HK1087102B - Pyrazole derivatives useful as cox-i inhibitors - Google Patents
Pyrazole derivatives useful as cox-i inhibitors Download PDFInfo
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Description
Technical Field
The present invention relates to pyrazole compounds having pharmaceutical activity, processes for their preparation and pharmaceutical compositions comprising them.
Background
Two cyclooxygenase isoenzymes, cyclooxygenase-I (COX-I) and cyclooxygenase-II (COX-II) (Proc. Nat. Acad. Sci. USA 88, 2692-2696(1991)) are known.
Conventional non-steroidal anti-inflammatory compounds (NSAIDs) have inhibitory activity against both COX-I and COX-II (J.biol.chem., 268, 6610-. The treatment with it can produce adverse effects on the gastrointestinal tract, such as bleeding, erosion, gastrointestinal ulcer, etc.
It has been reported that selective inhibition of COX-II has anti-inflammatory and analgesic effects comparable to conventional NSAIDs, but with less occurrence of certain gastrointestinal adverse effects (Pro.Nat.Acad.Sci.USA, 91, 3228-3232 (1994)). Thus, a variety of selective COX-II inhibitors have been prepared. However, these "selective COX-II inhibitors" have been reported to have certain side effects on the kidney and/or to be less effective on acute pain.
In addition, some compounds (e.g., SC-560, moxalactam, etc.) have certain selective inhibitory activity against COX-I. WO98/57910 describes certain compounds having this activity. However, their selectivity for inhibiting COX-I seems to be insufficient for these compounds to be used as clinically acceptable satisfactory analgesics because they cause gastrointestinal disorders.
WO02/055502 describes pyridine derivatives having cyclooxygenase-inhibiting activity, in particular cyclooxygenase-I-inhibiting activity. In addition, WO03/040110 describes certain triazole derivatives having cyclooxygenase inhibitory activity, in particular cyclooxygenase-I inhibitory activity. WO99/51580 describes triazole derivatives having inhibitory activity against cytokine production.
DISCLOSURE OF THE INVENTION
The present invention relates to pyrazole compounds having pharmaceutical activity, such as cyclooxygenase (hereinafter referred to as COX) inhibitory activity, to processes for their preparation, to pharmaceutical compositions containing them and to their use.
Accordingly, it is an object of the present invention to provide pyrazole compounds having COX inhibitory activity.
In yet another aspect, the present invention provides a process for preparing pyrazole compounds.
In a further aspect, the present invention provides a pharmaceutical composition comprising a pyrazole compound as an active ingredient.
In a further aspect, the present invention provides the use of a pyrazole compound for the manufacture of a medicament for the treatment or prevention of various diseases.
The novel pyrazole compounds of the present invention may be compounds of the following general formula (I) or salts thereof:
wherein R is1Is hydrogen or lower alkyl;
R2is lower alkyl optionally substituted by halogen, hydroxy, lower alkoxyimino or lower alkoxy; lower alkenyl; a cycloalkyl group; a cyano group; a lower alkanoyl group; a cycloalkyl carbonyl group; n, N-di (lower) alkylcarbamoyl; a carbamoyl group; n-lower alkoxy-N-lower alkylcarbamoyl; an amino group; di (lower) alkylamino; lower alkoxycarbonylamino; n, N-di (lower) alkylcarbamoylamino; n- (N, N-di (lower) alkylcarbamoyl) -N-lower alkylamino; halogen; a hydroxyl group; a carboxyl group; a lower alkoxycarbonyl group; aroyl; a heterocyclylcarbonyl group; a heterocyclic group; a lower alkylsulfonyl group; lower alkoxy optionally substituted with lower alkoxy, N-di (lower) alkylcarbamoyl or halogen; a cycloalkoxy group; a lower alkylthio group; or lower alkylsulfinyl;
R3Is lower alkyl optionally substituted by amino, carbamoylamino or lower alkylsulfonylamino; halogen; a cyano group; a hydroxyl group; a lower alkanoyloxy group; lower alkylenedioxy; lower alkoxy optionally substituted with: aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; a nitro group; an amino group; a heterocyclic group; a lower alkylthio group; a lower alkylsulfinyl group; or lower alkylA sulfonyl group;
R4is hydrogen; a cyano group; amino optionally substituted with phthaloyl or lower alkyl; an aryl group; a heterocyclic group; lower alkoxy; a hydroxyl group; lower alkylsulfonyloxy; a lower alkanoyloxy group; lower alkyl substituted with: tritylamino and lower alkoxycarbonyl, amino and carboxyl, amino and carbamoyl, or amino and hydroxyl; n-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyl optionally substituted with halogen; a carboxyl group; a lower alkylsulfonyl group; a sulfo group; a lower alkylsilyloxy group; a lower alkoxycarbonyl group; sulfamoyl optionally substituted with lower alkyl; carbamoyl optionally substituted with lower alkyl; a lower alkylthio group; a lower alkylsulfinyl group; a carbamoyloxy group; a thiourea group; or a group of the formula:
R5-G-J-
Wherein G is-CO-or-SO2-；
J is-N (R)6)-
(wherein R is6Is hydrogen or lower alkyl); and is
R5Is amino optionally substituted by lower alkoxycarbonyl or lower alkyl; lower alkyl optionally substituted with hydroxy, lower alkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy; hydrogen; a heterocyclic group; or an aryl group;
x is O, S, SO or SO2；
Y is CH or N;
z is lower alkylene or lower alkenylene; and is
m is 0 or 1;
provided that when R is4When it is hydrogen;
then R is3Is lower alkyl substituted by amino, carbamoylamino or lower alkylsulfonylamino; or is covered withLower alkoxy substituted with: aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino.
The object compound (I) of the present invention can be prepared by the following method.
Method (1)
Method (2)
In the above process, R1、R2、R3、R4X, Y, Z and m are as defined above,
xa is O or S, and
q is a hydroxyl group or an acid residue.
The compounds of formula (I) may contain one or more asymmetric centers and, therefore, they may exist as enantiomers or diastereomers. The present invention includes both isomer mixtures and individual isomers.
The compounds of formula (I) may also exist in tautomeric forms and the invention includes tautomeric mixtures and individual isomers.
The compounds of formula (I) and salts thereof may be in the form of solvates and are within the scope of the present invention. The solvate preferably includes a hydrate and an ethanolate.
Also included within the scope of the present invention are radiolabeled derivatives of compounds of formula (I) suitable for biological studies.
In the above and following description of the present specification, suitable examples of the various definitions falling within the scope of the present invention are described in detail below.
The term "lower" means a group having 1 to 6 carbon atoms, unless otherwise specified.
Thus, "lower alkyl" and the lower alkyl moiety in the terms "lower alkylthio", "lower alkylsulfinyl", "lower alkylsulfonyl" and "lower alkylsulfonylamino" refer to straight or branched aliphatic hydrocarbons such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl and the like, and preferably (C)1-C4) Alkyl, more preferably (C)1-C2) Alkyl, most preferably methyl.
"halogen" may include fluorine atom, chlorine atom, bromine atom and iodine atom, and preferably fluorine atom or chlorine atom, more preferably chlorine atom.
"lower alkyl substituted with halogen" means a monovalent group in which the above-mentioned lower alkyl is substituted with one or more (more preferably 1 to 5, most preferably 1 to 3) of the above-mentioned halogen atoms, such as fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, 2, 2, 2-trifluoroethyl, 2, 2, 2-trichloroethyl, 2, 2, 3, 3, 3-pentafluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl or the like, and is preferably substituted with halogen (C1-C4) Alkyl, more preferably substituted by halogen (C)1-C2) Alkyl, more preferably substituted by fluorine (C)1-C2) Alkyl, more preferably methyl substituted by fluorine, most preferably difluoromethyl or trifluoromethyl.
"lower alkyl substituted with hydroxy" means a monovalent group in which the above-mentioned lower alkyl is substituted with an OH group, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl, hydroxytert-butyl, hydroxyhexyl or the like, and is preferably substituted with hydroxy (C)1-C4) Alkyl, more preferably substituted by hydroxy (C)1-C3) An alkyl group.
"lower alkenyl" means a straight or branched chain aliphatic hydrocarbon having one or more carbon-carbon double bonds, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like, and preferably (C) 2-C4) Alkenyl, more preferably (C)2-C3) An alkenyl group.
"lower alkoxy" means a straight or branched chain aliphatic hydrocarbon oxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or the like, and preferably (C)1-C4) Alkoxy, more preferably (C)1-C2) Alkoxy, most preferably methoxy.
"cycloalkyl" and the cycloalkyl moiety in the terms "cycloalkylcarbonyl" and "cycloalkoxy" mean C3-C10Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bornyl, adamantyl and the like, and preferably C3-C6Cycloalkyl, more preferably C3-C5Cycloalkyl, most preferably cyclopropyl or cyclopentyl.
"Di (lower) alkylamino" means an amino group substituted by the same or different (lower) alkyl group as described above, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylpropylamino, butylethylamino or the like, and preferably [ di (C) alkyl1-C4) Alkyl radical]Amino group, more preferably [ di (C)1-C4) Alkyl radical ]Amino, most preferably dimethylamino.
"lower alkoxycarbonyl" and the lower alkoxycarbonyl moiety in the term "lower alkoxycarbonylamino" mean-CO2- [ (lower) alkyl)]For example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxyCarbonyl group, hexyloxycarbonyl group and the like, and preferably [ (C)1-C4) Alkoxy radical]A carbonyl group, more preferably an ethoxycarbonyl group or a tert-butoxycarbonyl group.
"lower alkanoyl" means carbonyl substituted with hydrogen or the above-mentioned (lower) alkyl, such as formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, pentanoyl, 2-dimethylpropanoyl, hexanoyl or the like, and preferably (C)1-C5) Alkanoyl group, more preferably (C)2-C3) Alkanoyl, most preferably acetyl.
"Cycloalkylcarbonyl" refers to carbonyl substituted with the above cycloalkyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, bornylcarbonyl, adamantylcarbonyl, and the like, and preferably [ (C)3-C6) Cycloalkyl radicals]Carbonyl group, more preferably [ (C)3-C5) Cycloalkyl radicals]Carbonyl, most preferably cyclopropylcarbonyl.
The N, N-di (lower) alkylcarbamoyl moiety in the "N, N-di (lower) alkylcarbamoyl" and the term "N, N-di (lower) alkylcarbamoyl" refer to a carbamoyl group substituted with the same or different lower alkyl group as described above, such as dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl, diisobutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl, ethylmethylcarbamoyl, methylpropylcarbamoyl, butylmethylcarbamoyl, ethylpropylcarbamoyl, butylethylcarbamoyl and the like, and preferably [ di (C) alkylcarbamoyl1-C4) Alkyl radical]Carbamoyl group, more preferably [ di (C)1-C2) Alkyl radical]Carbamoyl, most preferably dimethylcarbamoyl or ethylmethylcarbamoyl.
"lower alkoxy substituted by halogen" means a monovalent group in which the above-mentioned lower alkoxy group is substituted by one or more (more preferably 1 to 5, most preferably 1 to 3) of the above-mentioned halogen atoms, for example fluoromethoxy, chloromethylOxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, chloroethoxy, 2, 2-difluoroethoxy, 2, 2-dichloroethoxy, 2, 2, 2-trifluoroethoxy, 2, 2, 2-trichloroethoxy, 2, 2, 3, 3, 3-pentafluoroethoxy, fluoropropoxy, fluorobutoxy, fluorohexyloxy or the like, and is preferably halogen-substituted (C) 1-C4) Alkoxy, more preferably substituted by halogen (C)1-C2) Alkoxy, more preferably substituted by fluorine (C)1-C2) Alkoxy, more preferably ethoxy substituted with fluorine, most preferably 2, 2-difluoroethoxy.
"lower alkyl substituted with amino" means a monovalent group in which the above-mentioned lower alkyl is substituted with amino, such as aminomethyl, 2-aminoethyl, aminopropyl, 1-aminoisopropyl, 2-aminoisopropyl, aminobutyl, aminoisobutyl, aminot-butyl, aminohexyl or the like, and is preferably substituted with amino (C)1-C4) Alkyl, more preferably substituted by amino (C)1-C2) An alkyl group.
"lower alkyl substituted with carbamoylamino" means a monovalent group in which the above-mentioned (lower) alkyl is substituted with carbamoylamino (ureido), such as carbamoylaminomethyl, 2- (carbamoylamino) ethyl, carbamoylaminopropyl, 1- (carbamoylamino) isopropyl, 2- (carbamoylamino) isopropyl, carbamoylaminobutyl, carbamoylaminoisobutyl, carbamoylamino-t-butyl, carbamoylaminohexyl or the like, and preferably (C) substituted with carbamoylamino 1-C4) Alkyl, more preferably substituted by carbamoylamino (C)1-C2) An alkyl group.
"aryl" and the aryl moiety in the term "aroyl" refer to aromatic hydrocarbon radicals such as phenyl, naphthyl, indenyl or the like, and preferably (C)6-C10) Aryl, more preferably phenyl.
"aroyl" refers to a carbonyl group substituted with the above-mentioned aryl group, such as benzoyl, naphthoyl or the like, and preferably benzoyl.
"lower alkanoyloxy" means a monovalent group in which an oxygen atom is substituted with the above-mentioned lower alkanoyl group, lower alkanoyl such as formyl, acetyl, propionyl, butyryl, 2-methylpropionyl, pentanoyl, 2-dimethylpropanoyl, hexanoyl or the like, and preferably [ (C)1-C4) Alkanoyl radical]Oxy, more preferably [ (C)1-C2) Alkanoyl radical]Oxy, most preferably acetoxy.
"lower alkylene" means a straight or branched chain aliphatic hydrocarbon divalent group such as methylene, ethylene, 1-methylethylene, 2-methylethylene, propylene, methylpropylene, butylene, pentylene, hexylene, and the like, and preferably (C)1-C4) Alkylene, more preferably (C)1-C2) An alkylene group.
"lower alkylenedioxy" means-O- [ (lower) alkylene ]-an O-group. I.e. R in this case3Is a divalent group and is also substituted at the next carbon atom. Examples of such groups are methylenedioxy, ethylenedioxy, methylethylenedioxy, propylenedioxy and the like, and preferably [ (C)1-C4) Alkylene radical]Dioxy, more preferably [ (C)1-C2) Alkylene radical]Dioxy, most preferably methylenedioxy.
"lower alkoxy substituted by aryl" means a monovalent group in which the above-mentioned lower alkoxy is substituted by the above-mentioned aryl.
"lower alkoxy substituted by hydroxy" means a monovalent group in which the above-mentioned lower alkoxy is substituted by hydroxy.
"lower alkoxy substituted with cyano" means a monovalent group in which the above-mentioned (lower) alkoxy is substituted with cyano, such as cyanomethoxy, cyanoethoxy, cyanopropoxy, cyanobutoxy and the like, and is preferably substituted with cyano (C)1-C4) Alkoxy radicalRadical, more preferably substituted by cyano (C)1-C2) Alkoxy, most preferably cyanomethoxy.
"lower alkoxy substituted by amino" means a monovalent group in which the above-mentioned lower alkoxy is substituted by amino.
"lower alkoxy substituted by lower alkoxycarbonylamino" means lower alkoxy substituted by amino substituted by the above-mentioned lower alkoxycarbonyl.
"lower alkoxy substituted by lower alkylsulfonylamino" means a monovalent group in which the above-mentioned lower alkoxy is substituted by the above-mentioned lower alkylsulfonylamino.
"lower alkoxy substituted by carbamoylamino" means a monovalent group wherein the above-mentioned lower alkoxy is substituted by (carbamoyl) amino (urea), e.g., [ (carbamoyl) amino]Methoxy, [ (carbamoyl) amino]Ethoxy [ (carbamoyl) amino]Propoxy, [ (carbamoyl) amino]Cyanobutoxy, and the like, and is preferably substituted with [ (carbamoyl) amino group]Substituted (C)1-C4) Alkoxy, more preferably [ (carbamoyl) amino group]Substituted (C)1-C2) Alkoxy, most preferably carbamoylaminomethoxy.
"lower alkoxy (alkoky) carbonylamino" means an amino group substituted with the above-mentioned lower alkoxycarbonyl group.
"lower alkylsulfonylamino" refers to sulfonylamino substituted with lower alkyl as described above.
Suitable "heterocyclic group" may be a group containing at least one heteroatom selected from nitrogen, sulfur and oxygen atoms, and may include saturated or unsaturated monocyclic or polycyclic heterocyclic groups, and preferably the heterocyclic group may be an N-containing heterocyclic group, for example, an unsaturated 3-to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [ e.g., 4H-1, 2, 4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc. ], tetrazolyl [ e.g., 1H-tetrazolyl, 2H-tetrazolyl, etc. ], or the like; saturated 3-to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms [ e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, homopiperazinyl, etc. ]; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazopyridinyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [ e.g., tetrazolo [1, 5-b ] pyridazinyl, etc. ], quinoxalinyl, etc.; unsaturated 3-to 6-membered heteromonocyclic group containing an oxygen atom such as pyranyl, furyl and the like; saturated 3-to 6-membered heteromonocyclic groups containing an oxygen atom, such as 1H-tetrahydropyranyl, tetrahydrofuranyl and the like; unsaturated 3-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms, such as thienyl group and the like; unsaturated 3-to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [ e.g., 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 5-oxadiazolyl, etc. ], oxazolinyl [ e.g., 2-oxazolinyl, etc. ], etc.; saturated 3-to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [ e.g., morpholinyl, etc. ]; unsaturated fused heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [ e.g., benzofurazanyl, benzooxazolyl, benzooxadiazolyl, etc. ]; unsaturated 3-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [ e.g., 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc. ], etc.; saturated 3-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [ e.g., thiazolidinyl, etc. ]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [ e.g., benzothiazolyl, benzothiadiazolyl, etc. ]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms [ e.g., benzofuranyl group, benzodioxolyl group, chromanyl group, etc. ], and the like.
The "heterocyclic group" may be substituted with the above-mentioned lower alkyl group or oxo group, and among them, a piperidyl group, a pyrrolyl group, a 3-methyl-1, 2, 4-oxadiazol-5-yl group, an isoindole-1, 3-diketo-2-yl group or a 1-methyl-1H-imidazolyl group is preferable.
The heterocyclic moiety in the term "heterocyclylcarbonyl" refers to the above-mentioned heterocyclyl group, preferably piperidinyl.
"lower alkylsulfonyloxy" refers to sulfonyloxy substituted with the above lower alkyl.
"lower alkanoyl substituted with halogen" means the above-mentioned lower alkanoyl substituted with the above-mentioned halogen, for example, trifluoroacetyl group and the like.
"lower alkylsilyloxy" means a silyloxy group substituted with the same or different (lower) alkyl group as described above, for example, trimethylsilyloxy, triethylsilyloxy, t-butyldimethylsilyloxy or the like, and preferably t-butyldimethylsilyloxy.
"acid residue" means halogen (e.g., fluorine, chlorine, bromine, iodine), arylsulfonyloxy (e.g., benzenesulfonyloxy, toluenesulfonyloxy, etc.), alkanesulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, etc.), and the like.
Preference is given to compounds (I): r1Is hydrogen; r2Is lower alkyl optionally substituted by halogen, cycloalkyl, halogen, or lower alkoxy optionally substituted by halogen; r 3Is lower alkoxy; r4Is R5-G-J- (wherein G is-CO-or-SO)2-, J is-NH-, R5Is amino or lower alkyl); x is O; y is CH or N; z is lower alkylene; and m is 0 or 1.
Suitable salts of compound (I) are pharmaceutically acceptable conventional non-toxic salts, including metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, etc.), organic acid salts (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.), inorganic acid salts (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.), amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.) salts, or the like.
The process for producing the objective compound is described in detail below.
Method (1)
The target compound (Ia) or a salt thereof can be prepared by reacting compound (II) or a salt thereof with compound (III) or a salt thereof under acidic conditions (for example, using acetic acid).
Suitable salts of compounds (Ia) and (III) may be the same as the example salts of compound (I).
Suitable salts of compound (II) may be examples of acid addition salts of compound (I).
The reaction is carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol, isopropanol, etc.), tetrahydrofuran, dioxane, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
Depending on the starting materials, heterocycles are formed but no pyrazole ring is formed. In this case, dehydration is required in order to form a pyrazole ring.
The dehydration process is carried out at higher temperatures.
Method (2)
The target compound (Ib) or a salt thereof can be prepared by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof.
Suitable salts of compounds (Ia), (IV) and (V) may be example salts of compound (I).
When the compound (V) in which Q is a halogen is used for the reaction, the reaction is preferably carried out in the presence of a base such as an alkali metal (e.g., sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium, calcium, etc.), a hydride or hydroxide, or a carbonate or bicarbonate thereof.
When the compound (V) in which Q is a hydroxyl group is used for the reaction, the reaction is preferably carried out in the presence of diethyl azodicarboxylate and triphenylphosphine.
The reaction is usually carried out in a conventional solvent which adversely affects the reaction, such as water, dioxane, an alcohol (e.g., methanol, ethanol, etc.), acetonitrile, tetrahydrofuran, acetic acid, N-dimethylformamide, or a mixture thereof.
The reaction temperature is not critical and the reaction can be carried out under cooling to heating.
To illustrate the usefulness of the target compound (I), the pharmacological test data of the compound (I) are as follows.
[A] Analgesic activity:
effect on adjuvant arthritis in rats:
(i) the test method comprises the following steps:
the analgesic activity of a single dose of the drug on rat arthritis was studied.
Arthritis was induced by injecting the right hind footpad of 7-week-old Lewis rats with 50. mu.l of liquid paraffin containing 0.5mg of Mycobacterium tuberculosis (Difco laboratories, Detroit, Mich.). Arthritic rats were randomized (n-10) and drug treatment was performed according to the left hind paw pain threshold and body weight on day 22.
The drug (test compound) was administered and the pain threshold was measured 2 hours after administration. Hyperalgesia intensity was assessed by the Randall-Selitto method. The mechanical pain threshold of the left hind paw (non-injected hind paw) was determined by compression of the ankle joint using a balanced pressure gauge (Ugo Basile co. Rats are expressed in grams for scream or struggle threshold pressure. Drug-treated rat threshold pressure was compared to untreated rat threshold pressure. The dose at the ratio of 1.5 is the effective dose.
(ii) And (3) testing results:
| test Compound (example No.) | Dosage (mg/kg) | Coefficient of analgesia |
| 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 inhibitory Activity (whole blood assay):
(i) The test method comprises the following steps:
COX-I whole blood assay
Fresh blood was collected from volunteers with a syringe without anticoagulant. The subject had no significant inflammation and had not taken any medication for at least 7 days prior to blood collection.
Immediately after blood draw, a 500. mu.l aliquot of human whole blood was incubated with 2. mu.l of either dimethyl sulfoxide vehicle or the final concentration of test compound for 1 hour at 37 ℃ for clotting of the blood. Appropriate treatments (no incubation) were used as blank control. At the end of the incubation, 5. mu.l of 250mM indomethacin was added to stop the reaction. The blood was centrifuged at 6000 Xg for 5 minutes at 4 ℃ to obtain serum. A100. mu.l aliquot of serum was mixed with 400. mu.l of methanol to precipitate the proteins. Centrifuging at 4 deg.C at 6000 XgThe supernatant was obtained in 5 minutes and TXB was measured using an enzyme immunoassay kit according to the method provided by the manufacturer2. For the test compounds, thromboxane B was the result2(TXB2) The percent inhibition of the product relative to a control incubation containing the dimethylsulfoxide vehicle is expressed.
The data were analyzed by converting the indicated concentrations of test compounds to logarithmic values and performing a simple linear regression. IC (integrated circuit)50The values are calculated by the least squares method.
COX-II whole blood assay
Fresh blood was collected from volunteers into heparinized tubes with syringes. The subject had no significant inflammation and had not taken any medication for at least 7 days prior to blood collection.
Aliquots of 500. mu.l of human whole blood were incubated with 2. mu.l of dimethyl sulfoxide as vehicle or 2. mu.l of the test compound at the final concentration for 15 minutes at 37 ℃. Then incubated with 10. mu.l of 5mg/ml lipopolysaccharide at 37 ℃ for 24 hours to induce COX-II. Appropriate PBS treatment (without LPS) was used as a blank control. At the end of the incubation, the blood was centrifuged at 6000 Xg for 5 minutes at 4 ℃ to obtain plasma. Protein was precipitated by mixing 100. mu.l aliquots of plasma with 400. mu.l methanol. The supernatant was obtained by centrifugation at 6000 Xg for 5 minutes at 4 ℃ and subjected to radioimmunoassay kit in PGE according to the method provided by the manufacturer2Determination of prostaglandin E after conversion to its methyl oxime salt derivative2(PGE2)。
For the test compounds, the results are given as PGE2The percent inhibition of the product relative to a control incubation containing the dimethylsulfoxide vehicle is expressed. The data were analyzed by converting the indicated concentrations of test compounds to logarithmic values and performing a simple linear regression analysis. IC (integrated circuit)50The values are calculated by the least squares method.
(ii) And (3) testing results:
| test Compound (example No.) | COX-IIC50(μM) | COX-IIIC50(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 |
The above test results show that the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an inhibitory activity against COX, particularly a selective inhibitory activity against COX-I.
[C] Inhibitory Activity on platelet aggregation
(i) Method of producing a composite material
Preparation of platelet-enriched plasma
Blood was collected from healthy human volunteers into plastic tubes containing 3.8% sodium citrate (1/10 vol). The subject did not take any medication for at least 7 days prior to blood collection. After centrifugation at 1200rpm for 10 minutes, platelet-rich plasma was obtained from the supernatant fraction of the blood. After centrifugation of the remaining blood at 3000rpm for 10 minutes, platelet-free plasma was obtained.
Measuring platelet aggregation
Platelet aggregation was measured by nephelometry using an aggregometer (Hema tracker). Platelet-enriched plasma was preincubated for 2 minutes at 37 ℃ in a cuvette after addition of compound or vehicle. To measure the inhibitory effect of each compound, the maximum increase in light transmission at 7 minutes after addition of the agonist was determined from the aggregation curve. In this study, we used collagen as a platelet aggregation agonist. The final concentration of collagen was 0.5. mu.g/mL. The effect of each compound is expressed as the percent inhibition of agonist-induced platelet aggregation relative to control vehicle treatment. Data are mean ± s.e.m. of 6 experiments. IC (integrated circuit)50Values were obtained by linear regression as the concentration of compound required for agonist-induced platelet aggregation to produce 50% inhibition relative to control vehicle treatment.
The above test results show that the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an inhibitory activity against platelet aggregation. Therefore, the compound (I) or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of platelet aggregation-induced disorders such as thrombosis.
Furthermore, it was further confirmed that the compound (I) of the present invention has no non-selective NSAID side effects such as gastrointestinal disorders, bleeding, nephrotoxicity, cardiovascular side effects and the like.
As shown above, the object compound (I) of the present invention or a pharmaceutically acceptable salt thereof has COX inhibitory activity and excellent activities of anti-inflammatory, antipyretic, analgesic, antithrombotic, anticancer and the like.
Accordingly, the object compound (I) and pharmaceutically acceptable salts thereof can be used for the treatment and/or prevention of COX mediated diseases, inflammatory diseases, various pains, collagen diseases, autoimmune diseases, various immune diseases, thrombosis, cancer and neurodegenerative diseases, by systemic or topical administration to humans or animals.
More specifically, the object compound (I) and pharmaceutically acceptable salts thereof are useful for the treatment and/or prevention of inflammation of joints and muscles and acute and chronic pain [ e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral periarthritis, cervical spondylosis, etc. ]; lumbago; inflammatory skin diseases [ e.g., sunburn, burn, eczema, dermatitis, etc. ]; inflammatory eye diseases [ e.g., conjunctivitis, etc. ]; pulmonary diseases involving inflammation [ e.g., asthma, bronchitis, pigeon lover's disease, farmer's lung, etc. ]; gastrointestinal diseases accompanied by inflammation [ e.g., aphthous ulcer, Chrohn's disease, allergic gastritis, variola gastritis, ulcerative colitis, celiac disease, crohn's disease, irritable bowel syndrome, etc. ]; gingivitis; dysmenorrhea; post-operative or post-traumatic inflammation, pain and swelling [ post-odontectomy pain, etc. ]; fever, pain and other conditions that accompany inflammation, particularly conditions in which lipoxygenase and cyclooxygenase products are the causative factors; systemic lupus erythematosus, scleroderma, polymyositis, tendonitis, bursitis, nodular adventititis, rheumatic fever, Sjogren's syndrome, Behcet's disease, thyroiditis, type I diabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis, uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimer's disease, or the like.
In addition, the object compound (I) or a salt thereof is expected to be useful as a therapeutic and/or prophylactic agent for cardiovascular diseases or cerebrovascular diseases caused by hyperglycemia and hyperlipidemia.
The target compound (I) and a salt thereof are useful for preventive and therapeutic treatment of arterial thrombosis, arteriosclerosis, ischemic heart diseases [ e.g., angina pectoris (e.g., stable angina pectoris, unstable angina pectoris including frequent infarction, etc.), myocardial infarction (e.g., acute myocardial infarction, etc.), coronary thrombosis, etc. ], ischemic encephalopathy [ e.g., cerebral infarction (e.g., acute cerebral thrombosis, etc.), cerebral thrombosis (e.g., cerebral embolism, etc.), transient cerebral ischemia (e.g., transient ischemic attack, etc.), cerebral vasospasm after cerebral hemorrhage (e.g., cerebral vasospasm after subarachnoid hemorrhage, etc. ], pulmonary vascular diseases (e.g., pulmonary thrombosis, pulmonary embolism, etc.), peripheral circulation disorders [ e.g., arteriosclerosis obliterans, thromboangiitis obliterans (i.e., Buerger's disease), Raynaud's disease, diabetic complications (e.g., diabetic vascular disease), Diabetic neuropathy, etc.), phiebothrombosis (e.g., deep venous thrombosis, etc.), tumor complications (e.g., pressure thrombosis), abortion [ e.g., placental thrombosis, etc. ], restenosis and reocclusion [ e.g., restenosis and/or reocclusion after Percutaneous Transluminal Coronary Angioplasty (PTCA), restenosis and/or reocclusion after administration of thrombolytic drug (e.g., tissue fibrinolysin activating factor (TPA), etc.) ], thrombosis in vascular surgery, valve replacement, extracorporeal circulation [ e.g., surgery (e.g., open heart surgery, pump oxygenator, etc.) hemodialysis, etc. ], or in the case of transplantation, Disseminated Intravascular Coagulation (DIC), thrombotic thrombocytopenia, essential thrombocytosis, inflammation (e.g., nephritis, etc.), immunological diseases, atrophic thrombosis, paranoid thrombosis, etc. ], venous dilatation thrombosis, jumping thrombosis, mural thrombosis, and the like.
