CN1219764C - W-carboxyaryl substituted diphenyl ureas as RAF kinase inhibitors - Google Patents

W-carboxyaryl substituted diphenyl ureas as RAF kinase inhibitors Download PDF

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Publication number
CN1219764C
CN1219764C CNB008026858A CN00802685A CN1219764C CN 1219764 C CN1219764 C CN 1219764C CN B008026858 A CNB008026858 A CN B008026858A CN 00802685 A CN00802685 A CN 00802685A CN 1219764 C CN1219764 C CN 1219764C
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China
Prior art keywords
phenyl
acid
trifluoromethyl
urea
chloro
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CNB008026858A
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CN1341098A (en
Inventor
B·里德
J·迪马
U·基海尔
T·B·洛因格
W·J·斯科特
R·A·史密斯
J·E·伍德
M-K·莫纳汉
R·纳特罗
J·雷尼克
R·N·西布利
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Bayer Pharmaceuticals Corp
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Bayer Corp
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract

This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.

Description

The sym-diphenylurea that replaces with ω-carboxyl aryl is as the raf kinase inhibitor
The explanation of related application
The application is the part continuation application in 09/257,266 and 1999 year on the 25th 13 days 60/115,877 January of February in 1999.
Invention field
The present invention relates to one group of aryl urea treatment raf the purposes in disease mediated, and the pharmaceutical composition that is used for above-mentioned treatment.
Background of invention
P21 RasOncogene is the one of the main reasons of people's essence oncogenesis and development, and sudden change (Bolton etc., Ann.Rep.Med.Chem.1994,29,165-74 have taken place this gene of 30% cancer patients; Bos.Cancer.Res.1989,49,4682-9).The ras albumen of not mutated normal form be in the signal transduction cascade that points to by growth factor receptors in nearly all tissue key element (Avruch etc., Trends Biochem.Sci.1994,19,279-83).On the biological chemistry, ras is a kind of protein in conjunction with guanylic acid, and GTP is subjected to ras endogenous GTP enzymic activity and the proteic strict control of other adjustings in conjunction with the circulation that activated state combines with GDP between the tranquillization attitude.The endogenous GTP enzymic activity of sudden change ras in the cancer cells improves, so, this protein downstream effect thing, for example the raf kinases sends the composition growth signals.Therefore cause the cell cancerous growths that has these mutant (Magnuson etc., Semin.Cancer Biol.1994,5,247-53).Known, by suppressing the effect that the raf kinase signal pathway suppresses active ras, for example by giving raf kinase whose antibody or the coexpression dominant raf kinases or of deactivating as the dominant MEK of raf kinase substrate, can make transformant be returned to normal growth phenotype (referring to Daum etc., Trends Biochem.Sci.1994,19,474-80; Fridman etc., J.Biol.Chem.1994,269,30105-8).Kolch etc., (nature, 1991,349,426-28) further point out, in the relevant oncogene of film, suppress raf with sense-rna and express propagation capable of inhibiting cell.Similarly, all find in vitro and in vivo raf kinase inhibition (using antisense oligodeoxyribonucleotide) and various human tumor growth suppress relevant (Monia etc., Nat.Med.1996,2,668-75).
Summary of the invention
The invention provides compound as the raf kinase inhibitor.Because this enzyme is p21 RasThe downstream effect thing, inhibitor of the present invention can be used for pharmaceutical composition, is used for the people or beastly raf kinases path suppresses by indication, for example, is used for the treatment of kinase mediated tumour or cell cancerous growths by raf.Specifically, these compounds can be used for treating human or animal's cancer, mouse for example, and the essence cancer because the development of these cancers all depends on ras protein signal transduction cascade, thereby is easy to obtain medical treatment by interrupting cascade (for example by inhibition raf kinases).So The compounds of this invention can be used for treatment such as malignant cancer (for example lung cancer, carcinoma of the pancreas, thyroid carcinoma, bladder cancer or colorectal carcinoma), myelopathy (for example myelogenous leukemia) or adenoma essence cancers such as (for example villouss adenoma of colon).
So, the invention provides the compound of being referred to as the aryl urea, comprise aryl and heteroaryl analogue, they can suppress the raf path.The present invention also provides the method for the disease of treatment human or animal raf mediation.Therefore, the present invention relates to suppress the kinase whose compound of raf, ethyl is used for the treatment of compound, the composition and illegal that the kinase mediated cancer cells of raf rises to, comprising giving compound of Formula I or its salt of pharmaceutically approving:
A-D-B (I)
Wherein, D is-NH-C (O)-NH-,
A is that general formula is-L-(M-L 1) q40 carbon below contain substituted radical, wherein L is 5-6 unit ring, directly links to each other L with D 1Be one at least 5 yuan the substituted ring that contains, M is the bridging group of at least one atom, and q is integer 1-3; Ring L and L 1Respectively contain 0-4 nitrogen, oxygen or sulphur,
B replaces or non-replacement, following aryl of trinucleated 30 carbon or heteroaryl at the most, and wherein at least one 6 yuan of ring directly links to each other with D and contains 0-4 nitrogen, oxygen or sulphur,
L wherein 1Be selected from by at least one-SO 2R x,-C (O) R xWith-C (NR y) R zSubstituting group replace,
R yBe hydrogen, or the following carbon skeleton group of 24 carbon, can contain and be selected from N, the heteroatoms of S and O, but halo or to perhalogeno,
R zBe hydrogen, or the following carbon skeleton group of 30 carbon, can contain and be selected from N that the heteroatoms of S and O can be replaced by the carbon skeleton group below halogen, hydroxyl or other 24 carbon, this substituting group can contain and is selected from N, the heteroatoms of S and O, but and halo;
R xBe R zOr NR aR b, R wherein aAnd R bBe
A) hydrogen of respectively doing for oneself,
The carbon skeleton group that 30 carbon are following can contain and is selected from N, and the heteroatoms of S and O can be replaced by the carbon skeleton group below halogen, hydroxyl and other 24 carbon, and this substituting group can contain and is selected from N, and the heteroatoms of S and O also can be by halo; Or
-OSi (R f) 3, R fBe that the following carbon skeleton group of hydrogen or 24 carbon replaces, can contain to be selected from N that the heteroatoms of S and O can be replaced by the carbon skeleton group below halogen, hydroxyl and other 24 carbon, this substituting group can contain and is selected from N, and the heteroatoms of S and O also can be by halo; Or
B) R aAnd R bThe common heterocycle that forms a 5-7 unit, contain 1-3 and be selected from N, the heteroatoms of S and O, or the substituted heterocycle of a 5-7 unit, contain 1-3 and be selected from N, the heteroatoms of S and O, and replaced by the carbon skeleton group below halogen, hydroxyl or other 24 carbon, this substituting group can contain and is selected from N, and the heteroatoms of S and O also can be by halo; Or
C) R aAnd R bOne of them is-C (O)-and, C 1-5Divalent alkyl or C 1-5The bivalent substituted alkylidene group, it and L connect into one at least 5 yuan ring, C 1-5The substituting group of bivalent substituted alkylidene group is selected from the following carbon skeleton group of halogen, hydroxyl and 24 carbon, and this substituting group can contain and is selected from N, and the heteroatoms of S and O also can be by halo;
B wherein is substituted, and L is substituted, or L 1Further replaced, substituting group is selected from halogen, and perhalogeno, and Wn, n are 0-3;
W respectively is selected from-CN ,-CO 2R 7,-C (O) NR 7R 7,-C (O)-R 7,-NO 2,-OR 7-,-SR 7,-NR 7R 7,-NR 7C (O) OR 7,-NR 7C (O) R 7, the carbon skeleton group that Q-Ar and 24 carbon are following, this group can contain N, and the heteroatoms of S and O also can be by a replacement or polysubstituted, and substituting group is selected from-CN ,-CO 2R 7,-C (O)-R 7,-C (O) NR 7R 7,-OR 7-,-SR 7,-NR 7R 7,-NO 2,-NR 7C (O) R 7,-NR 7C (O) OR 7And halo or to perhalogeno; Each R 7Respectively be selected from the following carbon skeleton group of H or 24 carbon, can contain N, the heteroatoms of S and O also can be by halo,
Q is-O--S-,-N (R 7)-,-(CH 2) m-,-C (O)-,-CH (OH)-,-(CH 2) m-O-,-(CH 2) m-S-,-(CH 2) mN (R 7)-,-O (CH 2) m-,-CHX a-,-CX a 2-,-S-(CH 2) m-and-N (R 7) (CH 2) m-, m=1 to 3, X aIt is halogen;
Ar is 5 or 6 yuan a aromatic structure, contains the heteroatoms that 0-2 is selected from nitrogen, oxygen and sulphur, can be by halo or to perhalogeno, or by Z N1Replace, n1 is 0 to 3, and each Z is selected from-CN separately ,-CO 2R 7,-C (O) R 7,-C (O) NR 7R 7,-NO 2,-OR 7,-SR 7,-NR 7R 7,-NR 7C (O) OR 7,-NRUC (O) R 7And the following carbon skeleton group of 24 carbon, can contain N, the heteroatoms of S and O also can be by halogen-replacement or polysubstituted, and substituting group is selected from-CN ,-CO 2R 7,-COR 7,-C (O) NR 7R 7,-OR 7,-SR 7,-NO 2,-NR 7R 7,-NR 7C (O) R 7With-NR 7C (O) OR 7, R 7As previously mentioned.
In the general formula I, suitable heteroaryl B includes but not limited to that the aromatic nucleus or of 5-12 carbon atom is to the trinucleated loop systems, wherein at least one is an aromaticity, and wherein one or more intra-annular are one or more, and for example 1-4 carbon atom can be replaced by oxygen, nitrogen or sulphur atom.Each ring generally contains 3-7 atom.For example, B can be 2-or 3-furyl, 2-or 3-thienyl, 2-or 4-triazinyl, 1-, 2-or 3-pyrryl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-azoles base, 3-, the different azoles base of 4-or 5-, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or-4 pyridyl, 2-, 4-, 5-or 6-pyrimidyl, 1,2,3-triazole-1-,-4-or-the 5-base, 1,2,4-triazole-1-,-3-or-the 5-base, 1-or 5-tetrazyl, 1,2,3-diazole-4-or-the 5-base, 1,2,4-diazole-3-or-the 5-base, 1,3,4-thiadiazoles-2-or-the 5-base, 1,3,4-thiadiazoles-3-or-the 5-base, 1,2,3-thiadiazoles-4-or-the 5-base, 2-, 3-, 4-, 5-or 6-2H-sulfo-pyranyl, 2-, 3-or 4-4H-sulfo-pyranyl, 3-or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indyl, 1-, 2-, 4-or 5-benzimidazolyl-, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazoles base, 2-, 4-, 5-, 6-or 7-benzoxazolyl group, 3-, 4-, 5-, 6-or 7-benzisoxa azoles base, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazole base, 2-, 4-, 5-, 6-or 7-phendioxin, the 3-di azoly, 2-, 3-, 4-, 5-, 6-, 7-or 8 quinolyls, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 1-, 2-, 3-, 4-or 9-carbazyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridyl, or 2-, 4-, 5-, 6-, 7-or 8-quinazolyl, perhaps, the phenyl that can further be replaced, 2-or 3-thienyl, 1,3, the 4-thiadiazolyl group, the 3-pyrryl, the 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl etc.For example, B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl isophthalic acid, 2,4-thiadiazoles-2-base.
The moieties of groups such as suitable alkyl or alkoxyl group comprises methyl in this article, ethyl, and propyl group, butyl etc. comprise all straight chains and branched chain isomer, sec.-propyl for example, isobutyl-, sec-butyl, the tertiary butyl etc.
Suitable no heteroatoms aryl is phenyl and 1-and 2-naphthyl for example.
" cycloalkyl " refers to ring structure with or without alkyl substituent, for example " C at this 4Cycloalkyl " comprise methyl substituted cyclopropyl and cyclobutyl." cycloalkyl " also comprises the saturated heterocyclic group.
Suitable halogen comprises F, Cl, and Br and/or I if alkyl is replaced by halogen, then may be extremely full replacements (that is, all H atoms are replaced by halogen atom) of a replacement, also may be the not mixed replacements of same halogens.
The invention still further relates to the compound shown in the general formula I.
The invention still further relates to the pharmaceutically salt of approval of general formula I.The suitable pharmaceutically salt of approval is that those skilled in the art are familiar with, comprise mineral acid and organic acid subsalt, described acid is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol for example.In addition, pharmaceutically Ren Ke salt also comprises the acid salt of mineral alkali, for example contains alkali metal cation (Li for example +, Na +Or K +), alkaline earth metal cation (Mg for example + 2, Ca + 2Or Ba + 2) and the salt of ammonium cation, and the acid salt of organic bases, described organic bases comprises that described quaternary ammonium cation is from triethylamine, N by the ammonium and the quaternary ammonium cation of aliphatics or aromatic series replacement, N-diethylamide, N, N-dicyclohexylamine, Methionin, pyridine, N, N-dimethyl aminopyridine (DMAP), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU).
Many compound of Formula I have unsymmetrical carbon, thereby can exist with racemization or optical activity form.The method of enantiomorph and non-enantiomer mixture is that those skilled in the art are familiar with.The present invention includes the compound of Formula I any raf of having kinase inhibiting activity, isolating racemization or optical activity form.
General preparation method
Compound of Formula I can be prepared from by marketable material with known chemical reaction or process.But, following general preparation method still is provided, and partly provides detailed embodiment, to help the synthetic described inhibitor of those skilled in the art at the embodiment that describes working example.
Produce substituted aniline (March, Advanced Organic Chemistry, 3 with standard method RdVersion; JohnWiley:New York (1985) .Larock, Comprehensive Organic Transformations; VCHPublishders:New York (1989)).Shown in scheme I, according to a conventional method, with metal catalysts such as Ni, Pd or Pt, with H 2Or hydride transfer agent reduction nitro-aromatics such as formate, cyclohexadiene or hydroborate come synthesizing aryl aniline (Rylander.Hydrogenation Methods; Academic Press:London, UK (1985)).Also can use for example LiAlH 4Strong hydride ion source (Seyden-Penne.Reductions by theAlumono-and Borohydrides in Organic Synthesis; VCH Publishers:NewYork (1991)), or with for example zero-valent metals such as Fe, Sn or Ca, usually in acidic medium, directly reduce nitro-aromatic.Method (March.Advanced Organic Chemistry, 3 that many synthesizing nitryl aromatic hydrocarbons are arranged RdVersion; John Wiley:New York (1985) .Larock, Comprehensive Organic Transformations; VCH Publishders:New York (1989)).
Scheme I: nitro-aromatic is reduced into aryl aniline
According to a conventional method, use HNO 3Or other NO 2+The nitrated formation nitro-aromatic of fragrant members of a clan electricity in source.
Before the reduction, can further modify nitro-aromatic.Therefore, the nitro-aromatic that is replaced by potential leavings group (for example F, Cl, Br etc.) can with nucleophilic reagent generation substitution reactions such as thiolate (for example scheme II) or phenates.Nitro-aromatic also can carry out Ullman type linked reaction (scheme II).
Figure C0080268500131
Scheme II: the nucleophilic aromatic family that carries out with nitro-aromatic replaces
Nitro-aromatic can also carry out the crosslinked linked reaction by the transition metal mediation.For example, nitro-aromatic electrophilic reagent and aryl boric acid (Suzuki reactions such as the bromide of nitro-aromatic, iodide or trifluoromethanesulfonic acid thing, for example hereinafter), palladium mediated crosslinked linked reaction takes place in tin aryl SnAr2 (Stille reaction) or aryl zinc aryl nucleophilic reagents such as (Negishi reactions), obtains biaryl (5).
Nitro-aromatic or aniline can be handled by chlorsulfonic acid and be transformed into corresponding aryl sulfonyl chloride (7).Then, SULPHURYL CHLORIDE and fluorine source, for example KF reacts generation sulfonic acid fluoride (8).Sulfonic acid fluoride (8) and trimethyl silyl trifluoromethane are in the fluorine source, and for example there is reaction generation corresponding trifluoromethyl sulfone (9) down in halide atom acid three (dimethylamino) sulfonium (TASF).Perhaps, available for example zinc amalgam is reduced into aryl mercaptan (10) with SULPHURYL CHLORIDE 7.Mercaptan 10 and CHCl 2F reacts in the presence of alkali and generates trifluoromethyl mercaptan (11), and the latter can be with comprising CrO 3-diacetyl oxide changes into sulfone (12) (Sedova etc., Zh.Org.Khim.1970,6, (568) .) in interior multiple oxidizer oxygen.
Scheme III: the method for selected synthetic fluoro aryl sulfone
As scheme shown in the IV, aryl isocyanate (14) forms unsymmetrical urea with arylamines (13) reaction.The assorted aromatic ester of isocyanic acid can be by for example superpalite (two phosgene) of arylamine and phosgene or its counterpart of mixing, and (trichloromethyl carbonate (triphosgene) or N, N '-carbonyl dimidazoles (CDI) reaction is synthetic for carbonic acid two.This isocyanic ester can also be by heterocyclic carboxylic acid derivatives, and for example ester, acyl halide or acid anhydrides are reset generation by Curtius.Therefore, acid derivative 16 and the reaction of nitrine source are reset then, generate isocyanic ester.Corresponding carboxylic acid (17) can also be carried out Curtius with diphenylphosphine acid azide (DPPA) or similar reagents and be reset.
Scheme IV: the method for selected formation unsymmetrical urea
At last, the method be familiar with of available those skilled in the art is further handled the urea of gained.
The present invention also comprises the pharmaceutical composition that comprises the carrier of approving on compound of Formula I and the physiology.
The compounds of this invention can be by injection, suction or sprinkling or rectum, and per os, skin, parenteral give, or gives with the unit formulation formulation." injection gives " comprises vein, intramuscular, subcutaneous and parenteral injection, and uses infusion techn.Percutaneous drug delivery comprises external application or transdermal administration.One or more compounds can with one or more non-toxic carriers of pharmaceutically approving, and other activeconstituentss that depend on the needs coexistence.
