH and scheme P, using 1-(4-chlorobutyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：418.3(M+H) +。
Embodiment 838
N-[3-(1-{[1-(4-chlorphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-chloro-4-iodobenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 839
N-[3-(1-{[1-(3-methoxyphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：482.2(M+H) +。
Embodiment 840
N-(4-{1-[4-(1H-indole-1-yl) butyl]-the 4-piperidyl } phenyl) butyramide
According to method AH and scheme P, using 1-(4-chlorobutyl)-1H-indole and N-[4-(4-piperidyl) phenyl] butyramide prepares titled reference compound.
ESMS?m/e：418.2(M+H) +。
Embodiment 841
N-[3-(1-{[1-(2-methoxyphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-2-methoxybenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：482.2(M+H) +。
Embodiment 842
N-[3-(1-{[1-(3-chlorphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-chloro-3-iodobenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 843
2-[5-((4-[3-(isobutyryl amino) phenyl]-piperidino } methyl)-1H-indole-1-yl] essence of Niobe
According to method C and scheme Q1 (adopting CuBr replaced C u), use 2-iodo-benzoic acid methyl ester and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：510.2(M+H) +。
Embodiment 844
N-(3-{1-[3-(1H-indole-1-yl) propyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method AH and scheme P, using 1-(3-chloropropyl)-1H-indole and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：404.2(M+H) +。
Embodiment 845
2-methyl-N-{3-[1-(1-[4-(trifluoromethyl) phenyl]-1H-indole-5-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-4-(trifluoromethyl) benzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 846
N-(3-{1-[(1-[1,1 '-biphenyl]-2-base-1H-indole-5-yl) methyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 2-iodo-1,1 '-biphenyl and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：528.3(M+H) +。
Embodiment 847
2-methyl-N-[3-(1-{[1-(2-aminomethyl phenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-2-methylbenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：466.2(M+H) +。
Embodiment 848
2-methyl-N-[3-(1-{[1-(4-aminomethyl phenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-4-methylbenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：466.3(M+H) +。
Embodiment 849
N-[3-(1-{[1-(2-chlorphenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-chloro-2-iodobenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 850
2-methyl-N-{3-[1-(1-[3-(trifluoromethyl) phenyl]-1H-indole-5-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-(trifluoromethyl) benzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)δ7.80-6.94(m，12H)，6.69(d，1H，J＝3.6Hz)，3.36(s，2H)，3.10-3.00(m，2H)，2.58-2.42(m，2H)，2.16-2.02(m，2H)，1.85-1.75(m，4H)，1.25(d，6H，J＝7.2Hz)；ESMSm/e：520.2(M+H) +.
Embodiment 851
2-methyl-N-[3-(1-{[1-(2-nitrobenzophenone)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-2-Nitrobenzol and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：497.2(M+H) +。
Embodiment 852
N-[3-(1-{[1-(2-fluorophenyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：470.2(M+H) +。
Embodiment 853
2-methyl-N-[3-(1-{[1-(1-naphthyl)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodine naphthalene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：502.2(M+H) +。
Embodiment 854
N-[3-(1-{[1-(2, the 3-Dichlorobenzene base)-1H-indole-5-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1,2-two chloro-3-iodobenzenes and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1HNMR(400MHz，CDCl 3)δ7.68-6.94(m，12H)，6.68(d，1H，J＝2.8Hz)，3.69(s，2H)，3.15-3.02(m，2H)，2.54-2.42(m，2H)，2.18-2.02(m，2H)，1.88-1.76(m，4H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：520.1(M+H) +.
Embodiment 855
N-[3-(1-{[1-(2, the 3-Dichlorobenzene base)-1H-indole-7-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1,2-two chloro-3-iodobenzenes and N-{3-[1-(1H-indole-7-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 856
N-[3-(1-{[1-(3-methoxyphenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：482.3(M+H) +。
Embodiment 857
N-[3-(1-{[1-(2, the 3-Dichlorobenzene base)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1,2-two chloro-3-iodobenzenes and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 858
N-[3-(1-{[1-(3-chlorphenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-chloro-3-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.2(M+H) +。
Embodiment 859
2-methyl-N-[3-(1-{[1-(3-aminomethyl phenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-methylbenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：466.3(M+H) +。
Embodiment 860
N-[3-(1-{[1-(3-methoxyphenyl)-1H-indole-7-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-methoxybenzene and N-{3-[1-(1H-indole-7-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：482.3(M+H) +。
Embodiment 861
2-methyl-N-{3-[1-(1-[3-(trifluoromethyl) phenyl]-1H-indole-4-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-3-(trifluoromethyl) benzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.2(M+H) +。
Embodiment 862
N-[3-(1-{[1-(3, the 4-3,5-dimethylphenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-2-methyl propanamide and 4-iodo-1, the 2-dimethyl benzene prepares titled reference compound.
ESMS?m/e：480.0(M+H) +。
Embodiment 863
N-[3-(1-{[1-(3, the 4-difluorophenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1,3-two chloro-5-iodobenzenes and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.0(M+H) +。
Embodiment 864
N-[3-(1-{[1-(3, the 4-Dichlorobenzene base)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1,2-two chloro-4-iodobenzenes and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.0(M+H) +。
Embodiment 865
N-[3-(1-{[1-(2-chloro-4-fluoro-phenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 2-chloro-4-fluoro-1-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：504.0(M+H) +。
Embodiment 866
N-[3-(1-{[1-(2,4 difluorobenzene base)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 2,4-two fluoro-1-iodobenzenes and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：488.0(M+H) +。
Embodiment 867
2-methyl-N-[3-(1-{[1-(3-pyridine radicals)-1H-indole-7-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 3-iodine pyridine and N-{3-[1-(1H-indole-7-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：453.1(M+H) +。
Embodiment 868
N-{3-[1-(1H-indole-6-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide
According to method F and scheme R, using 1H-indole-6-formaldehyde and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：376.2(M+H) +。
Embodiment 869
2-methyl-N-[3-(1-{[1-(4-pyridine radicals)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 4-iodine pyridine and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 870
2-methyl-N-[3-(1-{[1-(2-pyridine radicals)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 2-iodine pyridine and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 871
N-[3-(1-{[1-(2-fluorophenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-fluoro-2-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：470.1(M+H) +。
Embodiment 872
N-[3-(1-{[1-(4-chlorphenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-chloro-4-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.1(M+H) +。
Embodiment 873
2-methyl-N-[3-(1-{[1-(3-pyridine radicals)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl] propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 3-iodine pyridine and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 874
N-[3-(1-{[1-(2, the 3-3,5-dimethylphenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-2,3-dimethyl benzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：480.1(M+H) +。
Embodiment 875
N-[3-(1-{[1-(3-fluorophenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-fluoro-3-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：470.1(M+H) +。
Embodiment 876
2-methyl-N-{3-[1-(1-[2-(trifluoromethyl) phenyl]-1H-indole-4-yl } methyl)-the 4-piperidyl] phenyl } propionic acid amide.
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-2-(trifluoromethyl) benzene and N-{3-[1-(1H-indole-5-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：520.1(M+H) +。
Embodiment 877
N-[3-(1-{[1-(2-chlorphenyl)-1H-indole-4-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-chloro-2-iodobenzene and N-{3-[1-(1H-indole-4-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：486.1(M+H) +。
Embodiment 878
N-[3-(1-{[1-(2, the 3-3,5-dimethylphenyl)-1H-indole-7-yl] methyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method C and scheme Q1 (adopting CuBr replaced C u), use 1-iodo-2,3-dimethyl benzene and N-{3-[1-(1H-indole-7-ylmethyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：480.0(M+H) +。
2-methyl-N-[3-(1-{5-oxo-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl] propionic acid amide.
According to method K and scheme E, use 5-chloro-1-[4-(trifluoromethyl) phenyl]-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：475.1(M+H) +。
N-(3-{1-[5-(4-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E, using 5-chloro-1-(4-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
N-(3-{1-[5-(3-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E, using 5-chloro-1-(3-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
N-(3-{1-[5-(3-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E, using 5-chloro-1-(3-chlorphenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.1(M+H) +。
N-(3-{1-[5-(4-chlorphenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E, using 5-chloro-1-(4-chlorphenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：441.1(M+H) +。
Embodiment 879
2-methyl-N-{3-[1-(3-oxo-3-phenyl propyl)-4-piperidyl] phenyl } propionic acid amide.
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 3-chloro-1-phenyl-1-acetone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：379.3(M+H) +。
Embodiment 880
N-(3-{1-[7-(2-fluorophenyl)-7-oxo heptyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 7-chloro-1-(2-fluorophenyl)-1-heptanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，δ8.17(s，br，1H)，8.06-6.88(m，8H)，3.08-2.94(m，4H)，2.62-2.48(m，1H)，2.48-2.38(m，1H)，2.38-2.15(m，2H)，2.02-1.92(m，2H)，1.84-1.77(m，4H)，1.77-1.66(m，2H)，1.62-1.46(m，2H)，1.46-1.29(M，4H)，1.21(d，6H，J＝6.8Hz)；ESMS?m/e：453.2(M+H) +.
Embodiment 881
N-(3-{1-[5-(2-fluorophenyl)-5-oxo amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 5-chloro-1-(2-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：425.2(M+H) +。
Embodiment 882
N-(3-{1-[6-(3-fluorophenyl)-6-oxo-hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 6-chloro-1-(3-fluorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：439.2(M+H) +。
Embodiment 883
N-(3-{1-[6-(2-fluorophenyl)-6-oxo-hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 6-chloro-1-(2-fluorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：439.2(M+H) +。
Embodiment 884
N-(3-{1-[7-(4-fluorophenyl)-7-oxo heptyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 7-chloro-1-(4-fluorophenyl)-1-heptanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：453.2(M+H) +。
Embodiment 885
N-(3-{1-[6-(4-chlorphenyl)-6-oxo-hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 6-chloro-1-(4-chlorphenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：455.1(M+H) +。
Embodiment 886
N-(3-{1-[7-(4-chlorphenyl)-7-oxo heptyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 7-chloro-1-(4-chlorphenyl)-1-heptanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：469.1(M+H) +。
Embodiment 887
N-(3-{1-[6-(4-fluorophenyl)-6-oxo-hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K and scheme E (use potassium carbonate to replace sodium carbonate, sodium iodide replaces potassium iodide), using 6-chloro-1-(4-fluorophenyl)-1-hexanone and 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. prepares titled reference compound.
ESMS?m/e：439.1(M+H) +。
Embodiment 888
N-(3-{1-[6-(3-acetyl group phenoxy group)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：559.5(M+H) +。
Embodiment 889
N-(3-{1-[6-(2-fluorophenoxy)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 2-fluorophenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：535.1(M+H) +。
Embodiment 890
N-(3-{1-[6-(4-fluorophenoxy)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.72-6.72(m，12H)，5.42-5.34(m，1H)，3.68-3.58(m，br，2H)，3.02-2.92(m，2H)，2.80-2.46(m，6H)，2.05-1.78(m，6H)，1.68-1.56(m，1H)，1.56-1.38(m，3H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：535.1(M+H) +.