The object compound (I) and a salt thereof can be used for adjunctive therapy with a thrombolytic drug (e.g., TPA or the like) or an anticoagulant (e.g., heparin or the like).
Furthermore, compound (I) may also be used to inhibit thrombosis during extracorporeal circulation (e.g. dialysis).
Specifically, examples are the following diseases: pain caused by or accompanied by rheumatoid arthritis, osteoarthritis, lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, juvenile arthritis, and the like; lumbago; neck-shoulder-arm syndrome; scapulohumeral periarthritis; pain and swelling after surgery or trauma.
Commercial kits containing the above pharmaceutical compositions may be provided with instructions for the above action.
For therapeutic purposes, the compounds (I) and pharmaceutically acceptable salts thereof of the present invention may be used in the form of pharmaceutical preparations comprising the compounds as active ingredients in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or external administration. The pharmaceutical preparation may be in the form of capsules, tablets, dragees, granules, inhalants, suppositories, solutions, lotions, suspensions, emulsions, ointments, gels, creams or the like. These formulations may, if desired, comprise: adjuvants, stabilizers, wetting or emulsifying agents, buffers and other additives commonly used.
For therapeutic purposes, the analgesic drug of the present invention can be used in the form of a pharmaceutical preparation suitable for oral, parenteral or external administration. The pharmaceutical preparation may be in the form of capsules, tablets, dragees, granules, inhalants, suppositories, solutions, lotions, suspensions, emulsions, ointments, gels or the like.
Specifically, the analgesic drug of the present invention can be administered systemically or topically to a human or animal to treat or prevent acute and chronic pain associated with acute and chronic inflammation.
Although the therapeutically effective dose of compound (I) should vary depending on the age and individual condition of each patient, the average single dose of compound (I) effective for the treatment of the above-mentioned diseases is about 0.01mg, 0.1mg, 1mg, 10mg, 50mg, 100mg, 250mg, 500mg and 1000 mg. Generally, the amount administered per day can be between about 0.01 mg/subject to about 1,000 mg/subject.
In the above and in the following description of the present invention, the meanings of the following abbreviations and acronyms are shown in the following table.
| Acronyms and acronyms | Full name |
| AcOEt or EtOAc | Ethyl acetate |
| AcOH | Acetic acid |
| BuOH, t-BuOH and the like | Butanol, t-butanol, etc |
| DME | 1, 2-dimethoxyethane |
| DMF | N, N-dimethylformamide |
| DMSO | Dimethyl sulfoxide |
| Et3N | Triethylamine |
| EtOH | Ethanol |
| IPE | Diisopropyl ether |
| MeOH | Methanol |
| PrOH, i-PrOH or IPA and the like | Propanol, isopropanol, etc |
| TFA | Trifluoroacetic acid |
| THF | Tetrahydrofuran (THF) |
| EDCI or WSCD | 1-ethyl-3- [ 3' - (dimethylamino) propyl]Carbodiimides |
| HOBt or HOBT | 1-hydroxybenzotriazoles |
| Pd/C | Palladium on carbon |
| MCBA or mCPBA or mCPBA | 3-Chloroperbenzoic acid |
| deg | Degree centigrade |
| min | Minute (min) |
| hr or h | Hour(s) |
| conc. | Concentrated |
| aq | Aqueous (e.g. aqueous NaHCO3 solution) |
The examples and preparations given below are only intended to illustrate the invention in more detail.
Examples 1 to 1
(1E) -1- [4- (methoxymethyloxy) phenyl ] -4-methyl-1-penten-3-one
A solution of 4-methoxymethoxybenzaldehyde (4.52g) and 3-methyl-2-butanone (4.69g) in ethanol (27ml) was added to a 1M aqueous solution of sodium hydroxide (5.4ml), and the mixture was stirred at room temperature overnight.
The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate/n-hexane to give the title compound as an oil (4.03g, 63.2%).
1H NMR(CDCl3)：δ 1.18(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).
Examples 1 to 2
(1S, 2R) -and (1R, 2S) -1, 2-epoxy-1- [4- (methoxymethyloxy) phenyl ] -4-methyl-3-pentanone
Mixing with 30% of H2O2(1.7ml) and a 3M aqueous solution (1.7ml) of sodium hydroxide were added to (1E) -1- [4- (methoxymethoxy) phenyl ] obtained in example 1-1]-4-methyl-1-penten-3-one (2.00g) in ethanol acetone ═ 3:1(34 ml). The mixture was stirred at room temperature overnight.
The mixture was concentrated in vacuo and then partitioned between ethyl acetate and water. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to obtain the objective compound (2.03g, 95%) as an oil.
1H NMR(DMSO-d6)：δ 1.05(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).
Examples 1 to 3
4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] -phenol
A mixture of (1S, 2R) -and (1R, 2S) -1, 2-epoxy-1- [4- (methoxymethoxy) phenyl ] -4-methyl-3-pentanone obtained in example 1-2 (2.10g) and 4-methoxyphenylhydrazine hydrochloride (1.76g) in ethanol ═ acetic acid 20:1(20ml) was stirred at 60 ℃ for 3 hours.
The mixture was concentrated in vacuo. To the residue were added ethyl acetate and 1M hydrochloric acid. The whole mixture was treated with activated carbon and filtered through a pad of celite. The filtrate was partitioned. The organic layer was washed successively with 1M hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residual solid was collected and washed with ethyl acetate to give the title compound (322.2mg, 12.5%) as a white powder.
1H NMR(CDCl3)：δ 1.33(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＝9.0Hz)，7.08(2H，d，J＝8.8Hz)，7.20(2H，d，J＝9.0Hz).MS(ESI+)：m/z 309(M+H).
Example 2
2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] -phenoxy } ethylcarbamic acid tert-butyl ester
Diethyl azodicarboxylate (259mg) was added to a mixture of 4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol (305mg), 2-tert-butoxycarbonylaminoethanol (479mg), and triphenylphosphine (390mg) in tetrahydrofuran (3ml) obtained in example 1-3. After stirring at room temperature for 7 hours, diethyl azodicarboxylate (17mg) and triphenylphosphine (26mg) were added to the reaction mixture.
After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 30% ethyl acetate/n-hexane, to give the title compound (396mg, 88.5%) as a solid.
1H NMR(CDCl3)：δ 1.34(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).
Example 3
2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride
4M hydrochloric acid/dioxane (2ml) was added to a solution of tert-butyl 2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] -phenoxy } ethylcarbamate (382mg) obtained in example 2 in dichloromethane (3ml) at 0 ℃.
After stirring at room temperature for 1 hour, the reaction mixture was concentrated in vacuo. The residue was crystallized from a mixture of isopropyl alcohol and ethyl acetate to obtain the objective compound (311mg, 94.7%) as a powder.
1H NMR(DMSO-d6)：δ 1.27(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).
Example 4
N- (2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } -ethyl) methanesulfonamide
Methanesulfonyl chloride (32.2mg) was added to a solution of 2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine hydrochloride (90.9mg) obtained in example 3 and triethylamine (71.1mg) in dichloromethane (2 ml). The mixture was stirred at room temperature for 2 hours.
The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and a mixture of 1M hydrochloric acid and brine. The aqueous layer was back-extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and isopropyl ether to give the title compound (78.0mg, 77.5%) as a white powder.
MP：162-163℃.
1H NMR(DMSO-d6)：δ 1.26(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.
Example 5
N- (2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
Trimethylsilyl isocyanate (41.4mg) was added to a solution of 2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride (93.0mg) and triethylamine (72.8mg) obtained in example 3 in methylene chloride (3ml), and the mixture was stirred at room temperature for 3 hours. Trimethylsilyl isocyanate (8.3mg) was added to the solution, and the mixture was stirred at room temperature for 1.5 hours. Trimethylsilyl isocyanate (13.8mg) and triethylamine (12.1mg) were added to the solution, and the mixture was stirred at room temperature for 1.5 hours.
The mixture was concentrated in vacuo and the residue partitioned between chloroform and a mixture of 1M hydrochloric acid and brine. The aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with 10% methanol/chloroform. The separated silica gel was extracted with 10% methanol/chloroform and the solvent was evaporated in vacuo. The residue was crystallized from a mixture of ethyl acetate and isopropyl ether to give the title compound (85.7mg, 90.6%) as a white powder.
MP：100-104℃.
1H NMR(DMSO-d6)：δ 1.26(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).
Example 6
2- {4- [3- (1-hydroxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
Tetrahydrofuran (10ml) containing tert-butyl 2- {4- [ 3-ethoxycarbonyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate (1.37g) was added dropwise to a solution of 0.93M methylmagnesium bromide in tetrahydrofuran (16ml) at 24-27 ℃ with cooling in a water bath.
After stirring at room temperature for 1 hour, the mixture was poured into a mixture of saturated aqueous ammonium chloride solution and ice. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 70% ethyl acetate/n-hexane, to give the title compound (1.17g, 88%) as an amorphous powder.
MS(ESI+)：m/z 468(M+H)
1H NMR(CDCl3)：δ 1.45(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).
Example 7
2- {4- [ 3-Isopropen-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
Methanesulfonyl chloride (367mg) and triethylamine (649mg) were successively added to a solution of tert-butyl 2- {4- [3- (1-hydroxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate (1.0g) obtained in example 6 and N, N-dimethylformamide (91.5mg) in dichloromethane (10ml), and the mixture was stirred at room temperature for 2 hours. Additional methanesulfonyl chloride and triethylamine were added and stirred at the same temperature until all starting material was consumed.
The reaction mixture was partitioned between ethyl acetate and 1M hydrochloric acid, and the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 30% ethyl acetate/n-hexane, to give the title compound (900mg, 93.6%) as an amorphous powder.
1H NMR(CDCl3)：δ 1.45(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).
Example 8
2- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
10% Pd-C50% wet weight (65mg) and 2- {4- [ 3-isopropenyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] obtained in example 7 were added]Method for producing phenoxy ethyl carbamic acid tert-butyl ester (645mg) in tetrahydrofuran (2ml) and methanol (4ml) The mixture is in H2(1atm) at room temperature for 3 hours.
The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and isopropyl ether to give the title compound (370mg, 57.1%) as a white powder.
1H NMR(CDCl3)：δ 1.34(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).
Example 9
2- {4- [3- (1-hydroxy-1-methylethyl) -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (624.4mg, 42.9%) was prepared as an amorphous powder using tert-butyl 2- {4- [3- (1-hydroxy-1-methylethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate in a similar manner to example 6.
1H NMR(CDCl3)：δ 1.45(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).
Example 10
2- {4- [ 3-Isopropenyl-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (495mg, 85.7%) was prepared as an oil using tert-butyl 2- {4- [3- (1-hydroxy-1-methylethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 9 by a similar method to that of example 7.
1H NMR(CDCl3)：δ 1.45(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＝8.8Hz)，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).
Example 11
2- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
An amorphous powdery title compound (220mg, quantitative) was prepared using tert-butyl 2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 10 in a similar manner to example 8.
1H NMR(CDCl3)：δ 1.34(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).
Example 12
2- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine dihydrochloride
An amorphous powdery title compound (257mg, quant.) was prepared using tert-butyl 2- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 11 by a similar method to that of example 3.
1H NMR(DMSO-d6)：δ 1.27(6H，d，J＝6.9Hz)，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).
Example 13
N- (2- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (49.9mg, 51.6%) was prepared as a white powder using 2- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine obtained in example 12 by a similar method to that of example 5.
MP：106-107℃.
1H NMR(DMSO-d6)：δ 1.27(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).
Example 14-1
5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-3-amine
Sodium (3.19g) was added portionwise to ethanol (160 ml). After all the sodium had dissolved, 4-methoxyphenylhydrazine hydrochloride (14.5g) was added to the solution in one portion. The mixture was stirred at room temperature for 10 minutes. 3- (4-benzyloxyphenyl) acrylonitrile (16.3g) was added to the mixture in one portion, and the mixture was refluxed for 3 days.
Insoluble material was filtered off and the filtrate was concentrated in vacuo. Ethyl acetate and water were added to the residue, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected, washed with water, ethyl acetate, and air-dried to obtain the objective compound (12.57g, 48.6%) as a powder.
1H NMR(DMSO-d6)：δ 2.49(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).
Example 14-2
5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-amine
MnO of2(3.5g) 5- [4- (benzyloxy) phenyl ] obtained in example 14-1 was added]-1- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-3-amine (12.54g) was dissolved in N, N-dimethylformamide (65ml), and the mixture was stirred at 60 ℃ for 2 hours. Adding MnO2(5.3g), the mixture was stirred at 60 ℃ for 1 hour.
The mixture was filtered through a pad of celite and the pad was washed with N, N-dimethylformamide. Ethyl acetate and water were added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The precipitate was collected, washed with water and air dried. The obtained powder was suspended in hot isopropyl ether, stirred and cooled, collected and washed with isopropyl ether to obtain the objective compound (11.70g, 93.8%) as a powder.
1H NMR(DMSO-d6)：δ 3.74(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＝9.0Hz)，7.03-7.13(4H，m)，7.34-7.47(5H，m).
MS(ESI+)：m/z 372(M+H).
Examples]5
5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -N, N-dimethyl-1H-pyrazol-3-amine
A37% aqueous formamide solution (6ml) and sodium cyanoborohydride (1.39g) were successively added to a solution of 5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-amine (2.75g) obtained in example 14-2 in methanol (30 ml). The reaction mixture was stirred at room temperature for 3 days, and the appropriate amount of 37% aqueous formamide and sodium cyanoborohydride were added occasionally to consume all of the starting material.
The reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate/chloroform, to give the title compound (0.88g, 29.8%) as an oil.
1H NMR(DMSO-d6)：δ 2.81(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).
Example 16
4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol
5- [4- (benzyloxy) phenyl obtained in example 15]Mixture of (E) -1- (4-methoxyphenyl) -N, N-dimethyl-1H-pyrazol-3-amine (0.83g) and 10% Pd-C50% wet weight (160mg) in acetic acid (8ml) in H2(1atm) at room temperature for 10 hours.
The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate/chloroform, and crystallized from a mixture of isopropyl ether and ethyl acetate to obtain the title compound (455mg, 70.8%) as a white powder.
1H NMR(DMSO-d6)：δ 2.80(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＝8.5Hz)，7.09(2H，d，J＝9.0Hz)，9.64(1H，s).
MS(ESI+)：m/z 310(M+H).
Example 17
2- {4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (477.1mg, 99.7%) was prepared as an oil using 4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol obtained in example 16 by a similar method to that of example 2.
1H NMR(CDCl3)：δ 1.45(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).
Example 18
5- [4- (2-Aminoethoxy) phenyl ] -1- (4-methoxyphenyl) -N, N-dimethyl-1H-pyrazol-3-amine hydrochloride
An amorphous title compound (454mg, quantitative) was prepared using tert-butyl 2- {4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 17 by a similar method to that of example 3.
1H NMR(DMSO-d6)：δ 2.83(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).
Example 19
N- (2- {4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
Preparation of an amorphous title compound (116mg, 55.7%) using 5- [4- (2-aminoethoxy) phenyl ] -1- (4-methoxyphenyl) -N, N-dimethyl-1H-pyrazol-3-amine hydrochloride obtained in example 18, the similar procedure to that of example 75 described below was employed.
1H NMR(DMSO-d6)：δ 2.81(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).
Example 20-1
5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-3-amine
The title compound (4.0g, 57.8%) was prepared in the form of powder using 3- (4-methoxymethoxyphenyl) acrylonitrile by a similar method to that of example 14-1.
1H NMR(DMSO-d6)：δ 2.49(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).
Example 20-2
5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-amine
The title compound (4.80g, quantitative) was prepared as an oil by the similar method to that of example 14-2 using 5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -4, 5-dihydro-1H-pyrazol-3-amine obtained in example 20-1.
1H NMR(DMSO-d6)：δ 3.36(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).
Example 21
3-chloro-5- [4- (methoxymethyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole
A mixture of 5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-amine (3.79g) obtained in example 20-2, lithium chloride (2.47g) and copper (II) chloride (3.13g) in acetonitrile (60ml) was stirred at room temperature for 10 minutes. Isoamyl nitrite (2.73g) was added to the mixture, and the mixture was stirred at room temperature for 1 hour.
The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 30% ethyl acetate/n-hexane. The solvent was evaporated in vacuo. The residue was crystallized from a mixture of isopropyl ether and ethyl acetate to obtain the title compound (2.38g, 59.3%) as a white powder.
1H NMR(CDCl3)：δ 3.48(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).
Examples22
4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol
To a solution of 3-chloro-5- [4- (methoxymethyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole (2.35g) obtained in example 21 in tetrahydrofuran (10ml) and methanol (10ml) was added 36% hydrochloric acid (0.34 ml). The reaction mixture was stirred at room temperature for 1 hour, at 50 ℃ for 1.5 hours, and at 60 ℃ for 1.5 hours.
The mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residual solid was collected and washed with a mixture of isopropyl ether and n-hexane to obtain the title compound (1.99g, 97.1%) as a white powder.
1H NMR(DMSO-d6)：δ 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).
200MHz 1H NMR(CDCl3)：δ 3.82(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).
Example 23
2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
A solution of 4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol (180mg) obtained in example 22 in N, N-dimethylformamide (2ml) was added to a 60% sodium hydride dispersion in mineral oil (31.1mg) with cooling in an ice bath. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a solution of 2-bromoethyl butyl (dimethyl) silyl ether (258mg) in N, N-dimethylformamide (2 ml).
After stirring at room temperature overnight, the mixture was poured into ice water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in ethanol (3.6 ml). To the solution was added 36% aqueous hydrochloric acid (0.3 ml). After stirring at room temperature for 3 hours, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with 70% ethyl acetate/n-hexane. The separated silica gel was extracted with 10% methanol/chloroform and the solvent was evaporated in vacuo. The residue was crystallized from a mixture of isopropyl ether and ethyl acetate to give the title compound (136.4mg, 66.1%) as a white powder.
MP：114.7-115.5℃.
1H NMR(DMSO-d6)：δ 3.64-3.73(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).
Example 24
2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (329.5mg, 22.3%) was prepared in an amorphous form using 4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol obtained in example 22, using a similar method to that of example 73 described below.
1H NMR(CDCl3)：δ 1.45(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).
Example 25
2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (1.31g, 97.8%) was prepared using 4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol obtained in example 22 by a similar method to that of example 2.
MS(ESI+)：m/z 444(M+H).
Example 26
2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride
The title compound (605.2mg, 85.4%) was prepared as a white powder using tert-butyl 2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 25 by a similar method to that of example 3.
1H NMR(DMSO-d6)：δ 3.14-3.23(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).
Example 27
N- (2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
The title compound (137.8mg, 82.8%) was prepared as a white powder using 2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine hydrochloride obtained in example 26 by a similar method to that of example 4.
MP：117-119℃.
1H NMR(DMSO-d6)：δ 2.94(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).
Example 28
N- (2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (174.6mg, 85.8%) was prepared as a white powder using 2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride obtained in example 26 by a similar method to that of example 75 described below.
MP：144.8-145.4℃.
1H NMR(DMSO-d6)：δ 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).
IR(ATR)：3423，3402，3203，3143，3010，2976，2943，2885，1651，1610，1583，1516cm-1.
MS(ESI+)：m/z 387(M+H).
Example 29-1
5- [4- (methoxymethyloxy) phenyl ] -1- (6-methoxy-3-pyridyl) -4, 5-dihydro-1H-pyrazol-3-amine
The title compound (1.63g, 41.2%) was prepared as a powder using 3- (4-methoxymethoxyphenyl) acrylonitrile and 2-methoxy-5-pyridylhydrazine dihydrochloride using a similar method to that of example 14-1.
H NMR (DMSO-d 6): 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).
Example 29-2
5- [4- (methoxymethyloxy) phenyl ] -1- (6-methoxy-3-pyridyl) -1H-pyrazol-3-amine
The title compound (1.77g, quantitative) was prepared as an oil by using 5- [4- (methoxymethyloxy) phenyl ] -1- (6-methoxy-3-pyridyl) -4, 5-dihydro-1H-pyrazol-3-amine obtained in example 29-1 in a similar manner to example 14-2.
1H NMR(DMSO-d6)：δ 3.37(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).
Example 30
5- { 3-chloro-5- [4- (methoxymethyloxy) phenyl ] -1H-pyrazol-1-yl } -2-methoxypyridine
The title compound (981.7mg, 57.9%) was prepared as a powder using 5- [4- (methoxymethyloxy) phenyl ] -1- (6-methoxy-3-pyridyl) -1H-pyrazol-3-amine obtained in example 29-2 by a similar method to that of example 21.
1H NMR(CDCl3)：δ 3.48(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).
Example 31
4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] -phenol
The title compound (2.15g, 80.5%) was prepared as a white powder using 5- { 3-chloro-5- [4- (methoxymethyloxy) phenyl ] -1H-pyrazol-1-yl } -2-methoxypyridine obtained in example 30 in a similar manner to example 22.
1H NMR(DMSO-d6)：δ 3.87(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).
Example 32
2- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
The title compound (140.9mg, 86%) was prepared as a white powder using 4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenol obtained in example 31 by a similar method to that of example 23.
MP：136.5-138.2℃.
1H NMR(DMSO-d6)：δ 3.65-3.74(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).
Example 33
2- {4- [ 3-chloro-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (964mg, 93.4%) was prepared as a white solid using 4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenol obtained in example 31 by a similar method to that of example 2.
1H NMR(DMSO-d6)：δ 1.37(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).
Example 34
2- {4- [ 3-chloro-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } -ethylamine dihydrochloride
An amorphous title compound (842mg, 98.6%) was prepared using tert-butyl 2- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 33 by a similar method to that of example 3.
1H NMR(DMSO-d6)：δ 3.15-3.24(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).
Example 35
N- (2- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (119.5mg, 62.4%) was prepared as a white powder using 2- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine dihydrochloride obtained in example 34 by a similar method to that of example 75 below.
MP：155.6-157.9℃.
1H NMR(DMSO-d6)：δ 3.27-3.34(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.
Example 36
5- [4- (benzyloxy) phenyl ] -3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazole
A mixture of 5- [4- (benzyloxy) phenyl ] -3-hydroxy-1- (4-methoxyphenyl) -1H-pyrazole (2.4g), 2-iodopropane (5.48g) and potassium carbonate (2.67g) in N, N-dimethylformamide (10ml) was stirred at 100 ℃ for 3 hours.
The reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate/n-hexane and the solvent was evaporated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to obtain the objective compound (2.14g, 80.1%) as a white powder.
1H NMR(DMSO-d6)：δ 1.31(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).
Example 37
4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] -phenol
To a solution of ammonium formate (954mg) in water (2ml), ethanol (10ml), a solution of 5- [4- (benzyloxy) phenyl ] -3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazole (2.09g) obtained in example 36 in tetrahydrofuran (10ml), and 10% palladium on carbon 50% by wet weight (200mg) were successively added. The mixture was refluxed for 1 hour.
The catalyst was removed by filtration and washed with ethyl acetate. The filtrate and combined washings were concentrated in vacuo. Ethyl acetate and water were added to the residue. The precipitate was collected, washed with water and ethyl acetate to give a first crop of the title compound (419mg) as a white powder. The filtrate was partitioned, and the organic layer was saturated with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were collected and washed with isopropyl ether to afford a second crop of the title compound (1.19g, 72.5%) as a white powder.
1H NMR(DMSO-d6)：δ 1.31(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).
Example 38
2- {4- [ 3-Isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
The title compound (147.3mg, 88.2%) was prepared as an oil using 4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol obtained in example 37 by a similar method to that of example 23.
1H NMR(CDCl3)：δ 1.40(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).
Example 39
2- {4- [ 3-Isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (520mg, 72.2%) was prepared as a white powder using 4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol obtained in example 37 by a similar method to that of example 2.
1H NMR(DMSO-d6)：δ 1.31(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).
Example 40
2- {4- [ 3-Isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride
An amorphous title compound (557mg, quantitative) was prepared using tert-butyl 2- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 39 by a similar method to that of example 3.
1H NMR(DMSO-d6)：δ 1.31(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).
EXAMPLE 41
N- (2- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
The title compound (125mg, 79.8%) was prepared as a white powder using 2- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine hydrochloride obtained in example 40 in a similar manner to example 4.
MP：167.9-168.0℃.
1H NMR(DMSO-d6)：δ 1.31(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).
Example 42
N- (2- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (76.3mg, 50.1%) was prepared as a white powder using 2- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride obtained in example 40 by a similar method to that described in example 75 below.
MP：139-140℃.
1H NMR(DMSO-d6)：δ 1.31(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).
Example 43
5- [4- (benzyloxy) phenyl ] -1- (6-methoxy-3-pyridyl) -1H-pyrazol-3-ol
To a solution of 3- (4-benzyloxyphenyl) propiolic acid (1g) and 1-hydroxybenzotriazole hydrate (643mg) in N-methylpyrrolidone (10ml) was added WSCD & HCl (912mg), and the mixture was stirred at room temperature for 10 minutes. In another flask, diisopropylethylamine (2.31g) was added to a suspension of 5-hydrazino-2-methoxypyridine dihydrochloride (1.26g) in N-methylpyrrolidone (4ml), and stirred at room temperature until the 5-hydrazino-2-methoxypyridine dihydrochloride was completely dissolved. The resulting hydrazine solution was added to the reaction flask, and the mixture was stirred at room temperature for 1.5 hours.
The mixture was partitioned between ethyl acetate and 0.1M hydrochloric acid and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloroethane (15ml), and tetrakis (triphenylphosphine) palladium (O) (45.8mg) was added. The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was crystallized from ethyl acetate to obtain the title compound (739mg, 49.9%) as a powder.
1H NMR(DMSO-d6)：δ 3.84(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).
Example 44
5- {5- [4- (benzyloxy) phenyl ] -3-isopropoxy-1H-pyrazol-1-yl } -2-methoxypyridine
The title compound (1.33g, quantitative) was prepared as a powder using 5- [4- (benzyloxy) phenyl ] -1- (6-methoxy-3-pyridyl) -1H-pyrazol-3-ol obtained in example 43 by a similar method to that of example 36.
1H NMR(CDCl3)：δ 1.40(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).
Example 45
4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenol
The title compound (442.5mg, 54.9%) was prepared as a powder using 5- {5- [4- (benzyloxy) phenyl ] -3-isopropoxy-1H-pyrazol-1-yl } -2-methoxypyridine obtained in example 44 by a similar method to that of example 37.
1H NMR(CDCl3)：δ 1.40(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).
Example 46
2- {4- [ 3-Isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
The title compound (94.6mg, 52.2%) was prepared as a white powder using 4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenol obtained in example 45 by a similar method to that of example 23.
MP：74-75℃.
1H NMR(CDCl3)：δ 1.40(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).
Example 47
2- {4- [ 3-Isopropoxy-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (515.3mg, 87.6%) was prepared as a powder using 4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenol obtained in example 45 by a similar method to that of example 2.
1H NMR(DMSO-d6)：δ 1.32(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).
Example 48
2- {4- [ 3-Isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine dihydrochloride
An amorphous title compound (531mg, quant.) was prepared using tert-butyl 2- {4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 47 in a similar manner to example 3.
1H NMR(DMSO-d6)：δ 1.32(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).
Example 49
N- (2- {4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (81.4mg, 60.2%) was prepared as a white powder using 2- {4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine dihydrochloride obtained in example 48, using a similar method to that described in example 75 below.
MP：120℃.
1H NMR(DMSO-d6)：δ 1.32(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＝8.8Hz)，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).
Example 50
N- (2- {4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
The title compound (94.4mg, 58.4%) was prepared using 2- {4- [ 3-isopropoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine dihydrochloride obtained in example 48, in a similar manner to example 4.
MP：121.0-121.6℃.
1H NMR(DMSO-d6)：δ 1.32(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).
Example 51
Methanesulfonic acid 2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl ester
To a solution of 2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethanol (2.72g) and triethylamine (1.55ml) in methylene chloride (30ml) was added dropwise methanesulfonyl chloride (0.86ml) under ice-cooling. The reaction mixture was warmed to room temperature and stirred for 1 hour.
The reaction mixture was quenched with water. The organic layer was separated, washed with 1N hydrochloric acid and water, dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain the objective compound (3.25g, 98.5%).
1 HNMR(CDCl3)：δ 2.929(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).
Example 52
2- (2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl) -1H-isoindole-1, 3(2H) -dione
A mixture of 2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl methanesulfonate (3.2g) obtained in example 51 and potassium peptidimide (1.6g) was stirred at 80 ℃ for 5 hours.
After cooling, the mixture was diluted with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (twice). The combined organic layers were washed with water (twice) and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound (1.55g, 43.5%) as a powder.
1H NMR(CDCl3)：δ 1.59(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).
Example 53
2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethanamine
A mixture of 2- (2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl) -1H-isoindole-1, 3(2H) -dione (1.5g) obtained in example 52 and hydrazine (2.93ml) in acetonitrile (30ml) was stirred at 60 ℃ for 5 hours.
