CN1761464A - Substituted p-diaminobenzene derivatives - Google Patents

Substituted p-diaminobenzene derivatives Download PDF

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CN1761464A
CN1761464A CNA2004800075074A CN200480007507A CN1761464A CN 1761464 A CN1761464 A CN 1761464A CN A2004800075074 A CNA2004800075074 A CN A2004800075074A CN 200480007507 A CN200480007507 A CN 200480007507A CN 1761464 A CN1761464 A CN 1761464A
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base
alkene
alkane
phenyl
amino
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N·汉津
M·罗特莱恩德
A·里岑
W·P·沃特森
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H Lundbeck AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms

Abstract

The present invention relates to aniline derivatives of the general formula I or pharmaceutically acceptable salts thereof and their use.

Description

Substituted right-diamino benzene derivant
Technical field
The present invention relates to is the substituted novel right-diamino benzene derivant of KCNQ family potassium-channel opener.This chemical compound can be used for preventing, treating and suppress the opening of KCNQ family potassium-channel is had the disease and the disease of response, and a kind of such disease is an epilepsy.
Background technology
Ion channel is to regulate the cell protein that the ion that comprises potassium, calcium, chloride and sodium flowed into and flowed out cell.Such passage is present in all animal and humans' the cell and influence comprises many processes of neuron transmission, muscle contraction and emiocytosis.
The mankind have the gene (Jentsch NatureReviews Neuroscience 2000,1,21-30) of the about coding of kind more than 70 potassium channel subelement, and these genes all have very big difference aspect 26S Proteasome Structure and Function.The neuron potassium channel of finding in brain mainly is responsible for keeping the repolarization of minus resting membrane electric potential and responsible control action current potential caudacoria.
A subclass of potassium channel gene is a KCNQ family.Shown that 4/5ths KCNQ gene mutation are the bases (JentschNature Reviews Neuroscience 2000,1,21-30) that comprise the some diseases of arrhythmia, deafness and epilepsy.
Think the molecule contact of the potassium channel that this KCNQ4 gene code is found in cochlea external capillary born of the same parents and vestibular apparatus I type hair cell, its sudden change can cause forming the heritability deafness.
KCNQ1 (KvLQT1) product of KCN1 (minimum K (+)-channel protein) gene in heart assembles and forms heart delayed rectifier sample K (+) electric current.The sudden change of this passage may cause a kind of 1 type heritability long QT syndrome (LQT1) of form and its formation with deafness, and relevant (RobbinsPharnzacolTlier 2001,90,1-19).
Found gene KCNQ2 and KCNQ3 in 1988 and show produce in the epilepsy of the mode of inheritance that it is being called as benign neonatal familial convulsions variation (Rogawski Trends inNeurosciences 2000,23,393-398).The albumen of KCNQ2 and KCNQ3 coded by said gene is confined to the generation of people and epilepsy and propagates relevant brain zone---(people such as Cooper in the pyramidal cell of cortex and Hippocampus, Proceedi77gs National Academy ofScie7zce U s A 2000,97,4914-4919).
KCNQ2 and KCNQ3 are two kinds of potassium channel subelements that form " M-electric current " when external the expression.Said M-electric current is a kind of potassium current of non--deactivation of finding in the neuronal cell of many types.In each cell type owing to be to cause unique lasting electric current in the action potential scope, so its aspect the controlling diaphragm irritability be dominance (Marrion AyanualReview Physiology 1997,59,483-504).The adjusting of M-electric current has remarkable effect to neuronal excitability, and for example the activation of this electric current will reduce neuronal excitability.Therefore the activator of the opener of these KCNQ passages or M-electric current will reduce neuronic overactivity and can be used for treatment, prevents or suppress epilepsy and be characterized as active over-drastic other disease of neuron and disease, excessive as neuronal excitability, comprise convulsibility disease, epilepsy and neuropathic pain.
Retigabine (D-23129 is disclosed in EP554543; N-(2-amino-4-(4-luorobenzyl amino)-phenyl) urethanes) with and analog.Retigabine be a kind of in vivo with the external convulsion chemical compound that all has wide spectrum and potent anticonvulsant properties.It is in a series of convulsion test of carrying out with rat and mice and at the genetic animal model---and be effective after by oral and intraperitoneal administration in the DBA/2 mouse model, said test comprises: electric inductive epilepsy, pentylenetetrazole, cocculin and the inductive epilepsy of N-methyl-D-aspartate ester (NMDA) (people such as Rostock, Epilepsy Research 1996,23,211-223).In addition, retigabine also is effective in the excited model of the tonsil of the partial seizure of complexity.In clinical trial, shown recently retigabine can effectively reduce the incidence rate of epileptic's epilepsy (people such as Bialer, Epilepsy Research 2002,51,31-71).
It is consistent to have shown that the pharmacology that retigabine activated K (+) electric current neuron in the neuronal cell and derivative this electric current and the pharmacology of the M-passage of being announced show, and it is at present with KCNQ2/3K (+) passage heteropolymer relevant.This shows that the activation of KCNQ2/3 passage may be the reason (people such as Wiclcenden that this material has some anti-convulsant activities, MolecularPharmacology 2000,58,591-600)-and may have similar application by other material that similar mechanism works.
Reported that also KCNQ 2 and 3 passages are raised (people such as Wickenden in the neuropathic pain model, Society for Neuroscience Abstracts 2002,454.7), and supposed potassium channel modulating agents all effective (people such as Schroder in neuropathic pain and epilepsy, Neuropharmacology 2001,40,888-898).
Shown that also retigabine is useful (Blackbum-Munro and Jensen European Journal of Pharmacology2003 in the neuropathic pain animal model, 460,109-116), and therefore hint that the KCNQ channel opener will can be used for treating the antalgesic that comprises neuropathic pain.
It is reported that KCNQ passage mRNA is confined in brain and other central nervous system zone relevant with pain (people such as Goldstein, Society for Neuroscienee Abstracts2003,53.8).
Except that the effect in neuropathic pain, the mRNA of KCNQ 2-5 means that in nervi trigeminus and dorsal root ganglion and the expression in the nuclei quintus afterbody sensation that the opener of these passages can also influence migraine pain handles (people such as Goldstein, Society forNeuroscienceAbstracts 2003,53.8).
The latest report proof is gone back the mRNA of expressing K CNQ3 and 5 in astrocyte and neurogliocyte except that the mRNA of KCNQ2.Therefore, KCNQ 2,3 and 5 passages can help the neuroprotective (people such as Noda, Society for Neuroscience Abstracts 2003,53.9) of regulating the synaptic activity among the CNS and helping the KCNQ channel opener.
Can prevent the expression of the inductive epilepsy state of rat kainic acid trailing edge neural degeneration and apoptosis labelling because shown retigabine; therefore; retigabine and other KCNQ regulator can show the effect (people such as Ebert that the neural degeneration aspect situation of epilepsy does not appear in protection; Epilepsia 2002; 43 Suppl 5,86-95).Its process with prevention patient epilepsy is relevant, promptly be anti--epileptogaenic.Shown that also retigabine has postponed another kind of epilepsy progressions model---and the process of rat hippocampus excitement (people such as Tober, European Journal OfPharmacology 1996,303,163-169).
Therefore, show that these character of retigabine and other KCNQ regulator can prevent the inductive neuron infringement of neuron overactivity institute, and can be used for treating neurodegenerative disease and alleviation epileptic's disease (or anti-epileptogaenic).
Knownly in clinical, treat for example gabapentin (people such as Watson very effective in this syndromic animal model of alcohol withdrawal syndrome and known other convulsion chemical compound with convulsion chemical compound such as benzodiazepine _ class and chlorethiazol, Neuropharmacology1997,36,1369-1375), therefore, expect that other convulsion chemical compound such as KCNQ opener are effective in this case.
For example found the mRNA (people such as Saganich of KCNQ 2 and 3 subelements in Hippocampus and the tonsil in the brain zone relevant with anxiety and affective behavior such as bipolar disorder, Journal ofNeuroscience 2001,21,4609-4624), it is reported, retigabine is effective (people such as Hartz in some anxiety-like behavior animal models, Journal ofPsychopharmacology 2003,17 suppl 3, A28, and in the treatment of bipolar disorder, used clinical other used convulsion chemical compound B16).
WO 200196540 discloses the application that is used for the insomnia by the regulator of expressing K CNQ2 and the formed M-electric current of KCNQ3 gene, and WO 2001092526 discloses and can treat the sleep disease with the KCNQ5 regulator.
WO01/022953 has described retigabine and has been used to prevent and treats neuropathic pain such as allodynia, hyperpathia pain, phantom pain, the neuropathic pain relevant with diabetic neuropathy and the application of relevant neuropathic pain with migraine.
WO02/049628 has described the application that retigabine is used for preventing, treat, suppress and improve anxiety disorder such as anxiety, generalized-anxiety disorder, panic anxiety, obsession, social phobia, behavior anxiety (pefformance anxiety), post-traumatic stress disorder, gross stress reaction, adjustment disorder, hypochondriacal disorder, separation anxiety disorder, agoraphobia and specific phobia.
WO97/15300 has described retigabine and has been used for the treatment of neurodegenerative disorders such as Alzheimer; Huntington Chorea; Sclerosis such as multiple sclerosis and amyotrophic lateral sclerosis; The Creutzfeld-Jalcob disease; Parkinson; AIDS or rubella virus, herpesvirus, Borrelia and the unknown inductive encephalopathy of pathogenic infection; The neural degeneration of wound-induced; The neuronal excitation transient state is as the state in drug withdrawal or poisoning; The application of the neurodegenerative disease of peripheral nervous system such as polyneuropathy and polyneuritis (polyneuritides).
Therefore, very need be the noval chemical compound of effective KCNQ family potassium channel openers.
Also need have the noval chemical compound of the character of improvement as retigabine with respect to the chemical compound that is known that KCNQ family potassium channel openers.Hope improves the parameter below one or more: half-life, clearance rate, selectivity, with interaction, bioavailability, effectiveness, preparation (formulability), chemical stability, metabolic stability, membrane permeability, dissolubility and the therapeutic index of other medicines treatment.The improvement of such parameter can cause the improvement such as following aspect:
Zero improves dosage regimen by the number that reduces by one day required dosage,
Zero is easy to many drug administrations in the patient,
● reduce side effect,
● enlarge therapeutic index,
● improve toleration or
● improve compliance.
General introduction of the present invention
An object of the present invention is to provide is the new compound of effective KCNQ family potassium channel openers.
Chemical compound of the present invention is substituted anil or its salt of general formula I
Wherein Y, U, X, Z, s, q, R 1, R 2And R 3Be defined as follows described.
The pharmaceutical composition that the invention still further relates to the chemical compound that comprises one or more formulas I with and use.
Detailed description of the present invention
Therefore, the present invention relates to substituted right-diamino benzene derivant or its salt of general formula I
Wherein s is 0 or 1;
U is O, S, SO 2, SO 2NR 11, CO-O or CO-NR 11Wherein
R 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 2And R 11Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Q is 0 or 1;
X is CO or SO 2Prerequisite be when X be SO 2The time q be 0;
Z is O or S;
R 1Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
R wherein 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Prerequisite is to work as R 2Be that halogen or cyano group are, s is 0; With
Prerequisite be when s be 1 and R 2U is O or S when being hydrogen atom or acyl group;
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-heterocycle alkane (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-Ar, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, NR 12R 12 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base, substituted NR randomly 12R 12 '-C 3-8-cycloalkanes (alkene) base, substituted NR randomly 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-heterocycle alkane (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Prerequisite is to work as R 3Be NR 12R 12 'The time, q is 0;
With
The group of Y expression XXIV, XXV, XXVI, XXVII, XXVIII, XXXXI or XXXXII:
Figure A20048000750700281
Or
Figure A20048000750700282
Wherein
This line is represented a kind of group shown in the Y to be connected to key on this carbon atom;
W is O or S;
V is N, C or CH;
T is N, NH or O;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3;
J is 0,1 or 2;
K is 0,1,2 or 3; With
Each R 5Be independently selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, C 1-6-alkane (alkene/alkynes) oxygen base, C 3-8-cycloalkanes (alkene) oxygen base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base, C 1-6-alkane (alkene/alkynes) oxygen base carbonyl, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 ', S-R 8And SO 2R 8, perhaps
Two R that adjoin 5Form a kind of one or two heteroatomic 5-8 person's ring that comprises with this aromatic group;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and Ar;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base-C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base-Ar and acyl group; Or
R 7And R 7 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises with this nitrogen-atoms; With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar and-NR 9R 9 'Wherein
R 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In one embodiment of the invention, the present invention relates to the chemical compound that s wherein is 1 formula I.
In another embodiment of the invention, the present invention relates to s wherein and be the chemical compound of 0 formula I.
In another embodiment of the invention, the present invention relates to wherein s and be 1 and U be the chemical compound of the formula I of O.
In another embodiment of the invention, the present invention relates to wherein s and be 1 and U be the chemical compound of the formula I of S.
In another embodiment of the invention, the present invention relates to wherein s and be 1 and U be SO 2The chemical compound of formula I.
In another embodiment, the present invention relates to wherein s be 1 and U be SO 2NR 11The chemical compound of formula I.In this compounds, SO 2NR 11Sulphur atom be connected on the phenyl ring of formula I, and nitrogen-atoms is connected to R 2On.
In another embodiment, the present invention relates to wherein s be 1 and U be the chemical compound of the formula I of CO-O.In this compounds, the carbonyl of CO-O is connected to the phenyl ring of formula I, and oxygen atom is connected to R 2On.
In another embodiment, the present invention relates to wherein s be 1 and U be CO-NR 11The chemical compound of formula I.In this compounds, CO-NR 11Carbonyl be connected on the phenyl ring of formula I, and nitrogen-atoms is connected to R 2On.
In another embodiment, the present invention relates to wherein R 11It is the chemical compound of the formula I of hydrogen atom.
In another embodiment, the present invention relates to wherein, X is the chemical compound of the formula I of CO.
In another embodiment, the present invention relates to wherein, X is SO 2The chemical compound of formula I, prerequisite be when X be SO 2The time, during q 0.
In another embodiment, the present invention relates to the chemical compound that q wherein is 0 formula I.
In another embodiment, the present invention relates to the chemical compound that q wherein is 1 formula I.
In another embodiment, the present invention relates to wherein q be 1 and Z be the chemical compound of the formula I of O.
In another embodiment, the present invention relates to wherein q be 1 and Z be the chemical compound of the formula I of S.
In another embodiment, the present invention relates to wherein that X is CO, q be 1 and Z be the chemical compound of the formula I of O.
In another embodiment, the present invention relates to wherein that X is CO, q be 1 and Z be the chemical compound of the formula I of S.
In another embodiment, the present invention relates to X wherein is that CO and q are the chemical compounds of 0 formula I.
In another embodiment, the present invention relates to wherein, X is SO 2With q be the chemical compound of 0 formula I.
In another embodiment, the present invention relates to wherein R 1Be selected from acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base-C6-alkane (alkene/alkynes) base.
One embodiment of the invention relate to wherein R 1Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the general formula I of-alkane (alkene/alkynes) base.
A preferred embodiment of the present invention relates to wherein R 1Be selected from hydrogen and C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to middle R 1Be C 1-6-alkane (alkene/alkynes) base, C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 1It is the chemical compound of the formula I of hydrogen atom.
In another embodiment, the present invention relates to wherein R 2Be selected from hydrogen, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base; Wherein
R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Prerequisite be when s be 1 and R 2When being hydrogen atom or acyl group, U is O or S.
Work as R 2Expression NR 10R 10 '-C 1-6Alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base or NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6During-alkane (alkene/alkynes) base, this nitrogen-atoms passes through C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base or C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base is connected on the remainder of this molecule.
In another embodiment, the present invention relates to wherein R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and cyano group;
Prerequisite is to work as R 2S is 0 when being halogen or cyano group; With
Prerequisite be when s be 1 and R 2U is O or S when being hydrogen atom.
In another embodiment, the present invention relates to wherein R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and cyano group;
Prerequisite is to work as R 2When being halogen or cyano group, s is 0; With
Prerequisite be when s be 1 and R 2U is O or S when being hydrogen atom.
In a preferred embodiment, the present invention relates to wherein R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base, halogen and cyano group;
Prerequisite is to work as R 2Be that halogen or cyano group are, s is 0.
In another embodiment, the present invention relates to wherein R 2It is the chemical compound of the formula I of hydrogen atom.
In another embodiment, the present invention relates to wherein R 2It or not the chemical compound of the formula I of hydrogen atom.
In another embodiment, the present invention relates to wherein R 2Be C 1-6-alkane (alkene/alkynes) base, C 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 2Be C 3-8-cycloalkanes (alkene) base, C typically 3-6The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein R 2It is the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to wherein R 2It or not the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to wherein R 2Be Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 2Be halogen atom, typically chlorine atom, bromine atoms or iodine atom the chemical compound of formula I.
In another embodiment, the present invention relates to wherein R 2Be halo-C 1-6-alkane (alkene/alkynes) base, halo-C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to the chemical compound of formula I, wherein R 2Not halo-C 1-6-alkane (alkene/alkynes) base typically is not halo-C 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 2It is the chemical compound of the formula I of cyano group.
In another embodiment, the present invention relates to wherein R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 10And R 10 'Be independently selected from hydrogen and C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is O and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base and halo-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is O and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base and halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is O and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is S and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base and Ar-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is S and R 2Be selected from C 1-6-alkane (alkene/alkynes) base and Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is S and R 2Be selected from C 3-8-cycloalkanes (alkene) base and Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein s is 0 and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and cyano group.
In another embodiment, the present invention relates to wherein s is 0 and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, Ar, halogen, halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and cyano group.
In another embodiment, the present invention relates to wherein s is 0 and R 2Be selected from C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base, halogen and cyano group.
In another embodiment, the present invention relates to wherein that s is 1, U is CO-O and R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is CO-O and R 2Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is CO-NR 11, R 11Be hydrogen atom and R 2Not C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base and Ar.
In another embodiment, the present invention relates to wherein that s is 1, U is CO-NR 11And R 2Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that s is 1, U is CO-NR 11And R 2Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 11It is hydrogen atom.
In another embodiment, the present invention relates to wherein R 3Be selected from heterocycle alkane (alkene) base, C 1-6The basic heterocycle alkane of-alkane (alkene/alkynes) (alkene) base, Ar-heterocycle alkane (alkene) base, Ar-C 1-6The basic heterocycle alkane of-alkane (alkene/alkynes) (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-heterocycle alkane (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, NR 12R 12 'The chemical compound of formula I; Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-heterocycle alkane (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Prerequisite is to work as R 3Be NR 12R 12 'The time, q is 0.
Work as R 3Expression NR 12R 12'-C 1-6-alkane (alkene/alkynes) base, NR 12R 12 '-C 3-8-cycloalkanes (alkene) base or NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6During-alkane (alkene/alkynes) base, nitrogen-atoms passes through C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base or C 3-8-cycloalkanes (alkene) base-C6-alkane (alkene/alkynes) base is connected on this X-(Z) p base.
In another embodiment, the present invention relates to wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base-C16-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-carbonyl-C 1-6-alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-Ar, NR 12R 12 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base, substituted NR randomly 12R 12 '-C 3-8-cycloalkanes (alkene) base and substituted HR randomly 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
Other-individual embodiment in, the present invention relates to wherein R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, NR 12R 12 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base and randomly substituted NR 12R 12 '-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In a preferred embodiment, the present invention relates to wherein R 3Be C 1-6-alkane (alkene/alkynes) base, C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein R 3Be C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3It is the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to wherein R 3It is the chemical compound of the formula I of heterocycle alkane (alkene) base.
In another embodiment, the present invention relates to wherein R 3It or not the chemical compound of the formula I of heterocycle alkane (alkene) base.
In another embodiment, the present invention relates to wherein R 3Be heterocycle alkane (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Not heterocycle alkane (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Not C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be Ar-oxygen base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base-Ar.
In another embodiment, the present invention relates to wherein R 3Not halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base-Ar.
In another embodiment, the present invention relates to wherein R 3Be NR 12R 12 'The chemical compound of formula I.
In another embodiment, the present invention relates to wherein R 3Not NR 12R 12 'The chemical compound of formula I.
In another embodiment, the present invention relates to wherein R 3Be randomly substituted NR 12R 12 '-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be different from randomly substituted NR 12R 12 '-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be randomly substituted NR 12R 12 '-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein R 3Be different from randomly substituted NR 12R 12 '-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein R 3Be randomly substituted NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 3Be different from randomly substituted NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 12And R 12 'Be independently selected from Ar-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-heterocycle alkane (alkene) base, hydroxyl-C 1-6Alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
The chemical compound of formula I.
In another embodiment, the present invention relates to wherein R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 12And R 12 'Be independently selected from hydrogen, C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and Ar.
In another embodiment, the present invention relates to wherein R 12And R 12 'In at least one is the chemical compound of the formula I of hydrogen atom.
In another embodiment, the present invention relates to wherein R 12And R 12 'In at least one is C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 12And R 12 'In at least one is the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is O and R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, ArC 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C3-s-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and halo-C 1-6-alkane (alkene/alkynes) base-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is O and R 3Be selected from C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base and halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is O and R 3Not C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is O and R 3Be C 1-6-alkane (alkene/alkynes) base, C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is S and R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is S and R 3Be selected from C 1-6-alkane (alkene/alkynes) base and Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 1, and Z is S and R 3Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 0, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-Ar, NR 12R 12 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base and randomly substituted NR 12R 12 '-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein that X is CO, q is 0, R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, NR 12R 12 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base and randomly substituted NR 12R 12 '-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein, X is SO 2, q is 0 and R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein, X is SO 2, q is 0 and R 3Be selected from C 1-6-alkane (alkene/alkynes) base and Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In a preferred embodiment, the present invention relates to wherein R 3Be that Ar and q are the chemical compounds of 1 formula I.
In a preferred embodiment, the present invention relates to wherein R 3Be that Ar and q are the chemical compounds of 0 formula I.
In a preferred embodiment, the present invention relates to wherein R when q is 0 3It or not the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to wherein, Y is the chemical compound of the formula I of formula XXIV, XXV, XXVII, XXXXI or XXXXII.
In another embodiment, the present invention relates to wherein, Y is the chemical compound of the formula I of formula XXIV.
In another embodiment, the present invention relates to wherein, Y is the chemical compound of the formula I of formula XXV.
In another embodiment, the present invention relates to wherein, Y is the chemical compound of the formula I of formula XXVII.
In another embodiment, the present invention relates to wherein, Y is the chemical compound of the formula I of formula XXXXI.
In another embodiment, the present invention relates to wherein, Y is the chemical compound of the formula I of formula XXXXII.
In another embodiment, the present invention relates to wherein, W is the chemical compound of the formula I of oxygen atom.
In another embodiment, the present invention relates to wherein, W is the chemical compound of the formula I of sulphur atom.
In another embodiment, the present invention relates to wherein, V is the chemical compound of the formula I of nitrogen-atoms.
In another embodiment, the present invention relates to wherein, V is the chemical compound of the formula I of CH.
In another embodiment, the present invention relates to wherein, T is the chemical compound of the formula I of nitrogen-atoms.
In another embodiment, the present invention relates to wherein, T is the chemical compound of the formula I of oxygen atom.
In another embodiment, the present invention relates to wherein each R 5Be independently selected from Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein each R 5Be independently selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic heterocycle alkane of-alkane (alkene/alkynes) (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base, C 3-8-cycloalkanes (alkene) oxygen base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base, Ar-oxygen base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 ', S-R 8And SO 2R 8, or two R that adjoin 5Form a kind of chemical compound that randomly comprises the formula I of one or two heteroatomic 5-8 person's ring with this aromatic group.
Work as R 5Expression NR 7R 7 '-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 '-C 3-8-cycloalkanes (alkene) base or NR 7R 7 '-C 3-8-cycloalkanes (alkene) base-C 1-6During-alkane (alkene/alkynes) base, this nitrogen-atoms passes through C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base or C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base is connected on the remainder of this molecule.
In another embodiment, the present invention relates to wherein each R 5Be independently selected from C 1-6-alkane (alkene/alkynes) base, Ar, C 1-6-alkane (alkene/alkynes) oxygen base, halogen ,-NR 7R 7 ',-S-R 8With-SO 2R 8, or two R that adjoin 5Form a kind of chemical compound that randomly comprises the formula I of one or two heteroatomic 5-8 person's ring with this aromatic group.
In a preferred embodiment, the present invention relates to wherein each R 5Be independently selected from C 1-6-alkane (alkene/alkynes) base, Ar, C 1-6-alkane (alkene/alkynes) oxygen base, Ar-oxygen base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl, halogen, halo-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 ', S-R 8And SO 2R 8, or two R that adjoin 5Form a kind of chemical compound that randomly comprises the formula I of one or two heteroatomic 5-8 person's ring with this aromatic group.
In another embodiment, the present invention relates to one of them R 5Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to one of them R 5Be C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to one of them R 5Be C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to one of them R 5It is the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to one of them R 5Be Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein not have R 5Be Ar-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to one of them R 5Be Ar-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein not have R 5It is the chemical compound of the formula I of Ar-C3-s-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to one of them R 5Be Ar-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein not have R 5Be Ar-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to one of them R 5Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) oxygen base.
In another embodiment, the present invention relates to one of them R 5Be C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) oxygen base.
In another embodiment, the present invention relates to one of them R 5Be C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) oxygen base.
In another embodiment, the present invention relates to one of them R 5It is the chemical compound of the formula I of Ar-oxygen base.
In another embodiment, the present invention relates to wherein not have R 5It is the chemical compound of the formula I of Ar-oxygen base.
In another embodiment, the present invention relates to one of them R 5Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base.
In another embodiment, the present invention relates to wherein not have R 5Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base.
In another embodiment, the present invention relates to one of them R 5Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base-carbonyl.
In another embodiment, the present invention relates to wherein not have R 5Be C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl.
In another embodiment, the present invention relates to one of them R 5It is the chemical compound of the formula I of halogen atom.
In another embodiment, the present invention relates to one of them R 5Be halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein not have R 5Be halo-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to one of them R 5Be halo-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to wherein not have R 5Be halo-C 3-8The chemical compound of the formula I of-cycloalkanes (alkene) base.
In another embodiment, the present invention relates to one of them R 5Be halo-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein not have R 5Be halo-C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to one of them R 5Be NR 7R 7 'The chemical compound of formula I.
In another embodiment, the present invention relates to wherein not have R 5Be NR 7R 7 'The chemical compound of formula I.
In another embodiment, the present invention relates to one of them R 5Be S-R 8The chemical compound of formula I.
In another embodiment, the present invention relates to one of them R 5Be SO 2R 8The chemical compound of formula I.
In another embodiment, the present invention relates to wherein two R that adjoin 5Form a kind of chemical compound that randomly comprises the formula I of one or two heteroatomic 5-8 person's ring with this aromatic group.
In a preferred embodiment, the present invention relates to wherein two R that adjoin 5Formation-(CH together 2) N '-CH 2-,-CH=CH-(CH 2) M '-,-CH 2-CH=CH-(CH 2) P ',-CH=CH-CH=CH-,-(CH 2) N '-O-,-O-(CH 2) M '-O-,-CH 2-O-(CH 2) P '-O-,-CH 2-O-CH 2-O-CH 2-,-(CH 2) N '-S-,-S-(CH 2) M '-S-,-CH 2-S-(CH 2) P '-S-,-CH 2-S-CH 2-S-CH 2-,-(CH 2) N '-NH-,-NH-(CH 2) M '-NH-,-CH 2-NH-(CH 2) P '-NH-,-CH=CH-NH-,-O-(CH 2) M '-NH-,-CH 2-O-(CH 2) P '-NH-or-O-(CH 2) P '-NH-CH 2-,-S-(CH 2) M '-NH-,-N=CH-NH-,-N=CH-O-or-chemical compound of the formula I of N=CH-S-, wherein m ' is 1,2 or 3, n ' be 2,3 or 4 and p ' be 1 or 2.
In another embodiment, the present invention relates to wherein two R that adjoin 5Formation-CH together 2-O-CH 2-the chemical compound of formula I.
In another embodiment, the present invention relates to wherein two R that adjoin 5The chemical compound of the formula I of formation-CH=CH-CH=CH-together.
In another embodiment, the present invention relates to wherein R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 7And R 7 'Be independently selected from hydrogen and C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to R 7And R 7 'In one be C 1-6-alkane (alkene/alkynes) base, C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 7And R 7 'All be C 1-6-alkane (alkene/alkynes) base, C typically 1-3The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In another embodiment, the present invention relates to wherein R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and Ar.
In a preferred embodiment, the present invention relates to wherein R 8Be selected from C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base and Ar.
In a preferred embodiment, the present invention relates to wherein R 8Be C 1-6The chemical compound of the formula I of-alkane (alkene/alkynes) base.
In a preferred embodiment, the present invention relates to wherein R 8It is the chemical compound of the formula I of Ar.
In another embodiment, the present invention relates to wherein, X is SO 2, q is 0 and R 3Be C 1-6-alkane (alkene/alkynes) base, prerequisite is R 3The chemical compound that is different from the formula I of methyl.
In another embodiment, the present invention relates to wherein that q is 0, R 3Be that methyl and X are different from SO 2The chemical compound of formula I.