Oral composition can be made the known appropriate method preparation in field according to any pharmaceutical composition.In order to improve the preparation mouthfeel, described composition can contain one or more following reagent: thinner, sweeting agent, spices, tinting material and sanitas.Tablet contains activeconstituents, and they mix with the non-toxic excipients of pharmaceutically approving, be fit to tablet manufacturing.Described vehicle is inert diluent for example, lime carbonate for example, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tamanori, for example Magnesium Stearate, stearic acid or talcum powder.Tablet can not have dressing, can wrap up with known technology yet, to postpone its disintegration and absorption in gi tract, provides secular continuous action.For example, can adopt time-delay material such as glyceryl monostearate or distearin.Described compound also can be made solid, releases form soon.
Oral preparations can also be a hard gelatin capsule, activeconstituents wherein mixes mutually with for example inert solid diluent such as lime carbonate, calcium phosphate or kaolin, or soft gelatin capsule, activeconstituents wherein is with water or for example peanut oil, whiteruss or olive wet goods oil mix.
Also can use and contain active substance and the suitable waterborne suspension of making the mixed with excipients of waterborne suspension.Described vehicle is a suspension agent, Xylo-Mucine for example, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, Polyvinylpyrolidone (PVP), tragakanta and Sudan Gum-arabic; Dispersion agent or wetting agent can be natural phospholipids, Yelkin TTS for example, or the condensation product of oxyethane and lipid acid, polyoxyethylene stearic acid ester for example, or the condensation product of oxyethane and long chain aliphatic alcohol, for example 17 oxygen ethene cetyl alcohols, or oxyethane and the condensation product of lipid acid with partial ester that hexitol becomes, for example single oleic acid polyoxyethylene sorbitan ester.Waterborne suspension also can contain one or more sanitass, for example ethyl p-hydroxybenzoate or n-propyl, one or more tinting materials, one or more spices and one or more sweeting agents, for example sucrose or asccharin.
Become in the dispersed powders or particle of waterborne suspension but be fit to add water, activeconstituents and dispersion agent or wetting agent, suspension agent and one or more sanitass mix.Suitable dispersion agent or wetting agent and suspension agent can mentioned abovely be example.Can also contain other vehicle, for example sweeting agent, spices and tinting material.
The form of compound can also be non-aqueous liquid preparation, oily suspensions for example, and this can be by being suspended in activeconstituents peanut oil, sweet oil, sesame oil or peanut wet goods vegetables oil or such as preparing in the mineral oil such as whiteruss.This oily suspensions can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.In order to improve mouthfeel, can add above-mentioned sweeting agent and spices.Described composition can be guaranteed the quality such as antioxidants such as xitix by adding.
The form of pharmaceutical composition of the present invention can also be an O/w emulsion.Oil phase can be such as sweet oil or peanut wet goods vegetables oil or mineral oil such as liquid beeswax for example, or their mixture.Suitable emulsifying agent can be natural gums such as tragakanta and Sudan Gum-arabic, or natural phospholipid, for example soybean lecithin or Yelkin TTS; The partial ester that lipid acid and dewatering hexitol form, for example but the oleic acid Isosorbide Dinitrate; The condensation product of described partial ester and oxyethane, for example single oleic acid Sorbitan ethoxylate.Described emulsion also can contain sweeting agent and spices.
Sweeting agent obtain syrup and elixirs such as also available for example glycerine, polypropylene glycol, sorbyl alcohol or sucrose.This class preparation also can contain demulcen, sanitas and spices and tinting material.
Described compound can also suppository form be used for rectum or vagina administration.This based composition can be solid-state under the described vehicle normal temperature by medicine and suitable non-stimulated mixed with excipients are prepared, but is liquid in rectal temperature or vagina temperature, and therefore, its can melt and discharge medicine at rectum or intravaginal.Such material comprises theobroma oil and polyoxyethylene glycol.
All use in the treatment plan of compound of Formula I in this article, and every day, oral dosage was good with the 0.01-200mg/kg body weight.Injection comprises vein, intramuscular, subcutaneous and parenteral injection and uses input technology, dosage every day be good with the 0.01-200mg/kg body weight.The per daily dose of rectal administration is good with the 0.01-200mg/kg body weight.External application every day dosage with every day 1 to 4 time, it is good not having each 0.1-200mg.Dosage every day that sucks is good with the 0.01-10mg/kg body weight.
Those skilled in the art will find out that concrete administering mode depends on multiple factor, and these are all considered often in conventional administration.Yet, it can also be seen that the concrete dosage of particular patient depends on the multiple factors such as severity of the activity, patient age, weight in patients, patient's general health, patient's sex, patient's diet, administration time, route of administration, the velocity of discharge, drug regimen and the current feelings of curing the disease that comprise used particular compound.Those skilled in the art also will find, the optimal treatment formula, and the therapeutic modality in promptly certain fate and the day administration number of times of compound of Formula I or its salt of pharmaceutically approving, those skilled in the art can determine with the conventional treatment test.
Obviously, concrete patient's physical record level depends on multiple factor, comprises the severity of activity, patient age, weight in patients, patient's general health, patient's sex, patient's diet, administration time, route of administration, the velocity of discharge, drug regimen and the current feelings of curing the disease of used particular compound.
One's own department or unit comprises the provisional application 60/115,877 and the non-provisional application 09/257,266 on February 25th, 1999 that on January 13rd, 1999 submitted to comprehensively with reference to all patent applications, patent and the publication quoted in the literary composition.
The compounds of this invention can be prepared by for example hereinafter described general method by known compound (or with the raw material that can be made by known compound as initiator).Can hereinafter described common method measure the kinase whose activity of the known raf of each compound.Following examples for illustrative purposes only, and are and non-limiting.
Embodiment
Unless otherwise mentioned, respond all in the glassware of flame drying or oven drying, carry out at dry argon gas or drying nitrogen direct draught, and carry out magnetic agitation.Sensitive liquid or solution shift with syringe or conduit, and introduce reaction vessel through rubber septum.Unless otherwise mentioned, " concentrating under reduced pressure " refers to concentrate at about 15mmHg with the Buchi rotatory evaporator.Unless otherwise mentioned, " under the high vacuum " expression 0.4-1.0mmHg vacuum tightness.
All temperature at this report all are not corrected ℃.Unless otherwise mentioned, all umbers and per-cent are all calculated by weight.
Directly the reagent of commodity in use level no longer is further purified.N-cyclohexyl-N '-(methylated polystyrene) carbodiimide is available from Calbiochem-Novabiochem Corp..3-tertiary butyl aniline; the 5-tertiary butyl-2-anisidine; 4-bromo-3-(trifluoromethyl) aniline; 4-chloro-3-(trifluoromethyl) aniline, 2-methoxyl group-5-(trifluoromethyl) aniline, the 4-tertiary butyl-2-N-methyl-p-nitroaniline; 3-amino-beta naphthal; 4-isocyanato ethyl benzoate, N-ethanoyl-4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline and isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester are enough bought, and are not further purified.3-amino-2 methoxy quinoline (E, Cho etc., WO98/00402; A.Cordi etc., EP542,609; IBID biological chemistry medical science and chemistry 3,1995,129), 4-(3-carbamyl phenoxyl)-1-oil of mirbane (K, Ikawa, pharmaceutical journal 79,1959,760; Chemical abstracts 53,1959,12761b), isocyanic acid 3-tertiary butyl phenyl ester (O.Rohr etc., DE2436108), isocyanic acid and 2-methoxyl group-5-(trifluoromethyl) phenyl ester (K, Inukai etc., JP42,025,067; IBID Kogyo The Chemicals 70,1967,491) synthetic method all is known.
Carry out thin-layer chromatography (TLC) with Whatman_ precoating glass lined silica gel 60A F-254 μ m plate.Observe thin plate with one or more following technology: (a) ultra-violet light-emitting, (b) be exposed to iodine steam, (c) thin plate is immersed in 10% phosphomolybdic acid ethanol solution, heating then, (d) thin plate is immersed in the cerous sulfate solution, heats then, and/or (e) thin plate is immersed in 2, in the acid ethanol solution of 4-dinitrophenyl hydrazine, heating then.Carry out column chromatography (flash chromatography) with 230-400 purpose EM Science_ silica gel.
Measure fusing point with Thomas-Hoover fusing point instrument or the automatic fusing point instrument of Mettler FP66, do not proofread and correct.Obtain fourier (Fourier) transform infrared spectroscopy with Mattson 4020 Galaxy Series spectrophotometers.With General Electric GN-Omega 300 (300MHz) spectrometer, with Me 4Si (d0.00) or remaining protonated solvent (CHCl 3, δ 7.26; MeOH, δ 3.30; DMSO, δ 2.49) as standard, measure proton (H 1) nucleus magnetic resonance (NMR) spectrum.With General Electric GN-Omega 300 (75MHz) spectrometer, with solvent (CDCl 3, δ 77.0; MeOD-d 3δ 49.0; MeOD-d 3δ 39.5) as standard, mensuration carbon ( 13C) NMR spectrum.With electron bombardment (EI) mass spectrum or fast atom bombardment MS (FAB), measure low resolution mass spectrum (MS) and high resolution mass spec (HRMS).Impact mass spectrum (EI-MS) with Hewlett Packard 5989A mass spectrograph electron gain, this device is furnished with a Vaccumetics desorb chemical ioni zation probe and is used to introduce sample.Ion source is maintained at 250 ℃.Use the 70eV electronic energy, 300 μ A catch electric current and carry out the electron bombardment ionization.With the upgrading stencilling of Kratos Concept 1-H spectrometer acquisition fast atom bombardment, i.e. liquid-cerium secondary ion mass spectrometry (SIMS) (FAB-MS).With Hewlett Packard MS-Engine (5989A), with methane or ammonia as reactant gases (1 * 10 -4To 2.5 * 10 -4Torr), obtain chemical ioni zation mass spectrum (CI-MS).(Vaccumetics Inc.) rose to 1.5 amperes from 0 ampere in 10 seconds, be retained to all micro-examples all disappear (about 1-2 minute) at 10 amperes directly to insert desorption ionization (DCI) probe.2 seconds/spoke, carry out scanning of the mass spectrum from 120-800amu.With being furnished with four-stage pump, variable-wavelenght detector, HewlettPackard 1100 HPLC of C-18 post and have the Ionized Finnigan LCQ of electrospray ion-catching mass spectrometer and obtain HPLC-electrospray mass spectrum (HPLC ES-MS).According to the amount of ions in the ion source, scan mass spectrum from 120-800amu with the corresponding variable ion time.With being furnished with HP-1 methyl silicagel column (0.33mM coating; Hewlett Packard 5890 chromatographs of 25m * 0.2mm) and Hewlett Packard 5971 mass selective detectors (70eV ionization energy) obtain meteorological chromatography-ion and select mass spectrum (GC-MS).By RoberstonMicrolit Labs, Madison NJ carries out ultimate analysis.
The NMR of all compounds, LRMS shows as consistent with the structure that requires with ultimate analysis or HRMS.
Write a Chinese character in simplified form with acronym and tabulate
AcOH acetate
Anh is anhydrous
The atm normal atmosphere
The BOC tert-butoxycarbonyl
CDI 1,1 '-carbonyl dimidazoles
Conc concentrates, and is dense
D days
Dec decomposes
The DMAC N,N-dimethylacetamide
DMPU 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2 (1H)-pyrimidone
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide (DMSO)
DPPA diphenylphosphine acid azide
EDCI 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide
The EtOAc ethyl acetate
EtOH ethanol (100%)
Et 2The O ether
Et 3The N triethylamine
H hour
The HOBT I-hydroxybenzotriazole
M-CPBA 3-chloro peroxide acid
MeOH methyl alcohol
Pet. ether sherwood oil (boiling point is between 30-60 ℃)
Temp. temperature
The THF tetrahydrofuran (THF)
The TFA trifluoroacetic acid
The Tf trifluoromethane sulfonyl group
A. the general method of synthesizing substituted amine
A1. the general method of synthesizing aryl amine: form ether earlier, saponification ester then, Curtius resets, and carbamate goes protection.Synthesizing of 2-amino-3-methoxynaphthalene
Figure C0080268500201
The 1st step: 3-methoxyl group-2-2-methyl naphthoate
3-hydroxyl-2-2-methyl naphthoate (10.1g, 50.1mmol) and K 2CO 3(7.96g 57.6mmol) stirred 15 minutes under the slurry room temperature that is become in DMF (200ml), then with methyl-iodide (3.43ml, 55.1mmol) reaction.Stir under the mixture room temperature and spend the night, add entry (200ml) then.Mixture (2 * 200ml) with EtOAc extraction gained.Merge organic layer, with saturated NaCl solution washing (100ml), dry (MgSO 4), concentrating under reduced pressure (about 0.4mmHg spends the night) obtains amber oily 3-methoxyl group-2-2-methyl naphthoate (10.30g): 1HNMR (DMSO-d 6) δ 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09Hz, 1H), 7.44 (s, 1H), 7.53 (app t, J=8.09Hz, 1H), 7.84 (d, J=8.09Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
Figure C0080268500202
The 2nd step: 3-methoxyl group-2-naphthoic acid
3-methoxyl group-2-2-methyl naphthoate (6.28g, 29.10mmol) and water (10ml) under the solution room temperature of MeOH (100ml), stir, and with 1N NaOH solution (33.4ml, 33.4mmol) reaction.Mixture heating up was refluxed 3 hours, be cooled to room temperature, with 10% citric acid solution acidifying.Mixture (2 * 100ml) with EtOAc extraction gained.Merge organic layer, with saturated NaCl solution washing, dry (MgSO 4), concentrating under reduced pressure.Develop residue with hexane, with hexane wash for several times, obtain 3-methoxyl group-2-naphthoic acid white solid (5.40g, 92%) then: 1H NMR (DMSO-d 6) δ 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.38 (d, J=8.09Hz, 1H), 7.91 (d, J=8.09Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).
Figure C0080268500211
Step 3:2-(N-(carbobenzoxy) amino-3-methoxynaphthalene
3-methoxyl group-2-naphthoic acid (3.36g, 16.6mmol) and Et 3(2.59ml 18.6mmol) to stir 15 minutes under the solution room temperature of dry toluene (70ml) preparation, splashes into DPPA (5.12g, toluene 18.6mmol) (10ml) solution to N then.The gained mixture was 80 ℃ of heating 2 hours.After being cooled to room temperature, with syringe inject benzylalcohol (2.06ml, 20mmol).Then with 80 ℃ of incubated overnight of mixture.The gained mixture is cooled to room temperature, with 10% citric acid solution termination reaction, with EtOAc extraction (2 * 100ml).Merge organic layer, with saturated NaCl solution washing, dry (MgSO 4), concentrating under reduced pressure.With column chromatography (14%EtOAc/86% hexane) purifying residue, obtain 2-(N-(carbobenzoxy) amine-3-methoxynaphthalene (5.1g, 100%): 1H NMR (DMSO-d 6) δ 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, 1H).
Step 4:2-amino-3-methoxynaphthalene
2-(N-(carbobenzoxy) amino-3-methoxynaphthalene (5.0g, 16.3mmol) with slurry room temperature that 10%Pd/C (0.5g) is become in EtOAc (70ml) under at H 2Spend the night under the atmosphere (balloon).Filter the gained mixture with Celite_, concentrating under reduced pressure gets 2-amino-3-methoxynaphthalene baby pink powder (2.40g, 85%): 1HNMR (DMSO-d 6) δ 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, J=8.0Hz, 1H), 7.56 (d, J=8.0Hz, 1H); EI-MS m/z 173 (M +).
A2. omega-amino-formyl radical aniline is synthetic: form the carbamyl yl pyridines earlier, then with the coupling of arylamines nucleophilic.Synthesizing of 4-(2-N-methylamino formyl radical-4-pyridyl oxygen) aniline
Step 1a: by the synthetic 4-chloro-N-methyl of Menisci reaction-2-pyridine carboxamide
Attention: this is a high risk, and the possible reaction of blast is arranged.N-methylformamide (250ml) solution of 4-chloropyridine (10.0g) at room temperature limit stirs just to wherein adding dense H 2SO 4(3.55ml), produce heat release.In this mixture, add H 2O 2(aqueous solution of 30wt% 17ml), adds FeSO then 47H 2O (0.56g), heat release once more.Lucifuge stirred 1 hour under the gained mixture room temperature, slowly rose to 45 ℃ with 4 hours then.After bubbling stops, be reflected at 60 ℃ and carried out 16 hours.The muddy brown solution of water (700ml) dilution gained adds 10%NaOH solution (250ml) then.With EtOAc extraction gained mixture (3 * 500ml).Organic layer use respectively saturated NaCl solution washing (3 * 150ml), merge washing lotion, dry (MgSO 4), by means of the EtOAc filtered through silica gel.The gained brown oil is with column chromatography (the 50%EtOAc/50% hexane is to the gradient of 80%EtOAc/20% hexane) purifying residue.The gained residue obtains 4-chloro-N-methyl-2-pyridine carboxamide at 0 ℃ of recrystallization after 72 hours: 1H NMR (CDCl 3) δ 3.04 (d, J=5.1Hz, 3H), 7.43 (dd, J=5.4,2.4Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1Hz, 1H); CI-MS m/z 171 ((M+H) +).
Step 1b: the hydrochloride that forms 4-chloropyridine-2-carbonyl chloride by pyridine carboxylic acid
Between 40 ℃-50 ℃, DMF (6.0ml) is slowly added SOCl 2(180ml).Solution stirred 10 minutes in this temperature range, in 30 minutes, add then in batches pyridine carboxylic acid (60.0g, 487mmol).Gained solution (acutely discharged SO in 16 hours 72 ℃ of heating 2), produce the yellow solid precipitation.The gained mixture is cooled to room temperature,, is concentrated into 200ml with toluene (500ml) dilution.Adding toluene/spissated process more than inciting somebody to action repeats 2 times.Filter gained near the exsiccant residue, (2 * 200ml) washings, drying is 4 hours under the high vacuum, obtains the hydrochloride of 4-chloropyridine-2-carbonyl chloride, is Huang-orange solids (92.0g, 89%) with toluene for solid.
