CN1913900B - Amino bustituted diaryl[a,d]cycloheptene analogs as muscarinic agonists and methods of treatment of neuropsychiatric disorders - Google Patents

Abstract

Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

Description

Diaryl [a, d] the cycloheptene analog that replaces as the amino of muscarinic agonist and the Therapeutic Method of neuropsychiatric disease

Background of invention

Invention field

Some aspect of present disclosure relates to the method for using compounds for treating neuropsychiatric disease, pain and other disease, these chemical compounds are regulated M-ChR, the activity of M1 hypotype particularly develops relevant neuronal activity thereby regulate with neuropsychiatric disease.Aspects more of the present invention also relate to and interactional chemical compound of this receptor subtype-selective and the method for differentiating described chemical compound.

Description of related art

The effect of mAChR mediation neurotransmitter acetylcholine in maincenter and peripheral nervous system, gastronintestinal system, heart, endocrine gland, lung and other tissue.M-ChR plays a significant role for more high-grade cognitive function in central nervous system and periphery parasympathetic nervous system.Five kinds of different M-ChR hypotypes have been differentiated, m1-m5.The m1 hypotype is the main hypotype of finding in the cerebral cortex, is considered to relevant with the control of cognitive function; M2 is the main hypotype of finding in the heart, is considered to relevant with the control of heart rate; It is relevant with gastrointestinal, urethral stimulant and perspiration and salivation that m3 is considered to; M4 is present in the brain, may be relevant with motion; And m5 is present in the brain, and some function of central nervous system that may be relevant with dopaminergic system is relevant.

Such as the situation relevant of Alzheimer, follow the loss of acetylcholine in the brain with cognitive impairment.This is considered to the result that cholinergic neuron in basal forebrain and the Hippocampus is degenerated, basal forebrain innervation association cortex wherein, and Hippocampus is with more level process is relevant.The effort that improves levels of acetylcholine concentrates on level and the metabolic enzyme acetylcholinesterase of blockage of acetylcholine (AChE) that improves the synthetic precursor choline of acetylcholine.It also is not very successful giving choline or phosphatidylcholine.The AchE inhibitor has demonstrated some therapeutic effect, but because the periphery acetylcholine stimulates and may cause the cholinergic side effect, comprise abdominal colic, nausea,vomiting,diarrhea, loss of appetite, lose weight, myopathy and depression.In about 1/3rd treatment patient, observe gastrointestinal side-effect.In addition,, also found to cause significant liver toxicity, in about 30% patient, observed liver transaminase and raise such as some AchE inhibitor of tacrine.The ill effect of AchE inhibitor has limited its clinical practice.

Also finding, is the weak agonist of m2 and m3 hypotype such as the known m1 muscarinic agonist of arecoline, and is not very effective in the treatment cognitive impairment, most likely because the side effect of dose limitation.

Need some in brain, to increase the chemical compound of acetylcholine signal or effect.Particularly, need be to all activated muscarinic agonist of various M-ChR hypotypes in maincenter and the peripheral nervous system.In addition, need have the more muscarinic agonist of high selectivity, as m1-or m4-selective reagent, both as pharmacological tool, again as medicine.

Summary of the invention

The chemical compound of disclosed herein formula I, II or XV:

Or its officinal salt, ester, amide or prodrug, wherein A is selected from

X is nitrogen, CH or CH ₂X ' is C or CH, when X ' is C, is two keys between X and X ' wherein, when X ' is CH, is singly-bound between X and X ' wherein; Each Y is selected from nitrogen, oxygen or CH respectively; Each W is selected from nitrogen, CH, oxygen or sulfur respectively; Each n is selected from 0,1,2,3 and 4 respectively; M is selected from 1,2 and 3; Each R ₁Be respectively the C that does not exist or be selected from hydrogen, halogen, amine, optional replacement respectively _1-20Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-20Alkenyl, the optional C that replaces _2-20Alkynyl, the optional C that replaces _1-20-alkoxyalkyl, and optional aryl and the aryl alkyl that replaces; L is not for existing or be selected from-NH (CH ₂) n-and-(CH ₂) n-; A, b, c and d are selected from carbon, nitrogen, oxygen and sulfur independently of one another, or independently of one another for not existing, condition is three's existence at least among a, b, c or the d, and at least one is a carbon among a, b, c or the d, and a of two vicinities, b, c or d not all are oxygen or not all are sulfur; E, f, g and h are selected from carbon, nitrogen, oxygen and sulfur independently of one another, or independently of one another for not existing, condition is that the three at least of e, f, g or h exists, and at least one of e, f, g or h be carbon, and the e of two vicinities, f, g or h not all are oxygen or not all are sulfur; R ₂, R ₃, R ₄And R ₅, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₂And R ₃, or R ₃And R ₄, or R ₄And R ₅Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring or hexa-atomic aryl rings part; R ₆, R ₇, R ₈And R ₉, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₆And R ₇, or R ₇And R ₈, or R ₈And R ₉Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part; Z is selected from NR ₁₁, oxygen, sulfur and CH ₂R ₁₀Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional aryl that replaces, optional aryl alkyl and the whole haloalkyl that replaces; And R ₁₁Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl and the optional aryl alkyl that replaces; R ₁₂And R ₁₃Be selected from hydrogen, halogen, the optional C that replaces respectively _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₁₂And R ₁₃Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part; And any key table empty and that solid line is represented shows the key that is selected from carbon-to-carbon singly-bound and carbon-to-carbon double bond; Condition is that the chemical compound of formula I or XV is not clozapine or N-desmethylclozapine.

In some embodiments, chemical compound has the structure that formula III or IV represent.

In some embodiments, described chemical compound is selected from:

In some embodiments, described chemical compound is selected from:

In some embodiments, a, b, c and d exist.In some embodiments, e, f, g and h exist.In some embodiments, a, b, c and d are carbon.In some embodiments, e, f, g and h are carbon.In some embodiments, R ₂Be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl and the optional C that replaces _1-6Alkoxyl.In some embodiments, alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, alkoxyl is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, sec-butoxy and tert-butoxy.In some embodiments, halogen is selected from fluorine, chlorine and bromine.In some embodiments, R ₂Be selected from hydrogen, methyl, methoxyl group and chlorine.In some embodiments, R ₃Be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _1-6Alkoxyl and NO ₂In some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, this alkoxyl is selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, sec-butoxy and tert-butoxy.In some embodiments, this halogen is selected from chlorine, bromine and iodine.In some embodiments, R ₃Be selected from hydrogen, methyl, methoxyl group, chlorine, bromine, iodine and NO ₂In some embodiments, R ₄Be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, whole haloalkyl, SO ₂R ₁₀And NO ₂In some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, this whole haloalkyl is a perfluoroalkyl.In some embodiments, this perfluoroalkyl is a trifluoromethyl.In some embodiments, this halogen is selected from fluorine, chlorine and bromine.In some embodiments, R ₁₀Be hydrogen or the optional C that replaces _1-6Alkyl, wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, R ₄Be selected from hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, SO ₂CH ₃And NO ₂In some embodiments, R ₅Be selected from hydrogen, halogen and the optional C that replaces _1-6Alkyl, wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group, and wherein in some embodiments, this halogen is selected from fluorine, chlorine and bromine.In some embodiments, R ₅Be hydrogen or chlorine.In some embodiments, R ₆Be hydrogen or the optional C that replaces _1-6Alkyl.In some embodiments, R ₆Be hydrogen.In some embodiments, R ₇Be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, whole haloalkyl, CN, SO ₂R ₁₀And NO ₂, wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group; Wherein in some embodiments, this halogen is selected from fluorine, chlorine and bromine; Wherein in some embodiments, this whole haloalkyl is a perfluoroalkyl; Wherein in some embodiments, this perfluoroalkyl is a trifluoromethyl.In some embodiments, R ₁₀Be hydrogen or the optional C that replaces _1-6Alkyl, wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, R ₇Be selected from hydrogen, methyl, chlorine, trifluoromethyl, SO ₂CH ₃, CN and NO ₂In some embodiments, R ₈Be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group, and wherein in some embodiments, halogen is selected from fluorine, chlorine and bromine.In some embodiments, R ₈Be selected from hydrogen, chlorine and bromine.In some embodiments, R ₉Be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl and whole haloalkyl; Wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group; Wherein in some embodiments, this halogen is selected from fluorine, chlorine and bromine; Wherein in some embodiments, this whole haloalkyl is a perfluoroalkyl; Wherein in some embodiments, this perfluoroalkyl is a trifluoromethyl.In some embodiments, R ₉Be selected from hydrogen, chlorine, methyl and trifluoromethyl.In some embodiments, R ₁Be selected from hydrogen, the optional C that replaces _1-6Alkyl and the optional aryl that replaces, wherein in some embodiments, this alkyl is selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, R ₁Be hydrogen.In some embodiments, X is a nitrogen.In some embodiments, Y is NH.In some embodiments, L does not exist or is selected from-NHCH ₂-,-NH-reaches-CH ₂-.In some embodiments, A is selected from:

And n is selected from 0,1 and 2.

The chemical compound method of synthesis type V or VI is also disclosed herein

Comprise making formula VII chemical compound and the reaction of formula VIII chemical compound,

Form the fused ring compound of formula IX,

And the chemical compound reaction that makes chemical compound and the formula X of formula IX,

The chemical compound of acquisition formula V, wherein X is a halogen; R ₁Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl and optional aryl and the aryl alkyl that replaces; R ₂, R ₃, R ₄And R ₅Be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₂And R ₃, or R ₃And R ₄, or R ₄And R ₅Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part; R ₆, R ₇, R ₈And R ₉Be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHRO ₁₀, NHCONHRO ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₆And R ₇, or R ₇And R ₈, or R ₈And R ₉Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part.

At least 220 kinds of dibenzo [b, e] [1,4] diaza is also disclosed herein [a, d] cycloheptene combination of compounds storehouse, but the chemical compound of the chemical compound of the chemical compound of these chemical compound through types VII and formula VIII and formula X reaction formation,

Wherein X is a halogen; R ₁Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl and optional aryl and the aryl alkyl that replaces; R ₂, R ₃, R ₄And R ₅, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₂And R ₃, or R ₃And R ₄, or R ₄And R ₅Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part; R ₆, R ₇R ₈And R ₉, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₆And R ₇, or R ₇And R ₈, or R ₈And R ₉Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part.

At least 220 kinds of dibenzo [b, e] [1,4] diaza is also disclosed herein [a, d] cycloheptene combination of compounds storehouse, but the chemical compound of the chemical compound of the chemical compound of these chemical compound through types VII and formula VIII and formula XII reaction formation,

Wherein X is a halogen; R ₁Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl and optional aryl and the aryl alkyl that replaces; R ₂, R ₃, R ₄And R ₅, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₂And R ₃, or R ₃And R ₄, or R ₄And R ₅Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part; R ₆, R ₇, R ₈And R ₉, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀, or R ₆And R ₇, or R ₇And R ₈, or R ₈And R ₉Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part.

Also disclose a kind of pharmaceutical composition herein, it comprises that the physiology goes up acceptable carrier, diluent or excipient or its combination; And the chemical compound of formula I, II or XV.

Also disclose the method for treatment neuropsychiatric disease herein, it comprises the administration of the patient being treated the chemical compound of formula I, the II of effective dose or XV.

Also disclose the method for treatment neuropsychiatric disease herein, it comprises formula I, the II of treatment effective dose or the chemical compound of XV is contacted with the patient.

Also disclose pharmaceutical composition herein, it comprises chemical compound and the neural psychopharmaceutical of formula I, II or XV.In some embodiments, neural psychopharmaceutical is selected from selectivity 5-hydroxy tryptamine reuptake inhibithors, noradrenaline reuptake inhibitor, dopamine agonist, muscarinic receptor antagonist, antipsychotic drug, 5-hydroxy tryptamine 2A antagonist and anti-phase 5-hydroxy tryptamine 2A agonist.In some embodiments, antipsychotic drug is selected from phenothiazines, phenyl butyl piperadione class (piperadine), debenzapine class, benzisoxidil class and lithium salts.In some embodiments, phenothiazines is selected from chlorpromazine (Thorazine

), mesoridazine (Serentil

), prochlorperazine (Compazine

) and thioridazine (Mellaril

).In some embodiments, phenyl butyl piperadione class is selected from haloperidol (Haldol

) and pimozide (Orap

).In some embodiments, the debenzapine class is selected from clozapine (Clozaril

), loxapine (Loxitane

), olanzapine (Zyprexa

) and Quetiapine (Seroquel

).In some embodiments, the benzisoxidil class is selected from resperidone (Resperidal ) and Ziprasidone (Geodon ).In some embodiments, lithium salts is a lithium carbonate.In some embodiments, antipsychotic drug is selected from clozapine (Clozaril), prochlorperazine mesylate (Compazine), Etrafon (Etrafon), Geodon, haloperidol (Haldol), droperidol (Inapsine), Luo Xite (Loxitane), mellaril (Mellaril), molindone hydrochloride (Moban), tiotixene (Navane), Orap, fluphenazine hydrochloride (Permitil), hydrochloric acid fluphenazine (Prolixin), promethazine (Phenergan), paspertin metoclopramide (Reglan), Wei Sitong (Risperdal), Serentil (Serentil), Seroquel (Seroquel), trifluoperazine (Stelazine), chlorprothixene (Taractan), Thorazine, triavil (Triavil), perphenazine (Trilafon) and Zyprexa (Zyprexa).In some embodiments, selectivity 5-hydroxy tryptamine reuptake inhibithors is selected from fluoxetine, fluvoxamine, Sertraline, paroxetine, citalopram, dextrorotation citalopram, sibutramine, duloxetine and venlafaxine and officinal salt or prodrug.In some embodiments, noradrenaline reuptake inhibitor is selected from thionisoxetine and reboxetine.In some embodiments, dopamine agonist is selected from sumatriptan, Almogran, naratriptan, Frova, rizatriptan, Zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole and bromocriptine.In some embodiments, anti-phase 5-hydroxy tryptamine 2A agonist be formula XIII chemical compound or its related analogs.

In some embodiments, 5-hydroxy tryptamine 2A antagonist is chemical compound or its related analogs of formula XIV.

Also disclose the method for treatment patient neuropsychiatric disease herein, it comprises the administration of the patient being treated the pharmaceutical composition of effective dose, and said composition comprises chemical compound and the neural psychotropic drugs of formula I, II or XV.

Also disclose the method for treatment patient neuropsychiatric disease herein, it comprises formula I, II or the chemical compound of XV and the administration for the treatment of the neural psychotropic drugs of effective dose of the patient being treated effective dose.In some embodiments, dosing step comprises the administration of almost carrying out chemical compound and the neural psychotropic drugs of formula I, II or XV simultaneously.In other embodiments, dosing step comprises a kind of chemical compound that at first carries out formula I, II or XV and the administration of neural psychotropic drugs, carries out the another kind of chemical compound of formula I, II or XV and the administration of neural psychotropic drugs then.In some embodiments, neuropsychiatric disease be selected from schizophrenia and relevant spy's property sent out psychosis, anxiety neurosis, sleep disorder, inappetence, affective disorder, manic-depressive illness as severe depression and have the depression of psychotic features and tourette's syndrome, drug induced psychosis, such as the psychosis of the neurodegenerative diseases secondary of Alzheimer or Heng Yandun disease.

DESCRIPTION OF THE PREFERRED

Present disclosure relates to compound or pharmaceutically acceptable salt thereof, ester, amide or the prodrug of formula I, II or XV in first aspect:

Wherein:

A is selected from

X is nitrogen, CH or CH ₂

X ' is C or CH, wherein when X ' is C, is two keys between X and the X ', and wherein when X ' is CH, is singly-bound between X and the X ';

Each Y is selected from nitrogen, oxygen or CH respectively;

Each W is selected from nitrogen, CH, oxygen or sulfur respectively;

Each n is selected from 0,1,2,3 and 4 respectively;

M is selected from 1,2 and 3;

Each R ₁Be respectively the C that does not exist or be selected from hydrogen, halogen, amine, optional replacement respectively _1-20Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-20Alkenyl, the optional C that replaces _2-20Alkynyl, the optional C that replaces _1-20-alkoxyalkyl and optional aryl and the aryl alkyl that replaces;

L is not for existing or be selected from-NH (CH ₂) n-and-(CH ₂) n-;

A, b, c and d are selected from carbon, nitrogen, oxygen and sulfur independently of one another, or independently of one another for not existing,

Condition is three's existence at least among a, b, c or the d,

Condition is that at least one is carbon among a, b, c or the d, and

Condition is that a, b, c or the d of two vicinities not all is oxygen or not all is sulfur;

E, f, g and h are selected from carbon, nitrogen, oxygen and sulfur independently of one another, or independently of one another for not existing,

Condition is three's existence at least among e, f, g or the h,

Condition is that at least one is carbon among e, f, g or the h, and

Condition is that e, f, g or the h of two vicinities not all is oxygen or not all is sulfur;

R ₂, R ₃, R ₄And R ₅, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀,

Or R ₂And R ₃, or R ₃And R ₄, or R ₄And R ₅Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part;

R ₆, R ₇, R ₈And R ₉, be selected from hydrogen, halogen, the optional C that replaces independently of one another _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀,

Or R ₆And R ₇, or R ₇And R ₈, or R ₈And R ₉Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part;

Z is selected from NR ₁₁, oxygen, sulfur and CH ₂

R ₁₀Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional aryl that replaces, optional aryl alkyl and the whole haloalkyl that replaces;

R ₁₁Be selected from hydrogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _3-8Cycloalkyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl and the optional aryl alkyl that replaces;

R ₁₂And R ₁₃Be selected from hydrogen, halogen, the optional C that replaces respectively _1-6Alkyl, the optional C that replaces _1-6Alkoxyl, the optional C that replaces _2-6Alkenyl, the optional C that replaces _2-6Alkynyl, the optional C that replaces _1-6-alkoxyalkyl, the optional C that replaces _1-6Alkylthio group, whole haloalkyl, CN, COR ₁₀, CONHR ₁₀, NHCONHR ₁₀, SO ₂NHR ₁₀, SO ₂R ₁₀, OSO ₂R ₁₀, assorted alkyl, NO ₂, NHCOR ₁₀,

Or R ₁₂And R ₁₃Common coupled ring carbon atom forms five yuan or hexatomic ring alkyl, heterocyclic radical or heteroaryl ring, or hexa-atomic aryl rings part.

Key table empty and that solid line is represented shows the key that is selected from carbon-to-carbon singly-bound and carbon-to-carbon double bond.The bright X of empty key table among formula I, II and the XV between X and the X ' can be connected by single or two keys with X '.

In certain embodiments, the chemical compound of formula I and XV does not comprise clozapine or N-desmethylclozapine, and its structure shows below:

In certain embodiments, in the chemical compound of formula I and XV, Y is nitrogen or CH.In other embodiments, in the chemical compound of formula II, Y is nitrogen, oxygen or CH.

Term " officinal salt " refers to a kind of preparation of chemical compound, and it can not stimulate being produced significantly by the organism of administration, and can not eliminate the biological activity and the characteristic of this chemical compound.Pharmaceutical salts can be passed through The compounds of this invention and inorganic acid reaction are obtained, and this mineral acid is such as being hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc.Pharmaceutical salts also can be by obtaining The compounds of this invention and alkali reaction formation salt, the salt of this formation such as be ammonium salt, as the alkali metal salt of sodium or potassium salt, as the alkali salt of calcium or magnesium salt, as organic alkali salt of hexanamine, N-methyl D-glucamine, three (methylol) methyl amine, and have salt as arginine, lysine amino acid, or the like.

Term " ester " refers to have formula-(R) chemical part of n-COOR ', and wherein R is independently selected from alkyl, cycloalkyl, aryl, heteroaryl (being connected by ring carbon atom) and heterolipid ring (connecting by ring carbon atom) with R ', and wherein n is 0 or 1.

" amide " for have n-C (O) NHR ' of formula-(R) or-(R) chemical part of n-NHC (O) R ', wherein R is independently selected from alkyl, cycloalkyl, aryl, heteroaryl (being connected by ring carbon atom) and heterolipid ring (connecting by ring carbon atom) with R ', and wherein n is 0 or 1.Amide can be aminoacid or the peptide molecule that is connected with molecule of the present invention, thereby forms prodrug.

Can be with any amine on the The compounds of this invention, hydroxyl or carboxylic side-chain esterification or amidatioon.Known method and the concrete group that is used for realizing this target of those skilled in the art, and these methods and concrete group are easy to find in list of references, as Greene and Wuts, ProtectiveGroups in Organic Synthesis (the protectiveness group in the organic synthesis), 3rd Ed., JohnWiley ﹠amp; Sons, New York, NY, 1999, it is all introduced herein.

" prodrug " refers to change in vivo the medicine of parent drug.Prodrug is normally useful, because in some cases, they are easier to administration than parent drug.For example, they can have a bioavailability that parent drug does not have by oral.Prodrug also can have than the better dissolubility of parent drug in pharmaceutical composition.The limiting examples of prodrug is a chemical compound of the present invention, it is used to promote the transmission of cross-cell membrane as ester (" prodrug "), this moment, water solublity was unfavorable for flowability, but metabolism is hydrolyzed to active entity carboxylic acid in case enter in the cell just, and this moment, water solublity was favourable.Another example of prodrug can be the small peptide (polyamino acid) with acidic-group Cheng Jian, and wherein peptide is demonstrated active part by metabolism.

