CN101142174B - Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist, and pharmaceutical compositions containing the same - Google Patents

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 the disease relevant with the activity of novel vanilloid receptor (Nagy etc., 2004, Eur.J.Pharmacol.500 351-369), can enumerate pain such as acute pain; Chronic pain, neuropathic pain, postoperative pain, rheumatic arthralgia; Osteoarthrosis pain, PHN, 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 segmental enteritis (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 (CGRP) 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 like bladder, kidney, lung, intestines and skin and the property in comprising the cns (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 plain heat stimulus of vanilla replied the minimizing with sense organ susceptibility, and even under inflammatory conditions, show hyperpathia (Caterina etc., 2000 hardly to heat stimulus; Science 288, pp306-313; Davis etc., 2000, Nature 405, pp183-187; Karai etc., 2004, J.Clin.Invest., 113, pp1344-1352).Recently, also through show novel vanilloid receptor maybe 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 of novel vanilloid receptor is neural, and it causes the release of neuropeptide again, and said 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 treat gastrointestinal illness such as stomach-oesophagus adverse current sick (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 said advancing of disease (Chan etc. in suffering the patient of irritable colon syndrome; 2003; Lancet, 361, pp385-391).Other research shows that being expressed among the patient who suffers inflammatory bowel of novel vanilloid receptor significantly increases.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 anaphylaxy and bronchial hyperpathia are very similar; And the proton of known endogenous ligands as novel vanilloid receptor and lipoxygenase product are to be responsible for the well-known key factor (Hwang etc. that asthma and chronic obstructive pulmonary disease develop; 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, promptly 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 RD; 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 in nerve fiber, exists 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 contraction 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 to treat 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 discloses some patents and the patented claim that relates to the vanilloid receptor antagonist of developing recently, has wherein fully described the above-mentioned information (Rami etc. that mention; 2004; Drug Discovery Today:Therapeutic Strategies, 1, pp97-104).

As based on the theoretical background of above-mentioned discussion extensively with the result who concentrates research, the inventor has synthesized through selectively acting and on novel vanilloid receptor, has the new compound of antagonistic activity and therefore accomplished the present invention.Surprisingly; Confirmed such compound be novel vanilloid receptor have active regulator especially; The substituent sym-Dibenzylurea that it has C2-C5 alkenyl or C2-C5 alkynyl and comprise amine on an one of which phenyl ring, dibenzyl acid amides or dibenzyl cinnyl structure.

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

Summary of the invention

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

[formula I]

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, NH, CHR ₁₁CHR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, halogen, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, or phenyl;

R ₁Be the C2-C5 alkenyl, or the C2-C5 alkynyl;

R ₂Be hydrogen, halogen, nitro, cyanic acid, C1-C5 alkyl; The C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxyl; The C1-C5 alkoxy carbonyl, the C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each 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, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and 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; The C1-C5 alkoxyl group, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl; The C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, hydroxyl, C2-C5 alkenyloxy, C1-C5 alkoxyl group (C1-C5) alkoxyl group; C1-C5 alkoxyl group (C1-C5) alkoxyl group (C1-C5) alkyl, C1-C3 alkylpiperazine base, piperazinyl (C1-C5) alkoxyl group, piperidyl (C1-C5) alkoxyl group, C1-C5 alkoxyl group (C1-C5) alkylamino; The C1-C7 alkylamino, morpholinyl, morpholinyl (C1-C5) alkyl oxy, THP trtrahydropyranyl oxygen base, 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, C1-C5 alkyl-carbonyl, C1-C5 alkylthio; The C1-C5 alkyl sulphonyl, C1-C5 alkoxy carbonyl, or piperidyl oxygen base, it is not substituted or is replaced by the C1-C5 alkoxy carbonyl; With

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxy carbonyl; The C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl; Halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl; The C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and C1-C5 alkoxy carbonyl, and R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

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

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, halogen, C1-C5 alkyl, or phenyl;

R ₁Be C2-C5 alkenyl or C2-C5 alkynyl;

R ₂Be hydrogen, halogen, nitro, cyanic acid, C1-C5 alkyl; The C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxyl; The C1-C5 alkoxy carbonyl, the C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each 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, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and 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; The C1-C5 alkoxyl group, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl; The C1-C5 alkyl-carbonyl, the C1-C5 alkoxy carbonyl, phenyl, or halogen, wherein phenyl can not be substituted or replace by being selected from following one or more substituting groups: carboxyl; The C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and C1-C5 alkoxy carbonyl; And

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxy carbonyl; The C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl; Halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl; The C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and C1-C5 alkoxy carbonyl, and R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

Another aspect of the present invention is the compound according to above-mentioned formula (I); Or its isomer or its pharmaceutical salts;

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, halogen, C1-C5 alkyl, or phenyl;

R ₁Be vinyl, ethynyl, propenyl, or proyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or phenyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₆, R ₇, and R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, nitro, vinyl, ethynyl, methylthio group, trifluoromethyl, methoxycarbonyl, or halogen; And

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, phenyl, phenyl (C1-C3) alkyl, or C1-C3 alkoxyl phenyl, wherein R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, trifluoromethyl, phenyl, or benzyl.

A preferred embodiment of the present invention relates to the compound of above-mentioned formula (I), and it has following one or more characteristic:

R wherein ₉Be-SO ₂R ₁₃And R ₁₀Be the compound of hydrogen, wherein R ₉More preferably be methane sulfonyl, the ethane alkylsulfonyl, trifluoromethane sulfonyl group, or ethene alkylsulfonyl, and most preferably be methane sulfonyl;

R wherein ₆Be the C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio, or the compound of halogen; R wherein ₆Be halo (C1-C3) alkyl, those compounds of the sec.-propyl or the tertiary butyl are preferred, and R wherein ₆The compound that is the sec.-propyl or the tertiary butyl is most preferred;

R wherein ₃It is the compound of hydrogen or C1-C5 alkyl; R wherein ₃Be hydrogen or methyl compound be most preferred;

R wherein ₄, R ₅, R ₇, and R ₈Preferably be hydrogen independently, C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio, or the compound of hydrogen; R wherein ₅, R ₇, and R ₈Those compounds that are hydrogen are most preferred;

R wherein ₁Be vinyl, ethynyl, propenyl, or proyl most preferably are the compounds of vinyl or ethynyl; Or

R wherein ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or the compound of phenyl; R most preferably ₂Be hydrogen, fluorine, chlorine, bromine, iodine, or methyl.

Another preferred embodiment of the present invention is the compound of above-mentioned formula (I), wherein

X is NHCH ₂, CH ₂=CH ₂, or C ≡ C;

R ₁Be vinyl or ethynyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or phenyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, R ₈, and R ₁₀Be hydrogen;

R ₆Be chlorine, the sec.-propyl or the tertiary butyl and particularly preferably be the sec.-propyl or the tertiary butyl; With

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

A compound that particularly preferred embodiment is formula (Ia) of the present invention

Wherein

X is NHCH ₂Or CH ₂=CH ₂

R ₁Be vinyl or ethynyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or phenyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, and R ₈Be hydrogen; And

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

Another embodiment preferred of the present invention relates to the compound of formula I, its isomer, or its pharmaceutical salts

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, NH, CHR ₁₁CHR ₁₂Or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, fluorine, or methyl;

R ₁Be vinyl, ethynyl, propenyl, or proyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, ethynyl, vinyl, carboxyl, or methoxycarbonyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, and R ₈Be hydrogen independently, fluorine, carboxyl, methyl, ethyl, propyl group, sec.-propyl; The tertiary butyl, nitro, vinyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen; Methoxy ethoxy, the methoxy ethoxy methyl, the N-METHYL PIPERAZINE base, methoxy ethyl is amino, hydroxyl, methoxyl group, allyl group oxygen base; Isohexyl is amino, isobutylamino (ammino), and sec.-propyl is amino, morpholinyl, morpholinyl oxyethyl group, or THP trtrahydropyranyl oxygen base;

R ₆Be C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl; And

R ₉And R ₁₀Be hydrogen or methane sulfonyl independently.

Another preferred embodiment of the present invention is the compound of above-mentioned formula I, wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, CHR ₁₁CHR ₁₂Or C ≡ C, wherein R ₁₁Be hydrogen or methyl and R ₁₂Be hydrogen;

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄, be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R5, R7 and R8 are hydrogen or fluorine;

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

And particularly preferably be the sec.-propyl or the tertiary butyl; With

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

Another embodiment preferred of the present invention is the compound of above-mentioned formula I, wherein

X is CR ₁₁=CR ₁₂, R wherein ₁₁Be hydrogen or methyl and R ₁₂Be hydrogen;

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R5, R7 and R8 are hydrogen or fluorine;

R ₆Be C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl; With

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

Another embodiment preferred of the present invention is the compound of above-mentioned formula I, wherein

X is C ≡ C;

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R5, R7 and R8 are hydrogen or fluorine;

R ₆Be C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl; With

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

Another embodiment preferred of the present invention is the compound of above-mentioned formula I, wherein

X is NHCH ₂,

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group,

Methoxy ethyl is amino,

Allyl group oxygen base, or THP trtrahydropyranyl oxygen base and particularly preferably be hydrogen or fluorine;

R5, R7 and R8 are hydrogen or fluorine;

R ₆Be C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl; With

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

Another embodiment preferred of the present invention is the compound of above-mentioned formula I, wherein

X is CHR ₁₁CHR ₁₂, R wherein ₁₁Be hydrogen or methyl and R ₁₂Be hydrogen;

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base and particularly preferably be hydrogen, fluorine or THP trtrahydropyranyl oxygen base;

R5, R7 and R8 are hydrogen or fluorine;

R ₆Be C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl;

And

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

Another embodiment preferred of the present invention is the compound of above-mentioned formula I, wherein

X is NH,

R ₁Be vinyl or ethynyl;

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

R ₃It is methyl;

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino,

Allyl group oxygen base, or THP trtrahydropyranyl oxygen base and particularly preferably be hydrogen or fluorine;

R5, R7 and R8 are hydrogen or fluorine;

R ₆Be C3-C5 alkyl or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl;

And

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

One embodiment of the invention relate to as above the further compound of the formula I of definition, and wherein X is CHR11-CHR12.These compounds have general formula (Ib).

Wherein

R ₁₁And R ₁₂Be hydrogen independently, halogen, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, or phenyl;

R ₁Be C2-C5 alkenyl or C2-C5 alkynyl;

R ₂Be hydrogen, halogen, nitro, cyanic acid, C1-C5 alkyl; The C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxyl; The C1-C5 alkoxy carbonyl, the C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each 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, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and 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; The C1-C5 alkoxyl group, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl; The C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, hydroxyl, C2-C5 alkenyloxy, C1-C5 alkoxyl group (C1-C5) alkoxyl group; C1-C5 alkoxyl group (C1-C5) alkoxyl group (C1-C5) alkyl, C1-C3 alkylpiperazine base, piperazinyl (C1-C5) alkoxyl group, piperidyl (C1-C5) alkoxyl group, C1-C5 alkoxyl group (C1-C5) alkylamino; The C1-C7 alkylamino, morpholinyl, morpholinyl (C1-C5) alkyl oxy, THP trtrahydropyranyl oxygen base, 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, C1-C5 alkyl-carbonyl; The C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, the C1-C5 alkoxy carbonyl, or unsubstituted or by the substituted piperidyl oxygen of C1-C5 alkoxy carbonyl base; R wherein ₆C3-C5 alkyl or halo (C1-C3) alkyl preferably, and particularly preferably be the sec.-propyl or the tertiary butyl; And

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxy carbonyl; The C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl; Halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl; The C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and C1-C5 alkoxy carbonyl, and R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

Preferably, in above-mentioned figure (Ib),

R ₁₁And R ₁₂Be methyl or hydrogen;

R ₁Be vinyl or ethynyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, or methoxycarbonyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, and R ₈Be hydrogen independently, fluorine, carboxyl, methyl, ethyl, propyl group, sec.-propyl; The tertiary butyl, nitro, vinyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen; Methoxy ethoxy, the methoxy ethoxy methyl, the N-METHYL PIPERAZINE base, methoxy ethyl is amino, hydroxyl, methoxyl group, allyl group oxygen base; Isohexyl is amino, isobutylamino (ammino), and sec.-propyl is amino, morpholinyl, morpholinyl oxyethyl group, or THP trtrahydropyranyl oxygen base; And

R ₆Be sec.-propyl, the tertiary butyl, or halo (C1-C3) alkyl and particularly preferably be the sec.-propyl or the tertiary butyl.

Even more preferably, in above-mentioned figure (Ib),

R ₁₁Be hydrogen or methyl, and R ₁₂Be hydrogen;

R ₁Be vinyl or ethynyl;

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

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R ₅, R ₇And R ₈Be hydrogen or fluorine;

R ₆It is the tertiary butyl;

R ₉Be hydrogen; And

R ₁₀The expression methane sulfonyl.

According to an importance of the present invention, in above-mentioned formula (I) and compound (Ib), R ₉Be hydrogen, R ₁₀Be methane sulfonyl and R ₁Ortho position with amino with respect to methane sulfonyl is incorporated into phenyl ring.Those preferred compounds have general formula (Ic).

R wherein ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈Has implication with X, wherein about formula I and the various embodiment preferred of compound (Ib) and the compound that characteristic also is applicable to formula (Ic) according to the various embodiments of above-mentioned definition.

According to one aspect of the present invention, in above-mentioned formula (I) and compound (Ib), R ₉Be hydrogen, R ₁₀Be methane sulfonyl and R ₁And R ₂All be incorporated into phenyl ring with the ortho position amino with respect to methane sulfonyl.Those preferred compounds have general formula (Id).

R wherein ₁, R ₂, R ₃, R ₄, R ₅, R ₆, R ₇, R ₈Has implication with X, wherein about formula I and the various embodiment preferred of compound (Ib) and the compound that characteristic also is applicable to formula (Id) according to the various embodiments of above-mentioned definition.

In formula (Ic) or compound (Id), most preferably

X is CHR ₁₁CHR ₁₂Or X is selected from NHCH ₂, CR ₁₁=CR ₁₂With C ≡ C;

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R ₅, R ₇And R ₈Be hydrogen or fluorine; And

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

Preferred embodiment according to compound of the present invention is selected from the group of being made up of following:

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethynyl-6-fluorophenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethynyl phenyl } NSC-249992,

N-(4-{1-(R)-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992,

(R)-N-(4-{1-[3-(the 4-tertiary butyl-benzyl)-urea groups]-ethyl }-2-fluoro-6-vinyl-phenyl)-NSC-249992,

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-methyl-6-vinyl-phenyl }-NSC-249992,

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-chloro-6-vinyl-phenyl }-NSC-249992,

3-(4-tert-butyl-phenyl) propynoic acid 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl acid amides,

3-(4-tert-butyl-phenyl) propynoic acid [1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acid amides,

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-5-ethynyl-4-methane sulfonyl amino-benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide,

3-(4-trifluoromethyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-methoxy ethoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-p-methoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide,

3-(2-allyl group oxygen base-4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(the 3-methylbutyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] propionic acid amide,

3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-USAF RH-1,

3-(4-tert-butyl-phenyl)-2-fluoro-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) propionic acid amide,

3-(4-tert-butyl-phenyl)-N-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl]-2-USAF RH-1,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-methyl propanamide,

3-[4-(tertiary butyl) phenyl]-[N-4-(methane sulfonyl is amino)-3-vinyl benzyl] propionic acid amide,

3-[4-(tertiary butyl) phenyl]-[N-3-fluoro-4-(methane sulfonyl is amino)-5-vinyl benzyl] propionic acid amide,

3-(the 4-tertiary butyl-phenyl)-N-(3-ethynyl-5-fluoro-4-methane sulfonyl amino-benzyl)-propionic acid amide,

N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992,

N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethynyl phenyl) NSC-249992,

N-{4-[3-(4-tert-butyl-phenyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992 and

Vinyl sulfonic acid (4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) acid amides.

According to preferred especially compound of the present invention be

(R)-N-(4-{1-[3-(the 4-tertiary butyl-benzyl)-urea groups]-ethyl }-2-fluoro-6-vinyl-phenyl)-NSC-249992,

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-5-ethynyl-4-methane sulfonyl amino-benzyl) acrylic amide,

(R)-3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] propionic acid amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-USAF RH-1,

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) propionic acid amide,

(R)-3-(4-tert-butyl-phenyl)-N-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl]-2-USAF RH-1,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethynyl-6-fluorophenyl } NSC-249992,

3-(4-tert-butyl-phenyl) propynoic acid 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl acid amides,

3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(2-methoxyl group-oxyethyl group)-phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl)-acrylic amide,

3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-p-methoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide,

3-(2-allyl group oxygen base-4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

(R)-3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-methyl propanamide,

3-[4-(tertiary butyl) phenyl]-[N-4-(methane sulfonyl is amino)]]-the 3-vinyl benzyl] propionic acid amide,

N-(4-{1-(R)-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992,

3-[4-(tertiary butyl) phenyl]-N-[3-fluoro-4-(methane sulfonyl amino)-5-vinyl benzyl] propionic acid amide and

(R)-N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992.

The structure of embodiments of the invention compound is presented in the table 1.

[table 1]

Compound according to formula of the present invention (I) can synthesize with chemical mode through following reaction scheme.Yet these only are to provide from illustrating the object of the invention, and are not intended to limit them.

[route 1]

Above-mentioned route 1 shows synthetic method with sym-Dibenzylurea of vinyl or ethynyl.At first, make the reaction of substituted benzylamine and tert-Butyl dicarbonate add the substituted benzylamine (2) with vinyl or ethynyl has vinyl or ethynyl with generation sym-Dibenzylurea (3) immediately with original position generation benzylamino manthanoate and to this reaction mixture.

[route 2]

Above-mentioned route 2 shows the whole bag of tricks of synthetic urea derivatives.At first, Boc verivate (4) reduction with the 4-nitro-benzylamine produces aniline compound (5).The consecutive position of iodo being introduced the amino of compound (5) produces compound (6).The iodization of compound (5) can also through use iodine and Sulfuric acid disilver salt 0 ℃ the acquisition of the ortho position of amino (Synth.Commun.1992,22,3215-3219).The vinyl tin hydride compounds is coupled to compound (6) has vinyl with generation compound (7).The amino of methane sulfonyl being introduced compound (7) is to produce compound (8).Use TFA (trifluoroacetic acid) to remove protection base (Boc) to produce benzylamine compound (9).According to synthesizing dibenzyl urea-derivatives (10) with route 1 said similar methods.

[route 3]

In the various reactions of synthetic urea derivatives, above-mentioned route 3 shows synthetic method with suggestion of optically active urea derivatives.Have optically active carbamide compound (17) according to above-mentioned route 3 is synthetic, wherein will be at R ₃The position has the reactant of methyl or ethyl as starting material.

[route 4]

Above-mentioned route 4 shows the method for the proposal of synthesis of acrylamide compound (19).Be dissolved among the DMF undersaturated aromatic substituted acrylic acid (18) and diethylcyanophosphonise and stirring.In this reaction soln, add benzylamine compound (2) and the solution stirring that obtains is spent the night to produce acrylamide compound (19).

[route 5]

Above-mentioned route 5 shows the another kind of method of synthesis of acrylamide compound.Use DMTMM{4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methylmorpholine muriate } (Tetrahedron Lett., 1999,40,5327) replacement diethylcyanophosphonise comes synthetic compound (20).

[route 6]

Above-mentioned route 6 shows the method for the recommendation of synthetic propiolyl amine compound (23).Make and have the reaction of triple-linked acid cpd (22) and benzylamine compound (2) to produce purpose compound (23).

[route 7]

Above-mentioned route 7 shows the method for the recommendation of synthesis of acrylamide derivatives (26).To have various substituent fatty acid ester compounds (24) hydrolysis in the alkene site of unsaturated fatty acids to produce lipid acid (25).According to route 4 said identical methods, use to have substituent unsaturated fatty acids (25) and come synthetic compound (26).

[route 8]

Above-mentioned route 8 shows synthetic method with recommendation of the substituent acrylamide compound of ethynyl (34).The consecutive position of amido of at first, iodine being introduced aniline compound (28) is to produce compound (29).Reduction iodine compound and in addition benzylamine is carried out Boc-protection to produce compound (30).Can also reduce through order and come synthetic compound (30) with iodization.Behind iodo, the amido of contiguous benzene is handled to produce compound (32) with methane sulfonyl with ethynyl substitution compound (30).The Boc-protection base of compound (32) is removed with preparation benzylamine compound (33).To have substituent benzylamine compound of ethynyl (33) and unsaturated fatty acids acid-respons to produce acrylamide compound (34).

[route 9]

Above-mentioned route 9 shows the method with the recommendation of the synthetic carbamide compound (35) of ethynyl substituting group.

[route 10]

Above-mentioned route 10 shows the novel method of using the synthetic carbamide compound of benzyl isocyanate ester cpds.

[route 11]

Above-mentioned route 11 shows the other reaction of synthetic various urea derivativess.Make and have the reaction of various substituent benzylamine compounds and (the 4-tertiary butyl-benzyl)-carboxylamine phenylester has vinyl with generation carbamide compound (10).

[route 12]

Route 12 shows the method for the recommendation of synthesizing the carbamide compound (39) with vinyl substituted base.

[route 13]

Route 13 shows the method for the recommendation of synthesizing the carbamide compound with ethane sulfuryl amino.Make the reaction of aniline compound and 2-monochloroethane SULPHURYL CHLORIDE have the amino compound (40) of vinylsulfonyl with generation.Make compound (40) and tributyl tin reaction produce compound (41).The protection base of removing compound (41) is with preparation benzylamine compound (42).Make benzylamine compound (42) with ethene sulfuryl amino and 4-tert-butyl-phenyl isocyanate reaction to produce amide compound (43).

[route 14]

Route 14 shows the method for the recommendation of synthesizing the carbamide compound with phenylacetylene base.Iodoaniline compound and phenylacetylene base are reacted to produce compound (44) through sonogashira reaction and phenylacetylene.Make compound (44) and sulfonyl methane anhydride reactant to produce compound (45).Handle compound (45) to produce benzylamine compound (46) with TFA.Aniline compound (46) and phenyl isocyanate are reacted to produce carbamide compound (47).The carbamide compound (48) that has the diphenylphosphino ethane part with lindlar catalyst reduction compound (47) with preparation.

[route 15]

Route 15 shows the synthetic various substituent acrylamide compounds that have.Make 3-tert.-butyl phenol and NIS reaction to produce compound (50).Compound (50) and methyl acrylate are reacted to produce compound (51).Compound (51) and alkylogen or alkoxyl group halogen are reacted to produce compound (52).Under alkaline condition, hydrolysis compound (52).Compound (53) reacts to produce compound (55) with benzylamine compound.

[route 16]

Route 16 also shows synthetic method with recommendation of various substituent acrylamide compounds.

[route 17]

Above-mentioned route 17 shows two kinds of methods of synthesizing propionyl amine compound (61).Through using DEPC (diethylcyanophosphonise) or DMTMM to obtain Amid compound (61).

[route 18]

Route 17 shows the method for synthetic (R)-N-[4-(1-amino-ethyl)-2-fluoro-6-ethenylphenyl] NSC-249992 (71).Butyl vinyl ether is coupled to Iodoaniline (62) to produce compound (63).The iodization of compound (62) can obtain through using NIS.Compound (64) with (R)-(+)-reaction of 2-methyl-2-propane-2-sulfinyl amine to be to produce 2-methylpropane-2--sulfinic acid [1-(4-amino-3-fluoro-5-iodophenyl) ethyl] acid amides (65).With 1N HCl solution reduction compound (65) to produce compound (67).According to route 3 similar methods synthetic compounds (71).

[route 19]

Route 17 shows synthetic concrete undersaturated amide compound (72), the method for amide compound (73) and carbamide compound (74).

The present invention also provides and comprises formula (I), and (Ia), (Ib), (Ic) or compound (Id), its isomer or its pharmaceutical salts are as the pharmaceutical composition of activeconstituents and pharmaceutical carrier.

In said pharmaceutical composition, as the formula (I) of activeconstituents, (Ia), (Ib), (Ic) or compound (Id), its isomer; Or thereby its pharmaceutical salts and pharmaceutical carrier exist prevention or treatment pain, acute pain, neuropathic pain, postoperative pain, migraine, arthrodynia with significant quantity; Neuropathy, nerve injury, diabetic neuropathy, neurodegeneration, apoplexy, nervosa/allergy/inflammatory dermatosis; Psoriatic, pruritus, pruigo, irritable bladder, irritable bowel syndrome, just anxious; Segmental enteritis, respiratory disease such as asthma or chronic obstructive pulmonary disease, the stimulation of skin, 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 compsn comprises formula (I), (Ia), and (Ib), (Ic) or compound (Id), 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 compsn comprises formula (I), (Ia), and (Ib), (Ic) or compound (Id), its isomer or its pharmaceutical salts and pharmaceutical carrier.

In above-mentioned, the said 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 MMi; Gastroduodenal ulcer, inflammatory diseases, otopathy, or heart trouble.

More specifically, the said illness relevant with novel vanilloid receptor is acute pain, chronic pain, neuropathic pain, postoperative pain, rheumatic arthralgia; Osteoarthrosis pain, PHN, 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 is irritated, or the variable force ischemia.

One preferred aspect, the present invention provides pharmaceutical composition to be used to treat 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, said pharmaceutical composition comprise according to formula (I), (Ia); (Ib), (Ic) or (Id) each compound, its isomer or its pharmaceutical salts are like top further definition.

More specifically, compound of the present invention can be used in the pharmaceutical composition, and said pharmaceutical composition is used to treat pain; Wherein said pain is to be selected from following illness: osteo-arthritis (" 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 osteo-arthritis, does not get rid of it yet and also comprises the treatment to other S&S of osteo-arthritis.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 osteo-arthritis with osteo-arthritis.

Term " inflammatory diseases in joint " comprises and relates in the joint the more or less disease of the inflammatory process of degree that said joint refers to for example at knee, in the hip etc.The instance of such disease is an osteo-arthritis.Term " inflammatory diseases in joint " also comprises the disease or the illness that possibly 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 through reducing the pain relevant with the motion in said joint.

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

When being used for this paper, term " osteo-arthritis (OA) " typically comprises and has movable joint property the disease of the obstacle in (movably, having synovia) joint.In primary (former) OA, in the modal form of said 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 through rest, and still, when PD, 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 possibly 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 through being called as the antibody of " rheumatic (" the rheumatoid ") factor " in the detection blood and/or being confirmed through 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 in the patient who suffers RA or AS, reducing the inflammation and/or the swelling of synovial membrane and helping to improve the joint.

" 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; Said 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 compsn, alleviating the pain that is experienced by the experimenter immediately.The result of another of treatment can be the generation again of prevent irritation, and said pain is former to be alleviated because of drug effect.Another result of treatment reduces 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.The minimizing of the muscle susceptibility that said treatment can suitably cause increasing, the muscle susceptibility of said increase are 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 relevant 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 through 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 said myofascial tissue was strained and lost their elasticity, the neurotransmitter that can between brain and health, send and receive information 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 to treat 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 to be used for the part or to use through skin.

In one aspect of the method, the present invention relates in the patient, suppress the method that the plain part of vanilla combines novel vanilloid receptor, said method comprises cell and the formula (I) of in the patient, expressing novel vanilloid receptor that make; (Ia), (Ib), (Ic) or compound (Id); 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 MMi, gastroduodenal ulcer, inflammatory diseases, said method comprise to its formula (I) of the administration treatment significant quantity that comprises the people of needs; (Ia), (Ib), (Ic) or compound (Id), its isomer, or its pharmaceutical salts.

In aforesaid method, said 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, said pain is to be selected from following illness or the pain relevant with it: osteo-arthritis (" OA "); Rheumatoid arthritis (" RA "), ankylosing spondylitis (" AS "), diabetic neuropathic pain; Non-inflammatory flesh skeletal pain (comprises fibromyalgia; Myofascial pain syndrome and backache), postoperative pain, the headache of migraine and other type.

In one aspect of the method, the present invention relates to formula (I), (Ia), (Ib), (Ic) or compound (Id), 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 (I), (Ia); (Ib), (Ic) or compound (Id), its isomer; Or its pharmaceutical salts is used to prevent or treat the application of the illness that relates to novel vanilloid receptor, and said 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 (I), (Ia), (Ib), (Ic) or compound (Id), its isomer, or the application of its pharmaceutical salts in the preparation medicine, said medicine is used to prevent or treat the illness that relates to novel vanilloid receptor.

In aspect preferred, the present invention relates to formula (I), (Ia), (Ib); (Ic) or compound (Id), 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 said 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 preferred especially, the present invention relates to use compound to be used to treat above-mentioned pain, wherein said pain is to be selected from following illness: osteo-arthritis (" 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 (I), (Ia), (Ib), (Ic) or compound (Id), 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, Ucar 35, or other be generally used for produce in the solvent of injection.The instance that is fit to of carrier comprises saline water, polyoxyethylene glycol, and ethanol, vegetables oil, tetradecyl isopropyl ester etc., but be not limited to them.For topical application, can compound of the present invention be prepared with the form of ointment or ointment.

Can also be with using 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 through in water-soluble solvent such as salt solution and 5% Vadex or at water-immiscible solvent such as vegetables oil, and the synthetic glycerol fatty acid ester more dissolves in high-grade fatty ester and the Ucar 35, suspension or emulsification and be mixed with injection.Preparation of the present invention can comprise the additive that any is commonly used, like 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, formulation and route of 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 compsn, 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 all means, like 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 said compound; When using the application of these compounds and method for compositions and these compounds and compsn, use all terms in this application all to have this area person skilled; 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, n-propyl, sec.-propyl, normal-butyl, isobutyl-, tertiary butyl institute illustration.

