CN101426778A

CN101426778A - N-substituted-azacyclylamines as histamine-3 antagonists

Info

Publication number: CN101426778A
Application number: CNA2007800139597A
Authority: CN
Inventors: 德里克·塞西尔·科乐; 玛格达·阿瑟兰; 约瑟夫·雷蒙德·斯托克; 艾伯特·琼·罗比肖; 金智寅; 威廉·罗纳德·索尔维比莱; 乔纳森·莱尔德·格罗斯
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2006-03-15
Filing date: 2007-03-08
Publication date: 2009-05-06

Abstract

The present invention provides a compound of formula (I) and the use thereof for the treatment of a central nervous system disorder related to or affected by the histamine-3 receptor.

Description

N-as histamine-3 antagonists is substituted-Azacyclyl amine

Technical field

Do not have

Background technology

Histamine-3 (H3) acceptor is a kind of in four kinds of Histamine Receptors hypotypes (H1-H4), and all these receptor subtypes all are the members of bigger G protein-coupled receptor (GPCR) superfamily of acceptor.The H3 acceptor is mainly expressed in central nervous system.It is positioned at the zone relevant with learning and memory in brain, such as pallium, hippocampus and striatum.The H3 acceptor works to regulate the release of histamine and other neurotransmitter as autoreceptor and heteroreceptor.As if in cortex, the H3 acceptor directly changes the release of GABA from the cortex relay cell.The antagonistic action of H3 acceptor causes GABA discharge to reduce and cortex choline system suppresses to remove, cause acetyl choline content raise (Brazil difficult to understand for the Buddhist nun (Bacciottini L) waits the people, and the behavior brain is studied (Behavioral Brain Research), 124, 2001, 183-194).Except that directly regulating the choline neurotransmission, the H3 acceptor also show the release of regulating Dopamine HCL, thrombotonin and norepinephrine (Lai Si (and Leurs, R.) people such as grade, pharmacology science trend (Trends in Pharmacological Sciences), 19, 1998, 177-183).The human minimizing that after death studies show that the brain histamine content may directly or via the choline system cause the middle cognitive decline (Pa Nula (Panula that occurs of Alzheimer (Alzheimer ' s disease), people such as P.), neuroscience (Neuroscience), 82 1998, 993-997).Reported the H3 agonist and damaged memory in the various tasks, such as Target Recognition, passive avoidance (the Blanc enlightening that (Blandina P.) waits the people, Britain's pharmacology magazine (British Journal ofPharmacology), 119 (8), 1996, 1656-1664) and social scent-memorizing (social olfactory memory) (Prast (Prast H.) waits the people, 734, 1996, 316-318), report H3 antagonist is rescued the infringement that causes in pharmacology or the heredity, promptly Miyazaki (Miyazaki S.) waits the people, life science (Life Sciences), 61, 1997, 355-361; Order black (Meguro K.) waits the people, pharmacology, biological chemistry and behavior (Pharmacology, Biochemistry andBehavior), 50, 1995, 321-325; Fox (Fox G.B.) waits the people, behavior brain research (Beharioral BrainResearch), and 131, 2002, 151-161; And Ke Mate (Komater, V.A.) people such as grade, psychopharmacology (Psychopharmacology), 167,2003,363-372.

Neuroanatomy, neurochemistry, pharmacology and behavioral data are supported the H3 receptor antagonist can improve the cognitive performance in the disease patient's condition (such as mild cognitive impairment and Alzheimer) together and can have the notion of therapeutic value in the treatments of the not enough Attention Deficit Hyperactivity Disorder (ADHD) of attention, schizophrenia, obesity and somnopathy.

Therefore, the object of the present invention is to provide to the H3 acceptor inhibitor and can in various or treatments relevant, be used as the compound of therapeutical agent by the central nervous system disorders of H3 acceptor influence with the H3 acceptor.

Another object of the present invention is to provide and can be used for treating relevant or by the methods of treatment and the medical composition of the central nervous system disorders of H3 acceptor influence with the H3 acceptor.

The invention is characterized in that the compound that is provided also can be used for further studying and illustrating the H3 acceptor.

Summary of the invention

The N-that the invention provides formula I is substituted-the Azacyclyl amine compound:

Wherein

X is CO, CH ₂Or SO _m

P and n are 1,2 or 3 integer independently of one another;

M is 0 or is 1 or 2 integer;

R ₁And R ₂Be H or the alkyl that is substituted according to circumstances independently of one another, or R ₁And R ₂Can form together with the atom that it connected and contain one or two extra heteroatomic 4 to 7 yuan of ring that are substituted according to circumstances that are selected from N, O or S according to circumstances;

R ₃Be NR ₄R ₅Or aryl or heteroaryl, each group is substituted according to circumstances;

R ₄And R ₅Form together with the atom that it connected and to contain one to three extra heteroatomic condensed-bicyclic that is substituted according to circumstances that is selected from N, O or S, three ring or 9 to 15 yuan of loop systems in Fourth Ring according to circumstances;

R ₆And R ₇Be H, halogen, OR independently of one another ₁₀Or the alkyl that is substituted according to circumstances separately, thiazolinyl, alkynyl, cycloalkyl, ring assorted alkyl, aryl or heteroaryl;

R ₈And R ₉Be H or the alkyl that is substituted according to circumstances separately, cycloalkyl or aryl independently of one another; And

R ₁₀Be H or the alkyl that is substituted according to circumstances; Or

Its steric isomer or its pharmaceutically acceptable salt.

The present invention provides also that to can be used for therapeutic treatment relevant with histamine-3 acceptor or by the method and composition of the central nervous system disorders of histamine-3 acceptor influence.

Description of drawings

Do not have

Embodiment

Alzheimer (AD) is characterised in that the carrying out property forfeiture of memory and cognitive function and is the modal cause of disease of elderly dementia's disease.Believe that AD influences about 1,000 5 hundred ten thousand to 2,000 ten thousand people in the world wide.The purpose of AD treatment also is to suffer from slightly improve or slow down at least to the patient of moderate disease memory and cognitive forfeiture and keep standalone feature except reversing disease process.AD be characterised in that neurotransmitter function many deficiencies (Muller (

H-J.), Europe neuropsychopharmacology (European Neuropsychopharmacology), 9,1999, S53-S59), the human in addition minimizing that after death studies show that the brain histamine content may directly or cause the cognitive decline relevant with AD via the choline system, and ((Panula P.) waits people, neuroscience (Neuroscience) to Pa Nula, 82 1998, 993-997).Reported histamine-3 (H3) receptor antagonist rescue the infringement that causes in pharmacology or the heredity (Miyazaki (and Miyazaki S.) waits the people, life science (Life Sciences), 61, 1997, 355-361; Order black (Meguro K.) waits the people, pharmacology, biological chemistry and behavior (Pharmacology, Biochemistry and Behavior), 50, 1995, 321-325; Fox (Fox G.B.) waits the people, behavior brain research (Beharioral Brain Research), and 131, 2002, 151-161; And Ke Mate (Komater V.A.) waits the people, psychopharmacology (Psychopharmacology), and 167,2003,363-372).Neuroanatomy, neurochemistry, pharmacology and behavioral data are supported the H3 receptor antagonist can improve the cognitive performance in the disease patient's condition (such as mild cognitive impairment and Alzheimer) and can have the viewpoint of therapeutic value in the treatments of the not enough Attention Deficit Hyperactivity Disorder (ADHD) of attention, schizophrenia, obesity and somnopathy.Therefore, seek the compound that suppresses the H3 acceptor and work in earnest as the H3 antagonist.

It is shocking, have now found that the N-of formula I is substituted-the Azacyclyl amine compound shows that H-3 avidity is together with significant subtype-selective and serve as the H-3 antagonist.Advantageously, described formula I compound is to be used for the treatment of relevant with the H-3 acceptor or by effective therapeutical agent of central nervous system (CNS) illness of H-3 acceptor influence.Therefore, the N-that the invention provides formula I is substituted-the Azacyclyl amine compound:

Wherein

X is CO, CH ₂Or SO _m

P and n are 1,2 or 3 integer independently of one another;

M is 0 or is 1 or 2 integer;

R ₄And R ₅Form together with the atom that it connected and to contain one to three extra heteroatomic condensed-bicyclic that is substituted according to circumstances that selects white N, O or S, three ring or 9 to 15 yuan of loop systems in Fourth Ring according to circumstances;

R ₁₀Be H or the alkyl that is substituted according to circumstances; Or

Its steric isomer or its pharmaceutically acceptable salt.

Should be appreciated that claim contains all possible steric isomer and prodrug.In addition, except as otherwise noted, otherwise expect that each alkyl, thiazolinyl, alkynyl, cycloalkyl, the assorted alkyl of ring, aryl or heteroaryl are substituted according to circumstances.

The part that is substituted according to circumstances can replace through one or more substituting groups.The substituting group of Cun Zaiing can be and is generally used for researching and developing pharmaceutical compound or modifies described compound with in the substituting group that influences its structure/activity, persistence, absorption, stability or other beneficial property one or more according to circumstances.Described substituent particular instance comprises that halogen atom, nitro, cyano group, sulphur cyanato-, cyanato-, oxo base, hydroxyl, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, amino, alkylamino, dialkyl amido, formyl radical, alkoxy carbonyl, carboxyl, alkyloyl are (such as C ₁-C ₆Alkyl-carbonyl), alkyl sulfenyl, alkyl sulphinyl, alkyl sulphonyl, carbamyl, alkylamidoalkyl, aryl (such as phenyl), aryloxy (such as phenoxy group), arylalkyl (such as phenmethyl), alkoxy aryl (such as benzyloxy), heterocyclic radical (for example heteroaryl, the assorted alkyl of ring) or cycloalkyl, be preferably halogen atom or low-carbon alkyl or low-carbon alkoxy.Unless certain illustrated is arranged in addition, otherwise can have 0-4 substituting group usually.When any aforementioned substituting group was represented or contained alkyl substituent, it can be straight or branched and can contain 12 carbon atoms at the most, preferred 6 carbon atoms at the most, more preferably 4 carbon atoms at the most.

The term alkyl is comprising (C as group or when containing the part of group (such as alkoxyl group, alkyl sulphinyl, halogenated alkoxy, alkylamino etc.) of moieties as used herein ₁-C ₁₀) straight chain and (C ₃-C ₁₂) side chain (unless otherwise defined) monovalent saturated hydrocarbon part.The example of stable hydrocarbon moieties includes, but is not limited to have the chemical group of 1-6 carbon atom, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, sec-butyl; The high-carbon homologue is such as n-pentyl, n-hexyl and its similar group.Especially comprise the described alkyl that is substituted according to circumstances in the definition of alkyl.Suitable alkyl replacement includes, but is not limited to CN, OH, NR ₁₀R ₁₁, halogen, phenyl, carbamyl, carbonyl, alkoxyl group or aryloxy.

The term haloalkyl represents to have the C of 1 to 2n+1 individual halogen atom that can be identical or different as used herein _nH _2n+1Group.The example of haloalkyl comprises CF ₃, CH ₂Cl, C ₂H ₃BrCl, C ₃H ₅F ₂Or its similar group.

Term halogen is represented fluorine, chlorine, bromine and iodine as used herein.

The term thiazolinyl is meant the (C that contains at least one two key as used herein ₂-C ₁₀) straight chain or (C ₃-C ₁₀) side chain monovalent hydrocarbon part.Described hydrocarbon alkenyl part can be single unsaturated or many unsaturated hydrocarbons alkenyl part and can E or the Z configuration exist.Compound plan of the present invention comprises all possible E and Z configuration.Single example unsaturated or many unsaturated hydrocarbons alkenyl part includes, but is not limited to such as vinyl, 2-propenyl, pseudoallyl, crot(on)yl, 2-isopentene group, butadienyl, 2-(butadienyl), 2, the chemical group of 4-pentadienyl, 3-(1, the 4-pentadienyl) and high-carbon homologue, isomer or its similar group.

Represent to have at least one triple-linked (C as term alkynyl used in specification sheets and the claim ₂-C ₁₀) straight chain or (C ₃-C ₁₀) side chain monovalent hydrocarbon part.Described hydrocarbon alkynyl partly can be single unsaturated or many unsaturated hydrocarbons alkynyl part.Single example unsaturated or many unsaturated hydrocarbons alkynyl part includes, but is not limited to proyl, butynyl, 1,3-diacetylene base, pentynyl, hexin base or its similar group.

As used herein the term cycloalkyl be meant that monocycle, dicyclo, three with 3-10 carbon atom encircle, condense, bridge joint or spiral shell monovalent saturated hydrocarbon part.The example of cycloalkyl moiety includes, but is not limited to the chemical group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, norcamphyl, adamantyl, spiral shell [4.5] decyl or its similar group.

The assorted alkyl of term ring represents to contain 1,2 or 35 to 7 yuan of cycloalkyl ring system that are selected from N, O or S and heteroatoms that can be identical or different and contain two keys according to circumstances as used herein.The example that is included in the assorted alkyl loop systems of ring in the term as shown here is following ring, wherein X ₁For NR ', O or S and R ' are H or optional substituting group as hereinbefore defined.

Term aryl is meant and has the aromatic carbon ring part of 20 carbon atoms (for example 6-20 carbon atom) at the most as used herein, described aromatic carbon ring partly can be single ring (monocycle) or condenses together or a plurality of rings of covalent bond (dicyclo, 3 rings at the most).The example of aryl moiety includes, but is not limited to the chemical group such as phenyl, 1-naphthyl, 2-naphthyl, xenyl, anthryl, phenanthryl, fluorenyl, indanyl, acenaphthenyl or its similar group.

The term heteroaryl is represented the heteroaromatic system as used herein, and described heteroaromatic system can be (for example) to be had the single ring (monocycle) of 5 to 11 ring memberses or condense together or a plurality of rings of covalent bond (dicyclo, 3 rings at the most).Heteroaryl is preferably 5 to 6 yuan of rings or 9 to 11 yuan of loop systems of condensed-bicyclic.Described ring can contain 1 to 4 heteroatoms that is selected from nitrogen, oxygen or sulphur, and wherein nitrogen-atoms or sulphur atom be according to circumstances through oxidation, or nitrogen-atoms is according to circumstances through quaternized.The example of heteroaryl moieties includes, but is not limited to: heterocycle, such as furans, thiophene, the pyrroles, pyrazoles, imidazoles oxazole isoxazole, thiazole, isothiazole oxadiazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, benzoglyoxaline benzoxazole, benzoisoxazole, benzothiazole, cumarone, thionaphthene, thianthrene, diphenylene-oxide, dibenzothiophene, indoles, indazole, azaindole, azaindazole, imidazopyridine, indoline, the pyrido indoles, quinoline, isoquinoline 99.9, quinazoline, quinoxaline, purine, tetrahydro carbazole, six hydrogen indolizine diindyl ketone, the tetrahydropyrans diindyl, tetrahydroquinoline, dihydro-dibenzo azatropylidene or its analogue are preferably benzoglyoxaline, indoles, indazole, azaindole or azaindazole.