Term " aromatic radical " refers to aromatic group, and it has at least one ring, and this ring has the conjugated pi electron system, and this group both comprised isocyclic aryl (for example, phenyl), also comprises heterocyclic aryl (for example, pyridine).This term comprises multi-ring (promptly sharing the right ring of adjacent carbon atom) group of monocycle or condensed ring.Term " carbocyclic ring " refers to a kind of chemical compound, and it contains one or more covalently closed circle structure, and the atom of formation ring skeleton is carbon atom.Therefore, carbocyclic ring and heterocycle distinguished in this term, and wherein the heterocycle skeleton comprises the atom that at least one is different from carbon atom.Term " heteroaryl " refers to contain at least one heterocyclic aromatic group.

The term of Shi Yonging " alkyl " refers to aliphatic group herein.Moieties can be " saturated alkyl ", refers to not comprise any alkene or alkynyl moiety.Moieties also can be " unsaturated alkyl " part, refers to comprise at least one alkene or alkynyl moiety." alkene " partly refers to the group is made up of at least two carbon atoms and at least one carbon-to-carbon double bond, and " alkynes " partly refers to the group be made up of at least two carbon atoms and at least one carbon-to-carbon triple bond.No matter moieties is saturated or unsaturated, all can be side chain, straight chain or ring.

Alkyl can have 1-20 carbon atom (no matter when occur herein, as the digital scope of " 1-20 ", refer to give each integer in the scope; For example " 1-20 carbon atom " refer to can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until the alkyl that comprises that 20 carbon atoms are formed,, designation number scope not at this moment although this definition also comprises term " alkyl ").Alkyl also can be the medium sized alkyl with 1-10 carbon atom.Alkyl also can be the low alkyl group with 1-5 carbon atom.The alkyl of The compounds of this invention can be appointed as " C ₁-C ₄Alkyl " or similarly specify.Only by way of example, " C ₁-C ₄Alkyl " refer in alkyl chain, have 1-4 carbon atom, promptly alkyl chain is selected from methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.

Alkyl can be substituted or be unsubstituted.When being substituted; substituent group is one or more group; it individually; be independently selected from cycloalkyl; aryl; heteroaryl; the heterolipid ring; hydroxyl; alkoxyl; aryloxy group; sulfydryl; alkylthio group; arylthio; cyano group; halogen; carbonyl; thiocarbonyl; the O-carbamyl; the N-carbamyl; the O-thiocarbamoyl; the N-thiocarbamoyl; the C-amide groups; the N-amide groups; the S-sulfoamido; the N-sulfoamido; the C-carboxyl; the O-carboxyl; the isocyanide acyl group; the sulfo-cyanato; different sulfo-cyanato; nitro; silicyl; three halo mesyl and amino comprise the derivant of single and disubstituted amino and protection thereof.Typical alkyl comprises, but is in no way limited to methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, vinyl, acrylic, cyclobutenyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc.When substituent group is described as " the optional replacement " time, substituent group can be replaced by an above-mentioned substituent group.

The substituent group " R " of appearance, no designation number word refers to be selected from the substituent group of alkyl, cycloalkyl, aryl, heteroaryl (by ring carbon atom Cheng Jian) and heterolipid ring (by ring carbon atom Cheng Jian) separately.

" O-carboxyl " refers to RC, and (=O) O-group, wherein R is for defined here.

" C-carboxyl " refers to-C that (=O) OR group, wherein R is for defined here.

" acetyl group " refer to-C (=O) CH ₃Group.

" three halo mesyls " refers to X ₃CS (=O) ₂-group, wherein X is a halogen.

" cyano group " refers to-the CN group.

" cyanato " refers to-the NCO group.

" sulfo-cyanato " refers to-the CNS group.

" different sulfo-cyanato " refers to-the NCS group.

" sulfinyl " refer to-S (=O)-and the R group, R is for defined here.

" S-sulfoamido " refer to-S (=O) ₂The NR group, R is for defined here.

" N-sulfoamido " refer to RS (=O) ₂The NH-group, R is for defined here.

" three halo methylsulfonyl amidos " refers to X ₃CS (=O) ₂The NR-group, X and R are for defined here.

" O-carbamyl " refer to-OC (=O)-the NR group, R is for defined here.

" N-carbamyl " refers to ROC, and (=O) NH-group, R is for defined here.

" O-thiocarbamoyl " refer to-OC (=S)-the NR group, R is for defined here.

" N-thiocarbamoyl " refers to ROC, and (=S) NH-group, R is for defined here.

" C-amide groups " refer to-C (=O)-NR ₂Group, R is for defined here.

" N-amide groups " refers to RC, and (=O) NH-group, R is for defined here.

Term " whole haloalkyl " refers to the alkyl that all hydrogen atoms are replaced by halogen atom.

Term " acyl group alkyl " refers to RC, and (=O) R '-group, R is for defined here, and R ' is the double-basis alkylidene.The limiting examples of acyl group alkyl can comprise CH ₃C (=O) CH ₂-, CH ₃C (=O) CH ₂CH ₂-, CH ₃CH ₂C (=O) CH ₂CH ₂-, CH ₃C (=O) CH ₂CH ₂CH ₂-etc.

Except as otherwise noted; when substituent group is thought " the optional replacement; " the time; refer to that substituent group can be the group that is replaced by one or more group; this one or more group individually; be independently selected from cycloalkyl; aryl; heteroaryl; the heterolipid ring; hydroxyl; alkoxyl; aryloxy group; sulfydryl; alkylthio group; arylthio; cyano group; halogen; carbonyl; thiocarbonyl; the O-carbamyl; the N-carbamyl; the O-thiocarbamoyl; the N-thiocarbamoyl; the C-amide groups; the N-amide groups; the S-sulfoamido; the N-sulfoamido; the C-carboxyl; the O-carboxyl; the isocyanide acyl group; the sulfo-cyanato; different sulfo-cyanato; nitro; silicyl; three halo mesyl and amino comprise the derivant of single and disubstituted amino and protection thereof.The protecting group that can form above-mentioned substituent protectiveness derivant is known to those skilled in the art, and can be at document, as finding among above-mentioned Greene and the Wuts.

Among the present invention, term " cycloalkyl " refers to be intended to comprise and only comprises three, four, five, six, seven and eight or more polynary ring of carbon atom.Yet cycloalkyl can be chosen wantonly and comprise one or more unsaturated bond, and they are located in the mode that does not produce fragrant pi-electron system.Some examples of " cycloalkyl " are carbocyclic ring cyclopropane, Tetramethylene., Pentamethylene., cyclopentenes, cyclopentadiene, cyclohexane extraction, cyclohexene, 1,1, cycloheptane or cycloheptene.

Term " heterocyclic radical " refers to three, four, five, six, seven and eight or more polynary ring, and wherein carbon atom constitutes described ring with 1-3 hetero atom.Yet heterocyclic radical can be chosen wantonly and comprise one or more unsaturated bond, and they are located in the mode that does not produce fragrant pi-electron system.Hetero atom is independently selected from oxygen, sulfur and nitrogen.

Heterocyclic radical can further comprise one or more carbonyl or thiocarbonyl functionality so that make this definition comprise oxo system and sulfo-system, as lactams, lactone, cyclic imides, epithio for acid imide, cyclic carbramates etc.

Heterocyclic ring also can be chosen wantonly with aromatic ring and condense, thereby this definition comprises twin nuclei.Usually these condensed heterocycle bases have a key with the optional phenyl ring that replaces.Benzo-fused heterocyclic radical example includes, but are not limited to Benzimidazolinone, tetrahydroquinoline, methylene-dioxy benzene ring structure.

Some examples of " heterocyclic radical " comprise, but be not limited to tetrahydric thiapyran, the 4H-pyrans, Pentamethylene oxide., piperidines, 1, the 3-bioxin, 1, the 3-diox, 1, the 4-bioxin, 1, the 4-diox, piperazine, 1, the 3-thioxane, 1, the 4-oxathiin, 1, the 4-thioxane, tetrahydrochysene-1, the 4-thiazine, 2H-1, the 2-oxazine, maleimide, butanimide, barbiturates, thiobarbituricacid, the dioxo piperazine, hydantoin, dihydrouracil, morpholine trioxane, six hydrogen-1,3, the 5-triazine, Tetramethylene sulfide, oxolane, pyrrolin, pyrrolidine, ketopyrrolidine, pyrrolidine-diones, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1, the 3-dioxole, 1, the 3-dioxolane, 1, the 3-dithiole, 1,3-two sulfur pentane isoxazoline isoxazole alkyl oxazoline oxazolidine oxazolidones, thiazoline, Thiazolidine and 1, the 3-oxathiolane.Linking to each other with heterocycle can be on heterocyclic hetero atom position or via heterocyclic carbon atom, or for benzo-fused derivant, via the carbon atom of benzene type ring.

Among the present invention, term " aryl " refers to carbocyclic ring aromatic rings system or member ring systems.In addition, term " aryl " comprises the condensed ring system, wherein at least two aromatic rings or at least one aryl and at least one C _3-8-cycloalkyl has at least one chemical bond.Some examples of " aryl " ring comprise optional phenyl, naphthyl, phenanthryl, anthryl, tetrahydro naphthyl, fluorenyl, indenyl and the indanyl that replaces.Term " aryl " relates to aromatic radical, comprises, for example; benzene type group; become ring carbon atom to link to each other by one, and optionally have one or more substituent group, this substituent group is selected from heterocyclic radical, heteroaryl, halogen, hydroxyl, amino, cyano group, nitro, alkylamidoalkyl, acyl group, C _1-6Alkoxyl, C _1-6Alkyl, C _1-6Hydroxy alkyl, C _1-6Aminoalkyl, C _1-6Alkyl amino, alkyl alkylthio group, alkyl sulphinyl, alkyl sulphonyl, sulfamoyl or trifluoromethyl.Aryl can be substituted in a para-position and/or a position.In other embodiments, aryl can be substituted at the ortho position.The representative example of aryl includes, but are not limited to phenyl, the 3-halogenophenyl, the 4-halogenophenyl, the 3-hydroxy phenyl, the 4-hydroxy phenyl, the 3-aminophenyl, the 4-aminophenyl, the 3-aminomethyl phenyl, the 4-aminomethyl phenyl, the 3-methoxyphenyl, the 4-methoxyphenyl, the 4-Trifluoromethoxyphen-l, the 3-cyano-phenyl, the 4-cyano-phenyl, 3,5-dimethylphenyl, naphthyl, the hydroxyl naphthyl, the hydroxymethyl phenyl, trifluoromethyl, alkoxyl phenyl, 4-morpholine-4-base phenyl, 4-pyrrolidine-1-base phenyl, 4-pyrazolyl phenyl, 4-triazolyl phenyl and 4-(2-oxo-pyrrolidine-1-yl) phenyl.

Among the present invention, term " heteroaryl " refers to the heteroaromatic group, and wherein one or more carbon atom in the aromatic ring is replaced by the hetero atom that one or more is selected from nitrogen, sulfur, phosphorus and oxygen.

In addition, among the present invention, term " heteroaryl " comprises the condensed ring system, wherein at least one aromatic ring and at least one hetero-aromatic ring, at least two hetero-aromatic rings, at least one hetero-aromatic ring and at least one heterocyclic ring, or at least one hetero-aromatic ring and total at least one chemical bond of at least one cycloalkyl ring.

Term " heteroaryl " is interpreted as the C that relates to armaticity _3-8Cyclic group, these groups further comprise an oxygen or sulphur atom or four nitrogen-atoms of as many as, or the combination of oxygen or sulphur atom and two nitrogen-atoms of as many as and replacement and the benzo-fused and condensed derivant of pyrido, for example, become ring carbon atom to connect by one.Heteroaryl can have one or more substituent group, and this substituent group is selected from halogen, hydroxyl, amino, cyano group, nitro, alkylamidoalkyl, acyl group, C _1-6-alkoxyl, C _1-6-alkyl, C _1-6-hydroxy alkyl, C _1-6-aminoalkyl, C _1-6-alkyl amino, alkyl alkylthio group, alkyl sulphinyl, alkyl sulphonyl, sulfamoyl or trifluoromethyl.In some embodiments, heteroaryl can be and has 0,1 or 2 substituent five and hexa-atomic aromatic heterocycle system, and these substituent groups can be same to each other or different to each other, and are selected from above-mentioned substituent group.The representative example of heteroaryl comprises, but be not limited to furan, benzofuran, thiophene, benzothiophene, the pyrroles, pyridine, indole oxazole benzoxazole isoxazole Ben isoxazole, thiazole, benzothiazole, isothiazole, imidazoles, benzimidazole, pyrazoles, indazole, tetrazolium, quinoline (quionoline), isoquinolin, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2, the 3-oxadiazole, 1,2, the 3-thiadiazoles, 1,2, the 4-thiadiazoles, triazole, benzotriazole, pteridine Fen oxazole oxadiazole, benzopyrazoles, quinolizine, cinnolines, phthalazines, quinazoline is with the not replacement of 1,4-Benzodiazine and single or disubstituted derivant.In some embodiments, substituent group is halogen, hydroxyl, cyano group, O-C _1-6-alkyl, C _1-6-alkyl, hydroxyl-C _1-6-alkyl and amino-C _1-6-alkyl.

In certain embodiments, the chemical compound that is selected from following structure disclosed herein:

R wherein ₁-R ₉, W, Y and Z as described here.

In some other embodiment, a kind of chemical compound that is selected from down array structure disclosed herein:

R wherein ₁, W, Y and Z as described here.

In certain embodiments, chemical compound disclosed herein with structure of representing among formula III or the formula IV.

R wherein ₁-R ₅, W, X, X ', Y and Z as described here.

In certain embodiments, a, b, c and d all exist, and the ring of Xing Chenging is a hexatomic ring thus.In another embodiment, e, f, g and h all exist, and the ring of Xing Chenging is a hexatomic ring thus.In some embodiments, a, b, c and d are carbon, and the ring of Xing Chenging is the optional phenyl ring that replaces thus.In another embodiment, e, f, g and h are carbon, and it forms the optional phenyl ring that replaces similarly.

In certain embodiments, R ₂Can be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl and the optional C that replaces _1-6Alkoxyl.In some embodiments, this alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In other embodiments, this alkoxyl can be selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, sec-butoxy and tert-butoxy.In another embodiment, this halogen can be selected from fluorine, chlorine and bromine.In certain embodiments, R ₂Can be selected from hydrogen, methyl, methoxyl group and chlorine.

In some embodiments, R ₃Can be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, the optional C that replaces _1-6Alkoxyl and NO ₂This alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group, and this alkoxyl can be selected from methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, sec-butoxy and tert-butoxy.In other embodiments, this halogen can be selected from chlorine, bromine and iodine.In other embodiments, R ₃Can be selected from hydrogen, methyl, methoxyl group, chlorine, bromine, iodine and NO ₂

In certain embodiments, R ₄Can be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, whole haloalkyl, SO ₂R ₁₀And NO ₂In some embodiments, this alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In other embodiments, this whole haloalkyl can be perfluoroalkyl, and it can be trifluoromethyl in some embodiments.In other embodiments, this halogen can be selected from fluorine, chlorine and bromine.Work as R ₄Be SO ₂R ₁₀The time, R ₁₀Can be hydrogen or the optional C that replaces _1-6Alkyl, this alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In certain embodiments, R ₄Can be selected from hydrogen, methyl, fluorine, chlorine, bromine, trifluoromethyl, SO ₂CH ₃And NO ₂

In some embodiments, R ₅Can be selected from hydrogen, halogen and the optional C that replaces _1-6Alkyl.This alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group, and halogen can be selected from fluorine, chlorine and bromine.In certain embodiments, R ₅Can be hydrogen or chlorine.

In certain embodiments, R ₆Can be hydrogen or the optional C that replaces _1-6Alkyl.This alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In some embodiments, R ₆Can be hydrogen.

In certain embodiments, R ₇Can be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, whole haloalkyl, CN, SO ₂R ₁₀And NO ₂This alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group, and this halogen can be selected from fluorine, chlorine and bromine.In some embodiments, this whole haloalkyl is a perfluoroalkyl, and it can be trifluoromethyl in some embodiments.At R ₇Can be SO ₂R ₁₀Embodiment in, R ₁₀Can be hydrogen or the optional C that replaces _1-6Alkyl, this alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.In certain embodiments, R ₇Can be selected from hydrogen, methyl, chlorine, trifluoromethyl, SO ₂CH ₃, CN and NO ₂

In some embodiments, R ₈Can be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl, this alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.This halogen can be selected from fluorine, chlorine and bromine.In certain embodiments, R ₈Can be selected from hydrogen, chlorine and bromine.

The embodiment of present disclosure comprises those embodiments, wherein R ₉Can be selected from hydrogen, halogen, the optional C that replaces _1-6Alkyl and whole haloalkyl.This alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group.This halogen can be selected from fluorine, chlorine and bromine.This whole haloalkyl can be perfluoroalkyl, and it can be trifluoromethyl in some embodiments.In some embodiments, R ₉Can be selected from hydrogen, chlorine, methyl and trifluoromethyl.

In some embodiments, R ₁Can be selected from hydrogen, the optional C that replaces _1-6Alkyl and the optional aryl that replaces.This alkyl can be selected from methyl, ethyl, propyl group, isopropyl, butyl, sec-butyl and the tert-butyl group, and this aryl can be phenyl or naphthyl.In other embodiments, R ₁Can be heteroaryl.In certain embodiments, R ₁Can be hydrogen.In certain embodiments, R ₁Do not exist.

In some embodiments, X can be nitrogen.In other embodiments, Y can be NH, and W can be nitrogen or CH.

In some embodiments of the chemical compound of formula I or formula XV, L does not exist or is selected from-NHCH ₂-,-NH-and-CH ₂-.In some embodiments of chemical compound of formula I or formula XV, A is selected from:

Wherein n is selected from 0,1 and 2.

Some embodiments of formula I, formula II or formula XV chemical compound comprise:

2,7-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

2-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

2,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-bromo-2-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

2-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza ,

6-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza

,

7-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-bromo-1-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-bromo-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

4,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-2-fluoro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

3,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

2-bromo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

3,7-two chloro-11-(piperazine-1-yl)-5H dibenzo [b, e] [1,4] diaza

,

8-bromo-3-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

3-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

3-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza

,

7-chloro-2-methyl isophthalic acid 1 (piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

2-methyl isophthalic acid 1-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza ,

8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

1,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-bromo-5-methyl isophthalic acid 1-(piperazine-1-yl)-5H dibenzo [b, e] [1,4] diaza

,

7,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza

,

11-(piperazine-1-yl)-5H dibenzo [b, e] [1,4] diaza

,

8-fluoro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza -8-nitrile,

8-bromo-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

3-fluoro-6-piperazine-1-base-11H-dibenzo [b, e] azepine

,

2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] oxygen azepine ,

8-chloro-2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

11-(piperazine-1-yl)-dibenzo [b, f] [1,4] sulfur azepine

,

11-(piperazine-1-yl)-2,3-dihydro-1,4-Ben Bing bioxin is [6,7-b] [1,4] benzothiazepine also

,

8-chloro-11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza

,

N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-and N, N-dimethyl-ethane-1, the 2-diamidogen,

N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N, N-diethyl-ethane-1, the 2-diamidogen,

8-chloro-11-(4-methyl-[1,4] diazepam-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

8-chloro-2-methoxyl group-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

N '-(5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N, N-dimethyl-ethane-1, the 2-diamidogen,

11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza

,

N '-(8-fluoro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-and N, N-dimethyl-ethane-1, the 2-diamidogen,

8-fluoro-11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza

,

N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-and N-methyl-ethane-1, the 2-diamidogen,

8-chloro-11-(anti--2,5-dimethyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-11-(3,5-dimethyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-11-(3-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-11-(3-phenyl-Piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-5-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-5-benzyl-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-iodo-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

2-iodo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-phenyl-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza ,

8-chloro-11-(piperidines-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-11-(morpholine-4-yl)-5H-dibenzo [b, e] [1,4] diaza ,

5-pi-allyl-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

,

6-chloro-11-(piperazine-1-yl)-5H dibenzo [b, e] [1,4] diaza

,

8-chloro-5-piperazine-1-base-11H-benzo [b] pyrido [2,3-e] [1,4] diaza

,

2-chloro-10-piperazine-1-base-5H-dibenzo [b, f] azepine ,

8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] sulfur azepine

,

8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

8-chloro-11-(4-methyl-piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

3-chloro-6-piperazine-1-base-11H-dibenzo [b, e] azepine

,

8-bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

7-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-chloro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-bromo-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

7-chloro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

8-bromo-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

2-bromo-8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

2,8-two bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

2-bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

2-bromo-7-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine

,

4-methyl isophthalic acid 1-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine ,

8-fluoro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-fluoro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-fluoro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

2-bromo-8-fluoro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

3-methoxyl group-8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

4,8-dimethyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

3-methoxyl group-11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine

,

2-bromo-11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine ,

6-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

2-bromo-8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine ,

7-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-phenyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

,

8-chloro-11-(piperidin-4-yl)-5H-dibenzo [b, e] [1,4] diaza

,

5-benzyl-8-chloro-11-(piperidin-4-yl)-5H-dibenzo [b, e] [1,4] diaza

,

8-bromo-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone,

5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone,

8-fluoro-5,10-dihydro-dibenzo [b, e] [1,4] diaza -11-ketone,

8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas ,

8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza

,

(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-(S)-1-pyrrolidine-2-base-methyl-amine,

1-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-piperidin-4-yl-amine,

1-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-pyrrolidine-3-base-amine,

(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-(R)-1-pyrrolidine-2-base-methyl-amine,

(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-pyrrolidine-3-base-amine,

8-chloro-11-(2,5-diaza-bicyclo-[2.2.1] heptan-2-yl)-5H-dibenzo [b, e] [1,4] diaza

,

Ethyl acetate-3-base-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl) amine,

7-bromo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza ,

7-bromo-2-methyl-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza

,

7-bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza ,

7-bromo-10-(piperazine-1-yl)-1,2,3,3a, 4,10a-six hydrogen-benzo [b] ring penta [e] [1,4] diaza ,

8-chloro-11-(4-luorobenzyl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-11-(4-fluorophenyl)-5H-dibenzo [b, e] [1,4] diaza ,

8-chloro-11-(4-nonyl phenyl)-5H-dibenzo [b, e] [1,4] diaza

,

8-chloro-11-(pyridine 4-yl)-5H-dibenzo [b, e] [1,4] diaza , and

8-chloro-11-(1H-pyrazoles 4-yl)-5H dibenzo [b, e] [1,4] diaza

On the other hand, present disclosure relates to the method for synthesis type V or formula VI chemical compound,

Comprise

Make the reaction of formula VII chemical compound and formula VIII chemical compound,

Form the fused ring compound of formula IX,

And formula IX chemical compound and formula X chemical compound are reacted,

Obtain the chemical compound of formula V or VI;

Wherein X is a halogen; And R ₁-R ₉Aforesaid.In some embodiments, be clozapine according to the synthetic formula V chemical compound of disclosed method, and in other embodiments, chemical compound is the N-desmethylclozapine.In some other embodiment, do not comprise clozapine or N-desmethylclozapine according to the synthetic formula V chemical compound of disclosed method.