" 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).

" alkylamino " comprises group-NR ' R ", wherein-R ' is an alkyl and R " is selected from hydrogen or alkyl.

" alkyl sulphonyl " comprises atomic group-S (O) ₂R, wherein R is the alkyl like this paper definition.Representational instance includes, but not limited to methane sulfonyl, ethylsulfonyl, sulfonyl propyl base, butyl alkylsulfonyl etc.

" alkylthio " comprises atomic group-S-R, and wherein R is the alkyl like this paper definition, can randomly define like this paper to be substituted.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 also is called 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.

" alkylhalide group " comprises that it is replaced by one or more halogens like further " alkyl " of definition of preceding text, and said halogen can be identical, and for example in trifluoromethyl or pentafluoroethyl group, or it can be different.

" hydroxyl " refers to atomic group-OH.

" nitro " refers to atomic group-NO ₂.

" piperidyl (C1-C5) oxygen base " refers to be incorporated into the piperidyl residue of " alkoxyl group " that further define like preceding text, and wherein said piperidyl preferably is connected in the C atom of " alkoxyl group " through nitrogen-atoms or through the contraposition-C-atom of piperidine ring.

" morpholinyl (C1-C5) alkoxyl group " refers to be incorporated into the morpholine residue of " alkoxyl group ", and wherein said morpholine ring preferably is incorporated into the C atom of " alkoxyl group " through the nitrogen-atoms of morpholine ring.

" THP trtrahydropyranyl oxygen base " refers to be incorporated into oxo, and (O-) THP trtrahydropyranyl of base, wherein said oxo group preferably is incorporated into the contraposition C atom of THP trtrahydropyranyl.

" alkylpiperazine base " refers to carry " alkyl " as substituent piperazine ring.Preferably said piperazine ring is incorporated into " alkyl " and is connected in second connection site through its nitrogen-atoms.

" piperidyl oxygen base " refers to be incorporated into oxo, and (O-) piperidyl of base, wherein said oxo group preferably is incorporated into the contraposition C atom of said piperidyl.

" 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 in USP or other general pharmacopeia, listing.

" 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, like acetate, propionic acid, caproic acid, pentamethylene propionic acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid; Succsinic acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, Hydrocerol A, phenylformic acid, 3-(4-(2-hydroxybenzoyl)) phenylformic acid; Styracin, racemic melic acid, methanesulfonic, ethane sulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, Phenylsulfonic acid; The 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; Tert.-butylacetic acid, dodecyl sulphate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, Triple Pressed Stearic Acid, the acid salt that muconic acid etc. form; Or (2) salt of when the acid proton that in parent compound, exists 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, said experimenter can be exposed to or susceptible in said disease, but do not experience this disease as yet or show the symptom of this disease).

" experimenter " comprises the people." people, " patient " and " experimenter " exchange use at this paper to term.

" 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 be depended 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 said disease or sufferer (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 possibly 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.

The mode of embodiment of the present invention

The present invention more specifically sets forth through 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.

Embodiment 1:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethenylphenyl } NSC-249992

Step 1: (4-nitrobenzyl) t-butyl carbamate

(1g, 5.302mmol 1eq.) place 100ml round-bottomed flask and be dissolved in saturated solution (NaHCO with 4-nitro-benzylamine HCl ₃: CH ₂Cl ₂=1: 1).To this solution add tert-Butyl dicarbonate (3.66ml, 15.906mmol, 3eq.) and stirred 3 hours.After confirming that with TLC reaction finishes, reaction soln is used dichloromethane extraction, water (2 times) and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=10/1) to produce light green solid (1.3171g).

IR (KBr pellet, cm ^-1): 3330,3080,301,2984,2916,1687,1513;

¹H?NMR(400MHz，CDCl ₃)：8.11(d，2H，J＝8.4Hz)，7.37(d，2H，J＝8.4Hz)，4.99(bs，1H)，4.37(d，2H，J＝5.6Hz)，1.39(s，9H).

Step 2: (4-aminobenzyl) t-butyl carbamate

(1.3071g, 5.880mmol 1eq.) place 100ml round-bottomed flask and be dissolved in methyl alcohol with (4-nitrobenzyl) t-butyl carbamate.Pd/c (10wt% of about substrate) is added in the reaction mixture.Air in the flask is replaced about 15 times with hydrogen.

With the solution that obtains stirring at room 2 hours.After confirming reaction process with TLC, with reaction soln filter through C salt and evaporation to produce light yellow solid (1.1451g).

IR (KBr pellet, cm ^-1): 3426,3346,3021,2995,2976,1687;

¹H?NMR(400MHz，CDCl ₃)：7.09(d，2H，J＝8.0Hz)，6.70(d，2H，J＝8.0Hz)，4.74(bs，1H)，4.20(d，2H，J＝5.0Hz)，3.34(bs，2H)，1.46(s，9H).

Step 3: (4-amino-3-iodine benzyl) t-butyl carbamate

With argon gas be full of 100ml two neck round-bottomed flasks and (1eq.) solution in methylene dichloride places flask for 986.2mg, 3.909mmol with (4-aminobenzyl) t-butyl carbamate.To this solution add iodine monochloride (698.2mg, 4.300mmol, 1.1eq.) and stirred 1 hour.After confirming that with TLC reaction finishes, add saturated hypo solution to this solution and also stir.Reaction soln is used dichloromethane extraction, and water (2 times) and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=3/1) to produce brown liquid (640mg).

(NaCl is pure, cm for IR ^-1): 3421,3349,2976,2929,1695;

¹H?NMR(400MHz，CDCl ₃)：7.49(d，1H，J＝2.0Hz)，6.98(dd，1H，J＝8.0，2.0Hz)，6.61(d，1H，J＝8.0Hz)，4.87(bs，1H)，4.07(d，2H，J＝4.0Hz)，3.98(bs，2H)，1.40(s，9H)

Step 4: (4-amino-3-vinyl benzyl) t-butyl carbamate

With argon gas be full of 50ml two neck round-bottomed flasks and with tetrakis triphenylphosphine palladium (0) (123.7mg, 0.107mmol, 0.06eq.) and lithium chloride (2.8eq.) solution in DMF places flask for 211.9mg, 4.998mmol.To this solution add (4-amino-3-iodine benzyl) t-butyl carbamate (621.4mg, 1.875mmol, 1eq.) and tributylvinyl tin (782.5mg, 2.678mmol, 1.5eq.). this mixture solution is heated to 90 ℃ to reflux a night.After confirming that with TLC reaction finishes, reaction soln is used dichloromethane extraction, water and brine wash through dried over sodium sulfate, are filtered and evaporation.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=3/1) to produce brown liquid.

Step 5: (4-methane sulfonyl amino-3-vinyl benzyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of 50ml with argon gas, and (1eq.) solution in methylene dichloride places flask for 343.0mg, 1.381mmol with (4-aminobenzyl) t-butyl carbamate.At 0 ℃, to this solution add sulfonyl methane acid anhydride (264.7mg, 1.519mmol, 1.1eq.), add subsequently pyridine (332.0 μ l, 4.413mmol, 2eq.) and stirred 1 hour.After confirming that with TLC reaction finishes, add saturated sodium hydrogen carbonate solution and stirred 5 minutes to this solution.Reaction soln is also used 5%HCl, saturated sodium hydrogen carbonate solution, water and brine wash with dichloromethane extraction.The solution that obtains through dried over sodium sulfate, is filtered and evaporation.The solid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1) to produce light yellow solid (161.6mg).

IR (KBr pellet, cm ^-1): 3414,3359,3269,3254,3083,2982,2927,1685;

¹H?NMR(400MHz，CDCl ₃)：7.35(d，1H，J＝8.0Hz)，7.33(d，1H，J＝2.0Hz)，7.14(dd，1H，J＝8.0，2.0Hz)，6.84(dd，1H，J＝17.2，10.8Hz)，6.44(bs，1H)，5.65(d，1H，J＝17.2Hz)，5.40(d，1H，J＝10.8Hz)，4.84(bs，1H)，4.23(d，2H，J＝5.6Hz)，2，91(s，3H)，1.39(s，9H)

Step 6:N-(4-amino methyl-2-ethenylphenyl) NSC-249992

(4-methane sulfonyl amino-3-vinyl benzyl) t-butyl carbamate (161.6mg) is placed 1 00ml round-bottomed flask and is dissolved in methylene dichloride.Add trifluoroacetic acid and stir a night to this solution.After confirming that with TLC reaction finishes, under reduced pressure concentrated reaction solution is to produce brown liquid (198.6mg).

Step 7:N-4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethenylphenyl NSC-249992

Be full of two neck round-bottomed flasks of 25ml and (1eq.) solution in methylene dichloride places flask for 27.7 μ l, 0.158mmol with the 4-tert-butyl benzyl amine with argon gas.To this solution add 4-dimethylaminopyridine (3.9mg, 0.032mmol, 0.2eq.) and tert-Butyl dicarbonate (43.6 μ l, 0.190mmol is 1.2eq.) and stirring at room 1 hour 30 minutes.With the solution that obtains be cooled to 0 ℃ and add N-(4-amino methyl-2-vinyl-phenyl)-NSC-249992 (35.7mg, 0.158mmol, 1eq.) and triethylamine (44.0 μ l, 0.316mmol, 2eq.) solution in methylene dichloride.With mixture solution in stirred overnight at room temperature.After confirming that with TLC reaction finishes, under reduced pressure remove methylene dichloride.Resistates is carried out column chromatography (n-hexane/ethyl acetate=1/2) to produce light yellow solid (35.6mg, 54.2%).

mp：108-109℃；

IR (KBr pellet, cm ^-1): 3413,3023,2961,2927,1735;

¹H?NMR(400MHz，CDCl ₃)：7.26(d，1H，J＝1.6Hz)，7.24(d，2H，J＝8.4Hz)，7.17(d，1H，J＝8.0Hz)，7.10(d，2H，J＝8.4Hz)，6.99(dd，1H，J＝8.0，1.6Hz)，6.80(dd，1H，J＝17.2，10.8Hz)，6.70(s，1H)，5.58(dd，1H，J＝17.2，0.8Hz)，5.31(dd，1H，J＝10.8，0.8Hz)，4.10(bs，2H)，4.20(s，2H)，2.83(s，3H)，1.21(s，9H)

Embodiment 2:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992

Step 1:4-amino methyl-2-fluoro-6-Iodoaniline

Be full of two neck round-bottomed flasks of 50ml and with 4-amino-(1eq.) solution in THF places flask to 3-fluoro-5-iodo-benzonitrile for 84.4mg, 0.322mmol, then is cooled to 0 ℃ with argon gas.To this solution add borine-THF complex solution (solution of 1.0M in THF, 0.64ml, 0.644mmol, 2eq.).The temperature of reaction mixture is elevated to room temperature.With reaction mixture heating and backflow.After confirming that with TLC reaction finishes, add 5%HCl and stirred 20 minutes to this solution.The solution that uses 1N KOH to alkalize and obtain extracts with ether, uses brine wash, through Na ₂SO ₄Dry.The liquid that obtains is under reduced pressure concentrated to produce light yellow solid (78.4mg, 80.5%).

IR (KBr pellet, cm ^-1): 3429,2923,2853,1626;

¹H?NMR(400MHz，CD ₃OD)：7.33(s，1H)，6.93(dd，1H，J＝11.6，2.0Hz)，3.58(s，2H)，

Step 2: (4-amino-3-fluoro-5-iodine benzyl) t-butyl carbamate

With argon gas be full of 25ml two neck round-bottomed flasks and with 4-amino methyl-2-fluoro-6-Iodoaniline (31.9mg, 0.120mmol, 1eq.) and triethylamine (1.1eq.) solution in methylene dichloride places flask and then be cooled to 0 ℃ for 18.4 μ l, 0.132mmol.To this solution add 4-dimethylaminopyridine (1.47mg, 0.012mmol, 0.1eq.) and tert-Butyl dicarbonate (27.6 μ l, 0.120mmol, 1eq.) and stirred 5 hours.After confirming that with TLC reaction finishes, reaction soln is used dichloromethane extraction, and water and brine wash through dried over sodium sulfate, and under reduced pressure concentrate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=5/1) to produce yellow liquid (9.8mg, 22.3%).

(NaCl is pure, cm for IR ^-1): 3451,3351,2975,2928,1698;

¹H?NMR(400MHz，CDCl ₃)：7.87(s，0.2H)，7.44(d，0.2H，J＝11.2Hz)，7.26(s，1H)，6.87(d，1H，J＝11.2Hz)，4.72(bs，2H)，4.08(d，2H，J＝4.4Hz)，1.39(s，9H)

Step 3: (4-amino-3-fluoro-5-vinyl benzyl) t-butyl carbamate

With argon gas be full of two neck round-bottomed flasks of 25ml and with four (triphenylphosphine palladium (0) (and 18.9mg, 0.016mmol, 0.06eq.) and lithium chloride (2.8eq.) solution in DMF places flask for 32.4mg, 0.765mmol.To this solution add (4-amino-3-fluoro-5-iodo-benzyl)-t-butyl carbamate (100mg, 0.273mmol, 1eq.) with tributylvinyl tin (119.7 μ l, 0.410mmol, 1.5eq.) and be heated to backflow 5 hours.After confirming that with TLC reaction finishes, the solution that obtains is used ethyl acetate extraction, water and brine wash are through dried over sodium sulfate and under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=5/1) to produce brown liquid (52.5mg, 72.2%).

(NaCl is pure, cm for IR ^-1): 3412,3088,2958,2925,1689;

¹H?NMR(400MHz，CDCl ₃)：7.53(d，1H，J＝2.0Hz)，7.39(dd，1H，J＝10.8，2.0Hz)，6.64(dd，1H，J＝17.6，11.2Hz)，5.69(d，1H，J＝17.6Hz)，5.42(d，1H，J＝11.2Hz)，4.36(s，2H)，1.49(s，9H)

Step 4: (3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of 25ml with argon gas, and (1eq.) solution in pyridine places flask and then is cooled to 0 ℃ for 27.3mg, 0.103mmol with (4-amino-3-fluoro-5-vinyl-benzyl)-t-butyl carbamate.To this solution add methane sulfonyl chloride (11.9 μ l, 0.154mmol, 1.5eq.) and one night of reflux.After confirming that with TLC reaction finishes, add solution (THF: H to this solution ₂O=2: 1) and NaOH (20.6mg, 0.515mmol is 5eq.) and stirring at room 1 hour.With 10%HCl acidification reaction solution, use ethyl acetate extraction, water and brine wash are through dried over sodium sulfate and evaporation.

The solid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1) to produce yellow liquid.

(NaCl is pure, cm for IR ^-1): 3349,3236,2956,2921,2850,1689;

¹H?NMR(400MHz，CDCl ₃)：7.27(s，1H)，7.10(dd，1H，J＝17.6，10.8Hz)，6.97(d，1H，J＝10.0Hz)，5.88(bs，1H)，5.73(d，1H，J＝17.6Hz)，5.39(d，1H，J＝10.8Hz)，4.87(bs，1H)，4.25(d，2H，J＝6.0Hz)，3.00(s，3H)，1.40(s，9H)

Step 5:N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992

(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl)-t-butyl carbamate (1ml) is placed the 25ml round-bottomed flask and is dissolved in methylene dichloride.Add trifluoroacetic acid (1ml) and stir a night to this solution.After confirming that with TLC reaction finishes, under reduced pressure concentrated reaction solution is to produce brown crude liquid (236.7mg).

Step 6:N-4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-fluoro-6-ethenylphenyl NSC-249992

Be full of two neck round-bottomed flasks of 25ml and with the 4-tert-butyl benzyl amine with argon gas

(1eq.) solution in methylene dichloride places flask for 59.3 μ l, 0.338mmol.To this solution add 4-dimethylaminopyridine (8.3mg, 0.068mmol, 0.2eq.) and di-tert-butyl dicarbonic acid ester (93.3 μ l, 0.406mmol is 1.2eq.) and stirring at room 3 hours.The solution that obtains is cooled to 0 ℃.Add 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl-ammonium, trifluoroacetate (121.1mg, 0.338mmol, 1eq.) with triethylamine (94.2 μ l, 0.676mmol, 2eq.) solution in methylene dichloride also with this mixture solution at one night of stirring at room.After confirming that with TLC reaction finishes, methylene dichloride is under reduced pressure removed.Remaining liquid is carried out column chromatography (n-hexane/ethyl acetate=1/1 (only ETHYLE ACETATE)) to produce white solid (35mg, 23.9%).

mp：163-164℃；

IR (KBr pellet, cm ^-1): 3376,3250,3057,2961,1636,1580,1319,1151;

¹H?NMR(400MHz，CD ₃OD)：7.42(d，1H，J＝1.6Hz)，7.33(d，2H，J＝8.4Hz)，7.19(d，2H，J＝8.4Hz)，7.15(dd，1H，J＝17.6，11.2Hz)，7.05(dd，1H，J＝10.8，1.6Hz)，5.79(d，1H，J＝17.6Hz)，5.36(d，1H，J＝11.2Hz)，4.33(s，2H)，4.29(s，2H)，3.00(s，3H)，1.28(s，9H)

Embodiment 3:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethynyl-6-fluorophenyl } NSC-249992

Step 1: (4-amino-3-fluoro-5-TMS ethynyl benzyl) t-butyl carbamate

With (4-amino-3-fluoro-5-iodine benzyl) t-butyl carbamate (100mg, 0.273mmol, 1eq.); Dichloro (two-triphenylphosphine), palladium (9.8mg, 0.014mmol; 0.05eq.) and cupric iodide (2.6mg; 0.014mmol 0.05eq.) solution in THF places the two neck round-bottomed flasks of 25ml, and stirring at room 30 minutes.(3eq.) (50.2 μ l, 0.355mmol 1.3eq.) also heat to reflux a night with (trimethyl silyl) ethynyl for 114.2 μ l, 0.819mmol to add triethylamine to this solution.Reaction soln under reduced pressure concentrates and carries out column chromatography (n-hexane/ethyl acetate=5/1) to produce brown liquid (84.0mg, 91.4%).

IR (NaCl, pure, cm ^-1): 3459,3360,2965,2148,1698;

¹H?NMR(400MHz，CDCl ₃)：7.00(d，1H，J＝0.8Hz)，6.91(dd，1H，J＝11.6，0.8Hz)，4.77(bs，1H)，4.36-3.91(m，2H)，4.15(s，2H)，1.46(s，9H)，0.27(s，9H).

Step 2: (3-ethynyl-5-fluoro-4-methane sulfonyl aminobenzyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of 25ml with argon gas, (1eq.) solution at methylene dichloride places flask and then is cooled to 0 ℃ for 80mg, 0.238mmol with (4-amino-3-fluoro-5-TMS ethynyl benzyl) t-butyl carbamate.To this solution add methane sulfonyl chloride (92.0 μ l, 1.189mmol, 5eq.) and triethylamine (99.5 μ l, 0.714mmol, 3eq.), and at one night of stirring at room.After confirming that with TLC reaction finishes, with saturated sodium hydrogen carbonate solution quencher reaction.The solution that obtains with dichloromethane extraction is with saturated CuSO ₄Solution, water and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.The solid that obtains is dissolved in solution (THF: H ₂O=2: 1).(47.6mg, 1.190mmol 5eq.), also used the 10%HCl acidifying in 3 hours in stirring at room to add NaOH to this solution.Solution is used ethyl acetate extraction, and water and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.The solid that obtains is carried out column chromatography (n-hexane/ethyl acetate=5/1) to produce brown solid (51.4mg, 63.0%).

mp：146-147℃；

IR (KBr pellet, cm ^-1): 3420,3288,2979,2933,2112,1691;

¹H?NMR(400MHz，CDCl ₃)：7.17(d，1H，J＝0.8Hz)，7.05(dd，1H，J＝10.8，0.8Hz)，6.38(bs，1H)，4.89(bs，1H)，4.20(d，2H，J＝6.0Hz)，3.40(s，1H)，3.18(s，3H)，1.39(s，9H).

Step 3:3-ethynyl-5-fluoro-4-methane sulfonyl aminobenzyl ammonium; Trifluoroacetate

(301.6mg, 0.881mmol 1eq.) place 50ml round-bottomed flask and be dissolved in methylene dichloride with (3-ethynyl-5-fluoro-4-methane sulfonyl aminobenzyl)-t-butyl carbamate.Add 10 trifluoroacetic acids and stir a night to this solution.After confirming that with TLC reaction finishes, under reduced pressure concentrated reaction solution is to produce brown crude liquid (564mg).

Step 4:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethynyl-6-fluorophenyl } NSC-249992

Be full of two neck round-bottomed flasks of 25ml with argon gas, and (1eq.) solution in methylene dichloride places flask for 83.0 μ l, 0.473mmol with the 4-tert-butyl benzyl amine.To this solution add 4-dimethylaminopyridine (11.6mg, 0.095mmol, 0.2eq.) and tert-Butyl dicarbonate (130.5 μ l, 0.568mmol is 1.2eq.) and stirring at room 3 hours.The solution that obtains is cooled to 0 ℃ and add 3-ethynyl-5-fluoro-4-methane sulfonyl aminobenzyl ammonium, trifluoroacetate (168.5mg, 0.473mmol, 1eq.), and triethylamine (131.9 μ l, 0.946mmol, 2eq.) solution in methylene dichloride.With mixture solution at one night of stirring at room.After confirming that with TLC reaction finishes, methylene dichloride is under reduced pressure removed.Remaining liquid is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (48.4mg, 23.7%).

mp：117-118℃；

IR (KBr pellet, cm ^-1): 3418,3051,2962,2112,1634,1582,1318,1152;

¹H?NMR(400MHz，CD ₃OD)：7.30(d，2H，J＝8.4Hz)，7.25(d，1H，J＝2.0Hz)，7.15(d，2H，J＝8.4Hz)，7.10(dd，1H，J＝10.8，2.0Hz)，4.26(s，2H)，4.25(s，2H)，3.44(s，1H)，3.06(s，3H)，1.25(s，9H)

Embodiment 4:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethenylphenyl } NSC-249992

Step 1: (4-amino-2-chloro-5-vinyl benzyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, with Pd (PPh3) ₄(0.06eq, 0.01mmol, 11.09mg) and LiCl (18.99mg) solution in DMF adds flask for 2.8eq, 0.45mmol.(60mg is 0.16mmol) with tributylvinyl tin (1.5eq, 0.24mmol, 74.71 μ l) and heat to reflux 12 hours to add (4-amino-2-chloro-5-iodo-benzyl)-t-butyl carbamate to this solution.After confirming that with TLC reaction finishes, under reduced pressure remove DMF, use the ethyl acetate extraction resistates.Water and brine wash ethyl acetate layer through dried over sodium sulfate, filter and under reduced pressure concentrate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=5/1) to produce deep yellow syrup (17.1mg, substrate recovery-35.7mg, 38.59%).

(NaCl is pure, cm for IR ^-1): 3359,3085,2976,1698,760;

¹H?NMR(400MHz，CDCl ₃)：7.19(s，1H)，6.65(s，1H)，6.60(dd，1H，J＝17.2，10.8Hz)，5.55(dd，1H，J＝17.2，0.8Hz)，5.27(dd，1H，J＝10.8，1.2Hz)，4.83(bs，1H)，4.22(d，2H，J＝6.0Hz)，1.37(s，9H)

Step 2: (2-chloro-4-methane sulfonyl amino-5-vinyl benzyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, (103.0mg, 0.37mmol) solution in methylene dichloride adds in the flask and then is cooled to 0 ℃ with (4-amino-2-chloro-5-vinyl-benzyl)-t-butyl carbamate.Slowly add methane sulfonyl chloride (5eq, 1.83mmol, 141.29 μ l) and triethylamine (3eq, 1.11mmol, 154.71 μ l) to this solution, and stirring at room 12 hours.After TLC confirmation reaction end, use NaHCO ₃Solution quencher reaction.Reaction soln is used dichloromethane extraction, uses CuSO ₄, water and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.With the liquid that obtains with solution (THF: H ₂O=2: 1) dilution, and adding NaOH (5eq, 1.85mmol, 74mg).With solution stirring 1 hour, then confirm that with TLC reaction finishes.With 10%HCl acidification reaction solution, use ethyl acetate extraction, water and brine wash, and through dried over sodium sulfate, filter and under reduced pressure concentrate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=3/1) to produce white solid (103.9mg, 79.03%).

mp：136～138℃；

IR (KBr pellet, cm ^-1): 3353,3025,2983,1683,1322,757;

¹H?NMR(400MHz，CDCl ₃)：δ7.42(s，1H)，7.39(s，1H)，6.76(dd，1H，J＝17.2，11.2Hz)，6.69(bs，1H)

Step 3:N-(4-amino methyl-5-chloro-2-ethenylphenyl) NSC-249992

(2-chloro-4-methane sulfonyl amino-5-vinyl-benzyl)-(103.9mg 0.29mmol) and with methylene dichloride dilutes t-butyl carbamate in adding in exsiccant 25ml round-bottomed flask.Add the CF that 5-6 drips to this solution ₃COOH also stirred 12 hours.After confirming that with TLC reaction finishes, use toluene under reduced pressure to concentrate the solution that obtains to produce brown syrup (98.1mg, 130.74%).

¹H?NMR(400MHz，CD ₃OD)：δ7.81(s，1H)，7.55(s，1H)，7.04(dd，1H，J＝17.2，10.8Hz)，5.88(d，1H，J＝17.2Hz)，5.47(d，1H，J＝10.8Hz)，4.27(s，2H)，2.98(s，3H).

Step 4:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethenylphenyl } NSC-249992

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and (29.38 μ l, 0.18mmol) solution in methylene dichloride adds flask with the 4-tert-butyl benzyl amine.Slowly add Boc to this solution ₂O (1.5eq, 0.27mmol, 151.78 μ l) and DMAP (0.2eq, 0.09mmol, 10.15mg) and stirred 5 hours.After confirming to produce the 1-tertiary butyl-4-isocyanide acyl methyl-benzene with TLC; To this solution add N-(4-amino methyl-5-chloro-2-vinyl-phenyl)-NSC-249992 (1eq, 0.18mmol, 46.3mg) and TEA (2eq; 0.36mmol, 50.17 μ l) and stirred 12 hours.After confirming reaction process, reaction soln is used dichloromethane extraction, water and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (15.5mg, 19.18%).

mp：140～142℃；

IR (KBr pellet, cm ^-1): 3366,2961,1635,1313,757;

¹H?NMR(400MHz，CDCl ₃)：δ7.42(s，1H)，7.40(s，1H)，7.28(d，2H，J＝8.4Hz)，7.16(d，2H，J＝8.4Hz)，6.68(dd，1H，J＝17.2，11.2Hz)，6.45(bs，1H)，5.60(d，1H，J＝17.2Hz)，5.41(d，1H，J＝11.2Hz)，4.36(s，2H)，4.27(s，2H)，2.93(s，3H)，1.23(s，9H).

Embodiment 5:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethynyl phenyl } NSC-249992

Step 1: (4-amino-2-chloro-5-TMS ethynyl benzyl) t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and with (4-amino-2-chloro-5-iodo-benzyl)-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.(1.3eq, 0.21mmol is 29.39mg) with triethylamine (3eq, 0.48mmol, 66.90 μ l) and heat to reflux 12 hours to add (TMS) ethynyl to this solution.After confirming that with TLC reaction finishes, the solution that obtains is used ethyl acetate extraction, water and brine wash through dried over sodium sulfate, are filtered and are 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 aminobenzyl) 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-benzyl)-t-butyl carbamate.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 to this solution.After confirming that with TLC reaction finishes, use NaHCO ₃Solution quencher reaction.Reaction soln is used dichloromethane extraction, use CuSO ₄, water and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.With the liquid that obtains with solution (THF: H ₂O=2: 1) dilution and to this solution add NaOH (5eq, 3.20mmol, 128mg).Mixture was stirred 1 hour.After confirming that with TLC reaction finishes, with the reaction soln acidifying, use ethyl acetate extraction with 10%HCl, water and brine wash through dried over sodium sulfate, are filtered, and are 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) NSC-249992

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-benzyl)-t-butyl carbamate.CF to 5～6 of this solution addings ₃COOH also stirred 12 hours.After confirming that with TLC reaction finishes, use toluene under reduced pressure to concentrate the solution that obtains 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-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethynyl phenyl } NSC-249992

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and (44.08 μ l, 0.27mmol) solution in methylene dichloride places flask with the 4-tertiary butyl-benzylamine.Slowly add Boc to this solution ₂O (1.5eq, 0.41mmol, 93.14 μ l) and DMAP (0.2eq, 0.05mmol, 6.59mg) and stirred 5 hours.After confirm producing the 1-tertiary butyl-4-isocyanide acyl methyl-benzene with TLC, to this solution add N-(4-amino methyl-5-chloro-2-ethynyl-phenyl)-NSC-249992 (1eq, 0.27mmol, 70mg) and TEA (2eq, 0.54mmol, 75.27 μ l) and stirring 12 hours.After confirming reaction process with TLC, reaction soln is used dichloromethane extraction, water and brine wash through dried over sodium sulfate, are filtered and are 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).