Embodiment 891
N-(3-{1-[6-(2-fluorophenyl)-6-(2-methoxyl group phenoxy group) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 2-methoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：547.0(M+H) +。
Embodiment 892
N-(3-{1-[6-(2-fluorophenyl)-6-(4-methoxyl group phenoxy group) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 2-methoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：547.1(M+H) +。
Embodiment 893
N-(3-{1-[6-(4-acetyl group phenoxy group)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(4-hydroxy phenyl) ethyl ketone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：559.2(M+H) +
Embodiment 894
N-(3-{1-[6-(3,4-dimethoxy phenoxy group)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 3,4-syringol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：577.6(M+H) +。
Embodiment 895
N-(3-{1-[6-(2-ethoxy phenoxy)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 2-thanatol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：561.1(M+H) +。
Embodiment 896
N-(3-{1-[6-(4-bromine phenoxy group)-6-phenyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-bromophenol and N-(3-{1-[6-hydroxyl-6-phenyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：577.0(M+H) +。
Embodiment 897
N-(3-{1-[6-(4-fluorophenoxy)-6-(4-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.22(s，br，1H)，7.74-6.70(m，12H)，5.05-4.94(m，1H)，3.66-3.52(m，br，2H)，3.02-2.83(m，br，2H)，2.81-2.58(m，br，4H)，2.58-2.36(m，br，2H)，2.02-1.66(m，br，6H)，1.66-1.46(m，br，1H)，1.46-1.35(m，br，3H)，1.26(d，6H，J＝6.0Hz)；ESMS?m/e：535.1(M+H) +.
Embodiment 898
N-(3-{1-[6-(4-methoxyl group phenoxy group)-6-phenyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-methoxyphenol and N-{3-[1-(6-hydroxyl-6-phenyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：529.6(M+H) +。
Embodiment 899
N-(3-{1-[6-(4-chlorophenoxy)-6-(4-chlorphenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-chlorophenol and N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：566.9(M+H) +。
Embodiment 900
N-(3-{1-[6-(4-bromine phenoxy group)-6-(4-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-bromophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：595.0(M+H) +。
Embodiment 901
N-(3-{1-[6-(4-chlorophenoxy)-6-(4-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-chlorophenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.93(s，1H)，7.72-6.68(m，12H)，5.06-4.98(m，1H)，3.66-3.50(m，br，2H)，3.02-2.82(m，br，2H)，2.80-2.57(m，br，4H)，2.57-2.38(m，br，2H)，2.02-1.76(m，br，6H)，1.64-1.48(m，br，1H)，1.48-1.36(m，br，3H)，1.25(d，6H，J＝6.8Hz)；
To C 33H 41Cl 2FN 2O 20.5ETOAc value of calculation: C, 66.55; H, 7.18; N, 4.43;
Measured value: C, 66.35; H, 6.86; N, 4.46;
ESMS?m/e：550.8(M+H) +。
Embodiment 902
N-(3-{1-[6-(4-chlorphenyl)-6-(4-fluorophenoxy) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.22(s，br，1H)，7.74-6.68(m，12H)，5.04-4.92(m，1H)，3.66-3.50(m，br，2H)，3.00-2.82(br，2H)，2.80-2.58(m，br，4H)，2.58-2.40(m，br，2H)，2.00-1.68(m，br，6H)，1.66-1.46(m，br，1H)，1.46-1.36(br，3H)，1.25(d，6H，J＝7.2Hz)；ESMS?m/e：551.1(M+H) +.
Embodiment 903
N-(3-{1-[6-(3-acetyl group phenoxy group)-6-phenyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-{3-[1-(6-hydroxyl-6-phenyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：541.2(M+H) +。
Embodiment 904
N-(3-{1-[6-(4-chlorophenoxy)-6-phenyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-chlorophenol and N-{3-[1-(6-hydroxyl-6-phenyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.28(s，1H)，7.78-6.70(m，13H)，5.08-4.98(m，1H)，3.64-3.46(m，br，2H)，3.02-2.82(br，2H)，2.82-2.56(m，br，4H)，2.56-2.34(m，br，2H)，2.05-1.75(m，br，6H)，1.64-1.48(m，br，1H)，1.48-1.34(br，3H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：533.1(M+H) +.
Embodiment 905
N-(3-{1-[6-(4-bromine phenoxy group)-6-(4-chlorphenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-bromophenol and N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：611.0(M+H) +。
Embodiment 906
N-(3-{1-[6-(4-chlorphenyl)-6-(4-methoxyl group phenoxy group) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-methoxyphenol and N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：563.1(M+H) +。
Embodiment 907
N-(3-{1-[6-(4-fluorophenyl)-6-(4-methoxyl group phenoxy group) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-methoxyphenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.11(8，1H)，7.65-6.84(m，12H)，5.21-5.10(m，1H)，3.66-3.56(m，br，2H)，3.02-2.82(br，2H)，2.82-2.56(m，br，4H)，2.54(s，3H)，2.53-2.32(m，br，2H)，2.02-1.70(m，br，6H)，1.64-1.48(m，br，1H)，1.48-1.34(br，3H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：547.1(M+H) +.
Embodiment 908
N-(3-{1-[6-(3-acetyl group phenoxy group)-6-(4-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：559.1(M+H) +。
Embodiment 909
N-(3-{1-[6-(4-fluorophenoxy)-6-phenyl hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-{3-[1-(6-hydroxyl-6-phenyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.05(s，br，1H)，7.72-6.70(m，13H)，5.06-4.96(m，1H)，3.66-3.51(m，2H)，3.01-2.82(m，br，2H)，2.82-2.57(m，br，4H)，2.57-2.34(m，br，2H)，2.05-1.78(m，br，6H)，1.64-1.52(m，br，1H)，1.52-1.16(m，br，3H)，1.25(d，6H，J＝7.2Hz)；ESMS?m/e：517.0(M+H) +.
Embodiment 910
N-(3-{1-[6-(2-acetyl group phenoxy group)-6-(2-fluorophenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(2-hydroxy phenyl) ethyl ketone and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：559.0(M+H) +。
Embodiment 911
N-[3-(1-{6-(4-fluorophenyl)-6-[2-fluoro-5-(trifluoromethyl) phenoxy group] hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[6-(4-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDC1 3)，HCl?saltδ8.23(s，br，1H)，7.74-6.88(m，11H)，5.20-5.12(m，1H)，3.68-3.52(m，br，2H)，3.02-2.82(m，br，2H)，2.82-2.60(m，4H)，2.58-2.38(m，br，2H)，2.12-2.02(m，br，1H)，2.02-1.80(m，br，5H)，1.68-1.52(m，br，1H)，1.52-1.36(br，3H)，1.25(d，6H，J＝7.2Hz)；ESMS?m/e：603.3(M+H) +.
Embodiment 912
N-(3-{1-[6-(3-acetyl group phenoxy group)-6-(4-chlorphenyl) hexyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.41(s，1H)，7.72-6.84(m，12H)，5.18-5.10(m，1H)，3.62-3.50(m，br，2H)，3.00-2.92(m，2H)，2.90-2.58(m，4H)，2.54(s，3H)，2.50-2.12(m，2H)，2.02-1.70(m，br，6H)，1.64-1.50(m，br，1H)，1.50-1.14(m，br，3H)，1.25(d，6H，J＝6.8Hz)；SMS?m/e：575.3(M+H) +.
Embodiment 913
N-[3-(1-{6-(2-fluorophenyl)-6-[2-fluoro-5-(trifluoromethyl) phenoxy group] hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.35(s，1H)，7.68-6.82(m，11H)，5.58-5.48(m，1H)，3.64-3.50(m，2H)，3.01-2.94(m，br，2H)，2.92-2.54(m，4H)，2.48-2.32(m，br，2H)，2.20-2.04(m，1H)，2.01-1.80(m，5H)，1.70-1.54(m，1H)，1.54-1.36(m，3H)，1.25(d，6H，J＝7.2Hz).
To C 34H 40ClF 5N 2O 20.6MeOH value of calculation: C, 63.12; H, 6.49; N, 4.25;
Measured value: C, 63.38; H, 6.61; N, 3.95;
ESMS?m/e：603.3(M+H) +。
Embodiment 914
N-[3-(1-{6-(4-chlorphenyl)-6-[2-fluoro-5-(trifluoromethyl) phenoxy group] hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[6-(4-chlorphenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：619.2(M+H) +。
Embodiment 915
N-[3-(1-{6-(3-fluorophenyl)-6-[2-fluoro-5-(trifluoromethyl) phenoxy group] hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[6-(3-fluorophenyl)-6-hydroxyl hexyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：603.3(M+H) +。
Embodiment 916
N-[3-(1-{6-(2-fluoro-5-(trifluoromethyl) phenoxy group]-6-phenyl hexyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-{3-[1-(6-hydroxyl-6-phenyl hexyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：585.3(M+H) +。
Embodiment 917
N-[3-(1-{7-(2-fluorophenyl)-7-[2-fluoro-5-(trifluoromethyl) phenoxy group] heptyl }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[7-(2-fluorophenyl)-7-hydroxyl heptyl]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：617.3(M+H) +。
Embodiment 918
N-(3-{1-[5-(4-fluorophenyl)-5-(4-methoxyl group phenoxy group) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-methoxyphenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：533.1(M+H) +。
Embodiment 919
N-(3-{1-[5-(4-bromine phenoxy group)-5-(4-fluorophenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-bromophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.94(s，br，1H)，7.68-6.64(m，12H)，5.12-5.04(m，1H)，3.68-3.52(m，br，2H)，3.01-2.82(br，2H)，2.78-2.58(m，br，4H)，2.57-2.38(m，br，2H)，2.05-1.80(m，br，6H)，1.64-1.38(m，br，2H)，1.25(d，6H，J＝7.2Hz)；ESMS?m/e：581.0(M+H) +.
Embodiment 920
N-(3-{1-[5-(4-chlorophenoxy)-5-(4-chlorphenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-chlorophenol and N-(3-{1-[5-(4-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.86(s，br，1H)，7.62-6.72(m，12H)，5.12-5.02(m，1H)，3.68-3.52(m，br，2H)，3.02-2.82(br，2H)，2.82-2.56(m，br，4H)，2.56-2.40(m，br，2H)，2.06-1.80(m，br，6H)，1.64-1.40(m，br，2H)，1.25(d，6H，J＝6.8Hz).