R ₄And R ₅The example of the condensed-bicyclic that forms together with the nitrogen-atoms that it connected, three rings or 9 to the 15 yuan of loop systems in Fourth Ring comprises indoles, indazole, benzoglyoxaline, 1H-carbazole, 2,3,4,9-tetrahydrochysene-1H-carbazole, 5,6,11,11b-tetrahydrochysene-1H-indolizine also [8,7-b] indoles, 1,2,5,6,11,11b-six hydrogen-3H-indolizine also [8,7-b] indoles, imidazo [4,5-b] pyridine, indoline, 1,2,3,4-tetrahydroquinoline, imidazoles or dibenzo [b, f] azatropylidene or its analogue.

Except as otherwise noted, otherwise the structure that this paper describes also plans to comprise all stereochemical forms of structure; Be the R and the S configuration of each asymmetric center.Therefore, the single three-dimensional chemical isomer of The compounds of this invention and enantiomer and non-enantiomer mixture are within the scope of the invention.Except as otherwise noted, otherwise only also planning to comprise, the structure that this paper described has one or more isotopic enrichment atoms and different compounds.For instance, have structure of the present invention but hydrogen through displacement of deuterium or tritium or carbon warp ¹³C or ¹⁴C enrichment carbon metathetical compound within the scope of the invention.

Can use program used for a long time that compound of the present invention is transformed salify, especially pharmaceutically acceptable salt.The acceptable acid addition salts that forms with alkali be (for example) metal-salt (such as basic metal or alkaline earth salt, for example sodium, potassium or magnesium salts) or with the salt of ammonia or organic amine (such as morpholine, thiomorpholine, piperidines, tetramethyleneimine, list, two or three low-carbon alkyl amine (for example ethyl-TERTIARY BUTYL AMINE, diethylamine, Diisopropylamine, triethylamine, Tributylamine or dimethyl propylamine) or monohydroxy, dihydroxyl or trihydroxy-low-carbon alkyl amine (for example singly, two or trolamine)) formation.Can form inner salt in addition.1-6 carbon atom represented in term " low-carbon (LC) " as used herein.Also comprise the salt that is not suitable for medicinal use but can be used for (for example) isolated or purified free cpds or its pharmaceutically acceptable salt.When compound of the present invention contains basic moiety, term " pharmaceutically acceptable salt " is meant the salt derived from organic acid and mineral acid as used herein, described organic acid and mineral acid such as acetate, propionic acid, lactic acid, citric acid, tartrate, Succinic Acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and similar known acceptable acid.When compound of the present invention contains carboxylicesters or phenol moieties and maybe can form the similar portions of base addition salt, also can form salt from organic bases and mineral alkali, be preferably an alkali metal salt (for example sodium, lithium or sylvite).

Compound of the present invention comprises ester, carbamate or other conventional prodrug forms, and it is generally the functional derivatives of The compounds of this invention and is easy to change into active part of the present invention in vivo.Therefore, method of the present invention contains with formula I compound or with not specific announcement but when dispensing and the time is converted into the above-mentioned various symptom of compounds for treating of formula I compound in vivo.The metabolite that also comprises The compounds of this invention, it is defined as the active substance that produced when introducing these compounds in biosystems.

Radicals R ₃-(CR ₈R ₉) _n-can be in ortho position, a position or the contraposition of-X-group.

The example of p is 1 and 2.

The example of n is 1.

R ₁And/or R ₂Example be H, methyl, ethyl, propyl group, hydroxyethyl.

R ₁And R ₂The example of the ring that forms together with the nitrogen that it connected is: the tetramethyleneimine that is substituted according to circumstances, morpholine, piperidines, piperazine, azepan, 1,4-Diazesuberane, azetidine, such as 2-crassitude, 2-phenmethyl tetramethyleneimine, pipecoline, 3-methyl piperidine or 4-methyl piperidine, 3, the 5-lupetidine, along 2,6-thebaine, 3-methylpiperazine or 4-methylpiperazine.

R ₃Example be the phenyl that is substituted according to circumstances, benzoglyoxaline (for example benzimidazolyl-2 radicals-yl), indoles (for example indoles-2-yl), and work as R ₃Be NR ₄R ₅(R wherein ₄And R ₅Be condensed-bicyclic, three ring or Fourth Rings together) time, example comprises indoles, indazole, benzoglyoxaline, the 1H-carbazole, 2,3 that is substituted according to circumstances, 4,9-tetrahydrochysene-1H-carbazole, 5,6,11,11b-tetrahydrochysene-1H-indolizine also [8,7-b] indoles, 1,2,5,6,11,11b-six hydrogen-3H-indolizine also [8,7-b] indoles, imidazo [4,5-b] pyridine, indoline, 1,2,3,4-tetrahydroquinoline, imidazoles or dibenzo [b, f] azatropylidene ring.

For example-NR ₁R ₂Go up or R ₃On optional substituent example be aryl (for example phenyl); halogen (fluorine for example; chlorine; bromine); alkyl (methyl for example; ethyl; propyl group; sec.-propyl; isobutyl-); alkoxyl group (for example methoxyl group); alkoxyalkyl (for example methoxy ethyl); oxo base (for example being the annular atoms of C=O); cyano group; methane amide; COO alkyl (for example ethoxy carbonyl); trifluoromethyl; hydroxyalkyl; phenylalkyl (phenmethyl for example; styroyl); aryl sulfonyl (for example phenyl sulfonyl); benzyloxy and methyl cycloalkyl (for example cyclopropyl methyl).

R ₆And/or R ₇Example be H, halogen (for example fluorine, chlorine), alkyl (for example methyl), alkoxyl group (for example methoxyl group).

R ₈Example be H and alkyl (for example methyl).

Preferred compound of the present invention is CO or CH for those X ₂Formula I compound.Another kind of preferred compound for those n be 1 and p be 1 or 2 formula I compound.Those R ₈And R ₉Formula I compound for H or methyl also is preferred independently of one another.

More preferably compound of the present invention is CO or CH for those X ₂And R ₁And R ₂Form the formula I compound of 5 yuan of rings together with the atom that it connected.Another kind of more preferably compound is CO or CH for those X ₂And R ₃Be NR ₄R ₅Or the formula I compound of the indoles that is substituted according to circumstances, indazole, phenyl or benzoglyoxaline ring.Another kind of more preferably compound is CO for those X; N is 1; P is 1 or 2; R ₁And R ₂Form 5 yuan of rings together with the atom that it connected; And R ₃Be NR ₄R ₅Or the formula I compound of benzoglyoxaline that is substituted according to circumstances or indole ring.Preferred formula I compound also is those R ₃Be benzoglyoxaline ring (in 2 connections of described benzoglyoxaline ring) or the R that is substituted according to circumstances ₃Be NR ₄R ₅And R ₄And R ₅Form the formula I compound of the indoles, indazole or the benzoglyoxaline ring that are substituted according to circumstances together with the atom that it connected.

Preferred compound of the present invention is:

N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

(3-S)-and N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

(3-R)-and N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(6-fluoro-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(6-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(5-fluoro-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(4-fluoro-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-[3-(1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-[4-(1H-indoles-1-ylmethyl) benzoyl] tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(2,3,4,9-tetrahydrochysene-1H-carbazole) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(2-Methyl-1H-indole-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(2-phenyl-1H-indoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(5-methoxyl group-1H-indoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(5-methoxyl group-2-phenyl-1H-indoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(7-azepine-1H-indoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(1H-benzo [d] imidazoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(2-methyl isophthalic acid H-benzo [d] imidazoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(5-hydroxyl-1H-indoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(1,2,3,4-tetrahydroquinoline-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(5-fluoro-1H-indoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(3-cyano-1 H-indol--1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(2-phenyl-1H-imidazoles-1-yl) methyl] benzoyl } tetramethyleneimine-3-base amine;

1 '-4-[(2-phenyl-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1 '-4-[(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1 '-4-[(6-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1 '-4-[(6-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1 '-4-[(5-fluoro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(2-R)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-2-methyl isophthalic acid, 3 '-bipyrrolidine;

(3 '-R)-1 '-4-[(2-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 '-S)-1 '-4-[(2-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-[4-(1H-indoles-1-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-[4-(1H-indazole-1-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(6-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(6-fluoro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(6-fluoro-1H-benzoglyoxaline-1-yl) and methyl] phenmethyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(5-fluoro-1H-benzoglyoxaline-1-yl) and methyl] phenmethyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(5-fluoro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(7-chloro-1H-indoles-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

9-{4-[(3 ' S)-1,3 '-bipyrrolidine-1-base carbonyl] phenmethyl-the 9H-carbazole;

(3 '-S)-1 '-4-[(1S)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 '-S)-1 '-4-[(1R)-1-(2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 '-S)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) phenmethyl]-1,3 '-bipyrrolidine;

(3 '-S)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

(3-S)-and N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

(3-R)-and N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(6-fluoro-1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(6-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(5-fluoro-1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-{4-[(4-fluoro-1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

N, N-dimethyl-1-[3-(1H-benzoglyoxaline-1-yl) methyl]-phenmethyl } tetramethyleneimine-3-base amine;

N, N-dimethyl 1-[4-(1H-indoles-1-ylmethyl) phenmethyl] tetramethyleneimine-3-base amine;

N, N-dimethyl 1-{[4-(2,3,4,9-tetrahydrochysene-1H-carbazole) methyl] phenmethyl } tetramethyleneimine-3-base amine;

(3 ' S)-1 '-[4-(1H-indol-3-yl methyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1-Methyl-1H-indole-3-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3S)-and N, N-dimethyl-1-{4-[(1-Methyl-1H-indole-3-yl) methyl] benzoyl } tetramethyleneimine-3-amine;

2-{4-[(3-piperidines-1-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-the 1H-benzoglyoxaline;

1 '-methyl of 4-[(1-ethyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

1 '-methyl of 4-[(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

1-methyl-2-{4-[(3-piperidines-1-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-the 1H-benzoglyoxaline;

1 '-[4-(1H-benzimidazolyl-2 radicals-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-1 '-(4-phenmethyl benzoyl)-1,3 '-bipyrrolidine;

(3 ' S)-1 '-methyl of 4-[(1-propyl group-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-methyl of 4-[(1-sec.-propyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-methyl of 4-[(1-isobutyl--1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-(4-{[1-(cyclopropyl methyl)-1H-benzimidazolyl-2 radicals-yl] methyl } benzoyl)-1,3 '-bipyrrolidine;

(3 ' S)-1 '-(4-{[1-(phenyl sulfonyl)-1H-benzimidazolyl-2 radicals-yl] methyl } benzoyl)-1,3 '-bipyrrolidine;

(3 ' S)-1 '-(4-{[1-(2-methoxy ethyl)-1H-benzimidazolyl-2 radicals-yl] methyl } benzoyl)-1,3 '-bipyrrolidine;

2-(2-{4-[(3 ' S)-1,3 '-bipyrrolidine-1 '-the Ji carbonyl] phenmethyl }-1H-benzoglyoxaline-1-yl) ethanol;

(3 ' S)-1 '-methyl of 4-[(1-ethyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-(4-{[1-(2-phenylethyl)-1H-benzimidazolyl-2 radicals-yl] methyl } benzoyl)-1,3 '-bipyrrolidine;

(3 ' S)-1 '-methyl of 4-[(1-ethyl-1H-benzimidazolyl-2 radicals-yl)] phenmethyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-methyl of 4-[(1-phenyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;

1 '-4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

The 5-methyl isophthalic acid-and 4-[(3-piperidines-1-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-the 1H-benzoglyoxaline;

4-fluoro-1-{4-[(3-piperidines-1-base tetramethyleneimine-1-yl) methyl] phenmethyl }-the 1H-benzoglyoxaline;

1 '-[4-(1H-benzoglyoxaline-1-ylmethyl)-3-chlorophenylmethyl]-1,3 '-bipyrrolidine;

1-{4-[(4-fluoro-1H-benzoglyoxaline-1-yl) methyl] phenmethyl }-N, N-dimethyl pyrrolidine-3-amine;

The 5-methyl isophthalic acid-(4-{[3-(pipecoline-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

The 5-methyl isophthalic acid-and 4-[(3-morpholine-4-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-the 1H-benzoglyoxaline;

The 5-methyl isophthalic acid-(4-{[3-(4-methyl piperidine-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

The 5-methyl isophthalic acid-(4-{[3-(4-methylpiperazine-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

The 5-methyl isophthalic acid-(4-{[3-(3-methyl piperidine-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

((2s)-1 '-4-[5-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine-2-yl) methyl alcohol;

N, N-dimethyl-1-{4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl] benzoyl } tetramethyleneimine-3-amine;

N-ethyl-N-methyl isophthalic acid-and 4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl] benzoyl } tetramethyleneimine-3-amine;

1-{2-chloro-4-[(3-piperidines-1-base tetramethyleneimine-1-yl) methyl] phenmethyl }-the 1H-benzoglyoxaline;

1-[4-(1H-benzoglyoxaline-1-ylmethyl)-2-anisoyl]-N, N-dimethyl pyrrolidine-3-amine;

1-[4-(1H-benzoglyoxaline-1-ylmethyl)-3-chlorophenylmethyl]-N-ethyl-N methylpyrrolidin-3-amine;

(2R)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl)-2-anisoyl]-2-methyl isophthalic acid, 3 '-bipyrrolidine;

2-phenmethyl-1 '-4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1 '-4-[(7-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(2R)-1 '-4-[(5-fluoro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-the 2-methyl isophthalic acid, 3 '-bipyrrolidine;

(2R)-the 2-methyl isophthalic acid '-4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1-[4-(1H-benzoglyoxaline-1-ylmethyl)-3-chlorophenylmethyl]-N, N-dimethyl pyrrolidine-3-amine;

(2S)-1 '-4-[(5-fluoro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-the 2-methyl isophthalic acid, 3 '-bipyrrolidine;

1-{4-[(3-azepan-1-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-5-methyl isophthalic acid H-benzoglyoxaline;

The 5-methyl isophthalic acid-(4-{[3-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

The 7-methyl isophthalic acid-and 4-[(3-piperidines-1-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-the 1H-benzoglyoxaline;

(2R)-1 '-4-[(5-fluoro-1H-benzoglyoxaline-1-yl) and methyl] phenmethyl }-the 2-methyl isophthalic acid, 3 '-bipyrrolidine;

