CN101910155A

CN101910155A - Be used for the treatment of biphenyl derivatives with histamine-obstacle that the H3 receptor modulators is relevant as histamine-H3 receptor modulators

Info

Publication number: CN101910155A
Application number: CN2008801234112A
Authority: CN
Inventors: 文森特·J·桑托拉; 乔纳森·A·科维尔; 斯科特·A·埃斯特拉达; 贾森·B·伊巴拉; 艾伯特·S·伦; 杰弗里·A·舒尔茨; 格雷姆·森普尔; 布赖恩·M·史密斯; 杰弗里·史密斯; 迈克尔·I·温豪斯
Original assignee: Arena Pharmaceuticals Inc
Current assignee: Arena Pharmaceuticals Inc
Priority date: 2007-10-30
Filing date: 2008-10-29
Publication date: 2010-12-08
Also published as: AU2008319310A1; JP2011502122A; EP2217592A1; WO2009058300A1; CA2702320A1

Abstract

The present invention discloses biphenyl derivatives and the pharmaceutical composition thereof of regulating the active formula of H3 Histamine Receptors (Ia).The compounds of this invention and pharmaceutical composition thereof relate to the method that is used for the treatment of histamine H 3-associated disorders, and described histamine H 3-associated disorders is for example cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the for example narcolepsy of obstacle of keeping alert while in bed, syndrome in shifts, sleepy as the pharmacotherapy side effect, help watchful maintenance that task finishes etc., cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea etc., attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, allergic response in the upper respiratory tract, rhinallergosis, nasal congestion, dull-witted, alzheimer's disease, pain etc.

Description

Be used for the treatment of biphenyl derivatives with histamine-obstacle that the H3 receptor modulators is relevant as histamine-H3 receptor modulators

Technical field

The present invention relates to regulate some formulas (Ia) compound and the pharmaceutical composition thereof of histamine H 3-receptor active.The compounds of this invention and pharmaceutical composition thereof relate to the method that is used for the treatment of histamine H 3-associated disorders, for example cognitive disorder (cognitive disorder), epilepsy (epilepsy), cerebral trauma (brain trauma), dysthymia disorders (depression), obesity (obesity), the for example narcolepsy (narcolepsy) of obstacle (disorder of sleep and wakefulness) of keeping alert while in bed, syndrome (shift-work syndrome) in shifts, sleepy (drowsiness as a side effect from a medication) as the pharmacotherapy side effect, help watchful maintenance (maintenance of vigilance to aid in completion of task) that task finishes etc., cataplexy (cataplexy), hypersomnia (hypersomnia), drowsiness syndrome (somnolence syndrome), jet lag (jet lag), sleep apnea (sleep apnea) etc.; Attention deficit companion hyperkinetic syndrome (attention deficit hyperactivity disorder, ADHD), the allergic response (allergic response in the upper airway) in the schizophrenia (schizophrenia), transformation reactions (allergy), the upper respiratory tract, rhinallergosis (allergic rhinitis), nasal congestion (nasal congestion), dull-witted (dementia), alzheimer's disease (Alzheimer ' s disease), pain (pain) etc.

Summary of the invention

One aspect of the present invention is contained some biphenyl derivatives and pharmaceutical salts, solvate and the hydrate of the formula of being selected from (Ia) compound:

Wherein:

Ring A be optional be substituted with one, two or three are selected from C ₁-C ₆The substituent heterocyclic radical of alkyl and oxo (oxo); Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent;

R ¹Be H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl or halogen;

R ²Be H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl or halogen;

R ³Be H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl or halogen;

R ⁴Be H or C ₁-C ₄Alkyl; And

N is 0,1 or 2.

One aspect of the present invention relates to the method for treatment histamine H 3-acceptor associated disorders in individuality, comprises The compounds of this invention or its pharmaceutical composition to the described individual drug treatment significant quantity that these needs are arranged.

One aspect of the present invention relates to the method for the treatment of histamine H 3-acceptor associated disorders, and described histamine H 3-acceptor associated disorders is selected from allergic response, rhinallergosis, nasal congestion, dementia, alzheimer's disease and the pain in cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the obstacle of keeping alert while in bed, narcolepsy, cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea etc., attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, the upper respiratory tract.

One aspect of the present invention relates to the method for the treatment of the obstacle of keeping alert while in bed.

One aspect of the present invention relates to the method for the treatment of cognitive disorder.

One aspect of the present invention relates to the method for the treatment of cataplexy.

One aspect of the present invention relates to the method for inducing awakening.

One aspect of the present invention relates to the method for the treatment of pain.

One aspect of the present invention relates to The compounds of this invention and is used for the treatment of purposes in the medicine of histamine H 3-acceptor associated disorders in preparation.

One aspect of the present invention relates to The compounds of this invention and is used for the treatment of purposes in the medicine that is selected from following obstacle in preparation: cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the obstacle of keeping alert while in bed, narcolepsy, cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea etc., attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, allergic response in the upper respiratory tract, rhinallergosis, nasal congestion, dull-witted, alzheimer's disease and pain.

One aspect of the present invention relates to The compounds of this invention and is used for the treatment of purposes in the medicine of the obstacle of keeping alert while in bed in preparation.

One aspect of the present invention relates to The compounds of this invention and is used for the treatment of purposes in the medicine of cognitive disorder in preparation.

One aspect of the present invention relates to The compounds of this invention and is used for the treatment of purposes in the medicine of cataplexy in preparation.

One aspect of the present invention relates to The compounds of this invention is used for inducing the medicine of awakening in preparation purposes.

One aspect of the present invention relates to The compounds of this invention and is used for the treatment of purposes in the medicine of pain in preparation.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method by the therapy for treating human or animal body.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method for treatment histamine H 3-acceptor associated disorders.

One aspect of the present invention relates to The compounds of this invention, and it is used in treatment and is selected from the method for following histamine H 3-acceptor associated disorders: allergic response, rhinallergosis, nasal congestion, dementia, alzheimer's disease and pain in cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the obstacle of keeping alert while in bed, narcolepsy, cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea, attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, the upper respiratory tract.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method for the treatment of the obstacle of keeping alert while in bed.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method for treatment cognitive disorder.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method for treatment cataplexy.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method for inducing awakening.

One aspect of the present invention relates to The compounds of this invention, and it is used in the method for treatment pain.

One aspect of the present invention relates to the compound that is used to prepare composition, comprises The compounds of this invention is mixed with pharmaceutical carrier.

Carry out along with this patent is disclosed, these and other aspect that this paper discloses will be stated in more detail.

Description of drawings

Fig. 1 demonstration is used for preparing two kinds of exemplary process that are used in the synthetic intermediate of The compounds of this invention.First method comprises reduction arylamino acid derivative, uses the amino alcohol of triphosgene cyclisation gained then, obtains the cyclic carbamate that 4-replaces.Second method comprises reduction arylamino ketone derivatives, uses the amino alcohol of triphosgene cyclisation gained then, obtains 5-and replaces the De oxazolidone.

Fig. 2 demonstration is introduced substituent R on the nitrogen of heterocycle (ring A) ⁵Two kinds of exemplary process.These two kinds of methods all are included in and make cyclic carbamate and alkyl derivative or alkoxy-alkyl derivative reaction under the alkali existence.Described step can be carried out before or after biphenyl partly forms.

The general of Fig. 3 display type (Ia) compound synthesized.First step is with trialkyl borate the aryl halide derivative to be changed into boric acid in the presence of alkali.Next, utilize the catalytic coupling of palladium to form the biphenyl part.Then, remove silicomethane protecting group and replace with leavings group.At last, react making between biphenyl derivatives and the cyclic amine in the presence of the alkali, obtain formula (Ia) molecule.

Fig. 4 demonstration is used for preparing the trifluoromethanesulfonic acid aryl ester that is used in the catalytic linked reaction of palladium.At first, utilize one kettle way (in one pot), described amine to be changed into t-butyl carbamate with the esterification of hydroxyphenyl amino acid derivative.Ester functional group is reduced, and alcohol is changed into cyclic carbamate with thionyl chloride.At last, use trifluoromethanesulfanhydride anhydride and alkali that phenolic groups is changed into the trifluoromethanesulfonic acid ester group.

Fig. 5 shows the general method that is used for preparation formula (Ia) molecule, and the right hand side of wherein said molecule is (R)-2-crassitude.At first, in the presence of alkali, make (R)-2-crassitude and use leavings group activatory arylalkyl derivatives reaction.Gained (R)-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl halogenide is changed into aryl boric acid, and carry out the catalytic coupling of palladium, obtain final compound.

Fig. 6 shows the method that is used for preparing the trifluoromethanesulfonic acid aryl ester that is used in the catalytic linked reaction of palladium.Make the reaction of phenol derivatives and 2-hippuric acid obtain aryl amino acid earlier.With this aryl amino acid esterification, and Boc (tertbutyloxycarbonyl) protection, be reduced into alcohol then.Carry out cyclisation by reacting, and gained De oxazolidinyl-phenol conversion is become the trifluoromethanesulfonic acid aryl ester with trifluoromethanesulfanhydride anhydride with thionyl chloride.

The general of Fig. 7 display type (Ia) compound synthesized.With 2-(4-hydroxy phenyl) acetogenin esterification, be reduced into glycol then.In the presence of trifluoromethanesulfanhydride anhydride, introduce the tetramethyleneimine part by making the reaction of primary alconol and secondary amine, phenol carry out trifluoromethanesulfonic acidization simultaneously.This triflate is coupled to boric acid derivatives, and described boric acid derivatives itself is by another kind of trifluoromethanesulfonic acid aryl ester or aryl halide preparation.

Fig. 8 shows three kinds of methods that are used for preparing the intermediate that is used in the preparation The compounds of this invention.In the first method in these methods, in the presence of Vanadium Pentoxide in FLAKES and methylsulfonic acid, make the reaction of 5-oxo-pyrrolidine-2-formic acid and methyl-phenoxide, obtain 5-(4-p-methoxy-phenyl) pyrrolidin-2-one, described 5-(4-p-methoxy-phenyl) pyrrolidin-2-one is then changed into triflate.Second method in these methods comprises that the cyclisation by the aluminum oxide mediation changes into 4-(4-chloro-phenyl-) pyrrolidin-2-one with 4-amino-3-(4-chloro-phenyl-) butanoic acid derivative.At last, can by handle with N-chloro-succinimide phenol derivatives then trifluoromethanesulfonic acidization prepare the trifluoromethanesulfonic acid chloro aryl ester intermediate that is used in the preparation chlorinated compound of the present invention.

Fig. 9 shows that the representativeness that is used in the trifluoromethanesulfonic acid aryl ester intermediate in the The compounds of this invention preparation is synthetic.With 2-(4-hydroxy phenyl) acetogenin esterification, protect with right-methoxy-benzyl group Pyrogentisinic Acid then.Change into leavings group then with the ester reduction, and with primary alconol, described leavings group is obtained tertiary amine by the pyrrolidin derivatives displacement.Use TFA (trifluoroacetic acid) that PMB (right-methoxy-benzyl) group is removed, and phenol conversion is become triflate then.

Figure 10 shows that the representativeness that is used in the trifluoromethanesulfonic acid aryl ester intermediate in the The compounds of this invention preparation is synthetic.In first step, 2-(4-p-methoxy-phenyl) acetogenin is reduced into corresponding primary alconol.Next, activate free hydroxyl group with leavings group, described leavings group is replaced with secondary amine.Then, methoxyl group is removed, and free-phenol is changed into triflate with boron tribromide.

The general of Figure 11 display type (Ia) compound synthesized, and wherein encircling A is 2-oxo-1,3-dioxolane-4-base.At first, with 1-(4-bromophenyl) ethane-1, the 2-glycol changes into corresponding dimethyl dioxolane, uses palladium catalyst to be coupled to the aryl boric acid derivative then.Then by described glycol being reformed (reform) with acid treatment, and subsequently with 1,1 '-carbonyl dimidazoles (CDI) reaction, obtain required heterocycle.

Figure 12 shows three kinds of general methods that are used for preparing the intermediate that is used in the preparation The compounds of this invention.First method is handled the gained oxyamine with CDI then by reduction aryl-3-oxypropionitrile derivative and is provided 2-oxo-1,3-oxazine alkane (oxazinane)-6-base.Second method provides 2-oxo-1 by making 1-amino-3-hydroxypropyl aryl derivatives and CDI reaction, 3-oxazine alkane-4-base intermediate.The third method is in the following way by 1, and 2-dihydroxy ethyl aryl derivatives provides 5-oxo morpholine-3-base intermediate via secondary amine, and described mode is handled with ethyl chloroacetate in the presence of sodium hydride then at first using sulfuric acid and acetonitrile treatment.

Figure 13 shows the general method that is used for preparation formula (Ia) compound, and wherein encircling A is 2-oxo-1 of the present invention, 3-dioxolane-4-base.The catalytic coupling of the palladium of 4-hydroxymethyl aryl halide and boric acid derivatives obtains the biphenyl intermediate, and described intermediate is oxidized, and in the presence of LDA with acetic acid ethyl reaction.The gained ester is reduced into 1, the 3-glycol, and by changing into 2-oxo-1,3-diox-4-radical derivative with the CDI processing.

Embodiment

Definition

With consistent, following definitions is used in this patent document in the whole text for clear.

Term " agonist " mean with acceptor for example the H3 Histamine Receptors interact and activate described acceptor and cause the characteristic physiology of described acceptor or part (moiety) that pharmacology is replied.For example, when described part is replied in the active cells with described receptors bind, perhaps strengthen the combination of GTP to film.

Term " antagonist " means as the lower section, described part with agonist (for example, endogenic ligand) identical site competitiveness is in conjunction with described acceptor, do not reply but do not activate in the cell of replying in the cell that the activated form by described acceptor causes and can suppress thus to be caused by agonist or partial agonist.Under the situation that lacks agonist or partial agonist, antagonist does not reduce in the baseline cell replys.

Term " contact " means puts specified part together, no matter is in vitro system or in vivo in the system.Therefore, histamine H 3 receptor and The compounds of this invention " are contacted " comprise to the individuality with histamine H 3 receptor (being preferably the mankind) administration The compounds of this invention and for example The compounds of this invention is incorporated in the following sample, cell product that described sample contained or purer goods (more purifiedpreparation) contain histamine H 3 receptor.

Be used interchangeably when term " need treatment " and term " have this needs " and relate to treatment, it means by the care-giver (for example is doctor, nurse, nurse practitioner etc. with regard to the mankind; With regard to animal (comprising non-human mammal) for the animal doctor) the relevant individuality or the animal of making need treat the judgement that maybe will benefit from treatment.This judgement is made based on various factors, and described factor is in care-giver's expertise scope and comprise relevant individuality or animal because disease, illness or the obstacle of available The compounds of this invention treatment and knowledge sick or will be sick.Therefore, The compounds of this invention can use by protectiveness or preventative mode; Or The compounds of this invention can be used for alleviating, suppress or improving described disease, illness or obstacle.

Term " individuality " means any animal and comprises Mammals, preferred mouse, rat, other rodent, rabbit, dog, cat, pig, ox, sheep, horse or primate, and most preferably be the mankind.

Term " inverse agonist " means the endogenous form that is bonded to described acceptor or is bonded to the part of the composition activated form of described acceptor; and described part suppresses to reply (baseline intracellular response) in the baseline cell that the activated form by described acceptor causes; make it be lower than observed active normal baseline level when lacking agonist or partial agonist, or reduce the combination of GTP film.Preferably, reply with the baseline when lacking inverse agonist and to compare, reply in the presence of inverse agonist in the described baseline cell and be reduced at least 30%, more preferably be reduced at least 50%, and most preferably be reduced at least 75%.

Term " regulate (modulate or modulating) " mean quantity, the quality of concrete active, function or molecule, reply or effect aspect increase or reduce.

Term " pharmaceutical composition " means and comprises at least a composition of active components, described activeconstituents includes but not limited to salt, solvate and the hydrate of The compounds of this invention, and described thus composition can hold out against relevant concrete effectively result's research in Mammals (such as but not limited to the mankind).Those skilled in the art should understand that and know and be suitable for determining that whether activeconstituents needs based on the technician and have required effective result's a technique means.

Term " treatment significant quantity " means and cause biological response or the medical active compound of replying or the amount of medicine in tissue, system, animal, individuality or the mankind, to reply be that researchist, animal doctor, doctor or other clinicists seek for described biological response or medicine, and it comprises following one or more:

(1) preventing disease for example may easily suffered from described disease, illness or obstacle but not experience as yet or show prevention described disease, illness or obstacle in the individuality of the pathology of described disease or symptom;

(2) suppress disease, for example suppress described disease, illness or obstacle (promptly stoping further developing of described pathology and/or symptom) experiencing or showing in the pathology of described disease, illness or obstacle or the semeiologic individuality; With

(3) alleviate disease, for example alleviate described disease, illness or obstacle (promptly reversing described pathology and/or symptom) experiencing or showing in the pathology of described disease, illness or obstacle or the semeiologic individuality.

Chemical group, chemical part or chemical based

Term " C ₁-C ₆Alkoxyl group " mean the C as herein defined that directly links to each other with Sauerstoffatom ₁-C ₆Alkyl is 1 to 5 carbon in some embodiments, and some embodiments are 1 to 4 carbon, and some embodiments are 1 to 3 carbon, and some embodiments are 1 to 2 carbon.Example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, isobutoxy, sec-butoxy etc.

Term " C ₁-C ₆Alkyl " mean the straight or branched carbon back that contains 1 to 6 carbon.Some embodiments are 1 to 5 carbon.Some embodiments are 1 to 4 carbon.Some embodiments are 1 to 3 carbon.Some embodiments are 1 to 2 carbon.Some embodiments are 1 carbon.The example of alkyl include but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, tert-pentyl, neo-pentyl, 1-methyl butyl [that is ,-CH (CH ₃) CH ₂CH ₂CH ₃], the 2-methyl butyl [that is ,-CH ₂CH (CH ₃) CH ₂CH ₃], n-hexyl etc.

Term " C ₁-C ₄Alkyl " mean the straight or branched carbon back that contains 1 to 4 carbon.Some embodiments are 1 to 3 carbon.Some embodiments are 1 or 2 carbon.Some embodiments are 1 carbon.C ₁-C ₄The example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.

Term " aryl " means the aromatics cyclic group that contains 6 to 10 carbon.Example comprises phenyl and naphthyl.

Term " halogen " or " halo " mean fluorine, chlorine, bromine or iodine group.

Term " heterocyclic (heterocyclic) " or " heterocyclic radical (heterocylyl) " mean the non-aromatic monocyclic that contains 3 to 8 annular atomses, wherein at least one annular atoms is the heteroatoms of heteroatoms or replacement, described heteroatoms be selected from but for example be not limited to O, S, S (=O), S (=O) ₂And NH, wherein said N is as described herein to be optionally substituted.In some embodiments, the optional oxo that is substituted with of described ring carbon atom, thus form carbonyl group.In some embodiments, the optional sulfo-(thioxo) that is substituted with of ring carbon atom, thus form thiocarbonyl (thiocarbonyl group).In some embodiments, the optional C that is substituted with of described ring carbon atom ₁-C ₆Alkyl.In some embodiments, the optional C that is substituted with of described theheterocyclic nitrogen atom ₁-C ₆Alkyl.In some embodiments, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxyl group.In some embodiments, ring carbon is substituted with C ₁-C ₆Alkyl.In some embodiments, ring nitrogen is substituted with C ₁-C ₆Alkyl.In some embodiments, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxyl group.

In some embodiments, described heterocyclic group is 3-, 4-, 5-, 6-or 7-unit ring.The example of heterocyclic group includes but not limited to aziridine-2-base, azetidine-2-base, azetidine-3-base, piperidines-2-base, piperidines-3-base, piperidin-4-yl, morpholine-2-Ji, morpholine-3-base, piperazine-2-base, piperazine-3-base, tetramethyleneimine-2-base, tetramethyleneimine-3-base, [1,3]-dioxolane-2-base, azepan-2-base, azepan-3-base, azepan-4-base, tetrahydrofuran (THF)-2-base, tetrahydrofuran (THF)-3-base, 2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base, 4-Yang Dai oxazolidine-2-base, 4-Yang Dai oxazolidine-5-base, 5-Yang Dai oxazolidine-2-base, 5-Yang Dai oxazolidine-4-base, 2-oxo-pyrrolidine-3-base, 2-oxo-pyrrolidine-4-base, 2-oxo-pyrrolidine-5-base, 3-oxo-pyrrolidine-2-base, 3-oxo-pyrrolidine-4-base, 3-oxo-pyrrolidine-5-base, 2-oxo-imidazole alkane-4-base, 4-oxo-imidazole alkane-2-base, 4-oxo-imidazole alkane-5-base, 2-oxo-piperidine-3-base, 2-oxo-piperidine-4-base, 2-oxo-piperidine-5-base, 2-oxo-piperidine-6-base, 3-oxo-piperidine-2-base, 3-oxo-piperidine-4-base, 3-oxo-piperidine-5-base, 3-oxo-piperidine-6-base, 4-oxo-piperidine-2-base, 4-oxo-piperidine-3-base, 2-oxo morpholine-3-base, 2-oxo morpholine-5-base, 2-oxo morpholine-6-base, 3-oxo morpholine-2-Ji, 3-oxo morpholine-5-base, 3-oxo morpholine-6-base, 2-oxo-1,3-oxazine alkane-4-base (2-oxo-1,3-oxazinan-4-yl), 2-oxo-1,3-oxazine alkane-5-base, 2-oxo-1,3-oxazine alkane-6-base, 4-oxo-1,3-oxazine alkane-2-base, 4-oxo-1,3-oxazine alkane-5-base, 4-oxo-1,3-oxazine alkane-6-base, 5-oxo-1,3-oxazine alkane-2-base, 5-oxo-1,3-oxazine alkane-4-base, 5-oxo-1,3-oxazine alkane-6-base, 6-oxo-1,3-oxazine alkane-2-base, 6-oxo-1,3-oxazine alkane-4-base, 6-oxo-1,3-oxazine alkane-5-base etc.

In some embodiments, described heterocyclic radical is 5-or 6-unit heterocyclic group.The example of 5-or 6-unit heterocyclic radical includes but not limited to Yang Dai oxazolidinyl, oxo-pyrrolidine base, oxo-imidazole alkyl, oxo-piperidine base, oxo morpholinyl and oxo-1, and 3-oxazine alkyl (oxo-1,3-oxazinanyl).

In some embodiments, the example of 5-or 6-unit heterocyclic group includes but not limited to 2-Yang Dai oxazolidinyl, 2-oxo-pyrrolidine base, 2-oxo-imidazole alkyl, 2-oxo-1,3-oxazine alkyl, 2-oxo-piperidine base, 3-oxo morpholinyl etc., as shown in table 1.

Table 1

Should be understood that, except as otherwise noted, as being allowed by each representative structure formula, the arbitrary heterocyclic group shown in the table 1 can be on any obtainable ring carbon keyed jointing.

In some embodiments, the example of 5-or 6-unit heterocyclic group includes but not limited to 2-Yang Dai oxazolidinyl, 2-oxo-1,3-oxazine alkyl etc.

In some embodiments, the example of 5-or 6-unit heterocyclic group includes but not limited to 2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base, 2-oxo-1,3-oxazine alkane-4-base, 2-oxo-1,3-oxazine alkane-5-base, 2-oxo-1,3-oxazine alkane-6-base etc.

In some embodiments, the example of 5-or 6-unit heterocyclic group includes but not limited to oxo-1,3-dioxolanyl, oxo-1,3-alkyl dioxin etc.

In some embodiments, the example of 5-or 6-unit heterocyclic group includes but not limited to 2-oxo-1,3-dioxolanyl, 2-oxo-1, and 3-alkyl dioxin etc., as shown in table 2.

Table 2

In some embodiments, the example of 5-or 6-unit heterocyclic group includes but not limited to 2-oxo-1,3-dioxolane-4-base, 2-oxo-1,3-diox-4-base etc.

Term used herein " hydrate " is meant The compounds of this invention or its salt, and it also comprises the water by the stoichiometry of non-covalent intermolecular forces bonding or nonstoichiometry amount.

Term " oxo " means substituting group=O, and therefore, as a result of, when carbon was replaced by " oxo " group, the new group that is obtained together by carbon and oxo was a carbonyl.

Term used herein " solvate " is meant The compounds of this invention or its salt, and it also comprises the stoichiometric or non-stoichiometric solvent by non-covalent intermolecular forces bonding.Preferred solvent is a volatility, nontoxic and/or be acceptable for be administered to the people with trace.

The compounds of this invention:

One aspect of the present invention relates to suc as formula some compounds shown in (Ia) and pharmaceutical salts, solvate and hydrate:

Wherein:

R ¹, R ², R ³, R ⁴, ring A and n have as this paper above with hereinafter described identical definition.

Should be understood that for clear, features more of the present invention of describing also can be in conjunction with providing in single embodiment in the context of the embodiment of separating.Conversely, for simplicity, the of the present invention various features of describing in the context of single embodiment also can separately provide or close with the subgroup of any appropriate and provide.Embodiment (relates to by for example being included in general chemical formula described herein (Ia) variable in (for example, R ¹, R ², R ³, R ⁴, ring A and n) chemical group of expression) all combinations comprised clearly in the present invention, just quoted clearly separately with various combinations as every kind, the degree that reaches is that described combination comprises the compound that obtains stable compound (that is, can be separated, characterize and test at biological activity compound).In addition, all subgroups of listed chemical group are closed in the embodiment of describing described variable, and all subgroups of purposes described herein and medical indications are closed also and are comprised clearly by the present invention, just close, and the subgroup of purposes and medical indications is combined in this paper and is quoted separately and clearly as every kind of chemical group and various subgroups.

" replacement " at least one hydrogen atom of showing chemical group is replaced by non-hydrogen substituting group or group as used herein, and described non-hydrogen substituting group or group can be unit price or divalence.When described substituting group or group are divalence, be interpreted as that then this group further is substituted with another substituting group or group.When the chemical group of this paper is " replacement ", it can have high to the full valency (full valance) that replaces; For example, methyl can be replaced by 1,2 or 3 substituting group, and methylene radical can replace by 1 or 2 substituting group, and phenyl can be replaced by 1,2,3,4 or 5 substituting group, and naphthyl can be by 1,2,3,4,5,6 or 7 substituting group replacement etc.Equally, " being substituted with one or more substituting groups " refers to the replacement of following group, and described group has a paramount substituent sum that allows by natural rule to described group of substituting group.In addition, when group is substituted with a more than group, a described more than group can be identical or they can be different.

The compounds of this invention also can comprise tautomeric form, for example keto-enol tautomerism body etc.Tautomeric form can be in the balance, or is locked into a kind of form by suitable replacement by three-dimensional.Should be understood that different tautomeric forms are in the scope of The compounds of this invention.

The compounds of this invention also can be included in all isotropic substances of the atom that occurs in intermediate and/or the final compound.Isotropic substance comprises having the same atoms number but those atoms of different mass number.For example, the isotropic substance of hydrogen comprises deuterium and tritium.

Be understood that and be understood that formula (Ia) compound and relevant chemical formula thereof may have one or more chiral centres, and therefore can be used as the existence of enantiomer and/or diastereomer.The present invention is understood that to extend and comprises all described enantiomers, diastereomer and their mixture, includes but not limited to racemic modification.Be understood that demonstration is arranged except as otherwise noted or in addition, the chemical formula that uses in the whole text in formula (Ia) compound and the disclosure is intended to represent all independent enantiomers and their mixture.

Radicals R ¹

In some embodiments, R ¹Be selected from H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

In some embodiments, R ¹Be selected from C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

In some embodiments, R ¹Be selected from methoxyl group, methyl, chlorine and fluorine.

In some embodiments, R ¹Be H.

In some embodiments, R ¹Be C ₁-C ₆Alkoxyl group.

In some embodiments, R ¹Be C ₁-C ₆Alkyl.

In some embodiments, R ¹Be halogen.

Radicals R ²

In some embodiments, R ²Be selected from H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

In some embodiments, R ²Be selected from C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

In some embodiments, R ²Be selected from methoxyl group, methyl, chlorine and fluorine.

In some embodiments, R ²Be H.

In some embodiments, R ²Be C ₁-C ₆Alkoxyl group.

In some embodiments, R ²Be C ₁-C ₆Alkyl.

In some embodiments, R ²Be halogen.

Radicals R ³

In some embodiments, R ³Be selected from H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

In some embodiments, R ³Be selected from C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

In some embodiments, R ³Be selected from methoxyl group, methyl, chlorine and fluorine.

In some embodiments, R ³Be H.

In some embodiments, R ³Be C ₁-C ₆Alkoxyl group.

In some embodiments, R ³Be C ₁-C ₆Alkyl.

In some embodiments, R ³Be halogen.

Radicals R ⁴

In some embodiments, R ⁴Be selected from H or C ₁-C ₄Alkyl.

In some embodiments, R ⁴Be H.

In some embodiments, R ⁴Be C ₁-C ₄Alkyl.

In some embodiments, R ⁴Be methyl.

Ring A

In some embodiments, ring A is substituted with one and is selected from C for optional ₁-C ₆The substituent heterocyclic radical of alkyl and oxo; Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is substituted with two and is selected from C for optional ₁-C ₆The substituent heterocyclic radical of alkyl and oxo; Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is substituted with three and is selected from C for optional ₁-C ₆The substituent heterocyclic radical of alkyl and oxo; Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is substituted with one or two and is selected from C for optional ₁-C ₆The substituent heterocyclic radical of alkyl and oxo; Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent.

In some embodiments, ring A for optional be substituted with one, two or three are selected from C ₁-C ₆The substituent heterocyclic radical of alkyl and oxo; Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from Yang Dai oxazolidinyl, oxo-pyrrolidine base, oxo-imidazole alkyl, oxo-piperidine base, oxo morpholinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from Yang Dai oxazolidinyl, oxo-pyrrolidine base, oxo-imidazole alkyl, oxo-piperidine base, oxo morpholinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with the substituting group that is selected from methyl, sec.-propyl and 2-methoxy ethyl.