To C 32H 39Cl 3N 2O 21.3MeOH value of calculation: C, 63.25; H, 7.07; N, 4.42;
Measured value: C, 63.41; H, 6.99; N, 4.17;
ESMS?m/e：553.0(M+H) +。
Embodiment 921
N-(3-{1-[5-(4-chlorophenoxy)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-chlorophenol and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.72-6.72(m，13H)，5.12-5.04(m，1H)，3.66-3.52(m，br，2H)，3.01-2.83(br，2H)，2.68-2.62(m，br，2H)，2.62-2.48(m，br，4H)，2.04-1.82(m，br，6H)，1.62-1.40(m，br，2H)，1.25(d，6H，J＝7.2Hz)；ESMS?m/e：519.1(M+H) +.
Embodiment 922
N-(3-{1-[5-(3-acetyl group phenoxy group)-5-(4-fluorophenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：545.1(M+H) +。
Embodiment 923
N-(3-{1-[5-(4-chlorphenyl)-5-(4-fluorophenoxy) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-(3-{1-[5-(4-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.05(s，br，1H)，7.74-6.68(m，12H)，5.08-4.99(m，1H)，3.67-3.56(m，br，2H)，3.02-2.82(br，2H)，2.80-2.57(m，br，4H)，2.57-2.38(m，br，2H)，2.05-1.80(m，br，6H)，1.64-1.40(m，br，2H)，1.25(d，6H，J＝7.2Hz).
To C 32H 39Cl 2FN 2O 21.3EtOAc value of calculation: C, 64.93; H, 7.24; N, 4.07;
Measured value: C, 65.01; H, 6.97; N, 3.85;
ESMS?m/e：537.1(M+H) +。
Embodiment 924
N-(3-{1-[5-(4-bromine phenoxy group)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-bromophenol and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.74-6.66(m，13H)，5.13-5.02(m，1H)，3.73-3.51(m，br，2H)，3.05-2.83(br，2H)，2.83-2.62(br，4H)，2.62-2.42(m，br，2H)，2.10-1.80(m，br，6H)，1.65-1.37(m，br，2H)，1.25(d，6H，J＝6.8Hz)；ESMS?m/e：562.9(M+H) +.
Embodiment 925
N-(3-{1-[5-(4-chlorphenyl)-5-(4-methoxyl group phenoxy group) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-methoxyphenol and N-(3-{1-[5-(4-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.13(s，br，1H)，7.72-6.70(m，12H)，5.08-4.97(m，1H)，3.72(s，3H)，3.66-3.50(m，br，2H)，3.03-2.82(br，2H)，2.80-2.54(m，br，4H)，2.53-2.17(m，br，2H)，2.08-1.78(m，br，6H)，1.65-1.38(m，br，2H)，1.25(d，6H，J＝6.8Hz).
To C 33H 42Cl 2N 2O 30.54CH 2Cl 2Value of calculation: C, 63.80; H, 6.88; N, 4.44;
Measured value: C, 63.84; H, 7.18; N, 4.00;
ESMS?m/e：549.1(M+H) +。
Embodiment 926
N-(3-{1-[5-(4-fluorophenoxy)-5-(4-fluorophenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.62-6.70(m，12H)，5.10-5.00(m，1H)，3.71-3.56(m，br，2H)，3.04-2.82(br，2H)，2.78-2.64(m，br，3H)，2.64-2.48(m，br，3H)，2.05-1.82(m，br，6H)，1.62-1.42(m，br，2H)，1.25(d，6H，J＝6.0Hz)；ESMSm/e：521.2(M+H) +.
Embodiment 927
N-(3-{1-[5-(3-acetyl group phenoxy group)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：526.9(M+H) +。
Embodiment 928
N-(3-{1-[5-(4-methoxyl group phenoxy group)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-methoxyphenol and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：515.6(M+H) +。
Embodiment 929
N-[3-(1-{5-[2-fluoro-5-(trifluoromethyl) phenoxy group]-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-[3-(1-{5-hydroxyl-5-[4-(trifluoromethyl) phenyl] amyl group }-the 4-piperidyl] phenyl-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：639.2(M+H) +。
Embodiment 930
N-[3-(1-{5-(3-chlorphenyl)-5-[2-fluoro-5-(trifluoromethyl) phenoxy group] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[5-(3-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.17(s，br，1H)，7.75-6.88(m，11H)，5.26-5.14(m，1H)，3.68-3.56(m，br，2H)，3.05-2.90(br，2H)，2.90-2.60(m，br，4H)，2.56-2.36(m，br，2H)，2.18-1.84(m，br，6H)，1.70-1.44(m，br，2H)，1.25(d，6H，J＝7.2Hz).
To C 33H 38Cl 2F 4N 2O 20.9EtOAc value of calculation: C, 60.98; H, 6.32; N, 3.89;
Measured value: C, 60.99; H, 6.17; N, 3.81;
ESMS?m/e：605.2(M+H) +。
Embodiment 931
N-[3-(1-{5-(2-fluorophenyl)-5-[2-fluoro-5-(trifluoromethyl) phenoxy group] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[5-(2-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.89(s，br，1H)，7.72-6.88(m，11H)，5.59-5.48(m，1H)，3.70-3.48(br，2H)，3.05-2.84(br，2H)，2.82-2.58(m，br，4H)，2.58-2.40(m，br，2H)，2.22-1.82(m，br，6H)，1.71-1.42(m，br，2H)，1.25(d，6H，J＝6.4Hz)；ESMS?m/e：589.3(M+H) +.
Embodiment 932
N-[3-(1-{5-(3-fluorophenyl)-5-[2-fluoro-5-(trifluoromethyl) phenoxy group] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[5-(3-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.79(s，br，1H)，7.63-6.82(m，11H)，5.24-5.15(m，1H)，3.70-3.56(br，2H)，3.04-2.84(br，2H)，2.82-2.60(m，br，4H)，2.60-2.42(m，br，2H)，2.20-1.83(m，br，6H)，1.70-1.44(m，br，2H)，1.25(d，6H，J＝6.4Hz)；ESMS?m/e：589.3(M+H) +.
Embodiment 933
N-(3-{1-[5-(3-acetyl group phenoxy group)-5-(4-chlorphenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(3-hydroxy phenyl) ethyl ketone and N-{3-[1-(5-(4-chlorphenyl)-5-hydroxyl amyl group)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ8.05(s，br，1H)，7.74-6.88(m，12H)，5.27-5.16(m，1H)，3.69-3.52(m，br，2H)，3.10-2.81(br，2H)，2.81-2.57(m，br，4H)，2.54(s，3H)，2.52-2.40(m，br，2H)，2.05-1.80(m，br，6H)，1.66-1.42(m，br，2H)，1.25(d，6H，J＝6.8Hz)；
To C 34H 42Cl 2N 2O 30.5CH 2Cl 21.0H 2The value of calculation of O: C, 63.46; H, 6.91; N, 4.30;
Measured value: C, 63.46; H, 7.09; N, 4.00;
ESMS?m/e：561.1(M+H) +。
Embodiment 934
N-[3-(1-{5-(4-chlorphenyl)-5-[2-fluoro-5-(trifluoromethyl) phenoxy group] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[5-(4-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
1H?NMR(400MHz，CDCl 3)，HCl?saltδ7.61-6.92(m，11H)，5.24-5.16(m，1H)，3.70-3.58(m，2H)，3.02-2.91(br，2H)，2.80-2.64(m，br，3H)，2.64-2.50(m，3H)，2.18-1.94(m，br，6H)，1.62-1.44(m，br，2H)，1.25(d，6H，J＝7.2Hz)；ESMS?m/e：605.3(M+H) +.
Embodiment 935
N-[3-(1-{5-(4-fluorophenyl)-5-[2-fluoro-5-(trifluoromethyl) phenoxy group] amyl group }-the 4-piperidyl) phenyl]-the 2-methyl propanamide
According to method A and option A N, use 2-fluoro-5-(trifluoromethyl) phenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：589.3(M+H) +。
Embodiment 936
N-(3-{1-[5-(4-bromine phenoxy group)-5-(4-chlorphenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-bromophenol and N-(3-{1-[5-(4-chlorphenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：597.2(M+H) +。
Embodiment 937
N-(3-{1-[5-(4-chlorophenoxy)-5-(4-fluorophenyl) amyl group]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-chlorophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxyl amyl group]-the 4-piperidyl phenyl)-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：537.3(M+H) +。
Embodiment 938
N-(3-{1-[5-(2-acetyl group phenoxy group)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 1-(2-hydroxy phenyl) ethyl ketone and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：527.0(M+H) +。
Embodiment 939
N-(3-{1-[5-(2-ethoxy phenoxy)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 2-thanatol and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：529.2(M+H) +。
Embodiment 940
N-(3-{1-[5-(4-fluorophenoxy)-5-phenylpentyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method A and option A N, use 4-fluorophenol and N-{3-[1-(5-hydroxyl-5-phenylpentyl)-4-piperidyl] phenyl }-the 2-methyl propanamide prepares titled reference compound.
ESMS?m/e：503.2(M+H) +。
Embodiment 941
N-(3-{1-[4-(4-fluorophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 4-chloro-1-(4-fluorophenyl)-1-butanone prepare titled reference compound.
ESMS?m/e：411.2(M+H) +。
Embodiment 942
2-methyl-N-(3-{1-[3-(1H-pyrroles-3-yl) propyl group]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 3-(3-bromopropyl)-1H-pyrroles prepare titled reference compound.
ESMS?m/e：354.2(M+H) +。
Embodiment 943
N-(3-{1-[4-(4-isopropyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 4-chloro-1-(4-isopropyl phenyl)-1-butanone prepare titled reference compound.
ESMS?m/e：435.2(M+H) +。
Embodiment 944
N-(3-{1-[4-(4-methoxyphenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 4-chloro-1-(4-methoxyphenyl)-1-butanone prepare titled reference compound.
ESMS?m/e：423.2(M+H) +。
Embodiment 945
2-methyl-N-(3-{1-[4-(4-aminomethyl phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 4-chloro-1-(4-aminomethyl phenyl)-1-butanone prepare titled reference compound.
ESMS?m/e：407.2(M+H) +。
Embodiment 946
N-(3-{1-[4-(4-tert-butyl-phenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-(4-tert-butyl-phenyl)-4-chloro-1-butanone prepare titled reference compound.
ESMS?m/e：449.2(M+H) +。
Embodiment 947
N-(3-{1-[4-(4-bromophenyl)-4-oxo butyl]-the 4-piperidyl } phenyl)-the 2-methyl propanamide
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 1-(4-bromophenyl)-4-chloro-1-butanone prepare titled reference compound.
ESMS?m/e：471.3(M+H) +。
Embodiment 948
2-methyl-N-(3-{1-[4-oxo-4-(2-thienyl) butyl]-the 4-piperidyl } phenyl) propionic acid amide.