Embodiment 6:N-(4-{1-(R)-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992

Step 1: (R)-[1-(4-nitrophenyl) ethyl] t-butyl carbamate

(50mg 0.25mmol) places 25ml round-bottomed flask and be dissolved in saturated solution (NaHCO with (R)-methyl-4-nitro-benzylamine HCl ₃: CH ₂Cl ₂=1: 1).To this solution add di-tert-butyl dicarbonic acid ester (135mg, 0.60mmol, 2.5eq) and stirred 3 hours.Use the methylene dichloride diluted reaction mixture, water and brine wash are through dried over sodium sulfate and under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=10/1) to produce light yellow solid (62.0mg, 94.38%).

[α] ^21.6 _D：-43.66℃(c?1.33，CHCl ₃)；

(NaCl is pure, cm for IR ^-1): 3403,3332,2977,2932,1697,1522,1347;

¹H?NMR(400MHz，CDCl ₃)：8.20(d，2H，J＝8.8Hz)，7.47(d，2H，J＝8.8Hz)，4.91(s，1H)，4.85(s，1H)，1.46(d，3H，J＝6.8Hz)，1.42(s，9H).

Step 2: (R)-[1-(4-aminophenyl) ethyl] t-butyl carbamate

(25mg 0.09mmol) places 25ml round-bottomed flask and be dissolved in methyl alcohol with (R)-[1-(4-nitrophenyl) ethyl] t-butyl carbamate.Add Pd (7mg, 30% of substrate to this solution.With the air in the hydrogen replacement flask, and stirred 2 hours.After confirming that with TLC reaction finishes, elimination Pd/C under reduced pressure removes methyl alcohol to produce transparent yellow liquid (21.7mg, 91.93%).

[α] ^22.0 _D：-69.75℃(c?1.02，CHCl ₃)；

(NaCl is pure, cm for IR ^-1): 3353,3035,2974,2937,1695,1623,1366;

¹H?NMR(400MHz，CDCl ₃)：7.10(d，2H，J＝8.0Hz)，6.40(d，2H，J＝8.0Hz)，4.70(s，2H)，3.60(s，2H)，1.42(s，12H).

Step 3: (R)-[1-(4-amino-3-iodophenyl) ethyl] t-butyl carbamate

(1eq.) solution in methylene dichloride places the two neck round-bottomed flasks of 50ml for 141.1mg, 0.60mmol with [1-(4-amino-phenyl)-ethyl]-t-butyl carbamate.(106.6mg, 0.66mmol is 1.1eq.) and stirring at room 1 hour to add iodine monochloride to this solution.After confirming that with TLC reaction finishes, with the solution that obtains with saturated Na ₂S ₂O ₃Solution, water and brine wash through dried over sodium sulfate, are filtered, and evaporation.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=5/1) to produce brown liquid (102.7mg).

[α] ²³ _D：+55.03℃(c?0.60，CHCl ₃)；

(NaCl is pure, cm for IR ^-1): 3423,3343,2973,296,1692,1498,1167;

¹H?NMR(400MHz，CDCl ₃)：7.48(d，1H，J＝1.6Hz)，7.01(d，1H，J＝8.4Hz)，6.62(d，1H，J＝8.4Hz)，4.63-4.57(m，2H)，1.35(s，9H)，1.32(d，3H，J＝6.8Hz).

Step 4: (R)-[1-(4-amino-3-ethenylphenyl) ethyl] t-butyl carbamate

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas, and with tetrakis triphenylphosphine palladium (0) (27.9mg, 0.02mmol, 0.06eq.) and lithium chloride (2.8eq.) solution in DMF places flask for 47.7mg, 1.13mmol.To this solution add [1-(4-amino-3-iodophenyl) ethyl] t-butyl carbamate (145.5mg, 0.40mmol, 1eq.) and tributylvinyl tin (176.2 μ l, 0.60mmol, 1.5eq.) and be heated to 90 ℃ to reflux a night.After confirming that with TLC reaction finishes, under reduced pressure remove DMF and use dichloromethane extraction.Water and saturated brine wash dichloromethane layer through dried over sodium sulfate, filter and under reduced pressure concentrate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=5/1) to produce brown liquid (76.3mg, 72.3%).

[α] ²³ _D：+59.07℃(c?0.43，CHCl ₃)；

(NaCl is pure, cm for IR ^-1): 3369,2972,2922,2852,1687;

¹H?NMR(400MHz，CDCl ₃)：7.14(d，1H，J＝1.6Hz)，6.96(dd，1H，J＝8.4，1.6Hz)，6.69(dd，1H，J＝17.6，11.2Hz)，6.58(d，1H，J＝8.4Hz)，5.56(dd，1H，J＝17.6，1.6Hz)，5.25(dd，1H，J＝11.2，1.6Hz)，4.64(bs，2H)，1.37-1.35(m，12H).

Step 5: (R)-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] t-butyl carbamate

Be full of two neck round-bottomed flasks of 100ml with argon gas, and (1eq.) solution in methylene dichloride places said flask and then is cooled to 0 ℃ for 358.5mg, 1.366mmol with (R)-[1-(4-amino-3-ethenylphenyl) ethyl] t-butyl carbamate.To this solution add sulfonyl methane acid anhydride (285.7mg, 1.640mmol, 1.2eq.) add subsequently pyridine (328.4 μ l, 4.098mmol, 2eq.) and stirred 1 hour.After confirming that with TLC reaction finishes, add saturated sodium hydrogen carbonate solution and stirred 5 minutes to this solution.The solution that obtains is used dichloromethane extraction, uses 5%HCl, saturated NaHCO ₃Solution, water and brine wash through dried over sodium sulfate, are filtered and evaporation.The solid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1) to produce light yellow solid (169.0mg, 47.2%).

[α] ²⁰ _D：+34.74℃(c?0.43，CHCl ₃)；

IR (KBr pellet, cm ^-1): 3361,3265,3080,2978,2929,2851,1682;

¹H?NMR(400MHz，CDCl ₃)：7.36(d，1H，J＝8.4Hz)，7.34(d.1H，J＝2.0Hz)，7.17(dd，1H，J＝8.4，2.0Hz)，6.83(dd，1H，J＝17.2，10.8Hz)，6.35(bs，1H)，5.66(d，1H，J＝17.2Hz)，5.40(d，1H，J＝10.8Hz)，4.82-4.63(m，2H)，2.92(s，3H)，1.38-1.36(m，12H).

Step 6: (R)-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] ammonium three fluoro-acetates

(158.4mg, 0.465 mmol 1eq.) place 100ml round-bottomed flask and be dissolved in methylene dichloride with [1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] t-butyl carbamate.To this solution add trifluoroacetic acid (179.2 μ l, 2.326mmol, 5eq.) and stir a night.After confirming that with TLC reaction finishes, under reduced pressure concentrated reaction solution is to produce brown crude liquid (236.7mg).

Step 7:

N-(4-{1-(R)-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992

Be full of two neck round-bottomed flasks of 25ml with argon gas, and (1eq.) solution in methylene dichloride places said flask for 14.8 μ l, 0.084mmol with the 4-tert-butyl benzyl amine.To this solution add 4-dimethylaminopyridine (2.1mg, 0.017mmol, 0.2eq.) and tert-Butyl dicarbonate (23.2 μ l, 0.101mmol is 1.2eq.) and stirring at room 3 hours.With the solution that obtains be cooled to 0 ℃ and add [1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] ammonium three fluoro-acetates (30mg, 0.084mmol, 1eq.) and triethylamine (23.4 μ l, 0.168mmol, 2eq.) solution in methylene dichloride.With mixture solution at one night of stirring at room.After confirming that with TLC reaction finishes, under reduced pressure remove methylene dichloride.Remaining liquid is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce light yellow solid (21.8mg, 60.4%).

mp：105.1-105.8℃；

[α] ²³ _D：-5.00℃(c?0.46，CHCl ₃)；

IR (KBr pellet, cm ^-1): 3418,3029,2963,2926,2869,1634;

¹H?NMR(400MHz，CDCl ₃)：7.33(d，1H，J＝1.6Hz)，7.30(d，1H，J＝8.4Hz)，7.26(d，2H，J＝8.0Hz)，7.11-7.08(m，3H)，6.81(dd，1H，J＝17.2，10.8Hz)，6.49(bs，1H)，5.62(d，1H，J＝17.2Hz)，5.37(d，1H，J＝10.8Hz)，4.77(q，1H，J＝6.8Hz)，4.64(bs，2H)，4.24(s，2H)，2.89(s，3H)，1.34(d，3H，J＝6.8Hz)，1.23(s，9H).

Embodiment 7:

(R)-N-(4-{1-[3-(the 4-tertiary butyl-benzyl)-urea groups]-ethyl }-2-fluoro-6-vinyl-phenyl)-NSC-249992

Step 1:1-(4-amino-3-fluorophenyl) ethane ketone

With argon gas be full of 25ml two neck round-bottomed flasks and with 2-fluoro-4-Iodoaniline (1500mg, the 6.33mmol) solution in DMF, acid chloride (II) (0.19mmol, 42.62mg); 1,3-two phenyl phosphino-propane (0.06eq, 0.38mmol; 156.65mg), thallium acetate (I) (6.96mmol, 1834.19mg); (2eq, 12.66mmol 1.64ml) place said flask to butyl vinyl ether.With reaction mixture heating and stirred 15 hours.In reaction mixture impouring THF solution, and then slowly add 10%HCl.With ethyl acetate extraction reaction mixture (300 * 3), use H ₂O and brine wash.The organic solution that merges is also followed with column chromatography (n-Hx: EA=3: 1) carry out purifying to produce light yellow solid (343.0mg, 35.40%) with dried over sodium sulfate.

mp：77～79℃；

IR (KBr pellet, cm ^-1): 3373,3326,1663,1296; ¹H NMR (400MHz, CDCl ₃): δ 7.53 (m, 2H), 6.69 (m, 1H), 3.41 (s, 2H), 2.43 (s, 3H).

Step 2:1-(4-amino-3-fluoro-5-iodophenyl) ethane ketone

With 1-(4-amino-3-fluorophenyl) ethane ketone (0.30mmol 45.6mg) adds acetonitrile, and then add NIS (0.33mol, 73.73mg).Reaction mixture was stirred 12 hours.With Sulfothiorine quencher reaction mixture.With EtOAC and H ₂O abstraction reaction mixture, the organic layer that merges with brine wash is also used Na ₂SO ₄Drying then concentrates in a vacuum.With remaining layer with column chromatography (n-Hx: EtOAc=7: 1) carry out purifying with generation brown solid (53.92mg, 64.43%).

mp：124～126℃；

IR (KBr pellet): 3455,3331,3073,2921,1659,1259cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ8.01(dd，1H，J＝1.6，1.2Hz)，7.65(dd，1H，J＝11.6，2.0Hz)，4.61(bs，2H)，2.46(s，3H).

Step 3:2-methylpropane-2--sulfinic acid [1-(4-amino-3-fluoro-5-iodophenyl) ethyl] acid amides

With 1-(4-amino-3-fluoro-5-iodophenyl) ethane ketone (0.36mmol, 100mg), Ti (OEt) ₄(0.59mmol, 122.68 μ l), (R)-(+)-(0.32mmol 39.27mg) adds THF solution to 2-methyl-2-propane sulfinyl amine.With reaction mixture heating and stirred 12 hours.After confirming that with TLC reaction finishes, reaction mixture is cooled to-40 ℃.With NaBH ₄(1.19mmol 45.08mg) adds in the reaction mixture.Reaction mixture was stirred 12 hours at-40 ℃.MeOH is added in the reaction mixture.Reaction mixture is heated to room temperature.Reaction mixture is filtered with C salt.Filtrating is extracted with EtOAC, uses H ₂O and brine wash are used Na ₂SO ₄Dry and then concentrated in a vacuum.With remaining layer with column chromatography (normal hexane: EtOAc=3: 1) carry out purifying with generation brown syrup (29.1mg, 20.30%).

[α] _D ²⁰：-6.0(CHCl ₃，c?0.24)；

IR (KBr pellet): 3322,3211,2974,1491,1051,717cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.34(s，1H)，6.96(dd，1H，J＝11.2，2.0Hz)，4.34(qd，1H，J＝6.4，2.8Hz)，3.33(d，1H，J＝2.0Hz)，1.41(d，3H，J＝6.4Hz)，1.18(s，9H).

Step 4:4-(1-amino-ethyl)-2-fluoro-6-Iodoaniline

(0.07mmol 29.1mg) adds MeOH 1ml with 2-methylpropane-2--sulfinic acid [1-(4-amino-3-fluoro-5-iodophenyl) ethyl] acid amides.Be added in 1 of 0.25ml, the 4NHCl in the 4-diox.Reaction mixture was stirred 12 hours.Concentrated reaction mixture in a vacuum.Use the glass filter filtration residue.To filtrate and concentrate in a vacuum to produce brown solid (31.2mg).

mp：180～182℃；

[α] _D ²⁰:+3.27 (CHCl ₃, c 0.41); IR (KBr pellet): 3354,3018,2966,1283,756cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.72(s，1H)，7.35(dd，1H，J＝11.2，2.0Hz)，4.41(q，1H，J＝6.8Hz)，1.58(d，3H，J＝6.8Hz)，1.30(s，3H).

Step 5: [1-(4-amino-3-fluoro-5-iodophenyl) ethyl] t-butyl carbamate

Be full of the double-neck flask of 25ml and with 4-(1-amino-ethyl)-(0.18mmol 50.0mg) is dissolved in THF to 2-fluoro-6-Iodoaniline with argon gas.Add BOC ₂O (0.20mol, 45.18mg), DMAP (0.02mol, 2.20mg), and TEA (0.23mol, 32.61mg).Reaction mixture was stirred 12 hours.Reaction mixture extracts with EtOAc, uses H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum.With resistates with column chromatography (normal hexane: EtOAc=7: 1) carry out purifying to produce solid (65.9mg, 94.44%).

mp：88～90℃；

[α] _D ²⁰：33.35(CHCl ₃，c?2.98)；

IR (KBr pellet): 3364,3026,2958,1696,1169cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.31(s，1H)，6.90(d，1H，J＝11.6Hz)，4.72(s，1H)，4.59(s，1H)，3.76(bs，2H)，1.38(s，9H)，1.3(d，3H，J＝6.8Hz).

Step 6: [1-(4-amino-3-fluoro-5-ethenylphenyl) ethyl] t-butyl carbamate

Under argon gas atmosphere with Pd (PPh ₃) ₄(0.01mmol, 11.79mg) and LiCl (0.48mmol 20.58mg) adds DMF.Add [1-(4-amino-3-fluoro-5-ethenylphenyl) ethyl] t-butyl carbamate (0.17mmol, 65.9mg) and tributylvinyl tin (0.25mmol, 74.52 μ l).Reaction mixture was stirred in backflow 12 hours.Reaction solvent is removed in a vacuum.Reaction mixture extracts with EtOAc, uses H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum.With resistates with column chromatography (normal hexane: EtOAc=7: 1) carry out purifying to produce yellow solid (23.4mg, 47.06%).

mp：59～61℃；

[α] _D ²⁰：+47.0(CHCl ₃，c?0.10)；

IR (KBr pellet): 3357,3088,2975,1696,1640,1168cm ^{-1 1}HNMR (400MHz, CDCl ₃): δ 6.93 (s, 1H), 6.81 (dd, 1H, J=11.6,2.0Hz), 6.65 (dd, 1H, J=17.2,11.2Hz), 5.29 (dd, 1H, J=11.2,1.2Hz), 4.64 (s, 1H), 4.61 (s, 1H), 3.66 (bs, 2H), 1.35 (s, 12H).

Step 7: [1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] t-butyl carbamate

With argon gas be full of 25ml double-neck flask and will [1-(4-amino-3-fluoro-5-ethenylphenyl) ethyl] t-butyl carbamate (0.08mmol is 23.4mg) in the adding methylene dichloride.Reaction mixture is cooled to 0 ℃.With methane sulfonyl chloride (0.40mmol, 32.32mmol) and TEA (0.24mmol 33.45mg) adds in the reaction mixture.Reaction mixture is heated to room temperature.Through adding NaHCO ₃Solution quencher reaction mixture.Use CH ₂Cl ₂The abstraction reaction mixture.The organic layer that merges is used CuSO, H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum.Resistates is added THF: H ₂O=2: 1soln. adding NaOH (0.40mmol, 16mg).Reaction mixture was stirred 12 hours.After confirming that with TLC reaction finishes, reaction mixture is with 10%HCl soln acidifying.Reaction mixture was stirred 12 hours.Reaction mixture is extracted with EtOAc, use H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum.Resistates is carried out purifying (normal hexane: EtOAc=7: 1) to produce brown syrup (20.2mg, 75.0%) with column chromatography.

[α] _D ²⁰：+110.0(CHCl ₃，c?0.05)；

IR (KBr pellet): 3235,2977,1685,1156cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.28(s，1H)，7.10(dd，1H，J＝18.0，11.2Hz)，6.95(d，1H，J＝10.4Hz)，6.16(s，1H)，5.73(d，1H，J＝17.6Hz)，5.37(d，1H，J＝11.2Hz)，4.80(s，1H)，4.69(s，1H)，2.99(s，3H)，1.35(s，12H).

Step 8:N-[4-(1-amino-ethyl)-2-fluoro-6-ethenylphenyl] NSC-249992

(0.06mmol 20.2mg) is dissolved in methylene dichloride, adds 5～6 CF with [1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] t-butyl carbamate ₃COOH.Reaction mixture was stirred 12 hours.Add toluene.Said reaction mixture is concentrated to produce brown syrup (20.8mg, 100.0%) in a vacuum.

¹H?NMR(400MHz，CD ₃OD)：δ7.60(s，1H)，7.25(dd，1H，J＝10.4，2.0Hz)，7.16(dd，1H，J＝18.0，11.2Hz)，5.89(d，1H，J＝17.6Hz)，5.43(d，1H，J＝11.2Hz)，4.48(q，1H，J＝6.8Hz)，3.02(s，3H)，1.61(d，3H，J＝6.8Hz).

Step 9:N-(4-{1-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-2-fluoro-6-ethenylphenyl) NSC-249992

Be full of the double-neck flask of 25ml and (2eq., 35.10 μ l 0.22mmol) add with the 4-tert-butyl benzyl amine with argon gas in methylene dichloride.With BOC ₂(0.2eq., 0.02mmol 2.69mg) slowly add for O (1.5eq., 0.17mmol, 37.95 μ l) and DMAP.Reaction mixture was stirred 5 hours.After confirming the synthetic 1-tertiary butyl-4-isocyanide acyl methylbenzene, add N-[4-(1-amino-ethyl)-2-fluoro-6-vinyl-phenyl]-NSC-249992 (0.11mmol, 40.0mg) and TEA (2eq., 0.58mmol, 80.84 μ l).Reaction mixture was stirred 12 hours.After confirming that with TLC reaction finishes, use the dichloromethane extraction reaction mixture, use H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum.Resistates is with column chromatography (normal hexane: EtOAc=1: 1) carry out purifying to produce white solid (21.7mg, 27.56%).

mp：89～91℃；

[α] _D ²⁰：-8.34(CHCl ₃，c?0.49)；

IR (KBr pellet): 337,3092,2963,1636,1154cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.29(d，2H，J＝8.0Hz)，7.27(s，1H)，7.13(d，2H，J＝8.0Hz)，7.09(dd，1H，J＝17.6，11.2Hz)，6.91(d，1H，J＝10.0Hz)，6.41(s，1H)，5.71(d，1H，J＝17.6Hz)，5.37(d，1H，J＝11.2Hz)，4.79(q，1H，J＝6.0Hz)，4.24(s，2H)，2.99(s，3H)，1.33(d，3H，J＝6.8Hz)，1.26(s，9H).

Embodiment 8:

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-methyl-6-vinyl-phenyl }-NSC-249992

Step 1:4-amino-3-methyl benzonitrile

With 4-iodo-2-aminotoluene (2000mg, 8.58mmol) and prussiate (1.15g, 12.87mmol 1.5eq) add pyridine.Reaction mixture is heated to 150～160 ℃, stirs 12 hours.Use the methylene dichloride diluted reaction mixture.Solution several with copper sulfate washing dilution.Use H ₂O (2 times) and brine wash mixture are then used Na ₂SO ₄Dry.With resistates with column chromatography (normal hexane: EtOAc=2: 1) carry out purifying to produce solid (786.5mg, 69.34%).

mp：78～80℃；

(NaCl is pure, cm for IR ^-1): 3403,3335,3220,2942,2220;

¹H?NMR(400MHz，CDCl ₃)：7.24(m，2H)，6.57(d，1H，J＝8.4Hz)，4.03(bs，2H)，2.08(s，9H).

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

With 4-amino-3-methyl-benzonitrile (786.5 μ l, 5.95mmol) and ICl (1.1eq, 6.55mmol 1.06g) add methylene dichloride.Reaction mixture stirred 12 hours.Through adding hypo solution quencher reaction mixture.Extract the aqueous solution with MC.Use H ₂The organic solution that O and brine wash merge is used Na ₂SO ₄Drying, and concentrate in a vacuum.With resistates with column chromatography (n-Hx: EA=3: 1) carry out purifying to produce solid (600.6mg, 39.11%).

mp：131～133℃；

IR (KBr pellet, cm ^-1): 3462,3366,2923,2214,1623;

¹H?NMR(400MHz，CDCl ₃)：δ7.22(d，1H，J＝2.0Hz)，7.21(m，1H)，2.16(s，3H)

Step 3: (4-amino-3-iodo-5-methyl-benzyl) t-butyl carbamate

With 4-amino-(200mg 0.77mmol) is dissolved in THF at 0 ℃ to 3-iodo-5-methyl benzonitrile.With borine-THF mixture (4eq, 3.10mmol, 3.10ml) slowly add in the said reaction mixture after, temperature of reaction is heated to backflow.Under situation about refluxing, reaction mixture was stirred 12 hours.After confirming that reaction finishes, add MeOH.Mixture was stirred 4 hours.Remove reaction solvent in a vacuum.Resistates is used ethyl acetate extraction, uses H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum to produce 4-amino methyl-2-iodo-6-methyl-aniline (194mg).

(195mg 0.76mmol) is dissolved in THF, then slowly adds BOC with 4-amino methyl-2-iodo-6-methyl-aniline ₂O (1.1eq, 0.21mmol, 47.48ml).Stirred reaction mixture reaches 12 hours.Reaction mixture is used ethyl acetate extraction, uses H ₂O and brine wash are used Na ₂SO ₄Drying concentrates in a vacuum.Resistates is carried out purifying (n-Hx: EA=5: 1) to obtain solid (73.2mg, 34.77%) with column chromatography.

mp：135～137℃；

IR (KBr pellet, cm ^-1): 3354,2995,1675,1617,726;

¹H?NMR(400MHz，CDCl ₃)：δ7.38(s，1H)，6.90(s，1H)，4.78(s，1H)，4.08(d，2H，J＝5.2Hz)，4.01(bs，2H)，2.16(s，3H)，1.42(s，9H)

Step 4: (4-amino-3-methyl-5-vinyl benzyl) t-butyl carbamate

With Pd (PPh ₃) ₄(0.06eq, 0.017mmol, 19.41mg) and LiCl (2.8eq, 0.74mmol 33.23mg) are dissolved in DMF.With (4-amino-3-iodo-5-methyl-benzyl) t-butyl carbamate (100mg, 0.28mmol) and tributylvinyl tin (1.5eq, 0.41mmol, 121.08 μ l) add said reaction mixture.Reaction mixture was stirred in backflow 12 hours.According to step 3 similar methods purification reaction mixture to obtain solid (61.8mg, 85.34%).

(NaCl is pure, cm for IR ^-1): 3373,2965,1697,1632;

¹H?NMR(400MHz，CDCl ₃)：δ6.99(s，1H)，6.85(s，1H)，6.69(dd，1H，J＝17.2，10.8Hz)，5.53(dd，1H，J＝17.2，1.6Hz)，5.24(dd，1H，J＝10.8，1.6Hz)，4.68(bs，1H)，4.10(d，2H，J＝5.2Hz)，3.70(bs，2H)，2.08(s，3H)，1.38(s，9H)

Step 5: (4-methane sulfonyl amino-3-methyl-5-vinyl benzyl) t-butyl carbamate

(30.9mg, 0.12mmol), methane sulfonyl chloride (10eq, 1.2 mmol, 91 μ l) and triethylamine (6eq, 0.36mmol, 50.17) add methylene dichloride with (4-amino-3-methyl-5-vinyl-benzyl)-t-butyl carbamate.Stirred reaction mixture 12 hours.Use with embodiment 8 step 4 similar methods purification reaction mixtures to obtain syrup (9.5mg, 23.70%).

(NaCl is pure, cm for IR ^-1): 3371,2961,1697,1513,1316;

¹H?NMR(400MHz，CDCl ₃)：δ7.27(s，1H)，7.06(s，1H)，7.01(dd，1H，J＝17.6，11.2Hz)，5.80(s，1H)，5.68(dd，1H，J＝17.7，0.8Hz)，5.33(dd，1H，J＝11.2，0.8Hz)，4.79(s，1H)，4.22(d，2H，J＝6.0Hz)，2.98(s，3H)，2.36(s，3H)，1.40(s，9H).

Step 6:N-(4-amino methyl-2-methyl-6-vinyl-phenyl)-NSC-249992

(85.9mg 0.09mmol) is dissolved in CH with (4-methane sulfonyl amino-3-methyl-5-vinyl benzyl) t-butyl carbamate ₂Cl ₂The CF that adds 5～6 ₃COOH.Reaction mixture was stirred 12 hours.Concentrated reaction mixture is to produce brown syrup (100.4mg).

¹H?NMR(400MHz，CD ₃OD)：δ7.57(d，1H，J＝1.6Hz)，7.28(d，1H，J＝1.6Hz)，7.17(dd，1H，J＝17.6，10.8Hz)，5.03(d，1H，J＝17.6Hz)，5.38(d，1H，J＝10.8Hz)，4.06(s，2H)，3.00(s，3H)，2.41(s，3H)

Step 7:N-{4-[3-(the 4-tertiary butyl-benzyl) urea groups methyl]-2-methyl-6-ethenylphenyl } NSC-249992

(1.5eq, 71.91 μ l 0.44mmol) add CH with the 4-tertiary butyl-benzylamine ₂Cl ₂And the then slow BOC that adds ₂O (1.5eq, 0.44mmol, 101.19 μ l) and DMAP (0.2eq, 0.06mmol, 7.08mg).After confirming the synthetic 1-tertiary butyl-4-isocyanide acyl methyl-benzene, with N-(4-amino methyl-2-methyl-6-vinyl-phenyl)-NSC-249992 (1eq, 0.29mmol, 70.5mg) and TEA (2eq, 0.58mmol, 80.84 μ l) join reaction mixture.Reaction mixture was stirred 12 hours.According to the step 9 purification reaction mixture of embodiment 7 to obtain N-{4-[3-(the 4-tertiary butyl-benzyl) urea groups methyl]-2-methyl-6-ethenylphenyl NSC-249992 (29.75mg, 23.9%).

mp：105～107℃；

IR (KBr pellet, cm ^-1): 3359,3280,2963,1636,1316; ¹H NMR (400MHz, CDCl ₃): δ 7.32 (s, 1H), 7.27 (d, 2H, J=8.0Hz), 7.16 (d, 2H, J=8.0Hz); 7.09 (s, 1H), 6.72 (dd, 1H, J=17.2,10.8Hz), 5.71 (d; 1H, J=17.6Hz), 5.37 (d, 2H, J=10.8Hz), 4.30 (d, 4H; J=10.0Hz), 3.42 (s, 3H), 2.23 (s, 3H), 1.22 (s, 9H)

Embodiment 9:

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-chloro-6-vinyl-phenyl }-NSC-249992

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.Stirred reaction mixture reaches 12 hours.With said reaction mixture according to carrying out purifying to obtain 4-amino-3-chloro-5-iodine benzonitrile (65.2mg, 35.80%) with step 2 similar methods of embodiment 8.

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-iodine benzyl) t-butyl carbamate

With 4-amino-(65.2mg 0.23mmol) is dissolved in THF at 0 ℃ to 3-chloro-5-iodine benzonitrile.With borine-THF mixture (4eq, 0.94mmol, 0.94ml) slowly add reaction mixture after, temperature of reaction is heated to backflow.Under situation about refluxing, reaction mixture was stirred 12 hours.After confirming that reaction finishes, add MeOH.Mixture was stirred 4 hours.Reaction solvent is removed in a vacuum.Resistates is used ethyl acetate extraction, uses H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum to produce 4-amino methyl-2-iodo-6-methyl-aniline (19.4mg).

(52.92mg 0.19mmol) is dissolved in THF, then slowly adds BOC with 4-amino methyl-2-chloro-6-Iodoaniline ₂O (1.1eq, 0.21mmol, 47.48ml).Reaction mixture was stirred 12 hours.Reaction mixture is used ethyl acetate extraction, uses H ₂O and brine wash are used Na ₂SO ₄Drying, and concentrate in a vacuum.With resistates with column chromatography (n-Hx: EA=5: 1) carry out purifying 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: (4-amino-3-chloro-5-vinyl benzyl) t-butyl carbamate

With Pd (PPh ₃) ₄(0.06eq, 0.01mmol, 18.15mg) and LiCl (2.8eq, 0.73mmol 30.86mg) are dissolved in DMF.With 4-amino-3-chloro-5-iodine benzyl) t-butyl carbamate (100mg, 0.26mmol) and tributylvinyl tin (1.5eq, 0.39mmol, 114.76 μ l) add.Reaction mixture was stirred in backflow 12 hours.With reaction mixture according to carrying out purifying to obtain solid (61.8mg, 85.34%) with step 3 similar methods.

mp：85～87℃；

IR (KBr pellet, cm ^-1): 3316,2977,1702,1635,725;

¹H?NMR(400MHz，CDCl ₃)：δ7.06(d，1H，J＝2.0Hz)，7.01(d，1H，J＝2.0Hz)，6.64(dd，1H，J＝17.6，11.2Hz)，5.56(dd，1H，J＝17.2，1.2Hz)，5.30(dd，1H，J＝11.2，1.2Hz)，4.72(bs，1H)，4.11(d，2H，J＝5.2Hz)，1.38(s，9H).

