CN100378072C - Heterocyclic methyl sulfone derivative - Google Patents
Heterocyclic methyl sulfone derivative Download PDFInfo
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- CN100378072C CN100378072C CNB2004800169993A CN200480016999A CN100378072C CN 100378072 C CN100378072 C CN 100378072C CN B2004800169993 A CNB2004800169993 A CN B2004800169993A CN 200480016999 A CN200480016999 A CN 200480016999A CN 100378072 C CN100378072 C CN 100378072C
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Abstract
A compound which inhibits the secretion and production of beta-amyloid protein. It is a compound represented by the general formula (1): (wherein R<1> represents an optionally substituted heterocyclic group; R<2> represents an optionally substituted cyclic hydrocarbon group or optionally substituted heterocyclic group; R<3> represents an optionally substituted cyclic hydrocarbon group or optionally substituted heterocyclic group; R<4> represents hydrogen or C1-6 alkyl; and X represents -S-, -SO-, or -SO2-), an N-oxide thereof, an S-oxide thereof, a salt thereof, or a solvate of any of these. Also provided is a medicine containing any of these.
Description
Technical field
The present invention relates to the inhibited new compound of generation secretion to amyloid beta, and the various diseases that causes by the generation diacrisis of amyloid beta, for example, degenerative brain disorder, mongolism, with calm other the relevant treatment of diseases medicine of amyloid.
Background technology
Degenerative brain disorder is to have the neurocyte sex change, come off and the neurodegenerative disease of the pathological characteristics that neuroneme that the formation of senile plaque is such changes.Degenerative brain disorder causes the dementia symptom of carrying out property damages such as memory, cognition, thinking, judgement, until final death.At present, also do not find this prevention and treatment of diseases effective means.
The main protein that is formed in senile plaque calm in the brain is amyloid beta (amyloid β protein, A β), and it is formed by 39～43 amino acid.It is generally acknowledged that amyloid beta shows the cell obstacle, cause degenerative brain disorder (non-patent literature 1) by this.By the amyloid beta of emiocytosis is mainly by 40 or 42 amino acids formed polypeptide, and particularly known compendency by 42 amino acids formed amyloid betas is stronger, and is calm in early days in brain, and cytotoxicity strong (non-patent literature 2).Amyloid beta produces in body ubiquitously, but also not clear and definite its original function.
Amyloid beta is generated through processing by the amyloid precursor protein (APP) as membranin.There is the case of finding the app gene sudden change among the familial Alzheimer patient.In addition, the generation secretory volume of amyloid beta increases to some extent in the cell of the known app gene that has imported this sudden change.Therefore, think that the generation excretory medicine that suppresses amyloid beta is effective to the prevention or the treatment of degenerative brain disorder.
Shear the process of amyloid beta from amyloid precursor protein, as the beta-secretase relevant, aspartate protease BACE (β side APP shears enzyme) (non-patent literature 3) and Asp1 (non-patent literature 4) have been reported with the shearing of amyloid beta N-terminal.In addition, for the gamma secretase of shearing C-terminal, point out senilism albumen to constitute its part (non-patent literature 5) strongly.Inhibitor to these beta-secretases and gamma secretase is reported (non-patent literature 6) to some extent, and they nearly all are peptides.
SMITH etc. have disclosed the compound that has the sulphonamide skeleton, suppresses the amyloid beta generation in patent documentation 1.In addition, BELANGER etc. has disclosed the compound that has bicyclic alkyl sulphonamide skeleton, suppresses gamma secretase in patent documentation 2.In addition, in patent documentation 3,4,5, disclosed the diaryl sulphones that suppresses gamma-secretase.In patent documentation 6, disclosed the agglutinative sulfo-naphthalene derivatives that suppresses amyloid.
Non-patent literature 1:Science, 259 volumes, 514 pages (1993)
Non-patent literature 2:Journal of Biological Chemistry, 270 volumes, 7013 pages (1995)
Non-patent literature 3:Science, 286 volumes, 735 pages (1999)
Non-patent literature 4:Molecular and Cellular Neuroscience, 16 volumes, 609 pages (2000)
Non-patent literature 5:Journal of Medicinal Chemistry, 44 volumes, 2039 pages (2001)
Patent documentation 1: the international brochure that discloses No. 00/50391
Patent documentation 2: the international brochure that discloses No. 01/70677
Patent documentation 3: the international brochure that discloses No. 02/081433
Patent documentation 4: the international brochure that discloses No. 02/081435
Patent documentation 5: the international brochure that discloses No. 03/18543
Patent documentation 6: Japanese patent laid-open 9-95444 communique
The announcement of invention
The purpose of this invention is to provide chemical structure with aforementioned known compound different, the generation secretion of amyloid beta is had good inhibition effect, has the compound as the desirable proterties of pharmaceuticals.
The present inventor carries out various researchs back and finds; heterocycle methylthiolation compound, heterocycle methylsulfinyl compound and heterocyclic methyl sulphones with following general formula (1) expression have good amyloid beta generation secretion inhibition; they are useful as the curative of the various diseases that the generation diacrisis by amyloid beta causes, thereby have finished the present invention.
That is, the invention provides following general formula (1)
Compound, its N-oxide compound, its S-oxide compound, its salt or its solvate of expression,
In the formula, R
1And R
3Expression can have substituent aromatic hydrocarbyl and maybe can have substituent aromatic heterocycle, R independently respectively
2Expression can have substituent saturated or undersaturated monocyclic type heteroaromatic base or undersaturated polycyclic heterocycle base, R
4Expression hydrogen atom or C
1-6Alkyl, X represent-S-,-SO-or-SO
2-.
In addition, compound, its N-oxide compound, its S-oxide compound, its salt or its solvate that the invention provides with above-mentioned general formula (1) expression is the pharmaceuticals of effective constituent.
The present invention also provides the medical composition of the carrier that allows in compound, its N-oxide compound, its S-oxide compound, its salt or its solvate and the pharmacy that contains above-mentioned general formula (1) expression.
The present invention also provides compound, its N-oxide compound, its S-oxide compound, its salt or the application of its solvate in the preparation of pharmaceuticals of above-mentioned general formula (1) expression.
In addition, the present invention also provides the treatment of diseases method by the generation diacrisis initiation of amyloid beta, the feature of this method is to give compound, its N-oxide compound, its S-oxide compound, its salt or its solvate of above-mentioned general formula (1) expression of significant quantity.
The present invention can provide the generation secretion to amyloid beta to have good inhibition effect, have the compound as the desirable proterties of pharmaceuticals.
The best mode that carries out an invention
The compound of mutual-through type (1) expression describes.
R
1And R
3But the aromatic hydrocarbyl exemplified by phenyl and the naphthyl of expression are preferably phenyl.
R
1And R
3The aromatic heterocycle of expression can exemplify has 1～4 heteroatomic 5～6 yuan of aromatic heterocycle that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, specifically can exemplify pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, azoles base, thiazolyl, different azoles base, isothiazolyl, pyridyl, pyrimidyl, tetrazyl, thiadiazolyl group, pyrazinyl, pyridazinyl etc.
Wherein, be preferably thienyl, pyrazolyl, imidazolyl, triazolyl, azoles base, thiazolyl, thiadiazolyl group, pyridyl, pyrimidyl and pyridazinyl, more preferably thienyl, pyridyl, pyrimidyl and pyridazinyl, particularly preferably thienyl, pyridyl and pyrimidyl.
R
2The saturated mono ring type heterocyclic radical of expression can exemplify has 1～4 heteroatomic 3～7 yuan of heterocyclic radical that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, specifically can exemplify pyrrolidyl, tetrahydrofuran base, oxetanyl, tetrahydro-thienyl, piperidyl, piperazinyl, high piperazinyl, morpholinyl, thio-morpholinyl, ethylenimine base, imidazolidyl, pyrazolidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, dioxolanyl, oxygen thia penta cyclic group, hexahydropyrimidine base etc.
Wherein, be preferably pyrrolidyl, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, piperazinyl, high piperazinyl, morpholinyl, thio-morpholinyl, imidazolidyl, pyrazolidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, be more preferably piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, hexahydropyrimidine base.
R
2The unsaturated monocyclic type heteroaromatic base of expression can exemplify to have 1～4 and is selected from nitrogen-atoms, heteroatomic 4～7 yuan heterocyclic radical of Sauerstoffatom and sulphur atom specifically can exemplify pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, azoles base, thiazolyl, different azoles base, isothiazolyl, triazinyl, tetrazyl, thiadiazolyl group, the di azoly, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, azoles quinoline base, thiazolinyl, different azoles quinoline base, the isothiazoline base, pyranyl, the dihydropyridine base, tetrahydro pyridyl, the dihydro-pyrimidin base, the tetrahydro pyridazine base, tetrahydro-pyrimidine base etc.
Wherein, be preferably pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, azoles base, thiazolyl, different azoles base, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, tetrazyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiadiazolyl group, pyrazinyl, pyridazinyl, tetrahydro pyridyl, dihydro-pyrimidin base, tetrahydro pyridazine base, be more preferably imidazolyl, pyridyl, pyrimidyl and thiazolyl.
R
2The unsaturated polycyclic heterocycle base of expression can exemplify to have 1～4 and is selected from nitrogen-atoms, heteroatomic 8～10 yuan heterocyclic radical of Sauerstoffatom and sulphur atom specifically can exemplify benzofuryl, benzothiazolyl, indyl, quinolyl, isoquinolyl, benzopyranyl, the benzoxazol base, benzothiazolyl, benzimidazolyl-, benzo dioxane base, benzothienyl, the benzisothiazole base, benzisoxa azoles base, chromenyl, chromanyl, heterochromatic thiazolinyl, the isochroman base, indolinyl, indazolyl, indolizinyl, pseudoindoyl, isoindolinyl, quinolizinyl, quinoxalinyl, quinazolyl, the cinnolines base, the benzo pyridazinyl, naphthyridinyl, purine radicals, thiazolidine and pyridyl, imidazopyridyl, the Triazolopyridine base, pyrrolopyridinyl, carbazyl, xanthenyl, acridyl, phenazinyl, fen piperazine base, phenothiazinyl, quinuclidinyl etc.
Wherein, be preferably benzofuryl, benzothiazolyl, indyl, quinolyl, isoquinolyl, benzopyranyl, the benzoxazol base, benzothiazolyl, benzimidazolyl-, benzo dioxane base, benzothienyl, the benzisothiazole base, benzisoxa azoles base, chromenyl, chromanyl, heterochromatic thiazolinyl, the isochroman base, indolinyl, indazolyl, indolizinyl, quinolizinyl, quinoxalinyl, quinazolyl, the cinnolines base, the benzo pyridazinyl, naphthyridinyl, imidazopyridyl and Triazolopyridine base are more preferably benzimidazolyl-, chromenyl, imidazopyridyl and Triazolopyridine base.
R
1And R
3The aromatic hydrocarbyl or the aromatic heterocycle of expression can be selected from halogen atom, C
1-6Alkyl, trihalomethyl group, C
1-6Alkoxyl group, C
2-6Alkenyl, formyl radical, C
2-6Alkyloyl, carboxyl, carboxyamino C
1-6Alkyl, C
1-6Alkoxycarbonyl amino C
1-6Alkyl, oxo base, nitro, cyano group, amidino groups, C
2-6Alkenyloxy, hydroxyl, thio group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkoxy carbonyl, formamyl, C
1-6Alkyl-carbamoyl, two (C
1-6Alkyl) formamyl, thiocarbamoyl, C
1-6Alkylthio formamyl, two (C
1-6Alkyl) thiocarbamoyl, sulfydryl, C
1-6Alkylthio, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, C
6-10Aromatic hydrocarbons-C
1-61～3 identical or different group of alkyl replaces.
As replacing R
1And R
3The aromatic hydrocarbyl of expression or the group of aromatic heterocycle are preferably halogen atom, C
1-6Alkyl, trihalomethyl group, C
1-6Alkoxyl group, cyano group, amidino groups, hydroxyl, C
1-6Alkylamino, two (C
1-6Alkyl) amino, formamyl, C
1-6Alkyl-carbamoyl, two (C
1-6Alkyl) formamyl is more preferably halogen atom, C
1-6Alkyl, trihalomethyl group, C
1-6Alkoxyl group and cyano group, special good is halogen atom and cyano group.In the halogen atom, be preferably chlorine atom and fluorine atom.
