CN101163670A

CN101163670A - Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same

Info

Publication number: CN101163670A
Application number: CNA2006800087634A
Authority: CN
Inventors: 徐永钜; 金熙斗; 朴亨根; 吴禹泽; 李庸实; 朴雪邻; 柳赪玹; 朴永镐; 申松锡; 金善映; 金镇官; 郑然守; 李玘和; 崔镇圭; 林庆珉; 高现珠; 牟周炫; 金星日; 裴埈浩
Original assignee: Amorepacific Corp
Current assignee: Amorepacific Corp
Priority date: 2005-03-19
Filing date: 2006-03-17
Publication date: 2008-04-16
Also published as: CN101142174A; CN101142174B

Abstract

This present invention relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receotor 1; VR1; TRPV1 )antagonist; and a pharmaceutical composition containing the same. The present invention provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, and heart disease.

Description

As the new compound of vanilloid receptor antagonist, its isomer or its pharmaceutical salts; With the pharmaceutical composition that comprises it

Technical field

The present invention relates to as novel vanilloid receptor (vallinoid rece tor trpvl; VR1; TRPV1) new compound of antagonist, its isomer or its pharmaceutical salts; With the pharmaceutical composition that comprises it.

Background technology

As disease (Nagy etc., 2004, the Eur.J.Pharmacol.500 relevant with the activity of novel vanilloid receptor, 351-369), can enumerate pain such as acute pain, chronic pain, neuropathic pain, postoperative pain, rheumatic arthralgia, osteoarthrosis pain, postherpetic neuralgia, neurodynia, headache and migraine (Petersen etc., 2000, pain, 88, pp125-133; Walker etc., 2003, J.Pharmacol.Exp.Ther., 304, pp56-62); Neural relevant disease such as neuropathy, the neuropathy that HIV is relevant, nerve injury, neurodegeneration and apoplexy (Park etc., 1999, Arch.Pharm.Res.22, pp432-434; Kim etc., 2005, J.Neurosci.25 (3), pp662-671); Diabetic neuropathy (Kamei etc., 2001, Eur.J.Pharmacol.422, pp83-86); Just anxious; Irritable bowel syndrome (Chan etc., 2003, Lancet, 361, pp385-391); Inflammatory bowel (Yiangou etc., 2001, Lancet, 357, pp1338-1339); Chylopoietic disease such as gastroduodenal ulcer and regional ileitis (Holzer P, 2004, Eur.J.Pharm.500, pp231-241; Geppetti etc., 2004, Br.J.Pharmacol., 141, pp1313-1320); Respiratory illness such as asthma, chronic obstructive pulmonary disease (Hwang etc., 2002, Curr Opin Pharm pp235-242; Spina etc., 2002, Curr Opin Pharm pp264-272); The urinary incontinence (Birder etc., 2002, Nat.Neuroscience, 5, pp856-860); Irritable bladder (Birder etc., 2001, Proc.Natl.Acad.Sci.98, pp13396-13401); Nervosa/allergy/inflammatory dermatosis such as psoriatic, and pruritus and pruigo (Southall etc., 2003, J.Pharmacol.Exp.Ther., 304, pp217-222); Skin, the stimulation of eyes or mucous membrane (Tominaga etc., 1998, Neuron 21 pp531-543); Hyperacusis; Tinnitus; Vestibular allergy (Balaban etc., 2003, Hear Res.175, pp165-70); (Scotland etc., 2004, Circ.Res.95, pp1027-1034 such as heart trouble such as variable force ischemia; Pan etc., 2004, Circulation, 110, pp1826-1831).

Novel vanilloid receptor (VR1) is capsaicine (a 8-methyl-N-vanillyl-6-nonene acid amides), the acceptor of the pungency composition in a kind of hot pepper (hot pepper).Also reported in 1997 its molecular cloning (Caterina etc., 1997, Nature 389, pp816-824).This receptor is non-selective cationic channel, and it is formed and belonged to TRP passage family by 6 membrane spaning domains.Recently, it is named as TRPV1.On the other hand, known novel vanilloid receptor is by stimulator such as capsaicine, Root and stem of Cholla toxin, heat, acid, arachidonic acid diethanolamide, activation such as lipid metabolism thing; Therefore its molecule as the deleterious stimulator of physics and chemistry in Mammals is integrated thing (integrator) and is played keying action (Tominaga etc., 1998, Neuron 21 pp531-543; Hwang etc., 2000, PNAS, 97, pp6155-6160).By endogenous/exogenous irritant the activation of novel vanilloid receptor is not only caused the transmission of noxious stimulus, also cause neuropeptide such as Substance P, therefore the release of CGRP (calcitonin-gene-related peptide) etc. caused neurogenic inflammation.Novel vanilloid receptor is expressed at the main Sensory neurone camber that imports into.Its also at various organs and tissue as bladder, kidney, lung, intestines and skin and the property during comprising the central nervous system (CNS) of brain and non-neuron tissue, reported expression (Mezey etc., 2000, PNAS, 97, pp3655-3660; Stander etc., 2004, Exp.Dermatol.13, pp129-139; Cortright etc., 2001, BBRC, 281, pp1183-1189).Particularly, TRPV1 acceptor knock-out mice shows the normal reaction to the stimulator that is harmful to health, but show the pain of the heat stimulus of vanilla element is replied minimizing with sense organ susceptibility, and even under inflammatory conditions, show hyperpathia (Caterina etc. hardly to heat stimulus, 2000, Science 288, pp306-313; Davis etc., 2000, Nature405, pp183-187; Karai etc., 2004, J.Clin.Invest., 113, pp1344-1352).Recently, also by show novel vanilloid receptor may be with allos with TRPV3 many bodies, the possibility that the form of another kind of TRP passage exists expect novel vanilloid receptor other effect (Smith etc., 2002, Nature, 418, pp186-190).

As mentioned above, the novel vanilloid receptor knock-out mice shows the reaction to the minimizing of heat or noxious stimulus, has therefore increased the possibility that vanilloid receptor antagonist can be used to prevent or treat various antalgesics.Recently, this possibility is by well-known vanilloid receptor antagonist, and anti-capsicine also reduces the hyperalgesic report support that is caused by the body-stimulating thing in inflammation and neuropathic pain model.(Walker etc., 2003, JPET, 304, pp56-62; Garcia-Martinez etc., 2002, Proc.Natl.Acad.Sci.99,2374-2379).In addition, the primary culture with processing esodic nerve cells such as novel vanilloid receptor agonist capsaicines causes the damage of neural function and the further death of neurocyte.The vanilloid receptor antagonist performance is to such damage of neural function and the defense reaction of nerve cell death (Holzer P, 1991, Pharmacological Reviews, 43, pp143-201; Mezey etc., 2000, PNAS, 97,3655-3660).Novel vanilloid receptor is at GI All Ranges, tensor muscle neuroganglion for example, and the flesh layer is expressed in mucous membrane and the epithelial cell.Particularly, novel vanilloid receptor is expressed at the inflammatory diseases camber of colon and ileum.

In addition, the activation sensation nerve of novel vanilloid receptor, it causes the release of neuropeptide again, and described neuropeptide is known to play a crucial role in the pathogeny of intestinal disease.Novel vanilloid receptor is at the developing nearest scientific literature and the magazine of acting on of gastrointestinal illness, Holzer P for example, 2004, Eur.J.Pharm.500, pp231-241; Geppetti etc., 2004, Br.J.Pharmacol., 141, fully set forth among the pp1313-1320 and put down in writing.As if according to these reference, vanilloid receptor antagonist is effective for preventing or treating gastrointestinal illness such as stomach-esophageal reflux disease (GERD) and gastro-duodenal ulcer (DU).Reported that the sensorineural quantity of expressing novel vanilloid receptor increases and the expression of such increase of known novel vanilloid receptor relates to described advancing of disease (Chan etc. in suffering the patient of irritable colon syndrome, 2003, Lancet, 361, pp385-391).Other studies show that being expressed in of novel vanilloid receptor suffers significantly to increase among the patient of inflammatory bowel.Generally speaking, as if vanilloid receptor antagonist also can effectively treat such enteropathy (Yiangou etc., 2001, Lancet, 357, pp1338-1339).The esodic nerve of expressing novel vanilloid receptor distributes in respiratory mucosa in a large number.Bronchial allergy and bronchial hyperpathia are very similar, and the proton of known endogenous ligands as novel vanilloid receptor and lipoxygenase product are the well-known key factor (Hwang etc. that are responsible for asthma and chronic obstructive pulmonary disease development, 2002, Curr.Opin.Pharm.pp235-242; Spina etc., 2002, Curr.Opin.Pharm.pp264-272).In addition, reported the air pollutant that causes the material of asthma as a kind of, be the particulate matter specific effect on novel vanilloid receptor and such effect suppressed by anti-capsicine, therefore point out the possible applicability (Veronesi etc. of vanilloid receptor antagonist for respiratory disease, 2001, NeuroToxicology, 22, pp795-810).The irritable bladder and the urinary incontinence are caused by various maincenter/peripheral neuropathies or damage, and capsaicine-reactive sensory nerve plays an important role in bladder function control and inflammation.In addition, in the urothelium (urothelial) of rat, reported the immunoreactivity of novel vanilloid receptor, and finding stimulates institute to cause (Birder etc. by the overactivity of capsaicine inductive bladder by the novel vanilloid receptor that exists in nerve fiber or by the various mediators that novel vanilloid receptor discharges, 2001, Proc.Natl.Acad.Sci.98, pp13396-13401).In addition, VR1 (TRPV1)-/-mouse is normal on dissecting, still compares with normal mouse, show the bladder contracts that causes by low convergent force of non-secretory, therefore show that novel vanilloid receptor influences the function of bladder (Birder etc., 2002, Nat.Neuroscience, 5, pp856-860).The plain agonist of some vanillas of developing recently is as the therapeutical agent that is used for the treatment of bladder disease.Keratinization of epidermis cell and one-level that novel vanilloid receptor is distributed in the people are imported (Denda etc., 2001, Biochem.Biophys.Res.Commun., 285, pp1250-1252 in the sensory nerve into; Inoue etc., 2002, Biochem.Biophys.Res.Commun., 291, pp124-129), and then relate to the transmission of various destructive stimuluses and pain such as skin irritation and itch, closely related with the neurogenicity/tetter that the non-neurogenicity factor is caused and the cause of disease of illness such as skin inflammation thus.This is by vanilloid receptor antagonist, anti-capsicine suppress the report of the inflammatory factor among the human skin cell support (Southall etc., 2003, J.Pharmacol.Exp.Ther., 304, pp217-222).

Based on above-mentioned information, the exploitation of various vanilloid receptor antagonists is underway, and some patents and the patent application that relate to the vanilloid receptor antagonist of developing are disclosed recently, above-mentioned information (the Rami etc. that mention have wherein fully been described, 2004, Drug Discovery Today:Therapeutic Strategies, 1, pp97-104).

As based on the theoretical background of above-mentioned discussion extensively and concentrate the result of research, the inventor to synthesize on novel vanilloid receptor, to have the new compound of antagonistic activity and therefore finished the present invention by selectively acting.Surprisingly; determined such compound be novel vanilloid receptor have active conditioning agent especially, it has therein the phenmethyl cinnamoyl amide structure that has at least two substituent xenyl urea structures on the phenyl ring or have branch not or surpass one times of branch's main chain.

Therefore, an object of the present invention is to provide new compound, its isomer and pharmaceutical salts thereof as effective antagonist of novel vanilloid receptor; With the pharmaceutical composition that comprises it.

The disclosure of the Invention content

The invention provides the new compound of formula (Ia), its isomer and/or pharmaceutical salts; With the pharmaceutical composition that comprises it.

[formula Ia]

Wherein,

X is CR ₁₁=CR ₁₂, or C ≡ C, wherein, R ₁₁And R ₁₂Be hydrogen independently, halogen, C1-C5 alkyl, or phenyl;

R ₁And R ₂Be hydrogen independently, carboxyl, C1-C5 alkyl, halogen, nitro, the C1-C5 alkoxyl group, halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkyl-carbonyl-amino, C1-C5 alkyl sulfonyl-amino, phenyl sulfonyl amino, C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₃Be hydrogen, C1-C5 alkyl, C1-C5 alkoxyl group, or halo (C1-C5) alkyl;

R ₄, R ₅, R ₆, R ₇, and R ₈Be hydrogen independently, carboxyl, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, the C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, phenyl, or halogen, wherein, phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl, halogen, nitro, the C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, the C1-C5 alkyl-carbonyl, the C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₉Be C1-C5 alkyl sulphonyl or C2-C5 alkenyl alkylsulfonyl; With

R ₁₀Be hydrogen;

Condition is if R ₃Be different from hydrogen, so R ₁₁And R ₁₂Not to be hydrogen simultaneously.

A compound that preferred aspect is formula (Ia) of the present invention, its isomer and/or pharmaceutical salts;

Wherein,

X is CR ₁₁=CR ₁₂Or C ≡ C, wherein, R ₁₁And R ₁₂Be hydrogen independently, fluorine, bromine, chlorine, iodine, methyl, ethyl, or propyl group;

R ₁And R ₂Be hydrogen independently, methyl, ethyl, propyl group, fluorine, chlorine, bromine, nitro, trifluoromethyl, methoxyl group, or oxyethyl group;

R ₃Be hydrogen, methyl, ethyl, or methoxyl group;

R ₄, R ₅, R ₆, R ₇And R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, nitro, vinyl, propenyl, methoxyl group, oxyethyl group, propoxy-, the C2-C5 alkynyl, trifluoromethyl, methylthio group, ethanoyl, methoxycarbonyl, phenyl, bromine, chlorine, or iodine,

Wherein,

Phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, the C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, the C1-C5 alkoxyl group, halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₉Be methane sulfonyl, ethane alkylsulfonyl, or vinylsulfonyl; And

R ₁₀Be hydrogen;

Condition is if R ₃Be different from hydrogen, so R ₁₁And R ₁₂Be not hydrogen simultaneously.

Other preferred aspect of the present invention is the compound according to above-mentioned formula (Ia), its isomer and/or pharmaceutical salts;

Wherein,

X is trans CR ₁₁=CR ₁₂Or C ≡ C, wherein, R ₁₁And R ₁₂Be hydrogen or methyl independently;

R ₁Be hydrogen, methyl, ethyl, propyl group, fluorine, chlorine, bromine, iodine, nitro, methoxyl group, or oxyethyl group;

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃Be hydrogen;

R ₄, R ₅, R ₇, and R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, nitro, vinyl, propenyl, methoxyl group, oxyethyl group, propoxy-, ethynyl, proyl, trifluoromethyl, methylthio group, ethanoyl, methoxycarbonyl, bromine, chlorine, or iodine;

R ₆Be halo (C1-C3) alkyl, sec.-propyl, or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

Preferred aspect of the present invention is the compound according to formula (Ia), its isomer and/or pharmaceutical salts;

Wherein, X is trans CR ₁₁=CR ₁₂Or C ≡ C, wherein, R ₁₁And R ₁₂Be hydrogen or methyl independently;

R ₁Be hydrogen, methyl, ethyl, propyl group, fluorine, chlorine, bromine, or iodine;

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃Be hydrogen;

R ₄Be hydrogen, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, nitro, vinyl, propenyl, methoxyl group, oxyethyl group, propoxy-, ethynyl, proyl, trifluoromethyl, methylthio group, ethanoyl, methoxycarbonyl, bromine, chlorine, or iodine;

R ₅, R ₇And R ₈All be hydrogen;

R ₆Be the sec.-propyl or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

Other preferred aspect of the present invention is the compound according to formula (Ia), its isomer and/or pharmaceutical salts;

Wherein

X is CR ₁₁=CH, CH=CR ₁₂, CR ₁₁=CR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂It all is methyl;

R ₁Be hydrogen, methyl, ethyl, propyl group, fluorine, chlorine, bromine, iodine, nitro, methoxy or ethoxy;

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃It is methyl;

R ₄, R ₅, R ₇And R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, nitro, vinyl, propenyl, methoxyl group, oxyethyl group, propoxy-, ethynyl, proyl, trifluoromethyl, methylthio group, ethanoyl, methoxycarbonyl, bromine, chlorine, or iodine;

R ₆Be halo (C1-C3) alkyl, sec.-propyl, or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

Wherein X is CR ₁₁=CH or C ≡ C, wherein R ₁₁It is methyl;

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃It is methyl;

R ₅, R ₇And R ₈All be hydrogen;

R ₆Be the sec.-propyl or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

Aspect of the present invention even preferred is the compound according to formula (Ia), its isomer and/or pharmaceutical salts;

Wherein, R ₁Thereby the ortho position with relative sulfuryl amino is incorporated into the compound that phenyl ring obtains formula (Ib).