In another embodiment, the present invention relates to wherein, X is SO 2, s be 1 and U be different from the chemical compound of 0 formula I.
In another embodiment, the present invention relates to wherein that s is 1, U is that O and X are different from SO 2The chemical compound of formula I.
In another embodiment, the present invention relates to wherein that X is CO, q is 0 and R 3Be C 1-6-alkane (alkene/alkynes) base, prerequisite is R 3The chemical compound that is different from the formula I of methyl.
In another embodiment, the present invention relates to wherein that s is 1, U is different from O, and X is CO, and q is 0 and R 3It is the chemical compound of the formula I of methyl.
In another embodiment, the present invention relates to wherein that s is 1, U is O, and X is CO, and q is 0 and R 3Be C 1-6-alkane (alkene/alkynes) base, prerequisite is R 3The chemical compound that is different from the formula I of methyl.
The molecular weight of The compounds of this invention can be different along with the difference of chemical compound.The molecular weight of formula I chemical compound generally is higher than 200 and less than 600, and more generally is higher than 250 and less than 550.
The chemical compound that one aspect of the present invention relates to general formula X XIX with and salt:
Figure A20048000750700461
Wherein f, s, q, U, X, Z, R 1, R 2, R 3And R 5Definition as mentioned above, f, s, q, U, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have defined implication under the formula I.Any one embodiment that formula I relates to also is the embodiment of formula XXIX.
In another embodiment, the present invention relates to the chemical compound that f wherein is 0 general formula X XIX.
In another embodiment, the present invention relates to by a substituent R 5Replace, as adjacent-,-or right-position on the chemical compound of substituted general formula X XIX.
In another embodiment, the present invention relates to by two R that independently select 5Substituent group replaces, as adjacent-and right-position is substituted ,-and right-position is substituted and at adjacent-and chemical compound of-substituted general formula X XIX.
In another embodiment, the present invention relates to by three independent R that select 5The chemical compound of the general formula X XIX that substituent group replaces.
The present invention relates to the compound or its salt of general formula X XX on the other hand:
Figure A20048000750700471
Wherein g, h, s, q, U, X, Z, R 1, R 2, R 3And R 5Definition as mentioned above, g, h, s, q, U, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have defined implication under the formula I.Any one embodiment that formula I relates to also is the embodiment of formula XXX.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XX on 1 of naphthyl by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XX on 2 of naphthyl by methylene chemical compound.
In another embodiment, the present invention relates to wherein that g is 0,1,2 or 3, typically the chemical compound of 0,1 or 2 general formula X XX.
In another embodiment, the present invention relates to wherein that h is 0,1 or 2, typically the chemical compound of 0 or 1 general formula X XX.
In another embodiment, the present invention relates to the chemical compound that wherein g and h are 0 general formula X XX.
In another embodiment, the present invention relates to by a substituent R 5The chemical compound of the general formula X XX that replaces, in an one particular aspects, g be 0 and h be 1 and in its another particular aspects, g be 1 and h be 0.
In another embodiment, the present invention relates to by two independent R that select 5The chemical compound of the general formula X XX that substituent group replaces, in an one particular aspects, g be 0 and h be 2, in its another particular aspects, g be 1 and h be 1 and aspect its another, g be 2 and h be 0.
In another embodiment, the present invention relates to by three R that independently select 5The chemical compound of the general formula X XX that substituent group replaces, in an one particular aspects, g be 0 and h be 3, in its another particular aspects, g be 1 and h be 2, g aspect its another be 2 and h be 1 and aspect its another, g be 3 and h be 0.
The present invention relates to the compound or its salt of general formula X XXI on the other hand:
Figure A20048000750700481
Wherein a, s, q, U, W, X, Z, R 1, R 2, R 3, and R 5Definition as mentioned above, a, s, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have defined implication under the formula I.Any one embodiment that formula I relates to also is the embodiment of formula XXXI.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXI on 2 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXI on 3 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to the chemical compound that a wherein is 0,1 or 2 general formula X XXI.
In another embodiment, the present invention relates to the chemical compound that a wherein is 0 general formula X XXI.
In another embodiment, the present invention relates to by a substituent R 5The chemical compound of the general formula X XXI that replaces.
In another embodiment, the present invention relates to by two R that independently select 5The chemical compound of the general formula X XXI that substituent group replaces.
The present invention relates to the compound or its salt of general formula X XXII on the other hand:
Figure A20048000750700491
Wherein b, c, s, q, U, W, X, Z, R 1, R 2, R 3And R 5Definition as mentioned above, b, c, s, q, U, W, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have defined implication under the formula I.Any one embodiment that formula I relates to also is the embodiment of formula XXXII.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXII on 2 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXII on 3 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to wherein that b is 0,1,2 or 3, typically the chemical compound of 0,1 or 2 general formula X XXII.
In another embodiment, the present invention relates to wherein that c is 0 or 1, typically the chemical compound of 0 general formula X XXII.
In another embodiment, the present invention relates to the chemical compound that wherein b and c are 0 general formula X XXII.
In another embodiment, the present invention relates to by a substituent R 5The chemical compound of the general formula X XXII that replaces, aspect one, b be 0 and c be 1 and aspect its another, b be 1 and c be 0.
In another embodiment, the present invention relates to by two R that independently select 5The chemical compound of the general formula X XXII that substituent group replaces, aspect one, b be 1 and c be 1 and aspect its another, b be 2 and c be 0.
In another embodiment, the present invention relates to by three R that independently select 5The chemical compound of the general formula X XXII that substituent group replaces, aspect one, b be 2 and c be 1 and aspect its another, b be 3 and c be 0.
The present invention relates to the compound or its salt of general formula X XXIII on the other hand:
Figure A20048000750700501
Wherein d, e, s, q, U, W, X, Z, R 1, R 2, R 3And R 5Definition as mentioned above, d, e, s, q, U, W, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have defined implication under the formula I.Any one embodiment that formula I relates to also is the scheme of formula XXXIII.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXIII on 4 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXIII on 5 of this heteroaromatic group by methylene chemical compound.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXIII on 6 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXIII on 7 of this heteroaromatic group by methylene chemical compound.
In another embodiment, the present invention relates to wherein that d is 0,1 or 2, typically the chemical compound of 0 or 1 general formula X XXIII.
In another embodiment, the present invention relates to the chemical compound that e wherein is 0,1 or 2 general formula X XXIII.
In another embodiment, the present invention relates to the chemical compound that wherein d and e are 0 general formula X XXIII.
In another embodiment, the present invention relates to by a substituent R 5The chemical compound of the general formula X XXIII that replaces, in an one particular aspects, d be 0 and e be 1 and in its another particular aspects, d be 1 and e be 0.
In another embodiment, the present invention relates to by two independent R that select 5The chemical compound of the general formula X XXIII that substituent group replaces, in an one particular aspects, d be 0 and e be 2, in its another particular aspects, d be 1 and e be 1 and aspect its another, d be 2 and e be 0.
In another embodiment, the present invention relates to by three independent R that select 5The chemical compound of the general formula X XXIII that substituent group replaces, aspect one, d be 1 and e be 2, aspect its another, d be 2 and e be 1 and aspect its another, d be 3 and e be 0.
The present invention relates to the compound or its salt of general formula X XXXIII on the other hand:
Wherein dd, s, q, U, V, X, Z, R 1, R 2, R 3And R 5Has defined implication under the formula I.Any one embodiment that formula I relates to also is the embodiment of formula XXXXIII.
In another embodiment, the present invention relates to wherein, V is nitrogen-atoms connects the general formula X XXIII of carbon atom thereon by methylene a chemical compound.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIII on the carbon atom that is denoted as " 1 " by methylene chemical compound.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIII on the carbon atom that is denoted as " 2 " by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIII on the carbon atom that is denoted as " 3 " by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIII on the carbon atom that is denoted as " 4 " by methylene chemical compound.
In another embodiment, the present invention relates to wherein that dd is 0,1 or 2, typically the chemical compound of 0 or 1 general formula X XXXIII.In one aspect of the invention, dd is 0.In another aspect of the present invention, dd is 0.
The present invention relates to the compound or its salt of general formula X XXXIV on the other hand:
Figure A20048000750700521
Wherein aa, s, q, T, U, X, Z, R 1, R 2, R 3And R 5Has defined implication under the formula I.Any one embodiment that formula I relates to also is the chemical compound of formula XXXXIV.
In one embodiment, the present invention relates to wherein, T is nitrogen-atoms connects the general formula X XXXIV of nitrogen-atoms thereon by methylene a chemical compound.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIV on the carbon atom that is denoted as " 1 " by methylene chemical compound.
In one embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIV on the carbon atom that is denoted as " 2 " by methylene chemical compound.
In another embodiment, the present invention relates to nitrogen-atoms wherein is connected to the general formula X XXXIV on the carbon atom that is denoted as " 3 " by methylene chemical compound.
In another embodiment, the present invention relates to the chemical compound that aa wherein is 0,1 or 2 general formula X XXI.In one embodiment, aa is 0.In another embodiment, general formula X XXXIV is by a substituent R 5Replace.In another embodiment, the chemical compound of general formula X XXI is by two independent R that select 5Substituent group replaces.
In a specific embodiment, the present invention relates to substituted right-diamino benzene derivant or its salt of general formula I a
Figure A20048000750700522
Wherein
S is 0 or 1;
U is O, S, SO 2, SO 2NR 11, CO-O or CO-NR 11R wherein 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C6-alkane (alkene/alkynes) base; Or R 2And R 11Former with this nitrogen in forming a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises;
Q is 0 or 1;
X is CO or SO 2Prerequisite be when X be SO 2The time q be 0;
Z is O or S;
R 1Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C1-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C6-alkane (alkene/alkynes) base;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; R wherein 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-CI6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or R 10And R 10 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Prerequisite is to work as R 2When being halogen or cyano group, s is 0; With
Prerequisite be when s be 1 and R 2When being hydrogen atom or acyl group, U is O or S.
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 1-6-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-heterocycle alkane (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-Ar, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base ,-NR 12R 12 'R wherein 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or R 12And R 12 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
With
The group of Y expression XXIV, XXV, XXVI, XXVII or XXVIII:
Wherein
This line is represented a kind of group shown in the Y to be connected to key on this carbon atom;
W is O or S;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3; With
Each R 5Be independently selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, acyl group, C 1-6-alkane (alkene/alkynes) oxygen base, C 3-8-cycloalkanes (alkene) oxygen base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 ', S-R 8With-SO 2R 8, perhaps two R that adjoin 5Form a kind of one or two heteroatomic 5-8 person's ring that comprises with this aromatic group;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and Ar;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar and acyl group; With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar and-NR 9R 9 'R wherein 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
In one embodiment, the chemical compound of preferably listing below with and salt:
4-[(benzofuran-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanes;
[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-urethanes;
[4-(4-fluoro-benzylamino)-2-aminomethyl phenyl]-carbamic acid propyl ester;
(4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-the 2-aminomethyl phenyl)-the carbamic acid propyl ester;
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
[2-chloro-4-(4-isopropyl-benzylamino)-phenyl]-urethanes;
[2-chloro-4-(4-fluoro-benzylamino)-phenyl]-carbamic acid propyl ester;
2-chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-the carbamic acid propyl ester;
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(benzofuran-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-methyl carbamate;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-carbamic acid isopropyl ester;
4-[(4-fluoro-benzyl)-(methyl) amino]-the 2-methoxyphenyl }-the carbamic acid propyl ester;
{ 4-(benzo [b] thiophene-2-ylmethyl-(methyl) amino)-2-methoxyl group-phenyl }-carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester;
2-methoxyl group-4-[methyl-(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
The 4-[(4-luorobenzyl)-(methyl)-amino]-the 2-isopropyl phenyl }-urethanes;
[4-(3-luorobenzyl amino)-2-methoxyphenyl]-urethanes;
[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-urethanes;
2-methoxyl group-4-[(3-methylthiophene-2-ylmethyl)-amino]-phenyl }-urethanes;
[4-(2,4-difluorobenzyl amino)-2-methoxyphenyl]-urethanes;
[2-cyclopentyloxy-4-(4-methoxy-benzyl amino)-phenyl]-urethanes;
[2-cyclopentyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes;
[4-(3-fluoro-2-methyl-benzyl amino)-2-benzene ethoxyl phenenyl]-urethanes;
[2-benzyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes;
[2-benzyloxy-4-(4-methyl sulfane base benzylamino)-phenyl]-urethanes;
4-[(benzo [b] thiene-3-yl-methyl)-amino]-2-cyclopentyloxy phenyl }-urethanes;
[4-(3-fluoro-2-methyl-benzyl amino)-2-isopropyl phenyl]-urethanes;
[2-benzyloxy-4-(3-methoxy-benzyl amino)-phenyl]-urethanes;
4-[(benzo [1,3] dioxole-5-ylmethyl)-amino]-the 2-isopropyl phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-cyano group-4-(4-isopropyl benzyl amino)-phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
The 4-[(4-isopropyl benzyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
2-methyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-methyl-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-urethanes;
2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-urethanes;
2-chloro-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl } urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[methyl-(4-methyl sulfane base-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the Ji propyl formate;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[methyl-(4-methyl sulfane base-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
2-cyano group-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(4-isopropyl benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(4-tert-butyl-benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-iodo-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[4-(4-tert-butyl-benzylamino)-2-iodophenyl]-carbamic acid propyl ester;
[2-iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-iodo-4-(4-methyl sulfane base-benzylamino)-phenyl]-carbamic acid propyl ester;
2-iodo-4-[4-(4-methyl piperazine-1-yl)-benzylamino]-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-urethanes;
[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
[4-(4-isopropyl benzyl amino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[2-trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[4-(4-dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
[2-cyano group-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-bromo-4-(4-isopropyl benzyl amino)-phenyl J-carbamic acid propyl ester;
[2-bromo-4-(4-tert-butyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-methyl sulfane base-benzylamino)-phenyl]-carbamic acid propyl ester;
N-{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl)-butyramide;
N-[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-butyramide;
N-[4-(4-tert-butyl-benzylamino)-2-methoxyphenyl]-butyramide;
N-[2-methoxyl group-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-furan-2-base-phenyl }-the carbamic acid propyl ester;
[2-furan-2-base-4-(4-isopropyl benzyl amino)-phenyl]-carbamic acid propyl ester;
[5-(4-luorobenzyl amino)-biphenyl-2-yl]-carbamic acid propyl ester;
5-[(5-chloro-thiophene-2-ylmethyl)-amino]-biphenyl-2-yl }-the carbamic acid propyl ester;
[5-(4-isopropyl benzyl amino)-biphenyl-2-yl]-carbamic acid propyl ester;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 2-phenyl-acetamides;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3, the 3-amide dimethyl butyrate;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl)-the 3-Phenylpropionamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyramide;
Valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclobutylcarboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclopentane carboxylic acid (2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-thiophene-2-base-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(3-methoxyl group-phenyl]-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chloro-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-methoxyl group-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-fluoro-phenyl-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-cyclohexyl propionic acid amide.;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2-dimethyl propylene amide;
N-[2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenoxy-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenyl-acetamides;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3, the 3-amide dimethyl butyrate;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-butyramide;
Valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclobutylcarboxylic acid (2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]=phenyl }-amide;
Cyclopentane carboxylic acid (2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-thiophene-2-base-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(3-methoxyphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-chlorphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-methoxyphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-fluorophenyl)-acetamide;
2,3-dihydro-benzo [1,4] dioxine-6-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
2,3-dihydro-benzofuran-5-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3-cyclohexyl propionic acid amide.;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-2,2-dimethyl propylene amide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 2-phenyl-acetamides;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-3, the 3-amide dimethyl butyrate;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 3-Phenylpropionamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-butyramide;
2,2,2-three chloro-N-{4-[(5-chloro-thiophene-2-ylmethyls)-(methyl) amino]-2-methyl-phenyl }-acetamide;
Cyclopropane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-amide;
Cyclobutylcarboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-aminomethyl phenyl J-amide;
Cyclopentane carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl ,-amide;
Cyclohexane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl)-amide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-thiophene-2-base-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl } j-2-(3-methoxyphenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the malonamic acid methyl ester;
2-(4-chlorphenyl)-N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-methoxyphenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-and methyl) amino]-the 2-aminomethyl phenyl }-2-(4-fluorophenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-3-cyclohexyl propionic acid amide.;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-phenyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-benzyq carbamate;
(2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl)-isobutyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the own ester of carbamic acid;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 4-nitrobenzyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-3-alkene ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-2-alkynes ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2,2-dimethyl propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl)-carbamic acid 2-benzyl chloride ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 3-chlorine propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyloxy ethyl ester;
3-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-1-methyl isophthalic acid-propyl group-urea;
1-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-(2-fluorophenyl)-urea;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2,2, the 2-trifluoroacetamide; With
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2, the 2-trifluoroacetamide.
Other-individual embodiment in, the chemical compound of preferably listing below with and salt:
4-[(benzofuran-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
(4-(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanes;
[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-urethanes;
[4-(4-fluoro-benzylamino)-2-aminomethyl phenyl]-carbamic acid propyl ester;
(4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-the 2-aminomethyl phenyl)-the carbamic acid propyl ester;
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
[2-chloro-4-(4-isopropyl-benzylamino)-phenyl]-urethanes;
[2-chloro-4-(4-fluoro-benzylamino)-phenyl]-carbamic acid propyl ester;
2-chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-the carbamic acid propyl ester;
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(benzofuran-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-methyl carbamate;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-carbamic acid isopropyl ester;
4-[(4-fluoro-benzyl)-(methyl) amino]-the 2-methoxyphenyl }-the carbamic acid propyl ester;
[4-[(benzo [b] thiophene-2-ylmethyl-(methyl) amino)-the 2-methoxyphenyl]-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester;
2-methoxyl group-4-[methyl-(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
The 4-[(4-luorobenzyl)-(methyl)-amino]-the 2-isopropyl phenyl }-urethanes;
[4-(3-luorobenzyl amino)-2-methoxyphenyl]-urethanes;
[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-urethanes;
2-methoxyl group-4-[(3-methylthiophene-2-ylmethyl)-amino]-phenyl }-urethanes;
[4-(2,4-difluorobenzyl amino)-2-methoxyphenyl]-urethanes;
[2-cyclopentyloxy-4-(4-methoxy-benzyl amino)-phenyl]-urethanes;
[2-cyclopentyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes;
[4-(3-fluoro-2-methyl-benzyl amino)-2-benzene ethoxyl phenenyl]-urethanes;
[2-benzyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes;
[2-benzyloxy-4-(4-methyl sulfane base benzylamino)-phenyl]-urethanes;
[4-[(benzo [b] thiene-3-yl-methyl)-amino]-2-cyclopentyloxy phenyl]-urethanes;
[4-(3-fluoro-2-methyl-benzyl amino)-2-isopropyl phenyl]-urethanes;
[2-benzyloxy-4-(3-methyl-benzyl amino)-phenyl]-urethanes;
[4-[(benzo [1,3] dioxole-5-ylmethyl)-amino]-the 2-isopropyl phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-cyano group-4-(4-isopropoxide benzyl amino)-phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
The 4-[(4-isopropyl benzyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
2-methyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-methyl-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-urethanes;
2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-urethanes;
2-chloro-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[methyl-(4-methyl sulfane base-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[methyl-(4-methyl sulfane base-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
2-cyano group-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(4-isopropyl benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(4-tert-butyl-benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-iodo-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[4-(4-tert-butyl-benzylamino)-2-iodophenyl]-carbamic acid propyl ester;
[2-iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-iodo-4-(4-methyl sulfane base-benzylamino)-phenyl]-carbamic acid propyl ester;
2-iodo-4-[4-(4-methyl piperazine-1-yl)-benzylamino]-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-urethanes;
[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
[4-(4-isopropyl benzyl amino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[2-trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[4-(4-dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
[2-cyano group-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-bromo-4-(4-isopropyl benzyl amino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-tert-butyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-methyl sulfane base-benzylamino)-phenyl]-carbamic acid propyl ester;
N-{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide;
N-[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-butyramide;
N-[4-(4-tert-butyl-benzylamino)-2-methoxyphenyl]-butyramide;
N-[2-methoxyl group-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-furan-2-base-phenyl }-the carbamic acid propyl ester;
[2-furan-2-base-4-(4-isopropyl benzyl amino)-phenyl]-carbamic acid propyl ester;
[5-(4-luorobenzyl amino)-biphenyl-2-yl]-carbamic acid propyl ester;
5-[(5-chloro-thiophene-2-ylmethyl)-amino]-biphenyl-2-yl }-the carbamic acid propyl ester;
[5-(4-isopropyl benzyl amino)-biphenyl-2-yl]-carbamic acid propyl ester;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 2-phenyl-acetamides;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3, the 3-amide dimethyl butyrate;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 3-Phenylpropionamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyramide;
Valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclobutylcarboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclopentane carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-thiophene-2-base-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(3-methoxyl group-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chloro-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-methoxyl group-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-fluoro-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-cyclohexyl propionic acid amide.;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2-dimethyl propylene amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenoxy-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2--phenyl-acetamides;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3, the 3-amide dimethyl butyrate;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-butyramide;
Valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclopentane carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl)-amide;
Cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-thiophene-2-base-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(3-methoxyphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-chlorphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-methoxyphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-fluorophenyl)-acetamide;
2,3-dihydro-benzo [1,4] dioxine-6-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
2,3-dihydro-benzofuran-5-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino] phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3-cyclohexyl propionic acid amide.;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-2,2-dimethyl propylene amide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 2-phenyl-acetamides;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-3, the 3-amide dimethyl butyrate;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 3-Phenylpropionamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-butyramide;
2,2,2-three chloro-N-{4-[(5-chloro-thiophene-2-ylmethyls)-(methyl) amino]-2-methyl-phenyl }-acetamide;
Cyclopropane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-amide;
Cyclobutylcarboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
Cyclopentane carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
Cyclohexane-carboxylic acid [4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl)-amide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-thiophene-2-base-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(3-methoxyphenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the malonamic acid methyl ester;
2-(4-chlorphenyl)-N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-methoxyphenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-fluorophenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-3-cyclohexyl propionic acid amide.;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-phenyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-benzyq carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-isobutyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the own ester of carbamic acid;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 4-nitrobenzyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-3-alkene ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-2-alkynyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2,2-dimethyl propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyl chloride ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 3-chlorine propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyloxy ethyl ester;
3-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-1-methyl isophthalic acid-propyl group-urea;
1-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-(2-fluorophenyl)-urea;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2,2, the 2-trifluoroacetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2, the 2-trifluoroacetamide;
N-{5-[(5-chloro-thiophene-2-ylmethyl)-amino]-4 '-dimethylamino-biphenyl-2-yl }-2-(4-fluorophenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methylamino]-phenyl }-2-(4-chlorphenyl)-acetamide;
[4-(3-fluoro-4-trifluoromethyl-benzylamino)-2-aminomethyl phenyl]-urethanes;
2-(4-fluorophenyl)-N-{2-methyl-4-[(6-is right-toloxyl pyridin-3-yl methyl)-amino]-phenyl }-acetamide;
N-{2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;
2-(4-fluorophenyl)-N-{2-methyl-4-[(6-5-flumethiazine-3-ylmethyl)-amino]-phenyl }-acetamide;
Valeric acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
3,3-dimethyl-N-{2-methyl-4-[(6-is right-toloxyl pyridin-3-yl methyl)-amino]-phenyl }-butyramide;
[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-urethanes;
N-(2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chlorphenyl)-propionic acid amide.;
[4-(4-chloro-benzylamino)-2-aminomethyl phenyl]-urethanes;
4-[(6-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-quinoline-3-base-phenyl }-urethanes;
4-[(5-dimethylamino-3-methyl-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl } 2-carbamic acid propyl ester;
3,3-dimethyl-N-{2-methyl-4-[(6-5-flumethiazine-3-ylmethyl)-amino]-phenyl }-butyramide;
N-(4-{[6-chloro-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-amino }-the 2-aminomethyl phenyl)-2-(4-chlorphenyl)-acetamide;
2-benzyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-S-ethyl thiocarbamate;
2-cycloalkyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-S-ethyl thiocarbamate;
N-{4-[(6-chloropyridine-3-ylmethyl)-amino]-the 2-aminomethyl phenyl }-2-(4-chlorphenyl)-acetamide;
4-[(7-dimethylamino-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
1-{2-cyclopentyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-3-ethyl-urea;
2-amino-4-methyl-valeric acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;
4-[(6-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
2-amino-4-methyl-valeric acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl-amide;
2-(4-fluorophenyl)-N-{2-methyl-4-[(4-methyl-2-phenyl pyrimidine-5-ylmethyl)-amino]-phenyl }-acetamide;
3,3-dimethyl-N-{2-methyl-4-[(2-phenyl pyrimidine-5-ylmethyl)-amino]-phenyl }-butyramide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-pyridin-3-yl-phenyl }-urethanes;
1-amino-cyclopropane-carboxylic acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl-amide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-pyridin-4-yl-phenyl }-urethanes;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-piperidines-1-base-acetamide;
N-(4-{[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-amino }-the 2-aminomethyl phenyl)-2,2-dimethyl propylene amide;
2,2-dimethyl-N-{2-methyl-4-[(6-phenoxypyridines-3-ylmethyl)-amino]-phenyl }-propionic acid amide.;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-pyrrolidine-1-base-acetamide;
[4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-(6-methoxypyridine-3-yl)-phenyl]-urethanes;
4-[(3-methyl-4-propoxycarbonyl amino-phenyl amino)-methyl]-essence of Niobe;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-morpholine-4-base-acetamide;
2,2-dimethyl-N-{2-methyl-4-[(3-methyl-5-phenyl-isoxazole azoles-4-ylmethyl)-amino]-phenyl }-propionic acid amide.;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-urethanes;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-2-(4-fluorophenyl)-acetamide; With
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-quinoline-5-base-phenyl }-urethanes.
According to an embodiment, the present invention relates to a kind of one or more pharmaceutically suitable carrier or diluent and wherein s, q, U, X, Z, Y, R of comprising 1, R 2And R 3Definition as mentioned above, a, b, c, d, e, f, g, h, s, q, U, X, Z, Y, W, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have the pharmaceutical composition of the compound or its salt of the formula I of defined implication under the formula I.Therefore, pharmaceutical composition of the present invention can comprise the compound or its salt of one or more formulas I, as the compound or its salt of a kind of formula I; Or the compound or its salt of two kinds of formula I; Or the compound or its salt of three kinds of formula I.
According to an embodiment, the present invention relates to comprise one or more pharmaceutically useful carriers or diluent and wherein f, s, q, U, X, Z, R 1, R 2, R 3And R 5Definition as mentioned above, f, s, q, U, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have the pharmaceutical composition of the chemical compound of the formula XXIX of defined implication under the formula XXIX.Therefore, pharmaceutical composition of the present invention can comprise the compound or its salt of one or more formulas XXIX, as the compound or its salt of a kind of formula XXIX; Or the compound or its salt of two kinds of formula XXIX; Or the compound or its salt of three kinds of formula XXIX.
According to an embodiment, the present invention relates to a kind of one or more pharmaceutically useful carriers or diluent and wherein g, h, s, q, U, X, Z, R of comprising 1, R 2, R 3And R 5Definition as mentioned above, g, h, s, q, U, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have the pharmaceutical composition of the chemical compound of the formula XXX of defined implication under the formula XXX.Therefore, pharmaceutical composition of the present invention can comprise the compound or its salt of one or more formulas XXX, as the compound or its salt of a kind of formula XXX; Or the compound or its salt of two kinds of formula XXX; Or the compound or its salt of three kinds of formula XXX.
According to an embodiment, the present invention relates to a kind of one or more pharmaceutically useful carriers or diluent and wherein a, s, q, U, W, X, Z, R of comprising 1, R 2, R 3And R 5Definition as mentioned above, a, s, q, U, W, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have the pharmaceutical composition of the chemical compound of the formula XXXI of defined implication under the formula XXXI.Therefore, pharmaceutical composition of the present invention can comprise the compound or its salt of one or more formulas XXXI, as the compound or its salt of a kind of formula XXXI; Or the compound or its salt of two kinds of formula XXXI; Or the compound or its salt of three kinds of formula XXXI.
According to an embodiment, the present invention relates to a kind of one or more pharmaceutically useful carriers or diluent and wherein b, c, s, q, U, W, X, Z, R of comprising 1, R 2, R 3And R 5Definition as mentioned above, b, c, s, q, U, W, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have the pharmaceutical composition of the formula XXXII of defined implication under the formula XXXII.Therefore, pharmaceutical composition of the present invention can comprise the compound or its salt of one or more formulas XXXII, as the compound or its salt of a kind of formula XXXII; Or the compound or its salt of two kinds of formula XXXII; Or the compound or its salt of three kinds of formula XXXII.
According to an embodiment, the present invention relates to a kind of one or more pharmaceutically useful carriers or diluent and wherein d, e, s, q, U, W, X, Z, R of comprising 1, R 2, R 3And R 5Definition as mentioned above, d, e, s, q, U, W, X, Z, R 1, R 2, R 3, R 5, R 6, R 6, R 7, R 7, R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'In any one correspondingly have the pharmaceutical composition of the chemical compound of the formula XXXIII of defined implication under the formula XXXIII.Therefore, pharmaceutical composition of the present invention can comprise the compound or its salt of one or more formulas XXXIII, as the compound or its salt of a kind of formula XXXIII; Or the compound or its salt of two kinds of formula XXXIII; Or the compound or its salt of three kinds of formula XXXIII.
