CN1717393A - Pyrazole derivatives useful as COX-I inhibitors - Google Patents
Pyrazole derivatives useful as COX-I inhibitors Download PDFInfo
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- CN1717393A CN1717393A CN 200380104548 CN200380104548A CN1717393A CN 1717393 A CN1717393 A CN 1717393A CN 200380104548 CN200380104548 CN 200380104548 CN 200380104548 A CN200380104548 A CN 200380104548A CN 1717393 A CN1717393 A CN 1717393A
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Abstract
A compound of the formula (I): wherein R1 is hydrogen or lower alkyl; R2 is lower alkyl, etc.; R3 is lower alkoxy, etc. ; R4 is hydroxy, etc.; X is O, S, etc.; Y is CH or N; Z is lower alkylene or lower alkenylene; and m is 0 or 1; or salts thereof, which are useful as a medicament.
Description
Technical field
The present invention relates to have pyrazole compound, its preparation method of pharmacologic activity and the medicinal compositions that comprises them.
Background technology
Known two kinds of cyclooxygenase isozymes, i.e. cyclooxygenase-I (COX-I) and cyclooxygenase-II (COX-II) (Proc.Nat.Acad.Sci.USA 88,2692-2696 (1991)).
Tradition nonsteroidal anti-inflammatory compound (NSAID) all has the activity of inhibition (J.Biol.Chem., 268,6610-6614 (1993) etc.) to COX-I and COX-II.Can produce undesirable action to gi tract with its treatment, for example hemorrhage, rotten to the corn, gastroenteritic ulcer etc.
It is reported that it is suitable with traditional NSAID that selectivity suppresses the anti-inflammatory of COX-II and analgesic activity, but some stomach and intestine undesirable action of less generation (Pro.Nat.Acad.Sci.USA, 91,3228-3232 (1994)).Therefore, prepared multiple choices COX-II inhibitor.Yet, it is reported that these " selective COX-2s-II inhibitor " have certain side effect to kidney and/or to the poor effect of acute pain.
In addition, some compounds (for example SC-560, N-22 etc.) have certain selection inhibition activity to COX-I.WO98/57910 has introduced has this more active compounds.Yet as if because they can cause gastrointestinal disturbance, its selectivity that suppresses COX-I also is not enough to these compounds are used as the analgesic agent of acceptable satisfaction clinically.
WO02/055502 has introduced some to have cyclooxygenase and suppresses active pyridine derivate, and especially cyclooxygenase-I suppresses active pyridine derivate.In addition, WO03/040110 has introduced some to have cyclooxygenase and suppresses active triazole derivative, and especially cyclooxygenase-I suppresses active triazole derivative.And WO99/51580 has introduced some pair cell factors and produces and have the active triazole derivative of inhibition.
Disclosure of the Invention
The present invention relates to have pharmacologic activity (for example cyclooxygenase (COX hereinafter referred to as) suppress active) pyrazole compound, its preparation method, comprise their medicinal compositions and uses thereof.
Therefore, one of the object of the invention provides and has COX and suppress active pyrazole compound.
On the one hand, the invention provides the method for preparing pyrazole compound again.
Advance on the one hand, the invention provides the medicinal compositions that comprises as the pyrazole compound of effective constituent.
More advance on the one hand, the invention provides pyrazole compound and be used for the treatment of or prevent purposes on the medicine of multiple disease in preparation.
Novel pyrazole compound of the present invention can be following general formula (I) compound or its salt:
R wherein
1Be hydrogen or low alkyl group;
R
2Be the optional low alkyl group that is replaced by halogen, hydroxyl, lower alkoxy imino-or lower alkoxy; Low-grade alkenyl; Cycloalkyl; Cyano group; Low-grade alkane acidyl; Naphthene base carbonyl; N, N-two (rudimentary) alkyl-carbamoyl; Formamyl; N-lower alkoxy-N-elementary alkyl amido methanoyl; Amino; Two (rudimentary) alkylamino; Elementary alkoxy carbonyl amino; N, N-two (rudimentary) alkyl-carbamoyl amino; N-(N, N-two (rudimentary) alkyl-carbamoyl)-N-low-grade alkyl amino; Halogen; Hydroxyl; Carboxyl; Elementary alkoxy carbonyl; Aroyl; The heterocyclic radical carbonyl; Heterocyclic radical; The low alkyl group alkylsulfonyl; Optional by lower alkoxy, N, the lower alkoxy that N-two (rudimentary) alkyl-carbamoyl or halogen replace; Cycloalkyloxy; Lower alkylthio; Or low alkyl group sulfinyl;
R
3The low alkyl group amino for optional quilt, that formamyl is amino or the low alkyl group sulfuryl amino replaces; Halogen; Cyano group; Hydroxyl; Lower alkanoyloxy; Low-grade alkylidene dioxy base; The optional lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino; Nitro; Amino; Heterocyclic radical; Lower alkylthio; The low alkyl group sulfinyl; Or low alkyl group alkylsulfonyl;
R
4Be hydrogen; Cyano group; Optional by the amino of phthaloyl or low alkyl group replacement; Aryl; Heterocyclic radical; Lower alkoxy; Hydroxyl; The low alkyl group sulfonyloxy; Lower alkanoyloxy; The low alkyl group that is replaced by following group: trityl amino and elementary alkoxy carbonyl, amino and elementary alkoxy carbonyl, amino and carboxyl, amino and formamyl or amino and hydroxyl; N-elementary alkoxy carbonyl-N-low-grade alkyl amino; The optional low-grade alkane acidyl that is replaced by halogen; Carboxyl; The low alkyl group alkylsulfonyl; Sulfo group; Low alkyl group silyl oxygen base; Elementary alkoxy carbonyl; The optional sulfamyl that is replaced by low alkyl group; The optional formamyl that is replaced by low alkyl group; Lower alkylthio; The low alkyl group sulfinyl; Carbamoyloxy group; Thioureido; Or the group of following structural formula:
R
5-G-J-
Wherein G be-CO-or-SO
2-;
J is-N (R
6)-
(R wherein
6Be hydrogen or low alkyl group); And
R
5For choosing wantonly by the amino of elementary alkoxy carbonyl or low alkyl group replacement; The optional low alkyl group that is replaced by hydroxyl, elementary alkoxy carbonyl amino, lower alkanoyloxy, amino or halogen; Lower alkoxy; Hydrogen; Heterocyclic radical; Or aryl;
X is O, S, SO or SO
2
Y is CH or N;
Z is low-grade alkylidene or lower alkenylene; And
M is 0 or 1;
Precondition is to work as R
4During for hydrogen;
R then
3Be the low alkyl group that quilt is amino, formamyl is amino or the low alkyl group sulfuryl amino replaces; Or the lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino.
Target compound of the present invention (I) can prepare by the following method.
Method (1)
Method (2)
In aforesaid method, R
1, R
2, R
3, R
4, X, Y, Z and m with above define identical,
Xa is O or S, and
Q is hydroxyl or sour residue.
Structural formula (I) compound can comprise one or more asymmetric centers, therefore, they can enantiomer or the form of diastereomer exist.The present invention includes isomer mixture and single various isomer.
Structural formula (I) compound also can tautomeric form exist, and the present invention includes tautomer mixture and single various isomer.
Structural formula (I) compound and its salt can be solvate forms, and it belongs to category of the present invention.Solvate preferably includes hydrate and ethylate.
Category of the present invention also comprises radiolabeled structural formula (I) compound derivatives that is suitable for biological study.
In the above and hereinafter explanation of specification sheets of the present invention, the suitable example that belongs to the various definitions of category of the present invention hereinafter describes in detail.
Except as otherwise noted, term " rudimentary " is meant the group with 1-6 carbon atom.
Therefore; low alkyl group in " low alkyl group " and term " lower alkylthio ", " low alkyl group sulfinyl ", " the low alkyl group alkylsulfonyl " and " low alkyl group sulfuryl amino " partly is meant the straight or branched aliphatic hydrocrbon; for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, hexyl etc., and preferred (C
1-C
4) alkyl, more preferably (C
1-C
2) alkyl, most preferable.
" halogen " can comprise fluorine atom, chlorine atom, bromine atoms and iodine atom, and preferred fluorine atom or chlorine atom, more preferably chlorine atom.
" low alkyl group that is replaced by halogen " is meant the univalent perssad that wherein above-mentioned low alkyl group is replaced by one or more (more preferably 1-5, most preferably 1-3) above-mentioned halogen atom, for example methyl fluoride, chloromethyl, difluoromethyl, dichloromethyl, two brooethyls, trifluoromethyl, trichloromethyl, fluoro ethyl, chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-three chloroethyls, 2,2,3,3,3-pentafluoroethyl group, fluoropropyl, fluorine butyl, fluorine hexyl or similar group, the and (C that is preferably replaced by halogen
1-C
4) the alkyl, (C that more preferably replaced by halogen
1-C
2) the alkyl, (C that more preferably replaced by fluorine
1-C
2) alkyl, the methyl that is more preferably replaced by fluorine, most preferably difluoromethyl or trifluoromethyl.
" low alkyl group that is replaced by hydroxyl " is meant the univalent perssad that wherein above-mentioned low alkyl group is replaced by the OH group, for example methylol, hydroxyethyl, hydroxypropyl, 1-hydroxyl sec.-propyl, 2-hydroxyl sec.-propyl, hydroxyl butyl, hydroxyl isobutyl-, the hydroxyl tertiary butyl, hydroxyl hexyl or similar group, the and (C that is preferably replaced by hydroxyl
1-C
4) the alkyl, (C that more preferably replaced by hydroxyl
1-C
3) alkyl.
" low-grade alkenyl " is meant the straight or branched aliphatic hydrocrbon with an above carbon-to-carbon double bond, for example vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, pentenyl, hexenyl etc., and preferred (C
2-C
4) thiazolinyl, more preferably (C
2-C
3) thiazolinyl.
" lower alkoxy " is meant straight or branched aliphatic series-oxyl, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy or similar group, and preferred (C
1-C
4) alkoxyl group, more preferably (C
1-C
2) alkoxyl group, methoxyl group most preferably.
Cycloalkyl moiety in " cycloalkyl " and term " naphthene base carbonyl " and " cycloalkyloxy " is meant C
3-C
10Cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, bornyl, adamantyl etc., and preferred C
3-C
6Cycloalkyl, more preferably C
3-C
5Cycloalkyl, most preferably cyclopropyl or cyclopentyl.
" two (rudimentary) alkylamino " is meant the amino that is replaced by identical or different above-mentioned (rudimentary) alkyl, for example dimethylamino, diethylamino, dipropyl amino, diisopropylaminoethyl, dibutylamino, diisobutyl amino, diamyl amino, dihexyl amino, ethylmethylamino, methyl-propyl amino, butyl methyl amino, ethyl propyl amino, butyl ethyl are amino or similar group, and preferred [two (C
1-C
4) alkyl] amino, more preferably [two (C
1-C
4) alkyl] amino, dimethylamino most preferably.
Elementary alkoxy carbonyl in " elementary alkoxy carbonyl " and the term " elementary alkoxy carbonyl amino " partly is meant-CO
2-[(rudimentary) alkyl], for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxy carbonyl etc., and preferred [(C
1-C
4) alkoxyl group] carbonyl, more preferably ethoxy carbonyl or tert-butoxycarbonyl.
" low-grade alkane acidyl " is meant the carbonyl that is replaced by hydrogen or above-mentioned (rudimentary) alkyl, for example formyl radical, ethanoyl, propionyl, butyryl radicals, 2-methylpropionyl, pentanoyl, 2,2-dimethyl propylene acyl group, caproyl or similar group, and preferred (C
1-C
5) alkyloyl, more preferably (C
2-C
3) alkyloyl, ethanoyl most preferably.
" naphthene base carbonyl " be meant by the carbonyl of above-mentioned cycloalkyl substituted, for example cyclopropyl carbonyl, cyclobutyl carbonyl, cyclopentylcarbonyl, cyclohexyl-carbonyl, suberyl carbonyl, bornyl carbonyl, adamantyl carbonyl etc., and preferred [(C
3-C
6) cycloalkyl] carbonyl, more preferably [(C
3-C
5) cycloalkyl] carbonyl, cyclopropyl carbonyl most preferably.
N in " N; N-two (rudimentary) alkyl-carbamoyl " and the term " N; N-two (rudimentary) alkyl-carbamoyl amino "; N-two (rudimentary) alkyl-carbamoyl partly is meant the formamyl that is replaced by above-mentioned identical or different low alkyl group; formyl-dimethylamino for example; the diethylamino formyl radical; the dipropyl formamyl; the diisopropylaminoethyl formyl radical; the dibutylamino formyl radical; the diisobutyl formamyl; the diamyl formamyl; the dihexyl formamyl; the ethylmethylamino formyl radical; the methyl-propyl formamyl; the butyl methyl formamyl; the ethyl propyl formamyl; butyl ethyl formamyl etc., and preferred [two (C
1-C
4) alkyl] formamyl, more preferably [two (C
1-C
2) alkyl] formamyl, most preferably formyl-dimethylamino or ethylmethylamino formyl radical.
" lower alkoxy that is replaced by halogen " is meant that wherein above-mentioned lower alkoxy is by one or more (more preferably 1-5,1-3 most preferably) univalent perssad that replaces of above-mentioned halogen atom, fluorine methoxyl group for example, the chlorine methoxyl group, difluoro-methoxy, the dichloro methoxyl group, the dibromo methoxyl group, trifluoromethoxy, the trichlorine methoxyl group, the fluorine oxyethyl group, chloroethoxy, 2, the 2-difluoroethoxy, 2,2-two chloroethoxies, 2,2, the 2-trifluoro ethoxy, 2,2,2-three chloroethoxies, 2,2,3,3,3-five fluorine oxyethyl groups, the fluorine propoxy-, the fluorine butoxy, fluorine hexyloxy or similar group, the and (C that is preferably replaced by halogen
1-C
4) the alkoxyl group, (C that more preferably replaced by halogen
1-C
2) the alkoxyl group, (C that more preferably replaced by fluorine
1-C
2) alkoxyl group, the oxyethyl group that is more preferably replaced, most preferably 2 by fluorine, the 2-difluoroethoxy.
" by the amino low alkyl group that replaces " is meant the univalent perssad that wherein above-mentioned low alkyl group is replaced by amino, the for example amino sec.-propyl of amino methyl, 2-amino-ethyl, aminopropyl, 1-, the amino sec.-propyl of 2-, amino butyl, aminoisobutyric base, the amino tertiary butyl, amino hexyl or similar group, the and (C that is preferably replaced by amino
1-C
4) the alkyl, (C that more preferably replaced by amino
1-C
2) alkyl.
" by the amino low alkyl group that replaces of formamyl " is meant the univalent perssad that wherein above-mentioned (rudimentary) alkyl is replaced by formamyl amino (urea groups); the for example amino butyl of formamyl amino methyl, 2-(formamyl amino) ethyl, formamyl aminopropyl, 1-(formamyl amino) sec.-propyl, 2-(formamyl amino) sec.-propyl, formamyl, formamyl aminoisobutyric base, the amino tertiary butyl of formamyl, the amino hexyl of formamyl or similar group, and preferably by the amino (C that replaces of formamyl
1-C
4) alkyl, more preferably by the amino (C that replaces of formamyl
1-C
2) alkyl.
Aryl moiety in " aryl " and the term " aroyl " is meant aromatic hydrocarbyl, for example phenyl, naphthyl, indenyl or similar group, and preferred (C
6-C
10) aryl, more preferably phenyl.
" aroyl " is meant the carbonyl that is replaced by above-mentioned aryl, for example benzoyl, naphthoyl or similar group, and preferred benzoyl.
" lower alkanoyloxy " is meant the univalent perssad that Sauerstoffatom is wherein replaced by above-mentioned low-grade alkane acidyl; low-grade alkane acidyl is formyl radical, ethanoyl, propionyl, butyryl radicals, 2-methylpropionyl, pentanoyl, 2 for example; 2-dimethyl propylene acyl group, caproyl or similar group, and preferred [(C
1-C
4) alkyloyl] oxygen base, more preferably [(C
1-C
2) alkyloyl] oxygen base, acetoxyl group most preferably.
" low-grade alkylidene " is meant straight or branched aliphatic hydrocrbon divalent group, for example methylene radical, ethylidene, 1-methyl ethylidene, 2-methyl ethylidene, propylidene, methyl propylidene, butylidene, pentylidene, hexylidene etc., and preferred (C
1-C
4) alkylidene group, more preferably (C
1-C
2) alkylidene group.
" low-grade alkylidene dioxy base " be meant-O-[(is rudimentary) and alkylidene group]-the O-group.Be the R of this situation
3Be substituted for divalent group and in next carbon atom.This examples of groups such as methylene radical dioxy base, ethylidene dioxy base, methyl ethylidene dioxy base, propylidene dioxy base etc., and preferred [(C
1-C
4) alkylidene group] dioxy base, more preferably [(C
1-C
2) alkylidene group] dioxy base, methylene radical dioxy base most preferably.
" lower alkoxy that is replaced by aryl " is meant the univalent perssad that wherein above-mentioned lower alkoxy is replaced by above-mentioned aryl.
" lower alkoxy that is replaced by hydroxyl " is meant the univalent perssad that wherein above-mentioned lower alkoxy is replaced by hydroxyl.
" lower alkoxy that is replaced by cyano group " is meant the univalent perssad that wherein above-mentioned (rudimentary) alkoxyl group is replaced by cyano group, for example cyano group methoxyl group, cyano group oxyethyl group, cyano group propoxy-, cyano group butoxy etc., the and (C that is preferably replaced by cyano group
1-C
4) the alkoxyl group, (C that more preferably replaced by cyano group
1-C
2) alkoxyl group, cyano group methoxyl group most preferably.
" by the amino lower alkoxy that replaces " is meant the univalent perssad that wherein above-mentioned lower alkoxy is replaced by amino.
" by the amino lower alkoxy that replaces of elementary alkoxy carbonyl " is meant the lower alkoxy of the amino replacement that is replaced by above-mentioned elementary alkoxy carbonyl.
" lower alkoxy that is replaced by the low alkyl group sulfuryl amino " is meant the univalent perssad that wherein above-mentioned lower alkoxy is replaced by above-mentioned low alkyl group sulfuryl amino.
" by the amino lower alkoxy that replaces of formamyl " is meant the univalent perssad that wherein above-mentioned lower alkoxy is replaced by (formamyl) amino (urea); for example [(formamyl) amino] methoxyl group, [(formamyl) amino] oxyethyl group, [(formamyl) amino] propoxy-, [(formamyl) amino] cyano group butoxy etc., the and (C that is preferably replaced by [(formamyl) amino]
1-C
4) the alkoxyl group, (C that more preferably replaced by [(formamyl) amino]
1-C
2) alkoxyl group, the amino methoxyl group of formamyl most preferably.
" lower alkoxy (alkoky) carbonylamino " is meant the amino that is replaced by above-mentioned elementary alkoxy carbonyl.
" low alkyl group sulfuryl amino " is meant the sulfuryl amino that is replaced by above-mentioned low alkyl group.
Suitable " heterocyclic radical " can be and comprise at least one and be selected from nitrogen, the heteroatomic group of sulphur and Sauerstoffatom, and can comprise saturated or unsaturated monocycle or encircle heterocyclic radical more, and preferred heterocyclic radical can be the heterocyclic radical that comprises N, the first heteromonocyclic group of unsaturated 3-to the 6-group that for example comprises 1-4 nitrogen-atoms, pyrryl for example, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [4H-1 for example, 2, the 4-triazolyl, 1H-1,2, the 3-triazolyl, 2H-1,2,3-triazolyl etc.], tetrazyl [1H-tetrazyl for example, 2H-tetrazyl etc.] etc.; The first heteromonocyclic group group [for example pyrrolidyl, imidazolidyl, piperidyl, piperazinyl, high piperazinyl etc.] of saturated 3-to 7-that comprises 1-4 nitrogen-atoms; The unsaturated annelated heterocycles base that comprises 1-5 nitrogen-atoms, for example indyl, pseudoindoyl, indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, imidazopyridyl, indazolyl, benzotriazole base, tetrazolo pyridazinyl [for example tetrazolo [1,5-b] pyridazinyl etc.], quinoxalinyl etc.; The first heteromonocyclic group of unsaturated 3-to the 6-group that comprises Sauerstoffatom, for example pyranyl, furyl etc.; The first heteromonocyclic group of saturated 3-to the 6-group that comprises Sauerstoffatom, for example 1H-THP trtrahydropyranyl, tetrahydrofuran base etc.; The heteromonocyclic group group of unsaturated 3-to 6-unit that comprises 1-2 sulphur atom, for example thienyl etc.; The heteromonocyclic group group of unsaturated 3-to 6-unit that comprises 1-2 Sauerstoffatom and 1-3 nitrogen-atoms, Li such as oxazolyl, isoxazolyl, oxadiazole base [for example 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2 ,], oxazolinyls such as 5-oxadiazole base [for example 2-oxazolinyl etc.] etc.; The heteromonocyclic group group of saturated 3-to 6-unit [for example morpholinyl etc.] that comprises 1-2 Sauerstoffatom and 1-3 nitrogen-atoms; The unsaturated annelated heterocycles base [for example benzo furazan base, benzoxazolyl, Ben Bing oxadiazole base etc.] that comprises 1-2 Sauerstoffatom and 1-3 nitrogen-atoms; The heteromonocyclic group group of unsaturated 3-to 6-unit that comprises 1-2 sulphur atom and 1-3 nitrogen-atoms, for example thiazolyl, thiadiazolyl group [for example 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.] etc.; The heteromonocyclic group group of saturated 3-to 6-unit [for example thiazolidyl etc.] that comprises 1-2 sulphur atom and 1-3 nitrogen-atoms; The unsaturated annelated heterocycles base [for example benzothiazolyl, diazosulfide base etc.] that comprises 1-2 sulphur atom and 1-3 nitrogen-atoms; Comprise the unsaturated annelated heterocycles base [for example benzofuryl, benzodioxole base, chromanyl etc.] of 1-2 Sauerstoffatom etc.
Described " heterocyclic radical " can be replaced by above-mentioned low alkyl group or oxo, wherein preferred piperidyl, pyrryl, 3-methyl isophthalic acid, 2,4-oxadiazole-5-base, isoindole-1,3-diketone-2-base or 1-methyl isophthalic acid H-imidazolyl.
Heterocyclic moiety in the term " heterocyclic radical carbonyl " is meant above-mentioned heterocyclic radical, preferred piperidyl.
" low alkyl group sulfonyloxy " is meant the sulfonyloxy that is replaced by above-mentioned low alkyl group.
" low-grade alkane acidyl that is replaced by halogen " is meant the above-mentioned low-grade alkane acidyl that is replaced by above-mentioned halogen, for example trifluoroacetyl group etc.
" low alkyl group silyl oxygen base " is meant the silyl oxygen base that is replaced by identical or different above-mentioned (rudimentary) alkyl, for example trimethyl silyl oxygen base, triethylsilyl oxygen base, t-butyldimethylsilyl oxygen base or similar group, and preferred t-butyldimethylsilyl oxygen base.
" sour residue " is meant halogen (for example fluorine, chlorine, bromine, iodine), aryl-sulfonyl oxygen (for example phenylsulfonyloxy, tosyloxy etc.), alkane sulfonyl oxy (for example mesyloxy, ethanesulfonyloxy group etc.) etc.
Preferred such compound (I): R
1Be hydrogen; R
2Be optional low alkyl group, cycloalkyl, halogen or the optional lower alkoxy that is replaced by halogen that is replaced by halogen; R
3Be lower alkoxy; R
4Be R
5-G-J-(wherein G be-CO-or-SO
2-, J is-NH-R
5Be amino or low alkyl group); X is O; Y is CH or N; Z is a low-grade alkylidene; And m is 0 or 1.
The acceptable acid addition salts of compound (I) is an acceptable conventional non-toxic salt on the pharmacology, comprise for example an alkali metal salt (for example, sodium salt of metal-salt, sylvite etc.) and alkaline earth salt (calcium salt for example, magnesium salts etc.), ammonium salt, organic alkali salt (front three amine salt for example, triethylamine salt, pyridinium salt, picoline salt, dicyclohexyl amine salt etc.), organic acid salt (acetate for example, maleate, tartrate, mesylate, benzene sulfonate, formate, tosylate, trifluoroacetate etc.), inorganic acid salt (hydrochloride for example, hydrobromide, vitriol, phosphoric acid salt etc.), amino acid (arginine for example, aspartic acid, L-glutamic acid etc.) salt or class are saloid.
Describe the method for preparing target compound below in detail.
Method (1)
Target compound (Ia) or its salt can pass through compound (II) or its salt and compound (III) or its salt prepared in reaction under acidic conditions (for example, using acetate).
The suitable salt of compound (Ia) and (III) can be identical with the example salt of compound (I).
The acceptable acid addition salts of compound (II) can be the acid salt example of compound (I).
Be reflected in the conventional solvent and carry out, solvent is water, alcohol (for example methyl alcohol, ethanol, propyl alcohol, Virahol etc.), tetrahydrofuran (THF), dioxane etc. or its mixture for example.
Temperature of reaction is inessential, and reaction is carried out being cooled under the heating condition usually.
According to starting raw material, form heterocycle but do not form the pyrazoles ring.In this case, need dehydration so that form the pyrazoles ring.
Dehydration is carried out under comparatively high temps.
Method (2)
Target compound (Ib) or its salt can pass through compound (IV) or its salt and compound (V) or the preparation of its reactant salt.
Compound (Ia), (IV) and suitable salt (V) can be the example salt of compound (I).
When Q is used in this reaction as the compound (V) of halogen, react and preferably exist alkali for example to carry out under basic metal (for example sodium, potassium etc.), alkaline-earth metal (for example magnesium, calcium etc.), hydride or oxyhydroxide or its carbonate or the supercarbonate.
When Q is used in this reaction as the compound (V) of hydroxyl, react preferably existing under diethylazodicarboxylate and the triphenylphosphine and carry out.
Reaction is carried out in the conventional solvent of disadvantageous effect reaction usually, and solvent is water, dioxane, alcohol (for example methyl alcohol, ethanol etc.), acetonitrile, tetrahydrofuran (THF), acetate, N for example, dinethylformamide or its mixture.
Temperature of reaction is inessential, and this reaction can be carried out being cooled under the heating condition.
For the availability of target compound (I) is described, the pharmacology test data of compound (I) is as follows.
[A] analgesic activities:
Effect to rat assist agent arthritis:
(i) testing method:
Research single dose medicine is to the analgesic activities of rat arthritis.
To the right back foot pad injection of the Lewis rat in 7 ages in week contain the 0.5mg tubercule bacillus (DifcoLaboratories, Detroit, thereby 50 μ l whiterusss Mich.) are induced sacroiliitis.With rats with arthritis random packet (n=10), carry out pharmacological agent according to the 22nd day left back pawl pain threshold and body weight.
Give medicine (test-compound), administration was measured the threshold of pain after 2 hours.By Randall-Selitto method evaluation hyperpathia intensity.(Italy) the compressing ankle joint is measured the mechanical threshold of pain of left back pawl (not Zhu She rear solid end) for Ugo Basile Co.Ltd., Varese with the equilibrium pressure instrument.Represent that with gram rat screams or the threshold of struggling is pressed.The rat threshold of drug treating is pressed and the contrast of untreated rat threshold pressure.1.5 the dosage of ratio is effective dose.
(ii) test result:
| Test-compound (embodiment number) | Dosage (mg/kg) | The analgesia coefficient |
| 23 | 3.2 | ＞1.5 |
| 28 | 3.2 | ＞1.5 |
| 61 | 3.2 | ＞1.5 |
| 181 | 3.2 | ＞＝1.5 |
| 240 | 3.2 | ＞＝1.5 |
| 248 | 3.2 | ＞＝1.5 |
| 250 | 3.2 | ＞＝1.5 |
| 254 | 3.2 | ＞＝1.5 |
| 267 | 3.2 | ＞＝1.5 |
[B] anti-COX-I and COX-II suppress active (whole blood assay):
(i) testing method:
The COX-I whole blood assay
Gather fresh blood with the syringe that does not have anti-coagulant from the volunteer.The subject does not have tangible inflammation and do not take any medicine at least in 7 days before blood collection.
Get behind the blood immediately the test-compound of people's whole blood of 500 μ l equal portions and 2 μ l methyl-sulphoxide solvents or ultimate density in 37 ℃ of incubations 1 hour so that blood clotting.Use and suitably handle (not incubation) as blank.When incubation finishes, add 5 μ l 250mM INDOMETHACIN with stopped reaction.Blood obtained serum in 4 ℃ in 5 minutes with 6000 * g centrifugation.100 μ l equal portions serum and 400 μ l methanol mixed are made protein precipitation.Obtain supernatant liquor in 4 ℃ with 6000 * g centrifugation 5 minutes, the method that provides according to manufacturer is with enzyme immunoassay kit measurement TXB
2For test-compound, the result is with thromboxane B
2(TXB
2) product represents with respect to the inhibition percentage of the contrast incubation that comprises the methyl-sulphoxide solvent.
Analytical data will indicate the test-compound of concentration to be converted into logarithmic value and to carry out simple linear regression.IC
50Value is calculated by method of least squares.
The COX-II whole blood assay
Gather fresh blood to the heparinization test tube with syringe from the volunteer.The subject does not have tangible inflammation and do not take any medicine at least in 7 days before blood collection.
With the test-compound of people's whole blood of 500 μ l equal portions and 2 μ l methyl-sulphoxide solvents or 2 μ l ultimate densities in 37 ℃ of incubations 15 minutes.Then with 10 μ l5mg/ml lipopolysaccharides in 37 ℃ of incubations 24 hours to induce COX-II.Use suitable substance P BS to handle (no LPS) as blank.When incubation finished, blood obtained blood plasma in 4 ℃ in 5 minutes with 6000 * g centrifugation.100 μ l equal portions blood plasma and 400 μ l methanol mixed are made protein precipitation.Obtained supernatant liquor in 4 ℃ in 5 minutes with 6000 * g centrifugation, use the radioimmunoassay test kit at PGE according to the method that manufacturer provides
2Measure PGE after being converted into its methyloxime salt derivative
2(PGE
2).
For test-compound, the result is with PGE
2Product is represented with respect to the inhibition percentage of the contrast incubation that comprises the methyl-sulphoxide solvent.Analytical data with indicating the test-compound of concentration to change logarithmic value into, carries out simple linear regression analysis.IC
50Value is calculated by method of least squares.
(ii) test result:
| Test-compound (embodiment number) | COX-I IC50(μM) | COX-II IC50(μM) |
| 23 | ＜0.01 | ＞0.1 |
| 28 | ＜0.01 | ＞0.1 |
| 61 | ＜0.01 | ＞0.1 |
| 181 | ＜0.01 | ＞0.1 |
| 240 | ＜0.01 | ＞0.1 |
| 248 | ＜0.01 | ＞0.1 |
| 250 | ＜0.01 | ＞0.1 |
| 254 | ＜0.01 | ＞0.1 |
| 267 | ＜0.01 | ＞0.1 |
Above-mentioned test result shows that acceptable salt has the inhibition activity of anti-COX, the selective inhibitory activity of especially anti-COX-I on The compounds of this invention (I) or its pharmacology.
[C] is to the inhibition activity of platelet aggregation
(i) method
Preparation thrombocyte enrichment blood plasma
Gather blood to the plastics tubing that comprises 3.8% Trisodium Citrate (1/10 volume) from healthy people volunteer.The subject did not take any medicine at least in 7 days before blood collection.After 1200rpm is centrifugal 10 minutes, partly obtain thrombocyte enrichment blood plasma from the supernatant liquor of blood.After 10 minutes, obtain PFP in the centrifugal residue blood of 3000rpm.
Measure platelet aggregation
Measure platelet aggregation according to turbidimetry with assembling meter (Hema Tracer).In cuvette, after adding compound or solvent, with thrombocyte enrichment blood plasma in 37 ℃ of preincubation 2 minutes.In order to measure the inhibition effect of every kind of compound, add agonist after, from assembling the maximum increased value of 7 minutes light of curve determination conduction.In this research, we use collagen as the platelet aggregation agonist.The ultimate density of collagen is 0.5 μ g/mL.The work of every kind of compound is represented with respect to the inhibition percentage of contrast vehicle treated in order to the platelet aggregation of agonist induction.Data are the mean number ± S.E.M. of 6 experiments.IC
50Value obtains by linear regression, and the platelet aggregation that is expressed as agonist induction produces 50% with respect to the contrast vehicle treated and suppresses required compound concentration.
Above-mentioned test result shows that acceptable salt has the inhibition activity of platelet aggregation-against on The compounds of this invention (I) or its pharmacology.Therefore, acceptable salt can be used for prevention or the disorder of treatment platelet aggregation inductive, for example thrombosis on compound (I) or its pharmacology.
In addition, confirm that further The compounds of this invention (I) does not have non-selective NSAID side effect, for example gastrointestinal dysfunction is hemorrhage, renal toxicity, cardiovascular side effects etc.
As implied above, on target compound of the present invention (I) or its pharmacology acceptable salt have COX suppress active and have good anti-inflammatory, bring down a fever, analgesia, antithrombotic form, the antitumour activity isoreactivity.
Therefore, by to human or animal system or topical, acceptable salt can be used for treating and/or preventing COX mediation property disease, inflammatory diseases, various pain, collagenosis, autoimmune disorder, various immunological disease, thrombosis, cancer and neurodegenerative disease on target compound (I) and its pharmacology.
More particularly, acceptable salt can be used for treating and/or preventing the inflammation and the acute and chronic pain [for example rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, urarthritis, adolescent arthritis, scapulohumeral periarthritis, cervical spondylosis etc.] of joint and muscle on target compound (I) and its pharmacology; Pain in the back; Inflammatory dermatosis [for example tan severely, burn, eczema, dermatitis etc.]; Inflammatory eye disease [for example conjunctivitis etc.]; The tuberculosis [for example asthma, bronchitis, colombophile's disease, farmer lung etc.] that relates to inflammation; Follow the gastrointestinal tract disease [for example aphthous ulcer, ChrohnShi disease, allergic gastritis, varioliform gastritis, ulcerative colitis, celiaca, Crohn disease, irritable intestine syndrome etc.] of inflammation; Oulitis; Dysmenorrhoea; Inflammation, pain and swelling after postoperative or the wound [pain etc. behind the odontectomy]; Follow heating, pain and other illness of inflammation, especially wherein lipoxygenase and cyclooxygenase product are the illness of pathogenic factors; Systemic lupus erythematous, scleroderma, polymyositis, tendonitis, bursitis, polyarteritis nodosa, rheumatic fever, Siogren Cotard, Behcet disease, thyroiditis, type i diabetes, nephrotic syndrome, reproducibility obstacle anaemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, mucocutaneous lymphnode syndrome, sarcoidosis, HodgkinShi disease, Alzheimer's or similar conditions.
In addition, re-set target compound (I) or its salt can be used as the medicine that treats and/or prevents of cardiovascular diseases that hyperglycemia and hyperlipidemia cause or cerebro-vascular diseases.
Target compound (I) and its salt can be used for preventative and the therapeutic treatment artery thrombosis, arteriosclerosis, ischemic heart disease [stenocardia (for example stable stenocardia for example, instability stenocardia, comprise and face infraction etc. frequently), myocardial infarction (for example Acute Myocardial Infarction etc.), Coronary thrombosis etc.], local asphyxia encephalopathy (HIE) [cerebral infarction (for example acute cerebral thrombosis formation etc.) for example, cerebral thrombosis (for example cerebral embolism etc.), transient ischemic attack (for example transient ischemic attack etc.), hematencephalon cerebral vasospasm (for example subarachnoid hemorrhage cerebral vasospasm etc.) etc.], (for example pulmonary thrombosis forms the lung vascular disease, pulmonary infarction etc.), peripheral circulation disorder [atherosclerosis obliterans for example, thromboangiitis obliterans (being the BuergerShi disease), the RaynaudShi disease, diabetic complication (diabetic angiopathy for example, diabetic neuropathy etc.), phiebothrombosis (for example degree of depth phlebothrombosis etc.) etc.], tumor complication (for example repressive thrombosis), miscarriage [for example placenta thrombosis etc.], restenosis and inaccessible again [percutaneous transluminal coronary angioplasty (PTCA) back restenosis and/or inaccessible more for example gives behind the thrombolytic agent restenosis and/or inaccessible (for example organizing fibrinolytic protein incitant (TPA) etc.) again], in vascular operation, prosthetic valve replacement, extracorporeal circulation [surgical operation (for example open cardiac operation for example, pump-oxygenator etc.) hemodialysis etc.] or the transplantation situation under thrombosis, disseminated inravascular coagulation (DIC), the thrombotic thrombocytopenia, the thrombocythemia of the special property sent out, inflammation (for example ephritis etc.), immunological disease, the atrophic thrombosis, crawl row thrombosis, the venectasia thrombosis, the jumping characteristic thrombosis, mural thrombus formation etc.
Target compound (I) and its salt can be used for accessory treatment with dissolved thrombus medicine (for example TPA etc.) or antithrombotics (for example heparin etc.).
And compound (I) also can be used for suppressing thrombosis during the extracorporeal circulation (for example dialysis).
Specifically, example is following disease: by rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, urarthritis, adolescent arthritis etc. cause or with pain; Pain in the back; Neck-shoulder-arms syndrome; Scapulohumeral periarthritis; Pain and swelling etc. after postoperative or the wound.
The merchant who comprises above-mentioned medicinal compositions sells can be with the item of the above-mentioned effect of explanation on the medicine box.
With regard to therapeutic purpose, acceptable salt can comprise as acceptable carrier blended medicinal preparations form on the described compound of effective constituent and the pharmacology and uses on The compounds of this invention (I) and its pharmacology, and that carrier for example is suitable for is oral, parenteral or outside organic or inorganic solid or the liquid excipient that gives.Medicinal preparations can be capsule, tablet, dragee, granula, inhalation, suppository, solution, lotion, suspensoid, emulsion, ointment, gel, creme or similar formulation.If desired, these preparations can comprise: auxiliary, stablizer, wetting agent or emulsifying agent, buffer reagent and other additive commonly used.
With regard to therapeutic purpose, that analgesic of the present invention can be suitable for is oral, the medicinal preparations form of parenteral or outside administration is used.Medicinal preparations can be capsule, tablet, dragee, granula, inhalation, suppository, solution, lotion, suspensoid, emulsion, ointment, gel or similar formulation.
Specifically, can to human or animal's systematicness or locality give analgesic of the present invention with treatment or prevention acute or chronic inflammation with acute and chronic pain.
Although the treatment effective dose of compound (I) should change according to each patient's age and individual state, the average single dose that is effective to treat the compound (I) of above-mentioned disease is about 0.01mg, 0.1mg, 1mg, 10mg, 50mg, 100mg, 250mg, 500mg and 1000mg.In general, the administered dose of every day can be between about 0.01mg/ individuality-Yue 1, between the 000mg/ individuality.
In above and hereinafter the introducing of specification sheets of the present invention, the meaning of following abbreviation and acronym is as shown in the table.
| Abbreviation and acronym | Full name |
| AcOEt or EtOAc | Ethyl acetate |
| AcOH | Acetate |
| BuOH, t-BuOH etc. | Butanols, the trimethyl carbinol etc. |
| DME | 1, the 2-glycol dimethyl ether |
| DMF | N, dinethylformamide |
| DMSO | Methyl-sulphoxide |
| Et3N | Triethylamine |
| EtOH | Ethanol |
| IPE | Diisopropyl ether |
| MeOH | Methyl alcohol |
| PrOH, i-PrOH or IPA etc. | Propyl alcohol, Virahol etc. |
| TFA | Trifluoroacetic acid |
| THF | Tetrahydrofuran (THF) |
| EDCI or WSCD | 1-ethyl-3-[3 '-(dimethylamino) propyl group] carbodiimide |
| HOBt or HOBT | I-hydroxybenzotriazole |
| Pd/C | Carbon carries palladium |
| MCBA or mCPBA or mcpba | 3-chlorine peroxybenzoic acid |
| deg | ℃=degree centigrade |
| min | Minute |
| Hr or h | Hour |
| conc. | Spissated |
| aq | Aqueous (for example NaHCO3 aqueous solution) |
Embodiment given below and preparation only are used to illustrate in greater detail the present invention.
Embodiment 1-1
(1E)-1-[4-(methoxymethoxy) phenyl]-4-methyl-1-pentene-3-ketone
1M aqueous sodium hydroxide solution (5.4ml) is added the solution that 4-methoxymethoxy phenyl aldehyde (4.52g) and 3-methyl-2-butanone (4.69g) are dissolved in ethanol (27ml), and mixture is in stirred overnight at room temperature.
Mixture distributes between ethyl acetate and water.Organic layer is through water, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel chromatography, with 10% ethyl acetate/normal hexane wash-out, obtains oily title compound (4.03g, 63.2%).
1H NMR(CDCl
3)：δ1.18(6H，d，J＝6.7Hz)，2.92(1H，m)，3.48(3H，s)，5.21(2H，s)，6.71(1H，d，J＝16.0Hz)，7.05(2H，d，J＝8.8Hz)，7.51(2H，d，J＝8.8Hz)，7.58(1H，d，J＝16.0Hz).
MS(ESI+)：m/z 257(M+Na).
Embodiment 1-2
(1S, 2R)-and (1R, 2S)-1,2-epoxy-1-[4-(methoxymethoxy) phenyl]-4-methyl-propione
With 30%H
2O
2(1.7ml) and 3M aqueous sodium hydroxide solution (1.7ml) add (1E)-1-[4-(methoxymethoxy) phenyl that embodiment 1-1 obtains]-4-methyl-1-pentene-3-ketone (2.00g) is dissolved in ethanol: the solution of acetone=3: 1 (34ml).Mixture is in stirred overnight at room temperature.
Vacuum concentrated mixture distributes between ethyl acetate and water then.Organic layer is through water, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates, and obtains oily target compound (2.03g, 95%).
1H NMR(DMSO-d6)：δ1.05(6H，d，J＝6.9Hz)，2.85(1H，m)，3.36(3H，s)，3.93(1H，d，J＝1.9Hz)，4.00(1H，d，J＝1.9Hz)，5.20(2H，s)，7.03(2H，d，J＝8-6Hz)，7.30(2H，d，J＝8.6Hz).MS(ESI)：m/z 273(M+Na).
Embodiment 1-3
4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl]-phenol
(1S with embodiment 1-2 acquisition, 2R)-and (1R, 2S)-1,2-epoxy-1-[4-(methoxymethoxy) phenyl]-4-methyl-propione (2.10g) and 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (1.76g) be at ethanol: the mixture in the acetate=20: 1 (20ml) stirred 3 hours in 60 ℃.
Vacuum concentrated mixture.Add ethyl acetate and 1M hydrochloric acid to resistates.With the whole mixtures of activated carbon treatment, filter through the Celite pad.Distribute filtrate.Through 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates organic layer successively.Collect residual solid,, obtain white powder target compound (322.2mg, 12.5%) with the ethyl acetate washing.
1H NMR(CDCl
3)：δ1.33(6H，d，J＝7.0Hz)，3.07(1H，m)，3.80(3H，s)，5.18(1H，s)，6.26(1H，s)，6.72(2H，d，J＝8.8Hz)，6.83(2H，d，J＝9.0H z)，7.08(2H，d，J＝8.8Hz)，7.20(2H，d，J＝9.0Hz).MS(ESI+)：m/z 309(M+H).
Embodiment 2
2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl]-phenoxy group } the ethyl carbamic acid tert-butyl ester
Diethylazodicarboxylate (259mg) is added 4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that embodiment 1-3 obtains] phenol (305mg), 2-tert-butoxycarbonyl monoethanolamine (479mg) and the mixture of triphenylphosphine (390mg) in tetrahydrofuran (THF) (3ml).After 7 hours, diethylazodicarboxylate (17mg) and triphenylphosphine (26mg) are added reaction mixture in stirring at room.
In stirring at room after 1 hour, the vacuum concentration reaction mixture.Resistates is purified through silica gel column chromatography, with 30% ethyl acetate/normal hexane wash-out, obtains solid target compound (396mg, 88.5%).
1H NMR(CDCl
3)：δ1.34(6H，d，J＝7.0Hz)，1.45(9H，s)，3.07(1H，m)，3.48-3.57(2H，m)，3.80(3H，s)，3.97-4.03(2H，m)，4.97(1H，br-s)，6.26(1H，s)，6.76-6.87(4H，m)，7.14(2H，d，J＝8.9Hz)，7.20(2H，d，J＝9.0Hz).
Embodiment 3
2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethylamine hydrochloride
4M hydrochloric acid/dioxane (2ml) is added 2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that embodiment 2 obtains in 0 ℃]-phenoxy group } the ethyl carbamic acid tert-butyl ester (382mg) is dissolved in the solution of methylene dichloride (3ml).
In stirring at room after 1 hour, the vacuum concentration reaction mixture.Resistates obtains Powdered target compound (311mg, 94.7%) through the crystalline mixture of Virahol and ethyl acetate.
1H NMR(DMSO-d6)：δ1.27(6H，d，J＝6.9Hz)，2.95(1H，m)，3.14-3.22(2H，m)，3.76(3H，s)，4.14-4.20(2H，m)，6.41(1H，s)，6.93(4H，d，J＝8.9Hz)，7.16(4H，d，J＝8.9Hz)，8.22(2H，br-s).
MS(ESI+)：m/z 352(M+H).
Embodiment 4
N-(2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group }-ethyl) Toluidrin
Methylsulfonyl chloride (32.2mg) is added 2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that embodiment 3 obtains] phenoxy group } ethylamine hydrochloride (90.9mg) and triethylamine (71.1mg) be dissolved in the solution of methylene dichloride (2ml).Mixture was in stirring at room 2 hours.
Vacuum concentrated mixture, resistates distributes between ethyl acetate and 1M hydrochloric acid and brinish mixture.With the ethyl acetate water layer of stripping.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates obtains white powder target compound (78.0mg, 77.5%) through the crystalline mixture of ethyl acetate and isopropyl ether.
MP：162-163℃.
1H NMR(DMSO-d6)：δ1.26(6H，d，J＝6.9Hz)，2.94(3H，s)，2.94(1H，m)，3.25-3.39(2H，m)，3.76(3H，s)，3.98-4.04(2H，m)，6.40(1H，s)，6.90(2H，d，J＝8.8Hz)，6.93(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.9Hz)，7.27(1H，s).
IR(KBr)：3122，2966，2897，2871，1614，1514cm
-1.
Embodiment 5
N-(2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Isocyanic acid trimethyl silyl ester (41.4mg) is added 2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that embodiment 3 obtains] phenoxy group } ethylamine hydrochloride (93.0mg) and triethylamine (72.8mg) be dissolved in the solution of methylene dichloride (3ml), and mixture was in stirring at room 3 hours.Add isocyanic acid trimethyl silyl ester (8.3mg), mixture was in stirring at room 1.5 hours.Add isocyanic acid trimethyl silyl ester (13.8mg) and triethylamine (12.1mg), mixture was in stirring at room 1.5 hours.
Vacuum concentrated mixture, resistates distributes between chloroform and 1M hydrochloric acid and brinish mixture.Use the chloroform extraction water layer.The organic layer that merges is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches with 10% methyl alcohol/chloroform through preparation type thin layer silica gel chromatographic purification.Isolating silica gel is through 10% methyl alcohol/chloroform extraction, vacuum evaporating solvent.Resistates obtains white powder target compound (85.7mg, 90.6%) through the crystalline mixture of ethyl acetate and isopropyl ether.
MP：100-104℃.
1H NMR(DMSO-d6)：δ1.26(6H，d，J＝6.9Hz)，2.94(1H，m)，3.27-3.36(2H，m)，3.76(3H，s)，3.89-3.96(2H，m)，5.52(2H，s)，6.14(1H，t，J＝5.6Hz)，6.39(1H，s)，6.89(2H，d，J＝8.7Hz)，6.93(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.9Hz).
IR(KBr)：3371，3190，2964，2873，1738，1684，1639，1614，1543，1512cm
-1.
MS(ESI+)：m/z 395(M+H).
Embodiment 6
2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
To contain 2-{4-[3-ethoxy carbonyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } tetrahydrofuran (THF) (10ml) of the ethyl carbamic acid tert-butyl ester (1.37g) is added dropwise to the solution that the 0.93M methyl-magnesium-bromide is dissolved in tetrahydrofuran (THF) (16ml) down in 24-27 ℃ and water-bath cooling.
After 1 hour, mixture is poured into the mixture of saturated aqueous ammonium chloride and ice in stirring at room.Use the ethyl acetate extraction mixture.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 70% ethyl acetate/normal hexane wash-out, obtains amorphous powder target compound (117g, 88%).
MS(ESI+)：m/z 468(M+H)
1H NMR(CDCl
3)：δ1.45(9H，s)，1.65(6H，s)，2.78(1H，s)，3.48-3.57(2H，m)，3.81(3H，s)，3.97-4.03(2H，m)，4.97(1H，br)，6.36(1H，s)，6.78-6.89(4H，m)，7.13(2H，d，J＝8.7Hz)，7.21(2H，d，J＝8.9Hz).
Embodiment 7
2-{4-[3-pseudoallyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Methylsulfonyl chloride (367mg) and triethylamine (649mg) are added 2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that embodiment 6 obtains successively] phenoxy group } the ethyl carbamic acid tert-butyl ester (1.0g) and N, dinethylformamide (91.5mg) is dissolved in the solution of methylene dichloride (10ml), and mixture was in stirring at room 2 hours.Add methylsulfonyl chloride and triethylamine again and stirring under uniform temp, up to consuming all starting raw materials.
Reaction mixture is distributed between ethyl acetate and 1M hydrochloric acid, and organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 30% ethyl acetate/normal hexane wash-out, obtains amorphous powder target compound (900mg, 93.6%).
1H NMR(CDCl
3)：δ1.45(9H，s)，2.21(3H，s)，3.48-3.57(2H，m)，3.81(3H，s)，3.97-4.03(2H，m)，4.98(1H，br-s)，5.12(1H，br-s)，5.59(1H，br-s)，6.56(1H，s)，6.77-6.87(4H，m)，7.14(2H，d，J＝8.7Hz)，7.22(2H，d，J＝8.9Hz).
MS(ESI+)：m/z 450(M+H).
Embodiment 8
2-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
2-{4-[3-pseudoallyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that 10%Pd-C 50% weight in wet base (65mg) and embodiment 7 obtained] phenoxy group } mixture of the ethyl carbamic acid tert-butyl ester (645mg) in tetrahydrofuran (THF) (2ml) and methyl alcohol (4ml) be at H
2(latm) under in room temperature hydrogenation 3 hours.
Remove by filter catalyzer.The washings of vacuum concentrated filtrate and merging.Resistates obtains white powder target compound (370mg, 57.1%) through the crystalline mixture of ethyl acetate and isopropyl ether.
1H NMR(CDCl
3)：δ1.34(6H，d，J＝7.0Hz)，1.45(9H，s)，3.07(1H，m)，3.48-3.57(2H，m)，3.80(3H，s)，3.97-4.03(2H，m)，4.97(1H，br-s)，6.26(1H，s)，6.76-6.87(4H，m)，7.14(2H，d，J＝8.9Hz)，7.20(2H，d，J＝9.0Hz).
MS(ESI+)：m/z 452(M+H).
Embodiment 9
2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation amorphous powder title compound (624.4mg, 42.9%), with 2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 6.
1H NMR(CDCl
3)：δ1.45(9H，s)，1.65(6H，s)，3.49-3.57(3H，m)，3.93(3H，s)，3.98-4.04(2H，m)，4.98(1H，br)，6.39(1H，s)，6.72(1H，d，J＝8.8Hz)，6.83(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.54(1H，dd，J＝2.8，8.8Hz)，8.07(1H，d，J＝2.8Hz).
MS(ESI+)：469(M+H).
Embodiment 10
2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation oily title compound (495mg, 85.7%), 2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl with embodiment 9 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 7.
1H NMR(CDCl
3)：δ1.45(9H，s)，2.20(3H，s)，3.49-3.57(2H，m)，3.92(3H，s)，3.98-4.04(2H，m)，4.99(1H，br-s)，5.15(1H，br-s)，5.60(1H，br-s)，6.58(1H，s)，6.72(1H，d，J＝8.8H z)，6.83(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.7Hz)，7.55(1H，dd，J＝2.6，8.8Hz)，8.09(1H，d，J＝2.6Hz).
MS(ESI+)：m/z 451(M+H).
Embodiment 11
2-{4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation amorphous powder title compound (220mg, quantitatively), with 2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 10 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 8.
1H NMR(CDCl
3)：δ1.34(6H，d，J＝6.8Hz)，1.45(9H，s)，3.07(1H，m)，3.48-3.57(2H，m)，3.92(3H，s)，3.98-4.04(2H，m)，4.98(1H，br)，6.28(1H，s)，6.71(1H，d，J＝8.9Hz)，6.82(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.56(1H，dd，J＝2.6，8.9Hz)，8.05(1H，d，J＝2.6Hz).
MS(ESI+)：m/z 453(M+H).
Embodiment 12
2-{4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethamine dihydrochloride
Preparation amorphous powder title compound (257mg, quantitatively), with 2-{4-[3-sec.-propyl-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 11 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 3.
1H NMR(DMSO-d6)：δ1.27(6H，d，J＝6.9H z)，2.96(1H，m)，3.15-3.23(2H，m)，3.85(3H，s)，4.15-4.21(2H，m)，6.47(1H，s)，6.86(1H，d，J＝8.8Hz)，6.97(2H，d，J＝8.8Hz)，7.20(2H，d，J＝8.8Hz)，7.62(1H，dd，J＝2.7，8.8Hz)，8.01(1H，d，J＝2.7Hz)，8.19(2H，s).
MS(ESI+)：m/z 353(M+H).
Embodiment 13
N-(2-{4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation white powder title compound (49.9mg, 51.6%) is with 2-{4-[3-sec.-propyl-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 12 acquisitions] phenoxy group } ethamine, the similar approach of employing embodiment 5.
MP：106-107℃.
1H NMR(DMSO-d6)：δ1.27(6H，d，J＝6.9Hz)，2.96(1H，m)，3.27-3.36(2H，m)，3.85(3H，s)，3.94(2H，t J＝5.5Hz)，5.52(2H，s)，6.15(1H，t，J＝5.6Hz)，6.45(1H，s)，6.85(1H，d，J＝8.8Hz)，6.93(2H，d，J＝8.7Hz)，7.16(2H，d，J＝8.7Hz)，7.60(1H，dd，J＝2.6，8.8Hz)，8.02(1H，d，J＝2.6Hz).
IR(KBr)：3400，3390，3379，3352，2960，1657，1608，1547，1512，1500cm
-1.
MS(ESI+)：m/z 396(M+H).
Embodiment 14-1
5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-amine
Sodium (3.19g) is added ethanol (160ml) in batches.After all sodium dissolves, with this solution of the disposable adding of 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (14.5g).Mixture was in stirring at room 10 minutes.To the disposable adding 3-of mixture (4-benzyloxy phenyl) vinyl cyanide (16.3g), mixture was refluxed 3 days.
Leach insolubles, vacuum concentrated filtrate.Ethyl acetate and water are added resistates, and mixture was in stirring at room 1 hour.The collecting precipitation thing, water, ethyl acetate washing successively, dry air obtains Powdered target compound (12.57g, 48.6%).
1H NMR(DMSO-d6)：δ2.49(1H，dd，J＝8.3，16.1Hz)，3.29(1H，dd，J＝10.2，16.1Hz)，3.60(3H，s)，4.69(1H，dd，J＝8.3，10.2Hz)，5.06(2H，s)，5.62(2H，s)，6.65(4H，s)，6.97(2H，d，J＝8.6Hz)，7.25(2H，d，J＝8.6Hz)，7.31-7.48(5H，m).
MS：(ESI+)：m/z 374(M+H).
Embodiment 14-2
5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-amine
With MnO
2(3.5g) add 5-[4-(benzyloxy) phenyl that embodiment 14-1 obtains]-1-(4-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-amine (12.54g) is dissolved in N, the solution of dinethylformamide (65ml), mixture stirred 2 hours in 60 ℃.Add MnO
2(5.3g), mixture stirred 1 hour in 60 ℃.
Mixture filters through the Celite pad, uses N, and dinethylformamide washs this pad.Add ethyl acetate and water to filtrate, mixture was in stirring at room 1 hour.The collecting precipitation thing washes the back dry air with water.The powder suspension that obtains in the isopropyl ether of heat, is stirred cooling, collect the back, obtain Powdered target compound (11.70g, 93.8%) with the isopropyl ether washing.
1H NMR(DMSO-d6)：δ3.74(3H，s)，4.84(2H，s)，5.08(2H，s)，5.73(1H，s)，6.87(2H，d，J＝9.0Hz)，6.96(2H，d，J＝9.0H z)，7.03-7.13(4H，m)，7.34-7.47(5H，m).
MS(ESI+)：m/z 372(M+H).
Embodiment 15
5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-N, N-dimethyl-1H-pyrazoles-3-amine
The 37% methane amide aqueous solution (6ml) and sodium cyanoborohydride (1.39g) are added 5-[4-(benzyloxy) phenyl that embodiment 14-2 obtains successively]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-amine (2.75g) is dissolved in the solution of methyl alcohol (30ml).In stirring at room reaction mixture 3 days, add an amount of 37% methane amide aqueous solution and sodium cyanoborohydride once in a while to consume whole starting raw materials.
The vacuum concentration reaction mixture, resistates distributes between ethyl acetate and water.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 20% ethyl acetate/chloroform wash-out, obtains oily target compound (0.88g, 29.8%).
1H NMR(DMSO-d6)：δ2.81(6H，s)，3.75(3H，s)，5.08(2H，s)，6.03(1H，s)，6.90(2H，d，J＝8.9Hz)，6.97(2H，d，J＝8.8Hz)，7.06-7.16(4H，m)，7.32-7.46(5H，m).
MS(ESI+)：m/z 400(M+H).
Embodiment 16
4-[3-(dimethylamino)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
5-[4-(benzyloxy) phenyl with embodiment 15 acquisitions]-1-(4-p-methoxy-phenyl)-N, N-dimethyl-1H-pyrazoles-3-amine (0.83g) and the mixture of 10%Pd-C 50% weight in wet base (160mg) in acetate (8ml) are at H
2(latm) under in room temperature hydrogenation 10 hours.
Remove by filter catalyzer.The washings of vacuum concentrated filtrate and merging.Resistates is purified through silica gel column chromatography, with 20% ethyl acetate/chloroform wash-out, with the crystalline mixture of isopropyl ether and ethyl acetate, obtains white powder target compound (455mg, 70.8%).
1H NMR(DMSO-d6)：δ2.80(6H，s)，3.74(3H，s)，5.96(1H，s)，6.69(2H，d，J＝8.5Hz)，6.89(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.5H z)，7.09(2H，d，J＝9.0Hz)，9.64(1H，s).
MS(ESI+)：m/z 310(M+H).
Embodiment 17
2-{4-[3-(dimethylamino)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation oily title compound (477.1mg, 99.7%) is with 4-[3-(dimethylamino)-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 16 acquisitions] phenol, the similar approach of employing embodiment 2.
1H NMR(CDCl
3)：δ1.45(9H，s)，2.93(6H，s)，3.48-3.54(2H，m)，3.79(3H，s)，3.97-4.03(2H，m)，4.97(1H，br)，5.85(1H，s)，6.79(2H，d，J＝8.7Hz)，6.81(2H，d，J＝9.0Hz)，7.10-7.27(4H，m).
Embodiment 18
5-[4-(2-amino ethoxy) phenyl]-1-(4-p-methoxy-phenyl)-N, N-dimethyl-1H-pyrazoles-3-amine hydrochlorate
Prepare amorphous title compound (454mg, quantitative), with 2-{4-[3-(dimethylamino)-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 17 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 3.
1H NMR(DMSO-d6)：δ2.83(6H，s)，3.16-3.25(2H，m)，3.75(3H，s)，4.13-4.18(2H，m)，6.06(1H，s)，6.91(2H，d，J＝9.0Hz)，6.94(2H，d，J＝8.8Hz)，7.12(2H，d，J＝9.0Hz)，7.17(2H，d，J＝8.8Hz)，8.05(2H，br-s).
MS(ESI+)：m/z 353(M+H).
Embodiment 19
N-(2-{4-[3-(dimethylamino)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Prepare amorphous title compound (116mg, 55.7%), 5-[4-(2-amino ethoxy) phenyl that obtains with embodiment 18]-1-(4-p-methoxy-phenyl)-N, N-dimethyl-1H-pyrazoles-3-amine hydrochlorate adopts the similar approach of following embodiment 75.
1H NMR(DMSO-d6)：δ2.81(6H，s)，3.29-3.34(2H，m)，3.74(3H，s)，3.92(2H，t，J＝5.6Hz)，5.53(2H，s)，6.03(1H，s)，6.15(1H，t，J＝5.6Hz)，6.88-6.92(4H，m)，7.04-7.14(4H，m).
IR (direct compression): 3344,3330,3321,1658,1651,1643,1612,1579,1564,1554,1529,1514cm
-1.
MS(ESI+)：m/z 396(M+H).
Embodiment 20-1
5-[4-(methoxymethoxy) phenyl]-1-(4-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-amine
Prepare Powdered title compound (4.0g, 57.8%),, adopt the similar approach of embodiment 14-1 with 3-(4-methoxymethoxy phenyl) vinyl cyanide.
1H NMR(DMSO-d6)：δ2.49(1H，dd，J＝8.3，16.1Hz)，3.30(1H，dd，J＝10.3，16.1Hz)，3.36(3H，s)，3.59(3H，s)，4.70(1H，dd，J＝8.3，10.3Hz)，5.16(2H，s)，5.62(2H，s)，6.65(4H，s)，6.97(2H，d，J＝8.6Hz)，7.25(2H，d，J＝8.6Hz).
MS(ESI+)：m/z 328(M+H).
Embodiment 20-2
5-[4-(methoxymethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-amine
Preparation oily title compound (4.80g, quantitatively), with 5-[4-(methoxymethoxy) phenyl of embodiment 20-1 acquisition]-1-(4-p-methoxy-phenyl)-4,5-dihydro-1 h-pyrazole-3-amine, the similar approach of employing embodiment 14-2.
1H NMR(DMSO-d6)：δ3.36(3H，s)，3.74(3H，s)，4.85(2H，s)，5.18(2H，s)，5.74(1H，s)，6.88(2H，d，J＝9.0Hz)，6.96(2H，d，J＝8.8Hz)，7.02-7.13(4H，m).
MS(ESI+)：m/z 326(M+H).
Embodiment 21
3-chloro-5-[4-(methoxymethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles
5-[4-(methoxymethoxy) phenyl that embodiment 20-2 is obtained]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-amine (3.79g), lithium chloride (2.47g) and cupric chloride (II) (3.13g) mixture in acetonitrile (60ml) in stirring at room 10 minutes.Add Isopentyl nitrite (2.73g) to this mixture, mixture was in stirring at room 1 hour.
Mixture distributes between ethyl acetate and saturated aqueous ammonium chloride.Organic layer is through saturated aqueous ammonium chloride and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 30% ethyl acetate/normal hexane wash-out.Vacuum evaporating solvent.Resistates obtains white powder target compound (2.38g, 59.3%) through the crystalline mixture of isopropyl ether and ethyl acetate.
1H NMR(CDCl
3)：δ3.48(3H，s)，3.82(3H，s)，5.17(2H，s)，6.36(1H，s)，6.85(2H，d，J＝9.0Hz)，6.95(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.9Hz)，7.20(2H，d，J＝9.0Hz).
MS(ESI+)：m/z 345(M+H).
Embodiment 22
4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
3-chloro-5-[4-(methoxymethoxy) phenyl that obtains to embodiment 21]-solution that 1-(4-p-methoxy-phenyl)-1H-pyrazoles (2.35g) is dissolved in tetrahydrofuran (THF) (10ml) and methyl alcohol (10ml) adds 36% hydrochloric acid (0.34ml).In stirring at room reaction mixture 1 hour, stirred 1.5 hours in 50 ℃ again, stirred 1.5 hours in 60 ℃ then.
Mixture is distributed between ethyl acetate and water.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Collect residual solid, the mixture washing with isopropyl ether and normal hexane obtains white powder target compound (1.99g, 97.1%).
1H NMR(DMSO-d6)：δ3.78(3H，s)，6.62(1H，s)，6.71(2H，d，J＝8.7Hz)，6.96(2H，d，J＝9.0Hz)，7.03(2H，d，J＝8.7Hz)，7.19(2H，d，J＝9.0Hz)，9.80(1H，s).
200MHz 1H NMR(CDCl
3)：δ3.82(3H，s)，5.24(1H，s)，6.35(1H，s)，6.75(2H，d，J＝8.6Hz)，6.84(2H，d，J＝9.0Hz)，7.07(2H，d，J＝8.6Hz)，7.18(2H，d，J＝9.0Hz).
MS(ESI+)：m/z 301(M+H).
Embodiment 23
2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
60% sodium hydride mineral oil dispersion liquid (31.1mg) is added 4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl that embodiment 22 obtains under ice bath cooling] phenol (180mg) is dissolved in N, the solution of dinethylformamide (2ml).In stirring at room reaction mixture 1 hour.Add 2-bromotrifluoromethane butyl (dimethyl) silyl ether (258mg) to reaction mixture and be dissolved in N, the solution of dinethylformamide (2ml).
After stirred overnight at room temperature, pour mixture into frozen water.Use the ethyl acetate extraction mixture.Organic layer is through water and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is dissolved in ethanol (3.6ml).Add 36% aqueous hydrochloric acid (0.3ml) to described solution.In stirring at room after 3 hours, vacuum concentrated mixture.Resistates distributes between ethyl acetate and saturated sodium bicarbonate aqueous solution.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches with 70% ethyl acetate/normal hexane through preparation type thin layer silica gel chromatographic purification.Isolating silica gel is through 10% methyl alcohol/chloroform extraction, vacuum evaporating solvent.Resistates obtains white powder target compound (136.4mg, 66.1%) through the crystalline mixture of isopropyl ether and ethyl acetate.
MP：114.7-115.5℃.
1H NMR(DMSO-d6)：δ3.64-3.73(2H，m)，3.77(3H，s)，3.97(2H，t，J＝4.9Hz)，4.86(1H，t，J＝5.4Hz)，6.68(1H，s)，6.91(2H，d，J＝8.9Hz)，6.96(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)，7.20(2H，d，J＝8.9Hz).
IR(KBr)：3521，1610，1518cm
-1.
MS(ESI+)：m/z 345(M+H).
Embodiment 24
2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Prepare amorphous title compound (329.5mg, 22.3%), 4-[3-chloro-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl that obtains with embodiment 22] phenol, adopt the similar approach of following embodiment 73.
1H NMR(CDCl
3)：δ1.45(9H，s)，3.48-3.57(2H，m)，3.81(3H，s)，4.00(2H，t，J＝5.1Hz)，4.96(1H，br)，6.35(1H，s)，6.81(2H，d，J＝8.8Hz)，6.84(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.9Hz).
MS(ESI+)：m/z 444(M+H).
Embodiment 25
2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation title compound (1.31g, 97.8%) is with 4-[3-chloro-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 22 acquisitions] phenol, the similar approach of employing embodiment 2.
MS(ESI+)：m/z 444(M+H).
Embodiment 26
2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethylamine hydrochloride
Preparation white powder title compound (605.2mg, 85.4%) is with 2-{4-[3-chloro-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 25 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 3.
1H NMR(DMSO-d6)：δ3.14-3.23(2H，m)，3.78(3H，s)，4.14-4.20(2H，m)，6.70(1H，s)，6.96(2H，d，J＝8.8Hz)，6.97(2H，d，J＝8.9Hz)，7.19(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.9Hz)，8.19(2H，br-s).
MS(ESI+)：m/z 344(M+H).
Embodiment 27
N-(2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Preparation white powder title compound (137.8mg, 82.8%) is with 2-{4-[3-chloro-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 26 acquisitions] phenoxy group } ethylamine hydrochloride, the similar approach of employing embodiment 4.
MP：117-119℃.
1H NMR(DMSO-d6)：δ2.94(3H，s)，3.27-3.34(2H，m)，3.76(3H，s)，4.02(2H，t，J＝5.5Hz)，6.69(1H，s)，6.90-7.01(4H，m)，7.14-7.25(4H，m)，7.28(1H，t，J＝5.7Hz).
IR(KBr)：1612，1516cm
-1.
MS(ESI+)：m/z 422(M+H).
Embodiment 28
N-(2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation white powder title compound (174.6mg, 85.8%), 2-{4-[3-chloro-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl that obtains with embodiment 26] phenoxy group } ethylamine hydrochloride, adopt the similar approach of following embodiment 75.
MP：144.8-145.4℃.
1H NMR(DMSO-d6)：δ3.27-3.34(2H，m)，3.77(3H，s)，3.93(2H，t，J＝5.5Hz)，5.52(2H，s)，6.15(1H，t，J＝5.7Hz)，6.68(1H，s)，6.92(2H，d，J＝9.0Hz)，6.97(2H，d，J＝9.0Hz)，7.15(2H，d，J＝9.0Hz)，7.20(2H，d，J＝9.0Hz).