In some embodiments, ring A is selected from Yang Dai oxazolidinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from Yang Dai oxazolidinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with the substituting group that is selected from methyl, sec.-propyl and 2-methoxy ethyl.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidinyl, 2-oxo-pyrrolidine base, 2-oxo-imidazole alkyl, 2-oxo-piperidine base, 3-oxo morpholinyl and 2-oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidinyl, 2-oxo-pyrrolidine base, 2-oxo-imidazole alkyl, 2-oxo-piperidine base, 3-oxo morpholinyl and 2-oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with the substituting group that is selected from methyl, sec.-propyl and 2-methoxy ethyl.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidinyl and 2-oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidinyl and 2-oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with the substituting group that is selected from methyl, sec.-propyl and 2-methoxy ethyl.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base; Wherein each ring A chooses wantonly and is substituted with the substituting group that is selected from methyl, sec.-propyl and 2-methoxy ethyl.

In some embodiments, ring A is selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The Yang Dai oxazolidinyl of alkyl substituent; Wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The oxo-pyrrolidine base of alkyl substituent; Wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The oxo-imidazole alkyl of alkyl substituent; Wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The oxo-piperidine base of alkyl substituent; Wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The oxo morpholinyl of alkyl substituent; Wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The oxo of alkyl substituent-1,3-oxazine alkyl; Wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional substituent Yang Dai oxazolidinyl that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent oxo-pyrrolidine base that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent oxo-imidazole alkyl that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent oxo-piperidine base that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent oxo morpholinyl that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional oxo-1 that is selected from methyl, sec.-propyl and 2-methoxy ethyl, 3-oxazine alkyl of being substituted with.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-Yang Dai oxazolidinyl of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-oxo-pyrrolidine base of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-oxo-imidazole alkyl of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-oxo-piperidine base of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 3-oxo morpholinyl of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-oxo-1 of alkyl substituent, 3-oxazine alkyl; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional substituent 2-Yang Dai oxazolidinyl that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 2-oxo-pyrrolidine base that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 2-oxo-imidazole alkyl that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 2-oxo-piperidine base that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 3-oxo morpholinyl that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 2-oxo-1 that is selected from methyl, sec.-propyl and 2-methoxy ethyl, 3-oxazine alkyl of being substituted with.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-Yang Dai oxazolidine-4-base of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-Yang Dai oxazolidine-5-base of alkyl substituent; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional C that is substituted with ₁-C ₆The 2-oxo-1 of alkyl substituent, 3-oxazine alkane-4-base; Wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is the optional substituent 2-Yang Dai oxazolidine-4-base that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 2-Yang Dai oxazolidine-5-base that is selected from methyl, sec.-propyl and 2-methoxy ethyl that is substituted with.

In some embodiments, ring A is the optional substituent 2-oxo-1 that a is selected from methyl, sec.-propyl and 2-methoxy ethyl, 3-oxazine alkane-4-base of being substituted with.

In some embodiments, ring A is 2-Yang Dai oxazolidine-4-base.

In some embodiments, ring A is 3-methyl-2-Yang Dai oxazolidine-4-base.

In some embodiments, ring A is 3-sec.-propyl-2-Yang Dai oxazolidine-4-base.

In some embodiments, ring A is 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base.

In some embodiments, ring A is 2-Yang Dai oxazolidine-5-base.

In some embodiments, ring A is a 2-oxo-1,3-oxazine alkane-4-base.

In some embodiments, ring A is selected from oxo-pyrrolidine base, oxo-1,3-dioxolanyl, oxo-1,3-alkyl dioxin, oxo morpholinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein, described C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

In some embodiments, ring A is selected from oxo-pyrrolidine base, oxo-1,3-dioxolanyl, oxo-1,3-alkyl dioxin, oxo morpholinyl and oxo-1,3-oxazine alkyl.

In some embodiments, ring A is selected from 2-oxo-pyrrolidine-4-base, 2-oxo-pyrrolidine-5-base, 2-oxo-1,3-dioxolane-4-base, 2-oxo-1,3-diox-4-base, 3-oxo morpholine-5-base and 2-oxo-1,3-oxazine alkane-6-base.

In some embodiments, ring A is 2-oxo-pyrrolidine-4-base.

In some embodiments, ring A is 2-oxo-pyrrolidine-5-base.

In some embodiments, ring A is a 2-oxo-1,3-dioxolane-4-base.

In some embodiments, ring A is a 2-oxo-1,3-diox-4-base.

In some embodiments, ring A is 3-oxo morpholine-5-base.

In some embodiments, ring A is a 2-oxo-1,3-oxazine alkane-6-base.

Variable n

In some embodiments, n is 0,1 or 2.

In some embodiments, n is 0 or 1.

In some embodiments, n is 0 or 2.

In some embodiments, n is 1 or 2.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

Combinations more of the present invention:

In some embodiments, R ¹And R ²All be H.

In some embodiments, R ¹And R ³All be H.

In some embodiments, R ²And R ³All be H.

In some embodiments, R ¹, R ²And R ³All be H.

Embodiments more of the present invention relate to formula (Ic) compound and pharmaceutical salts, solvate and hydrate:

Wherein:

R ⁴Be H or C ₁-C ₄Alkyl;

Ring A is selected from Yang Dai oxazolidinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent; And

N is 0,1 or 2.

Wherein:

R ⁴Be H or methyl;

Ring A is for being selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base; And

N is 0,1 or 2.

Embodiments more of the present invention relate to formula (Ie) compound and pharmaceutical salts, solvate and hydrate (Ie):

Wherein:

Ring A is for being selected from Yang Dai oxazolidinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent; And

N is 0,1 or 2.

Embodiments more of the present invention relate to formula (Ie) compound and pharmaceutical salts, solvate and hydrate:

Wherein:

N is 0,1 or 2.

Embodiments more of the present invention relate to formula (Ig) compound and pharmaceutical salts, solvate and hydrate:

Wherein:

N is 0,1 or 2.

Wherein:

Ring A is selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base; And

N is 0,1 or 2.

Embodiments more of the present invention relate to formula (Ii) compound and pharmaceutical salts, solvate and hydrate:

Wherein:

R ¹, R ²And R ³Independently be selected from H, C separately ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen;

Ring A is selected from Yang Dai oxazolidinyl, oxo-1,3-oxazine alkyl, oxo-pyrrolidine base, oxo-1,3-dioxolanyl, oxo-1,3-alkyl dioxin, oxo morpholinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent; And

N is 0,1 or 2.

Wherein:

R ¹, R ²And R ³Independently be selected from H, methoxyl group, methyl, chlorine and fluorine separately;

Ring A is selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base, 2-oxo-1,3-oxazine alkane-4-base, 2-oxo-pyrrolidine-4-base, 2-oxo-pyrrolidine-5-base, 2-oxo-1,3-dioxolane-4-base, 2-oxo-1,3-diox-4-base, 3-oxo morpholine-5-base and 2-oxo-1,3-oxazine alkane-6-base; And

N is 0,1 or 2.

Embodiments more of the present invention comprise each combination of one or more compounds of the group that is selected from following Table A and table B demonstration.

Table A

Table B

In addition, independent compound of the present invention and chemical classes (chemical genera), for example those compounds (comprising its diastereomer and enantiomer thereof) of listing in Table A and table B are contained all its pharmaceutical salts, solvate and particularly hydrate.

Formula of the present invention (Ia) compound can be prepared according to the relevant open source literature method that those skilled in the art use.Appear among hereinafter the work embodiment at the exemplary agents of these reactions and step.The protection and deprotection can be undertaken by step well known in the art (referring to, for example, Greene, T.W.and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 3 ^RdEdition, 1999[Wiley]; Incorporate document integral body into this paper as a reference).

Should be understood that, each compound of this paper disclosure and each diastereomer, each enantiomer and their mixture of each general formula are contained in the present invention, disclosed separately separately as them, had concrete stereochemistry ownership at each chiral carbon.By adopting separation that the known different methods of this area practitioner finishes independent isomer (for example, chirality HPLC by non-enantiomer mixture, recrystallization etc.) or the selectivity of isomer synthetic (for example, by the enantiomer selectivity synthetic etc.) separately.

Indication and prevent and/or treat method

Histamine [2-(imidazol-4 yl) ethylamine] is brought into play its physiological role by four kinds of different g protein coupled receptors (GPCR) (being called H1, H2, H3 and H4).Histamine H 3 receptor is identified first that in nineteen eighty-three definite at that time H3 acceptor is controlled the release of synthesizing of histamine and histamine (referring to Arrang et al.Nature 1983,302,832-7) as autoreceptor.At least four kinds of people's splice variants and three kinds of rat splice variants in pharmacology is measured, have attested functional activity (Passani et al., Trends in Pharmacol.Sci.2004,25,618-625).Rat histamine H 3 receptor and people's histamine H 3 receptor also demonstrate the composition activity, this means them even are not having also transducible signal under the situation of part.Histamine H 3 receptor also can be used as heteroreceptor regulate the release of (comprising serotonin, vagusstoff, Dopamine HCL and norepinephrine) of multiple other mediator (referring to Brown et al.Prog.Neurobiol.2001,63,637-672).Therefore, with regard to the part of histamine H 3 receptor, there is multiple treatment to use with regard to target, (summary is referring to Leurs et al.Nat.Rev.Drug.Discov.2005 in the effect of wherein said part performance antagonist or inverse agonist, 4,107-120 and Passani et al.Trends Pharmacol.Sci.2004,25,618-625).

Correspondingly, preclinical study has identified the multiple indication for the treatment of with histamine H 3 receptor antagonists and inverse agonist (for example The compounds of this invention) of being suitable for.Believe that the compound that this paper discloses can be used for treating and/or preventing several conditions and obstacle and alleviates its symptom.These compounds can be used for separately or be used for the treatment of and/or preventing disease and obstacle with other compound combination.Without limitation, these diseases and obstacle comprise following disease and obstacle.

Shown and to have strengthened awakening by histamine H 3 receptor antagonists (for example Lin J.S.et al.Brain Research 1990,523,325-330).This effect explanation H3 receptor antagonist can be used for keeping alert while in bed obstacle (Parmentier et al.J Neurosci.2002,22,7695-7711 and Ligneau et al.J.Pharmacol.Exp.Ther.1998,287,658-666).For example, histamine H 3 receptor antagonists and inverse agonist can be used for treating and different pathological status for example the sleep apnea drowsiness syndrome relevant with Parkinson's disease or the situation relevant with mode of life, due to for example working at night, excessively due to the work or due to the time difference the caused daytime sleepiness of sleep deprivation (referring to Passani et al., Trends Pharmacol.Sci.2004,25,618-625).Because drowsiness high popular (19-37% in the total population) and its cause the risk of operating irregularity and traffic accident, thus drowsiness be important public health problem.

Sleep apnea (being also referred to as sleep apnea) is common somnopathy, it is characterized by and breathe briefly interrupted between sleep period.These are called apneic outbreak and continue 10 seconds or longer, and take place repeatedly at All Through The Night.Part is clear-headed owing to do all one can to breathe to suffer from the people of sleep apnea, but they may be unaware of the obstacle in their sleep in the morning.Common type in the sleep apnea is obstructive sleep apneas (OSA), and it is that soft tissue relaxation owing to the throat rear portion blocks air flue thus and causes.Central sleep apnea (CSA) is owing to causing at the random of brain normal signal that breathes.The significant symptom of described obstacle is an over-drastic sleepiness in the daytime.Other symptom of sleep apnea comprises that the sleep of do not have having a rest, loud snoring (silent period is arranged after panting), sleeping, headache in early morning in the daytime, attention concentrate difficulty, irritability, forgetful, mood or behavior variation, weight increase, heart rate increase, anxiety and depression.

Although carried out research and the test in twenties years, know little about it based on the treatment that the obstructive sleep apneas is carried out of medicine.Oral administration methyl xanthine theophylline (chemically being similar to caffeine) can reduce apneic attack times, but also can produce such as palpitaition and the such side effect of insomnia.Theophylline is invalid in suffering from the adult of OSA usually, but is used for the treatment of CSA sometimes and suffers from apneic baby and children.At 2003 and 2004, reported that the particularly modern thymoleptic of some neuroactive drugs can reduce (comprising mirtazapine) incidence of obstructive sleep apneas.When other disposal can not be treated OSA fully, open medicine sometimes with treatment patient's sleepiness in the daytime or drowsiness.The scope of these medicines from stimulant for example amphetamine to anti-hypnolepsy medicine of modern times.Notice that in 2004 the use of medicine modafinil in this purposes increases.

In addition, histamine H 3 receptor antagonists and inverse agonist can for example be used for the treatment of narcolepsy (Tedford et al.Soc.Neurosci.Abstr.1999,25,460.3).Narcolepsy is a kind of neuroscience illness, its modal sleepiness (EDS), narcolepsy and REM obstacle or REM sleep obstacle excessively in the daytime of being characterized as.The principal character of narcolepsy is irresistible sleepiness excessively in the daytime (EDS), even behind competent nighttime sleep.The people that suffer from narcolepsy may be drowsy or sleeping through inappropriate when and where of being everlasting.In addition, nighttime sleep can be interrupted by frequent awakening.The classical symptom of narcolepsy comprises for example cataplexy, and described cataplexy is breaking out of muscle function forfeiture, and its scope is fallen from slight unable (for example neck or knee weakness are unable, facial muscle sagging maybe can not know speak) to health completely.Outbreak can for example be laughed by unexpected emotional reactions, indignation, be taken aback or fear cause, and sustainable several seconds to several minutes.The another kind of symptom of narcolepsy is a sleep paralysis, and it is that temporary transient can not talking maybe can not be moved when waking up.Other symptom comprise hypnagogic hallucination for example (its be when doze off, sleeping and/or (often being fearful) true to nature dreamlike experience of taking place when waking up) and automatism (described automatism appears when people's continuation activity during narcolepsy (speak, get things together etc.), but when waking up to the activity carried out less than remembering).In the daytime sleepiness, sleep paralysis and hypnagogic hallucination also occur in the philtrum of not suffering from narcolepsy, for example occur in to stand to sleep the extremely philtrum of shortage.It has been generally acknowledged that cataplexy is that narcolepsy is peculiar.

At present, getable treatment can be treated symptom but can not be treated basic reason at narcolepsy.For cataplexy and REM sleep symptom, open thymoleptic and suppress the other medicines that REM sleeps.Usually use for example following stimulant to treat drowsy: Methylphenidylacetate (Ritalin), amphetamine (Adderall), Dextrofenfluramine (Dexedrine), metamfetamine (Desoxyn), modafinil (Provigil) etc.Employed other medicines are morphine monomethyl ether and selegiline.Use clomipramine, imipramine or protriptyline to treat cataplexy, but this needs only just have in serious case.In the U.S., (gamma-hydroxybutyrate, GHB) (Xyrem) ratified to be used for the treatment of cataplexy and the excessively in the daytime sleepiness relevant with narcolepsy by food with Drug Administration to medicine gamma-hydroxybutyric acid ester (salt).

What cause people's interest is, shown recently modafinil (Provigil) can increase hypothalamic histamine release (Ishizuka et al.Neurosci.Lett.2003,339,143-146).

In addition, recently classical Doberman (Doberman) model that uses narcolepsy with non-imidazoles histamine H 3 receptor antagonists carry out studies show that histamine H 3 receptor antagonists can reduce the attack times of cataplexy and the time length of outbreak (Carruthers Ann.Meet.Eur.HIstamine Res.Soc.2004, Abs.p31).

To sum up, histamine H 3 receptor antagonists can be used for treating and/or preventing and the excessive relevant illness of sleepiness in the daytime with inverse agonist, for example hypersomnia, narcolepsy, sleep apnea, time zone change obstacle with relevant other obstacle (for example fibromyalgia and multiple sclerosis) (the Parmentier et al. of sleepiness excessively in the daytime, J.Neurosci.2002,22,7695-7711 and Ligneau et al.J.Pharmacol.Exp.Ther.1998,287,658-666).Other illness comprises the excessive drowsiness due to work in shifts, medical science obstacle (medical disorder), psychiatric disorders (psychiatric disorder), narcolepsy, the primary hypersomnia etc.Histamine H 3 receptor antagonists and inverse agonist also can temporarily be used to promote work in shifts person's awakening or watchful, sleep deprivation, postanestheticly stagger, as drowsy, military use of drug side effect etc.

In addition, awakening (wakefulness) is several brain functions prerequisites of (comprising attention, learning and memory), and is that behavior suitable when replying the environment violent change is needed.Shown that histamine H 3 receptor antagonists and inverse agonist can improve cognitive ability (cognitive performance) (Hancock and Fox in Milestones in Drug Therapy, ed.Buccafusco, 2003) in various animal models.These compounds can be used as short cognitive medicine (pro-cognitive agent) and can step up vigilance.Therefore, histamine H 3 receptor antagonists and inverse agonist can be used in wherein vigilance, attention and the memory impaired aging or sex change obstacle, for example are used in alzheimer's disease or other dementia.

Alzheimer's disease (AD) is a kind of neurodegeneration obstacle, and it is dull-witted common cause.Its Clinical symptoms is followed neural mental symptom and behavior for carrying out property cognitive decline and is changed.The most significant early symptom is the loss of memory, and it is usually expressed as not serious forgetful, describedly not serious forgetfully constantly becomes more remarkable with the progress of disease with regard to the relative preservation of memory far away.Cognitive (intelligence) damaged progress with disease extends to following field: the function of laughing, skillfully move, discerning and be closely related with brain frontal lobe and brain temporal lobe (for example make a strategic decision and plan).For AD,, there not be the method for healing at present although the medicine that symptom benefit (especially short-term memory damaged aspect) is provided is arranged.These medicines comprise for example E2020 (Aricept), lycoremine (Razadyne) and Li Fansi bright (Exelon) and nmda antagonist memantine for example of acetylcholinesterase depressant.

Histamine H 3 receptor antagonists and inverse agonist can be used for treatment or prevention cognitive disorder (Passani et al.Trends Pharmacol.Sci.2004,25,618-625), epilepsy (Vohora et al.Pharmacol.Biochem.Behav.2001,68,735-741), depressed (Perez-Garcia et al.Psychopharmacol.1999,142,215-220), attention deficit companion hyperkinetic syndrome (ADHD), (Fox et al.Behav.Brain Res.2002,131,151-61) and schizophrenia (Fox et al.J.Pharmacol.Exp.Ther.2005,313,176-190).The following concise and to the point description of these indications.Out of Memory please refer to following summary: Leurs et al, Nat.Rev.Drug.Discov.2005,4,107-120 and Vohora Investigational Drugs2004,7,667-673.Histamine H 3 receptor antagonists or inverse agonist also can be used as novel methods of treatment to recover cortex activity (cortical activation) (Passani et al. in comatose patient or cerebral trauma patient, Trends in Pharmacol.Sci.2004,25,618-625).

As mentioned above, histamine H 3 receptor antagonists and inverse agonist can be used for treatment or prevention epilepsy.Epilepsy (so-called epileptic seizures disease) is a chronic neuropathic disease, it is characterized by epileptic seizures for no reason repeatedly.According to the active mode of epileptic seizures, they can be described as part (part) outbreak or generalized seizure.The part epileptic seizures only relates to the part of brain, and the whole body epileptic seizures relates to whole cortex.Multiple different epilepsy syndrome is arranged, and every kind of epilepsy syndrome presents himself distinctive following characteristics combination: the type of epileptic seizures, the typical age of outbreak, EEG result, treatment and prognosis.Some common epileptic seizures syndromes comprise for example infantile spasm (west's syndrome (West syndrome)), childhood absence epilepsy and benign focal epilepsy of childhood (Benign Rolandic epilepsy (Benign Rolandic Epilepsy)), juvenile myoclonic epilepsy, temporal epilepsy, frontal lobe epilepsy and Lun-Jia syndrome (Lennox-Gastaut syndrome).

The compounds of this invention can with various known drug couplings.For example, The compounds of this invention can prevent the medicine of epileptic seizures or reduction epileptic seizures frequency to use with one or more; These medicines comprise Carbamzepine (common trade mark is called Tegretol), clobazam (Frisium), clonazepam (Klonopin), ethosuximide (Zarontin), felbamate (Felbatol), prophenytoin (Cerebyx), flurazepam (Dalmane), gabapentin (Neurontin), lamotrigine (Lamictal), Levetiracetam (Keppra), oxcarbazepine (Trileptal), mephenytoin (Mesantoin), phenylethyl barbituric acid (Luminal), Phenytoin Sodium Salt (Dilantin), Pregabalin (Lyrica), primidone (Mysoline), Sodium Valproate (Epilim), tiagabine (Gabitril), topiramate (Topamax), valproate semisodium (Depakote), valproic acid (Depakene or Convulex) and ammonia hexenoic acid (Sabril).Usually use other medicines so that the reactivity epileptic seizures is ended or epileptic seizures restless (seizure flurry) is interrupted; These medicines comprise diazepam (Valium) and lorazepam (Ativan).Only the medicine that uses in treatment intractable epilepsy persistent state comprises paraldehyde (Paral) and Sodital (Nembutal).

As mentioned above, histamine H 3 receptor antagonists or inverse agonist can be used as independent medicine or can with the other medicines coupling.For example, people such as Vohora have proved that histamine H 3 receptor antagonists can be used as antiepileptic drug or anti-epileptic outbreak medicine, also proved effect (the Vohora et al.Pharmacol.Biochem.Behav.2001 of combination of the known antiepileptic drug of the H3 receptor antagonist of inferior effective dose (subeffective dose) and inferior effective dose, 68,735-741).

People such as Perez-Garcia (Psychopharmacol.1999,142,215-220) tested histamine H 3 receptor agonist and antagonist ability to function to the experiment mice model of anxiety (overhead cross labyrinth (elevated plus-maze)) and depression (forced swimming test (forced swimming test)).They find that although described compound does not act on the anxiety model is significant, the H3 receptor antagonist has significant dose-dependent effects really in depression model.Therefore, histamine H 3 receptor antagonists or inverse agonist can have antidepressant effect.

Clinical depression is sad or melancholy state, and it has developed into the social function of individuality and/or activities of daily living are produced the destructive degree.Population for about 16%, clinical depression exert an influence at least one period in their life.Report according to the World Health Organization, clinical depression is the major cause that causes DB in the U.S. and other country at present, and anticipate the year two thousand twenty it will become second major cause (after heart trouble) that causes DB in worldwide.

The compounds of this invention can with various known drug couplings.For example, but The compounds of this invention can use with the medicine of one or more alleviate depression symptoms that can get at present.They comprise for example oxidase inhibitor (MAOI) (for example Nardil or Moclobemide (Manerix)), tricyclics, selective serotonin reuptake inhibitor (SSRI) (fluoxetine (Prozac) for example, paroxetine (Paxil), escitalopram (Lexapro) and Sertraline (Zoloft)), NRI (for example Reboxetine (Edronax)) and serotonin-NRI (SNRI) (for example venlafaxine (Effexor) and duloxetine (Cymbalta)).

As mentioned above, histamine H 3 receptor antagonists and inverse agonist can be used for treatment or prevention attention deficit companion hyperkinetic syndrome (ADHD).According to mental disorder diagnostic and statistical manual-IV-TR (Diagnostic and Statistical Manual of Mental Disorders-IV-TR), ADHD be the Childhood dysplasia of (great majority are before 7 years old) appears, it is characterized by the improper level of growth of attention-deficient and/or hyperactivity-impulsive action, and cause one or more main life activities (for example family's ability, partner (peer) ability, learning capacity, vocational ability, social ability or adaptive faculty) impaired.The adult also can be diagnosed as suffers from ADHD.

The line medicine great majority that are used for the treatment of ADHD are stimulant, and it is responsible in brain concentrating on by stimulating, zone wholwe-hearted and impulsion control plays a role.Sometimes will use stimulant treatment to be called reverse effect (paradoxical effect) with hyperactivity as the syndrome of feature usually, but not real reverse, be that stimulant activation brain suppresses mechanism and self-organization mechanism, this makes individuality have stronger self regulating power.Employed stimulant comprises for example Methylphenidylacetate (form with Ritalin, Ritalin SR and Ritalin LA is sold), Metadate, Metadate ER, Metadate CD, Concerta, Focalin, Focalin XR or Methylin.Described stimulant also comprises for example amphetamine [for example Dextrofenfluramine (form with Dexedrine, Dexedrine Spansules, Adderall and Adderall XR (trade name of the mixture of Dextrofenfluramine salt and Levamfetamine salt) is sold)], metamfetamine (form with Desoxyn is sold), Bupropion and Dopamine HCL and NRI (with trade name Wellbutrin listing).The non-stimulant medicine of treatment ADHD is Tomoxetine hydrochloride (Atomoxetine) (form with Strattera is sold), and it is a kind of NRI.Sometimes the other medicines that are used for ADHD comprise for example Benzphetamine, Provigil/Alertec/ modafinil and clonidine.Recently reported histamine H 3 receptor antagonists in the neonate rat model (rat pup model) of ADHD at least with same effectively (the Hancock and Fox in Milestones in Drug Therapy of Methylphenidylacetate (Ritalin), ed.Buccafusco, 2003).The compounds of this invention can with various known drug couplings.For example, The compounds of this invention can use with one or more medicines that is used for the treatment of ADHD and associated disorders.

As mentioned above, histamine H 3 receptor antagonists and inverse agonist can be used for treatment or prevention schizophrenia.Schizophrenia is a kind of psychiatric diagnosis, and it has described following mental disorder, and described mental disorder is feature with the perception of the fact with expressing damaged and tangible society or occupational function obstacle.Experiencing untreated schizoid people is feature to express mixed and disorderly idea and experience vain hope and phonism usually.Although think that at first described obstacle influence is cognitive, it also can cause the chronic problem (chronic problem) of behavior and emotion aspect.Often schizophrenia is described with " positive " symptom and " feminine gender " symptom.Positive symptom comprises vain hope, phonism and the disturbance of thought, and is considered to psychotic performance usually.It is because they are considered to the forfeiture or the shortage of normal feature or ability that negative symptoms is so named, and comprises following feature: downhearted, blunt or limited, the wordless and motivation shortage such as emotion and emotion.Some schizophrenia models are included in formal thought disorder and the plan difficulty in the 3rd group [promptly " division syndrome (disorganization syndrome)] ".

Usually use antipsychotic drug at a schizoid line pharmacological treatment.Antipsychotic drug only is considered to provide the remission of psychosis positive symptom.Newer atypical antipsychotic agents (for example leoponex, risperidone, olanzapine, Quetiapine, Ziprasidone and Aripiprazole) distributes owing to their favourable side effects and is better than older typical antipsychotic drug (for example chlorpromazine and haloperidol) usually.Although comparing with conventional antipsychotic drug, atypical antipsychotic agents has outer side effect of less cone and tardive dyskinesia, but as if for example weight increase, hyperglycemia and hypertriglyceridemia are relevant with the metabolic side effect for some in the atypical antipsychotic agents (particularly olanzapine and leoponex), when selecting suitable pharmacotherapy, must consider these metabolic side effects.

Histamine H 3 receptor antagonists or inverse agonist can be used for treatment of obesity, and (Hancock, Curr.Opin.Investig.Drugs 2003,4,1190-1197).The effect of neurone histamine in ingestion of food determined for many years, and for example Leptin, amylopectin (amylin) and Magainin (bombesin) have related to the conduction of neurone histamine release and/or signal with regard to the anoretic effect (anorectic action) in the cycle of ingesting (feeding cycle) with regard to known medium.In brain, with regard to regulating hypothalamic histamine release, relate to described H3 acceptor.And in-situ hybridization research has shown that histamine H 3 receptor mRNA expresses in the rat brown adipose tissue, this illustrated its effect in heat production is regulated (Karlstedt et al., Mol.Cell.Neurosci.2003,24,614-622).In addition, in various obesity preclinical models, histamine H 3 receptor antagonists is studied, and verified its can effectively reduce ingestion of food, reduces body weight and reduce overall fat (Hancock, et al.Eur.J.Pharmacol.2004 in mouse, 487,183-197).The most common medicine that is used for the treatment of obesity is the bent name of western cloth (Meridia) and an orlistat (Xenical), and these two kinds of medicines have limited effectiveness and significant side effects.Therefore, need novel anti-obesity medicine for example histamine H 3 receptor antagonists or inverse agonist.

Histamine H 3 receptor antagonists or inverse agonist also can be used for treating upper respiratory tract allergic response (United States Patent (USP) 5,217,986,5,352,707 and 5,869,479) (comprising rhinallergosis and nasal congestion).Rhinallergosis are chronic diseases of a lot of people's of influence frequent generation.Recently by quantitative PCR to the periphery histamine H 3 receptor express the analysis revealed H3 receptor mrna that carries out in people's nasal mucosa great expression (Varty et al.Eur.J.Pharmacol.2004,484,83-89).In addition, the nose that is combined in of histamine H 3 receptor antagonists and H1 receptor antagonist chlorphenamine alleviates and causes tangible nose to alleviate hyperemia in hyperemia (nasal decongestion) model and do not have and adopt the viewed hypertension effect of 2-adrenergic agonist components (hypertensive effect) (McLeod et al.Am.J.Rhinol.1999,13,391-399).Therefore, histamine H 3 receptor antagonists or inverse agonist can use separately or with the H1 receptor blocking agent coupling that is used for the treatment of rhinallergosis and nasal congestion.

Histamine H 3 receptor antagonists or inverse agonist with regard to management of pain, have the treatment potentiality (Medhurst et al.Biochemical Pharmacology (2007), 73 (8), 1182-1194).

Pharmaceutical composition

Another aspect of the present invention relates to pharmaceutical composition, and described composition contains one or more compounds described herein and one or more pharmaceutical carriers.Some embodiments relate to the pharmaceutical composition that contains The compounds of this invention and pharmaceutical carrier.

Embodiments more of the present invention comprise the method for producing pharmaceutical composition, and described method comprises that at least a compound of any compound embodiment that will disclose according to this paper mixes with pharmaceutical carrier.

Method by any appropriate prepares preparation, by the solid carrier preparation with required ratio uniform mixing active compound and liquid and/or fine pulverizing, then if desired, makes the gained mixture form required shape usually.

For example tackiness agent, weighting agent, acceptable wetting agent, film-making lubricant and disintegrating agent can be used in the tablet and capsule of oral administration conventional excipient.The liquid preparation that is used for oral administration can be following form: solution, emulsion, aqueous suspension, oiliness suspensoid and syrup.Selectively, oral preparations can be the form of dried powder agent, and described dried powder agent is water or another kind of suitable liquid vehicle recovery (reconstitute) before use.Can for example suspending agent, emulsifying agent, non-aqueous vehicle (comprising edible oil), sanitas, correctives and tinting material be added in the liquid preparation with other additive.Parenteral dosage forms can be prepared as follows: The compounds of this invention is dissolved in the suitable liquid vehicle, solution is carried out filtration sterilization, be loaded in suitable bottle or the ampoule then and sealing.These methods are the several examples that are used for preparing the multiple appropriate method of formulation well known in the art.