Consistent with this aspect, scheme 1 and 2 is described the synthetic of some chemical compounds disclosed herein.First series of steps that produces the intermediate lactams is especially as Liao et al.J.Med.Chem.1997, and 40,4146-4153 is described.Final step such as Liao et al.J.Med.Chem.1999,42,2235-2244 is described.Therefore, these two pieces of lists of references this all introducing for your guidance, are comprised any accompanying drawing.

Scheme 1

Scheme 2

In certain embodiments of the invention, construction unit A and B are selected from but are not limited to

A

B

On the other hand, present disclosure relates at least 10 or at least 30 or at least 50 or at least 100 or at least 200 or at least 220 kinds of dibenzo [b, e] [1,4] diaza

Combination of compounds storehouse, but these chemical compound through type VII chemical compounds and formula VIII chemical compound and formula XI chemical compound reaction formation,

Wherein X is a halogen; W is nitrogen, CH, oxygen, or sulfur; N is 1,2,3 or 4, and R ₁-R ₉Aforesaid.In some embodiments, combinatorial libraries comprises clozapine and/or N-desmethylclozapine.In some other embodiment, combinatorial libraries does not comprise clozapine or N-desmethylclozapine.

On the other hand, present disclosure relates at least 10 or at least 30 or at least 50 or at least 100 or at least 200 or at least 220 kinds of dibenzo [b, e] [1,4] diaza

Combination of compounds storehouse, but these chemical compound through type VII chemical compounds and formula VIII and formula XII reaction formation,

Wherein X is a halogen; W is nitrogen, CH, oxygen or sulfur; N is 1,2,3 or 4; And R ₁-R ₉Aforesaid.

" combinatorial libraries " of Shi Yonging refers to react all chemical compounds that form by the chemical compound in each chemical compound in the one dimension and other each dimension in the multidimensional chemical array herein.In the present disclosure, this array is a cubical array, all formula VII chemical compounds of one-dimensional representation, and second all formula VIII chemical compounds of dimension expression, and the third dimension is represented all formula X chemical compounds.Each chemical compound of formula VII can react with each chemical compound of formula VIII and each chemical compound of formula X, to form the chemical compound that is substituted of formula V or VI.All chemical compounds in formula V of Xing Chenging or the VI scope are in the present disclosure scope in this way.The less combinatorial libraries that the some or all of chemical compound reactions of the some or all of chemical compounds of through type VII and the some or all of chemical compounds of formula VIII and formula X form also is in the scope of present disclosure.

In some embodiments, disclosed herein and formula I, II or the XV chemical compound described, the activity of scalable M-ChR.

Term " adjusting " refers to that chemical compound disclosed herein changes the ability of M-ChR function.Regulator can activate the activity of M-ChR, depends on the activity that the compound concentration that is exposed to M-ChR could activate or suppress M-ChR, maybe can suppress the activity of M-ChR.Term " adjusting " also refers to by increasing or reduce the function that the probability that forms complex between M-ChR and natural binding partners changes M-ChR.Regulator can be increased in the probability that forms this complex between M-ChR and the natural binding partners, depending on the compound concentration that is exposed to M-ChR can increase or reduce the probability that forms complex between M-ChR and natural binding partners, maybe can reduce the probability that forms complex between M-ChR and natural binding partners.In some embodiments, the adjusting of M-ChR can be passed through U.S. Patent No. 5,707,798 described Receptor Selection and AmplificationTechnology (acceptor selection and amplification technique) (R-SAT) estimate, its disclosure is all introduced, for your guidance herein.

Term " activation " refers to increase the cell function of M-ChR." inhibition " refers to reduce the cell function of M-ChR to term.The function of M-ChR can be interaction or the catalytic activity with natural binding partners.

The term of Shi Yonging " contact " refers in the following manner chemical compound disclosed herein be taken to the target M-ChR herein, and promptly chemical compound can directly or indirectly influence the activity of M-ChR, refers to that directly self and M-ChR interact; Refer to indirectly and the active another kind of interaction of molecules that relies on of M-ChR.Should " contact " can in test tube, culture dish etc., finish.In test tube, contact can only comprise target compound and M-ChR, maybe can comprise intact cell.Also cell can be kept or grown in the Tissue Culture Dish, and in this environment, contact with chemical compound.Among the present invention, the ability of the M-ChR of particular compound influence and disease association, the i.e. IC of chemical compound ₅₀Can before testing in more complicated live body body, this chemical compound of use determine.For external cell, exist multiple method well known to those skilled in the art that this chemical compound is contacted with M-ChR, these methods include, but are not limited to direct cell microinjection and many membrane carrier technology of striding.Term " contact " also can refer to chemical compound disclosed herein is contacted with intravital target M-ChR.Therefore,, and chemical compound is taken to the intravital M-ChR of biology, then should contact in the scope of present disclosure if chemical compound disclosed herein or its prodrug are delivered medicine to organism.

In some embodiments, formula I, II or XV chemical compound can be the agonist of described receptor, and in other embodiments, chemical compound can be the antagonist of described receptor.In other embodiments, chemical compound can be the partial agonist of described receptor.In some cases, can be the part activator of receptor as the chemical compound of partial agonist, and in other cases, can be the part inhibitor of receptor.In other cases, chemical compound can be the tissue specificity regulator, and in other cases, chemical compound can be the gene specific regulator.

Some chemical compound disclosed herein can be used as the stereoisomer that comprises optical isomer and exists.The scope of present disclosure comprise all stereoisomers and these isomers two kinds of racemic mixture and can be according to the isolating single enantiomer of the method that those of ordinary skills know.

On the other hand, the disclosure relates to pharmaceutical composition, and it comprises that the physiology goes up acceptable carrier, diluent or excipient or its combination; And formula I, II or XV chemical compound.

Term " pharmaceutical composition " refers to chemical compound of the present invention and mixture such as other chemical constituent of diluent or carrier.Pharmaceutical composition is convenient to the administration of chemical compound to organism.Have multiple technology of giving drug compound in this area, that these technology include, but are not limited to is oral, injection, spraying, parenteral and topical.Pharmaceutical composition also can obtain by the inorganic or organic acid reaction with chemical compound and all example hydrochloric acids, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc.

Term " carrier " definition helps chemical compound is introduced the chemical compound of cell or tissue.For example, dimethyl sulfoxine (DMSO) is for carrier commonly used, because it helps many organic compound to be absorbed into the cell or tissue of organism.

Term " diluent " definition is diluted in the chemical compound in the water, and it is with the solubilized target chemical compound and stablize the biologic activity form of this chemical compound.Be dissolved in salt in the buffer solution in the art as the diluent utilization.A kind of buffer solution commonly used is phosphate buffered solution, because it has simulated the salt condition of human blood.Because buffer salt can be controlled the pH of solution when low concentration, so buffered diluent seldom changes the biological activity of chemical compound.

The carrier or the diluent of chemical compound biological activity and characteristic do not eliminated in term " physiology is last acceptable " definition.

Pharmaceutical composition described herein itself can be to patient's administration, or its with the pharmaceutical compositions of other active component (as in therapeutic alliance) or suitable carriers or mixed with excipients to patient's administration.The preparation of the application's chemical compound and the technology of administration be found in " Remington ' s Pharmaceutical Sciences (Remington pharmaceutical science), " MackPublishing Co., Easton, PA, 18 ^ThEdition, 1990.

For example, suitable route of administration can comprise oral, rectum, stride mucosa or enteral administration; Parenteral is sent, comprise in intramuscular, subcutaneous, intravenous, intramedullary injection and the sheath, directly in the ventricle, intraperitoneal, intranasal or intraocular injection.

Perhaps, can the part rather than the mode of whole body carry out compound administration, for example, by chemical compound being injected directly into kidney or heart area, usually with the form of depot (depot) or slow releasing preparation.In addition, can the directed drug delivery system carry out drug administration, for example, with the liposome form of tissue specificity antibody sandwich.Liposome will be directed to organ and be absorbed by this organ selectivity.

Pharmaceutical composition of the present invention can this be produced as known mode, for example, and by traditional mixing, dissolving, granulation, one-tenth ingot (dragee-making), grinding, emulsifying, encapsulation, filling (entrapping) or tabletting method.

Therefore, pharmaceutical composition used according to the invention can be made in a conventional manner, and this mode uses one or more physiology to go up acceptable carrier, and these carriers include pharmaceutically acceptable excipient and the adjuvant that helps reactive compound is processed into preparation.Appropriate formulation depends on the route of administration of selection.Can use this area any suitable know technology, carrier and excipient, described in above-mentioned Remington ' s pharmaceutical science.

For injection, medicine of the present invention can be formulated in the aqueous solution, preferably be formulated in the physiology compatible buffers or normal saline buffer solution such as Hanks ' s liquid, Ringer ' s liquid.For striding mucosa delivery, in preparation, use the penetrating agent that is suitable for treating penetration barriers.These penetrating agent are well known in the art.

For oral administration, can be by reactive compound and pharmaceutically suitable carrier well known in the art combination be easily prepared this chemical compound.These carriers can be formulated as The compounds of this invention tablet, pill, lozenge, capsule, liquid, gel, syrup, slurry, suspension etc., and it is oral to be used for patient to be treated.The pharmaceutical formulations that orally uses can be by mixing acquisitions with one or more solid excipient with drug regimen of the present invention, and the optional mixture that adds when needed after the proper supplementary material generation grinds, and handles particulate mixture and examine with acquisition tablet or lozenge.Particularly, suitable excipient is a filler, such as sugar, comprises lactose, sucrose, mannitol or sorbitol; Cellulose preparation, for example corn starch, wheaten starch, rice starch, potato starch, gelatin, Tragacanth, methylcellulose, hydroxypropyl methyl-cellulose, sodium carboxy methyl cellulose and/or polyvinylpyrrolidone (PVP).If need, can add disintegrating agent, as crospolyvinylpyrrolidone, agar or alginic acid or its salt, as sodium alginate.

For lozenge nuclear provides suitable coating.For this purpose, available spissated sugar juice, it can be chosen wantonly and comprise arabic gum, Talcum, polyvinylpyrrolidone, carbopol gel (caropol gel), Polyethylene Glycol and/or titanium dioxide, lacquer solution and appropriate organic solvent or solvent mixture.Dyestuff or pigment can be added in tablet or the lozenge coating to discern or to represent the combination of different activities chemical compound dosage.

The pharmaceutical formulations that can orally use comprises the plug-in type capsule made by gelatin and by gelatin and the sealing soft capsule made such as the plasticizer of glycerol or sorbitol.The plug-in type capsule can comprise active component, this composition with such as the filler of lactose, mix such as the binding agent of starch and/or such as the lubricant and the optional stabilizer of Talcum or magnesium stearate.In soft capsule, can or be suspended in suitable fluid with the reactive compound dissolving, in fatty oil, liquid paraffin or liquid macrogol.In addition, can add stabilizing agent.All preparations of oral administration should be the dosage that is suitable for oral administration.

For oral administration, compositions can adopt the tablet or the lozenge form of preparation in a conventional manner.

For inhalation, chemical compound used according to the invention adopts suitable propellant to send easily with spray form from pressurized package or aerosol apparatus, and this propellant for example is dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas.When using pressurized aerosol, dosage unit can be determined by the valve of sending metered amount.The capsule of for example gelatin that uses in inhaler or the insufflator and cartridge case can be mixed with inclusion compound and such as the mixture of powders of the suitable powder substrate of lactose or starch.

Chemical compound can be mixed with the parenteral that is used for by injection, as annotating or continuous infusion by group.The preparation that is used to inject can occur by unit dosage forms, as in ampoule bottle that has added antiseptic or multi-dose container.Compositions can adopt these forms, as the suspension in oiliness or the aqueous medium, solution or Emulsion, and can comprise into preparation reagent (formulatory agent), as suspending agent, stabilizing agent and/or dispersant.

The pharmaceutical preparation that is used for parenteral comprises the active compounds in water-soluble form aqueous solution.In addition, the suspension of reactive compound can be made into suitable oily injection suspensions.Suitable lipophilic solvent or medium comprise fatty oil, as Oleum Sesami, or such as the Acrawax of ethyl oleate or triglyceride, or liposome.Water injection suspension liquid can comprise the material that increases suspension viscosity, as sodium carboxy methyl cellulose, sorbitol or glucosan.Randomly, suspension also can comprise suitable stabilizers or increase the reagent of compound dissolution, to allow the preparation of highly concentrated solution.

Perhaps, active component can be powder type before using, and is used for and suitable media assembly such as the no heat source water of sterilization.

Chemical compound also can be mixed with the rectum compositions, as suppository or enema,retention, for example, comprises traditional suppository base, as cupu oil or other glyceride.

Except that previous formulations, chemical compound also can be mixed with depot formulation.These durative action preparations can be by implantation (for example, subcutaneous or intramuscular) or by the intramuscular injection administration.Therefore, for example, chemical compound can be prepared together with suitable polymerization or hydrophobic material (for example, as the Emulsion that can accept in the oil) or ion exchange resin, or makes the slightly soluble derivant, for example as slightly soluble salt.

The pharmaceutical carrier that is used for hydrophobic compound of the present invention is a cosolvent system, and it comprises benzyl alcohol, non-polar surfactant, can mix water-soluble organic polymer and water.The common cosolvent system that uses is the VPD cosolvent system, and this system is a kind of solution, contains 3%w/v benzyl alcohol, 8%w/v non-polar surfactant polysorbate80 ^TMAnd the 65%w/v Liquid Macrogol, in dehydrated alcohol, supply volume.Naturally, do not destroying under its dissolubility and the toxic characteristic situation, sizable variation can take place in the ratio of cosolvent system.In addition, can change the concordance of cosolvent component: for example, can other hypotoxicity non-polar surfactant replace polysorbate80 ^TMCan change the segment size of Polyethylene Glycol; Other biocompatible polymer can replace Polyethylene Glycol, as polyvinylpyrrolidone; And other sugar or polysaccharide can replace dextrose.

Perhaps, can use other delivery system of dewatering medicament chemical compound.Liposome and Emulsion are to send the medium of dewatering medicament or the well-known example of carrier.Also can use some organic solvent, as dimethyl sulfoxine, although be cost with bigger toxicity usually.In addition, can use lasting delivery systme to send chemical compound, as comprise the semi permeability substrate of the solid hydrophobic polymer of medicine.Set up the material of various lasting releases, and be well known to those skilled in the art.Depend on its chemical property, the capsule that continues to discharge can discharge several weeks of chemical compound, nearly more than 100 day.Depend on the chemical property and the biological stability of treatment reagent, can use other strategy of stabilize proteins.

The chemical compound lot that is used for drug regimen of the present invention can be the salt with equilibrium ion compatible on the medicine.Compatible salt can adopt many acid to form on the medicine, and these acid include, but are not limited to hydrochloric acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid etc.The dissolubility of salt in aqueous or other protonic solvent is tending towards greater than corresponding free acid or alkali form.

The pharmaceutical composition that is suitable for the present invention's use comprises some compositions, wherein comprises effective amount of actives, to realize its intended purposes.More specifically, the treatment effective dose refers to that chemical compound effectively prevents, alleviates or improve the amount of patient's time-to-live of disease symptoms or extended treatment.The definite of treatment effective dose is positioned within those skilled in the art's the limit of power fully, especially according to detailed disclosure provided herein.

Definite preparation, route of administration and the dosage of pharmaceutical composition of the present invention can doctor individual be looked patient's situation and is selected.(referring to as Fingl et al.1975, " The Pharmacological Basicof the Therapeutics (pharmacological basis of treatment) ", Ch.1p.1).Usually, the composition dosage scope of patient's administration be can be about 0.5-1000mg/kg patient's body weight.Look patient's needs, given one or many days in, dosage can be single dose or a series of twice or multidose.Should be pointed out that for nearly all particular compound of mentioning in the present disclosure, determined the human dosage of at least some situations of treatment.

Therefore, in most of the cases, the present invention will use human dosage about 0.1% to 500% of those same doses or establishment, more preferably from about 25% to 250% dosage.When human dosage is not established, be exactly that so suitable human dosage can be from ED for newfound medical compounds ₅₀Or ID ₅₀Value, or other the suitable value that comes from research in the external or body infers out that these values are through animal toxicity research and study on the efficiency qualify.

Although precise dosage is determined on the basis of each medicine, in most of the cases, still can be done some summaries about dosage.For example, dosage regimen every day for adult patient can be, oral dose is the various compositions of 0.1mg to 500mg, preferred 1mg to 250mg, as 5 to 200mg, or the intravenous of various compositions, subcutaneous or intramuscular dosage are 0.01mg to 100mg, preferred 0.1mg to 60mg, as 1 to 40mg pharmaceutical composition of the present invention or its officinal salt (calculating) according to free alkali, various compositions, every day, administration composition was 1-4 time.Perhaps, the present composition can be by continuous intravenous infusion administration, preferably with the various composition as many as 400mg dosage of every day.Therefore, the various compositions by oral administration every day accumulated dose in the 1-2000mg scope, parenteral every day accumulated dose usually in the 0.1-400mg scope.Suitably, with chemical compound successive administration a period of time, for example, a week or how all, or several months or several years.

But independent control dosage and at interval so that the blood plasma level of the active part that is enough to keep regulating action to be provided, or provides minimum effective drug concentration (MEC).Can change for each chemical compound MEC, but can estimate from vitro data.Essential dosage depends on personal feature and route of administration to reach MEC.Yet HPLC analyzes or bioassay can be used for determining plasma concentration.

Can also use the MEC value to determine dosing interval.Should use a kind of dosage regimen to carry out the administration of compositions, this scheme keeps blood plasma level to be higher than MEC in the time of 10-90%, in the time of preferred 30-90%, most preferably in the time of 50-90%.

Under the situation of topical or selectivity absorption, effective local concentration of medicine can be irrelevant with plasma concentration.

Certainly, the amount of composition of administration will depend on the patient who is receiving treatment, and depend on the order of severity, administering mode and prescriber's the judgement of patient's body weight, the state of an illness.

If need, compositions can be placed packing or distributing equipment, this packing or equipment comprise one or more unit dosage forms that comprises active component.For example, packing can comprise metal or plastic foil, as aluminum-plastic packaged.Packing or distributing equipment can have the administration description.Packing or distributing equipment also can have the bulletin with container combination, and this bulletin has reflected that for the form of government organs' regulation of management medicine production, use or sale government organs ratify this medicament forms and are used for people or beasts.For example, this bulletin can be the prescription drugs labelling of drugs approved by FDA, or the product inset of approval.The compositions of preparing in compatible pharmaceutical carrier that comprises The compounds of this invention also can prepare in suitable containers, place, and labelling is used for the indication treatment of diseases.

On the other hand, present disclosure relates to the method for the treatment of neuropsychiatric disease, and this method comprises the administration of described patient being treated the formula I or the II chemical compound of effective dose.In some embodiments, neuropsychiatric disease be selected from schizophrenia and relevant spy's property sent out psychosis, anxiety neurosis, sleep disorder, inappetence, affective disorder, manic-depressive illness as major depression and have the depression of psychotic features and tourette's syndrome, drug induced psychosis, such as the psychosis of the neurodegenerative diseases secondary of Alzheimer or Heng Yandun disease.

In some embodiments, formula I or XV chemical compound are clozapine, and in other embodiments, chemical compound is the N-desmethylclozapine.In some other embodiment, formula I or XV chemical compound do not comprise clozapine or N-desmethylclozapine.

On the other hand, the disclosure relates to the method for the treatment of neuropsychiatric disease, and this method comprises the formula I of effective therapeutic dose, II or XV chemical compound are contacted with described patient.

In some embodiments, present disclosure relates to pharmaceutical composition, and said composition comprises formula I, II or XV chemical compound and neural psychotropic drugs.