IR(ATR)：3423，3402，3203，3143，3010，2976，2943，2885，1651，1610，1583，1516cm
-1.
MS(ESI+)：m/z 387(M+H).
Embodiment 29-1
5-[4-(methoxymethoxy) phenyl]-1-(6-methoxyl group-3-pyridyl)-4,5-dihydro-1 h-pyrazole-3-amine
Prepare Powdered title compound (1.63g, 41.2%),, adopt the similar approach of embodiment 14-1 with 3-(4-methoxymethoxy phenyl) vinyl cyanide and 2-methoxyl group-5-pyridyl hydrazine dihydrochloride.
H NMR (DMSO-d6): δ 2.48-2.60 (1H, dd overlap), 3.23-3.34 (1H, dd overlap), 3.36 (3H, s), 3.68 (3H, s), 4.75 (1H, dd, J=8.6,10.0Hz), 5.16 (2H, s), 5.77 (2H, s), 6.56 (1H, d, J=8.8Hz), 6.98 (2H, d, J=8.6Hz), 7.15 (1H, dd, J=2.8,8.8Hz), 7.27 (2H, d, J=8.6Hz), 7.49 (1H, d, J=2.8Hz) .MS (ESI+): m/z 329 (M+H).
Embodiment 29-2
5-[4-(methoxymethoxy) phenyl]-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-amine
Preparation oily title compound (1.77g, quantitatively), with 5-[4-(methoxymethoxy) phenyl of embodiment 29-1 acquisition]-1-(6-methoxyl group-3-pyridyl)-4,5-dihydro-1 h-pyrazole-3-amine, the similar approach of employing embodiment 14-2.
1H NMR(DMSO-d6)：δ3.37(3H，s)，3.83(3H，s)，4.97(2H，s)，5.19(2H，s)，5.78(1H，s)，6.81(1H，d，J＝8.9Hz)，6.99(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.51(1H，dd，J＝2.7，8.9Hz)，7.92(1H，d，J＝2.7Hz).
MS(ESI+)：m/z 327(M+H).
Embodiment 30
5-{3-chloro-5-[4-(methoxymethoxy) phenyl]-the 1H-pyrazol-1-yl }-the 2-methoxypyridine
Prepare Powdered title compound (981.7mg, 57.9%), with 5-[4-(methoxymethoxy) phenyl of embodiment 29-2 acquisition]-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-amine, the similar approach of employing embodiment 21.
1H NMR(CDCl
3)：δ3.48(3H，s)，3.93(3H，s)，5.18(2H，s)，6.39(1H，s)，6.74(1H，d，J＝8.8Hz)，6.99(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz)，7.55(1H，dd，J＝2.7，8.8Hz)，8.05(1H，d，J＝2.7Hz).
MS(ESI+)：m/z 346(M+H).
Embodiment 31
4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl]-phenol
Preparation white powder title compound (2.15g, 80.5%) is with 5-{3-chloro-5-[4-(methoxymethoxy) phenyl of embodiment 30 acquisitions]-the 1H-pyrazol-1-yl }-the 2-methoxypyridine, the similar approach of employing embodiment 22.
1H NMR(DMSO-d6)：δ3.87(3H，s)，6.68(1H，s)，6.74(2H，d，J＝8.6Hz)，6.89(1H，d，J＝8.8Hz)，7.07(2H，d，J＝8.6Hz)，7.65(1H，dd，J＝2.7，8.8Hz)，8.09(1H，d，J＝2.7Hz)，9.86(1H，br-s).
MS(ESI+)：m/z 302(M+H).
Embodiment 32
2-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Preparation white powder title compound (140.9mg, 86%) is with 4-[3-chloro-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 31 acquisitions] phenol, the similar approach of employing embodiment 23.
MP：136.5-138.2℃.
1H NMR(DMSO-d6)：δ3.65-3.74(2H，m)，3.87(3H，s)，3.98(2H，t，J＝4.9Hz)，4.87(1H，t，J＝5.5Hz)，6.74(1H，s)，6.86-6.98(3H，m)，7.19(2H，d，J＝8.8Hz)，7.67(1H，dd，J＝2.8，8.8Hz)，8.10(1H，d，J＝2.8Hz).
IR(KBr)：3369，2960，1610，1502cm
-1.
MS(ESI+)：m/z 346(M+H).
Embodiment 33
2-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation white solid title compound (964mg, 93.4%) is with 4-[3-chloro-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 31 acquisitions] phenol, the similar approach of employing embodiment 2.
1H NMR(DMSO-d6)：δ1.37(9H，s)，3.22-3.33(2H，m)，3.87(3H，s)，3.95(2H，t，J＝5.7Hz)，6.74(1H，s)，6.86-7.04(4H，m)，7.19(2H，d，J＝8.7Hz)，7.67(1H，dd，J＝2.7，8.8Hz)，8.11(1H，d，J＝2.7Hz).
MS(ESI+)：m/z 445(M+H).
Embodiment 34
2-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group }-the ethamine dihydrochloride
Prepare amorphous title compound (842mg, 98.6%), with 2-{4-[3-chloro-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 33 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 3.
1H NMR(DMSO-d6)：δ3.15-3.24(2H，m)，3.87(3H，s)，4.19(2H，t，J＝4.9Hz)，6.76(1H，s)，6.90(1H，d，J＝8.8Hz)，6.99(2H，d，J＝8.8Hz)，7.23(2H，d，J＝8.8Hz)，7.68(1H，d，J＝2.7，8.8Hz)，8.10(1H，d，J＝2.7Hz)，8.20(2H，br-s).
MS(ESI+)：m/z 345(M+H).
Embodiment 35
N-(2-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation white powder title compound (119.5mg, 62.4%), 2-{4-[3-chloro-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl that obtains with embodiment 34] phenoxy group } the ethamine dihydrochloride, adopt the similar approach of following embodiment 75.
MP：155.6-157.9℃.
1H NMR(DMSO-d6)：δ3.27-3.34(2H，m)，3.87(3H，s)，3.94(2H，t，J＝5.5Hz)，5.53(2H，s)，6.15(1H，t，J＝5.5Hz)，6.75(1H，s)，6.89(1H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，7.19(2H，d，J＝8.8Hz)，7.66(1H，dd，J＝2.7，8.8Hz)，8.11(1H，d，J＝2.7Hz).
IR(KBr)：3425，3415，3319，1657，1610，1591，1581，1574，1500cm
-1.
Embodiment 36
5-[4-(benzyloxy) phenyl]-3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles
With 5-[4-(benzyloxy) phenyl]-3-hydroxyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles (2.4g), 2-iodopropane (5.48g) and salt of wormwood (2.67g) are at N, and the mixture in the dinethylformamide (10ml) stirred 3 hours in 100 ℃.
Pour reaction mixture into frozen water, use the ethyl acetate extraction mixture.Organic layer is through water and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 20% ethyl acetate/normal hexane wash-out, vacuum evaporating solvent.Resistates obtains white powder target compound (2.14g, 80.1%) through the mixture recrystallization of ethyl acetate and normal hexane.
1H NMR(DMSO-d6)：δ1.31(6H，d，J＝6.1Hz)，3.76(3H，s)，4.75(1H，m)，5.08(2H，s)，6.00(1H，s)，6.92(2H，d，J＝9.0Hz)，6.97(2H，d，J＝8.9Hz)，7.10-7.16(4H，m)，7.34-7.43(5H，m).
MS(ESI+)：m/z 415(M+H).
Embodiment 37
4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl]-phenol
Add 5-[4-(benzyloxy) phenyl that ethanol (10ml), embodiment 36 obtain successively to the solution of ammonium formiate (954mg) water-soluble (2ml)]-solution and 10% carbon that 3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles (2.09g) is dissolved in tetrahydrofuran (THF) (10ml) carries palladium 50% weight in wet base (200mg).Backflow mixture 1 hour.
Remove by filter catalyzer, wash with ethyl acetate.The washings of vacuum concentrated filtrate and merging.Add ethyl acetate and water to resistates.The collecting precipitation thing, water and ethyl acetate washing obtain first white powder target compound (419mg).Distribute filtrate, organic layer is saturated through sodium chloride aqueous solution, and the dried over mgso final vacuum concentrates.Collect remaining crystal,, obtain second batch of white powder target compound (1.19g, 72.5%) with the isopropyl ether washing.
1H NMR(DMSO-d6)：δ1.31(6H，d，J＝6.2Hz)，3.75(3H，s)，4.75(1H，m)，5.93(1H，s)，6.70(2H，d，J＝8.6Hz)，6.91(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.6Hz)，7.11(2H，d，J＝9.0Hz)，9.70(1H，s).
MS(ESI+)：m/z 325(M+H).
Embodiment 38
2-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Preparation oily title compound (147.3mg, 88.2%) is with 4-[3-isopropoxy-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 37 acquisitions] phenol, the similar approach of employing embodiment 23.
1H NMR(CDCl
3)：δ1.40(6H，d，J＝6.2Hz)，2.02(1H，t，J＝5.8Hz)，3.79(3H，s)，3.94-4.00(2H，m)，4.04-4.10(2H，m)，4.87(1H，m)，5.85(1H，s)，6.81(2H，d，J＝9.0Hz)，6.82(2H，d，J＝8.9Hz)，7.10-7.21(4H，m).
IR(neat)：3400，3369，2974，2933，1612，1514cm
-1.
MS(ESI+)：m/z 369(M+H).
Embodiment 39
2-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation white powder title compound (520mg, 72.2%) is with 4-[3-isopropoxy-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 37 acquisitions] phenol, the similar approach of employing embodiment 2.
1H NMR(DMSO-d6)：δ1.31(6H，d，J＝6.2Hz)，1.37(9H，s)，3.22-3.31(2H，m)，3.75(3H，s)，3.90-3.97(2H，m)，4.76(1H，m)，5.99(1H，s)，6.86-6.96(4H，m)，7.01(1H，t，J＝5.6Hz)，7.09-7.15(4H，m).
MS(ESI+)：m/z 467(M+H).
Embodiment 40
2-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethylamine hydrochloride
Prepare amorphous title compound (557mg, quantitative), with 2-{4-[3-isopropoxy-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 39 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 3.
1H NMR(DMSO-d6)：δ1.31(6H，d，J＝6.1Hz)，3.12-3.28(2H，m)，3.76(3H，s)，4.00-4.18(2H，m)，4.76(1H，m)，6.01(1H，s)，6.92(2H，d，J＝9.0Hz)，6.94(2H，d，J＝8.7Hz)，7.10-7.19(4H，m)，8.06(2H，br-s).
MS(ESI+)：m/z 368(M+H).
Embodiment 41
N-(2-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Preparation white powder title compound (125mg, 79.8%) is with 2-{4-[3-isopropoxy-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 40 acquisitions] phenoxy group } ethylamine hydrochloride, the similar approach of employing embodiment 4.
MP：167.9-168.0℃.
1H NMR(DMSO-d6)：δ1.31(6H，d，J＝6.1Hz)，2.94(3H，s)，3.27-3.36(2H，m)，3.75(3H，s)，3.98-4.05(2H，m)，4.76(1H，m)，6.00(1H，s)，6.88-6.94(4H，m)，7.12(2H，d，J＝9.0Hz)，7.14(2H，d，J＝8.9Hz)，7.29(1H，t，J＝5.8Hz).
IR(KBr)：3132，2979，2939，1612，1556，1518cm
-1.
MS(ESI+)：m/z 446(M+H).
Embodiment 42
N-(2-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation white powder title compound (76.3mg, 50.1%) is with 2-{4-[3-isopropoxy-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 40 acquisitions] phenoxy group } ethylamine hydrochloride, the similar approach that adopts following embodiment 75 to introduce.
MP：139-140℃.
1H NMR(DMSO-d6)：δ1.31(6H，d，J＝6.1Hz)，3.27-3.35(2H，m)，3.75(3H，s)，3.89-3.96(2H，m)，4.76(1H，m)，5.53(2H，s)，6.00(1H，s)，6.15(1H，t，J＝5.7Hz)，6.90(2H，d，J＝8.9Hz)，6.92(2H，d，J＝9.0Hz)，
7.08-7.15(4H，m).
IR(KBr)：3388，3350，3332，1658，1612，1579，1562，1554，1518cm
-1.
MS(ESI+)：m/z 411(M+H).
Embodiment 43
5-[4-(benzyloxy) phenyl]-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-alcohol
The solution that is dissolved in N-Methyl pyrrolidone (10ml) to 3-(4-benzyloxy phenyl) propynoic acid (1g) and I-hydroxybenzotriazole hydrate (643mg) adds WSCD.HCl (912mg), and mixture was in stirring at room 10 minutes.In another flask, diisopropylethylamine (2.31g) is added the 5-diazanyl-suspension of 2-methoxypyridine dihydrochloride (1.26g) in N-Methyl pyrrolidone (4ml), dissolve fully up to 5-diazanyl-2-methoxypyridine dihydrochloride in stirring at room.The hydrazine solution that obtains is added reaction flask, and mixture was in stirring at room 1.5 hours.
Mixture distributes between ethyl acetate and 0.1M hydrochloric acid, with the ethyl acetate water layer of stripping.The organic layer that merges is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is dissolved in ethylene dichloride (15ml), adds tetrakis triphenylphosphine palladium (0) (45.8mg).1 hour final vacuum of mixture backflow is concentrated.Resistates obtains Powdered target compound (739mg, 49.9%) through the ethyl acetate crystallization.
1H NMR(DMSO-d6)：δ3.84(3H，s)，5.10(2H，s)，5.87(1H，s)，6.83(1H，d，J＝8.7Hz)，7.00(2H，d，J＝8.7Hz)，7.16(2H，d，J＝8.7Hz)，7.29-7.48(5H，m)，7.54(1H，dd，J＝2.6，8.7Hz)，7.97(1H，d，J＝2.6Hz)，10.13(1H，s).
MS(ESI+)：m/z(M+H).
Embodiment 44
5-{5-[4-(benzyloxy) phenyl]-3-isopropoxy-1H-pyrazol-1-yl }-the 2-methoxypyridine
Prepare Powdered title compound (1.33g, quantitative), with 5-[4-(benzyloxy) phenyl of embodiment 43 acquisitions]-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-alcohol, the similar approach of employing embodiment 36.
1H NMR(CDCl
3)：δ1.40(6H，d，J＝6.2Hz)，3.92(3H，s)，4.86(1H，m)，5.05(2H，s)，5.87(1H，s)，6.69(1H，d，J＝8.8Hz)，6.91(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.35-7.43(5H，m)，7.51(1H，dd，J＝2.7，8.8Hz)，8.04(1H，d，J＝2.7Hz).
MS(ESI+)：m/z 416(M+H).
Embodiment 45
4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenol
Prepare Powdered title compound (442.5mg, 54.9%), with 5-{5-[4-(benzyloxy) phenyl of embodiment 44 acquisitions]-3-isopropoxy-1H-pyrazol-1-yl }-the 2-methoxypyridine, the similar approach of employing embodiment 37.
1H NMR(CDCl
3)：δ1.40(6H，d，J＝6.2Hz)，3.91(3H，s)，4.84(1H，m)，5.80(1H，s)，5.87(1H，s)，6.71(1H，d，J＝8.8Hz)，6.75(2H，d，J＝8.6Hz)，7.08(2H，d，J＝8.6Hz)，7.55(1H，dd，J＝2.7，8.8Hz)，8.00(1H，d，J＝2.7Hz).
MS(ESI+)：m/z 326(M+H).
Embodiment 46
2-{4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Preparation white powder title compound (94.6mg, 52.2%) is with 4-[3-isopropoxy-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 45 acquisitions] phenol, the similar approach of employing embodiment 23.
MP：74-75℃.
1H NMR(CDCl
3)：δ1.40(6H，d，J＝6.1Hz)，1.99(1H，t，J＝6.1Hz)，3.91(3H，s)，3.94-4.00(2H，m)，4.05-4.11(2H，m)，4.86(1H，m)，5.88(1H，s)，6.69(1H，d，J＝8.7Hz)，6.85(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.7Hz)，7.51(1H，dd，J＝2.7，8.7Hz)，8.03(1H，d，J＝2.7Hz).
IR(KBr)：3350，1612，1512，1500cm
-1.
MS(ESI+)：m/z 370(M+H).
Embodiment 47
2-{4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Prepare Powdered title compound (515.3mg, 87.6%), with 4-[3-isopropoxy-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 45 acquisitions] phenol, the similar approach of employing embodiment 2.
1H NMR(DMSO-d6)：δ1.32(6H，d，J＝6.2Hz)，1.37(9H，s)，3.22-3.34(2H，m)，3.84(3H，s)，3.92(2H，t，J＝5.7Hz)，4.77(1H，m)，6.06(1H，s)，6.84(1H，d，J＝8.8Hz)，6.91(2H，d，J＝8.8Hz)，7.01(1H，t，J＝5.5Hz)，7.16(2H，d，J＝8.8Hz)，7.58(1H，dd，J＝2.7，8.8Hz)，7.99(1H，d，J＝2.7Hz).
Embodiment 48
2-{4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } the ethamine dihydrochloride
Prepare amorphous title compound (531mg, quantitative), with 2-{4-[3-isopropoxy-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 47 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 3.
1H NMR(DMSO-d6)：δ1.32(6H，d，J＝6.1Hz)，3.15-3.24(2H，m)，3.84(3H，s)，4.19(2H，t，J＝4.9Hz)，4.77(1H，m)，6.07(1H，s)，6.85(1H，d，J＝8.8Hz)，6.97(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.8Hz)，7.60(1H，dd，J＝2.7，8.8Hz)，7.99(1H，d，J＝2.7Hz)，8.22(2H，br-s).
MS(ESI+)：m/z 369(M+H).
Embodiment 49
N-(2-{4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation white powder title compound (81.4mg, 60.2%), 2-{4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl with embodiment 48 acquisitions] phenoxy group } the ethamine dihydrochloride, the similar approach that adopts following embodiment 75 to introduce.
MP：120℃.
1H NMR(DMSO-d6)：δ1.32(6H，d，J＝6.2Hz)，3.27-3.36(2H，m)，3.84(3H，s)，3.94(2H，t，J＝5.5Hz)，4.77(1H，m)，5.52(2H，s)，6.06(1H，s)，6.15(1H，t，J＝5.6Hz)，6.84(1H，d，J＝8.8Hz)，6.93(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8H z)，7.58(1H，dd，J＝2.7，8.8Hz)，7.99(1H，d，J＝2.7Hz).
IR(KBr)：3400，3330，1658，1612，1514，1500cm
-1.
MS(ESI+)：m/z 412(M+H).
Embodiment 50
N-(2-{4-[3-isopropoxy-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Preparation title compound (94.4mg, 58.4%) is with 2-{4-[3-isopropoxy-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl of embodiment 48 acquisitions] phenoxy group } the ethamine dihydrochloride, the similar approach of employing embodiment 4.
MP：121.0-121.6℃.
1H NMR(DMSO-d6)：δ1.32(6H，d，J＝6.1Hz)，2.94(3H，s)，3.29-3.34(2H，m)，3.84(3H，s)，4.00-4.06(2H，m)，4.77(1H，m)，6.06(1H，s)，6.85(1H，d，J＝8.7Hz)，6.94(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.8Hz)，7.28(1H，br-s)，7.58(1H，dd，J＝2.7，8.7Hz)，7.99(1H，d，J＝2.7Hz).
IR(KBr)：3242，1612，1514，1502cm
-1.
MS(ESI+)：m/z 447(M+H).
Embodiment 51
Methylsulfonic acid 2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester
To 2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethanol (2.72g) and triethylamine (1.55ml) solution that is dissolved in methylene dichloride (30ml) is added dropwise to methylsulfonyl chloride (0.86ml) under ice-cooled.Reaction mixture is warming up to room temperature, stirred 1 hour.
With the quencher of reaction mixture water.Separate organic layer,, filter the back reduction vaporization, obtain target compound (3.25g, 98.5%) with 1N hydrochloric acid and water washing, dried over sodium sulfate.
1HNMR(CDCl
3)：δ2.929(3H，s)，3.072(2H，t，J＝6.7Hz)，4.427(2H，t，J＝6.7Hz)，6.739(1H，)，7.175(2H，d，J＝8.4Hz)，7.234(2H，d，J＝8.4Hz)，7.253(2H，d，J＝8.9Hz)，7.344(2H，d，J＝8.8Hz).
MS(ESI+)：m/z 467(M+Na).
Embodiment 52
2-(2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl)-1H-isoindole-1,3 (2H)-diketone
Methylsulfonic acid 2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl that embodiment 51 is obtained] phenyl } mixture of ethyl ester (3.2g) and peptide imide potassium (1.6g) is in 80 ℃ of stirrings 5 hours.
After the cooling, water and ethyl acetate diluted mixture thing.Separate water layer, with ethyl acetate extraction (twice).The organic layer that merges is through water (twice) and salt water washing, and dried over mgso is filtered the back reduction vaporization, obtains Powdered target compound (1.55g, 43.5%).
1H NMR(CDCl
3)：δ1.59(3H，s)，3.02(2H，t，J＝7.3Hz)，3.94(2H，t，J＝7.3Hz)，6.71(1H，s)，7.11(2H，d，J＝8.2Hz)，7.21(2H，d，J＝7.6Hz)，7.24(2H，d，J＝8.4Hz)，7.32(2H，d，J＝8.9Hz)，7.70-7.86(4H，m).
MS(ESI+)：m/z 518(M+Na).
Embodiment 53
2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethamine
The 2-that embodiment 52 is obtained (2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl)-1H-isoindole-1,3 (2H)-diketone (1.5g) and the mixture of hydrazine (2.93ml) in acetonitrile (30ml) were in 60 ℃ of stirrings 5 hours.
After the cooling, filtering mixt washs with acetonitrile.Reduction vaporization filtrate obtains oily target compound (1.1g, quantitative).
1H NMR(CDCl
3)：δ3.09(2H，dd，J＝5.6Hz，9.3Hz)，3.24(2H，dd，J＝5.6Hz，8.6Hz)，5.47(2H，s)，6.69(1H，s)，7.12(1H，d，J＝8.2Hz)，7.21(1H，d，J＝8.2Hz)，7.22(1H，d，J＝8.9Hz)，7.32(1H，d，J＝8.9Hz).
MS(ESI+)：m/z 366(M+1).
Embodiment 54
N-(2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl) Toluidrin
2-{4-[1-(4-chloro-phenyl-)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl that obtains to embodiment 53] phenyl } ethamine (400mg) and triethylamine (0.46ml) solution that is dissolved in methylene dichloride (20ml) is added dropwise to methylsulfonyl chloride (0.25ml) in room temperature.
Stir after 1 hour, with reaction mixture 1N hydrochloric acid quencher.Separate water layer, use twice of chloroform extraction.The organic layer that merges is through 1N hydrochloric acid, sodium hydrogen carbonate solution, water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates is purified (chloroform/methanol=4: 1) through silica gel column chromatography, obtains oily target compound (166mg, 34.2%).
1H NMR(CDCl
3)：δ2.899(3H，s)，2.904(2H，t，J＝6.9Hz)，3.417(2H，dt，J＝6.7，6.8Hz)，4.272(1H，t，J＝6.1Hz)，6.737(1H，s)，7.178(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4H z)，7.255(2H，d，J＝8.8Hz)，7.35(2H，d，J＝8.8Hz).
IR (film): 3346,1657,1597,1552,1496,1471,1236,1163,1136,1092,978,835,756cm
-1.
MS(ESI-)：442(M-1).
Embodiment 55
N-(2-{4-[1-(4-chloro-phenyl-)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl) urea
2-{4-[1-(4-chloro-phenyl-)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl that obtains to embodiment 53] phenyl } ethamine (300mg) and triethylamine (0.57ml) solution that is dissolved in methylene dichloride (10ml) is added dropwise to isocyanic acid trimethyl silyl ester (0.555ml) in room temperature.
After stirring is spent the night, with reaction mixture 1N hydrochloric acid quencher.Separate water layer, use twice of chloroform extraction.The organic layer that merges is through 1N hydrochloric acid, sodium hydrogen carbonate solution and water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates is purified (chloroform/methanol=4: 1) through silica gel column chromatography, obtains amorphous target compound (205mg, 61.1%).
1H NMR(CDCl
3)：δ2.83(2H，t，J＝7Hz)，3.43(2H，dt，J＝6.6Hz，6.8Hz)，4.41(2H，s)，4.61(1H，t，J＝5.4Hz)，6.72(1H，s)，7.16(4H，s)，7.25(2H，d，J＝8.8Hz)，7.34(2H，d，J＝8.8Hz).
IR (film): 3346,1657,1597,1552,1496,1471,1448,1375,1271,1236,1163,1136,1092,978,835,756cm
-1.
MS(ESI+)：m/z 431(M+Na).
Embodiment 56
4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] cyanobenzene
4-(4,4,4-three fluoro-3-oxobutanoyls)-cyanobenzene (1.0g), 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (760mg) and the mixture of sodium acetate (357mg) in acetate (10ml) were stirred 4 hours in 80 ℃.
After the cooling, pour reaction mixture into water and ethyl acetate.With twice of ethyl acetate extraction water layer.The organic layer that merges is through saturated sodium bicarbonate solution (twice), water and salt water washing, and reduction vaporization after the dried over sodium sulfate obtains crude product.This crude product is through silica gel column chromatography purification (50ml, normal hexane: ethyl acetate=5: 1-4: 1), grind with sherwood oil, obtain target compound (553mg, 38.8%).
1H NMR(CDCl
3)：δ3.84(3H，s)，6.82(1H，s)，6.9(2H，d，J＝9Hz)，7.2(2H，d，J＝9Hz)，7.33(2H，d，J＝8.6Hz)，7.62(2H，d，J＝8.6Hz).
IR (film): 2229,1610,1512,1468,1240,1161,1132,839cm
-1.
MS(ESI+)：m/z 366(M+Na).
Embodiment 57
4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzylamine hydrochloride
4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl that embodiment 56 is obtained] cyanobenzene (430mg), Pd/C (100mg) and the mixture of 1N hydrochloric acid (1.3ml) in methyl alcohol (43ml) stirred 5 hours under nitrogen atmosphere.
Use the paper filter filter reaction mixture, evaporated filtrate.After being dissolved in methyl alcohol, use the membrane filter filtering solution.Evaporated filtrate obtains crystal target compound (450mg, 93.6%).
1H NMR(CDCl
3)：δ3.79(3H，s)，4.04(2H，br-s)，6.69(1H，s)，6.85(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.9Hz)，7.24(2H，d，J＝9Hz)，7.42(2H，d，J＝9Hz).
IR (film): 2964,1512,1468,1238,1161,1130,976,837cm
-1.
MS(ESI+)：m/z 331(M-Cl-NH
3).
Embodiment 58
N-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
4-[1-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl that obtains to embodiment 57] benzylamine hydrochloride (100mg) and triethylamine (0.073ml) solution that is dissolved in chloroform (10ml) is added dropwise to methylsulfonyl chloride (0.04ml) in room temperature.
Stir after 1 hour, reaction mixture is distributed between chloroform and water.Organic layer is through water, sodium hydrogen carbonate solution and salt water washing, and dried over mgso is filtered the back reduction vaporization, obtains oily target compound (90mg, 81.2%).
1H NMR(CDCl
3)：δ2.93(3H，s)，3.82(3H，s)，4.32(2H，d，J＝6.2Hz)，4.71(1H，t，J＝6.2Hz)，6.73(1H，s)，6.86(2H，d，J＝9Hz)，7.21(2H，d，J＝9Hz)，7.21(2H，d，J＝8.3Hz)，7.31(2H，d，J＝8.3Hz).
IR (film): 3282,1514,1321,1240,1151,974,837cm
-1.
Mass spectrum (ESI+): m/z 426 (M+1).
Embodiment 59
4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] cyanobenzene
Preparation title compound (4.5g, 20.6%) with 4-(4,4-two fluoro-3-oxobutanoyls) cyanobenzene, adopts the similar approach of embodiment 56.
1H NMR(CDCl
3)：δ3.84(3H，s)，6.77(1H，t，J＝54.9Hz)，6.8(1H，s)，6.9(2H，d，J＝9Hz)，7.19(2H，d，J＝9Hz)，7.33(2H，d，J＝8.6Hz)，7.61(2H，d，J＝8.6Hz).
MS(ESI+)：m/z 348(M+Na).
Embodiment 60
1-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } methylamine hydrochloride
Preparation title compound (510mg, 45.4%) is with 4-[3-(difluoromethyl)-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 59 acquisitions] cyanobenzene, the similar approach of employing embodiment 57.
1H NMR(DMSO-d6)：δ3.35(3H，s)，3.79(2H，s)，7.1(1H，t，J＝54.5Hz)，6.95(1H，s)，6.99(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.8Hz)，7.3(2H，d，J＝8.3Hz)，7.49(2H，d，J＝8.3Hz).MS(ESI-)：m/z 365(M-HCl).
Embodiment 61
N-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
Preparation title compound (146mg, 65.5%) is with 1-{4-[3-(difluoromethyl)-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl of embodiment 60 acquisitions] phenyl } methylamine hydrochloride, the similar approach of employing embodiment 58.
1H NMR(CDCl
3)：δ2.90(3H，s)，3.82(3H，s)，4.31(2H，d，J＝6.2Hz)，4.73(1H，t，J＝6.2Hz)，6.72(1H，s)，6.77(1H，t，J＝55Hz)，6.86(2H，d，J＝9Hz)，7.19(2H，d，J＝9Hz)，7.22(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz).
IR (film): 3143,1518,1508,1452,1325,1244,1151,1074,1022,972,843,793cm
-1.
MS(ESI-)：m/z 406(M-1).
Embodiment 62
N-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } urea
1-{4-[3-(difluoromethyl)-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-5-yl that obtains to embodiment 60] phenyl } methylamine hydrochloride (100mg) solution that is dissolved in methylene dichloride (1ml) is added dropwise to triethylamine (0.163ml) and isocyanic acid trimethyl silyl ester (0.11ml) in room temperature.
Mixture adds saturated sodium bicarbonate solution (0.5ml) quencher in stirred overnight at room temperature.Mixture filters through Chemelute.Evaporation of eluate obtains solid after preparative thin-layer chromatography method (0.5mm, 10% methyl alcohol/chloroform) is purified.This solid is added ethyl acetate and normal hexane, filter the collecting precipitation thing, obtain target compound (160mg, 62.9%).
1H NMR(CDCl
3)：δ3.82(3H，s)，4.35(2H，d，J＝6Hz)，4.46(2H，br-s)，4.99(1H，t，J＝6Hz)，6.69(1H，s)，6.76(1H，t，J＝55.1Hz)，6.86(2H，d，J＝9Hz)，7.14-7.21(6H，m).
MS(ESI+)：m/z 395(M+Na).
IR (film): 1657,1608,1593,1550,15120,1510,1467,1338,1252,1171,1088,1030,837,796cm
-1.
Embodiment 63
4-[1-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] cyanobenzene
Preparation title compound (942mg, 86.8%) with 4-(4,4,4-three fluoro-3-oxobutanoyls) cyanobenzene, adopts the similar approach of embodiment 56.
1H NMR(CDCl
3)：δ2.39(3H，s)，6.82(1H，s)，7.15(2H，d，J＝8.9Hz)，7.21(2H，d，J＝8.8Hz)，7.33(2H，d，J＝8.3Hz)，7.62(2H，d，J＝8.3Hz).
MS(ESI+)：m/z 328(M+1).
Embodiment 64
1-{4-[1-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } methylamine hydrochloride
Preparation title compound (414mg, 92.1%) is with 4-[1-(4-aminomethyl phenyl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl of embodiment 63 acquisitions] cyanobenzene, the similar approach of employing embodiment 57.
1H NMR(DMSO-d6)：δ2.35(3H，d，J＝4.2Hz)，3.35(2H，s)，7.17(1H，s)，7.17-7.29(4H，m)，7.32(2H，d，J＝8.1Hz)，7.51(2H，d，J＝8.2Hz).
MS(ESI+)：m/z 332(M+1).
Embodiment 65
N-{4-[1-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } urea
Preparation title compound (81mg, 31.8%) is with 1-{4-[1-(4-aminomethyl phenyl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl of embodiment 64 acquisitions] phenyl } methylamine hydrochloride, the similar approach of employing embodiment 62.
1H NMR(CDCl
3)：δ2.36(3H，s)，4.35(2H，d，J＝5.9Hz)，4.50(2H，br-s)，5.02(1H，t，J＝5.5Hz)，6.71(1H，s)，7.16(4H，s)，7.20(4H，d，J＝5.7Hz).
IR (film): 3344,1658,1600,1552,1518,1236,1159,1134cm
-1.
MS(ESI+)：m/z 397(M+Na).
Embodiment 66
4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] cyanobenzene
Preparation title compound (1.05g, 73.8%) with 4-methyl isophthalic acid-(4,4,4-three fluoro-3-oxobutanoyls) benzene, adopts the hereinafter similar approach of embodiment 69 introductions.
MP：125.0-125.5℃.
1H NMR(CDC13)：δ2.39(3H，s)，6.74(1H，s)，7.10(2H，d，J＝8.1Hz)，7.19(2H，d，J＝8.2Hz)，7.45(2H，d，J＝8.7Hz)，7.65(2H，d，J＝8.7Hz).
MASS(ESI+)：m/z 350(M+Na).
Embodiment 67
1-{4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenyl } methylamine hydrochloride
Preparation title compound (830mg, 92.3%) is with 4-[5-(4-aminomethyl phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl of embodiment 66 acquisitions] cyanobenzene, adopt the hereinafter similar approach of embodiment 70 introductions.
1H NMR(DMSO-d6)：δ2.30(3H，d，J＝2.3Hz)，4.07(2H，s)，7.15(1H，s)，7.15(2H，d，J＝9.0Hz)，7.21(2H，d，J＝8.9Hz)，7.39(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz).
MS(ESI+)：m/z 332(M+1).
Embodiment 68
N-{4-[5-(4-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzyl } urea
Preparation title compound (65mg, 31.9%) is with 1-{4-[5-(4-aminomethyl phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl of embodiment 67 acquisitions] phenyl } methylamine hydrochloride, adopt the hereinafter similar approach of embodiment 72 introductions.
1H NMR(CDCl
3)：δ2.34(3H，s)，4.34(2H，d，J＝5.8H z)，4.56(2H，br-s)，5.23(1H，t，J＝5.8Hz)，6.71(1H，s)，7.07(2H，d，J＝8.7Hz)，7.13(2H，d，J＝8.7Hz)，7.24(4H，s).
IR (film): 3344,1658,1604,1552,1234,1159,1134cm
-1.
MS(ESI+)：397(M+Na).
Embodiment 69
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] cyanobenzene
With 4-methoxyl group-1-(4,4,4-three fluoro-3-oxobutanoyls) benzene (1.0g), 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (758mg) and the mixture of sodium acetate (367mg) in acetate (5ml) in stirred overnight at room temperature.
Then, reaction mixture is poured into water and ethyl acetate.With twice of ethyl acetate extraction water layer.The organic layer that merges is through water, saturated sodium bicarbonate solution (twice) and salt water washing, and reduction vaporization after the dried over sodium sulfate obtains crude product.This crude product is through silica gel column chromatography purification (50ml, normal hexane: ethyl acetate=10: 1-5: 1), obtain target compound (930mg, 66.7%).
1H NMR(CDCl
3)：δ3.84(3H，s)，6.72(1H，s)，6.9(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.46(2H，d，J＝8.7Hz)，7.66(2H，d，J＝8.7Hz).
MS(ESI+)：m/z 366(M+Na).
Embodiment 70
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzylamine hydrochloride
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl that embodiment 69 is obtained] cyanobenzene (400mg) and the mixture of 50% weight in wet base pd/C (400mg) in ethanol (10ml) and 1N hydrochloric acid (1.2ml) stirred 8 hours under nitrogen atmosphere.
Reduction vaporization filtrate behind the filtering mixt.Resistates washs through isopropyl ether, obtains Powdered target compound (400mg, 89.4%).
1H NMR(CDCl
3)：δ3.36(s，3H)，3.76(d，J＝2.4，2Hz)，6.94(d，J＝8.7，2Hz)，7.12(s，1H)，7.23(d，J＝8.7，2H z)，7.39(d，J＝8.4，2Hz)，7.59(d，J＝8.4，2Hz).
MS(ESI+)：m/z 348(M+1).
Embodiment 71
N-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzyl } Toluidrin
4-[5-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl that obtains to embodiment 70] benzylamine hydrochloride (150mg) and triethylamine (0.1ml) solution that is dissolved in methylene dichloride (10ml) is added dropwise to methylsulfonyl chloride (0.06ml) under ice-cooled.
Stir after 1 hour,, between chloroform and water, distribute the reaction mixture quencher.Use the chloroform extraction water layer.The organic layer that merges is through water, 1N hydrochloric acid, saturated sodium bicarbonate solution and salt water washing, and dried over mgso is filtered the back reduction vaporization.Resistates obtains target compound (67mg, 40.3%) through the high performance thin-layer chromatography stratographic analysis.
1H NMR(CDCl
3)：δ2.91(3H，s)，3.82(s，3H)，4.35(2H，d，J＝6.1Hz)，4.69(1H，t，J＝6.1Hz)，6.69(1H，s)，6.84(2H，d，J＝8.6Hz)，7.13(2H，d，J＝8.6Hz)，7.32(2H，d，J＝9Hz)，7.37(2H，d，J＝9Hz).
IR (film): 3207,1479,1456,1323,1252,1234,1146,1122,984,968,962,841,802cm
-1.
MS(ESI+)：m/z 448(M+Na).
Embodiment 72
N-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzyl } urea
4-[5-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl that obtains to embodiment 70] solution of benzylamine hydrochloride (150mg) water-soluble (8ml) and ethanol (4ml) is in the ice-cooled Zassol (100mg) of adding down.
Stir after 3 hours, reaction mixture is distributed between chloroform and water.Use the chloroform extraction water layer.The organic layer that merges is through water and salt water washing, and dried over mgso is filtered the back reduction vaporization.Resistates obtains target compound (105mg, 69%) through the high performance thin-layer chromatography stratographic analysis.
1H NMR(CDCl
3)：δ3.80(3H，s)，4.35(2H，d，J＝5.9Hz)，4.53(2H，br-s)，5.171(1H，t，J＝5.7Hz)，6.68(1H，s)，6.84(2H，d，J＝8.7Hz)，7.12(2H，d，J＝8.7Hz)，7.25(4H，s).
MS(ESI+)：m/z 413(M+Na).
Embodiment 73
2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
To 4-[1-(4-p-methoxy-phenyl)-3-Trifluoromethyl-1 H-pyrazoles-5-yl] phenol (500g) is dissolved in N, the solution of N-two-methylformamide (1.5L) ice-cooled in 25 minutes, add down sodium hydride (the mineral oil dispersion liquid, 77.8g).Mixture was warming up to room temperature in 10 minutes, then in stirring at room 30 minutes.With 2-tert-butoxycarbonyl amino-ethyl bromine (469g) (by tert-Butyl dicarbonate and 2-bromine ethylamine hydrochloride prepared in reaction) at N, in 25-28 ℃ of adding mixture, all mixtures stirred 6 hours in 60 ℃ reaction soln in the dinethylformamide (300ml) in 10 minutes.
After the standing over night, mixture is poured into the mixture of water (4.5L) and toluene (3L).Separate organic layer, with toluene (1.5L) aqueous layer extracted.The organic layer that merges is through water (1.5L * 3) and salt solution (1.5L) washing, and dried over mgso is filtered the back evaporation, obtains oily matter (1.02kg).Oily matter is purified through silica gel column chromatography [5L, normal hexane (10L), 50% ethyl acetate/normal hexane (30L)], obtains faint yellow oily target compound (680g, 95%).
MP：104.7-105.1℃.
1HNMR(CDCl
3)：δ1.45(3H，s)，3.53(2H，dt，J＝4Hz)，3.82(3H，s)，4.01(2H，t，J＝4Hz)，6.67(1H，s)，6.83(2H，d，J＝8Hz)，6.87(2H，d，J＝8Hz)，7.13(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).
Embodiment 74
2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethylamine hydrochloride
To the ethyl acetate of hydrogenchloride (4N, 1.0L) solution added Powdered 2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yls that embodiment 73 obtains in 5 ℃ in 20 minutes] phenoxy group the ethyl carbamic acid tert-butyl ester (500g).
After uniform temp down stirred 30 minutes, in stirring at room 1 hour, evaporating mixture obtained oily matter (543.12g).Oily matter is dissolved in toluene (1.5L).Then, normal hexane (200ml) and target compound (crystalline seed) are added/go into this solution.Mixture is in stirred overnight at room temperature.Filtering precipitate, with toluene (500ml * 2) and isopropyl ether (650ml) washing, dry back obtains white powder target compound (420.5g, 97%).
MP：166.8-168.0℃.
1HNMR(DMSO-d6)：δ3.185(2H，t，J＝5Hz)，3.8(3H，s)，4.215(2H，t，J＝5Hz)，6.96-7.05(4H，m)，7.1(1H，s)，7.22-7.33(4H，m).
Embodiment 75
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl that embodiment 74 is obtained] phenoxy group } ethylamine hydrochloride (400g) and sodium acetate (159g) be dissolved in mixture N, dinethylformamide (1.4L) and water (0.52L) in 50 ℃.Water (520ml) solution of potassium cyanate (157g) was added dropwise to this solution in 38-40 ℃ in 15 minutes.Complete soln stirred 2 hours in 50 ℃.
Filtering solution is used N down in uniform temp, dinethylformamide (0.68L) washing.Cooling filtrate is to room temperature, then with water (0.4L) and target compound (A04 N-type waferN) as crystalline seed adding filtrate, with mixture in stirring at room 30 minutes.In 30 minutes, water (2.76L) is added dropwise to mixture then, again with mixture in stirring at room 30 minutes.Filtering precipitate, water (0.8L * 3) washing is spent the night in 45 ℃ of drying under reduced pressure, acquisition white powder target compound (the A04 N-type waferN, 442.01g).
1HNMR(CDCl
3)：δ3.555(2H，dt，J＝5，6Hz)，3.81(3H，s)，3.995(2H，t，J＝5Hz)，4.67(2H，s)，5.37(1H，t，J＝6Hz)，6.66(1H，br-s)，6.79(2H，d，J＝8Hz)，6.845(2H，d，J＝6Hz)，7.11(2H，d，J＝8Hz)，7.19(2H，d，J＝8Hz).
1HNMR(DMSO-d6)：δ3.28-3.36(2H，m)，3.79(3H，s)，3.945(2H，t，J＝5Hz)，5.54(2H，br-s)，6.165(1H，t，J＝5Hz)，6.92-7.08(5H，m)，7.2(2H，d，J＝8Hz)，7.28(2H，d，J＝8Hz).
Embodiment 76
The 2-hydroxy-n-and 4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } ethanamide
4-[1-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl that obtains to embodiment 57] benzylamine hydrochloride (46.5mg) solution that is dissolved in methylene dichloride (1.5ml) adds diisopropylethylamine (135 μ L) and alpha-Acetoxyacetyl chloride (41.6 μ L) in 0 ℃.
In stirring at room after 3 hours, with the quencher of mixture water.With the whole mixture of ethyl acetate extraction.Organic layer is through the salt water washing, and dried over mgso is filtered the back evaporation, obtains oily matter (67mg).This oily matter is dissolved in methyl alcohol (1.5ml).(55mg) adds described solution with salt of wormwood., evaporate behind the filtering mixt after 3 hours in stirring at room, obtain oil, it is purified with preparative thin-layer chromatography method (0.5mm * 2,10% methyl alcohol/chloroform), obtain colorless oil (42.5mg).This oily matter is through mixtures of ethyl acetate, diisopropyl ether and normal hexane crystallization and in stirring at room.The filtering precipitate after drying obtains white powder target compound (33.9mg, 64.8%).
1HNMR(CDCl
3)：δ2.32(1H，t，J＝5.2Hz)，3.83(3H，s)，4.20(2H，d，J＝5.2Hz)，4.51(2H，d，J＝6.1Hz)，6.72(1H，s)，6.87(2H，d，J＝8.9Hz)，7.16-7.24(6H，m).
MS(ESI+)：428.2(M+Na).
Embodiment 77
The 2-hydroxy-n-(2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl) ethyl sulfonamide
To 2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethylamine hydrochloride and the triethylamine solution that is dissolved in chloroform adds methylsulfonyl chloride in room temperature.
Stir after 1 hour, pour reaction mixture into water and chloroform.Separate water layer, use chloroform extraction.The organic layer that merges is through water and salt water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates obtains target compound (27.7mg, 23.5%) through the silica gel column chromatography post crystallization of purifying.
1HNMR(CDCl
3)：δ2.78-2.91(2H，m)，3.16(2H，t，J＝5.1Hz)，3.32-3.43(2H，m)，3.82(3H，s)，3.96(2H，t，J＝5.1Hz)，4.65(1H，t，J＝6.2Hz)，6.72(1H，s)，6.87(2H，d，J＝9.0Hz)，7.12-7.27(6H，m).
MS(LC，ESI+)，470.21(MR+)，511.17(MHMeCN).
Embodiment 78-1
2-(4-ethanoyl phenoxy group) the ethyl carbamic acid tert-butyl ester
Be dissolved in N to 4-hydroxy acetophenone (10g) and 2-tert-butoxycarbonyl amino-ethyl bromine (24.7g), the solution of dinethylformamide (50ml) adds potassiumiodide (12.2g) and salt of wormwood (15.2g).
After 50 ℃ of stirrings were spent the night, water quencher mixture was with ethyl acetate extraction (3 times).The organic layer that merges is through 1N aqueous sodium hydroxide solution (2 times) and salt water washing, and dried over mgso obtains oily matter after the evaporation.This oily matter is purified through silica gel column chromatography [500ml, 20% ethyl acetate/normal hexane (1000ml), 30% ethyl acetate/normal hexane (1000ml)], obtains white solid target compound (19.89g, 96.9%).
1HNMR(CDCl
3)：δ1.46(9H，s)，2.56(3H，s)，3.52-3.60(2H，m)，4.09(2H，t，J＝5.1Hz)，6.93(2H，d，J＝8.9Hz)，7.93(2H，d，J＝8.9Hz).
MS(ESI+)：280.09(MH+).
Embodiment 78-2
2-[4-(4,4,4-three fluoro-3-oxobutanoyls) phenoxy group] the ethyl carbamic acid tert-butyl ester
2-(4-ethanoyl phenoxy group) the ethyl carbamic acid tert-butyl ester (15g), trifluoroacetic acid (8.95ml) and the mixture of sodium ethylate (8.77g) in ethanol (45ml) that embodiment 78-1 is obtained stirred 2.5 hours in 70 ℃.
Pour mixture into mixture hydrochloride aqueous solution (1N) and ethyl acetate.All mixture is through ethyl acetate extraction (2 times).Separate organic layer,, evaporate after the dried over mgso, obtain oily matter (25g) with saturated sodium bicarbonate solution and salt water washing.This oily matter is purified through silica gel column chromatography [500ml, 30% ethyl acetate/normal hexane (1000ml)], obtains oily matter.This oily matter is dissolved in ethyl acetate (5ml) under heating in water bath.(100ml) adds described solution with normal hexane, in 30 minutes under agitation cooling solution to room temperature.(100ml) adds this mixture with normal hexane.The filtering precipitate after drying obtains orange powder shape target compound (15.956g, 79.2%).
1HNMR(CDCl
3)：δ3.40-3.70(2H，m)，4.00-4.20(2H，m)，5.00(1H，br-s)，6.50(1H，s)，6.98(2H，d，J＝8.6Hz)，7.93(2H，d，J＝8.6Hz).
Embodiment 78-3
2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
To the suspension of 4-anisidine (100mg) in mixture acetate (2ml) and concentrated hydrochloric acid (0.4ml) in 5 minutes in 3 ℃ of solution that are added dropwise to Sodium Nitrite (61.6mg) water-soluble (0.1ml), stirred the mixture 1 hour in 3 ℃.In 10 minutes, be added dropwise to the solution that tin protochloride (641mg) is dissolved in concentrated hydrochloric acid (0.3ml) to this mixture in 0 ℃, stirred the mixture 1 hour in 0 ℃ then.Acetate (5ml) was added dropwise to described mixture in-20 ℃ to-10 ℃ in 2 minutes, then in-10 ℃ of solution quencher mixtures in 2 minutes with sodium hydroxide (336mg) water-soluble (2.24ml), be warming up to room temperature, obtain to comprise the solution of 4-p-methoxy-phenyl hydrazonium salt hydrochlorate.
2-[4-(4,4,4-three fluoro-3-oxobutanoyls)-phenoxy group with the acquisition of embodiment 78-2] ethyl carbamic acid tert-butyl ester solution (305mg) is in-10 ℃ of solution that add fronts, in stirring at room mixture 3 hours.Pour mixture the mixture of saturated sodium bicarbonate aqueous solution (150ml) and ethyl acetate (100ml) into, regulate pH to alkalescence with sodium bicarbonate powder.
Separate organic layer, with ethyl acetate (50ml * 2) aqueous layer extracted.The organic layer that merges is through saturated sodium bicarbonate aqueous solution and salt water washing, and dried over mgso is filtered the back evaporation, obtains oily matter (450mg).Oily matter is purified with silica gel column chromatography [35ml, 15% ethyl acetate/normal hexane (800ml)], obtain oily matter (343.2mg, 88.5%).This oily matter is dissolved in isopropyl ether (2ml), then normal hexane (6ml) is added this solution.All mixtures were in stirring at room 1 hour.Filtering precipitate washs with normal hexane (10ml) then, and drying under reduced pressure 2 hours obtains white powder target compound (280.6mg, 72.4%).
1HNMR (CDCl
3) data are consistent with authentic sample.
1HNMR(CDCl
3)：δ1.45(3H，s)，3.53(2H，dt，J＝4.4Hz)，3.82(3H，s)，4.01(2H，t，J＝4Hz)，6.67(1H，s)，6.83(2H，d，J＝8Hz)，6.87(2H，d，J＝8Hz)，7.13(2H，d，J＝8Hz)，7.23(2H，d，J＝8Hz).
Embodiment 79-1
1-[4-(benzyloxy) phenyl] the hydrazonium salt hydrochlorate
To the suspension of 4-benzyloxy-aniline (10g) in concentrated hydrochloric acid (100ml) in 10 minutes in-15 ℃ to-10 ℃ solution that are added dropwise to Sodium Nitrite (3.2g) water-soluble (l0ml), stirred the mixture 1 hour in 3 ℃ then.In 30 minutes, be added dropwise to solution that tin protochloride (33.5g) be dissolved in concentrated hydrochloric acid (80ml) in-20 ℃ to-10 ℃ to mixture, stirred the mixture 1 hour in 0 ℃ again.
After being cooled to-20 ℃, filtering precipitate, water (25ml), ethanol (25ml) and ether (50ml) washing, dry back obtains light brown powder shape target compound (10.637g, 100%).
NMR(DMSO-d6)：δ5.05(2H，s)，6.93-7.03(4H，m)，7.46-7.28(4H，m).
Embodiment 79-2
2-{4-[1-(4-benzyloxy phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethylamine hydrochloride
Preparation title compound (12.9g; 87.5%) 1-[4-(benzyloxy) phenyl that obtains with embodiment 79-1 ,] 2-[4-(4,4 that obtains of hydrazonium salt hydrochlorate and embodiment 78-2; 4-three fluoro-3-oxobutanoyls) phenoxy group] the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 78-3.
1HNMR(DMSO-d6)：δ3.10-3.30(2H，m)，4.19(2H，t，J＝6.3Hz)，5.14(2H，s)，6.98(2H，d，J＝8.7Hz)，7.09(1H，s)，7.09(2H，d，J＝8.9Hz)，7.49-7.22(9H，m).
Embodiment 80
N-(2-{4-[1-[4-(benzyloxy) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation title compound (10.57g, 84.3%) is with 2-{4-[1-(4-benzyloxy phenyl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl of embodiment 79-2 acquisition] phenoxy group }-ethylamine hydrochloride, the similar approach of employing embodiment 75.
1HNMR(CDCl
3)：δ3.57(2H，td，J＝5.7，5.0Hz)，4.01(2H，t，J＝5.0Hz)，4.57(1H，br-s)，5.06(2H，s)，5.20(1H，t，J＝5.7Hz)，6.66(1H，s)，6.80(2H，d，J＝8.7Hz)，6.93(2H，d，J＝9.0Hz)，7.12(2H，d，J＝8.7Hz)，7.21(2H，d，J＝9.0Hz)，7.35-7.42(5H，m).
Embodiment 81
N-(2-{4-[1-(4-hydroxy phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-phenoxy group } ethyl) urea
The N-that obtains to embodiment 80 (2-{4-[1-[4-(benzyloxy) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (10.33g) solution that is dissolved in methyl alcohol (100ml) adds carbon and carries palladium (10% weight in wet base, 2g), under nitrogen atmosphere in room temperature vigorous stirring mixture 3 hours.Filter whole mixtures, the evaporation back obtains oily matter (8.23g).Oily matter is purified with silica gel column chromatography [250ml, 3% methyl alcohol/chloroform (500ml), 5% methyl alcohol/chloroform (500ml) and 10% methyl alcohol/chloroform (500ml)], obtain oily target compound (8.07g, 95.4%).
1HNMR(DMSO-d6)：δ3.28-3.33(2H，m)，3.94(2H，t，J＝5.5Hz)，5.52(2H，br-s)，6.14(1H，br-t，J＝5.7Hz)，6.80(2H，d，J＝8.7Hz)，6.93(2H，d，J＝8.9Hz)，7.05(1H，s)，7.14(2H，d，J＝8.7Hz)，7.19(2H，d，J＝8.9Hz).
MS(ESI+)：407.10(MH+).
Embodiment 82
4-[5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenylacetate
The N-that obtains to embodiment 81 (2-{4-[1-(4-hydroxy phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) mixture of urea (148.5mg) in methylene dichloride (1.5ml) adds pyridine (163 μ L) and diacetyl oxide (45 μ L), and mixture is in the stirring at room stirring 3 hours that refluxes after 1 hour.
After the evaporation, mixture is purified with preparative thin-layer chromatography method (1.0mm, 10% methyl alcohol/chloroform), obtain oily matter.Oily matter in the crystalline mixture of room temperature with methylene dichloride and isopropyl ether, is obtained white powder target compound (138.6mg, 84.6%).
1HNMR(CDCl
3)：δ2.30(3H，s)，3.59(2H，td，J＝5.5，4.9Hz)，4.04(2H，t，J＝4.9Hz)，4.51(2H，br-s)，5.22(1H，br-t，J＝5.5Hz)，6.69(1H，s)，6.84(2H，d，J＝8.7Hz)，7.10(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.7Hz)，7.31(2H，d，J＝8.9Hz).
MS(LC，ESI+)：449.24(MH
+)，(ESI-)492.5(M-H+HCO
2 -).
Embodiment 83-1
1-(1,3-benzodioxole-5-yl) hydrazonium salt hydrochlorate
The preparation title compound (1.811g, quantitatively), with 3,4-(methylene radical dioxy base) aniline, the similar approach of employing embodiment 79-1.
1HNMR(DMSO-d6)：δ5.94(2H，s)，6.53(1H，dd，J＝2.2 8.2Hz)，6.80(1H，s)，6.83(1H，d，J＝8.2Hz).
MS(LS，ESI+)：153.9(MH+)193.99(MH+CH
3CN).
Embodiment 83-2
2-{4-[1-(1,3-benzodioxole-5-yl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation title compound (371.3mg; 56.7%); 2-[4-(4 with embodiment 78-2 acquisition; 4; 4-three fluoro-3-oxobutanoyls) phenoxy group] 1-(1 that obtains of the ethyl carbamic acid tert-butyl ester and embodiment 83-1; 3-benzodioxole-5-yl) hydrazonium salt hydrochlorate, the similar approach of employing embodiment 78-3.
NMR(CDCl
3)MA12.048：δ1.75(9H，s)，3.45-3.60(2H，m)，4.02(2H，t，J＝5.1Hz)，6.02(2H，s)，6.66-6.88(1H，m)，7.16(2H，d，J＝8.8Hz).
MS(LC，ESI+)：492.22(MH+)，533.26(MHMeCN+).
Embodiment 84
2-{4-[1-(1,3-benzodioxole-5-yl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethamine
Preparation title compound (181.2mg, 61.5%), 2-{4-[1-(1,3-benzodioxole-5-yl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl with embodiment 83-2 acquisition] phenoxy group } the ethyl carbamic acid tert-butyl ester, the similar approach of employing embodiment 74.
1HNMR(CDCl
3)：δ1.75(9H，s)，3.45-3.60(2H，m)，4.02(2H，t，J＝5.1Hz)，6.02(2H，s)，6.66-6.88(1H，m)，7.16(2H，d，J＝8.8Hz).
MS(LC，ESI+)：392.09(MH+)，433.16(MHMeCN+).
Embodiment 85
N-(2-{4-[1-(1,3-benzodioxole-5-yl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
Preparation title compound (181.2mg, 90.1%) is with 2-{4-[1-(1,3-benzodioxole-5-yl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl of embodiment 84 acquisitions] phenoxy group } ethamine, the similar approach of employing embodiment 75.
1HNMR(CDCl
3)：δ3.6(2H，td，J＝5.0，5.0Hz)，4.045(2H，t，J＝5Hz)，4.5(2H，br-s)，5.095(1H，br-t，J＝5Hz)，6.01(2H，s)，6.66(1H，s)，6.75-6.86(3H，m)，6.84(2H，d，J＝8Hz)，7.16(2H，d，J＝8Hz).
MS(LC，ESI+)：435.08(MH+).
Embodiment 86
2-(4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] and benzyl } amino)-2-oxoethyl-t-butyl carbamate
4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl that embodiment 57 is obtained] benzylamine hydrochloride, N-tert-butoxycarbonyl-glycine, WSCD and the mixture of I-hydroxybenzotriazole hydrate in triethylamine and methylene dichloride be in stirring at room.
Stir after 15 hours, pour reaction mixture into water and chloroform.Separate water layer, use chloroform extraction.The organic layer that merges is through water and salt water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates obtains target compound (93.5mg, 88.9%) through the silica gel column chromatography post crystallization of purifying.
1HNMR(CDCl
3)：δ1.43(9H，s)，3.82(3H，s)，3.82-3.85(2H，m)，4.475(2H，d，J＝6Hz)，6.71(1H，s)，6.87(2H，d，J＝8Hz)，7.14-7.26(6H，m).
MS(ESI+)：505(MH+).
Embodiment 87
2-amino-N-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } acetamide hydrochloride
Preparation title compound (62.3mg, 82.9%), the 2-that obtains with embodiment 86 ({ 4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } amino)-2-oxoethyl-t-butyl carbamate adopts the similar approach of embodiment 74.
1HNMR(DMSO-d6)：δ3.61(2H，s)，3.79(3H，s)，4.345(2H，d，J＝6Hz)，7.005(2H，d，J＝10Hz)，7.15(1H，s)，7.22-7.32(6H，m)，8.09(2H，br-s)，8.93(1H，br-t，J＝6Hz).
MS (ESI+): 405.33 (free, MH+).
Embodiment 88
N-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } ethanamide
4-[1-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazoles-5-yl that obtains to embodiment 57] benzylamine hydrochloride and the triethylamine solution that is dissolved in methylene dichloride is added dropwise to Acetyl Chloride 98Min. in 0 ℃.
After 1 hour,, use ethyl acetate extraction (3 times) in stirring at room with mixture saturated sodium bicarbonate aqueous solution quencher.The organic layer that merges evaporates after the dried over mgso through 1N hydrochloric acid, water and salt water washing, obtains oily matter, purifies with silica gel column chromatography (with 50% ethyl acetate/normal hexane wash-out), obtains oily matter.With this oily matter with the mixture of ethyl acetate and normal hexane in 50 ℃ of crystallizations, obtain solid target compound (52.2mg, 69.3%).
1HNMR(CDCl
3)：δ2.04(3H，s)，3.83(3H，s)，4.435(2H，d，J＝6Hz)，6.71(1H，s)，6.87(2H，d，J＝8Hz)，7.15-7.26(6H，m).IR(KBr)：1647cm
-1.
MS(ESI+)：412.1(M+Na).
Embodiment 89
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl]-phenyl } ethyl)-1-methyl isophthalic acid H-imidazoles-4-sulphonamide
Preparation title compound (72mg, 70.8%) is with 2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethylamine hydrochloride, the similar approach of employing embodiment 77.
1HNMR(CDCl
3)：δ2.83(2H，t，J＝8Hz)，3.26(2H，dt，J＝6Hz)，3.75(3H，s)，3.83(3H，s)，5.005(1H，t，J＝6Hz)，6.7(1H，s)，6.88(2H，d，J＝8Hz)，7.13(4H，s)，7.22(2H，d，J＝8Hz)，7.45-7.47(2H，m).
MS(ESI+)：528.1(MNa+).
Embodiment 90
N-((1R)-2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group }-the 1-methylethyl) urea
To (1R)-2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group }-solution that 1-methyl-ethylamine hydrochloride is dissolved in methylene dichloride adds triethylamine and isocyanic acid trimethyl silyl ester in 0 ℃.
Stir after 5 hours, water quencher mixture is used dichloromethane extraction.With the organic layer that the salt water washing merges, reduction vaporization after the dried over mgso, obtain oily matter, it is purified through preparative thin-layer chromatography method (1mm, ethyl acetate), obtains oily matter.With the crystalline mixture of oily matter, obtain white solid target compound (22.8mg, 88.1%) with isopropyl ether, ethyl acetate and normal hexane.
1HNMR(CDCl
3)：δ1.29(3H，d，J＝8Hz)，3.82(3H，s)，3.87-3.94(2H，m)，4.07-4.19(1H，m)，4.51(2H，s)，4.87(1H，d，J＝8Hz)，6.67(1H，s)，6.8-6.89(4H，m)，7.12(2H，d，J＝8Hz)，7.215(2H，d，J＝10Hz).
MS(ESI+)：435.3(MH+)，476.3(MH+MeCN).
Embodiment 91
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Preparation title compound (130mg, 71.8%) is with 2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } the ethamine dihydrochloride, the similar approach of employing embodiment 77.
1HNMR(CDCl
3)：δ3.03(3H，s)，3.555(2H，dt，J＝5，5Hz)，3.94(3H，s)，4.115(2H，t，J＝5Hz)，4.785(1H，br-t，J＝5Hz)，6.71(1H，s)，6.76(1H，d，J＝8Hz)，6.85(2H，d，J＝8Hz)，7.16(2H，d，J＝8Hz)，7.555(2H，dd，J＝8，2Hz)，8.085(1H，d，J＝2Hz).
MS(ESI+)：479.1(M+Na)+.
Embodiment 92
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenol
In stirring at room 4-methoxyl group-1-(4,4,4-three fluoro-3-oxobutanoyls) benzene (5.0g) and the mixture of p-hydroxybenzene hydrazonium salt hydrochlorate (3.59g) in acetate (30ml).
Stir after 15 hours, add toluene and water.Use the toluene extracting twice after separating water layer.The organic layer that merges is through water (twice) and salt water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates is purified through silica gel column chromatography, obtains crystal target compound (4.88g, 71.9%).
1H NMR(CDCl
3)：δ3.80(3H，s)，6.68(1H，s)，6.72(2H，d，J＝8.8Hz)，6.83(2H，d，J＝8.8Hz)，7.12(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz).
MS(ESI+)：m/z 357(M+Na).
Embodiment 93
2-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenoxy group } ethanol
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl that embodiment 92 is obtained] suspension of phenol (500mg), salt of wormwood (1.24g), potassiumiodide (1.49g) and 2-chloro-1-ethanol (0.60ml) is in 80 ℃ of stirrings 5 hours.
After the cooling, pour reaction mixture into water.Mixture is through ethyl acetate extraction twice, water and salt water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates is purified through silica gel column chromatography, obtains target compound (545mg, 96.4%).
1H NMR(CDCl
3)：δ2.03(1H，t，J＝5.8Hz)，3.81(3H，s)，3.94-4.01(2H，m)，4.09(2H，dd，J＝3.5，4.6Hz)，4.52(3H，s)，6.68(1H，s)，6.84(2H，d，J＝8.9Hz)，6.89(2H，d，J＝9Hz)，7.13(2H，d，J＝8.9Hz)，7.24(2H，d，J＝9Hz).
MASS(ESI+)：m/z 401(M+Na).
Embodiment 94
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] and phenoxy group } acetonitrile
4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl that embodiment 92 is obtained] suspension of phenol (2.0g), salt of wormwood (992mg), potassiumiodide (993mg) and chloromethyl cyanide (0.57ml) is in 80 ℃ of stirrings 4 hours.
After the cooling, pour reaction mixture into water.Mixture is through ethyl acetate extraction twice, water and salt water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates is purified through silica gel column chromatography, obtains oily target compound (1.75g, 78.3%).
1H NMR(CDCl
3)：δ3.81(3H，s)，4.79(2H，s)，6.69(1H，s)，6.86(2H，d，J＝8.8Hz)，6.96(2H，d，J＝9Hz)，7.14(2H，d，J＝8.8Hz)，7.31(2H，d，J＝9Hz).
MS(APCI+)：m/z 374(M+1).
Embodiment 95
2-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenoxy group } the ethyl carbamic acid tert-butyl ester
Preparation title compound (420mg, 21%) is with 4-[5-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl of embodiment 92 acquisitions] phenol, the similar approach of employing embodiment 73.
1H NMR(CDCl
3)：δ1.46(9H，s)，3.501-3.58(2H，m)，4.02(2H，t，J＝5.1Hz)，4.99(1H，br-s)，6.67(1H，s)，6.84(2H，d，J＝8.9Hz)，6.85(2H，d，J＝9Hz)，7.13(2H，d，J＝8.9Hz)，7.23(2H，d，J＝9Hz).
MS(ESI+)：m/z 500(M+Na).
Embodiment 96
2-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenoxy group } ethylamine hydrochloride
Preparation title compound (0.35g, 96.2%) is with 2-{4-[5-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl of embodiment 95 acquisitions] phenoxy group } the ethyl carbamic acid tert-butyl ester, with the similar approach of embodiment 74.
1H NMR(CDCl
3+CD
3OD)：δ3.2-3.5(4H，m)，3.81(3H，s)，4.2-4.35(2H，m)，6.70(1H，s)，6.84(2H，d，J＝8.6Hz)，6.95(2H，d，J＝8.6Hz)，7.13(2H，d，J＝8.6Hz)，7.25(2H，d，J＝8.6Hz).
MS(ESI+)：m/z 378(M-Cl).
Embodiment 97
N-(2-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] phenoxy group } ethyl) Toluidrin
2-{4-[5-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl that obtains to embodiment 96] phenoxy group } ethylamine hydrochloride (100mg) solution that is dissolved in methylene dichloride (5ml) and triethylamine (0.1ml) is added dropwise to methylsulfonyl chloride (38 μ l) in room temperature.
Stir after 2 hours, reaction mixture is distributed between chloroform and water.Use the chloroform extraction water layer.The organic layer that merges is through water and salt water washing, and dried over mgso is filtered the back reduction vaporization.Resistates is purified through high performance thin-layer chromatography, obtains crystal target compound (35mg, 31.8%).
1H NMR(CDCl
3)：δ3.03(3H，s)，3.56(2H，dt，J＝5，5.7Hz)，3.81(3H，s)，4.11(2H，t，J＝5Hz)，4.82(1H，t，J＝5.7Hz)，6.68(1H，s)，6.85(2H，d，J＝7.9Hz)，6.85(2H，d，J＝8.7Hz)，7.13(2H，d，J＝8.7Hz)，7.24(2H，d，J＝7.9Hz).
MS(ESI+)：m/z 478(M+Na).
Embodiment 98
N-(2-{4-[5-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenoxy group } ethyl) urea
2-{4-[5-(4-p-methoxy-phenyl)-3-(the trifluoromethyl)-1H-pyrazol-1-yl that obtains to embodiment 96] phenoxy group } solution of ethylamine hydrochloride (200mg) water-soluble (10ml) and ethanol (5ml) adds Zassol (314mg) in room temperature.
Stir after 15 hours, reaction mixture is distributed between ethyl acetate and water.Use the ethyl acetate extraction water layer.Wash the organic layer of merging with water, dried over sodium sulfate is filtered the back reduction vaporization.Resistates is through high performance thin-layer chromatography (chloroform: methyl alcohol=8: 1) carry out column chromatography and purify, obtain target compound (0.148g, 72.8%).
1H NMR(CDCl
3)：δ3.60(2H，dt，J＝5.6，5.0Hz)，3.81(3H，s)，4.04(2H，t，J＝5.0Hz)，4.50(2H，br-s)，5.12(1H，t，J＝5.6Hz)，6.68(1H，s)，6.84(2H，d，J＝8.8Hz)，6.85(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.8Hz)，7.22(2H，d，J＝8.9Hz).
MS(ESI+)：m/z 443(M+Na).
Embodiment 99
N-(2-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl)-2-hydroxyl ethyl sulfonamide
The solution that is dissolved in acetonitrile to 2-(2-{4-[1-(4-p-methoxy-phenyl)-3-difluoromethyl-1H-pyrazoles-5-yl] phenyl } ethyl)-1H-isoindole-1,3 (2H)-diketone adds the hydrazine monohydrate.