Step 4: (3-chloro-4-methane sulfonyl amino-5-vinyl benzyl) t-butyl carbamate

With (4-amino-3-chloro-5-vinyl benzyl) t-butyl carbamate (40.2mg, 0.14mmol), methane sulfonyl chloride (5eq, 0.71mmol, 55.15 μ l), and triethylamine (3eq, 0.42mmol, 58.34 μ l) adds in the methylene dichloride.Said reaction mixture was stirred 5 hours.Use with the step 5 similar methods purification reaction mixture of embodiment 8 to obtain title compound (30.7mg, 59.83%).

mp：133～135℃；

IR (KBr pellet, cm ^-1): 3353,2981,1691,1524,1322,740;

¹H?NMR(400MHz，CDCl ₃)：δ7.40(s，1H)，7.25(d，1H，J＝1.2Hz)，7.19(d，1H，J＝1.2Hz)，7.14(dd，1H，J＝17.6，11.2Hz)，6.18(s，1H)，5.70(d，1H，J＝17.2Hz)，5.34(d，1H，J＝11.2Hz)，4.88(s，1H)，4.24(d，2H，J＝6.0Hz)，3.00(s，3H)，1.40(s，9H).

Step 5:N-(4-amino methyl-2-chloro-6-ethenylphenyl) NSC-249992

With (3-chloro-4-methane sulfonyl amino-5-vinyl benzyl) t-butyl carbamate (30.7mg, 0.09mmol) and CF ₃COOH (5-6 drips) adds methylene dichloride.Reaction mixture was stirred 12 hours.Reaction mixture is concentrated to obtain title compound (33.4mg, 100%) in a vacuum.

¹H?NMR(400MHz，CD ₃OD)：δ7.75(d，1H，J＝1.6Hz)，7.55(d，1H，J＝2.0Hz)，7.22(dd，1H，J＝17.6，10.8Hz)，5.88(d，1H，J＝17.6Hz)，5.43(d，1H，J＝11.2Hz)，4.13(s，2H)，3.10(s，3H)

Step 6:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-chloro-6-ethenylphenyl } NSC-249992

With the 4-tert-butyl benzyl amine (1.5eq, 71.10 μ l, 0.44mmol), BOC ₂O (1.5eq, 0.44mmol, 101.19 μ l), and DMAP (0.2eq, 0.06mmol, 7.08mg) adding methylene dichloride.Reaction mixture was stirred 5 hours.Confirm the synthetic 1-tertiary butyl-4-isocyanide acyl methylbenzene with TLC after, (1eq, 0.29mmol is 108.6mg) with TEA (2eq, 0.58mmol, 80.84 μ l) adding reaction mixture with N-(4-amino methyl-2-chloro-6-ethenylphenyl) NSC-249992.Reaction mixture was stirred 12 hours and uses step 7 similar methods purifying with embodiment 8 to obtain title compound (23.0mg, 17.66%).

mp：165～167℃；

IR (KBr pellet, cm ^-1): 3333,2961,1625,1323,1155,765;

¹H?NMR(400MHz，CD ₃?OD)：δ7.52(d，1H，J＝1.6Hz)，7.33(d，1H，J＝1.6Hz)，7.31(d，2H，J＝8.4Hz)，7.18(dd，1H，J＝17.6，11.2Hz)，7.17(d，2H，J＝8.4Hz)，5.75(d，1H，J＝17.6Hz)，5.32(d，1H，J＝11.2Hz)，4.30(s，2H)，4.27(s，2H)，3.05(s，3H)，1.26(s，9H).

Embodiment 10:

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-trifluoromethyl-6-vinyl-phenyl }-NSC-249992

Step 1:4-iodo-2-5-trifluoromethylaniline

With the 2-5-trifluoromethylaniline (30mg, 0.21mmol) and ICl (1.1eq, 0.24mmol 38.97mg) add methylene dichloride.Reaction mixture was stirred 12 hours.Said reaction mixture according to step 2 purifying of embodiment 8 to obtain title compound (25.6mg, 42.48%).

(NaCl is pure, cm for IR ^-1): 3411,3066,1109,701;

¹H?NMR(400MHz，CDCl ₃)：δ7.61(d，1H，J＝2.0Hz)，7.46(dd，1H，J＝8.4，1.2Hz)，6.45(d，1H，J＝8.4Hz)，4.05(bs，2H).

Step 2:4-amino-3-trifluoromethyl benzonitrile

With 4-iodo-2-5-trifluoromethylaniline (50mg, 0.17mmol), Zn (CN) ₂(0.88eq, 0.15mmol, 18.00mg), and Pd (PPh ₃) ₄(0.1eq, 0.02mmol 19.64mg) add DMF.With Zn (CN) ₂(0.88eq, 0.15mmol, 18.00mg) and Pd (PPh ₃) ₄(0.1eq, 0.02mmol 19.64mg) add said reaction mixture.Reaction mixture was stirred 12 hours.According to the step 1 purification reaction mixture of embodiment 8 to obtain title product (31.4mg, 99.28%) as yellow solid.

Mp:54～56 ℃; IR (KBr pellet, cm ^-1): 3385,3263,2924,2220,1124,701

¹H?NMR(400MHz，CDCl ₃)：δ7.65(d，1H，J＝2.0Hz)，7.45(dd，1H，J＝8.4，2.0Hz)，6.69(d，1H，J＝8.4Hz)，4.65(s，2H).

Step 3:4-amino-3-iodo-5-trifluoromethyl benzonitrile

With 4-amino-3-trifluoromethyl benzonitrile (100mg, 0.54mmol) and ICl (1.1eq, 0.58mmol 96.00mg) add methylene dichloride.Mixture was stirred 12 hours.According to the step 2 purification reaction mixture of embodiment 8 to obtain title compound (30.5mg, 18.10%).mp：86～88℃；

IR (KBr pellet, cm ^-1): 3371,3080,2924,2226,1125,701;

¹H?NMR(400MHz，CDCl ₃)：δ8.02(d，1H，J＝1.6Hz)，7.35(dd，1H，J＝133.2，1.6Hz)，7.65(dd，1H，J＝10.0，1.6Hz)，5.20(d，2H，J＝22.0Hz).

Step 4: (4-amino-3-iodo-5-trifluoromethyl benzyl) t-butyl carbamate

With 4-amino-(1805.2mg 5.19mmol) is dissolved in THF at 0 ℃ to 3-iodo-5-trifluoromethyl benzonitrile.With borine-THF mixture (3eq, 17.36mmol, 17.36ml) slowly add reaction mixture after, temperature of reaction is heated to backflow.Under situation about refluxing, reaction mixture was stirred 12 hours.After confirming that reaction finishes, add MeOH.Said mixture was stirred 4 hours.Remove reaction solvent in a vacuum.Resistates is used ethyl acetate extraction, uses H ₂O and brine wash are used Na ₂SO ₄Dry and concentrated in a vacuum to produce 4-amino methyl-2-iodo-6-5-trifluoromethylaniline (55.1mg).

(2025.7mg 6.45mmol) is dissolved in THF, then slowly adds BOC with 4-amino methyl-2-iodo-6-trifluoromethyl-aniline ₂O (0.8eq, 5.16mmol, 1187.15 μ l).Reaction mixture was stirred 12 hours.Reaction mixture is used ethyl acetate extraction, uses H ₂O and brine wash, and use Na ₂SO ₄Drying concentrates in a vacuum.Resistates carries out purifying (n-Hx: EA=5: 1) to produce solid (1501.1mg, 55.94%) with column chromatography.

mp：120～122℃；

IR (KBr pellet, cm ^-1): 3387,2984,1687,1107,701;

¹H?NMR(400MHz，CDCl ₃)：δ7.43(d，1H，J＝160.4Hz)，7.27(d，1H，J＝37.2Hz)，4.92(s，1H)，4.54(s，2H)，4.13(s，2H)，1.41(s，9H).

Step 5: (4-amino-3-trifluoromethyl-5-vinyl benzyl) t-butyl carbamate

With Pd (PPh ₃) ₄(0.06eq, 0.014mmol, 16.64mg) and LiCl (2.8eq, 0.67mmol 28.49mg) add DMF.With (4-amino-3-iodo-5-trifluoromethyl benzyl) t-butyl carbamate (100mg, 0.24mmol) and tributylvinyl tin (1.5eq, 0.36mmol, 105.37 μ l) add reaction mixture.Said reaction mixture was stirred in backflow 12 hours.According to the step 4 purification reaction mixture of embodiment 8 to obtain title product, yellow syrup (51.5mg, 67.87%).

mp：90～92℃；

(NaCl is pure, cm for IR ^-1): 3357,2981,1702,1635,1116;

¹H?NMR(400MHz，CDCl ₃)：δ7.24(s，1H)，7.22(s，1H)，6.64(dd，1H，J＝17.2，6.4Hz)，5.57(dd，1H，J＝17.2，1.2Hz)，5.36(dd，1H，J＝10.8，1.2Hz)，4.71(s，1H)，4.15(s，2H)，4.14(d，2H?J＝5.2Hz)，1.39(s，9H)

Step 6: (4-methane sulfonyl amino-3-trifluoromethyl-5-vinyl benzyl) t-butyl carbamate

With (4-amino-3-trifluoromethyl-5-vinyl benzyl) t-butyl carbamate (235.6mg, 0.75mmol), methane sulfonyl chloride (5eq, 3.73mmol, 288.40 μ l), and triethylamine (3eq, 2.25mmol, 313.60 μ l) joins methylene dichloride.Reaction mixture was stirred 5 hours.With reaction mixture according to step 5 purifying of embodiment 8 to obtain title product, yellow syrup (89.3mg, 30.21%).

IR (KBr pellet, cm ^-1): 3361,2977,1692,1330,1152;

¹H?NMR(400MHz，CDCl ₃)：7.65(s，1H)，7.46(s，1H)，7.13(dd，1H，J＝11.2，17.6Hz)，6.09(s，1H)，5.73(d，1H，J＝17.6Hz)，5.42(d，1H，J＝11.2Hz)，4.90(s，1H)，4.29(d，2H，J＝5.6Hz)，3.07(s，3H)，1.40(s，9H)

Step 7:N-(4-amino methyl-2-trifluoromethyl-6-ethenylphenyl) NSC-249992

With (4-methane sulfonyl amino-3-trifluoromethyl-5-vinyl benzyl) t-butyl carbamate (89.3mg, 0.23mmol) and CF ₃COOH (5～6) joins methylene dichloride.Said mixture was stirred 12 hours.With said reaction mixture according to step 6 purifying of embodiment 8 to obtain title product (101.4mg, 100%).

¹H?NMR(400MHz，CD ₃OD)：8.02(s，1H)，7.77(s，1H)，7.27(dd，1H，J＝17.6，11.2Hz)，5.92(d，1H，J＝17.6Hz)，5.51(d，1H，J＝11.2Hz)，4.20(s，2H)，3.11(s，3H).

Step 8:N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-trifluoromethyl-6-ethenylphenyl } NSC-249992

With the 4-tertiary butyl-benzylamine (1.5eq, 15.20 μ l, 0.09mmol), BOC ₂O (1.5eq, 0.09mmol, 20.70 μ l), and DMAP (0.2eq, 0.01mmol 1.34mg) join methylene dichloride.Reaction mixture was stirred 5 hours.Confirm the synthetic 1-tertiary butyl-4-isocyanide acyl methylbenzene with TLC after, (1eq, 0.06mmol is 20.5mg) with TEA (2eq, 0.12mmol, 16.72 μ l) adding reaction mixture with N-(4-amino methyl-2-trifluoromethyl-6-ethenylphenyl) NSC-249992.Reaction mixture was stirred 12 hours and uses step 7 similar methods purifying with embodiment 8 to obtain title compound (10.7mg 36.88%).

mp：134～136℃；

IR (KBr pellet, cm ^-1): 3361,2962,1642,1261,1151;

¹H?NMR(400MHz，CDCl ₃)：δ7.64(s，1H)，7.44(s，1H)，7.28(d，2H，J＝8.0Hz)，7.16(d，2H，J＝8.0Hz)，7.11(dd，1H，J＝17.2，11.2Hz)，6.03(s，1H)，5.71(d，1H，J＝17.2Hz)，5.41(d，1H，J＝11.2Hz)，4.37(s，2H)，4.29(s，2H)，3.06(s，3H)，1.23(s，9H).

Embodiment 11:

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

Step 1: (the 4-tertiary butyl-phenyl)-propynoic acid methyl ester

Be full of two neck round-bottomed flasks of 100ml with argon gas, and (500mg, 2.34mmol) solution in toluene places said flask with the 4-tertiary butyl-Benzoyl chloride 99min..Add (the inferior phosphoranyl of triphenyl) acetate methyl ester (1.5eq to this solution; 3.52mmol; 1178.39mg) and 90～100 ℃ of backflows 12 hours. 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 said product (1) is placed said flask with argon gas, heating, and 250 ℃ of stirrings 90 minutes.With the dichloromethane extraction compound of reaction 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＝8.0Hz)，7.36(d，2H，J＝8.0Hz)，3.80(s，3H)，1.28(s，9H).

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

(21.7mg 0.11mmol) places the round-bottomed flask of 25ml and be dissolved in small amount of methanol with (the 4-tertiary butyl-phenyl)-propionic acid methyl ester.Slowly add K to this solution ₂CO ₃Solution, and stirred 1 hour.After confirming that with TLC reaction finishes, under reduced pressure remove methyl alcohol and use the ethyl acetate extraction resistates.With said ethyl acetate layer water and brine wash,, filter and under reduced pressure concentrate through dried over sodium sulfate.The liquid that obtains is carried out column chromatography (methyl alcohol: ETHYLE ACETATE=1: 1) to produce white liquid (20.8mg, 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 3:3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] propine acid amides

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas; And with N-(R)-[4-(1-amino-ethyl)-2-vinyl-phenyl]-NSC-249992 (110.55mg; 0.46mmol) and (the 4-tertiary butyl-phenyl)-propionic acid (110.4mg) solution in DMF places said flask for 1.2eq, 0.56mmol.To this solution add triethylamine (2eq, 0.92mmol, 128.23mg) and diethylcyanophosphonise (1.2eq, 0.56mmol, 83.76 μ l) and stirring 12 hours.After confirming that with TLC reaction finishes, under reduced pressure remove DMF, use the ethyl acetate extraction resistates.Ethyl acetate layer water and brine wash through dried over sodium sulfate, are filtered and are under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1) to produce yellow solid (54mg, 28.62%).

mp：89～91℃；

[α] ²⁰ _D：-30.72℃(CHCl ₃，c1.51)；

IR (KBr pellet, cm ^-1): 3259,3023,2965,2212,1628,1323;

¹H NMR (400MHz, CDCl ₃): 7.45 (d, 1H, J=2.0Hz), 7.44 (d, 2H, J=8.4Hz), 7.39 (d, 1H, J=8.4Hz), 7.32 (d, 2H; J=8.8Hz), 7.24 (dd, 1H, J=8.0,2.4Hz), 6.91 (dd, 1H, J=17.2,11.2Hz), 6.76 (s, 1H); 6.35 (d, 1H, J=8.0Hz), 5.70 (dd, 1H, J=17.6,0.8Hz), 5.42 (dd, 1H, J=10.8,0.8Hz); 5.15 (quintet, 1H, J=6.8Hz), 2.93 (s, 3H), 1.50 (d, 3H, J=6.8Hz), 1.26 (s, 9H)

Embodiment 12:3-(4-tert-butyl-phenyl) propynoic acid 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl acid amides

With (4-tert-butyl-phenyl) propynoic acid (step 2 of embodiment 11,0.16mmol, 33.0mg) and N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (step 6 of embodiment 2; 0.19mmol, 39.20mg), DEPC (1.2eq; 0.19mmol, 29.13 μ l), TEA (2eq; 0.32mmol, 44.60 μ l) mixture in DMF under argon gas atmosphere stirring at room 12 hours.After end, such as through TLC mensuration, through EtOAc (150ml * 3) abstraction reaction solution, organic phase is used H ₂The O washing, dry (Na ₂SO ₄), filter and concentrate.Carrying out silica gel column chromatography (normal hexane/EtOAc=2: 1), separate 3-(4-tert-butyl-phenyl) propynoic acid 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl acid amides (49.5mg, 0.11mmol, 72.25%).

mp：155～157℃；

IR (KBr pellet, cm ^-1): 3238,3026,2964,2223,1634,1321,1154;

¹H?NMR(400MHz，CDCl ₃)：δ7.51(d，1H，J＝8.8Hz)，7.45(d，2H，J＝8.4Hz)，7.35(s，1H)，7.14(dd，1H，J＝17.6，11.2Hz)，7.07(dd，1H，J＝10.0，1.6Hz)，6.28(t，1H，J＝5.6Hz)，6.03(s，1H)，5.80(d，1H，J＝17.6Hz)，5.45(d，1H，J＝11.2Hz)，4.51(d，2H，J＝6.0Hz)，3.06(s，3H)，1.28(s，9H)

Embodiment 13:3-(4-tert-butyl-phenyl) propynoic acid N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acid amides

With N-[4-(1-amino-ethyl)-2-fluoro-6-ethenylphenyl] NSC-249992 (0.03mmol, 10.0mg), (4-tert-butyl-phenyl) propynoic acid (step 2 of embodiment 11; 0.03mmol, 6.52mg), DEPC (0.03mmol; 5.46 μ l), and TEA (0.06mmol, 8.36 μ l) add DMF.Mixture was stirred 12 hours.According to embodiment 12 purification reaction mixtures to obtain title product (11.3mg, 95.09%).

mp：108～110℃；

[α] _D ²⁰：-14.54(CHCl ₃，c?0.81)；

IR (KBr pellet, cm ^-1): 3248,3025,2965,2211,1629,1323,1152; ¹HNMR (400MHz, CDCl ₃): δ 7.44 (d, 2H, J=8.4Hz), 7.38 (s, 1H), 7.34 (d, 2H, J=8.4Hz), 7.14 (dd; 1H, J=17.6,10.8Hz), 7.06 (dd, 1H, J=10.4,2.0Hz), 6.17 (d, 1H; J=7.6Hz), 5.80 (d, 1H, J=17.6Hz), 5.43 (d, 1H, J=10.8Hz), 5.15 (quintet, 1H; J=7.2Hz), 3.05 (s, 3H), 1.52 (d, 3H, J=6.8Hz), 1.28 (s, 9H)

Embodiment 14:

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] acrylic amide

Be full of two neck round-bottomed flasks of 25ml with argon gas, (21.1mg, 0.103mmol 1eq.) see with diethylammonium cyanic acid that (1.1eq.) solution in DMF places said flask to acid esters for 17.2 μ l, 0.113mmol with 3-(the 4-tertiary butyl-phenyl)-vinylformic acid.Add 1-(R)-(4-methane sulfonyl amino-3-vinyl-phenyl)-ethyl-ammonium to this solution, and three fluoro-acetic ester (36.7mg, 0.103mmol, 1eq.) and triethylamine (43.1 μ l, 0.309mmol, 3eq.) solution in DMF.Mixture solution is stirred a night.After confirming that with TLC reaction finishes, under reduced pressure remove DMF and said resistates is used ethyl acetate extraction.Water and brine wash ethyl acetate layer are also under reduced pressure removed ETHYLE ACETATE through dried over sodium sulfate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce light yellow solid (33.4mg, 76.0%).

mp：111.2-112.5℃；

[a] ²³ _D：-19.70℃(c?1.12，CHCl ₃)；

IR (KBr pellet, cm ^-1): 3428,3377,3274,3087,2964,2868,1655,1618;

¹H NMR (400MHz, CDCl ₃): 7.55 (d, 1H, J=15.6Hz), 7.39 (d, 1H, J=1.6Hz), 7.35 (d, 2H, J=8.0Hz), 7.29 (d, 3H; J=8.0Hz), 6.84 (dd, 1H, J=17.2,10.8Hz), 6.68 (bs, 1H), 6.33 (d, 1H, J=15.6Hz), 6.07 (d; 1H, J=8.0Hz), 5.63 (dd, 1H, J=17.2,0.8Hz), 5.34 (dd, 1H, J=10.8,0.8Hz); 5.15 (quintet, 1H, J=6.8Hz), 2.90 (s, 3H), 1.45 (d, 3H, J=6.8Hz), 1.24 (s, 9H)

Embodiment 15:

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Be full of two neck round-bottomed flasks of 25ml with argon gas, with 3-(4-tert-butyl-phenyl)-vinylformic acid (46.4mg, 0.227mmol, 1eq.) and diethylcyanophosphonise (1.1eq.) solution in DMF places said flask for 37.9 μ l, 0.250mmol.Be added in synthetic 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl-ammonium in the step 5 of embodiment 2 to this solution, and trifluoroacetate (81.4mg, 0.227mmol, 1eq.) and triethylamine (94.9 μ l, 0.681mmol, 3eq.) solution in DMF.With one night of said solution stirring.After confirming that with TLC reaction finishes, under reduced pressure remove DMF and resistates is used ethyl acetate extraction.With ethyl acetate layer water and brine wash,, and under reduced pressure remove ETHYLE ACETATE through dried over sodium sulfate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (80.9mg, 82.8%).

mp：182-183℃；

IR (KBr pellet, cm ^-1): 3418,3238,3073,2962,1654,1622,1321,1153;

¹H?NMR(400MHz，CD ₃OD)：7.53(d，1H，J＝16.0Hz)，7.47(d，2H，J＝8.4Hz)，7.45(d，1H，J＝2.0Hz)，7.40(d，2H，J＝8.4Hz)，7.15(dd，1H，J＝17.6，10.8Hz)，7.08(dd，1H，J＝10.4，2.0Hz)，6.58(d，1H，J＝16.0Hz)，5.81(d，1H，J＝17.6Hz)，5.35(d，1H，J＝10.8Hz)，4.47(s，2H)，2.98(s，3H)，1.29(s，9H)

Embodiment 16:

3-(4-tert-butyl-phenyl)-N-(3-fluoro-5-ethynyl-4-methane sulfonyl amino-benzyl) acrylic amide

Be full of two neck round-bottomed flasks of 25ml with argon gas, and with 3-(4-tert-butyl-phenyl)-vinylformic acid (66.6mg, 0.326mmol, 1eq.) and diethylcyanophosphonise (1.1eq.) solution in DMF places said flask for 54.4 μ l, 0.359mmol.Be added in the 3-fluoro-5-ethynyl-4-methane sulfonyl aminobenzyl-ammonium that obtains in the step 3 of embodiment 3 to this solution, and trifluoroacetate (116.3mg, 0.326mmol, 1eq.) and triethylamine (136.3 μ l 0.978mmol, 3eq.) solution in DMF.With one night of solution stirring.After confirming that with TLC reaction finishes, under reduced pressure remove DMF and use the ethyl acetate extraction resistates.Ethyl acetate layer water and brine wash through dried over sodium sulfate, are under reduced pressure removed ETHYLE ACETATE.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (109.6mg, 77.9%).

mp：149-150℃；

IR (KBr pellet, cm ^-1): 3413,3254,3069,2963,2107,1621,1325,1154;

¹H?NMR(400MHz，CD ₃OD)：7.54(d，1H，J＝16.0Hz)，7.48(d，2H，J＝8.4Hz)，7.41(d，2H，J＝8.4Hz)，7.30(d，1H，J＝2.0Hz)，7.19(dd，1H，J＝10.4，2.0Hz)，6.58(d，1H，J＝16.0Hz)，4.44(s，2H)，3.86(s，1H)，3.09(s，3H)，1.30(s，9H)

Embodiment 17:3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide

Be full of two neck round-bottomed flasks of exsiccant 25ml with argon gas; And with N-(4-amino methyl-2-vinyl-phenyl)-NSC-249992 (51mg; 0.23mmol) and 3-(the 4-tertiary butyl-phenyl)-vinylformic acid (55.26mg) solution in DMF places said flask for 1.2eq, 0.27mmol.To this solution add triethylamine (2eq, 0.46mmol, 64.12mg) and diethylcyanophosphonise (1.2eq, 0.27mmol, 41.88 μ l) and stirring 12 hours.After confirming that with TLC reaction finishes, reaction soln is used dichloromethane extraction, water and brine wash are filtered through dried over sodium sulfate, and under reduced pressure concentrate.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1) to produce white solid (48.4mg, 43.37%).

¹H?NMR(400?MHz，CDCl ₃)：7.59(d，1H，J＝15.6Hz)，7.37(d，2H，J＝8.0Hz)，7.34(s，1H)，7.31(d，1H，J＝10.4Hz)，7.18(d，2H，J＝8.0Hz)，6.82(dd，1H，J＝17.6，11.2Hz)，6.44(s，1H)，6.33(d，1H，J＝7.6Hz)，6.01(bs，1H)，5.65(d，1H，J＝17.6Hz)，5.39(d，1H，J＝11.2Hz)，4.47(d，2H，J＝5.6Hz)，2.91(s，3H)，1.24(s，9H).

Embodiment 18:

3-(4-trifluoromethyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide

According to embodiment 17 in the said identical method synthesis of acrylamide (90mg) of similar methods.

¹H?NMR(300MHz，CDCl ₃)：7.71(d，1H，J＝15.9Hz)，7.62(m，4H)，7.47(m，2H)，6.88(dd，1H，J＝17.4，11.1Hz)，6.53(d，1H，J＝15.6Hz)，6.27(bs，1H)，5.93(bs，1H)，5.74(d，1H，J＝17.4Hz)，5.51(d，1H，J＝11.1Hz)，4.59(d，2H，J＝6Hz)，3.01(s，3H)

Embodiment 19:

3-(4-methylthio group phenyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide

With acrylic amide (120mg) according to synthesize in the identical method described in the embodiment 11.

¹H?NMR(300MHz，CDCl3)：7.64(d，1H，J＝15.6Hz)，7.43(m，2H)，7.25(m，4H)，6.87(dd，1H，J＝17.1，6.6Hz)，6.36(d，1H，J＝15.3Hz)，6.26(bs，1H)，5.86(bs，1H)，5.74(d，1H，J＝17.1Hz)，5.50(d，1H，J＝11.1Hz)，4.58(d，2H，J＝6Hz)，3.00(s，3H)，2.50(s，3H)

Embodiment 20:3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-3-methyl-5-vinyl benzyl) acrylic amide

With N-(4-amino methyl-2-methyl-6-ethenylphenyl) NSC-249992 (1eq, 33.5mg, 0.14mmol); 3-(4-tert-butyl-phenyl) vinylformic acid (1.2eq, 0.17mmol, 34.18mg); DEPC (1.2eq, 0.17mmol, 25.49 μ l); And TEA (2eq, 0.28mmol, 39.03 μ l) adds DMF.Said mixture was stirred 12 hours.Reaction mixture carries out purifying to obtain white solid (29.83mg, 51.3%) according to embodiment 17.

Mp:182～184 ℃; IR (KBr pellet, cm ^-1): 3287,3069,2963,1655,1315

¹H?NMR(400MHz，CD ₃?OD)：δ7.52(d，1H，J＝15.6Hz)，7.46(d，2H，J＝8.4Hz)，7.43(s，1H)，7.40(d，2H，J＝8.4Hz)，7.16(s，！H)，7.15(dd，1H，J＝17.6，11.2Hz)，6.58(d，1H，J＝15.6Hz)，5.75(d，1H，J＝17.6Hz)，5.32(d，1H，J＝11.2Hz)，4.43(s，2H)，2.97(s，3H)，2.38(s，3H)，1.29(s，9H)

Embodiment 21.

3-(4-tert-butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With N-(4-amino methyl-2-chloro-6-ethenylphenyl) NSC-249992 (step 5 of embodiment 9,1eq, 33.4mg, 0.09mmol); 3-(4-tert-butyl-phenyl) vinylformic acid (1.2eq, 0.11mmol, 21.87mg); DEPC (1.2eq, 0.11mmol, 16.63 μ l); And TEA (2eq, 0.18mmol, 25.09 μ l) adds DMF.Mixture was stirred 12 hours.Reaction mixture according to embodiment 17 purifying to obtain white solid (20.8mg, 51.80%).

mp：157～159℃；

IR (KBr pellet, cm ^-1): 3248,3064,2962,1653,1321,701;

¹H?NMR(400MHz，CD ₃OD)：δ7.58(d，1H，J＝1.6Hz)，7.53(d，1H，J＝16.0Hz)，7.47(d，2H，J＝8.4Hz)，7.40(d，2H，J＝8.4Hz)，7.38(d，1H，J＝1.6Hz)，7.19(dd，1H，J＝17.6，11.2Hz)，6.59(d，1H，J＝16.0Hz)，5.79(d，1H，J＝17.6Hz)，5.34(d，1H，J＝11.2Hz)，4.46(s，2H)，3.05(s，3H)，1.29(s，9H).