Synthesizing of step 2:4-chloropyridine-2-carboxylate methyl ester hydrochloride
Between 40 ℃-48 ℃, DMF (10.0ml) is slowly added SOCl 2(300ml).Solution stirred 10 minutes in this temperature range, then with added in 30 minutes pyridine carboxylic acid (100g, 812mmol).Gained solution (acutely discharged SO in 16 hours 72 ℃ of heating 2), produce the yellow solid precipitation.The gained mixture is cooled to room temperature,, is concentrated into 200ml with toluene (500ml) dilution.Adding toluene/spissated process more than inciting somebody to action repeats 2 times.Filter gained near the exsiccant residue, solid washs with toluene (50ml), and high vacuum dry 4 hours down obtains 4-chloropyridine-2-carboxyl acyl chloride hydrochloride, is beige solid (27.2g, 16%).This material is temporary.
The filtrate of redness is added MeOH (200ml), and control speed keeps internal temperature to be lower than 55 ℃.Stirred 45 minutes under the room temperature, be cooled to 5 ℃, drip Et 2O (200ml).Filter the gained solid, use Et 2O (200ml) washing, 35 ℃ of drying under reduced pressure get 4-chloropyridine-2-carboxylate methyl ester hydrochloride white solid (110g, 65%): mp.108-112 ℃; 1H NMR (DMSO-d 6) δ 3.88 (s, 3H), 7.82 (dd, J=5.5,2.2Hz, 1H); 8.08 (d, J=2.2Hz, 1H); 8.68 (d, J=5.5Hz, 1H); 10.68 (br s, 1H); HPLC ES-MS m/z172 ((M+H) +).
Step 3a: by the synthetic 4-chloro-N-methyl of 4-chloropyridine-2-carboxylate methyl ester-2-pyridine carboxamide
(control speed keeps internal temperature to be lower than 5 ℃ for 89.0g, the methylamine THF solution (1L) of adding 2.0M in 0 ℃ of MeOH (75ml) suspension 428mmol) to 4-chloropyridine-2-carboxylate methyl ester hydrochloride.The gained mixture was placed 5 hours at 3 ℃, then concentrating under reduced pressure.The gained solid suspension in EtOAc (1L), is filtered.Filtrate is washed with saturated NaCl solution (500ml), dry (Na 2SO 4), concentrating under reduced pressure gets 4-chloro-N-methyl-2-pyridine carboxamide yellow crystals (71.2g, 97%): mp.41-43 ℃; 1H NMR (DMSO-d 6) δ 2.81 (s, 3H), 7.74 (dd, J=5.1,2.2Hz, 1H); 8.00 (d, J=2.2Hz, 1H); 8.61 (d, J=5.5Hz, 1H); 8.85 (br s, 1H); CS-MS m/z 171 ((M+H) +).
Step 3b: by the synthetic 4-chloro-N-methyl of 4-chloropyridine-2-carbonyl chloride-2-pyridine carboxamide
At 0 ℃, (7.0g 32.95mmol) adds methylamine THF (100ml) solution and MeOH (20ml) mixture of 2.0M in batches with 4-chloropyridine-2-carbonyl chloride hydrochloride.The gained mixture was placed 4 hours at 3 ℃, then concentrating under reduced pressure.The nearly drying solid of gained is suspended in EtOAc (100ml), filters.Filtrate is with saturated NaCl solution (2 * 100ml) washings, dry (Na 2SO 4), concentrating under reduced pressure, 4-chloro-N-methyl-2-pyridine carboxamide yellow crystals (4.95g, 88%): mp.37-40 ℃;
Figure C0080268500241
Step 4: synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline
(9.60g, (10.29g 91.7mmol), stirred 2 hours under the gained reddish-brown mixture room temperature to add potassium tert.-butoxide in dry DMF 88.0mmol) (150ml) solution to the 4-amino-phenol.To wherein add 4-chloro-N-methyl-2-pyridine carboxamide (15.0g, 87.9mmol) and K 2CO 3(6.50g, 47.0mmol), then 80 ℃ of heating 8 hours.Mixture is cooled to room temperature, is distributed between EtOAc (500ml) and the saturated NaCl (500ml).Return the collection water with EtOAc (300ml).Merge organic layer, with saturated NaCl solution (4 * 1000ml) washings, dry (Na 2SO 4), concentrating under reduced pressure.The gained solid is 35 ℃ of drying under reduced pressure 3 hours, 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline light brown solid (17.9g, 84%): 1H NMR (DMSO-d 6) δ 2.77 (d, J=4.8Hz, 3H), 5.17 (br s, 2H), 6.64,6.86 (AA ' BB ', four peaks, J=8.4Hz, 4H); 7.06 (dd, J=5.5,2.5Hz, 1H); 7.33 (d, J=2.5Hz, 1H); 8.44 (d, J=5.5Hz, 1H); 8.73 (br d, 1H); HPLCES-MS m/z 244 ((M+H) +).
A3: the general method of synthetic aniline: the addition reaction of nucleophilic aromatic family, nitro-aromatic reduction then.5-(4-amino-benzene oxygen) isoindole-1,3-diketone synthetic
Figure C0080268500242
Step 1:5-hydroxyl isoindole-1,3-diketone synthetic
To volatile salt (5.28g, 54.9mmol) with the mixture of dense AcOH (25ml) in slowly add the 4-hydroxyl phthalic (5.0g, 27.45mmol).The gained mixture heated 45 minutes at 120 ℃, the clarification that will form then, and the glassy yellow mixture was 160 ℃ of heating 2 hours.The gained mixture is incubated in 160 ℃, is concentrated into about 15ml, be cooled to room temperature then, regulate pH to 10 with 1N NaOH solution.This mixture is cooled to 0 ℃, slowly is acidified to pH5 with 1N HCl.Filter and collect the precipitation that forms, drying under reduced pressure gets 5-hydroxyl isoindole-1,3-diketone buff powder (3.24g, 72%): 1H NMR (DMSO-d 6) δ 7.00-7.03 (m, 2H), 7.55 (d, J=9.3Hz, 1H).
Figure C0080268500251
Step 2:5-(4-nitrophenoxy) isoindole-1,3-diketone synthetic
To NaH (1.1g, Dropwise 5-hydroxyl isoindole-1 while stirring in 0 ℃ of slurry of DMF 44.9mmol) (40ml), 3-diketone (3.2g, DMF 19.6mmol) (40ml) solution.Allow this bright orange green mixture return to room temperature, stirred 1 hour, then with syringe divide 3-4 to criticize to add 1-fluoro-4-oil of mirbane (2.67g, 18.7mmol).The mixture that forms is cooled to room temperature then 70 ℃ of heated overnight, slowly adds entry (150ml) dilution, and (2 * 100ml) extract with EtOAc.Merge organic layer, dry (MgSO 4), concentrating under reduced pressure obtains 5-(4-nitrophenoxy) isoindole-1,3-diketone yellow solid (3.3g, 62%): TLC (30%EtOA/70% hexane) R f0.28; 1HNMR (DMSO-d 6) δ 7.32 (d, J=12Hz, 2H), 7.52-7.57 (m, 2H), 7.89 (d, J=7.8Hz, 1H), 8.29 (d, J=9Hz, 2H), 11.43 (br s, 1H); CI-MS m/z 285 ((M+H) +, 100%).
Step 3:5-(4-amino-benzene oxygen) isoindole-1,3-diketone synthetic
Stir 5-(4-nitrophenoxy) isoindole-1 under the argon gas stream, the 3-diketone (0.6g, the 2.11mmol) solution that in dense AcOH (12ml) and water (0.1ml), is become, slowly add simultaneously iron powder (0.59g, 55.9mmol).Mixture at room temperature stirred 72 hours, and water (25ml) dilution then is with EtOAc (3 * 50ml) extractions.Merge organic layer, dry (MgSO 4), concentrating under reduced pressure obtains 5-(4-amino-benzene oxygen) isoindole-1,3-diketone brown solid (0.4g, 75%): TLC (50%EtOA/50% hexane) R f0.27; 1H NMR (DMSO-d 6) δ 5.14 (br, s, 2H), 6.62 (d, J=8.7Hz, 2H), 6.84 (d, J=8.7Hz, 2H), 7.03 (d, J=2.1Hz, 1H), 7.23 (dd, 1H), 7.75 (d, J=8.4Hz, 1H), 11.02 (s, 1H); HPLC EI-MS m/z 255 ((M+H) +, 100%).
A4: the general method of synthetic pyrryl aniline.Synthesizing of the 5-tertiary butyl-2-(2, the 5-dimethyl pyrrole) aniline
Step 1:1-(the 4-tertiary butyl-2-nitrophenyl)-2,5-dimethyl pyrrole synthetic
Stir 2-nitro-4-tertiary butyl aniline (0.5g, hexanaphthene 2.57mmol) (10ml) solution, simultaneously with syringe to wherein add AcOH (0.1ml) and acetonyl-acetone (0.299g, 2.63mmol).Reaction mixture was 120 ℃ of heating 72 hours, and azeotropic is removed volatile component.Reaction mixture is cooled to room temperature, uses CH 2Cl 2(10ml) 1N HCl (15ml) is used in dilution successively, 1N NaOH (15ml) and saturated NaCl (15ml) washing, dry ((MgSO 4), concentrating under reduced pressure.Gained orange-brown solid is through column chromatography (60g SiO 2The 6%EtOAc/94% hexane is to the 25%EtOAc/75% hexane gradient), get 1-(the 4-tertiary butyl-2-nitrophenyl)-2,5-dimethyl pyrrole orange-brown solid (0.34g, 49%): TLC (15%EtOA/85% hexane) R f0.67; 1H NMR (CDCl 3) d1.34 (s, 9H), 1.89 (s, 6H), 5.84 (s, 2H), 7.19-7.24 (m, 1H), 7.62 (dd, 1H), 7.88 (d, J=2.4Hz, 1H); CI-MS m/z 273 ((M+H) +, 50%).
Figure C0080268500262
Synthesizing of the step 2:5-tertiary butyl-2-(2, the 5-dimethyl pyrrole) aniline
1-(the 4-tertiary butyl-2-nitrophenyl)-2, (0.341g, 1.25mmol) slurry of 10%Pd/C (0.056g) and EtOAc (50ml) formation is at H for the 5-dimethyl pyrrole 2Stirred 72 hours under the atmosphere, filter with Celite_ then.Filtrate gets the 5-tertiary butyl-2-(2, the 5-dimethyl pyrrole) aniline yellow solids (0.30g, 99%): TLC (10%EtOA/90% hexane) R through concentrating under reduced pressure f0.43; 1H NMR (CDCl 3) δ 1.28 (s, 9H), 1.87-1.91 (m, 8H), 5.85 (brs, 2H), 6.73-6.96 (m, 3H), 7.28 (br s, 1H).
A5: replace the general method that synthesizes aniline by aniline by nucleophilic aromatic.Synthesizing of 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-aminotoluene HCl salt.
Figure C0080268500271
(5.45g, (10.86g 96.77mmol), stirs this black mixture under the room temperature, reach room temperature until beaker to add potassium tert.-butoxide in anhydrous dimethyl yl acetamide (75ml) solution 44.25mmol) to 4-amino-3-methylphenol.To wherein adding 4-chloro-N-methyl-2-pyridine carboxamide (step 3b of method A2; 7.52g 44.2mmol), 110 ℃ were heated 8 hours.Mixture is cooled to room temperature, water (75ml) dilution.With EtOAc (5 * 100ml) extraction organic layers.Merge organic layer, with saturated NaCl solution (200ml) washing, dry ((MgSO 4), concentrating under reduced pressure.In the dark oil thing that stays, add Et 2O (50ml) carries out ultrasonication.This solution then with the HCl (Et of 1M 2O solution; 100ml) reaction was stirred 5 minutes under the room temperature.Filter out formation dark pink solid (7.04g 24.1mmol), is stored in before the use in 0 ℃ the oxygen-free environment: 1H NMR (DMSO-d 6) δ 2.41 (s, 3H), 2.78 (d, J=4.4Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5,2.6Hz, 1H), 7.23 (dd, J=5.5,2.6Hz, 1H), 7.26 (d, J=2.6Hz, 1H), 7.55 (d, J=2.6Hz, 1H), 7.64 (d, J=8.8Hz, 1H), 8.55 (d, J=5.9Hz, 1H), 8.99 (q, J=4.8Hz, 1H).
A6: replace and remove to protect the general method for preparing aniline by hydroxyanilines by N-protected, nucleophilic aromatic.Synthesizing of 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline.
Figure C0080268500272
Synthesizing of step 1:3-chloro-4-(2,2,2-trifluoroacetyl group amino) phenol
(3.24g 58.00mmol) adds TFA (200ml) with iron while stirring.In this slurry, add 2-chloro-4-nitrophenols (10.0g, 58.0mmol) and trifluoroacetic anhydride (20ml).This grey slurry at room temperature stirred 6 days.Filter and remove iron powder, decompression concentrated solution.With the gray solid of gained water-soluble (20ml).In the gained yellow solution, add saturated NaHCO 3Solution (50ml).Remove the precipitation in the solution.In filtrate, slowly add the sodium hydrogen carbonate solution termination reaction, until seeing product and solution separating (determining) with a small-sized preparation test tube.With the EtOAc (yellow solution that 3 * 125ml) extractions are muddy slightly.Merge organic layer, with saturated NaCl solution (125ml) washing, dry ((MgSO 4), concentrating under reduced pressure. 1H NMR shows that the ratio of nitrophenols initiator and required product 3-chloro-4-(2,2,2-trifluoroacetyl group amino) phenol is 1: 1.Purifying is not directly used in later reaction with this crude product.
Step 2:4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloro-phenyl-(2,2, the 2-trifluoro) ethanamide
To rough 3-chloro-4-(2,2,2-trifluoroacetyl group amino) phenol (5.62g; 23.46mmol) anhydrous dimethyl yl acetamide (50ml) solution in add potassium tert.-butoxide (5.16g; 45.98mmol), stir this brown mixture under the room temperature, be cooled to room temperature until this flask.To wherein adding 4-chloro-N-methyl-2-pyridine carboxamide (step 3b of method A2; 1.99g 11.7mmol), heating is 4 days under 110 ℃ of argon atmosphers.Black mixture is cooled to room temperature, pours in the cold water (100ml).With EtOAc (3 * 75ml) extraction mixtures.Merge organic layer, concentrating under reduced pressure.The brown oil that stays by column chromatography (the 20%EtOAc/% sherwood oil is to the gradient of 40%EtOAc/% sherwood oil) purifying; obtain 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloro-phenyl-(2; 2, the 2-trifluoro) the ethanamide yellow solid (8.59g, 23.0mmol).
Synthesizing of step 3:4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline
(8.59g adds 1N NaOH solution (20ml) in anhydrous 4-dioxane (20ml) solution 23.0mmol) to rough 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloro-phenyl-(2,2, the 2-trifluoro) ethanamide.This brown solution was stirred 8 hours.In this solution, add EtOAc (40ml).With EtOAc (3 * 40ml) extract green organic layer, concentrate to remove solvent, obtain after leaving standstill the green oily matter of 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline (2.86g, 10.30mmol): 1H NMR (DMSO-d 6) δ 2.77 (d, J=4.8Hz, 3H), 5.51 (s, 2H), 6.60 (dd, J=8.5,2.6Hz, 1H), 6.76 (d, J=2.6Hz, 1H), 7.03 (d, J=8.5Hz, 1H), 7.07 (dd, J=5.5,2.6Hz, 1H), 7.27 (d, J=2.6Hz, 1H), 8.64 (d, J=5.5Hz, 1H), 8.75 (q, J=4.8Hz, 1H).
A7: the de-protected general method of acidylate aniline.Synthesizing of 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline
Figure C0080268500283
With 3-chloro-6-(N-ethanoyl)-4-(trifluoromethyl) phenylmethylether (4.00g, 6M HCl (24ml) suspension returning 14.95mmol) 1 hour.Allow the solution that forms be cooled to room temperature, during precipitation slightly.The mixture that water (20ml) dilution forms adds NaOH solid and saturated sodium bicarbonate solution then, is alkalescence until solution.Use CH 2Cl 2(3 * 50ml) extraction organic layers.Merge organic layer, dry (MgSO 4), through concentrating under reduced pressure get 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline brown oil (3.20g, 14.2mmol): 1H NMR (DMSO-d 6) δ 3.84 (s, 3H), 5.30 (s, 2H), 7.01 (s, 2H).
A8: the general method of synthetic ω-alkoxyl group-ω-carboxyl phenyl aniline.Synthesizing of 4-(3-(N-methylamino formyl radical)-4-methoxyl group phenoxy group) aniline.
Step 1:4-(3-methoxycarbonyl-4-methoxyl group phenoxy group)-1-oil of mirbane:
In the acetone soln of 4-(3-carboxyl-4-hydroxyphenoxy)-1-oil of mirbane (12mmol, according to method A13, step 1 is by 2, the 5-resorcylic acid makes), add K 2CO 3(5g) and methyl-sulfate (3.5ml).The mixture that forms refluxes and spends the night, and is cooled to room temperature then, filters with Celite_.The solution that concentrating under reduced pressure obtains is used SiO 2Absorb,, obtain 4-(3-methoxycarbonyl-4-methoxyl group phenoxy group)-1-oil of mirbane yellow powder (3g): mp.115-118 ℃ by column chromatography (50%EtOAc/50% hexane) purifying.
Figure C0080268500292
Step 2:4-(3-carboxyl-4-methoxyl group phenoxy group)-1-oil of mirbane:
4-(3-methoxycarbonyl-4-methoxyl group phenoxy group)-1-oil of mirbane (1.2g), KOH (0.33g) and water (5ml) form mixture in MeOH (45ml), and stirred overnight at room temperature refluxed 4 hours then.The mixture that forms is cooled to room temperature, concentrating under reduced pressure.With residue water-soluble (50ml), with 1N HCl solution furnishing acidity.Mixture with EtOAc (50ml) extraction formation.Dry (MgSO 4) organic layer, concentrating under reduced pressure gets 4-(3-carboxyl-4-methoxyl group phenoxy group)-1-oil of mirbane (1.04g)
Figure C0080268500301
Step 3:4-(3-(N-methylamino formyl radical)-4-methoxyl group phenoxy group)-1-oil of mirbane:
To 4-(3-carboxyl-4-methoxyl group phenoxy group)-1-oil of mirbane (0.50g, CH 1.75mmol) 2Cl 2Add SOCl in the solution in batches 2(0.64ml, 8.77mmol).The solution that forms was refluxed 18 hours, be cooled to room temperature then, concentrating under reduced pressure.The yellow solid that forms is dissolved in CH 2Cl 2(3ml), add methylamine solution in the solution that forms (the THF solution of 2.0M, 3.5ml 7.02mmol) (note: have gas to produce), stir 4 hours under the room temperature in batches.In the mixture that forms, add 1N NaOH solution, use CH then 2Cl 2(25ml) extraction.Organic layer drying (Na 2SO 4) behind the concentrating under reduced pressure 4-(3-(N-methylamino formyl radical)-4-methoxyl group phenoxy group)-1-oil of mirbane (0.50g, 95%).