[formula Ib]

Preferred embodiment according to the compound of the compound of formula (Ia) is selected from the group of being made up of following:

3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-phenmethyl)-2-methyl-acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-fluoro-5-iodo-4-methane sulfonyl amino-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-phenmethyl) propine acid amides,

(E)-3-(the 4-tertiary butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-methyl-4-methane sulfonyl amino-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3,5-two fluoro-4-methane sulfonyl amino-phenmethyls) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(2,5-two fluoro-4-methane sulfonyl amino-phenmethyls) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-chloro-5-iodo-4-methane sulfonyl amino-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-5-methyl-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-methyl-phenmethyl) acrylamide,

3-(the 4-tertiary butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-phenmethyl)-2-methyl-acrylamide,

3-(the 4-tertiary butyl-phenyl)-but-2-ene acid 3-fluoro-4-methane sulfonyl amino-phenmethyl acid amides,

3-(the 4-tertiary butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl aminophenyl) ethyl] the propine acid amides,

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl aminophenyl) ethyl]-the 2-Methacrylamide and

3-(the 4-tertiary butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl aminophenyl) ethyl]-2-methyl-acrylamide.

The present invention also provides the new compound of formula (II), its isomer and/or pharmaceutical salts; With the pharmaceutical composition that comprises it.

[formula II]

Wherein,

R ₁And R ₂Be hydrogen independently, halogen, nitro, cyano group, the C1-C5 alkyl, the C1-C5 alkoxyl group, halo (C1-C5) alkyl, carboxyl, C1-C5 alkoxy carbonyl, or C1-C5 alkylthio, condition is R ₁And R ₂At least one of them is different from hydrogen;

R ₄, R ₅, R ₇And R ₈Be hydrogen independently, carboxyl, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, the C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, phenyl, or halogen, wherein, phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl, halogen, nitro, the C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, the C1-C5 alkyl-carbonyl, the C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₆Be halo (C1-C3) alkyl or C1-C5 alkyl; With

R ₉Be the C1-C5 alkyl sulphonyl, C2-C5 alkenyl alkylsulfonyl, or trifluoromethane sulfonyl group.

A compound that preferred aspect is formula (II) of the present invention, its isomer, and/or its pharmaceutical salts;

Wherein,

R ₄, R ₅, R ₇And R ₈Be hydrogen independently, carboxyl, the C1-C5 alkyl, nitro, the C2-C5 alkenyl, the C1-C5 alkoxyl group, the C2-C5 alkynyl, halo (C1-C5) alkyl, the C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, the C1-C5 alkyl-carbonyl, the C1-C5 alkoxy carbonyl, phenyl, or halogen,

Wherein, phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl, halogen, nitro, the C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, the C1-C5 alkyl-carbonyl, the C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₆It is the C1-C5 alkyl; With

Preferred aspect of the present invention is the compound according to formula (II), its isomer, and/or its pharmaceutical salts;

Wherein,

R ₁And R ₂Be hydrogen independently, fluorine, chlorine, bromine, iodine, nitro, cyano group, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, or methoxycarbonyl, condition is R ₁And R ₂At least one of them is different from hydrogen;

R ₄, R ₅, R ₇And R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, nitro, vinyl, ethynyl, isobutyl-, methylthio group, or methoxycarbonyl;

R ₆It is the C3-C5 alkyl; With

R ₉Be methane sulfonyl, ethane alkylsulfonyl, or ethene alkylsulfonyl.

Aspect of the present invention even preferred is the compound according to formula (II), its isomer, and/or pharmaceutical salts;

Wherein,

R ₁And R ₂Be hydrogen independently, fluorine, chlorine, bromine, iodine, nitro, cyano group, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, or methoxycarbonyl; Condition is R ₁And R ₂At least one of them is different from hydrogen;

R ₄, R ₅, R ₇, and R ₈Be hydrogen;

R ₆Be the sec.-propyl or the tertiary butyl; With

R ₉It is methane sulfonyl.

Other preferred aspect of the present invention is the compound according to formula (II), its isomer and/or pharmaceutical salts;

Wherein

R ₁Be selected from fluorine, chlorine, methyl, ethyl, n-propyl, or nitro;

R ₂Be selected from fluorine, chlorine, methyl, ethyl, or iodine, and work as R ₁Be selected from methyl, ethyl, or during n-propyl, R ₂Also can be hydrogen;

R ₄, R ₅, R ₇And R ₈Be hydrogen independently, halogen, carboxyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, nitro, vinyl, ethynyl, isobutyl-, methylthio group, or methoxycarbonyl;

R ₆Be halo (C1-C3) alkyl or C3-C5 alkyl; With

R ₉It is methane sulfonyl.

Preferred aspect of the present invention is the compound according to formula (II), its isomer and/or pharmaceutical salts;

Wherein, R ₁Be incorporated into phenyl ring with ortho position with respect to sulfuryl amino.

Aspect of the present invention even preferred is the compound according to formula (II), its isomer and/or pharmaceutical salts;

Wherein, R ₁And R ₂With the ortho position combination with respect to sulfuryl amino, thereby described compound has the structure of general formula (IIa).

In formula (II) or compound (IIa), most preferably;

R ₁Be methyl or ethyl and

R ₂Be selected from hydrogen, fluorine, or chlorine.

Preferred embodiment according to the compound of the compound of formula (II) is selected from the group of being made up of following:

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-fluoro-6-iodo-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-5-chloro-2-iodo-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-ethyl-6-fluoro-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-fluoro-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-methyl-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-chloro-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-nitro-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2-iodo-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2,6-two fluoro-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2,5-two fluoro-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-chloro-6-methyl-phenyl } amsacrine,

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-5-chloro-2-ethyl-phenyl amsacrine and

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-fluoro-6-methyl-phenyl } amsacrine.

According to formula of the present invention (Ia), (Ib), (II) or compound (IIa) can synthesize with chemical mode by following reaction scheme.Yet these only are to provide for illustration purpose of the present invention, and are not inclined to and limit them.

[route 1]

Above-mentioned route 1 shows the recommend method of synthesis of acrylamide compound (3).Undersaturated aromatic substituted acrylic acid (2) reacts to produce acrylamide (3) with benzene methanamine and diethylcyanophosphonise.

[route 2]

Route 2 shows the another kind of method of synthesis of acrylamide compound.Described compound (6) uses DMTMM{4-(4,6-dimethoxy-1,3,5-triazines-2-yl) 4-methylmorpholine muriate } (Tetrahedron Lett., 1999,40,5327) substitute diethylcyanophosphonise and synthesize.

[route 3]

Route 3 shows the recommend method of compound stereoscopic specificity (sterospecific) acrylamide compound (9).Aromatic substituted acrylic acid (8) is created in the acrylamide (9) that has structural changes on the main chain with benzene methanamine (7) reaction.

[route 4]

Route 4 shows the recommend method of synthesis of acrylamide derivatives (12).Hydrolysis has various substituent ester cpds (10) to produce lipid acid (11) in the alkene site of undersaturated lipid acid.Has substituent undersaturated lipid acid (11) synthetic compound (12) according to using with route 3 described identical methods.

[route 5]

Above-mentioned route 5 shows the recommend method of synthetic propiolyl amine compound (15).Having triple-linked acid compound (14) reacts to produce target compound (15) with benzene methanamine compound (7).

[route 6]

Above-mentioned route 6 shows the recommend method of synthetic diphenyl-methyl carbamide compound (17).At first, the reaction of the benzene methanamine of replacement and tert-Butyl dicarbonate produces the carboxylamine benzene methyl with original position, adds the benzene methanamine of the replacement with methane sulfonyl (4) and triethylamine with dimethyl urea compound (17) to this reaction mixture immediately.

[route 7]

Above-mentioned route 7 shows the novel method of using the synthetic carbamide compound (19) of isocyanic acid benzene methyl (18).

[route 8]

The reaction of other of the synthetic various urea derivativess of route 8 demonstrations.Having various substituent benzene methanamine compounds reacts to produce carbamide compound (21) with (the 4-tertiary butyl-phenmethyl)-phenyl carbamate (20).

The present invention also provides pharmaceutical composition, and it comprises the formula (Ia) as activeconstituents, (Ib), (II) or compound (IIa), its isomer, or its pharmaceutical salts and pharmaceutical carrier.

In described pharmaceutical composition, as the formula (Ia) of activeconstituents, (Ib), (II) or compound (IIa), its isomer, thereby or its pharmaceutical salts and pharmaceutical carrier have prevention or treatment pain with significant quantity, acute pain, neuropathic pain, postoperative pain, migraine, arthrodynia, neuropathy, nerve injury, diabetic neuropathy, neurodegeneration, apoplexy, nervosa/allergy/inflammatory dermatosis, psoriatic, pruritus, pruigo, irritable bladder, irritable bowel syndrome, just anxious, regional ileitis, respiratory disease such as asthma, chronic obstructive pulmonary disease, skin, the stimulation of eyes or mucous membrane, gastroduodenal ulcer, inflammatory bowel or inflammatory diseases.

The present invention also provides pharmaceutical composition to be used to prevent the disease relevant with the unconventionality expression of pathological stimuli and/or novel vanilloid receptor with treatment, and wherein said composition comprises formula (Ia), (Ib), (II) or compound (IIa), its isomer or its pharmaceutical salts; And pharmaceutical carrier.

The present invention also provides pharmaceutical composition to be used to prevent the illness relevant with novel vanilloid receptor with treatment, and wherein said composition comprises formula (Ia), (Ib), and (II) or compound (IIa), its isomer or its pharmaceutical salts and pharmaceutical carrier.

In above-mentioned, the described illness relevant with novel vanilloid receptor is pain, migraine, arthrodynia, neurodynia, neuropathy, nerve injury, dermatosis, irritable bladder, irritable bowel syndrome, just anxious, respiratory disease, skin, eyes or mucous membrane irritation, gastroduodenal ulcer, inflammatory diseases, otopathy, or heart trouble.

More specifically, the described illness relevant with novel vanilloid receptor is acute pain, chronic pain, neuropathic pain, postoperative pain, rheumatic arthralgia, osteoarthrosis pain, postherpetic neuralgia, diabetic neuropathy, the neuropathy that HIV-is relevant, neurodegeneration, apoplexy, nervosa/allergy/inflammatory dermatosis, psoriatic, pruritus, pruigo, asthma, chronic obstructive pulmonary disease, the urinary incontinence, inflammatory bowel, hyperacusis, tinnitus, vestibular allergy, or variable force ischemia.

One preferred aspect, the invention provides pharmaceutical composition is used for the treatment of and is selected from following illness: pain, the inflammatory diseases in joint comprises the inflammatory autoimmune disease in joint, irritable bladder comprises the urinary incontinence, gastro-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel (IBD), nervosa/allergy/inflammatory dermatosis, psoriatic, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or pruigo, described pharmaceutical composition comprises according to formula (Ia), (Ib), and (II) or (IIa) each compound, its isomer or its pharmaceutical salts are as top further definition.

More specifically, compound of the present invention can be used in the pharmaceutical composition, described pharmaceutical composition is used for the treatment of pain, and wherein said pain is to be selected from following illness: osteoarthritis (" OA "), rheumatoid arthritis (" RA "), ankylosing spondylitis (" AS "), diabetic neuralgia, postoperative pain, non-inflammatory flesh skeletal pain (comprises fibromyalgia, myofascial pain syndrome and backache), the headache of migraine and other type or the pain relevant with it.

If think that compound of the present invention is effective to treat the pain relevant with osteoarthritis, do not get rid of it yet and also comprise treatment other S﹠S of osteoarthritis.Except reducing the pain relevant, can be the no energy minimization of keeping the mobility in joint and making it to the target of the pharmacy intervention of osteoarthritis with osteoarthritis.

Term " inflammatory diseases in joint " comprises and relates in the joint the more or less disease of the inflammatory process of degree that described joint refers to for example at knee, in the hip etc.The example of such disease is an osteoarthritis.Term " inflammatory diseases in joint " also comprises the disease or the illness that may relate to self-immunprocess, such as for example rheumatoid arthritis or ankylosing spondylitis.The present invention is the treatment pain relevant with these illnesss to the major objective of the treatment of " inflammatory diseases in joint ", but target also can be a function of directly or indirectly improving these affected joints, for example by reducing the pain relevant with the motion in described joint.

Therefore, a result who uses compound of the present invention to the patient of the inflammatory diseases that suffers described joint is with respect to the pain of using the pain that the experimenter suffered before compound of the present invention or the composition, reducing immediately the experimenter's experience that suffers described disease.Another result of described treatment can be the generation again of prevent irritation, and described pain is former to be reduced because of drug effect or other treatment.The other consequence of treatment can be to reduce the generation and/or the seriousness of the clinical symptom of the inflammatory diseases relate to the joint, and the inflammatory diseases in described joint is particularly including osteoarthritis, the rheumatoid arthritis ankylosing spondylitis.Described treatment can suitably cause the improvement of function of joint, such as reducing tetanic property, improves mobility.

When being used for this paper, term " osteoarthritis (OA) " typically comprises and has movable joint the disease of the obstacle in (movably, having synovia) joint.At primary (former) OA, in the modal form of described disease, no procatarxis sexual factor is conspicuous.Secondary cases OA is attributable to the potential reason.Pain and joint function disturbance are the cardinal symptoms of OA.The joint that the arthralgia of OA often is described to deep pain and is positioned to relate to.Typically, the pain of OA worsens because of the use in joint, alleviates by rest, and still, when progression of disease, it may continue.Disturb the pain at night of sleep to observe among the OA in the late period of hip especially, and can weaken.But the tetanic property that relates to the joint that occur in the morning or that after date occurs when dormant state may be significant continue usually to be less than 20 minutes.

Term " RA " refers to rheumatoid arthritis.RA causes the particularly chronic inflammatory autoimmune disease of the synovial membrane in the joint of immune system attack joint.The synovial membrane inflammation also causes swelling and pain.But the cardinal symptom of RA is arthralgia and tetanic other symptom comprises myalgia, anaemia and fever.The diagnosis of RA can be by being called as the antibody of " rheumatic (" the rheumatoid ") factor " in the detection blood and/or being confirmed by esr test.Other useful and common test is to detect " antinuclear antibody " or " proteins C reactive ".

" AS " represents ankylosing spondylitis, and it is chronic, and the autoimmune disease of progressivity is characterized in that sacroiliitis, and inflammation and joint be final can not the moving of spinal joint particularly.As the ongoing swelling of spinal joint (vertebra) and the result of stimulation, it causes pain and tetanic (usually time) in the morning at back.The tendon that connects and provide support to vertebra and the inflammation of ligament can cause rib, shoulder blade, hip, thigh, shin bone, heel and along the pain and the tenderness of the bone point of backbone.

Be used in the treatment pain relevant according to compound of the present invention if think with the inflammatory autoimmune disease in joint, this is meant uses compound of the present invention or combination of compounds of the present invention to reduce at least a pain symptom that the experimenter was experienced by the inflammatory autoimmune disease that suffers the joint, it comprises backache, arthralgia and the myalgia relevant with RA or AS.Except easing the pain, the treatment of the inflammatory autoimmune disease in joint can also comprise functional (promptly keep mobility, and make no energy minimization) of particularly reducing the inflammation and/or the swelling of synovial membrane and helping to improve the joint in the patient who suffers RA or AS.

" treatment of non-inflammatory flesh skeleton pain " refers to use compound of the present invention or combination of compounds of the present invention to alleviate the pain by the experimenter's experience that suffers non-inflammatory flesh skeleton pain, described non-inflammatory flesh skeleton pain comprises backache, fibromyalgia, and myofasical pain syndrome.A result of treatment can be with respect to using before compound of the present invention or the composition, alleviating the pain that is experienced by the experimenter immediately.The consequence of another of treatment can be the generation again of prevent irritation, and described pain is former to be alleviated because of drug effect.Another consequence of treatment can be to reduce to relate to non-inflammatory flesh skeleton pain and comprise backache, the generation of the clinical symptom of fibromyalgia and myofasical pain syndrome and/or seriousness.Described treatment can suitably cause the minimizing of the muscle susceptibility that increases, and the muscle susceptibility of described increase is characterised in that by the pain (allodynia) that under normal circumstances non-noxious stimulation caused or by the intensity (hyperpathia) of the pain of the increase that noxious stimulation caused.Finally, the treatment of non-inflammatory flesh skeleton pain can also improve and backache, fibromyalgia, the related symptoms relevant with myofasical pain syndrome.

Term " fibromyalgia " or " FMS " relate to such syndrome, its cause spreading all over support and the tissue in mobile bone and joint in general pain and tetanic.The existence of excessively touching a tender spot after fibromyalgia can be exerted pressure by 11 in 18 specificity muscle-tendon sites is at least diagnosed.