Can use the technology of well known to a person skilled in the art that The compounds of this invention is mixed with pharmaceutical composition.Those, suitable pharmaceutical carrier is known in the art except that mentioned in this article, for example referring to Remington, and The Science and Practice of Pharmacy, 20 ^ThEdition, 2000, Lippincott Williams ﹠amp; Wilkins, (Editors:Gennaro et al.).

For in being used in prevention or treatment, although possible is The compounds of this invention form administration with alligatoring material or pure chemistry material in selectable purposes, at present preferably described compound or activeconstituents provide with the pharmaceutical preparation that also contains pharmaceutical carrier or the form of pharmaceutical composition.

Therefore, the present invention also provides following pharmaceutical preparation, and described pharmaceutical preparation contains The compounds of this invention or its pharmaceutical salts, solvate, hydrate or derivative and one or more pharmaceutical carriers and/or preventative composition.Carrier must be " acceptable ", and the meaning is that other composition in carrier and the preparation is compatible, and is not excessively deleterious concerning its recipient.

Pharmaceutical preparation comprises that those pharmaceutical preparations or the form that are suitable for oral administration, rectal administration, intranasal administration, topical (comprise and contain clothes administration and sublingual administration), vagina administration or administered parenterally (comprising intramuscular administration, subcutaneous administration and intravenous administration) are suitable for inhalation, are blown into those pharmaceutical preparations of administration or transdermal patch administration.Transdermal patch is with the following delivering drugs of controllable rate: medicine that is provided for absorbing with efficient manner and the minimum degradation that makes medicine.Typically, the transdermal patch removable protective layer that comprises impermeable backing layer, single pressure sensitive adhesive layer and have release liner.Based on the needs of skilled worker (artisan), those skilled in the art should understand that and know the technology that is suitable for preparing required effective transdermal patch.

Therefore, The compounds of this invention and conventional auxiliary material, carrier or thinner can be made the form of pharmaceutical preparation and unitary dose thereof, with regard to above-mentioned form, The compounds of this invention can be used to orally use by following formulation: solid dosage (for example tablet or filling capsule) or liquid dosage form (for example solution, suspensoid, emulsion, elixir, gelifying agent or be filled with the capsule of these formulations); Form by suppository is used for rectal administration; Or be used for parenteral (comprising subcutaneous) by the form of sterile injectable solution agent and use.Aforementioned pharmaceutical compositions and unit dosage form thereof can comprise the conventional ingredient of conventional ratio and have or do not have other active compound or composition (principle), and above-mentioned unit dosage form can contain any suitable effective amount of actives that dosage range matches with used predetermined every day.

For oral administration, pharmaceutical composition can be following form: for example tablet, capsule, suspensoid or liquid preparation.Preferably pharmaceutical composition is made the dosage unit form that contains concrete amount activeconstituents.The example of described dose unit is capsule, tablet, powder agent, granule or suspensoid, and wherein conventional additives is for example lactose, N.F,USP MANNITOL, W-Gum or yam starch; Wherein tackiness agent is for example crystalline cellulose, derivatived cellulose, gum arabic, W-Gum or gelatin; Wherein disintegrating agent is for example W-Gum, yam starch or Xylo-Mucine; Wherein lubricant is for example talcum or Magnesium Stearate.Described activeconstituents also can come administration by injection by the form of composition, and wherein for example salt solution, dextrose or water can be used as suitable pharmaceutical carrier.

Activeconstituents in The compounds of this invention or its solvate or the neurological progression derivative useful as drug composition is particularly as H3 Histamine Receptors conditioning agent.In the context of " pharmaceutical composition ", define term " activeconstituents ", and mean the component of the pharmaceutical composition that main pharmacotoxicological effect is provided, and be considered to not provide " non-active ingredient " of medicine benefit opposite usually.

When using The compounds of this invention, dosage can change in wide region, such as concerning the doctor custom and known, dosage is adjusted to adapt to individual state under every kind of individual instances.Whether also whether for example, dosage depends on the character of disease to be treated and severity, patient's situation, employed compound, treatment is acute disease or chronic disease, prevent or other active compound of administration except that The compounds of this invention.Representative dosage of the present invention include but not limited to about 0.001mg to about 5000mg, about 0.001mg to about 2500mg, about 0.001mg to about 1000mg, 0.001mg about 500mg, 0.001mg about 250mg, about 0.001mg to 100mg, about 0.001mg about 50mg and about 0.001mg about 25mg extremely extremely extremely extremely.Can be in one day the administration multidose, particularly when think need be big relatively amount the time, described multidose is for example 2,3 or 4 dosage.Based on individual state and when patient's doctor or paramedic see fit, may need to raise or reduce dosage as herein described.

The amount of the activeconstituents of required use or its active salt or derivative not only changes with selected concrete salt in the treatment, and change, and finally determine by care physician or clinicist with the character of route of administration, the illness of being treated and patient's age and situation.Usually, those skilled in the art understand that data are extrapolated to another kind of model (for example mankind) in the body how will obtain in a kind of model system (being generally animal model).In some cases, these extrapolations can be only based on the weight ratio of a kind of animal model and another kind of animal model, described animal is preferably the mankind for for example Mammals, yet more commonly, these extrapolations are not simply based on body weight but combine multiple factor.Representational factor comprise factor that patient's type, age, body weight, sex, diet and medical condition, the severity of disease, route of administration, pharmacology considers for example activity, effectiveness, pharmacokinetics and the toxicology of used particular compound distribute, whether use drug delivery system, illness be chronic or acute, whether treat or prevent or except that The compounds of this invention whether and other active compound of administration and as the part of drug combination.Select to use the dosage regimen of The compounds of this invention and/or combination treatment illness according to various factors above-mentioned.Therefore, employed actual dosage regimen can alter a great deal, and therefore can depart from preferred dosage regimen, and those skilled in the art are appreciated that, can test dosage except that these typical ranges and dosage regimen, and when suitable, in the method for the invention available.

Required dosage can be expediently provides or provides with the form of broken dose with the form of single dose, and described broken dose comes administration with suitable interval, for example every day twice, three times, four times or more times sub-doses (sub-dose).Sub-doses itself can further be divided into for example a plurality of discrete loose form of medication that separate.Dosage every day can be divided into several (for example 2,3 or 4) part form of medication, particularly when thinking that the big relatively amount of administration is suitable.If suitable (depending on individual behavior), then may need to raise or reduce pointed dosage every day.

For by the The compounds of this invention pharmaceutical compositions, selected suitable pharmaceutical carrier can be solid, liquid or the two mixture.But solid preparation comprises powder agent, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more materials, and described material also can be used as thinner, correctives, solubilizing agent, lubricant, suspending agent, tackiness agent, sanitas, tablet disintegrant or coating material.

In powder agent, carrier is fine dispersed solids, and itself and fine dispersive active ingredient form mixture.

In tablet, active ingredient and carrier with necessary adhesive capacity with suitable mixed, and are pressed into required shape and size.

Powder agent and tablet can contain the active compound of different percentage amounts.Representational amount in powder agent or tablet can contain 0.5 to about 90% active compound, yet those skilled in the art will be appreciated that when need above-mentioned extraneous amount.For powder agent and tablet, suitable carriers is magnesiumcarbonate, Magnesium Stearate, talcum, sucrose, lactose, pectin, dextrin, starch, gelatin, tragakanta, methylcellulose gum, Xylo-Mucine, low melt wax, theobroma oil etc.Term " preparation " be intended to comprise to active compound with prepare as the coating material of carrier, provide active ingredient (having or do not have carrier) suppressed by vector to surround thus and therefore with carrier-bound capsule.Similarly, the present invention includes cachet and lozenge.Tablet, powder agent, capsule, pill, cachet and lozenge can be used as the solid form that is suitable for oral administration.

In order to prepare suppository, at first make low melt wax (for example mixture of glycerin fatty acid ester or theobroma oil) fusing, and for example by stirring with the active ingredient homodisperse therein.Then the uniform mixture of fusing is poured in the mould of suitable dimension, made its cooling and curing thus.

The preparation that is suitable for vagina administration can provide by following formulation: vaginal suppository, suppository (tampon), ointment, gelifying agent, paste (paste), foaming agent or sprays, they also contain suitable carrier known in the art except that activeconstituents.

Liquid preparation comprises solution, suspensoid and emulsion (for example aqueous pharmaceutical or water-propylene glycol solution agent).For example, the parenteral injection liquid preparation can be mixed with solution in the water-based polyglycol solution.Injection (for example sterile injectable water-based or oiliness suspensoid) can use suitable dispersion agent or wetting agent and suspending agent to prepare according to known technology.Aseptic injection also can be at nontoxic parenteral acceptable diluent or sterile injectable solution agent in the solvent or suspensoid (for example solution in 1,3 butylene glycol).Can accept and spendable vehicle and solvent are water, Ringer's solution and isotonic sodium chlorrde solution.In addition, usually aseptic fixed oil is used as solvent or suspension medium.For this purpose, can use the fixed oil of any gentleness, it comprises synthetic monoglyceride or triglyceride.In addition, lipid acid for example oleic acid can be used for preparing injection.

Therefore, The compounds of this invention can be mixed with and be used for administered parenterally (for example by injection (for example injecting or continuous infusion)), and can be present in ampoule, pre-filled syringe, small volume infusion container or the multi-dose container that is added with sanitas by unit dosage form.Pharmaceutical composition can be following form: the suspensoid in oiliness or aqueous vehicles, solution or emulsion, and can contain reagent preparation (formulatory agent) for example suspending agent, stablizer and/or dispersion agent.Selectively, activeconstituents can be powder type (its by sterile solid is carried out aseptic subpackaged or obtain by solution is carried out lyophilize) and restores to use suitable vehicle (for example aseptic pyrogen-free water) before use.

The aqueous formulation that is suitable for orally using can be prepared as follows: with solubilization of active ingredient or be suspended in the water and add suitable tinting material, correctives, stablizer and thickening material as required.

The aqueous suspension that is suitable for orally using can be prepared as follows: fine dispersive active ingredient is dispersed in the water that contains viscous substance, and described viscous substance is for example natural gum, synthetical glue, resin, methylcellulose gum, Xylo-Mucine or other known suspending agent.

The present invention also comprises such solid preparation, and it just changes into the liquid preparation that is used for oral administration before being expected at and using.Such liquid preparation comprises solution, suspensoid and emulsion.Except that active ingredient, these preparations also can contain tinting material, correctives, stablizer, buffer reagent, artificial sweetner, natural sweetener, dispersion agent, thickening material, solubilizing agent etc.

To the epidermis, The compounds of this invention can be mixed with ointment, ointment, lotion or transdermal patch with regard to topical.

For example, ointment and ointment can wherein add suitable thickening and/or jelling agent with water-based or oleaginous base preparation.Lotion can be prepared with water-based or oleaginous base, and also can contain one or more emulsifying agents, stablizer, dispersion agent, suspending agent, thickening material or tinting material usually.

Be suitable for that the preparation of topical comprises in the oral cavity: lozenge, it contains at the promoting agent in the matrix (flavored base) (being generally sucrose and gum arabic or tragakanta) of flavoring; Pastille (pastille), it contains at the inert base activeconstituents in gelatin and glycerine or sucrose and the gum arabic for example; And mouth wash shua, it contains the activeconstituents in the suitable liquid carrier.

For example use dropper (dropper), volumetric pipette (pipette) or atomizer that solution or suspensoid are applied directly in the nasal cavity by conventional means.Described preparation can provide by single dose form or multiple doses form.With regard to the multiple doses form of dropper or volumetric pipette, can use the solution of suitable pre-determined volume or suspensoid to realize administration multiple doses form by the patient.With regard to spraying, this can for example realize by metering atomisation pump.

Be administered to respiratory tract and also can realize, wherein in having the pressurized package of suitable propelling agent, provide activeconstituents by aerosol formulation.If The compounds of this invention or comprise their pharmaceutical composition with the form of the aerosol form of nasal aerosol (for example with) or by sucking administration, then it can for example use atomizer, spraying gun, pump formula spraying gun (pump nebulizer), suction apparatus, metered dose inhaler or dry powder inhaler to carry out.Be used for the medicament forms of The compounds of this invention with the form administration of aerosol can be prepared by well known to a person skilled in the art method.For example, for such preparation, can use solution or dispersion agent in The compounds of this invention Yu Shui, water/alcohol mixture or the acceptable acid addition salts aqueous solution, they use conventional additives, for example phenylcarbinol or other suitable sanitas, the absorption enhancer that is used to improve bioavailability, solubilizing agent, dispersion agent and other additive, and use conventional propellant when appropriate, for example comprise carbonic acid gas, CFC (for example Refrigerant 12, fluoro trichloromethane or dichloro tetrafluoro ethane) etc.Aerosol also can contain for example Yelkin TTS of tensio-active agent expediently.Drug dose can be controlled by metering valve is provided.

In the preparation that is intended to be administered to respiratory tract (comprising preparation in the nose), described compound can have little granularity (for example 10 microns or littler granularity) usually.Such granularity can for example obtain by micronization by methods known in the art.When needs, can use to be suitable for obtaining the activeconstituents sustained release formulation.

Selectively, activeconstituents can provide by the form of dried powder, and described dried powder is for example described compound in suitable powder matrix lactose, starch, the starch derivative powdered mixture in Vltra tears and the polyvinylpyrrolidone (PVP) for example for example.Expediently, powder carrier can form gel in nasal cavity.Powder composition can for example be present in capsule or cartridge case (cartridge) (for example gelatine capsule or gelatin cartridge case) or the Blister Package (blister pack) by unit dosage form, can pass through the described powder of sucker administration from described capsule or cartridge case or Blister Package.

Pharmaceutical preparation preferably is unit dosage form.In described form, preparation is subdivided into the unitary dose of the active ingredient that contains appropriate amount.Unit dosage form can be through the preparation of packing, contain the packing (for example through packing the tablet in bottle or ampoule, capsule and powder agent) of discrete number preparation.In addition, unit dosage form can be capsule, tablet, cachet or a lozenge itself, or it can be in the above-mentioned formulation that is packaged form of suitable number any one.

The tablet or the capsule that are used for oral administration are preferred compositions with the liquid preparation that is used for intravenous administration.

The compounds of this invention can be chosen wantonly as pharmaceutical salts and exist, and comprises that described medicinal non-toxic acid comprises mineral acid and organic acid by the medicinal acid addition salt of medicinal non-toxic acid preparation.Representative acid includes but not limited to acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, dichloro acetic acid, formic acid, fumaric acid, glyconic acid, L-glutamic acid, urobenzoic acid, Hydrogen bromide, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, oxalic acid, pounce on acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid (sulfuric), tartrate, oxalic acid, tosic acid etc., for example at Journal of Pharmaceutical Sciences, listed those pharmaceutical salts among the 66:1-19 (1977) are incorporated document integral body into this paper as a reference.

Described acid salt can be used as the synthetic direct product of compound and obtains.In selectable method, free alkali can be dissolved in the suitable solvent that contains suitable acid, by evaporating solvent separated salt or separated salt and solvent.Use method known to those skilled in the art, The compounds of this invention can form solvate with the standard low molecular weight solvent.

The compounds of this invention can be changed into " prodrug ".Term " prodrug " is meant the compound of using concrete chemical base group modification known in the art, and in being administered into individuality the time, these groups experience bio-transformations obtain parent compound.Therefore, prodrug can be regarded as containing using to change or to eliminate the The compounds of this invention of compound property in the transient state mode of one or more specialized nontoxic protectiveness groups.One general aspect in, adopt described " prodrug " method to be beneficial to oral absorption.At T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems Vol.14of the A.C.S.Symposium Series; With at Bioreversible Carriers in Drug Design, ed.Edward B.Roche, American Pharmaceutical Association and Pergamon Press provides comprehensive discussion in 1987, incorporates these two pieces of document integral body into this paper as a reference.

Embodiments more of the present invention comprise the method for producing the pharmaceutical composition that is used for " combination treatment ", comprise that at least a compound of any compound embodiment that will disclose according to this paper mixes with at least a known as disclosed herein medicament and pharmaceutical carrier.

It should be noted that when the H3 receptor modulators was used as activeconstituents in pharmaceutical composition, they not only were intended to use, and were intended to use in other non-human mammal in the mankind.In fact, the latest developments in the animal health field show, should consider companion animals (for example cat and dog) with in domestic animal (for example ox, chicken, fish etc.), use promoting agent for example the H3 receptor modulators be used for the treatment of disease or the obstacle relevant with the H3 acceptor.Believe that beyond all doubtly those skilled in the art can understand described compound purposes in these cases.

Hydrate and solvate

Can multiple oral and parenteral dosage forms administration The compounds of this invention.It is apparent to those skilled in the art that following formulation can comprise pharmaceutical salts, solvate or the hydrate of The compounds of this invention or The compounds of this invention as active ingredient.Except those methods mentioned in this article, be used to prepare and the usual method of discerning suitable hydrates and solvate is well known in the art; Referring to for example, 202-209 page or leaf, K.J.Guillory, " Generation of Polymorphs, Hydrates, Solvates; and Amorphous Solids, " in:Polymorphism in Pharmaceutical Solids, ed.Harry G.Brittan, Vol.95, Marcel Dekker, Inc., New York, 1999, incorporate document integral body into this for as a reference.Therefore, one aspect of the present invention relates to the hydrate and the solvate of formula described herein (Ia) compound, can and characterize described hydrate and solvate by the methods known in the art separation, described method is for example thermogravimetric analysis (TGA), TGA-mass spectrum, the infrared wide spectrum of TGA-, powder x-ray diffraction (XRPD), Ka Er Karl Fischer titration (Karl Fisher titration), high resolution X-ray diffraction etc.

Other purposes

Another object of the present invention relates to through radiolabeled The compounds of this invention, it is described in radiolabeled compound is not only used in vitro and in vivo radiophotography, but also with in measuring in vitro and in vivo, be used for locating and quantitatively comprise people's H3 Histamine Receptors at tissue sample, and be used for by through the inhibition of radiolabeled compound in conjunction with discerning the H3 histamine-3 receptors ligands.Another object of the present invention is the novel H3-receptor determination of exploitation, and described mensuration comprises described through radiolabeled compound.

The present invention includes through isotope-labeled The compounds of this invention.Through isotope-labeled compound or through radiolabeled compound is following those compounds, described compound is identical with the compound that this paper discloses, but just following true different: one or more atoms are by following atomic substitutions or replacement, and the atomic mass or the total mass number of the most common atom of atomic mass that described atom has or total mass number and natural discovery are different.The suitable radionuclide that can be attached in the The compounds of this invention includes but not limited to ²H (also writing D for deuterium), ³H (also writing T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I.Be attached to the concrete application that radionuclide in the radiolabeled compound of the present invention will depend on that radiolabeled compound.For example, for external H3 Histamine Receptors mark and competition assay, in conjunction with ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I or ³⁵The compound of S is normally the most useful.Use for radiophotography, ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br is normally the most useful.

Should be understood that " radiolabeled " or " compound of mark " is in conjunction with the formula (Ia) of at least one active nucleus, (Ic), (Ie), (Ig) or (Ii) compound; In some embodiments, described active nucleus is selected from ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Some isotope-labeled compounds of the present invention are used in compound and/or the substrate tissue distributes in the mensuration.In some embodiments, described radionuclide ³H and/or ¹⁴The C isotropic substance is useful in these researchs.In addition, for example deuterium is (that is, with higher isotope ²H) replacement can obtain by some treatment benefits of bringing than greater metabolic stability (for example, the transformation period increases or the minimizing of dosage requirement in the body), and so is preferred in some cases.The isotope-labeled compound of the present invention can prepare by replacing nonisotopically labelled reagent with isotope-labeled reagent by the similar method preparation of those methods that discloses in following and the drawings and Examples hereinafter usually.Other useful synthetic method is discussed hereinafter.In addition, should be understood that all atoms of representing can be isotropic substance or the rare emitting isotope or the active isotropic substances of non-radioactive of common appearance of described atom in The compounds of this invention.

The synthetic method that is used for emitting isotope is attached to organic compound is suitable for The compounds of this invention, and is well known in the art.These synthetic methods (for example, the tritium with activity level is attached in the target molecule) are as described below:

A. use the tritium gas catalytic reduction: this method obtains the product of high specific activity usually, and needs halogenation or unsaturated precursor.

B. use sodium borohydride [ ³H] reduction: this method is quite cheap and need contain for example precursor of aldehyde, ketone, lactone, ester etc. of reducible functional group.

C. use lithium aluminum hydride [ ³H] reduction: this method obtains product with theoretical specific activity almost.It also needs to contain for example precursor of aldehyde, ketone, lactone, ester etc. of reducible functional group.

D. tritium gas exposes mark: the following precursor that will contain exchangeable protons of existence that this method is included in suitable catalyst is exposed to tritium gas.

E. use methyl iodide [ ³H] N-methylates: adopt usually this method by with the high specific activity methyl iodide ( ³H) handle suitable precursor prepare O-methyl or N-methyl ( ³H) product.Generally speaking, this method allows higher specific activity, for example, and about 70-90Ci/mmol.

Be used for activity level ¹²⁵The synthetic method that I is attached in the target molecule comprises:

A. Sang De mayer and similar reaction: this method changes into diazonium salt with arylamines or heteroaryl amine, diazonium a tetrafluoro borate for example, and use Na subsequently ¹²⁵I changes into ¹²⁵The compound of I mark.Exemplary process is by Zhu, and G-D and colleague thereof be at J.Org.Chem., and 2002,67, report among the 943-948.

B. the ortho position iodine of phenol ( ¹²⁵I) change: this method allows ¹²⁵I is combined in the ortho position of phenol, and as by Collier, T.L and colleague thereof be at J.Labelled Compd.Radiopharm., and 1999,42, report among the S264-S266.

C. aromatic bromide and heteroaryl bromide are used ¹²⁵The I exchange: this method is one two step process normally.The first step is to use for example following method that aryl or heteroaryl bromide are changed into corresponding trialkyltin intermediate: at halogenation trialkyltin or six alkyl, two tin [for example, (CH ₃) ₃SnSn (CH ₃) ₃] exist down, carry out the catalytic reaction of Pd [that is Pd (Ph, ₃P) ₄] or by lithium aryl or heteroaryl lithium.Exemplary process is by Le Bas, and M.-D and colleague thereof be at J.Labelled Compd.Radiopharm.2001, and 44, report among the S280-S282.

Radiolabeled formula (Ia) H3 Histamine Receptors compound can be used in the screening assay with identification/assessing compound.Generally speaking, the ability that can be bonded to the H3-acceptor with regard to compound (that is the test compound) minimizing " radiolabeled formula (Ia) compound " of new synthetic or identification is estimated.Therefore, test compound is directly related with its binding affinity with the ability that " radiolabeled formula (Ia) compound " competition is bonded to the H3 Histamine Receptors.

The present invention combines with the H3 Histamine Receptors through the compound of mark.In one embodiment, described compound through mark has the IC less than about 500 μ M ₅₀, in another embodiment, described compound through mark has the IC less than about 100 μ M ₅₀, in another embodiment, described compound through mark has the IC less than about 10 μ M ₅₀, in another embodiment, described compound through mark has the IC less than about 1 μ M ₅₀, and in another embodiment, described inhibitor through mark has the IC less than about 0.1 μ M ₅₀

Based on the review to contents such as this specification sheetss, other purposes of disclosed acceptor and method will be conspicuous to those skilled in the art.

What can be appreciated that is that the step of the inventive method does not need to carry out any concrete number of times or do not need to be undertaken by any concrete order.Based on the investigation to the following embodiment of the present invention, other purpose of the present invention, benefit and novel feature can become apparent to those skilled in the art, and described embodiment is intended to describe rather than is intended to and limits.

Embodiment

Embodiment 1: The compounds of this invention synthetic

At exemplary synthetic being presented among Fig. 1 to 13 of The compounds of this invention, wherein said symbol has identical definition with the employed symbol of this specification sheets in the whole text.

The compounds of this invention and the synthetic of them further specify by following embodiment.Provide following embodiment further to define the present invention, right rather than limit the invention to the particular case of these embodiment.According to CS ChemDraw Ultra 7.0.1 version, AutoNom 2.2 editions or CS ChemDraw Ultra9.0.7 version to before this paper and the compound of describing afterwards name.Use popular name in some cases, and it should be understood that those skilled in the art can know these popular names.

Chemistry: proton magnetic resonance (PMR) ( ¹H NMR) spectrum record on the Bruker Avance-400 that is equipped with QNP (four nuclear probes (Quad Nucleus Probe)) or BBI (broadband is (Broad Band Inverse) oppositely) and z gradient.Chemical shift is counted (ppm) very much with hundred and is provided, and wherein the residual solvent signal is with for referencial use.Use NMR as follows abbreviation: s=is unimodal, d=is bimodal, dd=double doublet, ddd=doublet, dddd=triple bimodal, tt=three triplets of double doublet, the two triplets of dt=, t=triplet, td=, q=quartet, m=multiplet, wide unimodal, the wide triplet of bt=of bs=in pairs in pairs.Use SmithSynthesizer ^TMOr Emrys Optimizer ^TM(Biotage) carry out microwave radiation.Thin-layer chromatography (TLC) is at silica gel 60F ₂₅₄(Merck) carry out on, preparation of lamina chromatogram (preparation property TLC) is carried out on PK6F silica gel 60A 1mm plate (Whatman), and column chromatography use Kieselgel 60, and 0.063-0.200mm (Merck) carries out on silicagel column.Evaporation is reduced pressure on B ü chi Rotary Evaporators and is carried out.

LCMS explanation: HPLC pump: LC-10AD VP, Shimadzu Inc.; HPLC central controller: SCL-10A VP, Shimadzu Inc; UV detector: SPD-10A VP, Shimadzu Inc; Automatic sampler: CTC HTS, PAL, Leap Scientific; Mass spectrograph: have Turbo Ion Spray Source, the API 150EX of AB/MDS Sciex; Software: Analyst 1.2.

Embodiment 1.1:(R)-preparation of 4-(4-chloro-phenyl-) oxazolidine-2-ketone.

By dropping funnel to ice-cooled (R)-2-amino-2-(4-chloro-phenyl-) acetate (2.262g, 12.19mmol) in THF (tetrahydrofuran (THF), 49mL) add in the solution in borine (concentration is the tetrahydrofuran solution of 1.0M, 48.7mL, 48.7mmol).With reaction mixture restir 30 minutes, remove ice bath then, and its stirring is spent the night.Add methyl alcohol (25mL) by dropping funnel then.Stir after 30 minutes removal of solvent under reduced pressure.Resistates is suspended in the methylene dichloride (122mL) again, and (21.29mL 122mmol), and cools off mixture in ice bath to add diisopropyl ethyl amine.(3.98g 13.41mmol), causes gas to be emitted fast to add triphosgene then.After 30 minutes, remove ice bath, reaction mixture is stirred spend the night.Described solution is the HCl solution washing twice of 1M with ethyl acetate (300mL) dilution with concentration, uses the salt water washing then, and uses dried over sodium sulfate.Removal of solvent under reduced pressure.At purifying on the silicagel column (with the eluant solution of 40-100% ethyl acetate in hexane) resistates, obtain title compound by chromatography, it is white solid (790mg, 33%). ¹H?NMR(400MHz，CDCl ₃)δppm?4.14(dd，J＝8.72，6.95Hz，1H)，4.73(t，J＝8.72Hz，1H)，4.92-4.98(m，1H)，6.32(s，1H)，7.27-7.30(m，2H)，7.36-7.40(m，2H)。

Embodiment 1.2:(R)-preparation of 4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 3).

With (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.192g, 0.825mmol), 2-(dicyclohexyl phosphino-)-2 ', 4 ', 6 '-triisopropyl-1,1 '-biphenyl (0.020g, 0.041mmol), (R)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (0.163g, 0.825mmol), potassiumphosphate (525mg, 2.47mmol) and palladium (II) (3.70mg, 0.016mmol) mixture in tetrahydrofuran (THF) (4mL) places under the microwave radiation, continues 1 hour at 120 ℃.Filter reaction mixture, and wash with acetonitrile.Concentrating under reduced pressure filtrate, and by preparation property HPLC (use 25x 250Mm C18 post, last 55 minutes with the 10-75% acetonitrile/water wash-out that contains 0.1% trifluoroacetic acid) purifying.Merge the HPLC cut of gained and evaporate acetonitrile.With concentration is the Na of 2M ₂CO ₃Solution makes remainder water solution become alkalescence, and is saturated and with ethyl acetate extraction three times with sodium-chlor.The acetic acid ethyl ester extract dried over mgso that merges is filtered.(concentration is the diethyl ether solution of 1M, 1mL) and removal of solvent under reduced pressure to add HCl in filtrate.Then this material is suspended in the water again, freezing and freeze-drying obtains the hydrochloride (121mg, 38%) of title compound.C ₂₂H ₂₆N ₂O ₂The accurate mass calculated value: 350.5, measured value: LCMS m/z=351.3[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.34 (d, J=6.57Hz, 0.3H), 1.51 (d, J=6.57Hz, 2.7H), 1.72-1.84 (m, 1H), 2.03-2.24 (m, 2H), 2.31-2.42 (m, 1H), 3.07-3.22 (m, 2H), 3.25-3.33 (m, 2H), 3.53-3.60 (m, 1H), 3.61-3.71 (m, 1H), 3.74-3.84 (m, 1H), 4.19 (dd, J=8.59,6.57Hz, 1H), 4.82 (t, J=8.72Hz, 1H), 5.07 (dd, J=8.72,6.44Hz, 1H), 7.42-7.50 (m, 4H), and 7.62-7.70 (m, 4H).

Embodiment 1.3:(R)-preparation of 4-(4-bromobenzyl) oxazolidine-2-ketone.

(2.026g 8.30mmol) prepares the method similar methods of describing among use and the embodiment 1.1, obtains title compound, and it is white solid (929mg, 44%) by (R)-2-amino-3-(4-bromophenyl) propionic acid. ¹H?NMR(400MHz，CDCl ₃)δppm?2.84(dd，J＝6.57，2.78Hz，2H)，4.02-4.15(m，2H)，4.45(t，J＝8.21Hz，1H)，5.90(s，1H)，7.04-7.09(m，2H)，7.44-7.50(m，2H)。

Embodiment 1.4:(R)-and 4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 4).