After cooling, the mixture was filtered and washed with acetonitrile. The filtrate was evaporated under reduced pressure to give the objective compound (1.1g, quantitative) as an oil.
1H NMR(CDCl3)：δ 3.09(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).
Example 54
N- (2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl) methanesulfonamide
To a solution of 2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethylamine (400mg) obtained in example 53 and triethylamine (0.46ml) in methylene chloride (20ml) was added methanesulfonyl chloride (0.25ml) dropwise at room temperature.
After stirring for 1 hour, the reaction mixture was quenched with 1N hydrochloric acid. The aqueous layer was separated and extracted twice with chloroform. The combined organic layers were washed with 1N hydrochloric acid, sodium bicarbonate solution, water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol ═ 4:1) to obtain the objective compound (166mg, 34.2%) as an oil.
1H NMR(CDCl3)：δ 2.899(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＝8.4Hz)，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).
Example 55
N- (2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl) urea
To a solution of 2- {4- [1- (4-chlorophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethylamine (300mg) obtained in example 53 and triethylamine (0.57ml) in methylene chloride (10ml) was added dropwise trimethylsilyl isocyanate (0.555ml) at room temperature.
After stirring overnight, the reaction mixture was quenched with 1N hydrochloric acid. The aqueous layer was separated and extracted twice with chloroform. The combined organic layers were washed with 1N hydrochloric acid, sodium bicarbonate solution and water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol 4:1) to obtain an amorphous target compound (205mg, 61.1%).
1H NMR(CDCl3)：δ 2.83(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).
Example 56
4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzonitrile
A mixture of 4- (4, 4, 4-trifluoro-3-oxobutanoyl) -benzonitrile (1.0g), 4-methoxyphenylhydrazine hydrochloride (760mg) and sodium acetate (357mg) in acetic acid (10ml) was stirred at 80 ℃ for 4 hours.
After cooling, the reaction mixture was poured into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution (twice), water and brine, dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (50ml, n-hexane: ethyl acetate ═ 5:1-4:1), and triturated with petroleum ether to obtain the title compound (553mg, 38.8%).
1H NMR(CDCl3)：δ 3.84(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).
Example 57
4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzylamine hydrochloride
A mixture of 4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzonitrile (430mg), Pd/C (100mg) and 1N hydrochloric acid (1.3ml) obtained in example 56 in methanol (43ml) was stirred under a hydrogen atmosphere for 5 hours.
The reaction mixture was filtered through a paper filter and the filtrate was evaporated. After dissolving in methanol, the solution was filtered through a membrane filter. The filtrate was evaporated to give the target compound (450mg, 93.6%) as crystals.
1H NMR(CDCl3)：δ 3.79(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-NH3).
Example 58
N- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
To a solution of 4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzylamine hydrochloride (100mg) obtained in example 57 and triethylamine (0.073ml) in chloroform (10ml) was added methanesulfonyl chloride (0.04ml) dropwise at room temperature.
After stirring for 1 hour, the reaction mixture was partitioned between chloroform and water. The organic layer was washed with water, sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the title compound (90mg, 81.2%) as an oil.
1H NMR(CDCl3)：δ 2.93(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).
Example 59
4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzonitrile
The title compound (4.5g, 20.6%) was prepared using 4- (4, 4-difluoro-3-oxobutanoyl) benzonitrile using a similar method to that of example 56.
1H NMR(CDCl3)：δ 3.84(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).
Example 60
1- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } methanamine hydrochloride
The title compound (510mg, 45.4%) was prepared using 4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzonitrile obtained in example 59 in a similar manner to the preparation of example 57.
1H NMR(DMSO-d6)：δ 3.35(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).
Example 61
N- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
The title compound (146mg, 65.5%) was prepared using 1- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } methanamine hydrochloride obtained in example 60 by a similar method to that of example 58.
1H NMR(CDCl3)：δ 2.90(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).
example 62
N- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } urea
To a solution of 1- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } methylamine hydrochloride (100mg) obtained in example 60 in methylene chloride (1ml) were added dropwise triethylamine (0.163ml) and trimethylsilyl isocyanate (0.11ml) at room temperature.
The mixture was stirred at room temperature overnight and quenched by addition of saturated sodium bicarbonate solution (0.5 ml). The mixture was filtered through Chemelute. The eluate was evaporated and purified by preparative thin layer chromatography (0.5mm, 10% methanol/chloroform) to give a solid. The solid was added to ethyl acetate and n-hexane, and the precipitate was collected by filtration to obtain the objective compound (160mg, 62.9%).
1H NMR(CDCl3)：δ 3.82(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.
Example 63
4- [1- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzonitrile
The title compound (942mg, 86.8%) was prepared using 4- (4, 4, 4-trifluoro-3-oxobutanoyl) benzonitrile using a similar method to that of example 56.
1H NMR(CDCl3)：δ 2.39(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).
Example 64
1- {4- [1- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } methylamine hydrochloride
The title compound (414mg, 92.1%) was prepared using 4- [1- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzonitrile obtained in example 63, using a similar method to that of example 57.
1H NMR(DMSO-d6)：δ 2.35(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).
Example 65
N- {4- [1- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } urea
The title compound (81mg, 31.8%) was prepared using 1- {4- [1- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } methylamine hydrochloride obtained in example 64 by a similar method to that of example 62.
1H NMR(CDCl3)：δ 2.36(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).
Example 66
4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzonitrile
The title compound (1.05g, 73.8%) was prepared using 4-methyl-1- (4, 4, 4-trifluoro-3-oxobutanoyl) benzene using a similar method to that described in example 69 below.
MP：125.0-125.5℃.
1H NMR(CDCl3)：δ 2.39(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).
Example 67
1- {4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } methylamine hydrochloride
The title compound (830mg, 92.3%) was prepared using 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzonitrile obtained in example 66 by a similar method to that described in example 70 below.
1H NMR(DMSO-d6)：δ 2.30(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).
Example 68
N- {4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzyl } urea
The title compound (65mg, 31.9%) was prepared using 1- {4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenyl } methylamine hydrochloride obtained in example 67 by a similar method to that described in example 72 below.
1H NMR(CDCl3)：δ 2.34(3H，s)，4.34(2H，d，J＝5.8Hz)，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).
Example 69
4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzonitrile
A mixture of 4-methoxy-1- (4, 4, 4-trifluoro-3-oxobutanoyl) benzene (1.0g), 4-methoxyphenylhydrazine hydrochloride (758mg) and sodium acetate (367mg) in acetic acid (5ml) was stirred at room temperature overnight.
Then, the reaction mixture was poured into water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, saturated sodium bicarbonate solution (twice) and brine, dried over sodium sulfate and evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (50ml, n-hexane: ethyl acetate: 10:1-5:1) to obtain the objective compound (930mg, 66.7%).
1H NMR(CDCl3)：δ 3.84(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).
Example 70
4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzylamine hydrochloride
A mixture of 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzonitrile (400mg) obtained in example 69 and 50% by wet weight pd/C (400mg) in ethanol (10ml) and 1N hydrochloric acid (1.2ml) was stirred under a hydrogen atmosphere for 8 hours.
The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was washed with isopropyl ether to obtain the objective compound (400mg, 89.4%) as a powder.
1H NMR(CDCl3)：δ 3.36(s，3H)，3.76(d，J＝2.4，2Hz)，6.94(d，J＝8.7，2Hz)，7.12(s，1H)，7.23(d，J＝8.7，2Hz)，7.39(d，J＝8.4，2Hz)，7.59(d，J＝8.4，2Hz).
MS(ESI+)：m/z 348(M+1).
Example 71
N- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzyl } methanesulfonamide
To a solution of 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzylamine hydrochloride (150mg) obtained in example 70 and triethylamine (0.1ml) in dichloromethane (10ml) was added dropwise methanesulfonyl chloride (0.06ml) under ice-cooling.
After stirring for 1 hour, the reaction mixture was quenched and partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The combined organic layers were washed with water, 1N hydrochloric acid, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was analyzed by high performance thin layer chromatography to obtain the objective compound (67mg, 40.3%).
1H NMR(CDCl3)：δ 2.91(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).
Example 72
N- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzyl } urea
To a solution of 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzylamine hydrochloride (150mg) obtained in example 70 in water (8ml) and ethanol (4ml) was added sodium cyanate (100mg) under ice-cooling.
After stirring for 3 hours, the reaction mixture was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was analyzed by high performance thin layer chromatography to obtain the objective compound (105mg, 69%).
1H NMR(CDCl3)：δ 3.80(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).
Example 73
2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
To a solution of 4- [1- (4-methoxyphenyl) -3-trifluoromethyl-1H-pyrazol-5-yl ] phenol (500g) in N, N-dimethylformamide (1.5L) was added sodium hydride (mineral oil dispersion, 77.8g) under ice-cooling over 25 minutes. The mixture was warmed to room temperature over 10 minutes and then stirred at room temperature for 30 minutes. A reaction solution of 2-tert-butoxycarbonylaminoethyl bromide (469g) (prepared by reacting di-tert-butyl dicarbonate with 2-bromoethylamine hydrochloride) in N, N-dimethylformamide (300ml) was added to the mixture at 25 to 28 ℃ over 10 minutes, and the whole mixture was stirred at 60 ℃ for 6 hours.
After standing overnight, the mixture was poured into a mixture of water (4.5L) and toluene (3L). The organic layer was separated and the aqueous layer was extracted with toluene (1.5L). The combined organic layers were washed with water (1.5L. times.3) and brine (1.5L), dried over magnesium sulfate, filtered and evaporated to give an oil (1.02 kg). The oil was purified by silica gel column chromatography [5L, n-hexane (10L), 50% ethyl acetate/n-hexane (30L) ] to obtain the objective compound (680g, 95%) as a pale yellow oil.
MP：104.7-105.1℃.
1HNMR(CDCl3)：δ 1.45(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).
Example 74
2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride
To a solution of hydrogen chloride in ethyl acetate (4N, 1.0L) was added tert-butyl 2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate (500g) obtained in example 73 in the form of a powder over 20 minutes at 5 ℃.
After stirring at the same temperature for 30 minutes and at room temperature for 1 hour, the mixture was evaporated to obtain an oil (543.12 g). The oil was dissolved in toluene (1.5L). Then, n-hexane (200ml) and the objective compound (crystallization seed) were added to the solution. The mixture was stirred at room temperature overnight. The precipitate was filtered, washed with toluene (500 ml. times.2) and isopropyl ether (650ml) to obtain the title compound (420.5g, 97%) as a white powder after drying.
MP：166.8-168.0℃.
1HNMR(DMSO-d6)：δ 3.185(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).
Example 75
N- (2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine hydrochloride (400g) obtained in example 74 and sodium acetate (159g) were dissolved in a mixture of N, N-dimethylformamide (1.4L) and water (0.52L) at 50 ℃. A solution of potassium cyanate (157g) in water (520ml) was added dropwise to the solution over 15 minutes at 38-40 ℃. The whole solution was stirred at 50 ℃ for 2 hours.
The solution was filtered and washed with N, N-dimethylformamide (0.68L) at the same temperature. The filtrate was cooled to room temperature, then water (0.4L) and the objective compound (crystal form a 04) were added to the filtrate as crystallization seeds, and the mixture was stirred at room temperature for 30 minutes. Water (2.76L) was then added dropwise to the mixture over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. The precipitate was filtered, washed with water (0.8L. times.3), and dried under reduced pressure at 45 ℃ overnight to obtain the title compound (crystals of A04 type, 442.01g) as a white powder.
1HNMR(CDCl3)：δ 3.555(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)：δ 3.28-3.36(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).
Example 76
2-hydroxy-N- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } acetamide
To a solution of 4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzylamine hydrochloride (46.5mg) obtained in example 57 in methylene chloride (1.5ml) were added diisopropylethylamine (135. mu.L) and acetoxyacetyl chloride (41.6. mu.L) at 0 ℃.
After stirring at room temperature for 3 hours, the mixture was quenched with water. The whole mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give an oil (67 mg). The oil was dissolved in methanol (1.5 ml). Potassium carbonate (55mg) was added to the solution. After stirring at room temperature for 3 hours, the mixture was filtered and evaporated to give an oil, which was purified by preparative thin layer chromatography (0.5 mm. times.2, 10% methanol/chloroform) to give a colorless oil (42.5 mg). The oil was crystallized from a mixture of ethyl acetate, diisopropyl ether and n-hexane and stirred at room temperature. The precipitate was filtered and dried to obtain the title compound (33.9mg, 64.8%) as a white powder.
1HNMR(CDCl3)：δ 2.32(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).
Example 77
2-hydroxy-N- (2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl) ethanesulfonamide
To a solution of 2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethanamine hydrochloride and triethylamine in chloroform was added methanesulfonyl chloride at room temperature.
After stirring for 1 hour, the reaction mixture was poured into water and chloroform. The aqueous layer was separated and extracted with chloroform. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and then crystallized to obtain the objective compound (27.7mg, 23.5%).
1HNMR(CDCl3)：δ 2.78-2.91(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(MH+)，511.17(MHMeCN).
Example 78-1
2- (4-Acetylphenoxy) ethylcarbamic acid tert-butyl ester
To a solution of 4-hydroxyacetophenone (10g) and 2-tert-butoxycarbonylaminoethyl bromide (24.7g) in N, N-dimethylformamide (50ml) were added potassium iodide (12.2g) and potassium carbonate (15.2 g).
After stirring at 50 ℃ overnight, the mixture was quenched with water and extracted with ethyl acetate (3 times). The combined organic layers were washed with 1N aqueous sodium hydroxide (2 times) and brine, dried over magnesium sulfate and evaporated to give an oil. The oil was purified by silica gel column chromatography [500ml, 20% ethyl acetate/n-hexane (1000ml), 30% ethyl acetate/n-hexane (1000ml) ] to obtain the objective compound (19.89g, 96.9%) as a white solid.
1HNMR(CDCl3)：δ 1.46(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+).
Example 78-2
2- [4- (4, 4, 4-trifluoro-3-oxobutanoyl) phenoxy ] ethylcarbamic acid tert-butyl ester
A mixture of tert-butyl 2- (4-acetylphenoxy) ethylcarbamate (15g) obtained in example 78-1, trifluoroacetic acid (8.95ml) and sodium ethoxide (8.77g) in ethanol (45ml) was stirred at 70 ℃ for 2.5 hours.
The mixture was poured into a mixture of aqueous hydrogen chloride (1N) and ethyl acetate. The entire mixture was extracted with ethyl acetate (2 times). The organic layer was separated, washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give an oil (25 g). This oil was purified by silica gel column chromatography [500ml, 30% ethyl acetate/n-hexane (1000ml) ] to obtain an oil. The oil was dissolved in ethyl acetate (5ml) under heating in a water bath. N-hexane (100ml) was added to the solution and the solution was cooled to room temperature over 30 minutes with stirring. N-hexane (100ml) was added to the mixture. The precipitate was filtered and dried to obtain the target compound (15.956g, 79.2%) as an orange powder.
1HNMR(CDCl3)：δ 3.40-3.70(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).
Examples 78 to 3
2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
To a suspension of 4-methoxyaniline (100mg) in a mixture of acetic acid (2ml) and concentrated hydrochloric acid (0.4ml) was added dropwise a solution of sodium nitrite (61.6mg) in water (0.1ml) over 5 minutes at 3 ℃ and the mixture was stirred at 3 ℃ for 1 hour. To this mixture was added dropwise a solution of stannous chloride (641mg) in concentrated hydrochloric acid (0.3ml) at 0 ℃ over 10 minutes, and the mixture was stirred at 0 ℃ for 1 hour. Acetic acid (5ml) was added dropwise to the mixture over 2 minutes at-20 ℃ to-10 ℃ and the mixture was then quenched with a solution of sodium hydroxide (336mg) in water (2.24ml) over 2 minutes at-10 ℃ and warmed to room temperature to obtain a solution comprising 4-methoxyphenylhydrazine hydrochloride.
The solution of tert-butyl 2- [4- (4, 4, 4-trifluoro-3-oxobutanoyl) -phenoxy ] ethylcarbamate (305mg) obtained in example 78-2 was added to the foregoing solution at-10 ℃ and the mixture was stirred at room temperature for 3 hours. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate (150ml) and ethyl acetate (100ml), and the pH was adjusted to alkaline with sodium bicarbonate powder.
The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 ml. times.2). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and evaporated to give an oil (450 mg). The oil was purified by silica gel column chromatography [35ml, 15% ethyl acetate/n-hexane (800ml) ] to obtain an oil (343.2mg, 88.5%). The oil was dissolved in isopropyl ether (2ml), and n-hexane (6ml) was added to the solution. The entire mixture was stirred at room temperature for 1 hour. The precipitate was then filtered, washed with n-hexane (10ml), and dried under reduced pressure for 2 hours to obtain the title compound (280.6mg, 72.4%) as a white powder.
1HNMR(CDCl3) The data were consistent with authentic samples.
1HNMR(CDCl3)：δ 1.45(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).
Example 79-1
1- [4- (benzyloxy) phenyl ] hydrazine hydrochloride
To a suspension of 4-benzyloxyaniline (10g) in concentrated hydrochloric acid (100ml) was added dropwise a solution of sodium nitrite (3.2g) in water (10ml) over 10 minutes at-15 ℃ to-10 ℃ and the mixture was stirred at 3 ℃ for 1 hour. A solution of stannous chloride (33.5g) in concentrated hydrochloric acid (80ml) was added dropwise to the mixture over 30 minutes at-20 ℃ to-10 ℃ and the mixture was stirred at 0 ℃ for 1 hour.
After cooling to-20 ℃ the precipitate was filtered, washed with water (25ml), ethanol (25ml) and diethyl ether (50ml) and dried to give the title compound (10.637g, 100%) as a light brown powder.
NMR(DMSO-d6)：δ 5.05(2H，s)，6.93-7.03(4H，m)，7.46-7.28(4H，m).
Example 79-2
2- {4- [1- (4-Benzyloxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylamine hydrochloride
The title compound (12.9g, 87.5%) was prepared using 1- [4- (benzyloxy) phenyl ] hydrazine hydrochloride obtained in example 79-1 and tert-butyl 2- [4- (4, 4, 4-trifluoro-3-oxobutanoyl) phenoxy ] ethylcarbamate obtained in example 78-2 by a similar method to that used in example 78-3.
1HNMR(DMSO-d6)：δ 3.10-3.30(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).
Example 80
N- (2- {4- [1- [4- (benzyloxy) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (10.57g, 84.3%) was prepared using 2- {4- [1- (4-benzyloxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } -ethylamine hydrochloride obtained in example 79-2 by a similar method to that of example 75.
1HNMR(CDCl3)：δ 3.57(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).
Example 81
N- (2- {4- [1- (4-hydroxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -phenoxy } ethyl) urea
To a solution of N- (2- {4- [1- [4- (benzyloxy) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (10.33g) obtained in example 80 in methanol (100ml) was added palladium on carbon (10% wet weight, 2g), and the mixture was vigorously stirred at room temperature for 3 hours under a hydrogen atmosphere. The entire mixture was filtered and evaporated to give an oil (8.23 g). The oil was purified by silica gel column chromatography [250ml, 3% methanol/chloroform (500ml), 5% methanol/chloroform (500ml) and 10% methanol/chloroform (500ml) ] to obtain the objective compound (8.07g, 95.4%) as an oil.
1HNMR(DMSO-d6)：δ 3.28-3.33(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+).
Example 82
Phenyl 4- [5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] acetate
To a mixture of N- (2- {4- [1- (4-hydroxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (148.5mg) obtained in example 81 in methylene chloride (1.5ml) were added pyridine (163. mu.L) and acetic anhydride (45. mu.L), and the mixture was stirred at room temperature for 1 hour and then at reflux for 3 hours.
After evaporation, the mixture was purified by preparative thin layer chromatography (1.0mm, 10% methanol/chloroform) to give an oil. The oil was crystallized from a mixture of dichloromethane and isopropyl ether at room temperature to give the title compound (138.6mg, 84.6%) as a white powder.
1HNMR(CDCl3)：δ 2.30(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+HCO2 -).
Example 83-1
1- (1, 3-benzodioxol-5-yl) hydrazine hydrochloride
The title compound (1.811g, quant.) was prepared using 3, 4- (methylenedioxy) aniline in a similar manner to example 79-1.
1HNMR(DMSO-d6)：δ 5.94(2H，s)，6.53(1H，dd，J＝2.28.2Hz)，6.80(1H，s)，6.83(1H，d，J＝8.2Hz).
MS(LS，ESI+)：153.9(MH+)193.99(MH+CH3CN).
Example 83-2
2- {4- [1- (1, 3-benzodioxol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (371.3mg, 56.7%) was prepared using tert-butyl 2- [4- (4, 4, 4-trifluoro-3-oxobutanoyl) phenoxy ] ethylcarbamate obtained in example 78-2 and 1- (1, 3-benzodioxol-5-yl) hydrazine hydrochloride obtained in example 83-1 by a similar method to that of example 78-3.
NMR(CDCl3)MA12.048：δ 1.75(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+).
Example 84
2- {4- [1- (1, 3-benzodioxol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine
The title compound (181.2mg, 61.5%) was prepared using tert-butyl 2- {4- [1- (1, 3-benzodioxol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethylcarbamate obtained in example 83-2 by a similar method to that of example 74.
1HNMR(CDCl3)：δ 1.75(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+).
Example 85
N- (2- {4- [1- (1, 3-benzodioxol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
The title compound (181.2mg, 90.1%) was prepared using 2- {4- [1- (1, 3-benzodioxol-5-yl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine obtained in example 84, using a similar method to that of example 75.
1HNMR(CDCl3)：δ 3.6(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+).
Example 86
2- ({4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } amino) -2-oxoethyl-carbamic acid tert-butyl ester
A mixture of 4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzylamine hydrochloride, N-tert-butoxycarbonyl-glycine, WSCD and 1-hydroxybenzotriazole hydrate obtained in example 57 in triethylamine and dichloromethane was stirred at room temperature.
After stirring for 15 hours, the reaction mixture was poured into water and chloroform. The aqueous layer was separated and extracted with chloroform. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and then crystallized to obtain the objective compound (93.5mg, 88.9%).
1HNMR(CDCl3)：δ 1.43(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+).
Example 87
2-amino-N- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } acetamide hydrochloride
The title compound (62.3mg, 82.9%) was prepared using tert-butyl 2- ({4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } amino) -2-oxoethyl-carbamate obtained in example 86 by a similar method to that of example 74.
1HNMR(DMSO-d6)：δ 3.61(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 +).
Example 88
N- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } acetamide
To a solution of 4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzylamine hydrochloride obtained in example 57 and triethylamine in methylene chloride was added dropwise acetyl chloride at 0 ℃.
After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 times). The combined organic layers were washed with 1N hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated to give an oil which was purified by silica gel column chromatography (eluting with 50% ethyl acetate/N-hexane) to give an oil. The oil was crystallized from a mixture of ethyl acetate and n-hexane at 50 ℃ to obtain the objective compound (52.2mg, 69.3%) as a solid.
1HNMR(CDCl3)：δ 2.04(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).
Example 89
N- (2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] -phenyl } ethyl) -1-methyl-1H-imidazole-4-sulfonamide
The title compound (72mg, 70.8%) was prepared using 2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethylamine hydrochloride by a similar method to that of example 77.
1HNMR(CDCl3)：δ 2.83(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+).
Example 90
N- ((1R) -2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } -1-methylethyl) urea
To a solution of (1R) -2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } -1-methyl-ethylamine hydrochloride in dichloromethane was added triethylamine and trimethylsilyl isocyanate at 0 ℃.
After stirring for 5 hours, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give an oil which was purified by preparative thin layer chromatography (1mm, ethyl acetate) to give an oil. The oil was crystallized from a mixture of isopropyl ether, ethyl acetate and n-hexane to obtain the title compound (22.8mg, 88.1%) as a white solid.
1HNMR(CDCl3)：δ 1.29(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).
Example 91
N- (2- {4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
The title compound (130mg, 71.8%) was prepared using 2- {4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine dihydrochloride in analogy to the procedure of example 77.
1HNMR(CDCl3)：δ 3.03(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)+.
Example 92
4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenol
A mixture of 4-methoxy-1- (4, 4, 4-trifluoro-3-oxobutanoyl) benzene (5.0g) and p-hydroxyphenylhydrazine hydrochloride (3.59g) in acetic acid (30ml) was stirred at room temperature.
After stirring for 15 hours, toluene and water were added. The aqueous layer was separated and extracted twice with toluene. The combined organic layers were washed with water (twice) and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (4.88g, 71.9%) as crystals.
1H NMR(CDCl3)：δ 3.80(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).
Example 93
2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethanol
A suspension of 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenol (500mg), potassium carbonate (1.24g), potassium iodide (1.49g) and 2-chloro-1-ethanol (0.60ml) obtained in example 92 was stirred at 80 ℃ for 5 hours.
After cooling, the reaction mixture was poured into water. The mixture was extracted twice with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the objective compound (545mg, 96.4%).
1H NMR(CDCl3)：δ 2.03(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).
Example 94
{4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } acetonitrile
A suspension of 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenol (2.0g), potassium carbonate (992mg), potassium iodide (993mg) and chloroacetonitrile (0.57ml) obtained in example 92 was stirred at 80 ℃ for 4 hours.
After cooling, the reaction mixture was poured into water. The mixture was extracted twice with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the objective compound (1.75g, 78.3%) as an oil.
1H NMR(CDCl3)：δ 3.81(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).
Example 95
2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethylcarbamic acid tert-butyl ester
The title compound (420mg, 21%) was prepared using 4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenol obtained in example 92 by a similar method to that of example 73.
1H NMR(CDCl3)：δ 1.46(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).
Example 96
2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethylamine hydrochloride
The title compound (0.35g, 96.2%) was prepared using tert-butyl 2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethylcarbamate obtained in example 95 in a similar manner to the process described in example 74.
1H NMR(CDCl3+CD3OD)：δ 3.2-3.5(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).
Example 97
N- (2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethyl) methanesulfonamide
To a solution of 2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethylamine hydrochloride (100mg) obtained in example 96 in methylene chloride (5ml) and triethylamine (0.1ml) was added dropwise methanesulfonyl chloride (38. mu.l) at room temperature.
After stirring for 2 hours, the reaction mixture was partitioned between chloroform and water. The aqueous layer was extracted with chloroform. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by high performance thin layer chromatography to obtain the target compound (35mg, 31.8%) as crystals.
1H NMR(CDCl3)：δ 3.03(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).
Example 98
N- (2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] -phenoxy } ethyl) urea
To a solution of 2- {4- [5- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] phenoxy } ethylamine hydrochloride (200mg) obtained in example 96 dissolved in water (10ml) and ethanol (5ml) was added sodium cyanate (314mg) at room temperature.
After stirring for 15 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography using high performance thin layer chromatography (chloroform: methanol ═ 8:1) to obtain the objective compound (0.148g, 72.8%).
1H NMR(CDCl3)：δ 3.60(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).
Example 99
N- (2- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl) -2-hydroxyethanesulfonamide
To a solution of 2- (2- {4- [1- (4-methoxyphenyl) -3-difluoromethyl-1H-pyrazol-5-yl ] phenyl } ethyl) -1H-isoindole-1, 3(2H) -dione in acetonitrile was added hydrazine monohydrate.
After stirring overnight at 60 ℃, the mixture was filtered. The filtrate was evaporated to give 2- {4- [1- (4-methoxyphenyl) -3- (difluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethanamine as an orange oil.
To a solution of this oil and triethylamine in chloroform was added 2-hydroxyethanesulfonyl chloride at room temperature.
After stirring for 1 hour, the reaction mixture was poured into water and chloroform. The aqueous layer was separated and extracted with chloroform. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and then crystallized to obtain the objective compound (220mg, 76.1%).
1H NMR(CDCl3)：δ 2.875(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
To a suspension of AlCl3(45.9g) was added acetyl chloride (13.4ml) (ca. 5 ℃ C.), followed by the above I (25.7g) dropwise under ice cooling (5-10 ℃ C.). After stirring for 8 hours, the reaction mixture was poured into ice water. The organic layer was separated, washed with water (twice) and 1N HCl, saturated NaHCO3 solution and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give the crude product. This product was distilled under reduced pressure to obtain 105.8g (84%) of the following compound (P0001).
And (4) TLC (thin layer chromatography) inspection: ninhydrin/UV
b.p.1>91-117℃/0.7mmHg.E111271-1 12.6g
2>117℃/0.7mmHg.E111271-2 105.8g
Preparation 2
The above compound P0002 was prepared according to a similar procedure to P0001.
Mass Spectrometry (API-ES cation): 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) was added in three portions to a solution of compound P0001(2g) and ethyl trifluoroacetate (2.6ml) in DMF (10ml) under cooling in an ice bath. The reaction mixture was stirred at the same temperature for 45 minutes. The ice bath was then replaced by a water bath. The temperature of the reaction mixture was raised to 24.5 ℃ and slowly lowered to 22 ℃ over 1 hour. The mixture was stirred at room temperature for 1 hour, then a mixture of 1M HCl (12ml) and ice (40ml) was poured in. The whole mixture was extracted with AcOEt (20 ml). The organic layer was washed with H2O (30ml), saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with toluene. The obtained crystals were subjected to decantation washing with frozen n-hexane (10ml) and petroleum ether (5ml) to obtain compound P0003 as white crystals.
Mass spectrum (API-ES anion): 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＝8.3Hz)，8.08(2H，d，J＝8.3Hz)
Preparation 4
P0004 was prepared according to a similar procedure to that described for preparation 3 for P0003.
Mass spectrum (API-ES anion): 315(M-H) +
NMR JA24.112
200MHz 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
P0005 was prepared according to a similar procedure as described for preparation 3 for P0003.