Therefore, the invention provides a kind of pharmaceutical composition that is used for oral or parenteral, said pharmaceutical composition comprises compound or its salt and one or more pharmaceutically useful carrier or diluent of at least a formula I that treats effective dose or XXIX or XXX or XXXI or XXXII or XXXIII.
In one aspect, chemical compound of the present invention can be with the form of unique treatment active compound by administration.
In yet another aspect, chemical compound of the present invention can be with the form of a conjoint therapy part by administration, chemical compound promptly of the present invention can with have for example anti--convulsive other treatment compounds effective administering drug combinations.Such effect with anti--convulsive other chemical compound can comprise the effect to following aspect without limitation:
● ion channel such as sodium, potassium or calcium channel
Zero excitatory amino acid system for example blocks or regulates and control nmda receptor
● inhibitory nerve mediator system for example strengthens GABA and discharges, or blocking-up GABA-absorbs or
Zero membrane stabilizing action.
Present anti--convulsivant comprises Tiagabine, carbamazepine, sodium valproate, lamotrigine, gabapentin, pregabalin, ethosuximide, levetiracetam, phenytoin, topiramate, zonisamide and benzodiazepine _ and the member of group of barbiturates without limitation.
In one aspect, have been found that the potassium channel of chemical compound of the present invention to KCNQ family, particularly the potassium channel of KCNQ2 subelement has effect.
In one embodiment, the present invention relates to one or more application of chemical compound of the present invention in Therapeutic Method.Disease of preventing, treating or suppressing or situation are disease or the situations that the ion-flow rate increase of potassium channel KCNQ family potassium-channel is had response.Such disease or situation be central nervous system's disease or situation preferably.
Think that chemical compound of the present invention can be used for increasing the ion-flow rate in mammal such as the people's voltage-dependent potassium channel.
Think that chemical compound of the present invention can be used for preventing, treating or suppress the ion-flow rate increase of potassium channel such as KCNQ family potassium-channel is had the disease or the situation of response.Such disease or situation be central nervous system's disease or situation preferably.
Therefore, think that chemical compound of the present invention can be used for preventing, treating or suppress such as disease or disease as epilepsy disease, neuropathic pain and migraine headache disease, anxiety disorder and neurodegenerative disorders.
Therefore, think that chemical compound of the present invention can be used for preventing, treat or suppress disease or situation such as convulsions, epilepsy, anxiety disorder, neuropathic pain and neurodegenerative disorders.
Therefore, according to a specific embodiment, think that chemical compound of the present invention can be used for prevention, treatment or suppresses epilepsy disease such as convulsions, epilepsy and status epilepticus.
In one embodiment, think that chemical compound of the present invention can be used for prevention, treatment and suppresses convulsions.
In another embodiment, think that chemical compound of the present invention can be used for prevention, treatment and suppresses epilepsy, epilepsy and Epileptic fits.
In another embodiment, think that chemical compound of the present invention can be used for prevention, treatment and inhibition anxiety disorder such as anxiety and situation and the disease relevant with panic attack, agoraphobia, the panic disorder relevant with agoraphobia, with the irrelevant panic disorder of agoraphobia, the agoraphobia of no panic disorder history, specific phobia, social phobia and other specific phobia, obsession, posttraumatic stress disorder, acute stress disorder, generalized-anxiety disorder, because the anxiety disorder that general medical condition causes, the inductive anxiety disorder of material, separation anxiety disorder, adjustment disorder, the behavior anxiety, hypochondriacal disorder, because anxiety disorder and inductive anxiety disorder of material and not specific indicated anxiety disorder that general medical condition causes.
In another embodiment, think that chemical compound of the present invention can be used for preventing, treat and suppress neuropathic pain and migraine antalgesic such as allodynia, hyperpathia pain, phantom pain, the neuropathic pain relevant with diabetic neuropathy and relevant nerve (neupathic) pain with migraine.
In another embodiment, think that chemical compound of the present invention can be used for prevention, treatment and suppresses neurodegenerative disorders such as Alzheimer; Huntington Chorea; Multiple sclerosis; Amyotrophic lateral sclerosis; The Creutzfeld-Jakob disease; Parkinson; AIDS or rubella virus, herpesvirus, Borrelia and the inductive encephalopathy of unknown pathogenic infection; The neural degeneration of wound-induced; State in neuronal excitation transient state such as drug withdrawal or the poisoning; Neurodegenerative disease such as polyneuropathy and polyneuritis (polyneuritides) with peripheral nervous system.
In another embodiment, think that chemical compound of the present invention can be used for prevention, treatment and suppresses neurodegenerative disorders such as Alzheimer; Huntington Chorea; Multiple sclerosis; Amyotrophic lateral sclerosis; The Creutzfeld-Jakob disease; Parkinson; AIDS or rubella virus, herpesvirus, Borrelia and the unknown inductive encephalopathy of pathogenic infection; Neural degeneration with wound-induced.
In another embodiment, think chemical compound of the present invention can be used for preventing, treat and suppress neuronal excitation transient state such as drug withdrawal or poison in state.
The invention provides the chemical compound of the effect that shows in the test below one or more:
● " by the relative outflux of KCNQ2 passage "
It is the tolerance of chemical compound to the destination channel effect
● " maximal electroshock "
It is the tolerance that stimulates inductive epilepsy by method for electrically by non-specific CNS
● " the inductive epilepsy of pilocarpine "
Thereby the inductive epilepsy of pilocarpine usually is difficult to treat and reacted a kind of " drug-fast epilepsy " model with many existing epilepsys outbreak medicines
● " electric epilepsy-threshold value test " and " chemical epilepsy-threshold value test "
These model measurements begin down the threshold value of epilepsy at it, therefore, it is to survey these chemical compounds whether can postpone the model that epilepsy begins.
Zero " tonsil excitement "
With its tolerance as progression of disease, compare with the intact animal, when animals received further stimulated, the epilepsy in this model was more serious.
According to a particular aspects of the present invention, this chemical compound has the KCNQ2 activity, and when measuring with " by the relative outflux of KCNQ2 passage " described below test, it has less than 15000nM as the EC less than 10000nM 50
According to a particular aspects of the present invention, this chemical compound has the KCNQ2 activity, and when measuring with " by the relative outflux of KCNQ2 passage " described below test, it has less than 2000nM as the EC less than 1500nM 50
According to another particular aspects of the present invention, this chemical compound has the KCNQ2 activity, and when measuring with " by the relative outflux of KCNQ2 passage " described below test, it has less than 200nM as the EC less than 150nM 50
According to another particular aspects of the present invention, has ED in these chemical compounds described below " maximal electroshock " test less than 15mg/kg 50
According to another specified scheme of the present invention, has ED in these chemical compounds described below " maximal electroshock " test less than 5mg/kg 50
According to a particular aspects of the present invention, has ED in these chemical compounds described below " electric epilepsy-threshold value test " and " the chemical epilepsy-threshold value test " less than 5mg/kg 50
Some chemical compounds have seldom or do not have a clinical side effects.Therefore, in the model of the unwanted calmness of this chemical compound, cooling and ataxia effect, some chemical compounds are tested.
Some chemical compounds have the impaired or ataxia effect of convulsion effect and side effect such as locomotor activity as by the high therapeutic index between the ataxia effect that behavior measure showed on the swingle.This means that these chemical compounds of expection can be well tolerable by the patient, thereby make and before observing side effect, can use high dose.Therefore, expection has good compliance to this treatment and allows to carry out the high dose administration and makes and can carry out more effective treatment to the patient who uses other medicines will have side effect.
Definition
The term hetero atom refers to nitrogen, oxygen or sulphur atom.
Halogen refers to fluorine, chlorine, bromine or iodine.
C 1-6-alkane (alkene/alkynes) base and C 1-6The statement of-(alkane/alkene/alkynes) base refers to C 1-6-alkyl, C 2-6-alkenyl or C 2-6-alkynyl.
Term C 1-6-alkyl refers to side chain or the unbranched alkyl with 1 to 6 carbon atom, comprises methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group and 2-methyl isophthalic acid-propyl group without limitation.
Equally, C 2-6-alkenyl and C 2-6-alkynyl is specified respectively to be to have 2 to 6 carbon atoms and comprise two keys and triple-linked such group respectively, comprises vinyl, acrylic, cyclobutenyl, acetenyl, propinyl and butynyl without limitation.
C 1-3The statement of-alkane (alkene/alkynes) base refers to C 1-3-alkyl, C 2-3-alkenyl or C 2-3-alkynyl.
Term C 1-3-alkyl refers to side chain or the unbranched alkyl with 1 to 3 carbon atom, comprises methyl, ethyl, 1-propyl group and 2-propyl group without limitation.
Equally, C 2-3-alkenyl and C 2-3-alkynyl refers to respectively has 2 to 3 carbon atoms, comprises two keys and triple-linked such group respectively, comprises vinyl, acrylic, acetenyl and propinyl without limitation.
C 3-8-cycloalkanes (alkene) base and C 3-8The statement of-ring (alkane/alkene) base refers to C 3-8-cycloalkyl-or cycloalkenyl.
Term C 3-8-cycloalkyl refers to monocycle or the bicyclo-carbocyclic ring with 3 to 8 C-atoms, comprises cyclopropyl, cyclopenta, cyclohexyl or the like without limitation.
C 3-6-cycloalkanes (alkene) base and C 3-6The statement of-ring (alkane/alkene) base refers to C 3-6-cycloalkyl-or cycloalkenyl.
Term C 3-6-cycloalkyl refers to monocycle or the bicyclic carbocyclic ring with 3 to 6 C-atoms, comprises cyclopropyl, cyclopenta, cyclohexyl or the like without limitation.
Term C 3-8-cycloalkenyl refers to monocycle or the bicyclo-carbocyclic ring that has 3 to 8 C-atoms and comprise two keys.
It is monocycle or the bicyclo-ring system that is selected from the ring that carbon atom and heteroatomic atom form by 5 to 8 that term heterocycle alkane (alkene) base refers to wherein said ring; Prerequisite is that in the atom of said formation ring one or two is the independent hetero atom of selecting.Therefore, may to refer to wherein said ring be monocycle or the bicyclo-ring system that is selected from the ring that heteroatomic atom that 3-7 carbon atom and 1 or 2 is selected from N, S or O forms by 5 to 8 to term heterocycle alkane (alkene) base.The example of such ring system has morpholine, pyrrolidine, piperidines and piperazine.
Term halo-C 1-6-alkane (alkene/alkynes) base refers to the C that is replaced by one or more halogen atoms 1-6-alkane (alkene/alkynes) base comprises trifluoromethyl without limitation.Equally, halo-C 3-8-cycloalkanes (alkene) base refers to the C that is replaced by one or more halogen atoms 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base refers to heterocycle alkane (alkene) base that is replaced by one or more halogen atoms.
Term NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base refers to by NR 10R 10 'The C that replaces 1-6-alkane (alkene/alkynes) base; NR 12R 12 '-C 1-6-alkane (alkene/alkynes) base refers to by NR 12R 12 'The C that replaces 1-6-alkane (alkene/alkynes) base; And NR 7R 7 '-C 1-6-alkane (alkene/alkynes) base refers to by NR 7R 7 'The C that replaces 1-6-alkane (alkene/alkynes) base.2-amino-4-methyl-pentane is an example of such group, and this example is not to be used to limit.
Term NR 10R 10 '-C 3-8-cycloalkanes (alkene) base refers to by NR 10R 10 'The C that replaces 3-8-cycloalkanes (alkene) base; NR 12R 12 '-C 3-8-cycloalkanes (alkene) base refers to by NR 12R 12 'The C that replaces 3-8-cycloalkanes (alkene) base; And NR 7R 7 '-C 3-8-cycloalkanes (alkene) base refers to by NR 7R 7 'The C that replaces 3-8-cycloalkanes (alkene) base.1-amino-cyclopropane is an example of such group, and this example is not to be used to limit.
Term NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base refers to by NR 10R 10 'The C that replaces 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base refers to by NR 12R 12 'The C that replaces 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; And NR 7R 7 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base refers to by NR 7R 7 'The C that replaces 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
Work as NR 12R 12 '-C 1-6-alkane (alkene/alkynes) base, NR 12R 12 '-C 3-8-cycloalkanes (alkene) base, NR 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6When any one in-alkane (alkene/alkynes) base randomly is substituted, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base is randomly by one or more C that are independently selected from 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6The substituent group of-alkane (alkene/alkynes) base or Ar replaces.
The terminology used here acyl group refers to formoxyl, C 1-6The basic carbonyl of-alkane (alkene/alkynes), C 3-8The basic carbonyl of-cycloalkanes (alkene), Ar-carbonyl, Ar-C 1-6Basic carbonyl of-alkane (alkene/alkynes) or C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-carbonyl, wherein C 1-6-alkane (alkene/alkynes) base, C 3-8The definition of-cycloalkanes (alkene) base and Ar as mentioned above.
To form a kind of 5-8 person with nitrogen-atoms saturated or undersaturated when randomly comprising an other heteroatomic ring when two substituent groups, then a kind of monocycle ring system is formed by 5 to 8 atoms, and one or two said atom is the hetero atom that is selected from N, S or S.The example of such ring system has pyrrolidine, piperidines, piperazine, morpholine, pyrroles, oxazolidine, Thiazolidine, imidazolidine, azetidine, beta-lactam, tetrazolium and pyrazoles.
When two substituent groups of adjoining and its aromatic group that is attached thereto form together a kind of when randomly comprising one or two other heteroatomic 5-8 person and encircling, then this ring be by 5-8 be selected from 3-8 carbon atom and 0-2 individual be selected from N, S or O and heteroatomic atom formed.Such two substituent groups of adjoining can form together :-(CH 2)-CH 2-,-CH=CH-(CH 2) M "-,-CH 2-CH=CH-(CH 2) P ",-CH=CH-CH=CH-,-(CH 2) N "-O-,-O-(CH 2) M "-O-,-CH 2-O-(CH 2) P "-O-,-CH 2-O-CH 2-O-CH 2-,-(CH 2) N "-S-,-S-(CH 2) M "-S-,-CH 2-S-(CH 2) P "-S-,-CH 2-S-CH 2-S-CH 2-,-(CH 2) N "-NH-,-NH-(CH 2) M "-NH-,-CH 2-NH-(CH 2) N "-NH-,-CH=CH-NH-,-O-(CH 2) M "-NH-,-CH 2-O-(CH 2) P '-NH-or-O-(CH 2) P "-NH-CH 2-,-S-(CH 2) M "-NH-,-N=CH-NH-,-N-CH-O-or-N-CH-S-, wherein m " be 1,2 or 3, n " be 2,3 or 4 and p " be 1 or 2.
Term Ar refers to the aromatic systems of randomly substituted 5-10 carbon atom, and wherein 0,1,2,3 or 4 carbon atom hetero atom that can be independently selected from N, S or O is replaced.Such Ar examples of groups have randomly substituted phenyl, randomly substituted naphthyl (naphtyl), randomly substituted quinoline, randomly substituted indole, randomly substituted pyridine, randomly substituted pyrimidine, randomly substituted thiophene, randomly substituted furan, randomly substituted thiazole and randomly Bei replace the De oxazole.Such randomly substituted Ar base can be by one or more hydroxyl, halogen, C of being independently selected from 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base, C 3-8-alkane (alkene/alkynes) oxygen base, acyl group, nitro, cyano group ,-CO-NH-C 1-6-alkane (alkene/alkynes) base ,-CO-N (C 1-6-alkane (alkene/alkynes) base) 2,-NH 2,-NH-C 1-6-alkane (alkene/alkynes) base, N (C 1-6-alkane (alkene/alkynes) base) 2, S-C 1-6-alkane (alkene/alkynes) base ,-SO 2N (C 1-6-alkane (alkene/alkynes) base) 2With-SO 2NH-C 1-6-alkane (alkene/alkynes) base, SO 2-C 1-6-alkane (alkene/alkynes) base and SO 2O-C 1-6The substituent group of-alkane (alkene/alkynes) base replaces; Or two substituent groups of adjoining can form with this aromatic group and a kind ofly randomly comprise one or two hetero atom and can be saturated or undersaturated 5-8 person's ring.
Term C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-heterocycle alkane (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base, C 2-6-alkenyloxy, C 2-6-alkynyloxy group, C 3-8-cycloalkanes (alkene) oxygen base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-heterocycle alkane (alkene) base, Ar oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6The basic carbonyl of-alkane (alkene/alkynes), C 3-8The basic carbonyl of-alkane (alkene), Ar-carbonyl, Ar-C 1-6The basic carbonyl of-alkane (alkene), C 3-8-cycloalkanes (alkene) base-C 1-6The basic carbonyl of-alkane (alkene/alkynes) ,-CO-C 1-6-alkane (alkene/alkynes) base, S-C 1-6-alkane (alkene/alkynes) base, SO 2-C 1-6-alkane (alkene/alkynes) base and SO 2O-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, acyl group, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-alkane (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-cycloalkanes (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-Ar, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-Ar, halo-heterocycle alkane (alkene) base-Ar, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base or the like refers to wherein C 1-6-alkane (alkene/alkynes) base, C 2-6-alkenyl, C 2-6-alkynyl, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, Ar, cyano group, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8The definition of-cyano group alkane (alkene) base, halo-heterocycle alkane (alkene) base and acyl group group as mentioned above and so on.
The preferably pharmaceutically useful salt of salt of the present invention.Such salt comprises pharmaceutically useful acid-addition salts, pharmaceutically useful slaine, ammonium salt and alkanisation ammonium salt.
The pharmaceutically useful salt of the present invention is acid-addition salts preferably.Acid-addition salts of the present invention is the officinal salt that forms of The compounds of this invention and nontoxic acid preferably.Acid-addition salts comprises mineral acid and organic acid salt.
The representative instance of suitable mineral acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, sulfamic acid, phosphoric acid and nitric acid or the like.Can form such acid-addition salts with the method for well known to a person skilled in the art.Pharmaceutically acceptable other example inorganic or organic acid addition salt is included in J.Pharm.Sci.1977, listed officinal salt in 66,2 (they are introduced into as a reference) here.
Suitable organic acid representative instance comprises acetic acid, trichloroacetic acid, trifluoracetic acid, propanoic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, acetone acid, salicylic acid, succinic acid, ethyl sulfonic acid, tartaric acid, ascorbic acid, pounce on acid, gluconic acid, peaceful furancarboxylic acid, aspartic acid, stearic acid, Palmic acid, EDTA, glycolic, Para-Aminobenzoic, glutamic acid, two-methylene salicylic acid, methanesulfonic acid, ethane disulfonic acid, the itaconic acid, benzenesulfonic acid, right-toluenesulfonic acid, theophylline acetic acid, and 8-halo theophylline, for example 8-bromine theophylline or the like.The other example of pharmaceutically useful mineral acid or organic acid addition salt comprises J.Pharm.Sci.1977, listed officinal salt in 66,2 (they here are introduced into as a reference).
The example of slaine comprises lithium, sodium, potassium, magnesium salt or the like.
The example of ammonium salt and alkanisation ammonium salt comprise ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, just-butyl-, the second month in a season-butyl, tert-butyl-, tetramethyl ammonium or the like.
With regard to pharmaceutically useful acid-addition salts, the hydrate that also has The compounds of this invention to form.
Chemical compound of the present invention can have one or more asymmetric centers, and when separated, any optical isomer, pure or partially purified optical isomer itself or racemic mixture all are included in the scope of the present invention.
In addition, when in molecule, having two keys or saturated fully or fractional saturation ring system, can form geometric isomer.When separating, comprise any geometric isomer, pure or partially purified geometric isomer or its mixture in the scope of the invention.Equally, have the molecule that rotates limited key and can form geometric isomer.It also is included in the scope of the present invention.
In addition, any tautomeric form that some chemical compounds of the present invention can exist with different tautomeric forms and these chemical compounds can form also is included in the scope of the present invention.
Chemical compound of the present invention can and have solvent such as the solvation form of equal solvents such as water, ethanol exists with solvation form not.For purpose of the present invention, it is generally acknowledged this solvation form and not solvation form equivalence.
Some chemical compounds of the present invention comprise chiral centre and this compounds exists with isomer (being enantiomer) form.The present invention includes all such isomers and comprise any mixture of racemic mixture.
Can use known method, thereby for example by with the optics active acid its diastereoisomeric salt being separated and handling this optically active amines of release with alkali and come the racemic modification form is split.The another kind of method that racemic modification is split into optical antipode is so that be basic with the chromatograph of optics active matrix.For example, can also the racemic chemical compound of the present invention be split into its optical isomer with d-or 1-(tartrate, amygdalate or camsilate) salt classification crystallization.Can also come chemical compound of the present invention is split by forming non-enantiomer derivative.
Can be with well known to a person skilled in the art the other method that splits optical isomer.These class methods comprise J.Jaques, and A.Collet and S.Wilen are in " enantiomer, racemic modification and fractionation (Enantiomers, Racemates, and Resolutiohs) ", John Wiley and Sons, these methods of being discussed in New York (1981).
Can also prepare these optically active chemical compounds by the optical activity parent material.
Carry out chemical conversion by metabolic process when the present invention also is included in administration, become the prodrug of the The compounds of this invention of pharmacological active substance then.Such prodrug is the functional derivatives of the chemical compound of general formula I, XXIX, XXX, XXXI, XXXII or XXXIII normally, and it can easily transform the chemical compound of accepted way of doing sth I, XXIX, XXX, XXXI, XXXII or XXXIII in vivo.At for example " prodrug design (Design of Prodrugs) ", the H.Bundgaard chief editor, Elsevier, in 1985 to selecting and the conventional method of preparation suitable precursor medicaments derivative is described.
The present invention also comprises the active metabolite of The compounds of this invention.
No matter when, relating to formula I, XXIX, XXX, XXXI, during the chemical compound of XXXII or XXXIII, term epilepsy (epilepsy and epilepsies) is included in InternationalLeague Against epilepsy: the clinical amendment scheme of epilepsy and electroencephalography classification (Proposal for revised clinical and electroencephalographicclassification of seizures), Commission on Classification andTerminology of the International League AgainstEpilepsy.Epilepsia 1981 22:489-501 and International LeagueAgainst Epilepsy: the classification amendment scheme of epilepsy and epilepsy (Proposal for revisedclassification of epilepsies and epileptic syndromes), Commission on Classification and Terminology of theInternational League Against Epilepsy.Epilepsia193930 (4): be called as epilepsy among the 389-399, any in epilepsy and the Epileptic fits.
No matter when, relating to formula I, XXIX, XXX, XXXI, during the chemical compound of XXXII or XXXIII, the term anxiety disorder comprises and is called as panic attack, agoraphobia, the panic disorder relevant with agoraphobia, with the irrelevant panic disorder of agoraphobia, the agoraphobia of no panic disorder history, specific phobia, social phobia, obsession, posttraumatic stress disorder, acute stress disorder, generalized-anxiety disorder, because the anxiety disorder that general medical condition causes, the inductive anxiety disorder of material, separation anxiety disorder, the diagnosis of adjustment disorder and AmericanPsychiatric Association mental illness and statistics handbook (Diagnosticand statistical manual of mental disorders), the 4th edition, 1994:110-113, the situation and the disease of the anxiety disorder of the not certain illustrated of 393-444 and 623-627 definition.
Pharmaceutical composition
Chemical compound of the present invention normally is used with the form of its free alkali or officinal salt.Its representative instance as mentioned above.
If necessary, pharmaceutical composition of the present invention can comprise the chemical compound of formula I and other pharmacological active substance these materials as previously described.
Chemical compound of the present invention can with single dose or multiple dose by administration separately or with pharmaceutically useful carrier or excipient administering drug combinations.Can be according to routine techniques as at Remington:TheScience and Practice of Pharmacy, 19 Edition, Gennaro, Ed., MackPublishing Co., Easton, PA, disclosed these routine techniquess come pharmaceutical composition of the present invention is prepared with pharmaceutically useful carrier or diluent and any other known auxiliary agent and excipient in 1995.
These preparation of pharmaceutical compositions can be become the form of carrying out administration by any suitable route, as be prepared into by in oral, rectum, nose, lung, part (comprising cheek and Sublingual), percutaneous, the brain pond, intraperitoneal, vagina and parenteral (comprise in subcutaneous, intramuscular, the sheath, intravenous and intradermal) approach carries out the form of administration, the preferred oral approach.Should be realized that preferred approach will depend on by treatment individual ordinary circumstance and age, the character of being treated situation and selected active component.
Be used for pharmaceutical composition for oral administration and comprise solid dosage forms such as capsule, tablet, dragee, pill, lozenge, powder and granule.In suitable situation, thereby can be prepared it or can be prepared controlled release such as slow release or long-time release that active component is provided to it with coating such as enteric coating with well-known method in the prior art.
The liquid dosage form that is used for oral administration comprises solution, Emulsion, suspension, syrup and elixir.
The pharmaceutical composition that is used for parenteral comprises aseptic aqueous or non-aqueous injectable molten night, dispersion, suspension or Emulsion and the sterilized powder that is rearranged into sterile injectable solution or dispersion before use.Think that injectable depot formulations also within the scope of the invention.
The form of other suitable administration comprises suppository, spray, ointment, frost, gel, inhalant, skin patch, implant or the like.
Pharmaceutical composition of the present invention or these compositionss prepared in accordance with the present invention can be carried out administration by any suitable route, for example can be with tablet, capsule, powder, syrup or the like form oral administration or with the form parenteral of injection solution.For such preparation of compositions, can use well-known method in the prior art, and can use any pharmaceutically useful carrier, diluent, excipient or this area other additive commonly used.
A kind of typical oral dose be every day with one or more dosage as 1 to 3 dosed administration about 0.001 to about 100mg/kg body weight, be preferably every day about 0.01 to about 50mg/kg body weight, and more preferably be the dosage of every day about 0.05 to about 10mg/kg body weight.Exact dose will depend on any coexistence disease and the conspicuous to those skilled in the art other factors that administration frequency and mode, the character of being treated individual sex, age, body weight and ordinary circumstance, the situation for the treatment of and the order of severity and quilt are treated.
Said preparation can exist with unit dosage forms with the method that well known to a person skilled in the art.A kind of be used for every day the oral administration one or many such as every day oral administration 1 to 3 time the typical flat dosage form can comprise 0.05 to about 1000mg, preferred about 0.1 to about 500mg, and 0.5mg about 200mg extremely more preferably from about.
For in parenteral approach such as intravenous, the sheath, for intramuscular administration and the similar administration, typical doses is the only about half of of the used dosage of oral administration.
Chemical compound of the present invention normally is used with the form of dissociant or its officinal salt.An example is the base addition salts with chemical compound of free acid effectiveness.When chemical compound of the present invention comprised free acid, such salt can be prepared by with stoichiometric pharmaceutically acceptable alkali the solution of The compounds of this invention free acid or suspension being handled with usual manner.Typical example as mentioned above.
For parenteral, can use the solution of new compound of the present invention in aseptic aqueous solution, aqueous propylene glycol, aqueous vitamin E or Oleum sesami or Oleum Arachidis hypogaeae semen.If necessary, can be to suit buffering and at first this liquid diluent etc. is oozed of such aqueous solution with enough saline or glucose.This aqueous solution is specially adapted to intravenous, intramuscular, subcutaneous and intraperitoneal administration.Used sterile aqueous media can easily obtain with standard technique well known by persons skilled in the art.
Can be by active component and possible additive be dissolved in a part of solvent for injection, in the preferred sterilized water, this solution is adjusted to volume required, with this solution sterilization and fill it in suitable ampoule or the bottle and prepare injection solution.Can add this area any suitable additive commonly used, as isotonic agent, antiseptic, antioxidant or the like.
Suitable pharmaceutical carrier comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.
The example of solid carrier has lactose, Gypsum Fibrosum powder, sucrose, cyclodextrin, Pulvis Talci, agar, pectin, arabic gum, stearic acid and cellulosic lower alkyl ether, corn starch, potato starch, Pulvis Talci (talcum), magnesium stearate, gelatin, lactose, natural gum or the like.
Can use any other auxiliary agent that is usually used in such purpose or additive such as coloring agent, correctives, antiseptic or the like, prerequisite is that it can be compatible with active component.
The example of liquid-carrier has syrup, Oleum Arachidis hypogaeae semen, olive oil, phospholipid, fatty acid, fatty acid amine, polyethylene glycol oxide and water.Equally, this carrier or diluent can comprise any slow-release material well known in the prior art, as separately or be mixed with the glyceryl monostearate or the distearin of wax.
Then, can easily will carry out administration with the various dosage forms that are suitable for disclosed route of administration by formed pharmaceutical composition that new compound of the present invention and pharmaceutically useful carrier are combined.Said preparation can exist with unit dosage forms easily with the known method of pharmaceutical field.
The preparation that the present invention is suitable for oral administration can exist with the form of discrete unit such as capsule or tablet, the active component of its each self-contained predetermined quantity, and it can comprise the excipient that one or more are suitable.In addition, preparation that can oral acquisition can also be powder or granule, be arranged in the form of solution or suspension, oil-in-water or the Water-In-Oil liquid emulsion of aqueous or non-aqueous liquid.