According to method K (KI) and scheme E (potassium carbonate), using 2-methyl-N-[3-(4-piperidyl) phenyl] propionic acid amide. and 4-chloro-1-(2-thienyl)-1-butanone prepare titled reference compound.
ESMS?m/e：399.1(M+H) +。
The method of II. synthesizing each general formula
Each embodiment that describes in the I part only is the method that illustrates synthetic MCH1 antagonist.Synthetic method according to each embodiment can obtain further derivant.
In the method for generalized synthetic further derivant, may need each substituent group is protected and deprotection as amino, acylamino-, carboxylic acid and hydroxyl.The protection of these groups and deprotection are known in the art, can be referring to as Green, and T.W.and Wuts, P.G.M. (1991), Protection Groups in Organic Synthesis, second edition, John Wiley﹠amp; Sons, New York.
III. Orally administered composition
As a specific embodiment of the Orally administered composition of The compounds of this invention, 100mg chemical compound described herein is prepared with abundant dispersive lactose in small, broken bits, obtaining total amount is 580mg to 590mg, is filled in the O hard capsule.
IV. on cloned rat MCH1 receptor, each chemical compound is carried out pharmacological evaluation
Use method described below, on cloned rat MCH1 receptor, carry out pharmacology's performance evaluation of The compounds of this invention.
Host cell
Various host cells can be used to study various heterogenous expression protein.These cells include but not limited to: (assorted) mammal cell line through selecting, as Cos-7, CHO, LM (tk-), HEK923, Peak rapid 293 etc.; Insect cell line is as Sf9, Sf21 etc.; Amphibian cell line is as xenopus oocyte etc.
At 37 ℃ and 5% CO 2In the atmosphere, make the COS-7 cell on the 150mm culture plate, growth in DMEM (the Eagle culture medium of Dulbecco modification is supplemented with 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100Fg/ml streptomycin).To store up the COS-7 cell trypsinization of plate (stock plate) every 3-4 days, and divide the plate growth in 1: 6 ratio.
At 37 ℃ and 5% CO 2In the atmosphere, make HEKC 293 on the 150mm culture plate, growth in DMEM (replenishing 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100Fg/ml streptomycin).To store up 293 cell trypsinizations of plate every 3-4 days, and divide the plate growth in 1: 6 ratio.
At 37 ℃ and 5% CO 2In the atmosphere, make HEKC Peak rapid293 (Peakr293) on the 150mm culture plate, growth in DMEM (replenishing 10% hyclone, 10%L-glutamine, 50Fg/ml gentamycin).To store up the Peak rapid293 cell trypsinization of plate every 3-4 days, and divide the plate growth in 1: 12 ratio.
At 37 ℃ and 5% CO 2In the atmosphere, make l cell LM (tk-) on the 150mm culture plate, growth in DMEM (the Eagle culture medium of Dulbecco modification is replenished 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100Fg/ml streptomycin).To store up LM (tk-) the cell trypsinization of plate every 3-4 days, and divide the plate growth in 1: 10 ratio.
At 37 ℃ and 5% CO 2In the atmosphere, make Chinese hamster ovary (CHO) cell on the 150mm culture plate, growth in HAM=s F-12 culture medium (replenishing 10% calf serum, 4mM L-glutamine, 100 units/ml penicillin/100Fg/ml streptomycin).To store up the Chinese hamster ovary celI trypsinization of plate every 3-4 days, and divide the plate growth in 1: 8 ratio.
At 37 ℃ and 5% CO 2In the atmosphere, make mouse embryo fibroblasts NIH-3T3 cell on the 150mm culture plate, growth in DMEM (the Eagle culture medium of Dulbecco modification is replenished 10% calf serum, 4mM glutamine, 100 units/ml penicillin/100Fg/ml streptomycin).To store up the MH-3T3 cell trypsinization of plate every 3-4 days, and divide the plate growth in 1: 15 ratio.
At 27 ℃, no CO 2In the atmosphere, make Sf9 and Sf21 cell on 150mm tissue culture ware, in TMN-FH culture medium (being supplemented with 10% hyclone) with monolayer growth.The HighFive insect cell is on 150mm tissue culture ware, at Ex-Cell 400 TMGrowth in the culture medium (being supplemented with the L-glutamine) is equally at 27 ℃ and there is not CO 2Under the condition of atmosphere.
In some cases, the cell line with the adhesion monolayer growth can be converted to suspending nutrient solution, the large batch of even test material that is used for conventional receptor screening is provided to improve cell yield.
Transient expression
Can by following several method will be to be studied DNA transient expression in the cell line of various mammals, insecticide, Amphibian and other cell line of coded protein, described method includes but not limited to calcium phosphate transfection method, DEAE-glucosan infection protocol, liposome transfection method, virus transfection method, electroporation transfection method and microinjection infection protocol.These methods all require according to DNA, cell line and subsequently with the method for testing used with supporting experiment parameter optimization.
Below explanation is applied to the general operation of the calcium phosphate method of Peak rapid 293 cells: before transfection, collected the cell of adhesion in about 24 hours, and with 3.5 * 10 6The density of cell/ware is inoculated in the 150mm tissue culture ware once more, at 37 ℃, and 5%CO 2Middle overnight incubation.CaCl with 250F1 2And DNA (15Fg DNA is at 250mM CaCl 2In solution) mixed liquor add in the 5ml plastic tube, under slight the mixing, slowly add 2 * HBS (280mM NaCl, 10mM KCl, the 1.5mM Na of 500Fl subsequently 2HPO 4, 12mM glucosan and 50mM HEPES).Described mixed liquor was at room temperature cultivated 20 minutes, formed the DNA precipitation.Subsequently described DNA precipitation is added in the culture medium on each culture plate, at 37 ℃, 5%CO 2The middle cultivation 5 hours.After the cultivation, in each culture plate, add 5ml culture medium (DMEM, 10%FBS, 10%L-glut and 50 μ g/ml gentamycins).Then with cell at 37 ℃, 5%CO 2The middle cultivation 24 to 48 hours.
Below explanation is applied to the general operation of DEAE-glucosan method of Cos-7 cell: will be used for cells transfected in 24 hours before transfection divides the bottle growth, makes cell 70-80% fusion when transfection in each bottle.In brief, 8Fg receptor dna and any other required DNA of 8Fg (constituting (construct), antibiotic resistance labelling, analog carrier etc. as g matter expression vector, reporter gene) are added in complete DMEM of 9ml and the deae dextran mixture (the PBS solution of 10mg/ml).The COS-7 cell inoculation in T225 flask (divide and merge), with the PBS washing once, is added described DNA mixed liquor in each flask.With cell at 37 ℃, 5%CO 2The middle cultivation 30 minutes.After the cultivation, in each flask, add complete DMEM of 36ml and 80FM chloroquine, and continue to cultivate 3 hours.With described culture medium suction, the complete culture medium that contains 10%DMSO with 24ml was washed 2 minutes, subsequently suction subsequently.Then, in each flask, add the complete DMEM of 30ml with cell PBS washed twice.Subsequently cell culture is spent the night.Second day, collecting cell after trypsin is nitrated was inoculated once more according to the needs of the test-types that is carried out.
Below explanation is applied to the general operation of liposome transfection method of Chinese hamster ovary celI: will be used for cells transfected in 24 hours before transfection divides the bottle growth, makes cell 70-80% fusion when transfection in each bottle.Every 75cm 2The flask cell uses 10Fg DNA (can comprise the receptor dna of various ratios and the DNA of other needs (constituting (construct), antibiotic resistance labelling, analog carrier etc. as g matter expression vector, reporter gene)) to carry out transfection altogether.Liposome transfection is carried out in requirement (LipofectAMINE, GibcoBRL, Bethesda, MD) according to the manufacturer.Cells transfected is collected in transfection after 24 hours, use or inoculation once more according to the requirement of being tested.
Below explanation is applied to the general operation of electroporation transfection method of Cos-7 cell: will be used for cells transfected in 24 hours before transfection divides the bottle growth, makes that cell merged in the transfection time-division in each bottle.With the nitrated back of trypsin collecting cell, be suspended in their growth medium counting once more.With 4 * 10 6Individual cell suspension places the electroporation cuvette in 300Fl DMEM.In described cell suspending liquid, add the DNA of 8Fg receptor dna and other needs (as G αProtein expression carrier, reporter gene constitute (construct), antibiotic resistance labelling, analog carrier etc.), cuvette is placed BioRad Gene Pulser, carry out electric pulse (Gene Pulser is provided with: voltage 0.25kV, electric capacity 950FF).After the pulse, in each cuvette, add the complete DMEM of 800Fl, described suspension is transferred in the sterile test tube.In each test tube, add complete medium, make that final cell concentration is 1 * 10 5Cell/100Fl.Then carrying out flat board according to the needs pair cell of being tested cultivates.
Below with the general operation of the virus transfection method of the baculovirus infection of insecticide Sf9 cell explanation foreign protein matter.The coding region sub-clone of the DNA of coding receptor described herein can be advanced pBlueBacIII to the sequence 5 of existing restriction site or artificial reconstructed coding region to polypeptide ' and 3 ' the site on.In order to produce baculovirus, can be according to the method (in " Baculovirus Expression Vector System:Procedures andMethods Manual ", describing) of Pharmingen description, by dna structure cotransfection to 2 * 10 of coprecipitation of calcium phosphate method with 0.5Fg viral DNA (BaculoGold) and 3Fg coded polypeptide 6In autumn mythimna separata (Spodoptera frugiperda) insecticide Sf 9 cells.Subsequently described cell was cultivated 5 days down at 27 ℃.The supernatant of centrifugal collection cotransfection culture plate is with the viral plaque purification of reorganization.Method with virus infected cell, the viral liquid storage of preparation and titration virus liquid storage is described in the handbook of Pharmingen.Same principle is applicable to the expression of mammalian cell through retrovirus, Simliki forest virus and double-stranded DNA virus (as adenovirus, herpesvirus and vaccinia virus etc.).
Stably express
Can mix in the host cell different DNA is stable, make cell continuous expression foreign protein.Method and the above-mentioned method that those are used for transient expression that DNA is passed in the cell are similar, but require the auxiliary gene cotransfection so that target host cell all has drug resistance.Desired drug resistance can be used for selecting and having kept absorbing the cell of different DNA.An obtainable class drug resistant gene includes but not limited to neomycin, kanamycin and hygromycin.In order to study receptor, in mammalian cell (be not limited to mammalian cell, comprise CHO, HEK293, LM (tk-) etc.), carry out the proteinic stably express of heterologous receptor.