After 60 ℃ of stirrings are spent the night, filtering mixt.Evaporated filtrate obtains orange oily 2-{4-[1-(4-p-methoxy-phenyl)-3-(difluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethamine.
Be dissolved in the solution of chloroform in room temperature adding 2-hydroxyl ethyl sulfonyl chloride to this oily matter and triethylamine.
Stir after 1 hour, pour reaction mixture into water and chloroform.Use chloroform extraction after separating water layer.The organic layer that merges is through water and salt water washing, and dried over sodium sulfate is filtered the back reduction vaporization.Resistates obtains target compound (220mg, 76.1%) through the silica gel column chromatography post crystallization of purifying.
1H NMR(CDCl
3)：δ2.875(2H，t，J＝7Hz)，2.91-3.19(2H，m)，3.395(2H，dt，J＝6Hz)，3.83(3H，s)，3.985(2H，t，J＝5Hz)，4.44(1H，br-t，J＝6Hz)，6.7(1H，s)，6.765(1H，t，J＝55Hz)，6.875(2H，d，J＝10Hz)，7.12(6H，s).
MS(ESI+)：452.19(MH+).
Preparation 1
Hanging drop to AlCl3 (45.9g) adds Acetyl Chloride 98Min. (13.4ml) (about 5 ℃), is added dropwise to above-mentioned I (25.7g) at ice-cooled (5-10 ℃) down then.Stir after 8 hours, pour reaction mixture into frozen water.Separate organic layer, water (twice) and 1N HCl, saturated NaHCO3 solution and salt water washing, the MgSO4 drying is filtered the back reduction vaporization, obtains crude product.This product of underpressure distillation obtains following compound (P0001) 105.8g (84%).
TLC checks: triketohydrindene hydrate/UV
b.p.1＞91-117℃/0.7mmHg.E111271-1 12.6g
2＞117℃/0.7mmHg.E111271-2 105.8g
Preparation 2
Similar approach according to P0001 prepares above-claimed cpd P0002.
Mass spectrum (API-ES positively charged ion): 243 (M+Na)+200MHz 1H NMR (CDCl3, d): 1.91-2.05 (2H, m), 2.06 (3H, s), 2.59 (3H, s), 2.76 (2H, t, J=7.7Hz), 4.09 (2H, t, J=6.5Hz), 7.28 (2H, d, J=8.2Hz), 7.90 (2H, d, J=8.2Hz)
Preparation 3
60% sodium hydride (427mg) is added the solution that Compound P 0001 (2g) and Trifluoroacetic Acid Ethyl Ester (2.6ml) are dissolved in DMF (10ml) in three batches under ice bath cooling.Stirred reaction mixture is 45 minutes under uniform temp.Replace ice bath with water-bath then.The temperature of reaction mixture is warming up to 24.5 ℃, in 1 hour, temperature slowly is reduced to 22 ℃ again.Mixture is poured mixture 1M HCl (12ml) and ice (40ml) into then in stirring at room 1 hour.Extract whole mixtures with AcOEt (20ml).Organic layer is through H2O (30ml), saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, uses the toluene wash-out.The crystal that obtains obtains white crystal Compound P 0003 through refrigerated normal hexane (10ml) and sherwood oil (5ml) decantate.
Mass spectrum (API-ES negatively charged ion): 301 (M-H)+200MHz 1H NMR (DMSO-d6, d): 3.00 (2H, t, J=6.7Hz), 4.27 (2H, t, J=6.7Hz), 6.99 (1H, s), 7.48 (2H, d, J=8.3H z), 8.08 (2H, d, J=8.3Hz)
Preparation 4
The similar approach of introducing preparation P0003 according to preparation 3 prepares P0004.
Mass spectrum (API-ES negatively charged ion): 315 (M-H)+NMR JA24.112200MHz 1H NMR (CDCl3, d): 1.92-2.06 (2H, m), 2.06 (3H, s), 2.74-2.82 (2H, m), 4.10 (2H, t, J=6.5Hz), 6.55 (1H, s), 7.33 (2H, d, J=8.3Hz), 7.89 (2H, d, J=8.3Hz)
Preparation 5
The similar approach of introducing preparation P0003 according to preparation 3 prepares P0005.
Yellow crystals
Mass spectrum (API-ES positively charged ion): 259 (M+Na)+400MHz 1H NMR (CDCl3, d): 1.41 (3H, t, J=7.1Hz), 4.40 (2H, q, J=7.1Hz), 6.93 (2H, dJ=8.9Hz), 7.02 (1H, s), 7.96 (2H, d, J=8.9Hz)
Preparation 6
Similar approach according to P0003 obtains P0006.(preparation 3)
Preparation 7
The solution that 60% sodium hydride (233mg) is added in three batches P0001 (1g) and five fluorine ethyl propionates (0.93ml) under the ice bath cooling.In 24-27 ℃ and the following stirred reaction mixture some hrs of water-bath cooling, pour into then in the mixture of ice and 1M HCl (50ml).Whole mixture AcOEt extracting twice.The organic layer that merges washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates, and obtains oily P0007 (1.94g).
Mass spectrum (API-ES negatively charged ion): 309 (M-H)+200MHz 1H NMR (CDCl3, d): 2.90-3.05 (2H, m), 3.85-4.00 (2H, m), 6.62 (1H, s), 7.39 (2H, d, J=8.3Hz), 7.92 (2H, d, J=8.3Hz)
Preparation 8
The EtOH solution (18ml) of 20% sodium ethylate is added dropwise to the solution that P0001 (4.00g) and oxalic acid diethyl ester (5.95g) are dissolved in DMF (12ml) in 4-6 ℃.After uniform temp down stirs 1 hour, pour reaction mixture the mixture of frozen water (100ml) and dense HCl (5ml) into, extract with AcOEt.Use 1M HCl, H successively
2O and saturated sodium-chloride water solution washing, dried over mgso is used activated carbon treatment, filters through SiO2 (20ml) pad then.Wash this pad with AcOEt.The washings of vacuum concentrated filtrate and merging obtains oily P0008 (6.05g).
Mass spectrum (API-ES positively charged ion): 287 (M+Na)+, and (API-ES negatively charged ion) 263 (M-H)+200MHz 1H NMR (CDCl3, d): 1.42 (3H, t, J=7.1Hz), 2.96 (2H, t, J=6.5Hz), 3.93 (2H, t, J=6.5Hz), 4.40 (2H, q, J=7.1Hz), 7.06 (1H, s), 7.38 (2H, d, J=8.3Hz), 7.96 (2H, d, J=8.3Hz)
Preparation 9
Be dissolved in N to 4-dihydroxy benaophenonel (160g), Trifluoroacetic Acid Ethyl Ester (182ml) and ethanol (11ml), the solution of dinethylformamide (670ml) in 15 minutes in 0～35 ℃ add in batches sodium hydride (mineral oil suspension, 103g).Mixture in stirring at room 2 hours, was stirred 3 hours in 35～40 ℃ then.Described mixture is poured into the mixture of ice, dense hydrogenchloride (320ml) (water layer is 4L altogether) and diisopropyl ether (2L).Separate water layer, with diisopropyl ether (500ml * 2) extraction.The organic layer that merges evaporates after the dried over mgso through water (500ml * 4) and salt water washing, obtains the 415g solid.This solid is dissolved in diisopropyl ether (200ml) in 65 ℃.Add hexane (1.5L) in room temperature and under stirring to described drips of solution.In stirring at room after 1 hour, filtering suspension liquid, drying under reduced pressure obtains solid (first, 109.53g, 40%).Do similar processing with diisopropyl ether (20ml) and hexane (250ml) behind the mother liquid evaporation, obtain second batch of product (71.11g, 26%).P0009 (first and second batch of product total amount, 66.2%).
NMR(CDCl3)；5.65(1H，brs)，6.50(1H，s)，6.94(2H，d，J＝8.8Hz)，7.91(2H，d，J＝8.8Hz).
MS(ESI+)，255.1(M+Na)+.
Preparation 10
According to the similar approach of P0009 (S0203744), obtain Powdered target compound (56.195g, 102%).
NMR(CDCl3)；6.01(1H，t，J＝54Hz)，6.49(1H，s)，6.92(2H，d，J＝8.8Hz)，7.90(2H，d，J＝8.8Hz).
MS(ESI-)，213.3(M-H)+
Preparation 11
P0009 (100g), 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (82.4g) and the mixture of sodium acetate (42.6g) in acetate (550ml) were stirred 3 hours in 70 ℃.After being cooled to room temperature, pour mixture into water (4L), in stirring at room 1 hour.Filtering precipitate, water (250ml * 3) and Hex (500ml * 2) washing are spent the night in drying at room temperature, obtain powder (157.86g).Described powder is purified with ethyl acetate and hexane recrystallization, obtains Powdered P0011 (121.34g, 77%).
NMR(CDCl3)；3.82(3H，s)，5.08(1H，brs)，6.67(1H，s)，6.77(2H，d，J＝8.6Hz)，6.87(2H，d，J＝9.0Hz)，7.09(2H，d，J＝8.6Hz)，7.23(2H，d，J＝9.0Hz).
MS(ESI+)；357.1(M+Na)+.
Preparation 12
According to the similar approach of P0011, obtain solid target compound (3.2028g, 72%).NMR(DMSO-d6)；3.88(3H，s)，6.74(2H，d，J＝8.6Hz)，6.82(1H，s)，6.90(1H，d，J＝8.6Hz)，7.10(2H，d，J＝8.6Hz)，7.09(1H，t，J＝55Hz)，7.68(1H，dd，J＝8.6，2.7Hz)，8.12(1H，d，J＝2.7Hz).
MS(ESI+)；316.1(M-H)+，633.3(2M-H).
Preparation 13
According to the similar approach of P0011, obtain target compound.
Preparation 14
Solution to 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (3.43g) water-soluble (7.7ml) adds the solution that P0009 is dissolved in acetate (50ml).Then with mixture in the room temperature standing over night.Pour mixture into water (500ml), in stirring at room 1 hour.Filtering precipitate, water (100ml) washing in drying at room temperature, obtains brown solid P0014 (3.26g, 90%).
NMR(DMSO-d6)；3.88(3H，s)，6.75(2H，d，J＝8.6Hz)，6.92(1H，d，J＝8.5Hz)，7.06-7.15(3H，m)，7.73(1H，dd，J＝8.5，2.8Hz)，8.16(1H，d，J＝2.8Hz)，9.86(1H，s，OH).
MS(ESI-)；334.1(M-H)+，669.2(2M-1)+.
Preparation 15
According to the similar approach of P0014, obtain light brown powder shape target compound (13.58g, 91.7%).
NMR(DMSO-d6)；3.94(3H，s)，6.67(1H，s)，6.75(1H，t，J＝55Hz)，6.73-6.80(3H，m)，7.09(2H，d，J＝8.6Hz)，7.57(1H，dd，J＝8.6，2.6Hz)，8.07(1H，d，J＝2.6Hz).
MS(ESI-)；316.1(M-H)，633.3(2M-H).
Preparation 16
1M NaOH (1ml) is added P0016-1 (WO9427973 report) (1.31g) be dissolved in the solution of EtOH (5ml), mixture is in spending the night with enclosing the envrionment temperature stirring.Mixture distributes between AcOEt and H2O.Organic layer is through H2O, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane wash-out, obtains oily P0016 (900mg).
Mass spectrum (ESI+): 331 (M+H)+200MHz 1H NMR (DMSO-d6, d) :-0.05 (6H, s), 0.82 (9H, s), 0.94 (4H, d, J=6.0Hz), 2.38-2.52 (1H, m), 2.78 (2H, t, J=6.6Hz), 3.79 (2H, t, J=6.6Hz), 7.01 (1H, d, J=16.2H z), 7.29 (2H, d, J=8.1Hz), 7.65 (2H, d, J=8.1Hz), 7.65 (1H, d, J=16.2Hz)
Preparation 17
Similar approach according to P0016 prepares P0017 (6.41g).
Mass spectrum (API-ES positively charged ion): 255 (M+Na)+200MHz 1H NMR (CDCl3, d): 0.90-1.01 (2H, m), 1.11-1.20 (2H, m), 2.22 (1H, m), 3.49 (3H, s), 5.21 (2H, s), 6.78 (1H, d, J=16.0Hz), 7.05 (2H, d, J=8.7Hz), 7.52 (2H, d, J=8.7Hz), 7.58 (1H, d, J=16.0Hz)
Preparation 18
30%H2O2 (0.64ml) and 3M NaOH (0.64ml) are added 0.25MP0016 (1.03g) be dissolved in EtOH: the solution of acetone=3: 1.Mixture stirs in ambient temperature and spends the night.Vacuum concentrated mixture distributes between AcOEt and H2O.Organic layer is through H2O, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates, and obtains oily P0018 (792mg).
Mass spectrum (ESI+): 347 (M+H)+200MHz 1H NMR (DMSO-d6, d) :-0.05 (6H, s), 0.82 (9H, s), 0.92-1.04 (4H, m), 2.24 (1H, m), 2.75 (2H, t, J=6.7Hz), 3.76 (2H, t, J=6.7Hz), 3.86 (1H, d, J=1.9Hz), 4.19 (1H, d, J=1.9Hz), 7.24 (2H, d, J=8.4H z), 7.30 (2H, d, J=8.4Hz)
Preparation 19
Adopt the similar approach of P0018 to prepare P0019 (1.082g) with P0017 (1.0g).
Mass spectrum (API-ES positively charged ion): 271 (M+Na)+200MHz 1H NMR (DMSO-d6, d): 0.90-1.04 (4H, m), 2.24 (1H, m), 3.37 (3H, s), 3.88 (1H, d, J=1.9Hz), 4.17 (1H, d, J=1.9Hz), 5.20 (2H, s), 7.03 (2H, d, J=8.7Hz), 7.32 (2H, d, J=8.7Hz) 200MHz 1H NMR (CDCl3, d): 0.90-1.07 (2H, m), 1.12-1.26 (2H, m), 2.18 (1H, m), 3.48 (3H, s), 3.58 (1H, d, J=1.9Hz), 4.05 (1H, d, J=1.9Hz), 5.18 (2H, s), 7.04 (2H, d, J=8.7Hz), 7.23 (2H, d, J=8.7Hz)
Preparation 20
With P0005 (17.00g) in 70 ℃ of EtOH (68ml) and AcOH (170ml) that are dissolved in tepor.Be suspended in the P0005 of H2O (20ml) to the disposable adding of described solution.Mixture is poured the mixture of ice (500ml) and dense HCl (10ml) into then in 70 ℃ of stirrings 1.5 hours.Add diisopropyl ether (100ml), stirred the mixture 20 minutes in ambient temperature.The collecting precipitation thing is successively with 1M HCl, H2O and diisopropyl ether washing.Through air-dry overnight, obtain pale yellow powder shape P0020 (21.28g).
Mass spectrum (ESI+): 339 (M+H)+400MHz 1H NMR (CDCl3, d): 1.41 (3H, t, J=7.1H z), 3.82 (3H, s), 4.44 (2H, q, J=7.1Hz), 6.76 (2H, d, J=8.7Hz), 6.85 (2H, d, J=9.0Hz), 6.96 (1H, s), 7.08 (2H, d, J=8.7Hz), 7.24 (2H, d, J=9.0Hz)
Preparation 21
Adopt the similar approach of P0020 to prepare white powder P0021 with P0005.
Mass spectrum (ESI+): 340 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.31 (3H, t, J=7.1Hz), 3.88 (3H, s), 4.32 (2H, q, J=7.1Hz), 6.74 (2H, d, J=8.6Hz), 6.92 (1H, d, J=8.8Hz), 7.00 (1H, s), 7.09 (2H, d, J=8.6Hz), 7.71 (1H, dd, J=8.8,2.7Hz), 8.13 (1H, d, J=2.7Hz), 9.82 (1H, s)
Preparation 22
The solution that triphenylphosphine (831mg) is dissolved in THF (5ml) is added dropwise to the solution that E0118 (521.8mg) and carbon tetrabromide (1.15g) are dissolved in THF (5ml) in ambient temperature.In ambient temperature stirred reaction mixture 1 hour.Disposable adding carbon tetrabromide (573mg) and triphenylphosphine (415mg), restir 1 hour.Leach insolubles, wash with THF.The washings of vacuum concentrated filtrate and merging.Resistates is purified through silica gel column chromatography, uses AcOEt/ normal hexane=5%, 25% wash-out successively, obtains faint yellow wax P0022 (647.2mg).
mp.60-70℃
Mass spectrum (API-ES positively charged ion): 425,427 (M+H)+, and 447,449 (M+Na)+200MHz 1H NMR (CDCl3, d): 3.12-3.19 (2H, m), 3.52-3.60 (2H, m), 3.82 (3H, s), 6.72 (1H, s), 6.87 (2H, d, J=9.0Hz), 7.16-7.30 (6H, m)
Preparation 23
Similar approach according to P0022 prepares colorless oil P0023.
Mass spectrum (API-ES positively charged ion): 448,450 (M+Na)+400MHz 1H NMR (DMSO-d6, d): 3.14 (2H, t, J=7.2Hz), 3.74 (2H, t, J=7.2Hz), 3.88 (3H, s), 6.92 (1H, d, J=8.8Hz), 7.20 (1H, s), 7.27 (2H, d, J=8.4Hz), 7.32 (2H, d, J=8.4Hz), 7.76 (1H, dd, J=2.7,8.8Hz), 8.19 (1H, d, J=2.7Hz)
Preparation 24
(20.0g0 and P0024-0 (53.4g) are dissolved in the solution of DMF (200ml) in the ice-cooled NaH (4.27g) that adds down in batches to P0001.Reaction mixture is heated up in room temperature, and temperature keeps below 40 ℃.Stir after 5 hours, pour reaction mixture into ice-cold rare HCl, use twice of ethyl acetate extraction.The organic layer that merges is through water (twice) and salt water washing, and the MgSO4 drying is filtered the back reduction vaporization.Resistates is purified through silica gel column chromatography, and (500ml Hex:EtOAc), obtains crystal P0024 (12.12g).
mp：52.6-53.6℃
Embodiment 100
The solution that is dissolved in N,N-dimethylacetamide (15ml) to 4-dihydroxy benaophenonel (4.16g) and chloromethyl methyl ether (2.46g) in 0 ℃ in 15 minutes, add in batches sodium hydride (mineral oil suspension (60%), 1.22g).Stirred the mixture 30 minutes in ambient temperature.In 15 minutes, add 2-propyl alcohol (0.5ml), dithiocarbonic anhydride (2.56g) in 25 ℃ to reaction mixture, add in batches sodium hydride (mineral oil suspension (60%), 2.50g).Stirred the mixture 1.5 hours in ambient temperature, with the mixture of pouring ice and dense hydrogenchloride (8ml) (water layer sum 68ml) after toluene (20ml) dilution into.With ethyl acetate extraction gained mixture, the salt water washing is evaporated after the dried over mgso.Mixture in ethyl acetate (30ml) and water (20ml) adds the aqueous solution of iodine (3.88g) and sodium iodide (8.0g) in batches to gained resistates and sodium bicarbonate (13g) in 0 ℃.Add 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (3.80g) in 0 ℃ to mixture under the nitrogen atmosphere in batches.Stirred the mixture 3 hours in ambient temperature, separate organic layer, water and salt water washing are evaporated after the dried over mgso.In 0 ℃ of solution adding methyl iodide (4.0ml) and triethylamine (10ml) that is dissolved in ethyl acetate (30ml) to resistates.Stirred the mixture 30 minutes in ambient temperature, water and wet chemical washing are evaporated after the dried over mgso.Resistates is purified (80g) through silica gel column chromatography, with the mixture wash-out of ethyl acetate and toluene (1: 20), obtains 5-[4-(methoxymethoxy) phenyl of 7.56g]-1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles.
(80%, methylene dichloride 4.4g) (15ml) solution stirred the mixture 1 hour in 0 ℃ to add metachloroperbenzoic acid in 0 ℃ of solution that is dissolved in methylene dichloride (30ml) to dimethyl sulphide (7.56g).Use the wet chemical purging compound, evaporate after the dried over mgso.Resistates is purified (80g) through silica gel column chromatography, uses eluent ethyl acetate, obtains 5.43g 5-[4-(methoxymethoxy) phenyl]-1-(4-p-methoxy-phenyl)-3-(methylsulfinyl)-1H-pyrazoles (E0100).
mp.136.9-137.3℃
Mass spectrum; 373 (M+1)
IR(KBr)；1054cm-1
NMR(CDCl3，δ)；3.00(H，s)，3.48(H，s)，3.83(H，s)，5.17(H，s)，6.88(H，d，J＝9.0Hz)，6.92(H，s)，6.97(H，d，J＝8.8Hz)，7.14(H，d，J＝8.8Hz)，7.22(H，d，J＝9.0Hz)，
Embodiment 101
In 0 ℃ to 5-[4-(methoxymethoxy) phenyl]-solution that 1-(4-p-methoxy-phenyl)-3-(methylsulfinyl)-1H-pyrazoles (7.56g) is dissolved in methylene dichloride (20ml) adds metachloroperbenzoic acid (60%; 3.76g), mixture stirred 3 hours in 0 ℃.Use the sodium bicarbonate aqueous solution purging compound, evaporate after the dried over mgso.Resistates is purified through the toluene recrystallization, obtains 5-[4-(methoxymethoxy) phenyl of 5.07g]-1-(4-p-methoxy-phenyl)-3-(methylsulfonyl)-1H-pyrazoles (E0101).
mp.128.0-128.1℃
Mass spectrum; 389 (M+1)
IR(KBr)；1300cm-1
NMR(CDCl3，δ)；.3.29(3H，s)，3.48(3H，s)，3.83(3H，s)，5.17(2H，s)，6.88(2H，d，J＝9.0Hz)，6.93(1H，s)，6.98(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz)，7.24(2H，d，J＝9.0Hz)，
Preparation 25
To 5-[4-(methoxymethoxy) phenyl]-solution that 1-(4-p-methoxy-phenyl)-3-(methylsulfonyl)-1H-pyrazoles (0.93g) is dissolved in mixture tetrahydrofuran (THF) (10ml) and Virahol (5ml) in ambient temperature add hydrochloride aqueous solution (20%, 8ml).Stirred solution 3 hours is used ethyl acetate extraction, uses the salt water washing, evaporates after the dried over mgso, obtains 4-[1-(4-p-methoxy-phenyl)-3-(methylsulfonyl)-1H-pyrazoles-5-yl of 0.82g] phenol (P0025).
Mass spectrum; 345 (M+1)
NMR(DMSO-d6，δ)；3.32(3H，s)，3.79(3H，s)，6.73(2H，d，J＝8.6Hz)，7.01(2H，d，J＝8.9Hz)，7.05(1H，s)，7.08(2H，d，J＝8.6Hz)，7.27(2H，d，J＝8.9Hz)，9.84(1H，s)，
Preparation 26
The solution that is dissolved in DMF (40ml) to P0026-0 (5.0g) and imidazoles (3.3g) adds TBDMSCl (6.69g) in room temperature in batches.After stirring is spent the night, add entry and hexane.Use twice of hexane extraction after separating water layer.The organic layer that merges is through water (twice) and salt water washing, and the MgSO4 drying is filtered the back reduction vaporization, obtains the P0026 of 9.49g (98.3%).
IR (film): 2952.5,2935.1,1467.6,1255.4,1124.3,1097.3,838.9,777.2cm-1.
Preparation 27
The solution that is dissolved in DMF to P0027-0 (10g) and methylcarbonate (5.97g) adds sodium methylate (4.77g).Stirred the mixture 2 hours in ambient temperature.Pour mixture into contain the dense HCl of 8mL water, extract with AcOEt.Organic layer concentrates through the dried over mgso final vacuum.Resistates is purified through silica gel column chromatography, obtains orange solids.With its recrystallization, obtain white crystal P0027 with MeOH.
NMR(200MHz，CDCl3)3.75(3H，s)，3.96(2H，s)，5.14(2H，s)，7.02(2H，d，J＝8.9Hz)，7.34-7.45(5H，m)，7.93(2H，d，J＝8.9Hz)
Mass spectrum ESI 285 (M+H)+(file platform 7366-1)
Preparation 28
Be dissolved in 1 to triphenylphosphine oxide (294mg) under the ice bath cooling, the drips of solution of 2-ethylene dichloride (3ml) adds trifluoromethanesulfanhydride anhydride (198mg).When white precipitate occurring, under uniform temp, stirred the mixture 15 minutes.Be added dropwise to 1 of P0027 (300mg) to this mixture, 2-ethylene dichloride (2ml) adds Et3N (214mg) then.Backflow mixture 2 hours.Cooling mixture is to ambient temperature, and with H2O, saturated NaCl solution washing, MgSO4 is dry, and final vacuum concentrates.Resistates is purified through silica gel column chromatography, uses AcOEt/ normal hexane=5%, 10% wash-out successively.Resistates obtains white powder P0028 (166mg) through the IPE crystallization.
Mass spectrum (ESI+): 289 (M+Na)+200MHz 1H NMR (DMSO-d6, d): 3.76 (3H, s), 5.18 (2H, s), 7.11 (2H, d, J=8.8Hz), 7.33-7.48 (5H, m), 7.62 (2H, d, J=8.8Hz)
Preparation 29
Solid KOH (124mg) is dissolved in EtOH (5ml) in 50 ℃.Add P0028 (196mg) to solution.After uniform temp stirs 2 hours down, reaction mixture is cooled to ambient temperature.Mixture distributes between 1M HCl and CHCl3.With the CHCl3 water layer of stripping.The organic layer that merges is through MgSO4 drying, vacuum-evaporation.Collect remaining crystal,, obtain first white powder product P 0029 (87mg) with the IPE washing.The vacuum concentration mother liquor is collected remaining crystal, with the normal hexane washing, obtains second crowd of reddish powdery product P0029 (39mg).
Mass spectrum (ESI-): 251 (M-H)+200MHz 1H NMR (CDCl3, d): 5.10 (3H, s), 6.97 (2H, d, J=8.9Hz), 7.34-7.43 (5H, m), 7.56 (2H, d, J=8.9Hz)
Preparation 30
The solution that is dissolved in DMF (20ml) to P0030-0 (2g) and phosphonoacetic acid triethyl (2.32g) adds 60%NaH (490mg) at twice under the ice bath cooling.Under uniform temp, stirred the mixture 1 hour, and poured the frozen water that contains NH4Cl then into.White depositions is moments later collected in the mixture stirring, and water and 10%IPA solution washing obtain P0030.
200MHz 1H NMR(CDCl3，d)：1.33(3H，t，J＝7.2Hz)，4.25(2H，q，J＝7.2Hz)，5.10(2H，s)，6.31(1H，d，J＝16.0Hz)，6.97(2H，d，J＝8.7Hz)，7.32-7.50(7H，m)，7.64(1H，d，J＝16.0Hz)
Preparation 31
The solution that is dissolved in CH2Cl2 (28ml) to P0030 (2.79g) is added dropwise to bromine (1.66g) under the ice bath cooling.Under uniform temp, stirred the mixture 30 minutes.Distribute after reaction mixture being poured into 5% the Na2S2O3 aqueous solution.Organic layer is through the saturated NaHCO3 aqueous solution, saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Collect remaining crystal,, obtain pale yellow powder shape P0031 (3.07g) with the normal hexane washing.
200MHz 1H NMR(CDCl3，d)：1.38(3H，t，J＝7.2Hz)，4.35(2H，q，J＝7.2Hz)，4.81(1H，d，J＝11.8H z)，5.07(2H，s)，5.35(1H，d，J＝11.8Hz)，6.98(2H，d，J＝8.7Hz)，7.34(2H，d，J＝8.7Hz)，7.32-7.45(5H，m)
Preparation 32
Be dissolved in 95% the EtOH aqueous solution (20ml) in 50 ℃ of solid KOHs (1.73g) with 85%.Disposable adding P0031 (3.05g), backflow mixture 9 hours.Add the solution that 85%KOH (0.32g) is dissolved in the 95%EtOH aqueous solution (10ml) to described mixture, refluxed 5 hours.The ice bath cooling mixture, the collecting precipitation thing washs with EtOH.Crystal is suspended among AcOEt and the H2O, and the ice bath cooling is with 3M HCl and 1M HCl acidifying.Distribute mixture, organic layer washs through H2O, and MgSO4 is dry, and final vacuum concentrates.Collect residual solid,, obtain white powder P0032 (0.67g) with the washing of IPE-normal hexane.
200MHz 1H NMR(CDCl3，d)：5.10(3H，s)，6.97(2H，d，J＝8.9Hz)，7.34-7.43(5H，m)，7.56(2H，d，J＝8.9Hz)
Embodiment 102
The solution that is dissolved in N-Methyl pyrrolidone (1ml) to P0032 (99.9mg) and HOBT (64.2mg) adds WSCD.HCl (91.1mg), stirs the mixture 20 minutes in ambient temperature.In another flask, diisopropylethylamine (76.8mg) is added the suspension of E0102-0 (83.0mg) in N-Methyl pyrrolidone (1ml), stir in ambient temperature, up to whole E0102-0 dissolvings.E0102-0 solution is added reaction flask, stirred the mixture 1 hour in ambient temperature.Mixture distributes between AcOEt and H2O, and with the saturated NaHCO3 aqueous solution and saturated NaCl solution washing, MgSO4 is dry, and final vacuum concentrates.Resistates is dissolved in CH2Cl2 (3ml), stirred 24 hours in ambient temperature.Vacuum concentrated mixture.Remaining crystal is suspended in hot AcOEt, stirs cooling, collect the back, obtain white powder E0102 (90.9mg) with the AcOEt washing.
Mass spectrum (EsI+): 373 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.75 (3H, s), 5.08 (2H, s), 5.81 (1H, s), 6.90 (2H, d, J=9.0Hz), 6.96 (2H, d, J=9.0Hz), 7.10 (2H, d, J=9.0Hz), 7.12 (2H, d, J=9.0Hz), 7.32-7.47 (5H, m), 10.00 (1H, s)
Embodiment 103
Suspension in DMSO (0.5ml) adds methyl-sulfate (10.6mg) to E0102 (20.9mg) and K2CO3 (23.3mg), stirs the mixture 1 hour in ambient temperature.Mixture distributes between AcOEt and H2O, and organic layer is through saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Resistates is purified through the preparative thin-layer chromatography method, launches with AcOEt/ normal hexane=25%.With the crystal IPE crystallization that obtains, obtain white crystal E0103 (12.0mg).
Mass spectrum (ESI+): 387 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.76 (3H, s), 3.83 (3H, s), 5.08 (2H, s), 6.04 (1H, s), 6.92 (2H, d, J=9.0Hz), 6.97 (2H, d, J=9.0Hz), 7.11-7.17 (4H, m), 7.30-7.50 (5H, m) 200MHz 1H NMR (CDCl3, d): 3.80 (3H, s), 3.97 (3H, s), 5.04 (2H, s), 5.88 (1H, s), 6.82 (2H, d, J=9.0Hz), 6.88 (2H, d, J=8.9Hz), 7.11-7.21 (4H, m), and 7.34-7.43 (5H, m)
Embodiment 104
Suspension in DMF (6ml) adds methylcarbonate (0.56ml) to E0102 (818mg) and K2CO3 (911mg).Stirred the mixture 2 hours in 120 ℃.Add methylcarbonate (1ml) again, stirred 8 hours in 120 ℃.Mixture distributes between AcOEt and H2O, with the AcOEt water layer of stripping.The organic layer that merges is through saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out.With AcOEt (2.5ml) and normal hexane (5ml) crystallization, obtain white crystal E0104 (583mg).
200MHz 1H NMR(DMSO-d6，d)：3.76(3H，s)，3.83(3H，s)，5.08(2H，s)，6.04(1H，s)，6.92(2H，d，J＝9.0Hz)，6.97(2H，d，J＝9.0Hz)，7.11-7.17(4H，m)，7.30-7.50(5H，m)200MHz 1H NMR(CDCl3，d)：3.80(3H，s)，3.97(3H，s)，5.04(2H，s)，5.88(1H，s)，6.82(2H，d，J＝9.0Hz)，6.88(2H，d，J＝8.9Hz)，7.11-7.21(4H，m)，7.34-7.43(5H，m)
Preparation 33
With 10%Pd-C 50% weight in wet base (50mg) and E0104 (261mg) mixture in AcOEt (2ml) and MeOH (2ml) under H2 (1atm) in ambient temperature hydrogenation 1 day.Add 10%Pd-C 50% weight in wet base (50mg) again, with mixture under H2 (3.5atm) in ambient temperature hydrogenation 3 hours.Remove by filter catalyzer, the washings of vacuum concentrated filtrate and merging.Resistates is dissolved in AcOEt, and MgSO4 is dry, and final vacuum concentrates.With AcOEt-normal hexane crystalline residue, obtain white powder P0033 (146mg).
Mass spectrum (ESI+): 297 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.75 (3H, s), 3.83 (3H, s), 5.98 (1H, s), 6.70 (2H, d, J=8.6Hz), 6.91 (2H, d, J=8.9Hz), 7.01 (2H, d, J=8.6Hz), 7.12 (2H, d, J=8.9Hz), 9.69 (1H, s)
Preparation 34
Add EtOH (6ml), E0104 (558mg), THF (1ml) and 10%Pd-C 50% weight in wet base (60mg) successively to the H2O of ammonium formiate (455mg) (1ml) solution.Mixture was refluxed 1 hour.Remove by filter catalyzer.The washings of vacuum concentrated filtrate and merging.Resistates distributes between AcOEt and H2O, and with saturated NaCl solution washing organic layer, MgSO4 is dry, and final vacuum concentrates.With AcOEt (3ml) and the remaining crystal of normal hexane (3ml) recrystallization, obtain white crystal P0034 (335mg).
Mass spectrum (ESI+): 297 (M+H)+
Embodiment 105
Mixture in acetate (30ml) was in stirring at room 15 hours with P0003 (2.9g) and 4-p-methoxy-phenyl hydrazine (1.68g).After adding entry, extract mixture twice with toluene.The organic layer that merges is through water (twice), saturated NaHCO3, water and salt water washing, and the MgSO4 drying is filtered the back reduction vaporization.Resistates is through silica gel column chromatography purification (Hex/EtOAc=8: 1-4: 1), obtain the oily E0105 of 2.2g (57%).
IR (film): 1737.6,1511.9,1240.0,1159.0,1130.1cm-1.
Embodiment 106
Adopt the similar approach of E0105 to prepare E0106 with P0004.
Mass spectrum (ESI+): 420 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.79-1.94 (2H, m), 1.98 (3H, s), 2.60-2.68 (2H, m), 3.88 (3H, s), 3.98 (2H, t, J=6.5Hz), 6.92 (1H, d, J=8.9Hz), 7.18 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J=2.7,8.9Hz), 8.48 (1H, d, J=2.7Hz)
Embodiment 107
With P0007 (590mg) and 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (332mg), adopt the similar approach of E0105 to prepare E0107 (175.7mg).
Mass spectrum (ESI+): 455 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.96 (3H, s), 2.88 (2H, t, J=6.8Hz), 3.79 (3H, s), 4.20 (2H, t, J=6.8H z), 6.99 (2H, d, J=8.9Hz), 7.15 (1H, s), 7.17-7.30 (6H, m)
Embodiment 108
Adopt the similar approach of E0105 to prepare E0108 with P0007.
Mass spectrum (API-ES positively charged ion): 456 (M+H)+, 478 (M+Na)+200MHz 1H NMR (DMSO-d6, d): 1.96 (3H, s), 2.89 (2H, t, J=6.8Hz), 3.88 (3H, s), 4.21 (2H, t, J=6.8Hz), 6.92 (1H, d, J=8.8Hz), and 7.15-7.35 (4H, m), 7.21 (1H, s), 7.76 (1H, dd, J=2.7,8.8Hz), 8.17 (1H, d, J=2.7Hz)
Embodiment 109
Similar approach with E0105 prepares E0109.
Mass spectrum (ESI+) 409 (M+H)+, 431 (M+Na)+NMR:SE20.059 200MHz 1H NMR (DMSO-d6, d): 1.31 (3H, t, J=7.1Hz), 1.96 (3H, s), 2.87 (2H, t, J=6.8Hz), 3.79 (3H, s), 4.20 (2H, t, J=6.8Hz), 4.32 (2H, q, J=7.1Hz), 6.99 (2H, d, J=9.0Hz), 7.08 (1H, s), 7.16-7.28 (6H, m)
Embodiment 110
Similar approach according to E0105 prepares E0110.
Mass spectrum (ESI+): 410 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.32 (3H, t, J=7.1Hz), 1.96 (3H, s), 2.89 (2H, t, J=6.8Hz), 3.88 (3H, s), 4.21 (2H, t, J=6.8Hz), 4.33 (2H, q, J=7.1Hz), 6.92 (1H, d, J=8.8Hz), 7.12 (1H, s), and 7.19-7.32 (4H, m), 7.73 (1H, dd, J=2.7,8.8Hz), 8.14 (1H, d, J=2.7Hz)
Embodiment 111
Similar approach according to E0105 prepares E0111.
Mass spectrum (API-ES positively charged ion): 406 (M+H)+, 428 (M+Na)+200MHz 1H NMR (DMSO-d6, d): 1.96 (3H, s), 2.89 (2H, t, J=6.7Hz), 3.88 (3H, s), 4.21 (2H, t, J=6.7Hz), 6.92 (1H, d, J=8.8Hz), 7.20 (1H, s), 7.24 (2H, d, J=8.7Hz), 7.30 (2H, d, J=8.7Hz), 7.76 (1H, dd, J=2.7,8.8Hz), 8.18 (1H, d, J=2.7Hz)
Embodiment 112
Similar approach according to E0105 obtains E0112.
Embodiment 113
Similar approach according to E0105 obtains E0113.
Embodiment 114
Similar approach according to E0105 obtains E0114.
Embodiment 115
Similar approach according to E0105 obtains E0115.
Embodiment 116
Similar approach according to E0105 obtains E0116.
Embodiment 117
Similar approach according to E0105 obtains E0117.
Embodiment 118
Mixture in THF (40ml) was in stirring at room 5 hours with E0105 (2.0g) and 1N NaOH (15ml).After reaction is finished, with 1N HCl (15ml) the described mixture that neutralizes, with ethyl acetate extraction twice, with 1N HCl, saturated NaHCO3 and salt water washing, NA2SO4 drying, reduction vaporization after filtering.Resistates is through silica gel column chromatography purification (H/EA=2: 1-1: 1), obtain the crystal E0118 of 1.14g (64%).
mp：103-104℃
IR (film): 3396.0,1513.9,1467.6,1238.1,1160.9,1132.0cm-1.
Embodiment 119
Adopt the similar approach of E0118 to prepare E0119 with E0217.
IR (pure): 3359,3332,3325,1658,1651,1624,1614,1545,1533,1500cm-1
Mass spectrum (ESI+): 421 (M+E)+200MHz 1H NMR (DMSO-d6, d): 2.71-2.79 (2H, m), 3.28-3.39 (2H, m), 3.76 (2H, brs), 3.88 (3H, s), 5.47 (1H, br), 6.92 (1H, d, J=8.9Hz), 7.18 (1H, s), 7.24 (4H, s), 7.74 (1H, dd, J=2.7,8.9Hz), 7.80 (1H, t, J=5.9Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 120
Adopt the similar approach of E0118 to prepare E0120 with E0002.
IR (pure): 3433,3423,3398,3367,2945,1612,1500cm-1
Mass spectrum (ESI+): 378 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.62-1.77 (2H, m), 2.57-3.65 (2H, m), 3.34-3.44 (2H, m), 3.88 (3H, s), 4.48 (1H, t, J=5.1Hz), 6.92 (1H, d, J=8.9Hz), 7.17 (1H, s), 7.23 (4H, s), 7.76 (1H, dd, J=8.9,2.8Hz), 8.18 (1H, d, J=2.8Hz)
Embodiment 121
Adopt the similar approach of E0118 to prepare white powder E0121 with E0268.
mp.91-92℃
IR(KBr)：3491，3471，3437，2941，2239，1610，1508cm-1
Mass spectrum (ESI+): 336 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.65-3.73 (2H, m), 3.79 (3H, s), and 3.95-4.05 (2H, m), 4.87 (1H, t, J=5.4Hz), 6.93 (2H, d, J=8.8Hz), 7.00 (2H, d, J=9.0Hz), 7.16 (2H, d, J=8.8Hz), 7.28 (2H, d, J=9.0Hz), 7.32 (1H, s)
Embodiment 122
Adopt the similar approach of E0118 to prepare white powder E0122 with E0353.
mp.158-159℃
IR(KBr)：3399，2955，1707，1693，1647，1614，1566，1547，1529，1512cm-1
Mass spectrum (ESI+): 393 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.44 (3H, s), 3.66-3.74 (2H, m), 3.80 (3H, s), 3.96-4.02 (2H, m), 4.88 (1H, t, J=5.4H z), 6.94 (2H, d, J=8.7Hz), 7.02 (2H, d, J=8.9Hz), 7.22 (2H, d, J=8.7Hz), 7.26 (1H, s), 7.31 (2H, d, J=8.9Hz)
Embodiment 123
Adopt the similar approach of E0118 to prepare white powder E0123 with E0358.
mp.105-107℃
IR(KBr)：3529，3437，2956，1610，1570，1547，1529cm-1
Mass spectrum (ESI+): 337 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.65-3.73 (2H, m), 3.88 (3H .s), 3.96-4.02 (2H, m), 4.87 (1H, t, J=5.3Hz), 6.93 (1H, d, J=8.8Hz), 6.96 (2H, d, J=8.7Hz), 7.21 (2H, d, J=8.7Hz), 7.35 (1H, s), 7.73 (1H, dd, J=2.7,8.8Hz), 8.20 (1H, d, J=2.7Hz)
Embodiment 124
Adopt the similar approach of E0118 to prepare white powder E0124 with E0107.
mp.97-98℃
IR(KBr)：3427，2960，1608，1516cm-1
Mass spectrum (ESI+): 413 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.71 (2H, t, J=6.9Hz), 3.54-3.65 (2H, m), 3.79 (3H, s), 4.64 (1H, t, J=5.1Hz), 7.00 (2H, d, J=9.0Hz), 7.12 (1H, s), and 7.15-7.33 (4H, m), 7.29 (2H, d, J=9.0Hz)
Embodiment 125
Adopt the similar approach of E0118 to prepare E0125.
IR (pure): 3435,3425,3406,3398,3367,1691,1658,1647,1614,1547,1512cm-1
Mass spectrum (ESI+): 320 (M+H)+, 361 (M+CH3CN+H)+200MHz 1H NMR (DMSO-d6, d): 2.71 (2H, t, J=6.8Hz), 3.54-3.64 (2H, m), 3.79 (3H, s), 4.64 (1H, t, J=5.2Hz), 7.00 (2H, d, J=8.9H z), 7.15 (2H, d, J=8.3Hz), 7.23 (2H, d, J=8.3Hz), 7.29 (2H, d, J=8.9Hz), 7.34 (1H, s)
Embodiment 126
Adopt the similar approach of E0118 to prepare white powder E0126 with E0111.
mp.89-92℃
IR(KBr)：3481，2947，1608，1496cm-1
Mass spectrum (ESI+): 364 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.72 (2H, t, J=6.8Hz), 3.55-3.65 (2H, m), 3.88 (3H, s), 4.65 (1H, t, J=5.2H z), 6.92 (1H, d, J=B.8Hz), 7.16 (1H, s), 7.19-7.28 (4H, m), 7.77 (1H, dd, J=2.6,8.8Hz), 8.19 (1H, d, J=2.6Hz)
Embodiment 127
Adopt the similar approach of E0118 to prepare E0127 with E0108.
IR (pure): 3400,2951,1610,1502cm-1
Mass spectrum (API-ES positively charged ion): 414 (M+H)+, 436 (M+Na)+200MHz 1H NMR (DMSO-d6, d): 2.72 (2H, t, J=6.9Hz), 3.51-3.65 (2H, m), 3.88 (3H, s), 4.65 (1H, t, J=5.1Hz), 6.93 (1H, d, J=8.8Hz), and 7.15-7.35 (4H, m), 7.18 (1H, s), 7.77 (1H, dd, J=2.7,8.8Hz), 8.18 (1H, d, J=2.7Hz)
Embodiment 128
Adopt the similar approach of E0118 to prepare E0128 (104.4mg).
IR (pure): 3433,3423,3398,2947,2873,2243,1608cm-1
Mass spectrum (ESI+): 321 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.72 (2H, t, J=6.8Hz), 3.55-3.65 (2H, m), 3.88 (3H, s), 4.65 (1H, t, J=5.1Hz), 6.93 (1H, d, J=8.8Hz), 7.19 (2H, d, J=8.4Hz), 7.26 (2H, d, J=8.4Hz), 7.38 (1H, s), 7.76 (1H, dd, J=2.7,8.8Hz), 8.21 (1H, d, J=2.7Hz)
Embodiment 129
Similar approach according to E0118 obtains E0129.
Embodiment 130
Similar approach according to E0118 obtains E0130.
Embodiment 131
Similar approach according to E0118 obtains E0131.
Embodiment 132
Similar approach according to E0118 obtains E0132.
IR (film): 3392.2,1494.6,1236.2,1160.9,1133.9,1095.4,975.8,833.1cm-1.
Embodiment 133
Similar approach according to E0118 obtains E0133.
IR (film): 3374.8,1511.9,1471.4,1274.7,1232.3,1160.9,1133.9,977.7,842.7,811.9cm-1.
mp：82-83℃
Embodiment 134
Similar approach according to E0118 obtains E0134.
IR (film): 3386.4,1511.9,1471.4,1236.2,1159.0,1132.0,1047.2,975.8,817.7cm-1.
Embodiment 135
Similar approach according to E0118 obtains E0135.
IR (film): 3399.9,1610.3,1513.9,1459.9,1251.6,1172.5,1083.8,1033.7,836.9,802.2cm-1. (FS7081)
Embodiment 136
P0018 (277mg) and 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (209mg) were refluxed 2 hours at the mixture of EtOH: AcOH=20: 1 (6ml).Mixture distributes between AcOEt and H2O.Through 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates organic layer successively.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30%, 40%, 50% wash-out.Collect pure part, vacuum concentration.Resistates obtains white powder E0136 (95.6mg) with the crystallization of AcOEt/ normal hexane.
mp.111-112℃
IR(KBr)：3325，2931，1707，1693，1685，1658，1647，1564，1549，1514cm-1
Mass spectrum (ESI+): 335 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.69-0.77 (2H, m), 0.86-0.96 (2H, m), 1.93 (1H, m), 2.69 (2H, t, J=6.9Hz), 3.53-3.64 (2H, m), 3.76 (3H, s), 4.64 (1H, t, J=5.2Hz), 6.28 (1H, s), 6.92 (2H, d, J=9.0Hz), 7.05-7.19 (6H, m)
Embodiment 137
Adopt the similar approach of E0136 to prepare E0137 with P0018 (498.5mg).
Preparation 34
Adopt the similar approach of E0137 to prepare white powder P0034.
Mass spectrum (ESI+): 306 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.67-0.76 (2H, m), 0.84-0.94 (2H, m), 1.91 (1H, m), 3.76 (3H, s), 6.18 (1H, s), 6.68 (2H, d, J=8.7Hz), 6.91 (2H, d, J=9.0H z), 6.98 (2H, d, J=8.7Hz), 7.12 (2H, d, J=9.0Hz), 9.63 (1H, s)
Embodiment 138
In the ice-cooled drips of solution adding methylsulfonyl chloride (0.26ml) that is dissolved in down CH2Cl2 (20ml) to E0118 (1.0g) and Et3N (0.6ml).Stir after 1 hour, water quencher reaction mixture extracts with CHC13.Organic layer is washed with water, and the Na2SO4 drying is filtered the back evaporation, obtains 1.2g (99%) Off-white solid crude product E0138.
IR (film): 1513.9,1469.5,1351.9,1240.0,1166.7,1130.1,971.9,835.0,804.2cm-1.
Embodiment 139
Adopt the similar approach of E00138 to prepare E0139.
Mass spectrum (ESI+): 459 (M+H)+200MHz 1H NMR (DMSO-d6, d) 1.09-1.23 (3H, m), 2.98,3.29 (3H, s), 3.01 (2H, t, J=6.6Hz), 3.09 (3H, s), 3.43-3.77 (2H, m), 3.87 (3H, s), 4.42 (2H, t, J=6.6Hz), 6.88-6.92 (2H, m), 7.25 (2H, d, J=8.3Hz), 7.33 (2H, d, J=8.3Hz), 7.65-7.73 (1H, m), 8.15 (1H, d, J=2.6Hz)
Embodiment 140
Adopt the similar approach of E0138 to prepare E0140.
Mass spectrum (APCI+): 458 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.05-1.25 (3H, m), 2.96-3.03 (2H, m), 2.98,3.29 (3H, s), 3.08 (3H, s), and 3.40-3.85 (2H, m), 3.78 (3H, s), 4.42 (2H, t, J=6.6Hz), 6.86,6.88 (1H, s), 6.98 (2H, d, J=8.9Hz), 7.18-7.32 (6H, m)
Embodiment 141
Adopt the similar approach of E0138 to prepare E0141.
Mass spectrum (ESI+): 456 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.89-2.04 (2H, m), 2.52-2.73 (2H, m), 3.16 (3H, s), 3.88 (3H, s), 4.19 (2H, t, J=6.3Hz), 6.92 (1H, d, J=8.9Hz), 7.18 (1H, s), 7.21-7.31 (4H, m), 7.76 (1H, dd, J=2.6,8.9Hz), 8.19 (1H, d, J=2.6Hz)
Embodiment 142
Similar approach according to E0138 obtains E0142.
Embodiment 143
Similar approach according to E0138 obtains E0143.
Embodiment 144
This compound obtains according to the similar approach of E0138.
Embodiment 145
This compound obtains according to the similar approach of E0138.
Embodiment 146
This compound obtains according to the similar approach of E0138.
Embodiment 147
This compound obtains according to the similar approach of E0138.
Embodiment 148
Mixture in DMF (18ml) stirred 3.0 hours in 60 ℃ with E0138 (900mg) and peptide imide potassium (454mg).After adding entry, with EtOAc extractive reaction mixture, water and salt solution washed twice.Organic layer filters the back reduction vaporization through the Na2SO4 drying.Resistates is purified (50ml) through silica gel column chromatography, obtains the Powdered E0148 of 930mg (93%).
IR (film): 1772.3,1712.5,1240.0,1160.9,1130.1cm-1.
Embodiment 149
Adopt the similar approach of E0148 to prepare amorphous powder E0149 with E0139.
Mass spectrum (ESI+): 510 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.89-2.98 (2H, m), 2.98,3.27 (3H, s), 3.48,3.70 (2H, q, J=7.1,6.9Hz), 3.82 (2H, t, J=7.3Hz), 3.88 (3H, s), 6.83-6.88 (2H, m), 7.23 (2H, d, J=8.7Hz), 7.18 (2H, d, J=8.7Hz), 7.53-7.63 (1H, m), 7.79-7.89 (4H, m), 8.15 (1H, d, J=2.6Hz)
Embodiment 150
Adopt the similar approach of E0148 to prepare amorphous powder E0150 with E0140.
Mass spectrum (ESI+): 509 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.12,1.18 (3H, t, J=7.0,7.1Hz), 2.92 (2H, t, J=7.0Hz), 2.97,3.28 (3H, s), 3.47,3.71 (2H, q, J=7.1,7.0Hz), 3.78 (3H, s), 3.81 (2H, t, J=7.0Hz), 6.82,6.84 (1H, s), 6.94 (2H, d, J=9.0Hz), and 7.11-7.20 (6H, m), 7.79-7.89 (4H, m)
Embodiment 151
Adopt the similar approach of E0148 to prepare E0151 with E0038.
Mass spectrum (ESI+): 507 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.82-1.97 (2H, m), 2.59-2.67 (2H, m), 3.60 (2H, t, J=7.0Hz), 3.88 (3H, s), (6.91 1H, d, J=8.8H z), 7.14 (1H, s), 7.20 (2H, d, J=8.5Hz), 7.26 (2H, d, J=8.5Hz), 7.73 (1H, dd, J=8.8,2.8Hz), 7.78-7.89 (4H, m), 8.17 (1H, d, J=2.8Hz)
Embodiment 152
This compound obtains according to the similar approach of E0148.
Embodiment 153
This compound obtains according to the similar approach of E0148.
Embodiment 154
This compound obtains according to the similar approach of E0148.
Embodiment 155
This compound obtains according to the similar approach of E0148.
Embodiment 156
This compound obtains according to the similar approach of E0148.
Embodiment 157
This compound obtains according to the similar approach of E0148.
Embodiment 158
The solution that is dissolved in CH3CN (10ml) to E0148 (800mg) adds hydroxide hydrazine (87ul) in room temperature.Stir after 1 hour, reaction mixture is filtered, evaporation.Add methylene dichloride, stirred the mixture 1 hour, filter the back evaporation.Resistates is handled through 4NHCl/EtOAc, obtains the E0158 of 518mg (80%).
IR (film); 3403.74,1610.27,1511.92,1467.56,1238.08,1160.94,1130.08,1027.87,975.80,836.96,806.10cm-1.
Embodiment 159
This compound obtains according to the similar approach of E0158.
Embodiment 160
This compound obtains according to the similar approach of E0158.
Embodiment 161
This compound obtains according to the similar approach of E00158.
IR (film): 3428.8,1511.9,1467.6,1238.1,1160.9,1132.0cm-1.
Embodiment 162
This compound obtains according to the similar approach of E0158.
IR (film): 3371.0,1511.9,1471.4,1272.8,1230.4,1160.9,1133.9,975.8,842.7,810.0cm-1.
Embodiment 163
This compound obtains according to the similar approach of E0158.
mp：163.1-165.1℃
IR (film): 2973.7,1511.9,1471.4,1236.2,1159.0,1133.9cm-1.
Embodiment 164
This compound obtains according to the similar approach of E0158.
IR (film): 3369.0,1604.5,1513.9,1459.9,1251.6,1172.5,1083.8,1029.8,837.0,800.3cm-1.
Embodiment 165
The solution that is dissolved in acetonitrile (15ml) to E0395 (1.08g) adds hydrazine monohydrate (0.53ml).After 60 ℃ of stirrings are spent the night, filtering mixt.Evaporated filtrate obtains orange oily E0165 (814mg, 102%).
NMR(CDCl3)，2.76(2H，t，J＝6.5Hz)，2.98(2H，t，J＝6.5Hz)，3.94(3H，s)，6.73(1H，s)，6.76(1H，d，J＝8.9Hz)，7.22-7.12(4H，m)，7.57(1H，dd，J＝8.9，2.7Hz)，8.09(1H，d，J＝2.7Hz).
MS(ESI+)；363.3(MH+).
Embodiment 166
Adopt the similar approach of E0165 to prepare E0166 with E0046.
Mass spectrum (ESI+): 380 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.91-1.23 (3H, m), 2.59-2.79 (4H, m), 2.98,3.28 (3H, s), 3.48,3.71 (2H, q, J=7.2,7.0Hz), 3.87 (3H, s), 6.86-6.93 (2H, m), and 7.16-7.26 (4H, m), 7.64-7.73 (1H, m), 8.15 (1H, d, J=2.5Hz)
Embodiment 167
Adopt the similar approach of E0165 to prepare E0167 with E0150.
Mass spectrum (ESI+): 379 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.57-2.78 (4H, m), 2.97,3.29 (3H, s), 3.48,3.72 (2H, q, J=7.2,7.0Hz), 3.78 (3H, s), 6.83,6.85 (1H, s), 6.98 (2H, d, J=8.9Hz), and 7.06-7.26 (6H, m)
Embodiment 168
Adopt the similar approach of E0165 to prepare E0168 with E0048.
Mass spectrum (ESI+): 377 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.54-1.69 (2H, m), 2.49-2.64 (4H, m), 3.88 (3H, s), 6.92 (1H, d, J=8.7Hz), 7.17 (1H, s), 7.22 (4H, s), 7.75 (1H, dd, J=8.7,2.6Hz), 8.18 (1H, d, J=2.6Hz)
Embodiment 169
The solution that is dissolved in tetrahydrofuran (THF) (2ml) to E0165 (180mg) adds triethylamine (0.242ml) and tert-butoxycarbonyl acid anhydride (325mg) in room temperature.After stirred overnight at room temperature, water quencher mixture is with ethyl acetate (* 3) extraction.Organic layer evaporates after the dried over mgso through hydrochloride aqueous solution (1N), saturated sodium bicarbonate aqueous solution and salt water washing, obtains oily matter, it is used column chromatography (SiO2 25ml, 20% ethyl acetate/hexane) purifies, obtain oily E0169 (224mg, 97.5%).
NMR(CDCl3)；1.35(9H，s)，2.69(2H，t，J＝7.7Hz)，3.09-3.19(2H，m)，3.88(3H，s)，6.91(1H，d，J＝8.8Hz)，7.17(1H，s)，7.18-7.27(4H，m)，7.75(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.7Hz).
MS(ESI+)；485.2(M+Na).
Embodiment 170
This compound obtains according to the similar approach of E0169.
NMR(CDCl3)，1.45(9H，s)，3.49-3.57(2H，m)，3.82(3H，s)，4.01(2H，t，J＝5.1Hz)，6.67(1H，s)，6.82(2H，d，J＝8.7Hz)，6.87(2H，d，J＝9.0Hz)，7.13(2H，d，J＝8.7Hz)，7.22(2H，d，J＝9.0Hz).
MS(ESI+)，500.2(M+Na).
Embodiment 171
With E0158 (650mg), Boc2O (428mg) and the mixture of 1NNaOH (3.3ml) in THF (20ml) in stirring at room 15 hours.Add entry and EtOAc, separate water layer, extract with EtOAc.The organic layer that merges is through saturated NaHCO3, water and salt water washing, and the NA2SO4 drying is filtered the back reduction vaporization.Resistates is purified (Hex/EtOAc) through silica gel column chromatography, obtains the oily E0171 of 700mg (93%).
Embodiment 172
This compound obtains according to the similar approach of E0171.
Embodiment 173
This compound obtains according to the similar approach of E0171.
Embodiment 174
This compound obtains according to the similar approach of E0171.
IR (film): 1702.8,1513.9,1241.9,1164.8,1132.0cm-1.
Embodiment 175
Add NaH (35mg) to the THF (20ml) of E0171 (200mg) and MeI (0.14ml) solution in room temperature in batches.Then reaction mixture was heated 1 hour in 70 ℃.Almost no longer reaction.
Add MeI (0.3ml), NaH (40mg) and DMF successively.
Mixture stirred cooling then, water quencher 12 hours in 70 ℃.With twice of EtOAc aqueous layer extracted.The organic layer that merges is through water and salt water washing, and the MgSO4 drying is filtered the back evaporation.Resistates is purified through silica gel column chromatography, obtains 151mg (73%) oily E0175.
Embodiment 176
This compound obtains according to the similar approach of E0175.
Embodiment 177
Mixture in Et3N (53ul) and CH3CN (5ml) adds NaBH (OAc) 2 (240mg) in room temperature in batches to E0158 (150mg) and HCHO (46ul).Stir after 15 hours, with the quencher of mixture water, with EtOAc extraction 3 times.The organic layer that merges is through water and salt water washing, and the Na2SO4 drying is filtered the back reduction vaporization.Resistates is purified (CHCl3/MeOH) through silica gel column chromatography, handles with the 4NHCl/ dioxane, obtains the E0177 of 108mg (70%).
Embodiment 178
Methyl isocyanate (36.2mg) is added the solution that E0165 (199.3mg) and triethylamine (48.6mg) are dissolved in CH2Cl2 (2ml) under ice bath cooling.Reaction mixture is stirred 1 hour final vacuum down in uniform temp to be concentrated.Resistates distributes between AcOEt and 1M HCl.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is through AcOEt-normal hexane recrystallization.The powder that obtains is dissolved in CHCl3, through preparation type thin layer silica gel chromatographic purification, launches again with MeOH/CHCl3=10%.With the silica gel of 10%MeOH/CHCl3 extracting and separating, vacuum evaporating solvent.Collect residual solid,, obtain white powder E0178 (101.3mg) with the diisopropyl ether washing.
mp.149℃
IR(KBr)：3348，2947，2885，1626，1583，1529，1500cm-1
Mass spectrum (ESI+): 420 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.49-2.53 (3H, overlapping), 2.64-2.72 (2H, m), 3.15-3.26 (2H, m), 3.88 (3H, s), 5.72 (1H, q, J=4.5Hz), 5.89 (1H, t, J=5.7Hz), 6.92 (1H, d, J=8.8Hz), 7.17 (1H, s), 7.24 (4H, s), 7.76 (1H, dd, J=2.7,8.8Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 179
Adopt the similar approach of E0178 to prepare E0179 (80.7mg) with E0166.
Amorphous powder
IR (pure sample product): 3350,2950,2930,1707,1691,1674,1645,1641,1622,1614,1566,1549,1533,1510cm-1
Mass spectrum (ESI+): 437 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.09-1.23 (3H, m), 2.49-2.54 (3H, overlapping), 2.67 (2H, t, J=7.2Hz), 2.98,3.28 (3H, s), 3.15-3.28 (2H, m), 3.48,3.71 (2H, q, J=6.8,6.9Hz), 3.88 (3H, s), 5.73 (1H, q, J=4.6Hz), 5.90 (1H, t, J=5.6Hz), 6.86-6.93 (2H, m), 7.22 (4H, s), 7.64-7.73 (1H, m), 8.15 (1H, d, J=2.6Hz)
Embodiment 180
Adopt the similar approach of E0178 to prepare E0180 with E0294.
White powder
mp.155-157℃
IR(KBr)：3336，2968，1707，1693，1674，1621，1576，1533cm-1
Mass spectrum (ESI+): (M+H)+
200MHz 1H NMR(DMSO-d6，d)：0.96(3H，t，J＝7.1Hz)，2.64-2.72(2H，m)，2.91-3.05(2H，m)，3.15-3.26(2H，m)，3.88(3H，s)，5.76-5.84(2H，m)，6.92(1H，d，J＝8.8Hz)，7.17(1H，s)，7.24(4H，s)，7.76(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.7Hz)
Embodiment 181
This compound obtains according to the similar approach of E0178.
IR (film): 3343.9,1658.5,1608.3,1513.9,1457.9,1249.6,1029.8,836.9cm-1.
Embodiment 182
This compound obtains according to the similar approach of E0178.
IR (film): 1659.0,1608.8,1554.8,1485.4,1470.0,1240.4,1165.1,1134.3,1097.6,835.3cm-1.
Embodiment 183
This compound obtains according to the similar approach of E0178.
IR (film): 3249.8,1658.5,1608.3,1554.3,1469.5,1240.0,1164.8,1133.9,1097.3,975.8,835.0cm-1.
Embodiment 184
AcCl (23.3mg) is added the CH2Cl2 (2ml) that contains E0158 (107.4mg) and triethylamine (68.3mg) under the ice bath cooling.After uniform temp stirs 1 hour down, the vacuum concentration reaction mixture.Resistates distributes between AcOEt and 1M HCl.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Collect residual solid,, obtain white powder E0184 (84mg) with the diisopropyl ether washing.
mp.79-80℃
IR(KBr)：3307，3221，3093，2964，1689，1639，1554，1514cm-1
Mass spectrum (ESI+): 404 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.76 (3H, s), 2.65-2.73 (2H, m), and 3.18-3.31 (2H, m), 3.79 (3H, s), 6.99 (2H, d, J=8.9Hz), 7.12 (1H, s), 7.20 (4H, s), 7.28 (2H, d, J=8.9Hz), 7.92 (1H, t, J=5.4Hz)
Embodiment 185
With E0232 (155.3mg), methyl-chloroformate (35.8mg) and triethylamine (105mg), adopt the similar approach of E0184 to prepare E0185 (143.4mg).
Amorphous powder
IR (pure sample product): 3319,2954,1718,1711,1668,1660,1612,1545,1533,1500cm-1
Mass spectrum (ESI+): 178 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.67-2.75 (2H, m), 3.22-3.33 (2H, m), 3.50-3.60 (2H, overlapping), 3.53 (3H, s), 3.88 (3H, s), 6.92 (1H, d, J=8.8Hz), 7.18 (1H, s), 7.24 (4H, s), 7.28 (1H, t, J=6Hz), 7.75 (1H, dd, J=2.7,8.8Hz), 7.94 (1H, t, J=5.6Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 186
With E0158 (96.2mg), methyl-chloroformate (25.1mg) and triethylamine (61.2mg), adopt the similar approach of E0184 to prepare E0186 (59.3mg).
mp.78-80℃
IR(KBr)：3352，1739，1695，1658，1647，1549，1514cm-1
Mass spectrum (ESI+): 420 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.66-2.74 (2H, m), 3.14-3.25 (2H, m), 3.49 (3H, s), 3.79 (3H, s), 6.99 (2H, d, J=8.9Hz), 7.12 (1H, s), 7.12-7.32 (1H, m), 7.20 (4H, s), 7.28 (2H, d, J=8.9Hz)
Embodiment 187
With E0165 (113.6mg), Acetyl Chloride 98Min. (29.5mg) and triethylamine (41.2mg), adopt the similar approach of E0184 to prepare E0187 (63.4mg).
White powder
mp.97-98℃
IR(KBr)：3311，2956，1674，1641，1543，1500cm-1
Mass spectrum (ESI+): 405 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.76 (3H, s), 2.66-2.74 (2H, m), 3.19-3.30 (2H, m), 3.88 (3H, s), 6.92 (1H, d, J=8.8Hz), 7.18 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J=8.8,2.6Hz), 7.92 (1H, t, J=5.3Hz), 8.19 (1H, d, J=2.6Hz)
Embodiment 188
Adopt the similar approach of E0184 to prepare E0188 with E0165.
IR (pure): 3338,3020,2951,1716,1610,1527,1500cm-1
Mass spectrum (ESI+): 421 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.67-2.75 (2H, m), 3.14-3.25 (2H, m), 3.49 (3H, s), 3.88 (3H, s), 6.92 (1H, d, J=8.9Hz), 7.15-7.35 (5H, m), 7.18 (1H, s), 7.75 (1H, dd, J=2.7,8.9Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 189
Adopt the similar approach of E0184 to prepare E0189 with E0294.
IR (pure): 3352,2939,1691,1639,1533,1500cm-1
Mass spectrum (ESI+): 434 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.67-2.74 (2H, m), 2.74 (6H, s), 3.15-3.26 (2H, m), 3.88 (3H, s), 6.34 (1H, t, J=5.4Hz), 6.92 (1H, d, J=8.9Hz), 7.17 (1H, s), 7.23 (4H, s), 7.75 (1H, dd, J=8.9,2.7Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 190
This compound obtains according to the similar approach of E0189.
NMR(CDCl3)；2.78(3H，d，J＝5.0Hz)，3.56-3.64(2H，m)，3.82(3H，s)，4.03(2H，t，J＝5.1Hz)，4.2-4.4(1H，m，NH)，4.6-4.9(1H，m，NH)，6.67(1H，s)，6.80-6.91(4H，m)，7.13(2H，d，J＝8.8Hz)，7.22(2H，d，J＝9.0Hz).
MS(ESI+).457.1(M+Na).
IR(NBr)，1627.6cm-1
Embodiment 191
This compound obtains according to the similar approach of E0184.
IR (film): 3299.6,1658.5,1550.5,1515.8,1467.6,1240.0,1164.8,1132.0,975.8,829.2,755.9cm-1.
Embodiment 192
E0158 (250mg) is suspended in AcOEt (5ml), between AcOEt and saturated sodium bicarbonate aqueous solution, distributes.Organic layer washs through sodium chloride aqueous solution, and the dried over mgso final vacuum concentrates.Resistates is dissolved in glycol dimethyl ether (5ml), adds sulphonamide (181mg) back and refluxed 2 days.The vacuum concentration reaction mixture, resistates is purified through silica gel column chromatography, uses MeOH/CHCl3=1%, 2% and 3% wash-out successively.Amorphous powder with the crystallization of EtOH-diisopropyl ether obtains obtains white powder E0192 (153mg).
mp.127-128℃
IR(KBr)：3357，1707，1693，1647，1564，1549，1529，1514cm-1
Mass spectrum (ESI+): 441 (M+H)+400MHz 1H NMR (DMSO-d6, d): 2.76-2.80 (2H, m), 3.06-3.11 (2H, m), 3.79 (3H, s), 6.53 (2H, s), 6.53-6.61 (1H, broad), 7.00 (2H, d, J=8.9Hz), 7.12 (1H, s), 7.21 (2H, d, J=8.5H z), 7.24 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.9Hz)
Embodiment 193
Adopt the similar approach of E0192 to prepare E0193 with E0294.
White powder
mp.114-115℃
IR(KBr)：3489，3469，3458，3435，3425，3398，3363，3280，1647，1500cm-1
Mass spectrum (ESI+): 442 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.75-2.83 (2H, m), 3.00-3.20 (2H, m), 3.88 (3H, s), 6.45-6.67 (3H, m), 6.92 (1H, d, J=8.7Hz), 7.18 (1H, s), 7.21-7.31 (4H, m), 7.76 (1H, dd, J=2.6,8.7Hz), 8.19 (1H, d, J=2.6Hz)
Embodiment 194
Adopt the similar approach of E0192 to prepare E0194 with E0322.