The method similar methods of describing among use and the embodiment 1.2 is by (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.192g, 0.825mmol) and (R)-4-(4-bromobenzyl) oxazolidine-2-ketone (0.163g, 0.825mmol) preparation, obtain the hydrochloride (96mg, 53%) of title compound.C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.5, measured value: LCMS m/z=365.5[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.31 (d, J=6.57Hz, 0.3H), 1.50 (d, J=6.57Hz, 2.7H), 1.71-1.83 (m, 1H), 2.03-2.22 (m, 2H), 2.32-2.42 (m, 1H), 2.88-2.98 (m, 2H), 3.05-3.20 (m, 2H), 3.23-3.33 (m, 2H), 3.50-3.59 (m, 1H), 3.67 (d, J=6.57Hz, 1H), 3.73-3.82 (m, 1H), and 4.17-4.26 (m, 2H), 4.40-4.48 (m, 1H), 7.36 (d, J=8.34Hz, 2H), 7.43 (d, J=8.34Hz, 2H), 7.62 (dd, J=14.02,8.21Hz, 4H).

Embodiment 1.5:(R)-preparation of 3-methyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 5).

In argon gas atmosphere, to (R)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (and 0.155g, 0.784mmol) add in the solution in dimethyl formamide (3mL) sodium hydride (0.047g, 1.177mmol).Add then methyl iodide (0.098mL, 1.569mmol).The reaction mixture stirring is spent the night, and with ethyl acetate (50mL) dilution, is HCl solution (10mL, twice), the salt water washing of 1M with concentration, with dried over sodium sulfate and concentrated, obtains (R)-4-(4-chloro-phenyl-)-3-methyl-oxazolidine-2-ketone.

The method similar methods of describing among use and the embodiment 1.2 is by (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.183g, 0.784mmol) and (R)-4-(4-chloro-phenyl-)-3-methyl-oxazolidines of preparing above-2-ketone preparation, obtain the hydrochloride (153mg, 49%) of title compound.C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.5, measured value: LCMS m/z=365.6[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.35 (d, J=6.57Hz, 0.3H), 1.51 (d, J=6.57Hz, 2.7H), 1.72-1.84 (m, 1H), 2.06-2.23 (m, 2H), 2.32-2.43 (m, 1H), 2.73 (s, 3H), 3.07-3.22 (m, 2H), 3.25-3.32 (m, 2H), 3.53-3.60 (m, 1H), 3.61-3.71 (m, 1H), 3.75-3.82 (m, 1H), 4.15 (dd, J=8.84,7.07Hz, 1H), 4.73 (t, J=8.72Hz, 1H), 4.90 (dd, J=8.72,7.20Hz, 1H), 7.42-7.49 (m, 4H), and 7.65-7.75 (m, 4H).

Embodiment 1.6:(R)-preparation of 3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 6).

In the argon gas atmosphere, to (R)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (and 0.157g, 0.794mmol) add in the solution in dimethyl formamide (3mL) sodium hydride (0.048g, 1.192mmol).Add then 1-bromo-2-methyl ethyl ether (0.221g, 1.589mmol).The reaction mixture stirring is spent the night, and with ethyl acetate (50mL) dilution, is HCl solution (10mL, twice), the salt water washing of 1M with concentration, with dried over sodium sulfate and concentrated, obtains (R)-4-(4-chloro-phenyl-)-3-(2-methoxy ethyl)-oxazolidine-2-ketone.

The method similar methods of describing among use and the embodiment 1.2 is by (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.185g, 0.794mmol) and (R)-4-(4-chloro-phenyl-)-3-(2-methoxy ethyl)-oxazolidines of preparing above-2-ketone preparation, obtain the hydrochloride (116mg, 33%) of title compound.C ₂₅H ₃₂N ₂O ₃The accurate mass calculated value: 408.5, measured value: LCMS m/z=409.4[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.35 (d, J=6.57Hz, 0.3H), 1.51 (d, J=6.57Hz, 2.7H), 1.72-1.85 (m, 1H), 2.04-2.24 (m, 2H), and 2.32-2.42 (m, 1H), 2.94-3.03 (m, 1H), and 3.06-3.24 (m, 2H), 3.25-3.36 (m, 5H), 3.48 (t, J=5.31Hz, 2H), 3.52-3.70 (m, 3H), 3.74-3.83 (m, 1H), 4.18 (dd, J=8.84,6.57Hz, 1H), 4.74 (t, J=8.84Hz, 1H), 5.11 (dd, J=8.97,6.69Hz, 1H), 7.46 (d, J=8.08Hz, 4H), 7.69 (dd, 4H).

Embodiment 1.7:(R)-preparation of 3-sec.-propyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 7).

In the argon gas atmosphere, to (R)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (and 0.417g, 2.110mmol) add in the solution in dimethyl formamide (3mL) sodium hydride (0.048g, 1.192mmol), add then 2-iodopropane (0.420mL, 4.22mmol).The reaction mixture stirring is spent the night, and with ethyl acetate (50mL) dilution, is HCl solution (10mL, twice), the salt water washing of 1M with concentration, with dried over sodium sulfate and concentrated, obtains (R)-4-(4-chloro-phenyl-)-3-sec.-propyl-oxazolidine-2-ketone.

The method similar methods of describing among use and the embodiment 1.2 is by (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.185g, 0.794mmol) and (R)-4-(4-chloro-phenyl-)-3-sec.-propyl-oxazolidines of preparing above-2-ketone preparation, obtain the hydrochloride (200mg, 22%) of title compound.C ₂₅H ₃₂N ₂O ₂The accurate mass calculated value: 392.5, measured value: LCMS m/z=393.3[M+H] ⁺ ¹HNMR (400MHz, methyl alcohol-d ₄) δ ppm 1.01 (d, J=6.82Hz, 3H), 1.29 (d, J=7.07Hz, 3H), 1.34 (d, J=6.57Hz, 0.3H), 1.51 (d, J=6.57Hz, 2.7H) 1.73-1.84 (m, 1H), 2.04-2.22 (m, 2H), 2.32-2.43 (m, 1H), 3.07-3.23 (m, 2H), 3.25-3.33 (m, 2H), and 3.51-3.61 (m, 1H), 3.61-3.71 (m, 1H), 3.74-3.84 (m, 2H), 4.15 (dd, J=8.59,6.06Hz, 1H), 4.68 (t, J=8.84Hz, 1H), 5.04 (dd, J=8.97,6.19Hz, 1H), 7.48 (dd, J=20.21,8.34Hz, 4H), 7.69 (dd, J=14.27,8.21Hz, 4H).

Embodiment 1.8:(R)-and 3-methyl-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 8).

The method similar methods of describing among use and the embodiment 1.5 is by (R)-4-(4-bromobenzyl) oxazolidine-2-ketone (0.204g, 0.797mmol), methyl iodide (0.099mL, 1.593mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.186g, 0.796mmol) preparation, obtain the hydrochloride (179mg, 54%) of title compound.C ₂₄H ₃₀N ₂O ₂The accurate mass calculated value: 378.5, measured value: LCMSm/z=379.4[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.34 (d, J=6.32Hz, 0.3H), 1.51 (d, J=6.32Hz, 2.7H), 1.72-1.84 (m, 1H), 2.03-2.23 (m, 2H), 2.31-2.43 (m, 1H), 2.83-2.96 (m, 4H), 3.08-3.21 (m, 3H), 3.24-3.32 (m, 2H), 3.49-3.69 (m, 2H), 3.78 (d, J=4.04Hz, 1H), 4.06-4.17 (m, 2H), and 4.24-4.33 (m, 1H), 7.35 (d, J=8.08Hz, 2H), 7.43 (d, J=7.83Hz, 2H), 7.62 (dd, J=11.75,7.96Hz, 4H).

Embodiment 1.9:(R)-and 3-(2-methoxy ethyl)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 9).

The method similar methods of describing among use and the embodiment 1.6 is by (R)-4-(4-bromobenzyl) oxazolidine-2-ketone (0.201g, 0.785mmol), 1-bromo-2-methyl ethyl ether (0.148mL, 1.570mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.183g, 0.786mmol) preparation, obtain the hydrochloride (216mg, 60%) of title compound.C ₂₆H ₃₄N ₂O ₃The accurate mass calculated value: 422.6, measured value: LCMS m/z=423.2[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.32 (d, J=6.57Hz, 0.3H), 1.48 (d, J=6.57Hz, 2.7H) 1.71-1.82 (m, 1H), 2.03-2.19 (m, 2H), and 2.29-2.40 (m, 1H), 2.81 (dd, J=13.64,7.58Hz, 1H), 3.03-3.21 (m, 3H), and 3.22-3.31 (m, 2H), 3.33-3.43 (m, 4H), and 3.48-3.79 (m, 6H), 4.08-4.14 (m, 1H), and 4.21-4.32 (m, 2H), 7.32 (d, J=8.34Hz, 2H), 7.41 (d, J=8.34Hz, 2H), 7.59 (dd, J=12.88,8.34Hz, 4H).

Embodiment 1.10:(S)-and 3-methyl-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 11).

In the argon gas atmosphere, to (S)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-keto hydrochloride (0.202g, 0.504mmol) at first add sodium hydride (0.050g in the solution in dimethyl formamide (2mL), 1.260mmol), add then methyl iodide (0.031mL, 0.504mmol).The reaction mixture stirring is spent the night, and with ethyl acetate (20mL) dilution, is HCl solution (2mL, twice), the salt water washing of 1M with concentration, with dried over sodium sulfate and concentrated.Resistates is by preparation property HPLC purifying (use 21.2x 250Mm C18 post, last 55 minutes with the 10-75% acetonitrile/water wash-out that contains 0.1% trifluoroacetic acid).Merge the HPLC cut of gained and evaporate acetonitrile.With concentration is the Na of 2M ₂CO ₃Solution makes remainder water solution be alkalescence, and is saturated with sodium-chlor, and with ethyl acetate extraction three times.The acetic acid ethyl ester extract that merges also filters with dried over mgso.In filtrate, add HCl (concentration is the diethyl ether solution of 1M, 1mL), removal of solvent under reduced pressure.Then this material is suspended in the water again, freezing and freeze-drying obtains the hydrochloride (65mg, 31%) of title compound.C ₂₄H ₃₀N ₂O ₂The accurate mass calculated value: 378.5, measured value: LCMS m/z=379.5[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.32 (d, J=6.57Hz, 0.3H) 1.48 (d, J=6.57Hz, 2.7H), 1.70-1.82 (m, 1H), 2.00-2.22 (m, 2H), and 2.29-2.40 (m, 1H), 2.83-2.93 (m, 4H), and 3.04-3.18 (m, 3H), 3.22-3.30 (m, 2H), and 3.46-3.58 (m, 1H), 3.58-3.69 (m, 1H), and 3.70-3.80 (m, 1H), 4.05-4.15 (m, 2H), 4.24-4.32 (m, 1H), 7.33 (d, J=8.34Hz, 2H), 7.41 (d, J=8.08Hz, 2H), and 7.55-7.64 (m, 4H).

Embodiment 1.11:(S)-and 3-(2-methoxy ethyl)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 12).

Use with embodiment 1.10 in the method similar methods described by (S)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-keto hydrochloride (0.209g, 0.521mmol) and 1-bromo-2-methyl ethyl ether (0.098mL, 1.043mmol) preparation, obtain the hydrochloride (90mg, 38%) of title compound.C ₂₆H ₃₄N ₂O ₃The accurate mass calculated value: 422.6, measured value: LCMSm/z=423.2[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.32 (d, J=6.57Hz, 0.3H), 1.48 (d, J=6.57Hz, 2.7H), 1.71-1.82 (m, 1H), 2.02-2.19 (m, 2H), 2.29-2.39 (m, 1H), 2.81 (dd, J=13.64,7.58Hz, 1H), 3.08-3.18 (m, 3H), 3.22-3.31 (m, 2H), 3.33-3.43 (m, 4H), 3.48-3.80 (m, 6H), 4.08-4.15 (m, 1H), 4.21-4.33 (m, 2H), 7.32 (d, J=8.08Hz, 2H), 7.41 (d, J=8.08Hz, 2H), 7.59 (dd, J=12.76,8.21Hz, 4H).

Embodiment 1.12:(R)-and 4-(4-bromobenzyl)-1, the preparation of 3-oxazine alkane-2-ketone.

Use with embodiment 1.1 in the method similar methods described by (R)-3-amino-4-(4-bromophenyl) butyric acid (1.000g, 3.87mmol) preparation obtains title compound, it is white solid (749mg, 72%). ¹H NMR (400MHz, CDCl ₃) δ ppm 1.13 (t, J=6.82Hz, 1H), 1.69-1.82 (m, 2H), 1.91-2.02 (m, 1H), 3.63-3.75 (m, 1H), 4.15-4.27 (m, 1H), 4.30-4.38 (m, 1H), 5.82 (s, 1H), 7.07 (d, J=8.34Hz, 2H), 7.46 (d, J=8.34Hz, 2H).

Embodiment 1.13:(R)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl)-1, the preparation of 3-oxazine alkane-2-ketone (compound 10).

In the 5mL bottle, place (R)-4-(4-bromobenzyl)-1,3-oxazine alkane-2-ketone (0.147g, 0.544mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (00.127g, 0.544mmol), tetrakis triphenylphosphine palladium (0) (0.019g, 0.016mmol), benzene (3mL), ethanol (1mL) and concentration is the sodium carbonate solution (1mL) of 2M.Reaction mixture was heated 1 hour at 100 ℃ in microwave radiation.Separate top organic phase and filtration.From filtrate, remove desolvate after, by preparation property HPLC purifying resistates (use 25x 250Mm C18 post, last 55 minutes) with the 10-75% acetonitrile/water wash-out that contains 0.1% trifluoroacetic acid.Merge gained HPLC cut and evaporate acetonitrile.With concentration is the Na of 2M ₂CO ₃Solution makes remainder water solution be alkalescence, and is saturated with sodium-chlor, and with ethyl acetate extraction three times.The acetic acid ethyl ester extract that merges also filters with dried over mgso.In filtrate, add HCl (concentration is the diethyl ether solution of 1M, 1mL), removal of solvent under reduced pressure.Then this material is suspended in the water again, freezing and freeze-drying obtains the hydrochloride (17mg, 8%) of title compound.C ₂₄H ₃₀N ₂O ₂The accurate mass calculated value: 378.5, measured value: LCMS m/z=379.5[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.32 (d, J=6.32Hz, 0.3H), 1.48 (d, J=6.32Hz, 2.7H), 1.67-1.82 (m, 2H), 1.87-1.96 (m, 1H), 2.02-2.20 (m, 2H), 2.30-2.40 (m, 1H), 2.78 (dd, J=13.26,8.21Hz, 1H), 2.98 (dd, J=13.39,5.31Hz, 1H), and 3.03-3.19 (m, 2H), 3.23-3.31 (m, 2H), and 3.50-3.57 (m, 1H), 3.58-3.69 (m, 1H), 3.70-3.80 (m, 2H), 4.16-4.24 (m, 1H), 4.27-4.36 (m, 1H), 7.33 (d, J=7.83Hz, 2H), 7.41 (d, J=8.08Hz, 2H), 7.60 (dd, J=14.53,7.96Hz, 4H).

Embodiment 1.14:(S)-and 4-(4-bromobenzyl)-1, the preparation of 3-oxazine alkane-2-ketone.

(1.025g 3.97mmol) prepares the method similar methods of describing among use and the embodiment 1.1, obtains title compound, and it is white solid (730mg, 68%) by (S)-3-amino-4-(4-bromophenyl) butyric acid. ¹H?NMR(400MHz，CDCl ₃)δppm?1.68-1.82(m，1H)，1.91-2.01(m，1H)，2.78(d，J＝6.82Hz，2H)，4.15-4.24(m，1H)，4.30-4.38(m，1H)，5.91(s，1H)，7.07(d，J＝8.08Hz，2H)，7.46(d，J＝8.34Hz，2H)。

Embodiment 1.15:(S)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl)-1, the preparation of 3-oxazine alkane-2-ketone (compound 13).

The method similar methods of describing among use and the embodiment 1.13 is by (S)-4-(4-bromobenzyl)-1,3-oxazine alkane-2-ketone (0.137g, 0.507mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.118g, 0.507mmol) preparation, obtain the hydrochloride of title compound, it is white solid (125mg, 59%).C ₂₄H ₃₀N ₂O ₂The accurate mass calculated value: 378.5, measured value: LCMS m/z=379.5[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.32 (d, J=6.57Hz, 0.3H), 1.49 (d, J=6.57Hz, 2.7H), 1.66-1.82 (m, 2H), 1.87-1.96 (m, 1H), 2.01-2.19 (m, 2H), 2.29-2.41 (m, 1H), 2.77 (dd, J=13.39,8.08Hz, 1H), 2.98 (dd, J=13.39,5.31Hz, 1H), and 3.04-3.20 (m, 2H), 3.22-3.31 (m, 2H), and 3.49-3.57 (m, 1H), 3.58-3.68 (m, 1H), 3.71-3.80 (m, 2H), 4.17-4.24 (m, 1H), 4.28-4.35 (m, 1H), 7.32 (d, J=8.34Hz, 2H), 7.41 (d, J=8.08Hz, 2H), 7.59 (dd, J=13.52,8.21Hz, 4H).

The preparation of embodiment 1.16:5-(4-bromophenyl) oxazolidine-2-ketone.

(1.003g, (0.222g 5.86mmol), adds ethanol (10mL) then 4.69mmol) to add sodium borohydride in the slurries in THF (19mL) to 2-amino-1-(4-bromophenyl) ethyl ketone.The reacting slurry stirring is spent the night,, wash with water, with dried over sodium sulfate and concentrated with ethyl acetate (100mL) dilution.Resistates is suspended in the methylene dichloride (9.5mL), the adding triethylamine (1.306mL 9.37mmol), cools off mixture in acetone/the dry ice bath, and the adding triphosgene (0.486g, 1.639mmol).After 20 minutes, remove ice bath, reaction mixture was stirred 90 minutes.Reaction mixture is HCl solution (10mL) and the salt water washing of 1M with ethyl acetate (50mL) dilution with concentration, with dried over sodium sulfate and concentrated.On the silicagel column resistates being carried out purifying (solution of 25-75% ethyl acetate in methylene dichloride), obtain title compound by chromatography, it is white solid (579mg, 51%). ¹H?NMR(400MHz，CDCl ₃)δppm?3.50(t，J＝8.08Hz，1H)，3.99(t，J＝8.72Hz，1H)，5.59(t，J＝8.08Hz，1H)，5.70(s，1H)，7.27(d，J＝3.79Hz，2H)，7.52-7.57(m，2H)。

The preparation of embodiment 1.17:5-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 14).

The method similar methods of describing among use and the embodiment 1.13 is by 5-(4-bromophenyl) oxazolidine-2-ketone (0.142g, 0.554mmol) and (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.129g, 0.554mmol) preparation, obtain the hydrochloride of title compound, it is white solid (149mg, 67%).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 350.5, measured value: LCMS m/z=351.4[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.32 (d, J=6.57Hz, 0.3H), 1.49 (d, J=6.57Hz, 2.7H), 1.70-1.82 (m, 1H), 2.02-2.20 (m, 2H), 2.29-2.40 (m, 1H), 3.05-3.19 (m, 2H), 3.22-3.30 (m, 2H), 3.48-3.57 (m, 2H), 3.59-3.68 (m, 1H), 3.72-3.80 (m, 1H), 4.02 (t, J=8.84Hz, 1H), and 5.68-5.75 (m, 1H), 7.42 (d, J=8.34Hz, 2H), 7.49 (d, J=8.34Hz, 2H), 7.65 (dd, J=14.27,8.21Hz, 4H).

The preparation of embodiment 1.18:4-(2-(t-butyldimethylsilyl oxygen base) ethyl) phenyl-boron dihydroxide.

(4.893g, 15.52mmol) solution in THF (39mL) is cooled to-78 ℃ in ice/acetone bath with (4-bromobenzene oxyethyl group) (tertiary butyl) dimethylsilane.(concentration is the hexane solution of 2.5M, and 8.07mL 20.17mmol), stirred 90 minutes slowly to add n-Butyl Lithium in this solution.Add then tri-isopropylborate (14.32mL, 62.1mmol), restir 2 hours.Make reaction mixture be warmed to room temperature then, continue 90 minutes.By adding concentration is that the HCl solution (40mL) of 1M is with the muddy reaction mixture cancellation of gained.Use ethyl acetate (400mL) diluted reaction mixture then and separate water layer.Ethyl acetate layer salt water washing is with dried over sodium sulfate and concentrated.Resistates obtains title compound by chromatography purifying (with 20-50% ethyl acetate/dichloromethane wash-out) on silicagel column, and it is colorless oil (2.31g, 53%). ¹H?NMR(400MHz，CDCl ₃)δppm?0.00(s，6H)，0.88(s，9H)，2.87-2.94(t，J＝6.95Hz，2H)，3.87(t，J＝6.95Hz，2H)，7.36(d，J＝7.83Hz，2H)，8.16(d，J＝7.83Hz，2H)。

Embodiment 1.19:(R)-4-(4 '-preparation of (2-(t-butyldimethylsilyl oxygen base) ethyl) biphenyl-4-base) oxazolidine-2-ketone

With (R)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (0.205g, 1.037mmol), 4-(2-(t-butyldimethylsilyl oxygen base) ethyl) phenyl-boron dihydroxide (0.291g, 1.037mmol), 2-(dicyclohexyl phosphino-)-2 ', 4 ', 6 '-triisopropyl-1,1 '-biphenyl (0.025g, 0.052mmol), potassiumphosphate (0.661g, 3.11mmol) and palladium (II) (4.66mg, 0.021mmol) mixture in tetrahydrofuran (THF) (4mL) under microwave radiation 120 ℃ the heating 1 hour.Filter reaction mixture, solid washes with acetonitrile.Concentrated filtrate, resistates is gone up purifying by chromatography at silicagel column (with 0-60% ethyl acetate/hexane wash-out), obtains title compound, and it is colorless oil (134mg, 30%).C ₂₃H ₃₁NO ₃The accurate mass calculated value of Si: 397.6, measured value: LCMS m/z=398.3[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ ppm 0.0 (s, 6H), 0.88 (s, 9H), 2.86 (t, J=6.95Hz, 2H), 3.84 (t, J=6.95Hz, 2H), 4.16-4.27 (m, 1H), 4.75 (q, J=8.84Hz, 1H), 4.92-5.02 (m, 1H), 7.29 (d, J=8.08Hz, 2H), 7.35 (d, J=1.77Hz, 1H), 7.40 (d, J=8.34Hz, 2H), 7.49 (d, J=8.08Hz, 2H), 7.61 (d, J=8.34Hz, 2H).

Embodiment 1.20:(R)-4-(4 '-preparation of (2-hydroxyethyl) biphenyl-4-base) oxazolidine-2-ketone

To (R)-4-(4 '-(2-(t-butyldimethylsilyl oxygen base) ethyl) biphenyl-4-base) oxazolidine-2-ketone (0.130g, 0.327mmol) in IPA (Virahol, 1.3mL) in solution in add HCl (concentration is 4M De dioxane solution, 1.226mL, 4.90mmol).Reaction mixture was stirred 1 hour.Obtain title compound (105mg, 100%) after the removal of solvent under reduced pressure.C ₁₇H ₁₇NO ₃The accurate mass calculated value: 283.3, measured value: LCMS m/z=284.4[M+H] ⁺, TLC: in methylene dichloride: ethyl acetate=in 1: 1, Rf=0.32.

Embodiment 1.21: the preparation of methylsulfonic acid (R)-(2-(4 '-(2-Yang Dai oxazolidine-4-yl) biphenyl-4-yl)) ethyl ester

To (R)-4-(4 '-(2-hydroxyethyl) biphenyl-4-base) oxazolidine-2-ketone (0.105g, 0.371mmol) in DCM (methylene dichloride, 1.5mL) in solution in add triethylamine (0.129mL, 0.927mmol), add methylsulfonyl chloride (0.058mL then, 0.741mmol), reaction mixture was stirred 1 hour.Reaction mixture is HCl solution (10mL, twice) and the salt water washing of 1M with concentration successively with ethyl acetate (50mL) dilution, uses dried over sodium sulfate.Obtain title compound after the removal of solvent under reduced pressure.Methylene dichloride in 1: 1: carry out TLC, Rf=0.51 in the ethyl acetate.

Embodiment 1.22:(R)-preparation of 4-(4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 17).

The methylsulfonic acid (R) of pulp in the acetonitrile (2mL) in the bottle-(2-(4 '-(2-Yang Dai oxazolidine-4-yl) biphenyl-4-yl)) ethyl ester (0.04g will be contained in, 0.111mmol), tetramethyleneimine (0.014mL, 0.166mmol) and salt of wormwood (0.076g, mixture 0.553mmol) under microwave radiation 120 ℃ the heating 2 hours.Be dissolved in the water reaction mixture and freeze-drying.By preparation property HPLC resistates is carried out purifying (use 21.2x250Mm C18 post, last 55 minutes, with the 5-50% acetonitrile/water wash-out that contains 0.1% trifluoroacetic acid).Freeze-drying HPLC cut obtains the trifluoroacetate (7.5mg, 15%) of title compound.C ₂₁H ₂₄N ₂O ₂The accurate mass calculated value: 336.4, measured value: LCMS m/z=337.5[M+H] ⁺ ¹HNMR (400MHz, methyl alcohol-d ₄) δ ppm 1.77-1.86 (m, 2H), 1.92-2.02 (m, 2H), 2.84-2.98 (m, 4H), and 3.24-3.31 (m, 2H), 3.44-3.53 (m, 2H), 3.97 (dd, J=8.59,6.57Hz, 1H), 4.59 (t, J=8.72Hz, 1H), 4.84 (dd, J=8.72,6.44Hz, 1H), 7.22 (dd, J=19.96,8.34Hz, 4H), and 7.39-7.48 (m, 4H).

Embodiment 1.23:(S)-preparation of 3-methyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 15).

Steps A: (S)-preparation of 4-(4-chloro-phenyl-)-3-first base oxazolidine-2-ketone.

To (S)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (250mg, 1.27mmol) in DMF (dimethyl formamide, 5.0mL) add in the solution in sodium hydride (60% in mineral oil dispersion) (76mg, 1.90mmol), add then methyl iodide (0.159mL, 2.53mmol).With the gained mixture stirring at room 18 hours.Reaction mixture is HCl solution (2x10mL) washing of 1M with EtOAc (50mL) dilution with concentration, also uses the salt water washing with the EtOAc extracting twice.The organism MgSO that merges ₄Drying is filtered and is concentrated, and obtains title compound, and it is a yellow oil, 100% crude product yield.C ₁₀H ₁₀ClNO ₂The accurate mass calculated value: 211.0, measured value: LCMS m/z=211.8[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ ppm, 2.71 (s, 3H), 4.05 (dd, J=7.83,6.32Hz, 1H), 4.56-4.72 (m, 2H), 7.25 (d, J=8.59Hz, 2H), 7.41 (d, J=8.34Hz, 2H).

Step B:(S)-preparation of 3-methyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 15).

In bottle, add (R)-4-(2-(the 2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (295mg that is dissolved among the THF (4.0mL), 1.266mmol), (S)-4-(4-chloro-phenyl-)-3-Jia Ji oxazolidine-2-ketone (268mg, 1.266mmol), 2-(dicyclohexyl phosphino-)-2 ', 4 ', 6 '-triisopropyl-1, and 1 '-biphenyl (30mg, 0.063mmol), potassiumphosphate (806mg, 3.80mmol) and palladium (II) (5.69mg, 0.025mmol).The gained reaction mixture was heated 1 hour at 120 ℃ under microwave radiation.After 1 hour, LCMS shows that reaction finishes.The reaction mixture dilute with water, separation of organic substances.Water layer extracts with EtOAc.Concentrate the organism that merges, be dissolved in ACN/H ₂Among the O (containing AcOH), and by HPLC purifying (contain the acetonitrile solution of 0.1%TFA/contain the aqueous solution of 0.1%TFA).The cut concentration that merges is the Na of 2M ₂CO ₃Solution alkalizes and extracts 3 times with EtOAc.The organism MgSO that merges ₄Drying is filtered and is concentrated.Resistates is dissolved among the MeOH (5mL).(concentration is the Et of 1M successively to add HCl then ₂O solution, 1mL) and EtOAc (5mL).Concentrate the gained mixture, obtain the hydrochloride of title compound, it is white solid (408mg, 55% yield).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMS m/z=365.5[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm, 1.38 (d, J=6.32Hz, 3H), 1.62-1.76 (m, 1H), 1.94-2.11 (m, 2H), 2.17-2.32 (m, 1H), 2.65-2.75 (m, 3H), and 2.92-3.16 (m, 4H), 3.18-3.35 (m, 2H), 3.39-3.52 (m, 1H), 3.53-3.65 (m, 1H), 4.13 (dd, J=8.72,6.95Hz, 1H), 4.70 (t, J=8.84Hz, 1H), and 7.34-7.47 (m, 4H), 7.55-7.76 (m, 4H).

Embodiment 1.24:(S)-preparation of 3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 16).

Steps A: (S)-preparation of 4-(4-chloro-phenyl-)-3-(2-methoxy ethyl) oxazolidine-2-ketone.

To (S)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (250mg, 1.27mmol) add sodium hydride (60% in mineral oil dispersion) (76mg in the solution in DMF (5.0mL), 1.90mmol), add then 1-bromo-2-methyl ethyl ether (0.235mL, 2.53mmol).With the gained mixture stirring at room 18 hours.Reaction mixture is HCl solution (2x 10mL) washing of 1M with EtOAc (50mL) dilution with concentration, uses the EtOAc extracting twice, and uses the salt water washing.The organism MgSO that merges ₄Drying is filtered and is concentrated, and obtains yellow oil with 100% crude product yield.C ₁₂H ₁₄ClNO ₃The accurate mass calculated value: 255.1, measured value: LCMS m/z=256.5[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ ppm, 2.84-2.98 (m, 1H), 3.29 (s, 3H), 3.36-3.45 (m, 1H), 3.49-3.67 (m, 2H), 4.07 (dd, J=8.84,6.57Hz, 1H), 4.63 (t, J=8.84Hz, 1H), 4.97 (dd, J=8.84,6.82Hz, 1H), 7.25 (d, J=8.34Hz, 2H), 7.39 (d, J=8.34Hz, 2H).

Step B:(S)-preparation of 3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 16).