" the neural psychotropic drugs " of Shi Yonging refers to a kind of chemical compound herein, or combination of compounds, and it directly or indirectly influences brain neuron, or influence is sent to the signal of brain neuron.Therefore, neural psychotropic drugs can influence people's spirit, as people's emotion, sensation, nociperception, cognition, warning, memory etc.In certain embodiments, neural psychotropic drugs optional self-selectively 5-hydroxy tryptamine reuptake inhibithors or noradrenaline reuptake inhibitor or dopamine agonist, antipsychotic drug, 5-hydroxy tryptamine 2A antagonist and anti-5-hydroxy tryptamine 2A agonist.

In some embodiments, antipsychotic drug can be selected from phenothiazines, phenyl butyl piperadione class, debenzapine class, benzisoxidil class and lithium salts.The phenothiazines of chemical compound can be selected from chlorpromazine (Thorazine

), mesoridazine (Serentil

), prochlorperazine (Compazine ) and thioridazine (Mellaril ).The phenyl butyl piperadione class of chemical compound can be selected from haloperidol (Haldol

) and pimozide.The debenzapine class of chemical compound can be selected from clozapine (Clozaril

), loxapine (Loxitane

), olanzapine (Zyprexa

) and Quetiapine (Seroquel

).The benzisoxidil class of chemical compound can be selected from resperidone (Resperidal

) and Ziprasidone (Geodon

).Lithium salts is a lithium carbonate.In some embodiments, antipsychotic drug can be selected from Aripiprazole (Abilify), clozapine (Clozapine), clozapine (Clozaril), prochlorperazine mesylate, Etrafon, Geodon, haloperidol, droperidol, Luo Xite, Thioridazine Hydrochloride, molindone hydrochloride, tiotixene, olanzapine (Zyprexa), Orap, fluphenazine hydrochloride, the non-piperazine that draws of hydrochloric acid fluorine, promethazine, Quetiapine (Seroquel), paspertin metoclopramide, Wei Sitong, Serentil, Seroquel, trifluoperazine, chlorprothixene, Thorazine, triavil, perphenazine and Zyprexa, or its officinal salt.

In certain embodiments, selectivity 5-hydroxy tryptamine reuptake inhibithors is selected from fluoxetine, fluvoxamine, Sertraline, paroxetine, citalopram, dextrorotation citalopram, sibutramine, duloxetine and venlafaxine and officinal salt or prodrug.

In other embodiments, noradrenaline reuptake inhibitor is selected from thionisoxetine and reboxetine.

In another embodiment, dopamine agonist is selected from sumatriptan, Almogran, naratriptan, Frova, rizatriptan, Zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole and bromocriptine.

In another embodiment, anti-5-hydroxy tryptamine 2A agonist is ACP-103 or its analog.It refers to the chemical compound of formula XIII for " ACP-103, ".

In another embodiment, 5-hydroxy tryptamine 2A antagonist is M100,907 or its analog.For " M100,907, " it refers to the chemical compound of formula XIV.

On the other hand, present disclosure relates to the method for the treatment of patient's neuropsychiatric disease, and this method comprises the administration of described patient being treated the pharmaceutical composition of effective dose, and said composition comprises formula I, II or XV chemical compound and neural psychotropic drugs.On the other hand, the disclosure relates to the method for the treatment of patient's neuropsychiatric disease, and this method comprises formula I, II or XV chemical compound and the effectively neural psychotropic drugs administration of therapeutic dose of described patient being carried out effective therapeutic dose.

In certain embodiments, the patient can be mammal.Mammal is optional from mice, rat, rabbit, Cavia porcellus, Canis familiaris L., cat, sheep, goat, milch cow, such as monkey, orangutan and ape and people's primates.In some embodiments, the patient behaves.

In some embodiments, the dosing step in the said method comprises the administration of almost carrying out described formula I, II or XV chemical compound and described neural psychotropic drugs simultaneously.These embodiments comprise, but formula I or II chemical compound and neural psychotropic drugs are in identical administration composition, promptly comprise single tablet, pill or the capsule of two kinds of chemical compounds, or be used for the single solution or the drinkable single solution of intravenous injection, or in single lozenge or the patch.These embodiments also comprise, but each chemical compound is in independent administration composition, but the guiding patient almost uses these independent compositionss simultaneously, has promptly just used a kind of pill to be right after and has used another kind of pill, or just injected a kind of chemical compound and be right after the another kind of chemical compound of injection etc.

In other embodiments, dosing step comprises a kind of chemical compound that at first carries out formula I, II or XV and the administration of neural psychotropic drugs, carries out the administration of the neural psychotropic drugs of another kind of chemical compound of formula I, II or XV then.In these embodiments, can comprise a kind of compound compositions to patient's administration, then in a period of time, after a few minutes or several hours, administration comprises the another kind of compositions of another kind of chemical compound.These embodiments also comprise, and are conventional or continuously the patient is comprised a kind of administration of compound compositions, accept to comprise another kind of compound compositions simultaneously once in a while.

In certain embodiments, the neuropsychiatric disease by these methods and disclosure compounds for treating be selected from schizophrenia and relevant spy's property sent out psychosis, anxiety neurosis, sleep disorder, inappetence, affective disorder, manic depressive illness such as major depression and have the depression of psychotic features and tourette's syndrome, drug induced psychosis, such as the psychosis of the neurodegenerative diseases secondary of Alzheimer or Heng Yandun disease.

Embodiment

Embodiment 1: universal method 1 (GP1)

With amino benzoic Acid (1eq.), 2-fluoronitrobenzene (3eq.) and Cs ₂CO ₃DMF mixture heated to 140 (3eq.) ℃ 1 hour is cooled to room temperature then.Chemical compound is diluted with water, and wash with EtOAc (2x).

With EtOH and Na ₂S ₂O ₄(5eq.) be added to water, then the mixture that produces stirred 1h.(2M) is added to mixture with the HCl aqueous solution, then water extracted with EtOAc (3x), and concentrates the organic facies that merges.

Residue is placed CH ₂Cl ₂In, add hydrochloric acid 1-ethyl-3-(3-dimethylaminopropyl) carbodiimides (3eq.), the mixture that produces is at room temperature stirred 1h, concentrate then.Residue is diluted with EtOAc,, concentrate then with NaOH aqueous solution (2M) washing.

Residue is placed diox, in the time of 50 ℃, be added to TiCl then ₄(1.1eq., the content in toluene solution are 1M) and piperazine are (in the 5eq.) De diox mixture.The mixture stirring under 100 ℃ that produces is spent the night, be cooled to room temperature then.(2M) is added to mixture with the HCl aqueous solution, becomes acidity up to solution, then water extracted with EtOAc (2x).(2M) is added to water with the NaOH aqueous solution, up to obtaining alkaline solution, then the suspension that produces extracted with EtOAc (3x).The organic facies that merges is concentrated, then with the HPLC purification.

Embodiment 2:2,7-two chloro-11-(piperazine-1-yl)-5H dibenzo [b, e] [1,4] diaza

(166JO85F1)

According to GP1, (263mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 6.1mg target compound (166JO85F1) with 2-amino-5-chlorobenzoic acid with 4-chloro-2-fluoronitrobenzene.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 100/85.

Embodiment 3:2-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO85F6)

According to GP1, (212mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 5.3mg target compound (166JO85F6) MS (ESI) 313 (MH with 2-amino-5-chlorobenzoic acid with the 2-fluoronitrobenzene ⁺).MH ⁺Purity (UV/MS) be 100/95.

Embodiment 4:2,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO85F2)

According to GP1, (263mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 4.8mg target compound (166JO85F2) with 2-amino-5-chlorobenzoic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 99/99.

Embodiment 5:8-bromo-2-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO85F3)

According to GP1, (330mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 8.0mg target compound (166JO85F3) with 2-amino-5-chlorobenzoic acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)391(MH ⁺)。MH ⁺Purity (UV/MS) be 100/96.

Embodiment 6:2-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza

(166JO85F7)

According to GP1, (314mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 0.3mg target compound (189JO85F7) with 2-amino-5-chlorobenzoic acid with 4-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)381(MH ⁺)。MH ⁺Purity (UV/MS) be 100/95.

Embodiment 7:6-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza

(189JO77B)

According to GP1, (366mg, 1.5mmol) (69mg, 0.5mmol) reaction gets 28mg target compound (189JO77B) with the 2-amino benzoic Acid with 3-chloro-4-fluoro-5-nitro benzo trifluoride.MS(ESI)381(MH ⁺)。MH ⁺Purity (UV/MS) be 99/100.

Embodiment 8:7-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE35B)

According to GP1, (528mg, 3.0mmol) (138mg, 1.0mmol) reaction gets 5.0mg target compound (160FE35B) with the 2-amino benzoic Acid with 4-chloro-2-fluoronitrobenzene.MS(ESI)313(MH ⁺)。MH ⁺Purity (UV/MS) be 99/86.

Embodiment 9:8-bromo-1-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE36A)

According to GP1, (660mg, 3.0mmol) (172mg, 1.0mmol) reaction gets 5.0mg target compound (160FE36A) with 2-amino-6-chlorobenzoic acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)391(MH ⁺)。MH ⁺Purity (UV/MS) be 94/87.

Embodiment 10:8-bromo-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE40C)

According to GP1, (660mg, 3.0mmol) (152mg, 1.0mmol) reaction gets 7.9mg target compound (160FE40C) with 2-amino-5-ar-Toluic acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)371(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 11:4,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE41A)

According to GP1, (527mg, 3.0mmol) (172mg, 1.0mmol) reaction gets 4.6mg target compound (160FE41A) with 2-amino-3-chlorobenzoic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 95/70.

Embodiment 12:8-chloro-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE41B)

According to GP1, (527mg, 3.0mmol) (151mg, 1.0mmol) reaction gets 7.1mg target compound (160FE41B) with 2-amino-5-ar-Toluic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/94.

Embodiment 13:8-chloro-2-fluoro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE42A-F3)

According to GP1, (264mg, 1.5mmol) (78mg, 0.5mmol) reaction gets 21mg target compound (160FE42A-F3) with 2-amino-5-fluobenzoic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)331(MH ⁺)。MH ⁺Purity (UV/MS) be 99/98.

Embodiment 14:3,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE42B-F4)

According to GP1, (264mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 9.4mg target compound (160FE42B-F4) with 2-amino-4-chlorobenzoic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 99/97.

Embodiment 15:2-bromo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE43A-F6)

According to GP1, (528mg, 3.0mmol) (216mg, 1.0mmol) reaction gets 20mg target compound (160FE43A-F6) with 2-amino-5-bromobenzoic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)391(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 16:3,7-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE58D1)

According to GP1, (263mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 3.1mg target compound (160FE58D1) with 2-amino-4-chlorobenzoic acid with 4-chloro-2-fluoronitrobenzene.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 63/83.

Embodiment 17-8-bromo-3-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE58D3)

According to GP1, (330mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 1.1mg target compound (160FE58D3) with 2-amino-4-chlorobenzoic acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)391(MH ⁺)。MH ⁺Purity (UV/MS) be 90/85.

Embodiment 18:3-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE58D6)

According to GP1, (212mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 2.2mg target compound (160FE58D6) with 2-amino-4-chlorobenzoic acid with the 2-fluoronitrobenzene.MS(ESI)313(MH ⁺)。MH ⁺Purity (UV/MS) be 90/100.

Embodiment 19:3-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] phenodiazineAssorted (160FE58D7)

According to GP1, (314mg, 1.5mmol) (86mg, 0.5mmol) reaction gets 2.0mg target compound (160FE58D7) with 2-amino-4-chlorobenzoic acid with 4-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)381(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 20:7-chloro-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE58E1)

According to GP1, (263mg, 1.5mmol) (76mg, 0.5mmol) reaction gets 1.1mg target compound (160FE58E1) with 2-amino-5-ar-Toluic acid with 4-chloro-2-fluoronitrobenzene.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/90.

Embodiment 21:2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE58E6)

According to GP1, (212mg, 1.5mmol) (76mg, 0.5mmol) reaction gets 6.8mg target compound (160FE58E6) with 2-amino-5-ar-Toluic acid with the 4-fluoronitrobenzene.MS(ESI)293(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 22:2-methyl isophthalic acid 1-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] two Azepine

(160FE58E7)

According to GP1, (314mg, 1.5mmol) (76mg, 0.5mmol) reaction gets 1.2mg target compound (160FE58E7) with 2-amino-5-ar-Toluic acid with 4-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)361(MH ⁺)。MH ⁺Purity (UV/MS) be 100/85.

Embodiment 23:8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE74C)

According to GP1, (1.06g, 6.0mmol) (302mg, 2.0mmol) reaction gets 4.8mg target compound (160FE74C) with 2-amino-3-ar-Toluic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 97/90.

Embodiment 24:1,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(203FE03)

According to GP1, (1.06g, 6.0mmol) (343mg, 2.0mmol) reaction gets 3.1mg target compound (203FE03) with 2-amino-6-chlorobenzoic acid with 5-chloro-2-fluoronitrobenzene.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 100/99.

Embodiment 25:8-bromo-5-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO32)

According to GP1, (580mg, 2.6mmol) (200mg, 1.3mmol) reaction gets 1.6mg target compound (166JO32) with N-methyl ortho-aminobenzoic acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)371(MH ⁺)。MH ⁺Purity (UV/MS) be 90/74.

Embodiment 26: universal method 2 (GP2)

With amino benzoic Acid (1eq.), 2-fluoronitrobenzene (3eq.) or 2-chloronitrobenzene (3eq.) and Cs ₂CO ₃DMF mixture heated to 140 (3eq.) ℃ 1 hour is cooled to room temperature then.Mixture is diluted with water, with EtOAc washing (2x).

With EtOH and Na ₂S ₂O ₄(5eq.) be added to water, stir gained mixture 1h.(2M) is added in the mixture with the HCl aqueous solution, and water concentrates the organic facies that merges with EtOAc (3x) extraction then.

Residue is placed dimethylbenzene, the mixture that produces is stirred down in 130 ℃ spend the night.Mixture is with the EtOAc dilution, with saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄) and concentrate.

Residue is placed diox, and in the time of 50 ℃, add TiCl4 (1.1eq., the content in toluene are 1M) and piperazine (5eq.) De diox mixture.The mixture that produces is spent the night in 100 ℃ of stirrings, be cooled to room temperature then.Add HCl aqueous solution (2M) and be acid until solution in mixture, water extracts with EtOAc (2x) then.Add NaOH aqueous solution (2M) to aqueous phase and be alkalescence until solution, the float of generation extracts with EtOAc (3x).The organic facies that merges is concentrated, then with the HPLC purification.

Embodiment 27-7,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO28)

According to GP2, with 1, (1.26g, 6.0mmol) (274mg, 2mmol) reaction gets 16mg target compound (166JO28) to 2-two chloro-4-fluoro-5-Nitrobenzol with the 2-amino benzoic Acid.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 99/96.

Embodiment 28:11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza

(166JO23)

According to GP2, (1.25g, 6mmol) (274mg, 2mmol) reaction gets 12mg target compound (166JO23) with the 2-amino benzoic Acid with 4-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)347(MH ⁺)。MH ⁺Purity (UV/MS) be 81/98.

Embodiment 29:11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE19A)

According to GP2, (847mg, 6.0mmol) (274mg, 2mmol) reaction gets 16mg target compound (160FE19A) with the 2-amino benzoic Acid with 2-fluoro-Nitrobenzol.MS(ESI)279(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 30:8-fluoro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE19C)

According to GP2, with 2, (955mg, 6.0mmol) (274mg, 2mmol) reaction gets 8.9mg target compound (160FE19C) to the 5-difluoro nitrobenzene with the 2-amino benzoic Acid.MS(ESI)297(MH ⁺)。MH ⁺Purity (UV/MS) be 99/97.

Embodiment 31:11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza -8-nitrile (160FE19D)

According to GP2, (1.10g, 6.0mmol) (274mg, 2mmol) reaction gets 4.7mg target compound (160FE19D) with the 2-amino benzoic Acid with 4-chloro-3-cyanide-nitrophenyl.MS(ESI)304(MH ⁺)。MH ⁺Purity (UV/MS) be 100/86.

Embodiment 32:8-bromo-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE19E)

According to GP2, (1.32g, 6.0mmol) (274mg, 2mmol) reaction gets 15mg target compound (160FE19E) with the 2-amino benzoic Acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)357(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 33:8-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE19F)

According to GP2, (1.03g, 6.0mmol) (274mg, 2mmol) reaction gets 1.6mg target compound (160FE19F) with the 2-amino benzoic Acid with 4-chloro-3-Methylnitrobenzene.MS(ESI)293(MH ⁺)。MH ⁺Purity (UV/MS) be 70/70.

Embodiment 34: universal method 3 (GP3)

In 10 ℃, (17mg 0.12mmol) is added in the N methyl piperazine derivant (0.1mmol) that is dissolved in THF (2ml) with chloro-carbonic acid 1-chloro-ethyl ester.Then with the mixture heated backflow 18h that produces.Reduce temperature, THF is removed in decompression.Then methanol is added in the remaining grease, again with mixture in 65 ℃ the vibration 2h.Methanol is removed in decompression, and remaining crude product is with the HPLC purification.

Embodiment 35:3-fluoro-6-piperazine-1-base-11H-dibenzo [b, e] azepine

(160FE02)

According to GP3, with 3-fluoro-6-(4-methyl-piperazine-1-yl)-11H-dibenzo [b, e] azepine

(31mg, 0.1mmol) reaction get 8mg and are separated into The target compound of hydrochlorate (160FE02).MS(ESI)296(MH ⁺)。MH ⁺Purity (UV/MS) be 99/100.

Embodiment 36:2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] Diaza (160FE13A)

According to GP3, with 2-(trifyl oxygen base)-11-(4-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(39mg, 0.1mmol) reaction gets 3.0mg target compound (160FE13A).MS(ESI)427(MH ⁺)。MH ⁺Purity (UV/MS) be 95/98.

Embodiment 37:2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] The oxygen azepine (160FE13B)

According to GP3, with 2-(trifyl oxygen base)-11-(4-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] oxygen azepine (39mg, 0.1mmol) reaction gets 11mg target compound (160FE13B).MS(ESI)428(MH ⁺)。MH ⁺Purity (UV/MS) be 98/100.

Embodiment 38:8-chloro-2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE13C)

According to GP3, with 8-chloro-2-(trifyl oxygen base)-11-(4-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(42mg, 0.1mmol) reaction gets 3.2mg target compound (160FE13C).MS(ESI)461(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 39:8-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] Diaza (160FE13D)

According to GP3, with 8-(trifyl oxygen base)-11-(4-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(39mg, 0.1mmol) reaction gets 2.2mg target compound (160FE13D).MS(ESI)427(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 40: universal method 4 (GP4)

Under 50 ℃, (0.1mmol) De diox mixture is added to TiCl with suitable lactams ₄(1.1eq., the content in toluene are 1M) and amine are (in the 0.5mmol) De diox mixture or be added to TiCl ₄(2.2eq., the content in toluene are 1M) and amine are (in the 1.0mmol) De diox mixture.The mixture that produces is spent the night in 100 ℃ of stirrings, be cooled to room temperature then.(3mL 2M) is added in the aqueous mixture, and water is with EtOAc (2 * 4mL) extractions then with the HCl aqueous solution.(6mL 2M) is added to water, and the float of generation is with EtOAc (3 * 3mL) extractions with the NaOH aqueous solution.The organic facies that merges is concentrated, then with the HPLC purification.

Embodiment 41:11-(piperazine-1-yl)-dibenzo [b, f] [1,4] sulfur azepine

(160FE17A)

According to GP4, with 10H-dibenzo [b, f] [1,4] sulfur azepine (23mg, 0.1mmol) (43mg, 0.5mmol) reaction gets 3.1mg target compound (160FE17A) to-11-ketone with piperazine.MS(ESI)296(MH ⁺)。MH ⁺Purity (UV/MS) be 97/90.

Embodiment 42:11-(piperazine-1-yl)-2,3-dihydro-1,4-Ben Bing bioxin is [6,7-b] [1,4] benzo also The sulfur azepine

(160FE17B)

According to GP4, with 2,3-dihydro-1,4-Ben Bing bioxin is [6,7-b] [1,4] benzothiazepine also

(29mg, 0.1mmol) (43mg, 0.5mmol) reaction gets 1.9mg target compound (160FE17B) to-11 (12H)-ketone with piperazine.MS(ESI)354(MH ⁺)。MH ⁺Purity (UV/MS) be 99/95.

Embodiment 43:8-chloro-11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza

(160FE16A)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(25mg, 0.1mmol) (50mg, 0.5mmol) reaction gets 12mg target compound (160FE16A) to-11-ketone with high piperazine.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 99/93.

Implement 44:N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-and N, the N-dimethyl -ethane-1,2-diamidogen (160FE16D)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (25mg, 0.1mmol) and N, the N-dimethyl-ethylenediamine (44mg, 0.5mmol) reaction, 20mg target compound (160FE16D).MS(ESI)315(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 45:N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-and N, the N-diethyl -ethane-1,2-diamidogen (160FE16E)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (25mg, 0.1mmol) and N, the N-diethyl ethylenediamine (58mg, 0.5mmol) reaction, 3.9mg target compound (160FE16E).MS(ESI)343(MH ⁺)。MH ⁺Purity (UV/MS) be 99/94.