White powder
mp.142-143℃
IR(KBr)：3415，3323，3111，3093，3010，2962，1614，1516cm-1
Mass spectrum (ESI+): 429 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.68-0.76 (2H, m), 0.85-0.95 (2H, m), 1.92 (1H, m), 3.15-3.31 (2H, m), 3.76 (3H, s), and 4.00-4.07 (2H, m), 6.25 (1H, 1), 6.60 (2H, brs), 6.72 (1H, brs), 6.86-6.96 (4H, m), 7.10 (2H, d, J=8.7Hz), 7.13 (2H, d, J=8.9Hz)
Embodiment 195
This compound obtains according to the similar approach of E0192.
NMR(CDCl3)，3.50-3.59(2H，m)，3.82(3H，s)，4.14(2H，t，J＝4.9Hz)，6.68(1H，s)，6.80-6.90(4H，m)，7.15(2H，d，J＝8.8Hz)，7.22(2H，d，J＝9.0Hz).
IR(KBr)；1612，1552cm-1.
MS(ESI+)，479.1(M+Na).
Embodiment 196
Add MSCl (29ul) to the CHCl3 (10ml) of E0158 (100mg) and Et3N (53ul) solution in room temperature.Stir after 1 hour, pour reaction mixture into water and CHCl3.Extract with CHCl3 after separating water layer.The organic layer that merges is through water and salt water washing, and the Na2SO4 drying is filtered the back reduction vaporization.Resistates obtains the Powdered E0196 of 75mg (68%) through silica gel column chromatography purification (50ml) post crystallization.
IR (film): 3284.2,1513.9,1319.1,1240.0,1151.3,973.9cm-1.
Embodiment 197
Adopt the similar approach of E0196 to prepare E0197 with E0166.
mp.137-138℃
IR(KBr)：3222，1691，1684，1658，1645，1610，1566，1547，1531cm-1
Mass spectrum (ESI+): 458 (M+H)+200MHz 1H NMR (DMSO-d6, d) 1.09-1.22 (3H, m), 2.73-2.81 (2H, m), 2.80 (3H, s), 2.98,3.28 (3H, s), 3.09-3.30 (2H, m), 3.48,3.71 (2H, q, J=7.0,6.8Hz), 3.87 (3H, s), 6.88-6.93 (2H, m), 7.10 (1H, brs), 7.22 (2H, d, J=8.5Hz), 7.28 (2H, d, J=8.5Hz), 7.64-7.73 (1H, m), 8.15 (1H, d, J=2.5Hz)
Embodiment 198
Adopt the similar approach of E0196 to prepare E0198 with E0167.
mp.162-163℃
IR(KBr)：3224，1610，1547，1512cm-1
Mass spectrum (ESI+): 457 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.76 (2H, t, J=7.2Hz), 2.80 (3H, s), 2.98,3.29 (3H, s), 3.12-3.23 (2H, m), 3.48,3.73 (2H, q, J=7.2,6.9Hz), 3.78 (3H, s), 6.84,6.87 (1H, s), 6.98 (2H, d, J=9.0Hz), 7.09 (1H, t, J=5.7Hz), 7.16-7.26 (6H, m)
Embodiment 199
Adopt the similar approach of E0196 to prepare E0199 with E0234.
White powder
mp.155℃
IR(KBr)：3265，2974，2937，1682，1612，1512cm-1
Mass spectrum (ESI+): 458 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.15 (6H, d, J=6.8Hz), 2.94 (3H, s), 3.27-3.36 (2H, m), 3.68 (1H, m), 3.79 (3H, s), 4.03 (2H, t, J=5.5Hz), 6.93 (2H, d, J=8.8Hz), 6.98 (1H, s), 7.00 (2H, d, J=8.9Hz), 7.19 (2H, d, J=8.8Hz), 7.28 (2H, d, J=8.9Hz), 7.17-7.30 (1H overlaps)
Embodiment 200
Adopt the similar approach of E0196 to prepare E0200 with E0235.
White powder
mp.149-153℃
IR(KBr)：3321，1693，1658，1647，1610，1547，1510cm-1
Mass spectrum (ESI+): 413 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.93 (3H, s), 3.27-3.35 (2H, m), 3.79 (3H, s), 4.03 (2H, t, J=5.5Hz), 6.95 (2H, d, J=8.7Hz), 7.01 (2H, d, J=9.0Hz), 7.18 (2H, d, J=8.7Hz), 7.28 (2H, d, J=9.0Hz), 7.31 (1H, s), 7.15-7.31 (1H overlaps)
Embodiment 201
Adopt the similar approach of E0196 to prepare E0201 with E0294.
IR (pure): 3298,2952,2885,1612,1566,1547,1529cm-1
Mass spectrum (ESI+): 470 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.56 (6H, s), 2.71-2.79 (2H, m), and 3.07-3.17 (2H, m), 3.88 (3H, s), 6.92 (1H, d, J=8.7Hz), 7.18 (1H, s), 7.19-7.30 (5H, m), 7.77 (1H, dd, J=8.7,2.6Hz), 8.18 (1H, d, J=2.6Hz)
Embodiment 202
Adopt the similar approach of E0196 to prepare E0202 with E0322.
White powder
mp.166-168℃
IR(KBr)：3093，2964，2873，2854，1614，1516cm-1
Mass spectrum (ESI+): 428 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.68-0.76 (2H, m), 0.85-0.95 (2H, m), 1.92 (1H, m), 2.93 (3H, s), 3.27-3.36 (2H, m), 3.76 (3H, s), 3.98-4.04 (2H, m), 6.25 (1H, s), 6.90 (2H, d, J=8.7Hz), 6.92 (2H, d, J=8.9Hz), 7.11 (2H, d, J=8.7Hz), 7.13 (2H, d, J=8.9Hz), 7.27 (1H, t, J=5.8Hz)
Embodiment 203
This compound obtains according to the similar approach of E00196.
MS(ESI+)；454.1(MH+).IR(KBr)；1612.2，1515.8cm-1.NMR(CDCl3)，3.03(3H，s)，3.51-3.59(2H，m)，3.82(3H，s)，4.10(2H，t，J＝4.9Hz)，6.68(1H，s)，6.82(1H，d，J＝8.7Hz)，6.88(1H，d，J＝8.9Hz)，7.15(1H，d，J＝8.7Hz)，7.22(1H，d，J＝8.9Hz).
Embodiment 204
This compound obtains according to the similar approach of E0196.
NMR(DMSO-d6)；2.80(3H，s)，2.73-2.84(2H，m)，3.13-3.22(2H，m)，3.88(3H，s)，6.92(1H，d，J＝9.0Hz)，7.08-7.13(1H，m)，7.19(1H，s)，7.22-7.33(4H，m)，7.76(1H，dd，J＝9.0，2.6Hz)，8.19(1H，d，J＝2.6Hz).
MS(ESI+)，463.1(M+Na).
IR(KBr)，3136，1614，1554，1144cm-1.
Embodiment 205
This compound obtains according to the similar approach of E0196.
Embodiment 206
This compound obtains according to the similar approach of E0196.
mp：134.2-134.5℃
IR (film): 3284.2,1610.3,1513.9,1457.9,1321.0,1251.6,1151.3,1083.8,1031.7,838.9,802.2,757.9cm-1.
Embodiment 207
This compound obtains according to the similar approach of E00196.
IR (film): 3286.11,1606.41,1513.85,1457.92,1319.07,1251.58,1153.22,1081.87,1029.80,836.955cm-1.
Embodiment 208
This compound obtains according to the similar approach of E0196.
IR (film): 3284.2,1513.9,1317.1,1240.0,1153.2cm-1.
Embodiment 209
This compound obtains according to the similar approach of E0196.
IR (film): 3286.1,1511.9,1321.0,1230.4,1155.2,975.8,842.7,756.0cm-1.
Embodiment 210
This compound obtains according to the similar approach of E0196.
IR (film): 3284.2,1511.9,1469.5,1321.0,1236.2,1153.2,975.8,821.5,756.0cm-1.
Embodiment 211
This compound obtains according to the similar approach of E0196.
IR (film): 3289.9,1612.2,1513.9,1322.9,1251.6,1155.1,1085.7,1029.8,975.8,836.9,796.4cm-1.
Embodiment 212
This compound obtains according to the similar approach of E0196.
IR (film): 3266.8,1612.2,1469.5,1321.0,1240.0,1153.2,1097.3,975.8,835.0cm-1.
Embodiment 213
This compound obtains according to the similar approach of E0196.
IR (film): 3288.0,1612.2,1322.9,1240.0,1153.2,975.8,946.9cm-1.
Embodiment 214
With E0158 (180mg), formic acid (38ul) and WSCD (155mg) mixture in Et3N (0.3ml) and THF (5ml) in stirring at room 1 hour.After adding entry and EtOAc, separate water layer, use the EtOAc extracting twice.The organic layer that merges is used the Na2SO4 drying through 1NHCl, saturated NaHCO3, water and salt water washing, filters the back reduction vaporization.Resistates is through silica gel column chromatography purification (Hex/EtOAc=2: 1), obtain the Powdered E0214 of 136mg (70%).
IR (film): 1670.1,1513.9,1238.1,1160.9,1130.1cm-1.
Embodiment 215
After 15 hours, reaction mixture is poured E0158 (250mg), BocGly (132mg), WSCD (127mg) and HOBt (110mg) mixture in Et3N (114ul) and CH2Cl2 (30ml) into water and CHCl3 in stirring at room.Separate water layer, extract with CHCl3.The organic layer that merges is through water and salt water washing, and the Na2SO4 drying is filtered the back reduction vaporization.Resistates obtains the oily E0215 of 325mg (99%) through silica gel column chromatography analysis (50ml) post crystallization.
Embodiment 216
Adopt the similar approach of E0215 to prepare E0216.
Oil
IR (pure): 3431,3421,3404,3400,2939,1614,1570,1547cm-1
Mass spectrum (ESI+): 381 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.09-1.23 (3H, m), 2.72 (2H, t, J=6.9Hz), 2.98,3.29 (3H, s), 3.42-3.77 (4H, m), 3.88 (3H, s), 6.86-6.93 (2H, m), 7.19 (2H, d, J=8.5Hz), 7.24 (2H, d, J=8.5Hz), 7.65-7.74 (1H, m), 8.15 (1H, d, J=2.6Hz)
Embodiment 217
With E0294 and acetoxy acid, adopt the similar approach of E0215 to prepare E0217.
Oil
Mass spectrum (ESI+): 463 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.07 (3H, s), 2.69-2.77 (2H, m), 3.24-3.33 (2H, m), 3.88 (3H, s), 4.40 (2H, s), 6.92 (1H, d, J=8.7Hz), 7.18 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J=2.7,8.7Hz), 8.10 (1H, t, J=5.6Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 218
With E0294 and N-tert-butoxycarbonyl glycine, adopt the similar approach of E0215 to prepare E0218, just replace triethylamine with N-methylmorpholine (55.8mg).
Amorphous powder
IR (pure): 3315,1707,1693,1684,1676,1658,1649,1624,1614,1564,1547,1533,1510,1500cm-1
Mass spectrum (ESI+): 520 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 2.67-2.75 (2H, m), 3.22-3.33 (2H, m), 3.47 (2H, d, J=6.0Hz), 3.88 (3H, s), 6.80-7.00 (1H overlaps), 6.92 (1H, d, J=8.8H z), 7.17 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J=8.8,2.7Hz), 7.86 (1H, t, J=5.6Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 219
Adopt the similar approach of E0215 to prepare E0219.
Oil
IR(KBr)：3329，3313，3303，1620，1564，1547，1512cm-1
Mass spectrum (ESI+): 380 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.71 (2H, t, J=6.9Hz), 2.97,3.29 (3H, s), and 3.42-3.78 (4H, m), 3.78 (3H, s), 4.65 (1H, t, J=5.1Hz), 6.82,6.85 (1H, s), 6.98 (2H, d, J=8.9Hz), 7.12-7.27 (6H, m)
Embodiment 220
Adopt the similar approach of E0215 to prepare E0220.
Embodiment 221
Adopt the similar approach of E0215 to prepare E0221.
White powder
mp.95-101℃
IR(KBr)：3421，1693，1647，1603，1566，1549，1516cm-1
Mass spectrum (ESI+): 396 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.97,3.29 (3H, s), 3.42-3.74 (4H, m), 3.78 (3H, s), 3.95-4.00 (2H, m), 4.86 (1H, t, J=5.4Hz), 6.78,6.81 (1H, s), 6.91 (2H, d, J=8.8Hz), 6.98 (2H, d, J=8.8Hz), 7.16 (2H, d, J=8.8Hz), 7.23 (2H, d, J=8.8Hz)
Embodiment 222
Adopt the similar approach of E0215 to prepare E0222.
White powder
Mass spectrum (ESI+): 398 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.38 (3H, s), 3.65-3.74 (2H, m), 3.77 (3H, s), 3.78 (3H, s), 3.95-4.01 (2H, m), 4.87 (1H, t, J=5.4Hz), 6.89 (1H, s), 6.92 (2H, d, J=8.8Hz), 6.99 (2H, s, J=8.9Hz), 7.17 (2H, d, J=8.8Hz), 7.24 (2H, d, J=8.9Hz)
Embodiment 223
Adopt the similar approach of E0215 to prepare E0223.
White powder
mp.110-111℃
IR(KBr)：3425，2979，2945，1606，1570，1549cm-1
Mass spectrum (ESI+): 397 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.09-1.23 (3H, m), 2.98,3.28 (3H, s), and 3.42-3.73 (4H, m), 3.87 (3H, s), and 3.96-4.02 (2H, m), 4.87 (1H, t, J=5.3Hz), 6.82-6.97 (4H, m), 7.21 (2H, d, J=8.7Hz), 7.63-7.72 (1H, m), 8.14 (1H, d, J=2.6Hz)
Embodiment 224
Adopt the similar approach of E0215 to prepare E0224.
White powder
Mass spectrum (ESI+): 399 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.37 (3H, s), 3.66-3.74 (2H, m), 3.77 (3H, s), 3.88 (3H, s), 3.96-4.02 (2H, m), 4.87 (1H, t, J=5.5Hz), 6.88-6.97 (4H, m), 7.21 (2H, d, J=8.7Hz), 7.69 (1H, dd, J=2.7,8.8Hz), 8.16 (1H, d, J=2.7Hz)
Embodiment 225
Adopt the similar approach of E0215 to prepare E0225.
White powder
Mass spectrum (ESI+): 495 (M+H)+400MHz 1H NMR (DMSO-d6, d): 1.12,1.18 (3H, t, J=7.0Hz), 1.37 (9H, s), 2.97,3.29 (3H, s), 3.24-3.28 (2H, m), 3.48,3.45 (2H, q, J=7.0Hz), 3.78 (3H, s), 3.95 (2H, t, J=5.7Hz), 6.78,6.81 (1H, s), 6.91 (2H, d, J=8.8Hz), 6.98 (2H, d, J=8.8Hz), 7.00 (1H overlaps), 7.16 (2H, d, J=8.8Hz), 7.23 (2H, d, J=8.9Hz)
Embodiment 226
Adopt the similar approach of E0215 to prepare E0226.
White powder
Mass spectrum (ESI+): 497 (M+H)+400MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.25-3.29 (2H, m), 3.37 (3H, brs), 3.76 (3H, s), 3.78 (3H, s), 3.95 (2H, t, J=5.7Hz), 6.88 (1H, s), 6.91 (2H, d, J=8.8Hz), 6.99 (2H, d, J=8.9Hz), 6.97-7.00 (1H, br), 7.17 (2H, d, J=8.8Hz), 7.24 (2H, d, J=8.9Hz)
Embodiment 227
Adopt the similar approach of E0215 to prepare E0227.
White powder
Mass spectrum (ESI+): 498 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.33 (2H, m), 3.37 (3H, s), 3.77 (3H, s), 3.88 (3H, s), 3.93-3.99 (2H, m), 6.88-7.05 (5H, m), 7.22 (2H, d, J=8.6Hz), 7.69 (1H, dd, J=2.7,8.8Hz), 8.16 (1H, d, J=2.7Hz)
Embodiment 228
Adopt the similar approach of E0215 to obtain oily target compound (371.9mg, 96%).NMR(CDCl3)；1.43(9H，s)，3.65-3.73(2H，m)，3.79-3.82(2H，m)，3.82(3H，s)，4.03(2H，t，J＝5.2Hz)，6.67(1H，s)，6.79-6.89(4H，m)，7.14(2H，d，J＝8.7Hz)，7.22(2H，d，J＝9.0Hz).
MS(ESI+)；557.2(M+Na).
Embodiment 229
Similar approach according to E0289 obtains the white powder target compound.
NMR(DMSO-d6)，3.49-3.63(4H，m)，3.79(3H，s)，4.03(2H，t，J＝4.8Hz)，6.92-7.08(5H，m)，7.21(2H，d，J＝8.7Hz)，7.28(2H，d，J＝8.9Hz).
MS(ESI-)，433.2(M-H).
IR(KBr)；1683cm-1
Embodiment 230
This compound obtains according to the similar approach of E0215.
IR (film): 3320.82,1706.69,1668.12,1515.77,1249.65,1168.65,1031.73cm-1.
Embodiment 231
Mixture in dioxane (5.8ml) was in stirring at room 1.0 hours with E0215 (300mg) and 4NHCl.With the reaction mixture reduction vaporization, obtain the amorphous E0231 of 260mg (99%) then.
IR (film): 3226.3,1679.7,1513.9,1251.6,1083.8,1029.8,837.0cm-1.
Embodiment 232
Adopt the similar approach of E0231 to prepare E0232.
White powder
IR(KBr)：3458，3435，3404，3244，3078，3026，1671，1614，1579，1566，1554，1500cm-1
Mass spectrum (ESI+): 420 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.71-2.79 (2H, m), 3.30-3.41 (2H, m), 3.44-3.54 (2H, m), 3.88 (3H, s), 6.93 (1H, d, J=8.7Hz), 7.22 (1H, s), 7.22-7.33 (4H, m), 7.77 (1H, dd, J=2.7,8.7Hz), 8.10 (2H, br), 8.19 (1H, d, J=2.7Hz), 8.55 (1H, t, J=5.4Hz)
Embodiment 233
Adopt the similar approach of E0231 to prepare E0233.
White powder
mp.207-209℃
IR(KBr)：2966，2933，2871，2750，1606，1566，1549，1512cm-1
Mass spectrum (ESI+): 395 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.97,3.29 (3H, s), 3.17-3.22 (2H, m), 3.40-3.80 (2H, m), 3.78 (3H, s), 4.14-4.20 (2H, m), 6.80,6.83 (1H, s), and 6.94-7.01 (4H, m), 7.18-7.26 (4H, m), 8.13 (2H, brs)
Embodiment 234
Adopt the similar approach of E0231 to prepare E0234.
White powder
mp.129-142℃
IR(KBr)：3471，3437，2968，2933，1674，1639，1631，1612，1545，1512cm-1
Mass spectrum (ESI+): 380 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.15 (6H, d, J=6.9Hz), 3.16-3.22 (2H, m), 3.68 (1H, m), 3.79 (3H, s), 4.15-4.20 (2H, m), 6.94-7.05 (5H, m), 7.22 (2H, d, J=8.8Hz), 7.29 (2H, d, J=8.9Hz), 8.15 (2H, brs)
Embodiment 235
Adopt the similar approach of E0231 to prepare E0235.
White powder
mp.186-189℃
IR(KBr)：3209，3136，2968，2873，1647，1610，1547，1512cm-1
Mass spectrum (ESI+): 335 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.19 (2H, t, J=4.9Hz), 3.79 (3H, s), 4.18 (2H, t, J=4.9Hz), and 6.96-7.05 (4H, m), 7.21 (2H, d, J=8.8Hz), 7.29 (2H, d, J=9.0Hz), 7.32 (1H, s), 8.16 (2H, brs)
Embodiment 236
Adopt the similar approach of E0231 to prepare E0236.
White powder
Mass spectrum (ESI+): 378 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.04 (4H, d, J=6.1Hz), 3.04 (1H, m), 3.14-3.22 (2H, m), 3.80 (3H, s), 4.15-4.21 (2H, m), 6.93-7.05 (5H, m), 7.23 (2H, d, J=8.6Hz), 7.31 (2H, d, J=8.9Hz), 8.15 (2H, brs)
Embodiment 237
Adopt the similar approach of E0231 to prepare E0237.
Amorphous powder
IR(KBr)：3433，3425，3404，3043，3028，3022，2962，1658，1612cm-1
Mass spectrum (ESI+): 336 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.15-3.24 (2H, m), 3.88 (3H, s), 4.16-4.22 (2H, m), 6.94 (1H, d, J=8.8Hz), 7.01 (2H, d, J=8.7Hz), 7.25 (2H, d, J=8.7Hz), 7.36 (1H, s), 7.75 (1H, dd, J=2.6,8.8Hz), 8.10-8.30 (2H, br), 8.20 (1H, d, J=2.6Hz)
Embodiment 238
Adopt the similar approach of E0231 to prepare E0238.
White powder
mp.156-161℃
IR(KBr)：2970，1676，1647，1612，1550，1500cm-1
Mass spectrum (ESI+): 381 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.16 (6H, d, J=6.9Hz), 3.15-3.24 (2H, m), 3.68 (1H, m), 3.88 (3H, s), 4.16-4.22 (2H, m), 6.91-7.06 (4H, m), 7.26 (2H, d, J=8.7Hz), 7.75 (1H, dd, J=2.7,8.9Hz), 8.18 (1H, d, J=2.7Hz), 8.22 (2H, brs)
Embodiment 239
This compound obtains according to the similar approach of E0231.
IR (film): 3220.5,1679.7,1513.9,1461.8,1251.6,1081.9,1029.8,837.0,800.3cm-1.
Embodiment 240
Methylene dichloride (1ml) solution to E0267 (75.2mg) adds triethylamine (30.4ml) and isocyanic acid trimethyl silyl ester (36.9ml) in 0 ℃.Stir after 5 hours, water quencher mixture is used dichloromethane extraction.The organic layer that merges is through the salt water washing, and reduction vaporization after the dried over mgso obtains oily matter, purifies with preparation type TLC (1mm, ethyl acetate), obtains oily matter.With the crystalline mixture of described oily matter, obtain white solid E0240 (39.1mg, 51.2%) with isopropyl ether, ethyl acetate and hexane.
NMR(DMS0-d6)；3.27-3.32(2H，m)，3.79(3H，s)，3.94(2H，t，J＝5.6Hz)，5.52(2H，brs，NH2)，6.15(1H，t，J＝5.6Hz，NH)，6.94(2H，d，J＝8.8Hz)，7.00(2H，d，J＝8.9Hz)，7.07(1H，s)，7.20(2H，d，J＝8.8Hz)，7.28(2H，d，J＝8.9Hz).
MS(ESI+)；443.2(M+Na).
IR(KBr)，1685.5，1656.6cm-1.
Embodiment 241
Adopt the similar approach of E0240 to prepare E0241 with E0194.
White powder
mp.139-140℃
IR(KBr)：3458，3342，1691，1647，1604，1572，1529cm-1
Mass spectrum (ESI+): 404 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.28-3.36 (2H, m), 3.87 (3H, s), 3.92-3.98 (2H, m), 5.52 (2H, brs), 6.15 (1H, t, J=5.5Hz), 6.88-6.98 (4H, m), 7.10 (1H, t, J=54.4Hz), 7.22 (2H, d, J=8.7Hz), 7.69 (1H, dd, J=2.7,8.8Hz), 8.14 (1H, d, J=2.7Hz)
Embodiment 242
Adopt the similar approach of E0240 to prepare E0242.
White powder
mp.108-113℃
IR(KBr)：3492，3435，3425，3359，3298，1647，1614，1564，1549，1512cm-1
Mass spectrum (ESI+): 438 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.08-1.22 (3H, m), 2.97,3.29 (3H, s), 3.20-3.85 (4H, m), 3.78 (3H, s), 3.94 (2H, t, J=5.5Hz), 5.53 (2H, s), 6.15 (1H, t, J=5.6Hz), 6.79,6.81 (1H, s), 6.92 (2H, d, J=8.8Hz), 6.99 (2H, d, J=8.9Hz), 7.17 (2H, d, J=8.8Hz), 7.23 (2H, d, J=8.9Hz)
Embodiment 243
Adopt the similar approach of E0240 to prepare E0243 with E0234.
White powder
mp.144-145℃
IR(KBr)：3435，3369，3176，2970，1674，1612，1547，1514cm-1
Mass spectrum (ESI+): 423 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.15 (6H, d, J=6.9Hz), 3.27-3.36 (2H, m), 3.68 (1H, m), 3.79 (3H, s), 3.90-3.97 (2H, m), 5.53 (2H, s), 6.15 (1H, t, J=5.6Hz), 6.92 (2H, d, J=8.7Hz), 6.98 (1H, s), 7.00 (2H, d, J=8.9Hz), 7.18 (2H, d, J=8.7Hz), 7.28 (2H, d, J=8.9Hz)
Embodiment 244
Adopt the similar approach of E0240 to prepare E0244 with E0235.
White powder
mp.187-190℃
IR(KBr)：3379，3201，1649，1614，1579，1527，1506cm-1
Mass spectrum (ESI+): 378 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.27-3.34 (2H, m), 3.79 (3H, s), 3.94 (2H, t, J=5.5Hz), 5.52 (2H, brs), 6.14 (1H, t, J=5.6Hz), 6.94 (2H, d, J=8.8Hz), 7.00 (2H, d, J=9.0Hz), 7.17 (2H, d, J=8.8Hz), 7.24-7.31 (3H, m)
Embodiment 245
Adopt the similar approach of E0240 to prepare E0245.
White powder
mp.136-137℃
IR(KBr)：3433，3342，3221，1658，1612，1581，1549，1512cm-1
Mass spectrum (ESI+): 421 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.04 (4H, d, J=6.2Hz), 3.03 (1H, m), 3.27-3.36 (2H, m), 3.80 (3H, s), 3.90-3.97 (2H, m), 5.52 (2H, s), 6.14 (1H, t, J=5.6Hz), 6.93 (2H, d, J=8.8Hz), 6.97 (1H, s), 7.01 (2H, d, J=8.9Hz), 7.19 (2H, d, J=8.8H z), 7.30 (2H, d, J=8.9Hz)
Embodiment 246
Adopt the similar approach of E0240 to prepare E0246.
White powder
mp.173-176℃
IR(KBr)：3473，3334，1630，1624，1601，1583cm-1
Mass spectrum (ESI+): 379 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.27-3.36 (2H, m), 3.88 (3H, s), 3.92-3.98 (2H, m), 5.52 (2H, s), 6.14 (1H, t, J=5.7Hz), 6.93 (1H, d, J=8.8Hz), 6.97 (2H, d, J=8.8Hz), 7.21 (2H, d, J=8.8Hz), 7.35 (1H, s), 7.73 (1H, dd, J=2.7,8.8Hz), 8.20 (1H, d, J=2.7Hz)
Embodiment 247
Adopt the similar approach of E0240 to prepare E0247.
White powder
mp.145-147℃
IR(KBr)：3367，3174，2972，1689，1674，1610，1566，1502cm-1
Mass spectrum (ESI+): 424 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.16 (6H, d, J=6.9Hz), 3.28-3.37 (2H, m), 3.68 (1H, m), 3.88 (3H, s), 3.92-3.98 (2H, m), 5.52 (2H, s), 6.15 (1H, t, J=5.6Hz), 6.93 (1H, d, J=8.7Hz), 6.95 (2H, d, J=8.8Hz), 7.02 (1H, s), 7.22 (2H, d, J=8.8Hz), 7.73 (1H, dd, J=2.7,8.7Hz), 8.19 (1H, d, J=2.7Hz)]
Embodiment 248
Adopt the similar approach of E0240 to prepare E0248.
White powder
mp.150.8-151.0℃
IR(KBr)：3496，3361，3294，1705，1674，.1647，1603，1581，1568，1554，1516cm-1
Mass spectrum (ESI+): 393 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.71-0.77 (2H, m), 0.85-0.92 (2H, m), 1.92 (1H, m), 3.27-3.37 (2H, m), 3.76 (3H, s), 3.92 (2H, t, J=5.5Hz), 5.51 (2H, s), 6.14 (1H, t, J=5.5Hz), 6.24 (1H, s), 6.86-6.96 (4H, m), 7.07-7.15 (4H, m)
Embodiment 249
Adopt the similar approach of E0240 to obtain the amorphous target compound.
NMR(CDCl3)，3.56-3.64(2H，m)，3.94(3H，s)，4.04(2H，t，J＝4.9Hz)，4.50(2H，brs，NH2)，6.69(1H，s)，6.76(1H，d，J＝8.8Hz)，6.84(2H，d，J＝8.8Hz)，7.12(2H，d，J＝8.8Hz)，7.58(1H，dd，J＝8.8，2.8Hz)，8.05(1H，d，J＝2.8Hz).
MS(ESI+)，444.1(M+Na)+.IR(KBr)；1650.8，1608.3cm-1.
LCMS(ESI+)，422.27(MH+).
Embodiment 250
Similar approach according to E0240 obtains the white powder target compound.
NNR(CDCl3)，3.55-3.63(2H，m)，3.93(3H，s)，4.04(2H，t，J＝5.1Hz)，4.55(2H，brs，NH2)，5.23(1H，brt，J＝5.4Hz，NH)，6.67(1H，s)，6.75(1H，t，J＝55Hz)，6.75(1H，d，J＝8.4Hz)，6.88(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz)，7.56(1H，d，J＝8.4，2.9Hz)，8.04(1H，d，J＝2.9Hz).
LCMS(ESI+)，404.39(MH+).
IR(KBr)1649cm-1
MP，141.5-142.1℃.
Embodiment 251
Similar approach according to E0240 obtains Powdered target compound.
NMR(CDCl3)，3.56-3.64(2H，m)，3.82(3H，s)，4.03(2H，t，J＝5.0Hz)，4.42(2H，brs)，6.65(1H，s)，6.76(1H，t，J＝55Hz)，6.79-6.89(4H，m)，7.14(2H，d，J＝8.7Hz)，7.20(2H，d，J＝9.0Hz).
MS(ESI+)，425(M+Na)+.
Embodiment 252
(1N is 220ml) in 45 ℃ of water (300ml) solution that were added dropwise to Zassol (14.4g) in 5 minutes to ethanol (75ml) solution of E0267 (15.3g) and hydrochloride aqueous solution.After 4 hours,, use ethyl acetate extraction in 45 ℃ of stirrings with mixture saturated sodium bicarbonate aqueous solution quencher.The organic layer that merges evaporates after the dried over mgso through the salt water washing, obtains powder.With powder in room temperature～70 ℃ with ethyl acetate and hexane crystallization, obtain Powdered E0252 (12.628g, 81.2%).
The physical data of this compound is identical with the data of the authentic sample that obtains previously.
Embodiment 253
To methyl alcohol (1ml) solution of E0267 (200mg) in room temperature add methanol solution of sodium methylate (5.2M, 0.1ml).Stir after 20 minutes, evaporating mixture obtains resistates.Add tetrahydrofuran (THF) to resistates, mixture filters the back evaporation, obtains oily matter.Oily matter is dissolved in ethyl formate (2ml) back in stirred overnight at room temperature.Evaporating mixture is purified through preparation type TLC (1mm, 50% ethyl acetate/hexane), obtains oily matter, and it with isopropyl ether, ethyl acetate and hexane crystallization, is obtained white powder E0253 (162.8mg, 83%).
NMR(CDCl3)，3.68-3.76(2H，m)，3.82(3H，s)，4.06(2H，t，J＝5.0Hz)，6.68(1H，s)，6.80-6.89(4H，m)，7.14(2H，d，J＝8.7Hz)，7.22(2H，d，J＝9.0Hz)，8.22(1H，s).
MS(ESI+)，428.2(M+Na).
IR(KBr)，1660.4，1614.1cm-1.
Embodiment 254
Methylene dichloride (9ml) solution to E0267 (800mg) and triethylamine (0.7ml) is added dropwise to Acetyl Chloride 98Min. (0.18ml) in 0 ℃.After 1 hour, mixture saturated sodium bicarbonate aqueous solution quencher is with ethyl acetate (* 3) extraction in stirring at room.The organic layer that merges with evaporating after the dried over mgso, obtains oily matter through hydrochloride aqueous solution (1N), water and salt water washing, and it is purified with column chromatography (SiO2 100ml is with 50% ethyl acetate/hexane wash-out), obtains oily matter.Oily matter in 50 ℃ of crystalline mixtures with ethyl acetate and hexane, is obtained solid E0254 (768.6mg, 94.8%).
NMR(CDCl3).2.01(3H，s)，3.62-3.70(2H，m)，3.82(3H，s)，4.03(2H，t，J＝5.0Hz)，6.67(1H，s)，6.80-6.91(4H，m)，7.14(2H，d，J＝8.7Hz)，7.22(2H，d，J＝9.0Hz).
MP；109.8-110.2℃
IR(KBr)，1649cm-1.
MS(ESI+).442.1(M+Na).
Embodiment 255
Similar approach according to E0254 obtains the oily target compound.
NMR(CDCl3)，3.69(3H，s)，3.65-3.73(2H，m)，3.82(3H，s)，3.86(2H，d，J＝5.9Hz)，4.04(2H，t，J＝5.1Hz)，6.67(1H，s)，6.80-6.89(4H，m)，7.14(2H，d，J＝8.5Hz)，7.22(2H，d，J＝8.9Hz)，
MS(ESI+).515.2(M+Na).
IR(KBr，20727-10)，1722.1，1710.6，1673.9cm-1.
Embodiment 256
Similar approach according to E0254 obtains oily target compound (82mg, 78%).
MS(ESI+).458.2(M+Na).
IR (pure), 1699cm-1.
NMR(CDCl3)；3.54-3.62(2H，m)，3.69(3H，s)，3.82(3H，s)，4.02(2H，t)，6.67(1H，s)，6.80-6.89(4H，m)，7.13(2H，d，J＝8.9Hz)，7.22(2H，d，J＝9.0Hz).
Embodiment 257
Methylene dichloride (1ml) solution to E0275 (97.5mg) and pyridine (0.14ml) adds trifluoroacetic anhydride (60.6ml) in 0 ℃.After stirred overnight at room temperature, mixture with saturated sodium bicarbonate aqueous solution (0.5ml) quencher, is filtered with chemelute1001 (Varan), purify with preparation type TLC (1mm, 50% ethyl acetate/hexane), obtain solid E0257 (92.5mg, 76%).MS(ESI+)，496.1(M+Na).
IR(KBr)，1705cm-1.
NMR(CDCl3)，3.75-3.87(2H，m)，3.82(3H，s)，4.10(4.8H，t)，6.68(1H，s)，6.83(2H，d，J＝8.8Hz)，6.88(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.8Hz)，7.22(2H，d，J＝8.9Hz).
Embodiment 258
Be added dropwise to 1NNaOH (2.5ml) to the THF of E0327 (400mg) (5ml) solution in room temperature.The mixture stirring is spent the night, use 1N HCl and CHCl3 quencher then.Separate organic layer, water layer CHCl3 extracting twice.The organic layer that merges is through water and salt water washing, reduction vaporization after the Na2SO4 drying.Resistates washs through IPE, obtains the E0258 of 273mg (70.7%).
IR (film): 2971.8,1683.6,1629.6,1515.8,1315.2,1230.4,1159.0,1132.0,977.7,835.0cm-1.
Embodiment 259
Adopt the similar approach of E0258 to prepare white powder E0259.
Mass spectrum (ESI+): 355 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.63-3.78 (2H, m), 3.79 (3H, s), 3.95-4.00 (2H, m), 4.86 (1H, brs), 6.91 (2H, d, J=8.7Hz), 6.95 (1H, s), 6.99 (2H, d, J=8.9Hz), 7.16 (2H, d, J=8.7Hz), 7.24 (2H, d, J=8.9Hz), 12.88 (1H, brs)
Embodiment 260
Adopt the similar approach of E0258 to prepare E0260.
White powder
Mass spectrum (ESI+): 356 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.69-3.79 (2H, m), 3.88 (3H, s), and 3.96-4.02 (2H, m), 4.87 (1H, br), and 6.89-7.00 (4H, m), 7.20 (2H, d, J=8.8Hz), 7.70 (1H, dd, J=2.6,8.8Hz), 8.14 (1H, d, J=2.6Hz), 12.97 (1H, br)
Embodiment 261
Adopt the similar approach of E0258 to prepare E0261 with E0109.
White powder
Mass spectrum (ESI+): 339 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.70 (2H, t, J=6.9Hz), 3.59 (2H, t, J=6.9Hz), 3.79 (3H, s), 4.64 (1H, brs), 6.96-7.03 (3H, m), 7.12-7.28 (6H, m), 12.90 (1H, br)
Embodiment 262
Adopt the similar approach of E0258 to prepare E0262.
White powder
Mass spectrum (ESI+): 454 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.32 (2H, m), 3.79 (3H, s), 3.91-3.98 (2H, m), 6.90 (2H, d, J=8.7Hz), 6.90-7.03 (1H, overlap), 6.95 (1H, s), 6.99 (2H, d, J=8.9Hz), 7.16 (2H, d, J=8.7Hz), 7.24 (2H, d, J=8.9Hz)
Embodiment 263
Adopt the similar approach of E0258 to prepare E0263.
Amorphous powder
Mass spectrum (ESI+): 455 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.32 (2H, m), 3.88 (3H, s), 3.93-3.98 (2H, m), and 6.89-7.05 (5H, m), 7.20 (2H, d, J=8.7Hz), 7.70 (1H, dd, J=2.7,8.8Hz), 8.14 (1H, d, J=2.7Hz), 12.98 (1H, br)
Embodiment 264
Adopt the similar approach of E0258 to prepare E0264 with E0006.
White powder
Mass spectrum (ESI+): 340 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.71 (2H, t, J=6.9Hz), 3.56-3.64 (2H, m), 3.88 (3H, s), 4.64 (1H, br), 6.92 (1H, d, J=8.8Hz), 7.03 (1H, s), and 7.16-7.28 (4H, m), 7.72 (1H, dd, J=8.8,2.7Hz), 8.15 (1H, d, J=2.7Hz), 12.94 (1H, br)
Embodiment 265
4M HCl/AcOEt (0.4ml) is added the solution that E0378 (73mg) is dissolved in AcOEt (1ml).Enriched mixture final vacuum drying obtains amorphous powder E0265 (68.4mg).
IR (pure): 3440,2960,1739,1707,1691,1674,1647,1624,1614,1566,1549,1533,1500cm-1
Mass spectrum (ESI+): 400 (M+H)+200MHz 1H NMR (DMSO-d6, d): 2.73 (2H, t, J=6.9Hz), 3.62 (2H, t, J=6.9Hz), 3.89 (3H, s), 6.94 (1H, d, J=8.8Hz), 7.19-7.32 (5H, m), 7.52-7.70 (3H, m), 7.80 (1H, dd, J=8.8,2.7Hz), 8.22-8.28 (3H, m)
Embodiment 266
Adopt the similar approach of E0265 to prepare E0266.
Oil
IR (pure): 3435,2966,2935,1678,1662,1649,1612,1581,1566,1547,1533,1500cm-1
Mass spectrum (ESI+): 366 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.16 (6H, d, J=6.9Hz), 2.72 (2H, t, J=6.9Hz), 3.54-3.75 (3H, m), 3.89 (3H, s), 6.93 (1H, d, J=8.8Hz), 7.05 (1H, s), 7.13-7.35 (4H, m), 7.76 (1H, dd, J=2.7,8.8Hz), 8.19 (1H, d, J=2.7Hz)
Embodiment 267
The ethyl acetate from hydrogenchloride to ethyl acetate (1.9ml) solution of E0275 (765mg) (4N, 0.56ml) solution that add.Evaporating mixture obtains oily matter, uses diisopropyl ether and ethyl acetate in 65 ℃ of crystallizations it, obtains solid E0267 (766.8mg, 91.4%).
NMR(CDCl3)，3.30(2H，t，J＝5.0Hz)，3.79(3H，s)，4.18(2H，t，J＝5.0Hz)，6.62(1H，s)，6.83-6.88(4H，m)，7.10(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.8Hz).
NMR (DMSO-d6), 3.19 (2H, brs), 3.79 (3H, s), 4.18 (2H, t, J=5.0Hz), 6.96-7.01 (4H, m), 7.08 (1H, s), 7.23-7.29 (4H, m) .MS (ESI+), 378.3 (MH+, free).
IR(KBr，20727-2)，1612.2，1513.9cm-1.
Embodiment 268
P0011 (30g), chloromethyl cyanide (8.52ml), potassiumiodide (4.47g) and the mixture of salt of wormwood (14.9g) in acetone (150ml) were stirred 2.5 hours in 80 ℃ of backflows.After being cooled to room temperature, with mixture water (600ml) quencher, with ethyl acetate (300ml * 2,150ml) extraction.The organic layer that merges evaporates after the dried over mgso through salt solution (300ml) washing, obtains solid (36.34g).Use diisopropyl ether (60ml) and hexane (200ml) in the room temperature recrystallization this solid, obtain Powdered E0268 (31.5g, 94%).
NMR(CDCl3)，3.83(3H，s)，4.78(2H，s)，6.70(1H，s)，6.86-6.97(4H，m)，7.18-7.24(4H，m).
IR(KBr)，2051.9cm-1.
Embodiment 269
Similar approach according to E0268 obtains E0269.
White powder
Mass spectrum (ESI+): 346 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.69-0.77 (2H, m), 0.86-0.96 (2H, m), 1.92 (1H, m), 3.76 (3H, s), 5.16 (2H, s), 6.30 (1H, s), 6.93 (2H, d, J=9.0Hz), 7.02 (2H, d, J=8.8Hz), and 7.10-7.21 (4H, m)
Embodiment 270
Similar approach according to E0268 obtains Powdered target compound.
NMR(CDCl3)，3.95(3H，s)，4.78(2H，s)，6.71(1H，s)，6.76(1H，t，J＝55Hz)，6.76(1H，d，J＝8.4H z)，6.96(2H，d，J＝8.9Hz)，7.23(2H，d，J＝8.9Hz)，7.53(1H，dd，J＝8.4，2.6Hz)，8.08(1H，d，J＝2.6Hz).
MS(ESI+)，379(M+Na).
Embodiment 271
Similar approach according to E0268 obtains target compound.
Embodiment 272
Similar approach according to E0268 obtains target compound.
IR (film): 1612.2,1482.9,1234.2,1162.8,1132.0,1095.3,973.8,835.0cm-1.
Embodiment 273
Similar approach according to E0268 obtains target compound.
Embodiment 274
Similar approach according to E0268 obtains target compound.
mp.96-99℃
Mass spectrum; 389 (M+1)
NMR(CDCl3，δ)；1.98(1H，t，J＝6.1Hz)，3.29(3H，s)，3.83(3H，s)，3.93-4.01(2H，m)，4.06-4.11(2H，m)，6.86(2H，d，J＝8.8Hz)，6.88(2H，d，J＝9.0Hz)，6.93(1H，s)，7.14(2H，d，J＝8.8Hz)，7.23(2H，d，J＝9.0Hz)
Embodiment 275
Add ether (5ml) and the tetrahydrofuran (THF) (1ml) that contains E0268 (1.38g) to the suspension of lithium aluminium hydride (250mg) in ether (14ml) under the ice bath.In stirring at room mixture 1 hour.(50mg) adds mixture under ice bath with lithium aluminium hydride, then in stirring at room mixture 1 hour.Mixture water (0.3ml), aqueous sodium hydroxide solution (15%, 0.3ml) and water (0.9ml) quencher, then in stirring at room 30 minutes.Sal epsom and Celite are added mixture, and filtering suspension liquid washs with ether then.Evaporated filtrate obtains oily matter 1.307g.Oily matter is purified with column chromatography (SiO2,100ml is with 20% methyl alcohol/chloroform (500ml) wash-out), obtain oily E0275 (1.156g, 82.9%).
NMR(CDCl3)，3.09(2H，t，J＝5.1Hz)，3.82(3H，s)，3.99(2H，t，J＝5.1Hz)，6.67(1H，s)，6.82-6.89(4H，m)，7.14(2H，d，J＝8.9Hz)，7.23(2H，d，J＝9.0Hz).
MS(ESI+)，378(MH+).
Embodiment 276
The solution that is dissolved in tetrahydrofuran (THF) (270ml) to E0268 (27.43g) in room temperature add borine dimethyl sulphide complex compound (10M, 15ml).Mixture is in stirred overnight at room temperature.Then borine dimethyl sulphide complex compound (7.5ml) is added mixture.After stirred overnight at room temperature, with mixture methyl alcohol (100ml) quencher, reduction vaporization obtains oily matter.Oily matter is dissolved in tetrahydrofuran (THF) (150ml) and hydrochloric acid, and (6N, mixture 100ml) stirred 1 hour in 40～50 ℃ then.To mixture be added dropwise to successively aqueous sodium hydroxide solution (30%, 80ml), sodium bicarbonate and sodium-chlor.With ethyl acetate (* 4) extraction mixture.The evaporation organic layer obtains oily matter (31.86g), and oily matter is purified with column chromatography (SiO2,1L is with 20% ethanol/methylene and strong aqua/methyl alcohol/chloroform (0.025: 1: 4) wash-out), obtains oily matter.(4N 22ml) adds the solution that described oily matter is dissolved in ethyl acetate (50ml), and evaporating mixture obtains amorphous E0276 (22.87g, 69.4%) with the ethyl acetate solution of hydrogenchloride.
Embodiment 277
Adopt the similar approach of E0276 to prepare E0277.
White powder
mp.229-231℃
IR(KBr)：3084，2960，2885，2800，2731，2563，2519，2482，1606，1576，1516cm-1
Mass spectrum (ESI+): 350 (M+H)+200MHz 1H NMR (DMSO-d6, d): 0.69-0.77 (2H, m), 0.84-0.96 (2H, m), 1.93 (1H, m), 3.14-3.22 (2H, m), 3.76 (3H, s), 4.14-4.20 (2H, m), 6.26 (1H, s), 6.94 (4H, d, J=8.8Hz), 7.14 (4H, d, J=8.8 Hz), 8.21 (2H, brs)
Embodiment 278
Similar approach according to E0276 obtains the oily target compound, does not form hydrochloride.NMR(CDCl3)，3.09(2H，t，J＝5.2Hz)，3.94(3H，s)，3.99(2H，t，J＝5.2Hz)，6.77(1H，t，J＝54.9Hz)，6.67(1H，s)，6.74(2H，d，J＝7.5Hz)，6.87(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.7Hz)，7.55(1H，dd，J＝8.9，2.8Hz)，8.09(1H，d，J＝2.8Hz).
MS(ESI+)，361(MH+).
Embodiment 279
Similar approach according to E0276 obtains target compound.
Embodiment 280
Similar approach according to E0276 obtains target compound.
IR (film): 3423.0,1612.2,1469.5,1240.0,1164.8,1132.0,1095.4,975.8,836.9cm-1.
Embodiment 281
Similar approach according to E0276 obtains target compound.
mp.104-106℃
Mass spectrum; 388 (M+1)
IR(KBr)；1310cm-1
NMR(CDCl3，δ)；3.09(2H，t，J＝5.1Hz)，3.29(3H，s)，3.83(3H，s)，3.99(2H，t，J＝5.1Hz)，6.83(2H，d，J＝8.8Hz)，6.88(2H，d，J＝8.9Hz)，6.93(1H，s)，7.13(2H，d，J＝8.8Hz)，7.24(2H，d，J＝8.9Hz)，
Embodiment 282
Diethylazodicarboxylate (82.3mg) is added the solution that P0015 (100mg), P0015-1 (152mg) and triphenylphosphine (124mg) are dissolved in THF (2ml).After ambient temperature stirs 5 hours, the vacuum concentration reaction mixture.Resistates is purified through silica gel column chromatography, with viscosity oily AcOEt/CHCl3=5% wash-out, obtains E0282.
Mass spectrum (ESI+): 461 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.33 (2H, m), 3.87 (3H, s), 3.93-3.99 (2H, m), and 6.88-7.04 (5H, m), 7.10 (1H, t, J=54.4Hz), 7.21 (2H, d, J=8.7Hz), 7.69 (1H, dd, J=2.7,8.8Hz), 8.14 (1H, d, J=2.7Hz)
Embodiment 283
Adopt the similar approach of E0282 to prepare E0283 with P0020.
White powder
Mass spectrum (ESI+): 482 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.31 (3H, t, J=7.1Hz), 1.37 (9H, s), 3.22-3.32 (2H, m), 3.79 (3H, s), 3.91-3.98 (2H, m), 4.32 (2H, q, J=7.1Hz), 6.90 (2H, d, J=8.7Hz), 6.95-7.06 (1H overlaps), 6.99 (2H, d, J=8.9Hz), 7.01 (1H, s), 7.17 (2H, d, J=8.7Hz), 7.25 (2H, d, J=8.9Hz)
Embodiment 284
Adopt the similar approach of E0282 to prepare E0284.
White powder
Mass spectrum (ESI+): 483 (M+H)+200MHz 1H NMR (DMSO-d6, d): 1.31 (3H, t, J=7.1Hz), 1.37 (9H, s), 3.22-3.33 (2H, m), 3.88 (3H, s), 3.96 (2H, t, J=5.7Hz), 4.33 (2H, q, J=7.1Hz), 6.89-7.05 (1H, overlapping), 6.92 (1H, d, J=8.9Hz), 6.93 (2H, d, J=8.7Hz), 7.05 (1H, s), 7.21 (2H, d, J=8.7Hz), 7.72 (1H, dd, J=2.7,8.9Hz), 8.15 (1H, d, J=2.7Hz)
Embodiment 285
Similar approach according to E0282 obtains the oily target compound.
NMR(CDCl3)，1.45(9H，s)，3.50-3.58(2H，m)，3.94(3H，s)，4.02(2H，t，J＝5.1Hz)，6.70(1H，s)，6.75(1H，d，J＝8.4Hz)，6.85(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)，7.56(1H，dd，J＝8.4，2.9Hz)，8.08(1H，d，J＝2.9Hz).
MS(ESI+)，501.2(M+Na).
Embodiment 286
Similar approach according to E0282 obtains Powdered target compound.
NMR(CDCl3)，2.89(1H，d，J＝10.4Hz，NH)，3.23(3H，s)，3.67-3.78(1H，m)，3.81(3H，s)，3.99(1H，dd，J＝9.2，6.4Hz)，4.22(1H，dd，J＝9.2，5.0Hz)，6.67(1H，s)，6.81(2H，d，J＝8.9Hz)，6.86(2H，d，J＝6.0Hz)，7.10-7.29(13H，m)，7.49-7.54(6H，m).
MS(ESI+)，678.4(MH+).
Embodiment 287
Similar approach according to E0282 obtains the oily target compound.
NMR(CDCl3)，1.28(3H，d，J＝6.6Hz)，1.45(9H，s)，3.82(3H，s)，3.92(2H，d，J＝4.1Hz)，3.90-4.14(1H，m)，6.67(1H，s)，6.84(2H，d，J＝8.9Hz)，6.86(2H，d，J＝9.0Hz)，7.13(2H，d，J＝8.9Hz)，7.23(2H，d，J＝9.0Hz).
MS(ESI+)，514.2(M+Na).
Embodiment 288
Similar approach according to E0282 obtains the oily target compound.
NMR(CDCl3)，1.28(3H，d，J＝6.6Hz)，1.45(9H，s)，3.82(3H，s)，3.92(2H，d，J＝4.1Hz)，3.90-4.14(1H，m)，6.67(1H，s)，6.84(2H，d，J＝8.9Hz)，6.86(2H，d，J＝9.0Hz)，7.13(2H，d，J＝8.9Hz)，7.23(2H，d，J＝9.0Hz).
MS(ESI+)，514.2(M+Na).
Embodiment 289
AcOEt (1ml) solution with 4M HCl/AcOEt (1ml) adding E0282 (129mg) stirred the mixture 1 hour in ambient temperature.Remove supernatant liquor by decant.Wash remaining oily solid by decant with AcOEt (1ml).Add acetone (2ml) to resistates, the oiliness residual solid under agitation becomes white powder.Stirred 20 minutes in ambient temperature.The collecting precipitation thing is used washing with acetone, obtains white powder E0289 (91.4mg).
IR (pure): 2964,1705,1668,1660,1614,1581,1566,1531,1512cm-1
Mass spectrum (ESI+): 361 (M+H)+200MHz 1H NMR (DMSO-d6, d): 3.11-3.23 (2H, m), 3.87 (3H, s), and 4.12-4.28 (2H, m), 6.90-7.02 (4H, m), 7.11 (1H, t, J=54.3Hz), 7.26 (2H, d, J=8.6Hz), 7.71 (1H, dd, J=2.7,8.8Hz), 8.14 (1H, d, J=2.7Hz), 8.24 (2H, brs)
Embodiment 290
Similar approach according to E0289 obtains the white powder target compound.
NMR(DMSO-d6)，3.17-3.21(2H，m)，3.95(3H，s)，4.19(2H，t，J＝5.0Hz)，6.93(1H，d，J＝8.8Hz)，7.00(2H，d，J＝8.8Hz)，7.15(1H，s)，7.28(2H，d，J＝8.8Hz)，7.76(1H，dd，J＝8.8，2.6Hz)，8.18(1H，d，J＝2.6Hz).
MS(ESI+)，379.1(MH+).
IR(KBr)，1612.2cm-1.
Embodiment 291
Similar approach according to E0289 obtains the white powder target compound.
NMR(DMSO-d6)，2.60(3H，s)，3.28-3.33(2H，m)，3.79(3H，s)，4.25(2H，t，J＝4.7Hz)，7.04-6.96(4H，m)，7.09(1H，s)，7.22-7.31(4H，m).
MS(ESI-)，426.2(M+Cl)+.
IR(KBr)；1610.2，1515.8cm-1.
MP；189-189.2℃.
Embodiment 292
Similar approach according to E0289 obtains white amorphous target compound.
NMR(DEMSO-d6)，1.04(3H，d，J＝6.0Hz)，3.5-3.7(1H，m)，3.79(3H，s)，3.98(1H，dd，J＝10.1，6.9Hz)，4.11(1H，dd，J＝10.1，6.5Hz)，6.96-7.04(4H，m)，7.09(1H，s)，7.22-7.31(4H，m).
MS(ESI+)，392.2(MH+).
Embodiment 293
Similar approach according to E0289 obtains white amorphous target compound.
NMR(DEMSO-d6)，1.04(3H，d，J＝6.0Hz)，3.5-3.7(1H，m)，3.79(3H，s)，3.98(1H，dd，J＝10.1，6.9Hz)，4.11(1H，dd，J＝10.1，6.5Hz)，6.96-7.04(4H，m)，7.09(1H，s)，7.22-7.31(4H，m).
MS(ESI+)，392.2(MH+).IR(Neat)1612.2cm-1.
Embodiment 294
Similar approach according to E0289 obtains the white powder target compound.
NMR(DMSO-d6)；2.84-3.20(4H，m)，3.88(3H，s)，6.93(1H，d，J＝8.9Hz)，7.19(1H，s)，7.30-7.36(4H，m)，7.86(1H，dd，J＝8.9，2.7Hz)，8.19(1H，d，J＝2.7Hz).
MS(ESI+)；363.3(MH+).
IR(KBr)；1612.2，1500.3cm-1.
Embodiment 295
At N, the mixture in the dinethylformamide (6ml) stirred 6 hours in 75 ℃ with P0012 (0.5g), chloromethyl cyanide (0.2ml), potassiumiodide (525mg) and salt of wormwood (437mg).After being cooled to room temperature, the quencher of mixture water is with ethyl acetate (* 3) extraction.The organic layer that merges evaporates after the dried over mgso through water (* 3) and salt water washing, obtains solid E0295 (631.6mg, 112%).
NMR(CDCl3)，3.83(3H，s)，4.77(2H，s)，6.69(1H，s)，6.76(1H，t，J＝55Hz)，6.96-6.86(4H，m)，7.18-7.24(4H，m).
MS(ESI+)，378.1(M+Na).
Embodiment 296
Similar approach according to E0295 obtains the oily target compound.
NMR(CDCl3)；1.63(1H，t，J＝5.2Hz)，1.99-2.11(2H，m)，3.82(3H，s)，3.82-3.91(2H，m)，4.12(2H，t，J＝6.0Hz)，6.67(1H，s)，6.84(2H，d，J＝8.8Hz)，6.87(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.8Hz)，7.32(2H，d，J＝8.9Hz).
IR (pure); 1612,1514cm-1.
MS(ESI+)；393.1(MH+)，415.1(M+Na).
Embodiment 297
Similar approach according to E0205 obtains the oily target compound.
NMR(CDCl3)；3.03(3H，s)，3.83(3H，s)，4.97(2H，s)，6.70(1H，s)，6.88(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.8Hz)，7.17-7.26(4H，m).
IR(KBr)；1612.2，1513.9cm-1.
MS(ESI+)，449.1(M+Na).
Embodiment 298
Similar approach according to E0295 obtains the white solid target compound.
NMR(DMSO-d6)，3.65-3.73(2H，m)，3.79(3H，s)，3.98(2H，t，J＝4.7Hz)，4.87(1H，t，J＝5.4Hz)，6.93(2H，d，J＝8.7Hz)，7.00(2H，d，J＝8.9Hz)，7.07(1H，s)，7.19(2H，d，J＝8.7Hz)，7.28(2H，d，J＝8.9Hz).
MS(ESI+)，401.2(M+Na).
IR(KBr)；1610.3，1511.9cm-1.
Embodiment 299
Similar approach according to E0295 obtains the white solid target compound.
NMR(CDCl3)，2.01(1H，t，J＝6.1Hz)，3.82(3H，s)，3.93-4.10(4H，m)，6.66(1H，s)，6.76(1H，t，J＝55.1Hz)，6.85(2H，d，J＝8.7H z)，6.87(2H，d，J＝9.0Hz)，7.15(2H，d，J＝8.7Hz)，7.21(2H，d，J＝9.0Hz).
MS(ESI+)；383.2(M+Na).
IR(KBr)；1610.3，1513.9，1454.1cm-1.
Embodiment 300
Similar approach according to E0295 obtains the white powder target compound.
NMR(DMSO-d6)；3.78(3H，s)，4.43(2H，s)，6.80-7.53(12H，m，NH2)，MS(ESI+)；396.3(M+Na)+.
IR(KBr)；1681.6，1606.4cm-1.
Embodiment 301
This compound of similar approach alkanisation by E0295 obtains salt-free oily compound.Similar approach by E0172 forms hydrochloride then, obtains white powder E0301 (498.7mg, 49.6%).
NMR(DMSO-d6)，3.69(2H，t，J＝5.0Hz)，3.88(3H，s)，3.99(2H，t，J＝5.0Hz)，6.92(1H，d，J＝8.7Hz)，6.96(2H，d，J＝8.8Hz)，7.13(1H，s)，7.23(2H，d，J＝8.8Hz)，7.53(1H，dd，J＝8.7，2.9Hz)，8.18(1H，d，J＝2.9Hz).
MS (ESI+), 402.1 (M+Na)+, (freedom).
IR (pure), 1614,1552cm-1.
Embodiment 302
Similar approach according to E0295 obtains the white solid target compound.
NMR(CDCl3)；3.88(3H，s)，4.45(2H，s)，6.92(1H，d，J＝8.9Hz)，6.96(2H，d，J＝8.8Hz)，7.14(1H，s)，7.26(2H，d，J＝8.8Hz)，7.41(1H，brs，NH2)，7.56(1H，brs，NH2)，7.76(1H，dd，J＝8.9，2.5Hz)，8.18(1H，d，J＝2.5Hz).
MS(ESI+)；415.1(M+Na).
IR(KBr)；1693.2，1608.3cm-1.
Embodiment 303
Similar approach according to E0295 obtains the oily target compound.
NMR(CDCl3)；3.94(3H，s)，3.94-4.14(4H，m)，6.68(1H，s)，6.74(1H，d，J＝8.7Hz)，6.86(1H，t，J＝55.0Hz)，6.88(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.9Hz)，7.53(1H，dd，J＝2.6，8.7Hz)，8.08(1H，d，J＝2.6Hz).
MS(ESI+)；384.2(M+Na).
IR(KBr)，1805.1，1612.2cm-1.
Embodiment 304
Similar approach according to E0295 obtains the white powder target compound.
NMR(DMSO-d6)；3.88(3H，s)，4.44(2H，s)，6.98-9.89(4H，m)，7.10(1H，t，J＝54.3Hz)，7.24(2H，d，J＝8.8Hz)，7.39(1H，brs，NH2)，7.54(1H，brs，NH2)，7.70(1H，dd，J＝8.9，2.8Hz)，8.14(1H，d，J＝2.8Hz).
MS(ESI-)；373(M-H)+.
IR(KBr)；1662.3，1610.3cm-1.
Embodiment 305
Similar approach according to E0298 obtains target compound.
IR (film): 3388.3,1494.6,1236.2,1160.9,1133.9,1095.4,975.8,833.1cm-1.
Embodiment 306
Similar approach according to E0295 obtains target compound.
Mass spectrum; 384 (M+1)
Embodiment 307
Ether (5ml) suspension to lithium aluminium hydride (250mg) adds the tetrahydrofuran (THF) (1ml) that contains E0295 (630mg) under ice bath.In stirring at room after 1 hour, with mixture water (0.125ml), aqueous sodium hydroxide solution (15%, 0.125ml) and water (0.375ml) quencher, then in stirring at room 30 minutes.Sal epsom and Celite are added mixture, and filtering suspension liquid washs with ether.Evaporated filtrate obtains 0.5g oily matter.Oily matter is purified with column chromatography (SiO2,50ml is with ethanol/methylene/strong aqua (1/10/0.05) wash-out), obtain oily matter (300mg).Oily matter is dissolved in ethyl acetate, and the ethyl acetate solution of adding hydrogenchloride (4N, 1.6ml).Evaporating mixture obtains oily matter, and it with methyl alcohol and diisopropyl ether crystallization, is obtained Powdered E0307 (300mg, 42.7%).
NMR(DMSO-d6)，3.20(2H，t，J＝4.9Hz)，3.78(3H，s)，4.16(2H，t，J＝4.9Hz)，6.85(1H，s)，6.94-7.01(4H，m)，7.08(1H，t，J＝54.6Hz)，7.20-7.26(4H，m).
MS (ESI+), 360.3 (MH+, freedom).
IR(KBr，20727-7)，1612，1513.9cm-1.
Embodiment 308
Similar approach according to E0307 obtains target compound.
IR (film): 3401.8,1610.3,1511.9,1469.5,1240.0,1162.9,1130.1,975.8,827.3cm-1.
Embodiment 309
P0011 (200mg), chloromethyl sulfonate sodium (274mg), potassiumiodide (298mg) and the mixture of salt of wormwood (248mg) in 1-Methyl-2-Pyrrolidone (2ml) are spent the night in 150 ℃ of stirrings.After being cooled to room temperature, described mixture is poured into the mixture of hydrochloride aqueous solution (1N), salt solution and ethyl acetate.Separate water layer, with ethyl acetate (* 3) extraction.The organic layer reduction vaporization after dried over mgso that merges obtains oily matter.Oily matter is purified with column chromatography (SiO2100ml is with 15% ethanol/methylene wash-out), obtain the amorphous E0309 of brown (154.3mg, 60%).
MS(ESI-)；427.1(M-H).
NMR(DMSO-d6)，3.79(3H，s)，4.52(2H，s)，7.00(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.9Hz)，7.07(1H，s)，7.18(2H，d，J＝9.0Hz)，7.27(2H，d，J＝8.9Hz).
Embodiment 310
Add NaH to the DMF of P0011 (1.0g) (10ml) solution under water cooling (60% oily dispersion liquid 144mg), stirred 1 hour in batches.Add III (787mg) then, reaction mixture was stirred 5 hours in 50 ℃.The EtOAc extracting twice is used in the quencher of mixture water.With salt water washing 1 time, the MgSO4 drying is filtered the back reduction vaporization to organic layer after water washing 3 times.Resistates is purified (50ml) through silica gel column chromatography, obtains 803mg (55%) oily E0310.
Embodiment 311
Similar approach according to E0310 obtains target compound.
Embodiment 312
Mixture in EtOH (10ml) was in stirring at room 3 hours with E0310 (800mg) and cHCl (100ul).After adding sodium bicarbonate aqueous solution, evaporating mixture is used the EtOAc extracting twice.Organic layer is through water and salt water washing, and the MgSO4 drying is filtered the back reduction vaporization.Resistates (710mg) is purified (50ml) through silica gel column chromatography, obtains the E0312 of 570mg (93%).
IR (film): 3409.5,1612.2,1513.9,1467.6,1243.9,1162.9,1130.1,835.0,835.0cm-1.
Embodiment 313
Similar approach according to E0312 obtains target compound.
mp：122.3-122.5℃
IR (film): 3399.9,1612.2,1513.9,1456.0,1251.6,1174.4,1083.8,1033.7,836.9,800.3cm-1.
Embodiment 314
60% sodium hydride (39.7mg) is added the solution that P0011 (255mg) is dissolved in DMF (1.5ml).Mixture stirred 1 hour in ambient temperature.Add ethyl bromoacetate (153mg) to mixture.In ambient temperature stirred reaction mixture 1 hour, add the saturated ammonium chloride solution quencher then, extract whole mixtures with AcOEt.Organic layer is through H2O and sodium chloride aqueous solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out, obtains oily E0314 (217mg).
Mass spectrum (ESI+) 421 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.94(3H，t，J＝7.1Hz)，3.79(3H，s)，4.15(2H，q，J＝7.1Hz)，4.79(2H，s)，6.92(2H，d，J＝8.8Hz)，6.99(2H，d，J＝8.9Hz)，7.09(1H，s)，7.20(2H，d，J＝8.8Hz)，7.28(2H，d，J＝8.9Hz)
Embodiment 315
(E0315)
With toluene (0.5ml) solution of 1M diisobutyl aluminium hydride in-50 ℃ of THF (3ml) solution that are added dropwise to E0314 (98mg).Mixture stirred 1 hour in 5 ℃ then in-50 ℃ of stirrings 1 hour.Be added dropwise to toluene (0.5ml) solution of 1M diisobutyl aluminium hydride again.After 1 hour, add 10% sodium-potassium tartrate salt brine solution quencher reaction, in 5 ℃ of stirrings through Celite pad filtering mixt.Extract filtrate with AcOEt.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches with AcOEt/ normal hexane=60% through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts with 10%MeOH/CHCl3, and vacuum evaporating solvent obtains oily E0315 (54.5mg), and it leaves standstill and becomes solid.
IR(KBr)：3431，2931，1612，1564，1549，1512cm-1
Mass spectrum (ESI+): 379 (M+H)+
400MHz 1H NMR(DMSO-d6，d)：3.67-3.72(2H，m)，3.79(3H，s)，3.84-3.99(2H，m)，4.87(1H，t，J＝5.4Hz)，6.93(2H，d，J＝8.7Hz)，7.00(2H，d，J＝8.9Hz)，7.10(1H，s)，7.19(2H，d，J＝8.7Hz)，7.27(2H，d，J＝8.9Hz)
Embodiment 316
(E0316)
DMF (2ml) solution that 60% sodium hydride (52mg) is added P0020 (200mg) under the ice bath cooling.Mixture stirred 30 minutes down in uniform temp.Add bromoacetic acid (90.3mg) to this mixture.Reaction mixture stirred 2 hours in ambient temperature, added 1M HCl (3ml) quencher then.Add H2O (3ml) and diisopropyl ether (2ml), the mixture ice bath was stirred 30 minutes.The collecting precipitation thing with H2O and diisopropyl ether washing, obtains white powder E0316 (231.2mg).
Mass spectrum (ESI+): 397 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.31(3H，t，J＝7.1Hz)，3.79(3H，s)，4.32(2H，q，J＝7.1Hz)，4.68(2H，s)，6.88(2H，d，J＝8.8Hz)，7.00(2H，d，J＝8.9Hz)，7.02(1H，s)，7.18(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.9Hz)，13.05(1H，brs)
Embodiment 317
(E0317)
Adopt the similar approach of E0316 to prepare E0317.
White powder
Mass spectrum (ESI+): 398 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.31(3H，t，J＝7.1Hz)，3.88(3H，s)，4.33(2H，q，J＝7.1Hz)，4.70(2H，s)，6.92(2H，d，J＝8.8Hz)，6.89-7.00(1H，m)，7.06(1H，s)，7.22(2H，d，J＝8.8Hz)，7.73(1H，dd，J＝2.8，8.8Hz)，8.15(1H，d，J＝2.8Hz)，13.04(1H，brs)
Embodiment 318
(E0318)
Adopt the similar approach of E0316 to prepare E0318.
Oil
Mass spectrum (ESI+): 365 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：0.70-0.93(4H，m)，1.70-2.00(1H，m)，3.76(3H，s)，4.66(2H，s)，6.25(1H，s)，6.85(2H，d，J＝8.9Hz)，6.92(2H，d，J＝9.0Hz)，7.06-7.16(4H，m)，13.00(1H，brs)
Embodiment 319
(E0319)
Under the ice bath cooling, be added dropwise to boron trifluoride diethyl ether compound (89.5mg) (2.5 equivalent) to the THF of sodium borohydride (19.1mg) (2ml) suspension.Mixture stirred 30 minutes down in uniform temp.Disposable adding E0316 (100mg) stirred the mixture 5 hours in ambient temperature.Add 1M HCl (5ml), stirred the mixture 30 minutes in ambient temperature.Mixture extracts through AcOEt.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates obtains white powder E0319 (68.9mg) through the diisopropyl ether crystallization.