Step 4:4-(3-(N-methylamino formyl radical)-4-methoxyl group phenoxy group) aniline
4-(3-(N-methylamino formyl radical)-4-methoxyl group phenoxy group)-1-oil of mirbane (0.78g; 2.60mmol) and 10%Pd/C (0.20g) (slurry that forms among the 55ml stirred 2.5 days down in the nitrogen atmosphere (balloon) of 1atm, filtered with Celite_ then at EtOH.The solution of concentrating under reduced pressure gained obtains 4-(3-(N-methylamino formyl radical)-4-methoxyl group phenoxy group) aniline beige solid (0.68g, 96%): TLC (0.1%Et 3N/99.9%EtOAc) R f0.36.
A9: preparation contains the general method of the aniline of ω-alkyl phthalic imide.5-(4-amino-benzene oxygen)-2-methyl isoindole-1,3-diketone synthetic.
Figure C0080268500303
Step 1:5-(4-nitrophenoxy)-2-methyl isoindole-1,3-diketone synthetic
5-(4-nitrophenoxy) isoindole-1,3-diketone (A3 step 2; 1.0g, 3.52mmol) and NaH (0.13g, 5.27mmol) slurry that is become in DMF (15ml) at room temperature stirred 1 hour, add then methyl-iodide (0.3ml, 4.57mmol).Stir under the mixture room temperature that forms and spend the night, be cooled to 0 ℃ then, and add entry (10ml).Collect the solid that forms, drying under reduced pressure gets 5-(4-nitrophenoxy)-2-methyl isoindole-1,3-diketone glassy yellow solid (0.87g, 83%): TLC (35%EtAc/65% hexane) R f0.61.
Step 2:5-(4-amino-benzene oxygen)-2-methyl isoindole-1,3-diketone synthetic
5-(4-nitrophenoxy)-2-methyl isoindole-1, the 3-diketone (0.87g, 2.78mmol) and 10%Pd/C (0.10g) (slurry that forms among the 55ml stirs down in the nitrogen atmosphere (balloon) of 1atm and spends the night at MeOH.Filter the solution of concentrating under reduced pressure gained then with Celite_.The yellow solid that obtains is dissolved in EtOAc (3ml), uses SiO 2Filter (60%EtOAc/40% hexane), get 5-(4-amino-benzene oxygen)-2-methyl isoindole-1,3-diketone yellow solid (0.67g, 86%): TLC (40%EtOAc/60% hexane) R f0.27.
A10: by the general method of ω-alkoxy carbonyl aryl precursor and the synthetic omega-amino-formyl radical aniline of amine reaction.Synthesizing of 4-(2-(N-(2-morpholine-4-base ethyl) formamyl) pyridyl oxygen) aniline
Step 1:4-chloro-(synthesizing of 2-(N-(2-morpholine-4-base ethyl) formamyl) pyridine
To 4-chloropyridine-2-carboxylate methyl ester HCl salt (method A2 step 2; 1.01g (2.55ml, 19.4mmol), the solution of formation refluxed 20 hours, was cooled to room temperature, added entry (50ml) to drip 4-(2-amino-ethyl) morpholine in THF 4.86mmol) (20ml) solution.Mixture with EtOAc (50ml) extraction formation.Dry (MgSO 4) organic layer, concentrating under reduced pressure gets 4-chloro-(2-(N-(2-morpholine-4-base ethyl) formamyl) pyridine yellow oil (1.25g, 95%): TLC (10%MeOH/90%EtOAc) R f0.50.
Synthesizing of step 2:4-(2-(N-(2-morpholine-4-base ethyl) formamyl) pyridyl oxygen) aniline
The 4-amino-phenol (0.49g, 4.52mmol) and potassium tert.-butoxide (0.53g stirred under DMF 4.75mmol) (8ml) the solution room temperature 2 hours, add successively the 4-chloro-(2-(N-(2-morpholine-4-base ethyl) formamyl) pyridine (and 1.22g, 4.52mmol) and K 2CO 3(0.31g, 2.26mmol).The mixture that forms spends the night at 75 ℃, is cooled to room temperature, is distributed between EtOAc (25ml) and the saturated NaCl solution (25ml).Return the collection water with EtOAc (25ml).Merge organic layer, with saturated NaCl solution (3 * 25ml) washings, concentrating under reduced pressure.Brown solid (58g by column chromatography purification formation; gradient is 100%EtOAc to 25%MeOH/75%EtOAc); get 4-(2-(N-(2-morpholine-4-base ethyl) formamyl) pyridyl oxygen) aniline (1.0g, 65%): TLC (10%MeOH/90%EtOAc) R f0.32.
A11: the general method that nitro-aromatic is reduced into arylamines.Synthesizing of 4-(3-carboxyl phenoxy group) aniline
4-(3-carboxyl phenoxy group)-1-oil of mirbane (5.38g, 20.7mmol) and MeOH (120ml) slurry of 10%Pd/C (0.50g) stirred 2 days down in nitrogen atmosphere (balloon).Filter the mixture that forms with Celite_, concentrating under reduced pressure gets 4-(3-carboxyl phenoxy group) aniline brown solid (2.26g, 48%): TLC (10%MeOH/90%CH 2Cl 2) R f0.44.
A12: the synthetic general method that contains the aniline of isoindolone.Synthesizing of 4-(1-oxo isoindole-5-base oxygen) aniline
Synthesizing of step 1:5-hydroxyl isoindole-1-ketone
(19.8g, slowly add zinc powder in AcOH 121mmol) (500ml) solution (47.6g 729mmol), refluxed filtered while hot, concentrating under reduced pressure 40 minutes then in batches to the 5-hydroxyphthalimide.Repeat above reaction with same scale, merge the oily residue, with column chromatography purification (1.1kg, SiO 2Gradient: the 60%AcOH/40% hexane), get 5-hydroxyl isoindole-1-ketone (3.77g): TLC (100%EtOAc) R f0.17; HPLCES-MS m/z150 (M+H) +).
Figure C0080268500331
Synthesizing of step 2:4-(1-isoindolone-5-base oxygen)-1-oil of mirbane
To NaH (0.39g, add in 0 ℃ of slurry of DMF 16.1mmol) in batches 5-hydroxyl isoindole-1-ketone (2.0g, 13.4mmol).Allow the slurry that forms rise to room temperature, stirred 45 minutes, add 4-fluoro-1-oil of mirbane then, mixture was 72 ℃ of heating 3 hours.Mixture is cooled to 0 ℃, drips water, until forming precipitation.Collect the solid that forms, get 4-(1-isoindolone-5-base oxygen)-1-oil of mirbane dark yellow solid (3.23g, 89%): TLC100%EtOAc) R f0.35.
Figure C0080268500332
Synthesizing of step 3:4-(1-oxo isoindole-5-base oxygen) aniline
4-(1-isoindolone-5-base oxygen)-1-oil of mirbane (2.12g, 7.8mmol) and EtOH (50ml) slurry of 10%Pd/C (0.20g) in nitrogen atmosphere (balloon) stirring 4 hours down.Filter with Celite_.Concentrating under reduced pressure filtrate gets 4-(1-oxo isoindole-5-base oxygen) aniline dark yellow solid: TLC (100%EtOAc) R f0.15.
A13: the general method of synthetic omega-amino-formyl radical aniline: the acid amides by the EDCI-mediation forms reaction, reduces nitro-aromatic then.Synthesizing of 4-(3-N-methylamino formyl radical phenoxy group) aniline
Synthesizing of step 1:4-(3-ethoxy carbonyl phenoxy group)-1-oil of mirbane
4-fluoro-1-oil of mirbane (16ml, 150mmol), the 3-nipagin A (25g, 150mmol) and K 2CO 3(41g, 300mmol) mixture in DMF (125ml) refluxes and spends the night, and is cooled to room temperature, adds entry (250ml).With the EtOAc (mixture that 3 * 150ml) extractions form.Merge organic phase, water (3 * 100ml) and saturated NaCl solution (2 * 100ml) fine porcelain, dry (Na successively 2SO 4), concentrating under reduced pressure.By column chromatography (10%EtOAc/90% hexane) purifying, get 4-(3-ethoxy carbonyl phenoxy group)-1-oil of mirbane oily matter (38g).
Synthesizing of step 2:4-(3-carboxyl phenoxy group)-1-oil of mirbane
(5.14g, 17.9mmol) with 3: the solution of 1THF/ water (75ml) preparation adds LiOHH to vigorous stirring 4-(3-ethoxy carbonyl phenoxy group)-1-oil of mirbane simultaneously 2O (1.50g, water 35.8mmol) (36ml) solution.The 50 ℃ of heated overnight of mixture that form are cooled to room temperature then, and concentrating under reduced pressure transfers to pH2 with the HCl solution of 1M.Filter out the glassy yellow solid of formation, use hexane wash, get 4-(3-carboxyl phenoxy group)-1-oil of mirbane (4.40g, 95%).
Synthesizing of step 3:4-(3-(N-methylamino formyl radical) phenoxy group)-1-oil of mirbane
4-(3-carboxyl phenoxy group)-1-oil of mirbane (3.72g, 14.4mmol), EDCIHCl (3.63g, 18.6mmol), N-methylmorpholine (1.6ml, 14.5mmol) and methylamine (the TMF solution of 2.0M, 8ml is 16mmol) at CH 2Cl 2Form mixture (45ml), stirred 3 days under the room temperature, then concentrating under reduced pressure.Residue is dissolved in EtOAc (50ml), with HCl solution (50ml) extraction of 1M.(2 * 50ml) return collection water amalgamation liquid with EtOAc.Merge organic phase, with saturated NaCl solution (50ml) washing, dry (Na 2SO 4), concentrating under reduced pressure gets 4-(3-(N-methylamino formyl radical) phenoxy group)-1-oil of mirbane oily matter (1.89g).
Synthesizing of step 4:4-(3-(N-methylamino formyl radical) phenoxy group) aniline
4-(3-(N-methylamino formyl radical) phenoxy group)-1-oil of mirbane (1.89g, 6.95mmol) and 5%Pd/C (0.24g) in EtOAc (20ml), form slurry, stir down in nitrogen atmosphere (balloon) and spend the night.Filter the mixture that forms, concentrating under reduced pressure then with Celite_.With column chromatography purification residue (5%MeOH/95%CH 2Cl 2).Curings of spending the night under the oily matter vacuum that forms must 4-(3-(N-methylamino formyl radical) phenoxy group) aniline yellow solid (0.95g, 56%).
A14: the general method of synthetic omega-amino-formyl radical aniline: the acid amides by the EDCI-mediation forms reaction, reduces nitro-aromatic then.Synthesizing of 4-3-(5-methylamino formyl radical phenoxy group) aniline
Figure C0080268500351
Synthesizing of step 1:4-(3-(5-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane
(0.63g adds 5-hydroxy niacin methyl esters (2.0g, DMF 13.1mmol) (10ml) solution in DMF 26.1mmol) (20ml) slurry to NaH.The mixture that forms is added the 4-fluoronitrobenzene, and (1.4ml, in DMF 13.1mmol) (10ml) solution, 70 ℃ of heated overnight of the mixture of formation are cooled to room temperature then, add MeOH (5ml) earlier, add entry (50ml) then.Mixture with EtOAc (100ml) extraction formation.The concentrating under reduced pressure organic phase.By column chromatography (30%EtOAc/70% hexane) purifying residue, get 4-(3-(5-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane (0.60g).
Synthesizing of step 2:4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline
(0.60g 2.20mmol) forms mixture with 10%Pd/C to 4-(3-(5-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane in MeOH/EtOAc, stirred 72 hours down in nitrogen atmosphere (balloon).Filter the mixture that forms, concentrating under reduced pressure filtrate.By column chromatography (gradient: the 10%EtOAc/90% hexane is to the 30%EtOAc/70% hexane) purifying residue, get 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline (0.28g, 60%): 1HNMR (CDCl 3) δ 3.92 (s, 3H), 6.71 (d, 2H), 6.89 (d, 2H), 7.73 (, 1H), 8.51 (d, 1H), 8.87 (d, 1H).
A15: nitrated by parent's electricity, aniline is synthesized in reduction then.Synthesizing of 4-(3-methyl sulfamyl phenoxy group) aniline.
Figure C0080268500353
Synthesizing of step 1:N-methyl-3-bromobenzene sulphonamide
To the 3-bromobenzene sulfonyl chloride (2.5g, add in 0 ℃ of solution of THF 11.2mmol) (15ml) methylamine (the THF solution of 2.0M, 28ml, 56mmol).Allow the solution that forms rise to room temperature, stir under the room temperature and spend the night.The mixture that forms is distributed between EtOAc (25ml) and the 1M HCl solution (25ml).(2 * 25ml) return the collection water with EtOAc.Merge organic phase, and water (2 * 25ml) and saturated NaCl solution (25ml) washing, dry (MgSO 4), concentrating under reduced pressure gets N-methyl-3-bromobenzene sulphonamide white solid (2.8g, 99%).
Synthesizing of step 2:4-(3-(N-methyl sulfamyl) phenyl oxygen) benzene
Phenol (1.9g, 20mmol), K 2CO 3(6.0g, 40mmol) and CuI (4g 20mmol) forms slurry in DMF (25ml), to wherein add N-methyl-3-bromobenzene sulphonamide (2.5g, 10mmol), the mixture of formation reflux to stir and to spend the night, be cooled to room temperature, be distributed between EtOAc (50ml) and the 1N HCl solution (50ml).(2 * 50ml) return the collection water with EtOAc.Merge organic phase, and water (2 * 50ml) and saturated NaCl solution (50ml) washing, dry (MgSO 4), concentrating under reduced pressure gets 4-(3-(N-methyl sulfamyl) phenyl oxygen) benzene (0.30g).
Synthesizing of step 3:4-(3-(N-methyl sulfamyl) phenyl oxygen)-1-oil of mirbane
(0.30g, TFA 1.14mmol) (6ml) add NaNO to benzene in batches in 5 minutes in-10 ℃ solution to 4-(3-(N-methyl sulfamyl) phenyl oxygen) 2(0.097g, 1.14mmol).What form is introduced in-10 ℃ and stirred 1 hour, rises to room temperature then, concentrating under reduced pressure.Residue is distributed between EtOAc (10ml) and the water (10ml).Organic phase water (10ml) and saturated NaCl solution (10ml) washing, dry (MgSO 4), concentrating under reduced pressure, 4-(3-(N-methyl sulfamyl) phenyl oxygen)-1-oil of mirbane (0.20g).Purifying is not directly used in next step with this material.
Figure C0080268500363
Synthesizing of step 4:4-(3-(N-methyl sulfamyl) phenyl oxygen) aniline
The mixture that 4-(3-(N-methyl sulfamyl) phenyl oxygen)-1-oil of mirbane (0.30g) and 10%Pd/C (0.030g) form in EtOAc (20ml) stirs down in nitrogen atmosphere (balloon) and spends the night.Filter the mixture that forms, concentrating under reduced pressure filtrate with Celite_.By column chromatography (30%EtOAc/70% hexane) purifying residue, get 4-(3-(N-methyl sulfamyl) phenyl oxygen) aniline (0.070g).
A16: the modification of ω-ketone.4-(4-(1-(N-methoxyl group) imino-ethyl) phenoxybenzamine HCl salt
Figure C0080268500371
(according to the preparation of A13 step 4,1.0g 3.89mmol) adds O-methyl oxyamine HCl salt (0.65g, 7.78mmol, 2.0 equivalents) in the slurry that forms in EtOH (10ml) and pyridine (1.0ml) mixture to 4-(4-ethanoyl phenoxy group) aniline HCl salt.The solution that forms refluxed 30 minutes, was cooled to room temperature and concentrating under reduced pressure.The solid that water (10ml) development forms after water washing, gets 4-(4-(1-(N-methoxyl group) imino-ethyl) phenoxybenzamine HCl salt yellow solid (0.85g): TCL (50%EtOAc/50% sherwood oil) R f0.78; 1H NMR (DMSO-d 6) δ 3.90 (s, 3H), 5.70 (s, 3H); HPLC-MS m/z257 (M+H) +).
Synthesizing of A17:N-(ω-silyloxy alkyl) acid amides.4-(4-(synthesizing of 2-(N-(2-triisopropyl silyloxy) ethylamino formyl radical) pyridyl oxygen aniline.
Step 1:4-chloro-N-(2-triisopropyl silyloxy) ethylpyridine-2-methane amide
(according to A2 step 3b preparation, 1.5g adds triisopropyl silyl chloride (1.59g in dry DMF 7.4mmol) (7ml) solution to 4-chloro-N-(2-hydroxyethyl) pyridine-2-carboxamide, 8.2mmol, 1.1 equivalent) and imidazoles (1.12g, 16.4mmol, 2.2 equivalents).Stirred 3 hours under the yellow solution room temperature that forms, then concentrating under reduced pressure.Residue is distributed between water (10ml) and the EtOAc (10ml).With EtOAc (3 * 10ml) aqueous phase extracted.Merge organic phase, dry (MgSO 4), concentrating under reduced pressure gets 4-chloro-N-(2-triisopropyl silyloxy) ethylpyridine-2-methane amide orange (2.32g, 88%).Purifying is not directly used in next step with this material.