" myofasical pain syndrome " is chronic, non-sex change non-inflammatory flesh skeleton pain illness.The zone of the uniqueness in muscle or their the reticular tissue coverture (manadesma) of jewelry, expensive clothing and other valuables become and thicken unusually or tight.When described myofascial tissue was strained and lost their elasticity, the neurotransmitter that can send and receive information between brain and health sustained damage.Symptom is included in away from the muscle rigidity in the zone of trigger point and pain and rapid thorn Severe Pain or tingle and feeling of numbness.Modal trigger point is at neck, in back or the buttocks.

" backache " is common non-inflammatory flesh skeleton pain illness, and it can be acute or chronic.It can be caused by the multiple disease and the sufferer that influence lumbar vertebrae.Back pain is followed sciatica usually, and this relates to sciatic pain and at lower back, feel at buttocks and thigh back.

Compound of the present invention also is used for the treatment of the S﹠S such as the urinary incontinence of hyperactive bladder, the more particularly urgent urinary incontinence, stress incontinence, urgent urination, nycturia and/or frequent micturition.

Be preferably used for Orally administered according to pharmaceutical composition of the present invention.Alternatively, if the treatment tetter, the pharmaceutical composition that comprises The compounds of this invention can also be prepared is used for the part or use through skin.

In one aspect of the method, the present invention relates to suppress the method for the plain part of vanilla in conjunction with novel vanilloid receptor in the patient, described method comprises cell and the formula (Ia) of expressing novel vanilloid receptor in the patient that make, (Ib), (II) or compound (IIa), its isomer, or its pharmaceutical salts contact.

In one aspect of the method, the present invention relates to prevent or treat the method that is selected from following disease: pain, migraine, arthrodynia, neuropathy, nerve injury, dermatosis, irritable bladder, irritable bowel syndrome, just anxious, respiratory disease, skin, eyes or mucous membrane irritation, gastroduodenal ulcer, inflammatory diseases, described method comprises the formula (Ia) that comprises the individual administering therapeutic significant quantity that needs it to Mammals, (Ib), and (II) or compound (IIa), or its isomer, or its pharmaceutical salts.

In aforesaid method, described disease also is selected from acute pain, chronic pain, neuropathic pain, postoperative pain, diabetic neuropathy, neurodegeneration, apoplexy, nervosa/allergy/inflammatory dermatosis, psoriatic, pruritus, pruigo, asthma, chronic obstructive pulmonary disease, the urinary incontinence or inflammatory bowel.

Of the present invention one preferred aspect in, aforesaid method is the such pain of treatment, described pain is to be selected from following illness: osteoarthritis (" OA "), rheumatoid arthritis (" RA "), ankylosing spondylitis (" AS "), diabetic neuropathic pain, non-inflammatory flesh skeletal pain (comprising fibromyalgia, myofascial pain syndrome and backache), postoperative pain, the headache of migraine and other type, or the pain relevant with it.

In one aspect of the method, the present invention relates to formula (Ia), (Ib), (II) or compound (IIa), its isomer, or its pharmaceutical salts is as the application of the antagonist of novel vanilloid receptor.

In one aspect of the method, the present invention relates to formula (Ia), (Ib), (II) or compound (IIa), its isomer, or its pharmaceutical salts is used to prevent or treat the application of the illness that relates to novel vanilloid receptor, and described illness more specifically unconventionality expression and/or the abnormal activation with novel vanilloid receptor is relevant.

In one aspect of the method, the present invention relates to formula (Ia), (Ib), (II) or compound (IIa), its isomer, or the application of its pharmaceutical salts in the preparation medicine, described medicine is used to prevent or treat the illness that relates to novel vanilloid receptor.

In aspect preferred, the present invention relates to formula (Ia), (Ib), (II) or compound (IIa), its isomer, or its pharmaceutical salts is used for preventing or treating the application of the medicine that is selected from following illness in preparation, and described illness is selected from pain, the inflammatory autoimmune disease in joint, irritable bladder comprises the urinary incontinence, gastro-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel (IBD), nervosa/allergy/inflammatory dermatosis, psoriatic, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or pruigo.

In aspect particularly preferred, the present invention relates to use compound to be used for the treatment of above-mentioned pain, wherein said pain is to be selected from following illness: osteoarthritis (" OA "), rheumatoid arthritis (" RA "), ankylosing spondylitis (" AS "), diabetic neuropathic pain, postoperative pain, non-inflammatory flesh skeletal pain (comprising fibromyalgia, myofascial pain syndrome and backache), the headache of migraine and other type, or the pain relevant with it.

Hereinafter, will describe compound method and various vehicle, but the present invention is not limited to them.

Can be with according to formula of the present invention (Ia), (Ib), (II) or compound (IIa), its isomer or its pharmaceutical salts are prepared as and comprise pharmaceutical carrier, assistant agent, the pharmaceutical composition of thinner etc.For example, can be with compound dissolution of the present invention at oil, propylene glycol, or other be generally used for produce in the solvent of injection.The example that is fit to of carrier comprises physiological saline, polyoxyethylene glycol, and ethanol, vegetables oil, tetradecyl isopropyl ester etc., but be not limited to them.For topical application, compound of the present invention can be prepared with the form of ointment or ointment.

Can also will use with the form of its pharmaceutical salts according to compound of the present invention, and can be alone or in combination or the medicinal activity compound that mixes other use.

Compound of the present invention can be by in water-soluble solvent such as salt solution and 5% dextrose or at water-immiscible solvent such as vegetables oil, and the synthetic glycerol fatty acid ester more dissolves in high-grade fatty acid ester and the propylene glycol, suspension or emulsification and be mixed with injection.Preparation of the present invention can comprise the additive that any is commonly used, as solvating agent, and isotonic agent, suspension agent, emulsifying agent, stablizer and sanitas.

Preferred dosage level according to compound of the present invention depends on that various factors comprises, patient's situation and body weight, and the seriousness of disease specific, the path of formulation and administration and period, but can suitably select by those skilled in the art.Compound of the present invention is preferably with in the 0.001-100mg/kg body weight/day, and more preferably the amount in the 0.01-30mg/kg body weight/day scope is carried out administration.Administration can be once a day or with each divided dose one day for several times.Compound of the present invention is with 0.0001～10 weight % based on the total amount of composition, and preferably the amount of 0.001～1 weight % is used in the pharmaceutical composition.

Pharmaceutical composition of the present invention can be applied to mammalian subject by various paths, as rat, and mouse, domestic animal, people etc.The application process that can easily expect comprises oral and rectal administration; Intravenously, intramuscular, subcutaneous, intrauterine, endocranium and intracerebral ventricle injection.

The detailed description of the present invention's definition

When describing compound, the pharmaceutical composition that comprises described compound, use these compounds and method for compositions, during with the application of these compounds and composition, all has this area person skilled with in this application all terms, medicinal chemistry teacher for example, pharmacist or doctor be used implication usually.As an example, provide some definition of concrete group below:

" alkyl " comprises the aliphatic hydrocarbyl that unit price is saturated.Hydrocarbyl chain can be a straight or branched.This term is by group such as methyl, ethyl, and n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl is illustrated.

" alkoxyl group " comprises group-OR, and wherein R is an alkyl.Concrete alkoxyl group comprises, as an example, and methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy, 1,2-dimethyl butoxy etc.

" alkenyl " comprises the undersaturated alkyl of unit price olefinic, its be straight or branched and have at least one two key.Concrete alkenyl comprises vinyl (CH=CH ₂), positive propenyl (CH ₂CH=CH ₂), pseudoallyl (C (CH ₃)=CH ₂), etc.Preferably " alkenyl " is vinyl (vinyl).

" alkynyl " comprises the undersaturated alkyl of acetylene series, and it is a straight or branched, and has at least one triple bond.Preferred alkynyl is ethynyl (acetylene).

" alkyl sulphonyl " comprises atomic group-S (O) ₂R, wherein R is an alkyl as defined herein.Representational example includes, but not limited to methane sulfonyl, ethylsulfonyl, sulfonyl propyl base, butyl alkylsulfonyl etc.

" alkylthio " comprise atomic group-S-R wherein R be alkyl as defined above, can randomly be substituted as defined herein.Representative example includes, but are not limited to methylthio group, ethylmercapto group, rosickyite base, butylthio etc.

" amino " refers to atomic group-NH ₂.

" carboxyl " refers to atomic group-C (=O) OH.

" vinyl " refers to-CH=CH _s, it is also referred to as " vinyl " in this application.

" ethynyl " refers to-C ≡ CH.

" halo " or " halogen " refers to fluorine, chlorine, bromine and iodine.Preferred halogen group is a fluorine or chlorine.

" haloalkyl " comprises as mentioned further " alkyl " of definition, and it is replaced by one or more halogens, and described halogen can be identical, for example in trifluoromethyl or pentafluoroethyl group or its can be different.

" hydroxyl " refers to atomic group-OH.

" nitro " refers to atomic group-NO ₂.

" medicinal " means by the regulating and controlling mechanism approval of federation or government or being used for animal and more specifically being used for the people of listing in American Pharmacopeia or other general pharmacopeia.

" pharmaceutical salts " refers to the salt of compound of the present invention, and it is medicinal and has the ideal pharmacologically active of parent compound.These salt comprise: (1) and mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, the acid salt that phosphoric acid etc. form; Or and organic acid, as acetate, propionic acid, caproic acid, the pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-(2-hydroxybenzoyl)) phenylformic acid, styracin, amygdalic acid, methanesulfonic, ethane sulfonic acid, 1,2-ethane-disulfonic acid, the 2-hydroxyethanesulfonic acid, Phenylsulfonic acid, 4-chlorobenzenesulfonic acid, 2 naphthene sulfonic acid, 4-toluenesulphonic acids, camphorsulfonic acid, 4 methyl bicyclics [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tiary butylacetic acid, dodecyl sulphate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, the acid salt that muconic acid etc. form; Or (2) salt of when the acid proton that exists in parent compound is substituted, forming.

" pharmaceutical carrier " refers to use by it thinner of The compounds of this invention, assistant agent, vehicle or carrier.

" prevention " refer to reduce the risk that obtains disease or sufferer (promptly cause at least a clinical symptom of disease in the experimenter, not develop, described experimenter can be exposed to or susceptible in described disease, but do not experience this disease as yet or show the symptom of this disease).

" experimenter " comprises the people.Term " people, " " patient " and " experimenter " exchanges use at this paper.

" treatment significant quantity " refers to be enough to this disease is brought into play the amount of the compound of therapeutic action when being applied to the experimenter when treating disease." treatment significant quantity " can depend on compound, disease and its seriousness and experimenter's to be treated age, body weight etc. and changing.

" treatment " any disease or sufferer refer to improve in one embodiment described disease or illness (that is, retardance or minimizing advancing of disease or its at least a clinical symptom).In another embodiment, " treatment " refers to improve at least a body parameter, and it may can't help experimenter identification.In another embodiment, " treatment " refers to regulate and control disease or sufferer, (for example, can distinguish the stable of symptom) corporally, physiology ground (for example body parameter stablizes) or both.In another embodiment, " treatment " refer to slow down the outbreak of disease or sufferer.

Implement mode of the present invention

The present invention more specifically sets forth by the following example and experience example.It should be understood, however, that scope of the present invention is not subject to following embodiment and experience example.

The embodiment 1:3-[4-tertiary butyl-phenyl]-N-[3-fluoro-4-methane sulfonyl amino-phenmethyl] acrylamide

Step 1:2-fluoro-4-iodo-1-methane sulfonyl amino-benzene

With 2-fluoro-4-Iodoaniline (1.50g 6.33mmol), (700 μ l 9.50mmol) add CH for pyridine (1.02mL) and MsCl ₂Cl ₂(40mL).With reaction mixture stirring at room 1 hour.Use the 1.5NHCl termination reaction.The solution CH that obtains ₂Cl ₂, extract, under reduced pressure concentrate by anhydrous magnesium sulfate drying and with remaining liquid.Described resistates is carried out purifying to produce compound 37a (1.89g, 95%) with column chromatography (n-hexane/ethyl acetate=1/1). ¹H-NMR(300MHz，CDCl ₃)：δ3.01(s，3H)，6.51(s，1H)，7.30(t，1H，J＝8.3Hz)，7.47(dd，2H，J＝1.2，1.7Hz)

Step 2:4-cyano group-2-fluoro-1-methane sulfonyl amino-benzene

2-fluoro-4-iodo-1-methane sulfonyl amino-benzene is dissolved among the DMF (10mL).With Zn (CN) ₂(845mg, 7.2mmol) and Pd (PPh ₃) ₄(187mg 0.16mmol) adds mixture.Reaction mixture was stirred 1 hour 30 minutes at 80-90 ℃.(20mL) dilutes described reaction soln with ethyl acetate.Mixture water and salt solution are washed, under reduced pressure concentrate by anhydrous magnesium sulfate drying and with remaining liquid.Described resistates is carried out purifying (n-hexane/ethyl acetate=2/1) to produce compound 38a (1.03g, 80%) with column chromatography.

¹H-NMR(300MHz，CDCl ₃)：δ3.07(s，3H)，6.83(s，1H)，7.37(dd，1H，J＝9.5，1.7Hz)，7.41(d，1H，J＝9.8Hz)，7.65(t，1H，J＝8.0Hz)

Step 3:3-fluoro-4-methane sulfonyl aminobenzoic amine hydrochlorate

The 4-cyano group that will in step 2, prepare-2-fluoro-1-methane sulfonyl amino-benzene (1.03g) be dissolved in the methyl alcohol (20mL) and add the 10wt.%Pd/C of catalytic amount and spissated HCl (3mL) to carry out hydrogenation.With reaction soln stirring at room 1 hour.The solution that obtains dilutes with ether, filters by C salt, under reduced pressure concentrates and washs to produce title compound (1.13g, 92%) with ethyl acetate.

¹H NMR(300MHz，CD ₃OD)：δ3.02(s，3H)，4.11(s，2H)，7.27(d，1H，J＝8.5Hz)，7.33(dd，1H，J＝9.8，1.8Hz)，7.57(t，1H，J＝8.3Hz)

The step 4:3-[4-tertiary butyl-phenyl]-N-[3-fluoro-4-methane sulfonyl amino-phenmethyl] acrylamide

3-[4-(tertiary butyl) phenyl]-2-vinylformic acid (500mg, 2.45mmol) and oxalyl chloride (2.0eq, 0.43mL 4.89mmol) add methylene dichloride (10mL).DMF (5) is added mixture.Reaction mixture was stirred 2 hours.Reaction mixture is concentrated in a vacuum.(1.2eq, 748mg 2.94mmol) are dissolved in the methylene dichloride (10mL) with resistates and 3-fluoro-4-methane sulfonyl amine hydrochlorate.With Et ₃(2.4eq, 0.82mL 5.87mmol) add described mixture to N.Mixture was stirred 2 hours.With reaction mixture with column chromatography (EtOAc: normal hexane=1: 1) carry out purifying to produce the 3-[4-tertiary butyl-phenyl]-N-[3-fluoro-4-methyl sulphonyl amino-phenmethyl]-2-acrylamide (264mg, 27%).

¹H-NMR(300MHz，CDCl ₃)：δ1.30(s，9H)，3.00(s，3H)，4.54(d，2H，J＝6.2Hz)，5.93(bs，1H)，6.39(d，1H，J＝15.6Hz)，6.48(bs，1H)，7.15-7.09(m，2H)，7.39(d，2H，J＝8.4 Hz)，7.45(d，2H，J＝8.4Hz)，7.54(t，1H，J＝8.3Hz)，7.66(d，1H，J＝15.6Hz)

Embodiment 2:3-(the 4-tertiary butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-phenmethyl)-acrylamide

N-(4-amino methyl-2-chloro-phenyl)-amsacrine, (200mg 0.74mmol) reacts to obtain white solid (260mg, 83%) according to general method with 3-(the 4-tertiary butyl-phenyl)-vinylformic acid HCl salt.

¹HNMR (300MHz, CDCl3): 7.68 (d, 1H, J=15.6 Hz), 7.61 (d, 1H, J=8.1Hz), 7.43 (m, 5H), 7.26 (dd, 1H, J=2.1 and 8.1Hz), 6.78 (bs, 1H), 6.40 (d, 1H, J=15.6Hz), 6.03 (t, 1H, J=6.0Hz), 4.54 (d, 2H, J=6.0Hz), 3.00 (s, 3H), 1.33 (s, 9H).