Can replace R
2Saturated or the undersaturated monocyclic type heteroaromatic base of expression or the group of unsaturated polycyclic heterocycle base can exemplify base-Q
101-Q
102-Q
103-Q
104-Q
105-Q
106-Q
107, here, Q
101Expression singly-bound, C
1-6Alkylidene group, C
2-6Alkenylene or heterocyclic radical, Q
102The expression singly-bound ,-O-,-NH-,-CH=N-,-C (alkyl)=N-,-N (alkyl)-or-S-, Q
103The expression singly-bound ,-CO-,-CS-,-SO-,-SO
2-or-CONH-, Q
104Expression singly-bound, C
1-6Alkylidene group, C
2-6Alkenylene, C
3-8Cycloalkylidene, C
4-7Inferior cycloalkenyl group, aromatic hydrocarbyl or heterocyclic radical, Q
105The expression singly-bound ,-NH-or-N (alkyl)-, Q
106The expression singly-bound ,-O-,-CO-,-CS-,-SO
2-,-SO-or-S-, Q
107Expression hydrogen atom, halogen atom, hydroxyl, oxo base, C
1-6Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, azido-, cyano group, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
2-6Alkanoylamino, two (C
2-6Alkyloyl) amino, carboxyamino, C
1-6Alkoxycarbonyl amino, two (C
1-6Alkoxy carbonyl) amino, heterocyclic radical, aromatic hydrocarbyl, C
4-7Cycloalkenyl group, heterocycle-oxygen base or aromatic hydrocarbons-oxygen base.Here, C
1-6Alkylidene group or alkyl, C
2-6Alkenylene or alkenyl, C
3-7Cycloalkylidene or C
3-7Cycloalkyl, C
4-7Inferior cycloalkenyl group or C
4-7Cycloalkenyl group, heterocyclic radical, heterocycle-oxygen base, aromatic hydrocarbyl or aromatic hydrocarbons-oxygen base can be selected from halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyl, carboxyamino C
1-6Alkyl, C
1-6Alkoxycarbonyl amino C
1-6Alkyl, formyl radical, C
2-6Alkyloyl, oxo base, nitro, cyano group, azido-, amidino groups, C
2-6Alkenyloxy, hydroxyl, carboxyl, C
7-16Aralkyl, thio group, C
2-6Alkyloyl, C
2-6Sulfo-alkyloyl, thioformyl, amino, C
1-6Alkylamino, two (C
1-6Alkyl) amino, C
1-6Alkoxy carbonyl, formamyl, C
1-6Alkyl-carbamoyl, two (C
1-6Alkyl) formamyl, thiocarbamoyl, C
1-6Alkylthio formamyl, two (C
1-6Alkyl) thiocarbamoyl, C
1-6Alkoxy amino formyl radical amino, C
1-6Alkoxy amino formyl radical (C
1-6Alkyl) amino, C
2-6Alkanoylamino, C
2-6Alkyloyl (C
1-6Alkyl) amino, sulfo-C
2-6Alkanoylamino, sulfo-C
2-6Alkyloyl (C
1-6Alkyl) amino, amino, the formyl radical (C of formyl radical
1-6Alkyl) amino, amino, the thioformyl (C of thioformyl
1-6Alkyl) amino, C
2-6Alkanoyloxy, methanoyl, C
1-6Alkoxy-carbonyl oxy, carbamoyloxy, C
1-6Alkyl carbamoyloxy base, two (C
1-6Alkyl) carbamoyloxy, amino carbonyl amino, C
1-6Alkyl amino-carbonyl amino, two (C
1-6Alkyl) amino carbonyl amino, aminocarboxyl (C
1-6Alkyl) amino, C
1-6Alkyl amino-carbonyl (C
1-6Alkyl) amino, two (C
1-6Alkyl) aminocarboxyl (C
1-6Alkyl) amino, sulfydryl, C
1-6Alkylthio, C
1-6Alkyl sulphinyl, C
1-6Alkyl sulphonyl, amino-sulfonyl, C
1-6Alkyl amino sulfonyl, two (C
1-6Alkyl) amino-sulfonyl, amino-sulfonyl amino, C
1-6Alkyl amino sulfonyl amino, two (C
1-6Alkyl) amino-sulfonyl amino, amino-sulfonyl (C
1-6Alkyl) amino, C
1-6Alkyl amino sulfonyl (C
1-6Alkyl) amino, two (C
1-6Alkyl) amino-sulfonyl (C
1-6Alkyl) 1～3 amino group replaces.
More specifically, can replace R
2The group of the heterocyclic radical of expression is as described below.
As R
2, general formula more preferably
The group of expression, in the formula, R
10Expression hydrogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkyl sulphinyl C
1-6Alkyl, C
1-6Alkyl sulphonyl C
1-6Alkyl, carboxyl C
1-6Alkyl, heterocycle-C
1-6Alkyl or general formula-SO
2R
11(in the formula, R
11Expression C
1-6Alkyl, heterocyclic radical, C
1-6Alkyl-heterocyclic radical, heterocycle-C
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkylamino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, carboxyl C
1-6Alkyl, formamyl C
1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C
1-6Alkylamino or two (C
1-6Alkyl) R amino),
12Expression hydrogen atom, C
1-6Alkyl, hydroxyl or amino, here, R
11And R
12Can and R
11Bonded sulphur atom and R
12The bonded nitrogen-atoms forms the aliphatics heterocycle of 5 yuan or 6 yuan, R together
13Expression C
1-6Alkyl, halogen atom or cyano group.
As R
2, also can be following general formula preferably
The group of expression, in the formula, R
13Expression C
1-6Alkyl, halogen atom or cyano group, n are represented 0～6 integer.
As R
4, hydrogen atom particularly preferably.In addition, as X, from pharmacological effect, be preferably-SO
2-,-SO-, from pharmacological effect, particularly preferably-SO
2-.
Can replace above-mentioned R
1And R
2The aromatic hydrocarbyl of expression or the group of aromatic heterocycle, and can replace R
2Saturated or the undersaturated monocyclic type heteroaromatic base of expression or the group of unsaturated polycyclic heterocycle base are specific as follows described.
" heterocycle " represents to have as the component part of ring structure the ring of 1～4 heteroatoms (N, O, S etc.), can be saturated, unsaturated or aromatic ring, and can be the ring of monocycle or polycycle.In addition, polycyclic heterocycle comprises hetero ring type spiro-compounds and the heterogeneous ring compound with bridged ring structure.Be heterocycle-C
1-6The heterocyclic radical that alkyl isochronous " heterocycle " expression is derived from above-mentioned heterocycle.In addition, " heterocyclic radical " expression is from 1 valency group of " heterocycle " derivation.
Saturated monocyclic type heteroaromatic base can exemplify to have 1～4 and is selected from nitrogen-atoms, the group of heteroatomic 3～7 yuan of saturated rings structures of Sauerstoffatom and sulphur atom specifically can exemplify pyrrolidyl, tetrahydrofuran base, oxetanyl, tetrahydro-thienyl, piperidyl, piperazinyl, high piperazinyl, morpholinyl, thio-morpholinyl, the oxirane base, the thiacyclopentane base, two alkyl, the ethylenimine base, imidazolidyl, pyrazolidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, the oxazolidinyl, thiazolidyl, different oxazolidinyl, dioxolanyl, oxygen thia penta cyclic group, hexahydropyrimidine base etc.
Unsaturated or aromatic monocyclic type heteroaromatic base can exemplify to have 1～4 and is selected from nitrogen-atoms, heteroatomic 4～7 yuan heterocyclic radical of Sauerstoffatom and sulphur atom specifically can exemplify pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, triazolyl, azoles base, thiazolyl, different azoles base, isothiazolyl, triazinyl, tetrazyl, thiadiazolyl group, the di azoly, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidyl, imidazolidyl, pyrazolidyl, the oxazolidinyl, thiazolidyl, different oxazolidinyl, the isothiazole alkyl, pyranyl, the dihydropyridine base, tetrahydro pyridyl, the dihydrogen dazin base, the dihydro-pyrimidin base, the tetrahydro pyridazine base, tetrahydro-pyrimidine base etc.
The polycyclic heterocycle base can exemplify to have 1～4 and is selected from nitrogen-atoms, heteroatomic 8～14 yuan heterocyclic radical of Sauerstoffatom and sulphur atom specifically can exemplify benzofuryl, benzothiazolyl, indyl, quinolyl, isoquinolyl, benzopyranyl, the benzoxazol base, benzothiazolyl, benzimidazolyl-, benzo two alkyl, benzothienyl, the benzisothiazole base, benzisoxa azoles base, chromenyl, chromanyl, heterochromatic thiazolinyl, the isochroman base, indolinyl, indazolyl, indolizinyl, pseudoindoyl, isoindolinyl, quinolizinyl, quinoxalinyl, quinazolyl, the cinnolines base, the benzo pyridazinyl, naphthyridinyl, purine radicals, thiazolidine and pyridyl, imidazopyridyl, pyrrolopyridinyl, carbazyl, xanthenyl, acridyl, phenazinyl, fen piperazine base, phenothiazinyl, quinuclidinyl etc.
Halogen atom is represented chlorine atom, fluorine atom, bromine atoms and iodine atom, is preferably chlorine atom and fluorine atom.
C
1-6Alkyl is represented C
1-6The alkyl of straight or branched, but object lesson exemplified by methyl of this alkyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-methyl amyl, n-hexyl etc.
C
1-6Alkylidene group is represented C
1-6The alkylidene group of straight or branched, the object lesson of this alkylidene group can exemplify methylene radical, ethylidene, propylene, trimethylene, butylidene, pentylidene, hexylidene etc.
C
2-6Alkenyl is represented the C of straight or branched
2-6Alkenyl, but object lesson exemplified by vinyl of this alkenyl, allyl group, propenyl, butenyl, pentenyl etc.
C
2-6Alkenylene is represented the C of straight or branched
2-6Alkenylene, the object lesson of this alkenylene can exemplify vinylidene, propenylidene, crotonylidene, inferior pentenyl etc.
C
3-7Cycloalkyl can exemplify cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl.
C
4-7Cycloalkenyl group can exemplify cyclopentenyl, cyclohexenyl etc.
The combination example of cycloalkyl and alkyl can exemplify cycloalkyl-alkyl, particularly preferably C
3-7Cycloalkyl-C
1-6Alkyl.
C
1-7Alkoxyl group represents to have the alkoxyl group of abovementioned alkyl or cycloalkyl, can exemplify methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, pentyloxy, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base etc.
C
2-6Alkyloyl is represented a straight chain shape or a catenate C
2-6Alkyloyl can exemplify ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl etc.
R
1Particularly preferably 2,5-difluorophenyl or 2-fluoro-5-cyano-phenyl.R
3Particularly preferably 4-chloro-phenyl-, 4-fluorophenyl, 2,4 difluorobenzene base, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl-, 4-trifluoromethyl, 5-chloro-2-thienyl, 5-chloro-2-pyridyl, 6-chloro-3-pyridyl, 6-trifluoromethyl-3-pyridyl.
Can have steric isomer in the compound of general formula of the present invention (1) expression or derive from the optical isomer of chiral carbon atom, any in these steric isomers, optical isomer and their mixture all comprises in the present invention.In addition, the S-oxide compound of mixture of the present invention is present in the situation of the heterocyclic radical of sulfur atom-containing, and this S-oxide compound comprises any in monoxide and the dioxide.
Salt as the compound of general formula of the present invention (1) expression, so long as the salt that field of medicaments allows gets final product, it is not particularly limited, specifically can exemplify mineral acid salts such as hydrochloride, hydrobromate, hydriodate, phosphoric acid salt, nitrate and vitriol, organic sulfonic acid salts such as mesylate, 2-isethionate and tosilate, and organic carboxyl acid salts such as benzoate, acetate, propionic salt, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and amygdalate etc.
In addition, when the compound of general formula (1) expression has acidic-group, also can form the salt of alkalimetal ion or alkaline-earth metal ions.As solvate, so long as the solvate that field of medicaments allows gets final product, it is not particularly limited, specifically can exemplify hydrate, ethanol compound etc.
Below, the preparation method of the compound of general formula of the present invention (1) expression is described.
Combination by known general chemical preparation process can prepare compound, its salt and the solvate thereof of general formula of the present invention (1) expression, below describes possessing representational synthetic method.
Shown below is the representative preparation method of sulfide (1a), sulfenylation compound (1b) and the sulfonyl compound (1c) of general formula of the present invention (1) expression.
1) preparation method of sulfide (1a)
Utilize following method can prepare sulfide of the present invention (1a).
(in the formula, Y represents leavings group, R
1～R
4As previously mentioned.)
After forming compound (3) by alcohol derivate (2), in the presence of alkali, make gained compound (3) and mercaptan compound (R
3-SH) reaction can prepare sulfide of the present invention (1a).In this case, mercaptan compound can be used as an alkali metal salt or alkaline earth salt (for example, lithium salts, sodium salt, sylvite) use.
Compound (3) and mercaptan compound (R
3-SH) temperature of reaction is generally-20～200 ℃, is preferably room temperature～100 ℃.According to compound (3) or mercaptan compound (R
3-SH) kind difference is preferably sometimes in the temperature of reaction that is higher than this scope and reacts, and is preferably in tube sealing sometimes and reacts.Reaction times is generally 0.5 hour～and 1 day.
As alkali, the hydride that can exemplify basic metal or alkaline-earth metal (for example, lithium hydride, sodium hydride, potassium hydride KH, hydrolith), the amine of basic metal or alkaline-earth metal (for example, the amido lithium, amido sodium, lithium diisopropyl amido, dicyclohexyl amido lithium, hexamethyl dimethyl silanyl amido lithium, hexamethyl dimethyl silanyl amido sodium, hexamethyl dimethyl silanyl amido potassium), the rudimentary alkoxide of basic metal or alkaline-earth metal (for example, sodium methylate, sodium ethylate, potassium tert.-butoxide), basic metal, the oxyhydroxide of alkaline-earth metal or silver (for example, silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta), basic metal, the carbonate of alkaline-earth metal or silver (for example, yellow soda ash, salt of wormwood, cesium carbonate, silver carbonate), alkali-metal supercarbonate (for example, sodium bicarbonate, saleratus), lithium alkylide (for example, n-Butyl Lithium) or the alkyl Grignard reagent (for example, methyl-magnesium-bromide), mineral alkalis such as silver suboxide or amine are (for example, triethylamine, diisopropylethylamine, N-methylmorpholine), the alkalescence heterogeneous ring compound (for example, the dimethyl amine yl pyridines, pyridine, imidazoles, 2, the 6-lutidine, trimethylpyridine, 1,8-diazabicylo [5,4,0] 11-7-alkene, 1,5-diazabicylo [4,3,0] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicylo [2,2,2] octane) organic bases etc. such as.
As solvent, can exemplify pure series solvent, ether series solvent, halogen series solvent, aromatic series series solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent, water, also can mix use above more than 2 kinds.Wherein, be preferably methylene dichloride, tetrahydrofuran (THF), dimethyl formamide etc.
Used alcohol derivate (2) can adopt known method preparation in the above-mentioned preparation process, as the preparation method is known various examples is arranged, wherein one for example down shown in.In tetrahydrofuran (THF) or ether equal solvent, make R
1-C (=O)-R
4(that representative is R for the aldehydes or ketones of expression and equivalent or excessive organometallic reagent
2Organolithium reagent that-Li represents or R
2-MgCl or R
2The Grignard reagent of expression such as-MgBr) reaction can obtain alcohol derivate (2).For example, at R
2During for aromatic hydrocarbyl or aromatic heterocycle, paper J.Org.Chem.16 volume as H.Gilman etc., the paper Tetrahedron of 1788-1791 page or leaf (nineteen fifty-one) or F.Trecourt etc., 56 volumes, the records such as (2000) of 1349-1460 page or leaf, carry out metal exchange by adding alkyl lithium reagents or alkyl Grignard reagent in aryl halide or heteroaryl halogen, can easily make above-mentioned organometallic reagent.