Yellow crystal
Mass Spectrometry (API-ES cation): 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，d，J＝8.9Hz)，7.02(1H，s)，7.96(2H，d，J＝8.9Hz)
Preparation 6
P0006 was obtained according to a similar method to P0003. (preparation 3)
Preparation 7
60% sodium hydride (233mg) was added in three portions to a solution of P0001(1g) and ethyl pentafluoropropionate (0.93ml) under cooling in an ice bath. The reaction mixture was stirred at 24-27 ℃ for several hours with cooling in a water bath and then poured into a mixture of ice and 1M HCl (50 ml). The entire mixture was extracted twice with AcOEt. The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give P0007(1.94g) as an oil.
Mass spectrum (API-ES anion): 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
A solution of 20% sodium ethoxide in EtOH (18ml) was added dropwise to a solution of P0001(4.00g) and diethyl oxalate (5.95g) in DMF (12ml) at 4-6 ℃. After stirring at the same temperature for 1 hour, the reaction mixture was poured into a mixture of ice water (100ml) and concentrated HCl (5ml), and extracted with AcOEt. Washed successively with 1M HCl, H2O and saturated aqueous sodium chloride, dried over magnesium sulphate, treated with activated carbon and then filtered through a pad of SiO2(20 ml). The pad was washed with AcOEt. The filtrate and combined washings were concentrated in vacuo to give P0008(6.05g) as an oil.
Mass Spectrometry (API-ES cation): 287(M + Na) +, (API-ES anion)
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
To a solution of 4-hydroxybenzophenone (160g), ethyl trifluoroacetate (182ml) and ethanol (11ml) in N, N-dimethylformamide (670ml) was added sodium hydride (suspension in mineral oil, 103g) in portions over 15 minutes at 0-35 ℃. The mixture was stirred at room temperature for 2 hours and then at 35-40 ℃ for 3 hours. The mixture was poured into a mixture of ice, concentrated hydrogen chloride (320ml) (total 4L of aqueous layer) and diisopropyl ether (2L). The aqueous layer was separated and extracted with diisopropyl ether (500 ml. times.2). The combined organic layers were washed with water (500 ml. times.4) and brine, dried over magnesium sulfate and evaporated to yield 415g of a solid. The solid was dissolved in diisopropyl ether (200ml) at 65 ℃. Hexane (1.5L) was added dropwise to the solution at room temperature with stirring. After stirring for 1 hour at room temperature, the suspension was filtered and dried under reduced pressure to obtain a solid (first crop, 109.53g, 40%). A second crop of product (71.11g, 26%) was obtained by similar work-up with diisopropyl ether (20ml) and hexane (250ml) after evaporation of the mother liquor. P0009 (total of first and second batch, 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 a similar method to that of P0009(S0203744), the title compound (56.195g, 102%) was obtained in the form of powder.
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
A mixture of P0009(100g), 4-methoxyphenylhydrazine hydrochloride (82.4g) and sodium acetate (42.6g) in acetic acid (550ml) was stirred at 70 ℃ for 3 hours. After cooling to room temperature, the mixture was poured into water (4L) and stirred at room temperature for 1 hour. The precipitate was filtered, washed with water (250 ml. times.3) and Hex (500 ml. times.2), and dried at room temperature overnight to obtain a powder (157.86 g). The powder was purified by recrystallization from ethyl acetate and hexane to obtain P0011(121.34g, 77%) as a powder.
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 a similar method to P0011, the target compound (3.2028g, 72%) was obtained as a solid.
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 a similar method to that of P0011, the objective compound was obtained.
Preparation 14
To a solution of 4-methoxyphenylhydrazine hydrochloride (3.43g) in water (7.7ml) was added a solution of P0009 in acetic acid (50 ml). The mixture was then allowed to stand at room temperature overnight. The mixture was poured into water (500ml), and stirred at room temperature for 1 hour. The precipitate was filtered, washed with water (100ml) and dried at room temperature to give P0014(3.26g, 90%) as a brown solid.
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 a similar method to P0014, the title compound (13.58g, 91.7%) was obtained as a light brown powder.
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) was added to a solution of P0016-1 (reported in WO 9427973) (1.31g) in EtOH (5ml) and the mixture was stirred at ambient temperature overnight. The mixture was partitioned between AcOEt and H2O. The organic layer was washed with H2O, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane, to give P0016(900mg) as an oil.
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＝16.2Hz)，7.29(2H，d，J＝8.1Hz)，7.65(2H，d，J＝8.1Hz)，7.65(1H，d，J＝16.2Hz)
Preparation 17
P0017(6.41g) was prepared according to a similar method to P0016.
Mass Spectrometry (API-ES cation): 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) were added to a solution of 0.25MP0016(1.03g) in EtOH acetone 3: 1. The mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo and partitioned between AcOEt and H2O. The organic layer was washed with H2O, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give P0018(792mg) as an oil.
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＝8.4Hz)，7.30(2H，d，J＝8.4Hz)
Preparation 19
P0019(1.082g) was prepared from P0017(1.0g) by a similar method to that for P0018.
Mass Spectrometry (API-ES cation): 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
P0005(17.00g) was dissolved in gentle temperature EtOH (68ml) and AcOH (170ml) at 70 ℃. To the solution was added P0005 suspended in H2O (20ml) in one portion. The mixture was stirred at 70 ℃ for 1.5 h, then a mixture of ice (500ml) and concentrated HCl (10ml) was poured in. Diisopropyl ether (100ml) was added and the mixture was stirred at ambient temperature for 20 minutes. The precipitate was collected and washed sequentially with 1M HCl, H2O and diisopropyl ether. Air-dried overnight to give P0020(21.28g) as a pale yellow powder.
Mass spectrum (ESI +): 339(M + H) +
400MHz 1H NMR(CDCl3，d)：1.41(3H，t，J＝7.1Hz)，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
P0021 was prepared as a white powder using P0005 in a similar manner to P0020.
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
A solution of triphenylphosphine (831mg) in THF (5ml) was added dropwise at ambient temperature to a solution of E0118(521.8mg) and carbon tetrabromide (1.15g) in THF (5 ml). The reaction mixture was stirred at ambient temperature for 1 hour. Carbon tetrabromide (573mg) and triphenylphosphine (415mg) were added in one portion, and the mixture was stirred for additional 1 hour. The insoluble material was filtered off and washed with THF. The filtrate and combined washings were concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 5%, 25% in that order, to give P0022(647.2mg) as a pale yellow wax.
mp.60-70℃
Mass Spectrometry (API-ES cation): 425, 427(M + H) +, 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
P0023 was prepared as a colorless oil according to a similar procedure to P0022.
Mass Spectrometry (API-ES cation): 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
To a solution of P0001(20.0g) and P0024-0(53.4g) in DMF (200ml) was added NaH (4.27g) in portions under ice-cooling. The reaction mixture was warmed at room temperature, the temperature being kept below 40 ℃. After stirring for 5 hours, the reaction mixture was poured into ice-cold dilute HCl and extracted twice with ethyl acetate. The combined organic layers were washed with water (twice) and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (500ml, Hex: EtOAc) to obtain crystalline P0024(12.12 g).
mp：52.6-53.6℃
Example 100
To a solution of 4-hydroxybenzophenone (4.16g) and chloromethyl methyl ether (2.46g) in N, N-dimethylacetamide (15ml) was added sodium hydride (mineral oil suspension (60%), 1.22g) portionwise at 0 ℃ over 15 minutes. The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added 2-propanol (0.5ml), carbon disulphide (2.56g) and sodium hydride (suspension in mineral oil (60%), 2.50g) in portions over 15 minutes at 25 ℃. The mixture was stirred at ambient temperature for 1.5 h, diluted with toluene (20ml) and poured into a mixture of ice and concentrated hydrogen chloride (8ml) (total of 68ml of aqueous layer). The resulting mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated. To a mixture of the obtained residue and sodium hydrogencarbonate (13g) in ethyl acetate (30ml) and water (20ml) were added in portions an aqueous solution of iodine (3.88g) and sodium iodide (8.0g) at 0 ℃. To the mixture was added portionwise 4-methoxyphenylhydrazine hydrochloride (3.80g) under nitrogen at 0 ℃. The mixture was stirred at ambient temperature for 3 hours, the organic layer was separated, washed with water and brine, dried over magnesium sulphate and evaporated. To a solution of the residue in ethyl acetate (30ml) were added methyl iodide (4.0ml) and triethylamine (10ml) at 0 ℃. The mixture was stirred at ambient temperature for 30 minutes, washed with water and aqueous potassium carbonate, dried over magnesium sulphate and evaporated. The residue was purified by silica gel column chromatography (80g) eluting with a mixture of ethyl acetate and toluene (1:20) to give 7.56g of 5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole.
To a solution of dimethyl sulfide (7.56g) in methylene chloride (30ml) was added a solution of m-chloroperbenzoic acid (80%, 4.4g) in methylene chloride (15ml) at 0 ℃ and the mixture was stirred at 0 ℃ for 1 hour. The mixture was washed with aqueous potassium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by silica gel column chromatography (80g) and eluted with ethyl acetate to give 5.43g of 5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -3- (methylsulfinyl) -1H-pyrazole (E0100).
mp.136.9-137.3℃
Mass spectrometry; 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)，
Example 101
To a solution of 5- [4- (methoxymethyloxy) phenyl ] -1- (4-methoxyphenyl) -3- (methylsulfinyl) -1H-pyrazole (7.56g) in dichloromethane (20ml) was added m-chloroperbenzoic acid (60%, 3.76g) at 0 ℃ and the mixture was stirred at 0 ℃ for 3 hours. The mixture was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was purified by recrystallization from toluene to obtain 5.07g of 5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole (E0101).
mp.128.0-128.1℃
Mass spectrometry; 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 a solution of 5- [4- (methoxymethoxy) phenyl ] -1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazole (0.93g) in the mixture tetrahydrofuran (10ml) and isopropanol (5ml) was added aqueous hydrogen chloride (20%, 8ml) at ambient temperature. The solution was stirred for 3 hours, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated to yield 0.82g of 4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazol-5-yl ] phenol (P0025).
Mass spectrometry; 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
To a solution of P0026-0(5.0g) and imidazole (3.3g) in DMF (40ml) at room temperature was added TBDMSC1(6.69g) in portions. After stirring overnight, water and hexane were added. The aqueous layer was separated and extracted twice with hexane. The combined organic layers were washed with water (twice) and brine, dried over MgSO4, filtered and evaporated under reduced pressure to yield 9.49g (98.3%) of P0026.
IR (film): 2952.5, 2935.1, 1467.6, 1255.4, 1124.3, 1097.3, 838.9, 777.2cm-1.
Preparation 27
To a solution of P0027-0(10g) and dimethyl carbonate (5.97g) in DMF was added sodium methoxide (4.77 g). The mixture was stirred at ambient temperature for 2 hours. The mixture was poured into water containing 8mL of concentrated HCl and extracted with AcOEt. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain an orange solid. It was recrystallized from MeOH to obtain white crystals of P0027.
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 Spectrometry ESI 285(M + H) + (file platform 7366-1)
Preparation 28
Trifluoromethanesulfonic anhydride (198mg) was added dropwise to a solution of triphenylphosphine oxide (294mg) in 1, 2-dichloroethane (3ml) with cooling in an ice bath. When a white precipitate appeared, the mixture was stirred at the same temperature for 15 minutes. To the mixture was added dropwise P0027(300mg) in 1, 2-dichloroethane (2ml), followed by Et3N (214 mg). The mixture was refluxed for 2 hours. The mixture was cooled to ambient temperature, washed with H2O, saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 5% and 10% in this order. The residue was crystallized from IPE to obtain P0028(166mg) as a white powder.
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) was dissolved in EtOH (5ml) at 50 ℃. P0028(196mg) was added to the solution. After stirring at the same temperature for 2 hours, the reaction mixture was cooled to ambient temperature. The mixture was partitioned between 1M HCl and CHCl 3. The aqueous layer was back-extracted with CHCl 3. The combined organic layers were dried over MgSO4 and evaporated in vacuo. The residual crystals were collected and washed with IPE to give a first crop of product P0029(87mg) as a white powder. The mother liquor was concentrated in vacuo and the residual crystals were collected and washed with n-hexane to give a second crop of product P0029(39mg) as a reddish powder.
Mass Spectrometry (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
To a solution of P0030-0(2g) and triethyl phosphonoacetate (2.32g) in DMF (20ml) was added 60% NaH (490mg) in two portions under ice bath cooling. The mixture was stirred at the same temperature for 1 hour, and then poured into ice water containing NH4 Cl. The mixture was stirred for a while and a white precipitate was collected and washed with water and 10% aqueous IPA to 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
To a solution of P0030(2.79g) in CH2Cl2(28ml) was added dropwise bromine (1.66g) with cooling in an ice bath. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into 5% aqueous Na2S2O3 solution and partitioned. The organic layer was washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residual crystals were collected and washed with n-hexane to obtain P0031(3.07g) as a pale yellow powder.
200MHz 1H NMR(CDCl3，d)：1.38(3H，t，J＝7.2Hz)，4.35(2H，q，J＝7.2Hz)，4.81(1H，d，J＝11.8Hz)，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
85% solid KOH (1.73g) was dissolved in 95% aqueous EtOH (20ml) at 50 ℃. P0031(3.05g) was added in one portion and the mixture was refluxed for 9 hours. To the mixture was added a solution of 85% KOH (0.32g) in 95% aqueous EtOH (10ml) and refluxed for 5 hours. The mixture was cooled in an ice bath and the precipitate was collected and washed with EtOH. The crystals were suspended in AcOEt and H2O, cooled on an ice bath and acidified with 3M HCl and 1M HCl. The mixture was partitioned, the organic layer washed with H2O, dried over MgSO4 and concentrated in vacuo. The residual solid was collected and washed with IPE-n-hexane to give P0032(0.67g) as a white powder.
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)
Example 102
To a solution of P0032(99.9mg) and HOBT (64.2mg) in N-methylpyrrolidone (1ml) was added WSCD & HCl (91.1mg), and the mixture was stirred at ambient temperature for 20 minutes. In a separate flask, diisopropylethylamine (76.8mg) was added to a suspension of E0102-0(83.0mg) in N-methylpyrrolidone (1ml) and stirred at ambient temperature until all of the E0102-0 had dissolved. The E0102-0 solution was added to the reaction flask and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between AcOEt and H2O, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in CH2Cl2(3ml) and stirred at ambient temperature for 24 h. The mixture was concentrated in vacuo. The residual crystals were suspended in hot AcOEt, stirred for cooling, collected and washed with AcOEt to give E0102(90.9mg) as a white powder.
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)
Example 103
To a suspension of E0102(20.9mg) and K2CO3(23.3mg) in DMSO (0.5ml) was added dimethyl sulfate (10.6mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between AcOEt and H2O, the organic layer was washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography and developed with AcOEt/n-hexane 25%. The obtained crystals were crystallized from IPE to obtain E0103(12.0mg) as white crystals.
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)，7.34-7.43(5H，m)
Example 104
To a suspension of E0102(818mg) and K2CO3(911mg) in DMF (6ml) was added dimethyl carbonate (0.56 ml). The mixture was stirred at 120 ℃ for 2 hours. Dimethyl carbonate (1ml) was further added thereto, and the mixture was stirred at 120 ℃ for 8 hours. The mixture was partitioned between AcOEt and H2O and the aqueous layer was back-extracted with AcOEt. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/hexanes 30%. Crystallization from AcOEt (2.5ml) and n-hexane (5ml) gave E0104(583mg) as a white crystal.
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
A mixture of 10% Pd-C50% wet weight (50mg) and E0104(261mg) in AcOEt (2ml) and MeOH (2ml) was hydrogenated at H2(1atm) at ambient temperature for 1 day. An additional 10% Pd-C50% wet weight (50mg) was added and the mixture was hydrogenated at H2(3.5atm) at ambient temperature for 3 hours. The catalyst was removed by filtration and the filtrate and combined washings were concentrated in vacuo. The residue was dissolved in AcOEt, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from AcOEt-n-hexane to give P0033(146mg) as a white powder.
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
To a solution of ammonium formate (455mg) in H2O (1ml) were added EtOH (6ml), E0104(558mg), THF (1ml) and 10% Pd-C50% wet weight (60mg) in that order. The mixture was refluxed for 1 hour. The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was partitioned between AcOEt and H2O, the organic layer was washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residual crystals were recrystallized from AcOEt (3ml) and n-hexane (3ml) to obtain white crystals P0034(335 mg).
Mass spectrum (ESI +): 297(M + H) +
Example 105
A mixture of P0003(2.9g) and 4-methoxyphenylhydrazine (1.68g) in acetic acid (30ml) was stirred at room temperature for 15 hours. After addition of water, the mixture was extracted twice with toluene. The combined organic layers were washed with water (twice), saturated NaHCO3, water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex/EtOAc ═ 8:1-4:1) to give 2.2g (57%) of E0105 as an oil.
IR (film): 1737.6, 1511.9, 1240.0, 1159.0, 1130.1cm-1.
Example 106
E0106 was prepared similarly to E0105 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)
Example 107
E0107(175.7mg) was prepared in a similar manner to E0105 using P0007(590mg) and 4-methoxyphenylhydrazine hydrochloride (332 mg).
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＝6.8Hz)，6.99(2H，d，J＝8.9Hz)，7.15(1H，s)，7.17-7.30(6H，m)
Example 108
E0108 was prepared analogously to E0105 with P0007.
Mass Spectrometry (API-ES cation): 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)，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)
Example 109
E0109 was prepared in a similar manner to E0105.
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)
Example 110
E0110 was prepared according to a similar method to E0105.
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)，7.19-7.32(4H，m)，7.73(1H，dd，J＝2.7，8.8Hz)，8.14(1H，d，J＝2.7Hz)
Example 111
E0111 was prepared according to a similar method to E0105.
Mass Spectrometry (API-ES cation): 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)
Example 112
E0112 was obtained according to a similar method to E0105.
Example 113
E0113 was obtained according to a similar method to E0105.
Example 114
E0114 was obtained according to a similar method to E0105.
Example 115
E0115 was obtained according to a similar method to E0105.
Example 116
E0116 was obtained according to a similar method to E0105.
Example 117
E0117 was obtained according to a similar method to E0105.
Example 118
A mixture of E0105(2.0g) and 1N NaOH (15ml) in THF (40ml) was stirred at room temperature for 5 hours. After completion of the reaction, the mixture was neutralized with 1N HCl (15ml), extracted twice with ethyl acetate, washed with 1N HCl, saturated NaHCO3 and brine, dried over NA2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (H/EA ═ 2:1-1:1) to obtain 1.14g (64%) of crystalline E0118.
mp：103-104℃
IR (film): 3396.0, 1513.9, 1467.6, 1238.1, 1160.9 and 1132.0cm-1.
Example 119
E0119 was prepared by a similar method to E0118 with E0217.
IR (pure): 3359, 3332, 3325, 1658, 1651, 1624, 1614, 1545, 1533, 1500cm-1
Mass spectrum (ESI +): 421(M + H) +
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)
Example 120
E0120 was prepared analogously to E0118 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)
Example 121
E0121 was prepared as a white powder using E0268 in a manner analogous to E0118.
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)，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)
Example 122
E0122 was prepared as a white powder in a similar way to E0118 from 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＝5.4Hz)，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)
Example 123
E0123 was prepared as a white powder in a similar way to E0118 using 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)
Example 124
E0124 was prepared as a white powder using E0107 in a manner analogous to E0118.
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)，7.15-7.33(4H，m)，7.29(2H，d，J＝9.0Hz)
Example 125
E0125 was prepared analogously to E0118.
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＝8.9Hz)，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)
Example 126
E0126 was prepared as a white powder using E0111 in a similar way to E0118.
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＝5.2Hz)，6.92(1H，d，J＝8.8Hz)，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)
Example 127
E0127 was prepared using E0108 in a similar way to E0118.
IR (pure): 3400, 2951, 1610, 1502cm-1
Mass Spectrometry (API-ES cation): 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)，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)
Example 128
E0128(104.4mg) was prepared in a similar manner to E0118.
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)
Example 129
E0129 was obtained analogously to E0118.
Example 130
E0130 was obtained according to a similar method to E0118.
Example 131
E0131 was obtained according to a similar method to E0118.
Example 132
E0132 was obtained according to a similar method to E0118.
IR (film): 3392.2, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4, 975.8, 833.1cm-1.
Example 133
E0133 was obtained according to a similar method to E0118.
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℃
Example 134
E0134 was obtained according to a similar method to E0118.
IR (film): 3386.4, 1511.9, 1471.4, 1236.2, 1159.0, 1132.0, 1047.2, 975.8, 817.7cm-1.
Example 135
E0135 was obtained according to a similar method to E0118.
IR (film): 3399.9, 1610.3, 1513.9, 1459.9, 1251.6, 1172.5, 1083.8, 1033.7, 836.9, 802.2cm-1.(FS7081)
Example 136
A mixture of P0018(277mg) and 4-methoxyphenylhydrazine hydrochloride (209mg) in EtOH: AcOH ═ 20:1(6ml) was refluxed for 2 hours. The mixture was partitioned between AcOEt and H2O. The organic layer was washed successively with 1M HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 30%, 40%, 50%. The pure fractions were collected and concentrated in vacuo. The residue was crystallized from AcOEt/n-hexane to obtain E0136(95.6mg) as a white powder. mp.111-112 deg.C
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)
Example 137
E0137 was prepared with P0018(498.5mg) using a similar method to that of E0136.
Preparation 34
A white powder of P0034 was prepared in a similar manner to E0137.
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＝9.0Hz)，6.98(2H，d，J＝8.7Hz)，7.12(2H，d，J＝9.0Hz)，9.63(1H，s)
Example 138
To a solution of E0118(1.0g) and Et3N (0.6ml) in CH2Cl2(20ml) was added dropwise methanesulfonyl chloride (0.26ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water and extracted with CHCl 3. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to yield 1.2g (99%) of crude E0138 as a cream solid.
IR (film): 1513.9, 1469.5, 1351.9, 1240.0, 1166.7, 1130.1, 971.9, 835.0, 804.2cm-1.
Example 139
E0139 was prepared in a similar way to E00138.
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)
Example 140
E0140 was prepared using a similar method to E0138.
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)，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)
Example 141
E0141 was prepared using a similar method to E0138.
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)
Example 142
E0142 was obtained according to a similar method to E0138.
Example 143
E0143 was obtained according to a similar method to E0138.
Example 144
This compound was obtained according to a similar method to that of E0138.
Example 145
This compound was obtained according to a similar method to that of E0138.
Example 146
This compound was obtained according to a similar method to that of E0138.
Example 147
This compound was obtained according to a similar method to that of E0138.
Example 148
A mixture of E0138(900mg) and potassium peptidimide (454mg) in DMF (18ml) was stirred at 60 ℃ for 3.0 h. After addition of water, the reaction mixture was extracted with EtOAc, washed twice with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50ml) to obtain 930mg (93%) of E0148 as a powder.
IR (film): 1772.3, 1712.5, 1240.0, 1160.9, 1130.1cm-1.
Example 149
Amorphous powder E0149 was prepared using E0139 in a similar manner to E0148.
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)
Example 150
Amorphous powder E0150 was prepared from E0140 in a similar manner to E0148.
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)，7.11-7.20(6H，m)，7.79-7.89(4H，m)
Example 151
E0151 was prepared using E0038 in a similar manner to E0148.
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＝8.8Hz)，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)
Example 152
This compound was obtained according to a similar method to that of E0148.
Example 153
This compound was obtained according to a similar method to that of E0148.
Example 154
This compound was obtained according to a similar method to that of E0148.
Example 155
This compound was obtained according to a similar method to that of E0148.
Example 156
This compound was obtained according to a similar method to that of E0148.
Example 157
This compound was obtained according to a similar method to that of E0148.
Example 158
To a solution of E0148(800mg) in CH3CN (10ml) was added hydrazine hydroxide (87ul) at room temperature. After stirring for 1 hour, the reaction mixture was filtered and evaporated. Dichloromethane was added and the mixture was stirred for 1 hour, filtered and evaporated. The residue was treated with 4N HCl/EtOAc to give 518mg (80%) of E0158.
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.
Example 159
This compound was obtained according to a similar method to that of E0158.
Example 160
This compound was obtained according to a similar method to that of E0158.
Example 161
This compound was obtained according to a similar method to that of E00158.
IR (film): 3428.8, 1511.9, 1467.6, 1238.1, 1160.9 and 1132.0cm-1.
Example 162
This compound was obtained according to a similar method to that 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.
Example 163
This compound was obtained according to a similar method to that of E0158.
mp：163.1-165.1℃
IR (film): 2973.7, 1511.9, 1471.4, 1236.2, 1159.0 and 1133.9cm-1.
Example 164
This compound was obtained according to a similar method to that 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.
Example 165
To a solution of E0395(1.08g) in acetonitrile (15ml) was added hydrazine monohydrate (0.53 ml). After stirring overnight at 60 ℃, the mixture was filtered. The filtrate was evaporated to give E0165 as an orange oil (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+).
Example 166
E0166 was prepared using E0046 in a similar way to E0165.
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)，7.16-7.26(4H，m)，7.64-7.73(1H，m)，8.15(1H，d，J＝2.5Hz)
Example 167
E0167 was prepared using E0150 in a similar manner to E0165.
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)，7.06-7.26(6H，m)
Example 168
E0168 was prepared using E0048 in a similar way to E0165.
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)
Example 169
To a solution of E0165(180mg) in tetrahydrofuran (2ml) were added triethylamine (0.242ml) and tert-butoxycarbonyl anhydride (325mg) at room temperature. After stirring at room temperature overnight, the mixture was quenched with water and extracted with ethyl acetate (× 3). The organic layer was washed with aqueous hydrogen chloride (1N), saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give an oil which was purified by column chromatography (SiO 225 ml, 20% ethyl acetate/hexane) to give E0169 as an oil (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).
Example 170
This compound was obtained according to a similar method to that 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).
Example 171
A mixture of E0158(650mg), Boc2O (428mg) and 1NNaOH (3.3ml) in THF (20ml) was stirred at room temperature for 15 h. Water and EtOAc were added, the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, water and brine, dried over NA2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex/EtOAc) to yield 700mg (93%) of E0171 as an oil.
Example 172
This compound was obtained according to a similar method to that of E0171.
Example 173
This compound was obtained according to a similar method to that of E0171.
Example 174
This compound was obtained according to a similar method to that of E0171.
IR (film): 1702.8, 1513.9, 1241.9, 1164.8, 1132.0cm-1.
Example 175
To a solution of E0171(200mg) and MeI (0.14ml) in THF (20ml) was added NaH (35mg) portionwise at room temperature. The reaction mixture was then heated at 70 ℃ for 1 hour. Almost no reaction occurred.
MeI (0.3ml), NaH (40mg) and DMF were added successively.
The mixture was stirred at 70 ℃ for 12 hours, then cooled and quenched with water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography to give 151mg (73%) of E0175 as an oil.
Example 176
This compound was obtained according to a similar method to that of E0175.
Example 177
To a mixture of E0158(150mg) and HCHO (46ul) in Et3N (53ul) and CH3CN (5ml) was added NaBH (OAc)2(240mg) portionwise at room temperature. After stirring for 15 h, the mixture was quenched with water and extracted 3 times with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3/MeOH) and treated with 4N Cl/dioxane to give 108mg (70%) of E0177.
Example 178
Methyl isocyanate (36.2mg) was added under ice-bath cooling to a solution of E0165(199.3mg) and triethylamine (48.6mg) in CH2Cl2(2 ml). The reaction mixture was stirred at the same temperature for 1 hour and then concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from AcOEt-n-hexane. The powder obtained was dissolved in CHCl3 and purified by preparative thin layer silica gel chromatography on MeOH/CHCl3 ═ 10%. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residual solid was collected and washed with diisopropyl ether to give E0178(101.3mg) as a white powder.
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)
Example 179
E0179(80.7mg) was prepared using E0166 in a similar manner to E0178.
Amorphous powder
IR (pure sample): 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, overlap), 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)
Example 180
E0180 was prepared using E0294 in a similar manner to E0178.
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)
Example 181
This compound was obtained according to a similar method to that of E0178.
IR (film): 3343.9, 1658.5, 1608.3, 1513.9, 1457.9, 1249.6, 1029.8, 836.9cm-1.
Example 182
This compound was obtained according to a similar method to that 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.
Example 183
This compound was obtained according to a similar method to that 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.
Example 184
AcCl (23.3mg) was added to CH2Cl2(2ml) containing E0158(107.4mg) and triethylamine (68.3mg) with ice bath cooling. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residual solid was collected and washed with diisopropyl ether to give E0184(84mg) as a white powder.
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)，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)
Example 185
E0185(143.4mg) was prepared using E0232(155.3mg), methyl chloroformate (35.8mg) and triethylamine (105mg) in a similar manner to E0184.
Amorphous powder
IR (pure sample): 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)
Example 186
E0186(59.3mg) was prepared in a similar manner to E0184 using E0158(96.2mg), methyl chloroformate (25.1mg) and triethylamine (61.2 mg).
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)
Example 187
E0187(63.4mg) was prepared in a similar manner to E0184 using E0165(113.6mg), acetyl chloride (29.5mg) and triethylamine (41.2 mg).
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)
Example 188
E0188 was prepared using E0165 in a similar manner to E0184.
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)
Example 189
E0189 was prepared using E0294 in a similar manner to E0184.
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)
Example 190
This compound was obtained according to a similar method to that 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
Example 191
This compound was obtained according to a similar method to that 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.
Example 192
E0158(250mg) was suspended in AcOEt (5ml) and partitioned between AcOEt and saturated aqueous sodium bicarbonate. The organic layer was washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in dimethoxyethane (5ml), and sulfonamide (181mg) was added to the solution and the mixture was refluxed for 2 days. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with MeOH/CHCl3 ═ 1%, 2% and 3% in that order. The obtained amorphous powder was crystallized from EtOH-diisopropyl ether to obtain E0192(153mg) as a white powder.