The preparation of cell membrane
In order to carry out combination test, will through the transfectional cell particle suspending ice-cooled buffer (20mM TrisHCl, 5mM EDTA, pH7.4) in, through ultrasound wave homogenize 7 seconds.At 4 ℃, with cellular lysate under 200 * g centrifugal 5 minutes.Subsequently under 4 ℃, with 40,000 * g with centrifugal 20 minutes of the supernatant.The granule of gained is washed once with the homogenize buffer, be suspended in (referring to the bonded method of radioligand) in the binding buffer liquid.According to the method for Bradford (1976), adopt bovine serum albumin to measure protein concentration as standard specimen.Usually carry out the combination test immediately, be equipped with use but also can make film and in liquid nitrogen, store in batches.
Radioligand is in conjunction with test
Use plasmid pcDNA3.1-rMCH1-f (ATCC patent preserving number PTA-3505) to carry out radioligand to rat MCH1 receptor in conjunction with test.Plasmid pcDNA3.1-rMCH1-f comprises DNA and express necessary adjusting element in mammalian cell, and these elements are connected on the DNA of coding rat MCH1 receptor, so that express effectively.The regulation that is used for the microbial preservation budapest treaty of proprietary program according to international recognition, plasmid pcDNA3.1-rMCH1-f is preserved in American Type CultureCollection (American type culture collection July 5 calendar year 2001, ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, USA, and ATCC patent preserving number is PTA-3505.
Also can be as described below, use plasmid pEXJ.HR-TL231 (ATCC patent preserving number 203197) to carry out the combination test.Plasmid pEXJ.HR-TL231 coding people MCH1 receptor, the regulation that is used for the microbial preservation budapest treaty of proprietary program according to international recognition, be preserved in American Type Culture Collection (American type culture collection for No. 17 in JIUYUE, 1998, ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, USA, ATCC preserving number are 203197.
As mentioned above, according to calcium phosphate method and cell embrane method, use DNA transient transfection HEKC Peak rapid 293 cells (Peakr293 cell) of coding MCH1 receptor.Employing is from the Peakr293 cell, adopt 0.08nM[3H with the film of rat MCH1 receptor transfection in conjunction with test] compd A (synthesizing in following detailed description of compd A), use and cultivate buffer (by 50mM Tris pH7.4,10mM MgCl 2, 0.16mM PMSF, 1mM 1,10-phenanthroline and 0.2%BSA) implement.Under 25 ℃, carried out 90 minutes in conjunction with test.Filter by the fast vacuum on GF/C glass fiber filter (pre-soaking in 5%PEI, using 50nM pH is that 7.4 Tris is lavation buffer solution), stop to cultivate.In all tests, use the 10pM compd A to determine nonspecific combination.
Functional test
The function of use test can filter out the cell that has endogenous mammalian receptors.The existing cell that does not contain or contain the minute quantity endogenous recipient can carry out transfection with the endogenous recipient that is used for functional test.
Multiple spectrum test can be used to screen the receptor activation effect.These tests comprise as: conventional to phosphatidylinositols, cAMP, Ca ++And K +Test; Test these identical second message,second messengers' system, but can make amendment or adjustment so that method of testing faster, have more universality and more responsive; Report the cell-based platform (cell based platforms) of the more general cell incident that produces by receptor activation, described receptor activation such as metabolization, differentiation and cell division/propagation; High-caliber organism test, this class testing monitoring complex physical and behavior change, and think to have participated in as receptor activation activities such as cardiovascular, analgesia, appetizing, anxiety and calmness.
Radioligand is in conjunction with test result
Use above-mentioned each chemical compound of cloned rat MCH1 test.The binding affinity of each chemical compound as shown in Table I.
Ki(nM)
Embodiment numbers structure
rMCH1
Figure A0281721204581
Figure A0281721204591
Figure A0281721204611
Figure A0281721204631
Figure A0281721204651
Embodiment Structure ????Ki(nM) ????rMCH1
Figure A0281721204691
Figure A0281721204711
Figure A0281721204721
Figure A0281721204731
Example structure rMCH1
Kl(nM)
Figure A0281721204752
Figure A0281721204771
Figure A0281721204791
Figure A0281721204811
Figure A0281721204821
Figure A0281721204831
Figure A0281721204841
Figure A0281721204861
Figure A0281721204871
Figure A0281721204901
Figure A0281721204911
Example structure rMCH1
Kl(nM)
Figure A0281721204921
Figure A0281721204931
Figure A0281721204961
Figure A0281721204971
Figure A0281721204981
Figure A0281721204991
Figure A0281721205011
Figure A0281721205041
Figure A0281721205061
Figure A0281721205081
Figure A0281721205101
Example structure rMCH-1
Kl(nM)
Figure A0281721205111
Figure A0281721205131
Example structure rMCH-1
Kl(nM)
Figure A0281721205141
Figure A0281721205161
Figure A0281721205181
Figure A0281721205201
Example structure rMCH-1
Kl(nM)
Figure A0281721205202
Figure A0281721205221
Figure A0281721205231
Figure A0281721205241
Figure A0281721205251
Figure A0281721205261
Example structure rMCH-1
Kl(nM)
Figure A0281721205272
Figure A0281721205291
Figure A0281721205301
Figure A0281721205331
Figure A0281721205341
Figure A0281721205361
Figure A0281721205381
Figure A0281721205401
Example structure rMCH1
Kl(nM)
Figure A0281721205411
Figure A0281721205431
Figure A0281721205451
Figure A0281721205461
Figure A0281721205471
Figure A0281721205521
Figure A0281721205571
Figure A0281721205581
Figure A0281721205601
Figure A0281721205621
Figure A0281721205641
Figure A0281721205651
Figure A0281721205701
Figure A0281721205721
Figure A0281721205731
Figure A0281721205751
Figure A0281721205781
Figure A0281721205791
Figure A0281721205801
Figure A0281721205821
Figure A0281721205851
Figure A0281721205861
Example structure rMCH1
Kl(nM)
Figure A0281721205872
Figure A0281721205891
Example structure rMCH1
Kl(nM)
Figure A0281721205892
Figure A0281721205901
Figure A0281721205911
Example structure rMCH1
Kl(nM)
Figure A0281721205931
Figure A0281721205941
Example structure rMCH1
Kl(nM)
Figure A0281721205961
Figure A0281721205981
Figure A0281721205991
Example structure rMCH1
Kl(nM)
Figure A0281721206001
Figure A0281721206041
Figure A0281721206071
Figure A0281721206111
Figure A0281721206181
Figure A0281721206221
Figure A0281721206241
Figure A0281721206251
Figure A0281721206301
Figure A0281721206311
Figure A0281721206331
Figure A0281721206341
Figure A0281721206351
Figure A0281721206361
Figure A0281721206371
Figure A0281721206381
Figure A0281721206391
Figure A0281721206411
Figure A0281721206421
Figure A0281721206431
Example structure rMCH1
Kl(nM)
Figure A0281721206461
Example structure rMCH1
Kl(nM)
Figure A0281721206481
Example structure rMCH1
Kl(nM)
Figure A0281721206492
Example structure rMCH1
Kl(nM)
Figure A0281721206511
Figure A0281721206531
Figure A0281721206541
Figure A0281721206561
Figure A0281721206571
Figure A0281721206581
Figure A0281721206591
Figure A0281721206611
Figure A0281721206621
Figure A0281721206641
Example structure rMCH1
Kl(nM)
Figure A0281721206642
Figure A0281721206651
Figure A0281721206671
Figure A0281721206691
Figure A0281721206731
Example structure rMCH1
Kl(nM)
Figure A0281721206781
Table 2: to the binding affinity (Ki) of rat MCH1, people's dopamine D 2, people's histamine H 1 and people α-1a adrenoreceptor
Chemical compound ??rMCH1 ????hD2 ???hH1 ?hAlpha-1a
?Ki(nM) 1 ??Ki(nM) ???Ki(nM) ???Ki(nM)
????1 ??90 ??6092 ????823 ????49
????2 ??3.9 ??2839 ????700 ????32.1
????3 ??768 ??ND ????ND ????ND
????4 ??357 ??ND ????ND ????ND
????5 ??14.2 ??1139 ????1618 ????9.1
????6 ??274 ??ND ????ND ????ND
????7 ??1000 ??ND ????ND ????ND
????8 ??627 ??ND ????ND ????ND
????9 ??69 ??1430 ????1733 ????26.4
????10 ??2.8 ??862 ????461 ????19.4
????11 ??197 ??ND ????ND ????ND
????12 ??84 ??771 ????571 ????57
????13 ??11.9 ??551 ????ND ????61
????14 ??167 ??ND ????ND ????ND
????15 ??720 ??ND ????ND ????ND
????16 ??272 ??ND ????ND ????ND
????17 ??342 ??ND ????ND ????ND
????18 ??29.5 ??782 ????ND ????115
????19 ??506 ??ND ????ND ????ND
????20 ??21 ??470 ????ND ????41.3
????21 ??630 ??ND ????ND ????ND
Table 2: to the binding affinity (Ki) of rat MCH1, people's dopamine D 2, people's histamine H 1 and people α-1a adrenoreceptor
????22 ????52 ??5181 ??2277 ??284
????23 ????1036 ??ND ??ND ??ND
????24 ????67 ??1252 ??ND ??127
????25 ????463 ??ND ??ND ??ND
????26 ????192 ??1977 ??ND ??516
????27 ????91 ??503 ??ND ??130
????28 ????511 ??ND ??ND ??ND
????29 ????651 ??ND ??ND ??ND
????30 ????382 ??ND ??ND ??ND
????31 ????362 ??ND ??ND ??ND
????32 ????160 ??ND ??ND ??ND
????33 ????615 ??ND ??ND ??ND
????34 ????651 ??ND ??ND ??ND
????35 ????11.5 ??9654 ??2000 ??5,33
????36 ????62 ??12,026 ??2454 ??1489
????37 ????29.1 ??34,993 ??16,734 ??1087
????38 ????18.2 ??＞50000 ??6595 ??1592
????39 ????11.8 ??＞50000 ??6401 ??2937
????40 ????50 ??7451 ??273 ??12.3
????41 ????946 ??ND ??ND ??ND
????42 ????118 ??ND ??ND ??ND
????43 ????12 ??10,428 ??2560 ??434
????44 ????11.5 ??8673 ??11,092 ??704
Table 2: to the binding affinity (Ki) of rat MCH1, people's dopamine D 2, people's histamine H 1 and people α-1a adrenoreceptor
????45 ????1.6 ????42.2 ????3.4 ???18
????46 ????187 ????ND ????ND ???ND
????47 ????52 ????＞50000 ????36,907 ???＞50000
????48 ????6.7 ????735 ????6390 ???452
????49 ????7.1 ????471 ????39.1 ???140
????50 ????3.9 ????1077 ????304 ???161
????51 ????3.1 ????152 ????130 ???33.5
????52 ????3.8 ????244 ????264 ???13.2
????53 ????7.1 ????191 ????1320 ???221
????54 ????4.9 ????83 ????283 ???187
????55 ????5 ????162 ????1100 ???125
????56 ????22.3 ????435 ????32.5 ???55
????57 ????16.6 ????41,994 ????48,658 ???3206
????58 ????20.1 ????390 ????590 ???233
????59 ????12.9 ????262 ????46.9 ???49.1
????60 ????0.923 ????52 ????546 ???22.3
????61 ????13.6 ????281 ????969 ???310
????62 ????12.8 ????319 ????25,320 ???719
????63 ????22.4 ????766 ????25,307 ???1058
????64 ????14.8 ????313 ????6994 ???1142
????65 ????17 ????331 ????9390 ???1720
????66 ????3.3 ????132 ????3473 ???944
????67 ????5.9 ????133 ????2146 ???511
Table 2: to the binding affinity (Ki) of rat MCH1, people's dopamine D 2, people's histamine H 1 and people α-1a adrenoreceptor
????68 ????9.3 ????66 ??329 ????204
????69 ????32.5 ????46.6 ??＞50000 ????232
????70 ????50 ????1050 ??7998 ????1521
????71 ????6.6 ????119 ??1710 ????226
????72 ????31.4 ????41,454 ??33,096 ????645
????73 ????22.3 ????41,454 ??6522 ????381
????74 ????48.6 ????39,511 ??1862 ????333
????75 ????11.8 ????19,041 ??2844 ????2469
????76 ????44.6 ????41,454 ??39,710 ????10,965
????77 ????25.7 ????447 ??4178 ????167
????78 ????22.2 ????37.6 ??＞50000 ????1313
????79 ????19.4 ????244 ??507 ????722
????80 ????14.3 ????833 ??9789 ????620
????81 ????377 ????ND ??ND ????ND
????82 ????11.2 ????ND ??ND ????ND
????83 ????48.1 ????ND ??ND ????ND
????84 ????121 ????ND ??ND ????ND
????85 ????3.2 ????2449 ??3816 ????3021
V. compd A is synthetic
The synthetic method of compd A is below described.Compd A is to be used for the radio-labelled compound of above-mentioned radioligand in conjunction with test.