1-{4-[(3-azetidine-1-base tetramethyleneimine-1-yl) carbonyl] phenmethyl }-5-methyl isophthalic acid H-benzoglyoxaline;

1 '-[4-(1H-benzoglyoxaline-1-ylmethyl)-2-fluoro benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(7-fluoro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

1-(4-{[(3S)-3-azepan-1-base tetramethyleneimine-1-yl] carbonyl } phenmethyl)-7-fluoro-1H-benzoglyoxaline;

7-fluoro-1-(4-{[(3S)-3-piperidines-1-base tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

(3S)-and N-ethyl-1-{4-[(7-fluoro-1H-benzoglyoxaline-1-yl) methyl] benzoyl }-N-methylpyrrolidin-3-amine;

7-fluoro-1-(4-{[(3S)-3-(3-methyl piperidine-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

1-(4-{[(3S)-3-azetidine-1-base tetramethyleneimine-1-yl] carbonyl } phenmethyl)-7-fluoro-1H-benzoglyoxaline;

(3 ' S)-1 '-(4-{[2-(trifluoromethyl)-1H-benzoglyoxaline-1-yl] methyl } benzoyl)-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[1-(7-chloro-1H-indoles-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[1-(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1S)-1-(1H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1R)-1-(1H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1S)-1-(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1S)-1-(6-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1R)-1-(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(1R)-1-(6-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

(3S)-1-{4-[(1R)-and 1-(6-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl } tetramethyleneimine-3-amine;

(3S)-1-{4-[(1R)-and 1-(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl } tetramethyleneimine-3-amine;

(3 ' S)-1 '-4-[(5-chloro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3 ' S)-1 '-4-[(6-chloro-1H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine;

(3S)-and 1-{4-[(5-chloro-1H-benzoglyoxaline-1-yl) methyl] benzoyl } tetramethyleneimine-3-amine;

(3S)-1-{4-[(1S)-and 1-(6-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl } tetramethyleneimine-3-amine;

(3S)-1-{4-[(1S)-and 1-(5-chloro-2-methyl isophthalic acid H-benzoglyoxaline-1-yl) ethyl] benzoyl } tetramethyleneimine-3-amine;

(3 ' S)-1 '-4-[1-(5-chloro-1H-indoles-1-yl) ethyl] benzoyl }-1,3 '-bipyrrolidine;

1-(1-{4-[(3 ' S)-1,3 '-bipyrrolidine-1 '-the Ji carbonyl] phenyl } ethyl)-1H-indoles-5-formonitrile HCN;

The 2-methyl isophthalic acid-[1-(4-{[(1R, 4R)-5-methyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] carbonyl } phenyl]-the 1H-benzoglyoxaline;

1-{4-[(3-tetramethyleneimine-1-phenylpiperidines-1-yl) carbonyl] phenmethyl }-the 1H-benzoglyoxaline;

1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-1,3 '-the Lian piperidines;

1-(4-{[3-(2-methylpyrrolidin-1-yl) piperidines-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

4-(1H-benzoglyoxaline-1-ylmethyl)-N-(2-tetramethyleneimine-1-base ethyl) benzamide;

4-[(2-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl]-N-(2-tetramethyleneimine-1-base ethyl) benzamide;

1-(4-{[3-(4-methyl piperidine-1-yl) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-the 1H-benzoglyoxaline;

(2R, 3 ' R)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-2-methyl isophthalic acid, 3 '-bipyrrolidine;

(2S, 3 ' R)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-2-methyl isophthalic acid, 3 '-bipyrrolidine;

Its steric isomer; Or its pharmaceutically acceptable salt.

Can use separation of conventional synthetic method and use standard where necessary or disassemble technique to prepare compound of the present invention.For instance, can be prepared as follows formula I compound (wherein X is that CO and p are 1) (Ia): use the standard peptide formation condition to make phenylformic acid and the reaction of 3-hydroxyl pyrrolidine of formula II, such as under the situation that has I-hydroxybenzotriazole (HOBT) in solvent (such as methylene dichloride) with suitable carbodiimide (such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide) activating carboxy acid, to obtain the acid amides of formula III; The acid amides and the methane sulfonyl chloride of formula III are being reacted in solvent (such as methylene dichloride) under the situation that has alkali (such as diisopropylethylamine) to obtain corresponding methanesulfonates; And with amine HNR ₁R ₂In solvent (such as N, dinethylformamide (DMF)) under microwave condition the displacement described ester to obtain solemnity Ia compound.Advantageously, in initial coupling step, use chirality 3-hydroxyl pyrrolidine to allow the synthetic formula III compound of stereospecificity.Because replacement(metathesis)reaction is to carry out in the stereospecificity mode of configuration inversion, therefore use chirality formula III compound can obtain to stereospecificity the solemnity Ia of institute compound.Certainly, should be appreciated that use racemize 3-hydroxyl pyrrolidine will finally obtain required paratartarics Ia product.Reaction is showed among the flow process I.

Flow process I

Can be prepared as follows formula II compound (R wherein ₃Be benzimidazolyl-2 radicals-yl) (IIa) that is substituted according to circumstances: the phenylformic acid bromine methyl esters of formula IV is reacted to obtain corresponding nitrile compound with sodium cyanide in solvent (such as methyl-sulphoxide (DMSO)); With the described nitrile of HCI methanol solution hydrolysis to obtain corresponding diester; Optionally the described diester of saponification is to obtain the carboxylic acid of formula V; Use the standard peptide formation condition to make the acid of formula V and the phenylenediamine coupling of formula VI, for example under the situation that has I-hydroxybenzotriazole (HOBT) in solvent (such as methylene dichloride) with suitable carbodiimide (such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide) activating carboxy acid, to obtain corresponding amide; Via under 140 ℃, coming the described acid amides of cyclisation with acetic acid treatment, benzimidazolyl-2 radicals-based compound of basic hydrolysis solemnity IIa then to obtain.Reaction is showed among the flow process II, and wherein R ' is C ₁-C ₄Alkyl; R is aforesaid optional substituting group; And p is 0,1 or 2.

Flow process II

(wherein X is CO can be prepared as follows formula I compound; P is 1; And R ₃Be NR ₄R ₅) (Ib): the phenylformic acid bromine methyl esters that makes formula IV under the situation that has alkali (such as sodium hydride or potassium tert.-butoxide) with the cyclic amine reaction of formula VII to obtain formula VIII compound; The ester that comes hydrolyzing type VIII by acid hydrolysis or basic hydrolysis in suitable solvent (such as methanol) (for example sulfuric acid or lithium hydroxide) is to obtain the respective acids of formula IX: and make the 3-aminopyrrolidine compounds of the acid of formula IX and formula X exist under the situation of suitable coupler (such as the di-isopropyl carbodiimide) coupling to obtain solemnity Ib compound.Reaction is showed among the flow process III, and wherein R ' is C ₁-C ₄Alkyl.

Flow process III

The acid of formula IX can be changed into activated partial according to circumstances, such as changing into corresponding chloride of acid or change into mixed acid anhydride by handling with trimethyl-acetyl chloride and triethylamine by handling with oxalyl chloride; And the 3-amino-pyrrolidine coupling that can make activated acids and formula X is solemnity Ib compound to obtain.

Perhaps, can be prepared as follows formula Ib compound: the phenylformic acid of formula IX and oxalyl chloride are reacted to form corresponding chloride of acid; Make described chloride of acid and the coupling of 3-pyrrolidinol to obtain formula XI compound; Make the reaction of formula XI compound and methane sulfonyl chloride to obtain the corresponding methanesulfonates of formula XII; And make described methanesulfonates and amine HNR ₁R ₂Reaction is solemnity Ib compound to obtain.Reaction is showed among the flow process IV, and wherein Ms represents CH ₃SO ₂

Flow process IV

Also can come preparation formula Ib compound by the counter-rotating reaction sequence, the 3-amino-pyrrolidine that for example can make the chloromethyl benzoic acid chlorides of formula XIII and formula X under the situation that has appropriate base (such as diisopropylethylamine) coupling with the chloromethylbenzene methane amide that obtains formula XIV and the cyclammonium that can make described chloromethyl formula XIV compound and formula VII as mentioned in coupling described in the reaction process III to obtain required formula Ib compound.Reaction is showed among the flow process V.

Flow process V

Solemnity Ic compound comes preparation I compound (wherein X is SO to obtain for benzene sulfonyl chloride that can be by making formula XV and the 3-amino-pyrrolidine of formula X or the reaction of 3-amino piperidine ₂) (Ic).Reaction is showed among the flow process VI.

Flow process VI

Can pass through with suitable reductive agent (such as LiAlH ₄Or borine) solemnity Ib compound comes easily preparation I compound (wherein X is CH reduction-type Ia compound to obtain ₂And p is 1) (Id).Reaction is showed among the flow process VII.

Flow process VII

Can be as shown in flow process I, III, IV, V and VII and with corresponding 3-hydroxy piperidine or the high piperidines of 3-hydroxyl or piperidines-3-base amine or high piperidines-3-ylamine compounds substitutes the 3-hydroxyl pyrrolidine or tetramethyleneimine-3-base amine comes the compound (wherein p is 2 or 3) of preparation formula Ia, Ib and Id.

Advantageously, the invention provides a kind of method of preparation I compound, described method comprises exists under the situation that has solvent under the situation of microwave irradiation according to circumstances and amine HNR formula XVI compound ₁R ₂Reaction.Method is showed among the flow process VIII.

Flow process VIII

Be applicable to that the solvent in the method for the present invention comprises dimethyl formamide, acetonitrile, tetrahydrofuran (THF) or its analogue.

Advantageously, formula I compound of the present invention can be used for treating relevant with histamine-3 acceptor or by the CNS illness of histamine-3 acceptor influence, described illness comprises cognitive disorder (for example Alzheimer), mild cognitive impairment, the not enough Attention Deficit Hyperactivity Disorder of attention, schizophrenia, the loss of memory, somnopathy, obesity or its similar conditions.Therefore, the invention provides that a kind of treatment has the relevant with histamine-3 acceptor of the patient that needs or by the method for the central nervous system disorders of histamine-3 acceptor influence, described method comprises to described patient provides the aforesaid formula I compound for the treatment of significant quantity.Can provide compound by per os or without intestines dispensing or known therapeutical agent effectively can the throwing with any usual way that the patient who needs is arranged.

" provide " expression directly to throw and described compound or material about the term that the compound contained by the present invention or material are provided as used herein, or throw and form in vivo the compound of equivalent or prodrug, derivative or the analogue of material.

Method of the present invention comprises: the schizoid method of a kind of treatment; A kind of treatment and memory, cognitive or the not enough relevant disease of study or the method for cognitive disorder (such as Alzheimer or the not enough Attention Deficit Hyperactivity Disorder of attention); A kind of method for the treatment of mild cognitive impairment; The method of a kind of treatment dysplasia (such as schizophrenia); A kind ofly treat somnopathy or any interrelating with the H3 acceptor or relevant other CNS disease or the method for illness.

In one embodiment, the invention provides the method for the not enough Attention Deficit Hyperactivity Disorder of a kind of treatment children and adult attention (ADHD is also referred to as attention deficit disorder or ADD).Therefore, in this embodiment, the invention provides a kind of method for the treatment of the attention deficit disorder of pediatric patients.

Therefore, the invention provides the method for each symptom listed above of a kind of treatment patient (preferred human), described method comprises the aforesaid formula I compound that the treatment significant quantity is provided to described patient.Can provide compound by per os or without intestines dispensing or known therapeutical agent effectively can the throwing with any usual way that the patient who needs is arranged.

The treatment significant quantity that is provided in specific CNS treatment of conditions can change according to the very pathology of being treated, patient's build, age and reaction pattern, disease serious property, attending doctor's judgement and its similar factor.Generally, every day oral administration significant quantity can be about 0.01 to 1,000mg/kg, preferred about 0.5 to 500mg/kg and can be about 0.1 to 100mg/kg, preferred about 0.5 to 50mg/kg without the significant quantity of intestines dispensing.

In actually operating, by providing compound of the present invention separately or with compound or its precursor of one or more conventional medical supporting agents or excipient composition throwing and solid or liquid form.Therefore, the invention provides medical composition, described medical composition comprises the aforesaid formula I compound of pharmaceutically acceptable supporting agent and significant quantity.

In one embodiment, the present invention relates to comprise the composition of at least a formula I compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable supporting agents, vehicle or thinner.Described composition comprises treatment or the disease patient's condition of control central nervous system or the medical composition of symptom.In certain embodiments, described composition comprises the mixture of one or more formulas I compound.

In certain embodiments, the present invention relates to comprise the composition of at least a formula I compound or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable supporting agents, vehicle or thinner.Prepare described composition according to acceptable medical program.Pharmaceutically acceptable supporting agent be with composite in other composition compatible and at acceptable supporting agent biologically.

But per os or throw and formula I compound separately or with the medical supporting agent combination of routine without intestines ground.Applicable solid carriers can comprise that one or more also can serve as the material of seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression aid, tackiness agent, tablet disintegrant or wrapping material.In powder, supporting agent is and finely powdered activeconstituents blended finely powdered solid.In tablet, activeconstituents mixes with the supporting agent with essential compression property with proper ratio and is pressed into the shape and size of being wanted.Powder and tablet preferably contain 99% activeconstituents at the most.Suitable solid carriers comprises (for example) calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax and ion exchange resin.

In certain embodiments, provide formula I compound with the disintegrating tablet composite that is applicable to the paediatrics dispensing.

Liquid carrier can be used for preparing solution, suspension, emulsion, syrup and elixir.Activeconstituents can be dissolved in or be suspended in the pharmaceutically acceptable liquid carrier (such as water, organic solvent, both mixtures or pharmaceutically acceptable oil or fat).Liquid carrier can contain other suitable auxiliary pharmaceutical adjuvant, such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, seasonings, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or Osmolyte regulator.Be used for per os and comprise that without the suitable example of the liquid carrier of intestines dispensings water (especially contains above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium solution), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol, for example glycol) and its derivative and oils (for example through fractionated Oleum Cocois and peanut oil).For offeing medicine without intestines, supporting agent also can be oily ester, such as ethyl oleate and Isopropyl myristate.Use the sterile liquid supporting agent at the sterile liquid form composition that is used for without the intestines dispensing.The liquid carrier that is used for pressurized compositions can be halon or other pharmaceutically acceptable propelling agent.

In certain embodiments, provide the liquid medical composition, wherein said composition is applicable to the paediatrics dispensing.In other embodiments, liquid composition is syrup or suspension.

Can by (for example) intramuscular, intraperitoneal or subcutaneous injection throw with as the liquid medical composition of sterile solution or suspension.Also but intravenously is thrown and sterile solution.The composition that is used for oral administration can be taked the liquid or solid form.