Figure C0080268500381
Step 2:4-(4-(2-(N-(2-triisopropyl silyloxy) ethylamino formyl radical) pyridyl oxygen aniline
(0.70g once adds potassium tert.-butoxide (0.67g, 6.0mmol, 1.0 equivalents) in dry DMF 6.0mmol) (8ml) solution, cause heat release to the 4-hydroxyanilines.After thing to be mixed is cooled to room temperature, add DMF (4ml) solution of 4-chloro-N-(2-triisopropyl silyloxy) ethylpyridine-2-methane amide orange (2.32g, 6mmol, 1 equivalent) earlier, add K then 2CO 3(0.42g, 3.0mmol, 0.50 equivalent).The 80 ℃ of heated overnight of mixture that form.Add potassium tert.-butoxide (0.34g, 3mmol, 0.5 equivalent) once more, 80 ℃ of reheat of mixture 4 hours.With ice bath mixture is cooled to 0 ℃, slowly drips water (about 1ml) then.With EtOAc (3 * 10ml) extraction organic layers.Merge organic layer, with saturated NaCl solution (20ml) washing, dry (MgSO 4), concentrating under reduced pressure.By column chromatography (SiO 2, the 30%EtOAc/70% sherwood oil) and the brown oily residue of purifying, get 4-(4-(2-(N-(2-triisopropyl silyloxy) ethylamino formyl radical) the clarifying bright brown oil of pyridyl oxygen aniline (0.99g, 38%).
A18: by the oxidation Synthetic 2-pyridine carboxylic acid ester of 2-picoline.Synthesizing of 4-(5-(2-methoxycarbonyl) pyridyl oxygen) aniline
Figure C0080268500382
Step 1:4-(5-(2-methyl) pyridyl oxygen)-1-oil of mirbane
5-hydroxy-2-methyl pyridine (10.0g, 91.6mmol), 1-fluoro-4-oil of mirbane (9.8ml, 91.6mmol, 1.0 equivalents), K 2CO 3The mixture that (25g, 183mmol, 2.0 equivalents) form in DMF (100ml) refluxes and spends the night.The mixture that forms is cooled to room temperature, adds entry (200ml), with EtOAc (3 * 100ml) extractions.Merge organic phase, and water (2 * 100ml) and saturated NaCl solution (100ml) washing, dry (MgSO 4), concentrating under reduced pressure gets 4-(5-(2-methyl) pyridyl oxygen)-1-oil of mirbane brown solid (12.3g).
Synthesizing of step 2:4-(5-(2-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane
4-(5-(2-methyl) pyridyl oxygen)-1-oil of mirbane (1.70g, 7.39mmol) and tin anhydride (2.50g, 22.2mmol, 3.0 equivalents) refluxed 5 hours at the mixture of pyridine (20ml), be cooled to room temperature then.Filter the slurry that forms, concentrating under reduced pressure.Residue is dissolved in MeOH (100ml).In solution, add concentrated hydrochloric acid (7ml), refluxed 3 hours, be cooled to room temperature and concentrating under reduced pressure.Residue is distributed between EtOAc (50ml) and the 1NNaOH (50ml).With EtOAc (2 * 50ml) aqueous layer extracted.Merge organic phase, and water (2 * 50ml) and saturated NaCl solution (50ml) washing, dry (MgSO 4), concentrating under reduced pressure.Column chromatography (SiO 2, the 50%EtOAc/50% hexane) and the purifying residue, get 4-(5-(2-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane (0.70g).
Synthesizing of step 3:4-(5-(2-methoxycarbonyl) pyridyl oxygen) aniline
The mixture that 4-(5-(2-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane (0.50g) and 10%Pd/C (0.050g) form in EtOAc (20ml) spends the night under nitrogen atmosphere (balloon).Filter the mixture that forms, concentrating under reduced pressure filtrate with Celite_.By column chromatography ((SiO 2, the 70%EtOAc/30% hexane) and the purifying residue, get 4-(5-(2-methoxycarbonyl) pyridyl oxygen) aniline (0.40g).
Synthesizing of A19: ω-alkylsulfonyl phenylaniline.Synthesizing of 4-(4-sulfonyloxy methyl phenoxyl) aniline
Step 1:4-(4-sulfonyloxy methyl phenoxyl)-1-oil of mirbane:
To 4-(4-methylthio group phenoxy group)-1-oil of mirbane (2.0g, CH 7.7mmol) 2Cl 2(57-86%, 4.0g), stirring reaction is 5 hours under the room temperature (75ml) slowly to add m-CPBA in 0 ℃ of solution.In reaction mixture, add 1N NaOH solution (25ml).Organic phase is used 1N NaOH solution (25ml) successively, water (25ml) and saturated NaCl solution (25ml) washing, dry (MgSO 4), concentrating under reduced pressure gets 4-(4-sulfonyloxy methyl phenoxyl)-1-oil of mirbane solid (2.1g).
Step 2:4-(4-sulfonyloxy methyl phenoxyl)-1-aniline:
Method according to A18 step 3 becomes aniline with 4-(4-sulfonyloxy methyl phenoxyl)-1-nitrobenzene reduction.
B. the urea precursor is synthetic
B1: with the general method of CDI by the aniline synthesizing isocyanate.Synthesizing of isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester
Synthesizing of step 1:4-bromo-3-(trifluoromethyl) aniline HCl salt
To 4-bromo-3-(trifluoromethyl) aniline (64g, Et 267mmol) 2Drip the HCl solution (Et of 1M in O (500ml) solution 2O solution 300ml), stirred 16 hours under the mixture room temperature of formation.Filter out the pink-white precipitate of formation, use Et 2O (50ml) washing gets 4-bromo-3-(trifluoromethyl) aniline HCl salt (73g, 98%).
Figure C0080268500402
Step 2: isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester synthetic
(36.8g drips superpalite in toluene 133mmol) (278ml) suspension, and the mixture of formation refluxed 18 hours to 4-bromo-3-(trifluoromethyl) aniline HCl salt.The mixture that concentrating under reduced pressure forms.In residue, add toluene (500ml), concentrating under reduced pressure.In residue, add CH 2Cl 2(500ml), concentrating under reduced pressure.Repeat CH 2Cl 2Processing/enrichment step obtains amber oily thing-20 ℃ placement 16 hours, obtains isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester brown solid (35.1g, 86%): GC-MS m/z 265 (M +).
C. form the method for urea
C1a: by the general method of isocyanic acid ketone and the synthetic urea of aniline reaction.Synthesizing of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea
0 ℃, to isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester (14.60g, CH 65.90mmol) 2Cl 2(35ml) drip 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline (method A2 step 4,16.0g, CH 65.77mmol) in the solution 2Cl 2(35ml) suspension.Stirred 72 hours under the mixture room temperature that forms.Filter out the yellow solid of formation, use CH 2Cl 2(2 * 30ml) washings, decompression (about 1mmHg) drying gets N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea beige solid (28.5g, 93%): mp.207-209 ℃; 1H-NMR (DMSO-d 6) δ 2.77 (d, J=4.8Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5Hz, 1H), 7.62 (m, 4H), 8.11 (d, J=2.5Hz, 1H), 8.49 (d, J=5.5Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLC ES-MS m/z 465 (M+H) +).
C1b: by the general method of isocyanic ester and the synthetic urea of aniline reaction.Synthesizing of N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea
0 ℃, to isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester (method B1 step 2,8.0g, CH 30.1mmol) 2Cl 2(80ml) drip 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline (method A2 step 4,7.0g, CH 28.8mmol) in the solution 2Cl 2(40ml) suspension.Stirred 16 hours under the mixture room temperature that forms.Filter out the yellow solid of formation, use CH 2Cl 2(2 * 50ml) washings, 40 ℃ of decompressions (about 1mmHg) drying gets N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea light yellow solid (13.2g, 90%): mp.203-205 ℃; 1H-NMR (DMSO-d 6) δ 2.77 (d, J=4.8Hz, 3H), 7.16 (m, 3H), 7.37 (d, J=2.5Hz, 1H), 7.58 (m, 4H), 7.77 (d, J=8.8Hz, 1H), 8.11 (d, J=2.5Hz, 1H), 8.49 (d, J=5.5Hz, 1H), 8.77 (br d, 1H), 8.99 (s, 1H), 9.21 (s, 1H); HPLCES-MS m/z 509 (M+H) +).
C1c: by the general method of isocyanic ester and the synthetic urea of aniline reaction.N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(synthesizing of 2-methyl-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen) phenyl) urea
To 2-methyl-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen) aniline (method A5; 0.11g, CH 0.45mmol) 2Cl 2(1ml) add Et in the solution 3N (0.16ml) and isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester (0.10g, 0.45mmol).Stirred 6 hours under the brown solution room temperature that forms, add entry (5ml) then.(3 * 5ml) return the collection water with EtOAc.Merge organic phase, dry (MgSO 4), concentrating under reduced pressure, N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(2-methyl-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen) phenyl) urea brown oil (and 0.11g, 0.22mmol): 1H-NMR (DMSO-d 6) δ 2.27 (s, 3H), 2.77 (d, J=4.8Hz, 3H), 7.03 (d, J=2.6Hz, 1H), 7.11 (d, J=2.9Hz, 1H), 7.15 (dd, J=5.5,2.6Hz, 1H), 7.38 (d, J=2.6Hz, 1H), 7.62 (app d, J=2.6Hz, 2H), 7.84 (d, J=8.8Hz, 1H), 8.12 (s, 1H), 7.37 (d, J=2.5Hz, 1H), 7.58 (m, 4H), 7.77 (d, J=8.8Hz, 1H), 8.11 (d, J=2.5Hz, 1H), 8.50 (d, J=5.5Hz, 1H), 8.78 (q, J=5.2Hz, 1H), 9.52 (s, 1H); HPLC ES-MS m/z 479 (M+H) +).
C1d: by the general method of isocyanic ester and the synthetic urea of aniline reaction.Synthesizing of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea
To isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester (2.27g, CH 10.3mmol) 2Cl 2(308ml) once add in the solution Ursol D (3.32g, 30.7mmol).Stirred 1 hour under the mixture room temperature that forms, add CH 2Cl 2(100ml), concentrating under reduced pressure.The pink solid that forms is dissolved in the mixture of EtOAc (110ml) and MeOH (15ml), and clear soln is washed with 0.05N HCl.The concentrating under reduced pressure organic layer obtains impure N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea (3.3g): TLC (100%EtOAc) R f0.72.
C1e: by the general method of isocyanic ester and the synthetic urea of aniline reaction.Synthesizing of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-ethoxy carbonyl phenyl) urea
To 4-isocyanato ethyl benzoate (3.14g, CH 16.4mmol) 2Cl 2(3.21g, 16.4mmol), solution at room temperature stirs and spends the night (30ml) to add 4-chloro-3-(trifluoromethyl) aniline in the solution.The slurry that forms is with CH 2Cl 2(50ml) dilution, filter N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-ethoxy carbonyl phenyl) urea white solid (5.93g, 97%): TLC (40%EtOAc/60% hexane) R f0.44.
C1f: by the general method of isocyanic ester and the synthetic urea of aniline reaction.Synthesizing of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(3-carboxyl phenyl) urea
Figure C0080268500431
In isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester (1.21g, 8ml 5.46mmol)) solution, add 4-(3-carboxyl phenoxy group) aniline (method A11,0.81g, 5.76mmol), the mixture stirred overnight at room temperature that forms adds MeOH (8ml), restir 2 hours then.The mixture that concentrating under reduced pressure forms.Brown solid with 1: 1 EtOAc/ hexane solution development forms gets N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(3-carboxyl phenyl) urea beige solid (1.21g, 76%).
C2a: by aniline and N, N '-phosphinylidyne diimidazole reaction adds the general method that second kind of aniline synthesizes urea then.Synthesizing of N-(2-methoxyl group-5-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea
Figure C0080268500432
CH to 2-methoxyl group-5-(trifluoromethyl) aniline (0.15g) 2Cl 2(15ml) add CDI (0.13g) in 0 ℃ of solution.Allow the solution that forms rise to room temperature in 1 hour, stirred 16 hours under the room temperature, add 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline (0.18g) then.Stirred 72 hours under the yellow solution room temperature that forms, add entry (125ml) then.With EtOAc (2 * 150ml) aqueous phase extracted mixtures.Merge organic phase, with saturated NaCl solution (100ml) washing, dry (MgSO 4), concentrating under reduced pressure.Development (90%EtOAc/10% hexane) residue.Filter and collect the white solid that forms, wash with EtOAc.Concentrating under reduced pressure filtrate; the oily matter that column chromatography (gradient: the 33%EtOAc/67% hexane is to the 50%EtOAc/50% hexane) purifying stays; get N-(2-methoxyl group-5-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) light brown solid of urea (0.098g, 30%): TLC (100%EtOAc) R f0.62; 1H-NMR (DMSO-d 6) δ 2.76 (d, J=4.8Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461 ((M+H) +).
C2b: by aniline and N, N '-phosphinylidyne diimidazole reaction adds the general method that second kind of aniline synthesizes urea then.As N, the symmetrical urea of N '-phosphinylidyne diimidazole byproduct of reaction.Synthesizing of two (4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea
Figure C0080268500441
0 ℃, the anhydrous CH of 3-amino-2 methoxy quinoline (0.14g) is stirred on the limit 2Cl 2(15ml) solution, the limit is to wherein adding CDI (0.13g).In 1 hour, allow the solution that forms rise to room temperature, stirred 16 hours under the room temperature.Mixture that forms and the reaction of 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline (0.18g).Stirred 72 hours under the solution room temperature that forms, add entry (125ml) then.With EtOAc (2 * 150ml) aqueous phase extracted mixtures.Merge organic phase, with saturated NaCl solution (100ml) washing, dry (MgSO 4), concentrating under reduced pressure.Development (90%EtOAc/10% hexane) residue.Filter and collect the white solid that forms,, get two (4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea (0.081g, 44%): TLC (100%EtOAc) R with the EtOAc washing f0.50; 1H-NMR (DMSO-d 6) δ 2.76 (d, J=5.1Hz, 6H), 7.1-7.6 (m, 12H), 8.48 (d, J=5.4Hz, 1H), 8.75 (d, J=4.8Hz, 2H), 8.86 (s, 2H); HPLC ES-MS m/z 513 ((M+H) +).
C2c: the general method that synthesizes urea by aniline and isocyanic acid reactive ketone.Synthesizing of N-(2-methoxyl group-5-(trifluoromethyl) phenyl)-N '-(4-(1,3-dioxo isoindole-5-base oxygen) phenyl) urea
Figure C0080268500442
To isocyanic acid 2-methoxyl group-5-(trifluoromethyl) phenyl ester (0.10g, CH 0.47mmol) 2Cl 2(1.5ml) once add 5-(4-amino-benzene oxygen) isoindole-1,3-diketone (method A3 step 3 in the solution; 0.12g, 0.47mmol).The mixture that forms stirred 12 hours, added CH then 2Cl 2(10ml) and MeOH (5ml).The mixture that forms is used 1N HCl solution (15ml) and saturated NaCl solution (15ml) washing, dry (MgSO successively 4), concentrating under reduced pressure gets N-(2-methoxyl group-5-(trifluoromethyl) phenyl)-N '-(4-(1,3-dioxo isoindole-5-base oxygen) phenyl) urea white solid (0.2g, 96%): TLC (70%EtOAc/30% hexane) R f0.50; 1H-NMR (DMSO-d 6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3Hz, 1H), 7.80 (d, J=8.7Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC 472.0 ((M+H) +, 100%).
C2d: by aniline and N, N '-phosphinylidyne diimidazole reaction adds the general method that second kind of aniline synthesizes urea then.N-(the 5-tertiary butyl)-2-(2, the 5-dimethyl pyrrole) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea synthetic
Stir CDI (0.21g, CH 1.30mmol) 2Cl 2(2ml) solution once adds 5-(tertiary butyl)-2-(2, the 5-dimethyl pyrrole) aniline (method A4, step 2 simultaneously; 0.30g, 1.24mmol).The solution stirring at room that forms 4 hours, once add then 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline (0.065g, 0.267mmol).The 36 ℃ of heated overnight of mixture that form are cooled to room temperature then, with EtOAc (5ml) dilution.The mixture that forms is water (15ml) and 1N HCl solution (15ml) washing successively; silica gel (50g) filters; get N-(the 5-tertiary butyl)-2-(2; the 5-dimethyl pyrrole) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea yellow solid (0.033g, 24%): TLC (40%EtOAc/60% hexane) R f0.24; 1H-NMR (acetone-d 6) δ 1.37 (s, 9H), 1.89 (s, 6H), 2.89 (d, J=4.8Hz, 3H), 5.83 (s, 2H), 6.87-7.20 (m, 6H), 7.17 (dd, 1H), 7.51-7.58 (m, 3H), 8.43 (d, J=5.4Hz, 1H), 8.57 (d, J=2.1Hz, 1H), 8.80 (brs, 2H; HPLC ES-MS 512 ((M+H) +, 100%).
C3: with the combined method of the synthetic diphenyl urea of triphosgene
To remain one of link coupled aniline is dissolved in methylene dichloride (0.10M).In the methylene dichloride (1ml) in this solution (0.5ml) adding 8ml test tube.To wherein adding carbonic acid two (three chloromethyl esters) (dichloromethane solution of 0.12M, 0.2ml, 0.4 equivalent), add diisopropyl ethyl amine (dichloromethane solution of 0.35M, 0.2ml, 1.2 equivalents) then.This test tube is added a cover 80 ℃ of heating 5 hours, and postcooling was to room temperature in about 10 hours.Add second kind of aniline (0.10M, 0.5ml, 1.0 equivalents), add diisopropyl ethyl amine (dichloromethane solution of 0.35M, 0.2ml, 1.2 equivalents) then.80 ℃ of heating of the mixture that forms 4 hours are cooled to room temperature, add MeOH (0.5ml).The mixture concentrating under reduced pressure that forms, product is by the reversed-phase HPLC purifying.