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＝8.5Hz)，7.24(2H，d，J＝8.5Hz)，7.29(2H，d，J＝8.9Hz)
Example 193
E0193 was prepared in a similar manner to E0192 using 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(IH，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)
Example 194
E0194 was prepared by E0322 in a similar manner to E0192.
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)，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)
Example 195
This compound was obtained analogously to 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).
Example 196
To a solution of E0158(100mg) and Et3N (53ul) in CHCl3(10ml) was added MsCl (29ul) at room temperature. After stirring for 1 hour, the reaction mixture was poured into water and CHCl 3. The aqueous layer was separated and extracted with CHCl 3. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50ml) and crystallized to obtain 75mg (68%) of E0196 as a powder.
IR (film): 3284.2, 1513.9, 1319.1, 1240.0, 1151.3 and 973.9cm-1.
Example 197
E0197 was prepared in a similar manner to E0196 using 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)
Example 198
E0198 was prepared in a similar manner to E0196 using 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)
Example 199
E0199 was prepared by E0234 in a similar way to E0196.
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, overlap)
Example 200
E0200 was prepared by a method similar to E0196 using 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, overlap)
Example 201
E0201 was prepared in a similar way as E0196 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)，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)
Example 202
E0202 was prepared by E0322 in a similar way to E0196.
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)
Example 203
This compound was obtained according to a similar method to that 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).
Example 204
This compound was obtained analogously to 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.
Example 205
This compound was obtained analogously to E0196.
Example 206
This compound was obtained analogously to 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.
Example 207
This compound was obtained according to a similar method to that 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.
Example 208
This compound was obtained analogously to E0196.
IR (film): 3284.2, 1513.9, 1317.1, 1240.0, 1153.2cm-1.
Example 209
This compound was obtained analogously to E0196.
IR (film): 3286.1, 1511.9, 1321.0, 1230.4, 1155.2, 975.8, 842.7, 756.0cm-1.
Example 210
This compound was obtained analogously to E0196.
IR (film): 3284.2, 1511.9, 1469.5, 1321.0, 1236.2, 1153.2, 975.8, 821.5, 756.0cm-1.
Example 211
This compound was obtained analogously to 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.
Example 212
This compound was obtained analogously to E0196.
IR (film): 3266.8, 1612.2, 1469.5, 1321.0, 1240.0, 1153.2, 1097.3, 975.8, 835.0cm-1.
Example 213
This compound was obtained analogously to E0196.
IR (film): 3288.0, 1612.2, 1322.9, 1240.0, 1153.2, 975.8, 946.9cm-1.
Example 214
A mixture of E0158(180mg), formic acid (38ul) and WSCD (155mg) in Et3N (0.3ml) and THF (5ml) was stirred at room temperature for 1 hour. After addition of water and EtOAc, the aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were washed with 1n hcl, saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex/EtOAc ═ 2:1) to give 136mg (70%) of E0214 as a powder.
IR (film): 1670.1, 1513.9, 1238.1, 1160.9, 1130.1cm-1.
Example 215
After stirring a mixture of E0158(250mg), BocGly (132mg), WSCD (127mg) and HOBt (110mg) in Et3N (114ul) and CH2Cl2(30ml) at room temperature for 15 hours, the reaction mixture was poured into water and CHCl 3. The aqueous layer was separated and extracted with CHCl 3. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was analyzed by silica gel column chromatography (50ml) and crystallized to obtain 325mg (99%) of E0215 as an oil.
Example 216
E0216 was prepared in a similar manner to E0215.
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)
Example 217
E0217 was prepared analogously to E0215 using E0294 and acetoxyacetic acid.
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)
Example 218
E0218 was prepared similarly to E0215 using E0294 and N-tert-butoxycarbonylglycine, except that N-methylmorpholine (55.8mg) was used in place of triethylamine.
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, overlap), 6.92(1H, d, J ═ 8.8Hz), 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)
Example 219
E0219 was prepared analogously to E0215.
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)，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)
Example 220
E0220 was prepared similarly to E0215.
Example 221
E0221 was prepared similarly to E0215.
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)
Example 222
E0222 was prepared similarly to E0215.
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)
Example 223
E0223 was prepared similarly to E0215.
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)，3.42-3.73(4H，m)，3.87(3H，s)，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)
Example 224
E0224 was prepared similarly to E0215.
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)
Example 225
E0225 was prepared similarly to E0215.
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, overlap), 7.16(2H, d, J ═ 8.8Hz), 7.23(2H, d, J ═ 8.9Hz)
Example 226
E0226 was prepared similarly to E0215.
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)
Example 227
E0227 was prepared similarly to E0215.
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)
Example 228
The objective compound (371.9mg, 96%) was obtained as an oil in a similar manner to E0215.
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).
Example 229
The target compound was obtained as a white powder according to a similar method to that of E0289.
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
Example 230
This compound was obtained analogously to E0215.
IR (film): 3320.82, 1706.69, 1668.12, 1515.77, 1249.65, 1168.65, 1031.73cm-1.
Example 231
A mixture of E0215(300mg) and 4N HCl in dioxane (5.8ml) was stirred at room temperature for 1.0 h. The reaction mixture was then evaporated under reduced pressure to yield 260mg (99%) of amorphous E0231.
IR (film): 3226.3, 1679.7, 1513.9, 1251.6, 1083.8, 1029.8, 837.0cm-1.
Example 232
E0232 was prepared analogously to E0231.
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)
Example 233
E0233 was prepared by a similar method to E0231.
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)，6.94-7.01(4H，m)，7.18-7.26(4H，m)，8.13(2H，brs)
Example 234
E0234 was prepared by a similar method to E0231.
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)
Example 235
E0235 was prepared by a similar method to E0231.
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)，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)
Example 236
E0236 was prepared by a similar method to E0231.
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)
Example 237
E0237 was prepared by a similar method to E0231.
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)
Example 238
E0238 was prepared by a similar method to E0231.
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)
Example 239
This compound was obtained according to a similar method to that of E0231.
IR (film): 3220.5, 1679.7, 1513.9, 1461.8, 1251.6, 1081.9, 1029.8, 837.0, 800.3cm-1.
Example 240
To a solution of E0267(75.2mg) in dichloromethane (1ml) were added triethylamine (30.4ml) and trimethylsilyl isocyanate (36.9ml) at 0 ℃. After stirring for 5 hours, the mixture was quenched with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give an oil which was purified by preparative TLC (1mm, ethyl acetate) to give an oil. The oil was crystallized from a mixture of isopropyl ether, ethyl acetate and hexane to give E0240(39.1mg, 51.2%) as a white solid.
NMR(DMSO-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.
Example 241
E0241 was prepared by E0194 in a similar manner to E0240.
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)
Example 242
E0242 was prepared by a similar method to that of E0240.
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)
Example 243
E0243 was prepared by using E0234 in a similar way to E0240.
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)
Example 244
E0244 was prepared by a similar method to E0240 using 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)
Example 245
E0245 was prepared by a similar method to that of E0240.
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＝8.8Hz)，7.30(2H，d，J＝8.9Hz)
Example 246
E0246 was prepared by a similar method to that of E0240.
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)
Example 247
E0247 was prepared by a similar method to that of E0240.
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)]
Example 248
E0248 was prepared by a similar method to that of E0240.
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)
Example 249
An amorphous target compound was obtained using a similar method to that of E0240.
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+).
Example 250
The title compound was obtained as a white powder according to a similar method to E0240.
NMR(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℃.
Example 251
The target compound was obtained in powder form according to a similar method to that of E0240.
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)+.
Example 252
To a solution of E0267(15.3g) in ethanol (75ml) and aqueous hydrogen chloride (1N, 220ml) was added dropwise a solution of sodium cyanate (14.4g) in water (300ml) at 45 ℃ over 5 minutes. After stirring at 45 ℃ for 4 hours, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to give a powder. The powder was crystallized from ethyl acetate and hexane at room temperature to 70 ℃ to obtain E0252(12.628g, 81.2%) as a powder.
The physical data for this compound are identical to those obtained previously for the real sample.
Example 253
To a solution of E0267(200mg) in methanol (1ml) was added sodium methoxide methanol solution (5.2M, 0.1ml) at room temperature. After stirring for 20 minutes, the mixture was evaporated to give a residue. Tetrahydrofuran was added to the residue, and the mixture was filtered and evaporated to give an oil. The oil was dissolved in ethyl formate (2ml) and stirred at room temperature overnight. The mixture was evaporated and purified by preparative TLC (1mm, 50% ethyl acetate/hexane) to give an oil which was crystallized from isopropyl ether, ethyl acetate and hexane to give E0253(162.8mg, 83%) as a white powder.
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.
Example 254
To a solution of E0267(800mg) and triethylamine (0.7ml) in dichloromethane (9ml) was added dropwise acetyl chloride (0.18ml) at 0 ℃. After stirring at room temperature for 1 hour, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (× 3). The combined organic layers were washed with aqueous hydrogen chloride (1N), water and brine, dried over magnesium sulfate and evaporated to give an oil which was purified by column chromatography (SiO 2100 ml, eluting with 50% ethyl acetate/hexanes) to give an oil. The oil was crystallized from a mixture of ethyl acetate and hexane at 50 ℃ to give E0254(768.6mg, 94.8%) as a solid.
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).
Example 255
The target compound was obtained as an oil according to a similar method to that of E0254.
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.
Example 256
The target compound (82mg, 78%) was obtained as an oil according to a similar method to that of E0254.
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).
Examples257
To a solution of E0275(97.5mg) and pyridine (0.14ml) in dichloromethane (1ml) was added trifluoroacetic anhydride (60.6ml) at 0 ℃. After stirring at room temperature overnight, the mixture was quenched with saturated aqueous sodium bicarbonate (0.5ml), filtered with chemelute1001(Varian), and purified by preparative TLC (1mm, 50% ethyl acetate/hexane) to give E0257 as a solid (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).
Example 258
To a solution of E0327(400mg) in THF (5ml) was added dropwise 1N NaOH (2.5ml) at room temperature. The mixture was stirred overnight and then quenched with 1N HCl and CHCl 3. The organic layer was separated and the aqueous layer was extracted twice with CHCl 3. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was washed with IPE to yield 273mg (70.7%) of E0258.
IR (film): 2971.8, 1683.6, 1629.6, 1515.8, 1315.2, 1230.4, 1159.0, 1132.0, 977.7, 835.0cm-1.
Example 259
A white powder of E0259 was prepared by a method similar to that of E0258.
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)
Example 260
E0260 was prepared analogously to E0258.
White powder
Mass spectrum (ESI +): 356(M + H) +
200MHz 1H NMR(DMSO-d6，d)：3.69-3.79(2H，m)，3.88(3H，s)，3.96-4.02(2H，m)，4.87(1H，br)，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)
Example 261
E0261 was prepared analogously to E0258 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)
Example 262
E0262 was prepared analogously to E0258.
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)
Example 263
E0263 was prepared analogously to E0258.
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)，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)
Example 264
E0264 was prepared analogously to E0258 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)，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)
Example 265
4M HCl/AcOEt (0.4ml) was added to a solution of E0378(73mg) in AcOEt (1 ml). The mixture was concentrated and dried in vacuo to give amorphous powder E0265(68.4 mg).
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)
Example 266
E0266 was prepared analogously to E0265.
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)
Example 267
To a solution of E0275(765mg) in ethyl acetate (1.9ml) was added a solution of hydrogen chloride in ethyl acetate (4N, 0.56 ml). The mixture was evaporated to give an oil which was crystallised from diisopropyl ether and ethyl acetate at 65 ℃ to give E0267(766.8mg, 91.4%) as a solid.
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.
Example 268
A mixture of P0011(30g), chloroacetonitrile (8.52ml), potassium iodide (4.47g) and potassium carbonate (14.9g) in acetone (150ml) was stirred at reflux for 2.5 h at 80 ℃. After cooling to room temperature, the mixture was quenched with water (600ml) and extracted with ethyl acetate (300 ml. times.2, 150 ml). The combined organic layers were washed with brine (300ml), dried over magnesium sulphate and evaporated to give a solid (36.34 g). The solid was recrystallized from diisopropyl ether (60ml) and hexane (200ml) at room temperature to give E0268(31.5g, 94%) as a powder.
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.
Example 269
E0269 was obtained analogously to E0268.
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)，7.10-7.21(4H，m)
Example 270
The target compound was obtained in the form of powder according to a similar method to that of E0268.
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＝8.4Hz)，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).
Example 271
The target compound was obtained according to a similar method to that of E0268.
Example 272
The target compound was obtained according to a similar method to that of E0268.
IR (film): 1612.2, 1482.9, 1234.2, 1162.8, 1132.0, 1095.3, 973.8, 835.0cm-1.
Example 273
The target compound was obtained according to a similar method to that of E0268.
Example 274
The target compound was obtained according to a similar method to that of E0268.
mp.96-99℃
Mass spectrometry; 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)
Example 275
To a suspension of lithium aluminum hydride (250mg) in diethyl ether (14ml) was added diethyl ether (5ml) containing E0268(1.38g) and tetrahydrofuran (1ml) under ice-bath. The mixture was stirred at room temperature for 1 hour. Lithium aluminum hydride (50mg) was added to the mixture under ice bath, and then the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (0.3ml), aqueous sodium hydroxide (15%, 0.3ml) and water (0.9ml), and then stirred at room temperature for 30 minutes. Magnesium sulfate and celite were added to the mixture, and the suspension was filtered and washed with ether. The filtrate was evaporated to give 1.307g of oil. The oil was purified by column chromatography (SiO2, 100ml, eluting with 20% methanol in chloroform (500 ml)) to give E0275(1.156g, 82.9%) as an oil.
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+).
Example 276
To a solution of E0268(27.43g) in tetrahydrofuran (270ml) was added borane dimethylsulfide complex (10M, 15ml) at room temperature. The mixture was stirred at room temperature overnight. Borane dimethylsulfide complex (7.5ml) was then added to the mixture. After stirring at room temperature overnight, the mixture was quenched with methanol (100ml) and evaporated under reduced pressure to give an oil. The oil was dissolved in a mixture of tetrahydrofuran (150ml) and hydrochloric acid (6N, 100ml) and stirred at 40-50 ℃ for 1 hour. To the mixture were added dropwise aqueous sodium hydroxide (30%, 80ml), sodium bicarbonate and sodium chloride in this order. The mixture was extracted with ethyl acetate (× 4). The organic layer was evaporated to give an oil (31.86g), which was purified by column chromatography (SiO2, 1L, eluting with 20% methanol/dichloromethane and concentrated ammonia/methanol/chloroform (0.025:1: 4)) to give an oil. An ethyl acetate solution of hydrogen chloride (4N, 22ml) was added to a solution of the oil in ethyl acetate (50ml), and the mixture was evaporated to give amorphous E0276(22.87g, 69.4%).
Example 277
E0277 was prepared analogously to E0276.
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＝8.8Hz)，8.21(2H，brs)
Example 278
The title compound was obtained as an oil according to E0276 without formation of the hydrochloride salt.
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+).
Example 279
The target compound was obtained according to a similar method to that of E0276.
Example 280
The target compound was obtained according to a similar method to that of E0276.
IR (film): 3423.0, 1612.2, 1469.5, 1240.0, 1164.8, 1132.0, 1095.4, 975.8, 836.9cm-1.
Example 281
The target compound was obtained according to a similar method to that of E0276.
mp.104-106℃
Mass spectrometry; 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)，
Example 282
Diethyl azodicarboxylate (82.3mg) was added to a solution of P0015(100mg), P0015-1(152mg) and triphenylphosphine (124mg) in THF (2 ml). After stirring at ambient temperature for 5 hours, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% AcOEt/CHCl3 as a viscous oil to give 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)，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)
Example 283
E0283 was prepared similarly to E0282 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, overlap), 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)
Example 284
E0284 was prepared analogously to E0282.
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)
Example 285
The target compound was obtained as an oil according to a similar method to that of E0282.
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).
Examples286
The target compound was obtained in the form of powder according to a similar method to that of E0282.
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+).
Example 287
The target compound was obtained as an oil according to a similar method to that of E0282.
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).
Example 288
The target compound was obtained as an oil according to a similar method to that of E0282.
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).
Example 289
4M HCl/AcOEt (1ml) was added to a solution of E0282(129mg) in AcOEt (1ml) and the mixture was stirred at ambient temperature for 1 hour. The supernatant was removed by decantation. The residual oily solid was washed with AcOEt (1ml) by decantation. Acetone (2ml) was added to the residue and the oily residual solid turned into a white powder with stirring. Stir at ambient temperature for 20 minutes. The precipitate was collected and washed with acetone to give E0289(91.4mg) as a white powder.
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)，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)
Example 290
The target compound was obtained as a white powder according to a similar method to that of E0289.
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.
Example 291
The target compound was obtained as a white powder according to a similar method to that of E0289.
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℃.
Example 292
The white amorphous target compound was obtained according to a similar method to that of E0289.
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+).
Example 293
The white amorphous target compound was obtained according to a similar method to that of E0289.
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.
Example 294
The target compound was obtained as a white powder according to a similar method to that of E0289.
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.
Example 295
A mixture of P0012(0.5g), chloroacetonitrile (0.2ml), potassium iodide (525mg) and potassium carbonate (437mg) in N, N-dimethylformamide (6ml) was stirred at 75 ℃ for 6 hours. After cooling to room temperature, the mixture was quenched with water and extracted with ethyl acetate (× 3). The combined organic layers were washed with water (× 3) and brine, dried over magnesium sulphate and evaporated to give E0295(631.6mg, 112%) as a solid.
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).
Example 296
The target compound was obtained as an oil according to a similar method to E0295.
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).
Example 297
The title compound was obtained as an oil according to a similar procedure as E0205.
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).
Example 298
The title compound was obtained as a white solid according to a similar procedure to E0295.
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.
Example 299
The title compound was obtained as a white solid according to a similar procedure to E0295.
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＝8.7Hz)，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.
Example 300
The title compound was obtained as a white powder according to a similar method to E0295.
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.
Example 301
The present compound was alkylated by a similar method to E0295 to obtain an oily compound free of salt. The hydrochloride salt was then formed by a similar method to that of E0172 to obtain E0301(498.7mg, 49.6%) as a white powder.
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) +, (free).
IR (pure), 1614, 1552cm-1.
Example 302
The title compound was obtained as a white solid according to a similar procedure to E0295.
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.
Example 303
The target compound was obtained as an oil according to a similar method to E0295.
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.
Example 304
The title compound was obtained as a white powder according to a similar method to E0295.
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.
Example 305
The target compound was obtained according to a similar method to that of E0298.
IR (film): 3388.3, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4, 975.8, 833.1cm-1.
Example 306
The target compound was obtained according to a similar method to that of E0295.
Mass spectrometry; 384(M +1)
Example 307
To a suspension of lithium aluminum hydride (250mg) in diethyl ether (5ml) was added tetrahydrofuran (1ml) containing E0295(630mg) while cooling on ice. After stirring at room temperature for 1 hour, the mixture was quenched with water (0.125ml), aqueous sodium hydroxide (15%, 0.125ml) and water (0.375ml), and then stirred at room temperature for 30 minutes. Magnesium sulfate and celite were added to the mixture and the suspension was filtered and washed with ether. The filtrate was evaporated to give 0.5g of oil. The oil was purified by column chromatography (SiO2, 50ml, eluting with methanol/dichloromethane/concentrated aqueous ammonia (1/10/0.05)) to give an oil (300 mg). The oil was dissolved in ethyl acetate and a solution of hydrogen chloride in ethyl acetate (4N, 1.6ml) was added. The mixture was evaporated to give an oil which was crystallized from methanol and diisopropyl ether to give E0307(300mg, 42.7%) as a powder.
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 +, free).
IR(KBr，20727-7)，1612，1513.9cm-1.
Example 308
The target compound was obtained according to a similar procedure as for E0307.
IR (film): 3401.8, 1610.3, 1511.9, 1469.5, 1240.0, 1162.9, 1130.1, 975.8, 827.3cm-1.
Example 309
A mixture of P0011(200mg), chloromethylsulfonic acid sodium salt (274mg), potassium iodide (298mg) and potassium carbonate (248mg) in 1-methyl-2-pyrrolidone (2ml) was stirred at 150 ℃ overnight. After cooling to room temperature, the mixture was poured into a mixture of aqueous hydrogen chloride (1N), brine and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (× 3). The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure to give an oil. The oil was purified by column chromatography (SiO2100ml, eluting with 15% methanol/dichloromethane) to afford brown amorphous E0309(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).
Examples310
To a solution of P0011(1.0g) in DMF (10ml) was added NaH (60% oil dispersion, 144mg) in portions under water cooling, and stirred for 1 hour. Then III (787mg) was added and the reaction mixture was stirred at 50 ℃ for 5 hours. The mixture was quenched with water and extracted twice with EtOAc. The organic layer was washed 3 times with water and 1 time with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50ml) to obtain 803mg (55%) of E0310 as an oil.
Example 311
The target compound was obtained according to a similar procedure as for E0310.
Example 312
A mixture of E0310(800mg) and cHCl (100ul) in EtOH (10ml) was stirred at room temperature for 3 hours. After addition of aqueous sodium bicarbonate, the mixture was evaporated and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue (710mg) was purified by silica gel column chromatography (50ml) to obtain 570mg (93%) of E0312.
IR (film): 3409.5, 1612.2, 1513.9, 1467.6, 1243.9, 1162.9, 1130.1, 835.0, 835.0cm-1.
Example 313
The target compound was obtained according to a similar procedure as for E0312.
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.
Example 314
60% sodium hydride (39.7mg) was added to a solution of P0011(255mg) in DMF (1.5 ml). The mixture was stirred at ambient temperature for 1 hour. Ethyl bromoacetate (153mg) was added to the mixture. The reaction mixture was stirred at ambient temperature for 1 hour, then quenched by addition of saturated ammonium chloride solution and the whole mixture was extracted with AcOEt. The organic layer was washed with H2O and aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/hexanes 30% to give E0314(217mg) as an oil.
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)
Example 315
A1M solution of diisobutylaluminum hydride in toluene (0.5ml) was added dropwise to a solution of E0314(98mg) in THF (3ml) at-50 ℃. The mixture was stirred at-50 ℃ for 1 hour and then at 5 ℃ for 1 hour. A1M solution of diisobutylaluminum hydride in toluene (0.5ml) was added dropwise thereto. After stirring at 5 ℃ for 1 hour, the reaction was quenched by addition of 10% aqueous sodium potassium tartrate solution and the mixture was filtered through a celite pad. The filtrate was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with AcOEt/n-hexane 60%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give E0315(54.5mg) as an oil which became a solid on standing.
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)
Example 316
60% sodium hydride (52mg) was added to a solution of P0020(200mg) in DMF (2ml) with ice bath cooling. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added bromoacetic acid (90.3 mg). The reaction mixture was stirred at ambient temperature for 2 hours and then quenched by the addition of 1M HCl (3 ml). H2O (3ml) and diisopropyl ether (2ml) were added and the mixture was stirred in an ice bath for 30 minutes. The precipitate was collected and washed with H2O and diisopropyl ether to give E0316(231.2mg) as a white powder.
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)
Example 317
E0317 was prepared in a similar manner to E0316.
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)
Example 318
E0318 was prepared in a similar manner to E0316.
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)
Example 319
To a suspension of sodium borohydride (19.1mg) in THF (2ml) was added dropwise boron trifluoride diethyl etherate (89.5mg) (2.5 equiv) with cooling in an ice bath. The mixture was stirred at the same temperature for 30 minutes. E0316(100mg) was added in one portion and the mixture stirred at ambient temperature for 5 hours. 1M HCl (5ml) was added and the mixture stirred at ambient temperature for 30 minutes. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give E0319(68.9mg) as a white powder.
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)
Example 320
E0320 was prepared in a similar manner to E0319.
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)
Example 321
E0321 was prepared analogously to E0319.
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)
Example 322
E0322 was prepared analogously to E0319.
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)
Example 323
A solution of sodium sulfite (84.2mg) in H2O (1ml) was added to a solution of P0022(258.1mg) in EtOH (3ml) and stirred at 70 ℃ for 2H. When a white precipitate appeared, H2O (1ml) was added to dissolve the precipitate. The mixture was stirred at 80 ℃ overnight to obtain a clear solution. Stirring is continued for a further 28 hours at 80 ℃. The reaction mixture was acidified by 1M HCl (0.7ml), concentrated and dried in vacuo. The residue was dissolved in CHCl3, dried over magnesium sulfate, filtered to remove all insoluble material and concentrated in vacuo to give E0323(245mg) as an amorphous powder.
Mass spectrum (API-ES anion) 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)
Example 324
E0324 was prepared using P0023 in a similar manner to E0323.
Amorphous powder
Mass spectrum (API-ES anion): 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)
Example 325
DMF (41mg) was added to a solution of E0319(239mg) in thionyl chloride (0.6ml), and the mixture was stirred at 50 ℃ for 30 minutes. The reaction mixture was concentrated in vacuo. Toluene (3ml) was added to the residue and concentrated in vacuo. The residue was dissolved in THF (10ml), and a 28% aqueous ammonium hydroxide solution (0.5ml) and a solution of tetrabutylammonium hydrogen sulfate (19mg) in THF (4ml) were added dropwise under cooling in an ice bath. After stirring at ambient temperature for 30 minutes, the reaction mixture was partitioned between AcOEt and aqueous sodium chloride. The organic layer was washed with an aqueous sodium chloride solution and dried over magnesium sulfate. The residue was purified by silica gel column chromatography eluting with MeOH/CHCl3 ═ 2%, 5%. The pure fractions were collected and concentrated in vacuo. The residual solid was recrystallized from EtOH-diisopropyl ether to give E0325(72.6mg) as a white powder.
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)
Example 326
E0326 was prepared analogously to E0325.
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)
Example 327
A mixture of E0327-0(800mg) and E0327-1, methyl triphenylphosphinylidenacetate (850mg) in toluene was stirred at reflux for 5 h. The mixture was evaporated under reduced pressure and purified by silica gel column chromatography (50ml, Hex: EtOAc ═ 5:1) to give 795mg (85.5%) of E0327.
IR (film): 1718.3, 1637.3, 1513.9, 1241.9, 1166.7, 1132.0, 977.7, 837.0cm-1
Example 328
To a suspension of E0258(180mg) in toluene (5ml) at room temperature was added thionyl chloride (0.17 ml). The reaction mixture was stirred at 100 ℃ for 5 hours until the mixture became a clear solution. The mixture was then evaporated under reduced pressure (to a solid). THF was added followed by aqueous NH3 (37%). The mixture was stirred for 1 hour and quenched with water and extracted twice with EtOAc. The combined organic layers were washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give E0328(170mg, 95%) as a powder.
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.
Example 329
To a suspension of E0258(200mg) in toluene (4ml) at room temperature was added thionyl chloride (0.19 ml). The reaction mixture was stirred at 10 ℃ for 5 hours until the mixture became a clear solution. The mixture was then evaporated under reduced pressure (as a solid). THF was added followed by Me2NH (116 mg). The mixture was stirred for 1 hour and quenched with water and extracted twice with EtOAc. The combined organic layers were washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give E0329(45mg, 21%) as a powder.
The filtrate (58 mg).
mp：118-120℃
IR (film): 1650.8, 1608.3, 1511.9, 1469.5, 1240.0, 1159.0, 1133.9cm-1.
Example 330
A mixture of E0328(125mg) and Pd/C (100mg) in EtOH (10m) was stirred under an atmosphere of H2 for 3.0H. After filtration, the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOH, filtered through a disposable syringe-driven filter and evaporated to yield E0330(85 mg).
IR(KBr)：3342.0，1670.0，1511.9，1240.0，1160.9，1130.1cm-1.
Example 331
A mixture of E0138(300mg) and MeSNa (72mg) in DMF (6ml) was heated at 70 ℃ for 5 hours. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with water (twice) and brine, dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography to obtain E0331(270mg, quantitative).
Example 332
E0332 was prepared analogously to E0331 using 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)
Example 333
The target compound was obtained according to a similar procedure as E0331.
Example 334
The target compound was obtained according to a similar procedure as E0331.
Example 335
The target compound was obtained according to a similar procedure as E0331.
Example 336
The target compound was obtained according to a similar procedure as E0331.
Example 337
A mixture of E0331(250mg) and mcpba (165mg) in CH2Cl2 was stirred under ice cooling for 1 hour, followed by addition of mcpba (55 mg). After stirring for 1 hour under ice-cooling, the reaction mixture was partitioned between CHCl3 and saturated NaHCO 3. The organic layer was separated, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex/EtOAc) to yield 141mg (52%) of E0337.
IR (film): 1511.9, 1303.6, 1240.0, 1130.1cm-1.
Oxide: 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)
Example 338
The title compound was obtained according to a similar procedure as that for E0337.
IR (film): 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1126.2, 973.9, 823.5, 759.8cm-1.
Example 339
The title compound was obtained according to a similar procedure as that for E0337.
IR (film): 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1128.2, 973.9, 823.5, 759.8cm-1.
Example 340
The title compound was obtained according to a similar procedure as that for E0337.
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, 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)
Example 341
To a solution of E0336(450mg) in dichloromethane (45ml) at room temperature was added MCPBA (306 mg). After stirring for 1 hour, the reaction mixture was washed with saturated NaHCO3 (twice) and water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50ml) to give 470mg of E0341 as an oil.
Example 342
E0342 was prepared in a similar manner to E0341.
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)
Example 343
To a solution of E0336(450mg) in dichloromethane (45ml) at room temperature was added MCPBA (306 mg). After stirring for 1 hour, the reaction mixture was washed with saturated NaHCO3 (twice) and water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50ml) and recrystallized from EtOH to yield 168mg (44%) of E0343.
Example 344
3-Chloroperbenzoic acid (407mg) was added to a solution of E0342(666.3mg) in CH2Cl2(6ml) with ice-bath cooling. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with CHCl3, washed with 1M NaOH, 5% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from AcOEt-n-hexane to obtain E0344(565.2mg) as a white powder.