Mass spectrum (ESI+): 383 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.31(3H，t，J＝7.1Hz)，3.65-3.73(2H，m)，3.79(3H，s)，3.94-4.00(2H，m)，4.32(2H，q，J＝7.1Hz)，4.87(1H，t，J＝5.5Hz)，6.91(2H，d，J＝8.8Hz)，6.99(2H，d，J＝8.9Hz)，7.01(1H，s)，7.17(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.9Hz)
Embodiment 320
(E0320)
Adopt the similar approach of E0319 to prepare E0320.
White powder
Mass spectrum (ESI+): 384 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.31(3H，t，J＝7.1Hz)，3.65-3.74(2H，m)，3.88(3H，s)，3.96-4.02(2H，m)，4.33(2H，q，J＝7.1Hz)，4.87(1H，t，J＝5.4Hz)，6.89-6.96(3H，m)，7.05(1H，s)，7.21(2H，d，J＝8.7Hz)，7.72(1H，dd，J＝2.7，8.8Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 321
(E0321)
Adopt the similar approach of E0319 to prepare E0321.
White powder
mp.142-144℃
IR(KBr)：3246，2924，1612，1566，1547，1516cm-1
Mass spectrum (ESI+): 351 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：0.68-0.77(2H，m)，0.85-0.95(2H，m)，1.92(1H，m)，3.64-3.73(2H，m)，3.76(3H，s)，3.96(2H，t，J＝4.9Hz)，4.85(1H，t，J＝5.5Hz)，6.24(1H，s)，6.85-6.96(4H，m)，7.05-7.17(4H，m)
Embodiment 322
(E0322)
Adopt the similar approach of E0319 to prepare E0322.
White powder
mp.228-231℃
IR(KBr)：3082，2958，2885，2802，2733，2480，1606，1572，1512cm-1
Mass spectrum (ESI+): 350 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：0.69-0.77(2H，m)，0.83-0.96(2H，m)，1.93(1H，m)，3.14-3.22(2H，m)，3.76(3H，s)，4.14-4.20(2H，m)，6.27(1H，s)，6.93(4H，d，J＝8.8Hz)，7.14(4H，d，J＝8.8Hz)，8.24(2H，brs)
Embodiment 323
(E0323)
H2O (1ml) solution of S-WAT (84.2mg) is added EtOH (3ml) solution of P0022 (258.1mg), stirred 2 hours in 70 ℃.When white depositions occurring, H2O (1ml) is added so that the dissolution precipitation thing.Stir the mixture in 80 ℃ and to spend the night, obtain settled solution.In 80 ℃ of restir 28 hours.By 1M HCl (0.7ml) acidified reaction mixture, concentrate the final vacuum drying.Resistates is dissolved in CHCl3, and through dried over mgso, the whole insolubles final vacuums of filtering concentrate, and obtain amorphous powder E0323 (245mg).
Mass spectrum (API-ES negatively charged ion) 425 (M-H)+
200MHz 1H NMR(DMSO-d6，d)：2.61-2.69(2H，m)，2.78-2.91(2H，m)，3.79(3H，s)，7.00(2H，d，J＝8.9Hz)，7.12(1H，s)，7.17(2H，d，J＝8.6Hz)，7.22(2H，d，J＝8.6Hz)，7.29(2H，d，J＝8.9Hz)
Embodiment 324
(E0324)
Adopt the similar approach of E0323 to prepare E0324 with P0023.
Amorphous powder
Mass spectrum (API-ES negatively charged ion): 426 (M-H)+
200MHz 1H NMR(DMSO-d6，d)：2.61-2.69(2H，m)，2.83-2.92(2H，m)，3.88(3H，s)，6.92(1H，d，J＝8.8Hz)，7.17(1H，s)，7.23(4H，s)，7.75(1H，dd，J＝8.8，2.7Hz)，8.20(1H，d，J＝2.7Hz)
Embodiment 325
(E0325)
Thionyl chloride (0.6ml) solution with DMF (41mg) adding E0319 (239mg) stirred the mixture 30 minutes in 50 ℃.The vacuum concentration reaction mixture.Add toluene (3ml), vacuum concentration to resistates.Resistates is dissolved in THF (10ml), under the ice bath cooling, is added dropwise to THF (4ml) solution of 28% ammonium hydroxide aqueous solution (0.5ml) and 4-butyl ammonium hydrogen sulfate (19mg).After ambient temperature stirs 30 minutes, reaction mixture is distributed between AcOEt and sodium chloride aqueous solution.Organic layer washs through sodium chloride aqueous solution, dried over mgso.Resistates is purified through silica gel column chromatography, with MeOH/CHCl3=2%, 5% wash-out.Collect pure part, vacuum concentration.With EtOH-diisopropyl ether recrystallization residual solid, obtain white powder E0325 (72.6mg).
mp.131-132℃
IR(KBr)：3354，3184，3126，1707，1693，1676，1647，1564，1549，1516cm-1
Mass spectrum (ESI+): 426 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.95-3.04(2H，m)，3.21-3.30(2H，m)，3.79(3H，s)，6.87(2H，s)，7.00(2H，d，J＝8.9Hz)，7.14(1H，s)，7.23-7.33(6H，m)
Embodiment 326
(E0326)
Adopt the similar approach of E0325 to prepare E0326.
White powder
mp.139-140℃
IR(KBr)：3230，3132，1610，1568，1527，1500cm-1
Mass spectrum (ESI+): 441 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.58(3H，s)，2.90-3.00(2H，m)，3.25-3.33(2H，m)，3.88(3H，s)，6.93(1H，d，J＝8.9Hz)，6.97(1H，brs)，7.19(1H，s)，7.26(2H，d，J＝8.3Hz)，7.34(2H，d，J＝8.3Hz)，7.77(1H，dd，J＝8.9，2.8Hz)，8.19(1H，d，J＝2.8Hz)
Embodiment 327
(E0327-0) (E0327-1) (E0327)
The toluene mixture of E0327-0 (800mg) and E0327-1, triphenyl phosphinidene methyl acetate (850mg) refluxed stirred 5 hours.The reduction vaporization mixture is (50ml, Hex: EtOAc=5: 1), obtain the E0327 of 795mg (85.5%) after silica gel column chromatography is purified.
IR (film): 1718.3,1637.3,1513.9,1241.9,1166.7,1132.0,977.7,837.0cm-1
Embodiment 328
(E0328)
Toluene (5ml) suspension to E0258 (180mg) adds thionyl chloride (0.17ml) in room temperature.Reaction mixture was become settled solution up to mixture in 5 hours in 100 ℃ of stirrings.Then with mixture reduction vaporization (becoming solid).Add THF, add the NH3 aqueous solution (37%) then.The EtOAc extracting twice is used in water quencher after stirring the mixture 1 hour.The organic layer that merges is used the Na2SO4 drying through saturated NaHCO3, water and salt water washing, filters the back reduction vaporization, obtains Powdered E0328 (170mg, 95%).
IR(KBr)：3347.8，1671.9，1606.4，1513.9，1467.6，1388.5，1236.2，1164.8，1132.0，979.7，837.0cm-1.
Embodiment 329
(E0329)
Toluene (4ml) suspension to E0258 (200mg) adds thionyl chloride (0.19ml) in room temperature.Reaction mixture was become settled solution up to mixture in 5 hours in 10 ℃ of stirrings.Then with mixture reduction vaporization (becoming solid).Add THF, add Me2NH (116mg) then.The EtOAc extracting twice is used in water quencher after stirring the mixture 1 hour.The organic layer that merges is through saturated NaHCO3, water and salt water washing, and the Na2SO4 drying is filtered the back reduction vaporization, obtains Powdered E0329 (45mg, 21%).
Filtrate (58mg).
mp：118-120℃
IR (film): 1650.8,1608.3,1511.9,1469.5,1240.0,1159.0,1133.9cm-1.
Embodiment 330
(E0330)
EtOH (10m) mixture of E0328 (125mg) and Pd/C (100mg) was stirred 3.0 hours under H2 atmosphere.After the filtration, reduction vaporization filtrate.Resistates is dissolved in EtOH, filters with disposable syringe drive-type strainer, evaporation obtains E0330 (85mg).
IR(KBr)：3342.0，1670.0，1511.9，1240.0，1160.9，1130.1cm-1.
Embodiment 331
(E0331)
DMF (6ml) mixture of E0138 (300mg) and MeSNa (72mg) was heated 5 hours in 70 ℃.After the cooling, reaction mixture is distributed between EtOAc and water.Extract with EtOAc after separating water layer.The organic layer that merges is through water (twice) and salt water washing, and the Na2SO4 drying is filtered the back evaporation.Resistates is purified through silica gel column chromatography, obtains E0331 (270mg, quantitative).
Embodiment 332
(E0332)
Adopt the similar approach of E0331 to prepare E0332 with E0141.
Oil
Mass spectrum (ESI+): 408 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.73-1.89(2H，m)，2.03(3H，s)，2.40-2.52(2H，m)，2.62-2.70(2H，m)，3.88(3H，s)，6.92(1H，d，J＝8.8Hz)，7.18(1H，s)，7.24(4H，s)，7.76(1H，dd，J＝8.8，2.7Hz)，8.18(1H，d，J＝2.7Hz)
Embodiment 333
(E0333)
Similar approach according to E0331 obtains target compound.
Embodiment 334
(E0334)
Similar approach according to E0331 obtains target compound.
Embodiment 335
(E0335)
Similar approach according to E0331 obtains target compound.
Embodiment 336
(E0336)
Similar approach according to E0331 obtains target compound.
Embodiment 337
(E0337)
The CH2Cl2 mixture of E0331 (250mg) and mcpba (165mg) was stirred 1 hour down in ice-cooled, add mcpba (55mg) then.Reaction mixture is distributed between CHCl3 and saturated NaHCO3 after 1 hour in ice-cooled stirring down.Separate organic layer,, filter the back reduction vaporization with saturated NaHCO3, water and salt water washing, Na2SO4 drying.Resistates is purified (Hex/EtOAc) through silica gel column chromatography, obtains the E0337 of 141mg (52%).
IR (film): 1511.9,1303.6,1240.0,1130.1cm-1.
Oxide compound: FR267958
NMR(CDCl3)：2.599(s，3H)，2.85-3.21(m，4H)，3.828(s，3H)，6.721(s，1H)，6.872(d，J＝9.0Hz，2H)，7.141(s，4H)，7.179(d，J＝9.0Hz，2H).
MS：(M+Na)+431.1(M110092-2)
Embodiment 338
(E0338)
Similar approach according to E0337 obtains target compound.
IR (film): 1511.9,1469.5,1311.4,1282.4,1236.2,1126.2,973.9,823.5,759.8cm-1.
Embodiment 339
(E0339)
Similar approach according to E0337 obtains target compound.
IR (film): 1511.9,1469.5,1311.4,1282.4,1236.2,1128.2,973.9,823.5,759.8cm-1.
Embodiment 340
(E0340)
Similar approach according to E0337 obtains target compound.
IR (film): 1673.9,1616.1,1498.4,1477.2,1467.6,1390.4,1307.5,1290.1,1240.0,1160.9,1132.0,971.9, and 756.0cm-1.NMR (CDCl3): 2.76-2.94 (m, 4H), 3.927 (s, 3H), 3.943 (s, 3H), 6.728 (s, 1H), 6.752 (d, J=8.9Hz, 1H), 7.12-7.26 (m, 4H), 7.46-7.59 (m, 1H), 8.04-8.10 (m, 1H).
Mass spectrum (M+Na)+445.1 (FR267958-N)
Embodiment 341
(E0341)
Methylene dichloride (45ml) solution to E0336 (450mg) adds MCPBA (306mg) in room temperature.Stir after 1 hour, with saturated NaHCO3 (twice) and water washing, the Na2SO4 drying is filtered the back reduction vaporization with reaction mixture.Resistates is purified (50ml) through silica gel column chromatography, obtains 470mg oily E0341.
Embodiment 342
(E0342)
Adopt the similar approach of E0341 to prepare E0342.
White powder
mp.92-93℃
IR(KBr)：3080，2952，1612，1566，1547，1529，1500cm-1
Mass spectrum (ESI+): 424 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.87-2.00(2H，m)，2.51(3H，s)，2.56-2.78(4H，m)，3.88(3H，s)，6.92(1H，d，J＝8.9Hz)，7.19(1H，s)，7.21-7.31(4H，m)，7.76(1H，dd，J＝2.7，8.9Hz)，8.19(1H，d，J＝2.7Hz)
Embodiment 343
(E0343)
Methylene dichloride (45ml) solution to E0336 (450mg) adds MCPBA (306mg) in room temperature.Stir after 1 hour, with saturated NaHCO3 (twice) and water washing, the Na2SO4 drying is filtered the back reduction vaporization with reaction mixture.Resistates is purified (50ml) through silica gel column chromatography, uses the EtOH recrystallization, obtains the E0343 of 168mg (44%).
Embodiment 344
(E0344)
CH2Cl2 (6ml) solution that 3-chlorine peroxybenzoic acid (407mg) is added E0342 (666.3mg) under the ice bath cooling.Reaction mixture was stirred 1 hour in ambient temperature.Mixture is diluted with CHCl3, and with 1M NaOH, 5% sodium thiosulfate solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.With AcOEt-normal hexane recrystallization resistates, obtain white powder E0344 (565.2mg).
mp.121-122℃
IR(KBr)：3120，2954，1707，1693，1647，1612，1566，1547，1529，1500cm-1
Mass spectrum (ESI+): 440 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.93-2.06(2H，m)，2.67-2.75(2H，m)，2.96(3H，s)，3.04-3.13(2H，m)，3.88(3H，s)，6.92(1H，d，J＝8.8Hz)，7.19(1H，s)，7.19-7.31(4H，m)，7.76(1H，dd，J＝8.8，2.8Hz)，8.19(1H，d，J＝2.8Hz)
Embodiment 345
(E0345)
CH2Cl2 (3ml) suspension that oxalyl chloride (286mg) is added E0363 (0.43g) under the ice bath cooling.Add 1 DMF, under uniform temp, stirred the mixture 1 hour, then vacuum concentration.Adding the toluene final vacuum to resistates concentrates.Resistates is dissolved in THF (5ml), under the ice bath cooling, adds ammonium hydroxide aqueous solution (5ml).Stirred the mixture under uniform temp 1 hour, with the AcOEt dilution, with 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates successively.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=60% wash-out.Collect pure part, vacuum concentration is used the diisopropyl ether crystalline residue, obtains white powder E0345 (287.8mg).
Mass spectrum (ESI+): 381 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.97(3H，s)，2.89(2H，t，J＝6.8Hz)，3.87(3H，s)，4.21(2H，t，J＝6.8Hz)，6.91(1H，d，J＝8.8Hz)，6.98(1H，s)，7.22(2H，d，J＝8.4Hz)，7.28(2H，d，J＝8.4Hz)，7.38(1H，brs)，7.63-7.75(1H，brs)，7.72(1H，dd，J＝2.7，8.8Hz)，8.16(1H，d，J＝2.7Hz)
Embodiment 346
(E0346)
Mixture in methane amide (5ml) was in 70 ℃ of heating 5 hours with E0109 (449.1mg) and sodium methylate (238mg).Cooling mixture distributes between ethyl acetate and H2O to ambient temperature.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, uses CHCl3 earlier, uses MeOH/CHCl3=2%, 5% wash-out then, obtains white powder E0346 (235.7mg).
Mass spectrum (ESI+): 338 (M+H)+
400MHz 1H NMR(DMSO-d6，d)：2.70(2H，t，J＝6.9Hz)，3.56-3.62(2H，m)，3.79(3H，s)，4.65(1H，t，J＝5.1Hz)，6.92(1H，s)，6.99(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.3Hz)，7.20(2H，d，J＝8.3Hz)，7.27(2H，d，J＝8.9Hz)，7.33(1H，s)，7.64(1H，s)
Embodiment 347
(E0347)
Adopt the similar approach of E0346 to prepare E0347.
White powder
Mass spectrum (ESI+): 454 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.65-3.73(2H，m)，3.78(3H，s)，3.94-4.00(2H，m)，4.86(1H，t，J＝5.5Hz)，6.88(1H，s)，6.91(2H，d，J＝8.8Hz)，6.99(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.9Hz)，7.32(1H，s)，7.63(1H，s)
Embodiment 348
(E0348)
Adopt the similar approach of E0346 to prepare E0348.
White powder
Mass spectrum (ESI+): 355 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 3.65-3.74 (2H, m), 3.87 (3H, s), 3.96-4.05 (2H, m), 4.87 (1H, t, J=5.5Hz), 6.88-6.97 (4H, m), 7.20 (2H, d, J=8.7Hz), 7.37 (1H, brs), 7.67-7.73 (1H, brs, overlap), 7.71 (1H, dd, J=2.6,8.8Hz), 8.16 (1H, d, J=2.6Hz)
Embodiment 349
(E0349)
Adopt the similar approach of E0346 to prepare E0349.
White powder
Mass spectrum (ESI+): 453 (M+H)+
400MHz 1H NMR(DMSO-d6，d)：1.37(9H，s)，3.24-3.29(2H，m)，3.78(3H，s)，3.94(2H，t，J＝5.8Hz)，6.88(1H，s)，6.90(2H，d，J＝8.8Hz)，6.99(2H，d，J＝9.0Hz)，6.97-7.00(1H，br)，7.16(2H，d，J＝8.8Hz)，7.25(2H，d，J＝9.0Hz)，7.32(1H，brs)，7.62(1H，brs)
Embodiment 350
(E0350)
Adopt the similar approach of E0346 to prepare E0350.
White powder
Mass spectrum (ESI+): 454 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.37(9H，s)，3.22-3.33(2H，m)，3.88(3H，s)，3.93-3.99(2H，m)，6.88-7.10(4H，m)，6.91(1H，s)，7.20(2H，d，J＝8.7Hz)，7.36(1H，brs)，7.68(1H，brs)，7.71(1H，dd，J＝2.7，8.8Hz)，8.16(1H，d，J＝2.7Hz)
Embodiment 351
(E0351)
Adopt the similar approach of E0346 to prepare E0351.
mp.168-169℃
IR(KBr)：3381，3192，1705，1695，1674，1643，1614，1564，1549，1516cm-1
Mass spectrum (ESI+): 392 (M+H)+
400MHz 1H NMR(DMSO-d6，d)：3.79(3H，s)，4.43(2H，s)，6.93(2H，d，J＝8.9Hz)，7.00(2H，d，J＝9.0Hz)，7.08(1H，s)，7.21(2H，d，J＝8.9Hz)，7.28(2H，d，J＝9.0Hz)，7.40(1H，brs)，7.54(1H，brs)
Embodiment 352
(E0352)
Mixture in toluene (5ml) was in 100 ℃ of heating 40 minutes with E0346 (433.5mg) and N,N-dimethylacetamide dimethyl acetal (856mg).The vacuum concentration reaction mixture adds the toluene final vacuum to resistates and concentrates.Resistates is dissolved in toluene (5ml), adds hydroxylamine hydrochloride (893mg) and AcOH (3ml), mixture was in 100 ℃ of heating 1 hour.Mixture is cooled to ambient temperature, distributes between AcOEt and H2O, organic layer is through H2O, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=40%, 60%, 80% wash-out.Collect pure part, vacuum concentration.Resistates through the crystallization of AcOEt/ normal hexane, is obtained white powder E0352 (203mg).
mp.148-150℃
IR(KBr)：3431，3425，3406，1614，1547，1510cm-1
Mass spectrum (ESI+): 377 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.44(3H，s)，2.72(2H，t，J＝6.9Hz)，3.55-3.65(2H，m)，3.80(3H，s)，4.66(1H，t，J＝5.1Hz)，7.02(2H，d，J＝8.9Hz)，7.20(2H，d，J＝9.0Hz)，7.24(2H，d，J＝9.0Hz)，7.28-7.36(3H，m)
Embodiment 353
(E0353)
Adopt the similar approach of E0352 to prepare E0353.
Oil
Mass spectrum (ESI+): 435 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.03(3H，s)，2.44(3H，s)，3.80(3H，s)，4.17-4.22(2H，m)，4.25-4.35(2H，m)，6.97(2H，d，J＝8.7Hz)，7.02(2H，d，J＝9.0Hz)，7.23(2H，d，J＝8.7Hz)，7.27(1H，s)，7.31(2H，d，J＝9.0Hz)
Embodiment 354
(E0354)
CH2Cl2 (1ml) solution that diacetyl oxide (124mg) is added E0346 (102.6mg) and pyridine (241mg).In ambient temperature stirred reaction mixture 1 hour.Add diacetyl oxide (62mg) and pyridine (1ml), stir in ambient temperature and spend the night.Add diacetyl oxide (62mg), stirred 4 hours in ambient temperature.Vacuum concentrated mixture, resistates distributes between ethyl acetate and 1M HCl.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Collect residual solid,, obtain white powder E0354 (76.3mg) with the diisopropyl ether washing.
Mass spectrum (ESI+): 380 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.96(3H，s)，2.87(2H，t，J＝6.8Hz)，3.78(3H，s)，4.20(2H，t，J＝6.8Hz)，6.94(1H，s)，6.98(2H，d，J＝8.9Hz)，7.15-7.30(6H，m)，7.33(1H，s)，7.64(1H，s)
Embodiment 355
(E0355)
Adopt the similar approach of E0354 to prepare E0355.
White powder
Mass spectrum (ESI+): 397 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 2.03 (3H, s), 3.87 (3H, s), 4.16-4.21 (2H, m), 4.29-4.34 (2H, m), 6.88-6.98 (4H, m), 7.21 (2H, d, J=8.7Hz), 7.37 (1H, brs), 7.68-7.70 (1H, brs, overlap), 7.71 (1H, dd, J=2.7,8.8Hz), 8.16 (1H, d, J=2.7Hz)
Embodiment 356
(E0356)
Phosphoryl chloride (40.4mg) is added DMF (0.5ml) under the ice bath cooling.After uniform temp stirs 5 minutes down, disposable adding E0354 (50mg).Reaction mixture was stirred 1 hour down in uniform temp, add sodium bicarbonate aqueous solution quencher reaction.Use the ethyl acetate extraction mixture.Organic layer is through H2O, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates, and obtains oily E0356 (45.0mg).
Mass spectrum (ESI+): 403 (M+CH3CN+H)+
Mass spectrum (API-ES positively charged ion): 362 (M+H)+, 384 (M+Na)+
200MHz 1H NMR(DMSO-d6，d)：1.96(3H，s)，2.88(2H，t，J＝6.8Hz)，3.79(3H，s)，4.20(2H，t，J＝6.8Hz)，7.00(2H，d，J＝8.9Hz)，7.15-7.31(6H，m)，7.36(1H，s)
Embodiment 357
(E0357)
Adopt the similar approach of E0356 to prepare E0357.
Oil
Mass spectrum (ESI+): 378 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.02(3H，s)，3.79(3H，s)，4.15-4.21(2H，m)，4.29-4.34(2H，m)，6.93-7.04(4H，m)，7.18(2H，d，J＝8.8Hz)，7.24-7.31(3H，m)
Embodiment 358
(E0358)
Adopt the similar approach of E0356 to prepare E0358.
Oil
Mass spectrum (ESI+): 379 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.02(3H，s)，3.88(3H，s)，4.17-4.21(2H，m)，4.29-4.34(2H，m)，6.90-7.03(3H，m)，7.22(2H，d，J＝8.8Hz)，7.36(1H，s)，7.74(1H，dd，J＝2.7，8.9Hz)，8.20(1H，d，J＝2.7Hz)
Embodiment 359
(E0359)
Adopt the similar approach of E0356 to prepare E0359.
Amorphous powder
Mass spectrum (ESI+): 435 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.32 (2H, m), 3.79 (3H, s), 3.92-3.98 (2H, m), 6.90-7.08 (1H, br overlaps), 6.92 (2H, d, J=8.8Hz), 7.00 (2H, d, J=9.0Hz), 7.16 (2H, d, J=8.8Hz), 7.28 (2H, d, J=9.0Hz), 7.30 (1H, s)
Embodiment 360
(E0360)
Adopt the similar approach of E0356 to prepare E0360.
White powder
Mass spectrum (ESI+): 436 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 1.37 (9H, s), 3.22-3.32 (2H, m), 3.88 (3H, s), 3.93-3.99 (2H, m), 6.90-7.01 (1H, overlap), 6.92 (1H, d, J=8.8Hz), 6.95 (2H, d, J=8.8Hz), 7.21 (2H, d, J=8.8Hz), 7.34 (1H, s), 7.73 (1H, d, J=2.7,8.8Hz), 8.20 (1H, d, J=2.7Hz)
Embodiment 361
(E0361)
Adopt the similar approach of E0356 to prepare E0361.
Oil
Mass spectrum (ESI+): 363 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.96(3H，s)，2.89(2H，t，J＝6.8Hz)，3.88(3H，s)，4.21(2H，t，J＝6.8Hz)，6.92(1H，d，J＝8.8Hz)，7.22(2H，d，J＝8.3Hz)，7.30(2H，d，J＝8.3Hz)，7.41(1H，s)，7.75(1H，dd，J＝8.8，2.7Hz)，8.20(1H，d，J＝2.7Hz)
Embodiment 362
(E0362)
The CH2Cl2 (4ml) and pyridine (2ml) solution that the solution of Acetyl Chloride 98Min. (0.28ml) are added E0261 (441.6mg) under the ice bath cooling.In ambient temperature stirred reaction mixture 1 hour.Add Acetyl Chloride 98Min. (0.14ml), stirred 1 hour in ambient temperature.Add sodium bicarbonate aqueous solution quencher reaction, stir the mixture in ambient temperature and spend the night.To pH=2, use ethyl acetate extraction by 6M HCl acidifying mixture.Organic layer is through H2O and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates obtains white powder E0362 (405.3mg) through the diisopropyl ether crystallization.
Mass spectrum (ESI+): 381 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.96(3H，s)，2.87(2H，t，J＝6.8Hz)，3.79(3H，s)，4.20(2H，t，J＝6.8Hz)，6.96-7.02(3H，m)，7.15-7.27(6H，m)，12.91(1H，br)
Embodiment 363
(E0363)
Adopt the similar approach of E0362 to prepare E0363.
Oil
Mass spectrum (ESI+): 382 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.04(3H，s)，2.94(2H，t，J＝7.0Hz)，3.95(3H，s)，4.29(2H，t，J＝7.0Hz)，6.76(1H，d，J＝8.8Hz)，7.08(1H，s)，7.04-7.35(4H，m)，7.59(1H，dd，J＝2.7，8.8Hz)，8.12(1H，d，J＝2.7Hz)
Embodiment 364
(E0364)
Oxalyl chloride (264mg) is added the suspension of E0362 (395mg) in CH2Cl2 (5ml) under the ice bath cooling.Add 1 DMF, mixture stirred 1 hour in ambient temperature.Vacuum concentrated mixture adds the toluene final vacuum to resistates and concentrates.Resistates is dissolved in CH2Cl2 (30ml), and ice bath cooling adds N, and O-dimethyl hydroxylamine hydrochloride (203mg) and triethylamine (525mg) stir the mixture in ambient temperature and to spend the night.Mixture is diluted with AcOEt, and with 1M HCl, sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates successively.Resistates is purified through silica gel column chromatography, uses CHCl3 earlier, uses AcOEt/CHCl3=10%, 20% wash-out then, obtains oily E0364 (418.4mg).
Mass spectrum (ESI+): 424 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.97(3H，s)，2.88(2H，t，J＝6.8Hz)，3.38(3H，s)，3.77(3H，s)，3.78(3H，s)，4.20(2H，t，J＝6.8Hz)，6.94-7.03(3H，m)，7.16-7.27(6H，m)
Embodiment 365
(E0365)
With E0363 and N, the O-dimethyl hydroxylamine hydrochloride adopts the similar approach of E0364 to prepare oily E0365.
Mass spectrum (ESI+): 425 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.97(3H，s)，2.89(2H，t，J＝6.8Hz)，3.37(3H，s)，3.77(3H，s)，3.88(3H，s)，4.21(2H，t，J＝6.8Hz)，6.91(1H，d，J＝8.8Hz)，6.98(1H，s)，7.20-7.33(4H，m)，7.70(1H，dd，J＝2.8，8.8Hz)，8.15(1H，d，J＝2.8Hz)
Embodiment 366
(E0366)
THF (2ml) solution that under the ice bath cooling, adds E0364 (106.5mg) to the THF of 1.0M phenyl-magnesium-bromide (3.4ml) solution.After uniform temp stirs 1 hour down, pour mixture into the saturated NH4Cl aqueous solution, extract with AcOEt.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30%, 40%, 50% wash-out, obtains oily E0366 (107mg).
IR (pure): 3469,3435,3425,3406,3398,3369,2937,1647,1606,1512cm-1
Mass spectrum (ESI+): 399 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.72(2H，t，J＝6.9Hz)，3.56-3.66(2H，m)，3.80(3H，s)，4.65(1H，t，J＝5.1Hz)，7.02(2H，d，J＝8.9Hz)，7.20(1H，s)，7.22(4H，s)，7.34(2H，d，J＝8.9Hz)，7.52-7.68(3H，m)，8.25(2H，d，J＝8.5Hz)
Embodiment 367
(E0367)
Adopt the similar approach of E0366 to prepare white powder E0367.
mp.95-96℃
IR(KBr)：3498，3476，2966，1678，1649，1612，1547，1512cm-1
Mass spectrum (ESI+): 381 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.15(6H，d，J＝6.8Hz)，3.61-3.75(3H，m)，3.79(3H，s)，3.95-4.00(2H，m)，4.87(1H，t，J＝5.3Hz)，6.91(2H，d，J＝8.7Hz)，6.98(1H，s)，7.00(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.7Hz)，7.28(2H，d，J＝8.9Hz)
Embodiment 368
(E0368)
Adopt the similar approach of E0366 to prepare white powder E0368.
mp.132-133℃
IR(KBr)：3390，3334，3288，1707，1670，1612，1564，1549，1512cm-1
Mass spectrum (ESI+): 379 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.04(4H，d，J＝6.2Hz)，3.03(1H，m)，3.65-3.73(2H，m)，3.80(3H，s)，3.95-4.00(2H，m)，4.87(1H，t，J＝5.4Hz)，6.92(2H，d，J＝8.7Hz)，6.96(1H，s)，7.01(2H，d，J＝8.9Hz)，7.18(2H，d，J＝8.7Hz)，7.31(2H，d，J＝8.9Hz)
Embodiment 369
(E0369)
Adopt the similar approach of E0366 to prepare white powder E0369.
mp.108-109℃
IR(KBr)：3440，2966，1678，1610，1566，1549，1533，1502cm-1
Mass spectrum (ESI+): 382 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.16(6H，d，J＝6.9Hz)，3.64-3.74(3H，m)，3.88(3H，s)，3.96-4.02(2H，m)，4.87(1H，t，J＝5.4Hz)，6.93(1H，d，J＝8.9Hz)，6.94(2H，d，J＝8.7Hz)，7.02(1H，s)，7.21(2H，d，J＝8.7Hz)，7.74(1H，dd，J＝2.7，8.9Hz)，8.18(1H，d，J＝2.7Hz)
Embodiment 370
(E0370)
Adopt the similar approach of E0368 to prepare white powder E0370.
mp.104-106℃
IR(KBr)：3367，2947，1668，1610，1566，1549，1531cm-1
Mass spectrum (ESI+): 380 (M+H)+
2500MHz 1H NMR(DMSO-d6，d)：1.05(4H，d，J＝6.2Hz)，3.04(1H，m)，3.65-3.73(2H，m)，3.89(3H，s)，3.96-4.02(2H，m)，4.87(1H，t，J＝5.4Hz)，6.93(1H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，7.06(1H，s)，7.22(2H，d，J＝8.8Hz)，7.76(1H，dd，J＝2.6，8.8Hz)，8.21(1H，d，J＝2.6Hz)
Embodiment 371
(E0371)
Adopt the similar approach of E0366 to prepare white powder E0371.
Mass spectrum (ESI+): 480 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 1.15 (6H, d, J=6.9Hz), 1.37 (9H, s), 3.25-3.33 (2H, m), 3.68 (1H, m), 3.79 (3H, s), 3.91-3.98 (2H, m), 6.90 (2H, d, J=8.7Hz), 6.90-7.05 (1H overlaps), 6.97 (1H, s), 7.00 (2H, d, J=8.9Hz), 7.17 (2H, d, J=8.7Hz), 7.28 (2H, d, J=8.9Hz)
Embodiment 372
(E0372)
Adopt the similar approach of E0368 to prepare white powder E0372.
Mass spectrum (ESI+): 477 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 1.04 (4H, d, J=6.2Hz), 1.37 (9H, s), 3.04 (1H, m), 3.22-3.33 (2H, m), 3.80 (3H, s), 3.95 (2H, t, J=5.7Hz), 6.88-7.03 (1H, overlap), 6.91 (2H, d, J=8.7Hz), 6.97 (1H, s), 7.01 (2H, d, J=8.9Hz), 7.18 (2H, d, J=8.7Hz), 7.31 (2H, d, J=8.9Hz)
Embodiment 373
(E0373)
Adopt the similar approach of E0366 to prepare white powder E0373.
Mass spectrum (ESI+): 481 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.16(6H，d，J＝6.9Hz)，1.37(9H，s)，3.22-3.32(2H，m)，3.68(1H，m)，3.88(3H，s)，3.93-3.99(2H，m)，6.90-7.02(5H，m)，7.22(2H，d，J＝8.7Hz)，7.73(1H，dd，J＝2.7，8.8Hz)，8.18(1H，d，J＝2.7Hz)
Embodiment 374
(E0374)
Adopt the similar approach of E0368 to prepare white powder E0374.
Mass spectrum (ESI+): 479 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.05(4H，d，J＝6.2Hz)，1.37(9H，s)，3.04(1H，m)，3.23-3.33(2H，m)，3.89(3H，s)，3.93-3.99(2H，m)，6.89-7.08(5H，m)，7.22(2H，d，J＝8.7Hz)，7.76(1H，dd，J＝2.7，8.8Hz)，8.21(1H，d，J＝2.7Hz)
Embodiment 375
(E0375)
Adopt the similar approach of E0366 to prepare oily E0375 with E0364.
IR (pure): 3487,3469,3435,3408,3398,3369,2966,2933,1678,1512cm-1
Mass spectrum (ESI+): 365 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.19(6H，d，J＝7.9Hz)，2.70(2H，t，J＝6.9Hz)，3.54-3.75(3H，m)，3.79(3H，s)，4.64(1H，t，J＝5.1Hz)，7.00(2H，d，J＝8.9Hz)，7.02(1H，s)，7.16(2H，d，J＝8.6Hz)，7.21(2H，d，J＝8.6Hz)，7.29(2H，d，J＝8.9Hz)
Embodiment 376
(E0376)
Under the ice bath cooling, be added dropwise to THF (4ml) solution of E0364 (237.6mg) to ether (2.8ml) solution of 1.0M methyl-magnesium-bromide.After uniform temp stirs 30 minutes down, pour mixture into the saturated NH4Cl aqueous solution, extract with AcOEt.Through mixture, saturated sodium bicarbonate aqueous solution, the saturated sodium-chloride water solution washing of 1M HCl and saturated sodium-chloride water solution, the dried over mgso final vacuum concentrates organic layer successively.Resistates is dissolved in THF (1ml), adds 1M NaOH (0.4ml), in the ambient temperature some hrs that stirs the mixture.With 1MHCl (0.4ml) neutralise mixt, between AcOEt and saturated sodium-chloride water solution, distribute.Organic layer concentrates through the dried over mgso final vacuum.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=50% wash-out, obtains white powder E0376 (139.1mg).
Mass spectrum (ESI+): 337 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.54(3H，s)，2.70(2H，t，J＝6.9Hz)，3.55-3.64(2H，m)，3.80(3H，s)，4.65(1H，t，J＝5.1Hz)，7.00(2H，d，J＝8.9Hz)，7.01(1H，s)，7.15(2H，d，J＝8.5Hz)，7.21(2H，d，J＝8.5Hz)，7.29(2H，d，J＝8.9Hz)
Embodiment 377
(E0377)
Adopt the similar approach of E0376 to prepare oily E0377.
Mass spectrum (ESI+): 366 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.16(6H，d，J＝6.9Hz)，2.72(2H，t，J＝6.9Hz)，3.55-3.75(3H，m)，3.88(3H，s)，4.65(1H，t，J＝5.1Hz)，6.93(1H，d，J＝8.8Hz)，7.05(1H，s)，7.17-7.29(4H，m)，7.76(1H，dd，J＝8.8，2.7Hz)，8.19(1H，d，J＝2.7Hz)
Embodiment 378
(E0378)
Adopt the similar approach of E0376 to prepare oily E0378.
200MHz 1H NMR(DMSO-d6，d)：2.73(2H，t，J＝6.9Hz)，3.57-3.66(2H，m)，3.89(3H，s)，4.66(1H，t，J＝5.0Hz)，6.94(1H，d，J＝8.8Hz)，7.23(1H，s)，7.15-7.35(4H，m)，7.52-7.72(3H，m)，7.80(1H，dd，J＝2.7，8.8Hz)，8.23-8.32(3H，m)
Embodiment 379
(E0379)
Adopt the similar approach of E0376 to prepare white powder E0379.
Mass spectrum (ESI+): 338 (M+H)+
00MHz 1H NMR(DMSO-d6，d)：2.55(3H，s)，2.71(2H，t，J＝6.9Hz)，3.55-3.65(2H，m)，3.89(3H，s)，4.65(1H，t，J＝5.1Hz)，6.93(1H，d，J＝8.8Hz)，7.05(1H，s)，7.19(2H，d，J＝8.6Hz)，7.24(2H，d，J＝8.6Hz)，7.75(1H，dd，J＝2.7，8.8Hz)，8.19(1H，d，J＝2.7Hz)
Embodiment 380
(E0380)
E0376 (127mg), O-methyl hydroxylamine hydrochloride (47.3mg) and the mixture of pyridine in EtOH (3ml) were heated 1 hour in 60 ℃.Vacuum concentrated mixture, resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=40% wash-out.Collect pure part, vacuum concentration.Use the diisopropyl ether crystalline residue, obtain white powder E0380 (103.2mg).
mp.82-86℃
IR(KBr)：3359，3269，3246，2939，1549，1512cm-1
Mass spectrum (ESI+): 366 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.20(3H，s)，2.70(2H，t，J＝6.9Hz)，3.54-3.65(2H，m)，3.78(3H，s)，3.92(3H，s)，4.65(1H，t，J＝5.0Hz)，6.77(1H，s)，6.97(2H，d，J＝8.9Hz)，7.12-7.26(6H，m)
Embodiment 381
(E0381)
Adopt the similar approach of E0380 to prepare white powder E0381.
mp.94-95℃
IR(KBr)：3469，3433，3423，3404，3400，3371，1647，1549cm-1
Mass spectrum (ESI+): 267 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.20(3H，s)，2.71(2H，t，J＝6.8Hz)，3.55-3.65(2H，m)，3.87(3H，s)，3.92(3H，s)，4.65(1H，t，J＝5.0Hz)，6.81(1H，s)，6.90(1H，d，J＝8.8Hz)，7.18(2H，d，J＝8.7Hz)，7.23(2H，d，J＝8.7Hz)，7.69(1H，dd，J＝8.8，2.7Hz)，8.11(1H，d，J＝2.7Hz)
Embodiment 382
(E0382)
To methyl alcohol (21ml) solution of E0314 (100mg) add methylamine methyl alcohol (40%, 92ml) solution.After stirred overnight at room temperature, evaporating mixture obtains oily matter, and it is purified through preparation type TLC (1mm, 60% ethyl acetate/hexane), obtains oily E0382 (97mg, 100%).
NMR(CDCl3)，2.92(3H，d，J＝5.0Hz)，3.83(3H，s)，4.49(2H，s)，6.69(1H，s)，6.82-6.91(4H，m)，7.14-7.24(4H，m).
MS(ESI+)；428.2(M+Na).
IR (pure, 20727-11), 1693.2cm-1.
Embodiment 383
(E0383)
CH2Cl2 (2ml) solution that isocyanic acid tribromo-acetyl ester (62.4mg) is added E0118 (100mg) under the ice bath cooling.After ambient temperature stirs 3 hours, the vacuum concentration reaction mixture.Resistates is dissolved in THF (1ml), MeOH (1ml) and H2O (1ml).Salt of wormwood (153mg) is added reaction mixture, stir in ambient temperature and spend the night.Reaction mixture distributes between AcOEt and H2O.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Residual solid obtains white powder E0383 (84.1mg) with AcOEt-normal hexane recrystallization.
mp.169-170℃
IR(KBr)：3435，3332，3263，3209，1684，1610，1516cm-1
Mass spectrum (ESI+): 406 (M+H)+
400MHz 1H NMR(DMSO-d6，d)：2.84(2H，t，J＝6.8Hz)，3.79(3H，s)，4.10(2H，t，J＝6.8Hz)，6.30-6.70(2H，br)，7.00(2H，d，J＝9.0Hz)，7.14(1H，s)，7.21(2H，d，J＝8.4Hz)，7.26(2H，d，J＝8.4Hz)，7.29(2H，d，J＝9.0Hz)
Embodiment 384
(E0384)
CH2Cl2 (1ml) solution that isocyanic acid trimethyl silyl ester (42.7mg) is added E0158 (98.2mg) and triethylamine (30mg) under the ice bath cooling.Reaction mixture was stirred 1 hour vacuum concentration down in uniform temp.Resistates launches with MeOH/CHCl3=10% through preparation type thin layer silica gel chromatographic purification.With the silica gel of 10%MeOH/CHCl3 extracting and separating, filter the final vacuum evaporating solvent.Resistates obtains white powder E0384 (59.7mg) through ethyl acetate-diisopropyl ether crystallization.
mp.157-158℃
IR(KBr)：3406，3357，3330，3209，1704，1662，1614，1529，1520cm-1
Mass spectrum (ESI+): 405 (M+H)+
200MHz 1H NMR(DMSO-d6，d)NO06.067：2.62-2.70(2H，m)，3.13-3.24(2H，m)，3.79(3H，s)，5.42(2H，s)，5.93(1H，t，J＝5.4Hz)，7.00(2H，d，J＝8.8Hz)，7.12(1H，s)，7.21(4H，s)，7.29(2H，d，J＝8.8Hz)
Embodiment 385
(E0385)
Similar approach according to E0384 obtains target compound.
IR (film): 3343.9,1656.6,1604.5,1550.5,1515.8,1457.9,1342.2,1251.6,1029.8cm-1.
Embodiment 386
(E0386)
Similar approach according to E0384 obtains target compound.
IR (film): 3345.9,1654.6,1604.5,1556.3,1513.9,1465.6,1240.0,1160.9,1132.0cm-1.
Embodiment 387
(E0387)
Similar approach according to E0384 obtains target compound.
IR (film): 3345.9,1658.5,1602.6,1552.4,1236.2,1159.0,1133.9cm-1.
Embodiment 388
(E0388)
Similar approach according to E0384 obtains target compound.
IR (film): 3345.9,1658.5,1602.6,1552.4,1517.7,1236.2,1159.0,1133.9cm-1.
Embodiment 389
(E0389)
With the mixture of E0175 (150mg) and 4N HCl/ dioxane (6ml) in stirring at room.After 2 hours,, obtain oily E0389 (128mg, quantitative) with the reaction mixture reduction vaporization.
IR (film): 3403.7,1513.9,1467.6,1241.9,1162.9,1130.1cm-1.
Embodiment 390
(E0390)
Similar approach according to E0389 obtains target compound.
IR (film): 3428.8,1662.34,1612.2,1500.4,1461.8,1390.4,1292.1,1166.7,1087.7,1029.8cm-1.
Embodiment 391
(E0391)
Similar approach according to E0389 obtains target compound.
IR (film): 3403.74,2965.98,1610.27,1513.85,1461.78,1251.58,1170.58,1085.73,1029.80,836.955,800.314cm-1.
Embodiment 392
(E0392)
Similar approach according to E0389 obtains target compound.
IR (film): 3432.7,1511.9,1467.6,1240.0,1160.9,1130.1cm-1.
Embodiment 393
(E0393)
EtOH (10m) mixture of E0258 (100mg) and Pd/C (100mg) was stirred 3.0 hours under H2 atmosphere.Filter back reduction vaporization filtrate.Resistates is dissolved in EtOH, filters, evaporation, the E0393 of acquisition 93mg (93%) with disposable syringe drive-type strainer.
IR (film): 3019.9,1704.8,1513.9,1303.6,1238.1,1133.9cm-1.
Embodiment 394
(E0394)
Toluene (4ml) suspension to E0258 (200mg) adds thionyl chloride (0.19ml) in room temperature.Reaction mixture in 100 ℃ of stirrings 5 hours, is become settled solution up to mixture.Then with mixture reduction vaporization (becoming solid).Add THF, add the MeNH2 aqueous solution (37%) then.Stirred the mixture 1 hour, the EtOAc extracting twice is used in the water quencher.The organic layer that merges is through saturated NaHCO3, water and salt water washing, and the Na2SO4 drying is filtered the back reduction vaporization, obtains Powdered E0394 (63mg, 31%).
mp：155-157℃
IR (film) 3297.7,1662.3,1617.9,1513.9,1236.2,1162.9,1133.9cm-1
Embodiment 395
(E0395)
With E0399 (1.8g) and phthalimido potassium (potassium phtalimido) N (1.13g), dinethylformamide (6.6ml) suspension stirred 3 hours in 80 ℃.Add entry (700ml) to mixture, with mixtures of ethyl acetate and hexane (2: 1) (* 4) extraction.The organic layer that merges evaporates after the dried over mgso through aqueous sodium hydroxide solution (1N) (* 2) and salt water washing, obtains oily matter, and it is purified with column chromatography (SiO2 100ml is with 30% ethyl acetate/hexane wash-out), obtains oil (1.83g, 91.1%).(15ml) adds this oil with ethanol, then in stirring at room mixture 10 minutes.Filtering precipitate, with ethanol (3ml) washing, drying under reduced pressure obtains white solid E0395 (1.16g, 58%).
NMR(CDCl3)，3.00(2H，t，J＝7.6Hz)，3.93(2H，t，J＝7.6Hz)，3.94(3H，s)，6.73(1H，s)，6.73(1H，d，J＝8.7Hz)，7.13-7.26(4H，m)，7.49(1H，dd，J＝8.7，2.5Hz)，7.70-7.86(4H，m)，8.10(1H，d，J＝2.5Hz).
MS(ESI+)，515(M+Na).
Embodiment 396
(E0396)
6M HCl (0.045ml) is added the solution that E0168 (101.5mg) is dissolved in AcOEt (1ml) and EtOH (1ml).Enriched mixture, vacuum-drying obtains amorphous powder E0396 (94.8mg).
IR (pure): 3433,3020,2956,1668,1658,1612,1572,1543,1500cm-1
Mass spectrum (ESI+): 377 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.76-1.92(2H，m)，2.52-2.81(4H，m)，3.88(3H，s)，6.93(1H，d，J＝8.9Hz)，7.19(1H，s)，7.26(4H，s)，7.76(1H，dd，J＝8.9，2.7Hz)，8.19(1H，d，J＝2.7Hz)
Embodiment 397
(E0397)
Under ice-cooled, add NaH (1.1g) to the DMF (30ml) of P0002 (5.0g) and CF3COOEt (3.5ml) mixture.Reaction mixture is warming up to room temperature, stirred 1 hour in 40 ℃.With reaction mixture EtOAc extracting twice.Organic layer is through water and salt water washing, and the MgSO4 drying is filtered the back reduction vaporization.The acetate (20ml) that will contain resistates, sodium acetate (2.23g) and 4-p-methoxy-phenyl hydrazine (3.96g) was in stirring at room 15 hours.With twice of ethyl acetate extraction of mixture.The organic layer that merges is through water (twice), saturated NaHCO3, water and salt water washing, and the MgSO4 drying is filtered the back reduction vaporization.Resistates is through silica gel column chromatography purification (Hex/EtOAc=8: 1-4: 1), obtain the oily E0397 of 2.58g (36%).
Embodiment 398
(E0398)
Ethyl acetate (3ml) solution to E0312 (326.7mg) adds methylsulfonyl chloride (86.9ml) and triethylamine (0.181ml) in 0 ℃.,, extract after 40 minutes in 0 ℃ of stirring with ethyl acetate (* 3) with the quencher of mixture water.The organic layer that merges is through water and salt water washing, dried over sodium sulfate, and reduction vaporization obtains oily E0398 (351.3mg, 89%).
NMR(CDCl3)；3.09(3H，s)，3.82(3H，s)，4.22-4.26(2H，m)，4.52-4.59(2H，m)，6.68(1H，s)，6.75(2H，d，J＝8.7Hz)，6.87(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.7Hz)，7.22(2H，d，J＝8.9Hz).
Embodiment 399
(E0399)
Similar approach according to E0398 obtains faint yellow oily target compound (1.82g, 98.6%).
NMR(CDCl3)，2.91(3H，s)，3.07(2H，t，J＝6.8Hz )，3.94(3H，s)，4.43(2H，t，J＝6.8Hz)，6.75(1H，s)，6.78(1H，d，J＝8.2Hz)，7.17-7.26(4H，m)，7.58(1H，dd，J＝9.0，2.9Hz)，8.05(1H，d，J＝2.8Hz).
MS(ESI+)，442.1(MH+)，464.0(M+Na).
Embodiment 400
(E0400)
With the N of E0398 (351.3mg) and sodium methyl mercaptide (162mg), dinethylformamide (3ml) suspension stirred 3.5 hours in 60 ℃.With the quencher of mixture water, with ethyl acetate (* 3) extraction.The organic layer that merges evaporates after the dried over mgso through water and salt water washing, obtains oily matter.Oily matter is purified with column chromatography (SiO2 50ml is with 10% ethyl acetate/hexane wash-out), obtain oily E0400 (236.7mg, 75.3%).
NMR(CDCl3)；2.24(3H，s)，2.88(2H，t，J＝6.6Hz)，3.82(3H，s)，4.15(2H，t，J＝6.6Hz)，6.67(1H，s)，6.83(2H，d，J＝8.8Hz)，6.88(2H，d，J＝9.0Hz)，7.13(2H，d，J＝8.8Hz)，7.23(2H，d，J＝9.0Hz).
MS(ESI+)；431(M+Na).
Embodiment 401
(E0401)
Methylene dichloride (1ml) solution to E0400 (103.5mg) adds metachloroperbenzoic acid (134mg) in room temperature.After 1 hour, add the saturated sodium pyrosulfate aqueous solution (0.5ml) and Sulfothiorine pentahydrate (100mg) in stirring at room, in stirring at room 30 minutes to mixture.Mixture is evaporation after Chemelut 1001 (Varian) filters, and obtains oily matter, and it is purified through preparation type TLC (1mm, 50% ethyl acetate/hexane), obtains amorphous E0401 (105.9mg, 94.9%).
NMR(CDCl3)；3.07(3H，s)，3.45(2H，t，J＝5.3Hz)，4.44(2H，t，J＝5.3Hz)，3.83(3H，s)，6.69(1H，s)，6.69-6.90(4H，m)，7.15-7.26(4H，m).
MS(ESI+)；463.1(M+Na)+.IR(KBr，20727-8)，1612.2，1515.8cm-1.
Embodiment 402
(E0402)
Add metachloroperbenzoic acid (44.7mg) to methylene dichloride (1ml) solution of E0400 (104.8mg) in 0 ℃, stirred the mixture 1 hour in 0 ℃.Then metachloroperbenzoic acid (35mg) is added mixture.In 0 ℃ stir 30 minutes after, with mixture with the saturated sodium pyrosulfate aqueous solution (0.5ml) and Sulfothiorine pentahydrate (100mg) quencher, in stirring at room 30 minutes.Mixture is evaporation after Chemelut 1001 (Varian) filters, and obtains oily matter, and it is through preparation type TLC (1mm, ethyl acetate) purifies, obtain 2 parts: amorphous E0401 (TLC top) (40.7mg, 37.4%) and Powdered E0402 (TLC bottom) (60mg, 55%).
NMR(CDCl3)；2.70(3H，s)，2.99-3.27(2H，m)，3.83(3H，s)，4.40-4.46(2H，m)，6.68(1H，s)，6.84-6.90(4H，m)，7.15(2H，d，J＝8.7Hz)，7.22(2H，d，J＝9.0Hz).
MS(ESI+)；447.1(M+Na).
IR(KBr)；1612.2，1513.9cm-1.
Embodiment 403
(E0403)
Dichloromethane a heatable brick bed (1.5ml) solution to E0286 (500mg) adds methyl-phenoxide (0.5ml) and trifluoroacetic acid (1ml) successively.,, extract after 2 hours in stirring at room with ethyl acetate (* 3) with mixture saturated sodium bicarbonate aqueous solution quencher.Organic layer evaporates after dried over mgso, obtains oily matter, and it is purified with column chromatography (SiO2 50ml uses eluent ethyl acetate), obtains oily E0403 (302.5mg, 94.2%).
NMR(CDCl3)，3.77(3H，s)，3.80(3H，s)，3.80-3.87(1H，m)，4.21-4.28(2H，m)，6.67(1H，s)，6.80-6.89(4H，m)，7.13(2H，d，J＝8.7Hz)，7.22(2H，d，J＝8.9Hz).
MS(ESI+)，436.1(MH+).
Embodiment 404
(E0404)
(1N is 2ml) in stirring at room 3 hours with methyl alcohol (3ml) solution of E0403 (104.6mg) and aqueous sodium hydroxide solution.Evaporating mixture adds resistates with methyl alcohol, and evaporation obtains white powder, and it is purified with preparation type TLC (1mm, 20% methyl alcohol/chloroform), obtains Powdered E0404 (29.9mg, 29.5%).
NMR(DMSO-d6)，3.50-3.54(1H，m)，3.79(3H，s)，4.13-4.30(2H，m)，6.91-7.07(5H，m)，7.21(2H，d，J＝8.7Hz)；7.27(2H，d，J＝8.9Hz).
MS(ESI-).420.4(M-H).
IR(KBr)，1641，1616cm-1.
Embodiment 405
(E0405)
Methyl alcohol (2ml) solution to E0403 (106.6mg) adds concentrated ammonia solution (1ml).After stirred overnight at room temperature, evaporating mixture obtains solid, and it is purified with preparation type TLC (1mm, 20% methyl alcohol/chloroform), obtains solid E0405 (58.2mg, 56.5%).
NMR(CDCl3)，3.75-3.82(1H，m)，3.82(3H，s)，4.15-4.29(2H，m)，6.67(1H，s)，6.83-6.91(4H，m)，7.14(2H，d，J＝6.7Hz)，7.22(2H，d，J＝9.0Hz).
MS(ESI+).421.4(MH+)，462.4(MHMeCN)+.
IR(KBr)，1658cm-1.
Embodiment 406
(E0406)
Tetrahydrofuran (THF) (1ml) solution to E0403 (87.5mg) adds lithium aluminium hydride (30.5mg) in room temperature.In stirring at room after 2 hours, with mixture water (30ml), aqueous sodium hydroxide solution (15%, 30ml) and water (90ml) quencher, then in stirring at room 30 minutes.Sal epsom and Celite are added mixture, and filtering suspension liquid washs with tetrahydrofuran (THF).Evaporated filtrate obtains oily matter, and it is purified with preparation type TLC (0.5mm, 20% methyl alcohol/chloroform), obtains oily matter.The solution that is dissolved in ethyl acetate to described oily matter adds the ethyl acetate of hydrogenchloride, and (evaporating mixture obtains oily E0406 (43.5mg, 49%) then for 4N, 0.5ml) solution.
NMR(CDCl3)，3.64-4.13(5H，m)，3.76(3H，s)，6.60(1H，s)，6.73-6.85(4H，m)，7.07(2H，d，J＝8.5Hz)，7.16(2H，d，J＝8.9Hz).
MS (ESI+), and 408.1 (MH+) (freedom) .IR (pure, 20727-5), 1614.1cm-1.
Embodiment 407
(E0407)
To tetrahydrofuran (THF) (2ml) suspension of sodium hydride (34.8mg) in 0 ℃ of tetrahydrofuran (THF) (1ml) solution that adds E0347 (208mg), then in stirring at room mixture 20 minutes.Methyl iodide (54.2ml) is added mixture.After stirred overnight at room temperature, the quencher of mixture water is with ethyl acetate (* 3) extraction.The organic layer that merges is through water (* 3) and salt water washing, and reduction vaporization after the dried over mgso obtains oily matter, and it is purified through preparation type TLC (1mm, 30% ethyl acetate/hexane), obtains oily E0407 (160mg, 74.7%).
NMR(CDCl3)，1.45(9H，s)，2.97(3H，s)，3.59(2H，t，J＝5.5Hz)，3.82(3H，s)，4.0-4.15(2H，m)，6.67(1H，s)，6.80-6.91(4H，m)，7.13(2H，d，J＝8.8Hz)，7.23(2H，d，J＝9.0Hz).
MS(ESI+).514.2(M+Na).
Embodiment 408
(E0408)
CH2Cl2 (10ml) suspension that AcCl (0.31ml) is added E0347 (1.29g) and Et3N (0.66ml) under the ice bath cooling.Stirred the mixture 2 hours in ambient temperature.Add AcCl (0.31ml) and Et3N (0.66ml), stirred 3 hours in ambient temperature.Add H2O to mixture, stir a moment in ambient temperature.Collect the white precipitate that occurs,, obtain white powder E0408 (879.3mg) with H2O and diisopropyl ether washing.
Mass spectrum (ESI+): 396 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.03(3H，s)，3.78(3H，s)，4.15-4.19(2H，m)，4.29-4.33(2H，m)，6.89(1H，s)，6.93(2H，d，J＝8.8Hz)，6.98(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.9Hz)，7.32(1H，s)，7.63(1H，s)
Embodiment 409
(E0409)
In 0 ℃ of adding trifluoromethanesulfonic acid trimethyl silyl ester (85.6mg), add triethylamine (39mg) to the CH2Cl2 of E0374 (61.4mg) (2ml) solution then.Mixture distributes between AcOEt and H2O in 0 ℃ of stirring 30 minutes.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is through preparation type thin layer silica gel chromatographic purification, by the 28%NH3 aqueous solution: MeOH: CHCl3=1: launch at 10: 100.Isolating silica gel is through the 28%NH3 aqueous solution: MeOH: CHCl3=1: extraction in 10: 100, vacuum evaporating solvent.The vacuum-drying resistates is dissolved in EtOH (3ml) then.Add 1MHCl (0.0892ml), vacuum concentration to described solution.The vacuum-drying resistates obtains amorphous powder E0409 (37mg).
IR(KBr)：2958，1668，1662，1612，1581，1568，1549，1531，1500cm-1
Mass spectrum (ESI+): 379 (M+H)+
200MHz 1H NMR1.05(4H，d，J＝6.2Hz)，3.04(1H，m)，3.15-3.24(2H，m)，3.89(3H，s)，4.16-4.22(2H，m)，6.94(1H，d，J＝8.8Hz)，7.00(2H，d，J＝8.7Hz)，7.02(1H，s)，7.27(2H，d，J＝8.7Hz)，7.78(1H，dd，J＝2.7，8.8Hz)，8.14(2H，brs)，8.21(1H，d，J＝2.7Hz)
Embodiment 410
(E0410)
To 2-{4-[1-(4-p-methoxy-phenyl)-3-(methylsulfonyl)-1H-pyrazoles-5-yl] phenoxy group } ethamine (133mg; 0.342mmol) methylene dichloride (5ml) solution add isocyanic acid trimethyl silyl ester (118mg in ambient temperature; 1.03mmol) and triethylamine (1.39mg; 1.37mmol), stirred two days.Reaction mixture is through water and salt water washing, and dried over mgso is filtered the back evaporation.Purify through column chromatography (silica gel, methylene chloride=20/1), use re-crystallizing in ethyl acetate then, obtain the white crystal E0410 of 102mg (69%).
mp.165-167℃
Mass spectrum; 431 (M+1)
IR(KBr)；1650，1310CM-1
NMR(DMSO-d6，δ)；3.32(2H，q，J＝5.5Hz)，3.33(3H，s)，3.79(3H，s)，3.94(2H，t，J＝5.5Hz)，5.52(2H，s)，6.14(1H，t，J＝5.5Hz)，6.94(2H，d，J＝8.7Hz)，7.01(2H，d，J＝8.9Hz)，7.11(1H，s)，7.20(2H，d，J＝8.7Hz)，7.28(2H，d，J＝8.9Hz)，
Embodiment 411
(E0411)
DMF (1ml) solution of P0034 (64mg) is added 60%NaH (11.4mg) in 4 ℃, under uniform temp, stirred the mixture 30 minutes.Add bromoacetic acid (33mg) to mixture, stirred the mixture 2 hours in ambient temperature.Add 1M HCl (2ml) quencher reaction, extract mixture with AcOEt.Organic layer is through H2O and saturated NaCl solution washing, the MgSO4 drying, and vacuum concentration obtains crystal E0411 (73mg).
Mass spectrum (ESI+): 355 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.79(3H，s)，3.96(3H，s)，4.63(2H，s)，5.88(1H，s)，6.82(4H，d，J＝9.0Hz)，7.14(2H，d，J＝9.0Hz)，7.17(2H，d，J＝9.0Hz)
Embodiment 412
(E0412)
Boron trifluoride diethyl ether compound (137mg) is added THF (3ml) suspension of sodium borohydride (29.3mg) under ice bath cooling, under uniform temp, stirred the mixture 30 minutes.Contain the THF (3ml) of E0411 (137mg) to the disposable adding of reaction mixture, stirred the mixture 4 hours in ambient temperature.Add the frozen water quencher reaction that comprises 1M HCl (1ml), stirred the mixture 1 hour in ambient temperature.Extract mixture 2 times with AcOEt, the organic layer of merging is through the saturated NaHCO3 aqueous solution and saturated NaCl solution washing, MgSO4 drying, vacuum-evaporation.Resistates is purified through the preparative thin-layer chromatography method, launches by AcOEt/ normal hexane=50%.Use the IPE crystalline residue, obtain white powder E0412 (79.2mg).
mp.107-109℃
IR(KBr)：3334，2935，1693，1612，1564，1520cm-1
Mass spectrum (ESI+): 341 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.02(1H，t，J＝6.1Hz)，3.80(3H，s)，3.91-3.99(2H，m)，3.97(3H，s)，4.04-4.09(2H，m)，5.88(1H，s)，6.82(4H，d，J＝9.0Hz)，7.14(2H，d，J＝9.0Hz)，7.17(2H，d，J＝9.0Hz)
Embodiment 413
(E0413) (E0413-0)
Under the ice bath cooling, add 60%NaH (41.6mg) to the DMF of P0034 (237mg) (2ml) solution, stirred the mixture 1 hour in ambient temperature.DMF (1ml) to mixture adding E0413-0 (287mg) stirred the mixture 13 hours in ambient temperature, stirred 3 hours in 60 ℃.Add saturated NH4Cl aqueous solution quencher reaction, extract mixture with AcOEt.Organic layer is through H2O, saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Resistates is dissolved in EtOH (4ml), adds dense HCl (40 μ L).After ambient temperature stirs 2 hours, vacuum concentrated mixture.Resistates distributes between the AcOEt and the saturated NaHCO3 aqueous solution, and organic layer is through saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=40%, 60% wash-out.Resistates is through AcOEt (1ml) and IPE (2ml) crystallization.The crystal that obtains AcOEt (0.7ml) and IPE (1.5ml) recrystallization.Obtain white crystal E0413 (196.9mg).
Mp.114.9-116 (115) ℃ mass spectrum (ESI+): 341 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.65-3.73(2H，m)，3.75(3H，s)，3.83(3H，s)，3.94-3.99(2H，m)，4.86(1H，t，J＝5.4Hz)，6.04(1H，s)，6.87-6.96(4H，m)，7.10-7.16(4H，m)
Embodiment 414
(E0414)
Under the ice bath cooling, add 60%NaH (17.5mg) to the DMF of P0034 (100mg) (1ml) solution.Stirred the mixture 1 hour in ambient temperature.Mixture is cooled to 0 ℃.Add acetate 2-bromine ethyl ester (113mg) to mixture, stirred the mixture 24 hours in ambient temperature.Add saturated NH4Cl aqueous solution quencher reaction, extract mixture with AcOEt.Organic layer is through H2O, saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Resistates is dissolved in THF (0.9ml) and MeOH (0.9ml), adds 1MNaOH (0.4ml) to solution.Mixture stirred 1 hour in ambient temperature.Mixture is distributed between AcOEt and H2O, with the AcOEt water layer of stripping.The organic layer that merges is through saturated NaCl solution washing, and MgSO4 is dry, and final vacuum concentrates.Resistates obtains white crystal E0414 (82.4mg) through AcOEt (0.3ml)-IPE (0.9ml) crystallization.
Mass spectrum (ESI+): 341 (M+H)+
Preparation 35
To N '-[5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, the EtOH (10ml) of N-dimethyl urea (1.19g) and THF (10ml) solution add the H2O (2ml) and 10%Pd-C 50% weight in wet base (150mg) solution of ammonium formiate (509mg).Mixture was refluxed 1 hour.Catalyzer washs this pad through the filtering of Celite pad with EtOH.The washings of vacuum concentrated filtrate and merging.Add AcOEt and H2O to resistates.Collect the white precipitate that occurs, with H2O and IPE washing, obtain white powder N '-[5-(4-hydroxy phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (555mg) successively.
Mass spectrum (ESI+): 353 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.91(6H，s)，3.76(3H，s)，6.57(1H，s)，6.71(2H，d，J＝8.6Hz)，6.93(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.6Hz)，7.14(2H，d，J＝9.0Hz)，8.99(1H，s)，9.68(1H，s)
Obtain following compound by preparing 35 similar approach.
Preparation 36
N-[5-(4-hydroxy phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N ', N '-trimethyl-urea white powder
Mass spectrum (ESI+): 367 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.78(6H，s)，3.11(3H，s)，3.76(3H，s)，6.19(1H，s)，6.70(2H，d，J＝8.6Hz)，6.93(2H，d，J＝9.0Hz)，7.03(2H，d，J＝8.6Hz)，7.15(2H，d，J＝9.0Hz)，9.72(1H，s)
Preparation 37
4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
Powder
Mass spectrum (ESI+): 311 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.32(3H，t，J＝7.0Hz)，3.75(3H，s)，4.16(2H，q，J＝7.0Hz)，5.96(1H，s)，6.70(2H，d，J＝8.6Hz)，6.91(2H，d，J＝8.9Hz)，7.01(2H，d，J＝8.6Hz)，7.11(2H，d，J＝8.9Hz)，9.74(1H，brs)
Preparation 38
4-[3-isobutoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
White powder
Mass spectrum (ESI+): 339 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.02(6H，d，J＝6.6Hz)，2.10(1H，m)，3.79(3H，s)，3.98(6.6H，d，J＝2Hz)，5.38(1H，s)，5.87(1H，s)，6.72(2H，d，J＝8.6Hz)，6.81(2H，d，J＝9.0Hz)，7.07(2H，d，J＝8.6Hz)，7.16(2H，d，J＝9.0Hz)
Preparation 39
4-[3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
White powder
Mass spectrum (ESI+): 341 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.30(3H，s)，3.62-3.67(2H，m)，3.75(3H，s)，4.21-4.26(2H，m)，5.98(1H，s)，6.70(2H，d，J＝8.6Hz)，6.91(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.6Hz)，7.12(2H，d，J＝9.0Hz)，9.69(1H，s)
Preparation 40
4-[3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
White powder
Mass spectrum (ESI+): 355 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.13(3H，t，J＝7.0Hz)，3.49(2H，q，J＝7.0Hz)，3.65-3.71(2H，m)，3.75(3H，s)，4.20-4.25(2H，m)，5.99(1H，s)，6.70(2H，d，J＝8.6Hz)，6.91(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.6Hz)，7.12(2H，d，J＝9.0Hz)，9.72(1H，s)
Preparation 41
2-{[5-(4-hydroxy phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] the oxygen base }-N,N-dimethylacetamide
White powder
Mass spectrum (ESI+): 368 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.84(3H，s)，2.97(3H，s)，3.75(3H，s)，4.87(2H，s)，6.01(1H，s)，6.70(2H，d，J＝8.6Hz)，6.92(2H，d，J＝9.0Hz)，7.01(2H，d，J＝8.6Hz)，7.10(2H，d，J＝9.0Hz)，9.71(1H，s)
Preparation 42
4-[3-methoxyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 298(M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.84(6H，s)，6.05(1H，s)，6.73(2H，d，J＝8.6Hz)，6.85(1H，d，J＝8.8Hz)，7.05(2H，d，J＝8.6Hz)，7.59(1H，dd，J＝8.8，2.7Hz)，7.98(1H，d，J＝2.7Hz)，9.77(1H，s)
Preparation 43
4-[3-oxyethyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 312(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，3.84(3H，s)，4.18(2H，q，J＝7.0Hz)，6.03(1H，s)，6.73(2H，d，J＝8.6Hz)，6.84(1H，d，J＝8.7Hz)，7.05(2H，d，J＝8.6Hz)，7.57(1H，dd，J＝2.6，8.7Hz)，7.97(1H，d，J＝2.6Hz)，9.76(1H，s)
Preparation 44
4-[1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenol
Mass spectrum (ESI+): m/z=371.2 (M+Na).