Compound (3) with leavings group Y can be converted to leavings group by known method with hydroxyl by alcohol derivate (2) and make.The leavings group that Y represents can exemplify halogen atom (chlorine atom, bromine atoms, iodine atom etc.), can be by halogenated C
1-6Alkylsulfonyloxy (mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy etc.) can have substituent C
6-10Aromatic hydrocarbons sulfonyloxy etc.As the substituting group of aromatic hydrocarbons sulfonyloxy, can exemplify 1～3 halogen atom, can be by halogenated C
1-6Alkyl, C
1-6Alkoxyl group etc.As the better example of leavings group, can exemplify phenylsulfonyloxy, tolysulfonyl oxygen base, 1-naphthalene sulfonyl oxygen base, 2-naphthalene sulfonyl oxygen base etc.
In addition, as another synthesis method of sulfide (1a), can exemplify alcohol derivate (2) and mercaptan compound (R
3-SH) light prolongs reaction.Specifically, in the solvent at 1～3 normal triaryl phosphine (for example, triphenyl phosphine etc.) or trialkyl phosphine (for example, tributylphosphine) and 1～2 normal azodicarboxy acid compound (for example, diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, azo-2-carboxylic acid's two piperidines acid amides, azo-2-carboxylic acid two (dimethylformamide)) coexistence under, make alcohol derivate (2) and 1～3 normal mercaptan compound (R
3-SH) reaction can make compound (1a).
Temperature of reaction is generally-20～150 ℃, is preferably 0 ℃～80 ℃.Reaction times is generally 0.5 hour～and 5 days.As solvent, can exemplify ether series solvent, halogen series solvent, aromatic series series solvent, also can be above mix more than 2 kinds used.Wherein, be preferably tetrahydrofuran (THF).
2) preparation method of sulfenylation compound (1b)
Sulfenylation compound (1b) among the present invention can be as described below, prepares through the oxygenant oxidation solvent from sulfide (1a).
(in the formula, R
1～R
4As previously mentioned.)
Temperature of reaction is generally-20 ℃～200 ℃, is preferably 0 ℃～100 ℃, and the reaction times is generally 0.1 hour～and 7 days, be preferably 0.5 hour～2 days.As solvent, can exemplify pure series solvent, ether series solvent, halogen series solvent, aromatic series series solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent and water, also above mixing more than 2 kinds can be used.Wherein, be preferably methylene dichloride, chloroform, methyl alcohol and ethanol etc.
As oxygenant, can exemplify hydrogen peroxide, organo-peroxide (for example, peracetic acid, metachloroperbenzoic acid), metaperiodic acid salt (for example, sodium metaperiodate), nitryl, nitrogen tetroxide, halogen, N-halogenide are (for example, N-chloro-succinimide, N-bromine succinimide), hydroperoxide (for example, tertbutyl peroxide), the iodobenzene diacetate ester, dichloride iodobenzene, t-butyl hypochlorate, SULPHURYL CHLORIDE, singlet oxygen, ozone, selenium oxide, selenous acid etc.
If exemplify the example of concrete reaction conditions; then in methylene dichloride, tetrahydrofuran (THF)-water, methyl alcohol equal solvent; 0～100 ℃ of time that cost is about 1 hour～2 days; with 1～2 normal metachloroperbenzoic acid, sodium periodate or hydrogen peroxide sulfide (1a) is handled, can be made sulfenylation compound (1b).
In addition, when preparation has optically active sulfoxide (1b),, can use titanium tetraisopropylate/optically pure diethyl tartrate/tertbutyl peroxide, titanium tetraisopropylate/optically pure diethyl tartrate/peracetic acid etc. as oxygenant.
3-1) the preparation method of sulfonyl compound (1c)
As described below, by in solvent, using oxygenant oxidation sulfide (1a) or sulfenylation compound (1b), can make the sulfonyl compound (1c) among the present invention.
(in the formula, R
1～R
4As previously mentioned.)
Temperature of reaction is generally-20 ℃～150 ℃, is preferably 0 ℃～100 ℃, and the reaction times is generally 0.1 hour～and 7 days, be preferably 1 hour～5 days.
As solvent, can exemplify pure series solvent, ether series solvent, halogen series solvent, aromatic series series solvent, carboxylic acid series solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent and water, also can be above mix more than 2 kinds used.Wherein, be preferably methylene dichloride, chloroform, methyl alcohol, ethanol, acetate, water etc.
As oxygenant, can exemplify hydrogen peroxide, hydrogen peroxide-transition-metal catalyst (for example, ammonium molybdate, iron trichloride etc.), organo-peroxide (for example, peracetic acid, metachloroperbenzoic acids etc.), metaperiodic acid salt (for example, sodium metaperiodate etc.), Potassium Persulphate, permanganate (for example, potassium permanganate etc.), Sodium peroxoborate, halogen, N-halogenide (for example, N-chloro-succinimide, N-bromine succinimides etc.), hydroperoxide (for example, tertbutyl peroxide etc.), the iodobenzene diacetate ester, the dichloride iodobenzene, hypochlorous acid class (for example, clorox, t-butyl hypochlorate etc.), singlet oxygen, ozone, selenium oxide, selenous acid etc.Reaction conditions is preferably, in methylene dichloride, tetrahydrofuran (THF)-water or methyl alcohol, sulfide (1a) and 2～5 normal oxygenants (for example metachloroperbenzoic acid, sodium periodate, hydrogen peroxide, hydrogen peroxide-ammonium molybdate etc.) were reacted about 1 hour～5 days in 0 ℃～100 ℃.
3-2) the preparation method of sulfonyl compound (1c)
Sulfonyl compound (1c) also can be according to following method preparation.
(in the formula, Y
1Expression leavings group or hydroxyl, R
1～R
4As previously mentioned.)
In the presence of alkali, make according to known method or the sulfonyl compound (1d) and the electrophilic reagent (R that can make by method with this this benchmark of method
2-Y
1) reaction, can make the various R of having
2The sulfonyl compound (1c) of base.
Specifically, in the presence of the alkali of equivalent～excessive, make equivalent～excessive R
2-Y
1React with compound (1d).Temperature of reaction is generally-78 ℃～200 ℃, and the reaction times is generally 0.5 hour～and 1 day.
As solvent, can be used alone or as a mixture ether series solvent, halogen series solvent, aromatic series series solvent, nitrile series solvent, acid amides series solvent etc.Wherein, be preferably tetrahydrofuran (THF), glycol dimethyl ether, ether, dimethyl formamide, toluene etc.
As Y
1The leavings group of expression can exemplify halogen atom (chlorine atom, bromine atoms, iodine atom etc.), can be by halogenated C
1-6Alkylsulfonyloxy (mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy etc.) can have substituent C
6-10Aromatic hydrocarbons sulfonyloxy etc.As the substituting group of aromatic hydrocarbons sulfonyloxy, can exemplify 1～3 halogen atom, can be by halogenated C
1-6Alkyl, C
1-6Alkoxyl group etc.As having substituent C
6-10The object lesson of aromatic hydrocarbons sulfonyloxy can exemplify phenylsulfonyloxy, tolysulfonyl oxygen base, 1-naphthalene sulfonyl oxygen base, 2-naphthalene sulfonyl oxygen base etc.
As alkali, but the exemplified by alkyl groups lithium (for example, n-Butyl Lithium, s-butyl lithium, tert-butyl lithium), the hydride of basic metal or alkaline-earth metal (for example, lithium hydride, sodium hydride, potassium hydride KH, hydrolith), the amine of basic metal or alkaline-earth metal (for example, the amido lithium, amido sodium, lithium diisopropyl amido, dicyclohexyl amido lithium, hexamethyl dimethyl silanyl amido lithium, hexamethyl dimethyl silanyl amido sodium, hexamethyl dimethyl silanyl amido potassium), the rudimentary alkoxide of basic metal or alkaline-earth metal (for example, sodium methylate, sodium ethylate, potassium tert.-butoxide), basic metal, the oxyhydroxide of alkaline-earth metal or silver (for example, silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrated barta), basic metal, the carbonate of alkaline-earth metal or silver (for example, yellow soda ash, salt of wormwood, cesium carbonate, silver carbonate), alkali-metal supercarbonate (sodium bicarbonate for example, saleratus), silver suboxide etc.
3-3) the preparation method of sulfonyl compound (1c)
As described below, by making compound (3) and R
3-SO
2 -M
+(5) basic metal of Biao Shi-sulfinic acid, alkaline-earth metal or TBuA reactant salt also can make the sulfonyl compound (1c) among the present invention.
(in the formula, Y represents leavings group, M
+The expression metal ion, R
1～R
4As previously mentioned.)
Specifically, in the-sulfinic acid of equivalent～excessive or its salt (5) and solvent, make compound (3) reaction.Temperature of reaction is generally-20 ℃～200 ℃, is preferably room temperature～100 ℃.Difference because of the kind of compound (3) or-sulfinate (5) is preferably in sometimes under the temperature of reaction that is higher than this scope and reacts.In addition, be preferably in the tube sealing sometimes and react.Reaction times is generally 0.5 hour～and 3 days, be preferably 0.5 hour～1 day.
As solvent, can exemplify pure series solvent, ether series solvent, halogen series solvent, aromatic series series solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent, water etc., they can mix use.Wherein, be preferably butanols, glycol dimethyl ether, N-Methyl pyrrolidone, dimethyl formamide etc.
More than among the preparation method of illustrative compound of the present invention (1); sometimes must protect substituting groups such as nitrogen-atoms, hydroxyl, carboxyls; in this case; can adopt the known general protecting group that is suitable for being removed, these protecting groups can be removed by vitochemical common method where necessary.
Utilize the R of sulfide (1a), sulfenylation compound (1b) and sulfonyl compound (1c) that aforesaid method makes
1～R
4In 1 or a plurality of substituting group can further change structure.For example, R
1～R
4In any have by 1, under the substituent situation that 3-dioxolane-2-base replaces, by known method it being hydrolyzed to be converted to the compound that is replaced by formyl radical.In addition, R
1～R
4In any have under the substituent situation that is replaced by bromine, also can be converted into the compound that is replaced by formyl radical by known method.Formyl radical can be exchanged into carboxylic acid, replaces or does not have amino methyl, hydroxymethyl or 2-(alkoxy carbonyl) vinyl of replacement etc. by known method.In addition, the hydroxylic moiety of this hydroxymethyl can be converted to the group of ester, carbonic ether, carbamate, halogen, nitrile or sulphonate etc. by known method.In addition, these groups can be exchanged into the group of alkoxyl group, amine, acid amides, carboxylic acid or sulfide etc.2-(alkoxy carbonyl) vinyl can be converted to groups such as 2-carboxy ethyl by known method.Such conversion is all possible for the various functional groups beyond the hydroxyl, and its conversion method can be undertaken by technique known.Specifically, for example, R
2During for 2-chloro-4-pyridyl, make various amine reactions such as itself and alkylamine, dialkylamine, benzene methanamine, tetramethyleneimine, piperidines, morpholine, can make the pyridine derivate that 2 chlorine is replaced by these amine.In this case, if adopt 3,4-dimethoxy benzene methanamine then can obtain 3, and 4-dimethoxy benzene methylamino pyridine derivate is handled it with trifluoroacetic acid or nitric acid two ammonium ceriums, then can make the 2-aminopyrazole derivatives.In addition,, the 2-aminopyrazole derivatives is handled, then be can be exchanged into 2-methanesulfonamido pyridine derivate with methylsulfonyl chloride if in the presence of pyridine.Reagent, solvent and reaction conditions used in these switch process can adopt content known to a person of ordinary skill in the art.
The compound of the present invention (1) that utilizes aforesaid method to make can form salt or solvate by common method.
Compound of the present invention (1) is owing to the generation secretion to amyloid beta has stronger restraining effect, so various diseases that causes as generation diacrisis by amyloid beta, for example, degenerative brain disorder, mongolism, useful with the prophylactic treatment medicine of calm relevant other disease of amyloid.
When compound of the present invention used with pharmaceuticals as human body, the dosage adult was 1mg～1g in 1 day, was preferably 10mg～300mg.As the dosage of animal with pharmaceuticals, because of administration purpose (treatment or prevention), need the different and different of the kind of the kind of the animal disposed and the pathogenic bacteria of size, infection and degree, 1 day amount is 0.1mg～200mg corresponding to the 1kg the weight of animals generally, is preferably 0.5mg～100mg.This amount of 1 day can 1 day 1 time, also can divide 2～4 administrations.1 day amount also can surpass above-mentioned amount as required.
The medical composition that contains The compounds of this invention can be selected appropriate formulations according to medication, can be according to the modulator approach modulation of various preparations commonly used.As being the formulation of the medical composition of host with the The compounds of this invention, but the oral preparations such as suspension liquid of illustration tablet, powder, granule, capsule, solution, syrup, elixir, oiliness～water-based.
As injection, can in preparation, use stablizer, sanitas and solubility promoter, behind the container of also solution that contains these auxiliary agents can being packed into,, in use it is modulated into required preparation and re-uses by formation solid preparations such as lyophilizes.In addition, in the container of also 1 time dosage can being packed into, or the multiple dosing amount packed in the container.
In addition, as external preparation, but exemplary solutions agent, suspension agent, emulsion, ointment, gel, creme, lotion, sprays and adhesive preparation etc.
As solid preparation, can contain the additive that The compounds of this invention and pharmaceutical field allow, for example, can select preparationization then such as mixed filler class and extender class, tackiness agent class, disintegrating agent class, chaotropic agent class, wetting agent class, lubricant class as required.
As liquid preparation, can exemplify solution, suspension agent and emulsion etc., can contain outstanding floating agent and emulsifying agent etc. as additive.
Embodiment
Below, exemplify embodiment the present invention is specifically described, but scope of the present invention is not limited to following embodiment.Among the following embodiment, during the record of no E body, Z body, the gained compound is the either party in E body or the Z body.
Reference example 1:2-[(4-chloro-phenyl-) sulfonymethyl]-1,4-two fluorobenzene
Method 1:1) in 0 ℃, 2,5-two fluorophenyl methanol (5.00g, 34.7mmol) tetrahydrofuran (THF) (150ml) solution in add 4-chlorobenzene mercaptan (5.45g successively, 38.2mmo1), triphenyl phosphine (11.1g, 41.6mmol) and the diisopropyl azo-2-carboxylic acid (8.16ml, 41.6mmol).Stirring concentrated after 4 days to reaction soln under the room temperature.Residue obtained refining with silica gel column chromatography (1% ethyl acetate-hexane), acquisition is the 2-[(4-chloro-phenyl-of colorless oil) thiomethyl]-1,4-two fluorobenzene (2.68g, 29%).