Embodiment 22.3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl) ethyl propenoate with acid chloride (II) (1.4mg, 0.006mmole, 6mol%eq); Rac-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (7.5mg; 0.012mmole, 12mol%eq), and cesium carbonate (50.3mg; 0.155mmole, 1.5eq) add dry toluene.(36.2mg, 0.103mmol 1eq) add through sleeve pipe 3-(the 4-tertiary butyl-2-trifluoromethane sulfonyl group oxygen base phenyl) ethyl propenoate that will be in toluene solvant.Adding morpholine (Morphloline) (13.5 μ l, 0.155mmol, 1.5eq).Mixture was stirred in backflow 12 hours.After confirming that with TLC reaction finishes, reaction mixture is filtered with C salt.To filtrate concentrates in a vacuum, and then, (n-Hx: EA=12: 1) the purifying resistates is to obtain title product (16.7mg, 51.2%) with column chromatography.

¹H?NMR(400MHz，CDCl ₃)：δ7.98(d，J＝16.0Hz，1H)，7.41(d，J＝8.0Hz，1H)，7.05(dd，J＝8.0，1.6Hz，1H)，6.99(d，J＝1.6Hz，1H)，6.32(d，J＝16.0Hz，1H)，4.19(q，J＝7.2Hz，2H)，3.82(t，J＝4.8Hz，4H)，2.90(t，J＝4.8Hz，4H)，1.29-1.25(m12H)

Step 2:3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

(29.1mg, 0.092mmol 1eq) add methyl alcohol and H with 3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl) ethyl propenoate ₂O.Adding sodium hydroxide (36.7mg, 0.917mmole, 10eq).Stirred the mixture 12 hours.After confirming that reaction finishes, reaction mixture is cooled to 0 ℃.Use the 5%HCl acidified reaction mixture.Reaction solvent is under reduced pressure removed to obtain yellow solid (26.6mg, 100%).TLC: R _f=0.15 (normal hexane: EtOAc=2: 1/KMnO ₄).

(0.092mmol, 1eq.) (16.8 μ l, 0.110mmol 1.2eq) adds DMF under argon gas atmosphere with diethylammonium cyanic acid phosphine with 3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl) vinylformic acid 25.9mg.With N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (49.3mg, 0.138mmol, 1.2eq.) and triethylamine (38.5 μ l, 0.276mmol 3eq) add reaction mixture.After confirming that reaction finishes, remove reaction solvent in a vacuum.Resistates extracts with EtOAc, uses brine wash, uses Na ₂SO ₄Dry and then concentrated in a vacuum.(normal hexane: EtOAc=1: 1) the purifying resistates is to obtain the solid (28.2mg, 62.4%) that turns white with column chromatography.

Mp (℃): 171-173 ℃; IR (KBr pellet, cm ^-1): 3422,2959,2857,1649,1617,1322,1154; ¹H NMR (400MHz, CDCl ₃): 8.01 (d, J=15.6Hz, 1H), 7.53 (d, J=8.8Hz, 1H), 7.50 (s, 1H), 7.19 (dd; J=11.2,17.6Hz, 1H), 7.15-7.11 (m, 3H), 6.61 (d, J=15.6Hz, 1H), 5.84 (d; J=17.6Hz, 1H), 5.38 (d, J=11.2Hz, 1H), 4.51 (s, 2H), 3.88 (t, J=4.4Hz; 4H), 3.02 (s, 2H), 2.94 (t, J=4.4Hz, 4H), 1.32 (s, 9H)

Embodiment 23.

3-[the 4-tertiary butyl-2-(2-methoxyl group-oxyethyl group)-phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl)-acrylic amide

The step 1:4-tertiary butyl-1-iodo-2-(2-methoxy ethoxy) benzene

With NaH (21.0mg, 0.5250mmol, 60%disp.oil, 5eq) and the tertiary butyl-2-iodo-phenol (29.0mg, 0.105mmol 1eq) add DMF.(23.96 μ l, 0.26mmol 2.5eq) add mixture with chloroethyl methyl ether.At 90 ℃ with the reaction mixture stirred overnight.Through adding H ₂O quencher reaction mixture.After removing DMF in a vacuum, extract resistates with EtOAc.The organic layer that merges is used H ₂O and brine wash are used Na ₂SO ₄Drying then concentrates in a vacuum.(normal hexane: EtOAc=20: 1) purifying is to obtain liquid (32.0mg, 91.2%) with column chromatography with resistates.

¹H NMR (400MHz, CDCl ₃): δ 7.58 (d, J=8.4Hz, 1H), 6.82 (d, J=2.0Hz, 1H), 6.69 (dd, J=8.4,2.4Hz, 1H), 4.10 (t, J=4.8Hz, 2H), 3.75 (dd, J=4.8,4.4Hz, 2H), 3.43 (s, 3H), 1.22 (s, 9H); (NaCl is pure, cm for IR ^-1): 2960,2871,1713,1628,1607,1165.

Step 2:3-[the 4-tertiary butyl-2-(2-methoxy ethoxy) phenyl] methyl acrylate

With acid chloride (63.77mg, 0.2841mmol, 6%moleq) and 1.1 '-two (diphenylphosphino) ferrocene (314.99mg, 0.5682mmol, 12%mol eq) add DMF solution.With methyl acrylate (469.01 μ l, 5.2082mmol, 1.1eq), triethylamine (1.3171ml, 9.4694mmol, 2eq) and the 4-tertiary butyl-1-iodo-2-(2-methoxyl group-oxyethyl group)-benzene (1.5823g, 4.7347mmol 1eq) add.At 60 ℃ of stirred overnight reaction mixtures.With reaction mixture according to step 1 purifying to obtain red liquid (1.1156g, 83.5%).

¹H NMR (400MHz, CDCl ₃): δ 7.96 (d, J=16.0Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 6.99 (dd, J=8.0; 1.6Hz, 1H), 6.96 (d, J=1.6Hz, 1H), 6.52 (d, J=16.4Hz; 1H), 4.23 (q, J=7.2Hz, 2H), 4.19 (t, J=4.8Hz, 2H); 3.81 (t, J=4.8Hz, 2H), 3.47 (s, 3H), 1.33-1.30 (m, 12H); (NaCl is pure, cm for IR ^-1): 3408,2964,2869,1683,1624

Step 3:3-(the 4-tertiary butyl-2-morpholine (morpholie)-4-base-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-[the 4-tertiary butyl-2-(2-methoxy ethoxy) phenyl] ethyl propenoate (40.4mg, 0.132mmol, 1eq) and sodium hydroxide (52.8mg, 1.32mmole 10eq) add methyl alcohol and H ₂O.With reaction mixture according to step 2 purifying of embodiment 22 to obtain 3-[the 4-tertiary butyl-2-(2-methoxy ethoxy) phenyl] vinylformic acid (36.5mg, 77.3%).With 3-[the 4-tertiary butyl-2-(2-methoxy ethoxy)-phenyl] vinylformic acid (26.4mg, 0.095mmol, 1eq.); Diethylammonium cyanic acid phosphine (17.3 μ l, 0.114mmol, 1.2eq); N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (40.8mg, 0.1114mol, 1.2eq.); And triethylamine (39.7 μ l, 0.285mmol, 3eq) adding DMF.With mixture in stirred overnight at room temperature.According to embodiment 17 purification reaction mixtures to obtain the solid (28.4mg, 59.2%) that turns white.

IR (KBr pellet, cm ^-1): 3422,2959,2857,1649,1617,1322,1154;

¹H?NMR(400MHz，CDCl ₃)：7.79(d，J＝16.0Hz，1H)，7.48(s，1H)，7.38(d，J＝8.0Hz，1H)，7.08(dd，J＝11.2，17.6Hz，1H)，7.01(dd，J＝10.4，1.6Hz，1H)，6.95-6.89(m，2H)，6.60(d，J＝16.0Hz，1H)，5.74(d，J＝17.6Hz，1H)，5.28(d，J＝11.2Hz，1H)，4.39(s，2H)，4.10(t，J＝4.4Hz，2H)，3.71(t，J＝4.4Hz，2H)，3.64-3.60(m，2H)，3.34(s，2H)，2.91(s，3H)，1.22(s，9H)

Embodiment 24:

3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-3-trifluoromethyl-5-vinyl benzyl) acrylic amide

With N-(4-amino methyl-2-trifluoromethyl-6-ethenylphenyl) NSC-249992 (step 7 among the embodiment 10,1eq, 44.1mg; 0.13mmol), 3-(the 4-tertiary butyl-phenyl)-vinylformic acid (1.1eq, 0.15mmol; 29.99mg), DEPC (1.2eq, 0.16mmol; 23.67 μ l) and TEA (2eq, 0.26mmol, 36.24 μ l) add DMF.Reaction mixture was stirred 12 hours.According to embodiment 17 purification reaction mixtures to obtain white solid (55.4mg, 88.75%).

Mp:174～176 ℃; IR (KBr pellet, cm ^-1): 3257,3078,2964,1653,1326;

¹H?NMR(400MHz，CDCl ₃)：δ7.67(d，1H，J＝1.6Hz)，7.60(d，1H，J＝15.6Hz)，7.47(d，1H，J＝1.6Hz)，7.38(d，2H，J＝8.4Hz)，7.32(d，2H，J＝8.4Hz)，7.13(dd，1H，J＝17.6，10.8Hz)，6.65(s，1H)，6.62(t，1H，J＝6.0Hz)，6.39(d，1H，J＝16.0Hz)，5.71(d，1H，J＝17.6Hz)，5.39(d，1H，J＝11.2Hz)，4.49(d，2H，J＝5.6Hz)，3.07(s，3H)，1.26(s，9H).

Embodiment 25:3-[the 4-tertiary butyl-2-(4-N-METHYL PIPERAZINE-1-yl) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-[the 4-tertiary butyl-2-(4-N-METHYL PIPERAZINE-1-yl) phenyl] ethyl propenoate

With acid chloride (2.8mg, 0.013mmol, 6%mol eq), rac-2,2 '-two (diphenylphosphino) 1,1 '-dinaphthalene (16.2mg, 0.026mmol, 12%mol eq), and cesium carbonate (102.6mg, 0.315mmol 1.5eq) add dry toluene under argon gas atmosphere.Stir after 5 minutes, add 3-(the 4-tertiary butyl-2-trifluoromethane sulfonyl group-oxygen base phenyl) ethyl propenoate (74.0mg, 0.210mmol, 1eq) and N methyl piperazine (34.9 μ l, 0.315mmole, 1.5eq).Mixture was stirred 24 hours at 80 ℃.Reaction mixture according to step 1 purifying of embodiment 22 to obtain yellow liquid (50.8mg, 73.2%).

Step 2:

3-[the 4-tertiary butyl-2-(4-N-METHYL PIPERAZINE-1-yl) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

3-[the 4-tertiary butyl-2-(4-N-METHYL PIPERAZINE-1-yl) phenyl] ethyl propenoate (29.1mg, 0.092mmol, 1eq) and sodium hydroxide (36.7mg, 0.917mmole add methyl alcohol and H ₂O.Stirred the mixture 12 hours.Use the 5%HCl acidified reaction mixture.Reaction mixture concentrates to obtain yellow solid (27.8mg, 100%) in a vacuum.

(1eq.) (28.0 μ l, 0.185mmol 1.2eq) add DMF with diethylammonium cyanic acid phosphine for 46.6mg, 0.154mmol with 3-[the 4-tertiary butyl-2-(4-N-METHYL PIPERAZINE-1-yl) phenyl] vinylformic acid.Add N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (60.7mg, 0.169mmol, 1.1eq.) and triethylamine (64.4 μ l, 0.462mmol, 3eq).With reaction mixture in stirred overnight at room temperature.Remove reaction solvent in a vacuum.Extract resistates with EtOAc.The organic layer that merges is used brine wash, through dried over sodium sulfate and then concentrated in a vacuum.With resistates with column chromatography (MeOH: EtOAc=1: 1) carry out purifying to obtain solid (63.9mg, 71.3%).

IR (KBr pellet, cm ^-1): 3422,2959,2857,1649,1617,1322,1154;

¹H?NMR(400MHz，CDCl ₃)：7.96(d，J＝15.6Hz，1H)，7.54(d，J＝8.8Hz，1H)，7.49(s，1H)，7.26-7.09(m，4H)，6.62(d，J＝15.6Hz，1H)，5.84(d，J＝17.6Hz，1H)，5.39(d，J＝10.8Hz，1H)，4.51(s，2H)，3.03(s，4H)，2.87(s，4H)，2.51(s，4H)，1.32(s，9H)

Embodiment 26:3-[the 4-tertiary butyl-2-(2-piperidines-1-base-oxyethyl group) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-[the 4-tertiary butyl-2-(2-piperidines-1-base-oxyethyl group) phenyl] ethyl propenoate

With 3-(the 4-tertiary butyl-2-hydroxy phenyl) ethyl propenoate (59.0mg, 0.238mmol) and NaH (47.5mg, 60%disp.oil 5eq) add dry DMF.Reaction mixture is cooled to 0 ℃.(87.6mg 0.476mmol 2eq) adds with 1-(2-chloroethyl) piperidine hydrochlorate.With mixture heating up to 90 ℃.90 ℃ of stirring reactions 12 hours.Through adding H ₂O quencher reaction.With EtOAc abstraction reaction mixture, then use H ₂O and brine wash.With column chromatography (EtOAc) purifying resistates to obtain yellow liquid (14.0mg, 16.4%).

¹H NMR (400MHz, CDCl ₃): δ 7.86 (d, J=16.0Hz, 1H), 7.39 (d, J=8.8Hz, 1H), 6.95-6.93 (m, 2H); 4.15-4.09 (m, 4H), 2.77 (t, J=5.6Hz, 2H), 2.52 (s, 4H); 1.54 (quintet, J=5.6Hz, 4H), 1.42-1.36 (m, 2H), 1.23 (s, 9H)

Step 2:

3-[the 4-tertiary butyl-2-(2-piperidines-1-base-oxyethyl group) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

3-[the 4-tertiary butyl-2-(2-piperidines-1-base-oxyethyl group) phenyl] ethyl propenoate (14.0mg, 0.039mmol, 1eq) and sodium hydroxide (7.8mg, 0.195mmole 5eq) add methyl alcohol and H ₂O.With reaction mixture stirring at room 12 hours.With 5%HCl solution acidified reaction mixture.Reaction mixture is concentrated to obtain yellow solid (12.9mg, 100%) in a vacuum.

With 3-[the 4-tertiary butyl-2-(2-piperidines-1-base-oxyethyl group) phenylacrylic acid (0.039mmol; 1eq.), diethylammonium cyanic acid phosphine 7.1 μ l (0.0.047mmol, 1.2eq); N-(4-amino methyl-2-fluoro-6-ethenylphenyl)-NSC-249992 16.8mg (0.047mmol; 1.2eq.) and triethylamine 16.3 μ l (0.117mmol, 3eq) adding DMF.With said mixture in stirred overnight at room temperature.With reaction mixture according to embodiment 25 purifying to obtain solid (32.6mg, 100%).

¹H NMR (400MHz, CDCl ₃): 7.83 (d, J=16.0Hz, 1H), 7.44 (d, J=8.0Hz, 1H), 7.38 (s, 1H), 7.09 (dd, J=11.2; 18.0Hz, 1H), 7.03-6.99 (m, 2H), 6.96 (s, 1H), 6.55 (d, J=16.0Hz, 1H), 5.73 (d; J=17.6Hz, 1H), 4.04 (s, 2H), 4.25 (t, J=10.2Hz, 2H), 3.17 (t, J=10.2Hz, 2H); 2.97-2.92 (m, 9H), 1.66 (quintet, J=5.6Hz, 4H), 1.48-1.47 (m, 2H), 1.23 (s, 9H)

Embodiment 27:

3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl] methyl acrylate

With three (dibenzalacetone)-two palladiums (19.1mg, 0.021mmol), 1; 1 '-two (diphenylphosphino)-ferrocene (34.7mg, 0.063 mmol), 2-methoxy ethyl amine (72.5 μ l; 0.834mmol); And 3-(the 4-tertiary butyl-2-trifluoromethane sulfonyl group oxygen base phenyl)-(152.6mg, 0.417mmol 1eq) join in the dry toluene methyl acrylate.(203.8mg 0.623mmol) adds mixture with cesium carbonate.Reaction mixture was stirred 12 hours at 80 ℃.According to the step 1 purification reaction mixture of embodiment 27 to obtain green liquid (64.3mg, 52.9%).

¹H NMR (400MHz, CDCl ₃): δ 7.75 (d, J=16.0Hz, 1H), 7.25 (d, J=8.0Hz, 1H), 6.71 (dd; J=8.0,1.6Hz, 1H), 6.63 (d, J=1.6Hz, 1H), 6.24 (d; J=16.0Hz, 1H), 3.72 (s, 3H), 3.57 (t, J=5.2Hz, 2H); 3.33 (s, 3H), 3.29 (t, J=5.2Hz, 2H), 1.23 (s, 9H); (NaCl is pure, cm for IR ^-1): 3441,2960,2871,1713,1628,1607,1165.

Step 2:

3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

(64.3mg, 0.221mmol is 1eq) with sodium hydroxide (44.1mg, 1.103mmole, 5eq) adding methyl alcohol and H with 3-[the 4-tertiary butyl-2-(2-methoxy ethyl amino) phenyl] methyl acrylate ₂Among the O.Stirring at room reaction mixture 12 hours.Reaction mixture is with the acidifying of 5%HCl solution.Reaction mixture is concentrated to obtain yellow solid (50.2mg, 100%) in a vacuum.

(40.2 μ l, 0.265mmol 1.2eq) add DMF for 3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl] vinylformic acid (0.221mmol) and diethylammonium cyanic acid phosphine.Add N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (95.5mg, 0.265mmol) and triethylamine (92.4 μ l, 0.663mmol).Spend the night at the stirring at room reaction mixture.According to the step 2 purification reaction mixture of embodiment 24 to obtain green solid (77.8mg, 71.3%).

Mp (℃): 196-198; IR (KBr pellet, cm ^-1): 3434,3254,2961,1648,1608,1321,1153,974; ¹H NMR (400MHz, CDCl ₃): 7.76 (d, J=15.2Hz, 1H), 7.27 (s, 1H), 7.23 (d, J=8.4Hz, 1H), 7.07 (dd, J=17.6,10.8Hz; 1H), 6.97 (d, J=8.0Hz, 1H), 6.69 (d, J=8.0Hz, 1H), 6.34 (s, 1H), 6.23 (t, 8.0Hz; 1H), 5.71 (d, J=17.6Hz, 1H), 5.45 (d, J=10.4Hz, 1H), 4.46 (d, J=6.0Hz, 2H), 3.57 (t; J=5.2Hz, 2H), 3.32-3.28 (m, 5H), 2.99 (s, 3H), 2.51 (s, 3H), 1.23 (s, 9H)

Embodiment 28:

3-(the 4-tertiary butyl-2-p-methoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide

Step 1:3-(the 4-tertiary butyl-2-p-methoxy-phenyl) methyl acrylate

With salt of wormwood (59.0mg, 0.427mmol) and iodoethane (25.6 μ l 0.320mmol) add acetone.(50.0mg 0.213mmol) adds reaction mixture with 3-(the 4-tertiary butyl-2-hydroxy phenyl) methyl acrylate.Under situation about refluxing, reaction mixture was stirred 5 hours.Reaction solvent is removed in a vacuum.Extract resistates with EtOAc.The organic layer that merges is used brine wash,, under reduced pressure concentrate through dried over sodium sulfate.(normal hexane: EtOAc=10: 1) the purifying resistates is to obtain solid (56.4mg, 67.2%) with column chromatography.

IR (KBr pellet, cm ^-1): 2952,1686,1625,1439;

¹H?NMR(400MHz，CDCl ₃)：δ7.99(d，J＝16.8Hz，1H)，7.44(d，J＝8.0Hz，1H)，6.96(dd，J＝8.0，19.2Hz，2H)，4.13(dd，J＝6.8，13.6Hz，2H)，3.80(s，3H)，1.33(bs，9H).

Step 2:

3-(the 4-tertiary butyl-2-p-methoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide

With 3-(the 4-tertiary butyl-2-p-methoxy-phenyl) methyl acrylate (125mg, 1eq), and NaOH (75mg 1.88mmol) adds H ₂Among the O.Reaction mixture was stirred 12 hours.Reaction mixture is with the acidifying of 5%HCl solution.Reaction mixture concentrates to obtain solid (121mg, 100%) in a vacuum.

With 3-(the 4-tertiary butyl-2-p-methoxy-phenyl) vinylformic acid (121mg, 0.519mmol, 1eq); N-(4-amino methyl-2-fluoro-6-vinyl-phenyl)-NSC-249992 (148.8mg, 0.415mmol), DEPC (94.5 μ l; 0.62mmol, 1.2eq) and TEA (217 μ l 1.56mmol) add DMF.Reaction mixture was stirred 5 hours.Remove reaction solvent in a vacuum.Extract resistates with EtOAc.The organic layer that merges is used brine wash,, concentrate in a vacuum through dried over sodium sulfate.(normal hexane: EtOAc=1: 1) the purifying resistates is to obtain solid (96.2mg, 50.3%) with column chromatography.

Mp.:150-152 ℃; IR (KBr pellet, cm ^-1): 3435,1651,1616,1448,1321;

¹H?NMR(400MHz，CDCl ₃)：δ7.77(d，J＝15.6Hz，1H)，7.37(d，J＝9.2Hz，1H)，7.12(dd，J＝11.2，18.0Hz，1H)，7.01(dd，J＝10.4，1.6Hz，1H)，6.95-6.89(m，2H)，6.62(d，J＝15.6Hz，1H)，5.74(dd，J＝17.6，0.8Hz，1H)，5.28(d，J＝11.6Hz，1H)，4.39(s，2H)，3.79(s，3H)，2.92(d，J＝0.8Hz，3H)，1.23(s，3H).

Embodiment 29:

3-(the 4-tertiary butyl-2-hydroxy phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

The step 1:5-tertiary butyl-2 iodophenol

(1eq) (44.9mg 0.199mmol) adds anhydrous acetonitrile to the 3-tert.-butyl phenol under argon gas atmosphere with N-iodine succinimide for 30mg, 0.199mmol.Mixture was stirred 1 hour.Remove reaction solvent in a vacuum.Use CH ₂Cl ₂Extract resistates.The organic layer that merges is used H ₂O and brine wash through dried over sodium sulfate, and concentrate in a vacuum.(normal hexane: EtOAc=30: 1) purifying is to obtain yellow syrup (46.9mg, 85.1%) with column chromatography for resistates.

¹H NMR (400MHz, CDCl ₃): δ 7.46 (d, J=8.0Hz, 1H), 6.95 (s, 1H), 6.64 (dd, J=8.0,2.4Hz, 1H), 5.20 (bs, 1H), 1.20 (s, 9H); (NaCl is pure, cm for IR ^-1): 3489,2963,1561,1399,1304,1190

Step 2: (the 4-tertiary butyl-2-hydroxy phenyl) methyl acrylate

With acid chloride (16.8mg, 0.075mmol), 1.1 '-two (diphenylphosphino) ferrocene (49.9mg, 0.090mmol), triethylamine (418.1 μ l, 3.000mmol), and methyl acrylate (148.6 μ l 1.650mmol) join in the dry toluene.The adding 5-tertiary butyl-2-iodophenol (414.4mg, 1.500mmol).With reaction mixture 60 ℃ of stirred overnight.Remove reaction solvent in a vacuum.Resistates was carried out purifying to obtain solid (322.3mg, 91.7%) according to similar method of work.

¹H NMR (400MHz, CDCl ₃): δ 7.93 (d, J=16.0Hz, 1H), 7.31 (d, J=8.0Hz, 1H), 6.87 (dd, J=8.0,2.0Hz, 1H), 6.80 (d, J=1.6Hz, 1H), 6.53 (dd, J=16.0,2.0Hz, 1H), 3.75 (s, 3H), 1.21 (s, 9H); IR (KBr pellet, cm ^-1): 3362,2952,1686,1625,1439,1325

Step 3:3-(the 4-tertiary butyl-2-hydroxy phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-(the 4-tertiary butyl-2-hydroxyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) vinylformic acid (25.9mg; 0.092mmol), diethylammonium cyanic acid phosphine (19.85 μ l, 0.131mmol); N-(4-amino methyl-2-fluoro-6-ethenylphenyl)-NSC-249992 (46.8mg; 0.131mmol), and triethylamine (45.58 μ l 0.327mmol) add DMF under argon gas atmosphere.According to step 2 purification reaction mixture to obtain solid (30.1mg, 51%).

Mp (℃): 171-173; IR (KBr pellet, cm ^-1): 3422,2959,2857,1649,1617,1322,1154; ¹H NMR (400MHz, CDCl ₃): 7.74 (d, J=16Hz, 1H), 7.38 (S, 1H), 7.29 (d, 1H, J=804Hz), 7.08 (dd; 1H, J=15.6,11.2Hz), 7.01 (d, 1H, J=10.4Hz), 6.81 (d, 2H; J=11.2Hz), 6.65 (d, J=16Hz, 1H), 5.75 (d, J=17.6Hz, 1H), 5.28 (d; J=10.8Hz, 1H), 4.39 (s, 2H), 2.92 (s, 3H), 1.19 (s, 9H)

Embodiment 30:

3-(2-allyl group oxygen base-4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-(2-allyl group oxygen base-4-tert-butyl-phenyl) methyl acrylate

With 3-(the 4-tertiary butyl-2-hydroxyl-phenyl)-methyl acrylate (50mg, 0.21mmol), allyl group-iodide (29.26 μ l, 0.32mmol), and K ₂CO ₃(58.05mg 0.42mmol) adds acetone.With the reaction mixture stirred overnight.With column chromatography (normal hexane: EtOAc=10: 1) carry out purifying to obtain solid (51.4mg, 89.3%).

Mp.:170.5～171.2 ℃; IR (KBr pellet, cm ^-1): 3227,3076,1685,1651,1617,1153;

¹H?NMR(400MHz，CDCl ₃)：δ7.93(d，J＝16.0Hz，1H)，7.36(d，J＝8.0Hz，1H)，6.91(d，J＝8.0Hz，1H)，6.84(s，1H)，6.43(d，J＝16.0Hz，1H)，5.98(m，1H)，5.36(d，J＝17.2Hz，1H)，5.23(d，J＝10.4Hz，1H)，4.56(s，2H)，3.70(s，3H)，1.23(s，9H)

Step 2:

3-(2-allyl group oxygen base-4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-(the 2-allyl group oxygen base-4-tertiary butyl-phenyl) methyl acrylate (51.4mg, 0.18mmol, 1eq) and NaOH (37.5mg, 0.94mmol 5eq) add H ₂Among the O.Reaction mixture was stirred 12 hours.Reaction mixture is with the acidifying of 5%HCl solution.Concentrated reaction mixture is to obtain solid (46.8mg, 100%) in a vacuum.

With 3-(the 2-allyl group oxygen base-4-tertiary butyl-phenyl)-vinylformic acid (46.8mg, 0.18mmol), N-(4-amino methyl-2-fluoro-6-vinyl-phenyl)-NSC-249992 (78.83mg; 0.22mmol); DEPC (33.38 μ l, 0.22mmol, 1.2eq); And TEA (75.27 μ l, 0.54mmol) adding DMF.Reaction mixture was stirred 5 hours.Reaction mixture according to step 2 purifying of embodiment 27 to obtain solid (78.7mg, 89.9%).

Mp.:176.3～178.2 ℃; IR (KBr pellet, cm ^-1): 3440,3076,1652,1617,1321;

¹H?NMR(400MHz，CDCl ₃)：δ7.85(d，J＝15.6Hz，1H)，7.34(d，J＝8.0Hz，1H)，7.28(s，1H)，7.08(dd，J＝17.6，11.2Hz，1H)，7.01(d，J＝1.2Hz，1H)，6.98(s，J＝1.2Hz，1H)，6.90(dd，J＝8.0，1.6Hz，1H)，6.49(d，J＝16Hz，1H)，5.72(d，J＝17.6Hz，1H)，5.40(m，1H)，5.34(d，J＝6Hz，1H)，5.26(m，1H)，5.23(s，1H)，4.56(d，J＝1.2Hz，2H)，4.80(d，J＝5.6Hz，2H)，2.99(s，3H)，1.24(m，9H)

Embodiment 31:4-(the 5-tertiary butyl-2-[2-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl formamyl) vinyl] phenoxy)-piperidines-1-carboxylic acid tert-butyl ester

Step 1:4-[the 5-tertiary butyl-2-(2-methoxycarbonyl vinyl) phenoxy] piperidines-1-carboxylic acid tert-butyl ester

(24.7mg, 0.105mmole), (58.7mg, 0.210mmol), (43.7mg 0.316mmol) adds DMF to salt of wormwood to 4-methane sulfonyl oxygen phenylpiperidines-1-carboxylic acid tert-butyl ester with 3-(the 4-tertiary butyl-2-hydroxy phenyl) methyl acrylate.With the reaction mixture stirred overnight.Reaction mixture according to step 1 purifying of embodiment 30 to obtain solid (45.6mg, 100%).

¹H NMR (400MHz, CDCl ₃): δ 7.90 (d, J=16.4Hz, 1H), 7.39 (d, J=8.0Hz, 1H), 6.93 (d, J=8.0Hz; 1H), 6.85 (s, 1H), 6.41 (dd, J=8.0,2.8Hz, 1H), 4.50 (quintets; J=3.2Hz, 1H), 3.72 (s, 3H), 3.61 (m, 2H), 3.35 (m, 2H); 1.87 (m, 2H), 1.76 (m, 2H), 1.41 (s, 9H), 1.24 (s, 9H).