Embodiment 46:8-chloro-11-(4-methyl-[1,4] diazepam-1-yl)-5H-dibenzo [b, e] [1,4] two Azepine

(160FE16F)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(25mg, 0.1mmol) (57mg, 0.5mmol) reaction gets 5.7mg target compound (160FE16F) to-11-ketone with the high piperazine of 1-methyl.MS(ESI)341(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 47:8-chloro-2-methoxyl group-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE20A)

According to GP4, with 8-chloro-2-methoxyl group-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(28mg, 0.1mmol) (86mg, 1.0mmol) reaction gets 19mg target compound (160FE20A) to-11-ketone with piperazine.MS(ESI)342(MH ⁺)。MH ⁺Purity (UV/MS) be 99/100.

Embodiment 48:N '-(5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N, N-dimethyl-ethane -1,2-diamidogen (160FE20B)

According to GP4, with 5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (160FE15A) (21mg, 0.1mmol) and N, the N-dimethyl-ethylenediamine (88mg, 1.0mmol) reaction, 7.6mg target compound (160FE20B.MS(ESI)281(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 49:11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza

(160FE20C)

According to GP4, with 5,10-dihydro-dibenzo [b, e] [1,4] diaza

(21mg, 0.1mmol) (100mg, 1.0mmol) reaction gets 12mg target compound (160FE20C) to-11-ketone (160FE15A) with high piperazine.MS(ESI)293(MH ⁺)。MH ⁺Purity (UV/MS) be 95/95.

Embodiment 50:N '-(8-fluoro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-and N, the N-dimethyl -ethane-1,2-diamidogen (160FE20D)

According to GP4, with 8-fluoro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (160FE15C) (23mg, 0.1mmol) and N, the N-dimethyl-ethylenediamine (88mg, 1.0mmol) reaction, 11mg target compound (160FE20D).MS(ESI)299(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 51:8-fluoro-11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza

(160FE16A)

According to GP4, with 8-fluoro-5,10-dihydro-dibenzo [b, e] [1,4] diaza (23mg, 0.1mmol) (100mg, 1.0mmol) reaction gets 19mg target compound (160FE20E) to-11-ketone (160FE15C) with high piperazine.MS(ESI)311(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 52:N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-the N-methyl- Ethane-1,2-diamidogen (160FE22)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(25mg, 0.1mmol) (74mg, 1.0mmol) reaction gets 7.6mg target compound (160FE22) to-11-ketone with the N-methyl ethylenediamine.MS(ESI)301(MH ⁺)。MH ⁺Purity (UV/MS) be 92/83.

Embodiment 53:8-chloro-11-(anti--2,5-dimethyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] two Azepine

(160FE33A)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (25mg, 0.1mmol) with anti--2, the 5-lupetazin (114mg, 1.0mmol) reaction, 1.9mg target compound (160FE33A).MS(ESI)341(MH ⁺)。MH ⁺Purity (UV/MS) be 100/82.

Embodiment 54:8-chloro-11-(3,5-dimethyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] phenodiazine Assorted

(160FE33B)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(25mg, 0.1mmol) with 2, (114mg, 1.0mmol) reaction gets 18mg target compound (160FE33B) to the 6-lupetazin to-11-ketone.MS(ES1)341(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 55:8-chloro-11-(3-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE38)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(25mg, 0.1mmol) (100mg, 1.0mmol) reaction gets 30mg target compound (160FE38) to-11-ketone with the 2-methyl piperazine.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/89.

Embodiment 56:8-chloro-11-(3-phenyl-Piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE45)

According to GP4, with 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

(25mg, 0.1mmol) (162mg, 1.0mmol) reaction gets 27mg target compound (160FE45) to-11-ketone with the 2-phenylpiperazine.MS(ESI)389(MH ⁺)。MH ⁺Purity (UV/MS) be 100/89.

Embodiment 57:8-chloro-5-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(189JO25A)

NaH (12mg, 0.29mmol contain 60% in mineral oil) is added to 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64) (50mg is in the mixture of toluene 0.19mmol) (1.5mL) and DMF (0.5mL).Add then MeI (24ZL, 0.38mmol).After stirring the mixture 1h that produces, add saturated NaHCO ₃Aqueous solution (2mL) finishes reaction.Mixture is with extracted with diethyl ether, dry (Na ₂SO ₄) organic facies that merges and concentrating.Residue is placed toluene (2.0mL), and (98mg 1.1mmol), stirs 1h_ with the mixture that produces in 100 ℃ to add piperazine.In mixture, add then the HCl aqueous solution (1mL, 2M) and EtOAc (2mL).Each separates mutually, and adding NaOH aqueous solution after water is extracted with EtOAc (2mL) (2mL, 2M).(3 * 2mL) extract, dry (Na with EtOAc with alkaline water ₂SO ₄) organic facies that merges and concentrating.Residue is dissolved in DMF, gets 34mg target compound (189JO25A) with the HPLC purification.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 58:8-chloro-5-benzyl-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE46-PIPBN)

With 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE46) (51mg, 0.20mmol) with benzyl chloride (68mg, 0.4mmol) as embodiment 57 described methods react 8.4mg target compound (160FE46-PIPBN).MS(ESI)403(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 59:8-iodo-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO38)

With 8-bromo-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (166JO31) (60mg, 0.21mmol), NaI, (62mg, 0.42mmol), N, the N-dimethyl-ethylenediamine (2.2 μ L, 0.021mmol) and CuI (2mg, 0.01mmol) De diox (1ml) mixture heated in covering test tube 3 days.Reactant mixture is cooled to room temperature.Then mixture is splined on the SCX-2 ion exchange column, product is with CH ₂Cl ₂Eluting gets 49mg intermediate 8-iodine lactams.Under 50 ℃, (20mg, 0.060mmol) De diox (1mL) solution is added to TiCl with intermediate 8-iodine lactams ₄(0.051g is 0.60mmol) in the De diox mixture for (0.13mL, 0.13mmol, 1M in the toluene solution) and piperazine.The mixture that produces spends the night in 100 ℃ of stirrings, is cooled to room temperature then.(3mL 2M) is added to behind the mixture with EtOAc (2 * 4mL) aqueous phase extracted with the HCl aqueous solution.(6mL 2M) is added to water, and the float of generation is with EtOAc (3 * 3mL) extractions with the NaOH aqueous solution.Concentrate the organic facies that merges, get 4.1mg target compound (166JO38) with the HPLC purification.MS(ESI)405(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 60-2-iodo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO54)

2-bromo-8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (from the intermediate of GP1) (30mg, 0.09mmol) with the method for embodiment 59 react 7.0mg target compound (166JO54).MS(ESI)439(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 61:8-phenyl-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(189JO53)

Tetrakis triphenylphosphine palladium (0) (catalytic amount) is added to 8-bromo-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (166JO31) (30mg, 0.12mmol), phenylboric acid (18mg, 0.15mmol) and K ₂CO ₃(34mg, deoxidation toluene/EtOH/H 0.24mmol) ₂In O (1.5mL) mixture, the mixture of generation stirs down in 80 ℃ and spends the night.Mixture dilutes with EtOAc, with saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄) and concentrate 8-phenyl lactams crude product.Under 50 ℃, intermediate 8-phenyl lactams De diox (1mL) solution is added to TiCl ₄(0.103g is 1.2mmol) in the De diox mixture for (0.24mL, 0.24mmol, 1M in the toluene solution) and piperazine.The 100 ℃ of stirrings of mixture that produce are spent the night postcooling to room temperature.(3mL 2M) is added to mixture, then with EtOAc (2 * 4mL) aqueous phase extracted with the HCl aqueous solution.(6mL 2M) is added to water, and the float of generation is with EtOAc (3 * 3mL) extractions with the NaOH aqueous solution.The organic facies that merges is splined in the SCX-2 ion exchange column.Exchange column washs with MeOH, and product is again with NH then ₃(7N among the MeOH) eluting, the concentrated HPLC purification that reaches get 16mg target compound (189JO53).MS(ESI)355(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 62:8-chloro-11-(piperidines-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO69A)

(37mg 0.44mmol) is added to 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza with piperidines (166JO50) (90mg, purity 50% 0.218mmol) in the pyridine of crude product (2mL), under 160 ℃, heat 10h with the mixture that produces in covering test tube.Mixture concentrates the back with flash chromatography (SiO ₂, heptane: EtOAc8: 1-6: 1) get 12mg target compound (166JO69A).MS(ESI)312(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment: 63-8-chloro-11-(morpholine-4-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO69B)

As embodiment 62 described methods, with 8-chloro-11-methyl mercapto-5H-dibenzo [b, e] [1,4] diaza

(166JO50) (90mg, purity 50%, 0.218mmol) crude product and morpholine (38mg, 0.44mmol) react 11mg target compound (166JO69B.MS(ESI)314(MH ⁺)。MH ⁺Purity (UV/MS) be 100/98.

Embodiment 64:5-pi-allyl-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(166JO68)

With K ^t(343mg 3.1mmol) is added to 8-chloro-5 to OBu, 10-dihydro-dibenzo [b, e] [1,4] diaza

(500mg 2.0mmol) in De diox (10mL) mixture, under 60 ℃, stirs 1h with the mixture that produces to-11-ketone, is cooled to room temperature then.(0.42mL, 3.1mmol), the mixture of generation stirs 2h. down at 40 ℃ and adds MeOH (2mL) end reaction to methoxy-benzyl chlorine in adding.Mixture is with CH ₂Cl ₂Dilution, saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrate and flash chromatography (SiO ₂, heptane: EtOAc, 4: 1-3: 1) get the lactams (732mg) of intermediate to the methoxy-benzyl protection, purity 85%, not repurity is directly used in next step.

To (100mg adds NaH (16mg, 0.41mmol are 60%) in mineral oil in DMF 0.27mmol) (2mL) mixture, with the mixture heated to 60 that produces ℃, be cooled to room temperature subsequently to the lactams of methoxy-benzyl protection.(36 μ L, 0.41mmol), the mixture of generation at room temperature stirs behind the 3h with CH to add allyl bromide, bromoallylene ₂Cl ₂Dilution is with saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrate, flash chromatography (SiO ₂1) and concentrate, heptane: EtOAc8: 1-4:.Residue is placed trifluoroacetic acid (4mL), and the mixture of generation at room temperature stirs and spends the night, at 45 ℃ of 2h. that mixture is concentrated then, chromatography (SiO ₂1) and concentrate, heptane: EtOAc8: 1-4:.Residue is placed toluene (2mL), add N, and accelerine (48, μ L, 0.38mmol) and POCl ₃(35 μ L, 0.38mmol).Under 100 ℃, concentrate behind the mixture 2h that stirring produces.Residue is placed diox, and (65mg, 0.76mmol), the mixture of generation stirs 3h down at 100 ℃ to add piperazine.(3mL, 2M), water is with EtOAc (2 * 4mL) extractions then to add the HCl aqueous solution in mixture.(6mL, 2M), the float of generation is with EtOAc (3 * 3mL) extractions to add the NaOH aqueous solution to water.Concentrate the organic facies that merges, get 17mg target compound (166JO68) through the HPLC purification.MS(ESI)353(MH ⁺)。MH ⁺Purity (UV/MS) be 99/88.

Embodiment 65:6-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

(189JO68)

Under 140 ℃, with the 2-Methyl anthranilate (454mg, 3.0mmol), 3-chloro-2-fluoronitrobenzene (352mg, 2mmol) and CS ₂CO ₃(0.78g, DMF 2.4mol) (4mL) mixture stirs 2h.

With mixture with EtOAc (10mL) dilution, 2M NaOH aqueous solution (2 * 5mL) washings, dry (Na ₂SO ₄), concentrate and flash chromatography (SiO ₂The EtOAc-system) and reconcentration, toluene: heptane:.Residue is placed THF (10mL), add 1M LiOH (5mL) aqueous solution, the mixture of generation stirs 1H down in 80 ℃, is cooled to room temperature then.Add 2M HCl aqueous solution until pH2.Water extracts with EtOAc (3x).Dry (Na ₂SO ₄) organic facies that merges and concentrating.Residue is placed EtOH, add K ₂CO ₃(1.38g, 10mmol) and Na ₂S ₂O ₄(1.74g, aqueous mixtures 10mmol) stir the mixture 1h that produces.Mixture is with water dilution, 1M NaOH aqueous solution (2 * 5mL) washings, dry then (Na ₂SO ₄) and concentrate.

Residue is placed CH ₂Cl ₂In, adding hydrochloric acid 1-ethyl-3-(3-dimethylaminopropyl) carbodiimides (307mg, 1.6mmol).The mixture that produces at room temperature stirs 1h.Mixture is with EtOAc dilution, saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrate and through flash chromatography (SiO ₂, heptane: EtOAc, 2: 1) and must 21mg intermediate lactams.

The intermediate lactams is placed diox, and under 50 ℃, be added to TiCl ₄(73mg is 0.85mmol) in the De diox mixture for (0.19mL, 0.19mmol, 1M in the toluene) and piperazine.Stir the mixture overnight that produces down at 100 ℃, be cooled to room temperature then.Adding HCl aqueous solution in mixture (1mL, 2M), then with EtOAc (2 * 1mL) aqueous phase extracted.(2mL, 2M), the float of generation is with EtOAc (3 * 1mL) extractions to add the NaOH aqueous solution to aqueous phase.Concentrate the organic facies that merges, get 9.8mg target compound (189JO68) MS (ESI) 313 (MH through the HPLC purification ⁺).MH ⁺Purity (UV/MS) be 100/98.

Embodiment 66:8-chloro-5-piperazine-1-base-11H-benzo [b] pyrido [2,3-e] [1,4] diaza

(166JO63)

To 5-chloro-2-nitroaniline (345mg, 2mmol) and pyridine (162 μ L, 2mmol) add in the De diox mixture 2-chloronicotinoyl chloride (352mg, 2mmol), with the mixture stirring at room that produces 2 hours.Mixture is with CH ₂Cl ₂Dilution is with saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrate and methanol crystallization gets 271mg intermediate diaryl-amine.(100mg adds K in EtOH 0.32mmol) (0.5mL) mixture to the intermediate diaryl-amine ₂CO ₃(220mg, 1.6mmol) and Na ₂S ₂O ₄(278mg, water 1.6mmol) (0.5mL) mixture was with the mixture stirring at room that produces 1 hour.Mixture is concentrated, and residue places EtOAc/H ₂O also separates.With organic facies drying (Na ₂SO ₄), concentrate.Residue places dimethylbenzene again, is heated to 130 ℃ and spends the night, then with the EtOAc dilution, with saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrate, through quickflashing chromatography (SiO ₂, heptane: EtOAc) get the intermediate lactams.The intermediate lactams is placed diox and be added to TiCl under 50 ℃ ₄(187 μ L, 0.187mmol, 1M in the toluene) (73mg is 0.85mmol) in the De diox mixture with piperazine.The mixture that produces stirs down at 100 ℃ and spends the night, and is cooled to room temperature then.(1mL, 2M), water is with EtOAc (2 * 2mL) extractions then to add the HCl aqueous solution in mixture.(2mL, 2M), the float of generation is with EtOAc (3 * 1mL) extractions to add the NaOH aqueous solution to water.Concentrate the organic facies that merges, get 20mg target compound (166JO63) through the HPLC purification.MS(ESI)314(MH ⁺)。MH ⁺Purity (UV/MS) be 100/99.

Embodiment 67:2-chloro-10-piperazine-1-base-5H-dibenzo [b, f] azepine

(189JO39)

Under 75 ℃ of argon shields, to 2-chloro-5-(4-methoxy-benzyl)-5,11-dihydro-dibenzo [b, f] azepine

-11-ketone (189JO27) (150mg, CH 0.41mmol) ₂Cl ₂(10mL) add TiCl in the mixture ₄(0.6mL, 0.60mmol, 1M in the toluene) stirs 1h with the gained mixture.With mixture with saturated NH ₄Cl aqueous solution and CH ₂Cl ₂Dilution is cooled to room temperature with mixture again, respectively is separated.Water is with CH ₂Cl ₂(1 * 10mL) extraction, dry (Na ₂SO ₄) organic facies that merges and concentrate the product crude product (90mg, 90%) of protection, not repurity is directly used in next step.

Under 50 ℃, to TiCl ₄(283mg, (80mg 0.33mmol), stirs the float 1.5h that produce down at 100 ℃ 3.3mmol) to add the product crude product of protecting in De diox (4mL) solution for (0.18mL, 0.18mmol, 1M in the toluene) and piperazine.Mixture is cooled to room temperature.Then with EtOAc dilution, saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrated reaching through flash chromatography (Al ₂O ₃, CH ₂Cl ₂: MeOH, 1: 0-25: 1) get 64mg (63%) target compound (189JO39).MS(ESI)312(MH ⁺)。MH ⁺Purity (UV/MS) be 97/95.

Embodiment 68:8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] sulfur azepine (189JO16)

To 8-chloro-10H-dibenzo [b, f] [1,4] sulfur azepine

-11-ketone (189JO13) (38mg, 0.15mmol) and N, accelerine (46111, add POCl in toluene mixture 0.36mmol) ₃(27 μ L 0.29mmol), stir the mixture 2h that produces down at 100 ℃, concentrate then.(62mg, 0.73mmol), 100 ℃ are stirred the mixture 3h that produces down, are cooled to room temperature then to add toluene (2mL) and piperazine.(1mL, 2M), water is with EtOAc (2 * 2mL) extractions then to add the HCl aqueous solution to mixture.(3mL, 2M), the mixture of generation is with EtOAc (3 * 3mL) extractions to add the NaOH aqueous solution to water.Concentrate the organic facies that merges, and get 6.6mg target compound (189JO16) through the HPLC purification.MS(ESI)330(MH ⁺)。MH ⁺Purity (UV/MS) be 99/98.

Embodiment 68:8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO31)

With 8-chloro-10H-dibenzo [b, f] [1,4] oxygen azepine

-11-ketone (189JO29C) (17mg, 0.069mmol) and 2, two (the 4-methoxyphenyls)-1 of 4-, 3-dithio-2,4-diphosphetane-2,4-two sulfur (16mg, 0.040mmol) toluene (2mL) mixture in covering test tube, microwave heating (130 ℃, 20 minutes).Reactant mixture is cooled to room temperature, add MeI (18 μ L, 0.29mmol), the mixture of generation in covering test tube, microwave heating (120 ℃, 20 minutes).Mixture is concentrated, residue place pyridine (2mL) and add piperazine (25mg, 0.29mmol).Under 130 ℃, with the mixture heated overnight in covering test tube that produces, and then with microwave heating (160 ℃, 30 minutes).Mixture is concentrated, with EtOAc dilution and water washing.Organic facies is splined on the SCX-2 ion exchange column.With the MeOH column scrubber, product is with NH then ₃(7N among the MeOH) eluting gets 9.0mg (57%) target compound (189JO31).MS(ESI)314(MH ⁺)。MH ⁺Purity (UV/MS) be 92/100.

Embodiment 69:8-chloro-11-(4-methyl-piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO47)

With 8-chloro-10H-dibenzo [b, f] [1,4] oxygen azepine

-11-ketone (189JO29C) (30mg, 0.069mmol) and 2, two (the 4-methoxyphenyls)-1 of 4-, 3-dithio-2,4-diphosphetane-2,4-two sulfur (29mg, 0.040mmol) toluene (2mL) mixture microwave heating (130 ℃, 20 minutes) in covering test tube.Reactant mixture is cooled to room temperature, and (38 μ L, 0.29mmol), the mixture of generation is microwave heating (120 ℃, 20 minutes) in covering test tube to add MeI.Enriched mixture places pyridine (2mL) with residue, and the adding piperazine (24mg, 0.29mmol).Under 130 ℃,, and then use microwave heating (160 ℃, 30 minutes) with the mixture heated overnight in covering test tube that produces.Enriched mixture is with EtOAc dilution, water washing.With organic facies drying (Na ₂SO ₄), concentrate and through flash chromatography (SiO ₂, toluene: EtOAc: MeOH, 4: 2: 0-2: 2: 1) and must 8.9mg target compound (189JO47.MS(ESI)328(MH ⁺)。MH ⁺Purity (UV/MS) be 98/93.

Embodiment 70:3-chloro-6-piperazine-1-base-11H-dibenzo [b, e] azepine

(189JO60)

According to GP4, with 3-chloro-5,11-dihydro-dibenzo [b, e] azepine

(25mg 0.1mmol) with the piperazine reaction, gets 2.2mg target compound (189JO60) to-6-ketone (189JO59).MS(ESI)312(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 71: universal method 5 (GP5)

Under 40 ℃, with Methyl anthranilate (2.0mmol), 2-fluoronitrobenzene (1.0mmol) and Cs ₂CO ₃(0.65g, DMF 2.0mmol) (4mL) mixture stirs 2h.Mixture is with EtOAc (10mL) dilution and through (2 * 5mL) washings of 2M NaOH aqueous solution.

With EtOH, H ₂O, K ₂CO ₃(0.69g, 5mmol) and Na ₂S ₂O ₄(0.87g 5mmol) is added to the EtOAc phase, the mixture vigorous stirring 1h of generation.Tell water, (2 * 5mL) washings concentrate organic facies then with the 1MNaOH aqueous solution.