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)
Example 345
Oxalyl chloride (286mg) was added to a suspension of E0363(0.43g) in CH2Cl2(3ml) with ice bath cooling. 1 drop of DMF was added and the mixture was stirred at the same temperature for 1 hour and then concentrated in vacuo. Toluene was added to the residue and concentrated in vacuo. The residue was dissolved in THF (5ml) and aqueous ammonium hydroxide (5ml) was added under cooling in an ice bath. The mixture was stirred at the same temperature for 1 hour, diluted with AcOEt, washed successively with 1M HCl, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/n-hexane 60%. The pure fractions were collected, concentrated in vacuo and the residue was crystallized from diisopropyl ether to give E0345(287.8mg) as a white powder.
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)
Example 346
A mixture of E0109(449.1mg) and sodium methoxide (238mg) in formamide (5ml) was heated at 70 ℃ for 5 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl3 followed by MeOH/CHCl3 at 2%, 5% to afford E0346(235.7mg) as a white powder.
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)
Example 347
E0347 was prepared similarly to E0346.
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)
Example 348
E0348 was prepared similarly to E0346.
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)
Example 349
E0349 was prepared in a similar manner to E0346.
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)
Example 350
E0350 was prepared similarly to E0346.
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)
Example 351
E0351 was prepared similarly to E0346.
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)
Example 352
A mixture of E0346(433.5mg) and N, N-dimethylacetamide dimethyl acetal (856mg) in toluene (5ml) was heated at 100 ℃ for 40 minutes. The reaction mixture was concentrated in vacuo, toluene was added to the residue and concentrated in vacuo. The residue was dissolved in toluene (5ml), hydroxylamine hydrochloride (893mg) and AcOH (3ml) were added to the solution, and the mixture was heated at 100 ℃ for 1 hour. The mixture was cooled to ambient temperature, partitioned between AcOEt and H2O, the organic layer was washed with H2O, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 40%, 60%, 80%. The pure fractions were collected and concentrated in vacuo. The residue was crystallized from AcOEt/n-hexane to obtain E0352(203mg) as a white powder.
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)
Example 353
E0353 was prepared in a similar manner to E0352.
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)
Example 354
Acetic anhydride (124mg) was added to a solution of E0346(102.6mg) and pyridine (241mg) in CH2Cl2(1 ml). The reaction mixture was stirred at ambient temperature for 1 hour. Acetic anhydride (62mg) and pyridine (1ml) were added and stirred at ambient temperature overnight. Acetic anhydride (62mg) was added and stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residual solid was collected and washed with diisopropyl ether to give E0354(76.3mg) as a white powder.
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)
Example 355
E0355 was prepared similarly to E0354.
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)
Example 356
Phosphoryl chloride (40.4mg) was added to DMF (0.5ml) with ice bath cooling. After stirring at the same temperature for 5 minutes, E0354(50mg) was added in one portion. The reaction mixture was stirred at the same temperature for 1 hour, and an aqueous sodium hydrogencarbonate solution was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with H2O, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give E0356(45.0mg) as an oil.
Mass spectrum (ESI +): 403(M + CH3CN + H) +
Mass Spectrometry (API-ES cation): 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)
Example 357
E0357 was prepared similarly to E0356.
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)
Example 358
E0358 was prepared similarly to E0356.
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)
Example 359
E0359 was prepared similarly to E0356.
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, overlap), 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)
Example 360
E0360 was prepared in a similar manner to E0356.
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)
Example 361
E0361 was prepared in a similar manner to E0356.
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)
Example 362
A solution of acetyl chloride (0.28ml) was added to a solution of E0261(441.6mg) in CH2Cl2(4ml) and pyridine (2ml) with ice bath cooling. The reaction mixture was stirred at ambient temperature for 1 hour. Acetyl chloride (0.14ml) was added and stirred at ambient temperature for 1 hour. The reaction was quenched by the addition of aqueous sodium bicarbonate and the mixture was stirred at ambient temperature overnight. The mixture was acidified to pH 2 by 6M HCl and extracted with ethyl acetate. The organic layer was washed with H2O and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give E0362(405.3mg) as a white powder.
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)
Example 363
E0363 was prepared in a similar manner to E0362.
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)
Example 364
Oxalyl chloride (264mg) was added to a suspension of E0362(395mg) in CH2Cl2(5ml) with ice bath cooling. 1 drop of DMF was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo, toluene was added to the residue and concentrated in vacuo. The residue was dissolved in CH2Cl2(30ml), cooled in an ice bath, N, O-dimethylhydroxylamine hydrochloride (203mg) and triethylamine (525mg) were added and the mixture was stirred at ambient temperature overnight. The mixture was diluted with AcOEt, washed successively with 1M HCl, aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CHCl3 followed by AcOEt/CHCl3 at 10%, 20% to give E0364(418.4mg) as an oil.
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)
Example 365
Using E0363 and N, O-dimethylhydroxylamine hydrochloride, E0364 was prepared in a similar manner as oil 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)
Example 366
To a 1.0M solution of phenylmagnesium bromide in THF (3.4ml) was added a solution of E0364(106.5mg) in THF (2ml) with ice bath cooling. After stirring at the same temperature for 1 hour, the mixture was poured into a saturated aqueous NH4Cl solution and extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 30%, 40%, 50% to give E0366(107mg) as an oil.
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)
Example 367
A white powder E0367 was prepared by a similar method to E0366.
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)
Example 368
A white powder E0368 was prepared in a similar manner to E0366.
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)
Example 369
A white powder E0369 was prepared in a similar manner to E0366.
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)
Example 370
A white powder E0370 was prepared in a similar manner to E0368.
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)
Example 371
A white powder E0371 was prepared by a similar method to E0366.
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, overlap), 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)
Example 372
A white powder E0372 was prepared in a similar manner to E0368.
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)
Example 373
A white powder E0373 was prepared in a similar manner to E0366.
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)
Example 374
A white powder E0374 was prepared in a similar manner to E0368.
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)
Example 375
Oily E0375 was prepared using E0364 in a similar manner to E0366.
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)
Example 376
To a solution of 1.0M methylmagnesium bromide in diethyl ether (2.8ml) was added dropwise a solution of E0364(237.6mg) in THF (4ml) with cooling in an ice bath. After stirring at the same temperature for 30 minutes, the mixture was poured into a saturated aqueous NH4Cl solution and extracted with AcOEt. The organic layer was washed successively with a mixture of 1M HCl and saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in THF (1ml), 1M NaOH (0.4ml) was added and the mixture was stirred at ambient temperature for several hours. The mixture was neutralized with 1M HCl (0.4ml) and partitioned between AcOEt and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 50%, to give E0376(139.1mg) as a white powder.
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)
Example 377
An oil, E0377, was prepared in a similar manner to E0376.
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)
Example 378
Oily E0378 was prepared similarly to E0376.
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)
Example 379
A white powder E0379 was prepared in a similar manner to E0376.
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)
Example 380
A mixture of E0376(127mg), O-methylhydroxylamine hydrochloride (47.3mg) and pyridine in EtOH (3ml) was heated at 60 ℃ for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with AcOEt/hexanes 40%. The pure fractions were collected and concentrated in vacuo. The residue was crystallized from diisopropyl ether to give E0380(103.2mg) as a white powder.
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)
Example 381
A white powder E0381 was prepared in a similar manner to E0380.
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)
Example 382
To a solution of E0314(100mg) in methanol (21ml) was added a solution of methylamine in methanol (40%, 92 ml). After stirring at room temperature overnight, the mixture was evaporated to give an oil which was purified by preparative TLC (1mm, 60% ethyl acetate/hexane) to give E0382(97mg, 100%) as an oil.
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.
Example 383
Trichloroacetyl isocyanate (62.4mg) was added to a solution of E0118(100mg) in CH2Cl2(2ml) with ice bath cooling. After stirring at ambient temperature for 3 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in THF (1ml), MeOH (1ml) and H2O (1 ml). Potassium carbonate (153mg) was added to the reaction mixture and stirred at ambient temperature overnight. The reaction mixture was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residual solid was recrystallized from AcOEt-n-hexane to obtain E0383(84.1mg) as a white powder.
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)
Example 384
Trimethylsilyl isocyanate (42.7mg) was added to a solution of E0158(98.2mg) and triethylamine (30mg) in CH2Cl2(1ml) with cooling in an ice bath. The reaction mixture was stirred at the same temperature for 1 hour and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography on MeOH/CHCl3 ═ 10%. The separated silica gel was extracted with 10% MeOH/CHCl3, filtered and the solvent evaporated in vacuo. The residue was crystallized from ethyl acetate-diisopropyl ether to give E0384(59.7mg) as a white powder.
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)
Example 385
The title compound was obtained analogously to E0384.
IR (film): 3343.9, 1656.6, 1604.5, 1550.5, 1515.8, 1457.9, 1342.2, 1251.6, 1029.8cm-1.
Example 386
The title compound was obtained analogously to E0384.
IR (film): 3345.9, 1654.6, 1604.5, 1556.3, 1513.9, 1465.6, 1240.0, 1160.9, 1132.0cm-1.
Example 387
The title compound was obtained analogously to E0384.
IR (film): 3345.9, 1658.5, 1602.6, 1552.4, 1236.2, 1159.0, 1133.9cm-1.
Example 388
The title compound was obtained analogously to E0384.
IR (film): 3345.9, 1658.5, 1602.6, 1552.4, 1517.7, 1236.2, 1159.0, 1133.9cm-1.
Example 389
A mixture of E0175(150mg) and 4N HCl/dioxane (6ml) was stirred at room temperature. After 2 h, the reaction mixture was evaporated under reduced pressure to give E0389(128mg, quantitative) as an oil.
IR (film): 3403.7, 1513.9, 1467.6, 1241.9, 1162.9 and 1130.1cm-1.
Example 390
The title compound was obtained according to a similar procedure as E0389.
IR (film): 3428.8, 1662.34, 1612.2, 1500.4, 1461.8, 1390.4, 1292.1, 1166.7, 1087.7, 1029.8cm-1.
Example 391
The title compound was obtained according to a similar procedure as E0389.
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.
Example 392
The title compound was obtained according to a similar procedure as E0389.
IR (film): 3432.7, 1511.9, 1467.6, 1240.0, 1160.9 and 1130.1cm-1.
Example 393
A mixture of E0258(100mg) and Pd/C (100mg) in EtOH (10m) was stirred under an atmosphere of H2 for 3.0 hours. After filtration the filtrate was evaporated under reduced pressure. The residue was dissolved in EtOH, filtered through a disposable syringe-driven filter and evaporated to yield 93mg (93%) of E0393.
IR (film): 3019.9, 1704.8, 1513.9, 1303.6, 1238.1 and 1133.9cm-1.
Example 394
To a suspension of E0258(200mg) in toluene (4ml) at room temperature was added thionyl chloride (0.19 ml). The reaction mixture was stirred at 100 ℃ for 5 hours until the mixture became a clear solution. The mixture was then evaporated under reduced pressure (as a solid). THF was added followed by aqueous MeNH2 (37%). The mixture was stirred for 1 hour, quenched with water, and extracted twice with EtOAc. The combined organic layers were washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to yield E0394(63mg, 31%) as a powder.
mp：155-157℃
IR (film) 3297.7, 1662.3, 1617, 9, 1513.9, 1236.2, 1162.9, 1133.9cm-1
Example 395
A suspension of E0399(1.8g) and potassium phthalimide (potassium phthalimido) (1.13g) in N, N-dimethylformamide (6.6ml) was stirred at 80 ℃ for 3 hours. Water (700ml) was added to the mixture, and the mixture was extracted with ethyl acetate and hexane (2:1) (. times.4). The combined organic layers were washed with aqueous sodium hydroxide (1N) (× 2) and brine, dried over magnesium sulfate and evaporated to give an oil which was purified by column chromatography (SiO 2100 ml, eluting with 30% ethyl acetate/hexanes) to give an oil (1.83g, 91.1%). Ethanol (15ml) was added to the oil, and the mixture was stirred at room temperature for 10 minutes. The precipitate was filtered, washed with ethanol (3ml) and dried under reduced pressure to give E0395(1.16g, 58%) as a white solid.
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).
Example 396
6M HCl (0.045ml) was added to a solution of E0168(101.5mg) in AcOEt (1ml) and EtOH (1 ml). The mixture was concentrated and dried in vacuo to give amorphous powder E0396(94.8 mg).
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)
Example 397
To a mixture of P0002(5.0g) and CF3COOEt (3.5ml) in DMF (30ml) was added NaH (1.1g) under ice cooling. The reaction mixture was warmed to room temperature and stirred at 40 ℃ for 1 hour. The reaction mixture was extracted twice with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. Acetic acid (20ml) containing the residue, sodium acetate (2.23g) and 4-methoxyphenylhydrazine (3.96g) was stirred at room temperature for 15 hours. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water (twice), saturated NaHCO3, water and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Hex/EtOAc ═ 8:1-4:1) to give 2.58g (36%) of E0397 as an oil.
Example 398
To a solution of E0312(326.7mg) in ethyl acetate (3ml) were added methanesulfonyl chloride (86.9ml) and triethylamine (0.181ml) at 0 ℃. After stirring at 0 ℃ for 40 min, the mixture was quenched with water and extracted with ethyl acetate (× 3). The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give E0398(351.3mg, 89%) as an oil.
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).
Example 399
The title compound (1.82g, 98.6%) was obtained as a pale yellow oil according to a similar method to that of E0398.
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).
Example 400
A suspension of E0398(351.3mg) and sodium thiomethoxide (162mg) in N, N-dimethylformamide (3ml) was stirred at 60 ℃ for 3.5 hours. The mixture was quenched with water and extracted with ethyl acetate (× 3). The combined organic layers were washed with water and brine, dried over magnesium sulfate and evaporated to give an oil. The oil was purified by column chromatography (SiO 250 ml, eluting with 10% ethyl acetate/hexanes) to afford E0400 as an oil (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).
Example 401
To a solution of E0400(103.5mg) in dichloromethane (1ml) was added m-chloroperbenzoic acid (134mg) at room temperature. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogensulfate solution (0.5ml) and sodium thiosulfate pentahydrate (100mg) were added to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through Chemelut 1001(Varian) and evaporated to give an oil which was purified by preparative TLC (1mm, 50% ethyl acetate/hexane) to give 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.
Example 402
To a solution of E0400(104.8mg) in dichloromethane (1ml) was added m-chloroperbenzoic acid (44.7mg) at 0 ℃ and the mixture was stirred at 0 ℃ for 1 hour. M-chloroperbenzoic acid (35mg) was then added to the mixture. After stirring at 0 ℃ for 30 minutes, the mixture was quenched with saturated aqueous sodium hydrogen sulfate (0.5ml) and sodium thiosulfate pentahydrate (100mg), and stirred at room temperature for 30 minutes. The mixture was filtered through Chemelut 1001(Varian) and evaporated to give an oil which was purified by preparative TLC (1mm, ethyl acetate) to give 2 fractions: amorphous E0401(TLC upper) (40.7mg, 37.4%) and powdered E0402(TLC lower) (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.
Example 403
To a solution of E0286(500mg) in dichloromethane (1.5ml) were added in the order anisole (0.5ml) and trifluoroacetic acid (1 ml). After stirring at room temperature for 2 hours, the mixture was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (× 3). The organic layer was dried over magnesium sulfate and evaporated to give an oil which was purified by column chromatography (SiO 250 ml, eluting with ethyl acetate) to give E0403 as an oil (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+).
Example 404
A solution of E0403(104.6mg) in methanol (3ml) and aqueous sodium hydroxide (1N, 2ml) were stirred at room temperature for 3 hours. The mixture was evaporated, methanol was added to the residue and evaporated to give a white powder which was purified by preparative TLC (1mm, 20% methanol/chloroform) to give E0404 as a powder (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.
Example 405
To a solution of E0403(106.6mg) in methanol (2ml) was added concentrated aqueous ammonia (1 ml). After stirring overnight at room temperature, the mixture was evaporated to give a solid which was purified by preparative TLC (1mm, 20% methanol/chloroform) to give E0405 as a solid (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)，1658 cm-1.
Example 406
To a solution of E0403(87.5mg) in tetrahydrofuran (1ml) was added lithium aluminum hydride (30.5mg) at room temperature. After stirring at room temperature for 2 hours, the mixture was quenched with water (30ml), aqueous sodium hydroxide (15%, 30ml) and water (90ml), and then stirred at room temperature for 30 minutes. Magnesium sulfate and celite were added to the mixture and the suspension was filtered and washed with tetrahydrofuran. The filtrate was evaporated to give an oil which was purified by preparative TLC (0.5mm, 20% methanol/chloroform) to give an oil. To the solution of the oil in ethyl acetate was added a solution of hydrogen chloride in ethyl acetate (4N, 0.5ml) and the mixture was evaporated to give E0406 as an oil (43.5mg, 49%).
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 +), 408.1(MH +) (free), IR (pure, 20727-5), 1614.1cm-1.
Example 407
To a suspension of sodium hydride (34.8mg) in tetrahydrofuran (2ml) was added a solution of E0347(208mg) in tetrahydrofuran (1ml) at 0 ℃ and the mixture was stirred at room temperature for 20 minutes. Methyl iodide (54.2ml) was added to the mixture. After stirring at room temperature overnight, the mixture was quenched with water and extracted with ethyl acetate (× 3). The combined organic layers were washed with water (× 3) and brine, dried over magnesium sulfate and evaporated under reduced pressure to give an oil which was purified by preparative TLC (1mm, 30% ethyl acetate/hexane) to give E0407 as an oil (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).
Example 408
AcCl (0.31ml) was added to a suspension of E0347(1.29g) and Et3N (0.66ml) in CH2Cl2(10ml) with ice bath cooling. The mixture was stirred at ambient temperature for 2 hours. AcCl (0.31ml) and Et3N (0.66ml) were added and stirred at ambient temperature for 3 hours. H2O was added to the mixture and stirred for a while at ambient temperature. The white precipitate that appeared was collected and washed with H2O and diisopropyl ether to give E0408 as a white powder (879.3 mg).
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)
Example 409
To a solution of E0374(61.4mg) in CH2Cl2(2ml) at 0 ℃ was added trimethylsilyl trifluoromethanesulfonate (85.6mg), followed by triethylamine (39 mg). The mixture was stirred at 0 ℃ for 30 min and partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed over 28% aqueous NH3 solution: MeOH: CHCl3 ═ 1:10: 100. The isolated silica gel was extracted with 28% aqueous NH3 solution in MeOH: CHCl3 ═ 1:10:100 and the solvent was evaporated in vacuo. The residue was dried in vacuo and then dissolved in EtOH (3 ml). To the solution was added 1M HCl (0.0892ml) and concentrated in vacuo. The residue was dried in vacuo to give amorphous powder E0409(37 mg).
IR(KBr)：2958，1668，1662，1612，1581，1568，1549，1531，1500cm-1
Mass spectrum (ESI +): 379(M + H) +
200MHz 1H NMR
1.05(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)
Example 410
To a solution of 2- {4- [1- (4-methoxyphenyl) -3- (methylsulfonyl) -1H-pyrazol-5-yl ] phenoxy } ethanamine (133mg, 0.342mmol) in dichloromethane (5ml) at ambient temperature was added trimethylsilyl isocyanate (118mg, 1.03mmol) and triethylamine (1.39mg, 1.37mmol) and stirred for two days. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (silica gel, dichloromethane/methanol ═ 20/1) followed by recrystallization from ethyl acetate gave 102mg (69%) of E0410 as white crystals.
mp.165-167℃
Mass spectrometry; 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)，
Example 411
A solution of P0034(64mg) in DMF (1ml) was added to 60% NaH (11.4mg) at 4 ℃ and the mixture was stirred at the same temperature for 30 minutes. Bromoacetic acid (33mg) was added to the mixture, and the mixture was stirred at ambient temperature for 2 hours. The reaction was quenched by addition of 1M HCl (2ml) and the mixture was extracted with AcOEt. The organic layer was washed with H2O and saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo to give crystalline E0411(73 mg).
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)
Example 412
Boron trifluoride diethyl etherate (137mg) was added to a suspension of sodium borohydride (29.3mg) in THF (3ml) under cooling in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added E0411(137mg) in one portion of THF (3ml) and the mixture was stirred at ambient temperature for 4 hours. The reaction was quenched by the addition of ice water containing 1M HCl (1ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was extracted 2 times with AcOEt and the combined organic layers were washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and developed by AcOEt/n-hexane 50%. The residue was crystallized from IPE to give E0412(79.2mg) as a white powder.
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)
Example 413
To a solution of P0034(237mg) in DMF (2ml) was added 60% NaH (41.6mg) with ice bath cooling and the mixture was stirred at ambient temperature for 1 h. E0413-0(287mg) in DMF (1ml) was added to the mixture and the mixture was stirred at ambient temperature for 13 h and at 60 ℃ for 3 h. The reaction was quenched by addition of saturated aqueous NH4Cl solution and the mixture was extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in EtOH (4ml) and concentrated HCl (40. mu.L) was added. After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo. The residue was partitioned between AcOEt and saturated aqueous NaHCO3, the organic layer was washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 40%, 60%. The residue was crystallized from AcOEt (1ml) and IPE (2 ml). The crystals obtained were recrystallized from AcOEt (0.7ml) and IPE (1.5 ml). White crystals E0413(196.9mg) were obtained.
mp.114.9-116(115) deg.C Mass Spectrometry (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)
Example 414
To a solution of P0034(100mg) in DMF (1ml) was added 60% NaH (17.5mg) with ice bath cooling. The mixture was stirred at ambient temperature for 1 hour. The mixture was cooled to 0 ℃. 2-bromoethyl acetate (113mg) was added to the mixture, and the mixture was stirred at ambient temperature for 24 hours. The reaction was quenched by addition of saturated aqueous NH4Cl solution and the mixture was extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in THF (0.9ml) and MeOH (0.9ml), and 1M NaOH (0.4ml) was added to the solution. The mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between AcOEt and H2O and the aqueous layer was back-extracted with AcOEt. The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from AcOEt (0.3ml) -IPE (0.9ml) to give E0414(82.4mg) as white crystals.
Mass spectrum (ESI +): 341(M + H) +
Preparation 35
To a solution of N' - [5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (1.19g) in EtOH (10ml) and THF (10ml) was added a solution of ammonium formate (509mg) in H2O (2ml) and 10% Pd-C50% wet weight (150 mg). The mixture was refluxed for 1 hour. The catalyst was filtered through a celite pad and the pad was washed with EtOH. The filtrate and combined washings were concentrated in vacuo. AcOEt and H2O were added to the residue. The white precipitate that appeared was collected and washed successively with H2O and IPE to give N' - [5- (4-hydroxyphenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (555mg) as a white powder.
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)
The following compounds were obtained by a similar method to that of preparation 35.
Preparation 36
N- [5- (4-hydroxyphenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N ', N' -trimethylurea
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-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol
Powder of
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-methoxyphenyl) -1H-pyrazol-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-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-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-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-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-hydroxyphenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] oxy } -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-methoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-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-ethoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-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-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenol
Mass spectrum (ESI +): 371.2(M + Na) M/z.
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-methoxy-3-pyridyl) -1H-pyrazol-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-methoxy-3-pyridyl) -1H-pyrazol-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-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-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, 2-difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-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-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-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, 2-Difluoroethoxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-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-methoxyphenyl) -4-methyl-1H-pyrazol-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-methoxy-3-pyridyl) -4-methyl-1H-pyrazol-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 a solution of 4' -benzyloxyphenylethylketone (6.0g) in THF (120ml) at-60 deg.C was added 38ml of 1N lithium bis (trimethylsilyl) amide (LiHMDS) and the mixture was stirred at below-60 deg.C for 45 minutes. 1- (trifluoroacetyl) imidazole (3.4ml) was added to the solution, and the mixture was stirred at-60 ℃ for 1 hour and 0 ℃ for 30 minutes. The reaction mixture was quenched with 0.5N HCl, the mixture was poured into EtOAc and water, the EtOAc layer was separated, washed with brine, dried over MgSO4 and concentrated to give 1- [4- (benzyloxy) phenyl ] -4, 4, 4-trifluoro-2-methyl-1, 3-butanedione.
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
To a mixture of 4- (methylthio) aniline (6.3g) and concentrated HCl (45ml) was added dropwise water (18ml) containing NaNO2(3.6g) under ice-cooling. After stirring for 30 minutes, concentrated HCl (24ml) containing SnClH2O (28.6g) was added over 1 hour under ice-cooling. After stirring for 1 hour, filtration, washing with concentrated HCl and water and drying, 14.1g of solid [4- (methylthio) phenyl ] hydrazine hydrochloride are obtained.
Mass spectrum (ESI +): and M/z is 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
A mixture of 4-hydroxyphenyl ethyl ketone (20g), benzyl chloride (16.1ml), K2CO3(12.9g) and KI (2.21g) in EtOH (80ml) and H2O (1ml) was stirred at reflux for 4H. The reaction mixture was cooled and filtered. The crystals that appeared were dissolved in EtOAc and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 30.0g (94%) of 1- [4- (benzyloxy) phenyl ] -1-propanone as crystals.
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
1M NaOH (4.8ml) was added to a solution of 4-benzyloxybenzaldehyde (5g) and cyclopropylmethyl ketone (3.96g) in EtOH (24ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with H2O and EtOH. The mixture was stirred at ambient temperature for 20 minutes. The pale yellow crystals were collected and washed with H2O and 50% aqueous EtOH to give (2E) -3- [4- (benzyloxy) phenyl ] -1-cyclopropyl-2-propen-1-one (6.29 g).
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
(2E) -3- [4- (benzyloxy) phenyl ] -1-cyclopropyl-2-propen-1-one (6.25g) was suspended in EtOH (67.5ml), acetone (22.5 ml). To the mixture was added 30% aqueous hydrogen peroxide (4.5ml) and 3M NaOH (4.5ml), and the mixture was stirred at ambient temperature for 1 day. The mixture was diluted with H2O. The white precipitate was collected, washed with H2O and air dried to give { (2R, 3S) -3- [4- (benzyloxy) phenyl ] -2-oxiranyl } (cyclopropyl) methanone (6.27 g).
Powder of
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 a solution of 4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol (501mg) in CH2Cl2(5ml) was added trifluoromethanesulfonic anhydride (300. mu.l) and diisopropylethylamine (324. mu.l) with ice-bath cooling. The mixture was stirred at the same temperature for 2 hours. Further, trifluoromethanesulfonic anhydride (57. mu.l) and diisopropylethylamine (147. mu.l) were added, and stirring was continued at the same temperature for 1 hour. The mixture was washed with 1M HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 20%, to give 4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl trifluoromethanesulfonate (712.3mg) as an oil.
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)
The following compounds were obtained using a similar procedure to that of preparation 58.
Preparation 59
4- [ 3-Isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl trifluoromethanesulfonate
Oil-like substance
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-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl trifluoromethanesulfonate
Oil-like substance
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
A mixture of 4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyltriflate (679mg), zinc cyanide (279mg) and tetrakis (triphenylphosphine) palladium (0) (183mg) in DMF (4ml) was stirred at 85 ℃ for 5 hours. The reaction mixture was cooled to ambient temperature and AcOEt and H2O were added. Insoluble material was filtered through a celite pad. The filtrate was partitioned, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 20%. The pure fractions were collected and concentrated in vacuo to give 4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzonitrile (326mg) as a powder.
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)
The following compounds were obtained using a similar procedure to that of preparation 61.
Preparation 62
4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzonitrile
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-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] benzonitrile
Oil-like substance
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-methoxyphenyl) -1H-pyrazol-5-yl ] benzonitrile
Powder of
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-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzonitrile
Powder of
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
A solution of trifluoromethanesulfonic anhydride (207. mu.l) in CH2Cl2(1ml) was added, with ice-cooling, to a solution of 4- [1- (6-methoxy-3-pyridinyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenol (300mg) and pyridine (199. mu.l) in CH2Cl2(3 ml). The mixture was stirred at the same temperature for 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride (5 ml). The mixture was partitioned between AcOEt and 1M HCl. The mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenyl trifluoromethanesulfonate (439mg) as an oil.
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)
The following compounds were obtained using a similar procedure to that of preparation 66.
Preparation 67
4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl trifluoromethanesulfonate
Oil-like substance
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
A solution of 4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenylbenzyl ether (2.79g) and thioanisole (3.56g) in trifluoroacetic acid (25ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was recrystallized from AcOEt (15ml) and n-hexane (12ml) to yield the first product FR282117(1.48 g). The mother liquor was washed with H2O and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/hexanes 30%. The pure fractions were collected and concentrated in vacuo. The residual crystals were collected and washed with IPE to give a second crop of product, 4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol (457.2mg) as a white powder.
Mass spectrometry (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)
The following compounds were obtained using a similar procedure to that of preparation 68.
Preparation 69
4- [1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazol-5-yl ] phenol
Powder of
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)
The following compound was obtained by a similar method to that of example 596.
Preparation 70
4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-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) phenyl ] -1H-pyrazol-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-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzonitrile
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-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzonitrile
Mass spectrum (ESI +): and m/z is 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).
Example 415
A solution of 4M HCl in dioxane (3ml) was added to a solution of tert-butyl (2- {4- [3- (1-hydroxy-1-methylethyl) -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate (236mg) in CH2Cl2(3 ml). The reaction mixture was stirred at ambient temperature for 3 hours. 2-propanol (2ml) was added to dissolve the insoluble oil and stirred at ambient temperature for 4 hours. The mixture was concentrated in vacuo. The residue was suspended in CH2Cl2(3 ml). Methanesulfonyl chloride (127mg) and Et3N were added successively to adjust the pH of the reaction mixture to neutral. After stirring for 1 hour, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 50% AcOEt/N-hexane, to give N- (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide (118mg) as an oil.
1H NMR(CDCl3)δ 2.20(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)
Example 416
A mixture of 10% Pd-C50% wet weight (20mg) and N- (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide (118mg) in THF (1ml) and MeOH (1ml) was hydrogenated at H2(1atm) at ambient temperature for 1 day. The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with AcOEt/n-hexane 70%. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was recrystallized from AcOEt-IPE to give N- (2- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide (68.6mg) as a white powder.