1HNMR(400MHz，CDCl3)：2.15(3H，s)，3.78(3H，s)，6.79(2H，d，J＝8.9Hz)，6.8(2H，d，J＝8.6Hz)，7.01(2H，d，J＝8.6Hz)，7.13(2H，d，J＝8.9Hz).
Preparation 45
4-[3-cyclopropyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 308(M+H)
1HNMR(200MHz，CDCl3)：0.76-0.85(2H，m)，0.93-1.06(2H，m)，1.97-2.08(1H，m)，3.91(3H，s)，6.08(1H，s)，6.15(1H，s)，6.68-6.76(3H，m)，7.04(2H，d，J＝8.6Hz)，7.56(1H，dd，J＝2.7，6.2Hz)，8.02(1H，d，J＝2.7Hz)
Preparation 46
4-[3-(cyclopentyloxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 352(M+H)
1HNMR(200MHz，DMSOd6)：1.09-2.41(8H，m)，3.84(3H，s)，4.92-5(1H，m)，6.01(1H，s)，6.73(2H，d，J＝8.6Hz)，6.84(1H，d，J＝8.8Hz)，7.05(2H，d，J＝8.6Hz)，7.57(1H，dd，J＝2.7，8.8Hz)，7.97(1H，d，J＝2.7Hz)，9.76(1H，brs)
Preparation 47
4-[1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 365(M+H)
1HNMR(200MHz，DMSOd6)：3.76(3H，s)，4.8(1H，d，J＝9Hz)，4.89(1H，d，J＝9Hz)，6.15(1H，s)，6.71(2H，d，J＝8.6Hz)，6.93(2H，d，J＝8.9Hz)，7.03(2H，d，J＝8.6Hz)，7.14(2H，d，J＝8.9Hz)，9.74(1H，brs)
Preparation 48
4-[3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 347(M+H)
1HNMR(200MHz，DMSOd6)：3.76(3H，s)，4.43(2H，dt，J＝3.5，14.9Hz)，6.08(1H，s)，6.40(1H，tt，J＝3.5，54.6Hz)，6.71(2H，d，J＝8.6Hz)，6.92(2H，d，J＝9.0Hz)，7.02(2H，d，J＝8.6Hz)，7.14(2H，d，J＝9.0Hz)
Preparation 49
4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 366(M+H)
1HNMR(200MHz，CDCl3)：3.92(3H，s)，4.61(1H，d，J＝8.5Hz)，4.69(1H，d，J＝8.5Hz)，5.39(1H，brs)，5.97(1H，s)，6.72(1H，d，J＝8.9Hz)，6.76(2H，d，J＝8.5Hz)，7.09(2H，d，J＝8.5Hz)，7.51(1H，dd，J＝2.7，8.9Hz)，8.01(1H，d，J＝2.7Hz)
Preparation 50
4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 348(M+H)
1HNMR(200MHz，CDCl3)：3.92(3H，s)，4.46(2H，dt，J＝4.2，13.5Hz)，5.42(1H，brs)，5.93(1H，s)，6.16(1H，tt，J＝4.2，55.4Hz)，6.72(1H，d，J＝8.7Hz)，6.76(2H，d，J＝8.6Hz)，7.09(2H，d，J＝8.6Hz)，7.51(1H，dd，J＝2.7，8.7Hz)，8.01(1H，d，J＝2.7Hz)
Preparation 51
4-[1-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 281(M+H)
200MHz 1H NMR(DMSO-d6，d)：2.00(3H，s)，3.74(3H，s)，6.74(2H，d，J＝8.5Hz)，6.88(2H，d，J＝9.0Hz)，6.96(2H，d，J＝8.5Hz)，7.09(2H，d，J＝9.0Hz)，7.53(1H，s)，9.66(1H，s)
Preparation 52
4-[1-(6-methoxyl group-3-pyridyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenol
White powder
MS(ESI+)：m/z 282(M+H)
1HNMR(200MHz，DMSOd6)：2.01(3H，s)，3.83(3H，s)，6.75-6.85(3H，m)，7.01(2H，d，J＝8.6Hz)，7.53(1H，dd，J＝2.7，8.8Hz)，7.6(1H，s)，7.96(1H，d，J＝2.7Hz)，9.73(1H，brs)
Preparation 53
To 4 '-THF (120ml) solution of benzyloxy Propiophenone (6.0g) is in-60 ℃ of 1N two (trimethyl silyl) lithium amides (LiHMDS) that add 38ml, and mixture is being lower than-60 ℃ and was stirring 45 minutes down.Add 1-(trifluoroacetyl group) imidazoles (3.4ml), mixture stirred 30 minutes in 0 ℃ in-60 ℃ of stirrings 1 hour.Reaction mixture is poured mixture into EtOAc and water with 0.5N HCl quencher, separates the EtOAc layer, uses the salt water washing, concentrates after the MgSO4 drying, obtains 1-[4-(benzyloxy) phenyl]-4,4,4-three fluoro-2-methyl isophthalic acids, 3-dimethyl diketone.
Mass spectrum (ESI+): m/z=359.2 (m+Na).
1HNMR(400MHz，CDCl3)：1.36(1H，d，J＝7.2Hz)，1.52(2H，d，J＝7Hz)，5.16(2H，s)，7.02-7.08(2H，m)，7.37-7.44(5H，m)，7.92-7.98(2H，m).
Preparation 54
Mixture to 4-(methylthio group) aniline (6.3g) and dense HCl (45ml) is added dropwise to the water (18ml) that contains NaNO2 (3.6g) under ice-cooled.Stir after 30 minutes, in the ice-cooled dense HCl (24ml) that contains SnClH2O (28.6g) that in 1 hour, adds down.Stir after 1 hour, filter,, obtain 14.1g solid [4-(methylthio group) phenyl] hydrazonium salt hydrochlorate with dense HCl and water washing after drying.
Mass spectrum (ESI+): m/z=139.3 (M-NH2+1).
1HNMR(400MHz，DMSOd6)：2.42(3H，s)，3.75(2H，b.s)，6.97(2H，d，J＝8.7Hz)，7.24(2H，d，J＝8.7Hz)，10.24(1H，b.s).
Preparation 55
4-hydroxypropiophenone (20g), benzyl chloride (16.1ml), K2CO3 (12.9g) and KI (2.21g) the mixture backflow in EtOH (80ml) and H2O (1ml) was stirred 4 hours.The reaction mixture after-filtration.The crystal that occurs is dissolved in EtOAc and water.Separate organic layer, water and salt water washing, dried over mgso after-filtration.Reduction vaporization filtrate obtains 30.0g (94%) crystal 1-[4-(benzyloxy) phenyl]-1-acetone.
Mass spectrum (ESI+): m/z=263.2 (M+Na).
1HNMR(400MHz，CDCl3)：1.21(3H，t，J＝7.3Hz)，2.95(2H，q，J＝7.3Hz)，5.13(2H，s)，7(2H，d，J＝8.9Hz)，7.34-7.45(5H，m)，7.95(2H，d，J＝8.9Hz).
Preparation 56
With EtOH (24ml) solution of 1M NaOH (4.8ml) adding 4-benzyloxy phenyl aldehyde (5g) and Cyclopropyl Methyl Ketone (3.96g), mixture stirs in ambient temperature and spends the night.Reaction mixture is diluted with H2O and EtOH.Stirred the mixture 20 minutes in ambient temperature.Collect light yellow crystal,, obtain (2E)-3-[4-(benzyloxy) phenyl with H2O and 50%EtOH solution washing]-1-cyclopropyl-2-propylene-1-ketone (6.29g).
Light yellow crystal
MS(ESI+)：m/z 301(M+Na)
1HNMR(200MHz，CDCl3)：0.9-1.00(2H，m)，1.11-1.19(2H，m)，2.16-2.29(1H，m)，5.11(2H，s)，6.77(1H，d，J＝16.1Hz)，6.99(2H，d，J＝8.8Hz)，7.32-7.46(4H，m)，7.52(2H，d，J＝8.8Hz)，7.58(2H，d，J＝16.1Hz)
Preparation 57
With (2E)-3-[4-(benzyloxy) phenyl]-1-cyclopropyl-2-propylene-1-ketone (6.25g) is suspended in EtOH (67.5ml), acetone (22.5ml).Add hydrogen peroxide 30% aqueous solution (4.5ml) and 3M NaOH (4.5ml) to mixture, stirred the mixture 1 day in ambient temperature.Mixture is diluted with H2O.Collect white precipitate, with H2O washing, dry air, obtain (2R, 3S)-3-[4-(benzyloxy) phenyl]-the 2-Oxyranyle } (cyclopropyl) ketone (6.27g).
Powder
MS(ESI+)：m/z 317(M+Na)
1HNMR(200MHz，DMSOd6)：0.96-1.07(2H，m)，1.12-1.19(2H，m)，2.11-2.22(1H，m)，3.59(1H，d，J＝1.8Hz)，4.04(1H，d，J＝1.8Hz)，5.08(2H，s)，6.97(2H，d，J＝8.8Hz)，7.23(2H，d，J＝8.8Hz)，7.35-7.43(5H，m)
Preparation 58
To 4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] CH2Cl2 (5ml) solution of phenol (501mg) adds trifluoromethanesulfanhydride anhydride (300 μ l) and diisopropylethylamine (324 μ l) under the ice bath cooling.Mixture stirred 2 hours down in uniform temp.Add trifluoromethanesulfanhydride anhydride (57 μ l) and diisopropylethylamine (147 μ l) again, continue to stir 1 hour in uniform temp.Mixture is through 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=20% wash-out, obtains oily 4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl trifluoromethanesulfonate methanesulfonates (712.3mg).
MS(ESI+)：m/z 429(M+H)
1HNMR(200MHz，CDCl3)：3.81(3H，s)，3.98(3H，s)，5.97(1H，s)，6.85(2H，d，J＝9.0Hz)，7.11-7.32(6H，m)
Adopt the similar approach of preparation 58 to obtain following compound.
Preparation 59
4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl trifluoromethanesulfonate methanesulfonates oily matter
MS ESI+)：m/z 457(M+H)
1HNMR(200MHz，CDCl3)：1.40(6H，d，J＝6.1Hz)，3.81(3H，s)，4.89(1H，m)，5.94(1H，s)，6.84(2H，d，J＝9.0Hz)，7.14(2H，d，J＝9.0Hz)，7.20-7.32(4H，m)
Preparation 60
4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl trifluoromethanesulfonate methanesulfonates oily matter
MS(ESI+)：m/z 433(M+H)
1HNMR(200MHz，CDCl3)：3.82(3H，s)，6.46(1H，s)，6.86(2H，d，J＝9.0Hz)，7.17(2H，d，J＝9.0Hz)，7.23-7.32(4H，m)
Preparation 61
With 4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl trifluoromethanesulfonate methanesulfonates (679mg), zinc cyanide (279mg) and tetrakis triphenylphosphine palladium (0) DMF (4ml) mixture (183mg) stirred 5 hours in 85 ℃.Reaction mixture is cooled to ambient temperature, adds AcOEt and H2O.Insolubles is through the filtering of Celite pad.Distribute filtrate, organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=20% wash-out.Collect pure part, vacuum concentration obtains Powdered 4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] cyanobenzene (326mg).
mp.112-113℃
MS(ESI+)：m/z 306(M+H)，328(M+Na)
IR(KBr)：2929，2227，1568，1552，1541，1518cm-1
1HNMR(200MHz，CDCl3)：3.81(3H，s)，3.98(3H，s)，6.01(1H，s)，6.85(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)，7.30(2H，d，J＝8.5Hz)，7.57(2H，d，J＝8.5Hz)
Adopt the similar approach of preparation 61 to obtain following compound.
Preparation 62
4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] cyanobenzene
mp.96-97℃
MS(ESI+)：m/z 334(M+H)，356(M+Na)
1HNMR(200MHz，CDCl3)：1.40(6H，d，J＝6.1Hz)，3.81(3H，s)，4.89(1H，m)，5.98(1H，s)，6.84(2H，d，J＝9.0Hz)，7.14(2H，d，J＝9.0Hz)，7.30(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)
Preparation 63
4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] cyanobenzene oily matter
MS(ESI+)：m/z 375(M+H)
1HNMR(200MHz，CDCl3)：3.94(3H，s)，4.62(1H，d，J＝8.4Hz)，4.71(1H，d，J＝8.4Hz)，6.12(1H，s)，6.76(1H，d，J＝8.7Hz)，7.33(2H，d，J＝8.4Hz)，7.5(1H，dd，J＝2.7，8.7Hz)，7.62(2H，d，J＝8.4Hz)，7.97(1H，d，J＝2.7Hz)
Preparation 64
4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] cyanobenzene
Powder
MS(ESI+)：m/z 310(M+H)，332(M+Na)
1HNMR(200MHz，CDCl3)：3.83(3H，s)，6.50(1H，s)，6.87(2H，d，J＝9.0Hz)，7.16(2H，d，J＝9.0Hz)，7.30(2H，d，J＝8.5Hz)，7.60(2H，d，J＝8.5Hz)
Preparation 65
4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] the cyanobenzene powder
MS(ESI+)：m/z 311(M+H)，333(M+Na)
1HNMR(200MHz，CDCl3)：3.94(3H，s)，6.53(1H，s)，6.78(1H，d，J＝8.9Hz)，7.33(2H，d，J＝8.4Hz)，7.54(1H，dd，J＝2.7，8.9Hz)，7.64(2H，d，J＝8.4Hz)，7.99(1H，d，J＝2.7Hz)
Preparation 66
CH2Cl2 (1ml) solution of trifluoromethanesulfanhydride anhydride (207 μ l) is added 4-[1-(6-methoxyl group-3-pyridyl)-3-(2 under the ice bath cooling, 2,2-trifluoro ethoxy)-and 1H-pyrazoles-5-yl] CH2Cl2 (3ml) solution of phenol (300mg) and pyridine (199 μ l).Under uniform temp, stirred the mixture 1 hour.Add saturated aqueous ammonium chloride (5ml) quencher reaction.Mixture is distributed between AcOEt and 1M HCl.Mixture is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates, obtain oily 4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenyl trifluoromethanesulfonate methanesulfonates (439mg).
MS(ESI+)：m/z 498(M+H)
1HNMR(200MHz，CDCl3)：3.94(3H，s)，4.62(1H，d，J＝8.4Hz)，4.71(1H，d，J＝8.4Hz)，6.08(1H，s)，6.74(1H，d，J＝8.7Hz)，7.22-7.38(4H，m)，7.47(1H，dd，J＝2.7，8.7Hz)，8.01(1H，d，J＝2.7Hz)
Adopt the similar approach of preparation 66 to obtain following compound.
Preparation 67
4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] the phenyl trifluoromethanesulfonate methanesulfonates
Oily matter
MS(ESI+)：m/z 434(M+H)
1HNMR(200MHz，CDCl3)：3.94(3H，s)，6.49(1H，s)，6.76(1H，d，J＝8.9Hz)，7.23-7.34(4H，m)，7.52(1H，dd，J＝2.8，8.9Hz)，8.02(1H，d，J＝2.8Hz)
Preparation 68
With 4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] trifluoroacetic acid (25ml) solution of phenyl benzyl oxide (2.79g) and thioanisole (3.56g) stirs in ambient temperature and spends the night.Vacuum concentrated mixture.With AcOEt (15ml) and normal hexane (12ml) recrystallization resistates, obtain first product FR282117 (1.48g).Mother liquor is through H2O, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out.Collect pure part, vacuum concentration.Collect remaining crystal,, obtain second crowd of product white powder 4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl with the IPE washing] phenol (457.2mg).
Mass spectrum (ESI+): m/z 301 (M+H)
200MHz 1H NMR(DMSO-d6，d)：3.78(3H，s)，6.62(1H，s)，6.71(2H，d，J＝8.7Hz)，6.96(2H，d，J＝9.0Hz)，7.03(2H，d，J＝8.7Hz)，7.19(2H，d，J＝9.0Hz)，9.80(1H，s)
Adopt the similar approach of preparation 68 to obtain following compound.
Preparation 69
4-[1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles-5-yl] phenol
Powder
MS(ESI+)：m/z 313(M+H)
1HNMR(200MHz，DMSOd6)：2.50(3H，s)，3.77(3H，s)，6.49(1H，s)，6.70(2H，d，J＝8.6Hz)，6.94(2H，d，J＝9.0Hz)，7.02(2H，d，J＝8.6Hz)，7.16(2H，d，J＝9.0Hz)，9.71(1H，brs)
Adopt the similar approach of embodiment 596 to obtain following compound.
Preparation 70
4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenol
Mass spectrum (ESI+): m/z=373.1 (M+Na).
1HNMR(400MHz，CDCl3)：2.49(3H，s)，5.13(1H，b.s)，6.67(1H，s)，6.79(2H，d，J＝8.7Hz)，7.1(2H，d，J＝8.7Hz)，7.2(2H，d，J＝9.1Hz)，7.23(2H，d，J＝9.1Hz).
Preparation 71
4-{3-(difluoromethyl)-1-[4-(methylthio group) phenyl]-1H-pyrazoles-5-yl } phenol
Mass spectrum (ESI+) m/z=355.1 (M+Na)
1HNMR(400MHz，CDCl3)：2.49(3H，s)，5.17(1H，b.s)，6.65(1H，s)，6.76(1H，t，J＝55Hz)，6.78(2H，d，J＝8.7Hz)，7.1(2H，d，J＝8.7Hz)，7.2(4H，s).
Preparation 72
4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] cyanobenzene
Mass spectrum (ESI+): m/z=345.1,367.1 (m+H, m+Na).
1HNMR(400MHz，CDCl3)：3.96(3H，s)，6.8(1H，d，J＝8.8Hz)，6.85(1H，s)，7.36(2H，d，J＝8.4Hz)，7.57(1H，dd，J＝2.7，8.8Hz)，7.66(2H，d，J＝8.4Hz)，8.04(1H，d，J＝2.7Hz).
Preparation 73
4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] cyanobenzene
Mass spectrum (ESI+): m/z=327.1 (m+1).
1HNMR(400MHz，CDCl3)：3.95(3H，s)，6.77(1H，t，J＝54.8Hz)，6.79(1H，d，J＝8.8Hz)，6.82(1H，s)，7.36(2H，d，J＝8.4Hz)，7.54(1H，dd，J＝2.8，8.8Hz)，7.65(2H，d，J＝8.4Hz)，8.04(1H，d，J＝2.8Hz).
Embodiment 415
CH2Cl2 (3ml) solution that dioxane (3ml) solution of 4M HCl is added (2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate (236mg).Reaction mixture was stirred 3 hours in ambient temperature.Add 2-propyl alcohol (2ml) to dissolve insoluble oily matter, stirred 4 hours in ambient temperature.Vacuum concentrated mixture.Resistates is suspended in CH2Cl2 (3ml).Add methylsulfonyl chloride (127mg), Et3N successively, the pH value of reaction mixture is adjusted to neutrality.Stir after 1 hour the vacuum concentration reaction mixture.Resistates distributes between ethyl acetate and water.Use the ethyl acetate extraction mixture.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 50%AcOEt/ normal hexane wash-out, acquisition oily N-(2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin (118mg).
1H NMR(CDCl3)δ2.20(3H，s)，3.03(3H，s)，3.51-3.60(2H，m)，3.93(3H，s)，4.07-4.13(2H，m)，4.77(1H，t，J＝6.0Hz)，5.15(1H，brs)，5.60(1H，brs)，6.59(1H，s)，6.73(1H，d，J＝8.9Hz)，6.83(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.55(1H，dd，J＝2.6，8.8Hz)，8.09(1H，d，J＝2.6Hz)
Embodiment 416
With 10%Pd-C 50% weight in wet base (20mg) and N-(2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) mixture of Toluidrin (118mg) in THF (1ml) and MeOH (1ml) under H2 (1atm) in ambient temperature hydrogenation 1 day.Remove by filter catalyzer.The washings of vacuum concentrated filtrate and merging.Resistates launches by AcOEt/ normal hexane=70% through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts through 10%MeOH/CHCl3, vacuum evaporating solvent.With AcOEt-IPE recrystallization resistates, and acquisition white powder N-(2-{4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin (68.6mg).
White powder:
mp.96-97℃
IR(KBr)：3269，2970，1612，1512cm-1
MS(ESI+)：m/z 431(M+H)
1H NMR(DMSO-d6)δ1.27(6H，d，J＝6.9Hz)，2.88-2.99(1H，m)，2.92(3H，s)，3.92-3.35(2H，m)，3.85(3H，s)，3.99-4.06(2H，m)，6.46(1H，s)，6.88(1H，d，J＝8.7Hz)，6.94(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.28(1H，s)，7.60(1H，dd，J＝2.7，8.7Hz)，8.02(1H，d，J＝2.7Hz)
Adopt the similar approach of embodiment 416 to obtain following compound.
Embodiment 417
4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Oily matter
MS(ESI+)：m/z 422(M+H)
1HNMR(200MHz，)：1.34(6H，d，J＝7.0Hz)，1.46(9H，s)，3.08(1H，m)，3.80(3H，s)，4.30(2H，d，J＝5.9Hz)，4.81(1H，brs)，6.31(1H，s)，6.83(2H，d，J＝9.0Hz)，7.15-7.26(6H，m)
Embodiment 418
4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Oily matter
MS(ESI+)：m/z 423(M+H)
1HNMR(200MHz，CDCl3)：1.34(6H，d，J＝7Hz)，1.46(9H，s)，3.07(1H，m)，3.92(3H，s)，4.30(2H，d，J＝6.0Hz)，4.84(1H，brs)，6.33(1H，s)，6.72(1H，d，J＝8.8Hz)，7.15-7.26(4H，m)，7.56(1H，dd，J＝2.7，8.8Hz)，8.04(1H，d，J＝2.7Hz)
Embodiment 419
CH2Cl2 (2ml) solution that dioxane (2ml) solution of 4M HCl is added (2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate (269.7mg).In ambient temperature stirred reaction mixture 2 hours, vacuum concentration then obtained amorphous powder (2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine dihydrochloride (259mg).
MS(ESI+)：m/z 351(M+H)
1H NMR(DMSO-d6)δ2.10(3H，s)，3.15-3.23(2H，m)，3.86(3H，s)，4.16-4.24(2H，m)，5.15(1H，brs)，5.63(1H，brs)，6.85(1H，s)，6.86-7.00(3H，m)，7.18-7.25(2H，m)，7.66(1H，dd，J＝2.8，8.7Hz)，8.06(1H，d，J＝2.8Hz)，8.24(2H，brs)
Following compounds obtains by the similar approach of embodiment 419.
Embodiment 420
(2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
White powder
Mass spectrum (ESI+): 340 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.16-3.23(2H，m)，3.76(3H，s)，3.84(3H，s)，4.14-4.20(2H，m)，6.06(1H，s)，6.93(2H，d，J＝8.9Hz)，6.94(2H，d，J＝8.7Hz)，7.14(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.7Hz)，8.16(2H，brs)
Embodiment 421
(2-{4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
White powder
Mass spectrum (ESI+): 354 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，3.14-3.23(2H，m)，3.76(3H，s)，4.12-4.23(4H，m)，6.04(1H，s)，6.92(2H，d，J＝9.0Hz)，6.94(2H，d，J＝8.8Hz)，7.12(2H，d，J＝9.0Hz)，7.16(2H，d，J＝8.8Hz)，8.24(2H，brs)
Embodiment 422
(2-{4-[3-isobutoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Amorphous substance
Mass spectrum (ESI+): 382 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：0.97(6H，d，J＝6.7Hz)，2.03(1H，m)，3.14-3.23(2H，m)，3.76(3H，s)，3.90(2H，d，J＝6.6Hz)，4.14-4.20(2H，m)，6.06(1H，s)，6.92(2H，d，J＝9.0Hz)，6.94(2H，d，J＝8.8Hz)，7.08-7.19(4H，m)，8.23(2H，brs)
Embodiment 423
(2-{4-[3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Amorphous substance
Mass spectrum (ESI+): 384 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.15-3.23(2H，m)，3.31(3H，s)，3.62-3.67(2H，m)，3.75(3H，s)，4.14-4.27(4H，m)，6.06(1H，s)，6.92(2H，d，J＝8.9Hz)，6.95(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.8Hz)，8.20(2H，brs)
Embodiment 424
(2-{4-[3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Amorphous substance
Mass spectrum (ESI+): 398 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.13(3H，t，J＝7.0Hz)，3.15-3.24(2H，m)，3.50(2H，q，J＝7.0Hz)，3.66-3.71(2H，m)，3.76(3H，s)，4.13-4.27(4H，m)，6.07(1H，s)，6.93(2H，d，J＝8.9Hz)，6.95(2H，d，J＝8.7Hz)，7.13(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.7Hz)，8.13(2H，brs)
Embodiment 425
(2-{4-[3-methoxyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Amorphous substance
MS(ESI+)：m/z 341(M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.16-3.23(2H，m)，3.84(3H，s)，3.85(3H，s)，4.16-4.21(2H，m)，6.12(1H，s)，6.86(1H，d，J＝8.7Hz)，6.98(2H，d，J＝8.7Hz)，7.21(2H，d，J＝8.7Hz)，7.62(1H，dd，J＝2.5，8.7Hz)，7.99(1H，d，J＝2.5Hz)，8.24(2H，brs)
Embodiment 426
(2-{4-[3-oxyethyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Amorphous substance
MS(ESI+)：m/z 355(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，3.15-3.24(2H，m)，3.84(3H，s)，4.13-4.24(2H，m)，4.19(2H，q，J＝7.0Hz)，6.10(1H，s)，6.86(1H，d，J＝8.9Hz)，6.98(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.8Hz)，7.60(1H，dd，J＝2.7，8.9Hz)，7.98(1H，d，J＝2.7Hz)，8.19(2H，brs)
Embodiment 427
(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Mass spectrum (ESI+): m/z=392.2 (M+H).
1HNMR(400MHz，DMSOd6)：2.09(3H，s)，3.1-3.3(2H，m)，3.36(2H，b.s)，3.57(3H，s)，4.20(2H，t，J＝5Hz)，6.94(2H，d，J＝8.9Hz)，7.01(2H，d，J＝8.8Hz)，7.2(2H，d，J＝8.9Hz)，7.21(2H，d，J＝8.8Hz)，8.29(2H，br.s).
Embodiment 428
(2-{4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Mass spectrum (ESI+): m/z=394.1 (M (Free)+1, HCl salt).
1HNMR(200MHz，DMSOd6)：2.5(3H，s)，3.15-3.25(2H，m)，4.22(2H，t，J＝5Hz)，7(2H，d，J＝8.7Hz)，7.1(1H，s)，7.26(2H，d，J＝8.7Hz)，7.27(2H，d，J＝9.8Hz)，7.33(2H，d，J＝9.8Hz)，8.35(2H，b.s).
Embodiment 429
[2-(4-{3-(difluoromethyl)-1-[4-(methylthio group) phenyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] amine hydrochlorate
Mass spectrum (ESI-): m/z=410.0 (M-1).
1HNMR(400MHz，DMSOd6)：2.49(3H，s)，3.2(2H，t，J＝5Hz)，4.19(2H，t，J＝5Hz)，6.87(1H，s)，6.99(1H，d，J＝8.7Hz)，7.09(1H，t，J＝53.5Hz)，7.24(4H，d，J＝9.6Hz)，7.3(2H，d，J＝8.7Hz)，8.17(2H，b.s).
Embodiment 430
(2-{4-[3-cyclopropyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Amorphous powder
MS(ESI+)：m/z 351(M+H)
1HNMR(200MHz，DMSOd6)：0.70-0.78(2H，m)，0.86-1.02(2H，m)，1.88-1.99(1H，m)，3.10-3.20(2H，m)，3.85(3H，s)，4.15-4.21(2H，m)，6.31(1H，s)，6.86(1H，d，J＝8.9Hz)，6.96(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.60(1H，dd，J＝2.7，8.9Hz)，8.00(1H，d，J＝2.7Hz)，8.24(2H，brs)
Embodiment 431
(2-{4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Amorphous powder
MS(ESI+)：m/z 421(M+H)
1HNMR(200MHz，DMSOd6)：1.43-1.72(6H，m)，3.14-3.24(2H，m)，3.52-3.70(2H，m)，3.77-3.95(2H，m)，3.78(3H，s)，4.15-4.20(2H，m)，6.79(1H，s)，6.96(2H，d，J＝8.8Hz)，6.99(2H，d，J＝8.9Hz)，7.21(2H，d，J＝8.8Hz)，7.24(2H，d，J＝8.9Hz)，8.14(2H，brs)
Embodiment 432
(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Amorphous powder
MS(ESI+)：m/z 422(M+H)
1HNMR(200MHz，CDCl3)：1.42-1.75(6H，m)，3.14-3.24(2H，m)，3.52-3.70(2H，m)，3.73-3.94(2H，m)，3.87(3H，s)，4.16-4.22(2H，m)，6.83(1H，s)，6.91(1H，d，J＝8.9Hz)，6.99(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.8Hz)，7.69(1H，dd，J＝2.7，8.9Hz)，8.14(1H，d，J＝2.7Hz)，8.21(2H，brs)
Embodiment 433
5-[4-(2-amino ethoxy) phenyl]-N-ethyl-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide dihydrochloride
Amorphous powder
Mass spectrum (ESI+): m/z 396 (M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.23(3H，m)，2.98，3.29(3H，s)，3.13-3.25(2H，m)，3.43-3.78(4H，m)，3.87(3H，s)，4.16-4.22(2H，m)，6.84，6.86(1H，s)，6.91(1H，d，J＝8.7Hz)，7.00(2H，d，J＝8.7Hz)，7.25(2H，d，J＝8.7Hz)，7.61-7.74(1H，m)，8.13-8.20(3H，m)
Embodiment 434
(2-{4-[3-(cyclopentyloxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Amorphous powder
MS(ESI+)：m/z 395(M+H)
1HNMR(400MHz，DMSOd6)：1.57-1.91(8H，m)，3.16-3.21(2H，m)，3.84(3H，s)，4.17-4.21(2H，m)，4.95-5(1H，m)，6.08(1H，s)，6.85(1H，d，J＝8.8Hz)，6.98(2H，d，J＝8.8Hz)，7.2(2H，d，J＝8.8Hz)，7.59(1H，dd，J＝2.8，8.8Hz)，7.98(1H，d，J＝2.8Hz)，8.24(2H，brs)
Embodiment 435
(2-{4-[1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Oily matter
MS(ESI+)：m/z 408(M+H)
1HNMR(200MHz，DMSOd6)：3.13-3.24(2H，m)，3.76(3H，s)，4.15-4.21(2H，m)，4.82(1H，d，J＝9.0Hz)，4.91(1H，d，J＝9.0Hz)，6.23(1H，s)，6.92-6.99(4H，m)，7.13-7.21(4H，m)，8.20(2H，brs)
Embodiment 436
(2-{4-[3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Amorphous powder
MS(ESI+)：m/z 390(M+H)
1HNMR(200MHz，DMSOd6)：3.13-3.23(2H，m)，3.76(3H，s)，4.14-4.20(2H，m)，4.44(2H，dt，J＝3.5，14.9Hz)，6.16(1H，s)，6.41(1H，tt，J＝3.5，54.6Hz)，6.94(2H，d，J＝8.9Hz)，6.95(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.9Hz)，7.18(2H，d，J＝8.9Hz)，8.17(2H，brs)
Embodiment 437
(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Amorphous powder
MS(ESI+)：m/z 409(M+H)
1HNMR(200MHz，DMSOd6)：3.16-3.21(2H，m)，3.85(3H，s)，4.16-4.22(2H，m)，4.83(1H，d，J＝9.0Hz)，4.92(1H，d，J＝9.0Hz)，6.29(1H，s)，6.88(1H，d，J＝8.8Hz)，6.99(2H，d，J＝8.8Hz)，7.22(2H，d，J＝8.8Hz)，7.63(1H，dd，J＝2.7，8.8Hz)，8.03(1H，d，J＝2.7Hz)，8.19(2H，brs)
Embodiment 438
(2-{4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Powder
MS(ESI+)：m/z 391(M+H)
1HNMR(200MHz，DMSOd6)：3.15-3.24(2H，m)，3.85(3H，s)，4.16-4.22(2H，m)，4.46(2H，dt，J＝3.5，14.9Hz)，6.22(1H，s)，6.42(1H，tt，J＝3.5，54.5Hz)，6.87(1H，d，J＝8.9Hz)，6.99(2H，d，J＝8.7Hz)，7.22(2H，d，J＝8.7Hz)，7.62(1H，dd，J＝2.7，8.9Hz)，8.02(1H，d，J＝2.7Hz)，8.20(2H，brs)
Embodiment 439
4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] and benzyl } the amine hydrochlorate amorphous powder
MS(ESI+)：m/z 391(M+H)
1HNMR(200MHz，DMSOd6)：1.43-1.74(6H，m)，3.51-3.72(2H，m)，3.77-3.93(2H，m)，3.79(3H，s)，3.97-4.06(2H，m)，6.90(1H，s)，6.99(2H，d，J＝8.9Hz)，7.26(2H，d，J＝8.9Hz)，7.30(2H，d，J＝8.2Hz)，7.46(2H，d，J＝8.2Hz)，8.38(2H，brs)
Embodiment 440
5-[4-(amino methyl) phenyl]-N-ethyl-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide hydrochloride
Powder
MS(ESI+)：m/z 365(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.22(3H，m)，2.98，3.29(3H，s)，3.35-3.80(2H，m)，3.79(3H，s)，3.97-4.08(2H，m)，6.91，6.93(1H，s)，6.99(2H，d，J＝8.9Hz)，7.26(2H，d，J＝8.9Hz)，7.30(2H，d，J＝8.3Hz)，7.46(2H，d，J＝8.3Hz)，8.37(2H，brs)
Embodiment 441
4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } amine hydrochlorate oily matter
MS(ESI+)：m/z 322(M+H)
1HNMR(200MHz，DMSOd6)：1.27(6H，d，J＝6.8Hz)，2.96(1H，m)，3.77(3H，s)，3.95-4.03(2H，m)，6.51(1H，s)，6.94(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.9Hz)，7.25(2H，d，J＝8.2Hz)，7.45(2H，d，J＝8.2Hz)，8.45(2H，brs)
Embodiment 442
1-[5-[4-(amino methyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-2-methyl isophthalic acid-acetone hydrochloride
Amorphous powder
MS(ESI+)：m/z 350(M+H)
1HNMR(200MHz，DMSOd6)：1.16(6H，d，J＝6.9Hz)，3.68(1H，m)，3.80(3H，s)，4.01(2H，s)，7.01(2H，d，J＝8.9Hz)，7.10(1H，s)，7.26-7.34(4H，m)，7.46(2H，d，J＝8.2Hz)，8.33(2H，brs)
Embodiment 443
4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] and benzyl } the amine dihydrochloride
Oily matter
MS(ESI+)：m/z 392(M+H)
1HNMR(200MHz，DMSO-d6)：1.45-1.73(6H，m)，3.53-3.70(2H，m)，3.70-3.98(2H，m)，3.98-4.08(2H，m)，6.92(1H，d，J＝8.8Hz)，6.93(1H，s)，7.32-7.55(4H，m)，7.74(1H，dd，J＝2.7，8.8Hz)，8.15(1H，d，J＝2.7Hz)，8.38(2H，brs)
Embodiment 444
5-[4-(amino methyl) phenyl]-N-ethyl-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide dihydrochloride
Oily matter
MS(ESI+)：m/z 366(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.23(3H，m)，2.98，3.29(3H，s)，3.43-3.77(2H，m)，3.88(3H，s)，3.97-4.06(2H，m)，6.89-6.96(2H，m)，7.32-7.80(5H，m)，8.14-8.16(1H，m)，8.52(2H，brs)
Embodiment 445
4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] and benzyl } amine dihydrochloride amorphous powder
MS(ESI+)：m/z 323(M+H)
1HNMR(200MHz，DMSOd6)：1.28(6H，d，J＝6.9Hz)，2.86-3.05(1H，m)，3.85(3H，s)，3.96-4.06(2H，m)，6.57(1H，s)，6.88(1H，d，J＝8.8Hz)，7.26-7.53(4H，m)，7.66(1H，dd，J＝2.7，8.8Hz)，8.02(1H，d，J＝2.7Hz)，8.48(2H，brs)
Embodiment 446
1-[5-[4-(amino methyl) phenyl]-1-(6-methoxyl group-3-pyridyl)-1H-pyrazole-3-yl]-2-methyl isophthalic acid-acetone dihydrochloride
Oily matter
MS(ESI+)：m/z 351(M+H)
1HNMR(200MHz，DMSOd6)：1.17(6H，d，J＝6.8Hz)，3.68(1H，m)，3.89(3H，s)，3.98-4.06(2H，m)，6.95(1H，d，J＝8.8Hz)，7.13(1H，s)，7.36(2H，d，J＝8.2Hz)，7.51(2H，d，J＝8.2Hz)，7.80(1H，dd，J＝2.7，8.8Hz)，8.19(1H，d，J＝2.7Hz)，8.43(2H，brs)
Embodiment 447
(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenoxy group } ethyl) the amine hydrochlorate powder
MS(ESI+)：m/z 324(M+H)
200MHz 1H NMR(DMSO-d6，d)：2.02(3H，s)，3.17-3.26(2H，m)，3.74(3H，s)，4.13-4.19(2H，m)，6.89(2H，d，J＝9.0Hz)，6.98(2H，d，J＝8.7Hz)，7.10(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.7Hz)，7.57(1H，s)，8.05(2H，brs)
Embodiment 448
(2-{4-[1-(6-methoxyl group-3-pyridyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenoxy group } ethyl) the amine dihydrochloride
Oily matter
MS(ESI+)：m/z 325(M+H)
1HNMR(200MHz，DMSOd6)：2.03(3H，s)，3.16-3.24(2H，m)，3.83(3H，s)，4.18-4.24(2H，m)，6.84(1H，d，J＝8.7Hz)，7.01(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.56(1H，dd，J＝2.7，8.7Hz)，7.64(1H，s)，7.98(1H，d，J＝2.7Hz)，8.28(2H，brs)
Embodiment 449
(2-{4-[1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate
Amorphous powder
MS(ESI+)：m/z 356(M+H)
1HNMR(200MHz，DMSOd6)：2.52(3H，s)，3.14-3.23(2H，m)，3.77(3H，s)，4.15-4.21(2H，m)，6.57(1H，s)，6.95(4H，d，J＝8.9Hz)，7.17(4H，d，J＝8.9Hz)，8.22(2H，brs)
Following compound obtains by the similar approach of embodiment 428.
Embodiment 450
5-[4-(amino methyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-formonitrile HCN hydrochloride
Mass spectrum (ESI+): m/z=304.2 (M+1).
Embodiment 451
The solution that is dissolved in CH2Cl2 (2ml) to (2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine dihydrochloride (126.4mg) and Et3N (125 μ l) adds methylsulfonyl chloride (34.7 μ l) under the ice bath cooling.Mixture stirred 1 hour in ambient temperature.Add methylsulfonyl chloride (6.9 μ l) and Et3N (41.6 μ l) again, reaction mixture was stirred 30 minutes in ambient temperature.Vacuum concentrated mixture, resistates distributes between AcOEt and 1M HCl.With the AcOEt water layer of stripping.The organic layer that merges is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches with AcOEt/ normal hexane=70% through preparation type thin layer silica gel chromatographic purification.With the silica gel of 10%MeOH/CHCl3 extracting and separating, vacuum evaporating solvent.Resistates is through the AcOEt-IPE crystallization, obtains white powder N-(2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin (48.0mg).
mp.96-99℃
IR(KBr)：3205，3140，1612，1502cm-1
MS(ESI+)：m/z 429(M+H)
1H NMR(CDCl3)δ2.20(3H，s)，3.03(3H，s)，3.51-3.60(2H，m)，3.93(3H，s)，4.07-4.13(2H，m)，4.75(1H，t，J＝5.8Hz)，5.15(1H，brs)，5.60(1H，brs)，6.59(1H，s)，6.73(1H，d，J＝8.9Hz)，6.83(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.55(1H，dd，J＝2.6，8.8Hz)，8.09(1H，d，J＝2.6Hz)
Adopt the similar approach of embodiment 451 to obtain following compound.
Embodiment 452
N-(2-{4-[3-{[(dimethylamino) carbonyl] amino }-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Powder: mp.166-167 ℃
IR(KBr)：3309，3188，3182，3174，1657，1651，1643，1568，1514cm-1
Mass spectrum (ESI+): 474 (M+H)+
200MHz 1H NMR(CDCl3，d)：3.02(3H，s)，3.04(6H，s)，3.49-3.57(2H，m)，3.81(3H，s)，4.07(2H，t，J＝5.0Hz)，4.84(1H，t，J＝5.5Hz)，6.78(2H，d，J＝8.9Hz)，6.85(2H，d，J＝9.0Hz)，6.85(1H，s)，7.05(1H，s)，7.15(2H，d，J＝9.0Hz)，7.18(2H，d，J＝8.9Hz)
Embodiment 453
N-(2-{4-[3-[[(dimethylamino) carbonyl] (methyl) amino]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Amorphous substance
IR (pure): 1658,1649,1641,1631,1620,1612,1518,1502cm-1
Mass spectrum (ESI+): 488 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.79(6H，s)，2.94(3H，s)，3.12(3H，s)，3.30-3.34(2H，m)，3.76(3H，s)，4.02(2H，t，J＝5.4Hz)，6.26(1H，s)，6.92(2H，d，J＝8.7Hz)，6.94(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.7Hz)，7.16(2H，d，J＝8.9Hz)，7.29(1H，s)
Embodiment 454
N-(2-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
White powder: mp.112-114 ℃
IR(KBr)：3280，1612cm-1
Mass spectrum (ESI+): 423 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.94(3H，s)，3.29-3.34(2H，m)，3.87(3H，s)，4.03(2H，t，J＝5.4Hz)，6.75(1H，s)，6.89(1H，d，J＝8.8Hz)，6.96(2H，d，J＝8.7Hz)，7.20(2H，d，J＝8.7Hz)，7.29(1H，brs)，7.67(1H，dd，J＝2.7，8.8Hz)，8.11(1H，d，J＝2.7Hz)
Embodiment 455
N-(2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.103-104℃
IR(KBr)：3271，1612，1579，1560，1520，1514cm-1
Mass spectrum (ESI+): 418 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.94(3H，s)，3.28-3.33(2H，m)，3.76(3H，s)，3.83(3H，s)，3.98-4.05(2H，m)，6.05(1H，s)，6.88-6.96(4H，m)，7.09-7.17(4H，m)，7.27(1H，s)
Embodiment 456
N-(2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) ethyl sulfonamide
White powder: mp.117.8-118.0 ℃
IR(KBr)：3269，1612，1552，1520cm-1
Mass spectrum (ESI+): 432 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.18(3H，t，J＝7.3Hz)，3.04(2H，q，J＝7.3Hz)，3.26-3.34(2H，m)，3.75(3H，s)，3.83(3H，s)，3.96-4.03(2H，m)，6.05(1H，s)，6.91(2H，d，J＝8.9Hz)，6.92(2H，d，J＝9.0Hz)，7.09-7.17(4H，m)，7.32(1H，brs)
Embodiment 457
N-(2-{4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
White powder: mp.146-147 ℃
IR(KBr)：3130，1612，1518cm-1
Mass spectrum (ESI+): 432 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，2.94(3H，s)，3.27-3.36(2H，m)，3.75(3H，s)，3.98-4.05(2H，m)，4.17(2H，q，J＝7.0Hz)，6.03(1H，s)，6.91(2H，d，J＝8.8Hz)，6.92(2H，d，J＝9.0Hz)，7.12(2H，d，J＝9.0Hz)，7.14(2H，d，J＝8.8Hz)，7.29(1H，t，J＝5.8Hz)
Embodiment 458
N-(2-{4-[3-isobutoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
White powder: mp.164.3-165.2 ℃
IR(KBr)：3140，2952，2933，2870，1614，1518cm-1
Mass spectrum (ESI+): 460 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：0.97(6H，d，J＝6.8Hz)，2.03(1H，m)，2.94(3H，s)，3.27-3.36(2H，m)，3.75(3H，s)，3.90(2H，d，J＝6.6Hz)，3.99-4.05(2H，m)，6.05(1H，s)，6.88-6.96(4H，m)，7.12(2H，d，J＝9.0Hz)，7.14(2H，d，J＝8.8Hz)，7.28(1H，t，J＝5.8Hz)
Embodiment 459
N-(2-{4-[3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
White powder: mp.94.5-94.7 ℃
IR(KBr)：3319，2933，2891，1612，1520cm-1
Mass spectrum (ESI+): 462 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.94(3H，s)，3.29-3.35(2H，m)，3.30(3H，s)，3.62-3.67(2H，m)，3.75(3H，s)，3.98-4.05(2H，m)，4.22-4.27(2H，m)，6.05(1H，s)，6.89-6.95(4H，m)，7.10-7.17(4H，m)，7.28(1H，s)
Embodiment 460
N-(2-{4-[3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
White powder: mp.116.3-116.4 ℃
IR(KBr)：3141，2873，1612，1518cm-1
Mass spectrum (ESI+): 476 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.13(3H，t，J＝7.0Hz)，2.94(3H，s)，3.28-3.40(2H，m)，3.49(2H，q，J＝7.0Hz)，3.66-3.71(2H，m)，3.75(3H，s)，3.98-4.05(2H，m)，4.21-4.26(2H，m)，6.06(1H，s)，6.89-6.95(4H，m)，7.09-7.17(4H，m)，7.29(1H，brs)
Embodiment 461
N-(2-{4-[3-methoxyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.116-117.5℃
IR(KBr)：3126，1614，1520，1500cm-1
MS(ESI+)：m/z 419(M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.94(3H，s)，3.28-3.36(2H，m)，3.85(3H，s)，4.00-4.06(2H，m)，6.11(1H，s)，6.85(1H，d，J＝8.9Hz)，6.94(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.8Hz)，7.29(1H，s)，7.60(1H，dd，J＝2.6，8.9Hz)，8.00(1H，d，J＝2.6Hz)
Embodiment 462
N-(2-{4-[3-oxyethyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
White powder: mp.122.0-122.6 ℃
IR(KBr)：3242，1614，1518，1502cm-1
MS(ESI+)：m/z 433(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，2.94(3H，s)，3.29-3.35(2H，m)，3.84(3H，s)，4.00-4.06(2H，m)，4.19(2H，q，J＝7.0Hz)，6.10(1H，s)，6.85(1H，d，J＝8.8Hz)，6.94(2H，d，J＝8.7Hz)，7.18(2H，d，J＝8.7Hz)，7.29(1H，brs)，7.59(1H，dd，J＝2.7，8.8Hz)，7.99(1H，d，J＝2.7Hz)
Embodiment 463
N-(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Mass spectrum (ESI+): m/z=492.1 (M+Na).
1HNMR(400MHz，CDCl3)：2.15(3H，s)，3.03(3H，s)，3.53-3.57(2H，m)，
3.79(3H，s)，4.11(2H，t，J＝5.0Hz)，4.78(1H，t，J＝6.0Hz)，
6.81(2H，d，J＝9.0Hz)，6.86(2H，d，J＝8.8Hz)，7.08(2H，d，J＝8.8Hz)，7.13(2H，d，J＝9.0Hz).
Embodiment 464
N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio group) phenyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] Toluidrin
mp：122.7-122.8℃.
Mass spectrum (ESI+): m/z=476.1 (M+Na).
1HNMR(400MHz，CDCl3)：2.49(3H，s)，3.03(3H，s)，3.55(2H，dt，J＝4.9，6Hz)，4.1(2H，t，J＝4.9Hz)，4.8(1H，t，J＝6Hz)，6.66(1H，s)，6.76(1H，t，J＝55Hz)，6.83(2H，d，J＝8.8Hz)，7.16(2H，d，J＝8.8Hz)，7.22(4H，s).
Embodiment 465
N-{4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
Crystal.mp：125-126℃
Mass spectrum (ESI+): 449.0 (M+Na).
1HNMR(400MHz，CDCl3)：2.91(3H，s)，3.94(3H，s)，4.34(2H，d，J＝6.2Hz)，4.74(1H，t，J＝6.2Hz)，6.74(1H，s)，6.77(1H，d，J＝8.8Hz)，7.24(2H，d，J＝8.3Hz)，7.35(2H，d，J＝8.3Hz)，7.58(1H，dd，J＝2.7，8.8Hz)，8.03(1H，d，J＝2.7Hz).
Embodiment 466
N-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp：125.7-126.1℃
Mass spectrum (ESI+): m/z=431.0 (M+Na).
1HNMR(400MHz，CDCl3)：2.92(3H，s)，3.94(3H，s)，4.33(2H，d，J＝6.1Hz)，4.73(1H，b.s)，6.74(1H，s)，6.77(1H，t，J＝55Hz)，7.24(2H，d，J＝8.8Hz)，7.25(1H，d，J＝7.9Hz)，7.34(2H，d，J＝7.9Hz)，7.55(1H，dd，J＝2.3，8.8Hz)，8.03(1H，d，J＝2.3Hz).
Embodiment 467
N-(2-{4-[3-cyclopropyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.95-97℃
MS(ESI+)：m/z 429(M+H)
1HNMR(200MHz，)：0.70-0.78(2H，m)，0.87-0.98(2H，m)，1.87-1.99(1H，m)，2.94(3H，s)，3.20-3.52(2H，m)，3.85(3H，s)，3.99-4.05(2H，m)，6.30(1H，s)，6.85(1H，d，J＝8.8Hz)，6.93(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.7Hz)，7.27(1H，brs)，7.59(1H，dd，J＝2.7，8.8Hz)，8.00(1H，d，J＝2.7Hz)
Embodiment 468
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.149.1-150.3℃
Mass spectrum (ESI+): 499 (M+H)
1HNMR(200MHz，DMSOd6)：1.43-1.74(6H，m)，2.94(3H，s)，3.25-3.39(2H，m)，3.52-3.70(2H，m)，3.77-3.92(2H，m)，3.78(3H，s)，3.99-4.06(2H，m)，6.78(1H，s)，6.93(2H，d，J＝8.9Hz)，6.98(2H，d，J＝8.9Hz)，7.18(2H，d，J＝8.9Hz)，7.23(2H，d，J＝8.9Hz)，7.27(1H，brs)
Embodiment 469
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.158.8-159.1℃
Mass spectrum (ESI+): m/z 500 (M+H)
1HNMR(200MHz，DMSOd6)：1.43-1.74(6H，m)，2.94(3H，s)，3.22-3.40(2H，m)，3.52-3.69(2H，m)，3.75-3.91(2H，m)，3.87(3H，s)，4.00-4.07(2H，m)，6.82(1H，s)，6.90(1H，d，J＝8.8Hz)，6.96(2H，d，J＝8.8Hz)，7.22(2H，d，J＝8.8Hz)，7.28(1H，brs)，7.68(1H，dd，J＝2.7，8.8Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 470
N-ethyl-1-(4-p-methoxy-phenyl)-N-methyl-5-(4-{2-[(methylsulfonyl) amino] oxyethyl group } phenyl)-the 1H-pyrazole-3-formamide
mp.106.0-106.3℃
Mass spectrum (ESI+): m/z 473 (M+H)
1HNMR(200MHz，DMSOd6)：1.08-1.22(3H，m)，2.94(3H，s)，2.97，3.29(3H，s)，3.28-3.35(2H，m)，3.42-3.53，3.67-3.79(2H，m)，3.78(3H，s)，3.99-4.06(2H，m)，6.79，6.81(1H，s)，6.93(2H，d，J＝8.9Hz)，6.98(2H，d，J＝9Hz)，7.15-7.26(4H，m)，7.28(1H，brs)
Embodiment 471
N-ethyl-1-(6-methoxyl group-3-pyridyl)-N-methyl-5-(4-{2-[(methylsulfonyl) amino] oxyethyl group } phenyl)-the 1H-pyrazole-3-formamide
mp.110-111℃
Mass spectrum (ESI+): m/z 474 (M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.23(3H，m)，2.94(3H，s)，2.98，3.28(3H，s)，3.28-3.36(2H，m)，3.42-3.55，3.66-3.78(2H，m)，3.87(3H，s)，4.01-4.07(2H，m)，6.83，6.85(1H，s)，6.90(1H，d，J＝9.0Hz)，6.96(2H，d，J＝8.7Hz)，7.22(2H，d，J＝8.7Hz)，7.28(1H，brs)，7.61-7.75(1H，m)，8.14-8.16(1H，m)
Embodiment 472
N-(2-{4-[3-isobutyryl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.155.6-155.8℃
MS(ESI+)：m/z 459(M+H)
1HNMR(200MHz，DMSOd6)：1.16(6H，d，J＝6.9Hz)，2.94(3H，s)，3.25-3.40(2H，m)，3.68(1H，m)，3.88(3H，s)，4.01-4.07(2H，m)，6.93(1H，d，J＝8.7Hz)，6.96(2H，d，J＝8.7Hz)，7.02(1H，s)，7.23(2H，d，J＝8.7Hz)，7.28(1H，brs)，7.74(1H，dd，J＝2.7，8.7Hz)，8.18(1H，d，J＝2.7Hz)
Embodiment 473
N-(2-{4-[3-(cyclopentyloxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Oily matter
MS(ESI+)：m/z 473(M+H)
1HNMR(200MHz，DMSOd6)：1.51-2.00(8H，m)，2.94(3H，s)，3.24-3.39(2H，m)，3.84(3H，s)，4-4.06(2H，m)，4.98(1H，m)，6.07(1H，s)，6.84(1H，d，J＝8.8Hz)，6.94(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.8Hz)，7.28(1H，brs)，7.58(1H，dd，J＝2.7，8.8Hz)，7.99(1H，d，J＝2.7Hz)
Embodiment 474
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.131.3-131.4℃
MS(ESI+)：m/z 486(M+H)
1HNMR(200MHz，DMSOd6)：2.94(3H，s)，3.25-3.39(2H，m)，3.76(3H，s)，3.99-4.05(2H，m)，4.81(1H，d，J＝9.0Hz)，4.90(1H，d，J＝9.0Hz)，6.22(1H，s)，6.90-6.98(4H，m)，7.11-7.18(4H，m)，7.28(1H，brs)
Embodiment 475
N-(2-{4-[3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.145.0-145.1℃
MS(ESI+)：m/z 468(M+H)
1HNMR(200MHz，DMSOd6)：2.93(3H，s)，3.28-3.34(2H，m)，3.76(3H，s)，3.99-4.05(2H，m)，4.44(2H，dt，J＝3.5，14.9Hz)，6.15(1H，s)，6.41(1H，tt，J＝3.5，54.6Hz)，6.92(2H，d，J＝9.0Hz)，6.93(2H，d，J＝9.0Hz)，7.11-7.18(4H，m)，7.27(1H，brs)
Embodiment 476
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Oily matter
MS(ESI+)：m/z 487(M+H)
1HNMR(200MHz，DMSOd6)：2.94(3H，s)，3.29-3.35(2H，m)，3.85(3H，s)，4.00-4.06(2H，m)，4.83(1H，d，J＝9.0Hz)，4.92(1H，d，J＝9.0Hz)，6.28(1H，s)，6.87(1H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，7.19(2H，d，J＝8.8Hz)，7.28(1H，brs)，7.61(1H，dd，J＝2.7，8.9Hz)，8.03(1H，d，J＝2.7Hz)
Embodiment 477
N-(2-{4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Solid
MS(ESI+)：m/z 469(M+H)
1HNMR(200MHz，CDCl3)：3.03(3H，s)，3.51-3.60(2H，m)，3.92(3H，s)，4.07-4.13(2H，m)，4.46(2H，dt，J＝4.2，13.4Hz)，4.76(1H，t，J＝6Hz)，5.95(1H，s)，6.17(1H，tt，J＝4.2，55.4Hz)，6.72(1H，d，J＝8.8Hz)，6.83(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.49(1H，dd，J＝2.8，8.8Hz)，8.01(1H，d，J＝2.8Hz)
Embodiment 478
N-(2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl)-2-hydroxyl ethyl sulfonamide
mp.139.1-139.4℃
MS(ESI+)：m/z 452(M+H)
1HNMR(200MHz，DMSOd6)：3.18-3.35(4H，m)，3.69-3.77(2H，m)，3.78(3H，s)，3.97-4.04(2H，m)，4.90(1H，t，J＝5.6Hz)，6.69(1H，s)，6.90-7.01(4H，m)，7.14-7.26(5H，m)
Embodiment 479
N-(2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
Oily matter
Mass spectrum (ESI+): m/z 439 (M+H)
1HNMR(200MHz，CDCl3)：3.03(3H，s)，3.51-3.60(2H，m)，3.94(3H，s)，4.08-4.14(2H，m)，4.75(1H，t，J＝5.6Hz)，6.68(1H，s)，6.75(1H，d，J＝8.9Hz)，6.76(1H，t，J＝55Hz)，6.85(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.53(1H，dd，J＝2.7，8.9Hz)，8.08(1H，d，J＝2.7Hz)
Embodiment 480
N-{4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.179.3-179.6℃
MS(ESI+)：m/z 469(M+H)
1HNMR(200MHz，DMSOd6)：1.42-1.72(6H，m)，2.85(3H，s)，3.52-3.69(2H，m)，3.75-3.92(2H，m)，3.78(3H，s)，4.15(2H，s)，6.85(1H，s)，6.98(2H，d，J＝9Hz)，7.21-7.35(6H，m)，7.58(1H，brs)
Embodiment 481
N-ethyl-1-(4-p-methoxy-phenyl)-N-methyl-5-(4-{[(methylsulfonyl) amino] methyl } phenyl)-the 1H-pyrazole-3-formamide
mp.149.8-150.8℃
MS(ESI+)：m/z 443(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.21(3H，m)，2.86(3H，s)，2.98，3.29(3H，s)，3.40-3.78(2H，m)，3.78(3H，s)，4.13-4.17(2H，m)，6.86，6.88(1H，s)，6.98(2H，d，J＝9Hz)，7.21-7.35(6H，m)，7.58(1H，brs)
Embodiment 482
N-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.130.9-131.0℃
MS(ESI+)：m/z 400(M+H)
1HNMR(200MHz，DMSOd6)：1.27(6H，d，J＝6.9Hz)，2.84(3H，s)，2.96(1H，m)，3.76(3H，s)，4.14(2H，s)，6.47(1H，s)，6.93(2H，d，J＝8.9Hz)，7.11-7.21(4H，m)，7.30(2H，d，J＝8.2Hz)，7.56(1H，brs)
Embodiment 483
N-{4-[3-isobutyryl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.155.8-155.9℃
MS(ESI+)：m/z 428(M+H)
1HNMR(200MHz，)：1.16(6H，d，J＝6.9Hz)，2.86(3H，s)，3.68(1H，m)，3.79(3H，s)，4.15(2H，s)，7.00(2H，d，J＝8.9Hz)，7.06(1H，s)，7.22-7.35(6H，m)，7.58(1H，s)
Embodiment 484
N-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.182.6-182.9℃
MS(ESI+)：m/z 470(M+H)
1HNMR(200MHz，DMSOd6)：1.42-1.72(6H，m)，2.86(3H，s)，3.53-3.69(2H，m)，3.75-3.9(2H，m)，3.87(3H，s)，4.16(2H，s)，6.89(1H，s)，6.90(1H，d，J＝8.8Hz)，7.28(2H，d，J＝8.4Hz)，7.36(2H，d，J＝8.4Hz)，7.59(1H，s)，7.70(1H，dd，J＝2.7，8.8Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 485
N-ethyl-1-(6-methoxyl group-3-pyridyl)-N-methyl-5-(4-{[(methylsulfonyl) amino] methyl } phenyl)-the 1H-pyrazole-3-formamide
White powder
MS(ESI+)：m/z 444(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.23(3H，m)，2.86(3H，s)，2.98，3.29(3H，s)，3.49，3.72(2H，q，J＝7.1Hz)，3.87(3H，s)，4.16(2H，s)，6.88-6.93(2H，m)，7.28(2H，d，J＝8.3Hz)，7.36(2H，d，J＝8.3Hz)，7.56(1H，brs)，7.65-7.74(1H，m)，8.13-8.14(1H，m)
Embodiment 486
N-{4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin oily matter
MS(ESI+)：m/z 401(M+H)
1HNMR(200MHz，CDCl3)：1.34(6H，d，J＝6.9Hz)，2.86(3H，s)，3.03(1H，m)，3.90(3H，s)，4.28(2H，d，J＝6.1Hz)，5.19(1H，t，J＝6.1Hz)，6.34(1H，s)，6.72(1H，d，J＝8.8Hz)，7.21(2H，d，J＝8.2Hz)，7.29(2H，d，J＝8.2Hz)，7.56(1H，dd，J＝2.7，8.8Hz)，7.98(1H，d，J＝2.7Hz)
Embodiment 487
N-{4-[3-isobutyryl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.160.8-161.2℃
MS(ESI+)：m/z 429(M+H)
1HNMR(200MHz，DMSOd6)：1.16(6H，d，J＝6.8Hz)，2.86(3H，s)，3.68(1H，m)，3.88(3H，s)，4.16(2H，d，J＝5.5Hz)，6.93(1H，d，J＝8.8Hz)，7.09(1H，s)，7.29(2H，d，J＝8.3Hz)，7.36(2H，d，J＝8.3Hz)，7.59(1H，t，J＝5.5Hz)，7.76(1H，dd，J＝2.8，8.8Hz)，8.18(1H，d，J＝2.7Hz)
Embodiment 488
N-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.94.0-94.3℃
MS(ESI+)：m/z 388(M+H)
1HNMR(200MHz，DMSOd6)：2.85(3H，s)，3.76(3H，s)，3.84(3H，s)，4.14(2H，s)，6.12(1H，s)，6.92(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.20(2H，d，J＝8.2Hz)，7.30(2H，d，J＝8.2Hz)，7.57(1H，s)
Embodiment 489
N-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } the Toluidrin amorphous substance
MS(ESI+)：m/z 416(M+H)
1HNMR(200MHz，DMSOd6)：1.32(6H，d，J＝6.1Hz)，2.85(3H，s)，3.75(3H，s)，4.14(2H，s)，4.77(1H，m)，6.07(1H，s)，6.91(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.9Hz)，7.19(2H，d，J＝8.2Hz)，7.30(2H，d，J＝8.2Hz)，7.57(1H，brs)
Embodiment 490
N-{4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.130-131℃
Mass spectrum (ESI+): 457 (M+H)
1HNMR(200MHz，CDCl3)：2.92(3H，s)，3.93(3H，s)，4.33(2H，d，J＝6.0Hz)，4.54-4.71(1H，m)，4.62(1H，d，J＝8.4Hz)，4.70(1H，d，J＝8.4Hz)，6.04(1H，s)，6.73(1H，d，J＝8.8Hz)，7.22(2H，d，J＝8.3Hz)，7.33(2H，d，J＝8.3Hz)，7.52(1H，dd，J＝2.7，8.8Hz)，7.95(1H，d，J＝2.7Hz)
Embodiment 491
N-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin
mp.68.3-69.3℃
Mass spectrum (ESI+): 392 (M+H)
1HNMR(200MHz，DMSOd6)：2.85(3H，s)，3.77(3H，s)，4.14(2H，s)，6.76(1H，s)，6.96(2H，d，J＝8.9Hz)，7.17-7.24(4H，m)，7.32(2H，d，J＝8.2Hz)，7.58(1H，s)
Embodiment 492
N-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin oily matter
Mass spectrum (ESI+): 393 (M+H)
1HNMR(200MHz，DMSOd6)：2.86(3H，s)，3.86(3H，s)，4.16(2H，s)，6.82(1H，s)，6.89(1H，d，J＝8.8Hz)，7.26(2H，d，J＝8.3Hz)，7.35(2H，d，J＝8.3Hz)，7.59(1H，brs)，7.69(1H，dd，J＝2.7，8.8Hz)，8.1(1H，d，J＝2.7Hz)
Embodiment 493
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin
mp.165.0-166.0℃
MS(ESI+)：m/z 434(M+H)
1HNMR(200MHz，DMSOd6)：2.51(3H，s)，2.94(3H，s)，3.27-3.36(2H，m)，3.77(3H，s)，3.99-4.05(2H，m)，6.56(1H，s)，6.92(2H，d，J＝8.8Hz)，6.95(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.9Hz)，7.27(1H，t，J＝5.8Hz)
Embodiment 494
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl) benzsulfamide
Amorphous powder
Mass spectrum (ESI+): 503 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.64-2.72(2H，m)，2.91-3.02(2H，m)，3.88(3H，s)，6.91(1H，d，J＝9.0Hz)，7.03-7.21(5H，m)，7.56-7.80(7H，m)，8.18(1H，d，J＝2.6Hz)
Embodiment 495
N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl-5-(4-{2-[(methylsulfonyl) amino] ethyl } phenyl)-the 1H-pyrazole-3-formamide
Oily matter
Mass spectrum (ESI+): m/z 459 (M+H)
1HNMR(200MHz，CDCl3)：2.84-2.91(2H，m)，2.87(3H，s)，3.35-3.46(2H，m)，3.51(3H，s)，3.83(3H，s)，3.85(3H，s)，4.26(1H，t，J＝6.2Hz)，6.86(2H，d，J＝9.0Hz)，6.97(1H，s)，7.12-7.29(6H，m)
Embodiment 496
N-methoxyl group-1-(6-methoxyl group-3-pyridyl)-N-methyl-5-(4-{2-[(methylsulfonyl) amino] ethyl } phenyl)-the 1H-pyrazole-3-formamide
Oily matter
Mass spectrum (ESI+): m/z 460 (M+H)
1HNMR(200MHz，CDCl3)：2.80-2.93(2H，m)，2.88(3H，s)，3.36-3.47(2H，m)，3.50(3H，s)，3.85(3H，s)，3.94(3H，s)，4.28(1H，t，J＝6.2Hz)，6.75(1H，d，J＝8.8Hz)，6.98(1H，s)，7.20(4H，s)，7.56(1H，dd，J＝2.7，8.8Hz)，8.10(1H，d，J＝2.7Hz)
Embodiment 497
Isocyanic acid trimethyl silyl ester (73.8 μ l) is added the solution of (2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine dihydrochloride (115.4mg) and Et3N (114 μ l), stirred the mixture 1.5 hours in ambient temperature.Vacuum concentrated mixture, resistates distributes between AcOEt and 1M HCl.Water layer is stripped through AcOEt.The organic layer that merges is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches by 10%MeOH/CHCl3 through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts through 10%MeOH/CHCl3, vacuum evaporating solvent.Resistates is through the AcOEt-IPE crystallization, obtains white powder N-(2-{4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (40.1mg).
White powder: mp.94-98 ℃
IR(KBr)：3435，3388，3344，3333，1657，1631，1610，1577，1572，1562，1552，1502cm-1
1H NMR(DMSO-d6)δ2.10(3H，s)，3.28-3.27(2H，m)，3.86(3H，s)，3.91-3.97(2H，m)，5.15(1H，brs)，5.53(2H，s)，5.62(1H，brs)，6.16(1H，t，J＝5.5Hz)，6.84(1H，s)，6.88(1H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，7.19(2H，d，J＝8.8Hz)，7.64(1H，dd，J＝2.7，8.8Hz)，8.07(1H，d，J＝2.7Hz)
Following compounds obtains by the similar approach of embodiment 497.
Embodiment 498
N-(2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.108-111℃
IR(KBr)：3388，3342，1657，1631，1612，1593，1577，1562，1522cm-1
Mass spectrum (ESI+): 383 (M+H)+
200MHz 1H NMR(CDCl3，d)：3.54-3.62(2H，m)，3.79(3H，s)，3.96(3H，s)，3.98-4.04(2H，m)，4.44(2H，s)，5.03(1H，t，J＝5.5Hz)，5.88(1H，s)，6.78(2H，d，J＝8.8Hz)，6.82(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.8Hz)，7.16(2H，d，J＝8.9Hz)
Embodiment 499
N-(2-{4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
White powder: mp.154.2-154.4 ℃
IR(KBr)：3398，3332，1658，1631，1612，1566，1518cm-1
Mass spectrum (ESI+): 397 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，3.27-3.34(2H，m)，3.75(3H，s)，3.89-3.96(2H，m)，4.17(2H，q，J＝7.0Hz)，5.53(2H，s)，6.03(1H，s)，6.15(1H，t，J＝5.6Hz)，6.90(2H，d，J＝8.9Hz)，6.92(2H，d，J＝9.0Hz)，7.10-7.15(4H，m)
Embodiment 500
Imidazoles (680mg) and tert-butyldimethylsilyl chloride (903mg) are added 5-[4-{2-(hydroxyl) oxyethyl group successively under the ice bath cooling } phenyl]-DMF (15ml) solution of 1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (1.91g).After ambient temperature stirs 2 hours, mixture is distributed between AcOEt and H2O.Organic layer is through H2O and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Collect remaining crystal, with the normal hexane washing, acquisition 5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } oxyethyl group) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (2.34g).