In bottle, add (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (294mg, 1.263mmol), (S)-4-(4-chloro-phenyl-)-3-(2-methoxy ethyl) oxazolidine-2-ketone (323mg, 1.263mmol), 2-(dicyclohexyl phosphino-)-2 ', 4 ', 6 '-triisopropyl-1, and 1 '-biphenyl (30mg, 0.063mmol), potassiumphosphate (804mg, 3.79mmol), palladium (II) (5.67mg, 0.025mmol) and THF (4.0mL).The gained reaction mixture was heated 1 hour at 120 ℃ under microwave radiation.The reaction mixture dilute with water, separation of organic substances.Water layer extracts with EtOAc.Concentrate the organism that merges, be dissolved in ACN/H ₂Among the O (containing AcOH), and by HPLC purifying (contain the acetonitrile solution of 0.1%TFA/contain the aqueous solution of 0.1%TFA).The cut concentration that merges is the Na of 2M ₂CO ₃Solution alkalizes and extracts 3 times with EtOAc.The organism MgSO that merges ₄Drying is filtered and is concentrated.Resistates is dissolved among the MeOH (5mL).(concentration is the Et of 1M successively to add HCl then ₂O solution, 1mL) and EtOAc (5mL).Concentrate the gained mixture, obtain the hydrochloride of title compound, it is white solid (281mg, 50% yield).C ₂₅H ₃₂N ₂O ₃The accurate mass calculated value: 408.2, measured value: LCMSm/z=409.4[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.33 (d, J=6.32Hz, 3H), 1.56-1.72 (m, 1H), and 1.89-2.04 (m, 2H), 2.11-2.27 (m, 1H), and 2.81-3.14 (m, 6H), 3.27-3.43 (m, 4H), 3.45 (t, J=5.31Hz, 2H), 3.47-3.63 (m, 2H), 4.16 (dd, J=8.72,6.69Hz, 1H), 4.71 (t, J=8.84Hz, 1H), 5.08 (dd, J=8.84,6.57Hz, 1H), 7.40 (dd, J=16.04,8.21Hz, 4H), 7.61 (d, J=8.08Hz, 2H), 7.68 (d, J=8.34Hz, 2H).

Embodiment 1.25:(S)-preparation of 4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 2).

Steps A: (S)-preparation of 2-amino-2-(4-chloro-phenyl-) alcoholic acid.

At 0 ℃, by feed hopper last 45 fens clockwise (S)-2-amino-2-(4-chloro-phenyl-) acetate (10.0g, 53.9mmol) add in the solution in THF (216mL) the borine tetrahydrofuran complex that concentration is 1.0M (216mL, 216mmol).Remove ice bath, with reaction mixture stirring at room 3.25 hours.(6.79mL, 377mmol), (40.4mL 202mmol) (lasts dropping in 15 minutes) to add sodium hydroxide solution then to add entry.Reaction mixture is heated to 65 ℃ and stirred 18 hours.The concentrating under reduced pressure reaction mixture.Resistates is dissolved among the DCM (500mL), separates organic phase, and water (200mL) washing.Water is further used DCM (2x 250mL) extraction.Merge organism, use Na ₂SO ₄Drying, concentrating under reduced pressure obtains title compound, and it is white solid (8.55g, 92% yield).C ₈H ₁₀The accurate mass calculated value of ClNO: 171.1, measured value: LCMS m/z (%)=172.2 ([M+H] ⁺, ³⁵Cl, 100), 174.2 ([M+H] ⁺, ³⁷Cl, 33). ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 3.47-3.57 (m, 1H), 3.59-3.69 (m, 1H), 3.93 (dd, J=7.58,5.05Hz, 1H), 7.23-7.42 (m, 4H).

Step B:(S)-preparation of 4-(4-chloro-phenyl-) oxazolidine-2-ketone.

At 25 ℃, to (S)-2-amino-2-(4-chloro-phenyl-) ethylate hydrochlorate (2.00g, 9.61mmol) and diisopropyl ethyl amine (6.71mL 38.4mmol) adds triphosgene (3.14g in the solution in DCM (40mL), 10.6mmol), cause gas to be emitted in a large number.Mixture was stirred 18 hours and concentrating under reduced pressure.Solid residue is dissolved in the 5%HCl solution (50mL), with EtOAc (2x 75mL) extraction.Organic phase is used Na with salt solution (60mL) washing ₂SO ₄Drying is filtered and concentrating under reduced pressure.Rough resistates obtains title compound by purified by flash chromatography (40-100%EtOAc/ hexane), and it is transparent oily matter (0.400g, 21% yield).C ₉H ₈ClNO ₂The accurate mass calculated value: 197.0, measured value: LCMSm/z=198.1; ¹H NMR (400MHz, CDCl ₃) δ ppm 4.13 (dd, J=8.59,6.82Hz, 1H), 4.72 (t, J=8.72Hz, 1H), 4.91-4.97 (m, 1H), 6.44 (s, 1H), 7.27 (d, J=8.34Hz, 2H), 7.37 (d, J=8.59Hz, 2H).

Step C:(S)-preparation of 4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 2).

To (S)-4-(4-chloro-phenyl-) oxazolidine-2-ketone (0.150g, 0.759mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.212g, 0.911mmol), potassium acetate (0.483mL, 2.28mmol) and 2-dicyclohexyl phosphino--2 ', 4 ', 6 '-triisopropyl-1,1 '-biphenyl (18.1mg, 0.038mmol) add in the solution in anhydrous THF (4mL) palladium (II) (3.41mg, 0.015mmol).Reaction mixture was heated 45 minutes at 120 ℃ under microwave radiation.Reaction mixture is filtered pass through Celite ^TM, filter cake washs with EtOAc (30mL).Concentrated filtrate.Resistates is by preparation property HPLC purifying.With the cut freeze-drying that merges, obtain the trifluoroacetate (0.100g, 29% yield) of title compound.Described trifluoroacetate is converted into hydrochloride, and described hydrochloride is a white solid.C ₂₂H ₂₆N ₂O ₂The accurate mass calculated value: 350.2, measured value: LCMS m/z=351.3[M+H] ⁺ ¹H NMR (400MHz, DMSO-d ₆) δ ppm1.23 (s, 0.3H), 1.40 (d, J=5.31Hz, 2.7H), 1.54-1.70 (m, 1H), and 1.87-2.04 (m, 2H), 2.11-2.27 (bs, 1H), 2.96-3.23 (m, 4H), and 3.27-3.71 (m, 2H), 4.04 (dd, J=8.34,6.32Hz, 1H), 4.70 (t, J=8.59Hz, 1H), 4.96-5.03 (m, 1H), 7.42 (t, J=7.58Hz, 4H), 7.68 (dd, J=17.31,8.21Hz, 4H), 8.22 (s, 1H), 10.15 (s, 1H).

Embodiment 1.26:(S)-and 4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 1).

Steps A: (S)-preparation of 2-amino-3-(4-bromophenyl) third-1-alcohol.

With with embodiment 1.25, the similar mode of the mode of describing in the steps A prepares title compound.C ₉H ₁₂The accurate mass calculated value of BrNO: 229.0, measured value: LCMS m/z (%)=230.2; ¹HNMR (400MHz, CDCl ₃) δ ppm 2.84 (d, J=6.82Hz, 3H), 4.04-4.15 (m, 2H), 4.46 (t, J=8.21Hz, 1H), 5.62 (s, 1H), 7.07 (d, J=8.34Hz, 2H), 7.45-7.50 (m, 2H).

Step B:(S)-preparation of 4-(4-bromobenzyl) oxazolidine-2-ketone.

With with embodiment 1.25, the similar mode of the mode of describing among the step B prepares title compound.C ₁₀H ₁₀BrNO ₂The accurate mass calculated value: 255.0, measured value: LCMS m/z (%)=256.2[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ ppm 2.75-2.92 (m, 2H), 4.00-4.19 (m, 2H), 4.43 (t, J=8.21Hz, 1H), 5.94-6.07 (m, 1H), 7.06 (d, J=8.34Hz, 2H), 7.46 (d, J=8.34Hz, 2H).

Step C:(S)-and 4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) preparation of oxazolidine-2-ketone (compound 1).

To in ethanol/benzene (4mL, 1: 3EtOH: (the 4-bromobenzyl) oxazolidine-2-ketone (0.150g of (the S)-4-in mixture benzene), 0.586mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide (0.137g, 0.586mmol) and concentration be the aqueous sodium carbonate (0.586mL of 2.0M, 1.17mmol) solution in add tetrakis triphenylphosphine palladium (O) (20.3mg, 0.018mmol).Reaction mixture was heated 1 hour at 100 ℃ under microwave radiation.Separate organic phase, water extracts with EtOAc (25mL).The organism that concentrating under reduced pressure merges.By preparation property HPLC purifying resistates.With the pure fraction freeze-drying that merges, obtain the trifluoroacetate (0.152g, 56% yield) of title compound.C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMS m/z=365.2[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm1.34 (d, J=6.82Hz, 0.3H), 1.50 (d, J=6.57Hz, 2.7H), 1.72-1.85 (m, 1H), 2.01-2.22 (m, 2H), 2.31-2.43 (m, 1H), 2.87-2.99 (m, 2H), 3.05-3.22 (m, 2H), 3.24-3.31 (m, 2H), 3.50-3.60 (m, 1H), 3.60-3.71 (m, 1H), 3.73-3.82 (m, 1H), 4.15-4.26 (m, 2H), 4.44 (s, 1H), 7.35 (d, J=8.08Hz, 2H), 7.43 (d, J=8.08Hz, 2H), 7.62 (dd, J=13.26,8.21Hz, 4H).

Embodiment 1.27:(R)-and 4-(4 '-(2-(R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-keto hydrochloride (compound 3).

Steps A: (R)-preparation of 2-(tert-butoxycarbonyl amino)-2-(4-hydroxy phenyl) methyl acetate.

To refrigerative in ice bath (R)-(4-hydroxyl) phenylglycocoll (83.58g, 500.0mmol) thionyl chloride in the suspension in methyl alcohol (500mL) (36.5mL, 500mmol).Reaction mixture was stirred 18 hours at reflux temperature, be cooled to room temperature then.Add N then, the N-diisopropyl ethyl amine (87mL, 500mmol), last subsequently dripped in 1 hour in methyl alcohol (200mL) one contract tert-Butyl dicarbonate (109g, 500mmol).Cause gentle heat release, control described heat release by adding gradually, and temperature of reaction remains below reflux temperature always.Stir after 2 hours, show by LCMS, described reaction looks and does not finish, forms the free acid of about 5% described product.The pH of reaction mixture (being initially 10) has reduced to 4.Add more N, the N-diisopropyl ethyl amine is 9-10 up to pH.Add more and in methyl alcohol (10mL), one to contract that (3.2g 15mmol), and continues to stir one hour tert-Butyl dicarbonate again.Then solvent is reduced to half of initial volume, and gained solution is poured in the water (1.2L), form white depositions.After manual turn and making gained suspension leave standstill 1 hour, collect white solid by filtering.Then with this substance dissolves in hot Virahol (200mL, 60 ℃), in ice bath, be cooled to 10 ℃ afterwards, with a spot of pure products solution is carried out kind of a crystalline substance.After leaving standstill 1 hour and stirring once in a while, filter and collect white solid, wash with cold Virahol (50mL).Filtrate is concentrated into about 100mL, freezing in ice bath, filter then to provide second batch.The solids that merge 60 ℃ of dryings in vacuum drying oven obtain title compound to constant weight, and it is white solid (119.6g, 85%).C ₁₄H ₁₉NO ₅The accurate mass calculated value: 281.3; Measured value: LCMS m/z=282.5[M+H] ⁺. ¹H NMR (400MHz, DMSO-d ₆) δ 1.38 (s, 9H), 3.59 (s, 3H), 5.06 (d, J=7.84Hz, 1H), 6.71 (d, J=8.43Hz, 2H), 7.82 (d, J=8.48Hz, 2H), 7.61 (d, J=7.82Hz, 1H), 9.49 (s, 1H).

Step B:(R)-preparation of 2-hydroxyl-1-(4-hydroxy phenyl) ethyl carbamic acid tert-butyl ester.

In ice bath with (R)-2-(tert-butoxycarbonyl amino)-2-(4-hydroxy phenyl) methyl acetate (56.3g, 200.0mmol) in anhydrous THF (2.0L) solution be cooled to 5 ℃.(23.6g 620mmol), keeps internal reaction temperature to be lower than 25 ℃ to last 1 hour slow adding lithium aluminum hydride.Continue to stir 1 hour, last 45 minutes then and use 1N NH ₄Cl (150mL) will react careful cancellation, keep temperature to be lower than 30 ℃, add 0.3N HCl (400mL) then.Then the gained suspension filtered is passed through Celite ^TM, and wash with ethyl acetate (2.0L).Add 1N HCl (250mL) in filtrate, purpose is that water layer is acidified to pH1.Discard aqueous extract, MgSO is used in organic extract water (400mL), salt solution (200mL) flushing ₄Dry.Remove and to desolvate, then in vacuum drying oven 60 ℃ of dryings, obtain white solid (46.2g, 91%).C ₁₃H ₁₉NO ₄The accurate mass calculated value: 253.2; Measured value: LCMS m/z=254.3[M+H] ⁺ ¹H NMR (400MHz DMSO-d ₆) δ 1.36 (s, 9H), 3.42 (t, J=5.88Hz, 2H), 4.41 (m, 1H), 4.69 (t, J=5.70Hz, 1H), 6.67 (d, J=8.36Hz, 2H), 7.06 (m, 3H), 9.22 (s, 1H).

Step C:(R)-preparation of 4-(4-hydroxy phenyl) oxazolidine-2-ketone.

With (R)-2-hydroxyl-1-(4-hydroxy phenyl) ethyl carbamic acid tert-butyl ester (35g, 138mmol) solution in THF (420mL) is cooled to 1.2 ℃ of (inside; Ice bath).Cooling slowly adds thionyl chloride down, and (11.09mL, 152mmol), it is 3.0 ℃ that gentle heat release to temperature takes place.After add finishing, mixture is cooled to 0.5 ℃, kept 10-12 minute, warmly gradually rise to room temperature and stir and spend the night in this temperature.(385mL of collection) is concentrated into about 35mL with reaction mixture by underpressure distillation.Remaining slurries are in stirring at room and add MTBE (40mL).Product begins crystallization and separates out.Slurries were stirred 15 minutes and filtered.Filter cake MTBE washed twice.In vacuum drying oven, obtain title compound (15.05g, 60.8%) 50 ℃ of dryings.C ₉H ₉NO ₃The accurate mass calculated value, 179.06; Measured value: LCMSm/z=180.2[M+H] ⁺. ¹H NMR (400MHz, DMSO-d ₆) δ 3.93 (dd, J ₁=8Hz, J ₂=12Hz, 1H), 4.59 (t, J=8Hz, 1H), 4.81 (t, J=8Hz, 1H), 6.76 (d, J=8.8Hz, 2H), 7.12 (d, J=8.4Hz, 2H), 8.05 (s, 1H), 9.48 (s, 1H).

Step D: the preparation of trifluoromethanesulfonic acid (R)-(4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester.

To (R)-4-(4-hydroxy phenyl) oxazolidine-2-ketone (and 15.05g, 84mmol) in acetonitrile (180mL) slurries in add pyridine (20.38mL, 252mmol).Mixture is stirred in nitrogen atmosphere.(17.03mL 101mmol), keeps temperature of reaction at 17 to 20 ℃ (ice bath) slowly to add trifluoromethanesulfanhydride anhydride.Reaction mixture was stirred 30 minutes at 16 to 20 ℃, then stirring at room 1.5 hours.Removal of solvent under reduced pressure.Add entry (150mL), mixture was stirred 30 minutes.The solid collected by filtration throw out washes with water twice and reduces pressure air-dryly, obtains solids cake compresses (29.26g).At 25 ℃, above-mentioned solid is dissolved among the warm EtOH (125mL), slowly add entry (80mL) and mixture is fully stirred, keep internal temperature at 17 to 18 ℃.Mixture is spent the night 17-19 ℃ of stirring.The solid collected by filtration throw out is with 1: 1EtOH/H ₂The O washed twice and in vacuum drying oven 50 ℃ of dried overnight, obtain first subheading compound (18.7g).Mother liquor dilutes with more water, and second batch of solid of filtering separation is also dry, obtains title compound (2.77g).C ₁₀H ₈F ₃NO ₅The accurate mass of S: 311.01; Measured value: LCMS m/z=312.3[M+H] ⁺. ¹H NMR (400MHz, DMSO-d ₆)

4.02 (dd, J ₁=8Hz, J ₂=8Hz, 1H), 4.68 (t, J=8Hz, 1H), 5.01 (dd, J ₁=12Hz, J ₂=8Hz, 1H), 7.55 (s, 4H), 8.28 (s, 1H).

Step e: (R)-preparation of 1-(4-bromobenzene ethyl)-2-crassitude.

To the methylsulfonic acid in acetonitrile (1.2L) (4-bromobenzene ethyl) ester (120g, add in solution 0.43Mol) (R)-2-crassitude tartrate (121g, 0.516Mol), add then salt of wormwood (184g, 1.33Mol).With mixture heating up to 60 ℃, add entry (60mL), mixture is stirred in nitrogen atmosphere spend the night.Mixture is cooled to room temperature, filters and removal of solvent under reduced pressure.Resistates is absorbed among the EtOAc (400mL) ethyl acetate layer water (2x 150mL) washing.Organic layer extracts with 2N HCl (2x150mL).The aqueous acids layer extracts to pH 12-14 and with ethyl acetate (2x 150mL) with the 50%NaOH acidified aqueous solution.MgSO is used in organic layer water (2x 100mL) washing that merges ₄Dry and concentrated, obtain title compound (104.4g, 90% yield).C ₁₃H ₁₈The accurate mass calculated value of BrN: 267.06; Measured value: LCMS m/z=268.2. ¹H NMR (400MHz, CDCl ₃) δ 1.09 (d, J=6Hz, 3H), 1.38-1.48 (m, 1H), 1.66-1.96 (m, 3H), 2.14-2.34 (m, 3H), 2.7-2.83 (m, 2H), 2.97 (m, 1H), 3.22 (m, 1H), 7.09 (d, J=6.4Hz, 2H), 7.39 (d, J=6.4Hz, 2H).

Step F: (R)-preparation of 4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride.

With argon gas purge (R)-1-(4-bromobenzene ethyl)-2-crassitude (30.0g, the 112mmol) solution in anhydrous THF (300mL), in dry ice/acetone batch-78 ℃ of coolings.(91mL is 145mmol) to keep temperature of reaction at-72 ℃ to-68 ℃ to drip n-Butyl Lithium.Use more anhydrous THF (50mL) flushing funnel.After the adding of butyllithium finishes, mixture was stirred 15 minutes.-72 ℃ to-66 ℃ add tri-isopropylborate (104mL, 447mmol).Re-use more THF (50mL) flushing funnel.The adding of tri-isopropylborate makes reaction mixture reach room temperature (lasting 20 minutes) gradually after finishing, and stirring at room 1 hour.(2M is acid up to forming canescence suspension and mixture 130mL) to drip HCl.The mixture stirring is spent the night.Filter the white solid crystal,, obtain the HCl salt (26.538g, 88%) of title compound with THF (150mL) washing and drying under reduced pressure; C ₁₃H ₂₀BNO ₂The accurate mass calculated value: 233.1; Measured value: LCMS m/z=234.3[M+H] ⁺

Step G:(R)-preparation of 4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (R)-(4-(2-Yang Dai oxazolidine-4-yl) phenyl) (8.25g 26.5mmol) transfers in the 500mL three neck round-bottomed flasks that temperature sensor (temperature probe), condenser and nitrogen inlet are installed ester.(7.86g 29.2mmol), adds toluene (100mL) to the phenyl-boron dihydroxide hydrochloride then to add (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl).Stir the mixture, add yellow soda ash (8.99g, 85mmol) solution in water (33.0mL) 21 ℃ (it is 33 ℃ that heat release to temperature takes place).Mixture stirred in nitrogen atmosphere and heat rise to 40 ℃.Add (at about 40 ℃) Pd (PPh ₃) ₄(0.919g 0.795mmol), and is heated to 90 ℃ up to observing gentle reflux with reaction mixture.Mixture was stirred 80 minutes.Mixture is cooled to room temperature and stirs spend the night.Filter solid sediment, wash with water for several times and in vacuum drying oven 50 ℃ of dryings 3 hours, obtain title compound (9.11g, 98%), it is a free alkali.C ₂₂H ₂₆N ₂O ₂The accurate mass calculated value: 350.2; Measured value: LCMS m/z=351.2[M+H] ⁺ ¹H?NMR(400MHz，DMSO-d ₆))δ1.0(d，J＝6Hz，3H)，1.28(m，1H)，1.63(m，2H)，1.85(m，1H)，2.11(q，J ₁＝17.6Hz，J ₂＝8.8Hz，1H)，2.24(m，2H)，2.67-2.83(m，2H)，2.97(m，1H)，3.13(m，1H)，4.04(dd，J ₁＝8.4Hz，J ₂＝8.4Hz，1H)，4.69(t，J＝8.4Hz，1H)，4.98(t，J＝8Hz，1H)，7.32(d，J＝8Hz，2H)，7.41(d，J＝8Hz，2H)，7.57(d，J＝8Hz，2H)，7.68(d，J＝8Hz，2H)，8.22(s，1H)。

Step H:(R)-and 4-(4 '-(2-(R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-keto hydrochloride.

(9.11g 26.0mmol) transfers in the 250mL three neck round-bottomed flasks that temperature sensor, feed hopper and nitrogen inlet are installed with the free alkali of (R)-4-(4 '-(2-(R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone.Add ethanol (91mL), slurries are warmed to 40 ℃, obtain clear solution.It further is heated to 45 ℃ and dripping hydrochloric acid, and (concentration is the EtOH solution of 1.25M; 42.4mL, 53.0mmol).When adding about 85%HCl solution, described HCl salt begins crystallization.After add finishing, slurries were stirred 5 minutes at 47-48 ℃, be cooled to room temperature gradually and stir and spend the night.Remove EtOH by underpressure distillation and the volume of mixture is reduced to about 58mL, resistates becomes mashed prod.Add EtOH (10mL) and make it become slurries, filter described slurries.Solids cake compresses is with EtOH (10mL), MTBE washing, in vacuum drying oven 50 ℃ of dryings 3 hours.With above-mentioned solid (8.47g) recrystallization from EtOH (160mL), obtain title compound (7.68g, 80% yield) .C ₂₂H ₂₆N ₂O ₂The accurate mass calculated value: 350.2 (free alkalis); Measured value: LCMS m/z=351.2[M+H] ⁺. ¹H NMR (400MHz, DMSO-d ₆) δ 1.42 (d, J=6.4Hz, 3H), 1.64 (m, 1H), 1.95 (m, 2H), 2.18 (m, 1H), 3.13 (m, 4H), 3.35-3.52 (m, 2H), 3.62 (m, 1H), 4.04 (dd, J ₁=8.4Hz, J ₂=8.4Hz, 1H), 4.69 (t, J=8.4Hz, 1H), 4.98 (t, J=8Hz, 1H), 7.41 (dd, J ₁=6.8Hz, J ₂=6.8Hz, 4H), 7.65 (d, J=8Hz, 2H), 7.69 (d, J=8.4Hz, 2H), 8.25 (s, 1H), 10.67 (bs, 1H).

Embodiment 1.28:(R)-preparation of 3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-keto hydrochloride (compound 6).

Steps A: (R)-preparation of 3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

In the nitrogen atmosphere, under effectively stirring to sodium hydride (0.279g, 11.63mmol) (465mg, 60% dispersion in mineral oil) add in the slurries in DMF (15mL) (R)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-keto hydrochloride (1.5g, 3.88mmol), add then 1-bromo-2-methyl ethyl ether (0.437mL, 4.65mmol).With reaction mixture stirring at room 5 hours.Lcms analysis shows formation 51.8% product, and (m/z 409.4; [M+H] ⁺) and residue 48.2% starting material.Add 1-bromo-2-methoxy propane (128 μ L), and the reaction mixture stirring is spent the night in room temperature.Lcms analysis shows formation 92.6% product.Mixture water (35mL) dilutes and extracts with ethyl acetate (2x 30mL).Ethyl acetate layer extracts with the 2N HCl aqueous solution (2x 25mL).Merge water, successively use the washing of ethyl acetate (1x 25mL) and heptane (1x 25mL).Cooling (ice-water bath) water also alkalizes to pH 12-14 by the slow adding 50%NaOH aqueous solution, and extract with ethyl acetate (2x 25mL).Organic phase water (2x 25mL) washing that merges, dry (Na ₂SO ₄) and removal of solvent under reduced pressure, obtain brown oil.

Step B:(R)-preparation of 3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-keto hydrochloride.

With embodiment 1.28, the product of steps A is dissolved in the ethanol (1.5mL), and solution is fully stirred.(6.20mL, 7.75mmol) (concentration is the ethanolic soln of 1.25M) are spent the night the mixture stirring to add hydrochloric acid.Add MTBE, mixture was placed two days at about 4 ℃.Removal of solvent under reduced pressure is spent the night the resistates drying under reduced pressure, obtains HCl salt, and it is spumescence solid (1.02g, 59%).C ₂₅H ₃₂N ₂O ₃The accurate mass calculated value of (free alkali): 408.53; Measured value: 409.5[M+H] ⁺ ¹H NMR (Bruker, 400MHz, DMSO-d ₆) δ 1.43 (d, 3H, J=6.4Hz), 1.95 (m, 2H), 1.64 (m, 1H), 2.17 (m, 1H), 2.80 (m, 1H), 3.12 (m, 4H), 3.19 (s, 3H), 3.36 (m, 3H), 3.50 (m, 2H), 3.62 (m, 1H), 4.05 (dd, J ₁=6.8Hz, J ₂=6.8Hz, 1H), 4.65 (t, J=8.8Hz, 1H), 5.02 (t, J=8Hz, 1H), 7.41 (dd, J ₁=8Hz, J ₂=8Hz, 4H), 7.66 (d, J=8Hz, 2H), 7.72 (d, J=8Hz, 2H), 10.85 (bs, 1H).

Embodiment 1.29:(R)-preparation of 3-sec.-propyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-keto hydrochloride (compound 7).

Steps A: (R)-preparation of 3-sec.-propyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

In the nitrogen atmosphere, to sodium hydride (0.279g, 11.63mmol) (465mg, 60% dispersion in mineral oil) add in the slurries in DMF (15mL) (R)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-keto hydrochloride (1.5g, 3.88mmol), mixture is fully stirred.Add 2-iodopropane (0.465mL, 4.65mmol), with mixture stirring at room 4 hours.Lcms analysis shows about 18% product of formation.Reaction mixture is heated to 55 ℃ and stir and to spend the night.Lcms analysis shows about 60.5% product and about 39.5% starting material of residue.Successively add sodium hydride (0.186g, 60% dispersion) and 2-iodopropane (0.155mL), reaction mixture was stirred 2 hours at 55 ℃.After 2 hours, add more NaH (0.186g, 60% dispersion) and 2-iodopropane (0.155mL).Add another batch NaH (0.186g, 60% dispersion) and 2-iodopropane (0.155mL), mixture is stirred spend the night.Lcms analysis shows existence 79.4% product and about 20% starting material.Add last part NaH (0.186g, 60% dispersion) and 2-iodopropane (0.155mL), reaction mixture is stirred spend the night.Lcms analysis shows about 95% product.Reaction mixture is cooled to room temperature and water (35mL) dilution.Aqueous mixture extracts with ethyl acetate (2x 30mL).Described ethyl acetate layer extracts with the 2N HCl aqueous solution (2x 25mL).HCl is mutually successively with ethyl acetate (1x 25mL) and heptane (1x 25mL) washing.Cooling (ice bath) water also slowly alkalizes with the 50%NaOH aqueous solution, with ethyl acetate (2x 25mL) extraction.Ethyl acetate layer water (2x 25mL) washing, dry (Na ₂SO ₄) and removal of solvent under reduced pressure, obtaining product (free alkali), it is a waxy solid, 1.02g.C ₂₅H ₃₂N ₂O ₂Accurate mass: 392.53; Measured value: 393.3[M+H] ⁺ ¹H NMR (Bruker, 400MHz, DMSO-d ₆) δ 0.89 (d, J=8Hz, 3H), 1.0 (d, J=6.4Hz, 3H), 1.18 (d, J=6.8Hz, 3H), 1.28 (m, 1H), 1.62 (m, 2H), 1.84 (m, 1H), 2.11 (q, J=8.8Hz, 1H), 2.24 (m, 2H), 2.83-2.69 (m, 2H), 2.97 (m, 1H), 3.13 (m, 1H), 3.62 (m, 1H), 4.02 (dd, J ₁=6.4Hz, J ₂=6.4Hz, 1H), 4.59 (t, J ₁=8.8Hz, 1H), 4.99 (dd, J ₁=6.4Hz, J ₂=6.4Hz, 1H), 7.32 (d, J=8Hz), 7.47 (d, 2H, J=8.4Hz), 7.59 (d, 2H, J=8Hz), 7.69 (d, 2H, J=8Hz).

Step B:(R)-preparation of 3-sec.-propyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-keto hydrochloride.

With embodiment 1.29, the free alkali of steps A is dissolved in the ethanol (1.5mL), and (concentration is the ethanolic soln of 1.25M under agitation slowly to add HCl; 4.15mL; 2 equivalents).Adding MTBE is muddy up to solution.With mixture in stirred overnight at room temperature.Removal of solvent under reduced pressure, and drying under reduced pressure resistates obtain HCl salt, and it is spumescence solid (1.09g 65.5%, is defined as 95.5% purity by LCMS). ¹H?NMR(Bruker，400MHz，DMSO-d ₆)δ0.89(d，J＝6.8Hz，3H)，1.18(d，J＝6.8Hz，3H)，1.42(d，J＝6.4Hz，3H)，1.62(m，1H)，1.95(m，2H)，2.19(m，1H)，3.19-3.05(m，5H)，3.50(m，1H)，3.63(m，2H)，4.01(dd，J ₁＝6.4Hz，J ₂＝6.4Hz，1H)，4.59(t，J＝8.8Hz，1H)，5.0(dd，J ₁＝6.4Hz，J ₂＝6.4Hz，1H)，7.41(d，J＝8Hz，2H)，7.48(d，J＝8Hz，2H)，7.67(d，J＝8Hz，2H)，7.71(d，J＝8Hz，2H)，10.50(bs，1H)。

Embodiment 1.30:(R)-4-(2-methyl-4 '-preparation of (2-((R-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 19).