C4:, add the general method that second kind of aniline synthesizes urea then by a kind of aniline elder generation and phosgene reaction.N-(2-methoxyl group-5-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea
Figure C0080268500461
0 ℃, the CH of stirring phosgene 2Cl 2(20ml) (0.21g 1.30mmol), adds pyridine (0.32ml) to solution simultaneously, adds 2-methoxyl group-5-(trifluoromethyl) aniline (0.75g) then for the toluene solution of 1.9M, 2.07ml.Allow this yellow solution rise to room temperature, during form precipitation.Yellow mixture stirred 1 hour, then concentrating under reduced pressure.The solid that forms is handled with toluene (20ml), and (according to method A2 preparation, 0.30g), 80 ℃ of heating of the suspension of formation 20 hours are cooled to room temperature then to add 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline then.Sodium bicarbonate (2-3ml) furnishing alkalescence is used in mixture water (100ml) dilution that forms then.(2 * 250ml) extract this basic solution with EtOAc.Organic layer is used saturated NaCl solution washing respectively, merges then, dry (MgSO 4), concentrating under reduced pressure.Pink-brown the residue that forms is dissolved in MeOH, is adsorbed onto SiO 2(100g).Column chromatography (300g, SiO 2Gradient: 1%Et 3The N/33%EtOAc/66% hexane is to 1%Et 3N/99%EtOAc to 1%Et 3N/20%MeOH/79%EtOAc); 45 ℃ of concentrating under reduced pressure then; obtain warm dense EtOAc solution; after hexane (10ml) is handled; slowly form crystal, i.e. N-(2-methoxyl group-5-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) urea (0.44g): TLC (1%Et 3N/99%EtOAc) R f0.40.
D. the mutual conversion of urea
D1a: the omega-amino-phenylurea is to the conversion of ω-(aroylamino) phenylurea.N-(synthesizing of 4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methoxycarbonyl phenyl) carboxyamino phenyl) urea
To 4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea (method C1d; 0.050g, 1.52mmol), and isophthalic acid monomethyl ester (0.25g, 1.38mmol), HOBTH 2O (0.41g, 3.03mmol) and N-methylmorpholine (0.33ml, add in DMF 3.03mmol) (8ml) solution EDCIHCl (0.29g, 1.52mmol).Stir under the mixture room temperature that forms and spend the night, with EtOAc (25ml) dilution, water (25ml) and saturated NaHCO successively 3Solution (25ml) washing.With organic layer drying (Na 2SO 4), concentrating under reduced pressure.The solid that forms gets N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methoxycarbonyl phenyl) carboxyamino phenyl) urea (0.27g, 43%): mp121-122 through EtOAc solution (80%EtOAc/20% hexane) development; TLC (80%EtOAc/20% hexane) R f0.75.
D1b: ω-carboxyl phenyl urea is to the conversion of ω-(aryl-amino-carbonyl) phenylurea.N-(synthesizing of 4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methylamino formyl radical phenyl) formamyl phenyl) urea
0 ℃, to N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methoxycarbonyl phenyl) carboxyamino phenyl) urea (and 0.14g, 0.48mmol), 3-methylamino formyl radical aniline (0.080g, 0.53mmol), HOBTH 2O (0.14g, 1.07mmol) and N-methylmorpholine (0.5ml, add in DMF 1.07mmol) (3ml) solution EDCIHCl (0.10g, 0.53mmol).Allow the mixture that forms rise to room temperature, stirring is spent the night.In the mixture that forms, add entry (10ml), with extraction.The concentrating under reduced pressure organic layer.The yellow solid that forms is dissolved in EtOAc (3ml), use silica gel (17g then, gradient: the 70%EtOAc/30% hexane is to 10%MeOH/90%EtOAc), get N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methylamino formyl radical phenyl) formamyl phenyl) urea (0.097g, 41%): mp225-229; TLC (100%EtOAc) R f0.23.
The combined method that D1c: ω-carboxyl phenyl urea transforms to ω-(aryl-amino-carbonyl) phenylurea.N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(synthesizing of 4-(N-(3-(N-(3-pyridyl) formamyl) phenyl) formamyl phenyl) urea
N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(3-carboxyl phenyl) urea (method C1f; 0.030g, 0.067mmol) and N-cyclohexyl-N '-(methylated polystyrene) carbodiimide (55mg) 1, form mixture in the 2-methylene dichloride (1ml), add the CH of 3-aminopyridine 2Cl 2Solution (1M; 0.074ml, 0.074mmol).(if do not dissolve or become turbid, can add a small amount of DMSO).The mixture that forms is 36 ℃ of heated overnight.In the reaction solution of muddiness, add THF (1ml) then, continue heating 18 hours.Add poly-(4-(isocyanato methyl) vinylbenzene) (0.040g) in the mixture that forms, the mixture of formation stirred 72 hours for 36 ℃, was cooled to room temperature then, filtered.Filter the solution that forms with silica gel (1g).Concentrating under reduced pressure gets N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(N-(3-(N-(3-pyridyl) formamyl phenyl) formamyl) phenyl) urea (0.024g, 59%): TLC (70%EtOAc/30% hexane) R f0.12.
D2: ω-carbalkoxy aryl urea is to the conversion of omega-amino-formyl radical aryl urea.N-(synthesizing of 4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methylamino formyl radical phenyl) carboxyamino phenyl) urea.
Figure C0080268500482
To N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methoxycarbonyl phenyl) carboxyamino phenyl) urea sample (0.17g, 0.34mmol) middle methylamine (the THF solution of 2M that adds; 1ml 1.7mmol), stirs under the mixture room temperature of formation and spends the night, and concentrating under reduced pressure gets N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(3-methylamino formyl radical phenyl) carboxyamino phenyl) urea white solid: mp.247 then; TLC (100%EtOAc) R f0.35.
D3: ω-carbalkoxy aryl urea is to the conversion of ω-carboxyl carbonyl aryl urea.N-(synthesizing of 4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-carboxyl phenyl) urea.
To N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-ethoxy carbonyl phenyl) urea (method C1e; 5.93g, the adding KOH aqueous solution in MeOH 15.3mmol) (75ml) slurry (2.5N, 10ml, 23mmol).The mixture reflux that forms 12 hours is cooled to room temperature, concentrating under reduced pressure.Water (50ml) dilution residue transfers to pH2-3 with 1N HCl solution then.Collect the solid that forms, drying under reduced pressure gets N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-carboxyl phenyl) urea white solid (5.05g, 92%).
D4: ω-alkoxy ester is to the conversion of ω-alkylamide.N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(synthesizing of (4-(3-(5-(2-dimethyl aminoethyl) formamyl) pyridyl) oxygen phenyl) urea.
Figure C0080268500491
Step 1:N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-((synthesizing of 4-(3-(5-carboxyl pyridine base) oxygen phenyl) urea
By isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(5-methoxycarbonyl pyridyl) oxygen aniline (method A14, step 2), prepare N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-((4-(3-(5-methoxycarbonyl pyridyl) oxygen phenyl) urea according to method C1a.N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-((4-(3-(5-methoxycarbonyl pyridyl) oxygen phenyl) urea (0.26g, 0.56mmol) MeOH (10ml) suspension with KOH (0.14g, 2.5mmol) water (1ml) solution-treated, stirred 1 hour under the room temperature.The mixture that obtains transfers to pH5 with 1N HCl solution.Leach the precipitation of formation, wash with water.With gained solid solution EtOH (10ml), the solution that concentrating under reduced pressure forms.The EtOH/ concentration process repeats twice, gets N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-((4-(3-(5-carboxyl pyridine base) oxygen phenyl) urea (0.18g, 71%).
Step 2:N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(synthesizing of (4-(3-(5-(2-dimethyl aminoethyl) formamyl) pyridyl) oxygen phenyl) urea
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-((4-(3-(5-carboxyl pyridine base) oxygen phenyl) urea (0.050g, 0.011mmol), N, the N-dimethyl-ethylenediamine (0.22mg, 0.17mmol), HOBT (0.028g, 0.17mmol), N-methylmorpholine (0.035g, 0.28mmol) and EDCIHCL (0.032g 0.17mmol) stirs under the mixture room temperature that DMF (2.5ml) forms and spends the night.The solution that forms is distributed between EtOAc (50ml) and the water (50ml).Organic phase water (35ml) washing, dry (MgSO 4), concentrating under reduced pressure.Residue is dissolved in a small amount of methylene dichloride (about 2ml).In the solution that forms, drip Et 2O, N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-((4-(3-(5-(2-dimethyl aminoethyl) formamyl) pyridyl) oxygen phenyl) urea white precipitate (and 0.48g, 84%: 1H NMR (DMSO-d 6) δ 2.10 (s, 6H), 3.26 (s, H), 7.03 (d, 2H), 7.52 (d, 2H), 7.60 (m, 3H), 8.05 (s, 1H), 8.43 (s, 1H), 8.58 (t, 1H), 8.69 (s, 1H), 8.90 (s, 1H), 9.14 (s, 1H); PHLC ES-MS m/z 522 ((M+H) +).
D5:N-(ω-siloxy-alkyl) the de-protected general method of acid amides.N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(synthesizing of 4-(2-(N-(2-hydroxyl) ethylamino formyl radical) pyridyl oxygen phenyl) urea
Figure C0080268500501
(4-chloro-3-((trifluoromethyl) phenyl)-N '-((4-(2-(N-(2-triisopropyl siloxy-) ethylamino formyl radical) pyridyl oxygen phenyl) urea is (by method C1a preparation for 4-to N-; 0.25g, add tetrabutylammonium (the THF solution of 1.0M in anhydrous THF (2ml) solution 0.37mmol); 2ml).Stirred 5 minutes under the mixture room temperature, use water treatment (10ml) then.(3 * 10ml) extract this aqueous mixture with EtOAc.Merge organic layer, dry (MgSO 4), concentrating under reduced pressure.Column chromatography purification residue (SiO 2: gradient: 100% hexane is to the 40%EtOAc/60% hexane), get N-(4-chloro-3-((trifluoromethyl) phenyl)-N '-(4-(4-(2-(N-(2-hydroxyl) ethylamino formyl radical) pyridyl oxygen phenyl) urea white solid (0.019g, 10%).
Synthesizing of example compound
(the compound characteristic is seen each table)
Compound 1:4-(3-N-methylamino formyl radical phenoxy group) aniline is by method A13 preparation.By method C3,3-tertiary butyl aniline and carbonic acid two (three chloromethyl esters) reaction again with 4-(3-N-methylamino formyl radical phenoxy group) aniline reaction, forms urea.
Compound 2:4-fluoro-1-oil of mirbane with to glycoloyl benzene according to method A13 step 1 reaction, 4-(4-ethanoyl phenoxy group)-1-oil of mirbane.According to method A13 step 4 reduction 4-(4-ethanoyl phenoxy group)-1-oil of mirbane, get 4-(4-ethanoyl phenoxy group) aniline.According to method C3,3-tertiary butyl aniline and carbonic acid two (three chloromethyl esters) reaction again with 4-(4-ethanoyl phenoxy group) aniline reaction, forms urea.
Compound 3: according to method C2d, 3-tertiary butyl aniline and CDI reaction with the reaction of 4-(3-N-methylamino formyl radical-4-methoxyl group phenoxy group) aniline (A8 makes according to method), form urea again.
Compound 4:, the 5-tertiary butyl-2-anisidine is changed into the isocyanic acid 5-tertiary butyl-2-methoxyl group phenyl ester according to method B1.4-(3-N-methylamino formyl radical) aniline and this isocyanic ester by method A13 preparation react according to method C1a, form urea.
Compound 5: according to method C2d, the 5-tertiary butyl-2-anisidine and CDI reaction then with the 4-that makes according to method A8 (3-N-methylamino formyl radical-4-methoxyl group phenoxy group) aniline reaction, form urea.
Compound 6: prepare 5-(4-amino-benzene oxygen) isoindole-1,3-diketone by method A3.By method 2d, the 5-tertiary butyl-2-anisidine and CDI reaction, again with 5-(4-amino-benzene oxygen) isoindole-1,3-two reactive ketones form urea.
Compound 7: by the synthetic 4-of method A12 (1-oxo isoindole-5-base oxygen) aniline.By method 2d, the 5-tertiary butyl-2-anisidine and CDI reaction with 4-(1-oxo isoindole-5-base oxygen) aniline reaction, form urea again.
Compound 8: by synthetic 4-(the 3-N-methylamino formyl radical phenoxy group) aniline of method A13.By method C2a, 2-methoxyl group-5-(trifluoromethyl) aniline and CDI reaction again with 4-(3-N-methylamino formyl radical phenoxy group) aniline reaction, form urea.
Compound 9: by method A3 step 2,4-glycoloyl benzene and the reaction of 2-chloro-5-nitropyridine form 4-(4-ethanoyl phenoxy group)-5-nitropyridine.By method A8 step 4,4-(4-ethanoyl phenoxy group)-5-nitropyridine is reduced into 4-(4-ethanoyl phenoxy group)-5-aminopyridine.By method B1,2-methoxyl group-5-(trifluoromethyl) aniline is converted into isocyanic acid 2-methoxyl group-5-(trifluoromethyl) phenyl ester.By method C1, this isocyanic ester and 4-(4-ethanoyl phenoxy group)-5-aminopyridine reaction forms urea.
Compound 10: by method A13 step 1,4-fluoro-1-oil of mirbane with to the reaction of glycoloyl benzene, form 4-(4-ethanoyl phenoxy group)-1-oil of mirbane.By method A13 step 4,4-(4-ethanoyl phenoxy group)-1-nitrobenzene reduction is become 4-(4-ethanoyl phenoxy group) aniline.By method C3,5-(trifluoromethyl)-2-methoxyl group butylaniline and carbonic acid two (three chloromethyl esters) reaction then with 4-(4-ethanoyl phenoxy group) aniline reaction, forms urea.
Compound 11: by the synthetic 4-chloro-N-methyl of method A2 step 3a-2-pyridine carboxamide, press method A2 step 4 with the 3-amino-phenol, replace DMF with DMAC, reaction forms 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline.By method C4,2-methoxyl group-5-(trifluoromethyl) aniline and phosgene reaction again with 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction, form urea.
Compound 12: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine HCl salt and ammonia react forms 4-chloro-2-pyridine carboxamide.According to method A2 step 4, replace DMF with DMAC, 4-chloro-2-pyridine carboxamide and the reaction of 3-amino-phenol form 3-(2-formamyl-4-pyridyl oxygen) aniline.By method C2a, 2-methoxyl group-5-(trifluoromethyl) aniline and phosgene reaction again with 3-(2-formamyl-4-pyridyl oxygen) aniline reaction, form urea.
Compound 13: by the synthetic 4-chloro-N-methyl of method A2 step 3b-2-pyridine carboxamide.According to method A2 step 4, replace DMF with DMAC, 4-chloro-N-methyl-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline.By method C2a, 2-methoxyl group-5-(trifluoromethyl) aniline and CDI reaction then with 4-(2-(N-methylamino formyl radical)-4-pyridyloxy) aniline reaction, form urea.
Compound 14: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine HCl salt and ammonia gas react forms 4-chloro-2-pyridine carboxamide.According to method A2 step 4, replace DMF with DMAC, 4-chloro-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-formamyl-4-pyridyl oxygen) aniline.By method C4,2-methoxyl group-5-(trifluoromethyl) aniline and phosgene reaction again with 4-(2-formamyl-4-pyridyl oxygen) aniline reaction, form urea.
Compound 15: according to method C2d, 5-(trifluoromethyl)-2-anisidine and CDI reaction with 4-(3-(N-methylamino the formyl radical)-4-methoxyl group phenoxy group) aniline reaction for preparing by method A8, form urea then.
Compound 16: by the synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) of method A5-2-aminotoluene.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1c, this isocyanic ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-aminotoluene reaction forms urea.
Compound 17: by the synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) of method A6-2-chloroaniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline reaction forms urea.
Compound 18: by method A2 step 4,5-amino-2-methyl phenol with by method A2 step 3b synthetic 4-chloro-N-methyl-2-pyridine carboxamide reaction, form 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-4-monomethylaniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-4-monomethylaniline reaction forms urea.
Compound 19: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and ethylamine reaction.By method A2 step 4, the 4-chloropyridine of formation-N-ethyl-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen) aniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 20: by method A2 step 4,4-amino-2-chlorophenol with by method A2 step 3b synthetic 4-chloro-N-methyl-2-pyridine carboxamide reaction, form 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline reaction forms urea.
Compound 21:, 4-(4-methyl sulfo-phenoxy group)-1-nitrobenzene oxidation is become 4-(4-sulfonyloxy methyl phenoxyl)-1-oil of mirbane by method A19 step 1.By method A19 step 2, this nitrobenzene reduction is become 4-(4-sulfonyloxy methyl phenoxyl) aniline.By method C1a, isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester and 4-(4-sulfonyloxy methyl phenoxyl) aniline reaction forms urea.
Compound 22:, 4-(3-carbamyl phenoxyl)-1-nitrobenzene reduction is become 4-(3-carbamyl phenoxyl) aniline by method A15 step 4.By method C1a, isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester and 4-(3-carbamyl phenoxyl) aniline reaction forms urea.
Compound 23: by synthetic 5-(4-amino-benzene oxygen) isoindole-1 of method A3,3-diketone.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 5-(4-amino-benzene oxygen) isoindole-1,3-two reactive ketones form urea.
Compound 24: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and dimethyl amine reaction.By method A2 step 4, the 4-chloro-N of formation, N-dimethyl-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 25: by the synthetic 4-of method A12 (1-oxo isoindole-5-base oxygen) aniline.By method C2d, 5-(trifluoromethyl)-2-anisidine and CDI reaction with 4-(1-oxo isoindole-5-base oxygen) aniline reaction, form urea then.
Compound 26: by method A13 step 1,4-glycoloyl benzene and the reaction of 4-fluoronitrobenzene form 4-(4-ethanoyl phenoxy group) oil of mirbane.By method A13 step 4, this nitrobenzene reduction is become 4-(4-ethanoyl phenoxy group) aniline, change into 4-(4-(1-(N-methoxyl group) imino-ethyl) phenoxybenzamine HCl salt by method A16 again.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, (4-(1-(N-methoxyl group) imino-ethyl) phenoxybenzamine HCl reactant salt forms urea for this isocyanic ester and 4-.
Compound 27: by method A2 step 3b, synthetic 4-chloro-N-picoline methane amide.By method A2 step 4, this chloropyridine and the reaction of 4-amino-phenol form 4-(4-(2-(N ,-methylamino formyl radical) thiophenyl) aniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, (4-(2-(N-methylamino formyl radical) thiophenyl) aniline reaction forms urea for this isocyanic ester and 4-.