Powder
mp.86-87℃
MS(ESI+)：m/z 497(M+H)
1H NMR(CDCl3)δ0.09(6H，s)，0.90(9H，s)，1.42(3H，t，J＝7.1Hz)，3.82(3H，s)，3.94-3.97(2H，m)，4.01-4.04(2H，m)，4.44(2H，q，J＝7.1Hz)，6.83(2H，d，J＝8.7Hz)，6.85(2H，d，J＝8.9Hz)，6.96(1H，s)，7.11(2H，d，J＝8.7Hz)，7.24(2H，d，J＝8.9Hz)
Embodiment 501
With 5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } oxyethyl group) phenyl]-THF (3ml) solution of 1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (0.3g) is added dropwise to 1M methyl-magnesium-bromide solution (3ml) in ambient temperature.Reaction mixture was stirred 1 hour in ambient temperature, pour into then in the mixture of trash ice and saturated aqueous ammonium chloride.Extract mixture with AcOEt.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates, acquisition oily 2-[5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } oxyethyl group) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-2-propyl alcohol (0.27g).
Oily matter
MS(ESI+)：m/z 483(M+H)
1H NMR(CDCl3)δ0.09(6H，s)，0.90(9H，s)，1.65(6H，s)，3.81(3H，s)，3.94-3.97(2H，m)，4.01-4.04(2H，m)，6.35(1H，s)，6.82(2H，d，J＝8.8Hz)，6.85(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.9Hz)
Following compound adopts the similar approach of embodiment 501 to obtain.
Embodiment 502
N-(2-{4-[3-(1-hydroxyl-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
White powder: mp.147-152 ℃
IR(KBr)：3333，3271，2976，1676，1664，1658，1612，1547，1537，1516，1502cm-1
MS(ESI+)：m/z 411(M+H)
1H NMR(DMSO-d6)δ1.48(6H，s)，3.22-3.40(2H，m)，3.76(3H，s)，3.90-3.96(2H，m)，4.98(1H，s)，5.52(2H，s)，6.14(1H，t，J＝5.6Hz)，6.49(1H，s)，6.90(2H，d，J＝8.7Hz)，6.94(2H，d，J＝8.8Hz)，7.12(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.8Hz)
Embodiment 503
4-[3-(1-hydroxyl-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Powder
MS(ESI+)：m/z 438(M+H)
1HNMR(200MHz，DMSOd6)：1.39(9H，s)，1.49(6H，s)，3.76(3H，s)，4.11(2H，d，J＝6.1Hz)，5.01(1H，s)，6.54(1H，s)，6.94(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)，7.17(4H，brs)，7.4(1H，t，J＝6.1Hz)
Embodiment 504
4-[3-(1-hydroxyl-1-methylethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Powder
MS(ESI+)：m/z 439(M+H)
1HNMR(200MHz，DMSOd6)：1.39(9H，s)，1.49(6H，s)，3.85(3H，s)，4.12(2H，d，J＝6.1Hz)，5.05(1H，s)，6.59(1H，s)，6.86(1H，d，J＝8.8Hz)，7.20(4H，s)，7.40(1H，t，J＝6.1Hz)，7.62(1H，dd，J＝2.7，8.8Hz)，8.00(1H，d，J＝2.7Hz)
Embodiment 505
With 2-[5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } oxyethyl group) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-DMF (2ml) solution of 2-propyl alcohol (180mg) is added dropwise to the suspension of 60% sodium hydride mineral oil dispersion liquid (17mg) in DMF (1ml) under the ice bath cooling.After 10 minutes, add methyl iodide (63.5mg), stirred 1 hour in ambient temperature after 1 hour in stirred reaction mixture under the uniform temp.Add methyl iodide again up to consuming whole starting raw materials, add saturated ammonium chloride solution quencher reaction.Use the ethyl acetate extraction mixture.Organic layer is through H2O and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane wash-out, polarity changes gradually from 20%-80%, acquisition oily 5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } oxyethyl group) phenyl]-3-(1-methoxyl group-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles (32.2mg).
Mass spectrum (ESI+): 497 (M+H)
1H NMR(CDCl3)δ0.09(6H，s)，0.90(9H，s)，1.58(3H，s)，1.63(3H，s)，3.22(3H，s)，3.81(3H，s)，3.93-4.04(4H，m)，6.42(1H，s)，6.82(2H，d，J＝8.8Hz)，6.84(2H，d，J＝9.0Hz)，7.13(2H，d，J＝8.8Hz)，7.22(2H，d，J＝9.0Hz)
Embodiment 506
THF (0.24ml) solution of 1M tetra-n-butyl Neutral ammonium fluoride is added 5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } oxyethyl group) phenyl under the ice bath cooling]-THF (2ml) solution of 3-(1-methoxyl group-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles (98mg).Reaction mixture was stirred 1 hour down in uniform temp.Mixture distributes between ethyl acetate and H2O.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches by the 50%AcOEt/ normal hexane through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts through 10%MeOH/CHCl3, and vacuum evaporating solvent obtains oily 2-{4-[3-(1-methoxyl group-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol (66mg).
IR (pure): 3423,3398,3371,2976,2935,1647,1612,1566,1549,1512cm-1
MS(ESI+)：m/z 383(M+H)
1H NMR(CDCl3)δ1.60(3H，s)，1.63(3H，s)，2.03(1H，t，J＝6.1Hz)，3.22(3H，s)，3.81(3H，s)，3.91-4.00(2H，m)，4.05-4.10(2H，m)，6.43(1H，s)，6.83(2H，d，J＝8.9Hz)，6.84(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)，7.21(2H，d，J＝8.9Hz)
Embodiment 507
Dioxane (2ml) solution of 4M HCl is added 5-(4-{2-[(tert-butoxycarbonyl) amino under the ice bath cooling] oxyethyl group } phenyl)-CH2Cl2 (3ml) solution of 1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (300mg).After ambient temperature stirs 1 hour, the vacuum concentration reaction mixture.Resistates is dissolved in CH2Cl2 (3ml), adds Et3N (189mg) and isocyanic acid trimethyl silyl ester (108mg), mixture stirs in ambient temperature and spends the night.Restir 4 hours adds isocyanic acid trimethyl silyl ester and Et3N again to consume all starting raw materials.Vacuum concentrated mixture, resistates distributes between ethyl acetate and 1M HCl.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Remaining crystal is suspended in hot ethyl acetate, and cooling is also stirred, and collects the back with the ethyl acetate washing, obtains white powder 5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (217mg).
MS(ESI+)：m/z 425(M+H)
1H NMR(DMSO-d6)δ1.31(3H，t，J＝7.1Hz)，3.27-3.36(2H，m)，3.79(3H，s)，3.90-3.96(2H，m)，4.32(2H，q，J＝7.1Hz)，5.52(2H，s)，6.14(1H，t，J＝5.7Hz)，6.92(2H，d，J＝8.8Hz)，6.99(2H，d，J＝8.8Hz)，7.01(1H，s)，7.17(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.8Hz)
Embodiment 508
1M NaOH (5ml) is added 5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-THF (15ml) and MeOH (10ml) solution of 1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (1.75g).Reaction mixture is stirred vacuum concentration in ambient temperature.Resistates is dissolved in H2O,, successively with H2O and IPE washing, obtains white powder 5-(4-{2-[(aminocarboxyl) amino behind the collection white precipitate with 1M HCl acidifying] oxyethyl group } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid (1.58g).
MS(ESI+)：m/z 397(M+H)
1H NMR(DMSO-d6)δ3.15-3.55(2H，m)，3.90-3.97(2H，m)，5.52(2H，s)，6.14(1H，t，J＝5.7Hz)，6.89-7.03(5H，m)，7.17(2H，d，J＝8.8Hz)，7.24(2H，d，J＝8.9Hz)
Following compound obtains by the similar approach of embodiment 508.
Embodiment 509
5-(4-{[(tert-butoxycarbonyl) amino] methyl } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid
White powder
MS(ESI+)：m/z 424(M+H)
1HNMR(200MHz，DMSOd6)：1.38(9H，s)，3.79(3H，s)，4.11(2H，d，J＝6.1Hz)，6.99(2H，d，J＝8.9Hz)，7.01(1H，s)，7.20(4H，brs)，7.25(2H，d，J＝8.9Hz)，7.41(1H，t，J＝6.1Hz)，12.92(1H，brs)
Embodiment 510
5-(4-{[(tert-butoxycarbonyl) amino] methyl } phenyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-carboxylic acid
Powder
MS(ESI+)：m/z 425(M+H)
1HNMR(200MHz，CDCl3)：1.46(9H，s)，3.95(3H，s)，4.33(2H，d，J＝5.9Hz)，4.9(1H，brs)，6.76(1H，d，J＝8.8Hz)，7.07(1H，s)，7.19(2H，d，J＝8.4Hz)，7.27(2H，d，J＝8.4Hz)，7.58(1H，dd，J＝2.7，8.8Hz)，8.11(1H，d，J＝2.7Hz)
Embodiment 511
With 5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-trimethyl carbinol (5ml) mixture of 1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid (1.56g), two phenoxy group phosphoryl azides (1.62g) and Et3N (597mg) refluxed 3 hours.Vacuum concentrated mixture, resistates distributes between ethyl acetate and H2O.The organic layer that merges is through 1M HCl washed twice.With saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, uses eluent ethyl acetate, obtains amorphous powder [5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] t-butyl carbamate (519mg).
MS(ESI+)：m/z 468(M+H)
1H NMR(DMSO-d6)δ1.46(9H，s)，3.27-3.36(2H，m)，3.76(3H，s)，3.90-3.96(2H，m)，5.52(2H，s)，6.15(1H，t，J＝5.6Hz)，6.55(1H，s)，6.90(2H，d，J＝8.9Hz)，6.93(2H，d，J＝8.9Hz)，7.13(4H，d，J＝8.9Hz)，9.74(1H，s)
Embodiment 512
Dioxane (3ml) solution of 4M HCl is added [5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] CH2Cl2 (3ml) solution of t-butyl carbamate (478mg).Reaction mixture was stirred 5 hours vacuum concentration in ambient temperature.Resistates distributes between CHCl3 and saturated sodium bicarbonate aqueous solution.With the CHCl3 water layer of stripping.The organic layer that merges concentrates through the dried over mgso final vacuum.Resistates is purified through silica gel column chromatography, use CHCl3: MeOH: the 28%NH4OH aqueous solution=10: 1: 0.1 wash-outs, acquisition amorphous powder N-(2-{4-[3-amino-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (244.6mg).
MS(ESI+)：m/z 368(M+H)
IR (pure): 3400,3388,3342,3330,1658,1651,1643,1612,1579,1562,1554,1520cm-1
1H NMR(DMSO-d6)δ3.27-3.37(2H，m)，3.73(3H，s)，3.89-3.95(2H，m)，4.83(2H，s)，5.52(2H，s)，5.73(1H，s)，6.15(1H，t，J＝5.5Hz)，6.85-6.92(4H，m)，7.03-7.12(4H，m)
Embodiment 513
MeOH (2ml) solution that 37% formalin (0.23ml) and sodium cyanoborohydride (53mg) is added N-(2-{4-[3-amino-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (103.1mg).Reaction mixture was stirred 3 hours in ambient temperature.Add 37% formalin (0.23ml) and sodium cyanoborohydride (53mg) to mixture, reaction mixture was stirred 4 days in ambient temperature.Vacuum concentrated mixture, resistates distributes between ethyl acetate and H2O.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates passes through CHCl3: MeOH through preparation type thin layer silica gel chromatographic purification: the 28%NH4OH aqueous solution=launch at 100: 10: 1.With the silica gel of identical solvent extraction and separation, vacuum evaporating solvent, and acquisition amorphous powder N-(2-{4-[3-(dimethylamino)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (59.9mg).
MS(ESI+)：m/z 396(M+H)
1H NMR(DMSO-d6)δ2.81(6H，s)，3.27-3.36(2H，m)，3.74(3H，s)，3.89-3.96(2H，m)，5.52(2H，s)，5.78(1H，s)，6.15(1H，t，J＝5.7Hz)，6.87-6.92(4H，m)，7.05-7.15(4H，m)
Embodiment 514
To 4-[3-(dimethylamino)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] DMF (2ml) solution of phenol (98.7mg) adds 60% sodium hydride mineral oil dispersion liquid (15.3mg).Stirred the mixture 1 hour in ambient temperature.Be added dropwise to the DMF (1ml) that contains (2-bromine oxethyl)-tertiary butyl dimethylsilane (153mg) to reaction mixture, mixture stirs in ambient temperature and spends the night.Pour mixture into frozen water, with the AcOEt extraction, with H2O and saturated sodium-chloride water solution washing.With the AcOEt water layer of stripping.The organic layer that merges concentrates through the dried over mgso final vacuum.Resistates is dissolved in EtOH (2ml).Add concentrated hydrochloric acid (100 μ l) to solution, mixture stirred 3 hours in ambient temperature.Vacuum concentrated mixture, resistates distributes between AcOEt and saturated sodium bicarbonate aqueous solution, and with the saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.Resistates launches by AcOEt/ normal hexane=60% through preparation type thin layer silica gel chromatographic purification.Collect remaining crystal,, obtain white powder 2-{4-[3-(dimethylamino)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl with the IPE washing] phenoxy group } ethanol (97mg).
mp.120-122℃
IR(KBr)：3292，2924，1612，1577，1562，1531，1514cm-1
Mass spectrum (ESI+): 354 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.81(6H，s)，3.66-3.72(2H，m)，3.74(3H，s)，3.94-4.00(2H，m)，4.86(1H，br)，6.02(1H，s)，6.86-6.94(4H，m)，7.10(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.7Hz)
Following compound obtains by the similar approach of embodiment 514.
Embodiment 515
N-[5-[4-(2-hydroxyl-oxethyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N ', N '-trimethyl-urea
Oily matter
IR (pure): 3410,2931,1658,1649,1641,1631,1612,1518,1502cm-1
Mass spectrum (ESI+): 411 (M+H)+
200MHz 1H NMR(CDCl3，d)：2.08(1H，t，J＝5.9Hz)，2.89(6H，s)，3.33(3H，s)，3.81(3H，s)，3.92-4.00(2H，m)，4.05-4.10(2H，m)，6.15(1H，s)，6.84(4H，d，J＝9.1Hz)，7.14(2H，d，J＝9.1Hz)，7.19(2H，d，J＝9.1Hz)
Embodiment 516
2-{4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol white powder: mp.67.7-69.2 ℃
IR(ATR)：3363，2993，2956，2925，2837，1610，1577，1552，1508cm-1
Mass spectrum (ESI+): 355 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.42(3H，t，J＝7.1Hz)，2.01(1H，t，J＝6.0Hz)，3.79(3H，s)，3.92-4.00(2H，m)，4.04-4.10(2H，m)，4.29(2H，q，J＝7.1Hz)，5.87(1H，s)，6.77-6.85(4H，m)，7.14(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.9Hz)
Embodiment 517
2-{4-[3-isobutoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol oily matter
Mass spectrum (ESI+): m/z 383 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.03(6H，d，J＝6.8Hz)，2.02(1H，t，J＝6.1Hz)，2.11(1H，m)，3.79(3H，s)，3.91-4.09(4H，m)，3.99(2H，d，J＝6.8Hz)，5.88(1H，s)，6.77-6.86(4H，m)，7.09-7.21(4H，m)
Embodiment 518
2-{4-[3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Oily matter
Mass spectrum (ESI+): 385 (M+H)+
IR (pure): 3400,3390,3369,2935,1612,1517cm-1
200MHz 1H NMR(DMSO-d6，d)：3.31(3H，s)，3.62-3.73(4H，m)，3.75(3H，s)，3.94-3.99(2H，m)，4.22-4.27(2H，m)，4.85(1H，t，J＝5.5Hz)，6.04(1H，s)，6.89(2H，d，J＝8.8Hz)，6.92(2H，d，J＝8.9Hz)，7.08-7.15(4H，m)
Embodiment 519
2-{4-[3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Oily matter
IR (pure): 2972,2933,2873,1612,15S4,1518,1510cm-1
Mass spectrum (ESI+): 399 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.25(3H，t，J＝7.0Hz)，2.04(1H，t，J＝6.1Hz)，3.61(2H，q，J＝7.0Hz)，3.78-3.83(2H，m)，3.79(3H，s)，3.93-4.00(2H，m)，4.04-4.07(2H，m)，4.38-4.44(2H，m)，5.92(1H，s)，6.82(4H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz)，7.16(2H，d，J＝8.8Hz)
Embodiment 520
2-{[5-[4-(2-hydroxyl-oxethyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] the oxygen base }-N,N-dimethylacetamide
White powder: mp.106.6-107.1 ℃
IR(KBr)：3321，2939，1658，1643，1608，1518cm-1
MS(ESI+)：m/z 412(M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.84(3H，s)，2.97(3H，s)，3.65-3.73(2H，m)，3.75(3H，s)，3.94-4.00(2H，m)，4.87(1H，t，J＝5.1Hz)，4.87(2H，s)，6.07(1H，s)，6.90(2H，d，J＝8.8Hz)，6.92(2H，d，J＝9.0Hz)，7.11(2H，d，J＝9.0Hz)，7.12(2H，d，J＝8.8Hz)
Embodiment 521
2-{4-[3-methoxyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol white powder: mp.92.2-92.5 ℃
IR(KBr)：3325，1614，1525，1504cm-1
MS(ESI+)：m/z 342(M+H)+
200MHz 1H NMR(CDCl3，d)：2.01(1H，t，J＝6.1Hz)，3.92-4.10(4H，m)，3.92(3H，s)，3.97(3H，s)，5.91(1H，s)，6.70(1H，d，J＝8.5Hz)，6.85(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.52(1H，dd，J＝2.5，8.5Hz)，8.04(1H，d，J＝2.5Hz)
Embodiment 522
2-{4-[3-oxyethyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol white powder: mp.81-82 ℃
IR(KBr)：3303，3298，1612，1516cm-1
Mass spectrum (sample ID cox022145) is (ESI+): 356 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，3.65-3.74(2H，m)，3.84(3H，s)，3.95-4.01(2H，m)，4.19(2H，q，J＝7.0Hz)，4.87(1H，t，J＝5.4Hz)，6.09(1H，s)，6.85(1H，d，J＝8.8Hz)，6.93(2H，d，J＝8.8Hz)，7.16(2H，d，J＝8.8Hz)，7.58(1H，d，J＝2.6，8.8Hz)，7.99(1H，d，J＝2.6Hz)
Embodiment 523
The solution that is dissolved in DMF (100ml) to 5-(hydroxyl) phenyl-1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles (5.0g) and 2-bromine oxethyl-tertiary butyl dimethylsilane (6.87g) adds NaH (919mg, 50% oily dispersion liquid) in room temperature in batches.The reaction mixture stirring is spent the night.Water quencher reaction mixture.With twice of EtOAc aqueous layer extracted.The organic layer that merges is through water and salt solution washed twice.Drying is filtered the back reduction vaporization, the 5-[4-of acquisition (5.29g, 73%) (the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } oxyethyl group) phenyl]-1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles.
Mass spectrum (ESI+): m/z=507.1 (M+1), 529.0 (M+Na).
1HNMR(400MHz，CDCl3)：.07(3H，s)，.09(3H，s)，.9(9H，s)，2.15(3H，s)，3.78(3H，s)，3.62-4.13(4H，m)，6.79(2H，d，J＝8.5Hz)，6.88(2H，d，J＝8.7Hz)，7.05(2H，d，J＝8.7Hz)，7.13(2H，d，J＝8.5Hz).
Embodiment 524
2-{4-[1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethanol
mp 50.7-51.7℃
Mass spectrum (ESI+): 409 (M+H)+
1HNMR(200MHz，CDCl3)：1.99(1H，t，J＝6.0Hz)，3.80(3H，s)，3.92-4.00(2H，m)，4.05-4.10(2H，m)，4.62(1H，d，J＝8.5Hz)，4.70(1H，d，J＝8.5Hz)，5.95(1H，s)，6.79-6.92(4H，m)，7.07-7.18(4H，m)
Embodiment 525
2-{4-[3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Oily matter
Mass spectrum (ESI+): 391 (M+H)
1HNMR(200MHz，CDCl3)：1.99(1H，t，J＝6.1Hz)，3.80(3H，s)，3.92-4.00(2H，m)，4.05-4.09(2H，m)，4.47(2H，dt，J＝4.2，13.5Hz)，5.92(1H，s)，6.17(1H，tt，J＝4.2，55.5Hz)，6.79-6.87(4H，m)，7.09-7.20(4H，m)
Embodiment 526
2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethanol
mp.91.2-91.3℃
Mass spectrum (sample ID cox031168) is (ESI+): 410 (M+H)+
1HNMR(200MHz，CDCl3)：1.99(1H，t，J＝6.1Hz)，3.91(3H，s)，3.92-4.01(2H，m)，4.06-4.11(2H，m)，4.61(1H，d，J＝8.4Hz)，4.70(1H，d，J＝8.4Hz)，5.98(1H，s)，6.71(1H，d，J＝8.8Hz)，6.86(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，7.48(1H，dd，J＝2.7，8.8Hz)，8.02(1H，d，J＝2.7Hz)
Embodiment 527
2-{4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
Oily matter
Mass spectrum (ESI+): 392 (M+H)
1HNMR(200MHz，CDCl3)：3.92(3H，s)，3.93-4.00(2H，m)，4.06-4.11(2H，m)，4.46(2H，dt，J＝4.2，13.2Hz)，5.94(1H，s)，6.17(1H，tt，J＝4.2，55.5Hz)，6.71(1H，d，J＝9.0Hz)，6.86(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.48(1H，dd，J＝2.7，9.0Hz)，8.02(1H，d，J＝2.7Hz)
Embodiment 528
Carbonyl dimidazoles (1.26g) is added 5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-3-amino-1H-pyrazoles (2.4g) is dissolved in the solution of 1-Methyl-2-Pyrrolidone (22ml).After ambient temperature stirs 2 hours, add THF (7.4ml) solution of 2M dimethylamine, stirred the mixture 2 hours in ambient temperature.Reaction mixture distributes between ethyl acetate and H2O.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=80% wash-out, obtains amorphous powder N '-[5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (2.35g).
Mass spectrum (ESI+): 443 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.91(6H，s)，3.76(3H，s)，5.09(2H，s)，6.63(1H，s)，6.93(2H，d，J＝9.0Hz)，6.98(2H，d，J＝9.0Hz)，7.14(2H，d，J＝9.0Hz)，7.15(2H，d，J＝9.0Hz)，7.34-7.44(5H，m)，9.02(1H，s)
Embodiment 529
With N '-[5-[4-(hydroxyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (121.9mg), 2-(tertiary butyl-dimetylsilyl oxygen base) monobromoethane (166mg) and the mixture of salt of wormwood (95.6mg) in DMF (1.5ml) stirred 7 hours in 75 ℃.2-(t-butyldimethylsilyl oxygen base) monobromoethane (83mg) and KI (57.4mg) are added reaction mixture, and mixture spends the night in 75 ℃ of stirrings.Cooling mixture distributes between ethyl acetate and H2O to ambient temperature.With the ethyl acetate water layer of stripping.The organic layer that merges washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches with 5%MeOH/CHCl3 through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts through 10%MeOH/CHCl3, and vacuum evaporating solvent obtains amorphous powder N '-[5-[4-(2-hydroxyl-oxethyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (115mg).With amorphous powder 84.3mg AcOEt-IPE crystallization, obtain white powder N '-[5-[4-(2-hydroxyl-oxethyl) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (79.5mg).
mp.167.4-167.6℃
IR(KBr)：3317，1670，1612，1587，1572，1510cm-1
Mass spectrum (ESI+): 397 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.91(6H，s)，3.65-3.74(2H，m)，3.76(3H，s)，3.94-4.00(2H，m)，4.87(1H，t，J＝5.5Hz)，6.62(1H，s)，6.90(2H，d，J＝8.7Hz)，6.93(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.9Hz)，9.02(1H，s)
Embodiment 530
Diethylazodicarboxylate (308mg) is added N '-[5-[4-(hydroxyl)-phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (415mg), N-(2-hydroxyethyl) t-butyl carbamate (380mg) and triphenylphosphine (463mg) are dissolved in the solution of THF (5ml).Spend the night the vacuum concentration reaction mixture in the ambient temperature stirring.Dioxane (5ml) solution that adds 4M HCl to the CH2Cl2 of resistates (5ml) solution.After ambient temperature stirs 1.5 hours, the vacuum concentration reaction mixture.Resistates distributes between AcOEt and 1M HCl.Concentrate with AcOEt reextraction water layer final vacuum.Evaporate remaining H2O with methylbenzene azeotropic, obtain amorphous powder N '-[5-[4-(2-amino ethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea hydrochloride (580mg).
Mass spectrum (ESI+): 396 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.91(6H，s)，3.15-3.24(2H，m)，3.76(3H，s)，4.14-4.21(2H，m)，6.64(1H，s)，6.94(2H，d，J＝8.9Hz)，6.95(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.9Hz)，7.17(2H，d，J＝8.7Hz)，8.20(2H，brs)，9.04(1H，s)
Following compound obtains by the similar approach of embodiment 530.
Embodiment 531
N-[5-[4-(2-amino ethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N ', N '-trimethyl-urea hydrochloride
Amorphous substance
Mass spectrum (ESI+): 410 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.79(6H，s)，3.13(3H，s)，3.14-3.24(2H，m)，3.80(3H，s)，4.15-4.20(2H，m)，6.27(1H，s)，6.94(2H，d，J＝8.6Hz)，6.94(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.9Hz)，7.19(2H，d，J＝8.6Hz)，8.24(2H，brs)
Embodiment 532
2-{[5-[4-(2-amino ethoxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] the oxygen base }-the N,N-dimethylacetamide hydrochloride
Amorphous substance
MS(ESI+)：m/z 411(M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.84(3H，s)，2.97(3H，s)，3.14-3.24(2H，m)，3.76(3H，s)，4.14-4.20(2H，m)，4.88(2H，s)，6.09(1H，s)，6.93(2H，d，J＝9.0Hz)，6.95(2H，d，J＝8.8Hz)，7.07-7.29(4H，m)，8.21(2H，brs)
Embodiment 533
The solution that potassium cyanate (64.9mg) is dissolved in H2O (0.5ml) adds N '-[5-[4-(2-amino ethoxy) phenyl]-1-(4-methoxyl group-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea hydrochloride (172.8mg) and sodium acetate (65.6mg) are dissolved in the solution of mixture D MF (1.5ml) and H2O (0.5ml).Spend the night in the ambient temperature stirred reaction mixture.With H2O diluted mixture thing, between AcOEt and H2O, distribute.Water layer is stripped through AcOEt, saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches with 10%MeOH/CHCl3 through preparation type thin layer silica gel chromatographic purification.With the silica gel of 10%MeOH/CHCl3 extracting and separating, vacuum evaporating solvent.Use the AcOEt-IPE crystalline residue, obtain Powdered N '-[5-(4-{2-[(aminocarboxyl) amino] oxyethyl group phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N-dimethyl urea (87.0mg).
mp.193-196℃
IR(KBr)：3437，3421，1660，1649，1620，1612，1581，1562，1554，1529，1512cm-1
Mass spectrum (ESI+): 439 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.91(6H，s)，3.27-3.34(2H，m)，3.76(3H，s)，3.93(2H，t，J＝5.5Hz)，5.53(2H，s)，6.16(1H，t，J＝5.7Hz)，6.62(1H，s)，6.91(2H，d，J＝8.7Hz)，6.93(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.9Hz)，9.02(1H，s)
Following compound obtains by the similar approach of embodiment 533.
Embodiment 534
N-[5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N ', N '-trimethyl-urea
Powder: mp.158.6-159.0 ℃
IR(KBr)：3433，3369，1687，1658，1643，1612，1514，1500cm-1
Mass spectrum (ESI+): 453 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.79(6H，s)，3.12(3H，s)，3.27-3.34(2H，m)，3.76(3H，s)，3.93(2H，t，J＝5.5Hz)，5.53(2H，s)，6.15(1H，t，J＝5.6Hz)，6.25(1H，s)，6.91(2H，d，J＝8.7Hz)，6.94(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.7Hz)，7.15(2H，d，J＝8.9Hz)
Embodiment 535
N-(2-{4-[3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
White powder: mp.131-132 ℃
IR(KBr)：3435，3429，3388，3350，1658，1612，1562，1554，1518cm-1
Mass spectrum (sample ID cox022116) is (ESI+): 427 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.28-3.38(2H，m)，3.30(3H，s)，3.62-3.68(2H，m)，3.75(3H，s)，3.89-3.96(2H，m)，4.21-4.27(2H，m)，5.S3(2H，s)，6.05(1H，s)，6.15(1H，t，J＝5.7Hz)，6.91(2H，d，J＝8.9Hz)，6.92(2H，d，J＝9.0Hz)，7.10-7.15(4H，m)
Embodiment 536
N-(2-{4-[3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
White powder: mp.124.1-124.2 ℃
IR(KBr)：3388，3379，3340，1657，1643，1612，1562，1554，1518cm-1
Mass spectrum (ESI+): 441 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.13(3H，t，J＝7.0Hz)，3.27-3.36(2H，m)，3.49(2H，q，J＝7.0Hz)，3.66-3.71(2H，m)，3.75(3H，s)，3.89-3.96(2H，m)，4.21-4.26(2H，m)，5.53(2H，s)，6.06(1H，s)，6.15(1H，t，J＝5.7Hz)，6.91(2H，d，J＝8.8Hz)，6.92(2H，d，J＝9.0Hz)，7.10-7.15(4H，m)
Embodiment 537
2-{[5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] the oxygen base }-N,N-dimethylacetamide
White powder: mp.223-227 ℃
IR(KBr)：3402，3332，3201，3194，2925，1664，1612，1518，1502cm-1
MS(ESI+)：m/z 454(M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.84(3H，s)，2.97(3H，s)，3.27-3.35(2H，m)，3.75(3H，s)，3.89-3.96(2H，m)，4.87(2H，s)，5.53(2H，s)，6.07(1H，s)，6.15(1H，t，J＝5.5Hz)，6.91(2H，d，J＝8.9Hz)，6.93(2H，d，J＝9.0Hz)，7.11(2H，d，J＝9.0Hz)，7.13(2H，d，J＝8.9Hz)
Embodiment 538
N-(2-{4-[3-methoxyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
White powder: mp.192.6-192.7 ℃
IR(KBr)：3390，3352，3311，3305，1657，1610，1583，1568，1525，1502cm-1
MS(ESI+)：m/z 384(M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.27-3.36(2H，m)，3.34(3H，s)，3.85(3H，s)，3.91-3.97(2H，m)，5.53(2H，s)，6.11(1H，s)，6.15(1H，t，J＝5.7Hz)，6.85(1H，d，J＝8.7Hz)，6.94(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.59(1H，dd，J＝2.6，8.7Hz)，8.00(1H，d，J＝2.6Hz)
Embodiment 539
N-(2-{4-[3-oxyethyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
White powder: mp.133-138 ℃
IR(KBr)：3350，1657，1643，1612，1579，1562，1554，1518，1500cm-1；MS(ESI+)：m/z 398(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，3.28-3.35(2H，m)，3.84(3H，s)，3.91-3.97(2H，m)，4.19(2H，q，J＝7.0Hz)，5.53(2H，s)，6.09(1H，s)，6.16(1H，t，J＝5.6Hz)，6.85(1H，d，J＝8.8Hz)，6.94(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)，7.58(1H，dd，J＝2.7，8.8Hz)，8.00(1H，d，J＝2.7Hz)
Embodiment 540
N-(2-{4-[3-cyclopropyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.94-96℃
MS(ESI+)：m/z 394(M+H)
1HNMR(200MHz，DMSOd6)：0.72-0.78(2H，m)，0.87-0.95(2H，m)，1.87-2.01(1H，m)，3.23-3.42(2H，m)，3.85(3H，s)，3.90-3.97(2H，m)，5.52(2H，s)，6.12(1H，t，J＝5.6Hz)，6.30(1H，s)，6.85(1H，d，J＝8.8Hz)，6.92(2H，d，J＝8.7Hz)，7.13(2H，d，J＝8.7Hz)，7.58(1H，dd，J＝2.7，8.8Hz)，8.01(1H，d，J＝2.7Hz)
Embodiment 541
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.152.0-152.2℃
Mass spectrum (ESI+): 464 (M+H)
1HNMR(200MHz，DMSOd6)：1.42-1.73(6H，m)，3.27-3.36(2H，m)，3.53-3.67(2H，m)，3.73-3.96(2H，m)，3.78(3H，s)，3.90-3.97(2H，m)，5.51(2H，s)，6.14(1H，t，J＝5.7Hz)，6.77(1H，s)，6.92(2H，d，J＝8.8Hz)，6.98(2H，d，J＝9,0Hz)，7.17(2H，d，J＝8.8Hz)，7.23(2H，d，J＝9.0Hz)
Embodiment 542
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.164-167℃
Mass spectrum (ESI+): 465 (M+H)
1HNMR(200MHz，DMSOd6)：1.42-1.73(6H，m)，3.22-3.40(2H，m)，3.52-3.70(2H，m)，3.75-3.95(2H，m)，3.87(3H，s)，3.92-3.98(2H，m)，5.52(2H，s)，6.15(1H，t，J＝5.6Hz)，6.81(1H，s)，6.90(1H，d，J＝8.9Hz)，6.95(2H，d，J＝8.8Hz)，7.21(2H，d，J＝8.8Hz)，7.67(1H，dd，J＝2.7，8.9Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 543
5-(4-{2-[(aminocarboxyl) amino] oxyethyl group } phenyl)-N-ethyl-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
mp.146.3-146.7℃
MS(ESI+)：m/z 439(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.23(3H，m)，2.98，3.28(3H，s)，3.28-3.37(2H，m)，3.40-3.53，3.63-3.77(2H，m)，3.87(3H，s)，3.92-3.98(2H，m)，5.52(2H，s)，6.15(1H，t，J＝5.5Hz)，6.82，6.85(1H，s)，6.90(1H，d，J＝9.0Hz)，6.95(2H，d，J＝8.7Hz)，7.21(2H，d，J＝8.7Hz)，7.60-7.73(1H，m)，8.14-8.16(1H，m)
Embodiment 544
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.130-132℃
MS(ESI+)：m/z 451(M+H)
1HNMR(200MHz，DMSOd6)：3.27-3.33(2H，m)，3.76(3H，s)，3.90-3.96(2H，m)，4.81(1H，d，J＝9.0Hz)，4.90(1H，d，J＝9.0Hz)，5.52(2H，s)，6.14(1H，t，J＝5.6Hz)，6.21(1H，s)，6.89-6.98(4H，m)，7.12-7.18(4H，m)
Embodiment 545
N-(2-{4-[3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.138.6-139.1℃
MS(ESI+)：m/z 432(M+H)
1HNMR(200MHz，DMSOd6)：3.27-3.36(2H，m)，3.76(3H，s)，3.90-3.96(2H，m)，4.44(2H，dt，J＝3.5，14.9Hz)，5.52(2H，s)，6.11-6.17(1H，m)，6.15(1H，s)，6.41(1H，tt，J＝3.5，54.6Hz)，6.91(2H，d，J＝8.9Hz)，6.93(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)
Embodiment 546
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.134.8-134.9℃
MS(ESI+)：m/z 452(M+H)
1HNMR(200MHz，)：3.24-3.39(2H，m)，3.85(3H，s)，3.91-3.98(2H，m)，4.83(1H，d，J＝9Hz)，4.92(1H，d，J＝9Hz)，5.52(2H，s)，6.15(1H，t，J＝5.6Hz)，6.27(1H，s)，6.87(1H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，7.18(2H，d，J＝8.8Hz)，7.61(1H，dd，J＝2.7，8.8Hz)，8.04(1H，d，J＝2.7Hz)
Embodiment 547
N-(2-{4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.146.9-147.3℃
MS(ESI+)：m/z 434(M+H)
1HNMR(200MHz，DMSOd6)：3.23-3.40(2H，m)，3.85(3H，s)，3.91-3.97(2H，m)，4.45(2H，dt，J＝3.5，14.9Hz)，5.52(2H，s)，6.15(1H，t，J＝5.7Hz)，6.21(1H，s)，6.42(1H，tt，J＝3.5，54.6Hz)，6.86(1H，d，J＝8.8Hz)，6.94(2H，d，J＝8.8Hz)，6.94(2H，d，J＝8.8Hz)，7.60(1H，dd，J＝2.8，8.8Hz)，8.03(1H，d，J＝2.8Hz)
Embodiment 548
5-(4-{[(aminocarboxyl) amino] methyl } phenyl)-N-ethyl-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
mp.184.7-185.1℃
MS(ESI+)：m/z 408(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.22(3H，m)，2.98，3.29(3H，s)，3.41-3.78(2H，m)，3.78(3H，s)，4.16(2H，d，J＝6.0Hz)，5.54(2H，s)，6.44(1H，t，J＝6Hz)，6.84，6.86(1H，s)，6.99(2H，d，J＝8.9Hz)，7.2-7.27(6H，m)
Embodiment 549
N-{4-[3-sec.-propyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } the urea amorphous powder
MS(ESI+)：m/z 365(M+H)
1HNMR(200MHz，DMSOd6)：1.27(6H，d，J＝7.0Hz)，2.95(1H，m)，3.76(3H，s)，4.15(2H，d，J＝6.0Hz)，5.53(2H，s)，6.42(1H，t，J＝6.0Hz)，6.44(1H，s)，6.93(2H，d，J＝8.9Hz)，7.11-7.22(6H，m)
Embodiment 550
N-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] benzyl } urea mp.178.9-178.9 ℃
MS(ESI+)：m/z 435(M+H)
1HNMR(400MHz，DMSOd6)：1.47-1.70(6H，m)，3.55-3.66(2H，m)，3.78-3.89(2H，m)，3.87(3H，s)，4.17(2H，d，J＝6.0Hz)，5.55(2H，s)，6.45(1H，t，J＝6.0Hz)，6.86(1H，s)，6.91(1H，d，J＝8.8Hz)，7.24(4H，s)，7.70(1H，dd，J＝2.7，8.8Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 551
5-(4-{[(aminocarboxyl) amino] methyl } phenyl)-N-ethyl-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
mp.172.6-172.8℃
MS(ESI+)：m/z 409(M+H)
1HNMR(400MHz，DMSOd6)：1.13，1.19(3H，t，J＝7.0Hz)，2.98，3.29(3H，s)，3.48，3.72(2H，q，J＝7.0Hz)，3.87(3H，s)，4.18(2H，d，J＝6.0Hz)，5.55(2H，s)，4.45(1H，t，J＝6.0Hz)，6.87-6.93(2H，m)，7.24(4H，s)，7.67-7.73(1H，m)，8.14-8.16(1H，m)
Embodiment 552
N-{4-[3-sec.-propyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } urea
mp.139-144℃
MS(ESI+)：m/z 366(M+H)
1HNMR(200MHz，DMSOd6)：1.27(6H，d，J＝7.0Hz)，2.97(1H，m)，3.85(3H，s)，4.17(2H，d，J＝6.0Hz)，5.53(2H，s)，6.43(1H，t，J＝6.0Hz)，6.50(1H，s)，6.86(1H，d，J＝8.8Hz)，7.15-7.26(4H，m)，7.62(1H，dd，J＝2.8，8.8Hz)，8.02(1H，d，J＝2.7Hz)
Embodiment 553
N-{4-[3-isobutyryl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } urea
mp.157.0-157.3℃
MS(ESI+)：m/z 394(M+H)
1HNMR(200MHz，DMSOd6)：1.16(6H，d，J＝6.8Hz)，3.68(1H，m)，3.88(3H，s)，4.17(2H，d，J＝6.0Hz)，5.54(2H，s)，6.45(1H，t，J＝6.0Hz)，6.93(1H，d，J＝8.8Hz)，7.06(1H，s)，7.25(4H，s)，7.76(1H，dd，J＝2.7，8.8Hz)，8.18(1H，d，J＝2.7Hz)
Embodiment 554
N-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } urea
mp.206.0-260.9℃
MS(ESI+)：m/z 353(M+H)
1HNMR(200MHz，DMSOd6)：3.76(3H，s)，3.84(3H，s)，4.15(2H，d，J＝6.0Hz)，5.53(2H，s)，6.09(1H，s)，6.42(1H，t，J＝6.0Hz)，6.93(2H，d，J＝9Hz)，7.12-7.23(6H，m)
Embodiment 555
N-{4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } the urea solid
MS(ESI+)：m/z 381(M+H)
1HNMR(200MHz，DMSOd6)：1.31(6H，d，J＝6.1Hz)，3.76(3H，s)，4.15(2H，d，J＝6.0Hz)，4.76(1H，m)，5.53(2H，s)，6.04(1H，s)，6.43(1H，t，J＝6.0Hz)，6.92(2H，d，J＝8.9Hz)，7.10-7.22(6H，m)
Embodiment 556
N-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } urea
mp.125.5-126.2℃
Mass spectrum (ESI+): 357 (M+H)
1HNMR(200MHz，DMSOd6)：3.78(3H，s)，4.15(2H，d，J＝6.1Hz)，5.54(2H，s)，6.43(1H，t，J＝6.1Hz)，6.73(1H，s)，6.97(2H，d，J＝8.9Hz)，7.14-7.24(6H，m)
Embodiment 557
N-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } urea
mp.111-115℃
Mass spectrum (ESI+): 358 (M+H)
1HNMR(200MHz，DMSOd6)：3.87(3H，s)，4.17(2H，d，J＝6.0Hz)，5.54(2H，s)，6.44(1H，t，J＝6.0Hz)，6.79(1H，s)，6.89(1H，d，J＝.8Hz)，7.23(4H，s)，7.69(1H，dd，J＝2.7，8.8Hz)，8.11(1H，d，J＝2.7Hz)
Embodiment 558
N-(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenoxy group } ethyl) the urea amorphous powder
MS(ESI+)：m/z 367(M+H)
1HNMR(400MHz，DMSOd6)：2.02(3H，s)，3.32-3.36(2H，m)，3.74(3H，s)，3.92-3.96(2H，m)，5.51(2H，s)，6.15(1H，t，J＝5.6Hz)，6.89(2H，d，J＝8.9Hz)，6.94(2H，d，J＝8.8Hz)，7.08(2H，d，J＝8.8Hz)，7.09(2H，d，J＝8.9Hz)，7.55(1H，s)
Embodiment 559
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenoxy group } ethyl) the urea powder
MS(ESI+)：m/z 368(M+H)
1HNMR(400MHz，DMSOd6)：2.03(3H，s)，3.31-3.36(2H，m)，3.83(3H，s)，3.94-3.98(2H，m)，5.51(2H，s)，6.15(1H，t，J＝5.6Hz)，6.82(1H，d，J＝8.8Hz)，6.97(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz)，7.53(1H，dd，J＝2.7，8.8Hz)，7.62(1H，s)，7.98(1H，d，J＝2.7Hz)
Embodiment 560
N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp.141.2-142.2℃
MS(ESI+)：m/z 399(M+H)
1HNMR(200MHz，DMSOd6)：2.50(3H，s)，3.27-3.36(2H，m)，3.77(3H，s)，3.90-3.96(2H，m)，5.52(2H，s)，6.14(1H，t，J＝5.6Hz)，6.56(1H，s)，6.91(2H，d，J＝8.8Hz)，6.95(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，7.17(2H，d，J＝8.8Hz)
Embodiment 561
N-(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl) urea
mp.205-206℃
MS(ESI+)：m/z 406(M+H)
1HNMR(200MHz，DMSOd6)：2.64-2.72(2H，m)，3.13-3.24(2H，m)，3.88(3H，s)，5.42(2H，s)，5.95(1H，t，J＝5.6Hz)，6.92(1H，d，J＝8.9Hz)，7.17(1H，s)，7.24(4H，s)，7.75(1H，dd，J＝2.8，8.9Hz)，8.19(1H，d，J＝2.8Hz)
Embodiment 562
5-(4-{2-[(aminocarboxyl) amino] ethyl } phenyl)-N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
Oily matter
MS(ESI+)：m/z 243(M+H)
1HNMR(200MHz，CDCl3)：2.75-2.82(2H，m)，3.34-3.45(2H，m)，3.51(3H，s)，3.82(3H，s)，3.83(3H，s)，4.46(2H，s)，4.92(1H，t，J＝5.5Hz)，6.84(2H，d，J＝9.0Hz)，6.92(1H，s)，7.11(4H，s)，7.15(2H，d，J＝9.0Hz)
Embodiment 563
5-(4-{2-[(aminocarboxyl) amino] ethyl } phenyl)-N-methoxyl group-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
Oily matter
MS(ESI+)：m/z 425(M+H)
1HNMR(200MHz，CDCl3)：2.78-2.86(2H，m)，3.39-3.49(2H，m)，3.49(3H，s)，3.85(3H，s)，3.94(3H，s)，4.39(2H，s)，4.70(1H，t，J＝5.8Hz)，6.75(1H，d，J＝8.9Hz)，6.80(1H，s)，7.12-7.23(4H，m)，7.56(1H，dd，J＝2.7，8.9Hz)，8.05(1H，d，J＝2.7Hz)
Embodiment 564
60% sodium hydride mineral oil dispersion liquid (93.1mg) is cooled off the N-[5-[4-of property adding next time (benzyloxy) phenyl at ice bath]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N ', N '-dimethyl urea (1.43g) is dissolved in the solution of DMF (10ml).In ambient temperature stirred reaction mixture 1 hour.MeI (688mg) is added reaction mixture, stir in ambient temperature and spend the night.Mixture distributes between ethyl acetate and H2O.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt-normal hexane=75%, 80% wash-out, obtains oily N-[5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl]-N, N ', N '-trimethyl-urea (1.45g).
Mass spectrum (ESI+): 457 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.79(6H，s)，3.12(3H，s)，3.77(3H，s)，5.09(2H，s)，6.25(1H，s)，6.91-7.00(4H，m)，7.14-7.19(4H，m)，7.32-7.46(5H，m)
Embodiment 565
With N-(2-{4-[3-amino-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (111mg), lithium chloride (64mg) and cupric chloride (II) (81.2mg) mixture in acetonitrile (2ml) stirred 10 minutes in ambient temperature.Add Isopentyl nitrite (62.3mg) to this mixture, mixture stirred 3 hours in ambient temperature.Mixture distributes between ethyl acetate and saturated aqueous ammonium chloride.Organic layer is through saturated aqueous ammonium chloride, H2O and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches with MeOH/CHCl3=10% through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts through 10%MeOH/CHCl3, vacuum evaporating solvent.Resistates is through the AcOEt/IPE crystallization, obtains white powder N-(2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea (31.1mg).
mp.140-142℃
Mass spectrum (ESI+): 386 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：3.27-3.34(2H，m)，3.77(3H，s)，3.93(2H，t，J＝5.5Hz)，5.52(2H，s)，6.15(1H，t，J＝5.7Hz)，6.68(1H，s)，6.92(2H，d，J＝9.0Hz)，6.97(2H，d，J＝9.0Hz)，7.15(2H，d，J＝9.0Hz)，7.20(2H，d，J＝9.0Hz)
Embodiment 566
Diethylazodicarboxylate (0.17ml) is added dropwise to 3-methoxyl group-1-(4-p-methoxy-phenyl)-5-(4-hydroxy phenyl)-1H-pyrazoles (215.6mg), N-(2-hydroxyethyl) t-butyl carbamate (352mg) and the suspension of triphenylphosphine (286mg) in THF (3ml).Mixture stirred 7 hours in ambient temperature.Add triphenylphosphine (19.1mg) and diethylazodicarboxylate (11.5 μ l), mixture is stirred in ambient temperature spend the night.Vacuum concentrated mixture.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out, the acquisition oily (2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate (319mg).
Mass spectrum (ESI+): 440 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.45(9H，s)，3.47-3.56(2H，m)，3.80(3H，s)，3.96-4.03(2H，m)，3.97(3H，s)，4.96(1H，brs)，5.87(1H，s)，6.79(2H，d，J＝8.8Hz)，6.82(2H，d，J＝8.9Hz)，7.09-7.20(4H，m)
Following compound adopts the similar approach of embodiment 566 to obtain.
Embodiment 567
(2-{4-[3-isobutoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
White powder
Mass spectrum (ESI+): 482 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.03(6H，d，J＝6.7Hz)，1.45(9H，s)，2.11(1H，m)，3.48-3.57(2H，m)，3.79(3H，s)，3.97-4.03(2H，m)，4.97(1H，br)，5.88(1H，s)，6.79(2H，d，J＝8.7Hz)，6.82(2H，d，J＝8.9Hz)，7.09-7.19(4H，m)
Embodiment 568
(2-{4-[3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Solid
Mass spectrum (ESI+): 484 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.37(9H，s)，3.22-3.32(2H，m)，3.31(3H，s)，3.62-3.67(2H，m)，3.75(3H，s)，3.91-3.97(2H，m)，4.21-4.27(2H，m)，6.04(1H，s)，6.86-6.99(5H，m)，7.10-7.15(4H，m)
Embodiment 569
(2-{4-[3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
Mass spectrum (ESI+): 498 (M+H)+
200MHz 1H NMR (DMSO-d6, d): 1.09-1.21 (3H overlaps), 1.37 (9H, s), 3.25-3.34 (2H, m), 3.66-3.71 (2H, m), 3.75 (3H, s), 3.90-4.15 (4H, m), 4.21-4.26 (2H, m), 6.06 (1H, s), 6.86-6.96 (4H, m), 7.01 (1H, m), 7.12 (4H, d, J=8.9Hz)
Embodiment 570
(2-{4-[3-methoxyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Powder
MS(ESI+)：m/z 441(M+H)+
200MHz 1H NMR(CDCl3，d)：1.45(9H，s)，3.48-3.57(2H，m)，3.92(3H，s)，3.97(3H，s)，3.98-4.03(2H，m)，4.99(1H，br)，5.90(1H，s)，6.70(1H，d，J＝8.5Hz)，6.82(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.52(1H，dd，J＝2.5，8.5Hz)，8.03(1H，d，J＝2.5Hz)
Embodiment 571
(2-{4-[3-oxyethyl group-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
White powder
MS(ESI+)：m/z 455(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.33(3H，t，J＝7.0Hz)，1.37(9H，s)，3.22-3.33(2H，m)，3.84(3H，s)，3.92-3.98(2H，m)，4.19(2H，q)，6.08(1H，s)，6.85(1H，d，J＝8.8Hz)，6.92(2H，d，J＝8.8Hz)，7.02(1H，t，J＝5.5Hz)，7.16(2H，d，J＝8.8Hz)，7.58(1H，dd，J＝2.7，8.8Hz)，7.99(1H，d，J＝2.7Hz)
Embodiment 572
[2-(4-{3-(difluoromethyl)-1-[4-(methylthio group) phenyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] t-butyl carbamate
Mass spectrum (ESI+): m/z=498.2 (M+Na).
1HNMR(400MHz，CDCl3)：1.45(9H，s)，2.49(3H，s)，3.54(2H，q，J＝5.1Hz)，4.02(2H，t，J＝5.1Hz)，4.98(1H，b.s)，6.66(1H，s)，6.76(1H，t，J＝55.1Hz)，6.84(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.2(4H，s).
Embodiment 573
(2-{4-[3-cyclopropyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS ESI+)：m/z 451(M+H)
1HNMR(200MHz，CDCl3)：0.77-0.86(2H，m)，0.93-1.04(2H，m)，1.45(9H，s)，1.96-2.09(1H，m)，3.48-3.57(2H，m)，3.92(3H，s)，3.97-4.03(2H，m)，4.97(1H，brs)，6.10(1H，s)，6.71(1H，d，J＝8.8Hz)，6.81(2H，d，J＝8.8Hz)，7.11(2H，d，J＝8.8Hz)，7.53(1H，dd，J＝2.7，8.8Hz)，8.03(1H，d，J＝2.7Hz)
Embodiment 574
(2-{4-[3-(cyclopentyloxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS(ESI+)：m/z 494(M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，1.5-1.99(8H，m)，3.48-3.57(2H，m)，3.91(3H，s)，3.98-4.04(2H，m)，4.92-5.05(2H，m)，5.88(1H，s)，6.69(1H，d，J＝8.9Hz)，6.82(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，7.52(1H，dd，J＝2.7，8.9Hz)，8.02(1H，d，J＝2.7Hz)
Embodiment 575
(2-{4-[1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS(ESI+)：m/z 508(M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，3.48-3.57(2H，m)，3.81(3H，s)，3.97-4.03(2H，m)，4.62(1H，d，J＝8.5Hz)，4.70(1H，d，J＝8.5Hz)，4.95(1H，brs)，5.95(1H，s)，6.77-6.86(4H，m)，7.08-7.18(4H，m)
Embodiment 576
(2-{4-[3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS(ESI+)：m/z 490(M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，3.48-3.57(2H，m)，3.80(3H，s)，3.97-4.03(2H，m)，4.46(2H，dt，J＝4.3，13.4Hz)，4.96(1H，brs)，5.91(1H，s)，6.17(1H，tt，J＝4.3，55.5Hz)，6.77-6.88(4H，m)，7.09-7.18(4H，m)
Embodiment 577
(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS(ESI+)：m/z 509(M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，3.48-3.57(2H，m)，3.92(3H，s)，3.98-4.04(2H，m)，4.61(1H，d，J＝8.4Hz)，4.70(1H，d，J＝8.4Hz)，4.96(1H，brs)，5.97(1H，s)，6.71(1H，d，J＝8.8Hz)，6.83(2H，d，J＝8.8Hz)，7.13(2H，d，J＝8.8Hz)，7.48(1H，dd，J＝2.7，8.8Hz)，8.02(1H，d，J＝2.7Hz)
Embodiment 578
(2-{4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Solid
MS(ESI+)：m/z 513(M+Na)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，3.48-3.57(2H，m)，3.92(3H，s)，3.98-4.04(2H，m)，4.46(2H，dt，J＝4.2，13.4Hz)，4.96(1H，brs)，5.94(1H，s)，6.16(1H，tt，J＝4.2，55.5Hz)，6.71(1H，d，J＝8.8Hz)，6.83(2H，d，J＝8.9Hz)，7.13(2H，d，J＝8.9Hz)，7.48(1H，dd，J＝2.7，8.8Hz)，8.02(1H，d，J＝2.7Hz)
Embodiment 579
(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS(ESI+)：m/z 424(M+H)
200MHz 1H NMR(DMSO-d6，d)：1.37(9H，s)，2.01(3H，s)，3.23-3.33(2H，m)，3.74(3H，s)，3.92-3.98(2H，m)，6.86-6.95(4H，m)，7.05-7.12(4H，m)，7.55(1H，s)
Embodiment 580
(2-{4-[1-(6-methoxyl group-3-pyridyl)-4-methyl isophthalic acid H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
MS(ESI+)：m/z 425(M+H)
1HNMR(400MHz，CDCl3)：1.42(9H，s)，2.09(3H，s)，3.52-3.57(2H，m)，3.91(3H，s)，4.01-4.04(2H，m)，4.98(1H，brs)，6.68(1H，d，J＝8.8Hz)，6.87(2H，d，J＝8.8Hz)，7.08(2H，d，J＝8.8Hz)，7.48(1H，dd，J＝2.7，8.8Hz)，7.58(1H，s)，8.00(1H，d，J＝2.7Hz)
Embodiment 581
(2-{4-[1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Oily matter
Mass spectrum (ESI+): m/z 456 (M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，2.58(3H，s)，3.48-3.57(2H，m)，3.81(3H，s)，3.97-4.03(2H，m)，4.96(1H，m)，6.36(1H，s)，6.77-6.86(4H，m)，7.12(2H，d，J＝8.9Hz)，7.2(2H，d，J＝9.0Hz)
Embodiment 582
The solution that is dissolved in CH2Cl2 (3ml) to (2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) amine hydrochlorate (150mg) and triethylamine (121mg) adds trifluoromethanesulfanhydride anhydride (113mg).Stirred the mixture 2 hours in ambient temperature.Add triethylamine (92mg) again, continue to stir 4 hours in ambient temperature.Vacuum concentrated mixture.Resistates distributes between AcOEt and 1M HCl.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=50% wash-out, obtains oily 1,1, and 1-three fluoro-N-(2-{4-[3-methoxyl group-1-(4-methoxyl group-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) Toluidrin (109mg).
IR (pure): 2960,1612,1522cm-1
Mass spectrum (ESI+): 472 (M+H)+
200MHz 1H NMR(CDCl3，d)：3.60-3.73(2H，m)，3.80(3H，s)，3.97(3H，s)，4.06-4.12(2H，m)，5.45(1H，brs)，5.89(1H，s)，6.70-6.87(4H，m)，7.15(2H，d，J＝8.9Hz)，7.17(2H，d，J＝9.0Hz)
Embodiment 583
To 5-[4-(benzyloxy) phenyl]-3-hydroxyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles (2.0g) and the suspension adding ethyl sulfate (1.24g) of K2CO3 (2.23g) in DMSO (20ml).After ambient temperature stirs 2 hours, add 28% ammonium hydroxide aqueous solution and ice quencher reaction.Mixture distributes between AcOEt and H2O.Organic layer is through H2O and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=40% wash-out, vacuum evaporating solvent.Residual solid obtains Powdered 5-[4-(benzyloxy) phenyl through the IPE recrystallization]-3-oxyethyl group-1-(4-methoxyl group-phenyl)-1H-pyrazoles (1.44g).
Mass spectrum (ESI+): 401 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.32(3H，t，J＝7.0Hz)，3.76(3H，s)，4.17(2H，q，J＝7.0Hz)，5.08(2H，s)，6.03(1H，s)，6.92(2H，d，J＝9.0Hz)，6.97(2H，d，J＝8.8Hz)，7.09-7.16(4H，m)，7.32-7.46(5H，m)
Following compound adopts the similar approach of embodiment 583 to obtain.
Embodiment 584
5-{5-[4-(benzyloxy) phenyl]-3-oxyethyl group-1H-pyrazol-1-yl }-the 2-methoxypyridine
Oily matter; MS (ESI+): m/z 402 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.43(3H，t，J＝7.1Hz)，3.92(3H，s)，4.28(2H，q，J＝7.1Hz)，5.05(2H，s)，5.90(1H，s)，6.70(1H，d，J＝8.7Hz)，6.91(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，7.35-7.43(5H，m)，7.51(1H，dd，J＝2.6，8.7Hz)，8.04(1H，d，J＝2.6Hz)
Embodiment 585
To 4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] DMF (5ml) solution of phenol (515.5mg) adds 60% sodium hydride mineral oil dispersion liquids (79.7mg) in 3 ℃.Stirred the mixture 40 minutes in ambient temperature.Add the solution that (2-bromotrifluoromethane) t-butyl carbamate (558mg) is dissolved in DMF (2ml) to reaction mixture.Stirred the mixture 24 hours in 60 ℃.Pour reaction mixture into frozen water, extract with AcOEt.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is through the AcOEt crystallization, collects the back with the IPE washing, obtains first product white powder (2-{4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate (344mg).The vacuum concentration mother liquor, it is purified through silica gel column chromatography, use the AcOEt/CHCl3=10% wash-out, obtain the second batch of product Powdered (2-{4-[3-oxyethyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate (218mg).
Mass spectrum (ESI+): 454 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.42(3H，t，J＝7.1Hz)，1.45(9H，s)，3.48-3.57(2H，m)，3.80(3H，s)，3.97-4.03(2H，m)，4.29(2H，q，J＝7.1Hz)，5.87(1H，s)，6.79(2H，d，J＝9.0Hz)，6.82(2H，d，J＝8.9Hz)，7.00-7.19(4H，m)
Embodiment 586
With 5-[4-(benzyloxy) phenyl]-3-hydroxyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles (1.5g), 1-bromo-2-methylpropane (2.76g) and the suspension of Anhydrous potassium carbonate (1.67g) in DMF (10ml) adds the back and stirred 1 hour in 100 ℃.Pour mixture into frozen water, extract with AcOEt.Organic layer is through H2O, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out, obtains solid 5-[4-(benzyloxy) phenyl]-3-isobutoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles (1.64g).
Powder
Mass spectrum (ESI+): 429 (M+H)+
200MHz 1H NMR(CDCl3，d)：1.03(6H，d，J＝6.6Hz)，2.11(1H，m)，3.80(3H，s)，3.99(2H，d，J＝6.6Hz)，5.04(2H，s)，5.88(1H，s)，6.82(2H，d，J＝9.0Hz)，6.88(2H，d，J＝8.8Hz)，7.11-7.20(4H，m)，7.35-7.43(5H，m)
Adopt the similar approach of embodiment 586 to obtain following compound.
Embodiment 587
5-[4-(benzyloxy) phenyl]-3-(2-methoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles powder
Mass spectrum (ESI+): 431 (M+H)+
200MHz 1H NMR(CDCl3，d)：3.46(3H，s)，3.73-3.80(2H，m)，3.79(3H，s)，4.39-4.44(2H，m)，5.04(2H，s)，5.91(1H，s)，6.83(2H，d，J＝8.9Hz)，6.87(2H，d，J＝9.0Hz)，7.10-7.20(4H，m)，7.34-7.42(5H，m)
Embodiment 588
5-[4-(benzyloxy) phenyl]-3-(2-ethoxy ethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles
Oily matter
Mass spectrum (ESI+): 445 (M+H)+
400MHz 1H NMR(CDCl3，d)：1.25(3H，t，J＝7.0Hz)，3.61(2H，q，J＝7.0Hz)，3.79-3.82(2H，m)，3.80(3H，s)，4.39-4.42(2H，m)，5.04(2H，s)，5.91(1H，s)，6.82(2H，d，J＝8.9Hz)，6.88(2H，d，J＝8.7Hz)，7.12(2H，d，J＝8.7Hz)，7.17(2H，d，J＝8.9Hz)，7.36-7.41(5H，m)
Embodiment 589
2-{[5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-1H-pyrazole-3-yl] the oxygen base }-N,N-dimethylacetamide
Powder
Mass spectrum (ESI+): 458 (M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.84(3H，s)，2.97(3H，s)，3.76(3H，s)，4.87(2H，s)，5.09(2H，s)，6.08(1H，s)，6.92(2H，d，J＝9.0Hz)，6.98(2H，d，J＝8.8Hz)，7.09-7.17(4H，m)，7.34-7.43(5H，m)
Embodiment 590
5-[5-[4-(benzyloxy) phenyl]-3-(cyclopentyloxy)-1H-pyrazol-1-yl]-the 2-methoxypyridine
Solid
MS(ESI+)：m/z 442(M+H)
1HNMR(200MHz，CDCl3)：1.52-1.98(8H，m)，3.92(3H，s)，4.98-5.05(1H，m)，5.05(2H，s)，5.88(1H，s)，6.69(1H，d，J＝8.7Hz)，6.91(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.35-7.43(5H，m)，7.52(1H，dd，J＝2.7，8.7Hz)，8.04(1H，d，J＝2.7Hz)
Embodiment 591
5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles
Oily matter
MS(ESI+)：m/z 455(M+H)
1HNMR(200MHz，DMSOd6)：3.76(3H，s)，4.81(1H，d，J＝9.0Hz)，4.90(1H，d，J＝9.0Hz)，5.09(2H，s)，6.21(1H，s)，6.91-7.01(4H，m)，7.13-7.19(4H，m)，7.34-7.46(5H，m)
Embodiment 592
5-[4-(benzyloxy) phenyl]-3-(2, the 2-difluoroethoxy)-1-(4-p-methoxy-phenyl)-1H-pyrazoles
Oily matter
MS(ESI+)：m/z 437(M+H)
1HNMR(200MHz，CDCl3)：3.80(3H，s)，4.46(2H，dt，J＝4.2，13.5Hz)，5.04(2H，s)，5.91(1H，s)，6.17(1H，tt，J＝4.2，55.5Hz)，6.81-6.91(4H，m)，7.10-7.19(4H，m)，7.34-7.43(5H，m)
Embodiment 593
5-[5-[4-(benzyloxy) phenyl]-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazol-1-yl]-the 2-methoxypyridine
Oily matter
Mass spectrum (ESI+): 456 (M+H)
1HNMR(200MHz，CDCl3)：3.93(3H，s)，4.61(1H，d，J＝8.4Hz)，4.69(1H，d，J＝8.4Hz)，5.05(2H，s)，5.97(1H，s)，6.71(1H，d，J＝9Hz)，6.91(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.36-7.43(5H，m)，7.48(1H，dd，J＝2.7，9Hz)，8.04(1H，d，J＝2.7Hz)
Embodiment 594
5-[5-[4-(benzyloxy) phenyl]-3-(2, the 2-difluoroethoxy)-1H-pyrazol-1-yl]-the 2-methoxypyridine
Oily matter
MS(ESI+)：m/z 438(M+H)
1HNMR(200MHz，CDCl3)：3.93(3H，s)，4.46(2H，dt，J＝4.2，13.3Hz)，5.05(2H，s)，5.94(1H，s)，6.16(1H，tt，J＝4.2，55.4Hz)，6.71(1H，d，J＝8.8Hz)，6.91(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.8Hz)，7.35-7.43(5H，m)，7.48(1H，dd，J＝2.8，8.8Hz)，8.04(1H，d，J＝2.8Hz)
Embodiment 595
With 5-{5-[4-(benzyloxy) phenyl]-3-hydroxyl-1H-pyrazol-1-yl }-2-methoxypyridine (800mg), methylcarbonate (0.9ml) and the suspension of salt of wormwood (888mg) in DMF (8ml) stirred 5 hours in 120 ℃.Pour mixture into frozen water, extract with AcOEt.Organic layer is through H2O, saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out, obtains solid 5-{5-[4-(benzyloxy) phenyl]-3-methoxyl group-1H-pyrazol-1-yl }-2-methoxyl group-pyridine (1.069g).
Powder
MS(ESI+)：m/z 388(M+H)+
200MHz 1H NMR(CDCl3，d)：3.92(3H，s)，3.97(3H，s)，5.05(2H，s)，5.90(1H，s)，6.71(1H，d，J＝8.7Hz)，6.91(2H，d，J＝8.9Hz)，7.14(2H，d，J＝8.9Hz)，7.35-7.43(5H，m)，7.52(1H，dd，J＝2.6，8.7Hz)，8.05(1H，d，J＝2.6Hz)
Embodiment 596
With 4,4,4-three fluoro-1-[4-(2-hydroxyethyl) phenyl]-1, the solution that 3-dimethyl diketone (670mg) and (4-nitrophenyl) hydrazonium salt hydrochlorate (439mg) are dissolved in AcOH (5ml) and H2O (0.5ml) spends the night in the ambient temperature stirring.Vacuum concentrated mixture, resistates distributes between AcOEt and 1M HCl.Organic layer washs successively through 1M HCl (2 times), saturated sodium bicarbonate aqueous solution (3 times) and saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=10% and 15% wash-out, obtains oily acetate 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (501mg).
MS(ESI+)：m/z 420(M+H)+，442(M+Na)+
200MHz 1H NMR(DMSO-d6，d)：1.96(3H，s)，2.91(2H，t，J＝6.8Hz)，4.22(2H，t，J＝6.8Hz)，7.22-7.37(5H，m)，7.61(2H，d，J＝9.0Hz)，8.30(2H，d，J＝9.0Hz)
Adopt the similar approach of embodiment 596 to obtain following compound.
Embodiment 597
5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles
Mass spectrum (ESI+): m/z=439.1 (M+1), 461.2 (M+Na).
1HNMR(400MHz，CDCl3)：2.15(3H，s)，3.79(3H，s)，5.06(2H，s)，6.8(2H，d，J＝8.9Hz)，6.95(2H，d，J＝8.7Hz)，7.07(2H，d，J＝8.7Hz)，7.14(2H，d，J＝8.9Hz)，7.342-7.44(5H，m).
Embodiment 598
Acetate 2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester
Mass spectrum (ESI+): m/z=346.1 (M-Ac+2), 388.1 (M+1).
1HNMR(400MHz，CDCl3)：2.04(3H，s)，2.94(2H，t，J＝7Hz)，3.94(3H，s)，4.28(2H，t，J＝7Hz)，6.72(1H，s)，6.77(1H，t，J＝55Hz)，6.75(1H，d，J＝8.8Hz)，7.17(2H，d，J＝8.5Hz)，7.22(2H，d，J＝8.5Hz)，7.54(1H，dd，J＝3.9，8.8Hz)，8.08(1H，d，J＝3.9Hz).
Embodiment 599
The solution that is dissolved in H2O (0.5ml) to ammonium chloride (58.8mg) adds iron powder (368mg) and EtOH (2ml).The reaction mixture oil bath is heated up, adds acetate 2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (460.7mg) is dissolved in the solution of EtOH (3ml).Reflux after 3 hours, reaction mixture is cooled to ambient temperature, remove by filter insolubles.Vacuum concentrated filtrate.Resistates is dissolved in AcOEt, and with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.Resistates obtains Powdered acetate 2-{4-[1-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl through the IPE recrystallization] phenyl } ethyl ester (182.3mg).