Steps A: the preparation of 2-benzamido-2-(4-hydroxy-3-methyl phenyl) acetate.

At 0 ℃, to the Alpha-hydroxy urobenzoic acid (4.0g, 21mmol) add in the suspension in the vitriol oil (2mL) and Glacial acetic acid (18mL) ortho-cresol (5.5g, 51mmol).Making the cooling bath natural termination continue simultaneously to stir spends the night.Contain ice and NaHCO by being poured into ₃To react cancellation in the beaker (40g).Reaction mixture extracts (three times) with EtOAc, and water layer is acidified to pH 2 with dense HCl.Collect the throw out that forms, wash with water, drying under reduced pressure obtains title compound then, and it is pale pink toner end (2.9g, 50%).C ₁₆H ₁₅NO ₄The accurate mass calculated value: 285.1, measured value: LCMS m/z=286.3[M+H] ⁺

The preparation of step B:2-amino-2-(4-hydroxy-3-methyl phenyl) acetate.

At reflux temperature, (1.0g, 3.5mmol) solution in the 10%HCl aqueous solution (10mL) heated for 1 week with 2-benzamido-2-(4-hydroxy-3-methyl phenyl) acetate.After being cooled to room temperature, mixture with the MTBE washing once concentrates water then and obtains the brown solid resistates.Resistates is with the dilution of acetonitrile and water, and freezing and freeze-drying obtains the hydrochloride (0.67g, 88%) of title compound.C ₉H ₁₁NO ₃The accurate mass calculated value: 181.1, measured value: LCMS m/z=182.2[M+H] ⁺

The preparation of step C:2-(tert-butoxycarbonyl amino)-2-(4-hydroxy-3-methyl phenyl) methyl acetate.

(0.70g, 3.2mmol) suspension in MeOH (4mL) is cooled to 0 ℃ with 2-amino-2-(4-hydroxy-3-methyl phenyl) acetic acid hydrochloride of stirring.(0.25mL 3.4mmol), makes the ice bath natural termination to thionyl chloride then, red solution is stirred spend the night simultaneously.Ethyl-(2.8mL 16mmol), is placed on mixture in 0 ℃ of ice bath N-sec.-propyl third-2-amine then to drip N-.By part add one contract tert-Butyl dicarbonate (0.77g, 3.5mmol).Mixture was stirred 2 hours at 0 ℃, remove ice bath then and room temperature restir 2 hours.Enriched mixture obtains solid residue.Under reduced pressure, load on solid matter on the sinter funnel and wash with water.At pH 8, remaining solid distributes between EtOAc and water.Water layer is with EtOAc extracting twice again.Dried over sodium sulfate is used in the organism salt water washing that merges, and concentrates and obtains title compound, and it is baby pink solid (0.9g, 95%).C ₁₅H ₂₁NO ₅The accurate mass calculated value: 295.1, measured value: LCMS m/z=296.4[M+H] ⁺

The preparation of step D:2-hydroxyl-1-(4-hydroxy-3-methyl phenyl) ethyl carbamic acid tert-butyl ester.

At 0 ℃, (0.87g, (3.0mL concentration is the THF solution of 1M, 3.0mmol) 3.0mmol) to add lithium aluminum hydride in the solution in THF (20mL) to the 2-that is stirring (tert-butoxycarbonyl amino)-2-(4-hydroxy-3-methyl phenyl) methyl acetate.Remove cooling bath, mixture is stirred spend the night.To react cancellation by being poured on ice.Slurries dilute with EtOAc, with 10%HCl solution solution are adjusted to pH 2.Separate organic phase and use the salt water washing, use dried over sodium sulfate then.The evaporation volatile matter obtains title compound (0.60g, 76%).C ₁₄H ₂₁NO ₄The accurate mass calculated value: 267.2, measured value: LCMSm/z=268.4[M+H] ⁺

The preparation of step e: 4-(4-hydroxy-3-methyl phenyl) oxazolidine-2-ketone.

At 0 ℃, to the 2-hydroxyl-1-that is stirring (4-hydroxy-3-methyl phenyl) the ethyl carbamic acid tert-butyl ester (0.60g, 2.2mmol) thionyl chloride in the solution in THF (7mL) (0.18mL, 2.5mmol).Remove ice bath, with mixture in stirred overnight at room temperature.Evaporating solvent.Resistates washs with MTBE, and decantation and drying obtain title compound (0.37g, 84%).C ₁₀H ₁₁NO ₃The accurate mass calculated value: 193.1, measured value: LCMS m/z=194.2[M+H] ⁺

Step F: the preparation of trifluoromethanesulfonic acid (2-methyl-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester.

To the 4-that is stirring (4-hydroxy-3-methyl phenyl) oxazolidine-2-ketone (and 0.40g, 2.1mmol) add in the slurries in acetonitrile (6mL) pyridine (0.67mL, 8.3mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.53mL, 3.1mmol).Remove ice bath, at the transparent red solution of stirring at room.LCMS after 2 hours shows that reaction does not finish, and therefore adds another normal Tf ₂O (0.35mL, 2.1mmol).With reaction mixture restir 30 minutes.Evaporating solvent, resistates HCl solution washing.Slurries extract (three times) with EtOAc, and the salt water washing of the organism of merging is with dried over sodium sulfate and concentrated.Resistates obtains title compound and (contains small amount of impurities, 48Mg) by flash chromatography on silica gel method purifying.C ₁₁H ₁₀F ₃NO ₅The accurate mass calculated value of S: 325.0, measured value: LCMS m/z=326.2[M+H] ⁺

The preparation of step G:4-(2-methyl-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (2-methyl-4-(2-Yang Dai oxazolidine-4-yl) phenyl) ester (48mg, 0.15mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (40mg, 0.15mmol), tetrakis triphenylphosphine palladium (0) (5mg, 4 μ mol), (0.22mL concentration is the aqueous solution of 2.0M to yellow soda ash, 0.44mmol), the mixture of benzene (1mL) and ethanol (0.3mL) is incorporated in the suitable microwave bottle, and 100 ℃ of microwave radiations 90 minutes.Mixture is passed through with the EtOAc filtration

(diatomite) pad, concentrated filtrate.Resistates is by preparation property HPLC purifying.Merge suitable cut and freeze-drying and obtain title compound, it is tfa salt (14mg, 26%).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMS m/z=365.5[M+H] ⁺ ¹H NMR (400MHz, DMSO-d ₆) δ ppm 1.38 (d, J=6.5Hz, 3H), 1.61 (dddd, J=12.9,9.0,9.0,9.0Hz, 1H), 2.10-1.86 (m, 2H), 2.28-2.17 (m, 1H), and 3.10-2.91 (m, 2H), 3.29-3.16 (m, 2H), 3.60-3.40 (m, 2H), 3.66 (dddd, J=11.5,8.0,5.5,5.5Hz, 1H), 3.78 (s, 3H), 4.07 (dd, J=8.6,6.6Hz, 1H), 4.70 (dd, J=8.6,8.6Hz, 1H), 4.98 (dd, J=7.6,7.6Hz, 1H), 7.00 (d, J=7.8Hz, 1H), 7.09 (s, 1H), 7.30 (d, J=7.8Hz, 1H), 7.35 (d, J=8.2Hz, 2H), 7.45 (d, J=8.2Hz, 2H), 8.20 (s, 1H), 9.38 (bs, 1H).

The preparation of embodiment 1.31:4-(3-methyl-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 24).

Steps A: the preparation of 2-benzamido-2-(4-hydroxy-2-methyl phenyl) acetate.

At 0 ℃, to 2-benzamido-2-oxyacetic acid (4.0g, 21mmol) add in the suspension in the vitriol oil (2mL) and Glacial acetic acid (18mL) meta-cresol (5.4mL, 51mmol).Make the cooling bath natural termination, continue simultaneously to stir and spend the night.Contain ice and NaHCO by pouring into ₃In the beaker (40g) and will react cancellation.Reaction mixture extracts with EtOAc (three times).It is 1 and with EtOAc extraction (three times) that water is acidified to pH with dense HCl.From the merging organic phase salt water washing of acidizing extraction, with dried over sodium sulfate and concentrated.Half of resistates through preparation property HPLC purifying, obtains title compound then by flash chromatography on silica gel method purifying, and it is white solid (0.63g, 11%).C ₁₆H ₁₅NO ₄The accurate mass calculated value: 285.1, measured value: LCMS m/z=286.1[M+H] ⁺

The preparation of step B:2-amino-2-(4-hydroxy-2-methyl phenyl) acetate.

(0.63g, 2.2mmol) solution in the 10%HCl aqueous solution (10mL) was reflux temperature heating 6 days with 2-benzamido-2-(4-hydroxy-2-methyl phenyl) acetate.After being cooled to room temperature, mixture evaporates water then with MTBE (4 times) washing, obtains the hydrochloride of title compound, and it is the tawny powder, and this powder promptly is used in next reaction without being further purified.C ₉H ₁₁NO ₃The accurate mass calculated value: 181.1, measured value: LCMS m/z=182.2[M+H] ⁺

The preparation of step C:2-(tert-butoxycarbonyl amino)-2-(4-hydroxy-2-methyl phenyl) methyl acetate.

(0.48g, 2.2mmol) suspension in MeOH (2.2mL) is cooled to 0 ℃ with 2-amino-2-(4-hydroxy-2-methyl phenyl) acetic acid hydrochloride of stirring.(0.17mL 2.3mmol), makes ice bath natural termination (expire) to thionyl chloride then, continues simultaneously to stir and spends the night.Be placed on mixture in 0 ℃ of ice bath and drip N-ethyl-N-sec.-propyl third-2-amine (1.3mL, 7.3mmol), then by part add one contract tert-Butyl dicarbonate (0.48g, 2.2mmol).Mixture was stirred 20 hours, add then another normal one contract tert-Butyl dicarbonate (0.48g, 2.2mmol).After 16 hours, concentrated reaction mixture also is dissolved in resistates among the EtOH (5mL).(0.61g 7.3mmol), spends weekend with mixture in stirring at room to add sodium bicarbonate.After 60 hours, concentrated reaction mixture, resistates is handled to pH 2 with the DCM dilution and with rare HCl.Water DCM extracting twice.Dried over sodium sulfate is used in the organic phase salt water washing that merges, and concentrates and obtains title compound, and it is pale solid (0.56g, 86%).C ₁₅H ₂₁NO ₅The accurate mass calculated value: 295.1, measured value: LCMS m/z=296.2[M+H] ⁺

The preparation of step D:2-hydroxyl-1-(4-hydroxy-2-methyl phenyl) ethyl carbamic acid tert-butyl ester.

At 0 ℃, (0.55g, (1.9mL concentration is the THF solution of 1M, 1.9mmol) 1.9mmol) to add lithium aluminum hydride in the solution in THF (12mL) to the 2-that is stirring (tert-butoxycarbonyl amino)-2-(4-hydroxy-2-methyl phenyl) methyl acetate.Remove cooling bath and mixture stirred and spend the night.To react cancellation by being poured on ice.Slurries dilute with EtOAc, and with 10%HCl solution solution are adjusted to pH2.Separate organic phase, water is with EtOAc extracting twice again.The organic phase salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound (0.47g, 94%).C ₁₄H ₂₁NO ₄The accurate mass calculated value: 267.2, measured value: LCMS m/z=268.4[M+H] ⁺

The preparation of step e: 4-(4-hydroxy-2-methyl phenyl) oxazolidine-2-ketone.

At 0 ℃, to the 2-hydroxyl-1-that is stirring (4-hydroxy-2-methyl phenyl) the ethyl carbamic acid tert-butyl ester (0.46g, 1.7mmol) add in the solution in THF (6mL) thionyl chloride (0.14mL, 1.9mmol).Remove ice bath and with mixture in stirred overnight at room temperature.Evaporating solvent, resistates washs with MTBE.Collect MTBE solution and concentrated, obtain title compound and (contain small amount of impurities, 0.37g).C ₁₀H ₁₁NO ₃The accurate mass calculated value: 193.1, measured value: LCMS m/z=194.2[M+H] ⁺

Step F: the preparation of trifluoromethanesulfonic acid (3-methyl-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester.

To the 4-that is stirring (4-hydroxy-2-methyl phenyl) oxazolidine-2-ketone (and 0.10g, 0.52mmol) add in the slurries in acetonitrile (2mL) pyridine (0.17mL, 2.1mmol).Mixture is cooled to 0 ℃, and the dropping trifluoromethanesulfanhydride anhydride (0.13mL, 0.78mmol).After 30 minutes, evaporating solvent, resistates washs with (10: 1) MTBE/EtOAc.Collect the liquid and the evaporation of decantation, obtain title compound, it is that the oily solid (contains small amount of impurities, 0.18g).C ₁₁H ₁₀F ₃NO ₅The accurate mass calculated value of S: 325.0, measured value: LCMS m/z=326.3[M+H] ⁺

The preparation of step G:4-(3-methyl-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (3-methyl-4-(2-Yang Dai oxazolidine-4-yl) phenyl) ester (0.17g, 0.52mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.14g, 0.52mmol), tetrakis triphenylphosphine palladium (0) (19mg, 0.017mmol), (0.83mL concentration is the aqueous solution of 2.0M to yellow soda ash, 1.7mmol), benzene (2.2mL) and ethanol (0.62mL) is incorporated in the suitable microwave bottle and 100 ℃ of radiation 30 minutes under microwave condition.With EtOAc mixture being filtered passes through Pad, evaporating solvent.HPLC carries out purifying to resistates by preparation property, obtains title compound, and it is tfa salt (0.055g, 29% yield).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMSm/z=365.5[M+H] ⁺ ¹H NMR (400MHz, DMSO-d ₆) δ ppm 1.38 (d, J=6.5Hz, 3H), 1.68 (dddd, J=12.9,9.0,9.0,9.0Hz, 1H), 2.06-1.87 (m, 2H), 2.27-2.17 (m, 1H), 2.33 (s, 3H), 3.11-2.93 (m, 2H), 3.28-3.16 (m, 2H), 3.60-3.40 (m, 2H), 3.65 (dddd, J=11.4,8.0,5.5,5.5Hz, 1H), 3.97 (dd, J=8.4,6.2Hz, 1H), 4.77 (dd, J=8.6,8.6Hz, 1H), 5.18 (dd, J=8.5,6.5Hz, 1H), 7.43-7.38 (m, 3H), and 7.57-7.49 (m, 2H), 7.65 (d, J=8.3Hz, 2H), 8.14 (s, 1H), 9.36 (bs, 1H).

Embodiment 1.32:(S)-4-(2 '-methyl-4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone (compound 32).

The preparation of steps A: 2-(4-hydroxy-3-methyl phenyl) ethyl acetate.

To the 2-that is stirring (4-hydroxy-3-methyl phenyl) acetate (5.0g, 30mmol) add in the solution in dehydrated alcohol (150mL) vitriol oil (1.6mL, 30mmol).With mixture heating up to 75 ℃, continue 3H, remove heating unit then, with mixture in stirred overnight at room temperature.After 18 hours, the evaporation volatile matter, residue diluted with water, and be extracted into (three times) among the EtOAc.Dried over sodium sulfate is used in the organic extract salt water washing that merges, and evaporating solvent obtains title compound, and it is oily matter (5.8g, 100%).C ₁₁H ₁₄O ₃The accurate mass calculated value: 194.1, measured value: LCMS m/z=195.2[M+H] ⁺

The preparation of step B:4-(2-hydroxyethyl)-2-methylphenol.

At 0 ℃, (5.8g, (30mL concentration is the THF solution of 1.0M, 30mmol) 30mmol) to add lithium aluminum hydride in the solution in THF (149mL) to the 2-that is stirring (4-hydroxy-3-methyl phenyl) ethyl acetate.Remove cooling bath, stir the mixture in envrionment temperature.2.5 after hour, will react cancellation with frozen water, slurries are handled to pH 3 with the vitriol oil.Mixture extracts 4 times with EtOAc.The organic extract that merges is successively used the concentrated aqueous solutions and the salt water washing of Rochelle salt (Rochelle ' s salt).Extract obtains title compound with dried over sodium sulfate and concentrated, and it is rose pink solid (4.6g).C ₉H ₁₂O ₂The accurate mass calculated value: 152.1, measured value: LCMS m/z=135.2[M-H ₂O+H] ⁺

Step C: the preparation of trifluoromethanesulfonic acid (2-methyl-4-(2-(tetramethyleneimine-1-yl) ethyl) phenyl) ester.

To the 4-that is stirring (2-hydroxyethyl)-2-methylphenol (2.0g, 13mmol) add in the slurries in acetonitrile (44mL) tetramethyleneimine (5.5mL, 66mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (6.7mL, 39mmol).2.5 after hour, remove cooling bath, mixture stirred in envrionment temperature.After 1 hour, add more trifluoromethanesulfanhydride anhydride (3.0mL, 18mmol).After 30 minutes, add again in the reaction mixture trifluoromethanesulfanhydride anhydride (3.0mL, 39mmol).After 1 hour, evaporating solvent obtains black residue, and this resistates extracts with EtOAc (three times).The extract salt water washing that merges is with dried over sodium sulfate and concentrated.HPLC carries out purifying to resistates by preparation property, obtains title compound, and it is a tfa salt.This salt is dissolved among water and the EtOAc, uses 50% aqueous sodium hydroxide solution treating mixture then to pH 9.Separate each layer, water is with EtOAc extracting twice again.The organic extract salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound, and it is oily matter (0.52g, 12%).C ₁₄H ₁₈F ₃NO ₃The accurate mass calculated value of S: 337.1, measured value: LCMSm/z=338.5[M+H] ⁺ ¹H NMR (400MHz, DMSO-d ₆) δ ppm 1.71-1.63 (m, 4H), 2.30 (s, 3H), 2.51-2.45 (m, 4H), 2.66-2.60 (m, 2H), 2.78-2.72 (m, 2H), 7.28-7.21 (m, 2H), 7.34-7.31 (m, 1H).

Step D:(S)-4-(2 '-methyl-4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (2-methyl-4-(2-(tetramethyleneimine-1-yl) ethyl) phenyl) ester (0.23g, 0.69mmol), (4-(4 for (S)-4-, 4,5,5-tetramethyl--1,3,2-two oxa-boron pentamethylene-2-yls) oxazolidine-2-ketone (0.2.0g phenyl), 0.69mmol), tetrakis triphenylphosphine palladium (0) (0.024g, 0.021mmol), yellow soda ash (0.70mL concentration is the aqueous solution of 2.0M, 1.4mmol), the mixture of benzene (1.8mL) and ethanol (0.5mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 3 hours.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Resistates is by preparation property HPLC purifying.Merging suitable cut also neutralizes with 50% sodium hydroxide solution.Slurries extract (three times) with EtOAc.The organic phase salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound, and it is oily matter (0.15g, 62%).C ₂₂H ₂₆N ₂O ₂The accurate mass calculated value: 350.2, measured value: LCMSm/z=351.4[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ ppm 1.88-1.80 (m, 4H), 2.23 (s, 3H), 2.72-2.65 (m, 4H), and 2.91-2.76 (m, 4H), 4.25 (dd, J=8.6,6.9Hz, 1H), 4.76 (dd, J=8.6,8.6Hz, 1H), 4.99 (dd, J=8.6,7.1Hz, 1H), 6.28 (bs, 1H), 7.13-7.06 (m, 3H), 7.40-7.32 (m, 4H).

Embodiment 1.33:(R)-4-(2,6-two chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone (compound 18).

Steps A: (R)-preparation of 4-(3,5-two chloro-4-hydroxy phenyls) oxazolidine-2-ketone.

To (the R)-4-in suitable microwave bottle (4-hydroxy phenyl) oxazolidine-2-ketone (and 0.100g, 0.558mmol) add in the solution in DCM (10mL) N-chloro-succinimide (0.224g, 1.67mmol).With mixture under microwave condition 100 ℃ of radiation 3 hours.Water will react cancellation and extract (three times) with DCM.The organism salt water washing that merges is with dried over sodium sulfate and concentrated.HPLC carries out purifying to resistates by preparation property, obtains title compound, and it is white solid (35mg, 25%).C ₉H ₇Cl ₂NO ₃The accurate mass calculated value: 247.0, measured value: LCMS m/z=247.9, [M+H] ⁺

Step B: the preparation of trifluoromethanesulfonic acid (R)-(2,6-two chloro-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester.

To (the R)-4-that is stirring (3,5-two chloro-4-hydroxy phenyls) oxazolidine-2-ketone (0.40g, 1.6mmol) add in the slurries in acetonitrile (5mL) pyridine (0.52mL, 6.5mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.41mL, 2.4mmol).Remove ice bath, at the transparent red solution of stirring at room.After 2 hours, evaporating solvent obtains white residue, washs described resistates with MTBE/EtOAc (10: 1).The solvent of decantation is handled with rare HCl aqueous solution, uses EtOAc (three times) extraction mixture then.The organism salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound and (contains small amount of impurities, 0.72g).C ₁₀H ₆Cl ₂F ₃NO ₅The accurate mass calculated value of S: 378.9, measured value: LCMSm/z=380.1[M+H] ⁺

Step C:(R)-4-(2,6-two chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (R)-(2,6-two chloro-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester (0.6g, 1.6mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.4g, 1.6mmol), tetrakis triphenylphosphine palladium (0) (0.06g, 0.04mmol), yellow soda ash (2.4mL concentration is the 2.0M aqueous solution, 4.8mmol), the mixture of benzene (3.8mL) and ethanol (1.1mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 90 minutes.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.By preparation property HPLC purifying resistates.With suitable cut merging and concentrated.Resistates is handled to pH 14 with the 50%NaOH aqueous solution, then with DCM extraction (three times).The organism salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound, is that the HCl diethyl ether solution of 1M is handled described title compound with concentration then, obtains hydrochloride (0.04g, 6%).C ₂₂H ₂₄Cl ₂N ₂O ₂The accurate mass calculated value: 418.1, measured value: LCMS m/z=419.3[M+H] ⁺ ¹H NMR (400MHz, CDCl ₃) δ ppm 1.13 (d, J=6.0Hz, 3H), 1.51-1.39 (m, 1H), 2.01-1.66 (m, 3H), 2.22 (ddd, J=8.8,8.8,8.8Hz, 1H), and 2.41-2.31 (m, 2H), 2.96-2.80 (m, 2H), 3.09 (ddd, J=11.4,11.4,5.8Hz, 1H), 3.27 (ddd, J=8.8,8.8,2.4Hz, 1H), 4.22 (dd, J=8.4,7.0Hz, 1H), 4.77 (dd, J=8.7,8.7Hz, 1H), 4.98-4.91 (m, 1H), 6.63 (bs, 1H), 7.15 (d, J=8.0Hz, 2H), 7.31 (d, J=8.0Hz, 2H), 7.39 (s, 2H).

Embodiment 1.34:(R)-4-(2-chloro-4 '-preparation of (2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone (compound 20)

Steps A: (R)-preparation of 4-(3-chloro-4-hydroxy phenyl) oxazolidine-2-ketone.

To (R)-4-(4-hydroxy phenyl) oxazolidine-2-ketone (and 0.50g, 2.8mmol) add in the solution in DCM (20mL) N-chloro-succinimide (0.37g, 2.8mmol).With mixture stirring at room 18 hours.The water cancellation is reacted and is extracted (three times) with DCM.The organism that merges is with the salt water washing and use dried over sodium sulfate.Evaporating solvent, solid residue washs with MeOH.The MeOH that concentrates decantation obtains rough title compound (0.26g).C ₉H ₈ClNO ₃The accurate mass calculated value: 213.0, measured value: LCMSm/z=214.1, [M+H] ⁺

Step B: the preparation of trifluoromethanesulfonic acid (R)-(2-chloro-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester.

To impure (the R)-4-that is stirring (3-chloro-4-hydroxy phenyl) oxazolidine-2-ketone (and 0.26g, 1.2mmol) add in the slurries in acetonitrile (4mL) pyridine (0.39mL, 4.9mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.31mL, 1.8mmol).Stir transparent red solution at 0 ℃.After 1 hour, evaporating solvent obtains white residue, and this resistates dilutes with EtOAc and rare HCl aqueous solution.Mixture extracts (three times) with EtOAc.The organism salt water washing that merges is with dried over sodium sulfate and concentrated so that the title compound that contains impurity (0.30g) to be provided.C ₁₀H ₇ClF ₃NO ₅The accurate mass calculated value of S: 345.0, measured value: LCMS m/z=345.9[M+H] ⁺

Step C:(R)-preparation of 4-(2-chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

Will be from top trifluoromethanesulfonic acid (R)-(2-chloro-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester (0.3g, 0.9mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.2g, 0.9mmol), tetrakis triphenylphosphine palladium (0) (0.03g, 0.03mmol), yellow soda ash (1.3mL concentration is the aqueous solution of 2.0M, 2.6mmol), the mixture of benzene (2.0mL) and ethanol (0.57mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 90 minutes.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.So that title compound to be provided, it is tfa salt (0.09g, 28%) by preparation property HPLC purifying resistates.C ₂₂H ₂₅ClN ₂O ₂The accurate mass calculated value: 384.2, measured value: LCMS m/z=385.3[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.48 (d, J=6.6Hz, 3H), 1.76 (dddd, J=13.2,9.1,9.1,9.1, Hz, 1H), 2.25-2.01 (m, 2H), 2.41-2.30 (m, 1H), 3.21-3.03 (m, 2H), and 3.33-3.23 (m, 2H), 3.53 (dddd, J=15.8,6.8,6.8,6.8Hz, 1H), 3.66 (ddd, J=12.5,11.0,5.8Hz, 1H), 3.77 (ddd, J=13.1,8.0,5.3Hz, 1H), 4.18 (dd, J=8.8,6.2Hz, 1H), 4.80 (dd, J=8.8,8.8Hz, 1H), 5.05 (dd, J=8.8,6.2Hz, 1H), and 7.43-7.36 (m, 6H), 7.52-7.50 (m, 1H).

Embodiment 1.35:(S)-4-(2 '-chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone (compound 22).

The preparation of steps A: 2-(3-chloro-4-hydroxy phenyl) methyl acetate.

(10.0g 53.6mmol) adds the vitriol oil in the solution in MeOH (250mL) to 2-(3-chloro-4-hydroxy phenyl) acetate.The gained mixture was heated 16 hours at reflux temperature.Evaporation MeOH obtains oily matter, and this oily matter is distributed between water and EtOAc.Water extracts with EtOAc (three times).Dried over sodium sulfate is used in the organism salt water washing that merges, and evaporation obtains title compound (10.5g, 98%) then, and it is amber oily thing. ¹H?NMR(400MHz，DMSO-d ₆)δppm?3.57(s，2H)，3.64(s，3H)，6.09(d，J＝8.3Hz，1H)，7.02(dd，J＝8.3，2.1Hz，1H)，7.23(d，J＝2.1Hz，1H)，10.03(s，1H)。

The preparation of step B:2-(3-chloro-4-(4-methoxy-benzyl oxygen base) phenyl) methyl acetate.

To the 2-that is stirring (3-chloro-4-hydroxy phenyl) methyl acetate (2.19g, 10.9mmol) add PMBCl (right-the methoxy-benzyl muriate) (1.88g in the solution in acetone (27mL), 12.0mmol), tetrabutylammonium iodide (TBAI) (4.03g, 10.9mmol) and salt of wormwood (2.26g, 16.4mmol).Mixture was heated 60 hours at 55 ℃.Reaction mixture is with the hexane solution of 10% acetone and a small amount of DCM dilution, and of short duration heating is cooled to room temperature then and passes through

/ silicagel column.Described post concentrates colourless elutriant and obtains title compound with 10-20% acetone/hexane (700mL) washing, and it is the pale solid (3.4g, 97%) that contains small amount of impurities.TLC (20% acetone/hexane): Rf=0.27.

The preparation of step C:2-(3-chloro-4-(4-methoxy-benzyl oxygen base) phenyl) alcoholic acid.

At 0 ℃, (0.50g, (1.6mL concentration is the THF solution of 1M to methyl acetate, 1.6mmol) 1.6mmol) to add lithium aluminum hydride in the solution in THF (15mL) to the 2-that is stirring (3-chloro-4-(4-methoxy-benzyl oxygen base) phenyl).The cooling bath natural termination is stirred reaction mixture simultaneously spends the night.To react cancellation by being poured on ice, extract slurries (three times) with EtOAc then.The organism salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound and (contains small amount of impurities, 0.49g).

Step D: the preparation of methylsulfonic acid 3-chloro-4-(4-methoxy-benzyl oxygen base) styroyl ester.

At 0 ℃, to the 2-that is stirring (3-chloro-4-(4-methoxy-benzyl oxygen base) phenyl) ethanol (0.49g, 1.7mmol) add in the solution in DCM (4mL) triethylamine (0.70mL, 5.0mmol) and MsCl (0.16mL, 1.2mmol).Stir after 1 hour, will react cancellation by adding the 10%HCl aqueous solution (2mL).The mixture dilute with water is with DCM extraction (three times).The organism salt water washing that merges obtains title compound with dried over sodium sulfate is also concentrated, and it is that amber oily thing (contains small amount of impurities, 0.62g).TLC (50% acetone/hexane) R _f=0.60.

Step e: (R)-preparation of 1-(3-chloro-4-(4-methoxy-benzyl oxygen base) styroyl)-2-crassitude.

To the impure methylsulfonic acid that is stirring (3-chloro-4-(4-methoxy-benzyl oxygen base) styroyl) ester (0.60g, add in 1.6mmol) Phenylsulfonic acid (R)-2-crassitude ester (0.47g, 1.9mmol) and salt of wormwood (0.49g, 3.6mmol).Mixture was heated 18 hours at 60 ℃.The heterogeneous body mixture of white is cooled to room temperature, filters and concentrated filtrate.Resistates is dissolved in EtOAc and the water, handles to pH 2 with 10%HCl, water phase separated is used more than the EtOAc washed twice then.Water alkalizes to pH 9 with 50%NaOH then, subsequently with EtOAc extraction (three times).From the merging organic phase salt water washing of alkaline extraction, obtain title compound with dried over sodium sulfate is also concentrated, it is orange (containing small amount of impurities, 0.29g, 50%).C ₂₁H ₂₆ClN ₂O ₂The accurate mass calculated value: 359.2, measured value: LCMSm/z=360.4[M+H] ⁺

Step F: (R)-preparation of 2-chloro-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenol.