Residue is placed DMF (1mL), add toluene (4mL) and NaH (60mg, 1.5mmol is in the mineral oil 60%), the mixture of generation spends the night in 80 ℃ of stirrings, adds saturated NH then ₄The Cl aqueous solution finishes reaction.The mixture that produces is with EtOAc dilution, 2M NaOH aqueous solution (2 * 5mL) washings, dry (Na ₂SO ₄) and concentrate.Residue is placed diox, and (0.41g is 5mmol) in the De diox mixture to be added to TiCl4 (1.1mL, 1.1mmol, 1M in the toluene) and piperazine under 50 ℃.The mixture stirring under 100 ℃ that produces is spent the night, be cooled to room temperature then.(3mL, 2M), water is with EtOAc (2 * 4mL) extractions then to add the HCl aqueous solution in mixture.(6mL, 2M), the float of generation is with EtOAc (3 * 3mL) extractions to add the NaOH aqueous solution to aqueous phase.Concentrate the organic facies that merges, dry (Na ₂SO ₄) and with the HPLC purification.

Embodiment 72:8-bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO48A)

According to GP5, (220mg, 1mmol) (304mg, 2mmol) reaction gets 36mg target compound (189JO48A) with the 2 hydroxybenzoic acid methyl ester with 5-bromo-2-fluoronitrobenzene.MS(ESI)358(MH ⁺)。MH ⁺Purity (UV/MS) be 96/82.

Embodiment 73:11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO48B)

According to GP5, with the 2-fluoronitrobenzene (141mg, 1mmol) and the 2 hydroxybenzoic acid methyl ester (304mg, 2mmol) reaction, 5.2mg target compound (189JO48B).MS(ESI)280(MH ⁺)。MH ⁺Purity (UV/MS) be 99/99.

Embodiment 74:7-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO50A)

According to GP5, (175mg, 1mmol) (304mg, 2mmol) reaction gets 17mg target compound (189JO50A) with the 2 hydroxybenzoic acid methyl ester with 4-chloro-2-fluoronitrobenzene.MS(ESI)314(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 75:8-chloro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50B)

According to GP5, (175mg, 1mmol) (364mg, 2mmol) reaction gets 6.8mg target compound (189JO50B) with 2-hydroxyl-4-methoxyl methyl benzoate with 5-chloro-2-fluoronitrobenzene.MS(ESI)344(MH)。MH ⁺Purity (UV/MS) be 94/86.

Embodiment 76:8-bromo-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO50D)

According to GP5, (220mg, 1mmol) (364mg, 2mmol) reaction gets 14mg target compound (189JO50D with 2-hydroxyl-4-methoxybenzoic acid methyl ester with 5-bromo-2-fluoronitrobenzene.MS(ESI)388(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 77:3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO50E)

According to GP5, (141mg is 1mmol) with 2-hydroxyl-4-methoxybenzene first with the 2-fluoronitrobenzene

(364mg, 2mmol) reaction gets 33mg target compound (189JO50E) to the acid methyl ester.MS(ESI)310(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 78:7-chloro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO50F)

According to GP5, (175mg, 1mmol) (364mg, 2mmol) reaction gets 6.7mg target compound (189JO50F) with 2-hydroxyl-4-methoxyl methyl benzoate with 4-chloro-2-fluoronitrobenzene.MS(ESI)344(MH ⁺)。MH ⁺Purity (UV/MS) be 98/96.

Embodiment 79:8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO50H)

According to GP5, (175mg, 1mmol) (332mg, 2mmol) reaction gets 34mg target compound (189JO50H) with 2-hydroxy-3-methyl essence of Niobe with 5-chloro-2-fluoronitrobenzene.MS(ESI)328(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 80:8-bromo-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO51A)

According to GP5, (220mg, 1mmol) (332mg, 2mmol) reaction gets 20mg target compound (189JO51A) with 2-hydroxy-3-methyl essence of Niobe with 5-bromo-2-fluoronitrobenzene.MS(ESI)372(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 81:4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO51B)

According to GP5, (141mg, 1mmol) (332mg, 2mmol) reaction gets 1.8mg target compound (189JO51B) with 2-hydroxy-3-methyl essence of Niobe with the 2-fluoronitrobenzene.MS(ESI)294(MH ⁺)。MH ⁺Purity (UV/MS) be 99/98.

Embodiment 82:2-bromo-8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51D)

According to GP5, (175mg, 1mmol) (462mg, 2mmol) reaction gets 21mg target compound (189JO51D) with 5-bromo-2 hydroxybenzoic acid methyl ester with 5-chloro-2-fluoronitrobenzene.MS(ESI)392(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 83:2,8-two bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO51E)

According to GP5, (220mg, 1mmol) (462mg, 2mmol) reaction gets 0.7mg target compound (189JO51E) with 5-bromo-2 hydroxybenzoic acid methyl ester with 5-bromo-2-fluoronitrobenzene.MS(ESI)436(MH ⁺)。MH ⁺Purity (t1V/MS) be 94/99.

Embodiment 84:2-bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO51F)

According to GP5, (142mg, 1mmol) (462mg, 2mmol) reaction gets 10mg target compound (189JO51F) with 5-bromo-2 hydroxybenzoic acid methyl ester with the 2-fluoronitrobenzene.MS(ESI)358(MH ⁺)。MH ⁺Purity (UV/MS) be 95/99.

Embodiment 85:2-bromo-7-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO51G)

According to GP5, (175mg, 1mmol) (462mg, 2mmol) reaction gets 17mg target compound (189JO51G) with 5-bromo-2 hydroxybenzoic acid methyl ester with 4-chloro-2-fluoronitrobenzene.MS(ESI)392(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 86:11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine

(189JO54A)

According to GP5, (209mg, 1mmol) (304mg, 2mmol) reaction gets 19mg target compound (189JO54A) with the 2 hydroxybenzoic acid methyl ester with 2-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)348(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 87:4-methyl isophthalic acid 1-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine

(189JO54C)

According to GP5, (209mg, 1mmol) (332mg, 2mmol) reaction gets 15mg target compound (189JO54C) with 2-hydroxy-3-methyl essence of Niobe with 2-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)362(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 88:8-fluoro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO54E)

According to GP5, with 2, (159mg, 1mmol) (304mg, 2mmol) reaction gets 14mg target compound (189JO54E) to the 5-difluoro nitrobenzene with the 2 hydroxybenzoic acid methyl ester.MS(ESI)298(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 89:8-fluoro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO54F)

According to GP5, with 2, (159mg, 1mmol) (364mg, 2mmol) reaction gets 9.8mg target compound (189JO54F) to the 5-difluoro nitrobenzene with 2-hydroxyl-4-methoxyl methyl benzoate.MS(ESI)328(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 90:8-fluoro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO54G)

According to GP5, with 2, (159mg, 1mmol) (332mg, 2mmol) reaction gets 9.8mg target compound (189JO54G) to the 5-difluoro nitrobenzene with 2-hydroxy-3-methyl essence of Niobe.MS(ESI)312(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 91:2-bromo-8-fluoro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO54H)

According to GP5, with 2, (159mg, 1mmol) (462mg, 2mmol) reaction gets 11mg target compound (189JO54H) to the 5-difluoro nitrobenzene with 5-bromo-2 hydroxybenzoic acid methyl ester.MS(ESI)376(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 92:8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO58A)

According to GP5, (155mg, 1mmol) (304mg, 2mmol) reaction gets 24mg target compound (189JO58A) with the 2 hydroxybenzoic acid methyl ester with 4-fluoro-3-Methylnitrobenzene.MS(ESI)294(MH ⁺)。MH ⁺Purity (UV/MS) be 100/98.

Embodiment 93:3-methoxyl group-8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO58B)

According to GP5, (155mg, 1mmol) (364mg, 2mmol) reaction gets 27mg target compound (189JO58B) with 2-hydroxyl-4-methoxyl methyl benzoate with 4-fluoro-3-Methylnitrobenzene.MS(ESI)324(MH ⁺)。MH ⁺Purity (UV/MS) be 100/98.

Embodiment 94:4,8-dimethyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO58C)

According to GP5, (155mg, 1mmol) (332mg, 2mmol) reaction gets 24mg target compound (189JO58C with 2-hydroxy-3-methyl essence of Niobe with 4-fluoro-3-Methylnitrobenzene.MS(ESI)308(MH ⁺)。MH ⁺Purity (UV/MS) be 100/98.

Embodiment 95:3-methoxyl group-11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen nitrogen Assorted (189JO62A)

According to GP5, (209mg, 1mmol) (364mg, 2mmol) reaction gets 12mg target compound (189JO62A with 2-hydroxyl-4-methoxyl methyl benzoate with 2-fluoro-3-nitrobenzophenone trifluoride.MS(ESI)378(MH ⁺)。MH ⁺Purity (UV/MS) be 100/95.

Embodiment 96:2-bromo-11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine

(189JO62B)

According to GP5, (209mg, 1mmol) (462mg, 2mmol) reaction gets 11mg target compound (189JO62B with 5-bromo-2 hydroxybenzoic acid methyl ester with 2-fluoro-3-nitro benzo trifluoride.MS(ESI)426(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 97:6-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO69)

According to GP5, (352mg, 2mmol) (453mg, 3mmol) reaction gets 57mg target compound (189JO69) with the 2 hydroxybenzoic acid methyl ester with 3-chloro-2-fluoronitrobenzene.MS(ESI)314(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 98: universal method 6 (GP6)

Under 40 ℃, with Methyl anthranilate (1.0mmol), 2-fluoronitrobenzene (0.5mmol) and CS ₂CO ₃(0.33g, DMF mixture (3mL) 1.0mol) stirs 2h.With mixture with EtOAc (10mL) dilution, 2M NaOH aqueous solution (2 * 5mL) washings, dry (Na ₂SO ₄), concentrate, flash chromatography (SiO ₂, toluene: heptane: the EtOAc system) with concentrated.Residue is placed THF (4mL), add 1M LiOH (3mL) aqueous solution, the mixture of generation is cooled to room temperature then in 80 stirring 1h.Add 2M HCl aqueous solution and reach 2 until pH.With EtOAc (3x) aqueous phase extracted.Dry (Na ₂SO ₄) organic facies that merges and concentrating.Residue is placed EtOH, add K ₂CO ₃(0.35g, 2.55mmol) and Na ₂S ₂O ₄(0.44g, aqueous mixtures 2.5mmol) stir the mixture 1h that produces.Mixture is with water dilution, 1M NaOH aqueous solution (2 * 5mL) washings, dry then (Na ₂SO ₄) with concentrated.

Residue is placed CH ₃Among the CN, add hydrochloric acid 1-ethyl-3-(3-dimethyl esters aminopropyl) carbodiimides (143mg0.75mmol), I-hydroxybenzotriazole hydrate (160mg, 0.75mmol), triethylamine (311 μ L, 2.25mmol) and N, N-dimethyl aminopyridine (catalytic amount).The mixture that produces in covering test tube with microwave heating (140 ℃, 10min).With EtOAc diluted mixture thing, saturated NaHCO ₃Solution washing, dry (Na ₂SO ₄) with concentrated.Residue is placed diox, under 50 ℃, be added to TiCl ₄(0.55mL, 0.55mmol, 1M in the toluene) (0.22g is 2.5mmol) in the De diox mixture with piperazine.Stir the mixture overnight that produces down at 100 ℃, be cooled to room temperature then.(3mL, 2M), water is with EtOAc (2 * 4mL) extractions then to add the HCl aqueous solution in mixture.(6mL, 2M), the float of generation is with EtOAc (3 * 3mL) extractions to add the NaOH aqueous solution to aqueous phase.The organic facies that merges is concentrated, then with the HPLC purification.

Embodiment 99:2-bromo-8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO63A)

According to GP6, (78mg, 0.5mmo1) (231mg, 1mmo1) reaction gets 13mg target compound (189JO63A) with 5-bromo-2 hydroxybenzoic acid methyl ester with 4-fluoro-3-Methylnitrobenzene.MS(ESI)372(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 100:7-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (1889JO63B)

According to GP6, (88mg, 0.5mmol) (166mg, 1mmol) reaction gets 24mg target compound (189JO63B) with 2-hydroxy-3-methyl essence of Niobe with 4-chloro-2-fluoronitrobenzene.MS(ESI)328(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 101:8-phenyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

(189JO64)

To 8-bromo-10H-dibenzo [b, f] [1,4] oxygen azepine

-11-ketone (189JO56) (30mg, 0.12mmol), phenylboric acid (18mg, 0.15mmol) and K ₂CO ₃(34mg, the toluene/EtOH/H that sloughs oxygen 0.24mmol) ₂Add tetrakis triphenylphosphine palladium (0) (catalytic amount) in O (1.5mL) mixture, the mixture of generation in covering test tube, in microwave oven the heating (140 ℃, 15min).Mixture is with EtOAc dilution, saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄) with concentrate 8-phenyl lactams crude product.Under 50 ℃, intermediate 8-phenyl lactams De diox (1mL) mixture is added to TiCl ₄(0.27mL, 0.27mmol, 1M in the toluene) (0.103g is 1.2mmol) in the De diox mixture with piperazine.Under 100 ℃, stir the mixture overnight that produces, be cooled to room temperature then.(3mL, 2M), water is with EtOAc (2 * 4mL) extractions then to add the HCl aqueous solution in mixture.(6mL, 2M), the float of generation extracts with EtOAc (3x3mL) to add the NaOH aqueous solution to aqueous phase.The organic facies that merges is splined on the SCX-2 ion exchange column.After post washed with MeOH, product was with NH ₃(7N among the MeOH) eluting, concentrated reaching gets 16mg target compound (189JO64) through the HPLC purification.MS(ESI)356(MH ⁺)。MH ⁺Purity (UV/MS) be 100/99.

Embodiment 102:8-chloro-11-(piperidin-4-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE67A)

Under 50 ℃, (use zinc metal and Bromofume (0.8mmol) to be added to 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas 4-CBZ-piperidyl zinc iodide from 4-CBZ-piperidyl iodine (345mg, 1.0mmol) preparation)

(160FE64) (106mg, 0.4mmol) and PdCl ₂(PPh ₃) ₂(18mg is in dry THF 0.04mmol) (2ml) solution.Behind the oscillating reactions 16h, add saturated NH ₄The Cl aqueous solution finishes reaction.With the mixture twice that ether extraction produces, the ether of merging is with the salt water washing, drying (Na ₂SO ₄).After the filtration, the concentrating under reduced pressure organic facies gets the product crude product.Under-30 ℃, with BBr ₃(100 μ l) is added to the CH of product crude product ₂Cl ₂(1ml) in the solution.Reaction temperature will slowly rise to 0 ℃ then.TLC shows that initiation material changes fully, in succession with Et ₃N, H ₂O and EtOAc are added in the reactant mixture.Organic facies is with salt water washing and drying (Na ₂SO ₄).After the filtration, the concentrating under reduced pressure organic facies gets the product crude product, gets 2.3mg target compound (160FE67A) through the HPLC purification.MS(ESI)312(MH ⁺)。MH ⁺Purity (UV/MS) be 99/96.

Embodiment 103:5-benzyl-8-chloro-11-(piperidin-4-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE67B)

Separation of by-products 4.4mg target compound (160FE67B) as synthetic embodiment 102.MS(ESI)402(MH ⁺)。MH ⁺Purity (UV/MS) be 85/87.

Embodiment 104: universal method 7 (GP7)

With 2-amino benzoic Acid (1eq.), 2-fluoronitrobenzene (2eq. or 3eq.) and K ₂CO ₃DMF mixture (3eq.) be warming up to 100 ℃ 2 hours, be cooled to room temperature then.Organic facies is with 0.1MNaOH aqueous solution extraction (3x).The water that merges is with 4M HCl acidified aqueous solution, with EtOAc extraction (3x).Dry (Na ₂SO ₄) merging organic facies and concentrated.Residue is placed EtOH, add ₂CO ₃(5eq.) and Na ₂S ₂O ₄(5eq.) aqueous solution stirs the mixture 1h that produces.Mixture is concentrated, and residue places EtOAc again.Mixture with HCl aqueous solution (2M) acidify after, with EtOAc (3x) aqueous phase extracted, the organic facies that concentrate to merge.

Residue is placed dimethylbenzene, and the mixture of generation spends the night in 130 ℃ of stirrings.Mixture dilutes with EtOAc, saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄), concentrate and flash chromatography (SiO ₂, heptane: the EtOAc system).

Embodiment 105:8-bromo-5,10-dihydro-hexichol [b, e] [1,4] diaza

-11-ketone (166JO31)

According to GP7, (1.6g, 7.4mmol) (0.50g, 3.6mmol) reaction gets 331mg target compound (166JO31) with the 2-amino benzoic Acid with 5-bromo-2-fluoronitrobenzene.MS(ESI)289(MH ⁺)。MH ⁺Purity (UV) be 93%.

Embodiment 106:5,10-dihydro-dibenzo [b, e] [14] diaza

-11-ketone (160FE15A)

According to GP7, (847g, 6mmol) (274mg, 2.0mmol) reaction gets 130mg target compound (160FE15A) with the 2-amino benzoic Acid with the 2-fluoronitrobenzene.

Embodiment 107:8-fluoro-5,10-dihydro-dibenzo [b, e] [1,4] diaza -11-ketone (160FE15C)

According to GP7, with 2, (0.96g, 6mmol) (274mg, 2.0mmol) reaction gets 100mg target compound (160FE15C) to the 4-difluoro nitrobenzene with the 2-amino benzoic Acid.

Embodiment 108:8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64)

With N, (5.1ml, 40mmol) (2.8ml 30mmol) is added to 8-chloro-5 to the N dimethylaniline, 10-dihydro-dibenzo [b, e] [1,4] diaza with phosphorus oxychloride

(2.45g is in dry toluene 10mmol) (20ml) mixture for-11-ketone.Mixture is rocked 2h in 95 ℃.Reduce temperature then, use the oil pump decompression to remove excessive N, accelerine and phosphorus oxychloride.Remaining grease is dissolved in diox (20ml), adds Na ₂CO ₃Aqueous solution (10ml, 2M).Under 80 ℃, rock two-phase mixture 30min.Reduce temperature then, ether is added in the reactant mixture.Ether is with saturated NaCl solution washing, drying (Na ₂SO ₄), last concentrating under reduced pressure.The oil of gained places crystallization under the room temperature, and recrystallization (heptyl ether) gets 1.8g (69%) target compound (160FE64). ¹HNMR(CDCl ₃)δ7.61(dd，1H，J＝1.4，7.8Hz)，7.31(dt，1H，J＝1.5，8.0Hz)，7.15(d，1H，J＝2.5Hz)，7.02(m2H)，6.66(dd，1H，J＝1.0，7.8Hz)，6.58(d，1H，J＝8.4Hz)，4.94(bs，1H)。 ¹³C NMR(CDCl ₃)δ157.2，152.4，140.3，138.9，134.0，131.9，129.7，128.5，128.0，127.0，123.5，121.0，119.8。

Embodiment 109:8-chloro-11-methyl mercapto-5H-dibenzo [b, e] [1,4] diaza

(166JO50)

With 8-chloro-5,10-dihydro-dibenzo [b, e] [1,4] diaza

-11-ketone (500mg, 2.05mmol) with 2, two (the 4-methoxyphenyls)-1 of 4-, 3-dithio-2,4-two phosphetane-2, (480mg, toluene 1.19mmol) (4mL) mixture covers in test tube 4-sulfur, with microwave oven heating (120 ℃, 30 minutes).With mixture chromatography (SiO ₂, heptane: EtOAc, 2: 1) and must 599mg intermediate thio lactam.In the THF of intermediate thio lactam (10mL) mixture, add MeI (633 μ L, 10.3mmol), with the mixture heated backflow 4h that produces.Enriched mixture gets 610mg target compound crude product (166JO50) (purity 50%).

Embodiment 110-N, N-diethyl (2-bromobenzyl) amide (189JO10)

Under 0 ℃, to 2-bromo-benzoyl chloride (3.5g, CH 16mmol) ₂Cl ₂(3.2mL 32mmol), is cooled to room temperature with the mixture that produces (50mL) to be added dropwise to diethylamine in the mixture.After 30 minutes, add entry, mixture is with CH ₂Cl ₂Dilution, saturated NaHCO ₃Aqueous solution and saturated NH ₄Cl solution washing, drying (Na ₂SO ₄) and concentrate 3.9g (95%) target compound (189JO10). ¹H NMR(CDCl ₃)δ7.54(m，1H)，7.32(m，1H)，7.22(m，2H)，3.79(m，1H)，3.33(m，1H)，3.13(m，2H)，1.26(t，3H，J＝7.2Hz)，1.05(t，3H，J＝7.0Hz)， ¹³C NMR(CDCl ₃)δ168.5，139.0，132.8，130.0，127.61，127.59，119.3，42.8，39.0，14.0，12.6。

Embodiment 111:2-[4-chloro-2-aminomethyl phenyl)-(4-methoxy-benzyl)-amino]-N, the N-diethylbenzene Methanamide (189JO26)

To N, (1.41g, 5.50mmol) (1.01g adds NaO in the toluene of sloughing oxygen (14mL) mixture 7.15mmol) to N-diethyl (2-bromobenzyl) amide (189JO10) with 4-chloro-2-aminotoluene ^t(0.74g, 7.7mmol), (110mg is 0.17mmol) with Pd (OAc) for raceme BINAP for Bu ₂(18mg 0.08mmol), under 80 ℃ of argon shields, stirs 14h with the mixture that produces.Mixture concentrates, through flash chromatography (SiO with diatomite filtration ₂, heptane: EtOAc, 10: 1-4: 1) get unprotected intermediate ketone (1.05g), comprise about 15% impurity.