Step 2:4-(the 5-tertiary butyl-2-[2-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl formamyl) vinyl] phenoxy)-piperidines-1-carboxylic acid tert-butyl ester

With 4-[the 5-tertiary butyl-2-(2-methoxycarbonyl vinyl) phenoxy] piperidines-1-carboxylic acid tert-butyl ester (56.3mg, 0.135mol, 1eq) and NaOH (26.9mg 0.674mmol) adds H ₂O.Reaction mixture was stirred 12 hours.With 5%HCl solution acidified reaction mixture.Reaction mixture is concentrated to obtain solid (54.5mg, 100%) in a vacuum.

3-[the 4-tertiary butyl-2-(2-methoxy ethoxy)-phenyl] vinylformic acid (0.135mmol), diethylammonium cyanic acid phosphine (24.6 μ l, 0.162mmol; 1.2eq); N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (58.0mg, 0.162mmol), and triethylamine (56.4 μ l; 0.405mmol, 3eq) under argon gas atmosphere, add DMF.With the reaction mixture stirred overnight.With reaction mixture according to step 2 purifying of embodiment 27 to obtain solid (52.6mg, 100%).

Mp (℃): 122-124 ℃; IR (KBr pellet, cm ^-1): 3423,3086,2964,1655,1607,1420,1329,1275,1156;

¹H?NMR(400MHz，CDCl ₃)：7.87(d，J＝16.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，7.20(s，1H)，7.04(dd，J＝17.6，10.8Hz，1H)，6.94(d，J＝10.0Hz，1H)，6.88-6.80(m，3H)，6.45(d，J＝15.6Hz，1H)，5.66(d，J＝17.6Hz，1H)，5.29(d，J＝11.6Hz，1H)，4.42(d，J＝6.0Hz，1H)，4.06-3.98(m.1H)，3.61-3.57(m.2H)，3.30-3.24(m.2H)，2.94(s，3H)，1.86-1.82(m.2H)，1.76-1.70(m.2H)，1.37(s，9H)，1.22(s，9H)

Embodiment 32:3-[the 4-tertiary butyl-2-(the 3-methylbutyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-(the 4-tertiary butyl-2-butyl aminophenyl) methyl acrylate

Three (dibenzalacetones), two palladiums (5%, 0.04mmol, 37.49mmol); 1,1 '-two (diphenylphosphino) ferrocene (15%, 0.12mmol; 68.19mg), isoamylamine (1.64mmol, 190.87 μ l); And 3-(the 4-tertiary butyl-2-trifluoromethane sulfonyl group oxygen base phenyl) methyl acrylate (0.82mmol, 300mg) adding toluene.The adding cesium carbonate (1.23mmol, 400.76mg).Reaction mixture was stirred 12 hours at 80 ℃.According to the step 1 purification reaction mixture of embodiment 27 to obtain yellow syrup (100.5mg, 40.42%).

(NaCl is pure, cm for IR ^-1): 3353,3235,3028,2977,1685,1156;

¹H?NMR(400MHz，CDCl ₃)：δ7.80(d，1H，J＝15.6Hz)，7.33(s，1H)，7.30(d，1H，J＝8.0Hz)，6.78(d，1H，J＝8.0Hz)，6.77(s，1H)，6.28(d，1H，J＝15.6Hz)，3.77(s，3H)，3.17(t，2H，J＝7.6Hz)，1.64～1.53(m，1H)，1.28(s，9H)，1.94(d，6H，J＝6.8Hz).

Step 2:3-[the 4-tertiary butyl-2-(the 3-methylbutyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-(the 4-tertiary butyl-2-butyl aminophenyl) methyl acrylate (0.20mmol, 61.1mg) and NaOH (5eq, 1.00mmol 40.30mg) add the first alcohol and water.Reaction mixture was stirred 12 hours.Reaction mixture is with the acidifying of 5%HCl solution.Reaction residue is concentrated to obtain solid (39.34mg, 100%) in a vacuum.

With 3-[the 4-tertiary butyl-2-(3-methylbutyl amino) phenyl] vinylformic acid (0.13mmol, 39.34mg), N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (0.15mmol; 51.99mg), DEPC (1.2eq, 0.16mmol; 23.67 μ l); And TEA (2eq, 0.26mmol, 36.24 μ l) adds DMF.With the reaction mixture stirred overnight.According to the step 2 purification reaction mixture of embodiment 27 to obtain yellow solid (45.3mg, 61.54%).

mp：164～166℃；

IR (KBr pellet, cm ^-1): 3279,3239,3073,2957,1649,1611,1321,1153;

¹H?NMR(400MHz，CDCl ₃)：δ7.76(d，1H，J＝15.2Hz)，7.24(s，1H)，7.21(d，1H，J＝8.0Hz)，7.05(dd，1H，J＝17.6，11.2Hz)，6.94(d，1H，J＝10.0Hz)，6.65(d，1H，J＝8.0Hz)，6.62(s，1H)，6.38(s，1H)，6.21(d，1H，J＝14.8Hz)，6.12(s，1H)，5.69(d，1H，J＝17.6Hz)，5.34(d，1H，J＝11.2Hz)，4.44(d，2H，J＝6.4Hz)，3.13(t，2H，J＝7.2Hz)，2.98(s，3H)，1.65(dq，1H，J＝13.2，6.4Hz)，1.48(td，2H，J＝7.2Hz)，1.23(s，9H)，0.88(d，6H，J＝6.4Hz)，

Embodiment 33:3-(the 4-tertiary butyl-2-isobutylamino phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-(the 4-tertiary butyl-2-isobutylamino phenyl) methyl acrylate

Three (dibenzalacetone)-two palladiums (5%, 0.04mmol, 37.24mmol); 1,1 '-two (diphenylphosphino)-ferrocene (15%, 0.12mmol; 67.36mg), isobutylamine (1.62mmol, 160.98 μ l); And 3-(the 4-tertiary butyl-2-trifluoromethane sulfonyl group oxygen base-phenyl) methyl acrylate (0.81mmol, 298mg) adding toluene.The adding cesium carbonate (1.22mmol, 395.87mg).Reaction mixture was stirred 12 hours at 80 ℃.According to the step 1 purification reaction mixture of embodiment 27 to obtain yellow syrup (22.8mg, 10%).

(NaCl is pure, cm for IR ^-1): 3440,2961,1651,1597;

¹H?NMR(400MHz，CDCl ₃)：δ7.80(d，1H，J＝15.6Hz)，7.30(d，1H，J＝8.0Hz)，6.76(d，1H，J＝8.0Hz)，6.75(s，1H)，6.28(d，1H，J＝15.6Hz)，3.77(s，3H)，2.98(d，2H，J＝6.8Hz)，1.99～1.89(m，1H)，1.28(s，9H)，1.00(d，6H，J＝6.8Hz).

Step 2:3-(the 4-tertiary butyl-2-isobutylamino phenyl) vinylformic acid

With 3-(the 4-tertiary butyl-2-isobutylamino phenyl) methyl acrylate (0.08mmol, 22.8mg) and NaOH (0.39mmol 15.76mg) adds the first alcohol and water.Reaction mixture was stirred 12 hours.With reaction mixture with the acidifying of 5%HCl solution.Reaction mixture is concentrated to obtain solid (22.02 mg, 100%) in a vacuum.

¹H?NMR(400MHz，CD ₃OD)：δ7.86(d，1H，J＝15.2Hz)，7.82(d，1H，J＝8.0Hz)，7.63(s，1H)，7.58(d，1H，J＝8.0Hz)，6.59(d，1H，J＝15.6Hz)，3.18(d，2H，J＝7.2Hz)，2.21～2.12(m，1H)，1.33(s，9H)，1.10(d，6H，J＝6.8Hz)，

Step 3:

3-(the 4-tertiary butyl-2-isobutylamino phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-(the 4-tertiary butyl-2-isobutylamino phenyl) vinylformic acid (0.08mmol, 22.02mg), N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (0.08mmol; 31.54mg), DEPC (0.09mmol, 14.57 μ l); And TEA (2eq, 0.16mmol, 22.30 μ l) adds DMF.With the reaction mixture stirred overnight.According to the step 2 purification reaction mixture of embodiment 27 to obtain yellow solid (23.1mg, 57.60%).

Mp:165～167 ℃; IR (KBr pellet, cm ^-1): 3238,2957,1649,1608,1321,1154; ¹H NMR (400MHz, CD ₃OD): δ 7.76 (d, 1H, J=15.6Hz), 7.46 (s, 1H), 7.30 (d, 1H, J=8.0Hz), 7.16 (dd, 1H, J=17.6,11.2Hz); 7.09 (dd, 1H, J=10.4,1.2Hz), 6.67 (d, 1H, J=8.0Hz), 6.64 (s, 1H), 6.42 (d, 1H; J=15.2Hz), 5.82 (d, 1H, J=17.6Hz), 5.36 (d, 1H, J=11.2Hz), 4.47 (s, 2H), 2.29 (s, 3H); 2.96 (d, 2H, J=6.8Hz), 1.97～1.87 (m, 1H), 1.26 (s, 9H), 0.98 (d, 6H, J=6.8Hz)

Embodiment 34:3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-(the 4-tertiary butyl-2-trifluoromethane sulfonyl group oxygen base phenyl) ethyl propenoate

With 3-(the 4-tertiary butyl-2-hydroxy phenyl) ethyl propenoate (101.9mg, 0.410mmol) add methylene dichloride after, temperature of reaction is cooled to-78 ℃.Add 2, the 6-lutidine (119.5 μ l, 1.026mmol) with triflic anhydride (137.9 μ l, 0.820mmol, 2eq).Reaction mixture is warmed to room temperature.Through adding saturated NaHCO ₃Solution comes the quencher reaction.Use CH ₂Cl ₂The abstraction reaction mixture.Use H ₂The organic layer that O and brine wash merge is through dried over sodium sulfate.(normal hexane: EtOAc=10: 1) the purifying resistates is to obtain syrup (103.9mg, 72.4%) with column chromatography.

¹H NMR (400MHz, CDCl ₃): δ 7.77 (d, J=16.0Hz, 1H), 7.55 (d, J=8.4Hz, 1H), 7.34 (dd, J=8.0,1.6Hz, 1H), 7.25 (d, J=1.6Hz, 1H), 6.39 (d, J=16.0Hz, 1H), 4.20 (q, J=7.2Hz, 2H), 1.31-1.25 (m, 12H); (NaCl is pure, cm for IR ^-1): 2960,2871,1713,1628,1607,1165

Step 2:3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl) methyl acrylate

With three (dibenzalacetones), two palladiums (5%, 0.04mmol, 37.24mmol); 1,1 '-two (diphenylphosphino) ferrocene (15%, 0.12mmol; 67.36mg); (the 4-tertiary butyl-2-trifluoromethane sulfonyl group oxygen base phenyl)-(0.81mmol 298mg) adds toluene to methyl acrylate under argon gas atmosphere for isopropylamine (1.62mmol, 137.98 μ l) and 3-.(1.22mmol 395.87mg) adds reaction mixture with cesium carbonate.Reaction mixture was stirred 12 hours at 80 ℃.According to the step 1 purification reaction mixture of embodiment 22 to produce syrup (37.3mg, 17.28%).

IR (pellet that NaCl is pure, cm ^-1): 3428,2965,1725,1638;

¹H?NMR(400MHz，CDCl ₃)：δ7.76(d，1H，J＝15.6Hz)，7.29(d，1H，J＝8.0Hz)，6.71(d，1H，J＝8.4Hz)，6.68(s，1H)，6.27(d，1H，J＝15.6Hz)，3.77(s，3H)，3.74～3.67(m，1H)，1.28(s，9H)，1.24(d，6H，J＝6.4Hz)，

Step 3:3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl) vinylformic acid

With 3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl) methyl acrylate (0.14mmol, 37.7mg) and NaOH (0.68mmol 27.39mg) adds the first alcohol and water.With reaction mixture stirring at room 12 hours.With reaction mixture with the acidifying of 5%HCl solution.Mixture is concentrated to produce yellow solid (36.56mg, 100%) in a vacuum.

¹H?NMR(400MHz，CD ₃OD)：δ7.84(d，1H，J＝15.6Hz)，7.35(d，1H，J＝8.0Hz)，6.77(s，1H)，6.76(d，1H，J＝8.0Hz)，6.26(d，1H，J＝15.6Hz)，3.67～3.61(m，1H)，1.26(s，9H)，1.22(d，6H，J＝6.4Hz)，

Step 4:3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl) vinylformic acid (0.14mmol, 36.56mg), N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (0.15mmol; 55.17mg); DEPC (1.2eq, 0.17mmol, 25.49 μ l) and TEA (2eq; 0.28mmol, 39.02 μ l) and adding DMF.With the reaction mixture stirred overnight.According to the step 2 purification reaction mixture of embodiment 22 to produce yellow solid (38.9mg, 57.03%).

Mp:168～170 ℃; IR (KBr pellet, cm ^-1): 3236,3022,2964,1609,1321,1154 ¹H NMR (400MHz, CD ₃OD): δ 7.74 (d, 1H, J=15.6Hz), 7.46 (s, 1H), 7.31 (d, 1H, J=8.0Hz), 7.16 (dd, 1H, J=17.6; 10.8Hz), 7.09 (dd, 1H, J=10.4,1.6Hz), 6.71 (s, 1H), 6.69 (d, 1H, J=8.0Hz); 6.41 (d, 1H, J=15.6Hz), 5.82 (d, 1H, J=17.6Hz), 5.36 (d, 1H, J=11.2Hz), 4.47 (s; 2H), 3.74～3.64 (m, 1H), 2.99 (s, 3H), 1.26 (s, 9H), 1.21 (d, 6H, J=6.4Hz).

Embodiment 35:

(R)-3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] propionic acid amide

With N-[4-(1-the amino-ethyl)-2-fluoro-6-ethenylphenyl] methane sulfinyl amine (step 5 of embodiment 7; 0.08mmol, 30.6mg), 3-[the 4-tertiary butyl-2-(the 3-methylbutyl is amino) phenyl] propionic acid (0.09mmol; 18.65); DEPC (0.10mmol, 14.57 μ l) and TEA (0.16mmol, 22.49 μ l) add DMF.Reaction mixture was stirred 12 hours.According to embodiment 21 purification reaction mixtures to produce solid (27.2mg, 67.73%).

mp：154～156℃；

[α] _D ²⁰：+8.59(CHCl ₃，c?0.27)；

IR (KBr pellet): 3223,2963,1645,1261,1097 cm ^{-1 1}H NMR (400MHz, CDCl ₃): δ 7.25 (s, 1H), 7.24 (d, 2H, J=17.6,11.2Hz), 7.06 (d, 2H, J=8.0Hz), 6.86 (dd; 1H, J=10.4,2.0Hz), 5.84 (s, 1H), 5.71 (d, 1H, J=17.6Hz), 5.42 (d, 1H; J=6.8Hz), 5.39 (d, 1H, J=11.2Hz), 4.96 (q, 1H, J=6.4Hz), 3.00 (s, 3H), 2.87 (t; 2H, J=8.0Hz), 2.43 (t, 2H, J=8.0Hz), 1.30 (d, 3H, J=6.8Hz), 1.23 (s, 9H).

Embodiment 36: (R)-and 3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acrylic amide

With N-[4-(1-amino-ethyl)-2-fluoro-6-ethenylphenyl] methane sulfinyl amine (0.7mmol; 25.3mg), 3-[the 4-tertiary butyl-2-(the 3-methylbutyl is amino) phenyl] vinylformic acid (0.7mmol, 15.27mg); DEPC (0.08mmol; 12.75 μ l), and TEA (0.14mmol, 19.51 μ l) add DMF.Reaction mixture was stirred 12 hours.According to the similar methods purification reaction mixture of embodiment 21 to produce title product (36.1mg, 100.0%).

mp：127～129℃；

[α] _D ²⁰：-20.33(CH ₃OH，c?1.26)；

IR (KBr pellet): 3236,3087,2963,1734,1325,1151cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.55(d，1H，J＝15.6Hz)，7.35(d，2H，J＝8.4Hz)，7.29(d，2H，J＝8.4Hz)，7.06(dd，1H，J＝17.6，10.8Hz)，6.97(dd，1H，J＝10.4，1.6Hz)，6.33(d，1H，J＝17.6Hz)，6.26(s，1H)，6.06(d，1H，J＝7.6Hz)，5.69(d，1H，J＝17.6Hz)，5.33(d，1H，J＝11.2Hz)，5.12(q，1H，J＝7.2Hz)，2.98(s，3H)，1.43(d，3H，J＝7.2Hz)，1.24(s，9H).

Embodiment 37:

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-USAF RH-1

N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (0.15mmol, 54.21mg), 3-(the 4-tertiary butyl-phenyl)-2-methylacrylic acid (0.14mmol, 30mg); DEPC (1.2eq, 0.17mmol, 25.49 μ l); And TEA (2eq, 0.28mmol, 39.03 μ l) adds DMF.Reaction mixture was stirred 12 hours.According to the similar methods purification reaction mixture of embodiment 21 to produce title product (34.8mg, 55.96%).

mp：136～138℃；

IR (KBr pellet, cm ^-1): 3235,2962,1645,1321,1153;

¹H?NMR(400MHz，CDCl ₃)：δ7.37(d，2H，J＝8.4Hz)，7.35(s，1H)，7.31(s，1H)，7.26(d，2H，J＝8.4Hz)，7.12(dd，1H，J＝17.2，10.8Hz)，7.01(dd，1H，J＝10.0，1.6Hz)，6.48(s，1H)，5.75(d，1H，J＝17.2Hz)，5.39(d，1H，J＝10.8Hz)，4.49(d，2H，J＝6.4Hz)，3.02(s，3H)，2.11(s，3H)，1.30(s，9H).

Embodiment 38:

3-(4-tert-butyl-phenyl)-2-fluoro-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (1.1eq, 0.15mmol, 53.24mg); 3-(4-tert-butyl-phenyl)-2-perfluoroalkyl acrylate (1eq, 0.14mmol, 30mg); DEPC (1.2eq, 0.17mmol, 25.49 μ l); And TEA (2eq, 0.28mmol, 39.09 μ l) adds DMF under argon gas atmosphere.Reaction mixture was stirred 12 hours.According to the similar methods purification reaction mixture of embodiment 21 to produce title product (30.0mg, 48%).

mp：165～167℃；

IR (KBr pellet, cm ^-1): 3246,2920,1644,1323,1155;

¹H?NMR(400MHz，CDCl ₃)：δ7.54(dd，2H，J＝8.8，2.0Hz)，7.40(dd，2H，J＝8.0，2.0Hz)，7.35(s，1H)，7.24(d，1H，J＝2.4Hz)，7.14(ddd，1H，J＝17.6，10.8，2.0Hz)，7.06(d，1H，J＝10.0Hz)，6.95(dd，1H，J＝39.6，2.0Hz)，6.73(s，1H)，6.06(s，1H)，5.79(dd，1H，J＝17.2，1.2Hz)，5.44(dd，1H，J＝10.8，1.2Hz)，4.56(d，2H，J＝4.8Hz)，3.05(s，3H)，1.31(s，9H)

Embodiment 39:3-[the 4-tertiary butyl-2-(2-morpholine-4-base-oxyethyl group) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-[the 4-tertiary butyl-2-(2-morpholine-4-base-oxyethyl group)-phenyl] methyl acrylate

With 3-(the 4-tertiary butyl-2-hydroxy phenyl) methyl acrylate (step 2 of embodiment 29,101.5mg, 0.866mmole); 4-(2-chloroethyl) morpholine HCl (161.1mg, 0.866mmol, 2eq); And sodium hydride (86.6mg, 2.166mmol 5eq) add DMF under argon gas atmosphere.With the reaction mixture stirred overnight.After confirming that reaction finishes, under reduced pressure remove DMF.Resistates extracts with EtOAc.The organic layer that merges is used H ₂O and brine wash through dried over sodium sulfate, concentrate in a vacuum.With column chromatography (EtOAc) purifying resistates to produce syrup (33.0mg, 21.9%).

¹H?NMR(400MHz，CDCl ₃)：δ7.86(d，J＝16.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，6.93(dd，J＝8.0，1.6Hz，1H)，6.86(s，1H)，6.51(d，J＝16.0Hz，1H)，4.13(t，J＝6.0Hz，1H)，3.72(s，3H)，3.68(t，J＝5.2Hz，4H)，2.81(t，J＝5.2Hz，2H)，2.55(s，4H)，1.25(s，9H)

Step 2:

3-[the 4-tertiary butyl-2-(2-morpholine-4-base-oxyethyl group) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

3-[the 4-tertiary butyl-2-(2-morpholine-4-base-oxyethyl group) phenyl] propionic acid methyl ester (15.3mg, 0.044mmol, 1eq) and sodium hydroxide (8.8mg, 0.220mmole 5eq) add the first alcohol and water.Reaction mixture was stirred 12 hours.Reaction mixture is with the acidifying of 5%HCl solution.Reaction mixture is concentrated to produce solid (14.6mg, 100%) in a vacuum.

With 3-[the 4-tertiary butyl-2-(2-morpholine-4-base-oxyethyl group) phenyl] vinylformic acid (0.044mmol, 1eq.), diethylammonium cyanic acid phosphine (8.0 μ l; 0.053mmol, 1.2eq), N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (18.9mg; 0.053mmol, 1.2eq.), and TEA (18.4 μ l; 0.132mmol, 3eq) under argon gas atmosphere, add DMF.With reaction mixture in stirred overnight at room temperature.Remove DMF in a vacuum, extract resistates with EtOAc.Organic layer with brine wash merges through dried over sodium sulfate, and concentrates in a vacuum.With column chromatography (normal hexane: EtOAc=1: 1) the purifying resistates with produce solid (13.1mg, 53.2.%).

IR (KBr pellet, cm ^-1): 3434,3254,2961,1648,1608,1321,1153,974;

¹H?NMR(400MHz，CDCl ₃)：7.82(d，J＝16.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，7.29(s，1H)，7.08(dd，J＝17.6，10.8Hz，1H)，7.01(d，J＝10.4Hz，1H)，6.92(d，J＝8.0Hz，1H)，6.85(s，1H)，6.50(d，J＝16.0Hz，1H)，6.25(bs.1H)，5.72(d，J＝18.0Hz，1H)，5.75(d，J＝11.2Hz，1H)，4.48(d，J＝5.6Hz，2H)，4.14(t，J＝5.6Hz，2H)，3.65(t，J＝4.4Hz，4H)，2.99(s，3H)，2.88-2.81(m.2H)，2.56(s.4H)，1.23(s，9H)

Embodiment 40:

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

Step 1:3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base)-phenyl] methyl acrylate

(75.9mg is 0.324mmole) with 4-methanesulfonic tetrahydropyran-4-base ester (70.1mg, 0.389mmol with 3-(the 4-tertiary butyl-2-hydroxy phenyl) methyl acrylate; 1.2eq); And salt of wormwood (134.3mg, 0.972mmol 5eq) add DMF under argon gas atmosphere.Under the situation of heating, with the reaction mixture stirred overnight.Remove DMF in a vacuum.Extract resistates with EtOAc.The organic layer that merges is used H ₂O and brine wash through dried over sodium sulfate, and concentrate in a vacuum.With column chromatography purifying resistates to produce syrup (43.3mg).

With syrup and diacetyl oxide (174.5 μ l, 1.850mmole, 10eq) adding pyridine.With the reaction mixture stirred overnight.Through adding H ₂O quencher reaction.With EtOAc abstraction reaction mixture.With saturated CuSO ₄, H ₂The organic layer that O and brine wash merge through dried over sodium sulfate, and concentrates in a vacuum.(normal hexane: EtOAc=10: 1) purifying is to produce syrup (31.5mg, 43.2%) with column chromatography with resistates.

¹H?NMR(400MHz，CDCl ₃)：A-δ7.93(d，J＝16.4Hz，1H)，7.39(d，J＝8.0Hz，1H)，6.94(d，J＝8.0Hz，1H)，6.85(s，1H)，6.43(d，J＝16.0Hz，1H)，4.50(setp，J＝3.6Hz，1H)，3.92(m，2H)，3.73(s，3H)，3.55(m，2H)，1.97(m，2H)，1.81(m，2H)，1.24(s，9H)

Step 2:3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

With 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] methyl acrylate (31.5mg, 0.099mmol, 1eq) and sodium hydroxide (19.8mg 0.4955mmole) adds methyl alcohol and H ₂O.Reaction mixture was stirred 12 hours.Use the 5%HCl acidified reaction mixture.Mixture is concentrated to produce 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base)-phenyl] vinylformic acid (30.1mg, 100%) in a vacuum.

With 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] vinylformic acid (0.099mmol, 1eq), diethylammonium cyanic acid phosphine (18.1 μ l; 0.1119mmol, 1.2eq), N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (42.5mg; 0.119mmol, 1.2eq.), and TEA (41.4 μ l; 0.297mmol, 3eq) under argon gas atmosphere, add DMF.With reaction mixture in stirred overnight at room temperature.According to the similar methods purification reaction mixture of embodiment 20 to produce solid (35.6mg, 69.6%).

IR (KBr pellet, cm ^-1): 3423,3086,2964,1655,1607,1420,1329,1275,1156; ¹H NMR (400MHz, CDCl ₃): 7.87 (d, J=16.0Hz, 1H), 7.35 (d, J=8.0Hz, 1H), 7.23 (s, 1H), 7.03 (dd, J=17.2; 10.8Hz, 1H), 6.93 (d, J=9.6Hz, 1H), 6.87 (d, J=8.0Hz, 1H), 6.84 (s, 1H); 5.66 (d, J=17.6Hz, 1H), 5.29 (d, J=10.8Hz, 1H), 4.47-4.41 (m, 3H), 3.88 (t, J=5.6Hz; 2H), 3.49 (t, J=8.0Hz, 2H), 2.95 (s, 3H), 1.96-1.93 (m.2H), 1.75-1.74 (m.2H), 1.22 (s, 9H)

Embodiment 41:3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) propionic acid amide

Step 1:3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] propionic acid methyl ester

(14.4mg, 0.045mmole) palladium with 10wt.% adds MeOH with 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] methyl acrylate.With reaction mixture stirred overnight under hydrogen atmosphere.With C salt pad filter reaction mixture.To filtrate in a vacuum concentrate and with the column chromatography purifying with generation syrup (14.1mg, 97.3%).

¹H?NMR(400MHz，CDCl ₃)：δ7.01(d，J＝8.4Hz，1H)，6.83(dd，J＝8.0，1.6Hz，1H)，6.78(d，J＝1.6Hz，1H)，4.48(setp，J＝3.6Hz，1H)，3.90(setp，J＝3.6Hz，2H)，3.60(s，3H)，3.56(setp，J＝3.6Hz，2H)，2.85(t，J＝8.0Hz，2H)，2.56(t，J＝8.0Hz，2H)，2.00-1.93(m，2H)，1.79-1.71(m，2H)，1.23(s，9H)

Step 2:

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) propionic acid amide

With 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] propionic acid methyl ester (14.1mg, 0.044mmol, 1eq) and sodium hydroxide (8.8mg, 0.220mmole 5eq) add methyl alcohol and H ₂O.Reaction mixture was stirred 12 hours.With 5%HCl solution acidified reaction mixture.Reaction mixture is concentrated to produce 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] propionic acid (13.5mg, 100%) in a vacuum.

With 3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl] propionic acid (0.044mmol, 1eq.), diethylammonium cyanic acid phosphine 8.0 μ l (0.053mmol; 1.2eq); N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 19.0mg (0.053mmol, 1.2eq.), and TEA (18.4 μ l; 0.132mmol, 3eq) under argon gas atmosphere, add DMF.With reaction mixture in stirred overnight at room temperature.Remove DMF in a vacuum.Extract resistates with EtOAc.Resistates is used brine wash,, and concentrate in a vacuum through dried over sodium sulfate.(hexane: EtOAc=1: 1) the purifying resistates is to produce solid (23.4mg, 99.8%) with column chromatography.

IR (KBr pellet, cm ^-1): 3423,3086,2964,1655,1607,1420,1329,1275,1156; ¹H NMR (400MHz, CDCl ₃): 7.21 (s, 1H), 7.16-7.01 (m, 2H), 6.91 (s, 1H), 6.85 (d, J=8.0Hz, 1H); 6.32 (s, 1H), 5.97 (s, 1H), 5.69 (d, J=17.6Hz, 1H), 5.36 (d, J=11.2Hz; 1H), 4.44 (sept, J=3.6Hz, 1H), 4.33 (d, J=6.0Hz, 2H), 3.87 (sept, J=3.6Hz; 1H), 3.51 (sept, J=3.6Hz, 2H), 2.98 (s, 3H), 2.91-2.87 (m.3H), 2.50 (t; J=7.2Hz, 2H), 1.96-1.91 (m, 2H), 1.73-1.65 (m, 2H), 1.22 (s, 9H).

Embodiment 42:

(R)-3-(4-tert-butyl-phenyl)-N-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl]-2-USAF RH-1

With N-[4-(1-amino-ethyl)-2-ethenylphenyl] NSC-249992 (0.26mmol, 58.6mg), 3-(4-tert-butyl-phenyl)-2-methylacrylic acid (0.28mmol; 62.13mg), DEPC (1.2eq, 0.31mmol; 47.34 μ l); And TEA (2eq, 0.52mmol, 72.48 μ l) adds DMF under argon gas atmosphere.Reaction mixture was stirred 12 hours.According to the similar methods purification reaction mixture of embodiment 22 to produce solid (60.8mg, 54.87%).