To (the R)-1-that is stirring (3-chloro-4-(4-methoxy-benzyl oxygen base) styroyl)-2-crassitude (0.26g 0.72mmol) adds 2,2 in the solution in DCM (1.5mL), the 2-trifluoroacetic acid (1.5mL, 20mmol).After 10 minutes, will react cancellation and be adjusted to pH 9 with saturated sodium bicarbonate aqueous solution.Mixture is with DCM (three times) extraction, with the salt water washing and use dried over sodium sulfate.Evaporating solvent obtains title compound (70Mg).C ₁₃H ₁₈The accurate mass calculated value of ClNO: 239.1, measured value: LCMSm/z=240.1[M+H] ⁺

Step G: the preparation of trifluoromethanesulfonic acid (R)-(2-chloro-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl) ester.

To (the R)-2-chloro-4-that is stirring (2-(2-methylpyrrolidin-1-yl) ethyl) phenol (0.070g, 0.29mmol) in the slurries of acetonitrile (1mL), add pyridine (0.094mL, 1.2mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.074mL, 0.44mmol).After 2 hours, evaporating mixture obtains solid residue, washs described solid residue with MTBE/EtOAc (10: 1).The gained white solid does not contain required product, and it is discarded.In filtrate, add rare HCl aqueous solution.Use EtOAc (three times) extraction acidifying mixture then, dried over sodium sulfate is used in the salt water washing of the organic fraction of merging then.Evaporating solvent obtains title compound (0.11g).C ₁₄H ₁₇ClF ₃NO ₃The accurate mass calculated value of S: 371.1, measured value: LCMSm/z=372.2[M+H] ⁺

Step H:(S)-4-(2 '-chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (R)-(2-chloro-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl) ester (0.085g, 0.29mmol), (S)-(4-(4 for 4-, 4,5,5-tetramethyl--1,3,2-two oxa-boron pentamethylene-2-yls) oxazolidine-2-ketone (0.11g phenyl), 0.29mmol), tetrakis triphenylphosphine palladium (0) (0.010g, 0.0088mmol), (0.29mL concentration is the aqueous solution of 2.0M to yellow soda ash, 0.59mmol), the mixture of benzene (1.0mL) and ethanol (0.29mL) be incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 15 minutes.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (2.2mg, 20%).C ₂₂H ₂₅ClN ₂O ₂The accurate mass calculated value: 384.2, measured value: LCMS m/z=385.2[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.48 (d, J=6.6Hz, 3H), 1.81-1.70 (m, 1H), 2.22-2.02 (m, 2H), 2.41-2.32 (m, 1H), 3.10-3.01 (m, 1H), and 3.20-3.11 (m, 1H), 3.37-3.23 (m, 3H), 3.54 (dddd, J=15.6,6.6,6.6,6.6Hz, 1H), 3.66 (ddd, J=12.6,11.1,5.9Hz, 1H), 3.76 (ddd, J=13.2,8.1,5.3Hz, 1H), 4.20 (dd, J=8.7,6.4Hz, 1H), 4.84-4.75 (m, 1H), 5.07 (dd, J=8.8,6.4Hz, 1H), and 7.38-7.32 (m, 2H), 7.47-7.44 (m, 4H), 7.53-7.51 (m, 1H).

Embodiment 1.36:(S)-4-(3 '-fluoro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone (compound 23).

The preparation of steps A: 2-(2-fluoro-4-p-methoxy-phenyl) alcoholic acid.

At 0 ℃, (5.0g, (27mL concentration is the THF solution of 1.0M, 27mmol) 27mmol) to add borine-THF complex compound in the solution in THF (11mL) to the 2-that is stirring (2-fluoro-4-p-methoxy-phenyl) acetate.The cooling bath natural termination is stirred simultaneously spends the night.After 16 hours, will react cancellation up to stopping bubbling by carefully adding entry.By stirring neutralization solution with saturated sodium carbonate solution.Extract mixture (three times) with MTBE then.The organism salt water washing that merges obtains title compound with dried over sodium sulfate is also concentrated, and it is colorless oil (4.3g, 93%).C ₉H ₁₁FO ₂The accurate mass calculated value: 170.1, measured value: LCMS m/z=153.2[M-H ₂O+H] ⁺

Step B: the preparation of methylsulfonic acid (2-fluoro-4-anisole ethyl) ester.

At 0 ℃, to the 2-that is stirring (2-fluoro-4-p-methoxy-phenyl) ethanol (2.0g, 12mmol) add in the solution in THF (30mL) triethylamine (4.9mL, 35mmol) and methylsulfonyl chloride (1.1mL, 14mmol).The cooling bath natural termination is stirred simultaneously spends the night.After 16 hours, rare HCl will react cancellation by careful adding.Extract mixture (three times) with DCM.The organic fraction salt water washing that merges with dried over sodium sulfate and concentrated, obtains title compound, and it is amber oily thing (containing small amount of impurities, 3.2g, 110%).C ₁₀H ₁₃FO ₄The accurate mass calculated value of S: 248.1, measured value: LCMS m/z=153.2[M-MsOH+H] ⁺

Step C:(R)-preparation of 1-(2-fluoro-4-anisole ethyl)-2-crassitude.

To the methylsulfonic acid that is stirring (2-fluoro-4-anisole ethyl) ester (1.5g, 6.0mmol) add in the solution in acetonitrile (15mL) Phenylsulfonic acid (R)-2-crassitude ester (1.8g, 7.3mmol) and salt of wormwood (1.8g, 13mmol).Mixture was heated 18 hours at 60 ℃.White heterogeneous body mixture is cooled to room temperature, filters and evaporated filtrate.Resistates is dissolved in EtOAc and the water, handles to pH 2 with 10%HCl, water phase separated is also with more than the more EtOAc washed twice then.Then alkalize water to pH 9, then with EtOAc extraction (three times) with 50%NaOH.From the merging organic phase salt water washing of alkaline extraction, use dried over sodium sulfate, concentrate then and obtain title compound, it is orange (0.87g, 62%).C ₁₄H ₂₀The accurate mass calculated value of FNO: 237.2, measured value: LCMSm/z=238.0[M+H] ⁺

Step D:(R)-preparation of 3-fluoro-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenol.

At-78 ℃, (0.10g, (0.84mL concentration is the DCM solution of 1M, 0.84mmol) 0.42mmol) to drip boron tribromide in the solution in DCM (3mL) to (the R)-1-that is stirring (2-fluoro-4-anisole ethyl)-2-crassitude.After 1 hour, remove cooling bath, with mixture stirring at room 3.5 hours.Mixture is cooled to 0 ℃, and is the aqueous sodium carbonate of 2M and cancellation reaches pH 7 up to described mixture by adding concentration.Mixture extracts (three times) with DCM.The organic phase salt water washing that merges with dried over sodium sulfate and evaporation, obtains title compound, and this compound directly is used in next reaction without being further purified.C ₁₃H ₁₈The accurate mass calculated value of FNO: 223.1, measured value: LCMS m/z=224.3[M+H] ⁺

Step e: (R)-preparation of 3-fluoro-4-(2-(2-methylpyrrolidin-1-yl) ethyl) benzene.

To (the R)-3-fluoro-4-that is stirring (2-(2-methylpyrrolidin-1-yl) ethyl) phenol (0.10g, 0.45mmol) add in the slurries in acetonitrile (1.5mL) pyridine (0.15mL, 1.8mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.11mL, 0.67mmol).After 2 hours, evaporating mixture obtains the oily resistates, washs described resistates with MTBE/EtOAc (10: 1).The gained white solid does not contain required product, and it is discarded.Evaporated filtrate obtains title compound (containing small amount of impurities), and it is orange oily solid, and this solid directly is used in next reaction without being further purified.C ₁₄H ₁₇CF ₄NO ₃The accurate mass calculated value of S: 355.1, measured value: LCMS m/z=356.2[M+H] ⁺

Step F: (S)-4-(3 '-fluoro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (R)-(3-fluoro-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl) ester (0.13g, 0.45mmol), (S)-(4-(4 for 4-, 4,5,5-tetramethyl--1,3,2-two oxa-boron pentamethylene-2-yls) oxazolidine-2-ketone (0.16g phenyl), 0.45mmol), tetrakis triphenylphosphine palladium (.) (0.016g, 0.014mmol), (0.45mL concentration is the aqueous solution of 2.0M to yellow soda ash, 0.90mmol), the mixture of benzene (1.8mL) and ethanol (0.50mL) be incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 3.5 hours.With EtOAc mixture being filtered passes through Pad, evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (49mg, 24% yield).C ₂₂H ₂₅FN ₂O ₂The accurate mass calculated value: 368.2, measured value: LCMS m/z=369.2[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.47 (d, J=6.5Hz, 3H), 1.81-1.70 (m, 1H), 2.23-2.02 (m, 2H), and 2.42-2.32 (m, 1H), 3.21-3.07 (m, 2H), 3.35-3.25 (m, 3H), and 3.67-3.51 (m, 2H), 3.83-3.75 (m, 1H), 4.17 (dd, J=8.7,6.4Hz, 1H), 4.85-4.74 (m, 1H), 5.05 (dd, J=8.7,6.4Hz, 1H), 7.47 (d, J=8.4Hz, 2H), 7.50-7.42 (m, 3H), 7.68 (d, J=8.4Hz, 2H).

Embodiment 1.37:(R)-preparation of 4-(2-methoxyl group-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone (compound 21).

The preparation of steps A: 2-(tert-butoxycarbonyl amino)-2-(4-hydroxy 3-methoxybenzene base) methyl acetate.

(0.98g, 5.0mmol) suspension in MeOH (6.5mL) is cooled to 0 ℃ with 2-amino-2-(4-hydroxy 3-methoxybenzene base) acetate of stirring.(0.38mL 5.2mmol), makes the ice bath natural termination stir simultaneously and spends the night thionyl chloride then.After 16 hours, drip N, (4.3mL 25mmol), and is placed on mixture in 0 ℃ the ice bath N-diisopropyl ethyl amine.By part add one contract tert-Butyl dicarbonate (1.2g, 5.5mmol).After 2 hours, the evaporation volatile matter, residue diluted with water is then with EtOAc extraction (three times).Dried over sodium sulfate is used in the organic phase salt water washing that merges, and evaporating solvent obtains title compound, and it is amber oily thing.C ₁₅H ₂₁NO ₆The accurate mass calculated value: 311.1, measured value: LCMS m/z=312.2[M+H] ⁺

The preparation of step B:2-hydroxyl-1-(4-hydroxy 3-methoxybenzene base) ethyl carbamic acid tert-butyl ester

At 0 ℃, (1.5g, (5.8mL concentration is the THF solution of 1M, 5.8mmol) 4.8mmol) to add lithium aluminum hydride in the solution in THF (50mL) to the 2-that is stirring (tert-butoxycarbonyl amino)-2-(4-hydroxy 3-methoxybenzene base) methyl acetate.Remove cooling bath, mixture is stirred spend the night.To react cancellation by being poured on ice.Slurries dilute with EtOAc, with the 10%HCl aqueous solution solution are adjusted to pH4.Separate organic phase, water is with EtOAc extracting twice again.The organic phase salt water washing that merges is with dried over sodium sulfate and concentrated.Resistates obtains title compound by flash chromatography on silica gel method purifying, and it is tawny solid (0.50g, 36%).C ₁₄H ₂₁NO ₅The accurate mass calculated value: 283.1, measured value: LCMS m/z=284.4[M+H] ⁺

The preparation of step C:4-(4-hydroxy 3-methoxybenzene base) oxazolidine-2-ketone.

At 0 ℃, to the 2-hydroxyl-1-that is stirring (4-hydroxy 3-methoxybenzene base) the ethyl carbamic acid tert-butyl ester (0.5g, 1.8mmol) add in the solution in THF (7mL) thionyl chloride (0.14mL, 1.9mmol).Remove ice bath and with mixture in stirred overnight at room temperature.Evaporating solvent obtains title compound and (contains small amount of impurities, 0.37g).C ₁₀H ₁₁NO ₄The accurate mass calculated value: 209.1, measured value: LCMS m/z=210.0[M+H] ⁺

Step D: the preparation of trifluoromethanesulfonic acid (2-methoxyl group-4-(2-oxygen is for oxazolidine-4-yl) phenyl) ester.

To the 4-that is stirring (4-hydroxy 3-methoxybenzene base) oxazolidine-2-ketone (and 0.37g, 1.8mmol) add in the slurries in acetonitrile (6mL) pyridine (0.57mL, 7.1mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.45mL, 2.7mmol).After 30 minutes, remove ice bath, at the transparent red solution of stirring at room.After 30 minutes, evaporating solvent, resistates extracts with (10: 1) MTBE/EtOAc.In the liquid of decantation, add rare HCl aqueous solution.Separate each layer, water is with EtOAc extracting twice again.The organic phase that merges is with the salt water washing and use dried over sodium sulfate.Evaporating solvent obtains title compound, and it is that red oil (contains impurity, 0.77g).C ₁₁H ₁₀F ₃NO ₆The accurate mass calculated value of S: 341.0, measured value: LCMS m/z=342.2[M+H] ⁺

The preparation of step e: 4-(2-methoxyl group-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (2-methoxyl group-4-(2-Yang Dai oxazolidine-4-yl) phenyl) ester (0.75g, 2.2mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.59g, 2.2mmol), tetrakis triphenylphosphine palladium (0) (76mg, 0.066mmol), yellow soda ash (3.3mL concentration is the aqueous solution of 2.0M, 6.6mmol), the mixture of benzene (8mL) and ethanol (2.3mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 90 minutes.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (0.10g).C ₂₃H ₂₈N ₂O ₃The accurate mass calculated value: 380.2, measured value: LCMSm/z=381.3[M+H] ⁺ ¹H NMR (400MHz, DMSO-d ₆) δ ppm 1.38 (d, J=6.5Hz, 3H), 1.61 (dddd, J=12.9,9.0,9.0,9.0Hz, 1H), 2.08-1.86 (m, 2H), and 2.28-2.18 (m, 1H), 3.10-2.92 (m, 2H), 3.28-3.15 (m, 2H), 3.60-3.40 (m, 2H), 3.66 (dddd, J=11.4,8.0,5.5,5.5Hz, 1H), 3.78 (s, 3H), 4.08 (dd, J=8.5,6.6Hz, 1H), 4.70 (dd, J=8.6,8.6Hz, 1H), 4.98 (dd, J=8.1,8.1Hz, 1H), 7.00 (dd, J=7.8,1.4Hz, 1H), 7.09 (d, J=1.4Hz, 1H), 7.30 (d, J=7.8Hz, 1H), 7.35 (d, J=8.2Hz, 2H), 7.44 (d, J=8.2Hz, 2H), 8.20 (s, 1H), 9.38 (bs, 1H).

Embodiment 1.38:(S)-4-(2 '-methoxyl group-4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone (compound 33).

Steps A: the preparation of trifluoromethanesulfonic acid 2-methoxyl group-4-(2-(tetramethyleneimine-1-yl) ethyl) phenylester.

To the 4-that is stirring (2-hydroxyethyl)-2-methoxyphenol (high VANILLYL ALCOHOL MIN 98, homovanilly alcohol) (2.0g, 12mmol) add in the slurries in acetonitrile (40mL) tetramethyleneimine (5.0mL, 60mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (6.0mL, 36mmol).After 3 hours, remove cooling bath, mixture is stirred in envrionment temperature.After 18 hours, add pyridine (5.0mL, 62mmol) and more trifluoromethanesulfanhydride anhydride (5.0mL, 30mmol).After 1 hour, in reaction mixture, add once more trifluoromethanesulfanhydride anhydride (5mL, 30mmol).After 3 hours, evaporating solvent obtains black residue, extracts described resistates (three times) with EtOAc.The organic extract salt water washing that merges is used dried over sodium sulfate, then evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is a tfa salt.Described salt is dissolved among water and the EtOAc, handles described mixture to pH 9 with saturated sodium bicarbonate aqueous solution then.Separate each layer, water is with EtOAc extracting twice again.Dried over sodium sulfate is used in the organic extract salt water washing that merges, and evaporating solvent obtains title compound then, and it is oily matter (0.76g, 18%).C ₁₄H ₁₈F ₃NO ₄The accurate mass calculated value of S: 353.1, measured value: LCMS m/z=354.2[M+H] ⁺

Step B:(S)-4-(2 '-methoxyl group-4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-yl) preparation of oxazolidine-2-ketone.

With trifluoromethanesulfonic acid (2-methoxyl group-4-(2-(tetramethyleneimine-1-yl) ethyl) phenyl) ester (0.20g, 0.57mmol), (4-(4 for (S)-4-, 4,5,5-tetramethyl--1,3,2-two oxa-boron pentamethylene-2-yls) oxazolidine-2-ketone (0.16g phenyl), 0.57mmol), tetrakis triphenylphosphine palladium (0) (0.020g, 0.017mmol), yellow soda ash (0.57mL concentration is the aqueous solution of 2.0M, 1.1mmol), the mixture of benzene (1.5mL) and ethanol (0.4mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 12 hours.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (19Mg).C ₂₂H ₂₆N ₂O ₃The accurate mass calculated value: 366.2, measured value: LCMS m/z=367.4[M+H] ⁺ ¹H NMR (400MHz, DMSO-d ₆) δ ppm1.95-1.82 (m, 2H), 2.10-1.98 (m, 2H), 3.04-2.97 (m, 2H), and 3.15-3.04 (m, 2H), 3.60-3.40 (m, 4H), 3.78 (s, 3H), 4.06 (dd, J=8.5,6.4Hz, 1H), 4.70 (dd, J=8.6,8.6Hz, 1H), 4.97 (dd, J=7.5,7.5Hz, 1H), 6.96 (dd, J=7.7,1.4Hz, 1H), 7.06 (d, J=1.4Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 7.37 (d, J=8.2Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 8.18 (s, 1H), 9.72 (bs, 1H).

Embodiment 1.39:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-dioxolane-2-ketone (compound 26).

Steps A: 4-(4-bromophenyl)-2,2-dimethyl-1, the preparation of 3-dioxolane.

To 1-(4-bromophenyl) ethane-1, the 2-glycol (1.0g, 4.6mmol) in acetone (10mL) and 2, the 2-Propanal dimethyl acetal (11mL, 92mmol) add in the mixture in tosic acid pyridine (PPTs) (0.12g, 0.46mmol).After 16 hours, water cancellation reaction.The evaporation volatile matter extracts aqueous slurry (three times) with DCM.Dried over sodium sulfate is used in the organic phase salt water washing that merges, and evaporating solvent obtains title compound then, and it is yellow oil (1.2g, 98%). ¹H?NMR(400MHz，DMSO-d ₆)δppm1.39(s，3H)，1.45(s，3H)，3.55(dd，J＝8.0，8.0Hz，1H)，4.30(dd，J＝8.0，6.8Hz，1H)，5.05(dd，J＝6.8，6.8Hz，1H)，7.33(d，J＝8.3Hz，2H)，7.56(d，J＝8.3Hz，2H)。

Step B:(2R)-preparation of 1-(2-(4 '-(2,2-dimethyl-1,3-dioxolane-4-yl) biphenyl-4-yl) ethyl)-2-crassitude.

With 4-(4-bromophenyl)-2,2-dimethyl-1,3-dioxolane (0.50g, 2.0mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.52g, 2.0mmol), tetrakis triphenylphosphine palladium (0) (67mg, 0.058mmol), yellow soda ash (2.0mL concentration is the aqueous solution of 2.0M, 3.9mmol), the mixture of benzene (7.6mL) and ethanol (2.2mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 3 hours.With EtOAc mixture being filtered passes through

Pad, evaporating solvent obtains title compound and (contains small amount of impurities, 0.76g).C ₂₄H ₃₁NO ₂The accurate mass calculated value: 365.2, measured value: LCMS m/z=366.4[M+H] ⁺

Step C:1-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) ethane-1, the preparation of 2-glycol.

(2-(4 '-(2 to rough (2R)-1-, 2-dimethyl-1,3-dioxolane-4-yl) ethyl biphenyl-4-yl))-2-crassitude (0.60g, 1.6mmol (5mL concentration is 4M De dioxane solution to add hydrochloric acid in the solution in the) Yu diox (20mL), 20mmol) and water (0.5mL, 28mmol).With mixture stirring at room 60 hours.Reaction mixture neutralizes with 50% aqueous sodium hydroxide solution.The evaporation volatile matter also obtains containing the title compound of chloro-alcohol impurity by preparation property HPLC purifying resistates.C ₂₁H ₂₇NO ₃The accurate mass calculated value: 325.2, measured value: LCMS m/z=326.3[M+H] ⁺

Step D:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-dioxolane-2-ketone.

To the 1-that contains chloro-alcohol impurity (4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) ethane-1, the 2-glycol (0.20g, 0.62mmol) add in the solution in THF (12mL) CDI (0.60g, 3.7mmol).Mixture was stirred 30 minutes at 40 ℃, be cooled to room temperature then, use the cancellation of the 10%HCl aqueous solution afterwards.With mixture restir 20 minutes, then by adding saturated sodium bicarbonate aqueous solution neutralization reaction mixture.Mixture extracts (three times) with MTBE, and dried over sodium sulfate is used in the salt water washing of the organic phase of merging then.Evaporate volatile matter, and obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (3.1Mg).C ₂₂H ₂₅NO ₃The accurate mass calculated value: 351.2, measured value: LCMS m/z=352.3[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.47 (d, J=6.5Hz, 3H), 1.81-1.70 (m, 1H), 2.21-2.00 (m, 2H), 2.40-2.30 (m, 1H), 3.20-3.01 (m, 2H), 3.33-3.22 (m, 2H), 3.80-3.50 (m, 3H), 4.43 (dd, J=8.6,7.6Hz, 1H), 4.89 (dd, J=8.6,8.6Hz, 1H), 5.84 (dd, J=7.9,7.9Hz, 1H), 7.42 (d, J=8.2Hz, 2H), 7.52 (d, J=8.2Hz, 2H), 7.65 (d, J=8.3Hz, 2H), 7.71 (d, J=8.3Hz, 2H).

The preparation of embodiment 1.40:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) pyrrolidin-2-one (compound 25).

The preparation of steps A: 4-(4-chloro-phenyl-) pyrrolidin-2-one.

To 4-amino-3-(4-chloro-phenyl-)-butyric acid (baclofen) (1.0g, 4.7mmol) add in the solution in toluene (80mL) neutral alumina (1.4g, 14mmol).Mixture heating up to reflux temperature, is continued 16 hours, be cooled to room temperature and filtration then.Evaporated filtrate obtains title compound, and it is white solid (0.82g, 90%).C ₁₀H ₁₀The accurate mass calculated value of ClNO: 195.1, measured value: LCMSm/z=196.1[M+H] ⁺

The preparation of step B:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) pyrrolidin-2-one.

With 4-(4-chloro-phenyl-) pyrrolidin-2-one (0.15g, 0.77mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.21g, 0.77mmol), dicyclohexyl (2 ', 4 ', 6 '-tri isopropyl biphenyl-2-yl) phosphine (XPHOS) (18mg, 0.038mmol), potassiumphosphate (0.49g, 2.3mmol), palladium (3.4mg, 0.015mmol) and the mixture of THF (1.0mL) be incorporated in the bottle of sealing, then with described bottle in oil bath 100 ℃ the heating 26 hours.With acetonitrile mixture being filtered passes through

Pad, evaporating solvent.Resistates is dissolved among the EtOAc, and uses the 10%HCl solution washing.Handle water to pH 12 with the 50%NaOH aqueous solution then, and extract (three times) with EtOAc.The salt water washing of the organic phase from alkaline extraction that merges is used dried over sodium sulfate, then evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (3.8Mg).C ₂₃H ₂₈N ₂The accurate mass calculated value of O: 348.2, measured value: LCMS m/z=349.3[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.47 (d, J=6.5Hz, 3H), 1.76 (dddd, J=13.2,9.1,9.1,9.1Hz, 1H), and 2.20-2.00 (m, 2H), 2.40-2.30 (m, 1H), 2.53-2.45 (m, 1H), 2.78-2.70 (m, 1H), 3.19-3.02 (m, 2H), 3.32-3.22 (m, 3H), 3.46-3.39 (m, 1H), 3.58-3.48 (m, 1H), 3.63 (dddd, J=10.7,10.7,10.7,5.9Hz, 1H), 3.84-3.72 (m, 3H), 7.42-7.36 (m, 4H), 7.63-7.57 (m, 4H).

The preparation of embodiment 1.41:5-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) pyrrolidin-2-one (compound 30).

The preparation of steps A: 5-(4-p-methoxy-phenyl) pyrrolidin-2-one.

To the Vanadium Pentoxide in FLAKES that is stirring (0.64g, 4.5mmol), methylsulfonic acid (4.3mL, 67mmol) and methyl-phenoxide (0.93mL, add in mixture 8.5mmol) (S)-5-oxo-pyrrolidine-2-formic acid (Pyrrolidonecarboxylic acid) (1.0g, 7.8mmol).The mixture of cleaning was heated 30 minutes at 100 ℃.To react cancellation by being poured on ice.Aqueous slurry extracts (three times) with DCM.Merge organic extract, use the salt water washing, use dried over sodium sulfate, then evaporating solvent.By preparation property HPLC purifying resistates.Merge suitable cut and evaporating solvent.Resistates extracts (three times) with DCM.Merge organic extract, use the salt water washing, use dried over sodium sulfate, evaporating solvent obtains title compound then, and it is white solid (0.40g, 27%).C ₁₁H ₁₃NO ₂The accurate mass calculated value: 191.1, measured value: LCMS m/z=192.2[M+H] ⁺

The preparation of step B:5-(4-hydroxy phenyl) pyrrolidin-2-one.

At-78 ℃, (0.38g, (2.6mL concentration is the DCM solution of 1M, 2.6mmol) 2.0mmol) to drip boron tribromide in the solution in DCM (13mL) to 5-(4-p-methoxy-phenyl) pyrrolidin-2-one.After 1 hour, remove cooling bath, continue the mixture stirring to be spent the night in envrionment temperature.Evaporating solvent obtains the tawny solid.Reaction mixture dilutes with DCM, and by adding the sodium bicarbonate aqueous solution cancellation up to pH7.Filtering mixt is to collect title compound, and it is pale solid (0.20g, 57%).C ₁₀H ₁₁NO ₂The accurate mass calculated value: 177.2, measured value: LCMS m/z=178.1[M+H] ⁺

Step C: the preparation of trifluoromethanesulfonic acid (4-(5-oxo-pyrrolidine-2-yl) phenyl) ester.

To the 5-that is stirring (4-hydroxy phenyl) pyrrolidin-2-one (0.20g, 1.1mmol) add in the slurries in acetonitrile (4mL) pyridine (0.37mL, 4.5mmol).With mixture be cooled to 0 ℃ and drip trifluoromethanesulfanhydride anhydride (0.29mL, 1.7mmol).After 30 minutes, evaporating solvent, black residue is washed with (10: 1) MTBE/EtOAc.Make the solid precipitation that does not contain required product.The liquid that evaporation drains obtains containing the title compound of impurity, and it is oily solid (0.30g, 85%).C ₁₀H ₁₁NO ₂The accurate mass calculated value: 309.0, measured value: LCMS m/z=310.4[M+H] ⁺

The preparation of step D:5-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) pyrrolidin-2-one.

With trifluoromethanesulfonic acid (4-(5-oxo-pyrrolidine-2-yl) phenyl) ester (0.30g, 0.97mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.26g, 0.97mmol), tetrakis triphenylphosphine palladium (0) (0.034g, 0.029mmol), yellow soda ash (1.5mL concentration is the aqueous solution of 2.0M, 2.9mmol), the mixture of benzene (2.5mL) and ethanol (0.80mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 5 hours.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Resistates distributes between water and DCM.Water is with DCM extracting twice again.The organic phase salt water washing that merges is used dried over sodium sulfate, then evaporating solvent.By preparation property HPLC purifying resistates.Merge suitable cut and freeze-drying, obtain title compound, it is tfa salt (7.0mg, 1.6%).C ₂₃H ₂₈N ₂The accurate mass calculated value of O: 348.2, measured value: LCMS m/z=349.3[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.47 (d, J=6.5Hz, 3H), 1.76 (dddd, J=13.2,9.0,9.0,9.0Hz, 1H), 2.02-1.91 (m, 1H), and 2.18-2.02 (m, 2H), 2.40-2.30 (m, 1H), 2.48-2.42 (m, 2H), 2.62 (dddd, J=12.8,8.2,8.2,6.3Hz, 1H), 3.19-3.02 (m, 2H), 3.35-3.22 (m, 3H), 3.59-3.49 (m, 1H), 3.64 (ddd, J=16.6,10.8,5.9Hz, 1H), 3.76 (ddd, J=13.1,8.0,4.6Hz, 1H), and 4.87-4.82 (m, 1H), 7.43-7.38 (m, 4H), 7.65-7.60 (m, 4H).

Embodiment 1.42:6-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-oxazine alkane-2-ketone (compound 27).

Steps A: the preparation of 3-amino-1-(4-bromophenyl) third-1-alcohol.

(1.0g, 4.5mmol) solution in THF (89mL) is heated to reflux temperature with 3-(4-bromophenyl)-3-oxypropionitrile.(13mL concentration is the solution of 1M, 13mmol) to drip borine-THF complex compound.3.5 after hour, mixture is cooled to room temperature, adds MeOH (20mL) then.The evaporation volatile matter obtains white residue, then described resistates is dissolved among the MTBE.With concentration be 1M contain ether HCl solution-treated clear solution.Evaporating solvent, resistates distributes between water and DCM.Organic phase is kept somewhere.Water neutralizes with 50% aqueous sodium hydroxide solution, then with DCM extraction (three times).Dried over sodium sulfate is used in the organic phase salt water washing that merges.Evaporating solvent obtains the title compound of impure form, and it is colorless oil (0.85g), even with the not purified usefulness of described oily matter.C ₉H ₁₂The accurate mass calculated value of BrNO: 229.0, measured value: LCMS m/z=230.3[M+H] ⁺

Step B:6-(4-bromophenyl)-1, the preparation of 3-oxazine alkane-2-ketone.

(0.85g, 3.7mmol) with 1, (3.6g, 22mmol) solution in THF (74mL) is heated to 40 ℃ to 1 '-carbonyl dimidazoles with impure 3-amino-1-(4-bromophenyl) third-1-alcohol.After 18 hours, evaporating solvent, resistates extracts (three times) with water treatment and with DCM.The organic extract salt water washing that merges is with dried over sodium sulfate and evaporating solvent.By preparation property HPLC purifying resistates, merge suitable cut and evaporate volatile matter.Aqueous residue extracts (three times) with DCM, the salt water washing of the organic extract of merging, and evaporating solvent obtains title compound (45Mg).C ₁₀H ₁₀BrNO ₂The accurate mass calculated value: 255.0, measured value: LCMS m/z=256.5[M+H] ⁺

Step C:6-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-oxazine alkane-2-ketone.