White powder:
mp.96-97℃
IR(KBr)：3269，2970，1612，1512cm-1
MS(ESI+)：m/z 431(M+H)
1H NMR(DMSO-d6)δ 1.27(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)
the following compound was obtained in a similar manner to example 416.
Example 417
{4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Oil-like substance
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)
Example 418
{4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Oil-like substance
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)
Example 419
A solution of 4M HCl in dioxane (2ml) was added to a solution of tert-butyl (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate (269.7mg) in CH2Cl2(2 ml). The reaction mixture was stirred at ambient temperature for 2H and then concentrated in vacuo to give (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride (259mg) as an amorphous powder.
MS(ESI+)：m/z 351(M+H)
1H NMR(DMSO-d6)δ 2.10(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)
The following compounds were obtained by a similar method to example 419.
Example 420
(2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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)
Example 421
(2- {4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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)
Example 422
(2- {4- [ 3-isobutoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
Amorphous material
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)
Example 423
(2- {4- [3- (2-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
Amorphous material
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)
Example 424
(2- {4- [3- (2-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
Amorphous material
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)
Example 425
(2- {4- [ 3-methoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride
Amorphous material
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)
Example 426
(2- {4- [ 3-ethoxy-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride
Amorphous material
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)
Example 427
(2- {4- [1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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).
Example 428
(2- {4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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).
Example 429
[2- (4- {3- (difluoromethyl) -1- [4- (methylthio) phenyl ] -1H-pyrazol-5-yl } phenoxy) ethyl ] amine hydrochloride
Mass Spectrometry (ESI-): and M/z is 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).
Example 430
(2- {4- [ 3-cyclopropyl-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) 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)
Example 431
(2- {4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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)
Example 432
(2- {4- [1- (6-methoxy-3-pyridinyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) 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)
Example 433
5- [4- (2-Aminoethoxy) phenyl ] -N-ethyl-1- (6-methoxy-3-pyridinyl) -N-methyl-1H-pyrazole-3-carboxamide 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)
Example 434
(2- {4- [3- (cyclopentyloxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) 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)
Example 435
(2- {4- [1- (4-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
Oil-like substance
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)
Example 436
(2- {4- [3- (2, 2-Difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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)
Example 437
(2- {4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethyl) 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)
Example 438
(2- {4- [3- (2, 2-Difluoroethoxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride
Powder of
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)
Example 439
{4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] benzyl } amine hydrochloride
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)
Example 440
5- [4- (aminomethyl) phenyl ] -N-ethyl-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide hydrochloride
Powder of
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)
Example 441
{4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } amine hydrochloride oil
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)
Example 442
1- [5- [4- (aminomethyl) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -2-methyl-1-propanone 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)
Example 443
{4- [1- (6-methoxy-3-pyridyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] benzyl } amine dihydrochloride
Oil-like substance
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)
Example 444
5- [4- (aminomethyl) phenyl ] -N-ethyl-1- (6-methoxy-3-pyridyl) -N-methyl-1H-pyrazole-3-carboxamide dihydrochloride
Oil-like substance
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)
Example 445
{4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] 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)
Example 446
1- [5- [4- (aminomethyl) phenyl ] -1- (6-methoxy-3-pyridyl) -1H-pyrazol-3-yl ] -2-methyl-1-propanone dihydrochloride
Oil-like substance
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)
Example 447
(2- {4- [1- (4-methoxyphenyl) -4-methyl-1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
Powder of
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)
Example 448
(2- {4- [1- (6-methoxy-3-pyridyl) -4-methyl-1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride
Oil-like substance
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)
Example 449
(2- {4- [1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride
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)
The following compounds were obtained by a similar procedure to example 428.
Example 450
5- [4- (aminomethyl) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole-3-carbonitrile hydrochloride
Mass spectrum (ESI +): m/z is 304.2(M +1).
Example 451
To a solution of (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride (126.4mg) and Et3N (125. mu.l) in CH2Cl2(2ml) was added methanesulfonyl chloride (34.7. mu.l) with cooling in an ice bath. The mixture was stirred at ambient temperature for 1 hour. Additional methanesulfonyl chloride (6.9. mu.l) and Et3N (41.6. mu.l) were added and the reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo and the residue partitioned between AcOEt and 1M HCl. The aqueous layer was back-extracted with AcOEt. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with AcOEt/n-hexane 70%. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N- (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide (48.0mg) as a white powder.
mp.96-99℃
IR(KBr)：3205，314d，1612，1502cm-1
MS(ESI+)：m/z 429(M+H)
1H NMR(CDCl3)δ 2.20(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)
The following compounds were obtained in a similar manner to example 451.
Example 452
N- (2- {4- [3- { [ (dimethylamino) carbonyl ] amino } -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
Powder: mp.166-167 deg.C
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)
Example 453
N- (2- {4- [3- [ [ (dimethylamino) carbonyl ] (methyl) amino ] -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
Amorphous material
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)
Example 454
N- (2- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
White powder: mp.112-114 deg.C
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)
Example 455
N- (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 456
N- (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) ethanesulfonamide
White powder: mp.117.8-118.0 deg.C
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)
Example 457
N- (2- {4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
White powder: mp.146-147 deg.C
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)
Example 458
N- (2- {4- [ 3-isobutoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
White powder: mp.164.3-165.2 deg.C
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)
Example 459
N- (2- {4- [3- (2-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
White powder: mp.94.5-94.7 deg.C
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)
Example 460
N- (2- {4- [3- (2-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
White powder: mp.116.3-116.4 deg.C
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)
Example 461
N- (2- {4- [ 3-methoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 462
N- (2- {4- [ 3-ethoxy-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
White powder: mp.122.0-122.6 deg.C
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)
Example 463
N- (2- {4- [1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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).
Example 464
N- [2- (4- {3- (difluoromethyl) -1- [4- (methylthio) phenyl ] -1H-pyrazol-5-yl } phenoxy) ethyl ] methanesulfonamide
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).
Example 465
N- {4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
And (4) crystals. mp: 125-126 deg.C
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).
Example 466
N- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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).
Example 467
N- (2- {4- [ 3-cyclopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 468
N- (2- {4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 469
N- (2- {4- [1- (6-methoxy-3-pyridinyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 470
N-ethyl-1- (4-methoxyphenyl) -N-methyl-5- (4- {2- [ (methylsulfonyl) amino ] ethoxy } phenyl) -1H-pyrazole-3-carboxamide
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)
Example 471
N-ethyl-1- (6-methoxy-3-pyridyl) -N-methyl-5- (4- {2- [ (methylsulfonyl) amino ] ethoxy } phenyl) -1H-pyrazole-3-carboxamide
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)
Example 472
N- (2- {4- [ 3-isobutyryl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 473
N- (2- {4- [3- (cyclopentyloxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
Oil-like substance
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)
Example 474
N- (2- {4- [1- (4-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 475
N- (2- {4- [3- (2, 2-Difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 476
N- (2- {4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
Oil-like substance
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)
Example 477
N- (2- {4- [3- (2, 2-Difluoroethoxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
Solid body
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)
Example 478
N- (2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) -2-hydroxyethanesulfonamide
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)
Example 479
N- (2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
Oil-like substance
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)
Example 480
N- {4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 481
N-Ethyl-1- (4-methoxyphenyl) -N-methyl-5- (4- { [ (methylsulfonyl) amino ] methyl } phenyl) -1H-pyrazole-3-carboxamide
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)
Example 482
N- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 483
N- {4- [ 3-isobutyryl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 484
N- {4- [1- (6-methoxy-3-pyridinyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 485
N-Ethyl-1- (6-methoxy-3-pyridinyl) -N-methyl-5- (4- { [ (methylsulphonyl) amino ] methyl } phenyl) -1H-pyrazole-3-carboxamide
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)
Example 486
N- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
Oil-like substance
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)
Example 487
N- {4- [ 3-isobutyryl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 488
N- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 489
N- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
Amorphous material
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)
Example 490
N- {4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 491
N- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
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)
Example 492
N- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } methanesulfonamide
Oil-like substance
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)
Example 493
N- (2- {4- [1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide
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)
Example 494
N- (2- {4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl) benzenesulfonamide
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)
Example 495
N-methoxy-1- (4-methoxyphenyl) -N-methyl-5- (4- {2- [ (methylsulfonyl) amino ] ethyl } phenyl) -1H-pyrazole-3-carboxamide
Oil-like substance
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)
Example 496
N-methoxy-1- (6-methoxy-3-pyridyl) -N-methyl-5- (4- {2- [ (methylsulfonyl) amino ] ethyl } phenyl) -1H-pyrazole-3-carboxamide
Oil-like substance
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
Trimethylsilyl isocyanate (73.8. mu.l) was added to a solution of (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine dihydrochloride (115.4mg) and Et3N (114. mu.l), and the mixture was stirred at ambient temperature for 1.5 hours. The mixture was concentrated in vacuo and the residue partitioned between AcOEt and 1M HCl. The aqueous layer was back extracted with AcOEt. The combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed through 10% MeOH/CHCl 3. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N- (2- {4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (40.1mg) as a white powder.
White powder: mp.94-98 deg.C
IR(KBr)：3435，3388，3344，3333，1657，1631，1610，1577，1572，1562，1552，1502cm-1
1H NMR(DMSO-d6)δ 2.10(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)
The following compounds were obtained by a similar procedure to example 497.
Example 498
N- (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 499
N- (2- {4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
White powder: mp.154.2-154.4 deg.C
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)
Example 500
Imidazole (680mg) and tert-butyldimethylsilyl chloride (903mg) were added successively to a solution of ethyl 5- [4- {2- (hydroxy) ethoxy } phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (1.91g) in DMF (15ml) with cooling in an ice bath. After stirring for 2 hours at ambient temperature, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with H2O and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were collected and washed with n-hexane to give ethyl 5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (2.34 g).
Powder of
mp.86-87℃
MS(ESI+)：m/z 497(M+H)
1H NMR(CDCl3)δ 0.09(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)
Example 501
A solution of ethyl 5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (0.3g) in THF (3ml) was added dropwise to a 1M solution of methylmagnesium bromide (3ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 hour and then poured into a mixture of crushed ice and saturated aqueous ammonium chloride solution. The mixture was extracted with AcOEt. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 2- [5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -2-propanol (0.27g) as an oil.
Oil-like substance
MS(ESI+)：m/z 483(M+H)
1H NMR(CDCl3)δ 0.09(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)
The following compounds were obtained by a similar method to that of example 501.
Example 502
N- (2- {4- [3- (1-hydroxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
White powder: mp.147-152 deg.C
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)δ 1.48(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)
Example 503
{4- [3- (1-hydroxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Powder of
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)
Example 504
{4- [3- (1-hydroxy-1-methylethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Powder of
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)
Example 505
A solution of 2- [5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -2-propanol (180mg) in DMF (2ml) was added dropwise to a suspension of 60% sodium hydride mineral oil dispersion (17mg) in DMF (1ml) with cooling in an ice bath. After 10 minutes, iodomethane (63.5mg) was added, and the reaction mixture was stirred at the same temperature for 1 hour and then at ambient temperature for 1 hour. Further methyl iodide was added until all the starting material was consumed, and the reaction was quenched by addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate. The organic layer was washed with H2O and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane, and the polarity was gradually changed from 20% to 80% to give 5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -3- (1-methoxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazole (32.2mg) as an oil.
Mass spectrum (ESI +): 497(M + H)
1H NMR(CDCl3)δ 0.09(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)
Example 506
A1M solution of tetra-n-butylammonium fluoride in THF (0.24ml) was added, with cooling in an ice bath, to a solution of 5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -3- (1-methoxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazole (98mg) in THF (2 ml). The reaction mixture was stirred at the same temperature for 1 hour. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with 50% AcOEt/n-hexane. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2- {4- [3- (1-methoxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol (66mg) as an oil.
IR (pure): 3423, 3398, 3371, 2976, 2935, 1647, 1612, 1566, 1549, 1512cm-1
MS(ESI+)：m/z 383(M+H)
1H NMR(CDCl3)δ 1.60(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)
Example 507
A solution of 4M HCl in dioxane (2ml) was added, cooled on an ice bath, to a solution of ethyl 5- (4- {2- [ (tert-butoxycarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (300mg) in CH2Cl2(3 ml). After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated in vacuo. The residue was dissolved in CH2Cl2(3ml), Et3N (189mg) and trimethylsilyl isocyanate (108mg) were added, and the mixture was stirred at ambient temperature overnight. After stirring for an additional 4 hours, trimethylsilyl isocyanate and Et3N were added to consume all starting materials. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residual crystals were suspended in hot ethyl acetate, cooled and stirred, collected and washed with ethyl acetate to give ethyl 5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (217mg) as a white powder.
MS(ESI+)：m/z 425(M+H)
1H NMR(DMSO-d6)δ 1.31(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)
Example 508
1M NaOH (5ml) was added to a solution of ethyl 5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (1.75g) in THF (15ml) and MeOH (10 ml). The reaction mixture was stirred at ambient temperature and concentrated in vacuo. The residue was dissolved in H2O, acidified with 1M HCl, collected as a white precipitate and washed successively with H2O and IPE to give 5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylic acid (1.58g) as a white powder.
MS(ESI+)：m/z 397(M+H)
1H NMR(DMSO-d6)δ 3.15-3.55(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)
The following compounds were obtained by a similar method to example 508.
Example 509
5- (4- { [ (tert-Butoxycarbonyl) amino ] methyl } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-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)
Example 510
5- (4- { [ (tert-Butoxycarbonyl) amino ] methyl } phenyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazole-3-carboxylic acid
Powder of
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)
Example 511
A mixture of 5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylic acid (1.56g), diphenoxyphosphoryl azide (1.62g) and Et3N (597mg) in tert-butanol (5ml) was refluxed for 3 hours. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and H2O. The combined organic layers were washed twice with 1M HCl. Washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate, to give tert-butyl [5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] carbamate (519mg) as an amorphous powder.
MS(ESI+)：m/z 468(M+H)
1H NMR(DMSO-d6)δ 1.46(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)
Example 512
A solution of 4M HCl in dioxane (3ml) was added to a solution of tert-butyl [5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] carbamate (478mg) in CH2Cl2(3 ml). The reaction mixture was stirred at ambient temperature for 5 hours and concentrated in vacuo. The residue was partitioned between CHCl3 and saturated aqueous sodium bicarbonate. The aqueous layer was back-extracted with CHCl 3. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with CHCl3: MeOH: 28% aqueous NH4OH ═ 10:1:0.1, to give N- (2- {4- [ 3-amino-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (244.6mg) as an amorphous powder.
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)δ 3.27-3.37(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)
Example 513
37% aqueous formaldehyde (0.23ml) and sodium cyanoborohydride (53mg) were added to a solution of N- (2- {4- [ 3-amino-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (103.1mg) in MeOH (2 ml). The reaction mixture was stirred at ambient temperature for 3 hours. To the mixture were added 37% aqueous formaldehyde (0.23ml) and sodium cyanoborohydride (53mg), and the reaction mixture was stirred at ambient temperature for 4 days. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography on CHCl3: MeOH: 28% aqueous NH4OH as 100:10: 1. The separated silica gel was extracted with the same solvent, and the solvent was evaporated in vacuo to give N- (2- {4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (59.9mg) as an amorphous powder.
MS(ESI+)：m/z 396(M+H)
1H NMR(DMSO-d6)δ 2.81(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)
Example 514
To a solution of 4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol (98.7mg) in DMF (2ml) was added 60% sodium hydride mineral oil dispersion (15.3 mg). The mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added dropwise (2-bromoethoxy) -tert-butyldimethylsilane (153mg) in DMF (1ml), and the mixture was stirred at ambient temperature overnight. The mixture was poured into ice-water, extracted with AcOEt, washed with H2O and saturated aqueous sodium chloride. The aqueous layer was back-extracted with AcOEt. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in EtOH (2 ml). Concentrated hydrochloric acid (100. mu.l) was added to the solution and the mixture was stirred at ambient temperature for 3 hours. The mixture was concentrated in vacuo and the residue partitioned between AcOEt and saturated aqueous sodium bicarbonate, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed by AcOEt/n-hexane 60%. The residual crystals were collected and washed with IPE to give 2- {4- [3- (dimethylamino) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol (97mg) as a white powder.
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)
The following compound was obtained by a similar method to example 514.
Example 515
N- [5- [4- (2-hydroxyethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N ', N' -trimethylurea
Oil-like substance
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)
Example 516
2- {4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
White powder: mp.67.7-69.2 deg.C
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)
Example 517
2- {4- [ 3-isobutoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
Oil-like substance
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)
Example 518
2- {4- [3- (2-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
Oil-like substance
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)
Example 519
2- {4- [3- (2-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
Oil-like substance
IR (pure): 2972, 2933, 2873, 1612, 1554, 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)
Example 520
2- { [5- [4- (2-hydroxyethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] oxy } -N, N-dimethylacetamide
White powder: mp.106.6-107.1 deg.C
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)
Example 521
2- {4- [ 3-methoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
White powder: mp.92.2-92.5 deg.C
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)
Example 522
2- {4- [ 3-ethoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
White powder: mp.81-82 deg.C
IR(KBr)：3303，3298，1612，1516cm-1
Mass spectrum (sample ID cox022145) (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)
Example 523
To a solution of 5- (hydroxy) phenyl-1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazole (5.0g) and 2-bromoethoxy-tert-butyldimethylsilane (6.87g) in DMF (100ml) was added NaH (919mg, 50% oil dispersion) portionwise at room temperature. The reaction mixture was stirred overnight. The reaction mixture was quenched with water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed twice with water and brine. Drying, filtration and evaporation under reduced pressure gave (5.29g, 73%) 5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazole.
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).
Example 524
2- {4- [1- (4-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 525
2- {4- [3- (2, 2-Difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
Oil-like substance
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)
Example 526
2- {4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethanol
mp.91.2-91.3℃
Mass spectrum (sample ID cox031168) (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)
Example 527
2- {4- [3- (2, 2-Difluoroethoxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethanol
Oil-like substance
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)
Example 528
Carbonyldiimidazole (1.26g) was added to a solution of 5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -3-amino-1H-pyrazole (2.4g) in 1-methyl-2-pyrrolidone (22 ml). After stirring for 2 hours at ambient temperature, a 2M solution of dimethylamine in THF (7.4ml) was added and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/N-hexane ═ 80%, to give N' - [5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (2.35g) as an amorphous powder.
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)
Example 529
A mixture of N' - [5- [4- (hydroxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (121.9mg), 2- (tert-butyl-dimethylsilyloxy) ethyl bromide (166mg) and potassium carbonate (95.6mg) in DMF (1.5ml) was stirred at 75 ℃ for 7 hours. 2- (tert-Butyldimethylsilyloxy) ethyl bromide (83mg) and KI (57.4mg) were added to the reaction mixture, and the mixture was stirred at 75 ℃ overnight. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and H2O. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography on 5% MeOH/CHCl 3. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to yield N' - [5- [4- (2-hydroxyethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (115mg) as an amorphous powder. 84.3mg of the amorphous powder was crystallized from AcOEt-IPE to obtain N' - [5- [4- (2-hydroxyethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (79.5mg) as a white powder.
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)
Example 530
Diethyl azodicarboxylate (308mg) was added to a solution of N' - [5- [4- (hydroxy) -phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (415mg), tert-butyl N- (2-hydroxyethyl) carbamate (380mg) and triphenylphosphine (463mg) in THF (5 ml). Stir at ambient temperature overnight and concentrate the reaction mixture in vacuo. To the residue in CH2Cl2(5ml) was added 4M HCl in dioxane (5 ml). After stirring at ambient temperature for 1.5 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The aqueous layer was back-extracted with AcOEt and concentrated in vacuo. The remaining H2O was azeotropically evaporated with toluene to give N' - [5- [4- (2-aminoethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea hydrochloride (580mg) as an amorphous powder.
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)
The following compounds were obtained by a similar procedure to example 530.
Example 531
N- [5- [4- (2-aminoethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N ', N' -trimethylurea hydrochloride
Amorphous material
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)
Example 532
2- { [5- [4- (2-aminoethoxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] oxy } -N, N-dimethylacetamide hydrochloride
Amorphous material
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)
Example 533
A solution of potassium cyanate (64.9mg) in H2O (0.5ml) was added to a solution of N' - [5- [4- (2-aminoethoxy) phenyl ] -1- (4-methoxy-phenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea hydrochloride (172.8mg) and sodium acetate (65.6mg) in the mixture DMF (1.5ml) and H2O (0.5 ml). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with H2O and partitioned between AcOEt and H2O. The aqueous layer was back-extracted with AcOEt, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography on 10% MeOH/CHCl 3. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt-IPE to give N' - [5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N-dimethylurea (87.0mg) as a powder.
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)
The following compounds were obtained by a similar method to example 533.
Example 534
N- [5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N ', N' -trimethylurea
Powder: mp.158.6-159.0 deg.C
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)
Example 535
N- (2- {4- [3- (2-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
White powder: mp.131-132 deg.C
IR(KBr)：3435，3429，3388，3350，1658，1612，1562，1554，1518cm-1
Mass spectrum (sample ID cox022116) (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)，5.53(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)
Example 536
N- (2- {4- [3- (2-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
White powder: mp.124.1-124.2 deg.C
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)
Example 537
2- { [5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] oxy } -N, N-dimethylacetamide
White powder: mp.223-227 deg.C
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)
Example 538
N- (2- {4- [ 3-methoxy-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
White powder: mp.192.6-192.7 deg.C
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)
Example 539
N- (2- {4- [ 3-ethoxy-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea
White powder: mp.133-138 deg.C
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)
Example 540
N- (2- {4- [ 3-cyclopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 541
N- (2- {4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 542
N- (2- {4- [1- (6-methoxy-3-pyridinyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 543
5- (4- {2- [ (aminocarbonyl) amino ] ethoxy } phenyl) -N-ethyl-1- (6-methoxy-3-pyridinyl) -N-methyl-1H-pyrazole-3-carboxamide
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)
Example 544
N- (2- {4- [1- (4-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 545
N- (2- {4- [3- (2, 2-Difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 546
N- (2- {4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 547
N- (2- {4- [3- (2, 2-Difluoroethoxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 548
5- (4- { [ (aminocarbonyl) amino ] methyl } phenyl) -N-ethyl-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide
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)
Example 549
N- {4- [ 3-isopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } 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)
Example 550
N- {4- [1- (6-methoxy-3-pyridinyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-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)
Example 551
5- (4- { [ (aminocarbonyl) amino ] methyl } phenyl) -N-ethyl-1- (6-methoxy-3-pyridinyl) -N-methyl-1H-pyrazole-3-carboxamide
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)
Example 552
N- {4- [ 3-isopropyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-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)
Example 553
N- {4- [ 3-isobutyryl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-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)
Example 554
N- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-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)
Example 555
N- {4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } urea
Solid body
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)
Example 556
N- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-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)
Example 557
N- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-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)
Example 558
N- (2- {4- [1- (4-methoxyphenyl) -4-methyl-1H-pyrazol-5-yl ] phenoxy } ethyl) 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)
Example 559
N- (2- {4- [1- (6-methoxy-3-pyridyl) -4-methyl-1H-pyrazol-5-yl ] phenoxy } ethyl) urea
Powder of
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)
Example 560
N- (2- {4- [1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 561
N- (2- {4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-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)
Example 562
5- (4- {2- [ (aminocarbonyl) amino ] ethyl } phenyl) -N-methoxy-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide
Oil-like substance
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)
Example 563
5- (4- {2- [ (aminocarbonyl) amino ] ethyl } phenyl) -N-methoxy-1- (6-methoxy-3-pyridinyl) -N-methyl-1H-pyrazole-3-carboxamide
Oil-like substance
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)
Example 564
A60% sodium hydride mineral oil dispersion (93.1mg) was added in one portion to a solution of N- [5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N ', N' -dimethylurea (1.43g) in DMF (10ml) with cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 1 hour. MeI (688mg) was added to the reaction mixture and stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt-N-hexane 75%, 80% to give N- [5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] -N, N' -trimethylurea (1.45g) as an oil.
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)
Example 565
A mixture of N- (2- {4- [ 3-amino-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (111mg), lithium chloride (64mg) and copper (II) chloride (81.2mg) in acetonitrile (2ml) was stirred at ambient temperature for 10 minutes. Isoamylnitrite (62.3mg) was added to the mixture, and the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride, H2O and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography on MeOH/CHCl3 ═ 10%. The isolated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was crystallized from AcOEt/IPE to give N- (2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (31.1mg) as a white powder.
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)
Example 566
Diethyl azodicarboxylate (0.17ml) was added dropwise to a suspension of 3-methoxy-1- (4-methoxyphenyl) -5- (4-hydroxyphenyl) -1H-pyrazole (215.6mg), tert-butyl N- (2-hydroxyethyl) carbamate (352mg) and triphenylphosphine (286mg) in THF (3 ml). The mixture was stirred at ambient temperature for 7 hours. Triphenylphosphine (19.1mg) and diethyl azodicarboxylate (11.5. mu.l) were added and the mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 30%, to give tert-butyl (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate (319mg) as an oil.
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)
The following compounds were obtained using a similar procedure to example 566.
Example 567
(2- {4- [ 3-isobutoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
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)
Example 568
(2- {4- [3- (2-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Solid body
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)
Example 569
(2- {4- [3- (2-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
Mass spectrum (ESI +): 498(M + H) +
200MHz 1H NMR (DMSO-d6, d): 1.09-1.21(3H, overlap), 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),
example 570
(2- {4- [ 3-methoxy-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Powder of
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)
Example 571
(2- {4- [ 3-ethoxy-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
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)
Example 572
[2- (4- {3- (difluoromethyl) -1- [4- (methylthio) phenyl ] -1H-pyrazol-5-yl } phenoxy) ethyl ] carbamic acid tert-butyl ester
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).
Example 573
(2- {4- [ 3-cyclopropyl-1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 574
(2- {4- [3- (cyclopentyloxy) -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 575
(2- {4- [1- (4-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 576
(2- {4- [3- (2, 2-Difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 577
(2- {4- [1- (6-methoxy-3-pyridinyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 578
(2- {4- [3- (2, 2-Difluoroethoxy) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Solid body
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)
Example 579
(2- {4- [1- (4-methoxyphenyl) -4-methyl-1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 580
(2- {4- [1- (6-methoxy-3-pyridinyl) -4-methyl-1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 581
(2- {4- [1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Oil-like substance
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)
Example 582
To a solution of (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride (150mg) and triethylamine (121mg) in CH2Cl2(3ml) was added trifluoromethanesulfonic anhydride (113 mg). The mixture was stirred at ambient temperature for 2 hours. Triethylamine (92mg) was added thereto, and stirring was continued at ambient temperature for 4 hours. The mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/N-hexane ═ 50%, to give 1, 1, 1-trifluoro-N- (2- {4- [ 3-methoxy-1- (4-methoxy-phenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) methanesulfonamide (109mg) as an oil.
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)
Example 583
To a suspension of 5- [4- (benzyloxy) phenyl ] -3-hydroxy-1- (4-methoxyphenyl) -1H-pyrazole (2.0g) and K2CO3(2.23g) in DMSO (20ml) was added diethyl sulfate (1.24 g). After stirring for 2 hours at ambient temperature, the reaction was quenched by addition of 28% aqueous ammonium hydroxide and ice. The mixture was partitioned between AcOEt and H2O. The organic layer was washed with H2O and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/hexanes 40% and the solvent was evaporated in vacuo. The residual solid was recrystallized from IPE to give 5- [4- (benzyloxy) phenyl ] -3-ethoxy-1- (4-methoxy-phenyl) -1H-pyrazole (1.44g) as a powder.
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)
The following compounds were obtained in a similar manner to example 583.
Example 584
5- {5- [4- (benzyloxy) phenyl ] -3-ethoxy-1H-pyrazol-1-yl } -2-methoxypyridine
An oil; 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)
Example 585
To a solution of 4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenol (515.5mg) in DMF (5ml) at 3 ℃ was added 60% sodium hydride mineral oil dispersion (79.7 mg). The mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of tert-butyl (2-bromoethyl) carbamate (558mg) in DMF (2 ml). The mixture was stirred at 60 ℃ for 24 hours. The reaction mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from AcOEt, collected and washed with IPE to give tert-butyl (2- {4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate as a first product in the form of a white powder (344 mg). The mother liquor was concentrated in vacuo and purified by silica gel column chromatography eluting with AcOEt/CHCl3 ═ 10% to give a second crop of tert-butyl (2- {4- [ 3-ethoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate as a powder (218 mg).
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)
Example 586
A suspension of 5- [4- (benzyloxy) phenyl ] -3-hydroxy-1- (4-methoxyphenyl) -1H-pyrazole (1.5g), 1-bromo-2-methylpropane (2.76g) and anhydrous potassium carbonate (1.67g) in DMF (10ml) was added and stirred at 100 ℃ for 1 hour. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 30%, to give 5- [4- (benzyloxy) phenyl ] -3-isobutoxy-1- (4-methoxyphenyl) -1H-pyrazole (1.64g) as a solid.
Powder of
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)
The following compounds were obtained in a similar manner to example 586.