1H-NMR(400MHz，CDCl
3)δ：4.04(2H，s)，6.85-7.00(3H，m)，7.23(4H，s).
2) in 0 ℃, at the 2-[(4-chloro-phenyl-) thiomethyl]-1,4-two fluorobenzene (271mg, add in methylene dichloride 1.00mmol) (5ml) solution 3-chlorine peroxybenzoic acid (225mg, 1.30mmol) after, stirred 15 hours under the room temperature.Behind methylene dichloride diluting reaction solution, use the saturated potassium hydrogen carbonate aqueous solution and saturated common salt water washing successively.Dry (MgSO
4) back concentrating.With the residue obtained methylene dichloride (5ml) that is dissolved in, after 0 ℃ of cooling, add 3-chlorine peroxybenzoic acid (450mg, 2.60mmol), then in stirring at room 15 hours.Behind methylene dichloride diluting reaction solution, with the saturated potassium hydrogen carbonate aqueous solution and saturated common salt water washing.Dry (MgSO
4) back concentrates, and is residue obtained refining with silica gel column chromatography (9% ethyl acetate-hexane), obtains to be the title compound (210mg, 69%) of colorless solid material.
1H-NMR(400MHz，CDCl
3)δ：4.36(2H，s)，6.91(1H，td，J＝9.0，4.4Hz)，6.99-7.06(1H，m)，7.11(1H，ddd，J＝8.3，5.6，3.2Hz)，7.45(2H，d，J＝8.8Hz)，7.62(2H，d，J＝8.8Hz).
MS(m/z)：303(M
++H).
Method 2:1) 4-chlorobenzene mercaptan (3.86g, N 26.6mmol), add in dinethylformamide (120ml) solution salt of wormwood (4.00g, 29.0mmol) and 2-brooethyl-1,4-two fluorobenzene (5.00g, 24.2mmol) after, in stirring at room 3 hours.Use extracted with diethyl ether after in reaction soln, adding saturated ammonium chloride (50ml) and water (20ml).Combining extraction liquid, after water and the saturated common salt water washing, dry (MgSO
4), concentrate, residue obtained refining with silica gel column chromatography (1% ethyl acetate-hexane), acquisition is the 2-[(4-chloro-phenyl-of colorless oil) thiomethyl]-1,4-two fluorobenzene (6.41g, 98%).
2) in 0 ℃, at the 2-[(4-chloro-phenyl-) thiomethyl]-1, (6.54g adds H in methyl alcohol 24.1mmol) (100ml) solution to 4-two fluorobenzene
2O (16.4ml), 30%H
2O
2(16.4ml, 145mmol) and seven molybdic acids, six ammonium tetrahydrates (425mg 0.344mmol), stirs after 1 hour under the room temperature and stirred 15 hours.The solid that leaching is separated out is concentrated into approximately half with filtrate.Obtained aqueous solution with dichloromethane extraction after, the solid of previous gained is dissolved in the extraction liquid, water and saturated aqueous common salt wash successively then.Dry (MgSO
4) back concentrating, the residue obtained hexane recrystallization of using, acquisition is the title compound (6.34g, 87%) of colourless needle crystal.
Method 3: 4-chlorobenzene-sulfinic acid sodium (19.0g adds 2-brooethyl-1 in butanols 95.5mmol) (200ml) suspension liquid, 4-two fluorobenzene (12.3ml, 95.5mmol) after, reflux 5 hours.The solid that leaching is separated out is used the saturated common salt water washing, dry (MgSO after it is dissolved in methylene dichloride
4).After concentrating, the gained solid is carried out recrystallization, obtain to be the title compound (12.3g, 43%) of colourless needle crystal with hexane.
Reference example 2:4-(4-chloro-phenyl-sulfonymethyl) pyridine
Under 70 ℃ of heating, to the 4-chloromethyl pyridine hydrochloride (1.26g, 7.65mmol), 4-chlorobenzene-sulfinic acid sodium (1.52g, 7.65mmol) and potassium acetate (1.50g, 1-propyl alcohol (50ml) solution stirring 15.3mmol) 8 hours.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.The gained concentrated residue is passed through short column (silica gel, ethyl acetate), concentrating under reduced pressure elutriant.With silica gel column chromatography the gained concentrated residue is handled, to hexane: ethyl acetate (=2: be that the cut that elutriant obtains carries out concentrating under reduced pressure 3), obtain to be white in color solid title compound (1.26g, 62%).
1H-NMR(400MHz，CDCl
3)δ：4.29(2H，s)，7.06(2H，d，J＝6.1Hz)，7.47(2H，d，J＝8.8Hz)，7.59(2H，d，J＝8.5Hz)，8.57(2H，d，J＝6.1Hz).
MS(m/z)：268(M
++H).
Reference example 3:2-[(2, the 5-difluorophenyl)-hydroxymethyl] pyridine
Under argon atmospher, (572 μ l, (1.53M, 3.92ml 0.6mmol), stirred 30 minutes to splash into the hexane solution of n-Butyl Lithium in tetrahydrofuran (THF) 6mmol) (10ml) solution at the 2-bromopyridine in-78 ℃.Splash into 2 in this brown solution, (655 μ l 6mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.Use ethyl acetate extraction after in reaction solution, adding water.Decompression concentrates down behind the dry solvent, and is residue obtained refining with silica gel chromatography, obtains to be white in color solid title compound (120mg, 9%).
1H-NMR(400MHz，CDCl
3)δ：5.45(1H，br)，6.08(1H，s)，6.87-7.15(3H，m)，7.2-7.3(2H，m)，7.65(1H，m)，8.56(1H，m).
mp：65-66℃.
Reference example 4:2-[chloro-(2, the 5-difluorophenyl) methyl]-3-picoline hydrochloride
In argon atmospher, down (510mg, (1.5ml 3mmol), stirred 60 minutes under the room temperature to splash into the tetrahydrofuran solution of isopropyl-magnesium chloride in tetrahydrofuran (THF) 3mmol) (2.0ml) solution at 2-bromo-3-picoline in ice-cold.Under ice-cooled, splash into 2 in this brown solution, (328 μ l 3mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.After in reaction solution, adding saturated aqueous ammonium chloride, use ethyl acetate extraction.Decompression concentrates down behind the dry solvent, and is residue obtained with silica gel chromatography (hexane: ethyl acetate=8: 1) make with extra care, obtain to contain the mixture of title compound.Add thionyl chloride (2.0ml) and 1 dimethyl formamide therein, stirred 14 hours under the room temperature.Decompression obtains white precipitate after boiling off excessive thionyl chloride down.It is developed (trituration) with hexane and ether, obtain title compound (101mg, 12%).
1H-NMR(400MHz，CDCl
3)δ：2.37(3H，s)，6.95-7.10(2H，m)，7.28(1H，s)，7.7-7.8(2H，m)，8.11(1H，d，J＝6.3Hz)，8.72(1H，d，J＝4.9Hz).
mp：118-119℃.
MSm/z：254(M
++H).
Reference example 5:2-[(2, the 5-difluorophenyl)-hydroxymethyl]-the 5-picoline
In argon atmospher, down (510mg, (1.5ml 3mmol), stirred 60 minutes under the room temperature to splash into the tetrahydrofuran solution of isopropyl-magnesium chloride in tetrahydrofuran (THF) 3mmol) (2ml) solution at 2-bromo-5-picoline in ice-cooled.Under ice-cold, splash into 2 in this brown solution, (328 μ l 3mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.Use ethyl acetate extraction after in reaction solution, adding saturated aqueous ammonium chloride.Decompression concentrates down behind the dry solvent, and is residue obtained with silica gel chromatography (hexane: ethyl acetate=5: 1) make with extra care, obtain to be the title compound (130mg, 18%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：2.31(3H，s)，5.38(1H，br)，6.04(1H，s)，6.83-7.18(4H，m)，7.44(1H，dd，J＝2.0，8.0Hz)，8.37(1H，m).
MSm/z：236(M
++H).
Reference example 6:2-[(2, the 5-difluorophenyl)-hydroxymethyl]-the 4-picoline
In argon atmospher, down (334 μ l, (1.5ml 3mmol), stirred 60 minutes under the room temperature to splash into the tetrahydrofuran solution of isopropyl-magnesium chloride in tetrahydrofuran (THF) 3mmol) (2ml) solution at 2-bromo-4-picoline in ice-cooled.Under ice-cold, splash into 2 in this brown solution, (328 μ l 3mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.Use ethyl acetate extraction after in reaction solution, adding saturated aqueous ammonium chloride.Decompression concentrates down behind the dry solvent, and is residue obtained with silica gel chromatography (hexane: ethyl acetate=5: 1) make with extra care, obtain to be the title compound (456mg, 65%) of needle crystal.
1H-NMR(400MHz，CDCl
3)δ：2.30(3H，s)，5.48(1H，br-s)，6.02(1H，s)，6.83-7.13(5H，m)，8.38(1H，m).
mp：105-106℃.
MSm/z：236(M
++H).
Reference example 7:2-bromo-3-Methoxy Pyridine
In the nitrogen atmosphere, (605mg 15.1mmol), adds 2-bromo-3-pyridone (2.5g, dimethyl formamide 14.4mmol) (20ml) solution after 20 minutes slowly to add 60% oily sodium hydride in ice-cooled time in methyl alcohol (10ml).Decompression boils off methyl alcohol down from mixed solution, (0.94ml 15.1mmol), stirred 3 hours under the room temperature to add methyl-iodide.Reaction solution adds entry (50ml) and ether (50ml) after being concentrated into and doing.Divide and get organic layer, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The extraction liquid anhydrous magnesium sulfate drying, decompression is concentrated solution down, and (hexane: ethyl acetate=8: 1) refining, acquisition is the title compound (1.51g, 56%) of colourless needle crystal with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.90(3H，s)，7.12(1H，m)，7.21(1H，dd，J＝4.8，8.0Hz)，7.97(1H，m).
mp：34℃.
Reference example 8:3-allyloxy-2-bromopyridine
Synthesize equally with 2-bromo-3-Methoxy Pyridine, obtain to be the title compound (2.35g, 76%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：4.62(2H，m)，5.33(1H，dd，J＝1.2，10.4Hz)，5.47(1H，dd，J＝1.2，17.6Hz)，6.06(1H，m)，7.11(1H，dd，J＝1.2Hz，8.0Hz)，7.18(1H，dd，J＝4.8，8.0Hz)，7.98(1H，m).
MSm/z：215(M
++H).
Reference example 9:2-[(2, the 5-difluorophenyl)-hydroxymethyl]-3-Methoxy Pyridine
In argon atmospher, down (564mg, (1.5ml 3mmol), stirred 60 minutes under the room temperature to splash into the tetrahydrofuran solution of isopropyl-magnesium chloride in tetrahydrofuran (THF) 3mmol) (2ml) solution at 2-bromo-3-Methoxy Pyridine in ice-cooled.Under ice-cold, splash into 2 in this brown solution, (328 μ l 3mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.Use ethyl acetate extraction after in reaction solution, adding saturated aqueous ammonium chloride.Decompression concentrates down behind the dry solvent, with hexane gained needle crystal is developed, and obtains title compound (660mg, 88%).
1H-NMR(400MHz，CDCl
3)δ：3.71(3H，s)，5.56(1H，br，J＝6.0Hz)，6.16(1H，d，J＝6.0Hz)，6.75-7.00(3H，m)，7.14(1H，m)，7.26(1H，m)，8.18(1H，m).
mp：94-95℃.
MSm/z：252(M
++H).
Reference example 10:3-allyloxy-2-[(2, the 5-difluorophenyl)-hydroxymethyl] pyridine
In argon atmospher, (642mg, (1.5ml 3mmol), stirred 60 minutes under the room temperature to splash into the tetrahydrofuran solution of isopropyl-magnesium chloride in tetrahydrofuran (THF) 3mmol) (2ml) solution in the ice-cooled 3-allyloxy-2-bromopyridine that obtains at reference example 8 down.Under ice-cold, splash into 2 in this brown solution, (328 μ l 3mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.Use ethyl acetate extraction after in reaction solution, adding saturated aqueous ammonium chloride.Decompression concentrates down behind the dry solvent, with silica gel chromatography (hexane: ethyl acetate=4: 1) make with extra care residue obtained, obtain to be the title compound (375mg, 45%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：4.38(1H，m)，4.44(1H，m)，5.16(1H，m)，5.18(1H，m)，5.61(1H，br，J＝6.4Hz)，5.78(1H，m)，6.17(1H，d，J＝6.0Hz)，6.73-6.96(3H，m)，7.10(1H，m)，7.22(1H，m)，8.19(1H，m).
MSm/z：278(M
++H).
Reference example 11:3-[(2, the 5-difluorophenyl)-hydroxymethyl] pyridine
In argon atmospher, down (286 μ l, (1.5ml 3mmol), stirred 60 minutes under the room temperature to splash into the tetrahydrofuran solution of isopropyl-magnesium chloride in tetrahydrofuran (THF) 3mmol) (2ml) solution at the 3-bromopyridine in ice-cooled.Under ice-cold, splash into 2 in this brown solution, (328 μ l 3mmol), slowly are warming up to room temperature to the 5-difluorobenzaldehyde.Use ethyl acetate extraction after in reaction solution, adding saturated aqueous ammonium chloride.Decompression concentrates down behind the dry solvent, with silica gel chromatography (hexane: ethyl acetate=1: 1) make with extra care residue obtained, obtain to be the title compound (296mg, 45%) of needle crystal.
1H-NMR(400MHz，CDCl
3)δ：3.76(1H，br)，6.10(1H，s)，6.88-6.98(2H，m)，7.20-7.30(2H，m)，7.70(1H，m)，8.42(1H，d，J＝4.8Hz)，8.53(1H，m).
mp：79-80℃.
Reference example 12:5-[(2, the 5-difluorophenyl)-hydroxymethyl] pyrimidine
According to the method same, obtain to be the title compound (117mg, 18%) of oily matter by the 5-bromo pyrimi piperidine with reference example 11.
1H-NMR(400MHz，CDCl
3)δ：6.12(1H，s)，6.90-7.02(2H，m)，7.26(1H，m)，8.70(2H，s)，9.04(1H，s).