Compound 28: by the synthetic 5-(4-amino-benzene oxygen) of method A9-2-methyl isoindole-1,3-diketone.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 5-(4-amino-benzene oxygen)-2-methyl isoindole-1,3-two reactive ketones form urea.
Compound 29: by method A2 step 3b, synthetic 4-chloro-N-picoline methane amide.By method A2 step 4, this chloropyridine and the reaction of 3-amino-phenol form 3-(4-(2-(N-methylamino formyl radical) thiophenyl) aniline.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, (4-(2-(N ,-methylamino formyl radical) thiophenyl) aniline reaction forms urea for this isocyanic ester and 3-.
Compound 30: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and isopropylamine reaction.By method A2 step 4, the 4-chloro-N-sec.-propyl-2-pyridine carboxamide of formation.By method B1 5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester,, generates 4-(2-(N-sec.-propyl formamyl)-4-pyridyloxy) aniline with the reaction of 4-amino-phenol.By method C1a, (2-(N-sec.-propyl-formamyl-4-pyridine amino) aniline reaction forms urea for this isocyanic ester and 4-.
Compound 31: by synthetic 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline of method A14.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline reaction forms urea.By method 4D step 1 saponification N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(4-(3-(5-methoxycarbonyl pyridyl) oxygen) phenyl) urea, by method D4 step 2, gained acid and 4-(2-amino-ethyl) morpholine coupling form acid amides.
Compound 32: by synthetic 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline of method A14.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline reaction forms urea.By method 4D step 1 saponification N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(4-(3-(5-methoxycarbonyl pyridyl) oxygen) phenyl) urea, by method D4 step 2, gained acid and methylamine coupling form acid amides.
Compound 33: by synthetic 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline of method A14.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1a, this isocyanic ester and 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline reaction forms urea.By method 4D step 1 saponification N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(4-(3-(5-methoxycarbonyl pyridyl) oxygen) phenyl) urea, by method D4 step 2, gained acid and N, the coupling of N-dimethyl-ethylenediamine forms acid amides.
Compound 34: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, by method D1c, makes it and the coupling of 3-aminopyridine again.
Compound 35: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, again by method D1c, makes it and N-(4-fluorophenyl) piperazine coupling.
Compound 36: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, by method D1c, makes it and the coupling of 4-fluoroaniline again.
Compound 37: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, again by method D1c, makes it and 4-(dimethylamino) aniline coupling.
Compound 38: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, by method D1c, makes it and 5-amino-2-methoxypyridine coupling again.
Compound 39: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, by method D1c, makes it and 4-morpholinyl aniline coupling again.
Compound 40: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method B1,5-(trifluoromethyl)-2-anisidine is converted into isocyanic acid 5-(trifluoromethyl)-2-methoxyl group phenyl ester.By method C1f, this isocyanic ester and 4-(3-carboxyl phenoxy group) aniline reaction forms N-(5-(trifluoromethyl)-2-p-methoxy-phenyl)-N '-(3-carboxyl phenyl) urea, again by method D1c, makes it and N-(2-pyridyl) piperazine coupling.
Compound 41: by synthetic 4-(3-(the N-methylamino formyl radical) phenoxy group) aniline of method A13.By method C3,4-chloro-3-(trifluoromethyl) aniline is converted into isocyanic ester, form urea with 4-(3-(N-methylamino formyl radical) phenoxy group) aniline reaction then.
Compound 42: by synthetic 4-(the 2-N-methylamino formyl radical-4-pyridyl oxygen) aniline of method A2.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-N-methylamino formyl radical-4-pyridyl oxygen) aniline reaction forms urea.
Compound 43: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine HCl salt and ammonia react forms 4-chloro-2-pyridine carboxamide.According to method A2 step 4,4-chloro-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-formamyl-4-pyridyl oxygen) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-formamyl-4-pyridyl oxygen) aniline reaction forms urea.
Compound 44: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine HCl salt and ammonia react forms 4-chloro-2-pyridine carboxamide.According to method A2 step 4,4-chloro-2-pyridine carboxamide and the reaction of 3-amino-phenol form 3-(2-formamyl-4-pyridyl oxygen) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 3-(2-formamyl-4-pyridyl oxygen) aniline reaction forms urea.
Compound 45: by the synthetic 4-chloro-N-methyl of method A2 step 3a-2-pyridine carboxamide, amine method A2 step 4 and the reaction of 3-amino-phenol form 3-(2-(N-methylamino formyl radical-4-pyridyl oxygen) aniline then.By method C1a, (2-(N-methylamino formyl radical-4-pyridyl oxygen) aniline reaction forms urea for isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 3-.
Compound 46: by synthetic 5-(4-amino-benzene oxygen) isoindole-1 of method A3,3-diketone.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 5-(4-amino-benzene oxygen) isoindole-1,3-two reactive ketones form urea.
Compound 47: by the synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) of method A5-2-aminotoluene.By method C1c, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 5-(4-amino-benzene oxygen) isoindole-1,3-two reactive ketones form urea.
Compound 48: by synthetic 4-(3-(the N-methylamino alkylsulfonyl) phenyl oxygen) aniline of method A15.By method C1c, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(N-methylamino alkylsulfonyl) phenyl oxygen) aniline reaction forms urea.
Compound 49: by the synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) of method A6-2-chloroaniline.By method C1c, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline reaction forms urea.
Compound 50: by method A2 step 4,5-amino-2-methyl phenol and the 4-chloro-N-methyl that makes by method A2 step 3b-2-pyridine carboxamide reaction form 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-4-monomethylaniline.By method C1c, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-4-monomethylaniline reaction forms urea.
Compound 51: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and ethylamine reaction.The 4-chloro-N-ethyl-2-pyridine carboxamide that forms forms 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen) aniline according to method A2 step 4 and the reaction of 4-amino-phenol.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 52: by method A2 step 4,4-amino-2-chlorophenol and the 4-chloro-N-methyl that makes by method A2 step 3b-2-pyridine carboxamide reaction form 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline reaction forms urea.
Compound 53:, 4-(4-methyl sulfo-phenoxy group)-1-nitrobenzene oxidation is become 4-(4-sulfonyloxy methyl phenoxyl)-1-oil of mirbane by method A19 step 1.By method A19 step 2 this nitrobenzene reduction is become 4-(4-sulfonyloxy methyl phenoxyl) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(4-sulfonyloxy methyl phenoxyl) aniline reaction forms urea.
Compound 54: by method A15 step 1,4-bromobenzene sulfonyl chloride and methylamine reaction form N-methyl-4-bromobenzene sulphonamide.By method A15 step 2, N-methyl-4-bromobenzene sulphonamide becomes 4-(4-(N-methyl sulfamyl) phenoxy group) benzene with the phenol coupling.By method A15 step 3,4-(4-(N-methyl sulfamyl) phenoxy group) benzene is converted into 4-(4-(N-methyl sulfamyl) phenoxy group)-1-oil of mirbane.By method A15 step 4,4-(4-(N-methyl sulfamyl) phenoxy group)-1-nitrobenzene reduction is become 4-(4-(N-methyl sulfamyl) phenoxy group) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(4-(N-methyl sulfamyl) phenoxy group) aniline reaction forms urea.
Compound 55: by method A18 step 1,5-hydroxy-2-methyl pyridine and the coupling of 1-fluoro-4-oil of mirbane form 4-(5-(2-methyl) pyridyl oxygen)-1-oil of mirbane.According to this picoline of different carboxylic acid oxidative, by method A18 step 2, esterification becomes 4-(5-(2-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane then.By method A18 step 3, this nitrobenzene reduction is become 4-(5-(2-methoxycarbonyl) pyridyl oxygen) aniline.By method C1a, this oil of mirbane and the reaction of isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester form urea.
Compound 56: by method A18 step 1,5-hydroxy-2-methyl pyridine and the coupling of 1-fluoro-4-oil of mirbane form 4-(5-(2-methyl) pyridyl oxygen)-1-oil of mirbane.According to this picoline of different carboxylic acid oxidative, by method A18 step 2, esterification becomes 4-(5-(2-methoxycarbonyl) pyridyl oxygen)-1-oil of mirbane then.By method A18 step 3, this nitrobenzene reduction is become 4-(5-(2-methoxycarbonyl) pyridyl oxygen) aniline.By method C1a, this aniline and the reaction of isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester form N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-methoxycarbonyl)-5-pyridyl oxygen) phenyl) urea.By method D2, this methyl esters and methylamine reaction form N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-methoxyl group formamyl)-5-pyridyl oxygen) phenyl) urea.
Compound 57: C1d prepares N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea set by step.By method D1a, N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea and isophthalic acid monomethyl ester coupling, form urea.
Compound 58: C1d prepares N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea set by step.By method D1a, N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-aminophenyl) urea and isophthalic acid monomethyl ester coupling, form N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(3-methoxycarbonyl phenyl) carboxyamino phenyl) urea.By method D2, N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(3-methoxycarbonyl phenyl) carboxyamino phenyl) urea and methylamine reaction form corresponding methyl nitrosourea.
Compound 59: by method A2 step 3,4-chloropyridine-2-carbonyl chlorine and dimethyl amine reaction.The 4-chloro-N-dimethyl-2-pyridine carboxamide that forms forms 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline according to method A2 step 4 and the reaction of 4-amino-phenol.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 60: by method A13 step 1,4-glycoloyl benzene and the reaction of 4-fluoronitrobenzene form 4-(4-ethanoyl phenoxy group) oil of mirbane.By method 13 steps 4, this nitrobenzene reduction is become 4-(4-ethanoyl phenoxy group) aniline, be converted into 4-(4-(1-(N-methoxyl group) imino-ethyl) phenoxybenzamine HCl salt by method A16 again.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(4-ethanoyl phenoxy group) aniline reaction forms urea.
Compound 61: by the synthetic 4-(3-carboxyl phenoxy group) of method A13 step 2-1-oil of mirbane.By method A13 step 3,4-(3-carboxyl phenoxy group)-1-oil of mirbane and 4-(2-amino-ethyl) morpholine coupling, form 4-(3-(N-(2-morpholinyl ethyl) formamyl) phenoxy group)-1-oil of mirbane.By method A13 step 4,4-(3-(N-(2-morpholinyl ethyl) formamyl) phenoxy group)-1-nitrobenzene reduction is become 4-(3-(N-(2-morpholinyl ethyl) formamyl) phenoxy group) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(N-(2-morpholinyl ethyl) formamyl) phenoxy group) aniline reaction forms urea.
Compound 62: by the synthetic 4-(3-carboxyl phenoxy group) of method A13 step 2-1-oil of mirbane.By method A13 step 3,4-(3-carboxyl phenoxy group)-1-oil of mirbane and 1-(2-amino-ethyl) pyridine coupling, form 4-(3-(N-(2-pyridyl ethyl) formamyl) phenoxy group)-1-oil of mirbane.By method A13 step 4,4-(3-(N-(2-pyridyl ethyl) formamyl) phenoxy group)-1-nitrobenzene reduction is become 4-(3-(N-(2-pyridyl ethyl) formamyl) phenoxy group) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(N-(2-pyridyl ethyl) formamyl) phenoxy group) aniline reaction forms urea.
Compound 63: by the synthetic 4-(3-carboxyl phenoxy group) of method A13 step 2-1-oil of mirbane.By method A13 step 3,4-(3-carboxyl phenoxy group)-1-oil of mirbane and tetrahydrofurfuryl amine coupling, form 4-(3-(N-(2-tetrahydrofuran (THF) ylmethyl) formamyl) phenoxy group)-1-oil of mirbane.By method A13 step 4,4-(3-(N-(2-tetrahydrofuran (THF) ylmethyl) formamyl) phenoxy group)-1-nitrobenzene reduction is become 4-(3-(N-(2-tetrahydrofuran (THF) ylmethyl) formamyl) phenoxy group) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(N-(2-tetrahydrofuran (THF) ylmethyl) formamyl) phenoxy group) aniline reaction forms urea.
Compound 64: by the synthetic 4-(3-carboxyl phenoxy group) of method A13 step 2-1-oil of mirbane.By method A13 step 3,4-(3-carboxyl phenoxy group)-1-oil of mirbane and 2-aminomethyl-1,2-ethyl pyrrolidine coupling, form 4-(3-(N-((1-methylpyrrole alkyl) methyl) formamyl) phenoxy group)-1-oil of mirbane.By method A13 step 4,4-(3-(N-((1-methylpyrrole alkyl) methyl) formamyl) phenoxy group)-1-nitrobenzene reduction is become 4-(3-(N-((1-methylpyrrole alkyl) methyl) formamyl) phenoxy group) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(N-((1-methylpyrrole alkyl) methyl) formamyl) phenoxy group) aniline reaction forms urea.
Compound 65: by the synthetic 4-chloro-N-picoline methane amide of method A2 step 3b.By method A2 step 4, this chloropyridine and the reaction of 4-aminothiophenol form 4-(4-(2-(N-methylamino formyl radical) thiophenyl) aniline.By method C1a, (4-(2-(N-methylamino formyl radical) thiophenyl) aniline reaction forms urea for isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-.
Compound 66: by method A2 step 3b, 4-chloro-2-carbonyl chlorine and isopropylamine reaction.By method A2 step 4, the 4-chloro-N-sec.-propyl-2-pyridine carboxamide of formation and the reaction of 4-amino-phenol form 4-(2-(N-sec.-propyl formamyl)-4-pyridyl oxygen) aniline.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(2-(N-sec.-propyl formamyl)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 67: by synthetic N-(4-chloro-3-(trifluoromethyl) phenyl-N '-(4-ethoxy carbonyl phenyl) urea of method C1e.By method D3, (4-chloro-3-(trifluoromethyl) phenyl-N '-(4-ethoxy carbonyl phenyl) urea forms N-(4-chloro-3-(trifluoromethyl) phenyl-N '-(4-carboxyl phenyl) urea to saponification N-.By method D1b; (4-chloro-3-(trifluoromethyl) phenyl-N '-(4-carboxyl phenyl) urea and 3-methylamino formyl radical aniline coupling form N-(4-chloro-3-(trifluoromethyl) phenyl-N '-(4-(3-methylamino formyl radical phenyl) formamyl phenyl) urea to N-.
Compound 68: by the synthetic 5-(4-amino-benzene oxygen) of method A9-2-methyl isoindole-1,3-diketone.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 5-(4-amino-benzene oxygen)-2-methyl isoindole-1,3-two reactive ketones form urea.
Compound 69: by the synthetic 4-chloro-N-picoline methane amide of method A2 step 3.By method A2 step 4, this chloropyridine and the reaction of 3-aminothiophenol form 3-(4-(2-(N-methylamino formyl radical) thiophenyl) aniline.By method C1a, (4-(2-(N-methylamino formyl radical) thiophenyl) aniline reaction forms urea for isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 3-.
Compound 70: by the synthetic 4-of method A10 (2-(N-(2-morpholine-4-base ethyl) formamyl) aniline.By method C1a, (2-(N-(2-morpholine-4-base ethyl) formamyl) aniline reaction forms urea for isocyanic acid 4-chloro-3-(trifluoromethyl)-2-methoxyl group phenyl ester and 4-.
Compound 71: by synthetic 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline of method A14.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline reaction forms urea.By method D4 step 1 saponification N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(3-(5-methoxycarbonyl pyridyl) oxygen) phenyl) urea, corresponding acid forms acid amides with 4-(2-amino-ethyl) morpholine coupling.
Compound 72: by synthetic 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline of method A14.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline reaction forms urea.By method D4 step 1 saponification N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(3-(5-methoxycarbonyl pyridyl) oxygen) phenyl) urea, by method D4 step 2, corresponding acid forms acid amides with the methylamine coupling.
Compound 73: by synthetic 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline of method A14.By method C1a, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-(5-methoxycarbonyl) pyridyl oxygen) aniline reaction forms urea.By method D4 step 1 saponification N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(3-(5-methoxycarbonyl pyridyl) oxygen) phenyl) urea, by method D4 step 2, corresponding acid and N, the coupling of N-dimethyl-ethylenediamine forms acid amides.
Compound 74: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine HCl salt and the reaction of 2-hydroxyethyl amine form 4-chloro-N-(2-triisopropyl silyl oxygen) ethylpyridine-2-methane amide.By method A17; 4-chloro-N-(2-triisopropyl silyl oxygen) ethylpyridine-2-methane amide and the reaction of triisopropyl silyl chloride; with the reaction of 4-amino-phenol, form 4-(4-(2-(N-(2-triisopropyl silyl oxygen) ethylamino formyl radical pyridyl oxygen aniline then.By method C1a; (((reaction of N-(2-triisopropyl silyl oxygen) ethylamino formyl radical pyridyl oxygen benzene forms N-(4-chloro-3-((trifluoromethyl) phenyl-N '-4-(4-(2-(N-(2-triisopropyl silyl oxygen) ethylamino formyl radical pyridyl oxygen phenyl) urea to 2-to 4-for isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-.
Compound 75: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with the coupling of 3-aminopyridine.
Compound 76: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with N-(4-acetylphenyl) piperazine coupling.
Compound 77: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with the coupling of 4-fluoroaniline.
Compound 78: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with 4-(dimethylamino) aniline coupling.
Compound 79: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with the coupling of N-phenylethylenediamine.
Compound 80: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with the coupling of 2-methoxy ethyl amine.
Compound 81: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with 5-amino-2-methoxypyridine coupling.
Compound 82: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with 4-morpholinyl aniline coupling.
Compound 83: by synthetic 4-(the 3-carboxyl phenoxy group) aniline of method A11.By method C1f, isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-(3-carboxyl phenoxy group) aniline reaction forms urea, again by method D1c, with N-(2-pyridyl) piperazine coupling.