Example 587
5- [4- (benzyloxy) phenyl ] -3- (2-methoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazole
Powder of
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)
Example 588
5- [4- (benzyloxy) phenyl ] -3- (2-ethoxyethoxy) -1- (4-methoxyphenyl) -1H-pyrazole
Oil-like substance
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)
Example 589
2- { [5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazol-3-yl ] oxy } -N, N-dimethylacetamide
Powder of
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)
Example 590
5- [5- [4- (benzyloxy) phenyl ] -3- (cyclopentyloxy) -1H-pyrazol-1-yl ] -2-methoxypyridine
Solid body
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)
Example 591
5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazole
Oil-like substance
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)
Example 592
5- [4- (benzyloxy) phenyl ] -3- (2, 2-difluoroethoxy) -1- (4-methoxyphenyl) -1H-pyrazole
Oil-like substance
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)
Example 593
5- [5- [4- (benzyloxy) phenyl ] -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-1-yl ] -2-methoxypyridine
Oil-like substance
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)
Example 594
5- [5- [4- (benzyloxy) phenyl ] -3- (2, 2-difluoroethoxy) -1H-pyrazol-1-yl ] -2-methoxypyridine
Oil-like substance
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)
Example 595
A suspension of 5- {5- [4- (benzyloxy) phenyl ] -3-hydroxy-1H-pyrazol-1-yl } -2-methoxypyridine (800mg), dimethyl carbonate (0.9ml) and potassium carbonate (888mg) in DMF (8ml) was stirred at 120 ℃ for 5 hours. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with H2O, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/hexanes ═ 30% to give 5- {5- [4- (benzyloxy) phenyl ] -3-methoxy-1H-pyrazol-1-yl } -2-methoxy-pyridine (1.069g) as a solid.
Powder of
MS(ESI+)：m/z 388(M+H)+
200MHz 1H NMR(CDCl3，d)：3.92(3H，s)，3.97(3H，s)，5.05(2H，s)，S.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)
Example 596
A solution of 4, 4, 4-trifluoro-1- [4- (2-hydroxyethyl) phenyl ] -1, 3-butanedione (670mg) and (4-nitrophenyl) hydrazine hydrochloride (439mg) in AcOH (5ml) and H2O (0.5ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo and the residue partitioned between AcOEt and 1M HCl. The organic layer was washed successively with 1M HCl (2 times), saturated aqueous sodium bicarbonate (3 times), and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 10% and 15% to give 2- {4- [1- (4-nitrophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl acetate (501mg) as an oil.
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)
The following compound was obtained by a similar method to that of example 596.
Example 597
5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazole
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).
Example 598
Acetic acid 2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-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).
Example 599
To a solution of ammonium chloride (58.8mg) in H2O (0.5ml) were added iron powder (368mg) and EtOH (2 ml). The reaction mixture was oil-bathed and a solution of 2- {4- [1- (4-nitrophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl acetate (460.7mg) in EtOH (3ml) was added. After refluxing for 3 hours, the reaction mixture was cooled to ambient temperature and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The residue was dissolved in AcOEt, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from IPE to give 2- {4- [1- (4-aminophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl acetate (182.3mg) as a powder.
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)
Example 600
A mixture of acetic acid 2- {4- [1- (4-aminophenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl ester (165.6mg) and 2, 5-dimethoxytetrahydrofuran (112mg) in AcOH (3ml) was stirred at 50 ℃ for 3 hours. 2, 5-Dimethoxytetrahydrofuran (0.22ml) was added to the solution, and the mixture was stirred at 50 ℃ for 2 hours. The mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with AcOEt/n-hexane 20%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2- {4- [1- [4- (1H-pyrrol-1-yl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl acetate (136.1mg) as an oil.
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)
Example 601
1M NaOH (436. mu.l) was added to a solution of acetic acid 2- {4- [1- [4- (1H-pyrrol-1-yl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethyl ester (128mg) in THF (1.5ml) and MeOH (0.3ml) with cooling in an ice bath. The mixture was stirred at 0 ℃ to ambient temperature for 2 hours. The mixture was neutralized with 1M HCl (436. mu.l) and partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with AcOEt/n-hexane 50%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give 2- {4- [1- [4- (1H-pyrrol-1-yl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenyl } ethanol (96.5mg) as an amorphous powder.
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)
Example 602
A mixture of 10% Pd-C50% wet weight (100mg) and ethyl 5- (4-cyanophenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (1g) in THF (10ml), MeOH (5ml) and 1MHCl (2.9ml) was hydrogenated at H2(1atm) at ambient temperature for 6.5H. The catalyst was filtered off through a celite pad, and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was dissolved in EtOH and concentrated in vacuo. The residue was crystallized from AcOEt to give 5- [4- (aminomethyl) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylic acid ethyl ester hydrochloride (984mg) as a powder.
MS(ESI+)：m/z 352(M+H)+
1H NMR(DMSO-d6)δ 1.32(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)
The following compounds were obtained using a similar procedure to that of example 602.
Example 603
5- [4- (aminomethyl) phenyl ] -1- (6-methoxy-3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester dihydrochloride
Powder of
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)
Example 604
{4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } amine hydrochloride
Oil-like substance
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)
Example 605
{4- [ 3-isopropoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } amine hydrochloride
Powder of
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)
Example 606
Et3N (326mg) was added, followed by the addition of a solution of di-tert-butyl dicarbonate (594mg) in CH2Cl2(3ml) to a suspension of ethyl 5- [4- (aminomethyl) phenyl ] -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate hydrochloride (960mg) in CH2Cl2(9 ml). After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystallized from AcOEt/n-hexane to give ethyl 5- (4- { [ (tert-butoxycarbonyl) amino ] methyl } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (1.045g) as a powder.
MS(ESI+)：m/z 452(M+H)+
1H NMR(DMSO-d6)δ 1.31(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)
The following compound was obtained in a similar manner to example 606.
Example 607
5- (4- { [ (tert-Butoxycarbonyl) amino ] methyl } phenyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazole-3-carboxylic acid ethyl ester
Powder of
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)
Example 608
A mixture of ethyl 5- (4- { [ (tert-butoxycarbonyl) amino ] methyl } phenyl) -1- (4-methoxyphenyl) -1H-pyrazole-3-carboxylate (500mg) and sodium methoxide (239mg) in formamide (5ml) was stirred at 70 ℃ for 2 hours. The mixture was cooled to ambient temperature and partitioned between AcOEt and brine. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give tert-butyl {4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamate (512mg) as an oil.
MS(ESI+)：m/z 423(M+H)+
1H NMR(DMSO-d6)δ 1.38(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)
Example 609
Phosphoryl chloride (0.22ml) was added to DMF (2ml) with ice bath cooling. To the solution was added dropwise a solution of tert-butyl {4- [3- (aminocarbonyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamate (499mg) in DMF (3 ml). The reaction mixture was stirred at 4 ℃ for 1 hour. Phosphorus oxychloride (0.15ml) was added and the reaction mixture was stirred at 4 ℃ for 1 hour. The reaction was quenched by addition of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed with AcOEt/n-hexane 40%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give tert-butyl {4- [ 3-cyano-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzylcarbamate (136mg) as an oil.
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)
Example 610
To a solution of 5- [4- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethoxy) phenyl ] -1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazole (5.2g) in EtOH (200ml) was added concentrated HCl (20ml) at room temperature. After stirring for 2 hours, the reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (Hex/EtOAc ═ 2:1-1:1) to give 2- {4- [1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethanol crystals (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).
Example 611
To a solution of 4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenol (5.0g) in DMF (20m1) was added NaH (0.75g) (gas) over 25 minutes under ice cooling (5 to 20 ℃ C.), and the mixture was stirred at 3 ℃ for 10 minutes. A solution of tert-butyl N- (2-bromoethyl) carbamate (4.48g) in DMF (5ml) was added to the mixture over 10 minutes, stirred at 60 ℃ for 6 hours at 70 ℃ bath temperature and then allowed to stand overnight.
The mixture was poured into water (50ml) and EtOAc (30ml), separated and extracted with EtOAc (10 ml). The organic layer was washed with water (25X 3) and brine (25ml), dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (75ml, 15v/w, AcOEt/hexane (2:1-1:1)) and evaporated to give 7.0g of tert-butyl (2- {4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate as an oil.
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).
The following compound was obtained in a similar manner to example 611.
Example 612
(2- {4- [1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
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).
Example 613
To a suspension of (2- {4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride (7.5g) in H2O (150ml) and EtOH (75ml) at room temperature was added NaOCN (2.27 g). The pH was adjusted to 6.3 with 1N HCl. The mixture was stirred at pH6.0-7.0 for 5 hours. The reaction mixture was extracted with EtOAc and washed with diluted NaCl solution (twice). Dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (CH2Cl2/MeOH) and evaporated. The residue was crystallized from IPE/EtOH. Recrystallization from EtOH/H2O (final 50ml-50ml) gave, after drying, 4.10g (54%) of N- (2- {4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } 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).
HOR [ BA FT-IR ] of Windows Ver.4.08
(cm-1)：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.
The following compounds were obtained in a similar manner to example 613.
Example 614
N- (2- {4- [1- (4-methoxyphenyl) -4-methyl-3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } 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).
Example 615
N- [2- (4- {3- (difluoromethyl) -1- [4- (methylthio) phenyl ] -1H-pyrazol-5-yl } phenoxy) 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).
Example 616
N- (2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-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).
Example 617
N- {4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } urea crystal. mp: 147 deg.C, 149 deg.C
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).
Example 618
N- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-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).
Example 619
A mixture of N- (2- {4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (250mg) and mCPBA (326mg) in CH2Cl2(10ml) was stirred for 18 hours. Saturated NaHCO3 and CH2Cl2 were added. The aqueous layer was separated and extracted. The combined organic layers were washed with saturated NaHCO3 (twice), dried and evaporated to yield 207mg (79.9%) of the crude product. It was purified by preparative TLC column chromatography to give amorphous N- (2- {4- [1- [4- (methylsulfinyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } 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).
Example 620
A mixture of N- (2- {4- [1- [4- (methylthio) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea (250mg) and mCPBA (326mg) in CH2Cl2(10ml) was stirred for 18 hours. Saturated NaHCO3 and CH2Cl2 were added. The aqueous layer was separated and extracted. The combined organic layers were washed with saturated NaHCO3 (twice), dried and evaporated to yield 207mg (79.9%) of the crude product. It was purified by preparative TLC column chromatography to yield 116mg (43%) of amorphous N- (2- {4- [1- [4- (methylsulfonyl) phenyl ] -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } 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).
Example 621
To a solution of acetic acid 2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethyl ester (10g) in THF (120ml) and MeOH (30ml) was added 1NNaOH (60ml) at room temperature. The reaction mixture was stirred at the same temperature for 4 hours, then neutralized with 1n hcl (60ml), evaporated and extracted twice with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated to give the crude product. The residue was purified by silica gel column chromatography, crystallized with IPE, and filtered to obtain 3.0g of 2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethanol. The filtrate was evaporated and filtered to obtain 4.65g of second crystals.
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).
Example 622
To a solution of 2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethanol (7.4g) and Et3N (4.5ml) in CH2Cl2(75ml) was added MsCl (2.5ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water and separated. The aqueous layer was extracted with CH2Cl2, the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 10.5g (quantitative) of 2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenyl } ethyl methanesulfonate as an oil.
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).
Example 623
A mixture of 2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenyl } ethyl methanesulfonate (7.4g) and Ph (CO)2NK (3.88g) in DMF (50ml) was stirred at 60 ℃ for 8H. Water was added. The organic layer was extracted twice with EtOAc. The aqueous layer was washed with water (twice) and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was triturated with IPE, filtered and dried to yield 7.65g of solid 2- (2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethyl) -1H-isoindole-1, 3(2H) -dione.
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).
Example 624
A mixture of 2- (2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethyl) -1H-isoindole-1, 3(2H) -dione (5.0g) and NH2NH2(2.8ml) in CH3CN (50ml) was stirred at 60 ℃ for 8 hours. The reaction mixture was filtered. The filtrate was evaporated under reduced pressure. 4N HCl/dioxane was added followed by IPE. The product was triturated, filtered and dried under reduced pressure to yield 3.94g (90%) of solid (2- {4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenyl } ethyl) amine dihydrochloride.
Mass spectrum (ESI +): m/z is 345.2(M (free) +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).
The following compounds were obtained in a similar manner to example 602.
Example 625
{4- [1- (6-methoxy-3-pyridyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] benzyl } 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).
Example 626
{4- [3- (difluoromethyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] -benzyl } amine hydrochloride
Mass spectrum (ESI +): 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).
Example 627
To a solution of 5-hydrazino-2-methoxypyridine dihydrochloride (4.78g) and Et3N (7.01g) in EtOH (50ml) was added { (2R, 3S) -3- [4- (benzyloxy) phenyl ] -2-oxiranyl } (cyclopropyl) methanone (5.10g) and the mixture was refluxed for 9 hours. The mixture was concentrated in vacuo. AcOEt and 1M HCl were added to the residue and insoluble material was filtered off through a pad of Celite. The filtrate was partitioned, and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in CH2Cl2(50 ml). To the solution were added Et3N (5.26g) and methanesulfonyl chloride (2.98g) successively under cooling in an ice bath. The mixture was stirred at ambient temperature for 2 hours. The mixture was washed with 1M HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 20%, to give 5- {5- [4- (benzyloxy) phenyl ] -3-cyclopropyl-1H-pyrazol-1-yl } -2-methoxypyridine (4.20g) as a solid.
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)
Example 628
To a mixture of tert-butyl (2- {4- [1- (4-methoxyphenyl) -3-carboxy-1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate (313.9mg), piperidine (88.4mg), and 1-hydroxybenzotriazole (140mg) in DMF (3ml) was added water-soluble carbodiimide hydrochloride (199mg) with cooling in an ice bath. The mixture was stirred at ambient temperature overnight and then partitioned between AcOEt and H2O. The organic layer was separated, washed with 1M HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/hexanes 70%. The residue was crystallized from IPE to give tert-butyl 2- {4- [1- (4-methoxyphenyl) -3- (1-piperidinyl-carbonyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamate (332.5mg) as a white powder.
MS(ESr+)：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)
The following compound was obtained by a similar method to that of example 628.
Example 629
(2- {4- [1- (6-methoxy-3-pyridinyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Powder of
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)
Example 630
(2- {4- [3- { [ Ethyl (methyl) amino ] carbonyl } -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) carbamic acid tert-butyl ester
Powder of
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)
Example 631
2- {4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 632
2- {4- [1- (6-methoxy-3-pyridyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] phenoxy } 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)
Example 633
{4- [1- (4-methoxyphenyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
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)
Example 634
{4- [3- { [ Ethyl (methyl) amino ] carbonyl } -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
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)
Example 635
{4- [3- { [ methoxy (methyl) amino ] carbonyl } -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Solid body
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)
Example 636
{4- [1- (6-methoxy-3-pyridyl) -3- (1-piperidinylcarbonyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Oil-like substance
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)
Example 637
{4- [3- { [ Ethyl (methyl) amino ] carbonyl } -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Oil-like substance
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)
Example 638
{4- [3- { [ methoxy (methyl) amino ] carbonyl } -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Powder of
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)
Example 639
5- [4- (2-hydroxyethyl) phenyl ] -N-methoxy-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide
Oil-like substance
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)
Example 640
5- [4- (2-hydroxyethyl) phenyl ] -N-methoxy-1- (6-methoxy-3-pyridinyl) -N-methyl-1H-pyrazole-3-carboxamide
Oil-like substance
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)
Example 641
To a solution of tert-butyl {4- [3- (1-hydroxy-1-methylethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamate (1.1g) and Et3N (1.02g) was added methanesulfonyl chloride (576 mg). The mixture was stirred at ambient temperature overnight. The mixture was concentrated in vacuo. The residue was partitioned between AcOEt and 1M HCl. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 25%. The pure fractions were collected and concentrated in vacuo to give tert-butyl {4- [ 3-isopropenyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamate (857mg) as a solid.
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)
The following compound was obtained in a similar manner to example 641.
Example 642
{4- [ 3-isopropenyl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Oil-like substance
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)
Example 643
A solution of 0.76M isopropylmagnesium bromide in THF (8.5ml) was added dropwise to a solution of tert-butyl {4- [3- { [ methoxy (methyl) amino ] carbonyl } -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamate (1g) in THF (10ml) at 10-15 ℃. The mixture was stirred at ambient temperature for 4 hours. The reaction mixture was poured into a mixture of 1M HCl and ice. The mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with AcOEt/hexanes 20%, 25% and then 10% MeOH/CHCl 3. The combined pure fractions were concentrated in vacuo to give amorphous powder of tert-butyl {4- [ 3-isobutyryl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } carbamate (318 mg).
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)
The following compounds were obtained by a similar method to example 643.
Example 644
{4- [ 3-isobutyryl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] benzyl } carbamic acid tert-butyl ester
Oil-like substance
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)
Practice ofExample 645
To a solution of 4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] benzonitrile (197mg) in THF (2ml) was added lithium aluminum hydride (30mg) with cooling in an ice bath. The mixture was stirred at the same temperature for 1 hour, then at ambient temperature for 2 hours. 5% aqueous sodium potassium tartrate (ca.0.5ml) was added to quench the reaction. The mixture was diluted with AcOEt, dried over magnesium sulfate and filtered through a pad of celite. The filtrate was concentrated in vacuo to give {4- [1- (6-methoxy-3-pyridyl) -3- (2, 2, 2-trifluoroethoxy) -1H-pyrazol-5-yl ] benzyl } amine (200mg) as an oil.
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)
The following compounds were obtained in a similar manner to example 645.
Example 646
1- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } methanamine
Oil-like substance
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)
Example 647
1- {4- [ 3-chloro-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } methanamine
Powder of
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)
Example 648
A mixture of 5- [4- (benzyloxy) phenyl ] -3-amino-1- (4-methoxyphenyl) -1H-pyrazole (4.0g), lithium chloride (2.28g) and copper (II) chloride (2.90g) in acetonitrile (50ml) was stirred at ambient temperature for 10 min. Isoamyl nitrite (2.52g) was added to the mixture and the mixture was stirred at ambient temperature for 1.5 hours. To the reaction mixture was added a mixture of ethyl acetate and saturated aqueous ammonium chloride solution. The mixture was stirred at ambient temperature for a while and then partitioned. The aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 20% AcOEt/n-hexane. The pure fractions were collected and concentrated in vacuo to give 5- [4- (benzyloxy) phenyl ] -3-chloro-1- (4-methoxyphenyl) -1H-pyrazole (2.81g) as a solid.
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)
Example 649
A solution of 4-benzyloxyphenyl ethyl ketone (5g) in N, N-dimethylformamide dimethyl acetal (20ml) was refluxed for 24 hours. The mixture was concentrated in vacuo. The residue was dissolved in toluene and concentrated in vacuo. This step was repeated once more. The residue was dissolved in EtOH. To the solution was added 4-methoxyphenylhydrazine hydrochloride (3.63g), and the mixture was refluxed for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between AcOEt and 1M HCl. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 30%, to give 5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -4-methyl-1H-pyrazole (5.31g) as a powder.
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)
The following compounds were obtained in a similar manner to example 649.
Example 650
5- {5- [4- (benzyloxy) phenyl ] -4-methyl-1H-pyrazol-1-yl } -2-methoxypyridine
Powder of
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)
Example 651
A solution of tert-butyl nitrite (1.14ml) in CHCl3(3ml) was added dropwise to a solution of 5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -3-amino-1H-pyrazole (1.5g) and dimethyldisulfide (1.15ml) in CHCl3(10 ml). After the entire tert-butyl nitrite solution had been added, the reaction mixture was warmed to reflux. After the reflux had ceased, the mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane ═ 25%, to give 5- [4- (benzyloxy) phenyl ] -1- (4-methoxyphenyl) -3- (methylthio) -1H-pyrazole (635.2mg) as an oil.
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)
Example 652
A mixture of 3-cyano-1- (4-methoxyphenyl) -5- [4- (aminomethyl) phenyl ] -1H-pyrazole (90mg), trimethylsilyl isocyanate (152mg) and Et3N (0.18ml) in CH2Cl2(5ml) was stirred at room temperature. After stirring for 5 hours (checked by TLC), water and CHCl3 were added. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The magnesium sulfate was dried, filtered and evaporated under reduced pressure to give 48mg (52%) of N- {4- [ 3-cyano-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] 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).
Example 653
To a mixture of (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) amine hydrochloride (150mg) in CHCl3(2ml) and saturated aqueous sodium bicarbonate solution (1ml) was added thiophosgene (68.8mg) with cooling in an ice bath. The mixture was stirred at ambient temperature for 5 hours. 28% aqueous ammonium hydroxide (1ml) was added to the mixture and the mixture was stirred at ambient temperature overnight. To the mixture were added 28% aqueous ammonium hydroxide (1ml) and MeOH (1ml), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between AcOEt and H2O. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from ACOEt-IPE. The obtained powder was recrystallized from AcOEt-N-hexane to obtain N- (2- {4- [ 3-methoxy-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) thiourea (116mg) as a powder.
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)
Example 654
Methanesulfonyl chloride (328mg) in CH2Cl2(2ml) was added under ice-cooling to a solution of 5- [4- (2-hydroxyethyl) phenyl ] -N-methoxy-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide (840mg) and Et3N (334mg) in CH2Cl2(10 ml). The mixture was stirred at the same temperature for 1 hour. The mixture was diluted with CHCl3, washed with 1M HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with AcOEt/n-hexane 80%, 90%. The pure fractions were collected and concentrated in vacuo to give 2- {4- [3- { [ methoxy (methyl) amino ] carbonyl } -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl methanesulfonate (1.01g) as an oil.
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)
The following compounds were obtained by a similar method to example 654.
Example 655
Methanesulfonic acid 2- {4- [3- { [ methoxy (methyl) amino ] carbonyl } -1- (6-methoxy-3-pyridinyl) -1H-pyrazol-5-yl ] phenyl } ethyl ester
Oil-like substance
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)
Example 656
A mixture of 2- {4- [3- { [ methoxy (methyl) amino ] -carbonyl } -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl methanesulfonate (1.02g), 15-crown-5 (489mg), sodium azide (722mg) in hexamethylphosphoric triamide (6ml) was stirred at 55 ℃ for 1 hour. The mixture was poured into ice water and the mixture was extracted with AcOEt. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in MeOH (6 ml). To this solution was added a solution of 6M HCl (0.37ml) in MeOH (2ml) and 10% palladium on carbon (50% wet weight) (200 mg). The mixture was hydrogenated at ambient temperature for 2 hours under H2(1 atm). The catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 5- [4- (2-aminoethyl) phenyl ] -N-methoxy-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide hydrochloride (0.93g) as an oil.
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)
The following compounds were obtained in a similar manner to example 656.
Example 657
5- [4- (2-aminoethyl) phenyl ] -N-methoxy-1- (6-methoxy-3-pyridinyl) -N-methyl-1H-pyrazole-3-carboxamide hydrochloride
Oil-like substance
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)
Example 658
To a solution of 0.76M isopropylmagnesium bromide in THF (2.0ml) was added dropwise a solution of 5- (4- {2- [ (aminocarbonyl) amino ] ethyl } phenyl) -N-methoxy-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide (130mg) in THF (2ml) at 4 ℃. The mixture was stirred at ambient temperature overnight. A solution of 0.76M isopropylmagnesium bromide in THF (2.0ml) was further added to stir the mixture at 50 ℃ for 5 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with AcOEt. The organic layer was washed with 1M HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed through MeOH/CHC3 (10%). The separated silica gel was extracted with 10% MeOH/CHCl3, and the solvent was evaporated in vacuo to give N- (2- {4- [ 3-isobutyryl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl) urea (30mg) as an amorphous powder.
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)
The following compounds were obtained by a similar procedure to that of example 658.
Example 659
N- (2- {4- [ 3-isobutyryl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl) methanesulfonamide
Oil-like substance
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)
Example 660
N- (2- {4- [ 3-isobutyryl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethyl) urea
Oil-like substance
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)
Example 661
N- (2- {4- [ 3-isobutyryl-1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethyl) methanesulfonamide
Oil-like substance
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)
Example 662
To a cyclopropyl magnesium bromide solution (prepared by conventional methods with cyclopropyl bromide (257mg) and magnesium (57mg) in THF (1 ml)) at ambient temperature was added dropwise a solution of 5- (4- {2- [ (aminocarbonyl) -amino ] ethyl } phenyl) -N-methoxy-1- (4-methoxyphenyl) -N-methyl-1H-pyrazole-3-carboxamide (90mg) in THF (3 ml). The mixture was stirred at 50 ℃ for 5 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with AcOEt. The organic layer was washed with 1M HCl, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography, developed through MeOH/CHC3 (10%). The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo to give N- (2- {4- [3- (cyclopropylcarbonyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl) urea (23mg) as a powder.
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)
The following compounds were obtained by a similar method to that of example 662.
Example 663
N- (2- {4- [3- (cyclopropylcarbonyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenyl } ethyl) methanesulfonamide
Oil-like substance
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)
Example 664
N- (2- {4- [3- (cyclopropylcarbonyl) -1- (6-methoxy-3-pyridyl) -1H-pyrazol-5-yl ] phenyl } ethyl) methanesulfonamide
Oil-like substance
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 (8)
1. A compound of the following structural formula (I):
wherein R is1Is hydrogen or C1-C6An alkyl group;
R2is optionally halogen, hydroxy, C1-C6Alkoxyimino or C1-C6Alkoxy-substituted C1-C6An alkyl group; c1-C6An alkenyl group; c3-C10A cycloalkyl group; a cyano group; c1-C6An alkanoyl group; c3-C10A cycloalkyl carbonyl group; n, N-di (C)1-C6) An alkylcarbamoyl group; a carbamoyl group; N-C1-C6alkoxy-N-C1-C6An alkylcarbamoyl group; an amino group; two (C)1-C6) An alkylamino group; c1-C6An alkoxycarbonylamino group; n, N-di (C)1-C6) An alkylcarbamoylamino group; n- (N, N-di (C)1-C6) Alkylcarbamoyl) -N-C1-C6An alkylamino group; halogen; a hydroxyl group; a carboxyl group; c1-C6An alkoxycarbonyl group; aroyl; c1-C6An alkylsulfonyl group; optionally is covered with C1-C6Alkoxy, N-di (C)1-C6) Alkylcarbamoyl or halogen substituted C1-C6An alkoxy group; c3-C10A cycloalkoxy group; c1-C6An alkylthio group; or C1-C6An alkylsulfinyl group;
R3is C optionally substituted by amino or carbamoylamino1-C6An alkyl group; halogen; a cyano group; a hydroxyl group; c1-C6An alkanoyloxy group; c1-C6An alkylenedioxy group; c optionally substituted by1-C6Alkoxy groups: c6-C10Aryl, hydroxy, cyano, amino, C1-C6Alkoxycarbonylamino or carbamoylamino; a nitro group; or an amino group;
R4a group of the formula:
R5-G-J-
wherein G is-CO-; j is-N- (R) 6) - (wherein R)6Is hydrogen or C1-C6Alkyl groups); and is
R5Is optionally substituted by C1-C6Alkoxycarbonyl or C1-C6An alkyl-substituted amino group;
x is O;
y is CH;
z is C1-C6Alkylene or C1-C6An alkenylene group; and is
m is 0 or 1.
2. The compound of claim 1, wherein
R1Is hydrogen;
R2is optionally halogen, hydroxy, C1-C6Alkoxyimino or C1-C6Alkoxy-substituted C1-C6An alkyl group; c3-C10A cycloalkyl group; halogen; c optionally substituted by halogen1-C6An alkoxy group; or C1-C6An alkylthio group;
R3is C optionally substituted by1-C6Alkoxy groups: c6-C10Aryl, hydroxy, cyano, amino, C1-C6Alkoxycarbonylamino or carbamoylamino; and is
Z is C1-C6An alkylene group.
3. The compound of claim 2, wherein
R2Is C optionally substituted by halogen1-C6An alkyl group; c3-C10A cycloalkyl group; halogen; or C optionally substituted by halogen1-C6An alkoxy group;
R3is C1-C6An alkoxy group;
j is-NH-.
4. A compound of claim 3 which is
N- (2- {4- [ 3-chloro-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea,
n- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] benzyl } urea,
n- (2- {4- [3- (difluoromethyl) -1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea,
n- (2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea, or
N- (2- {4- [ 3-cyclopropyl-1- (4-methoxyphenyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea.
5. The compound of claim 4 which is N- (2- {4- [1- (4-methoxyphenyl) -3- (trifluoromethyl) -1H-pyrazol-5-yl ] phenoxy } ethyl) urea.
6. A process for preparing a compound of the formula:
wherein R is1、R2、R3、R4、R5、G、J、R6X, Y, Z and m are as defined in claim 1
The method comprises the steps of (1) carrying out,
1) reacting a compound of the formula:
reacting with a compound of the formula:
obtaining a compound of the formula:
in the above structural formula, R1、R2、R3、R4X, Y, Z and m are as defined above,
or
2) Reacting a compound of the formula:
with a compound of the formula (V):
R4——Z——Q (V)
obtaining a compound of the formula:
in the above structural formula: r1、R2、R3、R4Y and Z are as defined above,
xa is O and Q is a hydroxyl or acid residue.
7. A pharmaceutical composition comprising as an active ingredient a compound of claim 1 and a non-toxic pharmaceutically acceptable carrier or excipient.
8. Use of a compound according to claim 1 for the preparation of a medicament for the treatment and/or prophylaxis of the following diseases in humans or animals: inflammatory diseases, various pains, collagen diseases, autoimmune diseases, various immunological diseases, analgesia, thrombosis, cancer or neurodegenerative diseases.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2002-953019 | 2002-12-02 | ||
| AU2002953019A AU2002953019A0 (en) | 2002-12-02 | 2002-12-02 | Azole derivatives |
| AU2002-953602 | 2002-12-30 | ||
| AU2002953602A AU2002953602A0 (en) | 2002-12-30 | 2002-12-30 | New compounds |
| AU2003-902015 | 2003-04-29 | ||
| AU2003902015A AU2003902015A0 (en) | 2003-04-29 | 2003-04-29 | Azole derivatives |
| PCT/JP2003/014489 WO2004050632A1 (en) | 2002-12-02 | 2003-11-14 | Pyrazole derivatives useful as cox-i inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1087102A1 HK1087102A1 (en) | 2006-10-06 |
| HK1087102B true HK1087102B (en) | 2009-12-24 |
Family
ID=
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