N-[3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals) phenyl] acetamide
With saturated aqueous sodium carbonate (25mL), 4-{[(trifluoromethyl) sulfonyl] the oxygen base }-1; 2; 3; 6-tetrahydrochysene-1-pyridine-t-butyl formate (20mmol), 3-acetyl amino phenyl ylboronic acid (30mmol) and four (triphenylphosphines) close palladium (0) (1.15g) the mixture heated back flow reaction in dimethoxy-ethane (40mL) spend the night; obtain 4-[3-(acetylamino) phenyl-3,6-dihydro-1 (the 2H)-pyridine carboxylic acid tert-butyl ester.Use hydrochloric acid De dioxane solution with BOC group deprotection, then alkalization (pH11-12) obtains required product.
N-(3-bromopropyl) t-butyl carbamate
In the presence of dichloromethane and alkali, by 3-propantheline bromide hydrobromide and BOC 2O prepares titled reference compound.
N-3-[1-(3-aminopropyl)-1,2,3,6-tetrahydrochysene-pyridine radicals] phenyl } acetamide
According to option A, by N-(3-bromopropyl) t-butyl carbamate and N-[3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals) phenyl] acetamide is Yu the Bu of diox, catalytic amount 4NI and alkali is back flow reaction together, obtains 3-(4-[3-(acetylamino) phenyl]-3,6-dihydro-1 (2H)-pyridine radicals) the propyl carbamic acid tert-butyl ester.Use hydrochloric acid De dioxane solution with BOC group deprotection, then alkalization (pH11-12) obtains required product.
(4S)-3-([3-(4-[3-(acetylamino) phenyl]-3,6-dihydro-1 (2H)-pyridine radicals] propyl group) amino] carbonyl }-4-(3, the 4-difluorophenyl)-6-(methoxy)-2-oxo-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid methyl ester
By (6S)-6-(3, the 4-difluorophenyl)-4-(methoxy)-2-oxo-3,6-dihydro-1,5 (2H)-pyrimidine dioctyl phthalate 5-methyl ester l-(4-nitrobenzophenone) esters (according to disclosed PCT publication number WO 00/37026 preparation on June 29th, 2000) and N-3-[1-(3-aminopropyl)-1,2,3,6-tetrahydrochysene-4-pyridine radicals] phenyl } the prepared in reaction titled reference compound of acetamide.
1H?NMRδ8.90(t，1H，J＝3.6Hz)，7.75(s，1H)，7.50-7.00(m，8H)，6.68(s，1H)，6.03(br?s，1H)，4.67(s，2H)，3.71(s，3H)，3.47(s，3H)，3.38(ABm，2H)，3.16(m，2H)，2.71(t，2H，J＝5.4Hz)，2.56(m，4H)，2.35-1.90(br，2H)，2.17(s，3H)，1.82(p，2H，J＝7.2Hz)；ESMS，612.25(M+H) +.
Tritiate (4S)-3-{[(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group) amino] carbonyl }-4-(3, the 4-difluorophenyl)-6-(methoxy)-2-oxo-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid methyl ester ([ 3H] compd A)
According to Amersham Pharmacia Biotech, Cardiff, Wales carry out this and synthesize.In the presence of 5% palladium on carbon, with (4S)-3-({ [3-(4-[3-(acetylamino) phenyl]-3,6-dihydro-1 (2H)-pyridine radicals) propyl group] amino } carbonyl)-4-(3, the 4-difluorophenyl)-6-(methoxy)-2-oxo-1,2,3, the methanol solution of 4-tetrahydrochysene-5-pyrimidinecarboxylic acid methyl ester is exposed in the 1 atmospheric tritium gas atmosphere, and stirring is spent the night, through reversed-phase HPLC (Hypersil ODS, 4.6 * 100mm adopted methanol: H in 15 minutes 2O: Et 310: 90: 1 to 100: 0: 1 eluent of N, flow velocity 1.0mL/min, adopt radiochemistry and UV detector) behind the purification, obtain tritiate (4S)-3-{[(3-{4-[3-(acetylamino) phenyl]-piperidino } propyl group) amino] carbonyl }-4-(3, the 4-difluorophenyl)-6-(methoxy)-2-oxo-1,2,3,4-tetrahydrochysene-5-pyrimidinecarboxylic acid methyl ester ((+)-isomer).This product is used as radioligand at MCH1 in testing.According to identical method, replace tritium gas with hydrogen, obtain nonradioactive compd A.
VI. method in the body
The method in the following body implemented is with the effect of prediction MCH1 antagonist to treatment of obesity (3-days body weight and sugaring Evamilk), depression (forced swimming test), anxiety neurosis (social contacts test) and urinary disorders (DIRC and CSTI).
The MCH1 antagonist is to the effect (3 days) of body weight
The male Long Evans rat (Charles River) of body weight 180-200g is one group with 4 closes in 12 hours bright/black circulation cages, make their ad libs and drinking-water., carried out 3 days the tested compounds administration through twice of i.p. injection every day (behind preceding 1 hour of dark cycle and the light 2 hours).Every rat is weighed after the injection in each morning.All results are with weight (g) expression (meansigma methods ± SEM), analyze according to two-way analysis of variance of every day.The data one way analysis of variance to each time point is analyzed, and then carries out post hocNewman/Keuls test.Use GraphPad Prism (the 2.01st edition, GraphPadSoftware, Inc., San Diego CA) carries out data analysis.All data are represented with meansigma methods ± S.E.M.
The MCH1 antagonist is to the digestion effect of sugaring Evamilk
The male C57BL/6 mice (Charles River) of body weight 17-19g is one group with 4 or 5 and closes in 12 hours bright/black circulation cages with when beginning experiment, makes their ad libs and drinking-water.In 7 days, each mice is weighed, place independently cage, before entering the light circulation, made it drink the dense milk of sugaring (Nestle was in 1: 3 ratio dilute with water) 1 hour in 2-4 hour.Milk bottle weight recorded before and after the amount of institute's milk drink was drunk by weighing.In test that day, at milk drink preceding 30 minutes, mice is injected the solvent (0.01% lactic acid) of tested compounds (3,10 or the solution of 30mg/kg in 0.01% lactic acid), fenfluramine (solution of 10mg/kg in 0.01% lactic acid) through i.p..The amount (unit/ml s milk/kg body weight) of the milk that will drink in test days and the benchmark amount of drinking of a few days ago measuring each mice are relatively.Adopt one way analysis of variance that the data of each time point are analyzed.
Mandatory swim test (FST) to rat
Animal
All the test in adopt male Sprague-Dawley rat (Taconic Farms, NY).With rat with 5 in every cage, with 12: 12 hours lights: dark cycle is raised.Train 1 minute rat every day before carrying out performance testing, continuous 4 days.
Administration
Preceding 60 minutes of test period beginning to carry out 5 minutes chooses at random animals received single i.p. solvent (2.5%EtOH/2.5%Tween-80) administration, the bright (positive control of miboplatin; 60mg/kg) administration or test compounds administration.Use the 1cc tuberculin syringe, (Bridgeport NJ) injects for Becton-Dickinson, VWR Scientific to be with 26 3/8 needle tubings.Volume injected is 1ml/kg.
Experimental design
Be used for the method similar to aforesaid method (Porsolt etc., 1978) of this research, difference is that the depth of water of this method is 31cm.Adopting the darker depth of water in this experiment is to have supported their health for the pawl that prevents rat touches the bottom of tank.Each rat placed in the independent lucite tank (high 46cm * diameter 20cm, depth of water 31cm, water temperature 23-25 ℃) carry out swim test.Swim test always carried out 900 to 1700 hours, by carrying out test in 5 minutes after initial 15 minute debug phase, 24 hours.Before 5 minutes test periods 60 minutes give the rat drug treating.Behind the swim test, each rat is taken out from tank, dry and place cage 15 minutes, return subsequently in their cage through heating with handkerchief.Use color video camera that whole test process is recorded a video, note down so that scoring subsequently.
Behavior scoring
Test period at 5 minutes is estimated the behavior of rat every 5 seconds by single evaluation personnel (this evaluation personnel do not know for treatment conditions).The behavior of record is as follows:
1. motionless: rat swims in waterborne, and the action of not striking waters only is to make some to make their an emersed action;
2. climbing: rat is made positive behavior, and their fore paw is being drawn water, is generally towards wall and climbs;
3. swimming: rat is swum energetically, rather than only keeps their head height to go out the water surface, as moving along tank; With
4. heavy water: the whole health of rat immerses in the water.
Data analysis
With mandatory swim test data (motionless, swimming, climbing and heavy water) carry out at random, one way analysis of variance, and use Newman-Keuls test carrying out post hoc test.Use GraphPad Prism (the 2.01st edition, GraphPad Software, Inc., San Diego CA) carries out data analysis.All data are represented with meansigma methods ± S.E.M.