If carry out oral administration with solid carrier, then said preparation can be to be placed on tablette or piller form in the hard gelatin capsule with powder type, and perhaps it can be lozenge or lozenge form.
The quantity of this solid carrier can change in very wide scope, but is generally about 25mg to about 1g.
If the use liquid-carrier, then said preparation can be syrup, Emulsion, Perle or sterile injectable liquid such as aqueous or non-aqueous liquid suspension or solution form.
If necessary, pharmaceutical composition of the present invention can comprise the chemical compound of formula I, XXIX, XXX, XXXII or XXXIII and other disclosed these materials of pharmacological active substance such as front.
The representative instance of preparation prescription of the present invention is as follows:
1) comprise the tablet of 5.0mg (calculating) The compounds of this invention with free alkali form:
The chemical compound 5.0mg of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Lactose 60mg
Corn starch 30mg
Hydroxypropyl cellulose 2.4mg
Microcrystalline Cellulose 19.2mg
A type cross-linking sodium carboxymethyl cellulose 2.4mg
Magnesium stearate 0.84mg
2) comprise the tablet of 0.5mg (calculating) The compounds of this invention with free alkali form:
The chemical compound 0.5mg of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Lactose 46.9mg
Corn starch 23.5mg
Polyvidone 1.8mg
Microcrystalline Cellulose 14.4mg
A type cross-linking sodium carboxymethyl cellulose 1.8mg
Magnesium stearate 0.63mg
3) syrup, its every milliliter comprises:
The chemical compound 25mg of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Sorbitol 500mg
Hydroxypropyl cellulose 15mg
Glycerol 50mg
Methyl hydroxybenzoate 1mg
Propylparaben 0.1mg
Ethanol 0.005mL
Correctives 0.05mg
Saccharin sodium 0.5mg
Water adds to 1mL
4) injection solution, its every milliliter comprises:
The chemical compound 0.5mg of formula I, XXIX, XXX, XXXI, XXXII or XXXIII
Sorbitol 5.1mg
Acetic acid 0.05mg
Saccharin sodium 0.5mg
Water adds to 1mL
The preparation of The compounds of this invention
Figure A20048000750700931
Wherein a, b, c, d, e, f, g, h, s, q, U, W, X, Z, R 1, R 2, R 3, R 5, R 6, R 6 ', R 7, R 7 ', R 8, R 9, R 9 ', R 10, R 10 ', R 11, R 12And R 12 'Definition can and shown in flow chart, be prepared like that with method described below suc as formula the chemical compound of described general formula I of the present invention under the I.
The substituted 4-nitroaniline of general formula I X or XI can obtain by commercial sources, be described in the literature or can be prepared according to the known method of this area scholar person.S is 0 and R 2The chemical compound that is the general formula I X of substituted aryl as defined above or substituted heteroaryl such as furyl, thienyl, phenyl, pyridine radicals or XI particularly can be by R 2Be I or Br respective compound with this area chemistry personnel known crosslinked-coupling reaction such as Suzuki coupling, Stille coupling or other transition metal-catalyzed crosslinked-coupling reaction [D.W.Knight, " coupling reaction between sp2 carbon center ", Comprehensive OrganicSynthesis, the 3rd edition, the 481-520 page or leaf, Pergamon Press 1991] be prepared.Perhaps; the 4-nitroaniline of general formula I X or XI can be by the aniline that corresponding 2-protected or not protected form the replaces known nitration treatment [R.Behnisch of this area chemistry personnel; " Aromatische Nitro-Verbindungen "; Methoden derOrganische Chemie/ (Houben-Weyl); the 255th page; v.E16d, Thieme:1992] be prepared.This method particularly can be used for wherein, and U is S, SO 2, or SO 2NR 11General formula I X or the chemical compound of XI.Can also according to this area chemistry personnel known method by oxidation wherein U be that the chemical compound of the general formula I X of S or XI changes into wherein that U is SO 2General formula I X or the chemical compound of XI, for example can be by with 3-chloroperoxybenzoic acid or NaIO 4At the RuCl that exists as catalyst 3Situation under carry out oxidation and carry out.
The chemical compound of general formula X I can also form R by using by the chemical compound of general formula I X 3-(Z) qThe suitable electrophilicity reagent of-X base; without limitation as alkyl; aryl; or heteroaryl chloro-formate or carbamyl chloride; carbonic anhydride; acid fluoride; acid chloride; acid bromide RCOBr; acid iodide; active ester; active carbonic acid and activating reagent such as carbodiimide; sulfonic acid chloride; or isocyanates is at suitable solvent such as acetonitrile; oxolane; 1; the 2-dichloroethanes; or in the dichloromethane; under by routine heating or the suitable temperature that is obtaining under the meagre radiation such as room temperature or backflow; adding or do not adding alkali such as magnesium oxide; potassium carbonate; sodium hydride; trialkylamine; purification sodium-or potassium; sodium carbonate or potassium; sodium bicarbonate or potassium; or the reaction of carrying out under the situation of pyridine, well-known reaction is prepared among some this area chemistry personnel.
In addition, for R 2Other modification, can be with this area chemistry personnel known method R wherein 2Be that methyl, U are that oxygen and s are the chemical compound demethylations of 1 general formula X I, as in The suitable solvent such as dichloromethane, carrying out it is handled demethylation as under 0 ℃ or the room temperature in suitable temperature with Boron tribromide.Then, with this area chemistry personnel known method the phenol conversion of gained being become U wherein is that oxygen and s are the chemical compounds of 1 general formula X I.These class methods comprise: (a) with electrophilic reagent, as alkyl chloride, alkyl bromide, alkyl iodide, benzyl chloride, carbonic acid chlorine, carbonic acid bromine or carbonic anhydride under the situation that has suitable alkali such as potassium carbonate at The suitable solvent such as oxolane, N, under suitable temperature such as room temperature or reflux temperature, react in dinethylformamide or 1,2 dichloroethanes; (b) alkyl, benzyl or heteroaryl alkyl alcohol are reacted (O.MitsunobuSynthesis 1981,1) under the condition that is called as the Mitsunobu reaction.
Can reduce as having acid as the zinc under acetic acid or the aqueous hydrochloric acid situation or iron powder or existing suitable hydrogenation catalyst such as palladium to drape over one's shoulders hydrogen under the situation of activated carbon or the ammonium formate nitro in the chemical compound of mutual-through type XI under the temperature that suits or under ultrasonic radiation in The suitable solvent such as methanol, ethanol or oxolane with suitable Reducing agent, thereby obtain the aniline of general formula X II.Perhaps, can under the well-known condition of this area chemistry personnel, use stannic chloride (II) or sodium dithionite as Reducing agent.
With the aldehyde of the aforesaid general formula YCHO of definition of Y wherein in The suitable solvent such as methanol, ethanol, dimethylbenzene, oxolane, acetonitrile or its mixture under suitable temperature the aniline to the general formula X II that obtained carry out the known standard reductive alkylation reaction of this area chemistry personnel, form imine intermediate, it is separated with its in-situ reducing or by evaporating solvent or crystallization.In The suitable solvent such as ethanol, methanol or acetonitrile, under the situation of acid that adds or do not add catalytic quantity such as acetic acid, under suitable temperature, it is reduced into wherein R with Reducing agent such as sodium borohydride (sodium borohydrate) or sodium cyanoborohydride (sodium cyanoborohydrate) 1It is the chemical compound of the present invention of the general formula I of hydrogen.
For R 1Modification, can by carry out with suitable aldehyde and Reducing agent such as above-mentioned sodium cyanoborohydride the second time standard reductive alkylation process randomly to the wherein R of gained 1The chemical compound that is the general formula I of hydrogen carries out further derivatization.This process can be carried out the first time at the aldehyde with general formula YCHO and be carried out in position after the standard reductive alkylation reaction.Perhaps, can be by with LG wherein being the leaving group that suits such as the general formula R of iodide, bromide or sulphonic acid ester 1R is introduced in the electrophilicity substitution reaction that the suitable electrophilic reagent of-LG carries out under the known condition of this area chemistry personnel 1
For R 3, Z and the other modification of X, the chemical compound of the present invention of general formula I can obtain with the alternate selection approach of a kind of confession: can be by with suitable blocking group (PG 1) [the blocking group in the organic synthesis (Protective Groups in Organic Synthesis); the 3rd edition; T.W.Greene; P.G.M.Wuts; Wiley Interscience 1999] as be called the trifluoroacetyl group of TFA group by those skilled in the art; reagent by will forming blocking group such as trifluoro-acetic anhydride, react under suitable temperature in the 2-dichloroethanes and the aniline nitrogen in the substituted 4-nitroaniline of general formula I X protected are prepared as 1 in The suitable solvent.
The aniline of general formula X IV can well known to a person skilled in the art that aforesaid nitroreduction obtains by basis.Then, like that it is carried out the standard reductive alkylation reaction as mentioned above, thereby obtain the chemical compound of general formula X V with the aldehyde of general formula YCHO.
The chemical compound of general formula X V is carried out the standard reductive alkylation step second time as mentioned above like that, obtain wherein PG 1It is the chemical compound of the general formula X VI of TFA.Then, can use this area chemistry personnel known method, under suitable temperature, be hydrolyzed in The suitable solvent such as methanol as the use potassium carbonate and remove this TFA base, thereby obtain the chemical compound of general formula X VII.
R wherein 1The chemical compound of the present invention that is not hydrogen is by with forming R by the aniline of general formula X VII 3-(Z) qThe suitable electrophilicity reagent of-X group; as alkyl; aryl or heteroaryl chloro-formate or carbamyl chloride; acid chloride; acid bromide RCOBr; acid iodide; sulfonic acid chloride; isocyanates; carbonic anhydride; activated carbon anhydride and activator such as carbodiimide or this area known other material of chemistry personnel are at The suitable solvent such as acetonitrile; oxolane; 1, the 2-dichloroethanes; or under suitable temperature such as room temperature or reflux temperature, adding or do not adding alkali such as magnesium oxide in the dichloromethane; potassium carbonate; trialkylamine; or react under the situation of pyridine or obtain by aforesaid other method.
For R wherein 1Be the chemical compound of the present invention of the general formula I of hydrogen, with the known suitable blocking group (PG of this area chemistry personnel 2) chemical compound of [blocking group in the organic synthesis, the 3rd edition, T.W.Greene, P.G.M.Wuts, Wiley Interscience 1999] mutual-through type XV protects, and obtains the chemical compound of general formula X VIII.PG wherein 2The chemical compound of general formula X VIII that is called the tert-butyl carbonyl of Boc group by those skilled in the art particularly can be with the suitable reagent that forms blocking group such as tert-butyl carbonic anhydride in suitable solvent such as acetonitrile and reacting under the suitable temperature as under+80 ℃, thereby obtains wherein PG 2The chemical compound that is the general formula X VIII of Boc is prepared.Then, remove this TFA protecting group (PG1) as mentioned above like that, obtain the chemical compound of general formula X IX, such as mentioned above then, with forming R 3-(Z) qThe suitable electrophilic reagent of-X carries out derivatization to it, obtains the chemical compound of general formula X X.
Perhaps; the chemical compound that can prepare general formula X IX with three step processes as described below: the chemical compound that like that the chemical compound standard reductive alkylation of general formula X XXIV will be obtained general formula X XXV as mentioned above by the 4-nitroaniline; can in The suitable solvent such as oxolane, protect with for example heavy carbonic di-tert-butyl and dimethyl aminopyridine then it; thereby obtain the chemical compound of general formula general formula X XXVI, then as mentioned above like that with suitable Reducing agent such as Na 2S 2O 4It is reduced into the chemical compound of general formula X IX.
At last, can pass through PG with this area chemistry personnel known method 2Go protect the chemical compound of cause general formula X X to obtain wherein R 1It is the chemical compound of the present invention of the general formula I of hydrogen.Particularly can with the known method of this area chemistry personnel as with suitable acid for example trifluoracetic acid under the situation that does not have or exist solvent such as dichloromethane or toluene, this Boc blocking group is carried out cracking in the protection of going down of suitable temperature.
The chemical compound that perhaps, can prepare general formula I by following approach:
R wherein 2, U and s the chemical compound of the aforesaid general formula X XI of definition can obtain or can be prepared by commercial sources with this area known method of chemistry personnel.These methods comprise 5-fluoro-2-nitrophenol the aforesaid Mitsunobu-that is used for the chemical compound of synthetic general formula X I, alkylation by phenol-or acylation condition under the reaction carried out.Use Y-CH 2-NH-R 1The nucleophilic aromatic that the amine of type carries out replaces, and---the well-known reaction of a kind of this area chemistry personnel---obtained the chemical compound of general formula X XII.Perhaps, the standard reductive alkylation of the 4-nitroaniline that the chemical compound of general formula X XII can be by aforesaid general formula X XXIV is prepared.The chemical compound of general formula X XIII can be by also being prepared nitro under the aforesaid condition that is used for synthetic general formula X II chemical compound originally.The chemical compound of general formula X XIII and the aforesaid formation R that is used for general formula X I chemical compound 3-(Z) qThe reaction that the suitable electrophilic reagent of-X carries out has provided the chemical compound of the present invention of general formula I.
Perhaps, s is 0 and R 2The chemical compound that is the general formula I of substituted aryl as defined above or substituted heteroaryl such as furyl, thienyl, phenyl, pyridine radicals can be by corresponding R 2Be I or Br chemical compound by above-mentioned crosslinked-coupling reaction is prepared.
Embodiment
Analyze LC-MS data (LC-MS=LC/MS) and be being furnished with on the PE Sciex API 150EX instrument of APPI (atmospheric pressure photo-ionisation) ion source and Shimadzu LC-8A/SLC-10A LC system and obtain.Post: 30X4.6mm Waters Symmetry C18 post, granularity is 3.5 μ m; Solvent system: A=water/trifluoracetic acid (100: 0.05) and B=water/acetonitrile/trifluoracetic acid (5: 95: 0.03); Method: carried out linear gradient elution with 90%A to 100%B in 4 minutes, flow velocity is 2mL/ minute.LC/MS-TOF (time-of-flight) data are to go up at the trace of being furnished with Waters 2488/Sedex 754 detection systems (micromass) LCT 4-road MUX to obtain.Post: 30X4.6mm Waters Symmetry C18 post for example is 3.5 μ m; Solvent system: A=water/trifluoracetic acid (100: 0.05) and B=water/acetonitrile/trifluoracetic acid (5: 95: 0.03); Method: carried out linear gradient elution with 90%A to 100%B in 4 minutes, flow velocity is 2mL/ minute.The isolating ions value (m/z, wherein m is that molecular ion quality and z are electric charges) of actual measurement is designated as the molecular weight (M) by the fragment that randomly adds deduct of the abundantest isotopics.Have [M+3] +Or [M+2] +In the example of assignment, it is to be that calculate on the basis with the abundantest Isotopic Distribution that the m/z value of being reported is equivalent to have the summit that chooses the molecular ion peak of different isotopics and molecular weight M from some.By UV (254nm) integration and ELSD trace are measured purity.Retention time (RT) is minute being that unit expresses.
Preparation LC-MS-purification is to carry out on identical PE Sciex API 150EX instrument.Post: 50X20mm YMC ODS-A, granularity is 5 μ m; Method: carried out linear gradient elution with 80%A to 100%B in 7 minutes, flow velocity is 22.7mL/ minute.Detect with shunting MS and to carry out classification and collect.
1H NMR spectrum writes down under 500.13MHz or 250.13MHz, and it is respectively at Bruker Avance DRX500 or the enterprising line item of Bruker AC 250 instruments.With deuterate chloroform (99.8%D) or dimethyl sulfoxide (99.8%D) as solvent.With TMS as the internal reference standard.Chemical displacement value is that unit represents with the ppm-value.Come the multiplicity of NMR signal is represented with following abbreviation: s=is unimodal, and d=is bimodal, the t=triplet, the q=quartet, the qui=quintet, h=sextet, dd=double doublet, the two triplets of dt=, the two quartets of dq=, tt=three triplets, m=multiplet and br.s=are wide unimodal, br.d=is wide bimodal, the wide triplet of br.t=.
The preparation of intermediate
N-(right-luorobenzyl)-methyl amine is according to G.M.Singer and A.W.AndrewsJ.Med.Chem.1983, and 26,309 described methods are carried out synthetic.2-iodo-4-nitroaniline is according to J.J.Pak, T.J.R.Weakly and M.MHaley J.Amer.Chem.Soc.19999121, and 8182 described methods are prepared.
The preparation of the intermediate of general formula X I
(2-chloro-4-nitrobenzophenone)-urethanes.
With MgO (2.0g), 2-chloro-4-nitroaniline (3.768g, 21.83mmol) and the suspension of ethyl chloroformate (5mL) in acetonitrile (25mL) be heated to reflux temperature heating 4 hours, add more ethyl chloroformate (4mL) then.Continue to be heated to transforming (20 hours) fully, then with this reactant mixture SiO 2Stopper filters, and uses ethyl acetate as eluant.Vacuum evaporation (50 ℃) obtains 5.8g (yield is 100%) title compound crude product, and it is not used for next step with being further purified.LC/MS(m/z)245([M+H] +)；RT＝2.95，(UV，ELSD)96％，98.5％。 1H?NMR(DMSO-d 6)：1.27(t，3H)，4.19(q，2H)，8.06(d，1H)，8.19(dd，1H)，8.30(d，1H)，9.49(s，NH)。
Prepare following chemical compound with suitable chloro-formate similarly:
(2-chloro-4-nitrobenzophenone)-carbamic acid propyl ester.
Replacement property use propyl chloroformate. and oxolane.Make the title compound crystallization and pass through filtration by in this crude product, adding propyl ether its separation.Yield is 3.3g (62%), colorless solid NMR (DMSO-d 6): 0.94 (t, 3H), 1.67 (m, 2H), 4.10 (t, 2H), 8.06 (d, 1H), 8.20 (dd, 1H), 8.31 (d, 1H), 9.52 (s, NH).
(4-nitrobenzophenone)-carbamic acid propyl ester.
At room temperature, in acetone, react as solvent.This product is not carried out purification ground be used for next step.
(4-nitrobenzophenone)-urethanes.
At room temperature, in acetone, react as solvent.This product is not carried out purification ground be used for next step.
(2-methoxyl group-4-nitrobenzophenone)-methyl carbamate.
At room temperature, in acetone, react as solvent.This product is not carried out purification ground be used for next step.
(2-methoxyl group-4-nitrobenzophenone)-carbamic acid isopropyl ester.
At room temperature, in acetone, react as solvent.This product is not carried out purification ground be used for next step.
(2-methoxyl group-4-nitrobenzophenone)-carbamic acid propyl ester.
At room temperature, in acetone, react as solvent.This product is not carried out purification ground be used for next step.
(2-methoxyl group-4-nitrobenzophenone)-carbamic acid 4-fluorobenzene ester.
At room temperature, in acetone, react as solvent.This product is not carried out purification ground be used for next step.
(2-methyl-4-nitrobenzophenone)-urethanes.
This crude product is not used for next step with being further purified.
LC/MS(m/z)207.9([M-16] +)；RT＝2.69，(UV，ELSD)75％，99.7％。
(2-methyl-4-nitrobenzophenone)-carbamic acid propyl ester.
This crude product is not used for next step with being further purified.
LC/MS(m/z)223.1([M-15] +)；RT＝2.97，(UV，ELSD)62％，99.7％。
(2-bromo-4-nitrobenzophenone)-carbamic acid propyl ester.
With the ethyl acetate-hexane crystallization of this crude product. 1H?NMR(DMSO-d 6)：0.94(t，3H)，1.66(m，2H)，4.10(t，2H)，7.97(d，1H)，8.23(dd，1H)，8.44(d，1H)，9.28(br.s，NH)。
(2-iodo-4-nitrobenzophenone)-carbamic acid propyl ester.
Come this crude product is carried out purification by carry out crystallization with ethyl acetate-hexane.Light yellow spicule. 1H?NMR(DMSO-d 6)：0.94(t，3H)，1.66(m，2H)，4.09(t，2H)，7.79(d，1H)，8.24(dd，1H)，8.60(d，1H)，9.07(br.s，NH)。LC/MS(m/z)335.0([M-O] +)；RT＝3.40，(UV，ELSD)99％，100％。
(4-nitro-2-cyano-phenyl)-carbamic acid propyl ester.
Use sodium hydride as alkali alternatively, at room temperature add propyl chloroformate. then.With saturated aqueous sodium bicarbonate (NaHCO 3) crude product that pollutes of will this quilt in methanol two acylates handled 16 hours and with dodging the column chromatography purification. 1H?NMR(CDCl 3)：1.01(t，3H)，1.76(m，2H)，4.22(t，2H)，7.47(br.s，1H，NH)，8.43(dd，1H)，8.47(d，1H)，8.57(d，1H)。
Chemical compound below similarly preparing:
(4-nitro-2-cyano-phenyl)-urethanes.
1H?NMR(DMSO-d 6)：1.28(t，3H)，4.21(q，2H)，7.88(d，1H)，8.47(dd，1H)，8.68(d，1H)，10.34(s，1H，NH)。LC/MS(m/z)220.1([M+H] +)，RT＝2.46，(UV，ELSD)97％，98％。
(2-trifluoromethyl-4-nitrobenzophenone)-carbamic acid propyl ester.
1H?NMR(CDCl 3)：1.00(t，3H)，1.75(m，2H)，4.20(t，2H)，7.26(br.s，1H，NH)，8.41(dd，1H)，8.50(d，1H)，8.57(d，1H)。
(2-trifluoromethyl-4-nitrobenzophenone)-urethanes.
1H?NMR(CDCl 3)：1.37(t，3H)，4.31(q，2H)，7.25(br.s，1H，NH)，8.41(dd，1H)，8.50(d，1H)，8.57(d，1H)。
N-(2-methoxyl group-4-nitrobenzophenone)-butyramide.
To ice-cold (ice/water-bath) 2-methoxyl group-4-nitroaniline (4.00g, 23.8mmol) add in the solution in acetonitrile (40mL) and triethylamine (5mL) butyl chloride (2.66g, 25mmol).After 30 minutes, the suspension poured that obtains is arrived saturated sodium bicarbonate (NaHCO 3) in the aqueous solution (300mL).With its sonication after 10 minutes,, wash with water and its vacuum drying by filtering to isolate the title compound of yellowish-brown solid form.Yield is 5.34g, 94%.LC/MS(m/z)238.9([M+H] +)；RT＝2.69，(UV，ELSD)98％，99％。 1HNMR(DMSO-d 6)：0.91(t，3H)，1.60(m，2H)，2.47(t，2H)，3.98(s，3H，OMe)，7.79(s，1H)，7.88(dd，1H)，8.39(d，1H)，9.50(s，1H，NH)。
Similarly prepare following chemical compound with suitable acid chloride:
N-(2-methoxyl group-4-nitrobenzophenone)-3, the 4-dichloro-benzamide.
LC/MS(m/z)313.0([M+H-NO] +；RT＝3.72，(UV，ELSD)99％，100％。
1H?NMR(DMSO-d 6)：4.0(s，3H，OMe)，7.82(d，1H)，7.88(d，11I)，7.93(m，2H)，8.17(d，1H)，8.20(s，1H)，10.01(s，1H，NH)。
3,3-dimethyl-N-(n2 ethyl-4-nitrobenzophenone)-butyramide.
(5g 32.9mmol) adds tert-butyl chloroacetic chloride (5.3g, 1.2 equivalents) in the solution in acetonitrile (75mL) to 2-methyl-4-nitroaniline.The mixture of gained is assigned in the 15Smith Process bottle and with its sealing.Stirred 10 minutes down at 150 ℃ under microwave radiation with each bottle heating and with it.With the vacuum evaporation of merging to mixture, obtain 9.27g solid (100%), it is not used for next step with being further purified.
LC/MS(m/z)251.1([M+H] +)；RT＝3.01，(UV，ELSD)89％，99.6％。 1HNMR(DMSO-d 6)：1.05(s，9H)，2.33(s，2H)，2.36(s，3H)，7.91(d，1H)，8.05(dd，1H)，8.12(d，1H)，9.41(s，1H，NH)。
Chemical compound below similarly having prepared:
2,2-dimethyl-N-(2-methyl-4-nitrobenzophenone)-propionic acid amide..
LC/MS(m/z)237.1([M+H] +)；RT＝2.72，(UV，ELSD)96.7％，98.6％。 1H?NMR(DMSO-d 6)：1.26(s，9H)，2.31(s，3H)，7.61(d，1H)，8.05(dd，1H)，8.14(d，1H)，9.06(s，1H，NH)。
2-(4-fluorophenyl)-N-(2-methyl-4-nitrobenzophenone)-acetamide.
LC/MS(m/z)288.9([M+H] +)；RT＝2.90，(UV，ELSD)99.6％，99.4％。 1H?NMR(DMSO-d 6)：2.34(s，3H)，3.79(s，2H)，7.18(t，2H)，7.39(dd，2H)，7.91(d，1H)，8.06(dd，1H)，8.13(d，1H)，9.72(s，1H，NH)。
2-(4-fluorophenyl)-N-(2-iodine 4-nitrobenzophenone)-acetamide.
With ice-cold acetonitrile this product is washed. 1H?NMR(DMSO-d 6)：3.81(s，2H)，7.16-7.19(m，2H)，7.41-7.44(m，2H)，7.87(d，1H)，8.23(dd，1H)，8.62(d，1H)，9.66(bs，1H)。
(2-iodo-4-nitrobenzophenone)-urethanes.
With dodging column chromatography this product is carried out purification (silicon dioxide, heptane/ethyl acetate). 1HNMR(DMSO-d 6)：1.27(t，3H)，4.18(q，2H)，7.80(d，1H)，8.24(dd，1H)，8.60(d，1H)，9.05(s，1H)。
(2-(furan-2-yl)-4-nitrobenzophenone)-carbamic acid propyl ester.
With (2-iodo-4-nitrobenzophenone)-carbamic acid propyl ester (30mg, 0.086mmol), 0.9M potassium carbonate (K 2CO 3) aqueous solution (and 0.285mL, 0.257mmol), palladium (II) (5mg) and 2-furan boric acid (48mg, 0.428mmol) under microwave radiation, be heated in the bottle of mixture in acetone (2mL) in sealing+125 ℃ the heating 3 minutes.With the reactant mixture evaporation of gained and with title compound SiO 2Dodge column chromatography purification (5g, heptane-ethyl acetate gradient elution).Yield is 21mg, 84%. 1H NMR (CDCl 3): 1.00 (t, 3H), 1.75 (m, 2H), 4.18 (t, 2H), 6.62 (dd, 1H, furan), 6.79 (d, 1H, furan), 7.64 (d, 1H, furan), 8.16 (dd, 1H), 8.36 (br.s, 1H, NH), 8.39 (d, 1H), 8.48 (d, 1H).LC/MS(m/z)261.0([M+H] +)；RT＝1.57。
Prepare following chemical compound similarly with suitable boric acid:
(2-phenyl-4-nitrobenzophenone)-carbamic acid propyl ester.
This mixture is not carried out purification ground be used for next step.
(2-methoxyl group-4-nitrobenzophenone)-urethanes
Be dissolved in 2-methoxyl group-4-nitrobenzophenone amine (5.0g) in no Shui diox (30mL) and under 0 ℃ to wherein adding N, N-diisopropyl ethyl amine (7.8mL).Be arranged in the ethyl chloroformate (4.25mL) of diox (35mL) to wherein dripping, and the mixture of gained heated stir a whole night to room temperature and with it.Also (3 * 150mL) extract with ethyl acetate with this mixture to wherein adding entry (200mL).With merge the organic facies water (2 * 200mL) and saline (200mL) wash, carry out drying with sodium sulfate, filter, and with its vacuum evaporation.With this crude product ethyl alcohol recrystallization, obtain the title compound (4.45g, 62%) of colorless solid form.
1H?NMR(DMSO-d 6)：1.26(t，3H)，3.94(s，3H)，4.18(q，2H)，7.78(d，1H)，7.90(dd，1H)，8.09(d，1H)，8.99(s，1H)。
(2-hydroxyl-4-nitrobenzophenone)-urethanes
(2-methoxyl group-4-nitrobenzophenone)-urethanes (2.15g) is scattered in 1, is cooled to 0 ℃ in the 2-dichloroethanes (20mL) and with it.Be positioned at 1, the Boron tribromide (2.0mL) in the 2-dichloroethanes (10 mL) to wherein dripping.This reactant mixture was stirred 10 minutes down and at room temperature stirred 30 minutes at 0 ℃.This mixture is cooled to 0 ℃ again, and carefully to wherein adding entry (10mL).This reactant mixture is neutralized with saturated sodium bicarbonate aqueous solution and aqueous hydrochloric acid (5M).Mixture ethyl acetate (3 * 100mL) extractions with gained.With the organic facies water that merged (2 * 100mL) and saline (100mL) washing, use dried over mgso, filtration, and, obtain the title compound (1.96g, 97%) of brown solid with its vacuum evaporation.