MSm/z：205(M
+-OH)
Reference example 13:2-[(tert-butoxycarbonyl oxygen base)-(2, the 5-difluorophenyl) methyl]-1-methyl isophthalic acid H-benzoglyoxaline
Under the room temperature, to 2, the 5-difluorobenzaldehyde (164 μ l, 1.5mmol), the 1-tolimidazole (132mg, 1mmol), tert-Butyl dicarbonate (252 μ l, acetonitrile 1.1mmol) (3ml) solution stirring 20 hours.The precipitation that leaching generates is developed this precipitation by hexane, obtains to be white in color solid title compound (310mg, 83%).
1H-NMR(400MHz，CDCl
3)δ：1.45(9H，s)，3.86(3H，s)，6.9-7.0(2H，m)，7.12(1H，s)，7.22-7.35(3H，m)，7.45(1H，m)，7.77(1H，d，J＝8.0Hz).
mp：163-164℃.
MSm/z：375(M
++H).
Reference example 14:2-[(tert-butoxycarbonyl oxygen base)-(2, the 5-difluorophenyl) methyl]-1-methyl-5-chloro-1H-imidazoles
Under the room temperature, to 2, the 5-difluorobenzaldehyde (327 μ l, 3mmol), 5-chloro-1-Methylimidazole (187 μ g, 2mmol), tert-Butyl dicarbonate (504 μ l, acetonitrile 2.2mmol) (6ml) solution stirring 20 hours.The precipitation that leaching generates is developed this precipitation by hexane, obtains to be white in color solid title compound (472mg, 66%).
1H-NMR(400MHz，CDCl
3)δ：1.48(9H，s)，3.67(3H，s)，6.88-7.1(4H，m)，7.39(1H，m).
mp：125-126℃.
MSm/z：359(M
++H).
Reference example 15:2-[(2, the 5-difluorophenyl)-hydroxymethyl] thiazole
In-78 ℃, (180 μ g splash into hexane solution (1.57M, the 1.40ml of n-Butyl Lithium in tetrahydrofuran (THF) 2mmol) (10ml) solution at the 2-bromo thiazole, 2.2mmol), stir after 10 minutes, add 2, (238 μ l 2.2mmol), slowly are warming up to 0 ℃ while stir to the 5-difluorobenzaldehyde.Then, add aqueous ammonium chloride solution reaction is stopped, adding ether again, after ether layer water and the saturated common salt water washing, use anhydrous magnesium sulfate drying.Filter back decompression concentrated filtrate down.With silica gel chromatography (hexane: ethyl acetate=1: 1) make with extra care, obtain to be the title compound (358mg, 79%) of oily matter to residue obtained.
1H-NMR(400MHz，CDCl
3)δ：3.77(1H，d，J＝4.0Hz)，6.33(1H，d，J＝4.0Hz)，6.95-7.10(2H，m)，7.24(1H，m)，7.34(1H，d，J＝3.6Hz)，7.75(1H，d，J＝3.6Hz)，
MSm/z：228(M
++H).
Reference example 16:2-[(tert-butoxycarbonyl oxygen base)-(2, the 5-difluorophenyl) methyl]-1-(4-p-methoxy-phenyl)-1H-imidazoles
Under the room temperature, to 2, the 5-difluorobenzaldehyde (327 μ l, 3mmol), 1-(4-p-methoxy-phenyl) imidazoles (348mg, 2mmol), tert-Butyl dicarbonate (504 μ l, acetonitrile 2.2mmol) (6ml) solution stirring 20 hours.Concentrate this solution, with silica gel chromatography (hexane: ethyl acetate=5: 1～1: 1) make with extra care, obtain to be the title compound (774mg, 93%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：1.40(9H，s)，3.86(3H，s)，6.76(1H，s)，6.90-7.00(4H，m)，7.02(1H，s)，7.11(1H，s)，7.26(2H，m)，7.33(1H，m).
MSm/z：417(M
++H).
Reference example 17:5-chloro-2-pyridine mercaptan
2, the 5-dichloropyridine (296mg, add in ethanol 2.00mmol) (4ml) solution thiocarbamide (152mg, 2.00mmol) after, reflux 18 hours.Add potassium hydroxide (198mg, water 3.00mmol) (1ml) solution, reflux 3 hours after reaction mixture is cooled to room temperature.Add water after reaction mixture is cooled to room temperature, use washed with dichloromethane.After making water layer be acidity with acetate, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying, after the filtration, concentrating under reduced pressure filtrate, the gained solid washs the back leaching with ether, obtains to be the title compound (83mg, 0.57mmol, 29%) of yellow powder.
1H-NMR(400MHz，CDCl
3)δ：7.35(1H，dd，J＝9.3，2.4Hz)，7.46(1H，d，J＝9.3Hz)，7.64(1H，d，J＝2.4Hz).
MSm/z：146(M
++H).
Reference example 18:2,5-difluorophenyl-4-pyridyl methyl alcohol
In-78 ℃, to 1-bromo-2,5-two fluorobenzene (1.08ml, tetrahydrofuran (THF) 9.60mmol) (30ml) solution stirs, the hexane solution of adding n-Butyl Lithium (7.32ml, 11.5mmol).In-78 ℃, (uniform temp stirred 30 minutes down for 0.764ml, tetrahydrofuran (THF) 8.00mmol) (10ml) solution to add the 4-pyridylaldehyde in reaction mixture.Add ether after reaction mixture is warming up to room temperature, wash with saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, handles residue obtained with the flash chromatography on silica gel method.Concentrating under reduced pressure is by hexane: the cut that ethyl acetate=7: 3 wash-out portion obtains, gained solid be with diisopropyl ether washing back leaching, the title compound (1.15g, 5.20mmol, 65%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.25(1H，brs)，6.09(1H，s)，6.89-7.05(2H，m)，7.14-7.23(1H，m)，7.34(2H，d，J＝5.4Hz)，8.44(2H，d，J＝5.4Hz).
Reference example 19: tetrahydric thiapyran-4-alcohol
With tetrahydric thiapyran-4-ketone (5.00g 43.0mmol) is dissolved in methyl alcohol (100ml), ice-cooled add down sodium borohydride (1.6g, 42.3mmol) after, stirred 14 hours under the room temperature.The concentrating under reduced pressure reaction mixture adds water (50ml) in the gained concentrated residue, make fluidity be slightly acidic with 1N hydrochloric acid after, use extracted with diethyl ether.After extraction liquid is used 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, the organic layer anhydrous magnesium sulfate drying.Filter back concentrating under reduced pressure filtrate, obtain to be khaki solid title compound (4.40g, 37.2mmol, 87%).
1H-NMR(400MHz，CDCl
3)δ：1.47(1H，brs)，1.64-1.80(2H，m)，2.10-2.24(2H，m)，2.55-2.70(2H，m)，2.73-2.88(2H，m)，3.60-3.75(1H，m).
MSm/z：119(M
++H).
Reference example 20:5-two brooethyls-2-(2,5-two fluorobenzoyl) pyridine (compd A) and 5-brooethyl-2-(2,5-two fluorobenzoyl) pyridine (compd B)
Under the reflux, 2-[(2 in reference example 5 acquisitions, the 5-difluorophenyl)-hydroxymethyl]-5-picoline (7.50g, 31.9mmol) tetracol phenixin (100ml) solution in add N-bromine succinimide (17.0g, 95.7mmol) and catalytic amount 2,2 '-azo two (2-methyl propionitrile) also stirs.Reflux 24 hours postcooling to room temperature, filter the precipitation that generates.It is joined in the sodium thiosulfate solution, use chloroform extraction.Solution is used dried over sodium sulfate after using saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Decompression is concentrated solution down, and residue obtained (hexane: ethyl acetate=10: 1) refining, acquisition is the title compound A (3.91g, 31%) and the title compound B (3.34g, 34%) of oily matter with silica gel chromatography.
Compd A
1H-NMR(400MHz，CDCl
3)δ：6.70(1H，s)，7.12(1H，m)，7.24(1H，m)，7.39(1H，m)，8.12(1H，d，J＝8.4Hz)，8.19(1H，dd，J＝2.0，8.4Hz)，8.77(1H，d，J＝2.0Hz).
MSm/z：392(M
++H).
Compd B
1H-NMR(400MHz，CDCl
3)δ：4.52(2H，s)，7.12(1H，m)，7.21(1H，m)，7.39(1H，m)，7.94(1H，dd，J＝2.0，8.0Hz)，8.08(1H，d，J＝8.0Hz)，8.67(1H，d，J＝2.0Hz).
MSm/z：313(M
++H).
Reference example 21: acetate [6-(2,5-difluorophenyl carbonyl) pyridin-3-yl] methyl esters
Under the reflux, 2-[(2 in reference example 5 acquisitions, the 5-difluorophenyl)-hydroxymethyl]-5-picoline (2.64g, 11.2mmol) tetracol phenixin (60ml) solution in add N-bromine succinimide (6.0g, 33.6mmol) and catalytic amount 2,2 '-azo two (2-methyl propionitrile) also stirs.Reflux 7 hours postcooling to room temperature, it is joined in the sodium thiosulfate solution.Use extracted with diethyl ether, after solution with water and the saturated common salt water washing, use dried over sodium sulfate.Decompression is concentrated solution down, with the residue obtained toluene that is dissolved in, it is carried out concentrating once more.
With the residue obtained N that is dissolved in, in the dinethylformamide (20ml).(4.59g 56mmol), stirred 17 hours in 70 ℃ to add sodium acetate therein.After the cooling it is dissolved in ethyl acetate (100ml), water and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after the following concentrated solution of decompression.It is residue obtained that (hexane: ethyl acetate=5: 1) refining, acquisition is the title compound (600mg, 18%) of oily matter with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.12(3H，s)，5.19(2H，s)，7.10(1H，m)，7.19(1H，m)，7.37(1H，s)，7.88(1H，dd，J＝2.4，8.0Hz)，8.07(1H，d，J＝8.0Hz)，8.62(1H，d，J＝2.4Hz).
MSm/z：292(M
++H).
Reference example 22:2-[(2, the 5-difluorophenyl)-hydroxymethyl]-5-(1,3-dioxolane-2-yl) pyridine
((6.2g 100mmol), stirs 17 hours while heat in 90 ℃ to 5-two brooethyls-2-(2, the 5-two fluorobenzoyl) pyridine (compd A) that obtains at reference example 20 to add ethylene glycol among the 3.91g, pyridine solution 10mmol) (60ml).Decompression is concentrated solution down, with the residue obtained ether (200ml) that is dissolved in.Water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt are used anhydrous magnesium sulfate drying after it is washed.Decompression is concentrated solution down, the residue obtained ethanol (60ml) that is dissolved in.Ice-cooled add therein down sodium borohydride (190mg, 5mmol), in stirring at room 1 hour.Use ethyl acetate extraction after adding water, to use anhydrous magnesium sulfate drying behind the saturated aqueous common salt washing soln.Decompression is concentrated solution down, and residue obtained (hexane: ethyl acetate=5: 1～1: 1) refining, acquisition is the title compound (1.52g, 52%) of oily matter with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：4.0-4.2(4H，m)，5.84(1H，s)，6.10(1H，s)，6.91(1H，m)，6.99(1H，m)，7.09(1H，m)，7.26(1H，d，J＝8.0Hz)，7.76(1H，dd，J＝2.0，8.0Hz)，8.64(1H，d，J＝2.0Hz).
MSm/z：294(M
++H).
Reference example 23:3-chloro-4-[(2, the 5-difluorophenyl)-hydroxymethyl] pyridine
In-78 ℃, Diisopropylamine (1.4ml adds n-Butyl Lithium (6.3ml, 1.59M hexane solution) in tetrahydrofuran solution 10mmol) (14ml), stirs adding 3-chloropyridine after 10 minutes (1.13g, 10mmol).Add 2 after 30 minutes, (1.09ml 10mmol), slowly is warming up to 0 ℃, restir 10 minutes to the 5-difluorobenzaldehyde.Dilute with ethyl acetate (80ml) after adding aqueous ammonium chloride solution.Get organic layer, with saturated common salt water washing after drying.Filter, decompression is concentrated solution down, and the gained precipitation obtains title compound (1.33g, 52%) with the ethanol development.
1H-NMR(400MHz，CDCl
3)δ：4.87(1H，br)，6.26(1H，s )，6.90-7.02(3H，m)，7.58(1H，d，J＝4.8Hz)，8.47(1H，s)，8.48(1H，d，J＝4.8Hz).
mp：169-170℃.
MSm/z：255(M
+).
Reference example 24:2,5-two chloro-4-[(2,5-difluorophenyl)-hydroxymethyl] pyridine
In-78 ℃, Diisopropylamine (1.4ml adds n-Butyl Lithium (6.3ml, 1.59M hexane solution) in tetrahydrofuran solution 10mmol) (14ml), stir to add 2 after 10 minutes, the 5-dichloropyridine (1.48g, 10mmol).Add 2 after 30 minutes, (1.09ml 10mmol), slowly is warming up to 0 ℃, restir 10 minutes to the 5-difluorobenzaldehyde.Dilute with ethyl acetate (80ml) after adding aqueous ammonium chloride solution.Get organic layer, with saturated common salt water washing after drying.Filter, decompression is concentrated solution down, and the gained precipitation obtains title compound (1.93g, 67%) with the ethanol development.
1H-NMR(400MHz，CDCl
3)δ：2.64(1H，d，J＝4.0Hz)，6.28(1H，d，J＝4.0Hz)，6.89(1H，m)，7.02(2H，m)，7.64(1H，s)，8.30(1H，s).
mp：160-161℃.
MSm/z：289(M
+).
Reference example 25:(3,6-dichloropyridine-2-yl) (pyridin-4-yl) methyl alcohol
Under-78 ℃ of stirrings, 2, (1.02g splashes into tert-butyl lithium (1.51M pentane solution 4.6ml) to the 5-dichloropyridine in ether 6.89mmol) (20ml) solution.After 2 hours, (0.65ml 6.89mmol), adds water in-78 ℃ of stirrings after 1 hour in reaction solution, be warming up to room temperature to add Pyridine-4-Carboxaldehyde in reaction solution in-78 ℃ of stirrings.Mixed solution is used anhydrous sodium sulfate drying after with dichloromethane extraction, filters back concentrating under reduced pressure filtrate.With silica gel column chromatography the gained concentrated residue is handled, concentrating under reduced pressure is by methyl alcohol: methylene dichloride (=1: the cut that elutriant 50) obtains, the gained solid is with the leaching of ether washing back, and the title compound of the powder that obtains to be white in color (819mg, 3.21mmol).