Form per rectum that can conventional suppository or transvaginal are thrown and formula I compound.Dispensing for by sucking or be blown in the nose or in the segmental bronchus can be deployed into the aqueous solution or partially aqueous solution with formula I compound, and form that then can aerosol is used.Also can throw and formula I compound via using skin to paste through skin, described skin paste contain active compound and to described active compound be inertia, nontoxic and allow to be used for medicament that whole body absorbs to skin via the supporting agent of dermal delivery to blood flow.Described supporting agent can be taked various ways, such as emulsifiable paste and ointment, paste, gel and locking device.Emulsifiable paste and ointment can be oil-in-water-type or water-in-oil-type viscous liquid or semi-solid emulsion.The paste that the oil that contains activeconstituents or the absorbent powder in the hydrophilic petroleum constitute is also suitable by being scattered in.Various locking devices can be used for activeconstituents is released in the blood flow, contain activeconstituents and have or do not have the container of supporting agent or contain the semi-permeable membranes of the matrix of activeconstituents such as covering.Known other locking device in the document.

Medical composition is preferably taked unit dosage, for example tablet, capsule, powder, solution, suspension, emulsion, particle or suppository.In described form, composition is subdivided into the unitary dose that contains an amount of activeconstituents; Unit dosage can be packaging compositions, for example packs powder, bottle, peace bottle, pre-filled syringe or contains the anther sac of liquid.For instance, unit dosage self can be capsule or tablet, or it can be any described composition of the proper number of packaged form.

The treatment significant quantity of the formula I compound that provides to the patient will look throw and material, dispensing purpose (such as prevention or treatment), patient's states, dosing mode or similar factor and change.In treatment was used, formula I compound was to be enough to treat or to offer the patient who is subjected to the symptom puzzlement to the amount of the symptom of small part treatment symptom and its complication.The amount that enough realizes this purpose is " a treatment significant quantity " as indicated above.The dosage of desiring to be used for the treatment of case-specific must be determined with subjectivity by the attending doctor.Related parameter comprises very pathology and patient's build, age and reaction pattern.Generally, starting dose is about 5mg every day, and every day, dosage increased to every day about 150mg gradually so that required dosage level to be provided in patient's body.

In certain embodiments, the present invention relates to the prodrug of formula I compound.Term " prodrug " means the compound that can transform accepted way of doing sth I compound in vivo by metabolic way (for example by hydrolysis) as used herein.Under known various forms of prodrugs in the field, such as the form that is discussed in (for example) following document: Pa'anga's moral (Bundgaard) (volumes), prodrug design (Design of Prodrugs) likes to think only that company (Elsevier) (1985); Wei De people's (volume) such as (Widder), Enzymology method (Methods in Enzymology), the 4th volume, academic press (Academic Press) (1985); Clo Si Jiade-La Ersen people's (volume) " textbooks of prodrug design and application and medicinal design and research and development " (＂ Design and Application of Prodrugs such as (Krogsgaard-Larsen), Textbook of Drug Design andDevelopment ＂), the 5th chapter, 113-191 (1991), Pa'anga's moral people such as (Bundgaard), medicine is sent summary magazine (Journal of Drug Delivery Reviews), 8:1-38 (1992), Pa'anga's moral (Bundgaard), pharmaceutical journal (J.ofPharmaceutical Sciences), 77:285 and following (1988); And bung (Higuchi) and Si Tela (Stella) (volume) are as the prodrug (Prodrugs as Novel Drug Delivery Systems) of novel drugs delivery system, american chemical association (American Chemical Society) (1975).

For more being expressly understood and, hereinafter listing its particular instance for being illustrated more clearly in the present invention.Following example is only had an illustrative and should not be construed as and is limited the scope of the invention by any way and fundamental principle.Term HPLC and ¹H NMR represents high performance liquid chromatography and proton magnetic resonance (PMR) respectively.Term MS represents mass spectroscopy, and wherein (+) is meant and generally obtains the positive ion mode that M+1 (or M+H) absorbs (wherein M=molecular mass).At least by MS and ¹H NMR analyzes all compounds.Term DMF and THF represent dimethyl formamide and tetrahydrofuran (THF) respectively.In chemistry was graphic, term Ph represented phenyl.Except as otherwise noted, otherwise all umbers all are parts by weight.

Example 1

N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } preparation of tetramethyleneimine-3-base amine

Step 1.With 2-Phenylbenzimidazole (5mmol, 0.97g) be dissolved in THF/DMF (5:1,20mL) in and add sodium hydride (0.5g).After at room temperature stirring 10 minutes, and interpolation 4-(brooethyl) methyl benzoate (1.4g, 6mmo1).To react stirred overnight at room temperature, then with EtOAc (100mL) dilution and with saturated NaHCO ₃Washing is through MgSO ₄Dry and concentrated.Pass through HPLC ^*And MS[343.2m/e (M+H)] identify the gained resistates and use it for next step.

Step 2.4-(2-phenyl-benzoglyoxaline-1-the ylmethyl)-methyl benzoate that is obtained in the step 1 is dissolved in MeOH/ water (2:1,30mL), with lithium hydroxide (0.42g, 10mmol) handle, at room temperature stirred overnight is evaporated to remove MeOH, dilutes with 1N sodium hydroxide (50mL), with the EtOAc washing, extract with dense HCl acidifying and with EtOAc.Merge extract, through MgSO ₄Dry and concentrated.Pass through HPLC ^*And MS[329.2m/e (M+H)] identify the gained resistates and use it for next step.

Step 3.Be dissolved among the DCM (5mL) 4-(2-phenyl-benzoglyoxaline-1-the ylmethyl)-phenylformic acid (0.2mmol) that is obtained in the step 2 and interpolation oxalyl chloride (0.2mL, 0.4mmol, the 2M solution among the DCM) and DMF (2).Solution was at room temperature stirred 2 hours, then concentrate in a vacuum.Resistates is dissolved among the THF, with diisopropylethylamine (DIEA) (0.09mL, 0.5mmol) and 3-(dimethylamino) tetramethyleneimine (0.22mmol, 22 μ L) handle, at room temperature stirred overnight then concentrates.This resistates is dissolved in the mixture (1.5mL) of DMSO, MeOH and water and by anti-phase half preparation HPLC ¹Purifying is the title product (13mg) of powder of being white in color, by HPLC ²And MS[425.2m/e (M+H)] identified.

Example 2

(3-S)-and N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } tetramethyleneimine-3-base amine Preparation

Basically the same program described in the use-case 1 and use (3-S)-dimethylamino tetramethyleneimine in step 3 obtains title compound and is identified by HPLC and mass spectroscopy.MS[425.2] m/e (M+H), residence time 2.94min.

Example 3

(3-R)-and N, N-dimethyl-1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } system of tetramethyleneimine-3-base amine Be equipped with

Basically the same program described in the use-case 1 and use (3-R)-dimethylamino tetramethyleneimine in step 3 obtains title compound and is identified by HPLC and mass spectroscopy.MS[425.2] m/e (M+H), residence time 2.92min.

Example 4-7

N, N-dimethyl-1-{4-[(are substituted-1H-benzoglyoxaline-1-yl) methyl]-benzoyl } preparation of tetramethyleneimine-3-base amine

Basically the same program described in the use-case 1 and use suitable benzoglyoxaline in step 1 obtains the compound shown in the Table I and is identified by HPLC and mass spectroscopy.The HPLC condition: 0.02% TFA in the A=water is 10-95%B in 0.02% the TFA in the B=acetonitrile, 5min., 1.0mL/min, and 50 ℃, 215nm detects, Waters Xterra ^TM2 * 50mm tubing string.

Table I

Example 8-11

N-is substituted-1-[3-(1H-benzoglyoxaline-1-yl) methyl]-benzoyl } preparation of nitrogen heterocyclic-3-base amine

Basically the same program described in the use-case 1 and in step 1, use the 3-bromomethyl-benzoic acid methyl ester and in step 3, use suitable tetramethyleneimine-3-base-amine or piperidines-3-base-amine, obtain the compound shown in the Table II and by HPLC and mass spectroscopy or by ¹H NMR and mass spectroscopy are identified.

Table II

Example 12

1-[4-(1H-indoles-1-ylmethyl) benzoyl]-N, the preparation of N-dimethyl pyrrolidine-3-base amine

Step 1.(2.5g, 22mmol) solution in acetonitrile is added into 4-(chloromethyl) Benzoyl chloride (5.0g 26mmol) in the ice-cold solution in acetonitrile, stirred in room temperature 2 hours in temperature, then concentrated in a vacuum with 3-(dimethylamino) tetramethyleneimine.The gained resistates is suspended in the ether and filters to obtain solid 1-(4-chloromethylbenzene formyl radical)-3-(N, the N-dimethylamino) pyrrolidine hydrochloride that is white in color, by NMR and MS[267m/e (M+H)] identified.

Step 2.At room temperature handle indoles (29mg with sodium hydride (30mg); 0.25mmol) solution in DMF (5mL); stirred 10 minutes; with 1-(4-chloromethylbenzene formyl radical)-3-(N; the N-dimethylamino) pyrrolidine hydrochloride (113mg; 0.37mmol) processing, at room temperature stirred overnight and concentrated in a vacuum.The gained resistates is dissolved in the mixture (1.5mL) of DMSO, MeOH and water and, is identified by HPLC and mass spectroscopy by the title product (63mg) of anti-phase half preparation HPLC purifying with the powder that obtains being white in color.MS[348.2m/e (M+H)], residence time 2.58min.

Example 13-39

N, N-dimethyl 1-[4-(1H-indoles-1-ylmethyl) benzoyl] preparation of tetramethyleneimine-3-base amine

Basically the same program described in the use-case 12 and in step 2, use suitable Wyovin HNR ₄R ₅, obtain the compound shown in the Table III and identified by HPLC and mass spectroscopy.

Table III

Table III (continuing)

Example 40

The preparation of N-ethyl-N-methyl isophthalic acid-{ 4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl] benzoyl } tetramethyleneimine-3-amine

Step 1.(1g, the 3mmol) solution in DCM at room temperature stirred 2 hours and concentrated in a vacuum then to handle 4-(2-phenyl-benzoglyoxaline-1-ylmethyl)-phenylformic acid with oxalyl chloride (3mL, 6mmol, the 2M solution among the DCM) with two DMF.The gained resistates is dissolved among the DCM; with 3-pyrrolidinol (0.3mL; 3.6mmol) handle; at room temperature stirred 8 hours; then concentrate to obtain 1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl] benzoyl } tetramethyleneimine-3-alcohol, by HPLC and MS[398.4m/e (M+H)] identified.

Step 2.Under 0 ℃ with triethylamine (0.91mL; 6.6mmol) then with Methanesulfonyl chloride (0.25mL; 3.3mmol) processing 1-{4-[(2-phenyl-1H-benzoglyoxaline-1-yl) methyl] benzoyl tetramethyleneimine-3-alcohol (0.85g; 3mmol) the solution in DCM; at room temperature stirred overnight and concentrate methanesulfonic 1-[4-(2-phenyl-benzoglyoxaline-1-ylmethyl)-benzoyl with the powder that obtains being white in color]-tetramethyleneimine-3-base ester (1.4g), by HPLC and MS[476.3m/e (M+H)] identified.

Step 3.With N-ethyl dimethylamine (0.038mL; 0.45mmol) processing methanesulfonic 1-[4-(2-phenyl-benzoglyoxaline-1-ylmethyl)-benzoyl]-tetramethyleneimine-3-base ester (71mg; 0.15mmol) solution in DMF, at room temperature stirred overnight and concentrating in a vacuum.The gained resistates is dissolved in the mixture (1.5mL) of DMSO, MeOH and water and by anti-phase half preparation HPLC ¹Purifying is with the title product (6.4mg) of the powder that obtains being white in color, by HPLC ²And MS[439.6m/e (M+H)] identified residence time 1.48min.

Example 41-85

N-is substituted-1-[(heteroaryl methyl) benzoyl] preparation of tetramethyleneimine-3-ylamine compounds

Basically the same program described in the use-case 40 and in step 1, use institute's phenylformic acid of wanting and the suitable amine HNR of use in step 3 ₁R ₂, obtain the compound shown in the Table IV and by mass spectrum and HPLC or ¹H NMR analyzes and is identified.

Table IV

Table IV (continuing)

Table IV (continuing)

Example 86-88

N-is substituted-1-[3-(1H-benzoglyoxaline-1-yl) methyl] benzoyl]-preparation of tetramethyleneimine-3-ylamine compounds

Basically the same program described in the use-case 40 and in step 1, use 3-(benzoglyoxaline-1-ylmethyl) phenylformic acid and in step 3, use suitable amine HNR ₁R ₂, obtain the compound shown in the Table V and identified by HPLC and mass spectroscopy.

Table V

Example 89 and 90

N-is substituted-1-[2-(1H-benzoglyoxaline-1-yl) methyl) benzoyl]-preparation of tetramethyleneimine-3-ylamine compounds

Basically the same program described in the use-case 40 and in step 1, use 2-(benzoglyoxaline-1-ylmethyl) phenylformic acid and in step 3, use suitable amine HNR ₁R ₂, obtain the compound shown in the Table VI and identified by HPLC and mass spectroscopy.