1H?NM；R(DMSO-d 6)：1.25(t，3H)，4.17(q，2H)，7.64(d，1H)，7.74(dd，1H)，8.01(d，1H)，8.69(s，1H)，10.96(br.s，1H)。
(2-cyclopentyloxy-4-nitrobenzophenone)-urethanes
Under argon, with cyclopentanol (7.24mL, 376mM is arranged in anhydrous tetrahydro furan) join triphenylphosphine (1.44g, polystyrene bonding, 1.89mMol/g) in, then to wherein adding (2-hydroxyl-4-nitrobenzophenone)-urethane ester solution (25.6mL, 62mM are arranged in anhydrous tetrahydro furan) and diethyl azodiformate (7.24mL, 376mM is arranged in anhydrous tetrahydro furan).With this reactant mixture jolting at room temperature a whole night.This resin leached and with oxolane (THF) (35mL) and methanol (35mL) wash.With the organic facies vacuum evaporation that is merged.This crude product with dodging column chromatography purification (silica gel, heptane/ethyl acetate, gradient elution), is obtained the title compound (294mg, 64%) of faint yellow solid form.
1H?IVMR(DMSO-d 6)：1.27(t，3H)，1.59(m，2H)，1.76(m，2H)，1.87(m，2H)，1.94(m，2H)，4.19(q，2H)，5.01(h，1H)，7.72(d，1H)，7.86(dd，1H)，8.11(d，1H)，8.82(s，1H)。
Prepare following chemical compound with similar mode:
(4-nitro-2-benzene ethoxyl phenenyl)-urethanes
1H?NMR(DMSO-d 6)：1.28(t，3H)，3.15(t，2H)，4.19(q，2H)，4.38(t，2H)，7.23(t，1H)，7.32(t，2H)，7.36(d，2H)，7.80(d，1H)，7.88(dd，1H)，8.08(d，1H)，8.66(s，1H)。
(2-benzyloxy-4-nitrobenzophenone)-urethanes
1H?NMR(DMSO-d 6)：1.26(t，3H)，4.18(q，2H)，5.33(s，2H)，7.35(t，1H)，7.41(t，2H)，7.55(d，2H)，7.86(d，1H)，7.89(dd，1H)，8.06(d，1H)，8.95(s，1H)。
(2-isopropoxy-4-nitrobenzophenone)-urethanes
1H?NMR(DMSO-d 6)：1.27(t，3H)，1.33(d，6H)，4.19(q，2H)，4.84(h，1H)，7.78(d，1H)，7.86(dd，1H)，8.12(d，1H)，8.77(s，1H)。
The preparation of the intermediate of general formula X II
(4-amino-2-methoxyphenyl)-urethanes
(2-methoxyl group-4-nitrobenzophenone)-urethanes (2.20g) is dissolved in the ethanol (220mL).(26mL 6M) and iron powder (4.74g), and stirs this mixture 15 minutes down at 65 ℃ to wherein adding aqueous hydrochloric acid.After being cooled to room temperature, (3 * 200mL) extract with the saturated sodium bicarbonate aqueous solution neutralization and with ethyl acetate with this mixture.With this organic facies water (2 * 100mL) and saline (100mL) washing, use dried over mgso, filtration, and with its vacuum evaporation.With this dissolving crude product in ethanol (100mL), and use hydrochloric acid (26mL 6M) and the method for iron powder (3.7g) above repeating, obtains the title compound (1.80g, 93%) of dark-coloured grease form.
1H?NMR(DMSO-d 6)：1.19(t，3H)，3.67(s，3H)，4.01(q，2H)，4.97(s，2H)，6.08(dd，1H)，6.23(d，1H)，6.97(br.s，1H)，7.92(br.s，1H)。
(4-amino-2-iodophenyl)-urethanes.
1H?NMR(CDCl 3)：1.31(t，3H)，3.58(br.s，2H)，4.21(q，2H)，6.52(br.s，1H)，6.67(dd，1H)，7.12(d，1H)，7.60(br.d，1H)。
Change thing below similarly preparing:
N-(4-amino-2-iodophenyl)-2-(4-fluorophenyl)-acetamide.
1H?NMR(DMSO-d 6)：3.59(br.s，2H)，3.73(s，2H)，6.65(dd，1H)，7.05(d，1H)，7.09-7.12(m，3H)，7.34-7.37(m，2H)，7.82(d，1H)。
(4-amino-2-chlorphenyl)-urethanes.
To carrying out intensively stirred ice-cold (ice/water-bath) (2-chloro-4-nitrobenzophenone)-urethanes (5.8g, 21.8mmol) crude product aliquot ground adds zinc powder (20g) at oxolane (THF) (100mL) and in the solution in the acetic acid (12mL), simultaneously temperature maintenance is being lower than on 40 ℃ the temperature.This mixture is slowly heated to room temperature third and after react completely (1 hour), use SiO 2(20g) stopper filters it, uses ethyl acetate as eluant.With the solution for vacuum evaporation of gained and by carrying out purification by the solid-state crude product residue (4.9g) of yellow with oxolane (THF)/heptane recrystallization, obtain the title compound of 3.00g light yellow solid form, yield is 56%.LC/MS(m/z)214，216(M +)；RT＝1.18，(UV，ELSD)86％，97％。 1H?NMR(DMSO-d 6)：1.18(br.t，3H)，4.02(q，2H)，5.29(s，2H，NH 2)，6.45(dd，1H)，6.61(d，1H)，6.98(br.d，1H)，8.52(br.s，NHCO)。
Chemical compound below similarly preparing:
(4 amino-2-chlorphenyl)-carbamic acid propyl ester.
Yield is 84.6% (2.44g, colorless solid).LC/MS(m/z)228.1(M +)；RT＝1.53，(UV，ELSD)97.3％，99％。
(4-aminophenyl)-carbamic acid propyl ester.
Use SiO 2Dodge column chromatography purification (heptane-ethyl acetate gradient elution).Dark purple crystalline solid, yield are 3.066g, 63.3%.LC/MS(m/z)195([M+H] +)；RT＝1.18，(UV，ELSD)87％，98.3％。
(4-aminophenyl)-urethanes.
LC/MS (with/z) 180.8 ([M+H] +); RT=0.48, (UV, ELSD) 71%, 97%.
(4-amino-2-methoxyphenyl)-methyl carbamate.
LC/MS(m/z)197.0([M+H] +)；RT＝0.49，(UV，ELSD)71％，98％。
(4-amino-2-methoxyphenyl)-urethanes.
LC/MS(m/z)210.9([M+H] +)；RT＝0.98，(UV，ELSD)69％，97％。
(4-amino-2-methoxyphenyl)-carbamic acid isopropyl ester.
LC/MS(m/z)224.0(M +)；RT＝1.33，(UV，ELSD)63％，99％。
(4-amino-2-methoxyphenyl)-carbamic acid propyl ester.
LC/MS(m/z)224.9([M+H] +)；RT＝1.36，(UV，ELSD)70％，98％。
(4-amino-2-methoxyphenyl)-carbamic acid 4-fluorobenzene ester.
LC/MS(m/z)277.0([M+H] +)；RT＝1.64，(UV，ELSD)44％，93％。
(4-amino-2-methyl phenyl)-carbamic acid propyl ester.
LC/MS(m/z)208.1(M +)；RT＝1.16，(UV，ELSD)95％，100％。 1HNMR(CDCl 3)：0.96(t，3H)，1.68(m，2H)，2.17(s，3H，Me)，3.59(br.s，2H，NH 2)，4.09(t，2H)，6.14(br.s，1H，ArH)，6.51(m，2H)，7.32(br.s，1H，NH)。
(4-amino-2-methyl phenyl)-urethanes.
1H?NMR(CDCl 3)：1.28(t，3H)，2.16(s，3H，Me)，3.62(br.s，2H，NH 2)，4.19(q，2H)，6.16(br.s，1H，ArH)，6.5(m，2H)，7.31(br.s，1H，NH).LC/MS(m/z)195.1([M+H] +)；RT＝0.75，(UV，ELSD)70％，95％。
(4-amino-2-trifluoromethyl)-urethanes.
1H?NMR(CDCl 3)：1.30(t，3H)，3.77(br.s，2H，NH 2)，4.20(q，2H)，6.52(br.s，1H，ArH)，6.82(dd，1H)，6.87(unres.d，1H)，7.65(br.s，1H，NH).).LC/MS(m/z)248.1(M +)；RT＝1.65，(UV，ELSD)94％，90％。
(4-amino-2-trifluoromethyl)-carbamic acid propyl ester.
1H?NMR(CDCl 3)：0.96(t，3H)，1.69(m，2H)，3.76(br.s，2H，NH 2)，4.11(t，2H)，6.51(br.s，1H，ArH)，6.81(dd，1H)，6.87(d，1H)，7.61(br.s，1H，NH).LC/MS(m/z)261.9(M +)；RT＝2.06，(UV，ELSD)92％，98％。
(4-amino-2-cyano-phenyl)-urethanes.
1H?NMR(DMSO-d 6)：1.21(t，3H)，4.07(q，2H)，5.49(br.s，2H，NH 2)，6.81(m，2H，ArH)，7.04(d，1H)，9.09(br.s，1H，NH)。LC/MS(m/z)204.9(M +)；RT?1.05，(UV，ELSD)98％，99％。
(4-amino-2-cyano-phenyl)-carbamic acid propyl ester.
1H?NMR(CDCl 3)：0.98(t，3H)，1.71(m，2H)，3.72(br.s，2H，NH 2)，4.13(t，2H)，6.81(br.s，ArH)，6.82(d，1H)，6.89(dd，1H)，7.83(br.s，1H，NH)。LC/MS(m/z)220.1([M+H] +)；RT＝1.52，(UV，ELSD)98％，100％。
N-(4-amino-2-methoxyphenyl)-butyramide.
LC/MS(m/z)208.9([M+H] +)；RT＝0.77，(UV，ELSD)81％，95％。 1HNMR (DMSO-d 6): 0.89 (t, 3H), 1.56 (m, 2H), 2.22 (t, 2H), 3.4 (very wide is unimodal, NH 2), 3.69 (s, 3H, OMe), 6.08 (dd, 1H), 6.25 (d, 1H), 7.27 (d, 1H), 8.62 (s, 1H, NH).
N-(4-amino-2-methoxyphenyl)-3, the 4-dichloro-benzamide.
LC/MS(m/z)311.2(M +)；RT＝1.93，(UV，ELSD)100％，100％。 1HNMR(DMSO-d 6)：3.70(s，3H，OMe)，5.12(br.s，2H，NH 2)，6.15(dd，1H)，6.30(d，1H)，7.09(d，1H)，7.77(d，1H)，7.91(dd，1H)，8.17(d，1H)，9.46(s，1H，NH)。
N-(4-amino-2-methyl phenyl)-3, the 3-amide dimethyl butyrate.
LC/MS(m/z)221.1([M+H] +)；RT＝1.22，(UV，ELSD)53.7％，92.3％。 1H?NMR(DMSO-d 6)：1.02(s，9H)，2.02(s，3H)，2.11(s，2H)，4.89(br.s，2H，NH 2)，6.33(dd，1H)，6.38(d，1H)，6.82(d，1H)，8.83(s，1H，NH)。
N-(4-amino-2-methyl phenyl)-2-(4-fluorophenyl)-acetamide.
LC/MS(m/z)259.1([M+H] +)；RT＝1.36，(UV，ELSD)48.1％，91.4％。 1H?NMR(DMSO-d 6)：1.95(s，3H)，3.56(s，2H)，4.88(br.s，2H，NH 2)，6.31(dd，1H)，6.38(d，1H)，6.83(d，1H)，7.14(t，2H)，7.35(dd，2H)，9.16(s，1H，NH)。
N-(4-amino-2-methyl phenyl)-2,2-dimethyl propylene amide.
LC/MS(m/z)206.9([M+H] +)；RT＝0.59，(UV，ELSD)93％，95％。 1HNMR(DMSO-d 6)：1.19(s，9H)，1.98(s，2H)，4.87(br.s，2H，NH 2)，6.33(dd，1H)，6.39(d，1H)，6.71(d，1H)，8.55(s，1H，NH)。
[4-amino-2-(furan-2-yl)-phenyl]-carbamic acid propyl ester.
IH NMR (CDCl 3): 0.96 (t, 3H), 1.68 (m, 2H), 3.65 (br.s, 2H, NH 2), 4.10 (t, 2H), 6.50 (dd, 1H, furan), 6.58 (d, 1H, furan), 6.66 (dd, 1H), 6.91 (br.s (d of non-fractionation), 1H), 7.26 (br.s, ArH), 7.52 (d, 1H), 7.72 (br.s, 1H, NH) .LC/MS (m/z) 261.0 ([M+H] +); RT=1.57.
(2-phenyl-4-aminophenyl)-carbamic acid propyl ester.
LC/MS(m/z)271.1([M+H] +)；RT＝1.75，(UV，ELSD)57％，99％。
(4-amino-2-bromophenyl)-carbamic acid propyl ester.
With iron powder (20g, excessive) and (2-bromo-4-nitrobenzophenone)-carbamic acid propyl ester (2.183g, 7.20mmol) sonication 10 minutes at room temperature of the suspension in ethanol (80mL) and 6M aqueous hydrochloric acid (20mL).This mixture slowly is poured into saturated sodium bicarbonate (NaHCO 3) in the aqueous solution, filter and with ethyl acetate it is extracted.With merge organic solution with comprising NaHCO 3Wash 3 times, with sodium sulfate (Na 2SO4) carry out drying and, obtain the title compound of 1.67g light yellow oil form, its curing with its vacuum evaporation.Yield is 85%.LC/MS(m/z)271.9，273.8(M +)；RT＝1.30，(UV，ELSD)99％，100％。 1HNMR (DMSO-d 6): 0.90 (br.s (the not t of Chai Fening), 3H), 1.59 (br.s (the not m of Chai Fening), 2H), 3.94 (t, 2H), 5.31 (s, 2H, NH 2), 6.50 (dd, 1H), 6.80 (d of Chai Fening not, 1H), 6.96 (br.d, 1H), 8.51 (br.s, NHCO).
Chemical compound below preparing similarly:
(4-amino-2-iodophenyl)-carbamic acid propyl ester.
1H?NMR(CDCl 3)：0.97(t，3H)，1.69(m，2H)，3.59(br.s，2H，NH 2)，4.11(t，2H)，6.53(br.s，1H，ArH)，6.66(dd，1H)，7.11(d，1H)，7.61(br.s，1H，NH)。LC/MS(m/z)320.7([M+H] +)；RT＝1.71，(UV，ELSD)98％，99％。
Synthesizing of the intermediate of general formula X III-XXIII:
N-(4-amino-2-chlorphenyl)-2,2, the 2-trifluoroacetamide.
To 4-nitro-2-chloroaniline (17.2g, 0.1mol) 1, add in the suspension in the 2-dichloroethanes (100mL) trifluoro-acetic anhydride (16mL, 0.113mol).After 5 minutes, with the yellow solution vacuum evaporation that obtains.Such as mentioned above, with the xanchromatic N-(4-nitro-2-chlorphenyl)-2,2 of gained, 2-trifluoroacetamide solid reduces in oxolane (THF)-acetic acid with the Zn-powder.The crude product of gained is handled with 2M hydrochloric acid (150mL) and ether.The white precipitate of gained is leached, obtain the title compound of 14.7g hydrochloride form.With this aqueous solution saturated sodium bicarbonate (NaHCO 3) the aqueous solution neutralization, filter, obtain the pure product of title compound of 4.58g light gray solid form.1H?NB(DMSO-d 6)：5.54(br.s，2H，NH 2)，6.53(dd，1H)，6.70(d，1H)，7.02(d，1H)，10.79(br.s，1H9?NHCO)。LC/MS(m/z)239.8([M+H] +)；RT＝1.67，(UV)100％。
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2, the 2-trifluoroacetamide.
With N-(4-amino-2-chlorphenyl)-2,2,2-trifluoroacetamide (4.567g, 19.14mmol) and 5-chloro-thiophene-2-formaldehyde (carboxaldehyde) (3.97g, 27.1mmol) solution in dehydrated alcohol (50mL) be heated to reflux 15 minutes and with it in 70 ℃ of following vacuum evaporation (0.1mbar, 30 minutes).With the imines dissolving crude product of the crystalline solid forms of gained in methanol, then by part adding the sodium cyanoborohydride (NaBH that is arranged in methanol (50mL) and acetic acid (9mL) 3CN).The reactant mixture of gained at room temperature stirred 60 minutes and with its vacuum evaporation to small size.With this concentrated solution water extinguishing and at 30 minutes after-filtration, obtain the title compound of 6.98g (yield is 99%) brown-yellow solid form. 1H?NMR(DMSO-d 6)：4.43(d，2H)，6.63(dd，1H)，6.77(d，1H)，6.79(t，1H，NH)，6.94(d，1H)，6.97(d，1H)，7.10(d，1H)，10.85(br.s，1H，NHCO)。LC/MS(m/z)367.9(M +)；RT＝3.36，(UV，ELSD)99％，100％。
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2,2, the 2-trifluoroacetamide.
In 30 minutes, under condition of stirring to N{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl-2,2, the 2-trifluoroacetamide (3.28g, 8.88mmol), drip the sodium cyanoborohydride (NaBH that is arranged in methanol (10mL) in the mixture of 37% formalin (5mL) and acetic acid (3mL) 3CN) (1.1g).This reactant mixture was at room temperature left standstill 2 hours and it is poured in the water.After this grease solidifies, it is leached, wash with water and with its vacuum drying, obtain 3.26g light yellow-brown solid.Yield is 95%. 1HNMR(DMSO-d 6)：2.97(s，3H，NMe)，4.72(s，2H)，6.82(m，1H)，6.91(m，2H)，6.97(d，1H)，7.21(d，1H)，10.92(br.s，1H，NHCO)。LC/MS(m/z)382.0(M +)；RT＝3.66，(UV，ELSD)85％，98％。
(5-chloro-thiophene-2-ylmethyl)-[3-chloro-4-(2,2,2-three fluoro-acetyl-aminos)-phenyl]-carbamic acid uncle-butyl ester.
With N-(2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2, the 2-trifluoroacetamide (2.219g, 6.01mmol), the mixture heated of heavy carbonic di-tert-butyl (2g) and acetonitrile (3mL) to+80 ℃ until react completely (36 hours).During this period, the heavy carbonic di-tert-butyl (2 * 1.5g) that adds other quantity.With the reactant mixture vacuum evaporation of gained (80 ℃, 0.1mbar), obtain the title compound crude product, it is not used for next step with being further purified. 1H?NMR(DMSO-d 6)：1.44(s，9H)，4.94(s，2H)，6.81(d，1H)，6.93(d，1H)，7.25(dd，1H)，7.43(d，1H)，7.50(d，1H)，11.24(br.s，1H，NHCO)。LC/MS(m/z)366.9([M-Boc] +)；RT＝3.99，(UV，ELSD)87％，96％。
2-chloro-N (4)-(5-chloro-thiophene-2-ylmethyl)-N (4)-methyl-benzene-1, the 4-diamidogen.
To N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2,2,2-trifluoroacetamide (3.118g) adds potassium carbonate (K in the solution of methanol (MeOH) in (50mL) 2CO 3) (6.4g) solution in water (25mL) and this reactant mixture at room temperature is stirred to react completely (24 hours).The reactant mixture of gained is extracted with ethyl acetate, with saturated sodium bicarbonate (NaHCO 3) aqueous solution washs and with its evaporation, obtain 2.26g crineous grease.It is not used for next step with being further purified. 1H?NMR(DMSO-d 6)：2.71(s，3H，NMe)，4.47(s，2H)，4.71(br.s，2H，NH 2)，6.67-6.75(m，3H)，6.82(d，1H)，6.93(d，1H)。LC/MS(m/z)288.0([M+H] +)；RT＝2.07，(UV，ELSD)85％，98％。
Chemical compound below preparing similarly:
(4-amino-3-chlorphenyl)-(5-chloro-thiophene-2-ylmethyl)-carbamic acid uncle-butyl ester.
IH NMR (DMSO-d 6): 1.39 (br.s, 9H, uncle-Bu), 4.74 (s, 2H), 5.35 (br.s, 2H, NH 2), 6.67-6.74 (m, 2H), 6.77 (br.d, 1H), 6.90 (d, 1H), 6.97 (d, 1H).LC/MS(m/z)271.9([M-Boc] +)；RT＝3.73，(UV，ELSD)77％，97％。
4-fluoro-2-isopropoxy-1-Nitrobenzol
With 5-fluoro-2-nitrophenol (48g) be dissolved in anhydrous tetrahydro furan (THF) (300mL) in.To wherein adding triphenylphosphine (88g) and 2-propanol (47mL), and the mixture of gained is cooled to 0 ℃.To wherein dripping azodicarbonic acid diisopropyl ester (66mL).The mixture of gained heated stir a whole night to room temperature and with it.Vaporising under vacuum falls solvent and the mixture of gained is filtered (carrying out eluting at 1: 1 with heptane/ethyl acetate) with silicon dioxide.With solvent vacuum evaporation and with the mixture of gained with heptane/ethyl acetate (1: 1) recrystallization.By filtering organic facies is separated with this crystalline solid,, and, obtain the title compound (47.2g, 78%) of colorless oil form remaining product sudden strain of a muscle column chromatography purification (silica gel, heptane/ethyl acetate 9: 1) with solvent vacuum evaporation. 1H?NMR(DMSO-d 6)：1.30(d，6H)，4.85(h，1H)，6.93(m，1H)，7.34(dd，1H)，7.96(dd，1H)。
Chemical compound below similarly preparing:
2-cyclopentyloxy-4-fluoro-1-Nitrobenzol.
1H?NMR(DMSO-d 6)：1.57-1.78(m，6H)，1.86-1.94(m，2H)，6.90-6.97(m，1H)，7.27-7.32(m，1H)，7.98(dd，1H)。
2-benzyloxy-4-fluoro-1-Nitrobenzol.
1H?NMR(DMSO-d 6)：5.33(s，2H)，6.96-7.04(m，1H)，7.32-7.49(m，6H)，8.04(dd，1H)。
(4-luorobenzyl)-(3-isopropoxy-4-nitrobenzophenone)-(methyl)-amine
4-fluoro-2-isopropoxy-1-Nitrobenzol (1.0g) is dissolved in the anhydrous dimethyl sulphoxide (25mL).To wherein adding potassium carbonate (1.4g) and (4-luorobenzyl)-(methyl)-amine (0.84g).With the mixture heated to 90 of gained ℃ heating a whole night.After being cooled to room temperature, to wherein adding entry (75mL), (3 * 75mL) extract with ethyl acetate with the mixture of gained.Organic facies is carried out drying with sodium sulfate, filter, and, obtain the title compound (1.6g, 100%) of slightly yellowy solid form its vacuum evaporation.LC-MS(m/z)319.1([M+H] +)；RT＝3.43，(UV，ELSID)85％，96％。 1H?NMR(DMSO-d 6)：1.21(d，6H)，3.18(s，3H)，4.71(m，1H)，4.73(s，2H)，6.26(d，1H)，6.41(dd，1H)，7.17(m，2H)，7.25(m，2H)，7.84(d，1H)，
Chemical compound below similarly preparing:
(3-benzyloxy-4-nitrobenzophenone) (4-luorobenzyl) methyl amine.
LC-MS(m/z)320.9([M+H-NO 2] +)；RT＝3.54，(UV，ELSD)96％，100％。
(3-cyclopentyloxy-4-nitrobenzophenone) (4-luorobenzyl) methyl amine.
LC-MS(m/z)299.2([M+H-NO 2] +)RT＝3.64，(UV，ELSD)96％，100％。
4-(4-luorobenzyl)-(methyl)-amino-2-isopropoxy aniline
(4-luorobenzyl)-(3-isopropoxy-4-nitrobenzophenone)-(methyl)-amine (1.60g) is dissolved in the methanol (50mL).Ammonium formate (1.91g) and palladium (10%, be positioned on the charcoal, 0.21g), and this mixture at room temperature stirred 1.5 hours, this reactant mixture is filtered and with solvent vacuum evaporation.Be dissolved in residue in the small amount of methanol and to wherein adding dense aqueous sodium hydroxide (2mL).The mixture of gained is filtered (using ethyl acetate as eluant) by silicagel column,, obtain the title compound crude product (0.76g) of dark-coloured grease form, it is directly used in next step the solution for vacuum evaporation of gained.LC-MS(m/z)288.9([M+H] +)；RT＝1.91，(UV，ELSD)80％，72％，
(5-chloro-thiophene-2-ylmethyl)-(methyl)-(3-methyl-4-nitrobenzophenone)-amine
With 5-chloro-thiophene-2-formaldehyde (1.61g, 11.0mmol), 3-methyl-4-nitroaniline (1.52g, 10.0mmol) and Amberlite IRC-84 (100mg, H +Type) suspension in ortho-xylene (40mL) heated 5 hours down at 140 ℃ under nitrogen.After being cooled to room temperature, by removing by filter resin and evaporating volatile matter.Residue is dissolved in the acetonitrile (40mL) also once to wherein adding all sodium cyanoborohydride (1.26g, 20.0mmol), then, in 15 minutes with fractional form to wherein adding acetic acid (1mL), then to wherein adding formalin (37% aqueous solution, 2.23mL, 30.0mmol) and with this mixture restir 30 minutes.Evaporate volatile matter and residue is distributed between saturated sodium bicarbonate aqueous solution (100mL) and ethyl acetate (100mL), water is extracted with ethyl acetate (50mL).Organic layer is carried out drying with sodium sulfate, and solvent evaporated is analyzed residue with NMR.Incomplete N-methylate requirement with this reductive amination step repeat three times (use formalin, 7.4mL, 100mmol, and sodium cyanoborohydride, 2.07g 33mmol), has obtained to transform fully afterwards.After this, with this crude product FlashMaster system's purification (silicon dioxide carries out eluting with mixture of heptane/ethyl acetate), obtain the title compound (1.85g, 62%) of yellow oil form. 1H?NMR(CDCl 3)：2.64(s，3H)，3.11(s，3H)，4.66(s，3H)，6.52(d，1H)，6.60(dd，1H)，6.69(d，1H)，6.77(d，1H)，8.10(d，1H)。
N-(4)-(5-chloro-thiophene-2-ylmethyl)-2, N (4)-dimethyl-benzene-1,4-diamidogen
To (5-chloro-thiophene-2-ylmethyl)-(methyl)-(3-methyl-4-nitrobenzophenone)-amine (1.85g, 6.23mmol) and iron powder (2.09g, 37.4mmol) add 6N HCl (12.5mL in the suspension in ethanol (60mL), 75mmol), with this mixture+60 ℃ of following strong agitation 50 minutes.Then, it is poured in the saturated sodium bicarbonate aqueous solution (200mL), to wherein adding the pH of enough sodium carbonate with acquisition＞10.With the mixture of gained with ethyl acetate extract (200mL, then 2 * 100mL), extract is carried out drying and evaporates volatile material with sodium sulfate.With residue FlashMaster system's purification (silicon dioxide carries out eluting with mixture of heptane/ethyl acetate), obtain the title compound (1.51g, 91%) of brown oil form. 1H?NMR(CDCl 3)：2.16(s，3H)，2.79(s，3H)，3.32(br.s，2H)，4.39(s，3H)，6.58-6.65(m，4H)，6.72(d，1H)。
General formula X XXV, XXXVI that is undertaken by XXXIV and the intermediate of XIX synthetic:
(3-methyl-4-nitrobenzophenone)-(4-trifluoromethyl benzyl)-amine
With the 4-trifluoromethylated benzaldehyde (8191L, 6.00mmol), 3-methyl-4-nitroaniline (609mg, 4.00mmol) and Amberlite IRC-84 (200mg, H +Type) suspension in ortho-xylene (4mL) heated 6 hours down at 140 ℃ under nitrogen.Then, it is cooled to room temperature,, carries out drying, filter, evaporate volatile material then with sodium sulfate with ethyl acetate (5mL) dilution.Residue is dissolved in the acetonitrile (20mL) and once (503mg 8.00mmol), added acetic acid (1mL) with fractional form then in 15 minutes to wherein adding all sodium cyanoborohydrides.After having spent 30 minutes again, solvent evaporated is also distributed residue between ethyl acetate (50mL), saline (25mL) and 10% wet chemical (25mL).Organic layer is carried out drying with sodium sulfate, solvent evaporated, and residue carried out purification (silicon dioxide carries out eluting with mixture of heptane/ethyl acetate) in the FlashMaster system, obtain the title compound (1.02g, 82%) of yellow powder form. 1HNMR(CDCl 3)：2.59(s，3H)，4.50(d，2H)，4.76(br.t，1H)，6.40(d，1H)，6.43(dd，1H)，7.45(d，2H)，7.63(d，2H)，8.05(d，1H)。
(3-methyl-4-nitrobenzophenone)-(4-trifluoromethyl benzyl)-carbamic acid uncle-butyl ester
With (3-methyl-4-nitrobenzophenone)-(4-trifluoromethyl benzyl)-amine (1.02g, 3.29mmol), heavy carbonic di-tert-butyl (1.08g, 4.93mmol), dimethyl aminopyridine (201mg, 1.64mmol) and triethylamine (687 μ L, 4.93mmol) solution in acetonitrile (20mL) at room temperature stirs 18 hours (to remove carbon dioxide) in an opening flask.Evaporate volatile material and residue is dissolved in the ethyl acetate (50mL).This solution is washed (2 * 50mL) with saturated aqueous ammonium chloride, carry out drying with sodium sulfate, evaporate volatile material, and residue carried out purification (silicon dioxide in the FlashMaster system, carry out eluting with alkane/ethyl acetate mixture), obtain the title compound (1.17g, 86%) of light yellow viscosity grease form, it remains with the heptane of trace.