Embodiment 3:3-(the 4-tertiary butyl-phenyl)-N-(3-methyl-4-methane sulfonyl amino-phenmethyl)-acrylamide

With 3-methyl-4-methane sulfonyl aminobenzoic amine hydrochlorate (140mg, 0.56mmol), 3-(4-tert-butyl-phenyl) vinylformic acid (1.1eq, 0.13g), and DMTMM (1.1eq 0.185g) adds in the 25m tetrahydrofuran (THF).With reaction mixture stirring at room 12 hours.After confirming that with TLC reaction is finished, use the ethyl acetate extraction reaction mixture, wash and, it is filtered and under reduced pressure concentrates with 1N HCl solution by the organic layer that dried over mgso merges.The liquid that comes the purifying acquisition with column chromatography (n-hexane/ethyl acetate=2/1) is to produce solid (49mg).

¹H NMR(300MHz，CDCl ₃)：7.65(d，1H，J＝15.6Hz)，7.42(m，4H)，7.19(m，2H)，6.37(d，1H，J＝15.6Hz)，6.17(s，1H)，5.88(bs，1H)，5.50(bs，1H)，4.53(d，2H，J＝6.0Hz)，3.02(s，3H)，2.32(s，3H)，1.32(s，9H).

Embodiment 4:3-(the 4-tertiary butyl-phenyl)-N-(3,5-two fluoro-4-methane sulfonyl amino-phenmethyls)-acrylamide

According to general method, make N-(4-amino methyl-2,6-two fluoro-phenyl)-amsacrine, (100mg 0.37mmol) reacts to obtain white solid (150mg, 96%) with 3-(the 4-tertiary butyl-phenyl)-vinylformic acid HCl salt.

¹H NMR(300MHz，CDCl ₃)：8.69(t，1H，J＝6.0Hz)，7.51(d，2H，J＝8.4Hz)，7.45(d，1H，J＝15.6Hz)，7.43(d，2H，J＝8.4Hz)，7.09(d，2H，J＝8.4Hz)，6.63(d，1H，J＝15.6Hz)，4.39(d，2H，J＝6.0Hz)，3.02(s，3H)，1.28(s，9H).

Embodiment 5:3-(the 4-tertiary butyl-phenyl)-N-(2,5-two fluoro-4-methane sulfonyl amino-phenmethyls)-acrylamide

In the 25ml round-bottomed flask, add N-(4-amino methyl-2,5-two fluoro-phenyl)-sulfonyl methane amine hydrochlorate (125mg, 0.46mmol), 3-(4-tert-butyl-phenyl) vinylformic acid (1.2eq, 112mg) and DMTMM (1.2eq, 152mg).And to this mixture impouring 15ml tetrahydrofuran (THF) and stirring at room 12 hours.After confirming that with TLC reaction is finished, use the ethyl acetate extraction reaction mixture, wash with 1N HCl solution.Organic layer by dried over mgso merges filters it and under reduced pressure concentrate.The liquid that obtains with column chromatography (n-hexane/ethyl acetate=1/1) purifying is to produce solid (147mg).

¹H NMR(300MHz，CDCl ₃)：7.65(d，1H，J＝15.3Hz)，7.35(m，5H)，6.75(s，1H)，6.39(d，1H，J＝15.6Hz)，6.15(m，1H)，4.54(d，2H，J＝6.3Hz)，3.04(s，3H)，1.32(s，9H).

Embodiment 6:3-(4-tert-butyl-phenyl)-N-(3-chloro-5-iodo-4-methane sulfonyl amino-phenmethyl) acrylamide

Step 1:4-amino-3-chloro-5-iodine benzonitrile

With 4-amino-3-chloro-benzonitrile (100mg, 0.66mmol) and ICl (1.1eq, 0.72mmol 117.05mg) add methylene dichloride.Reaction mixture was stirred 12 hours.Make the reaction mixture quencher by adding hypo solution.Use the dichloromethane extraction aqueous solution.Use H ₂The organic solution that O and salt water washing merge is used Na ₂SO ₄Dry and concentrated in a vacuum.(n-Hx: EA=3: 1) purifying is to produce 4-amino-3-chloro-5-iodine benzonitrile (65.2mg, 35.80%) with column chromatography with resistates.

mp：121～123℃；

IR(KBr pellet，cm ^-1)：3365，2942，2221，1634，728；

¹H NMR(400MHz，CDCl ₃)：δ7.42(d，1H，J＝1.6Hz)，7.43(d，1H，J＝1.6Hz)，5.01(bs，2H).

Step 2:(4-amino-3-chloro-5-iodobenzene methyl) t-butyl carbamate

With 4-amino-(65.2mg 0.23mmol) is dissolved among the THF in 0 ℃ 3-chloro-5-iodine benzonitrile.With borine-THF mixture (4eq, 0.94mmol, 0.94ml) slowly add in the reaction mixture after, temperature of reaction is heated to backflow.Reaction mixture was stirred 12 hours under situation about refluxing.After confirming that reaction finishes, add MeOH.Mixture was stirred 4 hours.Remove reaction solvent in a vacuum.Use the ethyl acetate extraction resistates, use H ₂O and salt solution wash, and use Na ₂SO ₄Drying, and concentrate in a vacuum to produce 4-amino methyl-2-iodo-6-methyl-phenyl amine (19.4mg).

(52.92mg 0.19mmol) is dissolved among the THF, then slowly adds BOC with 4-amino methyl-2-chloro-6-iodophenyl amine ₂O (1.1eq, 0.21mmol, 47.48ml).Reaction mixture was stirred 12 hours.Use the ethyl acetate extraction reaction mixture, use H ₂O and salt solution wash, and use Na ₂SO ₄Carry out drying, and it is concentrated in a vacuum.With column chromatography (n-Hx: EA=5: 1) come the purifying resistates to obtain solid (34.37mg, 47.94%).

mp：113～115℃；

IR(KBr pellet，cm ^-1)：3343，1615，717；

¹H NMR(400MHz，CDCl ₃)：δ7.39(s，1H)，7.09(s，1H)，4.76(bs，1H)，4.05(bs，2H)，4.05(s，2H)，1.38(s，9H)

Step 3:(3-chloro-5-iodo-4-methane sulfonyl amino-benzene methyl) t-butyl carbamate

(254.7mg 0.67mmol) adds methylene dichloride under argon gas atmosphere with (4-amino-3-chloro-5-iodobenzene methyl) t-butyl carbamate.Methane sulfonyl chloride (5eq, 3.33mmol, 258.04 μ l) and TEA (3eq, 2.00mmol, 278.80 μ l) are added this mixture.Reaction mixture was stirred 5 hours.By adding NaHCO ₃The aqueous solution makes the reaction mixture quencher.Use the dichloromethane extraction mixture.Use CuSO ₄, H ₂The organic layer that O and salt water washing merge.Use Na ₂SO ₄Dry organic layer then concentrates it in a vacuum.With described resistates with column chromatography (THF: H2O=2: 1) carry out purifying to produce compound.(5eq, 3.33mmol 133.2mg) are dissolved in the methyl alcohol with compound and NaOH.Reaction mixture was stirred 12 hours.Mixture is carried out acidifying with 10%HCl soln.Use the ethyl acetate extraction mixture.Use H ₂The organic layer that O and salt water washing merge is used Na ₂SO ₄Drying, and then concentrate in a vacuum.With described resistates with column chromatography (n-Hx: EA=3: 1) carry out purifying to produce yellow solid (122.0mg, 39.78%).

Fusing point: 139～141 ℃; IR (KBr pellet, cm ^-1): 3350,2979,1682,1525,1326,769; ¹H NMR (400MHz, CDCl ₃): δ 7.66 (d, 1H, J=1.2Hz), 7.31 (d, 1H, J=1.6Hz), 7.25 (s, 1H), 4.88 (d, 1H, J=5.2Hz), 4.18 (d, 2H, J=6.4Hz), 3.24 (s, 3H), 1.40 (s, 9H).

Step 4:N-(4-amino methyl-2-chloro-6-iodo-phenyl)-amsacrine

With (3-iodo-4-methane sulfonyl amino-5-methylbenzene methyl) t-butyl carbamate (122.0mg, 0.27mmol) and CF ₃COOH (5～6) adds methylene dichloride.Mixture was stirred 12 hours.Mixture is concentrated in a vacuum to produce brown syrup (142.2 mg, 100%).

¹H NMR(400MHz，CD ₃OD)：8.00(d，1H，J＝2.0Hz)，7.65(d，1H，J＝1.6Hz)，4.08(s，2H)，3.25(s，3H)

Step 5:3-(4-tert-butyl-phenyl)-N-(3-chloro-5-iodo-4-methane sulfonyl amino-benzene methyl) acrylamide

With N-(4-amino methyl-2-chloro-6-iodophenyl) amsacrine (50mg, 0.11mmol) and 3-(the 4-tertiary butyl-phenyl)-vinylformic acid (1.2eq, 0.13mmol 25.84mg) add DMF.DEPC (1.2eq, 0.13mmol, 19.72 μ l) and TEA (2eq, 0.22mmol, 30.66 μ l) are added mixture.Reaction mixture was stirred 12 hours.With reaction mixture with column chromatography (n-Hx: EA=1: 1) carry out purifying to produce white solid (33.4 mg, 55.61%).

Fusing point: 173～175 ℃; IR (KBr pellet, cm ^-1): 3281,2958,1645,1364,760;

¹H NMR(400MHz，CD ₃ OD)：δ7.82(d，1H，J＝2.0Hz)，7.53(d，1H，J＝15.6Hz)，7.47(d，2H，J＝8.4Hz)，7.45(d，1H，J＝2.0Hz)，7.41(d，2H，J＝8.4Hz)，6.58(d，1H，J＝16.0Hz)，4.40(s，2H)，3.20(s，3H)，1.29(s，9H).

Embodiment 7:3-(the 4-tertiary butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-5-methylbenzene methyl) acrylamide

Step 1:2-chloro-4-iodo-6-aminomethyl phenyl amine

2-chloro-6-methyl-phenyl amine (50 μ l, 0.35mmol) and ICl (1.1eq, 0.39mmol 63.06mg) add methylene dichloride.Mixture was stirred 12 hours.Come the quencher mixture by adding sodium thiosulfate solution.Use the dichloromethane extraction mixture.(n-Hx: EA=7: 1) organic layer of purifying merging is to produce purple syrup (85.1mg, 90%) with column chromatography.

(NaCl is pure, cm for IR ^-1): 3389,3068,2974,760,721;

¹H NMR(400MHz，CDCl ₃)：δ7.35(d，1H，J＝1.6Hz)，7.17(m，1H)，3.82(bs，2H)，2.07(s，3H).

Step 2:4-amino-3-chloro-5-methyl benzonitrile

(85.1mg 0.32mmol) is dissolved in the pyridine with 2-chloro-4-iodo-6-methyl-phenyl amine.(0.96mmol 85mg) adds in the mixture with CuCN.Mixture was stirred in backflow 12 hours.Remove reaction solvent in a vacuum.Use the ethyl acetate extraction resistates.With the organic layer that the salt water washing merges, use Na ₂SO ₄Drying then concentrates it in a vacuum.With described resistates with column chromatography (n-Hx: EA=3: 1) carry out purifying to obtain solid (22.7mg, 43%).

Fusing point: 130～132 ℃;

IR (KBr pellet, cm ^-1): 3365,2221,728;

¹H NMR(400MHz，CDCl ₃)：δ7.36(s，1H)，7.15(s，1H)，4.46(bs，2H)，2.12(s，3H)

Step 3:(4-amino-3-chloro-5-methylbenzene methyl) t-butyl carbamate

4-amino-3-chloro-5-methyl-benzonitrile (499.4mg, 3.00mmol) and borine-TH mixture (4eq, 12.04mmol 12.04ml) add THF.Reaction mixture was stirred in backflow 3 hours.After confirming that reaction finishes, MeOH is slowly added in the described mixture.Remove MeOH in a vacuum, with the resistates ethyl acetate extraction.Use H ₂The organic layer that O and salt water washing merge is used Na ₂SO ₄Drying, and concentrate in a vacuum to produce as yellow syrupy 4-amino methyl-2-chloro-6-methyl-phenyl amine (19.4mg).

With 4-amino methyl-2-chloro-6-methyl-phenyl amine (571.5mg, 3.36mmol) and BOC ₂O (0.8eq, 2.69mmol, 618.29 μ l) adds THF.Mixture was stirred 12 hours.After with the ethyl acetate extraction reaction mixture, use H ₂The organic layer that O and salt water washing merge is used Na ₂SO ₄Drying then concentrates in a vacuum to obtain solid (481.1mg, 59%).

Fusing point: 112～114 ℃; IR (KBr pellet, cm ^-1): 3370,2964,1696,1623,728;

¹H NMR(400MHz，CDCl ₃)：δ6.99(s，1H)，6.82(s，1H)，4.66(bs，1H)，4.08(d，2H，J＝5.6Hz)，2.11(s，3H)，1.38(s，9H).

Step 4:(3-chloro-4-methane sulfonyl amino-5-methylbenzene methyl) t-butyl carbamate

(300mg, 1.11mmol), methane sulfonyl chloride (5eq, 5.55mmol, 428.81 μ l) and TEA (3eq, 3.33mmol, 464.13 μ l) add methylene dichloride with (4-amino-3-chloro-5-methylbenzene methyl) t-butyl carbamate.Reaction mixture was stirred 12 hours.By adding NaHCO ₃The aqueous solution comes the quencher reaction mixture.Use the dichloromethane extraction reaction mixture.(n-Hx: EA=3: 1) purified mixture is to produce yellow solid (153.8 mg, 40%) with column chromatography.

Fusing point: 144～146 ℃;

IR (KBr pellet, cm ^-1): 3208,2971,1697,1526,1140,758;

¹H NMR(400MHz，CDCl ₃)：δ7.13(s，1H)，7.01(s，1H)，6.75(bs，1H)，5.13(bs，1H)，4.16(d，2H，J＝4.8Hz)，3.02(s，3H)，2.39(s，3H)，1.40(s，9H).

Step 5:N-(4-amino methyl-2-chloro-6-aminomethyl phenyl) amsacrine

With (3-chloro-4-methane sulfonyl amino-5-methyl-phenmethyl)-t-butyl carbamate (153.8mg, 0.44mmol) and CF ₃COOH (5～6) adds methylene dichloride.Mixture was stirred 12 hours.Reaction solvent is concentrated in a vacuum to produce syrup (159.6mg, 100%).

¹H NMR(400MHz，CD ₃OD)：δ7.44(d，1H，J＝2.0Hz)，7.30(d，1H，J＝2.0Hz)，4.04(s，2H)，3.09(s，3H)，2.44(s，3H).

Step 6:3-(the 4-tertiary butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-5-methylbenzene methyl) acrylamide

With N-(4-amino methyl-2-chloro-6-aminomethyl phenyl) amsacrine (51.9mg, 0.14mmol) and 3-(the 4-tertiary butyl-phenyl)-vinylformic acid (1.2eq, 0.17mmol 35.11mg) add among the DMF.DEPC (1.2eq, 0.17mmol, 25.49 μ l) and TEA (2eq, 0.28mmol, 39.02 μ l) are added in the described mixture.Reaction mixture was stirred 12 hours.DMF concentrates in a vacuum.With described resistates with column chromatography (n-Hx: EA=1: 1) carry out purifying to produce white solid (59.6mg, 98%).Fusing point: 153～155 ℃;

IR (KBr pellet, cm ^-1): 3240,3065,2963,1656,1320,1152,701;

¹H NMR(400MHz，CDCl ₃)：δ7.59(d，1H，J＝15.6Hz)，7.37(d，2H，J＝8.4Hz)，7.32(d，2H，J＝8.4Hz)，7.07(s，1H)，7.34(d，1H，J＝15.6Hz)，6.11(s，1H)，6.06(t，1H，J＝5.6Hz)，4.42(d，2H，J＝5.6Hz)，3.02(s，3H)，1.25(s，9H).