Table VI

Example 91

1 '-{ 4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl] benzoyl }-1,3 '-preparation of bipyrrolidine hydrochloride

Step 1) 4-{[(4-methyl-2-nitrophenyl)-(2,2, the 2-trifluoroacetyl group) amino] methyl }-methyl benzoate

With the 60%NaH of hexane pre-wash portion in mineral oil (2.9g, 71.8mmol, 1.1eq) and at the nitrogen low suspension in dry DMF.In ice bath, cool off slurry and dropwise added 2,2,2-three fluoro-N-(4-methyl-2-nitrophenyl)-ethanamide (16.2g, 65.3mmol, 1.0eq) solution in dry DMF through 15 minutes.Remove cooling bath and mixture was stirred 30 minutes.Reaction mixture and dropwise added 4-bromomethyl-benzoic acid methyl ester (20g, 65.3mmol, 1.0eq) solution in dry DMF through 10 minutes once more.Reaction mixture at room temperature stirred 18 hours and vapourisation under reduced pressure to obtain resistates.Between ethyl acetate and water, divide resistates molten.Yi Shui and salt water washing organic layer in succession, dry (Na ₂SO ₄) and concentrate to obtain yellow solid.By column chromatography purifying yellow solid (silica gel 230-400 order: eluent CHCl ₃MeOH:0 → 5%) to obtain 4-{[(4-methyl-2-nitrophenyl)-(2,2, the 2-trifluoroacetyl group) amino] methyl } methyl benzoate, productive rate: 59%. ¹H?NMR(400MHz，CDCl ₃)：7.97(m，3H)；7.27(m，3H)；6.76(d，J＝8Hz，1H)；5.66?&?4.26(2H)；3.92(s，3H)；2.46(s，3H)。

Step 2) methyl 4-[(4-methyl-2-nitrophenyl amino)] methyl benzoate

With Tetrabutylammonium bromide (1.13g 3.5mmol) handles 4-{[(4-methyl-2-nitrophenyl with the 20% KOH aqueous solution (100mL)) (2,2, the 2-trifluoroacetyl group)-amino] methyl } (14.0g is 35mmol) in CH for methyl benzoate ₂Cl ₂In stirred solution.Reaction mixture is heated to 38 ℃ to be reached 3 hours and is cooled to room temperature.Separate each mutually and with CH ₂Cl ₂Aqueous phase extracted.With salt water washing ECDC extract and organic phase also, through anhydrous Na ₂SO ₄Drying and concentrated in a vacuum 4-[(4-methyl-2-nitrophenyl amino to obtain being orange solids) methyl]-methyl benzoate.Productive rate: 90%. ¹H?NMR(400MHz，CDCl ₃)：8.37(bs，1H)；8.02(m，3H)；7.40(d，J＝8Hz，2H)；7.19(d，J＝8Hz，1H)；6.63(d，J＝8Hz，1H)；4.60(d，J＝8Hz，2H)；3.91(s，3H)；2.35(s，1H)。

Step 3) 4-[(5-tolimidazole-1-yl) methyl] methyl benzoate

With 5%Pd/C (50% is moistening, 30% w/w) and hydrazine hydrate (5.8g 116mmol) handles 4-[(4-methyl-2-nitrophenyl amino) methyl] (7.0g is 23mmol) in CH for methyl benzoate ₃Stirred solution among the OH.Reaction mixture is heated to reflux temperature reaches 2 hours, be cooled to room temperature and filtration over celite.Evaporated filtrate is to obtain resistates.Resistates is dissolved in CH ₂Cl ₂In, with water washing, through anhydrous Na ₂SO ₄Drying and evaporation are to obtain 4-[(2-amino-4-aminomethyl phenyl amino) methyl] methyl benzoate, it is used for next step without being further purified.Productive rate: 93%. ¹H?NMR(400MHz，CDCl ₃)8.0(d，J＝8Hz，2H)；7.70(d，J＝8Hz，2H)；6.60(m，2H)；6.49(d，1H)；4.3(s，2H)；3.90(d，3H)；2.21(s，3H)。LCMS(ESI ⁺)271(MH+)。Handle thick 4-[(2-amino-4-aminomethyl phenyl amino with formic acid (1.0g)) methyl] (6g, the 22mmol) stirred solution in trimethyl orthoformate refluxed 2 hours methyl benzoate, were cooled to room temperature and vapourisation under reduced pressure.By using 1%MeOH/CHCl ₃Column chromatography purifying gained resistates to obtain 4-[(5-tolimidazole-1-yl) methyl] methyl benzoate.Productive rate: 16%. ¹H?NMR(400MHz，CDCl ₃)：8.0(d，J＝8Hz，1H)；7.93(s，1H)；7.62(s，1H)；7.26(s，1H)；7.21(d，J＝8Hz，2H)；7.08(m，2H)；5.39(s，2H)；3.90(s，3H)；2.47(s，3H)。LCMS(ESI ⁺)281(MH+)。

Step 4) methanesulfonic 1-{[4-(5-tolimidazole-1-yl) methyl] benzoyl }-tetramethyleneimine-3-base ester

With 4-[(5-tolimidazole-1-yl) methyl] methyl benzoate is hydrolyzed into corresponding phenylformic acid and the same program described in use-case 37 steps 1 and the step 2 basically, obtains methanesulfonic 1-{[4-(5-tolimidazole-1-yl) methyl] benzoyl } tetramethyleneimine-3-base ester. ¹H?NMR(400MHz，CDCl ₃)：7.93(s，1H)；7.62(s，1H)；7.46-7.53(m，2H)；7.07-7.22(m，4H)；5.37(s，2H)；5.37&5.24(bs，1H)；3.55-3.93(m，4H)；3.08?&?3.01(s，3H)；2.47(s，3H)；2.17-2.34(m，2H)。LCMS(ESI ⁺)414(MH+)。

Step 5) 1 '-4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-the bipyrrolidine hydrochloride

Basically the same program described in use-case 37 steps 3 and use methanesulfonic 1-{[4-(5-tolimidazole-1-yl) methyl] benzoyl-tetramethyleneimine-3-base ester and tetramethyleneimine be as initial substance, obtain title product and identified by NMR and mass spectroscopy. ¹H?NMR(300MHz，353K，DMSO-d ₆)：11.81(s?br，1H)；9.64(s，1H)；7.72(d，1H)；7.68(m，1H)；7.57(d，2H)；7.50(d，2H)；7.39(dd，1H)；5.78(s，2H)；3.97-3.67(m，4H)；3.52-2.95(m?br，5H)；2.50(s，3H)；2.29(m，2H)；2.05-1.91(m，4H)。LCMS(ESI ⁺)389.3(MH+)。

Example 92-117

1 '-preparation of { 4-[(is substituted-1H-benzoglyoxaline-1-yl) methyl] benzoyl }-tetramethyleneimine-3-base amine

Basically the same program described in the use-case 91 and in step 1, use ortho-nitrophenyl methane amide and in step 5, use the amine HNR that wants through suitably replacing ₁R ₂, obtain the compound shown in the Table VII and by ¹H NMR and mass spectroscopy are identified.

Table VII

Table VII (continuing)

Example 118

11-(4-{[3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-9-methoxyl group-11b-methyl isophthalic acid, 2,5,6,11,11b- Six hydrogen-3H-indolizine is the preparation of [8,7-b] indoles-3-ketone also

Step 1.With 6-methoxytryptamine (0.95g, 5mmol) with levulinic acid (0.7g, 6mmol) mixture in ethoxy ethanol heated 16 hours under reflux temperature, was cooled to room temperature and concentrated in a vacuum to obtain 9-methoxyl group-11b-methyl isophthalic acid, 2,5,6,11,11b-six hydrogen-indolizine also [8,7-b] indoles-3-ketone (0.97g), by NMR, HPLC and MS[271.2m/e (M+H)] identified.

Step 2.Handle 9-methoxyl group-11b-methyl isophthalic acid, 2,5 with sodium hydride (50mg); 6; 11,11b-six hydrogen-indolizine is [8,7-b] indoles-3-ketone (54mg also; 0.2mmol) solution in DMF; at room temperature stirred 10 minutes, with (4-chloromethyl-benzoyl)-N, N-dimethylamino tetramethyleneimine-3-amine hydrochlorate (72mg; 0.24mmol) processing, at room temperature stirred overnight and concentrated in a vacuum.The gained resistates is dissolved in the mixture (1.5mL) of DMSO, MeOH and water and by anti-phase half preparation HPLC ¹Purifying is with the title product (49mg) of the powder that obtains being white in color, by HPLC and MS[501.7m/e (M+H)] identified.

Example 119-126

11-(4-{[3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenmethyl)-9,11b-is through two replacements-1,2,5,6,11, and 11b-six Hydrogen-3H-indolizine is the preparation of [8,7-b] indoles-3-ketone compound also

Basically the same program described in the use-case 118 and use tryptamines and the levulinic acid that replaces through suitably in step 1 obtains the compound shown in the Table VIII and is analyzed by mass spectrum and HPLC to be identified.

Table VIII

Example 127

(3 ' S)-1 '-[4-(1H-indoles-1-ylmethyl) benzoyl]-1,3 '-preparation of bipyrrolidine

Step 1.Under 0 ℃ with tert-Butyl dicarbonate [(Boc) ₂O] (2.5g 1eq) handles (S)-3-amino-pyrrolidine (1mL, the 11.6mmol) solution in MeOH, at room temperature stirred overnight and concentrated in a vacuum to obtain resistates.

Step 2.With 1, and the 4-dibromobutane (13.9mmol, 1.7mL) and K ₂CO ₃(3.2g, the 23.2mmol) solution of the resistates of treatment step 1 in toluene 110 ℃ of following stirred overnight, is cooled to room temperature, with the EtOAc dilution, with water washing, through MgSO ₄Dry and concentrate in a vacuum with obtain the Boc-tetramethyleneimine also-tetramethyleneimine.

Step 3.With the Boc-tetramethyleneimine of step 2 also-tetramethyleneimine (1g, thick, 4.2mmol) at room temperature stirred 3 hours and be condensed into dense thick oily matter with the mixture of 2N HCl in diox.Oily matter is dissolved among the DCM, is cooled to 0 ℃, (0.8g 4.2mmol) handles, and stirs 2 hours to room temperature in temperature, with the EtOAc dilution, with saturated NaHCO with diisopropylethylamine (5eq) and 4-(chloromethyl) Benzoyl chloride ₃Washing is through MgSO ₄Dry and concentrate in a vacuum with obtain being brown buttery [1,3 '] bipyrrolidine-1 '-Ji-(4-chloromethyl-phenyl)-ketone (1.3g), by HPLC and MS[293m/e (M+H)] identified.

Step 4.Follow with [1 with sodium hydride (50mg), 3 '] bipyrrolidine-1 '-Ji-(4-chloromethyl-phenyl)-ketone (0.15mmol, (0.15mmol is 19mg) in DMF/THF mixture (1:4 43mg) to handle indoles, solution 2mL), at room temperature stirred overnight and concentrated in a vacuum.The gained resistates is dissolved in the mixture (1.5mL) of DMSO, MeOH and water and by anti-phase half preparation HPLC ¹Purifying is identified by HPLC and mass spectroscopy with the title product (8mg) of the powder that obtains being white in color.Residence time 1.86min., MS[374.2m/e (M+H)].

Example 128-144

(3 ' S)-1 '-[4-(heteroarylalkyl) benzoyl]-1,3 '-preparation of bipyrrolidine

Basically the same program described in the use-case 127 and in step 3, use 4-chloromethyl benzoic acid chlorides and in step 4, use the cyclammonium HNR that wants through suitably replacing ₄R ₅, obtain the compound shown in the Table I X and by mass spectrum and ¹HNMR or HPLC analyze and are identified.By using the corresponding racemic compound of standard chirality HPLC technology chiral separation to obtain compound (R wherein among the Table I X ₈Be (R) or (S) enantiomer).

Table I X

Table I X (continuing)

Example 159-163

(3S)-1-[4-(heteroarylalkyl) benzoyl]-preparation of tetramethyleneimine-3-amine

Basically same program described in the use-case 127 and use (S)-3-amino-pyrrolidine uses the 4-chloromethyl benzoic acid chlorides through suitably replacing and use the Wyovin HNR that wants in step 4 as initial substance and in step 3 ₄R ₅, obtain the compound shown in the Table X and by mass spectrum and ¹H NMR analyzes and is identified.By using the corresponding racemic compound of standard chirality HPLC technology chiral separation to obtain compound (R wherein in the Table X ₈Be (R) or (S) enantiomer).

Table X

Example 164

1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) phenmethyl]-1,3 '-preparation of bipyrrolidine hydrochloride

With the borine (1.0M in the tetrahydrofuran (THF); 0.8mL) under nitrogen, handle 1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-1; 3 '-solution of bipyrrolidine (0.16mmol) in anhydrous tetrahydro furan; heating is 1.5 hours under reflux temperature, with extra borine (1.0M in the tetrahydrofuran (THF), 0.8mL; 0.8mmol) handle; heating is 6 hours under reflux temperature, is cooled to room temperature, handles and concentrates in a vacuum with methyl alcohol (5mL).Handle the gained resistates with hydrogen chloride methanol solution (5mL), heating 1 hour and concentrated in a vacuum under reflux temperature.With this resistates be scattered in aqueous sodium hydroxide solution (2.5M, 5mL) in and with dichloromethane extraction.Extract is merged dry (sodium sulfate) and evaporation.By flash column chromatography (silica, methylene dichloride: purifying gained resistates methyl alcohol 9:1), then form hydrochloride, obtain being the title product of porous solid, identified [M+H] 361.2 by NMR and mass spectroscopy.

Example 165-172

1-[4-(heteroaryl methyl) phenmethyl] preparation of tetramethyleneimine-3-base amine hydrochlorate compound

Basically the same program described in the use-case 164 and use suitable 1-[4-(heteroaryl methyl) benzoyl] tetramethyleneimine-3-base amine is as initial substance, obtain the compound shown in the Table X I and by mass spectrum and ¹H NMR or HPLC analyze and are identified.

Table X I

Example 173-179

1-[3-(heteroaryl methyl) phenmethyl] preparation of tetramethyleneimine-3-base amine hydrochlorate compound

Basically the same program described in the use-case 164 and use suitable 1-[3-(heteroaryl methyl) benzoyl] tetramethyleneimine-3-base amine is as initial substance, obtain the compound shown in the Table X II and by ¹H NMR, HPLC and mass spectroscopy are identified.

Table X II

Example 180

1-[2-(1H-benzoglyoxaline-1-ylmethyl) phenmethyl] preparation of tetramethyleneimine-3-phenylpiperidines hydrochloride

Basically the same program described in the use-case 113 and use 1-[2-(1H-benzoglyoxaline-1-ylmethyl) benzoyl] tetramethyleneimine-3-phenylpiperidines is as initial substance, obtain title compound and by ¹H NMR, HPLC and mass spectroscopy are identified, [M+H] 375.3.

Example 181-201

Be substituted-1-[2-(1H-benzoglyoxaline-1-yl) methyl) benzoyl]-preparation of tetramethyleneimine-3-ylamine compounds

Basically the same program described in the use-case 127 and in step 3, use the suitable Boc protection tetramethyleneimine and the 4-chloromethyl-Benzoyl chloride of wanting, the compound shown in the acquisition Table X III and by ¹H NMR, HPLC and mass spectroscopy are identified.

Table X III

Example 202-205

1-[4-(1H-benzoglyoxaline-1-ylmethyl) phenmethyl] preparation of tetramethyleneimine-3-base amine hydrochlorate compound

Basically the same program described in the use-case 164 and use 1-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl that replaces through suitably]-tetramethyleneimine-3-base amine is as initial substance, obtain the compound shown in the Table X IV and by ¹H NMR and mass spectroscopy are identified.

Table X IV

Example 206 and 207

Basically the same program described in the use-case 40 and in step 1, use institute's phenylformic acid of wanting and the suitable amine HNR of use in step 3 ₁R ₂, obtain the compound shown in the Table X V and by ¹H NMR and mass spectroscopy are identified.