1H?NMR(CDCl 3)：1.44(s，9H)，2.58(s，3H)，4.95(s，2H)，7.16(dd，1H)，7.21(d，1H)，7.34(d，2H)，7.60(d，2H)，7.96(d，1H)。
(4-amino-3-aminomethyl phenyl)-(4-trifluoromethyl benzyl)-carbamic acid uncle-butyl ester
With Na 2S 2O 4(3.00g, 17.2mmol) solution in water (20mL) joins (3-methyl-4-nitrobenzophenone)-(4-trifluoromethyl benzyl)-carbamic acid uncle-butyl ester (1.41g, 3.44mmol) in the solution in oxolane (20mL), and the mixture of gained stirred 20 hours down at+55 ℃.After being cooled to room temperature, water is saturated with potassium carbonate, isolate organic layer, and (2 * 20mL) extract with ethyl acetate with water layer.With merge to such an extent that organic layer carries out drying with sodium sulfate, solvent evaporated, and residue carried out purification (silicon dioxide carries out eluting with mixture of heptane/ethyl acetate) in the FlashMaster system, obtain the title compound (1.09g, 83%) of white solid form.
1H?NMR(CDCl 3)：1.41(s，9H)，2.10(s，3H)，3.59(br.s，2H)，4.78(s，2H)，6.56(d，1H)，6.76(br.s，2H)，7.36(d，2H)，7.55(d，2H)。
Chemical compound of the present invention
Embodiment 1
1a{4-[(benzofuran-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
(0.35mL, the mixture of oxolane (THF) solution of (THF) solution of oxolane 0.035mmol) and 0.1M benzofuran-2-formaldehyde (0.35mL) kept 60 minutes down at 55 ℃ with 0.1M (4-amino-2-methyl phenyl)-carbamic acid propyl ester.Under vacuum, remove volatile material.In the residue of gained, add the 0.2M sodium cyanoborohydride (NaBH that is arranged in methanol 3CN) (0.5mL) and acetic acid (0.03mL).In that its sonication after 60 minutes, is separated title compound with this reactant mixture vacuum evaporation and with preparation LC/MS, obtain the 5.1mg colorless solid.Yield is 43%.LC/MS(m/z)339.2([M+H] +)；RT＝2.92，(UV，ELSD)94％，94％。
1b{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes.
LC/MS(m/z)323.9(M +)；RT＝2.67，(UV，ELSD)94％，100％。
1c{4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes.
LC/MS(m/z)340.0(M +)；RT＝2.87，(UV，ELSD)91％，100％。
1d{2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanes.
LC/MS(m/z)365.3([M-H] +)；RT＝2.89，(UV，ELSD)97％，99％。
1e[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-urethanes.
LC/MS(m/z)326.0(M +)；RT＝2.50，(UV，ELSD)84％，98％。
1f[4-(4-fluoro-benzylamino)-2-aminomethyl phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)317.1([M+H] +)；RT＝2.32，(UV，ELSD)82％，96％。
1g (4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-the 2-aminomethyl phenyl)-the carbamic acid propyl ester.
LC/MS(m/z)493.0([M+H] +)；RT＝3.18，(UV，ELSD)91％，97％。
1h{4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)317.1([M-H] +)；RT＝2.41，(UV，ELSD)76％，93％。
1i{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)382.0(M +)；RT＝2.96，(UV，ELSD)70％，87％。
1j{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)338.2(M +)；RT＝2.92，(UV，ELSD)85％，84％。
1k{4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)355.1([M+H] +)；RT＝3.08，(UV，ELSD)93％，97％。
11{2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)379.3([M-H] +)；RT＝3.08，(UV，ELSD)91％，95％。
1m[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)341.2([M+H] +)；RT＝2.71，(UV，ELSD)73％，96％。
1o{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes.
LC/MS(m/z)389.0([M+H] +)；RT＝3.24，(UV，ELSD)98％，99％。
1p{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes.
LC/MS(m/z)345.0([M+H] +)；RT＝3.21，(UV，ELSD)99％，100％。
1q{4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes.
LC/MS(m/z)361.0([M+H] +)；RT＝3.28，(UV，ELSD)95％，100％。
Ir[2-chloro-4-(4-isopropyl-benzylamino)-phenyl]-urethanes.
LC/MS(m/z)346.0(M +)；RT＝3.48，(UV，ELSD)95％，100％。
1s[2-chloro-4-(4-fluoro-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)337.1([M+H] +)；RT＝3.20，(UV，ELSD)97％，99％。
1t 2-chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-the carbamic acid propyl ester.
LC/MS(m/z)514.2([M+H] +)；RT＝3.52，(UV，ELSD)94％，99％。
1u{4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester.
LC/MS(m/z)337.0([M-1] +)；RT＝3.27，(UV，ELSD)94％，100％。
1v{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester.
LC/MS(m/z)403.9([M+H] +)；RT＝3.45，(UV，ELSD)99％，99％。
1w{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)356.9([M-H] +)；RT＝3.43，(UV，ELSD)98％，95％。
1x{4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester.
LC/MS(m/z)372.9([M-H] +)；RT＝3.49，(UV，ELSD)93％，99％。
1y{4-[(benzofuran-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester.
LC/MS(m/z)357.1([M-H] +)；RT＝3.37，(UV，ELSD)95％，98％。
1z{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-urethanes.
LC/MS(m/z)335.0(M +)；RT＝2.91，(UV，ELSD)99％，100％。
1aa{4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-methyl carbamate.
LC/MS(m/z)341.1(M；RT＝2.62，(UV，ELSD)96％，100％。
1ab{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-carbamic acid isopropyl ester.
LC/MS(m/z)400.0(M +)；RT＝2.93，(UV，ELSD)96％，100％。
1ac{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)367.9(M +)；RT＝2.66，(UV，ELSD)87.0％，95.0％。
1ad{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)324.0(M +)；RT＝2.60，(UV，ELSD)88.2％，96.5％。
1ae[2-cyano group-4-(4-isopropyl benzyl amino)-phenyl J-urethanes.
LC/MS(m/z)337.0(M +)；RT＝3.25，(UV，ELSD)90.8％，99.6％。
1af[2-iodo-4-(4-isopropyl-benzylamino)-phenyl 7-carbamic acid propyl ester.
LC/MS(m/z)452.0(M +)；RT＝3.72，(UV，ELSD)88.0％，97.7％。
1ag[4-(4-tert-butyl-benzylamino)-2-iodophenyl]-the carbamic acid propyl ester.
LC/MS(m/z)465.9([M-1] +)；RT＝3.85，(UV，ELSD)86.6％，96.6％。
1ah[2-iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)479.0([M+H] +)；RT＝3.54，(UV，ELSD)97.7％，99.8％。
1ai[2-iodo-4-(4-methyl sulfane base-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(Z)454.8([M-1] +)RT＝3.38，(UV，ELSD)98.0％，99.8％。
1aj{2-iodo-4-[4-(4-methyl piperazine-1-yl)-benzylamino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)508.9([M+H] +)；RT＝1.90，(UV，ELSD)62.0％，79.2％。
1ak{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)421.9(M +)；RT＝3.27，(IJV，ELSD)98.7％，98.5％。
1al{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)378.0(M +)；RT＝3.25，(UV，ELSD)97.7％，99.5％。
1am[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-urethanes.
LC/MS(m/z)394.2(M +)；RT＝3.70，(UV，ELSD)90.2％，97.9％。
1an[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-urethanes.
LC/MS(m/z)384.1(M +)；RT＝3.22，(UV，ELSD)84.4％，94.6％。
1ao{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)438.1([M+H] +)；RT＝3.47，(UV，ELSD)98.9％，99.9％。
1ap[4-(4-isopropyl benzyl amino)-2-trifluoromethyl-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)393.3([M-1] +)；RT＝3.60，(UV，ELSD)71.3％，74.1％。
1q[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)408.3(M +)；RT＝3.89，(UV，ELSD)91.1％，98.6％。
1ar[2-trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)421.1([M+H] +)；RT＝3.52，(UV，ELSD)99.2％，99.8％。
1as[4-(4-dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)394.3([M-1] +)；RT＝2.02，(UV，ELSD)63.4％，100.0％。
1at[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)398.1(M +)；RT＝3.40，(UV，ELSD)92.5％，98.1％。
1au{4-[(4-bromo-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)394.0([M+H] +)；RT＝3.15，(UV，ELSD)97.5％，89.8％。
1av{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)348.9(M +)；RT＝3.11，(UV，ELSD)99.7％，96.3％。
1aw[2-cyano group-4-(4-trifluoromethyl-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)378.3([M+H] +)；RT＝3.25，(UV，ELSD)99.6％，99.7％。
1ax{2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)447.9([M+H] +)；RT＝3.48，(UV，ELSD)99.3％，99.3％。
1ay{2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)402.9([M+H] +)；RT＝3.47，(UV，ELSD)95.7％，99.6％。
1az[2-bromo-4-(4-isopropyl benzyl amino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)406.1([M+H] +)；RT＝3.72，(UV，ELSD)80.2％，93.9％。
1ba[2-bromo-4-(4-tert-butyl-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)418.2(M +)；RT＝3.86，(UV，ELSD)87.2％，96.8％。
1bb[2-bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)431.0([M+H] +)；RT＝3.55，(UV，ELSD)95.9％，99.8％。
1bc[2-bromo-4-(4-methyl sulfane base-benzylamino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)409.0([M+H] +)；RT＝3.36，(UV，ELSD)98.4％，99.7％。
1bd N-{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide.
LC/MS(m/z)382.0(M +)；RT＝2.66，(UV，ELSD)95.9％，99.3％。
1be N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide.
LC/MS(m/z)339.2([M+H] +)；RT＝2.61，(UV，ELSD)96.4％，98.4％。
1bf N-[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-butyramide.
LC/MS(m/z)341.1([M+H] +)；RT＝2.49，(UV，ELSD)91.1％，100.0％。
1bg N-[4-(4-tert-butyl-benzylamino)-2-methoxyphenyl]-butyramide.
LC/MS(m/z)355.2([M+H] +)；RT＝2.65，(UV，ELSD)97.0％，100.0％。
1bh N-[2-methoxyl group-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide.
LC/MS(m/z)367.2([M+H] +)；RT＝2.79，(UV，ELSD)93.9％，96.6％。
1bi{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-furan-2-base-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)390.1(M +)；RT＝3.38，(UV，ELSD)92.9％，99.8％。
1bj[2-furan-2-base-4-(4-isopropyl benzyl amino)-phenyl]-the carbamic acid propyl ester.
LC/MS(m/z)393.2([M+H] +)；RT＝3.41，(UV，ELSD)89.9％，100.0％。
1bk[5-(4-luorobenzyl amino)-biphenyl-2-yl]-the carbamic acid propyl ester.
LC/MS(m/z)379.3([M+H] +)；RT＝3.06，(UV，ELSD)83.7％，99.7％。
1bl{5-[(5-chloro-thiophene-2-ylmethyl)-amino]-biphenyl-2-yl }-the carbamic acid propyl ester.
LC/MS(m/z)400.0(M +)；RT＝3.48，(UV，ELSD)89.8％，98.7％。
1bm[5-(4-isopropyl benzyl amino)-biphenyl-2-yl]-the carbamic acid propyl ester.
LC/MS(m/z)403.2([M+H] +)；RT＝3.37，(UV，ELSD)73.8％，98.7％。
1zz N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2, the 2-trifluoroacetamide.
The data of this chemical compound have been reported in the above in the intermediate of general formula X III-XXIII synthetic.
Embodiment 2
2a{4-[(4-fluoro-benzyl)-(methyl) amino]-the 2-methoxyphenyl }-the carbamic acid propyl ester.
With mixture heated to the 50 ℃ heating 60 minutes of (4-amino-2-methoxyphenyl)-carbamic acid propyl ester (0.3mL, 0.1M oxolane (THF) solution) and 4-fluorobenzaldehyde (0.3mL, 0.1M oxolane (THF) solution) and with its vacuum evaporation.In the residue of gained, add sodium cyanoborohydride (NaBH 3CN) (0.6mL, 0.2M methanol solution) and acetic acid (0.03mL).This reactant mixture was at room temperature kept 30 minutes, then to wherein adding formaldehyde (0.03mL, 37% aqueous solution) and acetic acid (0.03mL).After 30 minutes, with this reactant mixture vacuum evaporation.LC/MS separates this title compound with preparation, obtains the 4.3mg colorless solid, and yield is 41%. 1H?NMR(1∶4DMSO-H 6/DMSO-D 6)：8.04(br.s，NH)，7.25(m，2H)，7.13(m，3H)，6.36(s，1H)，6.24(d，1H)，4.53(s，2H，CH 2)，3.93(t，2H)，3.70(s，3H，OMe)，2.97(s，NMe)，1.57(m，2H)，0.89(t，3H)。LC/MS(m/z)347.2([M+H] +)；RT＝2.32，(UV，ELSD)96％，100％。
Similarly by suitable aniline and the following chemical compound of aldehyde preparation:
2b[4-(benzo [b] thiophene-2-ylmethyl-(methyl) amino)-2-methoxyl group-phenyl]-the carbamic acid propyl ester
1H?NMR(1∶4DMSO-H 6/DMSO-D 6)：8.07(br.s，NH)，7.86(d，1H)，7.76(d，1H)，7.30(m，4H)，6.49(s，1H)，6.36(d，1H)，4.83(s，2H，CH 2)，3.94(t，2H)，3.75(s，3H，OMe)，2.98(s，NMe)，1.58(m，2H)，0.89(t，3H))。LC/MS(m/z)385.0([M+H] +)；RT＝3.25，(UV，ELSD)99％，100％。
2c{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)367.9(M +)；RT＝3.07，(UV，ELSD)99％，100％。
2d{4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)412.1(M +)；RT＝3.12，(UV，ELSD)99％，100％。
2e{2-methoxyl group-4-[methyl-(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)348.0(M +)；RT＝2.46，(UV，ELSD)95％，100％。
2f{4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)398.0([M+2] +)；RT＝3.10，(UV，ELSD)97.0％，98.1％。
The 2g{4-[(4-isopropyl benzyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)355.2([M+H] +)；RT＝2.70，(UV，ELSD)85.4％，99.5％。
2h{2-methyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)380.3(M +)；RT＝3.18，(UV，ELSD)95.2％，98.5％。
2i{2-methyl-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)358.0(M +)；RT＝2.42，(UV，ELSD)97.9％，99.0％。
2j{4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-urethanes.
LC/MS(m/z)374.9([M+H] +)；RT＝3.92，(UV，ELSD)97.8％，100.0％。
2k{2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-urethanes.
LC/MS(m/z)387.3([M+H] +)；RT＝3.59，(UV，ELSD)99.9％，100.0％。
2l{2-chloro-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-urethanes.
LC/MS(m/z)363.1([M-1] +)；RT＝3.36，(UV，ELSD)92.1％，99.6％。
2m{4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester.
LC/MS(m/z)418.1([M+H] +)；RT＝3.80，(UV，ELSD)99.3％，100.0％。
2n{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)374.0([M+H] +)；RT＝3.77，(UV，ELSD)99.6％，99.9％。
2o{4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester.
LC/MS(m/z)389.2([M+H] +)；RT＝4.09，(UV，ELSD)99.6％，99.9％。
2p{2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)401.1([M+H] +)；RT＝3.81，(UV，ELSD)99.8％，100.0％。
2q{4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)435.9([M-1] +)；RT＝3.56，(UV，ELSD)99.4％，100.0％。
2r{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl } urethanes.
LC/MS(m/z)392.3(M +)；RT＝3.56，(UV，ELSD)99.0％，100.0％。
2s{4 (4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)395.3([M+H] +)；RT＝3.85，(UV，ELSD)99.0％，100.0％。
2t{4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)409.2([M+H] +)；RT＝3.98，(UV，ELSD)97.9％，99.8％。
2u{4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)421.2([M+H] +)；RT＝3.59，(UV，ELSD)92.9％，98.5％。
2v{4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes.
LC/MS(m/z)397.0([M-1] +)；RT＝3.48，(UV，ELSD)99.4％，99.9％。
2w{4-[(5-bromo-thiophene-2-ylmethyl)-methyl-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)449.9([M-1] +)；RT＝3.76，(UV，ELSD)99.5％，100.0％。
2x{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)405.9(M +)；RT＝3.73，(UV，ELSD)98.4％，100.0％。
2y{4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)409.2([M+H] +)；RT＝4.04，(UV，ELSD)99.3％，99.9％。
2z{4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)423.1([M+H] +)；RT＝4.29，(UV，ELSD)98.9％，99.7％。
2aa{4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)435.3([M+H] +)；RT＝3.77，(UV，ELSD)99.7％，99.9％。
2ab{4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)412.0(M +)；RT＝3.67，(UV，ELSD)99.3％，99.8％。
2ac{4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)407.0(M +)；RT＝3.39，(UV，ELSD)97.7％，99.6％。
2ad{4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)380.3([M+H] +)；RT＝3.83，(UV，ELSD)99.4％，99.9％。
2ae{2-cyano group-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)392.3([M+H] +)；RT＝3.44，(UV，ELSD)98.9％，99.9％。
2af{2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)462.1([M+H] +)；RT＝3.84，(UV，ELSD)98.2％，99.9％。
2ag{2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester.LC/MS(m/z)418.1([M+H] +)；RT＝3.83，(UV，ELSD)99.3％，100.0％。
2ah{2-bromo-4-[(4-isopropyl benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)420.2([M+H] +)；RT＝4.04，(UV，ELSD)98.8％，99.7％。
2ai{2-bromo-4-[(4-tert-butyl-benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)432.1(M +)；RT＝4.15，(UV，ELSD)99.3％，100.0％。
2aj{2-bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester.
LC/MS(m/z)447.0([M+H] +)；RT＝3.84，(UV，ELSD)98.4％，99.9％。
2zz N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2,2, the 2-trifluoroacetamide.
The data of this chemical compound have been reported in the above in the intermediate of general formula X III-XXIII synthetic.
Embodiment 3
The 3a{4-[(4-luorobenzyl)-(methyl)-amino]-the 2-isopropyl phenyl }-urethanes
4-(4-luorobenzyl)-(methyl)-amino-2-isopropoxy aniline (0.29g) is dissolved in no Shui diox (3mL).To wherein adding N, N-diisopropyl ethyl amine (0.27mL) and ethyl chloroformate (0.15mL) also at room temperature stir this reactant mixture a whole night.To wherein adding entry (5mL) and (3 * 10mL) extract with ethyl acetate with the mixture of gained.Organic facies is carried out drying and filtration with sodium sulfate.With solvent vacuum evaporation and with crude product sudden strain of a muscle column chromatography purification (silica gel is used heptane/ethyl acetate 19: 1,1% triethylamine gradient elution).With solvent vacuum evaporation, obtain the title compound (0.20g, 55%) of colorless oil form.LC-MS(m/z)361.3([M+H] +)；RT＝2.58，(UV，ELSD)90％，98％。
Embodiment 4
4a[4-(3-luorobenzyl amino)-2-methoxyphenyl J-urethanes
(84 μ L, 476mM) solution in joins in (4-amino-2-methoxyphenyl)-urethane ester solution (84 μ L, 0.476M absolute methanol solution) at absolute methanol with the 3-fluorobenzaldehyde.With the mixture heated to 40 of gained ℃ heating 30 minutes.Be dissolved in 1 with solvent vacuum evaporation and with remaining material, in the 2-dichloroethanes (1mL).To wherein adding sodium triacetoxy borohydride (20mg) and the mixture of gained was at room temperature kept 2 hours, interimly in the time of these two carry out 10 minutes sonications respectively.With silica gel (500mg) filtration and with 1,2-dichloroethanes (3mL) washs this post with this reactant mixture.With solvent vacuum evaporation, obtain title compound (5.7mg, 45%).
LC-MS(m/z)318.1(M +)；RT＝2.33，(UV，ELSD)93％，100％。
Prepare following chemical compound with similar mode:
4b[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-urethanes
LC-MS(m/z)341.3([M-1] +)；RT＝2.51，(UV，ELSD)86％，100％。
4c{2-methoxyl group-4-[(3-methylthiophene-2-ylmethyl)-amino]-phenyl }-urethanes
LC-MS(m/z)319.9(M +)；RT＝2.10，(UV，ELSD)79％，99％。
4d[4-(2,4-difluorobenzyl amino)-2-methoxyphenyl]-urethanes
LC-MS(m/z)337.2([M+H] +)；RT＝2.44，(UV，ELSD)93％，100％。
Embodiment 5
5a[2-cyclopentyloxy-4-(4-methoxy-benzyl amino)-phenyl] urethanes
(2-cyclopentyloxy-4-nitrobenzophenone)-urethanes (294mg) is dissolved in the ethanol (26mL).To wherein add zinc granule (1.63g) and aqueous hydrochloric acid (5.0mL, 2M).With the mixture of gained sonication 6.5 hours at room temperature, then it is at room temperature placed a whole night.To wherein adding saturated sodium bicarbonate aqueous solution (100mL) and this mixture being extracted (2 * 100mL) with ethyl acetate.Organic facies water (100mL) and saline (100mL) are washed, use dried over mgso, and with its vacuum evaporation.The grease of gained is dissolved in the methanol (1.82mL), and the aliquot (40 μ L) of this solution is mixed with 4-methoxybenzaldehyde (40 μ L, 0.466M methanol solution).With the mixture heated to 40 of gained ℃ heating 20 minutes.With solvent vacuum evaporation, and remaining material is dissolved in 1, in the 2-dichloroethanes (1mL).To wherein adding sodium triacetoxy borohydride (20mg) and the mixture of gained was at room temperature placed 2 hours, interimly in the time of these two carry out 10 minutes sonications respectively.This reactant mixture is filtered with silica gel (500mg), and with 1,2-dichloroethanes (3mL) washs this post.With solvent vacuum evaporation, obtain title compound (6.0mg, 84% derives from aldehyde).
LC-MS(m/z)384.1(M +)；RT＝2.40，(UV，ELSD)76％，96％。
Prepare following chemical compound with similar mode:
5b[2-cyclopentyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes
With this product preparation LC-MS purification.
LC-MS(m/z)386.2(M +)；RT＝3.22，(UV，ELSD)80％，91％。
5c[4-(3-fluoro-2-methyl-benzyl amino)-2-benzene ethoxyl phenenyl]-urethanes
With this product preparation LC-MS purification.
LC-MS(in/z)422.3(M +)；RT＝3.38，(UV，ELSD)84％，91％。
5d[2-benzyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes
With this product preparation LC-MS purification.
LC-MS(m/z)409.2([M+H] +)；RT＝3.30，(UV，ELSD)80％，89％。
5e[2-benzyloxy-4-(4-methyl sulfane base benzylamino)-phenyl]-urethanes
LC-MS(m/z)422.1(M +)；RT＝2.92，(UV，ELSD)83％，89％。
5f{4-[(benzo [b] thiene-3-yl-methyl)-amino]-2-cyclopentyloxy phenyl }-urethanes
With this product preparation LC-MS purification.
LC-MS(m/z)411.1([M+H] +)；RT＝3.12，(UV，ELSD)79％，85％。
5g[4-(3-fluoro-2-methyl-benzyl amino)-2-isopropyl phenyl]-urethanes
With this product preparation LC-MS purification.
LC-MS(m/z)361.2([M+H]+)；RT＝2.95，(UV，ELSD)77％，86％。
5h[2-benzyloxy-4-(3-methoxy-benzyl amino)-phenyl]-urethanes
LC-MS(m/z)407.3([M+H] +)RT＝2.81，(UV，ELSD)76％，87％。
5i{4-[(benzo [1,3] dioxole-5-ylmethyl)-amino]-the 2-isopropyl phenyl }-urethanes
LC-MS(m/z)372.1(M +)；RT＝2.24，(UV，ELSD)76％，86％。
Embodiment 6
6o N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-cyclohexyl propionic acid amide..
Method A:, add 3-cyclohexyl-propionyl (proionyl) chlorine (0.03mL) in 4-diamidogen (14mg) and the mixture of triethylamine (0.04mL) in acetonitrile (1mL) to 2-chloro-N (4)-(5-chloro-thiophene-2-ylmethyl)-N (4)-methyl-benzene-1.Vacuum evaporation is fallen volatile material and with preparation LC-MS title compound is separated.
Method B: to 2-chloro-N (4)-(5-chloro-thiophene-2-ylmethyl)-N (4)-methyl-benzene-1,4-diamidogen (470mg, 1.64mmol) and the chemical compound of sodium bicarbonate in acetonitrile (40mL) in add 3-cyclohexyl-propionyl (proionyl) chlorine (372mg, 2.13mmol).After 1 hour, with this reactant mixture water (100mL) and ice extinguishing.By filtering to isolate the title compound of Lycoperdon polymorphum Vitt-brown solid.Yield is 0.422g, 60%.
LC/MS(m/z)425.4([M+H] +)；RT＝4.09，(UV，ELSD)97％，100％。 1HNMR(DMSO-d 6)：0.87(m，2H)，1.05-1.29(m，4H)，1.47(q，2H)，1.56-1.76(m，5H)，2.29(t，2H)，2.91(s，3H)，4.67(s，2H)，6.76(dd，1H)，6.83(d，1H)，6.88(d，1H)，6.96(d，1H)，7.27(d，1H)。
With method A by corresponding aniline and suitable acid chloride, chloro-formate, carbamyl chloride, isocyanates or heavy carbonic di-tert-butyl (Boc 2O) similarly prepare following chemical compound.In the situation of acid chloride, use triethylamine as alkali.In the situation of chloro-formate and carbamyl chloride, use pyridine as alkali.In the situation of isocyanates and Boc2O, do not use alkali.In (4-amino-3-chlorphenyl)-(5-chloro-thiophene-2-the ylmethyl)-situation of carbamic acid uncle-butyl ester of using as aniline, after the evaporation residue was also being evaporated it with the solution-treated of 2% methyl phenyl ethers anisole in trifluoracetic acid and 1: 1 mixture of dichloromethane in 1 hour once more, is handling with preparation LC-MS then:
6a N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 2-phenyl-acetamides.
LC/MS(m/z)406.2([M+2] +)；RT＝3.58，(UV，ELSD)95.5％，100.0％。
6b N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3, the 3-amide dimethyl butyrate.
LC/MS(m/z)384.1(M +)；RT＝3.72，(UV，ELSD)98.3％，100.0％。
6c N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 3-Phenylpropionamide.
LC/MS(m/z)418.1(M +)；RT＝3.66，(UV，ELSD)98.8％，100.0％。
6d N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyramide.
LC/MS(m/z)356.1(M +)；RT＝3.32，(UV，ELSD)99.4％，100.0％。
The 6e valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl 7-amide.
LC/MS(m/z)371.1(M+H] +)；RT＝3.55，(UV，ELSD)98.3％，100.0％。
The 6f cyclopropane-carboxylic acid 2-chloro-4-[(5-(chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide.
LC/MS(m/z)355.0([M+H] +)；RT＝3.23，(UV，ELSD)98.6％，100.0％。
The 6g Cyclobutylcarboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide.
LC/MS(m/z)368.1(M +)；RT＝3.46，(UV，ELSD)93.4％，98.5％。
The 6h Cyclopentane carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide.
LC/MS(m/z)382.0(M +)；RT＝3.65，(UV，ELSD)95.2％，99.2％。
The 6i cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide.
LC/MS(m/z)396.1(M +)；RT＝3.83，(UV，ELSD)97.3％，99.8％。
6j N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-thiophene-2-base-acetamide.
LC/MS(m/z)412.0([M+2] +)；RT＝3.54，(UV，ELSD)79.3％，96.4％。
6k N-(2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(3-methoxyphenyl)-acetamide.
LC/MS(m/z)435.0([M+H] +)；RT＝3.54，(UV，ELSD)90.9％，100.0％。
6l N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chloro-phenyl)-acetamide.
LC/MS(m/z)438.0(M +)；RT＝3.78，(UV，ELSD)98.9％，100.0％。
6m N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-methoxyl group-phenyl)-acetamide.
LC/MS(m/z)436.0([M+2] +)；RT＝3.53，(UV，ELSD)92.0％，99.4％。
6n N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-fluoro-phenyl)-acetamide.
LC/MS(m/z)421.9(M +)；RT＝3.58，(UV，ELSD)92.2％，100.0％。
6p N-(2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2-dimethyl propylene amide.
LC/MS(m/z)357.0([M+H] +)；RT＝3.34，(UV，ELSD)96.4％，99.5％。
6q N-{2-chloro-5-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenoxy-acetamide.
LC/MS(m/z)406.9([M+H] +)；RT＝3.54，(UV，ELSD)93.9％，100.0％。
6r N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenyl-acetamides.
LC/MS(m/z)391.1([M+H] +)；RT＝3.29，(UV，ELSD)98.0％，100.0％。
6s N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3, the 3-amide dimethyl butyrate.
LC/MS(m/z)371.1([M+H] +)；RT＝3.40，(UV，ELSD)94.1％，98.1％。
6t N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-butyramide.