MS(ESI+)：m/z 390(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.96(3H，s)，2.87(2H，t，J＝6.8Hz)，4.20(2H，t，J＝6.8Hz)，5.46(2H，s)，6.54(2H，d，J＝8.7Hz)，6.95(2H，d，J＝8.7Hz)，7.07(1H，s)，7.18-7.28(4H，m)
Embodiment 600
With acetate 2-{4-[1-(4-aminophenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (165.6mg) and 2, the mixture of 5-dimethoxy-tetrahydrofuran (112mg) in AcOH (3ml) stirred 3 hours in 50 ℃.Add 2,5-dimethoxy-tetrahydrofuran (0.22ml) stirred the mixture 2 hours in 50 ℃.Mixture is distributed between ethyl acetate and H2O.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches with AcOEt/ normal hexane=20% through preparation type thin layer silica gel chromatographic purification.With the silica gel of 10%MeOH/CHCl3 extracting and separating, vacuum evaporating solvent, obtain oily acetate 2-{4-[1-[4-(1H-pyrroles-1-yl) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (136.1mg).
MS(ESI+)：m/z 440(M+H)+
200MHz 1H NMR(DMSO-d6，d)：1.95(3H，s)，2.88(2H，t，J＝6.8Hz)，4.20(2H，t，J＝6.8Hz)，6.29(2H，t，J＝2.0Hz)，7.18(1H，s)，7.23-7.32(4H，m)，7.39-7.47(4H，m)，7.69(2H，d，J＝8.8Hz)
Embodiment 601
1M NaOH (436 μ l) is added acetate 2-{4-[1-[4-(1H-pyrroles-1-yl) phenyl under ice bath cooling]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (128mg) is dissolved in the solution of THF (1.5ml) and MeOH (0.3ml).Mixture stirred 2 hours to ambient temperature in 0 ℃.Mixture with 1M HCl (436 μ l) neutralization, is distributed between AcOEt and H2O.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches with AcOEt/ normal hexane=50% through preparation type thin layer silica gel chromatographic purification.With the silica gel of 10%MeOH/CHCl3 extracting and separating, vacuum evaporating solvent, obtain amorphous powder 2-{4-[1-[4-(1H-pyrroles-1-yl) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenyl } ethanol (96.5mg).
IR(KBr)：3404，2924，2883，1612，1522cm-1
MS(ESI+)：m/z 398(M+H)+
200MHz 1H NMR(DMSO-d6，d)：2.67-2.75(2H，m)，3.55-3.65(2H，m)，4.64(1H，t，J＝5.1Hz)，6.30(2H，t，J＝2.0Hz)，7.16(1H，s)，7.19-7.28(4H，m)，7.40-7.48(4H，m)，7.70(2H，d，J＝8.9Hz)
Embodiment 602
With 10%Pd-C 50% weight in wet base (100mg) and 5-(4-the cyano-phenyl)-mixture of 1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (1g) in THF (10ml), MeOH (5ml) and 1MHCl (2.9ml) under H2 (1atm) in ambient temperature hydrogenation 6.5 hours.Catalyzer washs described pad through the filtering of Celite pad with MeOH.The washings of vacuum concentrated filtrate and merging.Resistates is dissolved in the EtOH final vacuum to be concentrated.Resistates obtains Powdered 5-[4-(amino methyl) phenyl through the AcOEt crystallization]-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester hydrochloride (984mg).
MS(ESI+)：m/z 352(M+H)+
1H NMR(DMSO-d6)δ1.32(3H，t，J＝7.1Hz)，3.80(3H，s)，4.01(2H，s)，4.33(2H，q，J＝7.1Hz)，7.00(2H，d，J＝9.0Hz)，7.14(1H，s)，7.28(2H，d，J＝9.0Hz)，7.31(2H，d，J＝8.3Hz)，7.47(2H，d，J＝8.3Hz)，8.30(2H，brs)
Following compound adopts the similar approach of embodiment 602 to obtain.
Embodiment 603
5-[4-(amino methyl) phenyl]-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester dihydrochloride
Powder
MS(ESI+)：m/z 353(M+H)
1HNMR(200MHz，DMSOd6)：1.32(3H，t，J＝7.1Hz)，3.88(3H，s)，3.97-4.06(2H，m)，4.34(2H，q，J＝7.1Hz)，6.94(1H，d，J＝8.7Hz)，7.17(1H，s)，7.35(2H，d，J＝8.2Hz)，7.51(2H，d，J＝8.2Hz)，7.78(1H，dd，J＝2.7，8.7Hz)，8.15(1H，d，J＝2.7Hz)，8.47(2H，brs)
Embodiment 604
4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } amine hydrochlorate
Oily matter
MS(ESI+)：m/z 310(M+H)
1HNMR(200MHz，DMSOd6)：3.76(3H，s)，3.85(3H，s)，3.91-4.26(2H，m)，6.16(1H，s)，6.93(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.9Hz)，7.26(2H，d，J＝8.2Hz)，7.45(2H，d，J＝8.2Hz)，8.41(2H，brs)
Embodiment 605
4-[3-isopropoxy-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } amine hydrochlorate
Powder
MS(ESI+)：m/z 338(M+H)
1HNMR(200MHz，DMSOd6)：1.32(6H，d，J＝6.2Hz)，3.76(3H，s)，4.00(2H，s)，4.77(1H，m)，6.11(1H，s)，6.93(2H，d，J＝8.9Hz)，7.15(2H，d，J＝8.9Hz)，7.25(2H，d，J＝8.2Hz)，7.44(2H，d，J＝8.2Hz)，8.31(2H，brs)
Embodiment 606
Et3N (326mg) is added, and the solution that then tert-Butyl dicarbonate (594mg) is dissolved in CH2Cl2 (3ml) adds 5-[4-(amino methyl) phenyl]-1-(4-the p-methoxy-phenyl)-1H-pyrazoles-suspension of 3-carboxylic acid, ethyl ester hydrochloride (960mg) in CH2Cl2 (9ml).After ambient temperature stirs 1 hour, the vacuum concentration reaction mixture.Resistates distributes between ethyl acetate and 1M HCl.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates obtains Powdered 5-(4-{[(tert-butoxycarbonyl) amino through AcOEt/ normal hexane recrystallization] methyl } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (1.045g).
MS(ESI+)：m/z 452(M+H)+
1H NMR(DMSO-d6)δ1.31(3H，t，J＝7.1Hz)，1.38(9H，s)，3.79(3H，s)，4.11(2H，d，J＝6.2Hz)，4.32(2H，q，J＝7.1Hz)，6.99(2H，d，J＝8.9Hz)，7.07(1H，s)，7.20(4H，s)，7.26(2H，d，J＝8.9Hz)，7.40(1H，t，J＝6.2Hz)
Adopt the similar approach of embodiment 606 to obtain following compound.
Embodiment 607
5-(4-{[(tert-butoxycarbonyl) amino] methyl } phenyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester
Powder
Mass spectrum (ESI+): m/z 453 (M+H)
1HNMR(200MHz，DMSOd6)：1.32(3H，t，J＝7.1Hz)，1.38(9H，s)，3.88(3H，s)，4.12(2H，d，J＝6.1Hz)，4.33(2H，q，J＝7.1Hz)，6.92(1H，d，J＝8.9Hz)，7.10(1H，s)，7.19-7.28(4H，m)，7.41(1H，t，J＝6.0Hz)，7.74(1H，dd，J＝2.7，8.9Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 608
With 5-(4-{[(tert-butoxycarbonyl) amino] methyl } phenyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-3-carboxylic acid, ethyl ester (500mg) and the mixture of sodium methylate (239mg) in methane amide (5ml) stirred 2 hours in 70 ℃.Mixture is cooled to ambient temperature, between AcOEt and salt solution, distributes.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates, the acquisition oily 4-[3-(aminocarboxyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate (512mg).
MS(ESI+)：m/z 423(M+H)+
1H NMR(DMSO-d6)δ1.38(9H，s)，3.78(3H，s)，4.11(2H，d，J＝6.1Hz)，6.93(1H，s)，6.98(2H，d，J＝8.9Hz)，7.19-7.43(8H，m)，7.64(1H，brs)
Embodiment 609
Phosphoryl chloride (0.22ml) is added DMF (2ml) under the ice bath cooling.Add { 4-[3-(aminocarboxyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } t-butyl carbamate (499mg) to described drips of solution and be dissolved in the solution of DMF (3ml).In 4 ℃ of stirred reaction mixtures 1 hour.Add phosphoryl chloride (0.15ml), reaction mixture was stirred 1 hour in 4 ℃.Add saturated sodium bicarbonate aqueous solution quencher reaction.Use the ethyl acetate extraction mixture.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates launches with AcOEt/ normal hexane=40% through preparation type thin layer silica gel chromatographic purification.Isolating silica gel is extracted with 10%MeOH/CHCl3, vacuum evaporating solvent, the acquisition oily 4-[3-cyano group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzylamino t-butyl formate (136mg).
MS(ESI+)：m/z 427(M+Na)+，(ESI-)：m/z 403(M-H)+
200MHz 1H NMR(CDCl3，d)：1.46(9H，s)，3.83(3H，s)，4.32(2H，d，J＝5.9Hz)，4.75(1H，br)，6.83(1H，s)，6.87(2H，d，J＝9.0Hz)，7.11-7.26(6H，m)
Embodiment 610
To 5-[4-(the 2-{[tertiary butyl (dimethyl) silyl] oxygen base } oxyethyl group) phenyl]-solution that 1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles (5.2g) is dissolved in EtOH (200ml) adds dense HCl (20ml) in room temperature.Stir after 2 hours, reaction mixture is distributed between EtOAc and water.Separate organic layer, wash with water, dried over mgso is filtered the back evaporation.Resistates through the silica gel chromatography analysis (Hex/EtOAc=2: 1-1: 1), obtain 2-{4-[1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group ethanol crystal (2.05g, 51%).
Mass spectrum (ESI+): e/z=415.1 (M+Na).
1HNMR(400MHz，CDCl3)：2.15(3H，s)，1.99(1H，t，J＝6.2Hz)，2.15(3H，s)，3.95-4.00(2H，m)，4.08-4.10(2H，m)，6.80(2H，d，J＝9Hz)，6.90(2H，d，J＝8.8Hz)，7.08(2H，d，J＝8.8Hz)，7.13(2H，d，J＝9Hz).
Embodiment 611
To 4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenol (5.0g) solution that is dissolved in DMF (20ml) added NaH (0.75g) (gas) at ice-cooled (5～20 ℃) down in 25 minutes, stirred 10 minutes in 3 ℃.DMF (5ml) solution of N-(2-bromotrifluoromethane) t-butyl carbamate (4.48g) was added mixture in 10 minutes, standing over night after 60 ℃ (bathing temperature for 70 ℃) stir 6 hours.
Pour mixture into water (50ml) and EtOAc (30ml), separate the back and extract with EtOAc (10ml).Organic layer evaporates after the MgSO4 drying through water (25 * 3) and salt solution (25ml) washing.Resistates is through silica gel column chromatography purification (75ml, 15v/w, AcOEt/ hexane (2: 1-1: 1)), evaporation back acquisition 7.0g oily (2-{4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate.
Mass spectrum (ESI+): m/z=516.1 (M+Na).
1HNMR(400MHz，CDCl3)：1.45(9H，s)，2.49(3H，s)，3.49-3.58(2H，m)，4.02(2H，t，J＝10.2Hz)，4.97(1H，b.s)，6.68(1H，s)，6.84(2H，d，J＝17.5Hz)，7.14(2H，d，J＝17.5Hz)，7.21(4H，s).
Adopt the similar approach of embodiment 611 to obtain following compound.
Embodiment 612
(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Mass spectrum (ESI+): m/z=514.2 (M+Na).
1HNMR(400MHz，CDCl3)：1.45(9H，s)，2.15(3H，s)，3.52-3.56(2H，m)，3.79(3H，s)，4.02(2H，t，J＝5.1Hz)，4.99(1H，b.s)，6.80(2H，d，J＝9.0Hz)，6.87(2H，d，J＝8.8Hz)，7.07(2H，d，J＝8.8Hz)，7.13(H，d，J＝9.0Hz).
Embodiment 613
To (2-{4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) suspension of amine hydrochlorate (7.5g) in H2O (150ml) and EtOH (75ml) adds NaOCN (2.27g) in room temperature.With 1N HCl with pH regulator to 6.3.Mixture was stirred 5 hours under the pH6.0-7.0 condition.With EtOAc extractive reaction mixture, with the NaCl solution washing (twice) of dilution.Dried over mgso is filtered the back evaporation.Resistates is evaporation after silica gel column chromatography is purified (CH2Cl2/MeOH).Resistates is through the IPE/EtOH crystallization.With EtOH/H2O (final 50ml-50ml) recrystallization, the N-of dry back acquisition 4.10g (54%) (2-{4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea.
Mass spectrum (ESI+): m/z=459.1 (m+Na)
1HNMR(400MHz，DMSOd6)：2.05(3H，s)，3.33(2H，q，J＝5.6Hz)，3.95(2H，t，J＝5.6Hz)，5.54(2H，b.s)，6.16(1H，t，J＝5.6Hz)，6.96(2H，d，J＝8.8Hz)，7.09(1H，s)，7.22(2H，d，J＝8.6Hz)，7.27(2H，d，J＝8.7Hz)，7.32(2H，d，J＝8.7Hz).
The HORIBA FT-IR (cm-1) of Windows Ver.4.08: 3399.89,3197.40,1650.77,1614.13,1554.34,1475.28,1459.85,1442.49,1232.29,1160.94,1126.22,1087.66,1049.09,970.019,827.312.
Following compound adopts the similar approach of embodiment 613 to obtain.
Embodiment 614
N-(2-{4-[1-(4-p-methoxy-phenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea
mp：150.5-151.1℃
Mass spectrum (ESI+): m/z=457.2 (m+Na).
1HNMR(400MHz，CDCl3)：2.15(3H，s)，3.6(2H，dt，J＝5，5.4Hz)，3.78(3H，s)，4.04(2H，t，J＝5Hz)，4.5(2H，b.s)，5.08(1H，t，J＝5.4Hz)，6.8(2H，d，J＝9Hz)，6.86(2H，d，J＝8.8Hz)，7.07(2H，d，J＝8.8Hz)，7.13(2H，d，J＝9Hz).
Embodiment 615
N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio group) phenyl]-1H-pyrazoles-5-yl } phenoxy group) ethyl] urea
mp：184.3-184.7℃
Mass spectrum (ESI+): m/z=441.1 (M+Na).
1HNMR(400MHz，DMSOd6)：2.5(3H，s)，3.33(2H，dt，J＝5.6，6.3Hz)，3.95(2H，t，J＝5.6Hz)，5.53(2H，b.s)，6.15(1H，t，J＝6.3Hz)，6.85(1H，s)，6.95(2H，d，J＝8.7Hz)，7.09(1H，t，J＝54.1Hz)，7.2(2H，d，J＝8.7Hz)，7.23(2H，d，J＝8.7Hz)，7.3(2H，d，J＝8.7Hz).
Embodiment 616
N-(2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl) urea
mp：194-196℃
Mass spectrum (ESI+): m/z=410.2 (M+Na).
1HNMR(400MHz，DMSOd6)：2.68(2H，t，J＝7.3Hz)，3.19(2H，dt，J＝5.6，7.3Hz)，3.88(3H，s)，5.42(2H，b.s)，5.95(1H，t，J＝5.6Hz)，6.91(1H，d，J＝8.8Hz)，6.93(1H，s)，7.11(1H，t，J＝54.4Hz)，7.23(4H，s)，7.7(1H，dd，J＝2.8，8.8Hz)，8.15(1H，d，J＝2.8Hz).
Embodiment 617
N-{4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] benzyl } the urea crystal.mp：147-149℃
Mass spectrum (ESI+): m/z=414.1 (M+Na).
1HNMR(400MHz，CDCl3)：3.93(3H，s)，4.37(2H，d，J＝6Hz)，4.52(2H，b.s)，5.08(1H，t，J＝6Hz)，6.73(1H，s)，6.77(1H，d，J＝8.8Hz)，7.18(2H，d，J＝8.3Hz)，7.27(2H，d，J＝8.3Hz)，7.59(1H，dd，J＝2.7，8.8Hz)，8.03(1H，d，J＝2.7Hz).
Embodiment 618
N-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } urea mass spectrum (ESI+): m/z=396.1 (m+Na).
1HNMR(400MHz，DMSOd6)：3.87(3H，s)，4.17(2H，d，J＝6Hz)，5.55(2H，b.s)，6.45(1H，t，J＝6Hz)，6.91(1H，d，J＝8.8Hz)，6.94(1H，s)，7.11(1H，t，J＝53.2Hz)，7.27(4H，s)，7.71(1H，dd，J＝2.7，8.8Hz)，8.14(1H，d，J＝2.7Hz).
Embodiment 619
With N-(2-{4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group ethyl) urea (250mg) and mCPBA (326mg) mixture in CH2Cl2 (10ml) stirred 18 hours.Add saturated NaHCO3 and CH2Cl2.Extract after separating water layer.The organic layer that merges washs (twice) through saturated NaHCO3, and the evaporation of dry back obtains crude product 207mg (79.9%).It is purified through preparation type TLC column chromatography, obtain amorphous N-(2-{4-[1-[4-(methylsulfinyl) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group ethyl) urea (207mg, 80%).
Mass spectrum (ESI+): 475.1 (m+Na).
1HNMR(400MHz，DMSOd6)：2.79(3H，s)，3.3-3.34(2H，m)，3.95(2H，t，J＝5.6Hz)，5.53(2H，b.s)，6.15(1H，t，J＝5.6Hz)，6.97(2H，d，J＝8.8Hz)，7.16(1H，s)，7.23(2H，d，J＝8.8Hz)，7.55(2H，d，J＝8.6Hz)，7.77(2H，d，J＝8.6Hz).
Embodiment 620
With N-(2-{4-[1-[4-(methylthio group) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group ethyl) urea (250mg) and mCPBA (326mg) mixture in CH2Cl2 (10ml) stirred 18 hours.Add saturated NaHCO3 and CH2Cl2.Extract after separating water layer.The organic layer that merges washs (twice) through saturated NaHCO3, the evaporation of dry back, the crude product of acquisition 207mg (79.9%).It is purified through preparation type TLC column chromatography, the amorphous N-of acquisition 116mg (43%) (2-{4-[1-[4-(methylsulfonyl) phenyl]-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea.
Mass spectrum (ESI+): m/z=491.0 (m+Na).
1HNMR(400MHz，DMSOd6)：3.28(3H，s)，3.28-3.34(2H，m)，3.96(2H，t，J＝5.4Hz)，5.54(2H，b.s)，6.16(1H，t，J＝5.4Hz)，6.99(2H，d，J＝8.4Hz)，7.18(1H，s)，7.25(2H，d，J＝8.4Hz)，7.61(2H，d，J＝8.4Hz)，8.01(2H，d，J＝8.4Hz).
Embodiment 621
To acetate 2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (10g) solution that is dissolved in THF (120ml) and MeOH (30ml) adds 1NNaOH (60ml) in room temperature.Reaction mixture was stirred 4 hours down in uniform temp, use 1NHCl (60ml) neutralization then, evaporation back EtOAc extracting twice.Water and salt water washing organic layer, dried over mgso is filtered the back evaporation, obtains crude product.Resistates is purified through silica gel column chromatography, uses the IPE crystallization, filters 2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-the pyridyl)-1H-pyrazoles-5-yl that obtains 3.0g] phenyl } ethanol.The evaporated filtrate after-filtration obtains second crowd of crystal 4 .65g.
Mass spectrum (ESI+): m/z=368.2 (M+Na).
1HNMR(400MHz，CDCl3)：1.49(1H，t，J＝5.8Hz)，2.87(2H，t，J＝6.5Hz)，3.88(2H，dt，J＝5.8，6.5Hz)，6.71(1H，s)，6.76(1H，t，J＝55Hz)，6.75(1H，d，J＝8.8Hz)，7.17(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4Hz)，7.55(1H，dd，J＝2.8，8.8Hz)，8.08(1H，d，J＝2.8Hz).
Embodiment 622
To 2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } CH2Cl2 (75ml) solution of ethanol (7.4g) and Et3N (4.5ml) is at the ice-cooled MsCl (2.5ml) that adds down.Stir after 1 hour, reaction mixture separates after the water quencher.Use the CH2Cl2 aqueous layer extracted, the organic layer that water and salt water washing merge, through dried over mgso, filter the back reduction vaporization, obtain methylsulfonic acid 2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl of oily 10.5g (quantitatively)] phenyl } ethyl ester.
Mass spectrum (ESI+): m/z=446.1 (M+Na).
1HNMR(400MHz，CDCl3)：2.9(3H，s)，3.06(2H，t，J＝6.8Hz)，3.94(3H，s)，4.42(2H，t，J＝6.8Hz)，6.73(1H，s)，6.76(1H，d，J＝8.8Hz)，6.77(1H，t，J＝55Hz)，7.19(2H，d，J＝8.6Hz)，7.23(2H，d，J＝8.6Hz)，7.55(1H，dd，J＝2.6，8.8Hz)，8.04(1H，d，J＝2.6Hz).
Embodiment 623
With methylsulfonic acid 2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (7.4g) and the mixture of Ph (CO) 2NK (3.88g) in DMF (50ml) stirred 8 hours in 60 ℃.Add entry.Extract organic layer twice with EtOAc.Water (twice) and salt solution washing water layer, dried over mgso is filtered the back reduction vaporization.Use the IPE grinding residues, filter after drying, acquisition 7.65g solid 2-(2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl)-1H-isoindole-1,3 (2H)-diketone.
Mass spectrum (ESI+): 475.2 (M+1), 497.2 (M+Na).
1HNMR(400MHz，CDCl3)：3(2H，t，J＝7.6Hz)，3.92(2H，t，J＝7.6Hz)，3.95(3H，s)，6.7(1H，s)，6.73(1H，d，J＝8.8Hz)，6.76(1H，t，J＝55Hz)，7.14(2H，d，J＝8.1Hz)，7.22(2H，d，J＝8.1Hz)，7.46(1H，dd，J＝2.7，8.8Hz)，7.71-7.73(2H，m)，7.83-7.85(2H，m)，8.1(1H，d，J＝2.7Hz).
Embodiment 624
2-(2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl)-1H-isoindole-1,3 (2H)-diketone (5.0g) and the mixture of NH2NH2 (2.8ml) in CH3CN (50ml) were stirred 8 hours in 60 ℃.Filter reaction mixture.Reduction vaporization filtrate.Add 4N HCl/ dioxane, add IPE then.Grinding product filters the back drying under reduced pressure, and acquisition 3.94g (90%) solid (2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl) the amine dihydrochloride.
Mass spectrum (ESI+): m/z=345.2 (M (freedom)+1).
1HNMR(400MHz，DMSOd6)：2.9-2.95(2H，m)，3.01-3.06(2H，m)，3.88(3H，s)，6.92(1H，d，J＝8.8Hz)，6.95(1H，s)，7.13(1H，t，J＝56.1Hz)，7.27(2H，d，J＝8.4Hz)，7.3(2H，d，J＝8.4Hz)，7.72(1H，dd，J＝2.8，8.8Hz)，8.15(1H，d，J＝2.8Hz).
Adopt the similar approach of embodiment 602 to obtain following compound.
Embodiment 625
4-[1-(6-methoxyl group-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] and benzyl } the amine dihydrochloride
Mass spectrum (ESI+): m/z=332.2 (M-NH2), 349.1 (M+H).
1HNMR(400MHz，DMSOd6)：3.88(3H，s)，6.94(1H，d，J＝9.6Hz)，7.25(1H，s)，7.37(2H，d，J＝8Hz)，7.53(2H，d，J＝8Hz)，7.8(1H，dd，J＝2.9，9.6Hz)，8.45(1H，d，J＝2.8Hz).
Embodiment 626
4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl]-benzyl } amine hydrochlorate
Mass spectrum (ESI+): m/z=314.2 (M-NH2), 331.1 (M+1).
1HNMR(400MHz，DMSOd6)：3.88(3H，s)，6.93(1H，d，J＝8.8Hz)，7.00(1H，s)，7.14(1H，t，J＝54Hz)，7.35(2H，d，J＝8.2Hz)，7.53(2H，d，J＝8.2Hz)，7.75(1H，dd，J＝2.7，8.8Hz)，8.15(1H，d，J＝2.7Hz).
Embodiment 627
The solution that is dissolved in EtOH (50ml) to 5-diazanyl-2-methoxypyridine dihydrochloride (4.78g) and Et3N (7.01g) add (2R, 3S)-3-[4-(benzyloxy) phenyl]-the 2-Oxyranyle (cyclopropyl) ketone (5.10g), refluxed 9 hours.Vacuum concentrated mixture.Add AcOEt and 1M HCl to resistates, insolubles is through the filtering of Celite pad.Distribute filtrate, wash organic layer with saturated sodium bicarbonate aqueous solution, the dried over mgso final vacuum concentrates.Resistates is dissolved in CH2Cl2 (50ml).Under the ice bath cooling, add Et3N (5.26g) and methylsulfonyl chloride (2.98g) successively to described solution.Stirred the mixture 2 hours in ambient temperature.Mixture is through 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=20% wash-out, obtains solid 5-{5-[4-(benzyloxy) phenyl]-3-cyclopropyl-1H-pyrazol-1-yl }-2-methoxypyridine (4.20g).
MS(ESI+)：m/z 398(M+H)
1HNMR(200MHz，DMSOd6)：0.69-0.78(2H，m)，0.87-0.97(2H，m)，1.89-1.99(1H，m)，3.85(3H，s)，5.09(2H，s)，6.30(1H，s)，6.85(1H，d，J＝8.8Hz)，6.99(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.8Hz)，7.34-7.46(5H，m)，7.60(1H，dd，J＝2.7，8.8Hz)，8.01(1H，d，J＝2.7Hz)
Embodiment 628
Under the ice bath cooling, add water-soluble carbodiimide hydrochloride (199mg) to (2-{4-[1-(4-p-methoxy-phenyl)-3-carboxyl-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate (313.9mg), piperidines (88.4mg) and the mixture of I-hydroxybenzotriazole (140mg) in DMF (3ml).Mixture stirs in ambient temperature and spends the night, and distributes between AcOEt and H2O then.Separate organic layer, with 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=70% wash-out.Resistates obtains white powder 2-{4-[1-(4-p-methoxy-phenyl)-3-(piperidino-carbonyl)-1H-pyrazoles-5-yl through the IPE crystallization] phenoxy group } ethyl) t-butyl carbamate (332.5mg).
MS(ESI+)：m/z 521(M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，1.53-1.79(6H，m)，3.48-3.57(2H，m)，3.67-3.81(2H，m)，3.82(3H，s)，3.88-4.02(2H，m)，3.98-4.04(2H，m)，4.96(1H，brs)，6.77(1H，s)，6.81(2H，d，J＝8.8Hz)，6.86(2H，d，J＝9.0Hz)，7.15(2H，d，J＝8.8Hz)，7.21(2H，d，J＝9.0Hz)
Following compound adopts the similar approach of embodiment 628 to obtain.
Embodiment 629
(2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Powder
MS(ESI+)：m/z 522(M+H)
1HNMR(200MHz，CDCl3)：1.45(9H，s)，1.54-1.78(6H，m)，3.49-3.57(2H，m)，3.69-3.82(2H，m)，3.86-3.99(2H，m)，3.94(3H，s)，3.99-4.05(2H，m)，4.96(1H，s)，6.73(1H，d，J＝8.8Hz)，6.79(1H，s)，6.84(2H，d，J＝8.8Hz)，7.16(2H，d，J＝8.8Hz)，7.50(1H，dd，J＝2.7，8.8Hz)，8.12(1H，d，J＝2.7Hz)
Embodiment 630
(2-{4-[3-{[ethyl (methyl) amino] carbonyl }-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) t-butyl carbamate
Powder
Mass spectrum (ESI+): m/z 496 (M+H)
1HNMR(200MHz，DMSOd6)：1.08-1.22(3H，m)，1.37(9H，s)，2.98，3.29(3H，s)，3.23-3.32(2H，m)，3.42-3.53，3.63-3.75(2H，m)，3.87(3H，s)，3.93-4.00(2H，m)，6.82，6.84(1H，s)，6.87-7.00(4H，m)，7.21(2H，d，J＝8.6Hz)，7.61-7.72(1H，m)，8.13-8.15(1H，m)
Embodiment 631
2-{4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
mp.121.9-123.8℃
Mass spectrum (ESI+): m/z 422 (M+H)
1HNMR(200MHz，DMSOd6)：1.42-1.74(6H，m)，3.53-3.70(2H，m)，3.65-3.73(2H，m)，3.70-3.92(2H，m)，3.78(3H，s)，3.95-4.00(2H，m)，4.86(1H，t，J＝5.4Hz)，6.77(1H，s)，6.91(2H，d，J＝8.8Hz)，6.98(2H，d，J＝8.9Hz)，7.16(2H，d，J＝8.8Hz)，7.23(2H，d，J＝8.9Hz)
Embodiment 632
2-{4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] phenoxy group } ethanol
mp.123.4-124.0℃
Mass spectrum (ESI+): m/z 423 (M+H)
1HNMR(200MHz，DMSOd6)：1.45-1.74(6H，m)，3.50-3.69(2H，m)，3.65-3.74(2H，m)，3.71-3.90(2H，m)，3.87(3H，s)，3.96-4.02(2H，m)，4.86(1H，t，J＝5.4Hz)，6.81(1H，s)，6.90(1H，d，J＝8.7Hz)，6.94(2H，d，J＝8.6Hz)，7.20(2H，d，J＝8.6Hz)，7.68(1H，dd，J＝2.7，8.7Hz)，8.14(1H，d，J＝2.7Hz)
Embodiment 633
4-[1-(4-p-methoxy-phenyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Amorphous powder
MS(ESI+)：m/z 491(M+H)
1HNMR(200MHz，CDCl3)：1.46(9H，s)，1.55-1.8(6H，m)，3.68-3.82(2H，m)，3.82(3H，s)，3.97-4.00(2H，m)，4.31(2H，d，J＝6.0Hz)，4.84(1H，brs)，6.82(1H，s)，6.86(2H，d，J＝9Hz)，7.15-7.25(6H，m)
Embodiment 634
4-[3-{[ethyl (methyl) amino] carbonyl }-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } t-butyl carbamate
Amorphous powder
MS(ESI+)：m/z 465(M+H)
1HNMR(200MHz，CDCl3)：1.20-1.31(3H，m)，1.46(9H，s)，3.11，3.40(3H，s)，3.61，3.85(2H，q，J＝7.1Hz)，3.82(3H，s)，4.31(2H，d，J＝5.8Hz)，4.86(1H，brs)，6.81-6.90(3H，m)，7.16-7.25(6H，m)
Embodiment 635
4-[3-{[methoxyl group (methyl) amino] carbonyl }-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } t-butyl carbamate
Solid
MS(ESI+)：m/z 467(M+H)
1HNMR(200MHz，CDCl3)：1.46(9H，s)，3.51(3H，s)，3.82(3H，s)，3.85(3H，s)，4.31(2H，d，J＝5.9Hz)，4.87(1H，brs)，6.86(2H，d，J＝9.0Hz)，6.96(1H，s)，7.15-7.26(6H，m)
Embodiment 636
4-[1-(6-methoxyl group-3-pyridyl)-3-(piperidino carbonyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Oily matter
MS(ESI+)：m/z 492(M+H)
1HNMR(200MHz，DMSOd6)：1.39(9H，s)，1.46-1.75(6H，m)，3.52-3.69(2H，m)，3.75-3.93(2H，m)，3.87(3H，s)，4.13(2H，d，J＝6.1Hz)，6.86(1H，s)，6.90(1H，d，J＝8.9Hz)，7.19-7.28(4H，m)，7.41(1H，t，J＝6.1Hz)，7.70(1H，dd，J＝2.7，8.9Hz)，8.13(1H，d，J＝2.7Hz)
Embodiment 637
4-[3-{[ethyl (methyl) amino] carbonyl }-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } t-butyl carbamate
Oily matter
MS(ESI+)：m/z 466(M+H)
1HNMR(200MHz，DMSOd6)：1.09-1.22(3H，m)，1.39(9H，s)，2.98，3.28(3H，s)，3.73-3.77(2H，m)，3.87(3H，s)，4.13(2H，d，J＝6.0Hz)，6.87-6.93(2H，m)，7.18-7.30(4H，m)，7.41(1H，t，J＝6.0Hz)，7.65-7.74(1H，m)，8.14(1H，d，J＝2.6Hz)
Embodiment 638
4-[3-{[methoxyl group (methyl) amino] carbonyl }-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] benzyl } t-butyl carbamate
Powder
MS(ESI+)：m/z 468(M+H)
1HNMR(200MHz，DMSOd6)：1.39(9H，s)，3.37(3H，s)，3.77(3H，s)，3.87(3H，s)，4.13(2H，d，J＝6.1Hz)，6.91(1H，d，J＝8.8Hz)，6.97(1H，s)，7.25(4H，s)，7.42(1H，t，J＝6.1Hz)，7.71(1H，dd，J＝2.7，8.8Hz)，8.15(1H，d，J＝2.7Hz)
Embodiment 639
5-[4-(2-hydroxyethyl) phenyl]-N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
Oily matter
MS(ESI+)：m/z 382(M+H)
1HNMR(200MHz，CDCl3)：1.44(1H，t，J＝5.8Hz)，2.83-2.90(2H，m)，3.51(3H，s)，3.82(3H，s)，3.85(3H，s)，3.84-3.89(2H，m)，6.86(2H，d，J＝9.0Hz)，6.96(1H，s)，7.13-7.26(6H，m)
Embodiment 640
5-[4-(2-hydroxyethyl) phenyl]-N-methoxyl group-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide
Oily matter
Mass spectrum (ESI+): m/z 383 (M+H)
1HNMR(200MHz，CDCl3)：2.84-2.91(2H，m)，3.51(3H，s)，3.85(3H，s)，3.81-3.92(2H，m)，3.95(3H，s)，6.74(1H，d，J＝8.6Hz)，6.97(1H，s)，7.20(4H，s)，7.55(1H，dd，J＝2.8，8.6Hz)，8.13(1H，d，J＝2.8Hz)
Embodiment 641
Solution to { 4-[3-(1-hydroxyl-1-methylethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } t-butyl carbamate (1.1g) and Et3N (1.02g) adds methylsulfonyl chloride (576mg).Stir the mixture in ambient temperature and to spend the night.Vacuum concentrated mixture.Resistates distributes between AcOEt and 1M HCl.Separate organic layer, with saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=25% wash-out.Collect pure part, vacuum concentration, the acquisition solid 4-[3-pseudoallyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate (857mg).
MS(ESI+)：m/z 420(M+H)
1HNMR(200MHz，)：1.46(9H，s)，2.21(3H，s)，3.81(3H，s)，4.30(2H，d，J＝5.9Hz)，4.84(1H，brs)，5.13(1H，brs)，5.60(1H，brs)，6.60(1H，s)，6.84(2H，d，J＝8.9Hz)，7.18-7.26(6H，m)
Following compound adopts the similar approach of embodiment 641 to obtain.
Embodiment 642
4-[3-pseudoallyl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Oily matter
MS(ESI+)：m/z 421(M+H)
1HNMR(200MHz，DMSOd6)：1.39(9H，s)，2.10(3H，s)，3.86(3H，s)，4.12(2H，d，J＝6.2Hz)，5.15(1H，brs)，5.63(1H，brs)，6.88(1H，s)，6.88(1H，d，J＝8.8Hz)，7.22(4H，s)，7.40(1H，t，J＝6.2Hz)，7.67(1H，dd，J＝2.7，8.8Hz)，8.06(1H，d，J＝2.7Hz)
Embodiment 643
THF (8.5ml) solution of 0.76M sec.-propyl bromination magnesium is added dropwise to { 4-[3-{[methoxyl group (methyl) amino] carbonyl }-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl in 10-15 ℃] benzyl } THF (10ml) solution of t-butyl carbamate (1g).Mixture stirred 4 hours in ambient temperature.Reaction mixture is poured into the mixture of 1M HCl and ice.Extract mixture with AcOEt.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=20%, 25% wash-out, uses the 10%MeOH/CHCl3 wash-out again.The pure part that vacuum concentration merges, the acquisition amorphous powder 4-[3-isobutyryl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate (318mg).
MS(ESI+)：m/z 450(M+H)
1HNMR(200MHz，CDCl3)：1.25(6H，d，J＝6.8Hz)，1.46(9H，s)，3.72-3.87(1H，m)，3.83(3H，s)，4.31(2H，d，J＝5.9Hz)，4.75-4.93(1H，m)，6.88(2H，d，J＝9Hz)，6.98(1H，s)，7.14-7.27(6H，m)
Following compound obtains by the similar approach of embodiment 643.
Embodiment 644
4-[3-isobutyryl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] and benzyl } t-butyl carbamate
Oily matter
MS(ESI+)：m/z 451(M+H)
1HNMR(200MHz，DMSOd6)：1.16(6H，d，J＝6.8Hz)，1.38(9H，s)，3.68(1H，m)，3.88(3H，s)，4.13(2H，d，J＝6.1Hz)，6.92(1H，d，J＝8.8Hz)，7.07(1H，s)，7.19-7.29(4H，m)，7.41(1H，t，J＝6.1Hz)，7.75(1H，dd，J＝2.7，8.8Hz)，8.17(1H，d，J＝2.7Hz)
Embodiment 645
To 4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] THF (2ml) solution of cyanobenzene (197mg) adds lithium aluminum hydride (30mg) under the ice bath cooling.Under uniform temp, stirred the mixture 1 hour, and stirred 2 hours in ambient temperature then.Add 5% sodium tartrate aqueous solutions of potassium (ca.0.5ml) quencher reaction.Mixture is diluted with AcOEt, and dried over mgso is after the filtration of Celite pad.Vacuum concentrated filtrate, the acquisition oily 4-[1-(6-methoxyl group-3-pyridyl)-3-(2,2, the 2-trifluoro ethoxy)-1H-pyrazoles-5-yl] and benzyl } amine (200mg).
MS((ESI+)：m/z 379(M+H)
1HNMR(200MHz，DMSOd6)：3.75(2H，s)，3.85(3H，s)，4.84(1H，d，J＝9Hz)，4.93(1H，d，J＝9Hz)，6.32(1H，s)，6.87(1H，d，J＝8.9Hz)，7.19(2H，d，J＝8.2Hz)，7.33(2H，d，J＝8.2Hz)，7.64(1H，dd，J＝2.7，8.9Hz)，8.03(1H，d，J＝2.7Hz)
Following compound adopts the similar approach of embodiment 645 to obtain.
Embodiment 646
1-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } methylamine oily matter
MS：(ESI+)：m/z 314(M+H)
1HNMR(200MHz，DMSOd6)：3.69(2H，s)，3.78(3H，s)，6.72(1H，s)，6.96(2H，d，J＝9Hz)，7.16(2H，d，J＝8.2Hz)，7.22(2H，d，J＝9Hz)，7.3(2H，d，J＝8.2Hz)
Embodiment 647
1-{4-[3-chloro-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } the methylamine powder
MS(ESI+)：m/z 315(M+H)
1HNMR(200MHz，DMSOd6)：3.70(2H，s)，3.86(3H，s)，6.78(1H，s)，6.89(1H，d，J＝8.7Hz)，7.20(2H，d，J＝8.3Hz)，7.33(2H，d，J＝8.3Hz)，7.69(1H，dd，J＝2.7，8.7Hz)，8.10(1H，d，J＝2.7Hz)
Embodiment 648
With 5-[4-(benzyloxy) phenyl]-3-amino-1-(4-p-methoxy-phenyl)-1H-pyrazoles (4.0g), lithium chloride (2.28g) and cupric chloride (II) acetonitrile (50ml) mixture (2.90g) stirred 10 minutes in ambient temperature.Add Isopentyl nitrite (2.52g) to mixture, stirred the mixture 1.5 hours in ambient temperature.The mixture that adds ethyl acetate and saturated aqueous ammonium chloride to reaction mixture.Stir the mixture a moment in ambient temperature, distribute then.With the ethyl acetate water layer of stripping.The organic layer that merges is through saturated aqueous ammonium chloride and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with 20%AcOEt/ normal hexane wash-out.Collect pure part, vacuum concentration obtains solid 5-[4-(benzyloxy) phenyl]-3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles (2.81g).
MS ESI+)：m/z 391(M+H)
1HNMR(200MHz，CDCl3)：3.81(3H，s)，5.05(2H，s)，6.35(1H，s)，6.84(2H，d，J＝9Hz)，6.89(2H，d，J＝8.9Hz)，7.12(2H，d，J＝8.9Hz)，7.19(2H，d，J＝9Hz)，7.34-7.43(5H，m)
Embodiment 649
With the N of 4-benzyloxy Propiophenone (5g), dinethylformamide dimethyl acetal (20ml) solution refluxed 24 hours.Vacuum concentrated mixture.Resistates is dissolved in the toluene final vacuum to be concentrated.Repeat this step more once.Resistates is dissolved in EtOH.Add 4-p-methoxy-phenyl hydrazonium salt hydrochlorate (3.63g), backflow mixture 3 hours to described solution.Reaction mixture is distributed between AcOEt and 1M HCl to ambient temperature.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=30% wash-out, obtains Powdered 5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-4-methyl isophthalic acid H-pyrazoles (5.31g).
MS(ESI+)：m/z 371(M+H)
200MHz 1H NMR(CDCl3，d)：2.10(3H，s)，3.79(3H，s)，5.06(2H，s)，6.80(2H，d，J＝8.9Hz)，6.94(2H，d，J＝8.8Hz)，7.09(2H，d，J＝8.8Hz)，7.14(2H，d，J＝8.9Hz)，7.31-7.48(5H，m)，7.55(2H，s)
Following compound adopts the similar approach of embodiment 649 to obtain.
Embodiment 650
5-{5-[4-(benzyloxy) phenyl]-4-methyl isophthalic acid H-pyrazol-1-yl }-the 2-methoxypyridine
Powder
MS(ESI+)：m/z 372(M+H)
200MHz 1H NMR(CDCl3，d)：2.10(3H，s)，3.91(3H，s)，5.06(2H，s)，6.68(1H，d，J＝8.8Hz)，6.96(2H，d，J＝8.7Hz)，7.09(2H，d，J＝8.7Hz)，7.36-7.52(6H，m)，7.59(1H，s)，8.02(1H，d，J＝2.7Hz)
Embodiment 651
CHCl3 (3ml) drips of solution of nitrite tert-butyl (1.14ml) is added 5-[4-(benzyloxy) phenyl]-CHCl3 (10ml) solution of 1-(4-p-methoxy-phenyl)-3-amino-1H-pyrazoles (1.5g) and dimethyl disulfide (1.15ml).After all nitrite tert-butyl solution adds, reaction mixture is warming up to backflow.After backflow stops, stirring the mixture 1 hour in ambient temperature.Vacuum concentrated mixture, resistates is purified through silica gel column chromatography, with AcOEt/ normal hexane=25% wash-out, obtains oily 5-[4-(benzyloxy) phenyl]-1-(4-p-methoxy-phenyl)-3-(methylthio group)-1H-pyrazoles (635.2mg).
Mass spectrum (ESI+): m/z 403 (M+H)
1HNMR(200MHz，CDCl3)：2.58(3H，s)，3.81(3H，s)，5.04(2H，s)，6.36(1H，s)，6.81-6.91(4H，m)，7.13(2H，d，J＝8.7Hz)，7.20(2H，d，J＝9Hz)，7.34-7.43(5H，m)
Embodiment 652
With 3-cyano group-1-(4-p-methoxy-phenyl)-5-[4-(amino methyl) phenyl]-1H-pyrazoles (90mg), isocyanic acid trimethyl silyl ester (152mg) and the mixture of Et3N (0.18ml) in CH2Cl2 (5ml) be in stirring at room.Stir after 5 hours and (check), add entry and CHCl3 through TLC.Separate organic layer.Use the EtOAc aqueous layer extracted.The organic layer that merges is through water and salt water washing.Dried over mgso is filtered the back reduction vaporization, obtains N-{4-[3-cyano group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl of 48mg (52%)] benzyl } urea.
Mass spectrum (ESI+): m/z=370.1 (M+Na).
1HNMR(200MHz，CDCl3)：3.83(H，s)，4.38(2H，d，J＝6Hz)，4.42(2H，b.s)，4.902-(1H，m)，6.82(1H，s)，6.87(2H，d，J＝9Hz)，7.15(2H，d，J＝8.3Hz)，7.19(2H，d，J＝9Hz)，7.26(2H，d，J＝8.3Hz).
Embodiment 653
Under the ice bath cooling, add thiophosgene (68.8mg) to (2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) CHCl3 (2ml) of amine hydrochlorate (150mg) and the mixture of saturated sodium bicarbonate aqueous solution (1ml).Stirred the mixture 5 hours in ambient temperature.Add 28% ammonium hydroxide aqueous solution (1ml) to mixture, stir the mixture in ambient temperature and spend the night.Add 28% ammonium hydroxide aqueous solution (1ml) and MeOH (1ml) to mixture, in stirring at room mixture 7 hours.Reaction mixture distributes between AcOEt and H2O.Organic layer is through saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Use the ACOEt-IPE crystalline residue.The powder that obtains is through AcOEt-normal hexane recrystallization, obtains Powdered N-(2-{4-[3-methoxyl group-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) thiocarbamide (116mg).
mp.141.6-142.3℃
MS(ESI+)：m/z 399(M+H)
1HNMR(200MHz，DMSOd6)：3.61-3.89(2H，m)，3.75(3H，s)，3.83(3H，s)，3.98-4.12(2H，m)，6.04(1H，s)，6.92(4H，d，J＝8.9Hz)，7.09(2H，brs)，7.13(4H，d，J＝8.9Hz)，7.77(1H，t，J＝5.2Hz)
Embodiment 654
CH2Cl2 (2ml) solution of methylsulfonyl chloride (328mg) is added 5-[4-(2-hydroxyethyl) phenyl under the ice bath cooling]-CH2Cl2 (10ml) solution of N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide (840mg) and Et3N (334mg).Under uniform temp, stirred the mixture 1 hour.With CHCl3 diluted mixture thing, with 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, the dried over mgso final vacuum concentrates.Resistates is purified through silica gel column chromatography, with the just own a heatable brick bed of AcOEt/=80%, 90% wash-out.Collect pure part final vacuum and concentrate, obtain oily methylsulfonic acid 2-{4-[3-{[methoxyl group (methyl) amino] carbonyl }-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (1.01g).
Mass spectrum (ESI+): m/z 460 (M+H)
1HNMR(200MHz，CDCl3)：2.89(3H，s)，3.05(2H，t，J＝6.8Hz)，3.51(3H，s)，3.83(3H，s)，3.85(3H，s)，4.41(2H，t，J＝6.8Hz)，6.86(2H，d，J＝9.0Hz)，6.97(1H，s)，7.18-7.26(6H，m)
Following compounds obtains by the similar approach of embodiment 654.
Embodiment 655
Methylsulfonic acid 2-{4-[3-{[methoxyl group (methyl) amino] carbonyl }-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester
Oily matter
Mass spectrum (ESI+): m/z 461 (M+H)
1HNMR(200MHz，CDCl3)：2.91(3H，s)，3.06(2H，t，J＝6.8Hz)，3.50(3H，s)，3.85(3H，s)，3.94(3H，s)，4.43(2H，t，J＝6.8Hz)，6.74(1H，d，J＝8.8Hz)，6.99(1H，s)，7.32(4H，s)，7.55(1H，dd，J＝2.7，8.8Hz)，8.09(1H，d，J＝2.7Hz)
Embodiment 656
With methylsulfonic acid 2-{4-[3-{[methoxyl group (methyl) amino]-carbonyl }-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl ester (1.02g), 15-hat-5 (489mg), the mixture of sodiumazide (722mg) in HMPA (6ml) stirred 1 hour in 55 ℃.Pour mixture into frozen water, extract mixture with AcOEt.Organic layer washs through saturated sodium-chloride water solution, and the dried over mgso final vacuum concentrates.Resistates is dissolved in MeOH (6ml).Add to this solution that 6M HCl (0.37ml) is dissolved in MeOH (2ml) and 10% carbon carries palladium (50% weight in wet base) solution (200mg).With mixture under H2 (1atm) in ambient temperature hydrogenation 2 hours.Remove by filter catalyzer.Vacuum concentrated filtrate obtains oily 5-[4-(2-amino-ethyl) phenyl]-N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide hydrochloride (0.93g).
Mass spectrum (ESI+): m/z 381 (M+H)
1HNMR(200MHz，DMSOd6)：2.79-3.16(4H，m)，3.38(3H，s)，3.77(3H，s)，3.79(3H，s)，6.95(1H，s)，6.99(2H，d，J＝9.0Hz)，7.15-7.36(6H，m)，8.00(2H，brs)
Following compound adopts the similar approach of embodiment 656 to obtain.
Embodiment 657
5-[4-(2-amino-ethyl) phenyl]-N-methoxyl group-1-(6-methoxyl group-3-pyridyl)-N-methyl isophthalic acid H-pyrazole-3-formamide hydrochloride
Oily matter
Mass spectrum (ESI+): m/z 382 (M+H)
1HNMR(200MHz，DMSOd6)：2.80-3.15(4H，m)，3.38(3H，s)，3.77(3H，s)，3.88(3H，s)，6.92(1H，d，J＝8.8Hz)，6.98(1H，s)，7.22-7.36(4H，m)，7.72(1H，dd，J＝2.7，8.8Hz)，8.02(2H，brs)，8.17(1H，d，J＝2.7Hz)
Embodiment 658
Be added dropwise to 5-(4-{2-[(aminocarboxyl) amino to the THF (2.0ml) of 0.76M sec.-propyl bromination magnesium solution in 4 ℃] ethyl } phenyl)-THF (2ml) solution of N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide (130mg).Stir the mixture in ambient temperature and to spend the night.Add THF (2.0ml) solution of 0.76M sec.-propyl bromination magnesium again, stirred the mixture 5 hours in 50 ℃.Reaction mixture is cooled to ambient temperature, adds saturated aqueous ammonium chloride quencher reaction.Extract mixture with AcOEt.Organic layer is through 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches by MeOH/CHC3 (10%) through preparation type thin layer silica gel chromatographic purification.Isolating silica gel extracts through 10%MeOH/CHCl3, vacuum evaporating solvent, acquisition amorphous powder N-(2-{4-[3-isobutyryl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl) urea (30mg).
MS(ESI+)：m/z 407(M+H)
1HNMR(200MHz，CDCl3)：1.25(6H，d，J＝6.8Hz)，2.77-2.85(2H，m)，3.37-3.48(2H，m)，3.72-3.87(1H，m)，3.83(3H，s)，4.32(2H，s)，4.57(1H，t，J＝4.9Hz)，6.89(2H，d，J＝8.9Hz)，6.96(1H，s)，7.14(4H，s)，7.24(2H，d，J＝8.9Hz)
Following compound adopts the similar approach of embodiment 658 to obtain.
Embodiment 659
N-(2-{4-[3-isobutyryl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl) Toluidrin
Oily matter
MS(ESI+)：m/z 442
1HNMR(200MHz，CDCl3)：1.26(6H，d，J＝6.9Hz)，2.84-2.91(2H，m)，2.87(3H，s)，3.35-3.46(2H，m)，3.73-3.87(1H，m)，3.84(3H，s)，4.21(1H，t，J＝6.1Hz)，6.89(2H，d，J＝9.0Hz)，6.99(1H，s)，7.13-7.29(6H，m)
Embodiment 660
N-(2-{4-[3-isobutyryl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl) urea
Oily matter
MS(ESI+)：m/z 408(M+H)
1HNMR(200MHz，CDCl3)：1.26(6H，d，J＝6.9Hz)，2.79-2.87(2H，m)，3.39-3.50(2H，m)，3.77-(1H，m)，3.95(3H，s)，4.35(2H，s)，4.57(1H，t，J＝5.4Hz)，6.78(1H，d，J＝8.9Hz)，6.98(1H，s)，7.17(4H，s)，7.60(1H，dd，J＝2.7，8.9Hz)，8.07(1H，d，J＝2.7Hz)
Embodiment 661
N-(2-{4-[3-isobutyryl-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl) Toluidrin
Oily matter
MS(ESI+)：m/z 443(M+H)
1HNMR(200MHz，CDCl3)：1.26(6H，d，J＝6.8Hz)，2.85-2.93(2H，m)，2.88(3H，s)，3.36-3.47(2H，m)，3.77(3H，m)，3.95(3H，s)，4.24(1H，t，J＝6.2Hz)，6.78(1H，d，J＝8.8Hz)，7.00(1H，s)，7.19(4H，s)，7.57(1H，dd，J＝2.7，8.8Hz)，8.11(1H，d，J＝2.7Hz)
Embodiment 662
Be added dropwise to 5-(4-{2-[(aminocarboxyl)-amino to cyclopropyl bromination magnesium solution (preparing in THF (1ml) with Cyclopropyl Bromide (257mg) and magnesium (57mg)) in ambient temperature by ordinary method] ethyl } phenyl)-THF (3ml) solution of N-methoxyl group-1-(4-p-methoxy-phenyl)-N-methyl isophthalic acid H-pyrazole-3-formamide (90mg).Stirred the mixture 5 hours in 50 ℃.Reaction mixture is cooled to ambient temperature, adds the saturated aqueous ammonium chloride quencher.Extract mixture with AcOEt.Organic layer is through 1M HCl, saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution washing, and the dried over mgso final vacuum concentrates.Resistates launches by MeOH/CHC3 (10%) through preparation type thin layer silica gel chromatographic purification.With the silica gel of 10%MeOH/CHCl3 extracting and separating, vacuum evaporating solvent, obtain Powdered N-(2-{4-[3-(cyclopropyl carbonyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl) urea (23mg).
Mass spectrum (ESI+): m/z 405 (M+H)
1HNMR(200MHz，CDCl3)：0.99-1.09(2H，m)，1.22-1.30(2H，m)，2.77-2.84(2H，m)，3.13(1H，m)，3.37-3.48(2H，m)，3.84(3H，s)，4.33(2H，s)，4.59(1H，t，J＝5.4Hz)，6.89(2H，d，J＝8.9Hz)，6.96(1H，s)，7.14(4H，s)，7.26(2H，d，J＝8.9Hz)
Following compound adopts the similar approach of embodiment 662 to obtain.
Embodiment 663
N-(2-{4-[3-(cyclopropyl carbonyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenyl } ethyl) Toluidrin
Oily matter
MS(ESI+)：m/z 440(M+H
1HNMR(200MHz，CDCl3)：0.99-1.09(2H，m)，1.22-1.31(2H，m)，2.80-2.91(2H，m)，2.87(3H，s)，3.14(1H，m)，3.35-3.46(2H，m)，3.84(1H，s)，4.22(1H，t，J＝5.7Hz)，6.90(2H，d，J＝9.0Hz)，6.99(1H，s)，7.12(4H，s)，7.27(2H，d，J＝9.0Hz)
Embodiment 664
N-(2-{4-[3-(cyclopropyl carbonyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenyl } ethyl) Toluidrin
Oily matter
Mass spectrum (ESI+): m/z 441 (M+H)
1HNMR(200MHz，CDCl3)：1.03-1.11(2H，m)，1.24-1.32(2H，m)，2.85-2.93(2H，m)，2.88(3H，s)，3.11(1H，m)，3.36-3.47(2H，m)，3.96(3H，s)，4.22(1H，t，J＝6.0Hz)，6.78(1H，d，J＝8.9Hz)，7.00(1H，s)，7.20(4H，s)，7.60(1H，dd，J＝2.7，8.9Hz)，8.13(1H，d，J＝2.7Hz)
Claims (12)
1. structural formula below a kind (I) compound or its salt:
R wherein
1Be hydrogen or low alkyl group;
R
2Be the optional low alkyl group that is replaced by halogen, hydroxyl, lower alkoxy imino-or lower alkoxy; Low-grade alkenyl; Cycloalkyl; Cyano group; Low-grade alkane acidyl; Naphthene base carbonyl; N, N-two (rudimentary) alkyl-carbamoyl; Formamyl; N-lower alkoxy-N-elementary alkyl amido methanoyl; Amino; Two (rudimentary) alkylamino; Elementary alkoxy carbonyl amino; N, N-two (rudimentary) alkyl-carbamoyl amino; N-(N, N-two (rudimentary) alkyl-carbamoyl)-N-low-grade alkyl amino; Halogen; Hydroxyl; Carboxyl; Elementary alkoxy carbonyl; Aroyl; The heterocyclic radical carbonyl; Heterocyclic radical; The low alkyl group alkylsulfonyl; Optional by lower alkoxy, N, the lower alkoxy that N-two (rudimentary) alkyl-carbamoyl or halogen replace; Cycloalkyloxy; Lower alkylthio; Or low alkyl group sulfinyl;
R
3The low alkyl group amino for optional quilt, that formamyl is amino or the low alkyl group sulfuryl amino replaces; Halogen; Cyano group; Hydroxyl; Lower alkanoyloxy; Low-grade alkylidene dioxy base; The optional lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino; Nitro; Amino; Heterocyclic radical; Lower alkylthio; The low alkyl group sulfinyl; Or low alkyl group alkylsulfonyl;
R
4Be hydrogen; Cyano group; Optional by the amino of phthaloyl or low alkyl group replacement; Aryl; Heterocyclic radical; Lower alkoxy; Hydroxyl; The low alkyl group sulfonyloxy; Lower alkanoyloxy; By the low alkyl group of trityl amino and elementary alkoxy carbonyl, amino and elementary alkoxy carbonyl, amino and carboxyl, amino and formamyl or amino and hydroxyl replacement; N-elementary alkoxy carbonyl-N-low-grade alkyl amino; The optional low-grade alkane acidyl that is replaced by halogen; Carboxyl; The low alkyl group alkylsulfonyl; Sulfo group; Low alkyl group silyl oxygen base; Elementary alkoxy carbonyl; The optional sulfamyl that is replaced by low alkyl group; The optional formamyl that is replaced by low alkyl group; Lower alkylthio; The low alkyl group sulfinyl; Formamyl oxygen base; Thioureido; Or the group of following structural formula:
R
5-G-J-
Wherein G be-CO-or-SO
2-; J is-N-(R
6)-(be R wherein
6Be hydrogen or low alkyl group); And R
5For choosing wantonly by the amino of elementary alkoxy carbonyl or low alkyl group replacement; The optional low alkyl group that is replaced by hydroxyl, elementary alkoxy carbonyl amino, lower alkanoyloxy, amino or halogen; Lower alkoxy; Hydrogen; Heterocyclic radical; Or aryl;
X is O, S, SO or SO
2
Y is CH or N;
Z is low-grade alkylidene or lower alkenylene; And
M is 0 or 1;
Precondition is to work as R
4During for hydrogen;
R then
3Be the low alkyl group that quilt is amino, formamyl is amino or the low alkyl group sulfuryl amino replaces; Or the lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino.
2. the compound of claim 1, wherein
R
1Be hydrogen;
R
2Be the optional low alkyl group that is replaced by halogen, hydroxyl, lower alkoxy imino-or lower alkoxy; Cycloalkyl; Halogen; The optional lower alkoxy that is replaced by halogen; Or lower alkylthio;
R
3Be the optional lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino;
R
4Group for following structural formula:
R
5-G-J-
R wherein
5, G is identical with the definition of claim 1 with J;
X is O or S; And
Z is a low-grade alkylidene.
3. the compound of claim 2, wherein
R
2Be the optional low alkyl group that is replaced by halogen; Cycloalkyl; Halogen; Or the optional lower alkoxy that is replaced by halogen;
R
3Be lower alkoxy;
R
4Group for following structural formula:
R
5-G-J-
Wherein G be-CO-or-SO
2-,
J is-NH-and
R
5Be amino or low alkyl group; And
X is O.
4. the compound of claim 3, it is
1) N-(2-{4-[3-chloro-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea,
2) N-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } Toluidrin,
3) N-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] benzyl } urea,
4) N-(2-{4-[3-(difluoromethyl)-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea,
5) N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea,
6) N-(2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea,
7) N-(2-{4-[3-cyclopropyl-1-(4-p-methoxy-phenyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea,
8) N-(2-{4-[3-(difluoromethyl)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea,
9) N-(2-{4-[1-(4-p-methoxy-phenyl)-3-(trifluoromethyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) ethanamide, or
10) N-(2-{4-[3-(2, the 2-difluoroethoxy)-1-(6-methoxyl group-3-pyridyl)-1H-pyrazoles-5-yl] phenoxy group } ethyl) urea.
5. method for preparing following structural formula compound or its salt:
R wherein
1Be hydrogen or low alkyl group;
R
2Be the optional low alkyl group that is replaced by halogen, hydroxyl, lower alkoxy imino-or lower alkoxy; Low-grade alkenyl; Cycloalkyl; Cyano group; Low-grade alkane acidyl; Naphthene base carbonyl; N, N-two (rudimentary) alkyl-carbamoyl; Formamyl; N-lower alkoxy-N-elementary alkyl amido methanoyl; Amino; Two (rudimentary) alkylamino; Elementary alkoxy carbonyl amino; N, N-two (rudimentary) alkyl-carbamoyl amino; N-(N, N-two (rudimentary) alkyl-carbamoyl)-N-low-grade alkyl amino; Halogen; Hydroxyl; Carboxyl; Elementary alkoxy carbonyl; Aroyl; The heterocyclic radical carbonyl; Heterocyclic radical; The low alkyl group alkylsulfonyl; Optional by lower alkoxy, N, the lower alkoxy that N-two (rudimentary) alkyl-carbamoyl or halogen replace; Cycloalkyloxy; Lower alkylthio; Or low alkyl group sulfinyl;
R
3The low alkyl group amino for optional quilt, that formamyl is amino or the low alkyl group sulfuryl amino replaces; Halogen; Cyano group; Hydroxyl; Lower alkanoyloxy; Low-grade alkylidene dioxy base; The optional lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino; Nitro; Amino; Heterocyclic radical; Lower alkylthio; The low alkyl group sulfinyl; Or low alkyl group alkylsulfonyl;
R
4Be hydrogen; Cyano group; Optional by the amino of phthaloyl or low alkyl group replacement; Aryl; Heterocyclic radical; Lower alkoxy; Hydroxyl; The low alkyl group sulfonyloxy; Lower alkanoyloxy; By the low alkyl group of trityl amino and elementary alkoxy carbonyl, amino and elementary alkoxy carbonyl, amino and carboxyl, amino and formamyl or amino and hydroxyl replacement; N-elementary alkoxy carbonyl-N-low-grade alkyl amino; The optional low-grade alkane acidyl that is replaced by halogen; Carboxyl; The low alkyl group alkylsulfonyl; Sulfo group; Low alkyl group silyl oxygen base; Elementary alkoxy carbonyl; The optional sulfamyl that is replaced by low alkyl group; The optional formamyl that is replaced by low alkyl group; Lower alkylthio; The low alkyl group sulfinyl; Formamyl oxygen base; Thioureido; Or the group of following structural formula:
R
5-G-J-
Wherein G be-CO-or-SO
2-; J is-N-(R
6)-(be R wherein
6Be hydrogen or low alkyl group); And R
5For choosing wantonly by the amino of elementary alkoxy carbonyl or low alkyl group replacement; The optional low alkyl group that is replaced by hydroxyl, elementary alkoxy carbonyl amino, lower alkanoyloxy, amino or halogen; Lower alkoxy; Hydrogen; Heterocyclic radical; Or aryl;
X is O, S, SO or SO
2
Y is CH or N;
Z is low-grade alkylidene or lower alkenylene; And
M is 0 or 1;
Precondition is to work as R
4During for hydrogen;
R then
3Be the low alkyl group that quilt is amino, formamyl is amino or the low alkyl group sulfuryl amino replaces; Or the lower alkoxy that is replaced by following group: aryl, hydroxyl, cyano group, amino, elementary alkoxy carbonyl amino, low alkyl group sulfuryl amino or formamyl amino;
This method comprises,
1) make following structural formula compound or its salt:
React under acidic conditions with following structural formula compound or its salt:
Obtain following structural formula compound or its salt:
In the said structure formula, R
1, R
2, R
3, R
4, X, Y, Z and m with above define identical,
Perhaps
2) make following structural formula compound or its salt:
With following structural formula compound (V) or its reactant salt:
R
4-Z-Q (V)
Obtain following structural formula compound or its salt:
In the said structure formula: R
1, R
2, R
3, R
4, Y and Z with above define identically, Xa is O or S, and Q is hydroxyl or sour residue.
6. medicinal compositions, it comprises as claim 1 compound of effective constituent and non-toxic pharmaceutical carrier or vehicle.
7. be used as claim 1 compound of medicine.
8. one kind treats and/or prevents diseases associated with inflammation, various pain, collagenosis, autoimmune disorder, various immunological disease, analgesia, thrombosis, cancer or neurodegenerative disease method, and this method comprises claim 1 compound that the human or animal is given significant quantity.
9. claim 1 compound is used for the treatment of and/or prevents purposes in human or animal's the medicine of following disease in preparation: diseases associated with inflammation, various pain, collagenosis, autoimmune disorder, various immunological disease, analgesia, thrombosis, cancer or neurodegenerative disease.
10. analgesic that comprises claim 1 compound, its can be used for treating and/or preventing by acute or chronic inflammation cause or with pain and do not cause gastrointestinal dysfunction.
11. the analgesic of claim 10, it can be used for treatment or prevents following disease and do not cause gastrointestinal dysfunction: rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, urarthritis or adolescent arthritis cause or with pain; Pain in the back; Neck-shoulder-arms syndrome; Scapulohumeral periarthritis; Postoperative or post-traumatic pain and swelling.
12. a merchant who comprises medicinal compositions and written material sells medicine box, described medicinal compositions comprises the compound (I) of claim 1 definition, and wherein said written material explanation compound (I) can maybe should be used for prevention or treatment diseases associated with inflammation, various pain, collagenosis, autoimmune disorder, various immunological disease, analgesia, thrombosis, cancer or neurodegenerative disease.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002953019A AU2002953019A0 (en) | 2002-12-02 | 2002-12-02 | Azole derivatives |
| AU2002953019 | 2002-12-02 | ||
| AU2002953602 | 2002-12-30 | ||
| AU2003902015 | 2003-04-29 |
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| Publication Number | Publication Date |
|---|---|
| CN1717393A true CN1717393A (en) | 2006-01-04 |
| CN100482647C CN100482647C (en) | 2009-04-29 |
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|---|---|---|---|
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| Country | Link |
|---|---|
| CN (1) | CN100482647C (en) |
| AU (1) | AU2002953019A0 (en) |
| ZA (1) | ZA200503120B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093344A (en) * | 2011-03-17 | 2011-06-15 | 南京工业大学 | N-substituted acetoxypyrazole compound containing thiazolethione or oxazolidinone, preparation method and use |
| CN102203068B (en) * | 2008-10-31 | 2014-03-19 | 东丽株式会社 | Cyclohexane derivative and pharmaceutical use thereof |
| CN105061315A (en) * | 2015-08-06 | 2015-11-18 | 大连理工大学 | A class of 1,5-diphenylpyrazole-3-carboxylic acid compounds and their applications |
| CN112661667A (en) * | 2020-12-28 | 2021-04-16 | 浦拉司科技（上海）有限责任公司 | Preparation method of trifluoroacetamidine |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP7071981B2 (en) * | 2016-09-07 | 2022-05-19 | エフジーエイチ バイオテック，インコーポレーテッド | Disubstituted pyrazole compounds for the treatment of diseases |
-
2002
- 2002-12-02 AU AU2002953019A patent/AU2002953019A0/en not_active Abandoned
-
2003
- 2003-11-14 CN CNB2003801045480A patent/CN100482647C/en not_active Expired - Fee Related
-
2005
- 2005-04-18 ZA ZA200503120A patent/ZA200503120B/en unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102203068B (en) * | 2008-10-31 | 2014-03-19 | 东丽株式会社 | Cyclohexane derivative and pharmaceutical use thereof |
| CN102093344A (en) * | 2011-03-17 | 2011-06-15 | 南京工业大学 | N-substituted acetoxypyrazole compound containing thiazolethione or oxazolidinone, preparation method and use |
| CN102093344B (en) * | 2011-03-17 | 2012-09-26 | 南京工业大学 | N-substituted acetoxy pyrazole compound containing thiazole thione or oxazolidinone, preparation method and application |
| CN105061315A (en) * | 2015-08-06 | 2015-11-18 | 大连理工大学 | A class of 1,5-diphenylpyrazole-3-carboxylic acid compounds and their applications |
| CN105061315B (en) * | 2015-08-06 | 2017-10-24 | 大连理工大学 | A class of 1,5-diphenylpyrazole-3-carboxylic acid compounds and their applications |
| CN112661667A (en) * | 2020-12-28 | 2021-04-16 | 浦拉司科技（上海）有限责任公司 | Preparation method of trifluoroacetamidine |
| CN112661667B (en) * | 2020-12-28 | 2023-02-03 | 浦拉司科技（上海）有限责任公司 | Preparation method of trifluoroacetamidine |
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| Publication number | Publication date |
|---|---|
| AU2002953019A0 (en) | 2002-12-12 |
| CN100482647C (en) | 2009-04-29 |
| ZA200503120B (en) | 2006-12-27 |
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