Table X V

Example 208

The preparation of 4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate

Step 1:4-(cyano methyl) methyl benzoate

Under 40 ℃ with 4-(brooethyl) methyl benzoate (52g, 0.227mol) solution in methyl-sulphoxide dropwise handles sodium cyanide (20g, the 0.41mol) solution in methyl-sulphoxide stirred 90 minutes, be cooled to room temperature, with the saturated sodium-chloride water solution stopped reaction and with ethyl acetate extraction.Wash through merging extract, through dried over sodium sulfate and under reduced pressure concentrated with saturated sodium-chloride water solution.(silica, hexane: ethyl acetate 0 → 5%) the purifying enriched material obtains 4-(cyano methyl) methyl benzoate (55%) via column chromatography. ¹H?NMR(400MHz，CDCl ₃)：8.05(d，J＝8Hz，2H)；7.42(d，J＝8Hz，2H)；3.93(s，3H)；3.81(s，2H)。[M+H]176。

Step 2:2-(4-(methoxycarbonyl) phenyl) acetate

(22.0g 0.125mol) reaches 8 hours in the stirred solution in methyl alcohol (550mL) under refluxad hydrogen chloride gas to be blasted 4-(cyano methyl) methyl benzoate.Reaction mixture is cooled to 20 ℃, restir 24 hours and filtration.Vapourisation under reduced pressure filtrate.The gained resistates is dissolved in the ether, in succession with the washing of water and saturated sodium bicarbonate aqueous solution, through dried over sodium sulfate and evaporation to obtain being the methyl esters of solid residue. ¹H?NMR(400MHz，CDCl ₃)：8.00(d，J＝8Hz，2H)；7.35(d，J＝8.4Hz，2H)；3.91(s3H)；3.70(s，3H)；3.68(s，2H)。GCMS：209(M+H)。(8.21g 0.039mmol) is dissolved in the methyl alcohol, and (1.58g 0.039mol) handles, and is heated to 50 ℃, stirs 4 hours, is cooled to room temperature, restir 24 hours and concentrated in a vacuum with sodium hydroxide with methyl esters.Between ether and water, divide the gained resistates molten.With dense HCl acidifying water layer.Remove the gained precipitation and dry 2-(4-(methoxycarbonyl) phenyl)-acetate (80%) to obtain being pale solid whole night under vacuum by filtering. ¹H?NMR(400MHz，DSMO-d ₆)：7.90(d，J＝8Hz，2H)；7.422(d，J＝8Hz，2H)；3.85(s，3H)；3.68(s，2H)。[M+H]195。

Step 3 and step 4:4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate

Under 0 ℃ with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.236g, 1.237mmol) and I-hydroxybenzotriazole (HOBT) (0.153g, 1.13mmol) processing 2-(4-(methoxycarbonyl) phenyl) acetate (0.2g, 1.03mmol) suspension in methylene dichloride, stirred 30 minutes, (0.12g 1.12mmol) handles, and at room temperature stirs 24 hours and with the water stopped reaction with phenylenediamine.Separate organic phase, in succession with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, through dried over sodium sulfate and under reduced pressure be concentrated into dry with obtain to be pale solid the acid amides of being wanted (68%).[M+H]285。(12.0g, 0.04mol) solution in acetate is heated to 140 ℃ and reaches 1 hour, is cooled to room temperature and under reduced pressure concentrates with described acid amides.With aqueous sodium hydroxide solution (1.0N, 100mL) in and gained resistates and with ethyl acetate extraction.Extract is merged, through dried over sodium sulfate and under reduced pressure concentrated.By column chromatography (silica, chloroform: the purifying enriched material solid title product (47%) that obtains being white in color methyl alcohol 0 → 5%). ¹H?NMR(400MHz，DMSO-d ₆)：7.95(d，J＝8Hz，2H)；7.52(s，2H)；7.325(d，J＝8Hz，2H)；7.23(m，2H)；4.30(s，2H)；3.89(s，3H)。[M+H]267。

Example 209

The preparation of methanesulfonic 1-(4-((1H-benzo [d] imidazoles-2-yl) methyl) benzoyl) tetramethyleneimine-3-base ester

Step 1:[4-(1H-benzimidazolyl-2 radicals-ylmethyl)-phenyl]-(3-hydroxyl-tetramethyleneimine-1-yl)-ketone

(1.50g, 0.037mol) (5g, the 0.019mol) solution in methyl alcohol are heated to 65 ℃, stir 3 hours and under reduced pressure concentrate with water treatment 4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate with sodium hydroxide.The gained resistates is soluble in water and with dense HCl acidifying.By filter to remove the gained precipitation and under vacuum drying whole night to obtain 4-((1H-benzo [d] imidazoles-2-yl) methyl) phenylformic acid (82.0%). ¹H?NMR(400MHz，DSMO-d ₆)：7.96(d，J＝8Hz，2H)，7.91(m，J＝9Hz，2H)，7.60(d，J＝8Hz，2H)，7.52(m，J＝6Hz，2H)，4.65(s，2H)。LCMS(ESI ⁺)253(M+H)。With a 4-((1H-benzo [d] imidazoles-2-yl) methyl) phenylformic acid (5.0g, 0.020mol) be dissolved in the methylene dichloride, be cooled to 0 ℃, with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (4.50g, 0.023mol), I-hydroxybenzotriazole (HOBT) (3.21g, 0.024mol) and diisopropylethylamine (6.41g, 0.049mol) handle, at room temperature stirred 30 minutes, be cooled to 0 ℃, (1.89g, the 0.021mol) solution-treated in methylene dichloride at room temperature stirred 24 hours and dilute with water with the 3-pyrrolidinol.Separate each mutually and in succession with saturated NaHCO ₃The aqueous solution, saturated NaCl solution washing organic phase are through dried over sodium sulfate and under reduced pressure be concentrated into dry to obtain being [4-(1H-benzimidazolyl-2 radicals-ylmethyl)-phenyl]-(3-hydroxyl-tetramethyleneimine-1-the yl)-ketone (34%) of yellow solid. ¹H?NMR(400MHz，DMSO-d ₆)：7.47(s，4H)，7.38(d，J＝7.6Hz，2H)，4.87(s，J＝4.2Hz，1H)，4.21(d，2H)，3.48(m，4H)，1.85(m，2H)。LCMS(ESI ⁺)322(M+H)。

Step 2: Methanesulfonic 1-(4-((1H-benzo [d] imidazoles-2-yl) methyl) benzoyl) tetramethyleneimine-3-base ester

With portion [4-(1H-benzimidazolyl-2 radicals-ylmethyl)-phenyl]-(3-hydroxyl-tetramethyleneimine-1-yl)-ketone (1.00g, 3.1mmol) be dissolved in the methylene dichloride, with diisopropylethylamine (0.60g, 4.6mmol) handle, be cooled to 0 ℃, (0.49g, 4.3mmol) solution in methylene dichloride is dropwise handled, and stirs 10 minutes down and concentrates to obtain solid residue under vacuum at 0 ℃ with methane sulfonyl chloride.(silica, chloroform: this resistates of purifying methyl alcohol 0 → 5%) obtains being the title product (62%) of yellow solid by column chromatography. ¹H?NMR(400MHz，CDCl ₃)：7.58(m，2H)，7.56(m，4H)，7.22(m，2H)，5.27(d，J＝5.4Hz1H)，4.35(s，2H)，3.93(s，1H)，3.80(s，1H)，3.63(m，4H)，3.09(m，3H)，2.31(m，2H)。[M+H]400。

Example 210

The preparation of 4-((1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate

With salt of wormwood (0.31g, 2.2mmol) processing 4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate (0.2g, 0.75mmol) solution in acetone, be cooled to 0 ℃, with methyl iodide (0.070mL, 1.1mmol) dropwise handle, heated 12 hours down at 40 ℃, be cooled to room temperature and filtration.Vapourisation under reduced pressure filtrate.By column chromatography (silica, chloroform) purifying gained resistates, obtain title product (28%). ¹H?NMR(400MHz，CDCl ₃)：7.98(d，J＝8.4Hz，2H)，7.7(m，1H)，7.37(m，5H)，4.38(s，2H)，3.9(s，3H)，3.5(s，3H)。[M+H]281。

Example 211

The preparation of methanesulfonic 1-(4-((1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) methyl) benzoyl) tetramethyleneimine-3-base ester

Basically the same program described in the use-case 209 and use 4-((1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate in step 1 obtains to be the title product of yellow solid, ¹H NMR (400MHz, CDCl ₃) 7.77 (m, 1H), 7.44-7.50 (m, 2H), 7.21-7.30 (m, 5H), 5.23 ﹠amp; 5.37 (bs, 1H), 4.37 (s, 2H), 3.93 (s, 1H), 3.75-3.82 (bs, 1H) 3.70-3.80 (m, 2H), 3.58-3.65 (m, 1H), 3.61 (s, 3H), 3.08 ﹠amp; 2.98 (s, 3H), 2.33-2.35 (m, 1H).[M+H]414。

Example 212

Fumaric acid 1,3 '-bipyrrolidine-1 '-Ji 4-[(1H-benzo [d] imidazoles-2-yl) methyl]-phenyl } preparation of ketone

With methanesulfonic 1-(4-((1H-benzo [d] imidazoles-2-yl) methyl) benzoyl) tetramethyleneimine-(0.8g, 2.0mmol) (1.14g, mixture 16mmol) place sealed tube and are heated to 110 ℃ and reach 3 hours 3-base ester with tetramethyleneimine.The cooling test tube is opened and the excessive tetramethyleneimine of vapourisation under reduced pressure carefully.By column chromatography (neutral alumina, chloroform: purifying gained resistates methyl alcohol 0 → 5%).Handle purified material to obtain the solid title product that is white in color with the fumaric acid in the ethanol/methylene. ¹H?NMR(300MHz，DMSO-d ₆)：7.48(m，2H)；7.45(d，2H)；7.39(d，2H)；7.12(m，2H)；6.64(s，2H)；4.23(s，2H)；3.75-3.22(m，6H)；2.89(m，1H)；2.59-2.49(m，2H)；2.08-1.79(m，2H)；1.70(m，4H)。[M+H]375.2。

Example 213-215

The preparation of { 4-[(1H-benzo [d] imidazoles-2-yl) methyl] phenyl } [(3-Azacyclyl) tetramethyleneimine-1-yl] ketone

Basically the same program described in the use-case 212 and use suitable methanesulfonic 1-(4-((1H-benzo [d] imidazoles-2-yl) methyl) benzoyl) tetramethyleneimine-3-base ester and the amine of wanting, the compound shown in the acquisition Table X VI and by ¹HNMR and mass spectroscopy are identified.

Table X VI

Example 216

1,3 '-bipyrrolidine-1 '-Ji { 4-[(1-ethyl-1H-benzo [d] imidazoles-2-yl) methyl] phenyl } } system of ketone hydrochloride Be equipped with

Step 1: methyl methanesulfonic 1-{4-[(1-ethyl-1H-benzo [d] imidazoles-2-yl)] benzoyl } tetramethyleneimine-3-base ester

With salt of wormwood (0.260g; 1.9mmol) processing methanesulfonic 1-{4-[(1H-benzo [d] imidazoles-2-yl) methyl] benzoyl-tetramethyleneimine-3-base ester (0.250g; 0.6mmol) stirred solution in DMF; be cooled to-5 ℃; (0.24g 1.5mmol) dropwise handled, and temperature is to room temperature with iodoethane through 20 minutes under 0 ℃; heated 3 hours down at 50 ℃, be cooled to room temperature and filtration.Concentrated filtrate in a vacuum.The gained resistates is dissolved in the ethyl acetate, with water washing, through dried over sodium sulfate and concentrated in a vacuum.By column chromatography (neutral alumina, chloroform: this resistates of purifying of methyl alcohol 100:0 → 98:2) obtains methanesulfonic 1-{4-[(1-ethyl-1H-benzo [d] imidazoles-2-yl) methyl] benzoyl } tetramethyleneimine-3-base ester (19%). ¹H?NMR(400MHz，CDCl ₃)：7.79-7.77(m，1H)，7.44-7.51(m，3H)，7.32-7.25(m，4H)，5.37?&?5.23(bs，1H)，4.36(s，2H)，4.05-4.10(q，J＝8Hz，2H)，3.93(bs，1H)，3.82(m，1H)，3.57-3.71(bs，2H)，3.08?&?3.00(s，3H)，2.33-2.36(m，1H)，2.17-2.21(m，1H)，1.18-1.22(t，J＝8Hz，3H)。[M+H]428。

Step 2:{1,3 '-bipyrrolidine-1 '-Ji 4-[(1-ethyl-1H-benzo [d] imidazoles-2-yl) and methyl] phenyl } the ketone hydrochloride

With methanesulfonic 1-{4-[(1-ethyl-1H-benzo [d] imidazoles-2-yl) methyl] benzoyl } tetramethyleneimine-3-base ester (0.06g; 0.14mmol) (0.08g, mixture 1.12mmol) place the microwave test tube and heated 15 minutes down at 110 ℃ with microwave irradiation with tetramethyleneimine.The excessive tetramethyleneimine of vapourisation under reduced pressure and by column chromatography (neutral alumina, chloroform: the purifying gained resistates of methyl alcohol 100:0 → 95:5).Handle purified material to obtain title product with the HCl diethyl ether solution. ¹H?NMR(300MHz，DMSO-d ₆)：7.83-7.73(m，2H)；7.56(d，2H)；7.48(d，2H)；7.48-7.43(m，2H)；4.63(s，2H)；4.44(q，2H)；4.03-3.25(m，7H)；3.07(m，2H)；2.30(m，2H)；2.14-1.84(m，4H)；1.27(t，3H)。[M+H]403.2。

Example 217-222

(3 ' S)-1 '-{ methyl of 4-[(1-alkyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-system of bipyrrolidine fumarate Be equipped with

Step 1:4-[(1-alkyl-1H-benzo [d] imidazoles-2-yl) methyl] methyl benzoate

With petroleum ether sodium hydride (60% dispersion liquid in the mineral oil, 48mg, 1.24mmol), it is suspended in N, in the dinethylformamide, be cooled to 0 ℃, with 4-[(1H-benzo [d] imidazoles-2-yl) methyl] methyl benzoate (300mg, 1.13mmol) solution-treated in DMF, stirred 10 minutes down at 0 ℃, at room temperature stirred 15 minutes, be cooled to 0 ℃, solution in DMF was dropwise handled through 10 minutes with selected bromoalkane or idoalkane (1.24mmol), at room temperature stirred 5 hours and under reduced pressure concentrated.Between water and methylene dichloride, divide the gained resistates molten.Separate organic phase, extremely dry through dried over sodium sulfate and vapourisation under reduced pressure.By flash column chromatography (silica, sherwood oil: ethyl acetate 8:2 to 1:1) this resistates of purifying is to obtain 4-[(1-alkyl-1H-benzo [d] imidazoles-2-yl) methyl] methyl benzoate.