Embodiment 8:3-(4-tert-butyl-phenyl)-N-(3-fluoro-5-iodo-4-methane sulfonyl amino-benzene methyl) acrylamide

Fill two neck round-bottomed flasks of 25ml with the solution of argon gas and 3-(the 4-tertiary butyl-phenyl)-vinylformic acid (59.4 mg, 0.291mmol, 1 equivalent), and the diethyl cyano group phosphine in DMF (48.6 μ l, 0.320mmol, 1.1 equivalents) places flask.Be added in N-(4-amino methyl-2-fluoro-6-iodophenyl) ethane sulphonamide (100mg, 0.291mmol, 1 equivalent) and the triethylamine (121.7 μ l, 0.873mmol, 3 equivalents) for preparing in the step 4 of embodiment 14 to solution.With described mixture at one night of stirring at room.After confirming that with TLC reaction finishes, with the solution dichloromethane extraction that obtains, use the salt water washing, pass through Na ₂SO ₄Carry out drying, filter and under reduced pressure concentrate.The solid that obtains with column chromatography (n-hexane/ethyl acetate=1/1) purifying is to produce yellow solid (59.8mg, 38.7%).

mp：139-140℃；

IR (KBr pellet, cm ^-1): 3423,3235,2960,2868,1648;

¹H NMR(400MHz，CD ₃OD)：7.69(s，1H)，7.53(d，1H，J＝15.6Hz)，7.49(d，2H，J＝8.4Hz)，7.40(d，2H，J＝8.4Hz)，7.17(dd，1H，J＝10.0，1.6Hz)，6.58(d，1H，J＝15.6Hz)，4.42(s，2H)，3.12(s，3H)，1.37(s，9H)

Embodiment 9:

3-(the 4-tertiary butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-methyl-phenmethyl)-acrylamide

With N-(4-amino methyl-2-fluoro-6-methyl-phenyl)-amsacrine and HCl salt (100mg, 0.35mmol) with 3-(the 4-tertiary butyl-phenyl)-vinylformic acid according to the general method reaction to obtain white solid (140mg, 96%).

¹H NMR(300MHz，CDCl ₃)：7.64(d，1H，J＝15.6Hz)，7.41(m，4H)，7.25(m，2H)，6.35(d，1H，J＝15.6Hz)，6.18(s，1H)，5.94(t，1H)，4.58(d，2H，J＝5.1Hz)，3.03(s，3H)，2.24(d，2H，J＝2.4Hz)，1.32(s，9H).

Embodiment 10:

3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-benzene methyl)-2-methyl-acrylamide

Synthesizing of step 1:3-(4-tert-butyl-phenyl)-ethyl 2-methacrylate

Be full of two neck round-bottomed flasks of 25 ml with argon gas, and with MgBr ₂(0.37mmol.) solution in tetrahydrofuran (THF) places flask to the Anaesthetie Ether compound for 1.2eq, 95.51mg.To add mixture at the TEA in the tetrahydrofuran (THF) (1ml) (1.54eq, 0.48mmol, 66.53 μ l) and triethyl-2-phosphine propionic ester (1.4eq, 0.43mmol, 94.50 μ l).Reaction soln was stirred 20 minutes.Slowly add tert.-butylbenzene formaldehyde (50 μ l, 0.31mmol) solution in tetrahydrofuran (THF) (1ml) and stirring 12 hours to this solution.Behind TLC confirmation reaction process, use NH ₄Cl quencher reaction.The solution ethyl acetate extraction that obtains, Na is passed through in water and salt water washing ₂SO ₄Dry.Described resistates is carried out purifying to produce E-isomer 22.0mg (rough substrate and E-isomer mixture 32.1mg) (29.00%) with column chromatography (n-hexane/ethyl acetate=80/1).

IR (KBr pellet, cm ^-1): 2963,1707,1634;

¹H NMR (400MHz, CDCl ₃): E-isomer NMR 7.59 (s, 1H), 7.35 (d, 2H, J=8.4Hz), 7.28 (d, 2H, J=8.4Hz), 4.19 (q, 2H, J=7.2Hz), 2.06 (d, 3H, J=1.6Hz), 1.27 (t, 3H, J=7.2Hz), 1.26 (s, 9H).

Step 2:3-(4-tert-butyl-phenyl)-2-methacrylic acid

(516.3mg 2.10mmol) places the round-bottomed flask of 25ml and be dissolved in small amount of methanol with 3-(the 4-tertiary butyl-phenyl)-2-methyl-ethyl propenoate.To this solution slowly add NaOH solution (3eq, 6.29mmol, 251.69mg) and stirred 12 hours.After confirming that with TLC reaction finishes, remove methyl alcohol under reduced pressure.Use the 10%HCl acidifying to produce white solid (411.5mg, 89.94%) solution that obtains.

mp：130～132℃；

IR (KBr pellet, cm ^-1): 2959,1671,1267;

¹H NMR(400MHz，CD ₃OD)：7.64(s，1H)，7.42(d，2H，J＝8.4Hz)，7.34(d，2H，J＝8.4Hz)，2.06(d，3H，J＝1.2Hz)，1.30(s，9H).

Step 3:3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-benzene methyl)-2-methyl-acrylamide

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and with 3-(the 4-tertiary butyl-phenyl)-2-methyl-vinylformic acid (200mg, 0.92mmol) and N-(4-amino methyl-phenyl)-Toluidrin (220.12mg) solution in DMF places flask for 1.2eq, 1.10mmol.Add TEA (2eq, 1.84mmol, 256.46 μ l) and diethylcyanophosphonise (1.2eq, 1.10mmol, 166.90 μ l) and stirred 12 hours to this solution.After confirming that with TLC reaction finishes, under reduced pressure remove DMF and use ethyl acetate extraction.Na is passed through in ethyl acetate layer water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains with column chromatography (n-hexane/ethyl acetate=2/1) purifying is to produce white solid (124.0mg, 33.80%).

mp：133～135℃；

IR (KBr pellet, cm ^-1): 3264,2961,1641,1621,1323;

¹H NMR(400MHz，CDCl ₃)：7.32(d，2H，J＝8.0Hz)，7.22(d，2H，J＝8.0Hz)，7.21(d，2H，J＝8.0Hz)，7.12(d，2H，J＝8.0Hz)，6.28(t，1H，J＝5.6Hz)，4.46(d，2H，J＝5.6Hz)，2.91(s，3H)，2.06(s，3H)，1.25(s，9H).

Embodiment 11:3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl aminophenyl) ethyl]-the 2-Methacrylamide

With N-[4-(1-amino-ethyl) phenyl] amsacrine (0.25mmol, 82.72mg) and 3-(4-tert-butyl-phenyl)-2-methacrylic acid (0.23mmol 50mg) adds DMF.DEPC (0.27mmol, 41.88 μ l) and TEA (0.46mmol, 64.11 μ l) are added described mixture.Mixture was stirred 12 hours.After removing DMF in a vacuum, use the ethyl acetate extraction resistates.With the organic layer H that merges ₂Na is used in O and salt water washing ₂SO ₄Dry and then concentrated in a vacuum.With described resistates with column chromatography (n-Hx: EA=2: 1 → 1: 2) carry out purifying to produce white solid (58.1mg, 60.99%).

Fusing point: 157～159 ℃;

[a] _D ²⁰-10.42(CHCl ₃，c1.49)；

IR (KBr pellet, cm ^-1): 3266,3015,2962,1615,1322;

¹H NMR (400MHz, CDCl ₃): δ 7.57 (s, 1H), 7.36 (d, 2H, J=8.8Hz), 7.31 (s, 1H), 7.27 (d, 2H, J=8.8Hz), 7.25 (d, 2H, J=8.4Hz), 7.16 (d, 2H, J=8.4Hz), 6.25 (d, 1H, J=7.2Hz), 5.16 (quintet, 1H, J=7.2Hz), 2.92 (s, 3H), 2.09 (s, 3H), 1.50 (d, 3H, J=7.2Hz), 1.29 (s, 9H).

Embodiment 12:3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-benzene methyl)-2-Methacrylamide

With N-(4-amino methyl-2-fluorophenyl) amsacrine (0.10mmol, 30.0mg) and 3-(4-tert-butyl-phenyl)-2-methacrylic acid (1.1eq, 0.11mmol, 21.68mg) be dissolved among the DMF, with DEPC (1.2eq, 0.12mmol, 18.21 μ l) and TEA (2eq, 0.20mmol, 27.88 μ l) and the adding mixture.Mixture was stirred 12 hours.Remove DMF in a vacuum.With described resistates with column chromatography (n-Hx: EtOAc=1: 1) carry out purifying to produce white solid (24.5 mg, 58.59%).

Fusing point: 83～85 ℃;

IR (KBr pellet, cm ^-1): 3288,3229,3092,2964,1647,1321,1155; ¹HNMR (400MHz, CDCl ₃): δ 7.45 (t, 1H, J=8.0Hz), 7.37 (d, 2H, J=8.0Hz), 7.35 (s, 1H), 7.24 (d, 2H, J=8.0Hz), 7.11～7.06 (m, 2H), 6.85 (s, 1H), 6.45 (t, 1H, J=6.0Hz), 4.49 (d, 2H, J=6.0Hz), 2.97 (s, 3H), 2.11 (s, 3H), 1.30 (s, 9H).

Embodiment 13:3-(the 4-tertiary butyl-phenyl)-but-2-ene acid 3-fluoro-4-methane sulfonyl amino-phenmethyl acid amides

Step 1:3-(4-tert-butyl-phenyl)-but-2-ene acid

Will (1.2eq, 0.25g) solution adds in the flask, and then it is cooled to 0 ℃ at the ethyl diethyl PA among the DMF of 4ml.To this solution add 60% sodium hydride (1.4eq, 1.27mmol, 51mg), then slowly be added in 4-tert.-butylbenzene benzoylformaldoxime among the 3ml DMF (0.16g, 0.91mmol).Mixture solution was stirred 4 hours.After confirming that with TLC reaction finishes, use the ethyl acetate extraction reaction mixture, and wash with water.The organic layer that merges is passed through MgSO ₄Carry out drying, filter and under reduced pressure concentrate.Be dissolved in the liquid that obtains in the MeOH/THF solution and add 1N NaOH solution, then reflux and spends the night.After confirming that with TLC reaction finishes, use the ethyl acetate extraction reaction mixture, and carry out acidifying with 1N HCl solution.The organic layer that merges is passed through MgSO ₄Carry out drying, filter and under reduced pressure concentrate.The solid that obtains with the column chromatography purifying is to produce title compound (134mg, 68.1%).

Step 2:

3-(the 4-tertiary butyl-phenyl)-but-2-ene acid-3-fluoro-4-methane sulfonyl amino-benzamide

To the round-bottomed flask of 50ml add N-(4-amino methyl-2-fluoro-phenyl)-sulfonyl methane amine hydrochlorate (0.14g, 0.55mmol), 3-(4-tert-butyl-phenyl)-but-2-ene acid (1.0eq, 0.12g) and DMTMM (1.2eq, 0.183g).To this mixture impouring 25ml tetrahydrofuran (THF), add triethylamine (excessive, 0.5ml) and stirring at room 12 hours.After confirming that with TLC reaction finishes, with the described reaction mixture of ethyl acetate extraction, with 1N HCl solution washing.The organic layer that merges is passed through MgSO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography (n-hexane/ethyl acetate=1/1) purifying to produce title compound (41.5mg).

¹H NMR(300MHz，CDCl ₃)：7.53(m，1H)，7.39(s，4H)，7.14(m，2H)，6.48(s，1H)，6.03(d，1H，J＝1.2Hz)，5.93(m，1H)，4.50(d，2H，J＝6Hz)，3.02(s，3H)，1.32(s，3H).

Embodiment 14:3-(the 4-tertiary butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl aminophenyl) ethyl]-the 2-Methacrylamide

With 3-(the 4-tertiary butyl-phenyl)-2-methacrylic acid (1.1eq, 0.14mmol, 31.01mg) and (R)-N-[4-(1-amino-ethyl)-2-fluorophenyl] (1eq, 0.13mmol 30mg) are dissolved among the DMF amsacrine.DEPC (1.2eq, 0.16mmol, 23.67 μ l) and TEA (2eq, 0.26mmol, 36.24 μ l) are added this mixture.Reaction mixture was stirred 12 hours.Remove DMF in a vacuum.

Described resistates ethyl acetate and H ₂O extracts.With the organic layer salt water washing that merges, use Na ₂SO ₄Drying, and concentrate in a vacuum.With described resistates (n-Hx: EtOAc=1: 1) carry out purifying to produce title compound (52.53 mg, 93.5%) as white solid with column chromatography.

Fusing point: 92～94 ℃;

[a] _D ²⁰：-21.06(CHCl ₃，c0.34)；

IR (KBr pellet, cm ^-1): 3335,3249,2964,1615,1509,1325,1163; ¹HNMR (400MHz, CDCl ₃): δ 7.49 (t, 1H, J=8.0Hz), 7.37 (d, 2H, J=8.0Hz), 7.30 (s, 1H), 7.26 (d, 2H, J=8.0Hz), 7.14 (s, 1H), 7.12 (d, 1H, J=3.6Hz), 6.61 (s, 1H), 6.08 (d, 1H, J=7.6Hz), 5.15 (qd, 1H, J=13.6,6.8Hz), 2.99 (s, 3H), 2.09 (s, 3H), 1.51 (d, 3H, J=6.8Hz),, 1.30 (s, 9H)

Embodiment 15:3-(4-tert-butyl-phenyl)-N-[4-(methane sulfonyl amino) phenmethyl] the propine acid amides

The step 1:(4-tertiary butyl-phenyl)-methyl propionate

Be full of two neck round-bottomed flasks of 100ml with argon gas, and the 4-tertiary butyl-Benzoyl chloride that will be in toluene (500mg, 2.34mmol) solution places flask.Refluxed 12 hours to this solution adding (the inferior phosphoranyl of triphenyl) methyl acetate (1.5eq, 3.52mmol, 1178.39 mg) and at 90～100 ℃.After confirming that with TLC reaction finishes, under reduced pressure remove toluene and carry out column chromatography (n-hexane/ethyl acetate=4/1) to produce yellow solid (product 1).

Be full of two neck round-bottomed flasks of 50ml and product (1) is placed flask with argon gas, heating was also stirred 90 minutes at 250 ℃.The compound of reaction dichloromethane extraction, and carry out column chromatography (n-hexane/ethyl acetate=25/1) to produce yellow liquid (product (2), 81.7mg, 19.69%).

IR (KBr pellet, cm ^-1): 2963,2224,1715,1506,1460;

¹H NMR(400MHz，CDCl ₃)：product(1)7.70～7.65(m，6H)，7.59(d，2H，J＝8.4Hz)，7.47～7.35(m，9H)，7.29(d，2H，J＝8.8Hz)；product(2)7.50(d，2H，J＝8.0 Hz)，7.36(d，2H，J＝8.0Hz)，3.80(s，3H)，1.28(s，9H).

Step 2:(4-tert-butyl-phenyl)-propionic acid

(21.7mg 0.11mmol) places the round-bottomed flask of 25ml and be dissolved in a spot of methyl alcohol with (the 4-tertiary butyl-phenyl)-methyl propionate.Add K to this solution ₂CO ₃Solution slowly and stirred 1 hour.

After confirming that with TLC reaction finishes, under reduced pressure remove methyl alcohol, and use the ethyl acetate extraction resistates.Water and salt water washing ethyl acetate layer pass through Na ₂SO ₄Drying is filtered, and then under reduced pressure concentrates.The liquid that obtains (methyl alcohol: ethyl acetate=1: 1) use the column chromatography purifying to produce white liquid (20.8 mg, 95.37%).

IR (KBr pellet, cm ^-1): 3419,2963,2214,1576,1460;

¹H NMR(400MHz，CDCl ₃)：7.44(d，2H，J＝8.8Hz)，7.40(d，2H，J＝8.4Hz)，1.30(s，9H).

Step 3:4-methane sulfonyl aminobenzoic amine hydrochlorate

(1.2g 4.0mmol) places 1 of the single neck round-bottomed flask of 50ml and impouring 30ml, 4-diox with the 4-methane sulfonyl aminobenzoic aminocarbamic acid tert-butyl ester.To described solution add c-HCl (excessive, 2ml) and stirred 4 hours.After confirming that with TLC reaction finishes, reaction soln is under reduced pressure concentrated.The solid that obtains is filtered with the ethyl acetate washing and with glass filter.The solid that obtains is air-dry to produce solid (0.947g, 100%).

¹H NMR(300MHz，DMSO)：7.38(d，2H，J＝8.4Hz)，7.17(d，2H，J＝8.4Hz)，3.89(s，2H)，2.94(S，3H).

Step 4:3-(4-tert-butyl-phenyl)-N-[4-(methane sulfonyl amino) phenmethyl] the propine acid amides

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and (the 4-tertiary butyl-phenyl)-propionic acid (24.5mg that will in step 2, prepare, 0.12mmol) and N-(4-amino methyl-phenyl)-amsacrine HCl (29.10mg) solution in DMF places flask for 1.2eq, 0.15mmol.Add TEA (2eq, 0.24mmol, 33.45 μ l) and diethylcyanophosphonise (1.2eq, 0.15mmol, 24.46 μ l) (1.2eq, 0.15mmol, 24.46 μ l) and stirred 12 hours to described solution.After confirming that with TLC reaction finishes, the solution ethyl acetate extraction that obtains, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography purifying (n-hexane/ethyl acetate=1/1) to produce white solid (10.1mg, 21.68%).

mp：128～130℃；

IR (KBr pellet, cm ^-1): 3258,2963,2220,1632,1154;

¹H NMR(400MHz，CDCl ₃)：7.39(d，2H，J＝8.4Hz)，7.30(d，2H，J＝8.0Hz)，7.24(d，2H，J＝8.4Hz)，7.14(d，2H，J＝8.0Hz)，6.72(s，1H)，6.20(t，1H，J＝5.2Hz)，4.44(d，2H，J＝6.0Hz)，2.93(s，3H)，1.23(s，9H)

Embodiment 16:

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl aminophenyl) ethyl] the propine acid amides

With (the 4-tertiary butyl-phenyl)-propionic acid (92.58mg, 0.46mmol) and N-[4-(1-amino-ethyl)-phenyl]-(1.2eq, 0.38mmol 124.1mg) add DMF to amsacrine under argon gas atmosphere.With TEA (2eq, 0.76mmol, 105.92mg) and diethylcyanophosphonise (1.2eq, 0.57mmol, 86.48 μ l) add described reaction mixture.Mixture was stirred 12 hours.