With 6-(4-bromophenyl)-1,3-oxazine alkane-2-ketone (0.045g, 0.18mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.047g, 0.18mmol), tetrakis triphenylphosphine palladium (0) (0.006g, 0.005mmol), yellow soda ash (0.18mL concentration is the aqueous solution of 2.0M, 0.35mmol), the mixture of benzene (0.68mL) and ethanol (0.20mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 3 hours.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is white tfa salt (15Mg).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMS m/z=365.6[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.47 (d, J=6.5Hz, 3H), 1.75 (dddd, J=13.2,9.0,9.0,9.0Hz, 1H), and 2.21-2.00 (m, 3H), 2.30-2.23 (m, 1H), and 2.41-2.31 (m, 1H), 3.20-3.02 (m, 2H), and 3.38-3.23 (m, 4H), 3.59-3.42 (m, 2H), and 3.70-3.60 (m, 1H), 3.75 (ddd, J=15.3,12.6,7.2Hz, 1H), 5.45 (dd, J=10.1,2.6Hz, 1H), 7.41 (d, J=8.1Hz, 2H), 7.49 (d, J=8.3Hz, 2H), 7.67-7.61 (m, 4H).

Embodiment 1.43:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-oxazine alkane-2-ketone (compound 28).

Steps A: 4-(4-bromophenyl)-1, the preparation of 3-oxazine alkane-2-ketone.

(0.10g, 0.44mmol) with 1, (0.70g, 0.44mmol) solution in THF (9mL) is heated to 40 ℃ to 1 '-carbonyl dimidazoles with 3-amino-3-(4-bromophenyl) third-1-alcohol.After 3 days, evaporating solvent, resistates distributes between water and DCM.Water is with DCM extracting twice again.The organic extract salt water washing that merges is with dried over sodium sulfate and concentrated.Make resistates stand acid and alkaline extraction condition.Organic extract salt water washing, and use dried over sodium sulfate.The solvent of evaporation extract obtains title compound, and it is a colorless oil.C ₁₀H ₁₀BrNO ₂The accurate mass calculated value: 255.0, measured value: LCMS m/z=256.4[M+H] ⁺

Step B:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-oxazine alkane-2-ketone.

With impure 4-(4-bromophenyl)-1,3-oxazine alkane-2-ketone (0.35g, 1.4mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.37g, 1.4mmol), tetrakis triphenylphosphine palladium (0) (0.047g, 0.041mmol), yellow soda ash (2.1mL concentration is the aqueous solution of 2.0M, 4.1mmol), the mixture of benzene (4.6mL) and ethanol (1.3mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 24 hours.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Resistates distributes between water and DCM.Water is with DCM extracting twice again.The organic phase salt water washing that merges is used dried over sodium sulfate, then evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is white tfa salt (3.0Mg).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMS m/z=365.5[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm1.47 (d, J=6.5Hz, 3H), 1.81-1.70 (m, 1H), 2.21-1.93 (m, 3H), and 2.40-2.27 (m, 2H), 3.20-3.02 (m, 2H), 3.33-3.23 (m, 3H), and 3.59-3.50 (m, 1H), 3.68-3.60 (m, 1H), 3.75 (ddd, J=13.1,7.9,5.3Hz, 1H), 4.38-4.25 (m, 2H), 4.73 (dd, J=7.4,5.3Hz, 1H), and 7.46-7.38 (m, 4H), 7.67-7.61 (m, 4H).

Embodiment 1.44:4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-diox-2-ketone (compound 29).

Steps A: (R)-(4 '-(2-(the 2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) preparation of methyl alcohol.

With (4-bromophenyl) methyl alcohol (0.50g, 2.7mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloric acid (0.72g, 2.7mmol), tetrakis triphenylphosphine palladium (0) (0.093g, 0.080mmol), yellow soda ash (4.0mL concentration is the aqueous solution of 2.0M, 8.0mmol), the mixture of benzene (10mL) and ethanol (3mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 90 minutes.With EtOAc mixture being filtered passes through

Pad, evaporating solvent.Crude material is distributed between water and DCM.Water is with DCM extracting twice again.The organic phase salt water washing that merges is used dried over sodium sulfate, then evaporating solvent.Obtain title compound by preparation property HPLC purifying resistates, it is white tfa salt (0.35g, 44%).C ₂₀H ₂₅The accurate mass calculated value of NO: 295.2, measured value: LCMSm/z=296.3[M+H] ⁺

Step B:(R)-4 '-preparation of (2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-formaldehyde.

(0.35g 1.2mmol) adds in the solution in DCM (5mL) methyl alcohol to (R) that stirring-(4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)

Molecular sieve (0.60g), N-oxidation N-methylmorpholine (NMO, N-methylmorpholine N-oxide) (0.21g, 1.8mmol) and Tetrapropyl ammonium perruthenate (TPAP, tetrapropylammonium perruthenate) (0.025g, 0.071mmol).After 3 days, mixture is filtered pass through

/ SiO ₂Filler is with DCM and EtOAc washing.Evaporating solvent obtains title compound, and it is oily matter (0.17g, 49%).C ₂₀H ₂₃The accurate mass calculated value of NO: 293.2, measured value: LCMS m/z=294.0[M+H] ⁺

The preparation of step C:3-hydroxyl-3-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) ethyl propionate.

At-78 ℃, (0.15mL, (0.44mL concentration is the hexane solution of 2.5M, 1.1mmol) 1.1mmol) to add n-Butyl Lithium in the solution in THF (1mL) to the diisopropyl ethyl amine that is stirring.After 15 minutes, add EtOAc (0.11mL, 1.1mmol) solution in THF (0.2mL).After 30 minutes, adding (R)-4 '-(2-(2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-formaldehyde (0.16g, 0.55mmol) solution in THF (0.2mL).After 30 minutes, remove cooling bath, make mixture reach envrionment temperature.After 2 hours, water will react cancellation and extract with EtOAc (three times).The organic extract that merges is with the salt water washing and use dried over sodium sulfate.Evaporating solvent obtains title compound, and it is amber oily thing (0.19g, 90%).C ₂₄H ₃₁NO ₃The accurate mass calculated value: 381.2, measured value: LCMS m/z=382.5[M+H] ⁺

Step D:1-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) the third-1, the preparation of 3-glycol.

At 0 ℃, to the 3-hydroxyl-3-that is stirring (4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) ethyl propionate (0.19g, 0.49mmol) (0.49mL concentration is the THF solution of 1.0M, 0.49mmol) to add lithium aluminum hydride in the solution in THF (3mL).Remove cooling bath, mixture is stirred in envrionment temperature spend the night.After 16 hours, will react cancellation and use EtOAc (three times) extraction with frozen water.The organic extract that merges is handled to pH 1 with rare HCl aqueous solution.Mixture water extraction (three times), the aqueous extract of He Binging alkalizes to pH 10 with 50%NaOH then.Basic solution is with EtOAc extraction (three times), and the organic extract of He Binging is with the salt water washing and use dried over sodium sulfate then.Evaporating solvent obtains title compound, and it is amber oily thing (0.13g, 77%).C ₂₂H ₂₉NO ₂The accurate mass calculated value: 339.2, measured value: LCMS m/z=340.4[M+H] ⁺

Step e: 4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1, the preparation of 3-diox-2-ketone.

At 0 ℃, to the 1-that is stirring (4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) the third-1, (0.13g 0.38mmol) adds 1 in the solution in THF (8mL) to the 3-glycol, 1 '-carbonyl dimidazoles (CDI) (0.061g, 0.38mmol).After 1 hour, remove cooling bath, mixture is stirred spend the night.After 18 hours, add more CDI (0.030g, 0.19mmol).After 1 hour, evaporating solvent, resistates distributes between water and EtOAc.Water is with EtOAc extracting twice again.The organic extract salt water washing that merges, and use dried over sodium sulfate.Evaporating solvent obtains title compound, and it is an amber oily thing (0.16g).By this material of preparation property HPLC purifying, obtain title compound, it is tfa salt (16mg, 8.8%).C ₂₃H ₂₇NO ₃The accurate mass calculated value: 365.2, measured value: LCMS m/z=366.4[M+H] ⁺ ¹H NMR (400MHz, methyl alcohol-d ₄) δ ppm 1.47 (d, J=6.5Hz, 3H), 1.75 (dddd, J=13.2,9.1,9.1,9.1Hz, 1H), 2.21-2.00 (m, 2H), 2.44-2.26 (m, 3H), and 3.20-3.03 (m, 2H), 3.33-3.23 (m, 2H), 3.57-3.50 (m, 1H), 3.64 (ddd, J=16.6,10.8,6.0Hz, 1H), 3.76 (ddd, J=13.1,8.0,5.3Hz, 1H), and 4.55-4.49 (m, 1H), 4.62 (ddd, J=11.0,11.0,3.7Hz, 1H), 5.69 (dd, J=10.4,3.6Hz, 1H), 7.42 (d, J=8.2Hz, 2H), 7.50 (d, J=8.3Hz, 2H), 7.64 (d, J=8.2Hz, 2H), 7.68 (d, J=8.3Hz, 2H).

The preparation of embodiment 1.45:5-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) morpholine-3-ketone (compound 31).

Steps A: 2-amino-2-(4-bromophenyl) alcoholic acid preparation.

To the 1-that is stirring (4-bromophenyl) second-1, the 2-glycol (3.0g, 14mmol) add in the solution in acetonitrile (25mL) vitriol oil (7.4mL, 0.14Mol).Gained solution stirring at room 1 hour, is heated to backflow then.After 2 hours, mixture is cooled to room temperature, adds entry (10mL).Remove acetonitrile by rotary evaporation.The gained aqueous slurry is heated to 100 ℃.After 2 hours, mixture is cooled to room temperature and adds DCM.Mixture was stirred 5 minutes, separate each layer then.More than the extraction once of organic layer water, then the organic extract that merges is kept somewhere.Aqueous extract is handled to pH 10 with the 50%NaOH aqueous solution, then with EtOAc extraction (three times).Dried over sodium sulfate is used in the EtOAc extract salt water washing that merges, and evaporating solvent obtains title compound (1.9g, 64%) then.C ₈H ₁₀The accurate mass calculated value of BrNO: 215.0, measured value: LCMS m/z=216.3[M+H] ⁺

The preparation of step B:5-(4-bromophenyl) morpholine-3-ketone.

(1.3g, 60% dispersion in mineral oil 32mmol) add 2-amino-2-(4-bromophenyl) ethanol (1.7g, 7.9mmol) solution in benzene (50mL) in the suspension in benzene (50mL) to the sodium hydride that is stirring.Mixture stirring at room 30 minutes, is cooled to 0 ℃ then.At 0 ℃, drip the cold soln of ethyl chloroacetate in benzene (50mL).Mixture was stirred 2.5 hours.To react cancellation by pouring among ice/MTBE, handle to pH 1 with 10%HCl then.Mixture is used the salt water washing, and is used dried over sodium sulfate with MTBE extraction (three times).Evaporating solvent obtains yellow residue.By the described resistates of flash chromatography on silica gel method purifying, obtain title compound, it is white solid (0.70g, 35%).C ₁₀H ₁₀BrNO ₂The accurate mass calculated value: 255.0, measured value: LCMS m/z=256.4[M+H] ⁺

The preparation of step C:5-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) morpholine-3-ketone.

With 5-(4-bromophenyl) morpholine-3-ketone (0.10g, 0.39mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl) ethyl) phenyl-boron dihydroxide hydrochloride (0.11g, 0.39mmol), tetrakis triphenylphosphine palladium (0) (0.014g, 0.012mmol), yellow soda ash (0.59mL concentration is the aqueous solution of 2.0M, 1.2mmol), the mixture of benzene (1.0mL) and ethanol (0.3mL) is incorporated in the suitable microwave bottle and under microwave condition 100 ℃ of radiation 30 minutes.Make mixture filter by Celite pad evaporating solvent with EtOAc.Obtain title compound by preparation property HPLC purifying resistates, it is tfa salt (20mg, 11%).C ₂₃H ₂₈N ₂O ₂The accurate mass calculated value: 364.2, measured value: LCMS m/z=365.5[M+H] ⁺ ¹HNMR (400MHz, DMSO-d ₆) δ ppm 1.38 (d, J=6.5Hz, 3H), 1.61 (dddd, J=12.9,8.9,8.9,8.9Hz, 1H), 2.11-1.85 (m, 2H), 2.27-2.17 (m, 1H), and 3.12-2.93 (m, 2H), 3.28-3.17 (m, 2H), 3.70-3.45 (m, 4H), 3.99 (dd, J=11.6,4.1Hz, 1H), 4.11 (s, 2H), and 4.70-4.65 (m, 1H), 7.45-7.40 (m, 4H), 7.69-7.63 (m, 4H), 8.46 (s, 1H), 9.34 (bs, 1H).

Embodiment 1.46:(S)-preparation of 4-(4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentamethylene-2-yls) phenyl) oxazolidine-2-ketone.

Add in the 500mL three neck round-bottomed flasks that temperature sensor, mechanical stirrer and nitrogen inlet are installed that trifluoromethanesulfonic acid (S)-(4-(2-Yang Dai oxazolidine-4-yl) phenyl) (20.0g 64.3mmol), adds toluene (250mL) to ester then.Mixture stirred in nitrogen atmosphere and add potassium acetate (13.87g, 141mmol), add 4,4,4 then ', 4 ', 5,5,5 ', 5 '-prestox-2,2 '-two (1,3,2-two oxa-boron pentamethylene) (24.48g, 96mmol), triphenylphosphine (1.011g, 3.86mmol) and PdCl ₂(PPh ₃) ₂(1.353g, 1.928mmol).Reaction mixture is heated gradually (by oil bath) to 100 ℃ (internal temperatures).The initial heat release that gentleness takes place, and internal temperature rises to 110 ℃.Reaction mixture is cooled to about 100 ℃ and kept 2 hours in this temperature.Lcms analysis shows that existence is less than 1% initial substance.Show that by LCMS initial substance has identical retention time with product; By the chromatography of ions data of extracting the formation of product is analyzed.

The reaction mixture heating more than 20 minutes, is cooled to about 30 ℃, adds entry (100mL), and mixture was fully stirred 30 minutes in room temperature.The product crystallization is separated out, by collecting described product.Filter cake washes with water once, uses 1 then: 1=toluene: heptane wash, in vacuum drying oven, obtain product in about 50 ℃ of dried overnight, and it is brown solid (16.09g).C ₁₅H ₂₀BNO ₄The accurate mass calculated value: 289.15, measured value: LCMS m/z=290.0[M+H] ⁺Be indicated as 92% purity by LCMS.

The solution of above-mentioned substance (16.09g) is dissolved in EtOAc (100mL), acetonitrile (50mL) and the methyl alcohol (20mL), is warmed to about 35 ℃.Make solution pass through silica filler.Then with EtOAc with described filler wash-out three times.The solvent that concentrating under reduced pressure merges (after the filler filtration).Add heptane, residual solvent exchanges with heptane.Concentrate gained heptane slurries (about 2-3 volume) and filtration.Filter cake obtains beige solid with heptane wash, with described solid in vacuum drying oven in about 50 ℃ of dryings, stay title compound (14.35g).C ₁₅H ₂₀BNO ₄The accurate mass calculated value: 289.15, measured value: LCMS m/z=290.0[M+H] ⁺Be defined as 95.7% by LCMS.

Embodiment 2:[ ³H] N-Alpha-Methyl-histamine competitive histamine H3 receptors bind mensuration

Histamine Receptors uses standard laboratory method as described below to carry out in conjunction with measuring.Use homogenate device (polytron) that the tissue of rat whole brain cortex is carried out homogenize, then contain proteinase inhibitor based on the damping fluid of HEPES in carry out differential centrifugation, thereby prepare rough membrane portions (membrane fraction) by rat whole brain cortex (whole rat brain cortex).Before use that film is freezing at-80 ℃.The refrigerated film thawed and be suspended in the ice-cold mensuration damping fluid that constitutes by the 50mMTRIS that contains 5mM EDTA (pH=7.4).In each hole of 96 hole assay plate, add 50 micrograms (μ g) membranin and test compound and [ ³H]-N-Alpha-Methyl-histamine (finally measuring concentration is 1 nanomolar concentration (nM)).The Imetit that uses different concns is as measuring positive control.With plate incubated at room temperature 30 minutes.Measure following termination: use cell harvestor (Perkin-Elmer) to make and measure the quick filtration of mixture by 96 hole glass fibre screen plates (GF/C).The film that captures is with cold mensuration damping fluid washing three times, then with plate 50 ℃ of dryings.In each hole, add 35 microlitres (μ L) flicker mixture (scintillation cocktail), and use TopCount 96 orifice plate scintillometer (Perkin-Elmer) to come recording film institute bonded radioactivity.

Following table has shown the just viewed activity of some compounds of the present invention.

Compound number	K _iIn conjunction with measuring (nM)
		7	1.3
12	0.8
		13	2.2
14	3.2
		15	1.1

Other compound more of the present invention has the activity of 0.6nM to 24.0nM in this mensuration.

Embodiment 3: rat polysomnography scheme.

Animal: with (225-350g) (Harlan of male sprague-Dawley rat (Sprague Dawley rat), San Diego, CA) with 12 hours: 12 hours illumination/dark cycle (in 6:30 illumination in the morning) to be housed in humidity respectively be that 30-70% and temperature are in the 20-22 ℃ of controlled facility, random food intake (Harlan-Teklad Western Res., Orange, CA, Rodent Diet 8604) and water.Make rat before operation, adapt at least three days to described animal facility.

Step:

With ketamine/xylazine mixture with rat anesthesia, and with regard to the preparation of undergoing surgery property of EEG and EMG record.Recover 2-3 after surgery after week, make rat adapt to polypropylene test cage at least three days.Testing the same day, and rat had been placed in the testing laboratory and adapts to spend the night.At 10 in second the morning to rat medicine-feeding test compound, be connected with recording unit and be put back in the testing laboratory, continue 3 hours.

Data analysis

In the trial period that lasts three hours, to EEG and EMG data carry out digitizing and with 10 seconds time unit (epoch) store.Then these data are carried out the vision scoring, and per 10 seconds time units are characterized by non--REM sleep, REM sleep or awakening outbreak.Behind administration vehicle or test compound, calculate total awakening time of described three hour trial period with regard to each rat.Derive the increase per-cent of awakening then with regard to each rat.

Following table has shown the increase per-cent that lasts viewed awakening in 1 hour after with 1.0mg/kg oral administration representation compound.

Compound number	The increase %+ of awakening/-s.e.
		2	54.4±15.8

Embodiment 4: people's histamine H 3-receptors bind mensuration-MDS Pharma Services (Taiwan).

Use MDS Pharma Services (Taiwan) to measure (catalog number is 239810) and test The compounds of this invention and people's histamine H 3 receptor bonded ability.Compounds more of the present invention and their corresponding activity values are presented in the following table.

Compound number	In conjunction with measure (Ki, nM)
		1	6.9
2	4.4

Other compound of the present invention has the activity of about 4.4nM to about 23nM in this mensuration.

Embodiment 5: measure the blocking-up to RAMH institute inductive drinking-water

When to the rodent administration, H3 agonist for example R-Alpha-Methyl-histamine (RAMH) induces drinking-water to reply (drinking response), and described drinking-water is replied the reverse that is sensitive to due to the H3 antagonist.Therefore, the blocking-up of RAMH institute inductive drinking-water be can be used as in the body at functional H3 antagonistic activity measure.In said determination, (closing illumination at 1130h) in a cage, and fed in per three passes of male sprague-Dawley rat (250-350g) under the 12h illumination of putting upside down circulation.1030h (on test same day), close rat separately in new cage and take food away.After 120 minutes, to rat medicine-feeding test product (vehicle or H3 antagonist, 0.3mg/kg, PO (oral)).After 30 minutes, take water and administration RAMH (vehicle or RAMH, 3mg/kg salt, SC (subcutaneous)) away.After administration RAMH10 minute, will water bottle place cage and allowed to drink 20 minutes through weighing.Determine the water consumption of every animal by the weight (being accurate to 0.1g) of each bottle of weighing.Is the minimizing per-cent that water is taken in according to following formula with data representation:

[((vehicle/RAMH)-(antagonist/RAMH))/((vehicle/RAMH)-(basis drinking-water: 1mL))] * 100

Compound number	The inhibition % of RAMH-inductive drinking-water
		4	109.5
5	50.6

11

83.3

One skilled in the art will recognize that, can carry out various changes, interpolation, replacement and variation and not deviate from purport of the present invention, and therefore think that described change, interpolation, replacement and variation are within the scope of the invention the exemplary embodiment that the present invention lists.Incorporate above-cited all reference (comprise but with the public publication that is limited to printing and temporary patent application and regular patent application) integral body into this paper as a reference.

Claims

1. compound, it is selected from formula (Ia) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

Ring A for optional be substituted with one, two or three are selected from C ₁-C ₆The substituent heterocyclic radical of alkyl and oxo; Each C wherein ₁-C ₆The optional C that is substituted with of alkyl ₁-C ₆Alkoxy substituent;

R ¹Be H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl or halogen;

R ²Be H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl or halogen;

R ³Be H, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl or halogen;

R ⁴Be H or C ₁-C ₄Alkyl; And

N is 0,1 or 2.

2. each compound, wherein R in the claim 1 to 2 ¹, R ²And R ³All be H.

3. the compound of claim 1, wherein R ¹Be selected from C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

4. the compound of claim 3, wherein R ¹Be selected from methoxyl group, methyl, chlorine and fluorine.

5. the compound of claim 1, wherein R ²Be selected from C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

6. the compound of claim 5, wherein R ²Be selected from methoxyl group, methyl, chlorine and fluorine.

7. the compound of claim 1, wherein R ³Be selected from C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen.

8. the compound of claim 7, wherein R ³Be selected from methoxyl group, methyl, chlorine and fluorine.

9. each compound, wherein R in the claim 1 to 8 ⁴Be H.

10. each compound, wherein R in the claim 1 to 8 ⁴Be C ₁-C ₄Alkyl.

11. each compound, wherein R in the claim 1 to 8 ⁴Be methyl.

12. each compound in the claim 1 to 11, wherein n is 0.

13. each compound in the claim 1 to 11, wherein n is 1.

14. each compound in the claim 1 to 11, wherein n is 2.

15. each compound in the claim 1 to 14 wherein encircles A and is selected from Yang Dai oxazolidinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

16. each compound in the claim 1 to 14, wherein encircle A and be selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base.

17. each compound in the claim 1 to 14 wherein encircles A and is selected from oxo-pyrrolidine base, oxo-1,3-dioxolanyl, oxo-1,3-alkyl dioxin, oxo morpholinyl and oxo-1,3-oxazine alkyl; Wherein each ring A chooses wantonly and is substituted with C ₁-C ₆Alkyl substituent; And wherein said C ₁-C ₆The optional C that is substituted with of alkyl substituent ₁-C ₆Alkoxy substituent.

18. each compound in the claim 1 to 14, wherein encircle A and be selected from 2-oxo-pyrrolidine-4-base, 2-oxo-pyrrolidine-5-base, 2-oxo-1,3-dioxolane-4-base, 2-oxo-1,3-diox-4-base, 3-oxo morpholine-5-base and 2-oxo-1,3-oxazine alkane-6-base.

19. the compound of claim 1, it is selected from formula (Ic) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

R ⁴Be H or C ₁-C ₄Alkyl;

N is 0,1 or 2.

20. the compound of claim 1, it is selected from formula (Ic) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

R ⁴Be H or methyl;

Ring A is selected from 2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base and 2-oxo-1,3-oxazine alkane-4-base; And

N is 0,1 or 2.

21. the compound of claim 1, it is selected from formula (Ig) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

N is 0,1 or 2.

22. the compound of claim 1, it is selected from formula (Ig) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

Ring A is selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base, 2-oxo-1,3-oxazine alkane-4-base; And

N is 0,1 or 2.

23. the compound of claim 1, it is selected from formula (Ii) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

R ¹, R ²And R ³Be selected from H, C independently of one another ₁-C ₆Alkoxyl group, C ₁-C ₆Alkyl and halogen;

N is 0,1 or 2.

24. the compound of claim 1, it is selected from formula (Ii) compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

Wherein:

R ¹, R ²And R ³Be selected from H, methoxyl group, methyl, chlorine and fluorine independently of one another;

Ring A is selected from 2-Yang Dai oxazolidine-4-base, 3-methyl-2-Yang Dai oxazolidine-4-base, 3-sec.-propyl-2-Yang Dai oxazolidine-4-base, 3-(2-methoxy ethyl)-2-Yang Dai oxazolidine-4-base, 2-Yang Dai oxazolidine-5-base, 2-oxo-1,3-oxazine alkane-4-base, 2-oxo-pyrrolidine-4-base, 2-oxo-pyrrolidine-5-base, 2-oxo-1,3-dioxolane-4-base, 2-oxo-1,3-oxazine alkane-6-base, 2-oxo-1,3-diox-4-base and 3-oxo morpholine-5-base; And

N is 0,1 or 2.

25. the compound of claim 1, it is selected from following compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

(S)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-ketone;

(S)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-ketone;

(R)-3-methyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-3-sec.-propyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-3-methyl-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-ketone;

(R)-3-(2-methoxy ethyl)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-ketone;

(R)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl)-1,3-oxazine alkane-2-ketone;

(S)-3-methyl-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-ketone;

(S)-3-(2-methoxy ethyl)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl) oxazolidine-2-ketone;

(S)-4-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) methyl)-1,3-oxazine alkane-2-ketone;

5-((4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(S)-3-methyl-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(S)-3-(2-methoxy ethyl)-4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone; And

(R)-4-(4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone.

26. the compound of claim 1, it is selected from following compound or pharmaceutically acceptable salt thereof, solvate and hydrate:

(R)-4-(2,6-two chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) oxazolidine-2-ketone;

(R)-4-(2-methyl-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-4-(2-chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-4-(2-methoxyl group-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-4-(2 '-chloro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

(R)-4-(3 '-fluoro-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

4-(3-methyl-4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone;

4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) pyrrolidin-2-one;

4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1,3-dioxolane-2-ketone;

6-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1,3-oxazine alkane-2-ketone;

4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1,3-oxazine alkane-2-ketone;

4-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl)-1,3-diox-2-ketone;

5-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) pyrrolidin-2-one;

5-(4 '-(2-((R)-2-methylpyrrolidin-1-yl) ethyl) biphenyl-4-yl) morpholine-3-ketone;

(S)-4-(2 '-methyl-4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone; And

(S)-4-(2 '-methoxyl group-4 '-(2-(tetramethyleneimine-1-yl) ethyl) biphenyl-4-base) oxazolidine-2-ketone.

27. pharmaceutical composition, it comprises in the claim 1 to 26 each compound and pharmaceutical carrier.

28. the method for a treatment histamine H 3-acceptor associated disorders in individuality comprises the pharmaceutical composition of in the claim 1 to 26 of the described individual drug treatment significant quantity that these needs are arranged each described compound or claim 27.

29. the method for claim 28, wherein said histamine H 3-acceptor associated disorders are selected from allergic response, rhinallergosis, nasal congestion, dementia, alzheimer's disease and pain in cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the obstacle of keeping alert while in bed, narcolepsy, cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea etc., attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, the upper respiratory tract.

30. the method for claim 28, wherein said histamine H 3-acceptor associated disorders is the obstacle of keeping alert while in bed.

31. the method for claim 28, wherein said histamine H 3-acceptor associated disorders is a cognitive disorder.

32. the method for claim 28, wherein said histamine H 3-acceptor associated disorders is a cataplexy.

33. a method of inducing awakening in individuality comprises in the claim 1 to 26 of the described individual drug treatment significant quantity that these needs are arranged each the compound or the pharmaceutical composition of claim 27.

34. the method for a treatment pain in individuality comprises in the claim 1 to 26 of the described individual drug treatment significant quantity that these needs are arranged each the compound or the pharmaceutical composition of claim 27.

35. each compound is used for the treatment of purposes in the medicine of histamine H 3-acceptor associated disorders in preparation in the claim 1 to 26.

36. each compound is used for the treatment of purposes in the medicine that is selected from following obstacle in preparation in the claim 1 to 26: cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the obstacle of keeping alert while in bed, narcolepsy, cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea etc., attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, allergic response in the upper respiratory tract, rhinallergosis, nasal congestion, dull-witted, alzheimer's disease and pain.

37. each compound is used for the treatment of purposes in the medicine of the obstacle of keeping alert while in bed in preparation in the claim 1 to 26.

38. each compound is used for the treatment of purposes in the medicine of cognitive disorder in preparation in the claim 1 to 26.

39. each compound is used for the treatment of purposes in the medicine of cataplexy in preparation in the claim 1 to 26.

40. each compound is used for inducing the purposes of the medicine of awakening in the claim 1 to 26 in preparation.

41. each compound is used for the treatment of purposes in the medicine of pain in preparation in the claim 1 to 26.

42. each compound in the claim 1 to 26, it is used in the method by therapy for treating human body or animal body.

43. each compound in the claim 1 to 26, it is used in the method for treatment histamine H 3-acceptor associated disorders.

44. each compound in the claim 1 to 26, it is used in treatment and is selected from the method for following histamine H 3-acceptor associated disorders: allergic response, rhinallergosis, nasal congestion, dementia, alzheimer's disease and pain in cognitive disorder, epilepsy, cerebral trauma, dysthymia disorders, obesity, the obstacle of keeping alert while in bed, narcolepsy, cataplexy, hypersomnia, drowsiness syndrome, jet lag, sleep apnea etc., attention deficit companion hyperkinetic syndrome (ADHD), schizophrenia, transformation reactions, the upper respiratory tract.

45. each compound in the claim 1 to 26, it is used in the method for the treatment of the obstacle of keeping alert while in bed.

46. each compound in the claim 1 to 26, it is used in the method for treatment cognitive disorder.

47. each compound in the claim 1 to 26, it is used in the method for treatment cataplexy.

48. each compound in the claim 1 to 26, it is used in the method for inducing awakening.

49. each compound in the claim 1 to 26, it is used in the method for treatment pain.

50. the preparation method for compositions comprises each compound in the claim 1 to 26 is mixed with pharmaceutical carrier.