Compound 84: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine HCl salt and the reaction of 2-hydroxyethyl amine form 4-chloro-N-(2-triisopropyl silyl oxygen) ethylpyridine-2-methane amide.By method A17; 4-chloro-N-(2-triisopropyl silyl oxygen) ethylpyridine-2-methane amide and the reaction of triisopropyl silyl chloride; with the reaction of 4-amino-phenol, form 4-(4-(2-(N-(2-triisopropyl silyl oxygen) ethylamino formyl radical pyridyl oxygen aniline then.By method C1a; ((reaction of 2-(N-(2-triisopropyl silyl oxygen) ethylamino formyl radical) pyridyl oxygen benzene forms N-(4-chloro-3-((trifluoromethyl) phenyl-N '-4-(4-(2-(N-(2-triisopropyl silyl oxygen) ethylamino formyl radical) pyridyl oxygen phenyl) urea to 4-for isocyanic acid 4-chloro-3-(trifluoromethyl) phenyl ester and 4-.This urea goes protection by method D5, gets N-(4-chloro-3-((trifluoromethyl) phenyl-N '-4-(4-(2-(N-(2-hydroxyl) ethylamino formyl radical) pyridyl oxygen phenyl) urea.
Compound 85: by synthetic 4-(2-(N-methylamino the formyl radical)-4-pyridyl oxygen) aniline of method A2.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 86: by the synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) of method A6-2-chloroaniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline reaction forms urea.
Compound 87: by method A2 step 4,4-amino-2-chlorophenol and the 4-chloro-N-methyl that makes by method A2 step 3-2-pyridine carboxamide reaction form 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline reaction forms urea.
Compound 88: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and ethylamine reaction.By method A2 step 4, the 4-chloro-N-ethyl-2-pyridine carboxamide of formation and the reaction of 4-amino-phenol form 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline reaction forms urea.
Compound 89:, by method A2 step 4 and the reaction of 3-amino-phenol, form 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline then by the synthetic 4-chloro-N-methyl of method A2 step 3a-2-pyridine carboxamide.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 90: then by method A2 step 4,5-amino-2-methyl phenol and the 4-chloro-N-methyl that makes by method A2 step 3b-2-pyridine carboxamide reaction form 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-4-monomethylaniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-4-monomethylaniline reaction forms urea.
Compound 91: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and dimethyl amine reaction.By method A2 step 4, the 4-chloro-N of formation, N-dimethyl-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 92: by the synthetic 4-chloro-N-picoline methane amide of method A2 step 3b.By method A2 step 4, this chloropyridine and the reaction of 4-aminothiophenol form 4-(4-(2-(N-methylamino formyl radical) thiophenyl) aniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, (4-(2-(N-methylamino formyl radical) thiophenyl) aniline reaction forms urea for isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-.
Compound 93: by the synthetic 4-chloro-N-picoline methane amide of method A2 step 3b.By method A2 step 4, this chloropyridine and the reaction of 3-aminothiophenol form 3-(4-(2-(N-methylamino formyl radical) thiophenyl) aniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, (4-(2-(N-methylamino formyl radical) thiophenyl) aniline reaction forms urea for isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 3-.
Compound 94: by the synthetic 4-of method A10 (2-(N-(2-morpholine-4-base ethyl) formamyl) pyridyl oxygen) aniline.By method B1,4-bromo-3-(trifluoromethyl) aniline is converted into isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-bromo-3-(trifluoromethyl) phenyl ester and 4-(2-(N-(2-morpholine-4-base ethyl) formamyl) pyridyl oxygen) aniline reaction forms urea.
Compound 95: by synthetic 4-(2-(N-methylamino the formyl radical)-4-pyridyl oxygen) aniline of method A2.By synthetic 4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline of method A7.By method B1,4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline is converted into isocyanic acid 4-chloro-2-methoxyl group-5-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 96: by the synthetic 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) of method A6-2-chloroaniline.By synthetic 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline of method A7.By method B1,4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline is converted into isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-2-chloroaniline reaction forms urea.
Compound 97: by method A2 step 4,4-amino-2-chlorophenol and the 4-chloro-2-pyridine carboxamide reaction that makes by method A2 step 3b form 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline.By synthetic 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline of method A7.By method B1,4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline is converted into isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester and 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen)-3-chloroaniline reaction forms urea.
Compound 98: the 4-chloro-N-methyl-2-pyridine carboxamide that makes by method A2 step 3a with by method A2 step 4 and the reaction of 3-amino-phenol, form 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline.By synthetic 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline of method A7.By method B1,4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline is converted into isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester and 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 99: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and ethylamine reaction.By method A2 step 4, the 4-chloro-N-ethyl-2-pyridine carboxamide of formation and the reaction of 4-amino-phenol form 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen) aniline.By synthetic 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline of method A7.By method B1,4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline is converted into isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester and 4-(2-(N-ethylamino formyl radical)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 100: by method A2 step 3b, 4-chloropyridine-2-carbonyl chlorine and dimethyl amine reaction.By method A2 step 4, the 4-chloro-N of formation, N-dimethyl-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline.By synthetic 4-chloro-2-methoxyl group-5-(trifluoromethyl) aniline of method A7.By method B1,4-chloro-2-methoxyl group 5-(trifluoromethyl) aniline is converted into isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester.By method C1a, isocyanic acid 4-chloro-2-methoxyl group 5-(trifluoromethyl) phenyl ester and 4-(2-(N, N-formyl-dimethylamino)-4-pyridyl oxygen) aniline reaction forms urea.
Compound 101:,,, form 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline with the reaction of 3-amino-phenol by method A2 step 4 by method A2 step 3a synthetic 4-chloro-N-methyl-2-pyridine carboxamide.By method A1 Synthetic 2-amino-3-methoxynaphthalene.By method C3,2-amino-3-methoxynaphthalene and carbonic acid two (three chloromethyl esters) reaction again with 3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction, forms urea.
Compound 102: by synthetic 4-(2-(N-methylamino the formyl radical)-4-pyridyl oxygen) aniline of method A2.By the synthetic 5-tertiary butyl-2-(2, the 5-dimethyl pyrrole) aniline of method A4.By method C2d, the 5-tertiary butyl-2-(2, the 5-dimethyl pyrrole) aniline reacts with CDI earlier, then with 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction, forms urea.
Compound 103: by the synthetic 4-chloro-N-methyl of method A2 step 3b-2-pyridine carboxamide.By method A2 step 4, replace DMF with DMAC, 4-chloro-N-methyl-2-pyridine carboxamide and the reaction of 4-amino-phenol form 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline.By method C2d, 3-amino-2 methoxy quinoline reacts with CDI earlier, then with 4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) aniline reaction, forms two (4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea.
Listed in the following table is embodiment synthetic compound according to above detailed description.
The compound of table among the 1-6 prepares according to above general method, and detailed process is referring to above, and feature is referring to form.
Table 1 3-tert-butyl-phenyl urea
The table 2:5-tertiary butyl-2-p-methoxy-phenyl urea
Figure C0080268500652
Figure C0080268500661
Table 3:5-(trifluoromethyl)-2-p-methoxy-phenyl urea
Figure C0080268500662
Figure C0080268500671
Figure C0080268500681
Table 4:3-(trifluoromethyl)-4-chloro-phenyl-urea
Figure C0080268500692
Figure C0080268500711
Table 5:3-(trifluoromethyl)-4-bromophenyl urea
Figure C0080268500741
Table 6:5-(trifluoromethyl)-4-chloro-2-p-methoxy-phenyl urea
Table 7: other ureas
Figure C0080268500751
If, can equally successfully obtain similar result with summarizing or concrete described reaction reagent and/or reaction conditions are replaced used those of above embodiment.
According to the above, those skilled in the art can not find that substance of the present invention is specific, and can carry out various modifications in spirit and scope of the invention, thereby adapt to different purposes and situation.

Claims (42)

1. compound is
A) compound shown in the general formula I or its salt of pharmaceutically approving:
A-D-B (I)
Wherein, D is-NH-C (O)-NH-,
A is that general formula is-L-M-L 1,
Wherein L is the phenyl of non-replacement or replacement, and substituting group is selected from halogen and C 1-10Alkyl,
L 1Be-C (O) R xThe pyridyl that replaces,
M is one or more bridging groups, be selected from-O-or-S-,
R xBe NR aR b, R wherein aAnd R bRespectively naturally:
A) hydrogen,
B) C 1-10Alkyl,
C) C of hydroxyl replacement 1-10Alkyl,
D) contain 1-3 N, the heteroatomic C of S or O 3-12Cycloalkyl, or
E)-OSi (R f) 3, R fBe C 1-10Alkyl,
B is non-replacement or substituted-phenyl, and substituting group is selected from halogen, Wn, and n=0-3, W is selected from:
A) C 1-10Alkyl,
B) C 1-10Alkoxyl group,
C) C 1-10Haloalkyl
D) contain 1-3 N, the heteroatomic C of S or O 3-12Heteroaryl, this heteroaryl can be by C 1-10Alkyl replaces; B) N-(5-(trifluoromethyl)-2-methoxyl group-phenyl)-N '-(4-(2-(N-(2-dimethylamino) ethylamino formyl radical)-4-pyridyl oxygen) phenyl) urea or its salt of pharmaceutically approving; Or
C) N-(5-(trifluoromethyl)-4-chloro-phenyl)-N '-(4-(2-(N-(2-dimethylamino) ethylamino formyl radical)-4-pyridyl oxygen) phenyl) urea or its salt of pharmaceutically approving.
2. compound according to claim 1, the B in the general formula I is a substituted-phenyl, substituting group is selected from: C 1-10Alkyl, C 1-10Alkoxyl group or C 1-10Haloalkyl.
3. compound according to claim 1, the B in the general formula I are the phenyl that 1-3 replaces, and substituting group is selected from chlorine, bromine, fluorine, fluoroform alkyl, methoxyl group and the tertiary butyl.
4. compound according to claim 1, wherein, L is the phenyl or the halogenophenyl of non-replacement.
5. compound according to claim 1, wherein, L is that 1-3 replaces or non-substituted-phenyl, substituting group is selected from chlorine or methyl.
6. compound according to claim 1, M wherein is-O-.
7. compound according to claim 2, M wherein is-O--.
8. compound according to claim 3, M wherein is-O-.
9. compound according to claim 4, M wherein is-O-.
10. compound according to claim 1, wherein, R aAnd R bEach is H or C naturally 1-10Alkyl.
11. compound according to claim 3, wherein, R aAnd R bEach is hydrogen or C naturally 1-10Alkyl.
12. compound according to claim 6, wherein, R aAnd R bEach is hydrogen or C naturally 1-10Alkyl.
13. compound according to claim 7, wherein, R aAnd R bEach is hydrogen or C naturally 1-10Alkyl.
14. compound according to claim 8, wherein, R aAnd R bEach is hydrogen or C naturally 1-10Alkyl.
15. compound according to claim 9, wherein, R aAnd R bEach is hydrogen or C naturally 1-10Alkyl.
16. compound according to claim 1 has following general formula:
A-D-B (I)
Wherein, D is-NH-C (O)-NH-,
The general formula of A is-L-M-L 1, wherein,
L is the phenyl that non-replacement or 1-3 replace, and substituting group is selected from methyl or halogen,
L 1Be-C (O) NR aR bThe pyridyl that replaces,
M is selected from-O-,-S-,
Wherein, R aAnd R bRespectively naturally: hydrogen, C 1-10The C that alkyl or hydroxyl replace 1-10Alkyl,
B is the phenyl of non-replacement or replacement, and substituting group is selected from halogen, Wn, and n=0-3, W is selected from: C 1-10Alkyl, C 1-10Alkoxyl group, halo or C 1-10Alkyl.
17. compound according to claim 1 has following general formula:
A-D-B (I)
Wherein, D is-NH-C (O)-NH-,
The general formula of A is-L-M-L 1, wherein,
L is a phenyl,
M is-O-,
L 1Be-C (O) NR aR bThe pyridyl that replaces,
R aAnd R bRespectively naturally: hydrogen or C 1-10Alkyl,
B is a substituted-phenyl, and substituting group is selected from: halogen, C 1-10Alkyl, C 1-10Alkoxyl group or C 1-10Haloalkyl.
18. compound according to claim 16, R wherein aAnd R bEach is H or C naturally 1-10Alkyl.
19. compound according to claim 17, R wherein aAnd R bEach is H or C naturally 1-10Alkyl.
20. according to the described compound of Formula I of claim 1 and pharmaceutically the approval salt, described salt is selected from:
A) mineral acid and organic acid subsalt, described acid is selected from: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, the 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol;
B) acid salt of organic and mineral alkali, described positively charged ion is selected from: alkali metal cation, alkaline earth metal cation, ammonium cation, the ammonium cation that ammonium cation that aliphatic group replaces and aromatic base replace.
21. according to the described compound of Formula I of claim 16 and pharmaceutically the approval salt, described salt is selected from:
A) mineral acid and organic acid subsalt, described acid is selected from: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, the 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol;
B) acid salt of organic and mineral alkali, described positively charged ion is selected from: alkali metal cation, alkaline earth metal cation, ammonium cation, the ammonium cation that ammonium cation that aliphatic group replaces and aromatic base replace.
22. compound of Formula I according to claim 17 and the salt of pharmaceutically approving thereof, described salt is selected from:
A) mineral acid and organic acid subsalt, described acid is selected from: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, the 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol;
B) the organic and cationic acid salt of mineral alkali, described positively charged ion is selected from: alkali metal cation, alkaline earth metal cation, ammonium cation, the ammonium cation that ammonium cation that aliphatic group replaces and aromatic base replace.
23. a pharmaceutical composition for the treatment of cancer comprises the compound shown in the described general formula I of claim 1 or its salt of pharmaceutically approving, and the carrier of approving on the physiology.
24. pharmaceutical composition according to claim 23 comprises compound shown in the described general formula I of claim 3.
25. pharmaceutical composition according to claim 23 comprises the compound shown in the described general formula I of claim 16.
26. pharmaceutical composition according to claim 23 comprises the compound shown in the described general formula I of claim 17.
27. compound according to claim 1 is selected from:
Following 2-methoxyl group-(5-trifluoromethyl) phenylurea:
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(3-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(4-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl sulphur) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(3-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea;
Following 4-chloro-3-(trifluoromethyl) phenylurea:
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(3-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea;
Following 4-bromo-3-(trifluoromethyl) phenylurea:
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl sulphur) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(3-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea;
Following 2-methoxyl group-4-chloro-5-(trifluoromethyl) phenylurea:
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea,
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(3-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea.
28. compound of Formula I according to claim 27 and the salt of pharmaceutically approving thereof, described salt is selected from:
A) mineral acid and organic acid subsalt, described acid is selected from: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, the 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol;
B) the organic and cationic acid salt of mineral alkali, described positively charged ion is selected from: alkali metal cation, alkaline earth metal cation, ammonium cation, the ammonium cation that ammonium cation that aliphatic group replaces and aromatic base replace.
29. the compound shown in the described general formula I of claim 1 is used to make the purposes of the medicine that suppresses raf growth of cancer cells that kinases mediates.
30. the compound shown in the described general formula I of claim 3 is used to make the purposes of the medicine that suppresses raf growth of cancer cells that kinases mediates.
31. the purposes of the medicine of the compound raf growth of cancer cells that kinases mediates shown in the described general formula I of claim 16.
32. the compound shown in the described general formula I of claim 17 is used to make the purposes of the medicine that suppresses raf growth of cancer cells that kinases mediates.
33. purposes according to claim 29, described compound is selected from:
Following 2-methoxyl group-(5-trifluoromethyl) phenylurea:
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(3-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(4-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl sulphur) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea,
N-(2-methoxyl group-(5-trifluoromethyl) phenyl)-N '-(3-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea;
Following 4-chloro-3-(trifluoromethyl) phenylurea:
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(3-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-formamyl-4-pyridyl oxygen) phenyl) urea,
N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea;
Following 4-bromo-3-(trifluoromethyl) phenylurea:
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl sulphur) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea,
N-(4-bromo-3-(trifluoromethyl) phenyl)-N '-(3-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea;
Following 2-methoxyl group-4-chloro-5-(trifluoromethyl) phenylurea:
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(3-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen) phenyl) urea,
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(2-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea,
N-(2-methoxyl group-4-chloro-5-(trifluoromethyl) phenyl)-N '-(3-chloro-4-(2-(N-methylamino formyl radical) (4-pyridyl oxygen)) phenyl) urea.
34. compound according to claim 1, wherein the optional substituting group on the B is selected from: methyl, trifluoromethyl, ethyl, n-propyl, normal-butyl, n-pentyl, sec.-propyl, the tertiary butyl, isobutyl-, methoxyl group, Cl, F.
35. pharmaceutical composition according to claim 23, described compound are N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-formamyl-4-pyridyl oxygen base) phenyl) urea or its salt of pharmaceutically approving.
36. pharmaceutical composition according to claim 23, described compound are N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen base) phenyl) urea or its salt of pharmaceutically approving.
37. pharmaceutical composition according to claim 23, the pharmaceutically salt of approval of described compound is selected from:
A) mineral acid and organic acid subsalt, described acid is selected from: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoromethanesulfonic acid, Phenylsulfonic acid, tosic acid, 1-naphthalene sulfonic aicd, the 2-naphthene sulfonic acid, acetate, trifluoroacetic acid, oxysuccinic acid, tartrate, citric acid, lactic acid, oxalic acid, succsinic acid, fumaric acid, toxilic acid, phenylformic acid, Whitfield's ointment, phenylacetic acid and tussol;
B) the organic and cationic acid salt of mineral alkali, described positively charged ion is selected from: alkali metal cation, alkaline earth metal cation, ammonium cation, the ammonium cation that ammonium cation that aliphatic group replaces and aromatic base replace.
38. pharmaceutical composition according to claim 23, the pharmaceutically salt of approval of described compound is P-TOLUENE SULFO ACID 99's salt of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-formamyl-4-pyridyl oxygen base) phenyl) urea.
39. pharmaceutical composition according to claim 23, the pharmaceutically salt of approval of described compound is P-TOLUENE SULFO ACID 99's salt of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen base) phenyl) urea.
40. compound according to claim 1, it is N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen base) phenyl) urea or its salt of pharmaceutically approving.
41. according to the described compound of claim 40, it is the pharmaceutically salt of approval of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen base) phenyl) urea.
42. according to the described compound of claim 41, it is P-TOLUENE SULFO ACID 99's salt of N-(4-chloro-3-(trifluoromethyl) phenyl)-N '-(4-(2-(N-methylamino formyl radical)-4-pyridyl oxygen base) phenyl) urea.
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