After confirming that with TLC reaction finishes, the solution dichloromethane extraction that obtains, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid (n-hexane/ethyl acetate=2/1) that obtains with the column chromatography purifying is to produce white solid (112mg, 61.40%).

mp：95～97℃；

[a] ²⁰ _D：-32.33℃(CHCl ₃，c 0.18)；

IR (KBr pellet, cm ^-1): 3257,3030,2965,2212,1627,1328;

¹HNMR(400MHz，CDCl ₃)：δ7.65(bs，1H)，7.40(d，2H，J＝8.4Hz)，7.32(d，2H，J＝8.4Hz)，7.25(d，2H，J＝8.4Hz)，7.17(d，2H，J＝8.4Hz)，6.57(bs，1H)，5.11(quin，1H，J＝6.8Hz)，2.92(s，3H)，1.46(d，3H，J＝6.8Hz)，1.25(s，9H).

Embodiment 17:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-2-fluoro-6-iodophenyl } amsacrine

Step 1:4-amino-3-fluorine benzonitrile

Be full of two neck round-bottomed flasks of 50ml with argon gas, and the solution of 2-fluoro-4-Iodoaniline (1g, 5.219mmol, 1 equivalent) in DMF is placed flask.Add cupric cyanide (I) (453.4mg, 5.063mmol, 1.2 equivalents) to solution, and reflux 5 hours.After confirming that with TLC reaction finishes, saturated sodium hydrogen carbonate solution is added solution and stirred 5 minutes.The solution dichloromethane extraction that obtains, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and evaporation.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1) to produce light yellow solid (461.6mg).

¹H NMR (400MHz, CDCl ₃): 8.02 (d, 2H, J=8.8Hz), 7.30 (d, 2H, J=8.8Hz), 7.03 (d, 2H, J=8.4Hz), 6.99 (d, 2H, J=8.4Hz), 5.51 (bs, 1H), 4.90 (q, 1H, J=6.8Hz), 2.44 (t, 2H, J=7.2Hz), 1.50 (sextet, 2H, J=7.2Hz), 1.26 (d, 3H, J=6.8Hz), 0.84 (t, 3H, J=7.2Hz)

Step 2:4-amino-3-fluoro-5-iodine benzonitrile

Be full of two neck round-bottomed flasks of 25ml with argon gas, and the solution of 4-amino-3-fluoro-benzonitrile (300mg, 2.204mmol, 1 equivalent) in methylene dichloride is placed flask.In solution, add iodine monochloride (393.6mg, 2.424mmol, 1.1 equivalents) and stirred 1 hour.After confirming that with TLC reaction finishes, add saturated hypo solution to the solution that obtains and also stir.With the reaction soln dichloromethane extraction, Na is passed through in water (2 times) and salt water washing ₂SO ₄Dry and under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=3/1) to produce brown liquid.

¹H NMR(400MHz，CDCl ₃)：7.64(t，1H，J＝1.6Hz)，7.32(t，0.3H，J＝1.6Hz)，7.18(dd，1H，J＝10.4，1.6Hz)，7.15(dd，0.3H，J＝10.4，1.6Hz)，4.63(bs，2H)，4.56(bs，0.6H)

Step 3:N-(4-cyano group-2-fluoro-6-iodophenyl) amsacrine

Be full of two neck round-bottomed flasks of 25ml and place flask also then to be cooled to 0 ℃ the 4-amino-solution of 3-fluoro-5-iodo-benzonitrile (1g, 3.818mmol, 1 equivalent) in methylene dichloride with argon gas.Add methane sulfonyl chloride (310.3 μ l, 4.009mmol, 1.05 equivalents) and triethylamine (1.06ml, 7.636mmol, 2 equivalents) to solution.The temperature of mixture solution is elevated to room temperature and is heated to the night of refluxing.After confirming that with TLC reaction finishes, under reduced pressure remove methylene dichloride.Add solution (THF: H to described solution ₂1) and NaOH (763.6mg, 19.090mmol, 5 equivalents) O=2:, and stirred 10 minutes.Ethyl acetate extraction is used in the solution that obtains 10%HCl acidifying, uses the salt water washing, passes through Na ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The solid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1) to produce orange solids.(388.3mg, substrate reclaims 599mg) (29.90% (74.57%)).

mp：145-147℃；

IR (KBr pellet, cm ^-1): 3432,3212,3088,3019,2937,2237,1317,1145;

¹H NMR(400MHz，CD ₃OD)：8.09(t，1H，J＝2.0Hz)，7.66(dd，1H，J＝9.6，2.0Hz)，3.15(s，3H)

Step 4:N-(4-amino methyl-2-fluoro-6-iodophenyl) amsacrine

Be full of two neck round-bottomed flasks of 50ml with argon gas, and the 4-amino-solution of 3-fluoro-5-iodo-benzonitrile (330mg, 0.970mmol, 1 equivalent) in tetrahydrofuran (THF) is placed flask, then is cooled to 0 ℃.In described solution, add borine-THF complex solution (1.0M, 1.94ml, 1.941mmol, 2 equivalents).The temperature of mixture solution is elevated to room temperature and is heated to backflow.

After confirming that with TLC reaction finishes, solution is cooled to 0 ℃.By slow adding methyl alcohol, the quencher reaction, the solution ethyl acetate extraction that obtains is used the salt water washing, passes through Na ₂SO ₄Dry.The liquid that obtains is under reduced pressure concentrated to produce yellow solid (237.5mg, 71.14%).

mp：1 24-126℃；

IR (KBr pellet, cm ^-1): 3439,3239,3069,2927,1610,1323,1152;

¹H NMR(400MHz，CD ₃OD)：7.80(s，1H)，7.30(dd，1H，J＝10.0，2.0Hz)，3.96(s，2H)，3.14(s，3H)

Step 5:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-2-fluoro-6-iodophenyl } amsacrine

With N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2-fluoro-6-iodo-phenyl } amsacrine (Boc) (27mg, 0.0426 mmol, 1 equivalent) places the round-bottomed flask of 25ml and is dissolved in methylene dichloride.In described solution, add trifluoroacetic acid (3.6118ul, 0.0469mmol, 1.1 equivalents) and at one night of stirring at room.After confirming that with TLC reaction finishes, reaction soln is confirmed with the sodium bicarbonate neutralization and with the pH test paper.With described solution dichloromethane extraction, use the salt water washing, pass through Na ₂SO ₄Dry and under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce light yellow solid (11mg, 48.39%).

IR：3408，1634，1567，1321；

¹H NMR(400MHz，CD ₃OD)1.30(s，9H)，3.15(s，3H)，4.30(s，2H)，7.36(d，1H，J＝8.4Hz)，7.20(d，1H，J＝8.4Hz)，7.69(d，1H，J＝1.6Hz)，7.15(dd，1H，J＝1.6，10.4Hz)

Embodiment 18:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-5-chloro-2-iodophenyl } amsacrine

Step 1:4-amino-2-chloro-5-iodine benzonitrile

Be full of two neck round-bottomed flasks of exsiccant 25ml and (50mg, 0.33mmol) solution in methylene dichloride places flask with 4-amino-2-chloro-benzonitrile with argon gas.In described solution, add ICl (1.1eq, 0.36mmol, 58.52mg) and stirred 12 hours.After confirming that with TLC reaction finishes, use Na ₂S ₂O ₃The quencher reaction.With the reaction soln dichloromethane extraction, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.With the liquid that obtains carry out column chromatography (n-hexane/ethyl acetate=3/1) with produce white solid (27.5mg, substrate recovery-9.6mg, rough-7.7mg). (30.20%).

mp：158～160℃；

IR (KBr pellet, cm ^-1): 3350,2922,2218,799;

¹H NMR(400MHz，CDCl ₃)：7.78(s，1H).6.75(s，1H)，4.67(bs，2H)

Step 2:4-amino methyl-5-chloro-2-iodophenyl amine

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas.(63.8mg, 0.23mmol) solution in tetrahydrofuran (THF) places flask and is cooled to 0 ℃ with 4-amino-2-chloro-5-iodo-benzonitrile.Slow adding borine-THF mixture in described solution (2eq, 0.46mmol, 0.4ml).The temperature of mixture raise and be heated to refluxed 12 hours.After confirming that with TLC reaction finishes, in described solution, slowly add methyl alcohol (generation bubble) and stirred 2 hours.Under reduced pressure remove methyl alcohol, use the ethyl acetate extraction resistates.Water and salt water washing ethyl acetate layer pass through Na ₂SO ₄Drying is filtered, and under reduced pressure concentrates to produce yellow syrup (46.5mg, 71.85%).

¹H NMR(400MHz，CD ₃OD)：7.56(s，1H)，6.72(s，1H)，3.72(s，2H)

Step 3:(4-amino-2-chloro-5-iodobenzene methyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml and with the 4-amino methyl-(445.1mg, 1.58mmol) solution in tetrahydrofuran (THF) places flask to 5-chloro-2-iodo-phenyl amine with argon gas.In described solution, slowly add Boc ₂O (1.2eq, 1.89mmol, 435.68ml) and stirred 12 hours.After confirming that with TLC reaction finishes, with the reaction soln ethyl acetate extraction, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography purifying (n-hexane/ethyl acetate=5/1) to produce white solid (502.9mg, 83.39%).

mp：117～119℃；

IR (KBr pellet, cm ^-1): 3325,2974,1683,125 1,755; 1HNMR (400MHz, CDCl3): 7.52 (s, 1H), 6.65 (s, 1H), 4.82 (bs, 1H), 4.17 (d, 2H, J=4.8 Hz), 4.05 (bs, 2H), 1.38 (s, 9H)

Step 4:(2-chloro-5-iodo-4-methane sulfonyl amino-benzene methyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas.(268.4mg, 0.70mmol) solution in methylene dichloride places flask and then is cooled to 0 ℃ with (4-amino-2-chloro-5-iodo-phenmethyl)-t-butyl carbamate.In described solution, slowly add methane sulfonyl chloride (5eq, 3.51mmol, 271.91 μ l) and TEA (3eq, 2.10mmol, 292.69 μ l), with described mixture solution stirring at room 12 hours.After confirming that with TLC reaction finishes, use NaHCO ₃Solution quencher reaction.With the reaction soln dichloromethane extraction, use CuSO ₄, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.With the liquid solution (THF: H that obtains ₂O=2: 1) dilution, add NaOH (5eq, 3.5mmol, 140mg) and stirred 1 hour.After confirming that with TLC reaction finishes, with reaction soln 10%HCl acidifying, use ethyl acetate extraction, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography (n-hexane/ethyl acetate=2/1) purifying to produce white solid (211.8mg, 65.53%).

mp：150～152℃；

IR (KBr pellet, cm ^-1): 3372,2986,1693,759;

¹H NMR(400MHz，CDCl ₃)：δ7.75(s，1Hz)，7.59(s，1Hz)，6.71(bs，1Hz)，5.09(bs，1H)，4.29(d，2H，J＝6.0Hz)，3.00(s，3Hz)，1.42(s，9Hz)

Step 5:N-(4-amino methyl-5-chloro-2-iodophenyl) amsacrine

(100mg 0.22mmol) places the round-bottomed flask of exsiccant 25ml and be dissolved in methylene dichloride with (2-chloro-5-iodo-4-methane sulfonyl amino-phenmethyl)-carbamic acid isopropyl ester.CF to 5～6 of described solution addings ₃COOH also stirred 12 hours.After confirming that with TLC reaction finishes, the solution that obtains uses toluene under reduced pressure to concentrate to produce brown syrup (102.1mg, 130.48%).

¹H NMR(400MHz，CD ₃OD)：δ8.05(s，1H))，7.59(s，1H)，4.19(s，2H))，3.05(s，3H)

Step 6:

N-4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-5-chloro-2-iodophenyl amsacrine

Be full of two neck round-bottomed flasks of exsiccant 25ml and (34.28 μ l, 0.28mmol) solution in methylene dichloride places flask with the 4-tertiary butyl-benzene methanamine with argon gas.In described solution, slowly add Boc ₂O (1.5eq, 0.32mmol, 72.44 μ l) and DMAP (0.2eq, 0.01mmol, 5.13mg), and stirred 5 hours, after confirming to produce the 1-tertiary butyl-4-isocyanide acyl methyl-benzene with TLC, in described solution, add N-(4-amino methyl-5-chloro-2-iodo-phenyl)-amsacrine (1eq, 0.28mmol, 74.6mg) and TEA (2eq, 0.56mmol, 58.54 μ l), and stirred 12 hours.After confirming reaction process, with the reaction soln dichloromethane extraction, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography purifying (n-hexane/ethyl acetate=1/1) to produce white solid (30.4mg, 20.04%).

mp：163～165℃；

IR (KBr pellet, cm ^-1): 3319,3024,2961,1638,1315,765;

¹H NMR(400MHz，CDCl ₃)：δ7.70(s，1H)，7.49(s，1H)，7.26(d，2H，J＝8.4Hz)，7.11(d，2H，J＝8.0Hz)，6.64(s，1H)，5.17(bs，2H)，4.25(s，2H)，4.22(s，2H)，2.92(s，3H)，1.21(s，9H).

Embodiment 19:

N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-2-ethyl-6-fluorophenyl } amsacrine

N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2-fluoro-6-vinyl-phenyl } (15.6mg 0.04mmol) is dissolved in the methyl alcohol amsacrine.The air that adds in described solution in Pd/C (10wt.%) and the flask is replaced with hydrogen.Reaction soln was stirred 1 hour.After confirming that with TLC reaction finishes, by C salt elimination Pd/C.Under reduced pressure remove methyl alcohol and carry out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (15.8mg, 100.0%).

¹H NMR(400MHz，CDCl ₃)：7.28(d，2H，J＝8.4Hz)，7.15(d，2H，J＝8.0Hz)，6.91(s，1H)，6.84(q，1H，J＝10.4Hz)，5.86(s，1H)，4.28(s，4H)，3.00(s，3H)，2.76(q，2H，J＝7.6Hz)，1.23(s，9H)，1.31(t，3H，J＝8.0Hz).

Embodiment 20:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-fluorophenyl } amsacrine

The 3-fluoro-4-methane sulfonyl aminobenzoic amine hydrochlorate (1.13g) that will prepare in the step 3 of embodiment 1 is dissolved among the DMF (6mL) and with methylene dichloride (35mL) and dilutes.In described solution, add 4-tert.-butylbenzene methyl isocyanate (1.09g) and TEA (1.2mL) and stirring at room 2 hours.Reaction soln is under reduced pressure concentrated, with ethyl acetate (20mL) dilution and water and saturated NaCl solution washing.The solution that obtains is under reduced pressure concentrated by anhydrous magnesium sulfate drying and with remaining liquid.Described resistates is carried out purifying to produce title compound (1.23g, 53%) with column chromatography (n-hexane/ethyl acetate=3/2).

mp：95℃.

¹H-NMR(CDCl ₃+CD ₃OD，300MHz)1.23(s，9H)，2.91(s，3H)，4.22(s，2H)，4.24(s，2H)，6.99-6.93(m，2H)，7.13(d，2H，J＝8.2 Hz)，7.26(d，2H，J＝8.4Hz)，7.34(t，1H，J＝8.3Hz)

LRMS(FAB)：408(M+H+).

Embodiment 21:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-aminomethyl phenyl } amsacrine

With N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-aminomethyl phenyl } amsacrine (22%) is according to synthetic with method identical described in the embodiment 20.