The mandatory swim test (FST) that mice is carried out
Animal
Use DBA/2 mice in all tests (Taconic Farms, NY).With mice with 5 in every cage, at 12: 12 hours lights: raise under the controlled condition of dark cycle.Train 1 minute rat every day before carrying out performance testing, continuous 4 days.This method comprises that the raising pipe of 1.5 inches of employings carries out simulative tube feeding (mock gavage).
Administration
Beginning to carry out swim test preceding 1 hour, choosing at random animal and accept single solvent (5%EtOH/5%Tween-80) administration, test compounds administration or miboplatin bright (60mg/kg) administration by oral gavage.
Experimental design
The method that is used for the mandatory swim test of mice is similar to the aforementioned method that is used for rat, but changes slightly.The tank that is used to test is 1 liter a beaker (diameter 10.5cm * high 15cm), the 23-25 ℃ of water 800ml that pack into (dark 10cm).Test period at 1300 to 1700 hours has only carried out one time 5 minutes swim test to every mice.Before 5 minutes test periods 30-60 minute gives drug treating.Behind the swim test, each mice is taken out from tank, dry and place cage 15 minutes, use color video camera that whole test process is recorded a video, note down so that scoring subsequently through heating with handkerchief.
Behavior scoring
With the playback on video monitor of 2-5 minute behavioral test, mark by the auditor.Write down the total time of motionless (animal swims in waterborne, only makes some and makes them buoyantly to move) and motion (swim and carry out not only) in order to keep floating and motion that make.
Data analysis
With mandatory swim test data (motionless, movement time, second) carry out at random, one way analysis of variance, and use Newman-Keuls test carrying out post hoc test.Use GraphPad Prism (the 2.01st edition, GraphPad Software, Inc., San Diego CA) carries out data analysis.All data are represented with meansigma methods ± S.E.M.
Social movable test (SIT)
Make rat carry out the training of 5 days by a definite date adaptation animal care equipment, before test, in independent cage, raised 5 days subsequently.Every day was to animal training 5 minutes.Social test is carried out according to the design and the method for (1997) such as aforementioned Kennett.In test that day, each of weight-matched carried out identical processing to rat (± 5%, be unfamiliar with mutually each other), return subsequently in their cage.Animal is divided into 5 processed group at random, 5 pairs every group, gives following a kind of i.p. and handle: test compounds (10,30 or 100mg/kg), solvent (1ml/kg) or chlorine nitrogen _ (5mg/kg).In test administration in preceding 1 hour.Subsequently each rat is placed white the transparent plastic test box or place (54 * 37 * 26cm, the floor is divided into 24 squares) in 15 minutes.Adopt air-conditioning to produce background noise, keeping room temperature is about 74 °F.(GR-SZ1 type, Elmwood Park NJ), make video recording to all processes with TDK (HG ultmate brand) or 30 minutes cassette tapes of Sony to adopt the JVC camera.All processes were carried out 1300-1630 hour.Use the positive doings of chronometer (226 type Sportsline 1/100 second, can distinguish) record, as self-cleaning, olfaction, bait, fight with, tumble, chase and creep up and down.Record upright (animal supports its whole health with its hind leg fully), self-cleaning (lick, sting and grab and take off health), the number of times of (pawl that promptly is animal is mobile repeatedly on the face at it) and the number of squares of being passed through wash one's face.Do not write down passive doings (animal lies in mutually on one side or be overlapping).By an observer who does not know described processing all behaviors are estimated subsequently.Behind each EOT, with the described case of the abundant wiping of wet paper towel.
Animal
(Taconic Farms NY) closes in the cage of bright/black circulation (0700 hour time of light) in 12 hours in pairs, makes their ad libs and drinking-water with male albino Sprague-Dawley rat.
Administration
With test compounds be dissolved in 100%v/v DMSO or 5%v/v lactic acid (SigmaChemical Co., St.Louis, MO) in.With chlorine nitrogen _ (Sigma Chemical Co., St.Louis MO) is dissolved in the distilled water.Solvent is made up of 50%DMSO (v/v) or 100% dimethyl acetylamide (DMA).All drug solutions are all finished in injection preparation in preceding 100 minutes, after the test solution are outwelled.The volume of institute's administered agents solution is 1ml/kg.
Data analysis
With social data (contacts time, the upright and square number that passes through) carry out at random, one way analysis of variance, and use Student-Newman-Keuls test carrying out post hoc test.Data are carried out test of normality (Shapiro-Wilk test).Use the GBSTAT program, the 6.5th edition (Dynamics Microsystems, Inc., Silver Spring, MD, 1997) carry out data analysis.
The body inner model of micturition reflex
The effect of chemical compound in micturition reflex according to the foregoing disclose document (as people such as maggi, 1987; " rhythmicity that expansion causes is shunk (distension-induced rhythmic contraction) " of Morikawa etc., 1992) describing (DIRC) and rat continuously slowly bladder inculcate (Continuous Slow Transvesicular Infusion) (CSTI) model estimate.
The DIRC model
Through the subcutaneous female Sprague Dawley rat anesthesia of using urethane (1.2g/kg) with the about 300g of body weight.With the PE240 cannula in trachea, for experiment provides the cleaning air flue.At the midfield otch, left and right sides ureter is separated.With each ureteral distally ligation (preventing that fluid from leaking from bladder), contiguous place PE10 cannula.Use 4-0 silk suture indentations sutured, stay the PE10 pipe and lead to outside to drain urine.Use the PE50 pipe to insert at distance urethra opening 2.5cm place, per urethra inserts bladder.Use adhesive tape that intubate is fixed to afterbody, be connected with pressure transducer.For preventing to leak from bladder, use the 4-0 silk thread that intubate is fastened, stretch out urethra opening outside.Be the beginning micturition reflex,, fill the normal saline (2ml at most) of 100 increments subsequently, until spontaneous bladder contraction (general 20-40mmHg shrank once in per 2 to 3 minutes) takes place at first by being exerted pressure the bladder emptying in the abdominal part bottom.In case produce rhythmic the contraction, give solvent (saline) or test compounds through i.v. or i.p., with to the active generation effect of bladder.Use 5-HT 1AAntagonist WAY-100635 is as positive control.Data be give before the medicine contraction at interval (second) (baseline) give solvent or test compounds after the contraction interval.
Continuously slow bladder is inculcated the rat model of (CSTI)
Use the male Sprague Dawley rat of the about 300g of body weight to study.(50mg/kg is i.p.) with rat anesthesia with pentobarbitone sodium.At the midfield otch, expose bladder, the little otch on the transeaical dome of polyethylene tube (PE 50) is introduced wherein, (pursestring suture) fixes intubate with the purse up suture.The other end of intubate is drawn in abdomen from back of the body cervical region through subcutaneous.Equally, another intubate (PE 50) is inserted stomach via the paramedian incision of abdominal part, free end is at the subcutaneous cervical region that extends.With the 4-0 silk suture external wounds is sewed up, animal is carried out suitable post-operative care so that its recovery.Second day, animal is placed the rat brake.With the opening of bladder intubate through three-way cock with pressure transducer and inculcate pump and be connected.Having an intravenous drip of physiological saline by the speed continuous irrigation with 100 μ l/min, the beginning bladder is blank to be shunk.Collect the blank contraction of software records repeatability with Power Lab online data.The blank curve of record baseline was administered directly to gastric through the gastric conduit with testing drug or solvent after 1 hour, monitored blank circulation 5 hours.Calculate each animal and handle the urinate pressure and the frequency of front and back (30 minutes at interval).From the frequency of urinating, calculate bladder capacity based on the constant infusion rate of 100 μ l/min.The effect of testing drug is with baseline, i.e. the percent of bladder capacity is represented before the administration.Use WAY 100635 positive contrasts to compare.
Body build-in test result
Table 2
MCH1 antagonist (embodiment numbering) is to the effect with the lower body inner model: 3 days body weight (3DBW), the dense milk of mice sugaring (mSwCM), the mandatory swim test of mice (mFST), the mandatory swim test of rat (rFST), DIRC model or CSTI models.
The embodiment numbering ??3D?BW ??mSwCM ??mFST ??rFST ???DIRC ??CSTI
????2 ????A ????B ????C ????D ????E ????F
????10 Do not carry out Do not carry out ????C Do not carry out ????E ????F
????39 ????A ????B Do not carry out ????D Do not carry out Do not carry out
????43 Do not carry out ????B ????C Do not carry out Do not carry out Do not carry out
????44 Do not carry out Do not carry out No effect Do not carry out Do not carry out Do not carry out
????89 Do not carry out ????B No effect Do not carry out Do not carry out Do not carry out
????90 Do not carry out No effect No effect Do not carry out Do not carry out Do not carry out
????91 Do not carry out Do not carry out ????C Do not carry out ????E ????F
????93 Do not carry out Do not carry out No effect Do not carry out Do not carry out Do not carry out
????95 Do not carry out ????B No effect Do not carry out Do not carry out Do not carry out
????99 ????A Do not carry out ????C Do not carry out ????E ????F
????105 Do not carry out ????B ????C Do not carry out Do not carry out Do not carry out
????106 Do not carry out ????B ????C Do not carry out ????E ????F
????112 Do not carry out Do not carry out No effect Do not carry out Do not carry out Do not carry out
????116 ????A Do not carry out ????C Do not carry out ????E ????F
A=is with respect to the matched group with vehicle treated, and weight increase significantly reduces
B=is with respect to the matched group with vehicle treated, and the milk of drinking significantly reduces
C=is with respect to the animal with vehicle treated, and motionless data significantly reduce, the administration of test oral administration.
D=is with respect to the animal with vehicle treated, and motionless data significantly reduce or the swimming vigor significantly improves
Significant prolongation is at interval shunk at the interval of E=before with respect to treated with medicaments
F=is with respect to original capacity, and bladder capacity enlarges markedly
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Claims (79)

1. chemical compound with following structure:
Figure A028172120002C1
R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CH 3,-CF 3,-COCH 3,-CO 2R 2, phenyl, phenoxy group or straight or branched C 1-C 7Alkyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R wherein 3Be aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 3,-CO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
Wherein X is O or NH; With
Wherein n is the integer of 0-5, comprises 0 and 5.
2. the chemical compound of claim 1, wherein R 1For the optional aryl that is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, COCH 3,-CO 2R 2, straight or branched C 1-C 7Alkyl;
R wherein 3Be phenyl;
Wherein A is H; With
Wherein X is O.
3. the chemical compound of claim 2, wherein R 2Be isopropyl.
4. the chemical compound of claim 3, wherein said chemical compound has following structure:
5. the chemical compound of claim 3, wherein said chemical compound has following structure:
6. the chemical compound of claim 1, wherein R 1Be hydrogen, straight or branched C 1-C 7Alkyl; And R wherein 3Be aryl.