1H-NMR(400MHz，CDCl
3)δ：4.64(1H，brd，J＝6.3Hz)，6.00(1H，brd，J＝6.3Hz)，7.27(1H，d，J＝8.6Hz)，7.31(2H，d，J＝5.8Hz)，7.67(1H，d，J＝8.6Hz)，8.57(2H，d，J＝5.8Hz).
MS(m/z)：254(M
+).
Reference example 26: dithiocarbonic acid S-(6-chloro-3-pyridyl) ester O-ethyl ester
(643mg 3.00mmol) is dissolved in 1N hydrochloric acid (10ml), splashes into Sodium Nitrite (207mg, water 3.00mmol) (1ml) solution in-5 ℃ with 5-amino-2-chloropyridine.In 60 ℃ the reaction mixture stirring after 30 minutes, is splashed into dithiocarbonic acid O-ethyl ester potassium (481mg, water 3.00mmol) (1ml) solution under uniform temp.To room temperature, add ethyl acetate in 1 hour postcooling of 80 ℃ of stirred reaction mixtures, wash with saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying, after the filtration, concentrating under reduced pressure filtrate.Handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=49: 1 wash-out portion obtains obtains to be the title compound (148mg, 0.63mmol, 21%) of yellow oil.
1H-NMR(400MHz，CDCl
3)δ：1.37(3H，t，J＝7.1Hz)，4.63(2H，t，J＝7.1Hz)，7.41(1H，d，J＝8.3Hz)，7.76(1H，dd，J＝8.3，2.4Hz)，8.45(1H，d，J＝2.4Hz).
MSm/z：234(M
++H).
Reference example 27:(2,6-two chloro-5-fluorine pyridin-3-yls) methyl alcohol
Ice-cold down, 2,6-two chloro-5-fluorine nicotinic acids (2.76g, 13.1mmol) and triethylamine (1.92ml, add in toluene 13.8mmol) (60ml) solution Vinyl chloroformate (1.32ml, 13.8mmol).Stir after 1 hour the concentrating under reduced pressure reaction mixture under the room temperature.
Residue is dissolved in tetrahydrofuran (THF) (30ml), and (524mg is in tetrahydrofuran (THF) 13.8mmol) (20ml) suspension liquid to splash into lithium aluminum hydride in-78 ℃.After reaction mixture is warming up to 0 ℃, splash into 1N aqueous sodium hydroxide solution (3.25ml).With concentrating under reduced pressure filtrate behind the diatomite elimination precipitate.Handle residue obtained with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains obtains to be the title compound (1.93g, 9.85mmol, 75%) of orange solids.
1H-NMR(400MHz，CDCl
3)δ：2.18(1H，brs)，4.77(2H，s)，7.77(1H，d，J＝7.8Hz).
mp：65-67℃.
Reference example 28:3-(tert-butyl diphenyl siloxy-methyl)-5-fluorine pyridine
(2, the 6-two chloro-5-fluorine pyridin-3-yls) methyl alcohol that obtains at reference example 27 (18.9g, 96.2mmol) and triethylamine (32.2ml adds 10% palladium-carbon catalyst (3.20g) in ethanol 231mmol) (650ml) solution, stirring is 7 hours under nitrogen atmosphere.With concentrating under reduced pressure filtrate behind the diatomite elimination catalyzer, in residue obtained, add saturated sodium bicarbonate aqueous solution, use chloroform extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.
With the residue obtained methylene dichloride (600ml) that is dissolved in, (14.8ml, 106mmol) (25.0ml, 96.3mmol), and then (1.18g 9.63mmol), stirred 14 hours under the room temperature to add 4-dimethylaminopyridine with the tertiary butyl chloride diphenyl silane to add triethylamine.Reaction mixture filters back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Handle residue obtained with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=19: 1 wash-out portion obtains obtains to be the title compound (30.0g, 81.9mmol, 85%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：1.10(9H，s)，4.78(2H，s)，7.36-7.49(7H，m)，7.63-7.70(4H，m)，8.32(1H，s)，8.36(1H，d，J＝2.4Hz).
MSm/z：366(M
++H).
Reference example 29:[5-(tert-butyl diphenyl siloxy-methyl)-3-fluorine pyridine-2-yl] (2, the 5-difluorophenyl) methyl alcohol
In-78 ℃, and the hexane solution of adding n-Butyl Lithium in ether (250ml) (30.0ml 46.8mmol), adds N again, N, and N ', N '-Tetramethyl Ethylene Diamine (7.06ml, 46.8mmol).In-20 ℃ the reaction mixture stirring after 30 minutes, is cooled to-78 ℃, adds 3-(tert-butyl diphenyl siloxy-methyl)-5-fluorine pyridine (15.5g, ether 42.5mmol) (50ml) solution again.Stir under uniform temp after 30 minutes, add 2, (6.04g 42.5mmol), stirred 2 hours the 5-difluorobenzaldehyde.After adding water earlier add saturated sodium bicarbonate aqueous solution again in reaction mixture, use extracted with diethyl ether, the organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Handle residue obtained with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains obtains to be the title compound (17.0g, 33.5mmol, 79%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：1.10(9H，s)，4.78(2H，s)，5.12(1H，d，J＝6.6Hz)，6.22(1H，d，J＝6.6Hz)，6.87-7.04(3H，m)，7.33-7.48(7H，m)，7.61-7.70(4H，m)，8.32(1H，s).
MSm/z：508(M
++H).
Reference example 30:(2, the 5-difluorophenyl) (3-fluoro-5-hydroxy-methyl pyridine-2-yl) methyl alcohol
At [5-(tert-butyl diphenyl siloxy-methyl)-3-fluorine pyridine-2-yl] (2, the 5-difluorophenyl) methyl alcohol (853mg, 1.68mmol) tetrahydrofuran (THF) (7ml) solution in add the tetrahydrofuran solution of tetrabutylammonium (1.04ml 1.04mmol), stirred 5 hours under the room temperature.Behind the concentrating under reduced pressure reaction mixture,, wash with saturated sodium bicarbonate aqueous solution with the residue obtained ethyl acetate that is dissolved in.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Handle residue obtained with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains obtains to be white in color solid title compound (413mg, 1.53mmol, 91%).
1H-NMR(400MHz，CDCl
3)δ：1.91(1H，t，J＝5.4Hz)，4.79(2H，d，J＝5.4Hz)，5.16(1H，d，J＝6.6Hz)，6.23(1H，d，J＝6.6Hz)，6.75-7.04(3H，m)，7.46(1H，d，J＝9.8Hz)，8.41(1H，s).
mp：94-96℃.
MSm/z：270(M
++H).
Reference example 31:6-(2, the 5-difluorophenyl) hydroxymethyl-5-fluorine niacinamide
(406mg adds potassium permanganate (795mg, water 7.03mmol) (9ml) solution, reflux 4 hours to (2, the 5-difluorophenyl) (the 3-fluoro-5-hydroxy-methyl pyridine-2-yl) methyl alcohol that obtains at reference example 30 in acetone 1.51mmol) (9ml) solution.Behind diatomite elimination precipitate, make filtrate be acid with 1N hydrochloric acid, extract with methylene dichloride then.The organic layer anhydrous sodium sulfate drying, after the filtration, concentrating under reduced pressure filtrate.Residue obtained mixed solvent washing back leaching with hexane and methylene dichloride obtains white solid (367mg).
N at gained solid (240mg), add 1H-benzotriazole-1-base oxygen base tripyrrole alkyl hexafluorophosphate (666mg in dinethylformamide (8ml) solution, 1.28mmol), benzotriazole-1-alcohol (173mg, 1.28mmol) and N-ethyl diisopropylamine (0.595ml, 3.41mmol) and ammonium chloride (91mg, 1.71mmol), stirred 9 hours under the room temperature.Add ethyl acetate in reaction mixture, after washing successively with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt, the organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.Handle residue obtained with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 4 wash-out portion obtains.
With the residue obtained ethanol (8ml) that is dissolved in, in 0 ℃ add sodium borohydride (30mg, 0.79mmol).Stirring added water after 1 hour to reaction mixture under the room temperature, used dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, handles residue obtained with the flash chromatography on silica gel method.The cut that concentrating under reduced pressure is obtained by eluent ethyl acetate portion obtains to be white in color solid title compound (118mg, 0.42mmol, 42%).
1H-NMR(400MHz，CDCl
3)δ：4.97(1H，d，J＝6.6Hz)，6.27(1H，d，J＝6.6Hz)，6.91-7.06(3H，m)，7.87(1H，dd，J＝9.4，1.6Hz)，8.81(1H，s).
mp：162-164℃.
MSm/z：283(M
++H).
Reference example 32:2-[(2, the 5-difluorophenyl) hydroxymethyl]-6-(1,3-dioxolane-2-yl) pyridine
In argon atmospher, in ice-cold following at 2-bromo-6-(1,3-dioxolane-2-yl) pyridine (2.7ml, 24.8mmol) tetrahydrofuran (THF) (20ml) solution in splash into the tetrahydrofuran solution (2.0M of isopropyl-magnesium chloride, 12.4ml, 24.8mmol), stirred 3 hours under the room temperature.Under ice-cooled, splash into 2 in this brown solution, (2.7ml 24.8mmol), slowly is warming up to room temperature to the 5-difluorobenzaldehyde, stirs 16 hours.After in reaction solution, adding saturated aqueous ammonium chloride, use ethyl acetate extraction, again water, saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Handle residue obtained with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be the title compound (2.90g, 9.89mmol, 40%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.09-4.21(4H，m)，5.43(1H，d，J＝4.4Hz)，5.90(1H，s)，6.11(1H，d，J＝4.4Hz)，6.87-6.95(1H，m)，6.99-7.05(1H，m)，7.10-7.15(1H，m)，7.23(1H，d，J＝7.8Hz)，7.48(1H，d，J＝7.8Hz)，7.72(1H，t，J＝7.8Hz).
MSm/z：294(M
++H).
Reference example 33:1-[3-(t-butyldimethylsilyloxy base) propyl group] piperidines-2-ketone
In 0 ℃, piperidines-2-ketone (5.00g, slowly add in tetrahydrofuran solution 50.5mmol) (200ml) sodium hydride (60% oiliness, 2.22g, 55.6mmol) after, in stirring at room 3 hours.(14.1ml 60.6mmol) and N, behind the dinethylformamide (20ml), stirred 4 days under the room temperature to add (3-bromine propoxy-)-tertiary butyl dimethylsilane in reaction solution.Use ethyl acetate extraction after in reaction solution, adding water.Use dried over mgso after extraction liquid water and the saturated common salt water washing, concentrate.Handle residue obtained with silica gel column chromatography, concentrate by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains obtains to be the title compound (6.44g, 23.8mmol, 47%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：0.05(6H，s)，0.89(9H，s)，1.74-1.85(6H，m)，2.36(2H，t，J＝6.0Hz)，3.27-3.32(2H，m)，3.39-3.43(2H，m)，3.65(2H，t，J＝6.3Hz)
MSm/z：272(M
++H).
Reference example 34:3-bromo-1-[3-(t-butyldimethylsilyloxy base) propyl group] piperidines-2-ketone
Under the argon atmospher, in-78 ℃ at 1-[3-(t-butyldimethylsilyloxy base) propyl group] (542mg splashes into tert-butyl lithium (1.50M pentane solution, 1.40ml to piperidines-2-ketone in tetrahydrofuran solution 2.00mmol) (5ml), 2.10mmol) after, stirred 15 minutes in-78 ℃.(1.16g, behind tetrahydrofuran solution 2.40mmol) (5ml), the limit is stirred 3 hours limits and slowly is warming up to-40 ℃ to add tetrabutylammonium tribromide in reaction solution.Be warming up to room temperature in-40 ℃ after in reaction solution, adding water.With ethyl acetate to the gained mixture extraction after, extraction liquid water and saturated common salt water washing.With concentrating after the dried over mgso, handle residue obtained with the silica gel flash column chromatography then, concentrate by hexane: the cut of ethyl acetate=wash-out portion acquisition in 2: 3, acquisition is the title compound (72.8mg, 0.208mmol, 10%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：0.05(6H，s)，0.89(9H，s)，1.74-1.88(3H，m)，2.18-2.32(3H，m)，3.28-3.48(4H，m)，3.65(2H，t，J＝6.1Hz)，4.53-4.57(1H，m).
MSm/z：350(M
++H).
Embodiment 1:2-[[(4-chloro-phenyl-) alkylsulfonyl] (cyclohexyl) methyl]-1,4-two fluorobenzene
2-[(4-chloro-phenyl-with reference example 1 acquisition) alkylsulfonyl methyl]-1; 4-two fluorobenzene (240mg; 0.793mmol) be dissolved in toluene (20ml); add hexalin (0.11ml; 1.0mmol) and cyano group methylene tri normal-butyl phosphorane (250mg; 1.0mmol) after, reflux is 14 hours under argon atmospher.Behind the reaction solution naturally cooling, add hexalin (0.22ml, 2.1mmol) and cyano group methylene tri normal-butyl phosphorane (500mg, 2.08mmol) after, reflux is 14 hours under argon atmospher.Concentrating under reduced pressure behind the reaction solution naturally cooling, and gained residue silica gel chromatography (hexane: ethyl acetate=30: 1) refining, obtain white solid.The gained white solid with hexane wash after, the title compound (188mg, 62%) of the powder that obtains to be white in color.
Fusing point: 107～109 ℃
1H-NMR(400MHz，CDCl
3)δ：0.92-1.08(1H，m)，1.08-1.22(1H，m)，1.22-1.50(3H，m)，1.60-1.75(3H，m)，1.75-1.88(1H，m)，2.37(1H，brd，J＝12.5Hz)，2.48-2.62(1H，m)，4.44(1H，d，J＝7.6Hz)，6.68-6.80(1H，m)，6.86-6.95(1H，m)，7.30(2H，dm，J＝8.6Hz)，7.38-7.52(1H，m)，7.49(2H，dm，J＝8.6Hz).