¹H-NMR(300MHz，CD ₃OD)：δ1.29(s，9H)，2.33(s，3H)，2.94(s，3H)，4.28(s，4H)，7.35-7.09(m，7H)IR(neat)cm ^-1：3368，2960，1635，1567，1504，1321.Mass(LC)404.1[M+H]+

Embodiment 22:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-chloro-phenyl-} amsacrine

With N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-chloro-phenyl-} amsacrine (10%) is according to synthetic with method identical described in the embodiment 20.

mp：60-61℃；

¹H-NMR(CDCl ₃，300MHz)：1.29(s，9H)，2.97(s，3H)，4.35(d，4H，J＝5.9Hz)，4.64(bs，2H)，6.70(bs，1H)，7.23-7.15(m，3H)，7.36-7.31(m，3H)，7.57(d，1H，J＝8.3Hz)；

IR(neat，cm ^-1)：3353，2960，1635，1571，1496，1329；

LRMS(ESI)：m/z 424.0(M+H+).

Embodiment 23:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-nitrophenyl } amsacrine

Step 1:N-(4-cyano group-2-nitrophenyl) amsacrine

(700mg 6.1mmol) is dissolved at-78 ℃ and dropwise adds 4-amino-3-nitro-benzonitrile (500mg, 3.1mmol) solution in THF (10mL) among the THF (15mL) and in described solution with KH.After described reaction soln is stirred 30 minutes, in described solution, dropwise add methylsulfonyl chloride (0.35mL, 4.6mmol) and stirred 3 hours.The quencher of reaction soln water, and the solution that obtains diluted with ethyl acetate.With organic phase water and salt water washing, by anhydrous magnesium sulfate drying and under reduced pressure concentrated.Described resistates is carried out purifying (n-hexane/ethyl acetate=5/1) to produce nitrile (120mg, 16%) with column chromatography.

¹H-NMR(300MHz，CDCl ₃)：δ3.24(s，3H)，7.90(dd，1H，J＝8.8，2.0Hz)，8.03(d，1H，J＝8.8Hz)，8.59(d，1H，J＝2.0Hz)

Step 2:N-[4-(amino methyl)-2-nitrophenyl] amsacrine

(120mg 0.50mmol) is dissolved in THF (5.0mL) with nitrile.In described solution, dropwise add 1M BH ₃(1.5mL) solution in toluene and refluxing 2 hours.

Adding 2N HCl (1.0mL) in described solution also then refluxed 1 hour.The solution that obtains is under reduced pressure concentrated to produce rough amine (48mg, 39%).Amine compound is used for step 3 and without purge process.

Step 3:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-the 2-nitrophenyl } amsacrine

According to identical method described in the embodiment 20, the reaction of the amine compound that will prepare in step 2 and tert.-butylbenzene methyl isocyanate is to produce urea (10%).

mp＝177-178℃；

¹H-NMR(CDCl ₃，300MHz)1.29(s，9H)，3.10(s，3H)，4.35(d，2H，J＝5.7Hz)，4.40(d，2H，J＝5.9Hz)，4.73(bs，1H)，4.81(bs，1H)，7.23(d，2H，J＝8.3Hz)，7.36(d，2H，J＝8.4Hz)，7.58(d，1H，J＝6.6Hz)，7.81(d，1H，J＝8.8Hz)，8.12(s，1H)，9.64(bs，1H).

IR(neat，cm ^-1)：3317，2958，2927，2860，1632，1534；

LRMS(ESI)：m/z435(M+H+).

Embodiment 24:N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2-iodo-phenyl }-amsacrine

According to general method N-(4-amino methyl-2-iodo-phenyl)-amsacrine and HCl salt (297mg is 0.820mmol) with the 4-tertiary butyl-phenmethyl)-phenyl carbamate are reacted to obtain white solid (152mg).

¹H NMR(300MHz，CDCl ₃)：7.68(d，1H，J＝1.8Hz)，7.46(d，1H，J＝8.1Hz)，7.32(m，2H)，7.19～7.15(m，3H)，6.63(br，1H)，5.20(dt，2H，J＝21Hz)，4.27(d，2H，J＝5.1Hz)，4.22(d，2H，J＝5.7Hz)，2.95(s，3H)，1.28(s，9H).IR(neat，cm ^-1)：3322，2962，1634，1566，1487，1384，1327.

Embodiment 25:N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2,6-two fluoro-phenyl }-amsacrine

(100mg 0.36mmol) reacts to obtain white solid (18mg, 12%) with (the 4-tertiary butyl-phenmethyl)-phenyl carbamate to make N-(4-amino methyl-2,6-two fluoro-phenyl)-amsacrine and HCl salt according to general method.

¹H NMR(300MHz，CD ₃OD)：7.29(d，2H，J＝8.4Hz)，7.17(d，2H，J＝8.4Hz)，6.98(d，2H，J＝9.0Hz)，6.17(bt，1H)，6.06(bt，1H)，4.32(d，2H，J＝6.3Hz)，4.26(d，2H，J＝6.0Hz)，3.03(s，3H)，1.23(s，9H).

Embodiment 26:N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2,5-two fluoro-phenyl }-amsacrine

Step 1:(4-amino-2,5-difluoro phenmethyl) t-butyl carbamate

Be full of the two neck round-bottomed flasks of exsiccant 50ml with argon gas.With 4-amino-2, (0.5g, 3.24mmol) solution in tetrahydrofuran (THF) places flask and is cooled to 0 ℃ 5-difluoro benzonitrile.Slow adding borine-THF mixture in described solution (2eq, 6.49mmol, 6.49ml).The temperature of mixture raise and be heated to refluxed 18 hours.After confirming that with TLC reaction finishes, in described solution, slowly add methyl alcohol (generation bubble) and stirred 2 hours.Under reduced pressure remove methyl alcohol and with the resistates ethyl acetate extraction.Wash ethyl acetate layer with water, pass through MgSO ₄Drying is filtered and is under reduced pressure concentrated to produce yellow syrup.Be dissolved in the tetrahydrofuran (THF) liquid of above-mentioned acquisition and the slow BOC of adding ₂(1.0eq is 0.71g) in room temperature and stirred 12 hours for O.After confirming that with TLC reaction finishes, with the reaction soln ethyl acetate extraction, MgSO is passed through in water and salt water washing ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography (n-hexane/ethyl acetate=4/1) purifying to produce white solid (0.43g, 51.2%).

Step 2:(2,5-two fluoro-4-methane sulfonyl phenmethyls) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas.(0.43g, 1.66mmol) solution in methylene dichloride places flask and then is cooled to 0 ℃ with (4-amino-2,5-difluoro phenmethyl)-t-butyl carbamate.In described solution, slowly add methane sulfonyl chloride (1.2eq, 1.99mmol, 0.16ml) and pyridine (excessive, 0.5ml, and mixture solution refluxed 12 hours.After confirming that with TLC reaction finishes, with reaction soln 10%HCl acidifying, use dichloromethane extraction, MgSO is passed through in water and salt water washing ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains uses column chromatography (n-hexane/ethyl acetate=2/1) purifying to produce white solid (0.41g, 73.5%).

¹H NMR(300MHz，CDCl ₃)：δ7.32(m，1H)，7.19(m，1H)，6.72(bs，1H)，4.95(bs，1H)，4.30(d，2H，J＝6.3Hz)，3.05(s，3H)，1.46(s，9H)

Step 3:2,5-two fluoro-4-methane sulfonyl benzene methanamine hydrochlorides

(0.41g 1.22mmol) places single neck round-bottomed flask of 50ml and impouring 30ml 1,4-diox with (2,5-two fluoro-4-methane sulfonyl phenmethyls) t-butyl carbamate.In described solution, add c-HCl (excessive, 2ml) and stirred 4 hours.After confirming that with TLC reaction finishes, reaction soln is under reduced pressure concentrated.The solid that obtains is filtered with the ethyl acetate washing and with glass filter.The solid that obtains is air-dry to produce solid (0.24g, 72.5%).

Step 4:

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2,5-two fluoro-4-methane sulfonyl phenyl } amsacrine

With 2, (70mg, 0.26mmol) (1.1eq 80mg) places single neck round-bottomed flask of 25ml and impouring 15ml acetonitrile to 5-two fluoro-4-methane sulfonyl benzene methanamine hydrochlorides with 4-tert.-butylbenzene methyl carbamic acid phenyl ester.To this solution add triethylamine (excessive, 0.5ml) and stirred 18 hours.After confirming that with TLC reaction finishes, reaction soln is under reduced pressure concentrated.The material that obtains is also used 1M HCl solution washing with dichloromethane extraction, pass through MgSO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/3) to produce title compound (64mg).

¹H NMR(300MHz，CDCl ₃)：7.35(d，2H，J＝8.1Hz)，7.29(m，1H)，7.23(m，2H)，7.14(m，1H)，6.78(s，1H)，4.84(m，2H)，4.34(m，4H)3.02(s，3H)，1.30(s，9H).

Embodiment 27:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-2-chloro-6-aminomethyl phenyl } amsacrine

With the 4-tertiary butyl-benzene methanamine (1.5eq, 72.85 μ l, 0.45mmol) be dissolved in the methylene dichloride after, with BOC ₂(0.2eq, 0.06mmol 7.33mg) add described mixture for O (1.5eq, 0.45mmol, 103.49 μ l) and DMAP.Reaction mixture was stirred 5 hours.Confirm the 1-tertiary butyl-4-isocyanide acyl methyl-benzene synthetic with TLC after, with N-(4-amino methyl-2-chloro-6-methyl-phenyl)-amsacrine (1eq, 0.30mmol, 107.7mg) and TEA (2eq, 0.60mmol, 83.63 μ l) adding mixture.Reaction mixture was stirred 12 hours.Remove reaction solvent in a vacuum.With the resistates dichloromethane extraction.With the organic layer H that merges ₂Na is used in O and salt water washing ₂SO ₄Drying, and then concentrate in a vacuum.With described resistates with column chromatography (n-Hx: EA=1: 1) carry out purifying to produce white solid (31.3 mg, 24%).

Fusing point: 170～172 ℃;

IR (KBr pellet, cm ^-1): 3325,2961,1624,1572,1319,767; ¹H NMR (400MHz, CD ₃OD): δ 7.31 (d, 2H, J=8.4Hz), 7.22 (d, 1H, J=1.6Hz), 7.17 (d, 2H, J=8.4Hz), 7.10 (d, 1H, J=1.2Hz), 4.25 (d, 4H, J=6.4Hz), 3.05 (s, 3H), 2.39 (s, 3H), 1.26 (s, 9H).

Embodiment 28:N-{4-[3-(4-tert.-butylbenzene methyl)-urea groups methyl]-5-chloro-2-ethylphenyl } amsacrine

Step 1:(4-amino-2-chloro-5-TMS acetylenylbenzene methyl) t-butyl carbamate

With argon gas be full of exsiccant 25ml two neck round-bottomed flasks and with (4-amino-2-chloro-5-iodo-phenmethyl)-t-butyl carbamate (60mg, 0.16mmol), CuI (0.05eq, 0.008mmol, 1.52mg) and PdCl ₂(PPh3) ₂Solution in DMF places flask.With solution stirring at room 30 minutes.In described solution, add (TMS) acetylene (1.3eq, 0.21mmol, 29.39mg) and triethylamine (3eq, 0.48mmol, 66.90 μ l) and be heated to backflow 12 hours.After confirming that with TLC reaction finishes, the solution ethyl acetate extraction that obtains, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=6/1) to produce orange solids (44.9mg, 81.17%).

mp：104～106℃；

IR (KBr pellet, cm ^-1): 3356,2962,2143,1698,843;

¹H NMR(400MHz，CDCl ₃)：7.17(s，1H)，6.61(s，1H)，4.77(bs，1H)，4.14(d，2H，J＝6.0Hz)，1.35(s，9H)，0.15(s，9H).

Step 2:(2-chloro-5-ethynyl-4-methane sulfonyl amino-benzene methyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas.(225.3mg, 0.64mmol) solution in methylene dichloride places flask and then is cooled to 0 ℃ with (4-amino-2-chloro-5-TMS ethynyl-phenmethyl)-t-butyl carbamate.In described solution, slowly add methane sulfonyl chloride (5eq, 3.20mmol, 247.60 μ l) and triethylamine (3eq, 1.92mmol, 267.61 μ l), and stirring at room 12 hours.After confirming that with TLC reaction finishes, reaction soln NaHCO ₃The solution quencher.With the reaction soln dichloromethane extraction, use CuSO ₄, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.With the liquid solution (THF: H that obtains ₂O=2: 1) dilution, in described solution, add NaOH (5eq, 3.20mmol, 128mg).Described mixture was stirred 1 hour.After confirming that with TLC reaction finishes, with reaction soln 10%HCl acidifying, use ethyl acetate extraction, water and salt water washing, and cross Na ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=3/1) to produce white solid (182.6mg, 79.70%).

mp：138～140℃；

IR (KBr pellet, cm ^-1): 3371,3025,2987,1694,1327,701;

¹H NMR(400MHz，CDCl ₃)：δ7.53(s，1H)，7.40(s，1H)，6.99(bs，1H)，5.06(s，1H)，4.23(d，2H，J＝6.0Hz)，2.95(s，3H)，1.35(s，9H).

Step 3:N-(4-amino methyl-5-chloro-2-ethynyl phenyl) amsacrine

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and (182.6mg, 0.51mmol) solution in methylene dichloride places flask with (2-chloro-5-ethynyl-4-methane sulfonyl amino-phenmethyl)-t-butyl carbamate.In described solution, add 5～6 CF ₃COOH also stirred 12 hours.After confirming that with TLC reaction finishes, use toluene that the solution that obtains is under reduced pressure concentrated to produce brown syrup (98.1mg, 114.23%).

¹H NMR(400MHz，CD ₃OD)：δ7.69(s，1H)，7.66(s，1H)，4.22(s，2H)，4.04(s，1H)，3.03(s，3H).

Step 4:N-{4-[3-(4-tert.-butylbenzene methyl) urea groups methyl]-5-chloro-2-ethynyl phenyl } amsacrine

Be full of two neck round-bottomed flasks of exsiccant 25ml and (44.08 μ l, 0.27mmol) solution in methylene dichloride places flask, slowly adds Boc in described solution with the 4-tertiary butyl-benzene methanamine with argon gas ₂O (1.5eq, 0.41mmol, 93.14 μ l) and DMAP (0.2eq, 0.05 mmol, 6.59mg) and stirred 5 hours.Behind the 1-tertiary butyl-4-isocyanide acyl methyl-benzene that confirms to produce with TLC, in described solution, add N-(4-amino methyl-5-chloro-2-ethynyl-phenyl)-amsacrine (1eq, 0.27mmol, 70mg) and TEA (2eq, 0.54mmol, 75.27 μ l) and stirred 12 hours.After confirming reaction process with TLC, the reaction soln dichloromethane extraction, Na is passed through in water and salt water washing ₂SO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (20.20mg, 16.73%).

mp：116～118℃；

IR (KBr pellet, cm ^-1): 3282,3025,2961,2202,1636,1329,762;

¹H NMR(400MHz，CDCl ₃)：δ7.53(s，1H)，7.46(s，1H)，7.27(d，2H，J＝8.4Hz)7.14(d，2H，J＝8.0Hz)，6.91(bs，1H)，4.30(s，2H)，4.25(s，2H)3.44(s，3H)，3.02(s，1H)，2.95(s，3H)，1.22(s，9H).

Step 5:N-{4-[3-(4-tert.-butylbenzene methyl)-urea groups methyl]-5-chloro-2-ethylphenyl } amsacrine

With N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-5-chloro-2-ethynyl-phenyl-amsacrine (30mg, 0.19mmol) and Lindler ' catalyzer add in the methyl alcohol.Reaction mixture was stirred 1 hour under hydrogen atmosphere.Reaction mixture is filtered with C salt pad.Filtrate concentrates in a vacuum and then (n-Hx: EtOAc=1: 1) purifying is to produce yellow syrup (25.6mg, 85%) with column chromatography.

(NaCl is pure, cm for IR ^-1): 3309,3022,2964,1636,1322,1153,757;

¹H NMR(400MHz，CDCl ₃)：δ7.22(d，2H，J＝8.0Hz)，7.18(d，1H，J＝8.8Hz)，7.08(d，2H，J＝8.4Hz)，7.00(s，1H)，6.91(d，1H，J＝8.0Hz)，6.63(s，1H)，5.26(bs，2H)，4.15(d，2H，J＝10.8Hz)，2.86(s，3H)，2.5 1(q，2H，J＝7.6Hz)，1.20(s，9H)，1.08(t，3H，J＝7.6Hz).

Embodiment 29:

N-{4-[3-(the 4-tertiary butyl-phenmethyl)-urea groups methyl]-2-fluoro-6-methyl-phenyl }-amsacrine

With N-(4-amino methyl-2-fluoro-6-methyl-phenyl)-amsacrine and HCl salt (200mg, 0.70mmol) with 3-(the 4-tertiary butyl-phenmethyl)-phenyl carbamate according to the general method reaction to obtain white solid (31mg, 11%).