7. the chemical compound of claim 6, wherein R 2Be isopropyl; And A is a hydrogen.
8. the chemical compound of claim 7, wherein said chemical compound has following structure:
9. the chemical compound of claim 7, wherein said chemical compound has following structure:
Figure A028172120003C4
10. chemical compound with following structure:
Figure A028172120003C5
R wherein 1For by optional aryl or the heteroaryl that replaces of one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-OCH 3, phenoxy group, condensed Pentamethylene. base, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
R wherein 2Be straight or branched C 1-C 4Alkyl or cyclopropyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; With
Wherein n is the integer of 1-5, comprises 1 and 5.
11. the chemical compound of claim 10, wherein R 1For by the optional aryl that replaces of one or more following groups :-F ,-Cl ,-Br ,-I or straight or branched C 1-C 4Alkyl; With
Wherein A is H.
12. the chemical compound of claim 11, wherein R 2Be isopropyl; With
Wherein n is 2.
13. the chemical compound of claim 12, wherein said chemical compound has following structure:
14. the chemical compound of claim 12, wherein said chemical compound has following structure:
Figure A028172120004C2
15. the chemical compound of claim 12, wherein said chemical compound has following structure:
16. the chemical compound of claim 10, wherein R 1Be thienyl;
And wherein A is H.
17. the chemical compound of claim 16, wherein R 2Be isopropyl.
18. the chemical compound of claim 17, wherein said chemical compound has following structure:
Figure A028172120005C1
19. chemical compound with following structure:
Figure A028172120005C2
Wherein W is
Figure A028172120005C3
Or
Figure A028172120005C4
Each R wherein 1Independent is hydrogen, methyl or ethyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R wherein 3Be hydrogen, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl;
Wherein each A independently be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 3,-CO 2R 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
Wherein X is O, NR 3, CO or can not exist; And
Wherein Y is hydrogen, aryl or heteroaryl, and wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl.
20. the chemical compound of claim 19, wherein W is
Figure A028172120005C5
And wherein X is O or can exist.
21. the chemical compound of claim 20, wherein R 2Be isopropyl.
22. the chemical compound of claim 21, wherein said chemical compound has following structure:
Figure A028172120006C1
23. the chemical compound of claim 21, wherein said chemical compound has following structure:
Figure A028172120006C2
24. the chemical compound of claim 19, wherein W is
25. the chemical compound of claim 24, wherein A be-H ,-F ,-Cl ,-Br.
26. the chemical compound of claim 25, wherein R 2Be isopropyl; And A is a hydrogen.
27. the chemical compound of claim 26, wherein said chemical compound has following structure:
Figure A028172120006C4
28. chemical compound with following structure:
Figure A028172120006C5
Wherein W is
Figure A028172120007C1
Or
R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-OCH 3,-CO 2CH 3,-CF 3, phenyl, straight or branched C 1-C 7Alkyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 1,-CO 2R 1, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl or phenyl;
Wherein each B independently be-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-COR 1,-CO 2R 1,-OCH 3,-OCF 3,-CF 3, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl or aryl, phenoxy group or benzyloxy, wherein aryl, phenoxy group or benzyloxy are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-COR 1,-CO 2R 1,-OCH 3,-OCF 3,-CF 3Or straight or branched C 1-C 7Alkyl.
29. the chemical compound of claim 28, wherein W is
30. the chemical compound of claim 29, wherein R 1For hydrogen or by the optional phenyl that replaces of one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl.
31. the chemical compound of claim 30, wherein R 2Be isopropyl.
32. the chemical compound of claim 31, wherein said chemical compound has following structure:
33. the chemical compound of claim 31, wherein said chemical compound has following structure:
Figure A028172120008C1
34. chemical compound with following structure:
Figure A028172120008C2
R wherein 1Be hydrogen, straight or branched C 1-C 7Alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optional is replaced by one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-CF 3,-OCH 3, straight or branched C 1-C 3Alkyl;
R wherein 2Be straight or branched C 3-C 4Alkyl or cyclopropyl;
R wherein 3For-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CF 3,-OCH 3Perhaps straight or branched C 1-C 3Alkyl, a fluoroalkyl or Polyfluoroalkyl, or with the indole partial C 6And C 7Condensed phenyl ring;
R wherein 4For hydrogen or the optional aryl that is replaced by one or more following groups :-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-CF 3, straight or branched C 1-C 3Alkyl;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl; With
Wherein n is the integer of 2-4, comprises 2 and 4.
35. the chemical compound of claim 34, wherein R 3For-H ,-F ,-Cl ,-Br ,-I ,-CN ,-NO 2,-OCF 3Or-OCH 3With
R wherein 4For hydrogen or by the optional phenyl that replaces of one or more following groups :-F ,-Cl or-CF 3
36. the chemical compound of claim 35, wherein R 1For hydrogen or by the optional phenyl that replaces of one or more following groups :-F ,-Cl ,-Br ,-CN ,-NO 2,-CF 3,-OCH 3Perhaps straight or branched C 1-C 3Alkyl.
37. the chemical compound of claim 36, wherein R 2Be isopropyl.
38. the chemical compound of claim 37, wherein said chemical compound has following structure:
Figure A028172120009C1
39. the chemical compound of claim 37, wherein said chemical compound has following structure:
40. the chemical compound of claim 37, wherein said chemical compound has following structure:
41. chemical compound with following structure:
Each R wherein 1Independent is hydrogen or CH 3
R wherein 2Be straight or branched C 1-C 4Alkyl or cyclopropyl;
R wherein 3Be benzyl or phenyl, wherein benzyl or phenyl optional by methylene-dioxy or one or more-F or-Cl replaces;
Wherein A be-H ,-F ,-Cl ,-Br ,-CN ,-NO 2, straight or branched C 1-C 7Alkyl, a fluoroalkyl or Polyfluoroalkyl;
Wherein X is (CH 2) 2, COCH 2Or CONH.
42. the chemical compound of claim 41, wherein R 3Be phenyl by the optional replacement of one or more-F; With
Wherein A is a hydrogen.
43. the chemical compound of claim 42, wherein X is CONH.
44. the chemical compound of claim 43, wherein R 2Be methyl.
45. the chemical compound of claim 44, wherein said chemical compound has following structure:
Figure A028172120010C1
46. the chemical compound of claim 44, wherein said chemical compound has following structure:
Figure A028172120010C2
Wherein each Y independently be hydrogen or-F.
47. the chemical compound of claim 46, wherein said chemical compound has following structure:
48. the chemical compound of claim 46, wherein said chemical compound has following structure:
49. the chemical compound of claim 41, wherein R 3For by methylene-dioxy or one or more-F or-the optional benzyl that replaces of Cl.
50. the chemical compound of claim 49, wherein said chemical compound has following structure:
Figure A028172120011C2
Wherein each Y independently be hydrogen or-F.
51. the chemical compound of claim 50, wherein said chemical compound has following structure:
52. the chemical compound of claim 1 to 51, wherein said chemical compound are the chemical compound of enantiomeric pure.
53. the chemical compound of claim 1 to 51, described chemical compound are the chemical compound of diastereisomericallypure pure.
54. the chemical compound of claim 52 and 53, described chemical compound are the chemical compound of the pure and mild diastereisomericallypure pure of enantiomer isomer.
55. a Pharmaceutical composition, described Pharmaceutical composition comprise in the claim 1 to 51 of therapeutic dose each chemical compound and pharmaceutically acceptable carrier.
56. the Pharmaceutical composition of claim 55, the consumption of wherein said chemical compound is the about 500mg of about 0.01mg-.
57. the Pharmaceutical composition of claim 56, the consumption of wherein said chemical compound is the about 60mg of about 0.1mg-.
58. the Pharmaceutical composition of claim 57, the consumption of wherein said chemical compound is the about 20mg of about 1mg-.
59. the Pharmaceutical composition of claim 55, wherein said carrier are liquid, described compositions is a solution.
60. the Pharmaceutical composition of claim 55, wherein said carrier are solid, described compositions is a tablet.
61. the Pharmaceutical composition of claim 55, wherein said carrier are gel, described compositions is a suppository.
62. a method for preparing Pharmaceutical composition, described method comprise each chemical compound in the claim 1 to 51 of treatment effective dose is mixed with pharmaceutically acceptable carrier.
63. a treatment suffers from the patient's who is selected from following disease method: depression, anxiety neurosis, urinary incontinence or obesity, this method comprise in the claim 1 to 51 that gives described patient treatment effective dose each chemical compound.
64. the method for claim 63, wherein said treatment effective dose is between the about 1000mg of about 0.03-every day.
65. the method for claim 64, wherein said treatment effective dose is between the about 300mg of about 0.30-every day.
66. the method for claim 65, wherein said treatment effective dose is between the about 100mg of about 1.0-every day.
67. the method for claim 63, wherein said disease are depression.
68. the method for claim 63, wherein said disease are anxiety neurosis.
69. the method for claim 63, wherein said disease are obesity.
70. the method for claim 63, wherein said disease are urinary incontinence.
71. a method that alleviates weight in patients, this method comprise in the claim 1 to 51 that gives the amount that the patient effectively alleviates weight in patients each chemical compound.
72. a treatment suffers from the patient's of depression method, this method comprises in the claim 1 to 51 of the amount that gives the depression that the patient effectively treats the patient each chemical compound.
73. a treatment suffers from the patient's of anxiety neurosis method, this method comprises in the claim 1 to 51 of the amount that gives the anxiety neurosis that the patient effectively treats the patient each chemical compound.
74. a method that alleviates the urinary incontinence that the patient causes owing to the bladder hyperkinesia, this method comprise in the claim 1 to 51 of the amount that gives the urinary incontinence that the patient effectively alleviates the patient each chemical compound.
74. the method that the slimming patient of needs is carried out obesity control, this method comprise in the claim 1 to 51 that gives the amount that the patient effectively alleviates weight in patients each chemical compound.
75. the method that the patient through fat-reducing is carried out obesity control, this method comprise in the claim 1 to 51 that gives the amount that the patient effectively keeps its existing amount of losing weight each chemical compound.
76. treatment patient's bladder hyperactive method, this method comprise in the claim 1 to 51 that gives the hyperactive amount of bladder that the patient effectively treats the patient each any chemical compound.
78. a method for the treatment of patient disease, wherein patient's symptom can be by alleviating with the MCH1 antagonist for treating, and wherein the MCH1 antagonist is each a chemical compound in the claim 1 to 51.
79. a method that alleviates the symptom of patient disease, this method comprise the MCH1 antagonist of the amount that gives the effective mitigation symptoms of patient, wherein the MCH1 antagonist is each a chemical compound in the claim 1 to 51.
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