Ultimate analysis: C
19H
19ClF
2O
2S: theoretical value: C59.29; H4.98; Cl9.21; F9.87; S8.33. measured value: C59.11; H4.93; Cl9.18; F9.82; S8.49.
Embodiment 2:4-[(4-chloro-phenyl-alkylsulfonyl) (cyclopentyl) methyl] pyridine
Under argon atmospher; 4-(the 4-chloro-phenyl-alkylsulfonyl methyl) pyridine (70mg that reference example 2 is obtained; 0.261mmol), cyclopentanol (49 μ l, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, toluene 0.538mmol) (5ml) vlil 3 days.After being cooled to room temperature, in reaction solution, add cyclopentanol (49 μ l, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, 0.538mmol), reflux 22 hours under argon atmospher then.Be cooled to concentrating under reduced pressure reaction solution after the room temperature.Handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: (=2: the 1) cut that obtains of elutriant obtains to be white in color solid title compound (77mg, 88%) to ethyl acetate.The gained solid obtains to be white in color the solid title compound with hexane-ether washing after-filtration.
Fusing point: 133～135 ℃
1H-NMR(400MHz，CDCl
3)δ：0.92-1.08(1H，m)，1.44-1.83(6H，m)，2.33-2.45(1H，m)，2.78-2.90(1H，m)，3.88(1H，d，J＝10.3Hz)，7.03(2H，d，J＝5.1Hz)，7.32(2H，d，J＝8.6Hz)，7.43(2H，d，J＝8.6Hz)，8.46(2H，d，J＝5.6Hz).
Ultimate analysis: C
17H
18ClNO
2S: theoretical value: C60.80; H5.40; Cl10.56; N4.17; S9.55. measured value: C60.76; H5.44; Cl10.68; N4.20; S9.61.
Embodiment 3:4-[(4-chloro-phenyl-alkylsulfonyl) (tetrahydropyran-4-base) methyl] pyridine
Under argon atmospher; 4-(the 4-chloro-phenyl-alkylsulfonyl methyl) pyridine (70mg that reference example 2 is obtained; 0.261mmol), tetrahydropyrans-4-alcohol (51 μ l, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, toluene 0.538mmol) (5ml) vlil 3 days.After being cooled to room temperature, in reaction solution, add tetrahydropyrans-4-alcohol (51 μ l, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, 0.538mmol), reflux 22 hours under argon atmospher then.Be cooled to concentrating under reduced pressure reaction solution after the room temperature.Handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: (=1: the 2) cut that obtains of elutriant obtains to be white in color solid title compound (65mg, 71%) to ethyl acetate.The gained solid is with hexane-ether washing after-filtration, the title compound of the powder that obtains to be white in color.
Fusing point: 208～209 ℃
1H-NMR(400MHz，CDCl
3)δ：1.22-1.42(2H，m)，1.60-1.75(1H，m)，2.30-2.40(1H，m)，2.78-3.01(1H，m)，3.41(1H，td，J＝11.7，2.4Hz)，3.51(1H，td，J＝11.9，2.0Hz)，3.80-3.93(1H，m)，3.87(1H，d，J＝8.6Hz)，3.98-4.06(1H，m)，7.00-7.12(2H，m)，7.30(2H，d，J＝8.8Hz)，7.43(2H，d，J＝8.6Hz)，8.47(2H，d，J＝5.4Hz).
MS(m/z)：352(M
++H).
Embodiment 4:4-[(1-phenmethyl piperidin-4-yl) (4-chloro-phenyl-alkylsulfonyl) methyl] pyridine
Under argon atmospher; 4-(the 4-chloro-phenyl-alkylsulfonyl methyl) pyridine (70mg that reference example 2 is obtained; 0.261mmol), 1-phenmethyl piperidines-4-alcohol (103mg, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, toluene 0.538mmol) (5ml) vlil 3 days.After being cooled to room temperature, in reaction solution, add 1-phenmethyl piperidines-4-alcohol (103mg, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, 0.538mmol), reflux 22 hours under argon atmospher then.Be cooled to concentrating under reduced pressure reaction solution after the room temperature.Handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by methyl alcohol: methylene dichloride (=1: the 10) cut that obtains of elutriant.Residue obtained refining with high speed liquid chromatography (making the mixed solvent system of water/acetonitrile/formic acid), obtain amorphous title compound (40mg, 35%).
1H-NMR(400MHz，CDCl
3)δ：1.21-1.37(2H，m)，1.49-1.70(1H，m)，1.92-2.01(1H，m)，2.03-2.14(1H，m)，2.25-2.35(1H，m)，2.52-2.65(1H，m)，2.79-2.85(1H，m)，2.90-3.00(1H，m)，3.47(2H，s)，3.86(1H，d，J＝8.1Hz)，7.02-7.12(2H，m)，7.20-7.38(7H，m)，7.43(2H，d，J＝8.5Hz)，8.45.(2H，d，J＝5.4Hz).
HRMS(FAB)：C
24H
26O
2N
2ClS(M
++H)
Theoretical value: 441.1404. measured value: 441.1387
Embodiment 5:4-[(4-chloro-phenyl-alkylsulfonyl) (1-methyl piperidine-4-yl) methyl] pyridine
Under argon atmospher; 4-(the 4-chloro-phenyl-alkylsulfonyl methyl) pyridine (70mg that reference example 2 is obtained; 0.261mmol), 1-methyl piperidine-4-alcohol (62 μ l, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (62 μ l, toluene 0.538mmol) (5ml) vlil 3 days.After being cooled to room temperature, in reaction solution, add 1-methyl piperidine-4-alcohol (62 μ l, 0.538mmol) and cyano group methylene tri normal-butyl phosphorane (129mg, 0.538mmol), reflux 22 hours under argon atmospher then.Be cooled to concentrating under reduced pressure reaction solution after the room temperature.Handle residue obtained with silica gel column chromatography, concentrating under reduced pressure is by methyl alcohol: methylene dichloride (=1: the 50) cut that obtains of elutriant.Residue obtained refining with high speed liquid chromatography (making the mixed solvent system of water/acetonitrile/formic acid), obtain title compound (31mg, 33%) as white solid.The gained solid is with the washing of hexane-ether, the title compound of the powder that obtains to be white in color.
Fusing point: 176～177 ℃
1H-NMR(400MHz，CDCl
3)δ：1.22-1.38(2H，m)，1.50-1.68(1H，m)，1.88-1.99(1H，m)，2.00-2.10(1H，m)，2.25(3H，s)，2.30-2.40(1H，m)，2.50-2.63(1H，m)，2.74-2.83(1H，m)，2.89-2.95(1H，m)，3.86(1H，d，J＝8.3Hz)，7.08(2H，d，J＝4.6Hz)，7.30(2H，d，J＝8.6Hz)，7.44(2H，d，J＝8.6Hz)，8.46(2H，d，J＝5.6Hz).
Ultimate analysis: C
18H
21ClN
2O
2S: theoretical value: C59.25; H5.80; Cl9.72; N7.68; S8.79. measured value: C59.00; H5.76; Cl9.75; N7.61; S8.77.
Embodiment 6:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyridine
With the 2-[(2 that reference example 3 obtains, 5-difluorophenyl)-hydroxymethyl] pyridine (88mg, 0.40mmol) be dissolved in thionyl chloride (2.0ml) after, the dimethyl formamide that adds catalytic amount stirred 15 hours.The concentrating under reduced pressure reaction solution adds two alkane and concentrated in residue.With the residue obtained dimethyl formamide (5ml) that is dissolved in, under nitrogen atmosphere, add 4-chlorobenzene mercaptan (79mg, 0.55mmol) and salt of wormwood (226mg, 1.64mmol), in 50 ℃ of stirrings 1 hour.After reaction solution is cooled to room temperature, add ether (50ml), water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.With silica gel chromatography (hexane: ethyl acetate=10: 1) residue is handled, obtained to be the title compound (128mg, 92%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：5.89(1H，s)，6.80-7.27(7H，m)，7.38(1H，d，J＝7.6Hz)，7.48(1H，m)，7.65(1H，m)，8.63(1H，m)。
MSm/z：348(M
++H).
Embodiment 7:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-the 3-picoline
Under the nitrogen atmosphere, 2-[chloro-(2 in reference example 4 acquisitions, the 5-difluorophenyl) methyl]-3-picoline hydrochloride (94mg, 0.32mmol) dimethyl formamide (5ml) solution in add 4-chlorobenzene mercaptan (70mg, 0.49mmol) and salt of wormwood (265mg, 1.92mmol), stirred 1 hour in 50 ℃.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=10: 1) handle, acquisition is the title compound (103mg, 89%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.21(3H，s)，5.87(1H，s)，6.77(1H，m)，7.00-7.19(5H，m)，7.36(1H，m)，7.45(1H，m)，8.45(1H，dd，J＝1.2，4.8Hz).
MSm/z：362(M
++H).
Embodiment 8:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-the 4-picoline
With the 2-[(2 that reference example 6 obtains, 5-difluorophenyl)-hydroxymethyl]-the 4-picoline (235mg, 0.53mmol) be dissolved in thionyl chloride (2.0ml) after, the dimethyl formamide that adds catalytic amount stirred 16 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (217mg, 1.5mmol) and salt of wormwood (828mg, 6.0mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=10: 1) handle, acquisition is the title compound (290mg, 809%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.31(3H，s)，5.82(1H，s)，6.80-7.0(3H，m)，7.15(2H，d，J＝8.8Hz)，7.16(1H，m)，7.21(2H，d，J＝8.8Hz)，7.45(1H，m)，8.45(1H，d，J＝5.6Hz).
MSm/z：362(M
++H).
Embodiment 9:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-3-Methoxy Pyridine
With the 2-[(2 that reference example 9 obtains, 5-difluorophenyl)-hydroxymethyl]-3-Methoxy Pyridine (251mg, 1.0mmol) be dissolved in thionyl chloride (2.0ml) after, the dimethyl formamide that adds catalytic amount stirred 16 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (289mg, 2.0mmol) and salt of wormwood (1.10g, 8.0mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=10: 1) handle, acquisition is the title compound (256mg, 58%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.77(3H，s)，6.25(1H，s)，6.82(2H，m)，7.15(2H，d，J＝8.4Hz)，7.10-7.20(2H，m)，7.25(2H，d，J＝8.8Hz)，7.52(1H，m)，8.24(1H，m).
MSm/z：378(M
++H).
Embodiment 10:3-allyloxy-2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyridine
With 3-allyloxy-2-[(2 that reference example 10 obtains, 5-difluorophenyl)-hydroxymethyl] pyridine (370mg, 1.33mmol) be dissolved in thionyl chloride (2.0ml) after, the dimethyl formamide that adds catalytic amount stirred 16 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (217mg, 1.5mmol) and salt of wormwood (828mg, 6.0mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=10: 1) handle, acquisition is the title compound (256mg, 68%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：4.46(2H，m)，5.24(1H，d，J＝10.6Hz)，5.28(1H，d，J＝17.2Hz)，5.90(1H，m)，6.29(1H，d，J＝1.2Hz)，6.82(2H，m)，7.15(2H，d，J＝8.4Hz)，7.06-7.20(2H，m)，7.24(2H，d，J＝8.4Hz)，7.50(1H，m)，8.24(1H，m).
MSm/z：404(M
++H).
Embodiment 11:3-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyridine
With the 3-[(2 that reference example 11 obtains, 5-difluorophenyl)-hydroxymethyl] pyridine (87mg, 0.39mmol) be dissolved in thionyl chloride (1.0ml) after, the dimethyl formamide that adds catalytic amount stirred 14 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (5ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (84mg, 0.58mmol) and salt of wormwood (323mg, 2.34mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=1: 1) handle, acquisition is the title compound (131mg, 96%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：5.73(1H，s)，6.84-6.96(2H，m)，7.18(2H，m)，7.19(2H，m)，7.15-7.22(2H，m)，7.71(1H，m)，8.49(1H，dd，J＝1.6，4.8Hz)，8.58(1H，d，J＝2.0Hz).
MSm/z：348(M
++H).
Embodiment 12:5-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyrimidine
With the 5-[(2 that reference example 12 obtains, 5-difluorophenyl)-hydroxymethyl] pyrimidine (111mg, 0.5mmol) be dissolved in thionyl chloride (1.0ml) after, the dimethyl formamide that adds catalytic amount stirred 16 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (5ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (108mg, 0.75mmol) and salt of wormwood (414mg, 3.0mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.Residue is with silica gel chromatography (hexane: ethyl acetate=4: 1) handle, obtain to be the title compound of oily matter and the mixture of authenticating compound (202mg) not.
1H-NMR(400MHz，CDCl
3)δ：5.66(1H，s)，6.96(2H，m)，7.17-7.34(5H，d)，8.70(2H，s)，9.09(1H，s).
MSm/z：349(M
++H).
Embodiment 13:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl] pyridine
2-[[(4-chloro-phenyl-in embodiment 6 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyridine (120mg, 0.345mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (80mg), add 30% aquae hydrogenii dioxidi (6ml) again, stirred 24 hours.The precipitation that leaching generates is carried out recrystallization with ethanol to it, obtains to be the title compound (96mg, 73%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.93(1H，s)，6.87-7.00(2H，m)，7.28(1H，m)，7.37(2H，d，J＝8.8Hz)，7.53(2H，d，J＝8.8Hz)，7.60(1H，d，J＝8.0Hz)，7.71(1H，m)，8.00(1H，m)，8.59(1H，m).
mp：171-172℃.
MSm/z：380(M
++H).
Ultimate analysis: C
18H
12ClF
2NO
2S: theoretical value: C, 56.92; H, 3.18; N, 3.69; S, 8.44; Cl, 9.33; F, 10.00. measured value: C, 56.76; H, 3.19; N, 3.77; S, 8.55; Cl, 9.27; F, 10.02.
Embodiment 14:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-the 3-picoline
Adopt method similarly to Example 13,2-[[(4-chloro-phenyl-by embodiment 7 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl]-the 3-picoline is synthetic, recycle silicon glue chromatography is made with extra care (hexane: ethyl acetate=5: 1), acquisition is the title compound (35mg, 35%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：2.36(3H，s)，6.18(1H，s)，6.89-7.02(2H，m)，7.17(1H，m)，7.37(2H，d，J＝8.4Hz)，7.46(1H，d，J＝7.2Hz)，7.53(2H，d，J＝8.4Hz)，8.06(1H，m)，8.53(1H，d，J＝4.0Hz).
mp：142-143℃.