1HNMR(300MHz，DMSO-d6+CDCl ₃)：8.70(s，1H)，7.25(d，2H，J＝8.1Hz)，7.14(d，2H，J＝8.4Hz)，7.04(d，1H，J＝8.1Hz)，7.02(d，1H，J＝8.4Hz)，5.55(bs，2H)，4.29(s，2H)，4.23(s，2H)，2.87(s，3H)，2.19(d，3H，J＝2.7Hz)，1.22(s，9H).

EXPERIMENTAL EXAMPLE: biopotency test

1. ⁴⁵Ca flows into test

1) separation and the primary culture thereof of the backbone dorsal root ganglion (DRG) of neonate rat

The SD rat in newborn (2-3 days ages or less than 2-3 days ages) is placed on ice 5 minutes with anesthesia and with 70% ethanol disinfection.The DRG of all parts of dissection spinal cord (Wood etc., 1988, J.Neurosci.8 pp3208-3220) and with it is collected in the DME/F12 substratum, adds 1.2g/l sodium bicarbonate, the gentamicin of 50mg/l in described substratum.DRG is continued at 37 ℃ of incubations 30 minutes in the trypsinase of the collagenase of 200 U/ml and 2.5mg/ml respectively.With replenishing with the DME/F12 substratum washing neuroganglion of 10% horse serum 2 times, the pasteur pipet of chiseling by fire grinds, by the Nitex80 membrane filtration to obtain unicellular suspension and described suspension washed once more.It is carried out centrifugal, then the cell density with certain level is resuspended in the cell culture medium.As cell culture medium, will replenish, and add NGF (nerve growth factor) to regulate the ultimate density of 200ng/ml with the same medium dilution (1: 1) that the C6 glioma cell of answer print regulates 2 days of using foreign currency of the DME/F12 substratum of 10% horse serum.Cell cultures after 2 days, is replaced described substratum with the substratum of no Ara-C just to kill at adding cytosine arabinoside (Ara-C, 100 μ M) in the substratum of the non-neurocyte of splitted.With the cell of resuspension with the density plating in 1500-2000 neurone/hole on the Terasaki flat board of-D-guanylic acid bag quilt poly-in advance with 10 μ g/ml.

2) ⁴⁵Ca flows into experiment

By with HEPES (10mM, pH7.4)-buffered do not have Ca ²⁺, Mg ²⁺HBSS (H-HBSS) washing 4 times, come the DRG neurocyte of balance from 2 days primary culture.From each hole, remove the solution in each hole.To in H-HBSS, comprise test compounds add capsaicine (final concentration 0.5 μ M) and ⁴⁵The substratum of Ca (final concentration 10 μ Ci/ml) adds in each hole and room temperature incubation 10 minutes.With H-HBSS washing Terasaki plate 5 times and in drying at room temperature.In each hole, add 0.3%SDS (10 μ l) with wash-out ⁴⁵Ca.After adding the flicker mixture to each hole, flow in the neurone by calculating the radioactivity measurement ⁴⁵The amount of Ca.Test compounds is calculated as per-cent in the inhibition of the maximum reaction of the capsaicine of the concentration of 0.5 μ M at the antagonistic activity of novel vanilloid receptor.Generally speaking, all embodiment of the present invention show good to superior between 40 and 500nM between the IC50 value, wherein most compounds has the IC50 value that is lower than 600nM.

[table 1]

Calcium current is gone into result of experiment

Embodiment	Calcium absorption test (IC ₅₀，μM)	Embodiment	Calcium absorption test (IC ₅₀，μM)
Embodiment	Calcium absorption test (IC ₅₀，μM)	Embodiment	Calcium absorption test (IC ₅₀，μM)	1	0.49	16	0.10
2	0.26	17	0.29	1	0.49	16	0.10
2	0.26	17	0.29	3	0.29	18	0.53
4	0.31	19	0.15	3	0.29	18	0.53
4	0.31	19	0.15	5	0.21	20	0.30
6	0.35	21	0.083	5	0.21	20	0.30
6	0.35	21	0.083	7	0.36	22	0.24
8	0.18	23	0.24	7	0.36	22	0.24
8	0.18	23	0.24	9	0.36	24	0.39
10	0.44	25	0.47	9	0.36	24	0.39
10	0.44	25	0.47	11	0.046	26	0.56
12	0.12	27	0.19	11	0.046	26	0.56
12	0.12	27	0.19	13	0.15	28	0.29
14	0.041	29	0.073	13	0.15	28	0.29
14	0.041	29	0.073	15	0.59

2. analgesic activity test: test by induce the mouse that carries out to struggle with phenyl-p-quinone

Male ICR mouse (mean body weight 25g) is maintained in check photoenvironment (opened/closed in 12 hours in 12 hours) to experimentize.The peritoneal injection of chemical irritant phenyl-p-quinone of animals received 0.3ml (be dissolved in and comprise in the 5% alcoholic acid salt solution, to dosage be 4.5mg/kg) after 6 minutes, calculates the quantity that belly shrinks in 6 minute period subsequently.Animal (10 animal/groups) intraperitoneal is received in the test compounds solution of the 0.2ml in the carrier of ethanol/tween 80/salt solution (10/10/80), injects phenyl-p-quinone after 30 minutes.Think the quantity of reacting with respect in the saline control group, it is the indication of analgesic effect that the number of times of the struggle of testing drug compound reaction is reduced.Suppress equation (% suppresses=(C-T)/C * 100) by % and calculate analgesic effect, wherein C and T represent to be illustrated respectively in the number of times (table 2) of the struggle in contrast and the compound-control group.

[table 2]

For test result by the analgesic activity of phenyl-struggle that the p-quinone causes

Embodiment	Dosage (mg/kg)	Analgesic activity (% inhibition)
Embodiment	Dosage (mg/kg)	Analgesic activity (% inhibition)	11	1	56
14	1	42	11	1	56
14	1	42	20	1	82
21	1	58	20	1	82
21	1	58	29	1	54

Industrial applicibility

As explained above, will be used for prevention and treatment pain, antimigraine according to compound of the present invention, arthralgia, neuralgia, neuropathy, neurotrosis, disease of skin, cysterethism, IBS, just anxious, respiratory disorder, skin, eyes or MMi, gastroduodenal ulcer, inflammatory disease, otopathy, and heart disease etc.

More specifically, be used for prevention and treatment acute pain, chronic pain, neuropathic pain according to compound of the present invention, postoperative pain, rheumatic arthralgia, osteoarthrosis pain, PHN, diabetic neuropathy, the neuropathy that HIV-is relevant, neurodegeneration apoplexy, nerve/allergia/inflammatory dermatosis, psoriasis, pruritus, pruigo, asthma, chronic obstructive pulmonary disease, the urinary incontinence, inflammatory bowel disease, hyperakusis, tinnitus, vestibular is irritated, and the variable force ischemia.

Claims

1. the compound of formula (Ia), its isomer and/or pharmaceutical salts;

Wherein,

R ₃Be hydrogen, C1-C5 alkyl, C1-C5 alkoxyl group, or halo (C1-C5) alkyl;

R ₄, R ₅, R ₆, R ₇, and R ₈Be hydrogen independently, carboxyl, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, the C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, phenyl, or halogen, wherein, phenyl can be unsubstituted or is selected from following one or more substituting groups replacements: carboxyl, C1-C5 alkyl, halogen, nitro, the C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, the C1-C5 alkyl-carbonyl, the C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₉Be C1-C5 alkyl sulphonyl or C2-C5 alkenyl alkylsulfonyl; And

R ₁₀Be hydrogen;

2. according to the compound of claim 1, its isomer and/or pharmaceutical salts;

Wherein,

R ₃Be hydrogen, methyl, ethyl, or methoxyl group;

R ₄, R ₅, R ₆, R ₇And R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, sec-butyl, nitro, vinyl, propenyl, methoxyl group, oxyethyl group, propoxy-, C2-C5 alkynyl, trifluoromethyl, methylthio group, ethanoyl, methoxycarbonyl, phenyl, bromine, chlorine, or iodine, wherein, phenyl can be unsubstituted or is selected from following one or more substituting groups replacements: carboxyl, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, the C1-C5 alkoxyl group, halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, the C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₉Be methane sulfonyl, ethane alkylsulfonyl, or vinylsulfonyl; And

R ₁₀Be hydrogen;

3. according to the compound of claim 1, its isomer and/or pharmaceutical salts;

Wherein,

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃Be hydrogen;

R ₆Be halo (C1-C3) alkyl, sec.-propyl, or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

4. according to the compound of claim 1 or 3, its isomer and/or pharmaceutical salts;

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃Be hydrogen;

R ₅, R ₇And R ₈All be hydrogen;

R ₆Be the sec.-propyl or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

5. according to the compound of claim 1, its isomer and/or pharmaceutical salts;

Wherein

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃It is methyl;

R ₆Be halo (C1-C3) alkyl, sec.-propyl, or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

6. according to the compound of claim 1 or 5, its isomer and/or pharmaceutical salts;

Wherein X is CR ₁₁=CH or C ≡ C, wherein R ₁₁It is methyl;

R ₂Be hydrogen, methyl, fluorine, or chlorine;

R ₃It is methyl;

R ₅, R ₇And R ₈All be hydrogen;

R ₆Be the sec.-propyl or the tertiary butyl;

R ₉It is methane sulfonyl; And

R ₁₀Be hydrogen.

7. according to each compound of claim 1-6, its isomer and/or pharmaceutical salts;

R wherein ₁Thereby be incorporated into the described compound of phenyl ring with ortho position and have the structure of formula (Ib) with respect to sulfuryl amino:

8. according to each compound among claim 1 or the 3-7, its isomer and/or pharmaceutical salts, wherein said compound is selected from the group of being made up of following:

3-(the 4-tertiary butyl-phenyl)-but-2-ene acid 3-fluoro-4-methylsulfonyl amino-phenmethyl acid amides,

9. according to each compound among the claim 1-8, its isomer and/or pharmaceutical salts, wherein said compound is selected from the group of being made up of following:

3-(the 4-tertiary butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl aminophenyl) ethyl]-the 2-Methacrylamide,

3-(the 4-tertiary butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl aminophenyl) ethyl] the propine acid amides and

3-(the 4-tertiary butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-phenyl) ethyl]-2-methyl-acrylamide.

10. the compound of formula (II), its isomer and/or pharmaceutical salts;

Wherein,

R ₄, R ₅, R ₇And R ₈Be hydrogen independently, carboxyl, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, the C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, phenyl, or halogen, wherein, phenyl can be unsubstituted or is selected from following one or more substituting groups replacements: carboxyl, C1-C5 alkyl, halogen, nitro, the C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, the C1-C5 alkyl-carbonyl, the C1-C5 alkylthio, C1-C5 alkyl sulphonyl, or C1-C5 alkoxy carbonyl;

R ₆Be halo (C1-C3) alkyl or C1-C5 alkyl; And

11. according to the compound of claim 10, its isomer and/or pharmaceutical salts;

Wherein,

R ₁And R ₂Be hydrogen independently, halogen, nitro, cyano group, the C1-C5 alkyl, the C1-C5 alkoxyl group, halo (C1-C5) alkyl, carboxyl, C1-C5 alkoxy carbonyl, or C1-C5 alkylthio, condition is R ₁And R ₂One of them is different from hydrogen at least;

R ₆It is the C1-C5 alkyl; With

12. according to the compound of claim 10 or 11, its isomer and/or pharmaceutical salts;

Wherein,

R ₁And R ₂Be hydrogen independently, fluorine, chlorine, bromine, iodine, nitro, cyano group, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, or methoxycarbonyl, condition is R ₁And R ₂One of them is different from hydrogen at least;

R ₆It is the C3-C5 alkyl; And

R ₉Be methane sulfonyl, ethane alkylsulfonyl, or ethene alkylsulfonyl.

13. according to each compound of claim 10 to 12, its isomer and/or pharmaceutical salts;

Wherein,

R ₁And R ₂Be hydrogen independently, fluorine, chlorine, bromine, iodine, nitro, cyano group, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, or methoxycarbonyl; Condition is R ₁And R ₂One of them is different from hydrogen at least;

R ₄, R ₅, R ₇, and R ₈Be hydrogen;

R ₆Be the sec.-propyl or the tertiary butyl; And

R ₉It is methane sulfonyl.

14. according to the compound of claim 10, its isomer and/or pharmaceutical salts, wherein

R ₁Be selected from fluorine, chlorine, methyl, ethyl, n-propyl, or nitro;

R ₂Be selected from fluorine, chlorine, methyl, ethyl, or iodine, and work as R ₁Be selected from methyl, ethyl, or during n-propyl, R ₂Also hydrogen;

R ₆Be halo (C1-C3) alkyl or C3-C5 alkyl; And

R ₉It is methane sulfonyl.

15. according to each compound of claim 11-14, its isomer and/or pharmaceutical salts, wherein R ₁Be incorporated into phenyl ring with ortho position with respect to sulfuryl amino.

16. according to each compound among the claim 11-15, its isomer and/or pharmaceutical salts, wherein R ₁And R ₂All with the ortho position combination with respect to sulfuryl amino, thereby described compound has the structure of general formula (IIa):

17. according to the compound of claim 15 or 16, its isomer and/or pharmaceutical salts, wherein,

R ₁Be methyl or ethyl and

R ₂Be selected from hydrogen, fluorine, or chlorine.

18. according to each compound of claim 11-13, its isomer or its pharmaceutical salts:

Wherein said compound is selected from the group of being made up of following:

19. according to each compound of claim 11 to 16, its isomer, or its pharmaceutical salts,

Wherein said compound is selected from the group of being made up of following:

N-{4-[3-(the 4-tertiary butyl-phenmethyl) urea groups methyl]-2-chloro-6-methyl-phenyl amsacrine and

20. according to each compound of aforementioned claim, it is as medicine.

21. a pharmaceutical composition, it comprises according to each compound among the claim 1-19, its isomer, or its pharmaceutical salts, and pharmaceutical carrier.

22. a pharmaceutical composition that is used to prevent the illness relevant with the pathological stimuli of treatment and novel vanilloid receptor and/or unconventionality expression, wherein said composition comprise according to each compound among the claim 1-19, its isomer, or its pharmaceutical salts; And pharmaceutical carrier.

23. according to the pharmaceutical composition of claim 21 or 22, it is used for the treatment of and is selected from following illness:

Pain, the inflammatory diseases in joint, irritable bladder comprises the urinary incontinence, gastro-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel (IBD), nervosa/allergy/inflammatory dermatosis, psoriatic, asthma, chronic obstructive pulmonary disease, pruritus, or pruigo.

24. pharmaceutical composition according to claim 23, wherein said pain is to be selected from following illness or relevant with it: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, non-inflammatory flesh skeleton pain (comprises fibromyalgia, myofasical pain syndrome and backache), the headache of migraine and other type.

25. according to each pharmaceutical composition of claim 21-24, it is Orally administered to it is characterized in that it is suitable for.

26. a method that in the patient, suppresses the plain part of vanilla in conjunction with novel vanilloid receptor, it comprise make the cell of expressing novel vanilloid receptor among the patient with according to each compound of claim 1-19, its isomer, or its pharmaceutical salts contact.

27. one kind is prevented or treats the method that is selected from following illness: pain, the inflammatory diseases in joint, irritable bladder, comprise the urinary incontinence, gastro-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel (IBD), nervosa/allergy/inflammatory dermatosis, psoriatic, asthma, chronic obstructive pulmonary disease, pruritus, or pruigo, its comprise to needs its administration treatment significant quantity that comprises the people according to each compound of claim 1-19, its isomer, or its pharmaceutical salts.

28. method according to claim 27, wherein said pain is to be selected from following illness or relevant with it: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, non-inflammatory flesh skeleton pain (comprises fibromyalgia, myofasical pain syndrome and backache), the headache of migraine and other type.

29. be used to prevent or the application of the illness that the unconventionality expression of treatment and novel vanilloid receptor and/or abnormal activation are relevant according to each compound, its isomer or its pharmaceutical salts of claim 1-19.

30. according to the application that each compound, its isomer or its pharmaceutical salts of claim 1-19 is used to prepare medicine, described medicine is used for prevention or treatment is selected from pain, the inflammatory diseases in joint, irritable bladder, comprise the urinary incontinence, gastro-duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel (IBD), nervosa/allergy/inflammatory dermatosis, psoriatic, asthma, chronic obstructive pulmonary disease, pruritus, or the illness of pruigo.

31. application of compound according to claim 30, wherein said illness is a pain, or it is to be selected from following illness or relevant with it: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, postoperative pain, non-inflammatory flesh skeleton pain (comprising fibromyalgia, myofasical pain syndrome and backache), the headache of migraine and other type.