[α] _D ²⁰-24.96(CHCl ₃，c?0.125)；Mp：97～99℃；

IR (KBr pellet, cm ^-1): 3272,2964,1646,1322;

¹H NMR (400MHz, CDCl ₃): δ 7.45 (d, 1H, J=2.0Hz), 7.39 (s, 1H), 7.36 (d, 2H, J=8.0Hz), 7.30 (s, 1H); 7.25 (d, 2H, J=8.0Hz), 6.91 (dd, 1H, J=17.2,11.2Hz), 6.72 (s, 1H), 6.14 (d; 1H, J=7.6Hz), 5.69 (d, 1H, J=17.2Hz), 5.42 (d, 1H, J=11.2Hz), 5.18 (quintet, 1H; J=6.8Hz), 2.94 (s, 3H), 2.09 (s, 3H), 1.52 (d, 3H, J=6.8Hz), 1.30 (s, 9H).

Embodiment 43:3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-methyl propanamide

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

(40.9mg 0.19mmol) adds methyl alcohol with 10wt.% palladium carbon with 3-(4-tert-butyl-phenyl)-2-methylacrylic acid.At H ₂Under the gas reaction mixture was stirred 5 hours.With C salt filter reaction mixture.To filtrate and concentrate in a vacuum to obtain title compound (39.1mg, 93.47%). ¹H?NMR(400MHz，CD ₃OD)：δ7.25(d，2H，J＝8.4Hz)，7.07(d，2H，J＝8.4Hz)，2.92(q，1H，J＝6.4Hz)，2.67～2.54(m，2H)，1.25(s，9H)，1.08(d，3H，J＝6.8Hz).

Step 2:3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-methyl propanamide

With N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (0.10mmol, 35.0mg), 3-(4-tert-butyl-phenyl)-2 Methylpropionic acid (0.11mmol; 23.65mg), DEPC (0.12mmol, 18.21 μ l); And TEA (0.20mmol, 27.8 μ l) adds DMF under argon gas atmosphere.Reaction mixture was stirred 12 hours.According to the similar methods purification reaction mixture of embodiment 21 to produce solid (37.1mg, 83.14%).

Mp:156～158 ℃; IR (KBr pellet, cm ^-1): 3288,3229,2964,1647,1321,1155

¹H?NMR(400MHz，CDCl ₃)：δ7.26(d，2H，J＝8.4Hz)，7.20(s，1H)，7.10(dd，1H，J＝17.6，11.2Hz)，7.06(d，2H，J＝8.4Hz)，6.79(dd，1H，J＝10.4，1.6Hz)，6.20(s，1H)，5.72(d，1H，J＝17.2Hz)，5.67(t，1H，J＝6.0Hz)，5.40(d，1H，J＝11.2Hz)，4.30(d，2H，J＝6.0Hz)，3.02(s，3H)，3.00～2.89(m，1H)，2.66～2.60(m，1H)，2.51～2.43(m，1H)，1.26(s，9H)，1.19(d，3H，J＝6.8Hz).

Embodiment 44:N-{4-[3-(4-benzyl chloride base) urea groups methyl]-2-ethenylphenyl } NSC-249992

As described in the route 12, (4-methane sulfonyl amino-3-vinyl benzyl) t-butyl carbamate (50mg, 0.153mmol) and triethylamine (0.1ml) and 4-chlorobenzylamine (26mg) exist under the situation at acetonitrile solvent and stir a night.From reaction mixture, remove solvent, and pass through the column chromatography purifying to produce purpose compound (9mg).

¹H?NMR(300MHz，CDCl ₃)：7.45(s，1H)，7.41(m，2H)，7.29(m，4H)，6.90(dd，1H，J＝17.7，11.1Hz)，6.44(bs，1H)，5.73(d，1H，J＝17.4Hz)，5.55(s，1H)，5.48(d，1H，J＝11.1Hz)，4.90(bs，1H)，4.34(m，4H)，2.99(s，3H)

Embodiment 45:3-[4-(tertiary butyl) phenyl]-N-[4-(methane sulfonyl is amino)-3-vinyl benzyl] propionic acid amide

Step 1: tertiary butyl N-[4-(methane sulfonyl is amino)-3-vinyl benzyl] carbamate

(1.0g 2.3mmol) is dissolved in toluene (20mL) to carbamate with tertiary butyl N-[4-(methane sulfonyl is amino)-3-iodine benzyl].Tributylvinyl tin (0.8mL, 2.8mmol) and Pd (PPh3) ₄(140mg 0.12mmol) dropwise adds.In backflow, reaction mixture was stirred 4 hours.Remove toluene in a vacuum.Extract resistates with EtOAc.Use H ₂O, the organic layer that brine wash merges is through MgSO ₄Drying, and concentrate in a vacuum.(EtOAc: normal hexane=1: 2) purifying is to produce title compound (740mg, 97%) with column chromatography with resistates.

¹H-NMR(300MHz，CDCl ₃)：δ1.44(s，9H)，2.96(s，3H)，4.29?d，2H，J＝5.9Hz)，4.86(bs，1H)，5.46(dd，1H，J＝11.0，0.93Hz)，5.71(dd，1H，J＝17.0，0.93Hz)，6.32(bs，1H)，6.87(dd，1H，J＝17.0，11.0Hz)，7.20(dd，1H，J＝8.3，1.8Hz)，7.38(d，1H，J＝2.0Hz)，7.41(d，1H，J＝8.2Hz)

Step 2:N-[4-(amino methyl)-2-ethenylphenyl] NSC-249992

(100mg is 0.23mmol) with TFA (0.4ml) adding methylene dichloride (2mL) with tertiary butyl N-[4-(methane sulfonyl amino)-3-vinyl benzyl] carbamate.Reaction mixture is stirred in ambient temperature overnight.Reaction mixture is concentrated to produce title compound (100%) in a vacuum.

Step 3:3-[4-(tertiary butyl) phenyl]-N-[4-(methane sulfonyl is amino)-3-vinyl benzyl] propionic acid amide

N-[4-(amino methyl)-2-ethenylphenyl] NSC-249992 (0.23mol) is suspended in the methylene dichloride and use triethylamine, use 3-(the 4-tertiary butyl-phenyl)-propionic acid and DMTMM (40mg) processing subsequently.The mixture that obtains was stirred at ambient temperature 2 days and under reduced pressure concentrated.Rough resistates carries out column chromatography (hexane/ethyl acetate=3/2) to produce white solid (73%).

¹H-NMR(300MHz，CDCl ₃)：δ1.28(s，9H)，2.51(t，2H，J＝7.6Hz)，2.92-2.97(m，5H)，4.38(d，2H，J＝5.9Hz)，5.47(d，1H，J＝11.0Hz)，5.62(bs，1H)，5.69(d，1H，J＝18.0Hz)，6.23(bs，1H)，6.84(dd，1H，J＝17.0，11.0Hz)，7.09-7.14(m，3H)，7.25-7.41(m，4H)

IR (pure) cm ^-11 3295,2960,1648,1541,1324,1152

Mass(FAB)：415[M+H]+

Embodiment 46:

3-[4-(tertiary butyl) phenyl]-N-[3-fluoro-4-(methane sulfonyl is amino)-5-vinyl benzyl] propionic acid amide

Title compound (63%) is synthesized according to the method that is similar to the method that is used for synthetic embodiment 45.

¹H-NMR(300MHz，CDCl ₃)：δ1.28(s，9H)，2.52(t，2H，J＝7.6Hz)，2.96(t，2H，J＝7.7Hz)，3.05(s，3H)，4.39(d，2H，J＝6.0Hz)，5.44(d，1H，J＝11.0Hz)，5.69(bs，1H)，5.76(d，1H，J＝17.0Hz)，5.92(bs，1H)，6.92(d，1H，J＝10.0Hz)，7.08-7.18(m，3H)，7.22-7.32(m，3H)

IR (pure) cm 1 3233,2922,1646,1540,1317,1151

Mass(FAB)433[M+H]+

Embodiment 47:

3-(the 4-tertiary butyl-phenyl)-N-(3-ethynyl-5-fluoro-4-methane sulfonyl amino-benzyl)-propionic acid amide

Title compound (90%) is synthesized according to the method that is similar to the method that is used for synthetic embodiment 45.

¹H-NMR(300MHz，CDCl ₃)：δ1.28(s，9H)，2.49～2.54(t，2H)，2.92～2.97(t，2H)3.23(s，3H)，3.46(s，1H)，4.32(d，2H，J＝6.1Hz)，5.68(bs，1H)，6.39(bs，1H)，6.99～7.02(d，2H，J＝10.6?Hz)，7.09～7.18(m，3H)，7.28～7.31(m，2H)

IR (pure) cm-1 3269,2959,1581,1482,1332,1154

Mass(FAB+)431[M+H]+

Embodiment 48:

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-5-methoxyl group-2-vinyl-phenyl }-NSC-249992

Step 1: (4-amino-2-methoxyl group-benzyl)-t-butyl carbamate

With 2-methoxyl group-4-nitro-benzonitrile (1.78g, 10mmol) and Pd/C (4 little spoon) be suspended among the MeOH that comprises c-HCl, said mixture is carried out hydrogenation 4 hours under the 40psi hydrogen pressure.Reaction mixture is filtered through C salt, and will filtrate under reduced pressure concentrates to produce yellow solid (1.58g, 70%).Solid is dissolved in THF, solution is cooled to 0 ℃.(1.43g 14mmol) adds solution, adds Boc subsequently with triethylamine ₂O, in envrionment temperature with the reaction mixture stirred overnight.Come the quencher reaction through adding entry and EtOAc, separate organic phase.Extract water three times with EtOAc, and,, filter, under reduced pressure concentrate through anhydrous MgSO4 drying with the organic layer that brine wash merges.Rough resistates is carried out column chromatography (hexane/ethyl acetate=1/1 is to 1/2) to produce white solid (1.3g, 73%).

¹HNMR(300MHz，CDCl3)：7.03(d，1H，J＝8.4Hz)，6.23(m，2H)，4.91(bs，1H)，4.18(d，2H，J＝5.7Hz)，3.78(s，3H)，3.72(bs，2H)，1.44(s，9H).

Step 2: (4-amino-5-iodo-2-methoxyl group-benzyl)-t-butyl carbamate

At 0 ℃, to iodine and AgNO ₂Suspension in methylene dichloride adds (4-amino-2-methoxyl group-benzyl)-t-butyl carbamate, and (restir is 30 minutes at ambient temperature for 1.3g, the 5.15mmol) solution in methylene dichloride, and mixture stirred 30 minutes at 0 ℃.Use Na ₂S ₂O ₃The quencher reaction.Reaction soln is used dichloromethane extraction, water and brine wash, dry through anhydrous MgSO4, filter and under reduced pressure concentrate.The liquid that obtains is carried out column chromatography (hexane/ethyl acetate=2/1) to produce (4-amino-5-iodo-2-methoxyl group-benzyl)-t-butyl carbamate (925mg, 47%).

¹HNMR(300MHz，CDCl3)：7.45(s，1H)，6.28(s，1H)，4.88(bs，1H)，4.14(d，2H，J＝6.0Hz)，4.08(bs，2H)，3.77(s，3H)，1.45(s，9H).

Step 3: (4-amino-2-methoxyl group-5-vinyl-benzyl)-t-butyl carbamate

Under argon gas, to (4-amino-5-iodo-2-methoxyl group-benzyl)-t-butyl carbamate (700mg, 1.85mmol) and tributylvinyl tin (783mg, 2.68mmol) solution in toluene add Pd (PPh3) 4 (214mg, 0.19mmol).Under situation about refluxing, with the mixture heating up that obtains 8 hours, filter through C salt, then under reduced pressure concentrate.Rough resistates is carried out column chromatography (hexane/ethyl acetate=2/1 is to 1/1) to produce (4-amino-2-methoxyl group-5-vinyl-benzyl)-t-butyl carbamate (220mg, 43%).

¹HNMR (300MHz, CDCl3): 7.18 (s, 1H), 6.67 (dd, 1H, J=11 and 17Hz), 6.19 (s, 1H); (5.53 dd, 1H, J=0.9 and 17Hz), 5.20 (dd, 1H, J=0.9 and 11Hz), 4.91 (bs, 1H); 4.20 (d, 2H, J=6.0Hz), 3.79 (s, 3H), 1.44 (s, 9H).

Step 4:

(4-methane sulfonyl amino-2-methoxyl group-5-vinyl-benzyl)-t-butyl carbamate

(220mg 0.79mmol) adds triethylamine (132L) in the ice-cold solution in methylene dichloride, adds methane sulfonyl chloride (72L) subsequently to (4-amino-2-methoxyl group-5-vinyl-benzyl)-t-butyl carbamate.Mixture is warmed to room temperature and stirred 4 hours.The water quencher is reacted, and reaction soln is used dichloromethane extraction, and water and brine wash are through anhydrous MgSO ₄Drying is filtered, and under reduced pressure concentrates.Handled the resistates obtain 2 hours with 1N NaOH/MeOH/THF (1/2/1), then neutralize through adding 1N HCl.Behind evaporation methyl alcohol, water is added resistates.The mixture that obtains is extracted with EtOAc, the organic layer that merges is used brine wash, dry through anhydrous MgSO4, filter and under reduced pressure concentrate.Rough resistates is carried out column chromatography (hexane/ethyl acetate=1/1) to produce white solid (260mg, 92%).

¹HNMR (300MHz, CDCl3): 7.38 (s, 1H), 7.04 (s, 1H), 6.77 (dd, 1H; J=11 and 17Hz), 6.52 (bs, 1H), 5.63 (d, 1H, J=17Hz), 5.37 (d; 1H, J=11Hz), 5.02 (bs, 1H), 4.28 (d, 2H, J=6.0Hz); 3.79 (s, 3H), 2.96 (s, 3H), 1.45 (s, 9H).

Step 5:N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-5-methoxyl group-2-vinyl-phenyl }-NSC-249992

(220mg, 0.73mmol) (100mg 0.88mmol) handled 1 hour the ice-cold solution in methylene dichloride (4-methane sulfonyl amino-2-methoxyl group-5-vinyl-benzyl)-t-butyl carbamate, then under reduced pressure concentrated with trifluoroacetic acid.(100mg, part 0.27mmol) is suspended in the methylene dichloride and with triethylamine and handles, and uses (the 4-tertiary butyl-benzyl)-phenyl carbamate (92mg, 0.32mmol) processing subsequently with rough resistates.The mixture that obtains was heated 3 days under situation about refluxing, and under reduced pressure concentrate.Rough resistates is carried out column chromatography (hexane/ethyl acetate=1/2) to produce white solid (8.8mg, 7.0%).

¹HNMR (300MHz, CDCl ₃): 7.39 (s, 1H), 7.34 (d, 2H, J=8.1Hz), 7.24 (d, 2H, J=8.1Hz), 7.00 (s; 1H), 6.77 (dd, 1H, J=11 and 17Hz), 6.59 (bs, 1H), 5.63 (d, 1H, J=17Hz); 5.37 (d, 1H, J=11Hz), 4.93 (bs, 1H), 4.77 (bs, 1H), 4.32 (d; 4H, J=5.1Hz), 3.76 (s, 3H), 2.93 (s, 3H), 1.30 (s, 9H).

Embodiment 49:

3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-2-methoxyl group-5-vinyl-benzyl)-acrylic amide

HCl salt (220mg with 4-methane sulfonyl amino-2-methoxyl group-5-vinyl-benzylamine and preparation in synthetic embodiment 48; 0.73mmol) ice-cold solution in methylene dichloride is with trifluoroacetic acid (100mg; 0.88mmol)) handled 1 hour, then under reduced pressure concentrate.(50mg 0.13mmol) is suspended in the methylene dichloride, and handles with triethylamine, uses 3-(the 4-tertiary butyl-phenyl)-vinylformic acid (30mg) and DMTMM (40mg) to handle subsequently with the part of rough resistates.The mixture that obtains is stirred 2 days at ambient temperature, and under reduced pressure concentrate.Rough resistates is carried out column chromatography (hexane/ethyl acetate=3/2) to produce white solid (11mg, 19%).

¹HNMR (300MHz, CDCl3): 7.63 (d, 2H, J=16Hz), 7.45 (s, 1H), 7.43 (d, 2H, J=8.1Hz), 7.38 (d; 2H, J=8.1Hz), 7.09 (s, 1H), 6.74 (dd, 1H, J=11 and 17Hz), 6.48 (s, 1H), 6.36 (d; 1H, J=16Hz), 6.12 (t, 1H), 5.63 (d, 1H, J=17Hz), 5.37 (d, 1H, J=11Hz); 4.54 (d, 2H, J=6.0Hz), 3.90 (s, 3H), 2.96 (s, 3H), 1.32 (s, 9H).

Embodiment 50:1-(4-amino-3-fluoro-5-vinyl-benzyl)-3-(the 4-tertiary butyl-benzyl)-urea

Step 1:1-(4-amino-3-fluoro-benzyl)-3-(the 4-tertiary butyl-benzyl)-urea

(0.46g, 3.28mmol) (1.1eq 1.02g) places the round-bottomed flask of 50ml with 4-tertiary butyl benzylamino phenyl formate with 4-amino-3-flunamine hydrochloride.To this mixture impouring 20ml acetonitrile and add triethylamine (excessive, 0.5ml), refluxed 12 hours.After confirming that with TLC reaction finishes, reaction mixture use ethyl acetate extraction, with 1N HCl solution washing, and the organic layer of merging passed through MgSO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=1/1).

Productive rate: 0.5g, 46.4%

Step 2:1-(4-amino-3-fluoro-5-iodo-benzyl)-3-(the 4-tertiary butyl-benzyl)-urea

With 1-(4-amino-3-fluoro-benzyl)-3-(the 4-tertiary butyl-benzyl)-urea (0.25g, 0.76mmol) and Ag ₂SO ₄(1.1eq 0.26g) places the round-bottomed flask of 50ml, then is cooled to 0 ℃.Impouring 20ml ethanol is also by a part adding I in this mixture ₂(1.0eq, 0.193g), stirring at room 3 hours.After confirming that with TLC reaction finishes,, and under reduced pressure concentrate through C salt filter reaction mixture.

Step 3:1-(4-amino-3-fluoro-5-vinyl-benzyl)-3-(the 4-tertiary butyl-benzyl)-urea

With 1-(4-amino-3-fluoro-5-iodo-benzyl)-3-(the 4-tertiary butyl-benzyl)-urea (0.17g, 0.37mmol) and Pd (PPh ₃) ₄(0.05eq 21.3mg) places the round-bottomed flask of 50ml.And (1.1eq 0.13g), refluxed 2 hours to add 20ml toluene and tributyl (vinyl) tin through syringe to this reaction mixture.After confirming that with TLC reaction finishes, use the ethyl acetate extraction reaction mixture, with 1M KF solution washing.And the organic layer that merges passed through MgSO ₄Drying is filtered and is under reduced pressure concentrated.The liquid that obtains is carried out column chromatography (n-hexane/ethyl acetate=2/1).

Productive rate: 88mg, 66.9%

Embodiment 51:

3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl-benzyl)-2-phenyl-acrylic amide

Step 1:3-(the 4-tertiary butyl-phenyl)-2-phenyl-vinylformic acid

(489mg, 3.59mmol) (573mmg, 3.53mmol), TEA (5ml) and diacetyl oxide (5ml) add round-bottomed flask with 4-tert.-butylbenzene formaldehyde with phenylacetic acid.With reaction mixture heating and stirred overnight.With the reaction mixture impouring 5%HCl aqueous solution (30ml).Extract the aqueous solution with MC (30ml * 3).The organic layer that merges is passed through MgSO ₄Drying, and then concentrate in a vacuum.Rough resistates is carried out column chromatography (hexane/ethyl acetate=4/1) to produce white solid (382mg, 73%).

¹HNMR(300MHz，CDCl ₃)：7.88(s，1H)，7.37～7.35(m，4H)，7.23～7.21(m，2H)，7.14(d，2H，J＝8.4Hz)，7.96(d，2H，J＝8.4Hz)1.20(s，9H)

Step 2:

3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl-benzyl)-2-phenyl-acrylic amide

Make 4-methane sulfonyl amino-3-vinyl-benzylamine and HCl salt (153mg; 0.582mmol) react to obtain 3-(the 4-tertiary butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl-benzyl)-2-phenyl-acrylic amide (130.8mg, 46%) with 3-(the 4-tertiary butyl-phenyl)-2-phenyl-vinylformic acid (160.4mg).

¹HNMR(300MHz，CDCl ₃)：7.84(s，1H)，7.43～7.38(m，3H)，7.32(d，2H，J＝8.1Hz)，7.26～7.22(m，3H)，7.11(m，2H)，7.01(m，2H)，6.89(m，2H)，6.12(br，1H)，5.76(t，1H，J＝5.4Hz)，4.40(d，1H，J＝6Hz)，2.95(s，3H)，1.19(s，9H).

IR(cm-1)：2962，1654，1606，1513，1365，1154.

Embodiment 52:N-(4-methane sulfonyl amino-3-vinyl-benzyl)-2,3-phenylbenzene-acrylic amide

Step 1:2,3-phenylbenzene-vinylformic acid

According to similar methods, make phenylacetic acid (1.94g, 14.24mmol) and phenyl aldehyde (1.491g, 14.05mmol), the reaction of TEA (5ml) and diacetyl oxide (5ml) is to obtain 2,3-phenylbenzene-vinylformic acid. ¹HNMR(300MHz，CDCl ₃)：8.06(s，1H)，7.49(m，3H)，7.37～7.19(m，5H)，7.16(m，2H).

Step 2:N-(4-methane sulfonyl amino-3-vinyl-benzyl)-2,3-phenylbenzene-acrylic amide

Make 4-methane sulfonyl amino-3-vinyl benzylamine and HCl salt (131mg; 0.499mmol) and through 2 of reported method preparation; (115mg 0.512mmol) reacts 3-phenylbenzene-vinylformic acid, to obtain N-(4-methane sulfonyl amino-3-vinyl-benzyl)-2; 3-phenylbenzene-propionic acid amide (146mg, 68%).

¹HNMR(300MHz，CDCl3)：7.85(s，1H)，7.37(m，3H)，7.29(m，3H)，7.07(m，4H)，6.94(m，3H)，6.84(s，1H)，5.87(t，1H，J＝5.7Hz)，5.63(dd，1H，J＝17.4，1.2Hz)，3.38(s，1H，J＝10.8，0.9)，4.44(d，2H，J＝6.3Hz)，2.90(s，3H).

IR(cm-1)：3176，1652，1595，1515，1311.

Embodiment 53: (R)-N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992

With N-[4-(1-amino-ethyl)-2-ethenylphenyl] NSC-249992 (236.7mg, 0.985mmol, 1eq.) and triethylamine (274.6 μ l, 1.970mmol 2eq.) add methylene dichloride.Reaction mixture is cooled to 0 ℃.Adding 4-tert.-butylbenzene based isocyanate (192.5 μ l, 1.083mmol, 1.3eq.).Reaction mixture was stirred 40 minutes.Remove methylene dichloride in a vacuum.(n-Hx: EA=2: 1) the purifying resistates is to produce the title compound (155.4mg, 38%) as white solid with column chromatography.

IR (KBr pellet, cm ^-1): 3350,3025,2962,2863,1648;

¹H?NMR(400MHz，CDCl ₃)：7.30(d，1H，J＝1.6Hz)，7.18(d，2H，J＝8.4Hz)，7.15(d，1H，J＝8.4Hz)，7.08(d，2H，J＝8.4Hz)，7.03(dd，1H，J＝8.4，1.6Hz)，6.96(s，1H)，6.80(dd，1H，J＝17.2，11.2Hz)，5.55(d，1H，J＝17.2Hz)，5.26(d，1H，J＝11.2H)，4.81(q，1H，J＝6.4Hz)，2.83(s，3H)，1.25(d，3H，J＝6.4Hz)，1.18(s，9H)

Embodiment 54: (R)-N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-2-TMS ethynyl phenyl) NSC-249992

Step 1: (R)-[1-(4-amino-3-trimethyl silane (sianyl) ethynyl phenyl) ethyl] t-butyl carbamate

With [1-(4-amino-3-iodo-phenyl)-ethyl]-t-butyl carbamate (100mg, 0.276mmol, 1eq.), dichloro (bi triphenyl phosphine) palladium (9.8mg, 0.014mmol, 0.05eq.) and cupric iodide (2.6mg, 0.014mmol 0.05eq.) are dissolved in THF.After stirring 30 minutes, with triethylamine (115.4 μ l, 0.828mmol, 3eq.) and (trimethyl silyl) ethynyl (49.6 μ l, 0.359mmol 1.3eq) add in the reaction mixture.With the reaction mixture stirred overnight.Evaporation reaction mixture in a vacuum.(n-Hx: EA=5: 1) the purifying resistates is to produce the title compound (70.8mg) as yellow liquid with column chromatography.

[α] ²³ _D:+40.80 ° (c 0.2, CHCl ₃); (NaCl is pure, cm for IR ^-1): 3374,2974,2928,2141,1694; ¹H NMR (400MHz, CDCl ₃): 7.23 (d, 1H, J=1.6Hz), 7.05 (dd, 1H, J=8.4,1.6Hz), 6.64 (d, 1H, J=8.4Hz), 4.73-4.71 (m, 1H), 4.63 (bs, 1H), 4.09 (bs, 2H), 1.42 (s, 9H), 1.39 (d, 3H, J=6.8Hz), 0.26 (s, 9H)

Step 2: (R)-[1-(4-methane sulfonyl amino-3-TMS ethynyl phenyl) ethyl] t-butyl carbamate

With (R)-[1-(4-amino-3-three base silane ethyl-acetylene base phenyl) ethyl] t-butyl carbamate (67.9mg, 0.20mmol, 1eq.), the sulfonyl methane acid anhydride (39.1mg, 0.23mmol, 1.1eq.) and pyridine (49.0 μ l, 0.61mmol 3eq) add methylene dichloride.In room temperature mixture was stirred 5 hours.Through adding saturated NaHCO ₃Solution quencher reaction mixture.Use the dichloromethane extraction reaction mixture.The organic layer that merges is used 5%HCl, saturated NaHCO ₃Solution, and H ₂The O washing through dried over sodium sulfate, and concentrates in a vacuum.With resistates with the column chromatography purifying to produce as solid title product (50.4mg, 79.6%).

[α] ²³ _D:+42.88 ° (c 0.41, CHCl ₃); IR (KBr pellet): 3410,2972,2929,2152,1678cm ^-1

¹H?NMR(400MHz，CDCl ₃)：δ7.53(d，1H，J＝8.4Hz)，7.40(d.1H，J＝2.0Hz)，7.28(dd，1H，J＝8.4，2.0Hz)，6.94(bs，1H)，4.83(d，2H，J＝7.6Hz)，4.72(bs，1H)，2.99(s，3H)，1.42-1.40(m，12H)，0.29(s，9H).

Step 3: (R)-N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-2-TMS ethynyl phenyl) NSC-249992

(300mg, 0.724mmol 1eq) add methylene dichloride with [1-(4-methane sulfonyl amino-3-TMS ethynyl-phenyl)-ethyl]-t-butyl carbamate.(279 μ l, 3.619mmol 3eq.) add mixture with trifluoroacetic acid.Reaction mixture was stirred 24 hours.Mixture is concentrated to produce the title compound (440.1mg) as liquid in a vacuum.

With (R)-N-[4-(1-amino-ethyl)-2-TMS ethynyl phenyl] NSC-249992 (75.0mg, 0.242mmol, 1eq.) and triethylamine (67.5 μ l, 0.484mmol 2eq.) is dissolved in methylene dichloride.Mixture is cooled to 0 ℃.(47.2 μ l, 0.266mmol 1.1eq.) add in the reaction mixture with 4-tert.-butylbenzene based isocyanate.Reaction mixture was stirred 40 minutes.Remove reaction solvent in a vacuum.(n-Hx: EA=2: 1) the purifying resistates is to produce as solid title compound (45.3mg, 39%) with column chromatography.

Mp:118.5-119.5 ℃; [α] ²³ _D-24.79 ° (c 0.63, CHCl ₃), IR (KBr pellet, cm ^-1): 3406,2962,2928,2868,2150,1649; ¹H NMR (400MHz, CDCl ₃): 7.43 (d, 1H, J=8.4Hz), 7.35 (d, 1H, J=2.0Hz), 7.24 (d, 2H; J=8.8Hz), 7.21 (dd, 1H, J=8.4,2.0Hz), 7.09 (d, 2H, J=8.8Hz); 6.86 (bs, 1H), 6.40 (bs, 1H), 4.86 (q, 1H, J=6.8Hz), 2.91 (s; 9H), 1.34 (q, 1H, J=6.8Hz), 1.22 (s, 9H), 0.21 (s, 9H)

Embodiment 55: (R)-N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethynyl phenyl) NSC-249992

(11mg 0.023mmol) is dissolved in THF to NSC-249992 with (R)-N-(4-{1-[3-(the 4-tertiary butyl-phenyl) urea groups] ethyl }-2-TMS ethynyl-phenyl).Reaction mixture is cooled to 0 ℃.(solution in 3eq.) adds in the reaction mixture for 0.068ml, 0.068mmol at THF with the TBuA fluorochemical of 1.0M.Reaction mixture was stirred 1.5 hours.Reaction mixture is concentrated and with column chromatography (n-Hx: EA=1: 1) carry out purifying to produce as solid title compound (7.0mg, 74%) in a vacuum.

mp：88.4-89.4℃；[α] ²³ _D-28.19°(c?0.31，CHCl ₃)；

IR (KBr pellet, cm ^-1): 3410,2961,2926,2855,2104,1645;

¹H?NMR(400MHz，CDCl ₃)：7.49(d，1H，J＝8.4Hz)，7.39(d，1H，J＝1.6Hz)，7.26(d，3H，J＝8.8Hz)，7.10(d，2H，J＝8.8Hz)，6.89(bs，1H)，6.22(bs，1H)，4.96(bs，1H)，4.89(q，1H，J＝6.8Hz)，3.40(s，1H)，2.94(s，3H)，1.36(d，3H，J＝6.8Hz)，1.23(s，9H).