Step 2:(3 ' S)-1 '-{ methyl of 4-[(1-alkyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-the bipyrrolidine fumarate

(0.8mmol) is dissolved in the methyl alcohol with benzoic ether, and (2.5M 2.0mmol) handles, heating 4 hours and concentrated in a vacuum under refluxing with aqueous sodium hydroxide solution.Be scattered in resistates in the water and with excessive formic acid acidifying.By filter removing the gained precipitation, with water washing and under vacuum drying whole night to obtain corresponding phenylformic acid.(0.381mmol) is dissolved among the DMF with phenylformic acid, with 1-(3-dimethyl-aminopropyl)-3-ethyl-carbodiimide hydrochloride (87.7mg, 0.457mmol) and I-hydroxybenzotriazole (56.6mg, 0.419mmol) handle, at room temperature stirred 30 minutes, with (3 ' S)-1,3 '-bipyrrolidine (79.8mg, 0.57mmol) solution-treated in DMF, at room temperature stirred 6 hours and concentrated in a vacuum.Between wet chemical (1.0M) and methylene dichloride, divide this resistates molten.Separate organic phase, with water washing, through dried over sodium sulfate and under reduced pressure concentrated.By flash column chromatography (silica, methylene dichloride: this enriched material of purifying methyl alcohol 20:1 to 10:1), then handle to obtain the compound shown in the Table X VII with the fumaric acid in the methylene chloride.By ¹The compound among the Table X VII is identified in H NMR and mass spectroscopy.

Table X VII

Example 223

2-(2-{4-[(3 ' S)-1,3 '-bipyrrolidine-1 '-the Ji carbonyl] phenmethyl }-1H-benzoglyoxaline-1-yl) the ethanol fumarate Preparation

Basically same program described in the use-case 217-222 and use 4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate and 2-(2-bromine oxethyl) tetrahydrochysene-2H-pyrans are as initial substance; obtain (3 ' S)-1 '-methyl of 4-[(1-(2-(tetrahydrochysene-pyrans-2-base oxygen base)-ethyl)-1H-benzimidazolyl-2 radicals-yl)] and benzoyl }-1; 3 '-bipyrrolidine, [M+H] 503.2.With the hydrogenchloride in ether handle a (3 ' S)-1 '-{ methyl of 4-[(1-(2-(tetrahydrochysene-pyrans-2-base oxygen base)-ethyl)-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine, at room temperature stir and concentrate in a vacuum.Between wet chemical (1.0M) and methylene dichloride, divide the gained resistates molten.Separate organic phase, with water washing, through dried over sodium sulfate and under reduced pressure concentrated.Handle this resistates to obtain title product with the fumaric acid in methylene chloride. ¹H?NMR(300MHz，DMSO-d ₆+TFA)：7.94(m，1H)，7.79(m，1H)，7.57(d，2H)，7.57(m，2H)，7.49(d，2H)，6.65(s，2H)，4.74(s，2H)，4.58(t，2H)，3.92(m，2H)，3.80(t，2H)，3.74(m，2H)，3.51(m，2H)，3.44-3.06(br.s，3H)，2.33(m，1H)，2.21(m，1H)，1.99(m，4H)。[M+H]419.17。

Example 224

(3 ' S)-1 '-methyl of 4-[(1-styroyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-the bipyrrolidine fumarate Preparation

Step 1:4-(1-styroyl-1H-benzimidazolyl-2 radicals-ylmethyl) methyl benzoate

With (2-bromotrifluoromethane) benzene (209mg, 1.13mmol) and salt of wormwood (143mg 0.90mmol) handles 4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate (200mg, 0.75mmol) solution in acetonitrile.With microwave irradiation reaction mixture was heated 2 hours down at 100 ℃.Under reduced pressure remove solvent and between water and methylene dichloride, divide resistates molten.Separate organic phase, through dried over sodium sulfate and concentrated in a vacuum.(silica, sherwood oil: purifying gained resistates ethyl acetate 8:2 to 1:1) obtains 4-(1-styroyl-1H-benzimidazolyl-2 radicals-ylmethyl)-methyl benzoate (30%) by flash column chromatography.[M+H]371.2。

Step 2:(3 ' S)-1 '-{ methyl of 4-[(1-styroyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-the bipyrrolidine fumarate

Basically the same program described in the use-case 217-222 step 2 and use 4-(1-styroyl-1H-benzimidazolyl-2 radicals-ylmethyl)-methyl benzoate obtain title product as initial substance. ¹H?NMR(300MHz，DMSO-d ₆)：7.54-7.61(m，1H)，7.41-7.49(m，3H)，7.16-7.32(m，7H)，7.08(dd，2H)，6.64(s，2H)，4.34-4.43(m，2H)，4.06-4.20(m，2H)，3.38-3.62(m，5H)，3.32(dd，1H)，2.80-2.94(m，3H)，2.42-2.58(m，2H)，1.93-2.08(m，1H)，1.76-1.90(m，1H)，1.63-1.74(m，4H)，[M+H]379.22。

Example 225

(3 ' S)-1 '-[4-(1H-benzimidazolyl-2 radicals-ylmethyl) benzoyl]-1,3 '-preparation of bipyrrolidine

(2.5M 3.75mmol) handles 4-((1H-benzo [d] imidazoles-2-yl) methyl) methyl benzoate (400mg, the 1.5mmol) solution in methyl alcohol, heating 3 hours and concentrated in a vacuum under reflux temperature with aqueous sodium hydroxide solution.Be scattered in the gained resistates in the water and with excessive formic acid acidifying.By filter removing the gained precipitation, with water washing and under vacuum drying whole night to obtain solid 4-((1H-benzo [d] imidazoles-2-yl) methyl) phenylformic acid (92%) that is white in color, [M+H] 253.2.With 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (183mg, 0.952mmol) and I-hydroxybenzotriazole (134mg, 0.873mmol) processing 4-((1H-benzo [d] imidazoles-2-yl) methyl) phenylformic acid (200mg, 0.79mmol) solution in DMF, at room temperature stirred 3 hours, with (3 ' S)-1,3 '-bipyrrolidine (166.6mg, 1.19mmol) solution-treated in DMF, at room temperature stirred 6 hours and concentrated in a vacuum.Between wet chemical (1.0M) and methylene dichloride, divide this resistates molten.With the water washing organic phase, through dried over sodium sulfate and under reduced pressure concentrated.By flash column chromatography (silica, methylene dichloride: purifying enriched material methyl alcohol 20:1 to 10:1), obtain title compound (73%), identified by mass spectroscopy.[M+H]253.2。

Example 226

(3 ' S)-1 '-{ methyl of 4-[(1-phenyl-IH-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-system of bipyrrolidine fumarate Be equipped with

With pyridine (34 μ L, 0.42mmol), then with phenyl-boron dihydroxide (50.7mg, 0.42mmol), venus crystals (II) (56mg, 0.31mmol) and 4

The molecular sieve processing (3 ' S)-1 '-[4-(1H-benzimidazolyl-2 radicals-ylmethyl) benzoyl]-1,3 '-(78mg, the 0.21mmol) solution in methylene dichloride at room temperature stirred 24 hours and filtered bipyrrolidine.Vapourisation under reduced pressure filtrate and between wet chemical (1.0M) and methylene dichloride, divide the gained resistates molten.Separate organic phase, with water washing, through dried over sodium sulfate and under reduced pressure concentrated.By flash column chromatography (silica, methylene dichloride: purifying gained resistates methyl alcohol 98:2 to 90:10).Handle purified material obtaining title product with the fumaric acid in methylene chloride, ¹H NMR (300MHz, DMSO-d ₆): 7.65-7.73 (m, 1H), 7.49-7.62 (m, 3H), 7.39-7.48 (m, 2H), 7.35 (d, 2H), 7.16-7.29 (m, 2H), 7.05-7.15 (m, 3H), 6.61 (s, 2H), 4.22 (s, 2H), 3.00-3.78 (m, 7H), 2.54-2.66 (m, 2H), 1.97-2.11 (m, 1H), 1.63-1.89 (m, 5H).[M+H]451.33。

Example 227

(3 ' S)-1 '-(4-{[1-(phenyl sulfonyl)-1H-benzimidazolyl-2 radicals-yl] methyl }-benzoyl)-1,3 '-the rich horse of bipyrrolidine The preparation of acid esters

Under inert atmosphere, incite somebody to action (3 ' S)-1 '-[4-(1H-benzimidazolyl-2 radicals-ylmethyl) benzoyl]-1; 3 '-bipyrrolidine (100mg; 0.267mmol) solution in anhydrous methylene chloride is cooled to 0 ℃; with triethylamine (TEA) (32mg; 0.32mmol) handle, then dropwise add benzene sulfonyl chloride (51.7mg, 0.293mmol) solution in anhydrous methylene chloride; stirred 1 hour down at 0 ℃, temperature to room temperature reaches 1 hour and under reduced pressure concentrates.With the gained resistates at methylene dichloride and 5%NaHCO ₃Divide molten between the aqueous solution.Separate organic phase, with water washing, through dried over sodium sulfate and under reduced pressure concentrated to obtain resistates.Handle this resistates obtaining title compound with the fumaric acid in methylene chloride, ¹H NMR (300MHz, DMSO-d ₆+ TFA): 7.96 (d, 1H), 7.90 (d, 2H), 7.78-7.66 (m, 2H), 7.59 (m, 2H), 7.49 (d, 2H), 7.45-7.29 (m, 4H), 6.63 (s, 2H), 4.67 (s, 2H), 3.58-3.41 (m, 4H), 3.10-2.76 (m, 5H), 2.19 (m, 1H), 2.00 (m, 1H), 1.91-1.73 (m, 4H).[M+H]515.1。

Example 228

With the NaOH aqueous solution (4.15mL, 1N, 4.15mmol) processing 4-((1H-indol-3-yl) methyl) methyl benzoate (tetrahedron wall bulletin (Tet.Lett.) 44 (2003) 4589-4591) (0.50g, 1.88mmol) solution in methyl alcohol, be heated to that reflux temperature reaches 3 hours and concentrate in a vacuum.The gained solid residue is dissolved in H ₂Among the O and with the HCl acidifying.By filter removing gained precipitation and dry to obtain 0.468g (99%) solid 4-((1H-indol-3-yl) methyl) phenylformic acid that is white in color.(0.275g, 1.2mmol/g 0.33mmol) pack in the microwave bottle with the PS-carbodiimide.((1H-indol-3-yl) methyl)-(0.070g is 0.28mmol) in CH for phenylformic acid to add 4-in bottle ₃(0.045g is 0.33mmol) in CH for solution among the CN, HOBT ₃Solution among the CN, (S)-1,3 '-(0.065g is 0.31mmol) in CH for bipyrrolidine ₃Solution among the CN and 0.11mL triethylamine.Reaction mixture was shone 6 minutes down and then under reduced pressure concentrates at 110 ℃ in Ai Murui optimizer (Emry ' s Optimizer).By purification by flash chromatography gained resistates obtaining 0.064g (68%) the solid title product that is white in color, fusing point 141-153 ℃, by H ¹NMR and mass spectroscopy are identified.MS(ES)m/z?372.2。

Example 229

(3 ' S)-1 '-{ 4-[(1-Methyl-1H-indole-3-yl) methyl] benzoyl }-1,3 '-preparation of bipyrrolidine

Step 1:4-((1-Methyl-1H-indole-3-yl) methyl) methyl benzoate

(0.250g, 0.94mmol) solution in THF dropwise is added into NaH (0.048g is 1.19mmol) in the suspension in THF with 4-((1H-indol-3-yl) methyl) methyl benzoate.Mixture was stirred 15 minutes, and (0.154g 1.08mmol) handles, and stirs 30 minutes and concentrates in a vacuum with methyl iodide.With the gained solid residue at CH ₂Cl ₂With H ₂Divide molten between the O.Separate organic phase, through Na ₂SO ₄Dry and be concentrated into dry to obtain 4-((1-Methyl-1H-indole-3-yl) methyl) methyl benzoate.

Step 2:(3 ' S)-1 '-{ 4-[(1-Methyl-1H-indole-3-yl) methyl] benzoyl }-1,3 '-bipyrrolidine

Basically same program described in the use-case 167 and use 4-((1-Methyl-1H-indole-3-yl) methyl) methyl benzoate obtain to be white in color the solid title product as initial substance, and fusing point 73-78 ℃, by H ¹NMR and mass spectroscopy are identified.MS(ES)m/z?388.2；MS(ES)m/z?410.2。

Example 230

(3S)-and N, N-dimethyl-1-{4-[(1-Methyl-1H-indole-3-yl) methyl] benzoyl } preparation of tetramethyleneimine-3-amine

Basically the same program described in the use-case 228 and use 4-((1-Methyl-1H-indole-3-yl) methyl) methyl benzoate and (S)-N, N-dimethyl pyrrolidine-3-amine is as initial substance, the acquisition solid title compound that is white in color, fusing point 101-105 ℃, by H ¹NMR and mass spectroscopy are identified.MS(ES)m/z?362.2；MS(ES)m/z?723.4。

Example 231

(3 ' S)-1 '-(4-phenmethyl benzoyl)-1,3 '-preparation of bipyrrolidine hydrochloride

At room temperature in succession with 0.85mL triethylamine and solid phosphofluoric acid benzotriazole-1-base-oxygen base tripyrrole Wan Phosphonium (1.2g, 2.4mmol) processing 3-(tetramethyleneimine also) pyrrolidine hydrochloride (0.44g, 2.1mmmol) and 4-phenmethyl phenylformic acid (0.34g is 1.6mmmol) in CH ₂Cl ₂In mixture, under nitrogen, stirred 16 hours, with CH ₂Cl ₂Dilution, Yi Shui and salt water washing in succession is through MgSO ₄Dry and concentrated in a vacuum.Through the chromatogram purification enriched material.Handle purified material to obtain title compound, by H with the HCl diethyl ether solution ¹NMR and mass spectroscopy are identified.