LC/MS(m/z)343.0([M+H] +)；RT＝3.01，(UV，ELSD)77.8％，88.9％。
The 6u valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide.
LC/MS(m/z)357.1([M+H] +)；RT＝3.24，(UV，ELSD)95.7％，100.0％。
The 6v cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide.
LC/MS(m/z)340.8(M +)；RT＝2.93，(UV，ELSD)97.6％，100.0％。
The 6w Cyclobutylcarboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl]-amide.
LC/MS(m/z)355.0([M+H] +)；RT＝3.15，(UV，ELSD)95.1％，100.0％。
The 6x Cyclopentane carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide.
LC/MS(m/z)368.8([M+H] +)；RT＝3.34，UV，ELSD)99.0％，100.0％。
The 6y cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide.
LC/MS(m/z)384.0([M+2] +}；RT＝3.50，(UV，ELSD)98.2％，100.0％。
6z N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-thiophene-2-base-acetamide.
LC/MS(m/z)397.0([M+H] +)；RT＝3.24(UV，ELSD)94.8％，100.0％。
6aa N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(3-methoxyphenyl)-acetamide.
LC/MS(m/z)420.9([M+H] +)；RT＝3.26，(UV，ELSD)64.6％，99.8％。
6ab N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-chlorphenyl)-acetamide.
LC/MS(m/z)425.0([M+H] +)；RT＝3.50，(UV，ELSD)98.9％，100.0％。
6ac N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-methoxyphenyl)-acetamide.
LC/MS(m/z)421.2([M+H] +)；RT＝3.24，(UV，ELSD)95.3％，99.6％。
6ad N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-fluorophenyl)-acetamide.
LC/MS(m/z)409.0([M+H] +)；RT＝3.31，(UV，ELSD)97.2％，100.0％。
6ae 2,3-dihydro-benzo [1,4] dioxine-6-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino J-phenyl)-amide.
LC/MS(m/z)434.9([M+H] +)；RT＝3.21，(UV，ELSD)92.7％，100.0％。
6af 2,3-dihydro-benzofuran-5-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide.
LC/MS(m/z)419.3([M+H] +)；RT＝3.26，(UV，ELSD)81.6％，94.8％。
6ag N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3-cyclohexyl propionic acid amide..
LC/MS(m/z)411.1([M+H] +)；RT＝3.89，(UV，ELSD)95.3％，99.5％。
6ah N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-2,2 dimethyl propylene amide.
LC/MS(m/z)350.1(M +)；RT＝2.98，(UV，ELSD)91.8％，99.1％。
6ai N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methylamino]-2-methyl-phenyl }-the 2-phenyl-acetamides.
LC/MS(m/z)384.1(M；RT＝3.04，(UV，ELSD)95.8％，100.0％。
6aj N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-3, the 3-amide dimethyl butyrate.
LC/MS(m/z)364.1(M +)；RT＝3.10，(UV，ELSD)93.0％，99.7％。
6ak N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 3-Phenylpropionamide.
LC/MS(rn/z)399.1([M+H] +)；RT＝3.12，(UV，ELSD)98.2％，99.9％。
6al N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-butyramide.
LC/MS(m/z)337.3([M+H] +)；RT＝2.68，(UV，ELSD)92.5％，99.7％。
6am 2,2,2-three chloro-N-(4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-acetamide.
LC/MS(m/z)411.9([M+H] +)；RT＝3.65，(UV，ELSD)97.3％，100.0％。
The 6an cyclopropane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl)-amide.
LC/MS(m/z)335.1([M+H] +)；RT＝2.58，(UV，ELSD)86.4％，97.8％。
The 6ao Cyclobutylcarboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide.
LC/MS(m/z)348.0(M +)；RT＝2.79，(UV，ELSD)95.4％，100.0％。
The 6ap Cyclopentane carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide.
LC/MS(m/z)363.2([M+H] +)；RT＝2.99，(UV，ELSD)97.7％，99.9％。
The 6aq cyclohexane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide.
LC/MS(m/z)377.1([M+H] +)；RT＝3.16，(UV，ELSD)88.0％，97.5％。
6ar N-(4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-thiophene-2-base-acetamide.
LC/MS(m/z)390.0(M +)；RT＝3.02，(UV，ELSD)97.2％，99.9％。
6as N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(3-methoxyphenyl)-acetamide.
LC/MS(m/z)416.0([M+2] +)；RT＝3.03，(UV，ELSD)92.9％，100.0％。
6at N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the malonamic acid methyl ester.
LC/MS(m/z)366.1(M +)；RT＝2.53，(UV，ELSD)94.5％，100.0％。
6au 2-(4-chlorphenyl)-N-{4-[(5-chloro-thiophene-2-ylmethyl-(methyl) amino]-the 2-aminomethyl phenyl }-acetamide.
LC/MS(m/z)418.1(M +)；RT＝3.31，(UV，ELSD)97.3％，99.9％。
6av N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-methoxyphenyl)-acetamide.
LC/MS(m/z)415.2([M+H] +)；RT＝2.99，(UV，ELSD)87.8％，98.1％。
6aw N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-fluorophenyl)-acetamide.
LC/MS(m/z)403.2([M+H] +)；RT＝3.10，(UV，ELSD)94.5％，99.9％。
6ax N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-3-cyclohexyl propionic acid amide..
LC/MS(m/z)405.1([M+H] +)；RT＝3.61，(UV，ELSD)92.6％，98.9％。
6ba{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-phenyl carbamate.
LC/MS(m/z)406.2(M +)；RT＝3.78，(UV，ELSD)96.3％，99.4％。
6bb{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-benzyq carbamate.
LC/MS(m/z)422.1([M+2] +)；RT＝3.91，(UV，ELSD)92.7％，99.3％。
6bc{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-isobutyl carbamate.
LC/MS(m/z)388.1([M+2] +)；RT＝3.99，(UV，ELSD)99.0％，100.0％。
6bd{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyl carbamate.
LC/MS(m/z)386.0(M +)；RT＝4.03，(UV，ELSD)97.1％，99.9％。
6be{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the own ester of carbamic acid.
LC/MS(m/z)415.9([M+2] +)；RT＝4.44，(UV，ELSD)91.7％，98.9％。
6bf 2-chloro-4-(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl)-carbamic acid 4-nitrobenzyl ester.
LC/MS(m/z)465.0(M +)；RT＝3.80，(UV，ELSD)91.7％，97.9％。
6bg{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-3-alkene ester.
LC/MS(m/z)383.9(M +)；RT＝3.82，(UV，ELSD)93.9％，99.6％。
6bh{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-2-alkynes ester.
LC/MS(m/z)384.0([M+2] +)；RT＝3.61，(UV，ELSD)76.3％，99.0％。
6bi{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2,2-dimethyl propyl ester.
LC/MS(m/z)399.9(M +)；RT＝4.11，(UV，ELSD)98.8％，99.6％。
6bj{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyl chloride ester.
LC/MS(m/z)453.9(M +)；RT＝4.12，(UV，ELSD)97.5％，99.8％。
6bk{2-chloro-4[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 3-chlorine propyl ester.
LC/MS(m/z)407.9([M+2] +)；RT＝3.72，(UV，ELSD)88.7％，97.5％。
6bl{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyloxy ethyl ester.
LC/MS(m/z)464.0(M +)；RT＝3.86，(UV，ELSD)89.1％，98.7％。
6bm 3-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-1-methyl isophthalic acid-propyl group-urea.
LC/MS(m/z)388.1([M+3] +)；RT＝3.38，(UV，ELSD)86.0％，99.5％。
6bo 1-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-(2-fluorophenyl)-urea.
LC/MS(m/z)425.0([M+2] +)；RT＝3.65，(UV，ELSD)94.9％，99.9％。
Embodiment 7
7a N-(4-{[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-amino }-the 2-aminomethyl phenyl)-2,2-dimethyl propylene amide.
With N-(4-amino-2-methyl phenyl)-2,2-dimethyl propylene amide (300mg, 1.45mmol) and 5-(4-chlorophenoxy)-1, (360mg, 1.45mmol) mixture in acetonitrile (4mL) is heating under 170 ℃ under the microwave radiation and was stirring 20 minutes 3-dimethyl-1H-pyrazoles-4-formaldehyde.The reactant mixture of gained is carefully joined in the solution of sodium cyanoborohydride (0.36g) in methanol, then to wherein adding acetic acid (1mL).After 60 minutes, it is distributed between ethyl acetate and saturated sodium bicarbonate aqueous solution and organic layer is evaporated.Use SiO 2Dodge column chromatography title compound is separated, carry out eluting, make it from ethyl acetate, to precipitate with heptane then with heptane-ethyl acetate.Yield is 112mg, 18%.LC/MS-TOF(m/z)441；RT＝2.34，(UV，ELSD)98％，100％。 1H?NMR(DMSO-d 6)：1.18(s，9H)，1.96(s，3H)，2.15(s，3H)，3.47(s，3H)，3.75(d，2H)，5.4(t，1H，NH)，6.29(dd，1H)，6.33(d，1H)，6.24(d，1H)，6.99(d，2H)，7.41(d，2H)，8.58(s，1H，NH)。
Similarly prepare following chemical compound by corresponding aniline and aldehyde:
7b 2,2-dimethyl-N-{2-methyl-4-[(6-phenoxypyridines-3-ylmethyl)-amino]-phenyl }-propionic acid amide..
LC/MS-TOF(m/z)390；RT＝2.54，(L1V，ELSD)90％，100％。
7c 2,2-dimethyl-N-{2-methyl-4-[(3-methyl-5-phenyl-isoxazole azoles-4-ylmethyl)-amino]-phenyl }-propionic acid amide..
LC/MS-TOF(m/z)378；RT＝2.82，(UV，ELSD)97％，100％。 1HNMR(DMSO-d 6)：1.19(s，9H)，1.96(s，3H)，2.3(s，3H)，4.11(d，2H)，5.85(t，1H，NH)，6.42(overlappingm，2H)，6.79(d，1H)，7.55(m，3H)，7.72(d，2H)，8.61(s，1H，NH)。
7d 2-(4-fluorophenyl)-N-{2-methyl-4-[(6-5-flumethiazine-3-ylmethyl)-amino]-phenyl }-acetamide.
LC/MS-TOF(m/z)418.4([M+H] +)；RT＝2.75，(UV，ELSD)99％，100％。 1H?NMR(DMSO-d 6)：1.98(s，3H)，3.54(s，2H)，4.39(d，2H)，6.28(t，1H，NH)，6.36(dd，1H)，6.43(d，1H)，6.91(d，1H)，7.14(t，2H)，7.35(dd，2H)，7.85(d，1H)，7.99(dd，1H)，8.74(d，1H)，9.21(s，1H，NH)。
7e 3,3-dimethyl-N-{2-methyl-4-[(6-5-flumethiazine-3-ylmethyl)-amino]-phenyl }-butyramide.
LC/MS-TOF(m/z)380.5([M+H] +)；RT＝2.75，(UV，ELSD)97％，99％。
7f 2-(4-fluorophenyl)-N-{2-methyl-4-[(6-p-toloxyl pyridin-3-yl methyl)-amino]-phenyl)-acetamide.
LC/MS(m/z)456.2([M+H] +)；RT＝2.79，(UV，ELSD)82.5％，99.8％。
7g 3,3-dimethyl-N-{2-methyl-4-[(6-p-toloxyl pyridin-3-yl methyl)-amino]-phenyl }-butyramide.
LC/MS(m/z)418.3([M+H] +)；RT＝2.75，(UV，ELSD)62％，93％。
7h N-(4-{[6-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-amino }-the 2-aminomethyl phenyl)-2-(4-fluorophenyl)-acetamide.
LC/MS(m/z)467.2([M+H] +)；RT＝2.65，(UV，ELSD)72％，96％。
7i N-{4-[(6-chloropyridine-3-ylmethyl)-amino]-the 2-aminomethyl phenyl }-2-(4-fluorophenyl)-acetamide.
LC/MS(m/z)384.1([M+H)+)；RT＝2.46，(UV，ELSD)87％，99％。
7j 2-(4-fluorophenyl)-N-{2-methyl-4-[(4-methyl-2-phenyl pyrimidine-5-ylmethyl)-amino]-phenyl }-acetamide.
LC/MS(m/z)441.4([M+H] +)；RT＝2.97，(UV，ELSD)90％，100％。
7k 3,3-dimethyl-N-{2-methyl-4-[(2-phenyl pyrimidine-5-ylmethyl)-amino]-phenyl }-butyramide.
LC/MS-TOF(m/z)389.6([M+H] +)；RT＝2.83，(UV，ELSD)89％，95％。
Embodiment 8
8a{4-[(5-dimethylamino-3-methyl-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester
With (4-amino-2-methyl phenyl)-carbamic acid propyl ester (21mg, 0.10mmol) and 5-dimethylamino-3-methyl-benzo [b] thiophene-2-formaldehyde (26mg, 0.12mmol) solution in acetonitrile (0.5mL) with Personal Chemistry Smith Syntesizer microwave device 170 ℃ of heating 2 minutes down.After being cooled to room temperature, (25mg, the 0.40mmol) solution in methanol (0.1mL) add acetic acid (50 μ L) then and also this mixture were stirred 30 minutes to wherein adding sodium cyanoborohydride.It is distributed between saturated sodium bicarbonate aqueous solution (10mL) and ethyl acetate (10mL) and organic layer carried out drying with sodium sulfate and it is evaporated.Preparation LC-MS provide title compound (32mg, yield are 77%).
LC/MS-TOF(m/z)412.4([M+H] +)；RT＝2.02，(UV，ELSD)81％，97％。
Similarly prepare following chemical compound by suitable aniline and aldehyde:
8b[4-(3-fluoro-4-trifluoromethyl-benzylamino)-2-aminomethyl phenyl]-urethanes
LC/MS(m/z)371.2([M+H] +)；RT＝3.10，(UV，ELSD)83％，96％。
8c[4-(4-chloro-benzylamino)-2-aminomethyl phenyl]-urethanes
LC/MS(m/z)319.0([M+H] +)；RT＝2.57，(UV，ELSD)79％，95％。
8d{4-[(6=methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester
LC/MS-TOF(m/z)384.4(M +)；RT＝3.07，(UV，ELSD)97％，94％。
8e{4-[(7-dimethylamino-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester
LC/MS-TOF(m/z)398.4([M+H] +)；RT＝2.64，(UV，ELSD)97％，100％。
8f{4-[(6-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes
LC/MS-TOF(m/z)370.4(M +)；RT＝2.79，(LW，ELSD)98％，99％。
8g 4-[(3-methyl-4-propoxycarbonyl amino-phenyl amino)-methyl]-essence of Niobe
LC/MS(m/z)356.1(NI)；RT＝2.52，(UV，ELSD)80％，100％。
Embodiment 9
9a N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide
Under 0 ℃, to (4-amino-3-aminomethyl phenyl)-(4-trifluoromethyl-benzyl)-carbamic acid uncle-butyl ester (500mg, 1.31mmol) add pyridine (159 μ L in the solution in anhydrous tetrahydro furan (10mL), 1.97mmol), then to wherein drip butyl chloride (164 μ L, 1.58mmol).After 5 minutes, this reactant mixture is heated continue to stir 1 hour to room temperature and with it.Then, this reactant mixture is diluted with ethyl acetate, wash, use dried over mgso then with 2N HCl and sodium bicarbonate aqueous solution (twice) and saline.Be dissolved in solvent vacuum evaporation and with residue in 1: 1 the dichloromethane and trifluoracetic acid mixture.After 30 minutes, this mixture at room temperature is evaporated to drying, residue is dissolved in the ethyl acetate (10mL), with this solution saturated sodium bicarbonate aqueous solution washed twice, wash twice with water, carry out drying with sodium sulfate then.Solvent evaporated and with the residue ethyl acetate: heptane carries out recrystallization, obtains the title compound (226mg, 49%) of colorless solid form.
1H?NMR(DMSO-d 6)：0.90(t，3H)，1.58(sextet，2H)，2.01(s，3H)，2.19(t，2H)，4.35(d，2H)，6.24(t，1H)，6.32(dd，1H)，6.41(d，1H)，6.87(d，1H)，7.55(d，2H)，7.67(d，2H)，8.91(s，1H).LC/MS(m/z)350.2(M +)；RT＝2.77，(UV，ELSD)95％，100％。
Chemical compound below preparing similarly:
9b[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-urethanes
Yield: 254mg (55%).
LC/MS(m/z)353.2([M+H] +)；RT＝2.93，(W1，ELSD)97％，100％。
1H?NMR(DMSO-d 6)：1.19(br.s，3H)，2.03(s，3H)，4.02(q，2H)，4.35(s，2H)，6.29(br.s，1H)，6.33(dd，1H)，6.41(d，1H)，6.86(br.d，1H)，7.55(d，2H)，7.67(d，2H)，8.39(br.s，1H)。
Embodiment 10
10a N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-piperidines-1-base-acetamide
To (4-amino-3-aminomethyl phenyl)-(4-trifluoromethyl-benzyl)-carbamic acid uncle-butyl ester (15.2mg, 40 μ mol) add O-(7-azepine benzo triazol-1-yl)-N in the solution in DMF (100 μ L), N, N ', N '-tetramethylurea hexafluorophosphate (HATU, 27.4mg, 72 μ mol) and solution in DMF (100 μ L), then to wherein adding i-PR 2NEt (25 μ L, 144 μ mol) and piperidines-1-base-acetic acid (8.6mg, 60 μ mol).The mixture of gained was at room temperature vibrated 3 hours, thereafter, with its with ethyl acetate (10mL) dilution, with saturated aqueous ammonium chloride wash (2 * 10mL), carry out drying with sodium sulfate, and it evaporated.Residue is carried out purification (silicon dioxide in the FlashMaster system; carry out eluting with mixture of heptane/ethyl acetate); obtain [3-methyl-4-(2-piperidines-1-base-acetyl-amino)-phenyl]-(4-the trifluoromethyl benzyl)-carbamic acid uncle-butyl ester (10.7mg, 53%) of white solid form.It is dissolved in dichloromethane (200 μ L) and the trifluoracetic acid (200 μ L), and this solution was at room temperature placed 30 minutes, thereafter, evaporate volatile material and with residue 0.1mmHg and+40 ℃ of following vacuum dryings 1 hour.Obtain the trifluoracetic acid addition salts of the title compound of yellow semi-solid form with quantitative yield.
LC/MS-TOF(m/z)406.4([M+H] +)；RT＝2.02，(UV，ELSD)99％，98％。
Similarly prepare following chemical compound by aniline and carboxylic acid:
10b N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-pyrrolidine-1-base-acetamide
LC/MS-TOF(m/z)392.3([M+H] +)，RT＝2.04，(UV，ELSD)98％，99％。
10c N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-morpholine-4-base-acetamide
LC/MS-TOF(m/z)408.3([M+H] +)；RT＝1.98，(UV，ELSD)99％，100％。
10d (S)-2-amino-4-methyl-valeric acid [2-methyl-4-(4-trifluoromethyl benzyl amino)-phenyl]-amide
LC/MS-TOF(m/z)394([M+H] +)；RT＝2.12，(UV，ELSD)75％，73％。
10e (R)-2-amino-4-methyl-valeric acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide
LC/MS-TOF(m/z)394([M+H] +)；RT＝2.29，(UV，ELSD)89％，100％。
10f 1-amino-cyclopropane-carboxylic acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide
LC/MS-TOF(m/z)365；RT＝1.98，(UV，ELSD)94％，89％。
Embodiment 11 valeric acids 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide
To N (4)-(5-chloro-thiophene-2-ylmethyl)-2, N (4)-dimethyl-benzene-1,4-diamidogen (54mg, 0.20mmol) and triethylamine (84L, 0.60mmol) add in the solution in anhydrous tetrahydro furan (1mL) valeric chloride (36, L, 0.30mmol) and this mixture was at room temperature stirred 1 hour, it saturated sodium bicarbonate aqueous solution (5mL) and ethyl acetate (5mL) between distributed thereafter.Organic layer is carried out drying with sodium sulfate, evaporate volatile material, residue is carried out purification (silicon dioxide carries out eluting with mixture of heptane/ethyl acetate) in the FlashMaster system, obtain the title compound (61mg, 86%) of white solid form.
LC/MS(m/z)351.3([M+H] +)；RT＝3.06，(UV，ELSD)100％，99％。
Embodiment 12
12a 2-benzyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-S-ethyl thiocarbamate
(3-benzyloxy-4-nitrobenzophenone) (4-luorobenzyl) methyl amine (50mg) is dissolved in the oxolane (2mL).To wherein adding acetic acid (0.1mL) and zinc powder (200mg) and with the mixture sonication of gained 1 hour.To wherein adding other zinc powder (100mg) and proceeding 1 hour sonication.This reactant mixture is filtered (500mg) and it is evaporated to drying with silicon dioxide.To wherein adding 1,2-dichloroethanes (1mL) is then to wherein adding surpalite (0.03mL).This reactant mixture was at room temperature placed 15 minutes, be heated to 80 ℃ of heating 3 hours then.After being cooled to room temperature, to wherein adding triethylamine (0.12mL).The aliquot (1/4th) of gained mixture mixed with sulfo-ethanol (0.026mL) and the mixture of gained is at room temperature vibrated a whole night.This mixture is evaporated to drying, it is dissolved in the dimethyl sulfoxide (0.2mL) and with preparation LC-MS it is handled, obtain the 7.6mg title compound.Yield: 52%.
LC-MS(m/z)425.2([M+H] +)；RT＝3.35，(UV，ELSD)95％，99％。
Similarly prepare following chemical compound by suitable nitro compound and nucleopilic reagent:
12b{2-cyclopentyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-S-ethyl thiocarbamate
LC-MS(m/z)403.1([M+H] +)；RT＝3.30，(UV，ELSD)99％，100％。
12c 1-{2-cyclopentyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-3-ethyl-urea
Replace sulfo-ethanol with ethamine.
LC-MS(m/z)386.2([M+H] +)；RT＝2.08，(UV，ELS9)97％，100％。
Embodiment 13
13a N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4 chlorphenyl)-acetamide
With 2-chloro-N (4)-(5-chloro-thiophene-2-ylmethyl)-N (4)-methyl-benzene-1,4-diamidogen (100mg) joins the solution of the 4-chlorophenyl acetyl chloride (69mg) of the vial that is arranged in serum cap at anhydrous acetonitrile (2mL).This reactant mixture is heated to 150 ℃ of heating 15 minutes in microwave device.This reactant mixture is poured in the saturated sodium bicarbonate aqueous solution (5mL) and extracts with ethyl acetate (5mL).Organic facies water (5mL) and saline (5mL) are washed, carry out drying, filter and it is evaporated to drying with sodium sulfate.This crude product with dodging column chromatography purification (with heptane/ethyl acetate gradient elution), is obtained the 25.2mg title compound.Yield: 16%.
LC-MS(m/z)441.2([M+2] +)；RT＝3.83，(UV，ELSD)91％，99％。
Chemical compound below preparing similarly (2-phenyl propionyl chloride is to be prepared by the 2-phenylpropionic acid being heated in thionyl chloride, evaporating subsequently):
13b N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chlorphenyl)-propionic acid amide.
LC-MS(m/z)453.0(M +)；RT＝4.01，(UV，ELSD)91％，99％。
Embodiment 14
14a{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-urethanes.
(4-amino-2-iodophenyl)-urethanes (2.3g) and 5-chloro-thiophene-2-formaldehyde (1.15g) be dissolved in the methanol (8mL) and with it in the sealed glass pipe, be heated to 130 ℃ of heating 3 minutes at the microwave radiation line.After being cooled to room temperature, to wherein add sodium cyanoborohydride (4.7g) in methanol (10mL) solution and the mixture of gained is heated to 130 ℃ of heating 5 minutes under microwave radiation in the sealed glass pipe.After being cooled to room temperature, this mixture being poured in the water (50mL) and extracting with ethyl acetate (50mL).Water is extracted with ethyl acetate (50mL) and organic facies water (twice of 80mL) and the saline (twice of 80mL) that is merged is washed.With the organic facies dried over mgso, filter and under vacuum, remove and desolvate.With the grease of gained sudden strain of a muscle column chromatography purification (silica gel is with heptane/ethyl acetate gradient elution).With products therefrom You diox/water lyophilizing, obtain the title compound (2g, 63%) of orange solids form.
1H?NMR(CDCl 3)：1.31(t，3H)，4.02(b，1H)，4.21(q，2H)，4.35(d，2H)，6.53(b，1H)，6.63(dd，1H)，6.75(s，2H)，7.06(d，1H)，7.63(bs，1H)。
Chemical compound below preparing similarly:
14b N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-2-(4-fluorophenyl)-acetamide.
1H?NMR(CDCl 3)：3.72(s，2H)，4.01(b9?1H)，4.35(d，2H)，6.62(dd，1H)，6.75(s，2H)，7.00(d，1H)，7.09-7.12(m，3H)，7.35(dd，2H)，7.85(d，1H)。
Embodiment 15
N-{5-[(5-chloro-thiophene-2-ylmethyl)-amino]-4 '-dimethylamino-biphenyl-2-yl }-2-(4-fluorophenyl)-acetamide.
Will 4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-urethanes (270mg), 4-dimethylaminophenyl boric acid (445mg) and palladium (II) (about 10mg) be suspended in the acetone (5mL).To wherein adding potassium carbonate (0.54mL, 5M aqueous solution) and this mixture being heated 10 minutes down at 125 ℃ in microwave synthesizer in the sealed glass pipe.After being cooled to room temperature, t separates organic facies, it is evaporated on silica gel, and it is handled (with heptane/ethyl acetate gradient elution) three times with dodging column chromatography.With solid acetonitrile recrystallization three times of gained, obtain the title compound of 38mg colorless solid form.The mother solution that is merged is evaporated on silica gel and it is handled with the sudden strain of a muscle column chromatography.With the product recrystallizing methanol of gained, obtain second output (12mg), with itself and output merging for the first time, obtain 50mg (19%) title compound altogether.
1H?NMR(DMSO-d 6)：2.91(s，6H)，3.44(s，2H)，4.39(d，2H)，6.32(t，1H)，6.51(dd，2H)，6.61(d，2H)，6.93(dd，2H)，7.02-7.04(m，3H)，7.07-7.10(m，2H)，7.22-7.23(m，2H)，9.01(s，1H)。
LC-MS(m/z)494.2(M +)；RT＝2.50，(UV，ELSD)95％，99％。
Embodiment 16
16a 4-[(5-chloro-thiophene-2-ylmethyl)-amino j-2-quinoline-3-base-phenyl }-urethanes
Will 4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-urethanes (15mg), 3-quinoline boric acid (29.7mg), palladium (II) (about 1mg), potassium carbonate (0.035mL, the 5M aqueous solution) and acetone (2mL) mixes and with its in the pipe of sealing in microwave synthesizer 125 ℃ of down heating 10 minutes, this reactant mixture is extracted with ethyl acetate (4mL), with the organic facies water (2 * 2mL) and saline (2 * 2mL) wash, use dried over mgso, filter.Under vacuum, remove and desolvate, with crude product preparation LC-MS purification.With collected fraction vacuum evaporation, it is dissolved in the ethyl acetate (5mL) again, (2 * 2mL) wash with saturated sodium bicarbonate aqueous solution (3mL), water (3mL) and saline with organic facies.With the organic facies dried over mgso, filter and under vacuum, remove and desolvate, obtain title compound (5mg, 33%).
LC-MS(m/z)438.0([M+H] +)；RT＝2.32，(UV，ELSD)89％，100％。
Chemical compound below similarly preparing:
16b{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-pyridin-3-yl-phenyl }-urethanes
LC-MS(m/z)388.2([M+H] +)；RT＝2.01，(UV，ELSD)97％，100％。
16c 4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-pyridin-4-yl-phenyl }-urethanes
LC-MS(m/z)388.1([M+H] +)；RT＝1.95，(UV，ELSD)98％，100％。
16d[4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-(6-methoxypyridine-3-yl)-phenyl]-urethanes
LC-MS(m/z)418.3([M+H] +)；RT＝2.37，(UV，ELSD)79％，100％。
16e{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-quinoline-5-base-phenyl }-urethanes
LC-MS(m/z)430.8([M+H] +)；RT＝2.13，(UV，ELSD)79％，99％。
External and in vivo test
To chemical compound of the present invention carried out test and its-kind or multiple below model in shown effect.
Relative outflux by the KCNQ2 passage
Its right-kind of KCNQ2 screening scheme that is used for chemical compound of the present invention is assessed illustrates.This experimental measurement the relative outflux by the KCNQ2 passage, and it is to have under the situation of following change according to people such as Tang (people such as Tang W., J.Biomol.Scree77.2001,6,325-331) method of the described hERG of being used for potassium channel is carried out.
On experiment same day, the Chinese hamster ovary celI of the voltage-gated KCNQ2 passage of the stably express of enough numbers is carried out coating with the density that is enough to produce list-fused layer.Before test-inoculate day with these cells and with it with 1 μ Ci/ml[ 86Rb] load a whole night.On the same day of experiment, these cells are washed with the buffer agent that comprises HBSS-.With these cells with medicine pre-cultivated 30 minutes and under the situation of 30 minutes medicines of continued presence again, stimulated with inferior Cmax of 15mM KCl be somebody's turn to do 86Rb +Outflux.Cultivating suitable time after date, taking out supernatant and it is counted in liquid scintillation counter (Tricarb).With cell 2mM NaOH dissolving and right 86Rb +Quantity is counted.Calculate relative outflux ((CPM Supernatant/ (CPM Supernatant+ CPM Cell)) C Chemical compound/ (CPM Supernatant/ (CPM Supernatant+ CPM Cell)) 15nM KCl) * 100-100.