The mixture that will comprise intermediate is dissolved in DMF (20ml).(0.90mL, 6.6mmol), gradation adds NaH (0.23g, 5.6mmol is in the mineral oil 60%) then to methoxy-benzyl chlorine in adding.The mixture of gained adds saturated sodium bicarbonate solution and finishes reaction behind stirring at room 1h.Mixture dilutes through EtOAc, saturated sodium bicarbonate aqueous solution washing, dry (Na ₂SO ₄), concentrate flash chromatography (SiO ₂, toluene: EtOAc 10: 1) and must 1.66g target compound (189JO26). ¹H NMR(CDCl ₃)δ7.35(m，2H)，7.20(m，1H)，7.9-6.99(m，4H)，6.91(m，2H)，6.80(m，2H)，4.84/4.54(Abq，2H，J＝16.2Hz)，3.74(s，3H)，3.18(m，2H)，3.03(m，1H)，2.48(m，1H)，2.17(s，3H)，1.01(t，3H，J＝7.2Hz)，0.97(t，3H，J＝7.0Hz)， ¹³C NMR(CDCl ₃)δ169.6，158.7，146.53，146.51，137.0，131.3，130.9，130.4，129.6，129.3，128.7，127.8，127.4，126.3，122.8，121.4，114.0，57.1，55.3，43.3，39.0，19.1，13.9，12.9.MS(ESI)437(MH ⁺)。

Embodiment 112:2-chloro-5-(4-methoxy-benzyl)-5,11-dihydro-dibenzo [b, f] azepine

-11- Ketone (189JO27)

Under-20 ℃, to diisopropylamine (1.09mL, 7.8mmol) and N, N, N, N-tetra-methylenedimine (1.17mL, 7.8mmol) dry THF (19mL) mixture add n-BuLi (5.54mL, 1.4M in the hexane), stirred the mixture that produces down 5 minutes at-20 ℃.Then with 2[(4-chloro-2-aminomethyl phenyl)-(4-methoxy-benzyl)-amino]-N, (1.36g, dry THF 3.1mmol) (38mL) mixture adds N diethylbenzene Methanamide (189JO26), stirs the mixture 4h that produces down at-20 ℃.Add saturated NH ₄The Cl aqueous solution finishes reaction.Mixture dilutes through EtOAc, water washing, dry (Na ₂SO ₄), concentrate and flash chromatography (SiO ₂, toluene: heptane, 7: 1-1: 0) get 665mg (59%) target compound (189JO27). ¹HNMR(CDCl ₃)δ8.15(dd，1H，J＝1.8，8.0Hz)，7.43(m，1H)，7.24(m，4H)，7.17(d，1H，J＝8.6Hz)，7.12(dd，1H，J＝2.4，8.6Hz)，7.00(dt，1H，J＝0.8，7.0Hz)，6.81(m，2H)，5.09(s，2H)，4.00(s，2H)，3.75(s，3H)； ¹³CNMR(CDCl ₃)δ190.3，159.1，149.5，146.2，134.1，132.4，131.3，131.1，129.1，129.0，128.6，127.3，126.4，123.4，121.0，118.5，114.2，55.5，19.3.MS(ESI)364(MH ⁺)。

Embodiment 123:2-(4-chloro-2-nitro-phenyl sulfenyl)-benzoic acid methyl ester (189JO09)

(176mg, 1mmol) (275 μ L add CS in DMF 2mmol) (5mL) mixture with thio-methyl salicylate to 5-chloro-2-nitro fluorobenzene ₂CO ₃(652mg 2mmol), at room temperature stirs 2h with the mixture that produces.With mixture through CH ₂Cl ₂Dilution, water washing, drying (Na ₂SO ₄), concentrate and flash chromatography (SiO ₂, heptane: toluene, 1: 10-1: 4) get 300mg (92%) target compound (189JO09). ¹H NMR(CDCl ₃)δ8.15(d，1H，J＝2.4Hz)，7.94(m，1H)，7.53-7.46(m，3H)，7.34(dd，1H，2.4，8.6Hz)，6.95(d，1H，J＝8.8Hz)，3.82(s，3H)。

Embodiment 114:2-(2-amino-4-chlorphenyl sulfenyl)-benzoic acid methyl ester (189JO11)

(232mg adds SnCl in EtOH 0.72mmol) (5mL) mixture to 2-(4-chloro-2-nitro-phenyl sulfenyl)-benzoic acid methyl ester (189JO09) ₂2H ₂(812mg, 3.6mmol), the mixture of generation stirs 2h to O under 80 ℃, concentrate then.Residue is handled with ice, added Na then ₂CO ₃Reach 10 until pH.Add EtOAc, slurry is with diatomite filtration.With EtOAc phase Yi Shui and salt water washing, drying (Na ₂SO ₄) with concentrate 149mg (70%) target compound (189JO11). ¹HNMR(CDCl ₃)δ8.02(dd，1H，J＝1.6，7.8Hz)，7.39(d，1H，J＝8.2Hz)，7.29(m，1H)，7.15(dt，1H，J＝1.2，7.8Hz)，6.87(d，1H，J＝2.2Hz)，6.80(dd，1H，J＝2.2，8.2Hz)，6.76(dd，1H，J＝1.2，8.0Hz)，3.96(s，3H)。

Embodiment 115-8-chloro-10H-dibenzo [b, f] [1,4] sulfur azepine -11-ketone (189JO13)

With 2-(2-amino-4-chlorphenyl sulfenyl)-benzoic acid methyl ester (189JO11) (149mg, 0.51mmol) and AlMe ₃The CH of (355 μ L, 0.71mmol, 2M in the toluene) ₂Cl ₂(3mL) the mixture stirring at room is 6 days, carefully adds entry then.Mixture is with CH ₂Cl ₂Dilution, 2M HCl acidified aqueous solution.Tell organic facies, dry (Na ₂SO ₄), concentrate and flash chromatography (heptane: EtOAc, 5: 1-3: 1) get 38mg (29%) target compound (189JO13).MS(ESI)262(MH ⁺)。

Embodiment 116-2-(chloro-2-nitro-phenoxy group)-benzoic acid methyl ester (189JO29A)

With CS ₂CO ₃(1.30g, (352mg, 2mmol) (0.52mL in DMF 4mmol) (6mL) mixture, at room temperature stirs 2h with the mixture that produces with the 2 hydroxybenzoic acid methyl ester 4mmol) to be added to 5-chloro-2-nitro fluorobenzene.Mixture is through CH ₂Cl ₂Dilution, water washing, drying (Na ₂SO ₄), concentrate and flash chromatography (SiO ₂, heptane: EtOAc, 10: 1-4: 1) get 505mg (82%) target compound (189JO29A). ¹H NMR(CDCl ₃)δ8.02(dd，1H，J＝1.8，7.8Hz)，7.96(d，1H，J＝1.9Hz)，7.59(dt，1H，J＝2.0，7.6Hz)，7.39(dd，1H，J＝2.5，9.0Hz)，7.24(dt，1H，J＝1.2，7.6Hz)，7.13(dd，1H，J＝1.2，8.0Hz)，6.74(d，1H，J＝9.0Hz)，3.77(s，3H)。

Embodiment 117-8-chloro-10H-dibenzo [b, f] [1,4] oxygen azepine

-11-ketone (189JO29C)

Pd (catalytic amount, content 5% on carbon) is added to 2-(chloro-2-nitro-phenoxy group)-benzoic acid methyl ester (189JO29A), and (505mg is in EtOAc 1.64mmol) (20mL) solution, with the mixture hydrogenation (H that produces ₂, 1atm.) 48h is then with diatomite filtration and concentrated.Residue is placed toluene (6mL), add NaH (160mg, 4.0mmol is in the mineral oil 60%).Under 80 ℃, the mixture stirring that produces is spent the night, add saturated NH then ₄The Cl aqueous solution finishes reaction.The mixture that produces dilutes water washing, drying (Na through EtOAc ₂SO ₄), concentrate and flash chromatography (SiO ₂, toluene: EtOAc, 4: 1), get 171mg (42%) target compound (189JO29C). ¹H NMR(CDCl ₃)δ8.12(bs，1H)，7.95(dd，1H，J＝1.8，8.0Hz)，7.54(dt，1H，J＝1.8，8.0Hz)，7.29-7.19(m，3H)，7.08(dd，1H，J＝2.3，8.6Hz)，7.04(d，1H，J＝2.3Hz)。MS(ESI)246(MH ⁺)。

Embodiment 118:3-chloro-5,11-dihydro-dibenzo [b, e] azepine

-6-ketone (189JO59)

To 5-chloro-2-aminomethyl phenyl isocyanates (100 μ L, CCl 0.73mmol) ₄(118L, 0.88mmol) and 2, two (isopropyl cyanide) (catalytic amounts) of 2 '-azo are with the mixture backflow 20h that produces (2mL) to add sulfonic acid chloride in the mixture.Mixture is cooled to room temperature, then with CH ₂Cl ₂Dilution, saturated NaHCO ₃Solution washing, drying (Na ₂SO ₄) with concentrated.Mixture is placed benzene (2mL), add AlCl ₃(160mg, benzene 1.2mmol) (1mL) mixture.The mixture that produces stirs 4h down in 80 ℃, then, is cooled to room temperature.Mixture is filtered short column (SiO ₂, heptane: EtOAc, 1: 1) and must 25mg (14%) target compound (189JO59). ¹HNMR(CDCl ₃)δ8.18(bs，1H)，7.92(dd，1H，J＝1.2，7.8Hz)，7.46(dt 1H，J＝1.4，7.4Hz)，7.34(dt，1H，J＝1.2，7.4Hz)，7.23(m，2H)，7.07(m，2H)，3.92(s 2H)。MS(ESI)244(MH ⁺)。

Embodiment 119:8-bromo-10H-dibenzo [b, f] [1,4] oxygen azepine

-11-ketone (189JO56)

With the 2 hydroxybenzoic acid methyl ester (1.0mL, 10.0mmol), 5-bromo-2-fluoronitrobenzene (0.62mL, 5.0mmol) and CS ₂CO ₃(3.3g, DMF 10.0mol) (12mL) mixture stirs 2h in 40 ℃.Mixture is with EtOAc dilution, 2M NaOH solution washing.Be added to EtOH, H to EtOAc ₂O, K ₂CO ₃(2.8g, 20mmol) and Na ₂S ₂O ₄(3.5g, 20mmol), with the mixture vigorous stirring 1h that produces.Tell water, organic facies concentrates then with 1M NaOH solution washing.Residue is placed DMF (1mL), add toluene (4mL) and NaH (60mg, 1.5mmol is in the mineral oil 60%) then, the mixture of generation spends the night in 80 ℃ of stirrings, adds saturated NH then ₄The Cl aqueous solution finishes reaction.The mixture that produces dilutes 2M NaOH solution washing, drying (Na through EtOAc ₂SO ₄), concentrate, by short SiO ₂Post filters, and concentrate and heptane: the EtoAc crystallization gets 130mg target compound (189JO56).MS(ESI)290(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 120: universal method 8 (GP8)

The diamidogen (1.8eq..) of BOC-protection is added to 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza

(166JO50) (purity 50% is in pyridine solution 1eq.).With the mixture 110 ℃ of heating 66h in covering test tube that produce.Mixture is concentrated the back with CH ₂Cl ₂: trifluoroacetic acid (2: 1 ratios) dilution.The mixture overnight that stirring at room produces concentrates then.Residue is placed CH ₂Cl ₂In, with saturated NaHCO ₃Solution washing.Organic facies is splined on the SCX-2 ion exchange column.After post washed with MeOH, product was with NH ₃(7N among the MeOH) eluting, concentrate and through the HPLC purification.

Embodiment 121:(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-(S)-the 1-pyrrolidine -2-base-methyl-amine (166JO51)

According to GP8, with 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [[1,4] diaza

(166JO50) (50mg, 0.11mmol) with (S)-(2-amino methyl)-1-N-(tert-butoxycarbonyl amino)-pyrrolidine (39mg, 0.2mmol) reaction, 3.0mg target compound (166JO51).MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/92.

Embodiment 122:1-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-piperidin-4-yl- Amine (166JO55)

According to GP8, with 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza

(166JO50) (50mg, 0.11mmol) (39mg, 0.2mmol) reaction gets 6.5mg target compound (166JO55) with 4-(tert-butoxycarbonyl amino)-amino piperidine.MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/99.

Embodiment 123:1-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-pyrrolidine-3- Base-amine (166JO64)

According to GP8, with 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza

(166JO50) (100mg, 0.22mmol) (73mg, 0.4mmol) reaction gets 8.1mg target compound (166JO64) with 3-(tert-butoxycarbonyl amino) pyrrolidine.MS(ESI)313(MH ⁺)。MH ⁺Purity (UV/MS) be 100/94.

Embodiment 124:(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-(R)-the 1-pyrrolidine -2-base-methyl-amine (166JO70)

According to GP8, with 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza

(166JO50) (100mg, 0.22mmol) with (R)-(2-amino methyl)-1-N-(tert-butoxycarbonyl amino)-pyrrolidine (78mg, 0.4mmol) reaction, 7.6mg target compound (166JO70).MS(ESI)327(MH ⁺)。MH ⁺Purity (UV/MS) be 100/90.

Embodiment 125:(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl)-pyrrolidine-3-base- Amine (166JO74)

According to GP8, with 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza (166JO50) (100mg, 0.22mmol) (73mg, 0.4mmol) reaction gets 7.7mg target compound (166JO74) with 3-amino-1-N-(tert-butoxycarbonyl amino) pyrrolidine.MS(ESI)313(MH ⁺)。MH ⁺Purity (UV/MS) be 100/90.

Embodiment 126:8-chloro-11-(2,5-diaza-bicyclo-[2.2.1] heptan-2-yl)-5H-dibenzo [b, E] [1,4] diaza (166JO39-2)

According to GP8, with 8-chloro-11-methyl sulfenyl-5H-dibenzo [b, e] [1,4] diaza

(166JO50) (50mg, 0.11mmol) with N-(tert-butoxycarbonyl amino)-2, (34mg, 0.2mmol) reaction gets 15mg target compound (166JO39-2) to 5-diazabicylo [2.2.1] heptane.MS(ESI)324(MH ⁺)。MH ⁺Purity (UV/MS) be 93/100.

Embodiment 127: ethyl acetate-3 base-(8-chloro-5H-dibenzo [b, e] [1,4] diaza

-11-yl) Amine (189JO65)

To 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64) (30mg, 0.11mmol) add in De diox (2.0mL) solution 3-amino-azetidine-1-carboxylic acid tertiary butyl ester (59mg, 0.34mmol) and CS ₂CO ₃(74mg, 0.23mmol), the mixture of generation in covering test tube with microwave heating (170 ℃, 40 minutes).Mixture dilutes with EtOAc, water washing, drying (Na ₂SO ₄) with concentrated.Residue is placed CH ₂Cl ₂(2mL), add trifluoroacetic acid (1mL).The mixture that produces concentrates after stirred overnight at room temperature.Residue is placed CH ₂Cl ₂In, with saturated NaHCO ₃Solution washing.Organic facies is splined on the SCX-2 ion exchange column.Post washs with MeOH, and product is with NH then ₃(7N among the MeOH) eluting, concentrated reaching get 16mg target compound (189JO65) through the HPLC purification.MS(ESI)299(MH ⁺)。MH ⁺Purity (UV/MS) be 97/90.

Embodiment 128: universal method 9 (GP9)

With 3-amino methyl ester (1eq.), 5-bromo-2-fluoronitrobenzene (1eq.) and K ₂CO ₃DMF mixture (4eq.) is cooled to room temperature then in 60 ℃ of heating 1 hour.Mixture is with CH ₂Cl ₂Dilution, saturated NH ₄Cl solution washing, drying (Na ₂SO ₄) with concentrated.Residue is placed EtOH, add K ₂CO ₃(5eq.) and Na ₂S ₂O ₄Aqueous mixtures (5eq.), the mixture 1h that vigorous stirring produces.Water extracts with EtOAc (3x), dry (Na ₂SO ₄) organic facies that merges and concentrating.

Residue is placed CH ₃Among the CN, add H ₂SO ₄(10vol-%, 98%), the mixture of generation stirs 1h in 80 ℃.Mixture is with CH ₂Cl ₂Dilution, saturated NaHCO ₃Solution washing, drying (Na ₂8O ₄), concentrate, through flash chromatography (SiO ₂The EtOAc-system) and concentrate and to obtain the intermediate lactams, heptane:.

Residue is placed diox and is added to TiCl4 (1.1eq., 1M in the toluene) and piperazine (5eq.) De diox mixture in 50 ℃.Stir the mixture overnight that produces down at 100 ℃, be cooled to room temperature then.Add HCl aqueous solution (2M) and be acid until solution in mixture, water extracts with EtOAc (2x) then.Add NaOH aqueous solution (2M) to water and be alkalescence until solution, the float of generation extracts with EtOAc (3x).The organic facies that concentrate to merge and through quickflashing chromatography (SiO ₂, CH ₂CI ₂: MeOH, NH ₃(7N among the MeOH))-system.

Embodiment 129:7-bromo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza (166JO47)

According to GP9, (440mg, 2.0mmol) (920mg, 3.0mmol) reaction gets 4.0mg target compound (166JO with 3-alanine methyl ester hydrochloride with 5-bromo-2-fluoronitrobenzene ₄7).MS(ESI)309(ME)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 130:7-bromo-2-methyl-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza

(166JO95)

According to GP9, (440mg, 2.0mmol) (787mg, 3.0mmol) reaction gets 12mg target compound (166JO95) with 3-aminobutyric acid methyl ester with 5-bromo-2-fluoronitrobenzene.MS(ESI)323(MH ⁺)。MH ⁺Purity (UV/MS) be 100/100.

Embodiment 131:7-bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] phenodiazine Assorted

(189JO20)

According to GP9, (440mg, 2.0mmol) (394mg, 1.5mmol) reaction gets 9.8mg target compound (166JO20) with 3-amino-3-phenylpropionic acid carbethoxy hydrochloride with 5-bromo-2-fluoronitrobenzene.MS(ESI)385(MH ⁺)。MH ⁺Purity (UV/MS) be 97/88.

Embodiment 132:-7-bromo-10-(piperazine-1-yl)-1,2,3,3a, 4,10a-six hydrogen-benzo [b] ring penta [e] [1,4] diaza

(166JO46)

According to GP2, with 5-bromo-2-fluoronitrobenzene (110mg, 0.5mmol) and suitable-2-amino-1-Cyclopentane carboxylic acid hydrochlorate (138mg, 0.75mmol) reaction, 3.0mg target compound (166JO46).MS(ESI)349(MH ⁺)。MH ⁺Purity (UV/MS) be 99/88.

Embodiment 133: universal method 10 (GP10)

At room temperature, (0.4mmol) is added to 8 with zincon, 5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64) (53mg, 0.2mmol) and PdCl ₂(PPh ₃) ₂(9mg is in dry THF 0.02mmol) (1ml) solution.(1-16h TLC), adds saturated NH then until transforming fully in the jolting reaction ₄The Cl aqueous solution finishes reaction.The mixture that produces is with the ether extracting twice, and the ether of merging is with salt water washing, Na ₂SO ₄Dry.Organic facies is filtered the back concentrating under reduced pressure and is got the product crude product, with column chromatography purification (heptane: the EtOAc-system).

Embodiment 134:8-chloro-11-(4-luorobenzyl)-5H-dibenzo [b, e] [1,4] diaza (160FE59)

According to GP10, with 4-luorobenzyl chlorination zinc (0.8ml, 0.5M among the THF, 0.4mmol) with 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64) (53mg, 0.2mmol) reaction gets 52mg target compound (160FE59.MS(ESI)337(MH ⁺)。MH ⁺Purity (UV/MS) be 90/90.

Embodiment 134:8-chloro-11-(4-fluorophenyl-5H-dibenzo [b, e] [1,4] diaza

(160FE70)

According to GP10, with 4-fluorophenyl zinc chloride (0.5ml, 0.5M among the THF, 0.4mmol) with 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas (160FE64) (26mg, 0.1mmol) reaction gets 23mg target compound (160FE70).MS(ESI)323(MH ⁺)。MH ⁺Purity (UV/MS) be 98/100.

Embodiment 135: universal method 11 (GP11)

(1ml 1M) is added to 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas with aqueous sodium carbonate under the room temperature

(160FE64) (53mg, and 0.2mmol) (26mg, 0.1mmol), Pd (PPh ₃) ₄(10mg) and suitable acid reagent (in the 0.12mmol) De dioxane solution.Then mixture is transformed (TLC) in 80 ℃ of joltings fully until ium chloride (imidoyl chloride).Temperature is reduced, in reactant mixture, add ether and water.Ether is with salt water washing, Na ₂SO ₄Dry.Organic facies is filtered the back concentrating under reduced pressure and is got the product crude product, uses column chromatography purification (heptane: the EtOAc system).

Embodiment 136:8-chloro-11-(4-nonyl phenyl)-5H-dibenzo [b, e] [1,4] diaza

(160FE63)

According to GP11, with 4-nonyl benzene ylboronic acid (30mg, 0.12mmol) with 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64) (26mg, 0.1mmol) reaction gets 25mg target compound (160FE63).MS(ESI)431(MH ⁺)。MH ⁺Purity (UV/MS) be 85/85.