Embodiment 56:N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] methyl }-the 2-ethenylphenyl) NSC-249992

With N-[4-(1-amino-ethyl)-2-vinyl-phenyl]-NSC-249992 (236.7mg, 0.985mmol) and triethylamine (274.6 μ l, 1.970mmol 2eq) add methylene dichloride.Reaction mixture is cooled to 0 ℃.(192.5 μ l, 1.083mmol 1.3eq.) add mixture with 4-tert.-butylbenzene based isocyanate.Reaction mixture was stirred 40 minutes.Remove reaction solvent in a vacuum.(n-Hx: EA=2: 1) purifying is to produce the title compound (155.4mg, 47%) as white solid with chromatography with resistates.

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)

Embodiment 57:N-{4-[3-(4-tert-butyl-phenyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992

With N-(4-amino methyl-2-fluoro-6-ethenylphenyl) NSC-249992 (37.8mg, 0.11mmol), the 1-tertiary butyl-4-isocyanide acyl benzene (1.2eq, 0.13mmol, 22.49 μ l), and TEA (3eq, 0.33mmol, 45.99 μ l) adds methylene dichloride.Reaction mixture was stirred 12 hours.Use the dichloromethane extraction reaction mixture.The organic layer that merges is used H ₂O and brine wash are through dried over sodium sulfate and concentrated in a vacuum.(n-Hx: EA=1: 1) the purifying resistates is to produce the title compound (26.1mg, 55%) as white solid with column chromatography.

Mp：167～170℃；

IR (KBr pellet, cm ^-1): 3328,3246,3072,2961,1320,1152;

¹H?NMR(400MHz，CD ₃OD)：δ7.44(s，1H)，7.26(d，2H，J＝8.0Hz)，7.23(d，2H，J＝8.0Hz)，7.16(dd，1H，J＝17.6，11.2Hz)，7.09(dd，1H，J＝10.4，1.6Hz)，6.89(s，1H)，5.82(d，1H，J＝17.6Hz)，5.35(d，1H，J＝11.2Hz)，4.35(s，2H)，2.99(s，3H)，1.37(s，9H).

Embodiment 58: vinyl sulfonic acid (4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) acid amides

Step 1: vinyl sulfonic acid (4-{1-[1-(2, the 2-dimethyl propyl) vinyl is amino] ethyl }-the 2-iodophenyl) acid amides

With 4-{1-[1-(2, the 2-dimethyl propyl) vinyl is amino] ethyl }-(218.1mg 0.65mmol) is dissolved in methylene dichloride to the 2-Iodoaniline.Reaction mixture is cooled to 0 ℃.2-monochloroethane SULPHURYL CHLORIDE (3eq, 1.95mmol, 203.64 μ l) and pyridine (3eq, 1.95mmol, 157.71 μ l) are added mixture.Reaction mixture was stirred 48 hours.After confirming end of synthesis, remove reaction solvent in a vacuum.Use the dichloromethane extraction resistates.The organic layer that merges is used H ₂O and brine wash are through NaSO ₄Drying, and concentrate in a vacuum.(n-Hx: EA=3: 1) the purifying resistates is to produce the title compound (104.9mg, 78%) as brown solid with column chromatography.

mp：112～114℃；

[α] _D ²⁰+31.69(CHCl ₃，c?1.74)；

IR (KBr pellet, cm ^-1): 3323,2976,1693,736; ¹H NMR (400MHz, CDCl ₃): δ 7.66 (s, 1H), 7.47 (dd, 1H, J=8.4,8.0Hz), 7.22 (d, 1H, J=8.4Hz), 6.59 (s; 1H), 6.54 (qd, 1H, J=16.8,10.0,1.2Hz), 6.20 (d, 1H, J=16.4Hz); 5.91 (d, H, J=10.0Hz), 4.77 (bs, 1H), 4.65 (bs, 1H), 1.36 (s, 12H)

Step 2: [1-(4-ethene sulfuryl amino-3-ethenylphenyl) ethyl] t-butyl carbamate

With [1-(4-ethene sulfuryl amino-3-iodophenyl) ethyl] t-butyl carbamate (58.4mg, 0.13mmol), Pd (PPh ₃) ₄(9.10mg), (15.43mg), and TEA (1.5eq, 0.19mmol, 56.99 μ l) adds DMF to LiCl for 2.8eq, 0.19mmol for 0.06eq, 0.0078mmol.At 90 ℃ reaction mixture was stirred 12 hours.Remove DMF in a vacuum.Use the ethyl acetate extraction resistates.The organic layer that merges is used H ₂O and brine wash through dried over sodium sulfate, and concentrate in a vacuum.(N-Hx: EA=3: 1) the purifying resistates is to produce the title compound (24.8mg, 18%) as brown liquid with column chromatography.

mp：80～82℃；

[α] _D ²⁰：+6.21(CHCl ₃，c?0.47)；

(NaCl is pure, cm for IR ^-1): 3347,2958,1686; ¹H NMR (400MHz, CDCl ₃): 7.30 (t, 1H, J=1.2Hz), 7.28 (s, 1H), 7.12 (dd, 1H, J=8.0; 1.2Hz) 6.80 (q, 1H, J=6.4,10.8Hz), 6.50 (dq, 1H, J=10.8,6.4; 0.8Hz), 6.41 (s, 1H), 5.86 (d, 1H, J=10.0Hz), 5.62 (d, 1H; J=17.6Hz), 5.37 (d, 1H, J=11.2Hz), 4.75 (s, 1H), 4.68 (s, 1H).

Step 3: vinyl sulfonic acid (4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) acid amides

With [1-(4-ethene sulfuryl amino-3-vinyl-phenyl)-ethyl]-t-butyl carbamate (20.0mg, 0.04mmol) and CF ₃COOH (5eq, 0.22mmol, 17.04 μ l) is dissolved in methylene dichloride.Reaction mixture was stirred 12 hours.Concentrated reaction mixture is to produce [1-(4-ethene sulfuryl amino-3-vinyl-phenyl)-ethylamine (15.6mg, 76%).

With vinyl sulfonic acid [4-(1-amino-ethyl)-2-vinyl-phenyl]-acid amides (15.6mg, 0.04mmol), 4-tert.-butylbenzene based isocyanate (1.2eq, 0.053mmol, 9.45 μ l), and TEA (1.2eq, 0.12mmol, 16.73 μ l) adds MC.Reaction mixture was stirred 5 hours.Use the dichloromethane extraction reaction mixture.The organic layer that merges is used H ₂O and brine wash are through dried over sodium sulfate and concentrated in a vacuum.With resistates with column chromatography (n-Hx: EA=3: 1-＞2: 1) purifying to produce title compound (34.2mg, 40%).

mp：60～62℃；

[α] _D ²⁰-17.57(CHCl ₃，c?0.28)；

(NaCl is pure, cm for IR ^-1): 3346,3189,2962,1649,1318;

¹H?NMR(400MHz，CD ₃?OD)：7.59(d，1H，J＝1.6Hz)，7.27(t，1H，J＝2.4Hz)，7.26(s，1H)，7.25(s，2H)，7.23(s，2H)，7.10(q，1H，J＝11.2，6.4Hz)，6.69(q，1H，J＝6.8，9.6Hz)，6.02(d，1H，J＝16.4Hz)，5.90(d，1H，J＝10.0Hz)，5.77(dd，1H，J＝1.2，17.6Hz)，5.33(dd，1H，J＝1.2，10.8Hz)，1.45(d，3H，J＝6.8Hz)，1.27(s，9H).

Embodiment 59:N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-2-phenylacetylene base phenyl) NSC-249992

Step 1: [1-(4-amino-3-phenylacetylene base phenyl) ethyl] t-butyl carbamate

(1eq.), (0.05eq.) (0.069mmol 0.05eq.) adds THF to dichloro (bi triphenyl phosphine) palladium with cupric iodide 13.1mg for 48.4mg, 0.069mmol for 500mg, 1.380mmol with [1-(4-amino-3-iodophenyl) ethyl] t-butyl carbamate.After 30 minutes, (3eq) (197.0 μ l, 1.794mmol 1.3eq) add reaction mixture with the phenylacetylene base for 577.0 μ l, 4.140mmol with TEA in stirring at room.Under situation about refluxing, with the reaction mixture stirred overnight.Remove reaction solvent in a vacuum.(n-Hx: EA=5: 1) the purifying resistates is to produce the title compound (452.7mg) as yellow liquid with column chromatography.

[α] ²³ _D-4.80°(c?0.83，CHCl ₃)；

(NaCl is pure, cm for IR ^-1): 3433,2968,2922,2852,2198,1684;

¹H?NMR(400MHz，CDCl ₃)：7.44-7.40(m，2H)，7.26(-7.16(m，4H)，6.97(dd，1H，J＝8.0，1.2Hz)，6.56(d，1H，J＝8.0Hz)，4.76(d，1H，J＝7.6Hz)，4.58(bs，1H)，1.33(s，9H)，1.31(d，3H，J＝7.2Hz).

Step 2: [1-(4-methane sulfonyl amino-3-phenylacetylene base phenyl) ethyl] t-butyl carbamate

(1eq.) (302.7mg, 0.737mmol 1.2eq.) add methylene dichloride with the sulfonyl methane acid anhydride for 487.1mg, 1.448mmol with [1-(4-amino-3-phenylacetylene base phenyl) ethyl] t-butyl carbamate.Reaction mixture is cooled to 0 ℃.(348.1 μ l, 4.344mmol 3eq.) add in the reaction mixture with pyridine.Reaction mixture was stirred 1 hour.Through adding saturated NaHCO ₃Solution quencher reaction.Use the dichloromethane extraction reaction mixture.The organic layer that merges is used 5%HCl, saturated NaHCO ₃Solution, H ₂O follows brine wash and passes through Na ₂SO ₄Drying then concentrates in a vacuum.(n-Hx: EA=5: 1) the purifying resistates is to produce title compound (300mg, 83%) with column chromatography.

mp：157-158℃；

[α] ²³ _D+45.52°(c?0.31，CHCl ₃)；

IR (KBr pellet, cm ^-1): 3362,3253,3013,2974,2930,1684; ¹HNMR (400MHz, CDCl ₃): 7.51 (d, 1H, J=8.4Hz), 7.48-7.45 (m, 2H), 7.42 (d.1H, J=2.0Hz), 7.35-7.31 (m, 3H), 7.24 (dd, 1H, J=8.4,2.0Hz), 6.91 (s, 1H), 4.72 (bs, 2H), 2.97 (s, 3H), 1.39-1.36 (m, 12H).

Step 3:N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-2-phenylacetylene base phenyl) NSC-249992

With [1-(4-methane sulfonyl amino-3-phenylacetylene base phenyl) ethyl] t-butyl carbamate (300mg, 0.724mmol) and trifluoroacetic acid (279 μ l, 3.619mmol 3eq) add methylene dichloride.Reaction mixture was stirred 24 hours.Remove reaction solvent in a vacuum to produce 1-(4-methane sulfonyl amino-3-phenylacetylene base phenyl) ethylamine (440.1mg, 100%).With N-[4-(1-amino-ethyl)-2-phenylacetylene base phenyl] NSC-249992 (440.1mg, 1.40mmol) and TEA (390.3 μ l, 2.800mmol 2eq) add methylene dichloride.Reaction mixture is cooled to 0 ℃.(248.8 μ l, 1.540mmol 1.3eq.) add said mixture with 4-tert.-butylbenzene based isocyanate.Reaction mixture was stirred 1 hour.Remove methylene dichloride in a vacuum.(n-Hx: EA=2: 1) the purifying resistates is to produce as solid title compound (241.4mg, 35%) with column chromatography.

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)；

mp：103-104℃；

[α] ²³ _D：-38.55°(c?0.33，CHCl ₃)；

IR (KBr pellet): 3375,3056,2962,2903,2260cm ^-1

Embodiment 60:N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-styryl phenyl) NSC-249992

(50mg, 0.102mmol 1eq.) and with the palladium lime carbonate that plumbous (Lindlar catalyzer) suppresses add methyl alcohol with N-(4-{1-[3-(the 4-tertiary butyl-phenyl)-urea groups]-ethyl }-2-phenylacetylene base phenyl)-NSC-249992.With reaction mixture at H ₂Stirred 12 hours under the atmosphere.Reaction mixture is filtered with C salt pad.Concentrated filtrate in a vacuum.(n-Hx: EA=2: 1) the purifying resistates is to produce title compound (16mg, 32%) with column chromatography.

[α] ²³ _D-8.80°(c?0.5，CHCl ₃)；

IR (KBr pellet, cm ^-1): 3407,3025,2962,2927,1648,1543;

¹H?NMR(400MHz，CDCl ₃)：7.39(d，1H，J＝8.4Hz)，7.25-7.00(m，11H)，6.72(d，1H，J＝12.4Hz)，6.44(d，1H，J＝12.4Hz)，6.38(bs，1H)，4.83(q，1H，J＝6.8Hz)，2.60(s，3H)，1.29(d，3H，J＝6.8Hz)，1.22(s，9H).

EXPERIMENTAL EXAMPLE: biopotency test

1. ⁴⁵Ca flows into test

1) separation and the primary culture thereof of the backbone DRGs (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, in said substratum, adds 1.2g/l sodium hydrogencarbonate, the qingfengmeisu qiong of 50mg/l.DRG is continued at 37 ℃ of incubations 30 minutes in the trypsinase of the collagenase of 200U/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 through fire grinds, through the Nitex80 membrane filtration to obtain unicellular suspension and said 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, with replenishing, and add NGF (NGFF) 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 said 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 gathering with 10 μ g/ml in advance-Terasaki flat board that the D-guanylic acid encapsulates on.

2) ⁴⁵Ca flows into experiment

Through not having Ca with HEPES (10mM, pH 7.4)-buffered 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 through calculating the radioactivity measurement ⁴⁵The amount of Ca.Test compounds is calculated as the per-cent in the inhibition of the maximum response of the capsaicine of the concentration of 0.5 μ M to the antagonistic activity of novel vanilloid receptor.Generally speaking, all embodiment of the present invention show good to superior between 20 and 500nM between the IC50 value, wherein most compounds has the IC50 value that is lower than 200nM.

[table 2]

Calcium current is gone into the result of test

Embodiment	Antagonist
		Calcium absorption test (IC 50，μM)
	1		0.16
2		0.098
	3		0.18

4	0.17
		5	0.49
6	0.082
		7	0.039
8	0.31
		9	0.13
11	0.079
		12	0.087
13	0.15
		14	0.05
15	0.034
		16	0.047
17	0.058
		21	0.16
22	0.25
		23	0.067
27	0.076
		28	0.073
30	0.068
		32	0.49
34	0.17
		35	0.033
36	0.054
		37	0.049
38	0.27
		40	0.29
41	0.043
		42	0.022
43	0.067
		45	0.063
46	0.025
		47	0.17

53	0.099
		55	0.17
57	0.5
		58	0.45

3. analgesic activity test: test through 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 equality (% suppresses=(C-T)/C * 100) through % and calculate analgesic effect, wherein C and T represent to be illustrated respectively in contrast and compound-control group in the number of times (table 3) of struggle.

[table 3]

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

Embodiment	Dosage (mg/kg)	Analgesic activity (% inhibition)
			2	?0.3	57％
6	1	56％
			14	1	58％
15	1	60％
			16	1	68％
17	1	63％
			25	1	64％
41	1	44％
			45	1	82％
46	1	43％

Industrial applicability

As above set forth, will be used for prevention and treatment pain, migraine, arthrodynia, neurodynia according to compound of the present invention; Neuropathy, nerve injury, dermatosis, irritable bladder; Irritable bowel syndrome, just anxious, respiratory disease, skin, eyes or MMi; Gastroduodenal ulcer, inflammatory diseases, otopathy and heart trouble etc.

More specifically, be used for prevention and treatment acute pain, chronic pain, neuropathic pain, postoperative pain, rheumatic arthralgia according to compound of the present invention; Osteoarthrosis pain, PHN, 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, the irritated and variable force ischemia of vestibular.

Claims (24)

1. the compound of formula (I), its isomer or its pharmaceutical salts:

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, CHR ₁₁CHR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, halogen, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, or phenyl; R ₁Be C2-C5 alkenyl or C2-C5 alkynyl;

R ₂Be hydrogen, halogen, nitro, cyanic acid, C1-C5 alkyl; The C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxyl; The C1-C5 alkoxy carbonyl, the C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each 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, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and 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; The C1-C5 alkoxyl group, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl; The C1-C5 alkyl-carbonyl, C1-C5 alkoxy carbonyl, hydroxyl, C2-C5 alkenyloxy, C1-C5 alkoxyl group (C1-C5) alkoxyl group; C1-C5 alkoxyl group (C1-C5) alkoxyl group (C1-C5) alkyl, C1-C3 alkylpiperazine base, piperazinyl (C1-C5) alkoxyl group, piperidyl (C1-C5) alkoxyl group, C1-C5 alkoxyl group (C1-C5) alkylamino; The C1-C7 alkylamino, morpholinyl, morpholinyl (C1-C5) alkyl oxy, THP trtrahydropyranyl oxygen base, 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, C1-C5 alkyl-carbonyl; The C1-C5 alkylthio, the C1-C5 alkyl sulphonyl, the C1-C5 alkoxy carbonyl, or unsubstituted or by the substituted piperidyl oxygen of C1-C5 alkoxy carbonyl base; And

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C1-C5 alkoxy carbonyl; The C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each phenyl can be unsubstituted or replace by being selected from following one or more substituting groups: carboxyl, C1-C5 alkyl; Halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl; The C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and C1-C5 alkoxy carbonyl, and R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

2. according to compound, its isomer or its pharmaceutical salts of the formula (I) of claim 1,

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, halogen,

C1-C5 alkyl, or phenyl;

R ₁Be C2-C5 alkenyl or C2-C5 alkynyl;

R ₂Be hydrogen, halogen, nitro, cyanic acid, C1-C5 alkyl; The C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, carboxyl; The C1-C5 alkoxy carbonyl, the C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each 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, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and 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; The C1-C5 alkoxyl group, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl; The C1-C5 alkyl-carbonyl, the C1-C5 alkoxy carbonyl, phenyl, or halogen, wherein phenyl can not be substituted or replace by being selected from following one or more substituting groups: carboxyl; The C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl and C1-C5 alkoxy carbonyl; And

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl; The C1-C5 alkoxy carbonyl, the C1-C5 alkylthio, phenyl, or phenyl (C1-C3) alkyl, wherein each 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, C1-C5 alkoxyl group; Halo (C1-C5) alkyl, C1-C5 alkyl-carbonyl, C1-C5 alkylthio, C1-C5 alkyl sulphonyl

With the C1-C5 alkoxy carbonyl, and R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, trifluoromethyl, phenyl, or phenyl (C1-C3) alkyl.

3. according to each compound of aforementioned claim, its isomer or its pharmaceutical salts;

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, halogen,

C1-C5 alkyl, or phenyl;

R ₁Be vinyl, ethynyl, propenyl, or proyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or phenyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₆, R ₇, and R ₈Be hydrogen independently, carboxyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, nitro, vinyl, ethynyl, methylthio group, trifluoromethyl, methoxycarbonyl, or halogen; And

R ₉And R ₁₀Be hydrogen independently ,-SO ₂R ₁₃,-SOR ₁₃, C1-C5 alkyl, C1-C5 alkoxyl group, halo (C1-C5) alkyl, C2-C5 alkenyl, phenyl, phenyl (C1-C3) alkyl, or C1-C3 alkoxyl phenyl, wherein R ₁₃Be hydrogen, amino, C1-C5 alkyl, C2-C5 alkenyl, trifluoromethyl, phenyl, or benzyl.

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

Wherein

X is NHCH ₂, CH ₂=CH ₂, or C ≡ C;

R ₁Be vinyl or ethynyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or phenyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, R ₈, and R ₁₀Be hydrogen;

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

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

5. the compound that has formula (Ia) according to claim 1, its isomer, or its pharmaceutical salts;

Wherein

X is NHCH ₂Or CH ₂=CH ₂

R ₁Be vinyl or ethynyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, methoxycarbonyl, or phenyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, and R ₈Be hydrogen; And

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

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

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, CHR ₁₁CHR ₁₂Or C ≡ C, wherein R ₁₁And R ₁₂Be hydrogen independently, fluorine or methyl;

R ₁Be vinyl, ethynyl, propenyl, or proyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, ethynyl, vinyl, carboxyl, or methoxycarbonyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, and R ₈Be hydrogen independently, fluorine, carboxyl, methyl, ethyl, propyl group, sec.-propyl; The tertiary butyl, nitro, vinyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen; Methoxy ethoxy, the methoxy ethoxy methyl, the N-METHYL PIPERAZINE base, methoxy ethyl is amino, hydroxyl, methoxyl group, allyl group oxygen base; Isohexyl is amino, isobutylamino (ammino), and sec.-propyl is amino, morpholinyl, morpholinyl oxyethyl group, or THP trtrahydropyranyl oxygen base;

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

R ₉And R ₁₀Be hydrogen or methane sulfonyl independently.

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

Wherein

X is NHCH ₂, CR ₁₁=CR ₁₂, CHR ₁₁CHR ₁₂Or C ≡ C, wherein R ₁₁Be hydrogen or methyl and

R ₁₂Be hydrogen;

R ₁Be vinyl or ethynyl;

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

R ₃Be hydrogen or methyl;

R ₄, be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R ₅, R ₇And R ₈Be hydrogen or fluorine;

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

R ₉Be hydrogen and R ₁₀The expression methane sulfonyl.

8. according to the compound of claim 1, wherein X is CHR11-CHR12.

9. according to the compound of claim 8,

Wherein

X is CHR ₁₁-CHR ₁₂

R ₁₁And R ₁₂Be methyl or hydrogen;

R ₁Be vinyl or ethynyl;

R ₂Be hydrogen, fluorine, chlorine, bromine, iodine, nitro, cyanic acid, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, methoxyl group, oxyethyl group, trifluoromethyl, carboxyl, or methoxycarbonyl;

R ₃Be hydrogen, methyl, or ethyl;

R ₄, R ₅, R ₇, and R ₈Be hydrogen independently, fluorine, carboxyl, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl; Nitro, vinyl, ethynyl, trifluoromethyl, methoxycarbonyl, halogen, methoxymethoxy; Methoxy ethoxy, methoxy propoxy, the methoxy ethoxy methyl, the N-METHYL PIPERAZINE base, methoxy ethyl is amino, hydroxyl, methoxyl group; Allyl group oxygen base, isohexyl is amino, isobutylamino (ammino), sec.-propyl is amino, morpholinyl, morpholinyl oxyethyl group, or THP trtrahydropyranyl oxygen base; And

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

10. according to claim 8 and 9 each compounds, wherein

R ₁₁Be hydrogen or methyl, and R ₁₂Be hydrogen;

R ₁Be vinyl or ethynyl;

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

R ₄Be hydrogen, fluorine, methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxyl group, methoxy ethyl is amino, allyl group oxygen base, or THP trtrahydropyranyl oxygen base;

R ₅, R ₇And R ₈Be hydrogen or fluorine;

R ₆It is the tertiary butyl; R ₉Be hydrogen; And R ₁₀The expression methane sulfonyl.

11. according to the compound of the formula (Id) of claim 1, or its pharmaceutical salts;

R1 wherein, R2, R3, R4, R5, R6, R7, R8 and X have each implication of aforementioned claim.

12. a compound, its isomer, or its pharmaceutical salts, wherein said compound is selected from the group of being made up of following:

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethynyl-6-fluorophenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-5-chloro-2-ethynyl phenyl } NSC-249992,

N-(4-{1-(R)-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992,

(R)-N-(4-{1-[3-(the 4-tertiary butyl-benzyl)-urea groups]-ethyl }-2-fluoro-6-vinyl-phenyl) NSC-249992,

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-methyl-6-vinyl-phenyl } NSC-249992,

N-{4-[3-(the 4-tertiary butyl-benzyl)-urea groups methyl]-2-chloro-6-vinyl-phenyl } NSC-249992,

3-(4-tert-butyl-phenyl) propynoic acid 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl acid amides,

3-(4-tert-butyl-phenyl) propynoic acid [1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acid amides,

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-5-ethynyl-4-methane sulfonyl amino-benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide,

3-(4-trifluoromethyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-chloro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-morpholine-4-base-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-methoxy ethoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-p-methoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide,

3-(2-allyl group oxygen base-4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(the 3-methylbutyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-sec.-propyl aminophenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] propionic acid amide,

3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-USAF RH-1,

3-(4-tert-butyl-phenyl)-2-fluoro-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) propionic acid amide,

3-(4-tert-butyl-phenyl)-N-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl]-2-USAF RH-1,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-methyl propanamide,

3-[4-(tertiary butyl) phenyl]-N-[4-(methane sulfonyl is amino)-3-vinyl benzyl] propionic acid amide,

3-[4-(tertiary butyl) phenyl]-N-[3-fluoro-4-(methane sulfonyl is amino)-5-vinyl benzyl] propionic acid amide,

3-(the 4-tertiary butyl-phenyl)-N-(3-ethynyl-5-fluoro-4-methane sulfonyl amino-benzyl)-propionic acid amide,

N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992,

N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethynyl phenyl) NSC-249992,

N-{4-[3-(4-tert-butyl-phenyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992 and

Vinyl sulfonic acid (4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) acid amides.

13. according to the compound of claim 12, its isomer, or its pharmaceutical salts, wherein said compound is selected from the group of being made up of following:

(R)-N-(4-{1-[3-(the 4-tertiary butyl-benzyl)-urea groups]-ethyl }-2-fluoro-6-vinyl-phenyl)-NSC-249992,

3-(4-tert-butyl-phenyl)-N-[1-(R)-(4-methane sulfonyl amino-3-vinyl-phenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-5-ethynyl-4-methane sulfonyl amino-benzyl) acrylic amide,

(R)-3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] propionic acid amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-USAF RH-1,

3-[the 4-tertiary butyl-2-(tetrahydropyran-4-base oxygen base) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) propionic acid amide,

(R)-3-(4-tert-butyl-phenyl)-N-[1-(4-methane sulfonyl amino-3-ethenylphenyl) ethyl]-2-USAF RH-1,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-fluoro-6-ethenylphenyl } NSC-249992,

N-{4-[3-(4-tertiary butyl benzyl) urea groups methyl]-2-ethynyl-6-fluorophenyl } NSC-249992,

3-(4-tert-butyl-phenyl) propynoic acid 3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl acid amides,

3-(4-tert-butyl-phenyl)-N-(4-methane sulfonyl amino-3-vinyl benzyl) acryloyl ammonium,

3-[the 4-tertiary butyl-2-(2-methoxyl group-oxyethyl group)-phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl)-acrylic amide,

3-[the 4-tertiary butyl-2-(the 2-methoxy ethyl is amino) phenyl]-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

3-(the 4-tertiary butyl-2-p-methoxy-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl-benzyl) acrylic amide,

3-(2-allyl group oxygen base-4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl) acrylic amide,

(R)-3-(4-tert-butyl-phenyl)-N-[1-(3-fluoro-4-methane sulfonyl amino-5-ethenylphenyl) ethyl] acrylic amide,

3-(4-tert-butyl-phenyl)-N-(3-fluoro-4-methane sulfonyl amino-5-vinyl benzyl)-2-methyl propanamide,

3-[4-(tertiary butyl) phenyl]-N-[4-(methane sulfonyl is amino)-3-vinyl benzyl] propionic acid amide,

N-(4-{1-(R)-[3-(4-tertiary butyl benzyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992,

3-[4-(tertiary butyl) phenyl]-N-[3-fluoro-4-(methane sulfonyl amino)-5-vinyl benzyl] propionic acid amide and (R)-N-(4-{1-[3-(4-tert-butyl-phenyl) urea groups] ethyl }-the 2-ethenylphenyl) NSC-249992.

14. according to the compound of claim 1 or 12, it is as medicine.

15. a pharmaceutical composition, its comprise as activeconstituents according to each compound, its isomer or its pharmaceutical salts of claim 1-13, and pharmaceutical carrier.

16. 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 compsn comprise according to each compound, its isomer or its pharmaceutical salts among the claim 1-13; And pharmaceutical carrier.

17. according to the pharmaceutical composition of claim 15 or 16, it is used to treat and 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.

18. pharmaceutical composition according to claim 17; Wherein said pain is to be selected from following illness or relevant with it: osteo-arthritis, rheumatoid arthritis, ankylosing spondylitis; Diabetic neuropathic pain; Postoperative pain, non-inflammatory flesh skeleton pain, the headache of migraine and other type.

19. according to the pharmaceutical composition of claim 18, wherein said non-inflammatory flesh skeleton pain comprises fibromyalgia, myofasical pain syndrome and backache.

20. according to each pharmaceutical composition of claim 15-19, it is Orally administered to it is characterized in that it is suitable for.

21. 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 1-13.

22. according to the application that each compound, its isomer or its pharmaceutical salts of claim 1-13 is used to prepare medicine, said 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.

23. according to the application of compound of claim 22, wherein said illness is a pain, or it is to be selected from following illness or relevant with it: osteo-arthritis; Rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain; Postoperative pain; Non-inflammatory flesh skeleton pain, the headache of migraine and other type.

24. according to the application of compound of claim 23, wherein said non-inflammatory flesh skeleton pain comprises fibromyalgia, myofasical pain syndrome and backache.