Chemical compound of the present invention has the EC less than 20000nM 50, its EC 50In most applications less than 2000nM and in many cases less than 200nM.Therefore, think that chemical compound of the present invention can be used for treatment and KCNQ family potassium channel diseases associated.
Electrophysiology patch clamp record.
Derive from voltage-activatory KCNQ2 electric current (people such as Hamill OP, the Pflgers Arch1981 of mammal Chinese hamster ovary celI with the patch clamp recording technique of routine record in full cell patch pincers configuration; 391:85-100).The cell of KCNQ2 passage that makes the voltage activated with stably express is at CO 2Under normal cell culture condition, grow in the cultivating container and behind coating, carried out the electrophysiology record with it in 1-7 days.By with voltage with the increment (perhaps using slope scheme (ramp protocol)) of 5-20mV film from-100mV to-40mV keep current potential progressively increase to+80mV activates KCNQ2 potassium channel (people such as Tatulian L, J Neuroscience2001; 21 (15): 5535-5545).Inductive electrophysiology effect is assessed to these chemical compounds on the basis of the various parameters of this voltage-activatory KCNQ2 electric current.Especially to its to the activation threshold value of this electric current and to the effect of inductive maximum current study.
In this test, some chemical compounds of the present invention are studied.Think that this activation threshold value moves to left or inductive maximum potassium current increase reduced the activity in the neuroid, thereby make these chemical compounds can be used for disease such as epilepsy that neuronal activity increases.
Maximal electroshock
This test is carried out with Corneal electrode in the male mice group, in this test, the square wave electric current that gives 0.4 second 26mA with the induced character be the convulsions of THE (people such as Wlaz, Epilepsy Research 1998,30,219-229).
The inductive epilepsy of pilocarpine
The inductive epilepsy of pilocarpine is inductive by coming for male mice peritoneal injection pilocarpine (250mg/kg), and the epilepsy activity that causes the posture forfeiture in 30 minutes is observed (people such as Starr, PharmacologyBioclaemistny andBehavior 1993,45,321-325)
Electricity epilepsy-threshold value test
(people such as Kimball, Radiation Research 1957 1-12) measure the threshold value intermediate value of inducing as to the THE of the response of male mice cornea galvanic shock with the modification of this to-and-fro method (up-and-down method).(0.4s obtains galvanic shock under 50Hz) and observes with regard to its epilepsy activity first mice of each group at 14mA.If observe epilepsy, then the electric current with next mice reduces 1mA, still, if do not observe epilepsy, then its electric current is increased 1mA.15 mices to the treatment group are all repeated this operation.
Chemistry epilepsy-threshold value test
By regularly in each group male mice side tail vein, importing pentylenetetrazole (5mg/ml, speed is 0.5ml/ minute) measure dosage threshold value (people such as Nutt, J Pharmacy and Pharmacology, 1986 of inducing the required pentylenetetrazole of clonism, 38,697-698).
The tonsil excitement
Undergo surgery to rat, three utmost point electrodes are implanted in its back of the body outside tonsil.After operation, this animal is recovered, make then and respectively organize the substrate that rat is accepted test compound or this medicine of various dosage., behind the discharge threshold of every day+25 μ A, begin animal is stimulated in week at 3-5, and note the order of severity of each inducement epilepsy, the persistent period of epilepsy and the persistent period of discharge back electricity.(Racine.Electroephalography?andClinical?Neurophysiology?1972，32，281-294)。
Side effect
By measure mice the time on this rotarod device of still staying measure central nervous system's side effect (people such as Capacio, Drug and Chemical Toxicology 1992,15,177-201); Perhaps measure its locomotor activity and come central nervous system's side effect measured that ((people such as Watson, Neuropharmacology 1997,36,1369-1375) by the number of infrared beam of crossing the test cage is counted.Radiotelemetry emitter by rectal probe or implanted energy measurement temperature is measured cooling effect (people such as Keeney, Physiology and Behaviour 2001,74, the 177-184 of said chemical compound to animal nucleome temperature.
Pharmacokinetics
Deliver medicine to Spraque Dawley rat by i.v. and p.o., blood sampling is measured the pharmacokinetics character of said chemical compound in 20 hours thereafter.Plasma concentration is measured with LC/MS/MS.

Claims (36)

1. substituted general formula I right-diamino benzene derivant or its salt
Wherein
S is 0 or 1;
U is O, S, SO 2, SONR 11, CO-O or CONR 11Wherein
R 11Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Or
R 2And R 11Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Q is 0 or 1;
X is CO or SO 2Prerequisite be when X be SO 2The time q be 0;
Z is O or S;
R 1Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base;
R 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 1-6-alkane (alkene/alkynes) base, NR 10R 10 '-C 3-8-cycloalkanes (alkene) base and NR 10R 10 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 10And R 10 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 10And R 10 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
Prerequisite is R 2When being halogen or cyano group, s is 0; With
Prerequisite be when s be 1 and R 2U is O or S when being hydrogen atom or acyl group;
R 3Be selected from C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-heterocycle alkane (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, Ar-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) oxygen base-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-heterocycle alkane (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-heterocycle alkane (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, halo-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 3-8The basic Ar of-cycloalkanes (alkene), halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base-Ar, halo-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base-Ar, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-heterocycle alkane (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, cyano group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base, acyl group-C 3-8-cycloalkanes (alkene) base, acyl group-heterocycle alkane (alkene) base, acyl group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group-C 1-6-alkane (alkene/alkynes) base-C 3-8-cycloalkanes (alkene) base, acyl group-C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, NR 12R 12 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base, substituted NR randomly 12R 12 '-C 3-8-cycloalkanes (alkene) base, substituted NR randomly 12R 12 '-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base; Wherein
R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-heterocycle alkane (alkene) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, Ar-oxygen base C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-heterocycle alkane (alkene) base, hydroxyl-C 1-6-alkane (alkene/alkynes) base, hydroxyl-C 3-8-cycloalkanes (alkene) base, hydroxyl-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base and cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, or
R 12And R 12 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto;
With
The group of Y expression XXIV, XXV, XXVI, XXVII, XXVIII, XXXI or XXXXII:
Figure A2004800075070005C1
Or
Figure A2004800075070005C2
Wherein
This line is represented a kind of group shown in the Y to be connected to key on this carbon atom;
W is O or S;
V is N, C or CH;
T is N, NH or O;
A is 0,1,2 or 3;
B is 0,1,2,3 or 4;
C is 0 or 1;
D is 0,1,2 or 3;
E is 0,1 or 2;
F is 0,1,2,3,4 or 5;
G is 0,1,2,3 or 4;
H is 0,1,2 or 3;
J is 0,1 or 2;
K is 0,1,2 or 3; With
Each R 5Be independently selected from a C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-C 3-8-cycloalkanes (alkene) base, Ar-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, Ar-oxygen base-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, acyl group, C 1-6-alkane (alkene/alkynes) oxygen base, C 3-8-cycloalkanes (alkene) oxygen base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) oxygen base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl, halogen, halo-C 1-6-alkane (alkene/alkynes) base, halo-C 3-8-cycloalkanes (alkene) base, halo-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base ,-CO-NR 6R 6 ', cyano group, cyano group-C 1-6-alkane (alkene/alkynes) base, cyano group-C 3-8-cycloalkanes (alkene) base, cyano group-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 ', S-R 8And SO 2R 8, or
Two R that adjoin 5Form a kind of one or two heteroatomic 5-8 person's ring that comprises with this aromatic group;
R 6And R 6 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base and Ar;
R 7And R 7 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8Cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar, heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base-C 3-8-cycloalkanes (alkene) base, heterocycle alkane (alkene) base-C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base-Ar and acyl group; Or
R 7And R 7 'Form a kind of 1,2 or 3 saturated or undersaturated ring of other heteroatomic 5-8 person that randomly comprises together with its nitrogen-atoms that is attached thereto; With
R 8Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, Ar and-NR 9R 9 'R wherein 9And R 9 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base and C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base.
2. chemical compound as claimed in claim 1, wherein R 1Be C 1-6-alkane (alkene/alkynes) base or hydrogen atom.
3. as any described chemical compound among the claim 1-2, wherein s is 0.
4. as any described chemical compound among the claim 1-2, wherein s is 1.
5. chemical compound as claimed in claim 4, wherein U is an oxygen atom.
6. as any described chemical compound, wherein a R among the claim 1-5 2Be selected from hydrogen, C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, halogen, halo-C 1-6-alkane (alkene/alkynes) base and cyano group;
Prerequisite is to work as R 2When being halogen or cyano group, s is 0; With
Prerequisite be when s be 0 and R 2U is O or S when being hydrogen atom.
7. as any described chemical compound among the claim 1-6, wherein Z is an oxygen atom.
8. as any described chemical compound among the claim 1-6, wherein Z is a sulphur atom.
9. as any described chemical compound among the claim 1-8, wherein q is 0.
10. as any described chemical compound among the claim 1-8, wherein q is 1.
11. as any described chemical compound among the claim 1-10, wherein X is CO.
12. as any described chemical compound, wherein a R among the claim 1-11 3Be C 1-6-alkane (alkene/alkynes) base, C 3-8-cycloalkanes (alkene) base, C 3-8-cycloalkanes (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base-C 1-6-alkane (alkene/alkynes) base, heterocycle alkane (alkene) base, Ar, Ar-C 1-6-alkane (alkene/alkynes) base, Ar-oxygen base-C 1-6-alkane (alkene/alkynes) base, Ar-C 1-6-alkane (alkene/alkynes) oxygen base-C 1-6-alkane (alkene/alkynes) base, C] 6-alkane (alkene/alkynes) oxygen base-carbonyl-Cl-alkane (alkene/alkynes) is basic, halo-C 1-6-alkane (alkene/alkynes) base, NR 12W2 ', substituted NR randomly 12R 12 '-C 1-6-alkane (alkene/alkynes) base and randomly substituted NR 12R 12 '-C 3-8-cycloalkanes (alkene) base.
13. chemical compound as claimed in claim 12, wherein R 12And R 12 'Be independently selected from hydrogen, C 1-6-alkane (alkene/alkynes) base and Ar.
14. as any described chemical compound among the claim 1-13, wherein Y is formula XXIV.
15. as any described chemical compound among the claim 1-13, wherein Y is formula XXV.
16. as any described chemical compound among the claim 14-15, wherein W is an oxygen atom.
17. as any described chemical compound among the claim 14-15, wherein W is a sulphur atom.
18. as any described chemical compound among the claim 1-13, wherein Y is formula XXVII.
19. as any described chemical compound among the claim 1-13, wherein Y is formula XXXXI.
20. chemical compound as claimed in claim 19, wherein V is a nitrogen-atoms.
21. chemical compound as claimed in claim 19, wherein V is CH.
22. as any described chemical compound among the claim 1-13, wherein Y is formula XXXXII.
23. chemical compound as claimed in claim 22, wherein T is a nitrogen-atoms.
24. chemical compound as claimed in claim 22, wherein T is an oxygen atom.
25. as any described chemical compound, wherein each R among the claim 1-24 5Be independently selected from C 1-6-alkane (alkene/alkynes) base, C 1-6-alkane (alkene/alkynes) base-heterocycle alkane (alkene) base, Ar, C 1-6-alkane (alkene/alkynes) oxygen base, Ar-oxygen base, C 1-6-alkane (alkene/alkynes) oxygen base-carbonyl, halogen, halo-C 1-6-alkane (alkene/alkynes) base, NR 7R 7 ', S-R 8And SO 2R 8, or
Two R that adjoin 5Form a kind of one or two heteroatomic 5-8 person's ring that randomly comprises with this aromatic group.
26. chemical compound as claimed in claim 25, wherein R 7And R 7 'All be C 1-6-alkane (alkene/alkynes) base.
27. chemical compound as claimed in claim 25, wherein R 8Be selected from C 1-6-alkane (alkene/alkynes) base and Ar.
28. as any described chemical compound among the claim 1-27, said chemical compound is selected from:
4-[(benzofuran-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-urethanes;
[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-urethanes;
[4-(4-fluoro-benzylamino)-2-aminomethyl phenyl]-carbamic acid propyl ester;
(4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-the 2-aminomethyl phenyl)-the carbamic acid propyl ester;
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
2-methyl-4-[(5-phenyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[4-(4-isopropyl-benzylamino)-2-aminomethyl phenyl]-carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-urethanes;
[2-chloro-4-(4-isopropyl-benzylamino)-phenyl]-urethanes;
[2-chloro-4-(4-fluoro-benzylamino)-phenyl]-urethanes;
2-chloro-4-{[4-(4-chloro-benzenesulfonyl)-3-methyl-thiophene-2-ylmethyl]-amino }-phenyl)-the carbamic acid propyl ester;
4-[(5-methyl-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(benzofuran-2-ylmethyl)-amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-urethanes;
(4-(benzo [b] thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-methyl carbamate;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-carbamic acid isopropyl ester;
4-[(4-fluoro-benzyl)-(methyl) amino]-the 2-methoxyphenyl }-the carbamic acid propyl ester;
[4-(benzo [b] thiophene-2-ylmethyl-(methyl) amino)-2-methoxyl group-phenyl]-carbamic acid propyl ester;
4-[(5-ammonia-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-methoxyl group-phenyl }-the carbamic acid propyl ester;
2-methoxyl group-4-[methyl-(5-methyl-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
The 4-[(4-luorobenzyl)-(methyl)-amino]-the 2-isopropyl phenyl }-urethanes;
[4-(3-luorobenzyl amino)-2-methoxyphenyl]-urethanes;
[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-urethanes;
2-methoxyl group-4-[(3-methylthiophene-2-ylmethyl)-amino]-phenyl }-urethanes;
[4-(2,4-difluorobenzyl amino)-2-methoxyphenyl]-urethanes;
[2-cyclopentyloxy-4-(4-methoxy-benzyl amino)-phenyl]-urethanes;
[2-cyclopentyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes;
[4-(3-fluoro-2-methyl-benzyl amino)-2-benzene ethoxyl phenenyl]-urethanes;
[2-benzyloxy-4-(3-fluoro-2-methyl-benzyl amino)-phenyl]-urethanes;
[2-benzyloxy-4-(4-methyl sulfane base benzylamino)-phenyl]-urethanes;
4-[(benzo [b] thiene-3-yl-methyl)-amino]-2-cyclopentyloxy phenyl }-urethanes;
[4-(3-fluoro-2-methyl-benzyl amino)-2-isopropyl phenyl]-urethanes;
[2-benzyloxy-4-(3-methoxy-benzyl amino)-phenyl]-urethanes;
4-[(benzo [1,3] dioxole-5-ylmethyl)-amino]-the 2-isopropyl phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-cyano group-4-(4-isopropyl benzyl amino)-phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
The 4-[(4-isopropyl benzyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
2-methyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-methyl-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-urethanes;
2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-urethanes;
2-chloro-4-[methyl-(4-methyl sulfane base-benzyl)-amino]-phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-chlorphenyl }-the carbamic acid propyl ester;
2-chloro-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl } urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[methyl-(4-trifluoromethyl-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[methyl-(4-methyl sulfane base-benzyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(4-isopropyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[methyl-(4-trifluoromethyl-benzyl) amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[methyl-(4-methyl sulfane base-benzyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
4-[(4-tert-butyl-benzyl)-(methyl) amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
2-cyano group-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(4-isopropyl benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(4-tert-butyl-benzyl)-(methyl) amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-iodo-4-(4-isopropyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[4-(4-tert-butyl-benzylamino)-2-iodophenyl]-carbamic acid propyl ester;
[2-iodo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-iodo-4-(4-methyl sulfane base-benzylamino)-phenyl]-carbamic acid propyl ester;
2-iodo-4-[4-(4-methyl piperazine-1-yl)-benzylamino]-phenyl }-the carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-urethanes;
[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-urethanes;
[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-urethanes;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-2-trifluoromethyl-phenyl }-the carbamic acid propyl ester;
[4-(4-isopropyl benzyl amino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[4-(4-tert-butyl-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[2-trifluoromethyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[4-(4-dimethylamino-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
[4-(4-methyl sulfane base-benzylamino)-2-trifluoromethyl-phenyl]-carbamic acid propyl ester;
4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-cyano-phenyl }-the carbamic acid propyl ester;
[2-cyano group-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
2-bromo-4-[(5-bromo-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
2-bromo-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the carbamic acid propyl ester;
[2-bromo-4-(4-isopropyl benzyl amino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-tert-butyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-trifluoromethyl-benzylamino)-phenyl]-carbamic acid propyl ester;
[2-bromo-4-(4-methyl sulfane base-benzylamino)-phenyl]-carbamic acid propyl ester;
N-{4-[(5-bromo-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-methoxyphenyl }-butyramide;
N-[4-(4-isopropyl benzyl amino)-2-methoxyphenyl]-butyramide;
N-[4-(4-tert-butyl-benzylamino)-2-methoxyphenyl]-butyramide;
N-[2-methoxyl group-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-furan-2-base-phenyl }-the carbamic acid propyl ester;
[2-furan-2-base-4-(4-isopropyl benzyl amino)-phenyl]-carbamic acid propyl ester;
[5-(4-luorobenzyl amino)-xenyl-2-yl]-carbamic acid propyl ester;
5-[(5-chloro-thiophene-2-ylmethyl)-amino]-biphenyl-2-yl }-the carbamic acid propyl ester;
[5-(4-isopropyl benzyl amino)-biphenyl-2-yl]-carbamic acid propyl ester;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 2-phenyl-acetamides;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3, the 3-amide dimethyl butyrate;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the 3-Phenylpropionamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyramide;
Valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclobutylcarboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclopentane carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-amide;
Cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl) (methyl) amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-thiophene-2-base-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(3-methoxyl group-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chloro-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-methoxyl group-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-fluoro-phenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-cyclohexyl propionic acid amide.;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2-dimethyl propylene amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenoxy-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-the 2-phenyl-acetamides;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3, the 3-amide dimethyl butyrate;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-butyramide;
Valeric acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclopropane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclobutylcarboxylic acid 2-chloro-4-((5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclopentane carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
Cyclohexane-carboxylic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-thiophene-2-base-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(3-methoxyphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-chlorphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-methoxyphenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2-(4-fluorophenyl)-acetamide;
2,3-dihydro-benzo [1,4] dioxine-6-formic acid 2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-amide;
2,3-dihydro-benzofuran-5-formic acid 2-chloro-4-[(5-chloro-thiophene-2 ylmethyl)-amino]-phenyl }-amide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-3-cyclohexyl propionic acid amide.;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-2,2-dimethyl propylene amide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 2-phenyl-acetamides;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-3, the 3-amide dimethyl butyrate;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-the 3-Phenylpropionamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-butyramide;
2,2,2-three chloro-N-{4-[(5-chloro-thiophene-2-ylmethyls)-(methyl) amino]-2-methyl-phenyl }-acetamide;
Cyclopropane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-2-methyl-phenyl }-amide;
Cyclobutylcarboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
Cyclopentane carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
Cyclohexane-carboxylic acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-thiophene-2-base-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(3-methoxyphenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-the malonamic acid methyl ester;
2-(4-chlorphenyl)-N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-methoxyl group phenoxy group)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-2-(4-fluorophenyl)-acetamide;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-3-cyclohexyl propionic acid amide.;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-phenyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-benzyq carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-isobutyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-butyl carbamate;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-the own ester of carbamic acid;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 4-nitrobenzyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-3-alkene ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid fourth-2-alkynes ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2,2-dimethyl propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyl chloride ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 3-chlorine propyl ester;
2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-carbamic acid 2-benzyloxy ethyl ester;
3-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-1-methyl isophthalic acid-propyl group-urea;
1-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-3-(2-fluorophenyl)-urea;
N-[2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2,2, the 2-trifluoroacetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-amino]-phenyl }-2,2, the 2-trifluoroacetamide;
N-{5-[(5-chloro-thiophene-2-ylmethyl) amino]-4 '-dimethylamino-biphenyl-2-yl }-2-(4-fluorophenyl)-acetamide;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chlorphenyl)-acetamide;
[4-(3-fluoro-4-trifluoromethyl-benzylamino)-2-aminomethyl phenyl]-urethanes;
2-(4-fluorophenyl)-N-{2-methyl-4-[(6-p-toloxyl pyridin-3-yl methyl)-amino]-phenyl }-acetamide;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-butyramide;
2-(4-fluorophenyl)-N-{2-methyl-4-[(6-5-flumethiazine-3-ylmethyl)-amino]-phenyl 2-acetamide;
Valeric acid 4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-the 2-aminomethyl phenyl }-amide;
3,3-dimethyl-N-{2-methyl-4-[(6-is right-toloxyl pyridin-3-yl methyl)-amino]-phenyl }-butyramide;
[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-urethanes;
N-{2-chloro-4-[(5-chloro-thiophene-2-ylmethyl)-(methyl) amino]-phenyl }-2-(4-chlorphenyl)-propionic acid amide.;
[4-(4-chloro-benzylamino)-2-aminomethyl phenyl]-urethanes;
4-[(6-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-quinoline-3-base-phenyl }-urethanes;
4-[(5-dimethylamino-3-methyl-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
3,3-dimethyl-N-{2-methyl-4-[(6-5-flumethiazine-3-ylmethyl)-amino]-phenyl }-] butyramide;
N-(4-{[6-(4-cyano-benzene oxygen)-pyridin-3-yl methyl]-amino }-the 2-aminomethyl phenyl)-2-(4-fluorophenyl)-acetamide;
2-benzyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-S-ethyl thiocarbamate;
2-cyclopentyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-S-ethyl thiocarbamate;
N-{4-[(6-chloropyridine-3-ylmethyl)-amino]-the 2-aminomethyl phenyl }-2-(4-fluorophenyl)-acetamide;
4-[(7-dimethylamino-benzo [b] thiophene-2-ylmethyl) amino]-the 2-aminomethyl phenyl }-the carbamic acid propyl ester;
1-{2-cyclopentyloxy-4-[(4-luorobenzyl)-(methyl) amino]-phenyl }-3-ethyl-urea;
2-amino-4-methyl-valeric acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;
4-[(6-methoxyl group-benzo [b] thiophene-2-ylmethyl)-amino]-the 2-aminomethyl phenyl }-urethanes;
2-amino-4-methyl-valeric acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;
2-(4-fluorophenyl)-N-{2-methyl-4-[(4-methyl-2-phenyl pyrimidine-5-ylmethyl)-amino]-phenyl }-acetamide;
3,3-dimethyl-N-{2-methyl-4-[(2-phenyl pyrimidine-5-ylmethyl)-amino]-phenyl }-butyramide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-pyridin-3-yl-phenyl }-urethanes;
1-amino-cyclopropane-carboxylic acid [2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-amide;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-pyridin-4-yl-phenyl }-urethanes;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-piperidines-1-base-acetamide;
N-(4-{[5-(4-chlorophenoxy)-1,3-dimethyl-1H-pyrazoles-4-ylmethyl]-amino }-the 2-aminomethyl phenyl)-2,2-dimethyl propylene amide;
2,2-dimethyl-N-{2-methyl-4-[(6-phenoxypyridines-3-ylmethyl)-amino]-phenyl }-propionic acid amide.;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-pyrrolidine-1-base-acetamide;
[4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-(6-methoxypyridine-3-yl)-phenyl]-urethanes;
4-[(3-methyl-4-propoxycarbonyl amino-phenyl amino)-methyl]-essence of Niobe;
N-[2-methyl-4-(4-trifluoromethyl-benzylamino)-phenyl]-2-morpholine-4-base-acetamide;
2,2-dimethyl-N-{2-methyl-4-[(3-methyl-5-phenyl-isoxazole azoles-4-ylmethyl)-amino]-phenyl }-propionic acid amide.;
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl }-urethanes;
N-{4-[(5-chloro-thiophene-2-ylmethyl)-amino]-the 2-iodophenyl-2-(4-fluorophenyl)-acetamide and
4-[(5-chloro-thiophene-2-ylmethyl)-amino]-2-quinoline-5-base-phenyl }-urethanes
Or its salt.
29. one kind comprises one or more pharmaceutically useful carriers or diluent and as the pharmaceutical composition of any described chemical compound among the claim 1-28.
30. pharmaceutical composition as claimed in claim 29 is used for increasing the application of ion flow of mammal such as people's potassium channel.
31. be used to prevent, treat or suppress the increase of potassium channel intermediate ion stream is had the application as claimed in claim 30 of the disease or the situation of response, such disease or situation be central nervous system's disease or situation preferably.
32. application as claimed in claim 31, wherein said disease or disease are selected from epilepsy disease such as convulsions, epilepsy and status epilepticus.
33. application as claimed in claim 31 is characterized in that said disease or situation are selected from neuropathic pain and migraine antalgesic such as allodynia, hyperpathia pain, phantom pain, the neuropathic pain relevant with diabetic neuropathy and the relevant neuropathic pain with migraine.
34. application as claimed in claim 31, it is characterized in that said disease or situation be selected from anxiety disorder such as anxiety, generalized-anxiety disorder, panic anxiety, obsession, social phobia, behavior anxiety, post-traumatic stress disorder, gross stress reaction, adjustment disorder, hypochondriacal disorder, separation anxiety disorder, agoraphobia, specific phobia, because anxiety disorder and the inductive anxiety disorder of material that general medical condition causes.
35. application as claimed in claim 31 is characterized in that said disease or situation are selected from neurodegenerative disorders such as Alzheimer, Huntington Chorea, multiple sclerosis, amyotrophic lateral sclerosis, the inductive encephalopathy of AIDS-and other and the neural degeneration that infects relevant encephalopathy, Creutzfeld-Jakob disease, parkinson, wound-induced that are caused by rubella virus, herpesvirus, Borrelia and unknown pathogen.
36. application as claimed in claim 31 is characterized in that said disease or situation are selected from the state in neuronal excitation transient state such as drug withdrawal or the poisoning.
CNA2004800075074A 2003-03-21 2004-03-18 Substituted p-diaminobenzene derivatives Pending CN1761464A (en)

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CN103073455A (en) * 2011-10-25 2013-05-01 中国科学院上海药物研究所 Novel KCNQ potassium channel agonist, and preparation method and application thereof
CN105017085A (en) * 2014-04-28 2015-11-04 中国科学院上海药物研究所 Novel KCNQ potassium channel agonist and preparation method and application thereof
CN108707087A (en) * 2018-06-29 2018-10-26 河北医科大学 A kind of 4-（To trifluoromethyl benzyl）Fluoro- 1,2,4 triphenylamine derivatives of -3- and its pharmaceutical composition and purposes

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US9353048B2 (en) 2011-10-25 2016-05-31 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Compound as KCNQ potassium channel agonist, preparation method therefor and use thereof
WO2013060097A1 (en) * 2011-10-25 2013-05-02 中国科学院上海药物研究所 Novel compound as kcnq potassium channel agonist, preparation method therefor and use thereof
CN103073455B (en) * 2011-10-25 2015-08-19 中国科学院上海药物研究所 Kcnq potassium channel agonist, Preparation Method And The Use that one class is novel
CN103073455A (en) * 2011-10-25 2013-05-01 中国科学院上海药物研究所 Novel KCNQ potassium channel agonist, and preparation method and application thereof
CN105017085B (en) * 2014-04-28 2018-06-29 中国科学院上海药物研究所 A kind of kcnq potassium channel agonist, preparation method and use
WO2015165352A1 (en) * 2014-04-28 2015-11-05 中国科学院上海药物研究所 Novel kcnq potassium channel agonist, and preparation method therefor and use thereof
CN105017085A (en) * 2014-04-28 2015-11-04 中国科学院上海药物研究所 Novel KCNQ potassium channel agonist and preparation method and application thereof
US10077245B2 (en) 2014-04-28 2018-09-18 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences KCNQ potassium channel agonists, method of preparation and method of use thereof
US10316008B2 (en) 2014-04-28 2019-06-11 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences KCNQ potassium channel agonist, and preparation method therefor and use thereof
CN108707087A (en) * 2018-06-29 2018-10-26 河北医科大学 A kind of 4-（To trifluoromethyl benzyl）Fluoro- 1,2,4 triphenylamine derivatives of -3- and its pharmaceutical composition and purposes
WO2020001298A1 (en) * 2018-06-29 2020-01-02 河北医科大学 4-(p-trifluoromethylbenzyl)-3-floro-1,2,4 triphenylamine derivative, pharmaceutical composition of same, and uses thereof
CN108707087B (en) * 2018-06-29 2020-10-16 河北医科大学 4- (p-trifluoromethyl benzyl) -3-fluoro-1, 2,4 triphenylamine derivative, and pharmaceutical composition and application thereof
US11247966B2 (en) 2018-06-29 2022-02-15 Hebei Medical University 4-(p-trifluoromethylbenzyl)-3-fluoro-1,2,4-triphenylamine derivative and pharmaceutical composition and applications thereof

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AR043652A1 (en) 2005-08-03

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