Embodiment 137:8-chloro-11-(pyridin-4-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE69A)

According to GP11, with 4-pyridine-4-boric acid (14mg, 0.12mmol) with 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas

(160FE64) (26mg, 0.1mmol) reaction gets 9.3mg target compound (160FE69A.MS(ESI)306(MH ⁺)。MH ⁺Purity (UV/MS) be 98/95.Embodiment 138:8-chloro-11-(1H-pyrazoles-4-yl)-5H-dibenzo [b, e] [1,4] diaza

(160FE59)

According to GP11, with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoles (22mg, 0.12mmol) with 8,5-two chloro-5H-dibenzo [b, e] [1,4] diazas (160FE64) (26mg, 0.1mmol) reaction gets 8.7mg target compound (160FE69B.MS(ESI)295(MH)。MH ⁺Purity (UV/MS) be 95/100.

Embodiment 139: functional screening

Acceptor selection and the amplifying technique (R-SAT) of using U.S. Patent No. 5,707,798 to describe have been tested the activity of several chemical compounds disclosed herein to M-ChR, and its disclosure is in this all introducing, as a reference.These chemical compounds are to M1, and the effect (eff) and the ability of M2 and M3 receptor (are expressed as pEC ₅₀) be listed in table 1.

Table 1.

Title	M1		M2		M3
							eff	pEC 50	eff	pEC 50	eff	pEC 50
	2,7-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO85F1)	-2		-14		-
2-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO85F6)							-5		8		-
	2,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO85F2)	1		24		-

Title	M1		M2		M3
							8-bromo-2-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO85F3)	10		29	5.5	-
	2-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza (166JO85F7)	10		19		-
6-chloro-11-(piperazine-1-yl)-8-methyl ester trifluoroacetate-5H-dibenzo [b, e] [1,4] diaza (189JO77B)							-		-		-
	7-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE35B)	48	6.6	53	5.4	-
8-bromo-1-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE36A)							66	6.9	105	5.6	4
	8-bromo-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE40C)	8		44	5.4	-
4,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE41A)							78	7.2	118	6.0	44	6.8
	8-chloro-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE41B)	14		28	5.9	-
8-chloro-2-fluoro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE42A-F3)							32	6.8	121	5.5	-
	3,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE42B-F4)	34	6.9	58	5.8	-
2-bromo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FF43A-F6)							6		19		-

3,7-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE58D1)	15		19		-
							8-bromo-3-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE58D3)	31	6.6	34	6.5	-
3-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE58D6)	16		27	5.7	-
							3-chloro-11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza (160FE58D7)	11		-		-
7-chloro-2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [[1,4] diaza (160FE58E1)	-3		5		-
							2-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE58E6)	1		9		-
2-methyl isophthalic acid 1-(piperazine-1-yl)-8-methyl ester trifluoroacetate-5H-dibenzo [b, e] [1,4] diaza (160FE58E7)	15		14		-
							8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE74C)	92	7.2	162	6.0	16
1,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (203FE03)	-		84	5.7	-
							8-bromo-5-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO32)	92	6.4	75	5.6	-
7,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO28))	32	7.1	8		-

3,7-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE58D1)	15		19		-
							11-(piperazine-1-yl)-8-trifluoromethyl-5H-dibenzo [b, e] [1,4] diaza (166JO23)	53	6.5	131	5.5	-
11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE19A)	38	6.1	70	5.6	-
							8-fluoro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE19C)	32	6.7	95	5.7	-
11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza -8-nitrile (160FE19D)	49	6.6	106	6.0	-
							8-bromo-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE19E)	63	7.2	121	6.3	13
8-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE19F)	49	6.8	98	6.0	-

3-fluoro-6-piperazine-1-base-11H-dibenzo [b, e] azepine (160FE02)	23		55	6.1	-
							2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE13A)	-8		9		-
2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] oxygen azepine (160FE13B)	-11		4		-
							8-chloro-2-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE13C)	-2		16		-
8-(trifyl oxygen base)-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE13D)	19		62	5.6	-
							11-(piperazine-1-yl)-dibenzo [b, f] [1,4] sulfur azepine (160FE17A)	4		41	6.5	-
11-(piperazine-1-yl)-2,3-dihydro-1,4-Ben Bing bioxin is [6,7-b] [1,4] benzothiazepine also (160FE17B)	6		28		-
							8-chloro-11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza (160FE16A)	37	7.0	82	6.2	-
N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N, N-dimethyl-ethane-1,2-diamidogen (160FE16D)	4		11		-
							N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N, N-diethyl-ethane-1,2-diamidogen (160FE16E)	6		9		-
8-chloro-11-(4-methyl-[1,4] diazepam-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE16F)	18		50	5.9	-
							8-chloro-2-methoxyl group-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE20A)	7		7		-
N '-(5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N, N-dimethyl-ethane-1,2-diamidogen (160FE20B)	10		20		-
							11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza (160FE20C)	18		25		-
N '-(8-fluoro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N.N-dimethyl-ethane-1,2-diamidogen (160FE20D)	7		21		-
							8-fluoro-11-[1,4] diazepam-1-base-5H-dibenzo [b, e] [1,4] diaza (160FE16A)	25	6.7	67	6.6	-
N '-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-and N-methyl-ethane-1,2-diamidogen (160FE22)	5		8		-

8-chloro-11-(anti--2,5-dimethyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE33A) 8-chloro-11-(3,5-dimethyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE33B)	8 18		24 97	5.6	- -
							8-chloro-11-(3-methyl-piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE38)	28	7.0	159	5.8	19
8-chloro-11-(3-phenyl-Piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE45)	5		23		-
							8-chloro-5-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (189JO25A)	65	7.1	138	5.9	14
8-chloro-5-benzyl-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE46-PIPBN)	41	6.3	16		-
							8-iodo-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO38)	75	7.2	187	6.0	-
2-iodo-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO54)	3		10		-
							8-phenyl-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (189JO53)	-		104	5.7	-
8-chloro-11-(piperidines-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO69A)	47	5.8	9		-
							8-chloro-11-(morpholine-4-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO69B)	11		6		-
5-pi-allyl-8-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO68)	12		46	5.8	-
							6-chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza (189JO68)	-		71	5.4	-
8-chloro-5-piperazine-1-base-11H-benzo [b] pyrido [2,3-e] [1,4] diaza (166JO63)	51	5.5	7		-
							2-chloro-10-piperazine-1-base-5H-dibenzo [b, f] azepine (189JO39)	2		3		-
8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] sulfur azepine (189JO16)	11		52	5.9	- -

8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO31)	52	7.0	58	6.0	-
							8-chloro-11-(4-methyl-piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO47)	13		46	5.8	-
3-chloro-6-piperazine-1-base-11H-dibenzo [b, e] azepine (189JO60)	-		113	5.9	-
							8-bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO48A)	-		70	5.9	-
11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO48B)	-		58	5.7	-
							7-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50A)	-		53	5.9	-
8-chloro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50B)	-		19		-
							8-bromo-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50D)	-		21		-
3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50E)	-		45	5.6	-
							7-chloro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50F)	-		44	6.0	-
8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO50H)	-		71	6.2	-
							8-bromo-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51A)	-		48	5.8	-
4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51B)	-		22		-
							2-bromo-8-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51D)	-		13		-
2,8-two bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51E)	-		6		-
							2-bromo-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51F)	-		9		-

2-bromo-7-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO51G)	-		15		-
							11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine (189JO54A)	-		58	5.9	-
4-methyl isophthalic acid 1-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine (189JO54C)	-		75	6.1	-
							8-fluoro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO54E)	-		48	5.6	-
8-fluoro-3-methoxyl group-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO54F)	-		49	5.6	-
							8-fluoro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO54G)	-		50	5.8	-
2-bromo-8-fluoro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO54H)	-		21		-
							8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO58A)	-		76	5.5	-
3-methoxyl group-8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO58B)	-		45	5.5	-
							4,8-dimethyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO58C)	-		46	6.1	-
3-methoxyl group-11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine (189JO62A)	-		17		-
							2-bromo-11-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine (189JO62B)	-		11		-
6-chloro-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO69)	-		-		-
							2-bromo-8-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO63A)	-		17		-
7-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO63B)	-		28	6.4	-
							8-phenyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine (189JO64)	-		33	5.9	-
8-chloro-11-(piperidin-4-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE67A)	57	6.2	31	5.7	-

5-benzyl-8-chloro-11-(piperidin-4-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE67B)	12		5		-
							(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-(S)-1-pyrrolidine-2-base-methyl-amine (166JO51)	77	6.3	23		-
1-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-piperidin-4-yl-amine (166JO55)	6		95	5.6	-
							1-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-pyrrolidine-3-base-amine (166JO64)	8		36	5.5	-
(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-(R)-1-pyrrolidine-2-base-methyl-amine (166JO70)	4		5		-
							(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl)-pyrrolidine-3-base-amine (166JO74)	10		18		-
8-chloro-11-(2,5-diaza-bicyclo-[2.2.1] heptan-2-yl)-5H-dibenzo [b, e] [1,4] diaza (166JO39-2)	34	6.6	49	5.6	-
							Ethyl acetate-3-base-(8-chloro-5H-dibenzo [b, e] [1,4] diaza -11-yl) amine (189JO65)	-		17		-
7-bromo-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza (166JO47)	56	5.6	3		-
							7-bromo-2-methyl-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza (166JO95)	16		23		-
7-bromo-2-phenyl-4-(piperazine-1-yl)-2,3-dihydro-1H-benzo [b] [1,4] diaza (189JO20)	3		19		-
							7-bromo-10-(piperazine-1-yl)-1,2,3,3a, 4,10a-six hydrogen-benzo [b] ring penta [e] [1,4] diaza (166JO46)	50	5.8	12		-
8-chloro-11-(4-luorobenzyl)-5H-dibenzo [b, e] [1,4] diaza (160FE59)	3		7		-
							8-chloro-11-(4-fluorophenyl)-5H-dibenzo [b, e] [1,4] diaza (160FB70)	13		4		-
8-chloro-11-(4-nonyl phenyl)-5H-dibenzo [b, e[1,4] diaza (160FE63)	1		8		-
							8-chloro-11--(pyridin-4-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE69A)	6		6		-
8-chloro-11-(1H-pyrazoles-4-yl)-5H-dibenzo [b, e] [1,4] diaza (160FE59)	9		3		-

Claims (48)

1. the chemical compound that has formula I structure:

Or its officinal salt, wherein:

A has structure

Wherein each key table of representing of dotted line among the A and solid line shows the carbon-to-carbon singly-bound;

A, b, c and d are carbon;

E, f, g and h are carbon;

X is a nitrogen;

X ' is C;

L does not exist;

N is 1;

Y is a nitrogen;

W is a nitrogen;

R ₁Be hydrogen;

R ₂, R ₃, R ₄Be hydrogen;

R ₆, R ₈, R ₉Be hydrogen;

R ₅The C that be selected from halogen, replaces arbitrarily _1-6Alkyl, the C that replaces arbitrarily _1-6Alkoxyl, the C that replaces arbitrarily _2-6Thiazolinyl, the C that replaces arbitrarily _2-6Alkynyl, whole haloalkyl and CN;

R ₇The C that be selected from halogen, replaces arbitrarily _1-6Alkyl, the C that replaces arbitrarily _1-6Alkoxyl, the C that replaces arbitrarily _2-6Thiazolinyl, the C that replaces arbitrarily _2-6Alkynyl, whole haloalkyl and CN;

Z is selected from NR ₁₁, oxygen, sulfur and CH ₂

R ₁₁The C that be selected from hydrogen, replaces arbitrarily _1-6Alkyl, the C that replaces arbitrarily _3-8Cycloalkyl, the C that replaces arbitrarily _2-6Thiazolinyl, the C that replaces arbitrarily _2-6Alkynyl and the aralkyl that replaces arbitrarily; And

Each key table that dotted line and solid line are represented shows carbon-to-carbon double bond;

Wherein the group of above-mentioned any replacement can be selected from one or more following substituent groups replacements: cycloalkyl; aryl; heteroaryl; the heterolipid ring; hydroxyl; alkoxyl; aryloxy group; sulfydryl; alkylthio group; arylthio; cyano group; halogen; the O-carbamyl; the N-carbamyl; the O-thiocarbamoyl; the N-thiocarbamoyl; the C-amide groups; the N-amide groups; the S-sulfoamido; the N-sulfoamido; the C-carboxyl; the O-carboxyl; the isocyanide acyl group; the sulfo-cyanato; different sulfo-cyanato; nitro; silicyl; three halo mesyl and amino.

2. chemical compound as claimed in claim 1, wherein R ₅The C that be selected from halogen, replaces arbitrarily _1-6Alkyl.

3. chemical compound as claimed in claim 2, wherein said alkyl is selected from methyl, ethyl, propyl group and butyl.

4. chemical compound as claimed in claim 3, wherein said propyl group is an isopropyl.

5. chemical compound as claimed in claim 3, wherein said butyl are the sec-butyl or the tert-butyl group.

6. chemical compound as claimed in claim 2, wherein said halogen is selected from fluorine, chlorine and bromine.

7. chemical compound as claimed in claim 1, wherein R ₅Be chlorine.

8. chemical compound as claimed in claim 1, wherein R ₇The C that be selected from halogen, replaces arbitrarily _1-6Alkyl, whole haloalkyl and CN.

9. chemical compound as claimed in claim 8, wherein said alkyl is selected from methyl, ethyl, propyl group and butyl.

10. chemical compound as claimed in claim 9, wherein said propyl group is an isopropyl.

11. chemical compound as claimed in claim 9, wherein said butyl are the sec-butyl or the tert-butyl group.

12. chemical compound as claimed in claim 8, wherein said halogen is selected from fluorine, chlorine and bromine.

13. chemical compound as claimed in claim 8, wherein said whole haloalkyl are perfluoroalkyl.

14. chemical compound as claimed in claim 13, wherein said perfluoroalkyl are trifluoromethyl.

15. chemical compound as claimed in claim 1, wherein R ₇Be selected from methyl, chlorine, trifluoromethyl and CN.

16. chemical compound as claimed in claim 1 is selected from:

4,8-two chloro-11-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-5H-dibenzo [b, e] [1,4] diaza

8-chloro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

8-bromo-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

4-methyl isophthalic acid 1-(piperazine-1-yl)-8-trifluoromethyl-dibenzo [b, f] [1,4] oxygen azepine

8-fluoro-4-methyl isophthalic acid 1-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

With

4,8-dimethyl-11-(piperazine-1-yl)-dibenzo [b, f] [1,4] oxygen azepine

17. chemical compound as claimed in claim 1, wherein R ₅Be selected from the ethyl of fluorine, bromine, the methyl that replaces arbitrarily, replacement arbitrarily, the propyl group that replaces arbitrarily, the butyl that replaces arbitrarily, any C that replaces _2-6Thiazolinyl, the C that replaces arbitrarily _2-6Alkynyl, whole haloalkyl and CN.

18. chemical compound as claimed in claim 17, wherein said butyl are the sec-butyl or the tert-butyl group.

19. chemical compound as claimed in claim 1, wherein

R ₅Be selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, whole haloalkyl and CN;

R ₇Be selected from halogen, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, whole haloalkyl and CN;

R ₁₁Be selected from R ₁₁Be selected from hydrogen, C _1-6Alkyl, the C that replaces arbitrarily _3-8Cycloalkyl, C _2-6Thiazolinyl, C _2-6Alkynyl and aralkyl.

20. the method for synthesis type V chemical compound,

Comprise making formula VII chemical compound and the reaction of formula VIII chemical compound,

Form the fused ring compound of formula IX,

And the reaction of the chemical compound of the chemical compound of formula IX and formula X,

To obtain the chemical compound of formula V, wherein:

X is a halogen;

W is a nitrogen;

R ₁Be hydrogen;

R ₂, R ₃, R ₄Be hydrogen;

R ₆, R ₈, R ₉Be hydrogen;

R ₅The C that be selected from halogen, replaces arbitrarily _1-6Alkyl, the C that replaces arbitrarily _2-6Thiazolinyl, the C that replaces arbitrarily _2-6Alkynyl, whole haloalkyl and CN; And

R ₇The C that be selected from halogen, replaces arbitrarily _1-6Alkyl, the C that replaces arbitrarily _2-6Thiazolinyl, the C that replaces arbitrarily _2-6Alkynyl, whole haloalkyl and CN;

Wherein the group of above-mentioned any replacement can be selected from one or more following substituent groups replacements: cycloalkyl; aryl; heteroaryl; the heterolipid ring; hydroxyl; alkoxyl; aryloxy group; sulfydryl; alkylthio group; arylthio; cyano group; halogen; the O-carbamyl; the N-carbamyl; the O-thiocarbamoyl; the N-thiocarbamoyl; the C-amide groups; the N-amide groups; the S-sulfoamido; the N-sulfoamido; the C-carboxyl; the O-carboxyl; the isocyanide acyl group; the sulfo-cyanato; different sulfo-cyanato; nitro; silicyl; three halo mesyl and amino.

21. pharmaceutical composition comprises that the physiology goes up the chemical compound of acceptable carrier and claim 1.

22. compositions as claimed in claim 21, described carrier are diluent or excipient or its compositions.

23. pharmaceutical composition comprises the chemical compound of claim 1 and the medicine of treatment neuropsychiatric disease.

24. compositions as claimed in claim 23, wherein said neural psychotropic drugs are selected from selectivity 5-hydroxy tryptamine reuptake inhibithors, noradrenaline reuptake inhibitor, dopamine agonist, muscarinic receptor antagonist, antipsychotic drug, 5-hydroxy tryptamine 2A antagonist and anti-phase 5-hydroxy tryptamine 2A agonist.

25. compositions as claimed in claim 24, wherein said antipsychotic drug are selected from phenothiazines, phenyl butyl piperadione class, debenzapine class, benzisoxidil class and lithium salts.

26. compositions as claimed in claim 25, wherein said phenothiazines is selected from chlorpromazine, mesoridazine, prochlorperazine and thioridazine.

27. compositions as claimed in claim 25, wherein said phenyl butyl piperadione class is selected from haloperidol and pimozide.

28. compositions as claimed in claim 25, wherein said debenzapine class is selected from clozapine, loxapine, olanzapine and Quetiapine.

29. compositions as claimed in claim 25, wherein said benzisoxidil class is selected from risperidone and Ziprasidone.

30. compositions as claimed in claim 25, wherein said lithium salts are lithium carbonate.

31. compositions as claimed in claim 24, wherein said antipsychotic drug are selected from clozapine, prochlorperazine mesylate, Etrafon, Geodon, haloperidol, droperidol, Luo Xite, mellaril, molindone hydrochloride, tiotixene, Orap, fluphenazine hydrochloride, hydrochloric acid fluphenazine, promethazine, paspertin metoclopramide, Wei Sitong, Serentil, Seroquel, trifluoperazine, chlorprothixene, Thorazine, triavil, perphenazine and Zyprexa.

32. compositions as claimed in claim 24, wherein said selectivity 5-hydroxy tryptamine reuptake inhibithors is selected from fluoxetine, fluvoxamine, Sertraline, paroxetine, citalopram, dextrorotation citalopram, sibutramine, duloxetine and venlafaxine and officinal salt thereof.

33. compositions as claimed in claim 24, wherein said noradrenaline reuptake inhibitor is selected from thionisoxetine and reboxetine.

34. compositions as claimed in claim 24, wherein said dopamine agonist is selected from sumatriptan, Almogran, naratriptan, Frova, rizatriptan, Zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole and bromocriptine.

35. compositions as claimed in claim 24, wherein said 5-hydroxy tryptamine 2A antagonist is the chemical compound of formula XIV

36. be used for the treatment of the described chemical compound of the claim 1 of neuropsychiatric disease.

37. be used for the treatment of the described compositions of the claim 21 of neuropsychiatric disease.

38. be used for the treatment of the described compositions of the claim 22 of neuropsychiatric disease.

39. chemical compound as claimed in claim 36, wherein said neuropsychiatric disease are selected from the psychosis of schizophrenia and relevant spy's property sent out psychosis, anxiety neurosis, sleep disorder, inappetence, emotion disease, tourette's syndrome, drug induced psychosis and neurodegenerative diseases secondary.

40. chemical compound as claimed in claim 39, the depression that wherein said emotion disease is selected from severe depression, manic depressive illness and has psychotic features.

41. chemical compound as claimed in claim 39, wherein said neurodegenerative diseases are selected from Alzheimer and Heng Yandun disease.

42. as claim 37 or 38 described compositionss, wherein said neuropsychiatric disease is selected from the psychosis of schizophrenia and relevant spy's property sent out psychosis, anxiety neurosis, sleep disorder, inappetence, emotion disease, tourette's syndrome, drug induced psychosis and neurodegenerative diseases secondary.

43. compositions as claimed in claim 42, the depression that wherein said emotion disease is selected from severe depression, manic depressive illness and has psychotic features.

44. compositions as claimed in claim 42, wherein said neurodegenerative diseases are selected from Alzheimer and Heng Yandun disease.

45. described chemical compound of claim 1 or claim 21 or the 22 described compositionss purposes in the medicine of the preparation treatment neuropsychiatric disease relevant with the M1 receptor.

46. the purposes of each described compositions of described chemical compound of claim 1 or claim 21-35 in the psychosis of preparation treatment schizophrenia and relevant spy's property sent out psychosis, anxiety neurosis, sleep disorder, inappetence, emotion disease, tourette's syndrome, drug induced psychosis and neurodegenerative diseases secondary.

47. purposes as claimed in claim 46, the depression that wherein said emotion disease is selected from severe depression, manic depressive illness or has psychotic features.

48. purposes as claimed in claim 46, wherein said neurodegenerative diseases are selected from Alzheimer and Heng Yandun disease.