Example 232

(3 ' S)-1 '-{ methyl of 4-[(1-ethyl-1H-benzimidazolyl-2 radicals-yl)] phenmethyl }-1,3 '-preparation of bipyrrolidine

To 1,3 '-bipyrrolidine-1 '-Ji (4-((1-ethyl-1H-benzo [d] imidazoles-2-yl) methyl) phenyl) ketone (69mg, 0.172mmol, 1eq) add borine-tetrahydrofuran complex (860 μ L in the solution in anhydrous tetrahydro furan (3mL), 0.860mmol, the 1M in the tetrahydrofuran (THF)) and reaction mixture is heated to refluxes and stirred 3 hours.Reaction mixture is cooled to room temperature, by dropwise adding methyl alcohol stopped reaction and vapourisation under reduced pressure solvent.Handle resistates and heating 1 hour under refluxing with the hydrogenchloride in methyl alcohol (5mL).Vapourisation under reduced pressure solvent and between methylene dichloride and 1.0N aqueous sodium hydroxide solution, divide resistates molten.Separate organic layer and drying (sodium sulfate) and remove solvent in a vacuum.By flash column chromatography purifying resistates to obtain title product (65%). ¹H?NMR(300MHz，DMSO-d ₆)：7.74-7.86(m，2H)，7.43-7.56(m，6H)，6.64(s，2H)，4.62(s，2H)，4.46(q，2H)，4.22(s，2H)，4.00-4.10(m，1H)，3.44-3.55(m，1H)，3.24-3.40(m，6H)，3.09-3.18(m，1H)，2.35-2.45(m，1H)，2.12-2.24(m，1H)，1.91-2.02(m，4H)，1.27(t，3H)。389.22(M+H)。

Example 233

(2R, 3 ' R)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-2-methyl isophthalic acid, 3 '-system of bipyrrolidine hydrochloride Be equipped with

Basically the same program described in the use-case 40 and in step 1, use 4-(1H-benzoglyoxaline-1-ylmethyl) phenylformic acid and in step 3, use (2R)-2-crassitude, obtain to be yellow solid title product and by mass spectrum and ¹HNMR analyzes and is identified.MS[389.2m/e(M+H]。

Example 234

(2S, 3 ' R)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-2-methyl isophthalic acid, 3 '-system of bipyrrolidine hydrochloride Be equipped with

Basically the same program described in the use-case 40 and in step 1, use 4-(1H-benzoglyoxaline-1-ylmethyl) phenylformic acid and in step 3, use (2S)-2-crassitude, obtain to be yellow solid title product and by mass spectrum and ¹HNMR analyzes and is identified.MS[389.2m/e(M+H]。

Example 235

HumanHistamine Methyl in the H3 recipient cell systemHistamine The bonded assessment

Assess the avidity of test compounds in the following manner to histamine 3 (H3) acceptor.Growth is through the HEK293T of stable transfection cell in the DMEM that contains 10% heat inactivation FBS and G-418 (500 μ g/ml).Scrape cell from culture plate, be transferred in the centrifuge tube, by in fertile (Sorvall) RT7Plus whizzer of rope centrifugal (2000rpm, 10 minutes, 4 ℃) and washing is once in PBS.Centrifugal of gained is stored under-80 ℃ until use.With the cell resuspending in damping fluid (50mM Tris, pH=7.5) in and place Du Ensi (Dounce) clarifixator, inhale and beat (douncing) 10 times with the cell that homogenizes.By centrifugal (Suo Wo (Sorvall) RT7 Plus, 1800rpm, 10 minutes, 4 ℃) the homogenate rotation is descended.But supernatant liquor is placed Lay (Corex) pipe and rotates decline by centrifugal (Suo Wo (Sorvall) RC 5c Plus, 17,000rpm, 20 minutes, 4 ℃).With centrifugal resuspending in damping fluid (50mM Tris, pH7.5) in.Use the Micro-BCA protein determination to measure protein concn (μ g/ μ l).Set up in conjunction with calibrating in 96 hole microtiter plates, cumulative volume is 250 μ L.Under the situation that has the 10 general pyrroles of μ M chlorobenzene (clobenpropit), measure non-specific binding.Final radioligand concentration is 1nM.Use the final approximate range of Beckman (Beckman) Biomek2000 with test compounds serial dilution to 100 μ M to 100pM.Film is suspended in the damping fluid, uses the mechanical clarifixator of dimension Qu Si (Vitris) that is located at power shelves 5 to homogenize with 2 times 10 pulse per second (PPS)s.10 μ g films are added in each hole.After 30 ℃ are down cultivated 1 hour, by add ice-cold buffer and with Pai Kadefeitemeite collector (PackardFiltermate Harvester) via with 1 hour GF/B strainer of 1%PEI preimpregnation fast filtration come termination reaction.Culture plate is added in each hole 37 ℃ of following dryings 1 hour and with the little flicker scintillator of 60 μ L (Microscint Scintillant).Go up the CPM that measures every hole at Pai Kade top counting NXT (Packard Top Count NXT).With nM is that unit measures the Ki value.From IC ₅₀(that is, replacing the specificity bonded competition ligand concentration of 50% radioligand) calculating K i.The CPM value is expressed as specificity in conjunction with % and to the compound concentration curve plotting.Use the 4 fitting process matched curve of parameter logarithm and definite IC ₅₀Value.Use old-Pu (Cheng-Prusoff) equation from IC ₅₀Calculating K i:pKi=IC ₅₀/ 1+ (L/Kd), the concentration of the L=free radioactivity part that is used for examining and determine wherein, and Kd is the dissociation constant of the radioligand of acceptor.Measure the L that each is tested by the aliquots containig (corresponding to the sample that is added into each hole) through diluting radioligand is counted, and before under the condition identical, measure Kd with described clone/radioligand.

Histamine The ring-type AMP calibrating of acceptor H3 antagonistic activity

To stablize the H3 cell in tissue culture flasks maintains among the DMEM that contains high glucose, 10%FBS, 1 * penicillin/streptomycin, 500 μ g/ml GY18 until experiment.Remove substratum and add twice of 500 μ M IBMX washed cell with PBS w/Ca++ and Mg++.Then come isolated cell and resuspending in same buffer by rapping the flask sidewall.In 96 hole culture plates, 2,000 cells in every hole and 1 μ M histamine added 10 μ M not this Kelin (forskolin) add that various concentration compounds cultivated 30 minutes down at 30 ℃ with cumulative volume 30 μ L.The final test compound concentration is in 10-4M to 10-9.5M scope under full log10 dilution degree (full logdilution).Specification sheets according to manufacturers uses uncommon special Hunter (HitHunter) cAMP test kit (disco is irrigated company (Discoverx), catalog number (Cat.No.) 900041) to measure ring-type AMP content.Use top counting (Top Count) (Pai Kade (Packard)) to detect chemiluminescence signal.Think that accepting 10 μ M not adds that the ring-type AMP content in the control cells of 100nM histamine is 0% in this Kelin, and think that accepting 10 μ M not adds that the 100nM histamine adds that the ring-type AMP content in the cell of the general pyrrole of 1 μ M chlorobenzene is 100% in this Kelin.Data representation is for contrast % and use Pu Ruisen (Prizm) software to analyze.Use following equation calculating K b value: KB=EC ₅₀Or IC ₅₀/ [1+ (part/Kd)].Data is showed among the following table XVIII.

For Table X VIII

A＝≤10nM

B＝10.1nM-25.0nM

C＝25.1nM-50.0nM

D＝50.1nM-100nM

E＝>100nM

Table X VIII

Example number H3 is in conjunction with Ki (nM) cAMP Kb (nM)

1 D B

2 D B

3 E E

4 E --

5 E --

6 D --

7 C --

8 E --

9 B B

10 C --

11 D --

12 D A

13 E B

14 E --

15 E --

16 E --

17 E B

18 E --

19 E --

20 E --

21 E --

22 E A

23 E B

24 E --

25 E A

26 E --

27 E --

28 B --

Example number H3 is in conjunction with Ki (nM) cAMP Kb (nM)

29 E --

30 -- --

31 E --

32 E --

33 E --

34 E --

35 -- --

36 E --

37 D --

38 E --

39 E --

40 D --

41 A A

42 E --

43 E --

44 E C

45 E --

46 B A

47 A A

48 B A

49 D A

50 C B

51 E E

52 D A

53 B A

54 B A

55 B --

56 B A

57 C B

58 B A

59 A A

60C C B

61 C A

62 C B

63 B A

64 C B

65 A A

66 B A

67 A --

68 A --

69 C --

70 A B

71 D --

72 C --

73 C --

74 -- --

75 A A

76 B --

77 A A

78 B B

Example number H3 is in conjunction with Ki (nM) cAMP Kb (nM)

79 A A

80 C --

81 A A

82 A --

83 A --

84 A --

85 A A

86 E --

87 E --

88 E --

89 E --

90 E --

91 A --

92 B --

93 A --

94 E --

95 D --

96 E --

97 E --

98 B --

99 C --

100 D --

101 E --

102 E --

103 A A

104 A --

105 A --

106 A --

107 A --

108 E --

109 A --

110 A --

111 B --

112 A --

113 A --

114 A --

115 A --

116 A

117 A

118 E --

119 E --

120 C --

121 D --

122 E --

123 C --

124 E --

125 C B

126 E C

127 B A

128 C A

Example number H3 is in conjunction with Ki (nM) cAMP Kb (nM)

129 C A

130 D A

131 B A

132 E A

133 B A

134 E A

135 E A

136 A A

137 A A

138 E B

139 -- --

140 A A

141 A A

142 A A

143 A --

144 A --

145 A --

146 A --

147 A --

148 A --

149 A --

150 A --

151 A --

152 A --

153 A A

154 A --

155 A A

156 A --

157 A --

158 A --

159 B --

160 E --

161 D --

162 E --

163 E --

164 A A

165 A --

166 A A

167 B

168 A A

169 B --

170 A --

171 -- --

172 A --

173 E --

174 E --

175 E --

176 E --

177 B --

178 A A

Example number H3 is in conjunction with Ki (nM) cAMP Kb (nM)

179 A --

180 E --

181 B --

182 C --

183 B --

184 A A

185 C --

186 C --

187 A --

188 B --

189 A --

190 A --

191 A --

192 B --

193 B --

194 C --

195 B --

196 B --

197 B --

198 C --

199 A --

200 A --

201 B --

202 A A

203 B --

204 A --

205 B --

206 A --

207 A --

212 B --

213 C --

214 A --

215 C --

216 A --

217 A --

218 A --

219 B --

220 B --

221 C --

222 B --

223 D --

224 A --

225 -- --

226 B --

227 E --

228 A --

229 B --

230 E --

231 A --

232 C --

Example number H3 is in conjunction with Ki (nM) cAMP Kb (nM)

233 C

234 B

Claims

1. formula I compound:

Wherein

X is CO, CH ₂Or SO _m

P and n are 1,2 or 3 integer independently of one another;

M is 0 or is 1 or 2 integer;

R ₁₀Be H or the alkyl that is substituted according to circumstances; Or

Its steric isomer or its pharmaceutically acceptable salt.

2. compound according to claim 1, wherein X is CO or CH ₂

3. compound according to claim 1 and 2, wherein n be 1 and p be 1 or 2.

4. according to the described compound of arbitrary claim, wherein R in the claim 1 to 3 ₈And R ₉Be H or methyl independently of one another.

5. according to the described compound of arbitrary claim, wherein R in the claim 1 to 4 ₁And R ₂Form 5 yuan of rings together with the atom that it connected.

6. according to the described compound of arbitrary claim, wherein R in the claim 1 to 5 ₃Be NR ₄R ₅Or the indoles that is substituted according to circumstances, indazole, phenyl or benzoglyoxaline ring.

7. according to the described compound of arbitrary claim, wherein R in the claim 1 to 5 ₃Be NR ₄R ₅Or at the benzoglyoxaline ring that is substituted according to circumstances of 2 connections of described benzoglyoxaline ring; And R ₄And R ₅Form indoles, indazole or the benzoglyoxaline ring that is substituted according to circumstances together with the atom that it connected.

8. compound according to claim 1, it is a kind of in following each thing:

(3 ' S)-[4-(1H-indoles-1-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-[4-(1H-indazole-1-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

9-{4-[(3 ' S)-1,3 '-bipyrrolidine-1-base carbonyl] phenmethyl-the 9H-carbazole;

(3 '-S)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) phenmethyl]-1,3 '-bipyrrolidine;

(3 '-S)-1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-1 '-[4-(1H-indol-3-yl methyl) benzoyl]-1,3 '-bipyrrolidine;

1 '-[4-(1H-benzimidazolyl-2 radicals-ylmethyl) benzoyl]-1,3 '-bipyrrolidine;

(3 ' S)-1 '-(4-phenmethyl benzoyl)-1,3 '-bipyrrolidine;

(3 ' S)-1 '-methyl of 4-[(1-phenyl-1H-benzimidazolyl-2 radicals-yl)] benzoyl }-1,3 '-bipyrrolidine;-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) methyl] benzoyl }-1,3 '-bipyrrolidine;

((2s)-1 '-4-[(5-methyl isophthalic acid H-benzoglyoxaline-1-yl) and methyl] benzoyl }-1,3 '-bipyrrolidine-2-yl) methyl alcohol;

1 '-[4-(1H-benzoglyoxaline-1-ylmethyl)-2-fluoro benzoyl]-1,3 '-bipyrrolidine;

1 '-[4-(1H-benzoglyoxaline-1-ylmethyl) benzoyl]-1,3 '-the Lian piperidines;

Its steric isomer; Or

The salt that it is pharmaceutically acceptable.

9. a treatment has the relevant with histamine-3 acceptor of the patient that needs or by the method for the central nervous system disorders of histamine-3 acceptor influence, its comprise to described patient provide treat significant quantity according to the described formula I compound of arbitrary claim in the claim 1 to 8.

10. method according to claim 9, wherein said illness are cognitive disorder, dysplasia or somnopathy.

11. method according to claim 9, wherein said illness are cognitive disorder.

12. method according to claim 9, wherein said illness are selected from by the Alzheimer (group that Alzheimer ' sdisease), learning disorder, attention deficit disorder and schizophrenia are formed.

13. a method that suppresses the H3 acceptor, it comprises makes contacting according to the described formula I compound of arbitrary claim in the claim 1 to 8 or its steric isomer or pharmaceutically acceptable salt of described acceptor and significant quantity.

14. a medical composition, it comprises pharmaceutically acceptable supporting agent and according to the described formula I compound of arbitrary claim in the claim 1 to 8 or its steric isomer or pharmaceutically acceptable salt.

15. a method for preparing formula I compound according to claim 1,

Described method comprises makes formula XVI compound

Wherein X, n, p, R ₃, R ₆, R ₇, R ₈And R ₉As hereinbefore defined,

With R wherein ₁And R ₂Amine HNR as hereinbefore defined ₁R ₂React existing under the situation that has solvent under the situation of microwave irradiation according to circumstances;

Change into its pharmaceutically acceptable salt in case of necessity;

And/or

Separate its particular stereoisomer.