Ultimate analysis: C
19H
14ClF
2NO
2S: theoretical value: C, 57.94; H, 3.58; N, 3.56; S, 8.12; Cl, 9.00; F, 9.65. measured value: C, 58.03; H, 3.66; N, 3.78; S, 8.12; Cl, 9.13; F, 9.59.
Embodiment 15:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-the 5-picoline
1) sulfenyl 2-[[(4-chloro-phenyl-)]-(2, the 5-difluorophenyl) methyl]-the 5-picoline
With the 2-[(2 that reference example 5 obtains, 5-difluorophenyl)-hydroxymethyl]-the 5-picoline (125mg, 0.53mmol) be dissolved in thionyl chloride (1.0ml) after, the dimethyl formamide that adds catalytic amount stirred 14 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (5ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (115mg, 0.80mmol) and salt of wormwood (438mg, 3.18mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=10: 1) handle, acquisition is the title compound (120mg, 66%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.29(3H，s)，5.83(1H，s)，6.80-6.93(2H，m)，7.16(2H，m)，7.20(2H，m)，7.28(1H，m)，7.43(1H，m)，8.41(1H，d，J＝0.8Hz).
MSm/z：362(M
++H).
2) alkylsulfonyl 2-[[(4-chloro-phenyl-)]-(2, the 5-difluorophenyl) methyl]-the 5-picoline
Adopt method similarly to Example 13, by the 2-[[(4-chloro-phenyl-that obtains by above-mentioned reaction) sulfenyl]-(2, the 5-difluorophenyl) methyl]-the 5-picoline is synthetic, obtains to be the title compound (91mg, 73%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：2.33(3H，s)，5.89(1H，s)，6.88-7.01(2H，m)，7.37(2H，d，J＝8.8Hz)，7.48-7.56(2H，m)，7.53(2H，d，J＝8.8Hz)，7.99(1H，m)，8.42(1H，s).
mp：159-160℃.
Ultimate analysis: C
19H
14ClF
2NO
2S: theoretical value: C, 57.94; H, 3.58; N, 3.56; S, 8.12; Cl, 9.00; F, 9.56. measured value: C.57.88; H, 3.61; N, 3.68; S, 8.27; Cl, 9.11; F, 9.70.
Embodiment 16:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-the 4-picoline
Adopt method similarly to Example 13,2-[[(4-chloro-phenyl-by embodiment 8 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl]-the 4-picoline is synthetic, recycle silicon glue chromatography is made with extra care (hexane: ethyl acetate=3: 1), acquisition is the title compound (140mg, 95%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：2.36(3H，s)，5.88(1H，s)，6.88-7.02(2H，m)，7.09(1H，d，J＝5.2Hz)，7.37(2H，d，J＝8.8Hz)，7.41(1H，m)，7.52(2H，d，J＝8.8Hz)，7.97(1H，m)，8.43(1H，d，J＝5.2Hz).
mp：116-117℃.
Ultimate analysis: C
19H
14ClF
2NO
2S: theoretical value: C, 57.94; H, 3.58; N, 3.56; S, 8.12; Cl, 9.00; F, 9.65. measured value: C, 57.80; H, 3.66; N, 3.72; S, 8.29; Cl, 9.05; F, 9.71%.
Embodiment 17:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-3-Methoxy Pyridine
Adopt method similarly to Example 13, by the 2-[[(4-chloro-phenyl-of embodiment 9 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl]-3-Methoxy Pyridine is synthetic, uses ethyl alcohol recrystallization again, obtains to be the title compound (71mg, 87%) of colourless column crystallization.
1H-NMR(400MHz，CDCl
3)δ：3.72(3H，s)，6.62(1H，s)，6.90-7.04(2H，m)，7.09(1H，m)，7.24(1H，m)，7.35(2H，d，J＝8.8Hz)，7.53(2H，d，J＝8.8Hz)，8.18(1H，m)，8.30(1H，m).
mp：184-185℃.
Ultimate analysis: C
19H
14ClF
2NO
3S: theoretical value: C, 55.68; H, 3.44; N, 3.42; S, 7.82; Cl, 8.65; F, 9.27. measured value: C, 55.68; H, 3.45; N, 3.60; S, 7.98; Cl, 8.74; F, 9.23.
Embodiment 18:3-allyloxy-2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl] pyridine
Adopt method similarly to Example 13,3-allyloxy-2-[[(4-the chloro-phenyl-that obtains by embodiment 10) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyridine is synthetic, uses alcohol crystalization again, acquisition is the title compound (135mg, 80%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：4.38(1H，m)，4.46(1H，m)，5.29(1H，dd，J＝1.2，10.4Hz)，5.35(1H，dd，J＝1.2，17.2Hz)，5.93(1H，m)，6.68(1H，s)，6.91-7.04(2H，m)，7.08(1H，m)，7.22(1H，dd，J＝4.8，8.4Hz)，7.34(2H，d，J＝8.8Hz)，7.53(2H，d，J＝8.8Hz)，8.17(1H，m)，8.31(1H，m).
mp：119-120℃.
Ultimate analysis: C
21H
16ClF
2NO
3S: theoretical value: C, 57.87; H, 3.70; N, 3.21; S, 7.36; Cl, 8.13; F, 8.72. measured value: C, 57.90; H, 3.75; N, 3.37; S, 7.51; Cl, 8.20; F, 8.73.
Embodiment 19:3-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl] pyridine
Adopt method similarly to Example 13, the 3-[[(4-chloro-phenyl-that obtains by embodiment 11) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyridine is synthetic, and recycle silicon glue chromatography is made with extra care (hexane: ethyl acetate=4: 1), acquisition is the title compound (118mg, 86%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.68(1H，s)，6.91-7.07(2H，m)，7.34(1H，m)，7.40(2H，d，J＝8.4Hz)，7.57(2H，d，J＝8.4Hz)，7.76(1H，m)，8.04(1H，m)，8.53(1H，d，J＝2.0Hz)，8.59(1H，m).
mp：130-131℃.
Ultimate analysis: C
18H
12ClF
2NO
2S: theoretical value: C, 56.92; H, 3.18; N, 3.69; S, 8.44; Cl, 9.33; F, 10.00. measured value: C, 56.87; H, 3.16; N, 3.74; S, 8.51; Cl, 9.34; F, 10.00.
Embodiment 20:4-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl] pyridine
With reference example 18 obtain 2,5-difluorophenyl-4-pyridyl methyl alcohol (75mg, 0.34mmol) be dissolved in thionyl chloride (1.0ml) after, the dimethyl formamide that adds catalytic amount stirred 14 hours.Decompression is concentration of reaction solution down, adds two alkane reconcentration in residue.This residue is dissolved in dimethyl formamide (5ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (74mg, 0.51mmol) and salt of wormwood (281mg, 2.04mmol), in 50 ℃ of stirrings 1 hour.Reaction solution adds ether (50ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.Residue is with silica gel column chromatography (hexane: ethyl acetate=1: 1) handle, obtain to contain the 4-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl] mixture of pyridine.
In this methyl alcohol (12ml) solution, add seven molybdic acids, six ammonium tetrahydrates (60mg), add 30% aqueous hydrogen peroxide solution (6ml) again, stirred 65 hours.In reaction solution, add ethyl acetate (80ml), water and saturated common salt water washing.Behind anhydrous magnesium sulfate drying, decompression is concentrated solvent down.The residue silica gel chromatography (hexane: ethyl acetate=4: 1～1: 1) refining, obtain title compound (51mg, 39%).Then, use ethyl alcohol recrystallization, obtain colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.64(1H，s)，6.91-7.06(2H，m)，7.40(2H，d，J＝8.0Hz)，7.45(2H，d，J＝4.8Hz)，7.58(2H，d，J＝8.0Hz)，7.70(1H，s)，8.61(2H，d，J＝4.8Hz).
mp：126-127℃.
Ultimate analysis: C
18H
12ClF
2NO
2S: theoretical value: C, 56.92; H, 3.18; N, 3.69; S, 8.44; Cl, 9.33; F, 10.00. measured value: C, 56.66; H, 3.16; N, 3.83; S, 8.58; Cl, 9.32; F, 9.99.
Embodiment 21:5-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl] pyrimidine
Adopt method similarly to Example 13,5-[[(4-chloro-phenyl-by embodiment 12 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl] pyrimidine synthesizes, recycle silicon glue chromatography is made with extra care (hexane: ethyl acetate=5: 1), acquisition is the title compound (71mg of colourless column crystallization, 87%: yield is the 5-[(2 by reference example 12,5-two fluorine-based bases)-hydroxymethyl] pyrimidine 2 steps of setting out).
1H-NMR(400MHz，CDCl
3)δ：5.65(1H，s)，6.93-7.10(2H，m)，7.43(2H，d，J＝8.8Hz)，7.61(2H，d，J＝8.8Hz)，7.73(1H，m)，8.90(2H，s)，9.21(1H，s).mp：136-137℃.
Ultimate analysis: C
17H
11ClF
2N
2O
2S: theoretical value: C, 53.62; H, 2.91; N, 7.36; S, 8.42; Cl, 9.31; F, 9.98. measured value: C, 53.64; H, 2.83; N, 7.44; S, 8.61; Cl, 9.34; F, 9.96.
Embodiment 22:3-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-4-hydroxychromen-2-ketone
Under the room temperature, 2,5-difluorobenzaldehyde (109 μ l, 1mmol), 4 hydroxy coumarin (162mg, 1mmol), (144.6mg adds Glacial acetic acid (60mg in ethanol 1mmol) (4ml) solution to the 4-chlorothio-phenol, 1mmol) and pyridine (80.5 μ l 1mmol), stirred 24 hours.The precipitation that leaching generates is washed it with small amount of ethanol, obtains to be white in color solid title compound (345mg, 80%)
1H-NMR(400MHz，CDCl
3)δ：6.16(1H，s)，6.95-7.12(3H，m)，7.24-7.27(1H，m)，7.27(2H，d，J＝8.8Hz)，7.32(1H，t，J＝7.6Hz)，7.43(2H，d，J＝8.8Hz)，7.56(1H，m)，7.94(1H，dd，J＝1.6，7.6Hz).
mp：146-147℃.
MSm/z：431(M
++H).
Embodiment 23:3-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-4-methoxyl group chromen-2-one (compd A) and 3-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-2-methoxyl group chromene-4-ketone (compd B)
Under the room temperature, at the 3-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-4-hydroxychromen-2-ketone (118mg, 0.274mmol) benzene-methyl alcohol (10: 1) solution in slowly add the hexane solution (0.41ml of the trimethylsilyl diazomethane of 2N, 0.822mmol), restir 5 minutes.Add acetate after solution becomes colorless, decompression is concentration of reaction solution down.
It is dissolved in methyl alcohol (12ml), adds 30% aquae hydrogenii dioxidi (6ml) and seven molybdic acids, six ammonium tetrahydrates (60mg), stirred 20 hours.In reaction solution, add ethyl acetate (50ml), water and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after decompression concentrate down.(hexane: ethyl acetate=5: 1～3: 1) refining, acquisition is the non-polar compound (22mg, 17%) of needle crystal to residue, and with hexane polar compound (9.0mg, 7%) is solidified, and obtains white solid with silica gel chromatography.The NOE of non-polar compound (nuclear Overhauser effect, nuclear Overhauser effect) test-results is to observe NOE between 5 hydrogen of methoxyl group and chromene ketone.In addition; and the fragrant ring hydrogen of the chromene ketone of polar compound between do not observe NOE; but and the difluoro phenyl ring on 6 hydrogen between observe NOE; so determine that non-polar compound is the 3-[[(4-chloro-phenyl-) alkylsulfonyl]-(2; the 5-difluorophenyl) methyl]-4-methoxyl group chromen-2-one (compd A); polar compound is the 3-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-2-methoxyl group chromene-4-ketone (compd B).
Compd A
1H-NMR(400MHz，CDCl
3)δ：4.13(3H，s)，6.39(1H，s)，6.88(1H，m)，6.98(1H，m)，7.3-7.4(2H，m)，7.43(2H，d，J＝8.8Hz)，7.58(1H，m)，7.70(2H，d，J＝8.8Hz)，7.73(1H，m)，8.09(1H，m).
mp：178-179℃.
Ultimate analysis: C
23H
15ClF
2O
3S: theoretical value: C, 57.93; H, 3.17; S, 6.72; Cl, 7.43; F, 7.97. measured value: C, 57.59; H, 3.14; S, 6.85; Cl, 7.52; F, 8.01.
Compd B
1H-NMR(400MHz，CDCl
3)δ：4.23(3H，s)，6.54(1H，s)，6.89(1H，m)，6.96(1H，m)，7.41(2H，d，J＝8.4Hz)，7.4-7.46(2H，m)，7.63(1H，m)，7.73(2H，d，J＝8.4Hz)，8.02(1H，m)，8.14(1H，dd，J＝1.6，8.0Hz).
mp：162-163℃.
FAB-MS:477.0366 (C
23H
16ClF
2O
5S, calculated value: 477.0375).
Embodiment 24:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-1-methyl isophthalic acid H-benzoglyoxaline
2-[(tert-butoxycarbonyl oxygen base in reference example 13 acquisitions)-(2, the 5-difluorophenyl) methyl]-(204mg, 0.545mmol) the middle trifluoroacetic acid (2.0ml) that adds stirred 30 minutes under the room temperature 1-methyl isophthalic acid H-benzoglyoxaline.Decompression is concentration of reaction solution down, adds two alkane concentrating under reduced pressure again in residue.This residue is dissolved in thionyl chloride (1.0ml), adds 1 dimethyl formamide, stirred 16 hours under the room temperature.Decompression is concentration of reaction solution down, adds two alkane concentrating under reduced pressure again in residue.Then, residue is dissolved in dimethyl formamide (5.0ml), add again 4-chlorobenzene mercaptan (118mg, 0.82mmol) and salt of wormwood (451mg 3.27mmol), stirred 2 hours in 50 ℃.After being placed to room temperature, add ether (60ml), water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.With silica gel chromatography (hexane: ethyl acetate=10: 1～5: 1) it is made with extra care, obtain to be the title compound (195mg, 89%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：3.67(3H，s)，5.91(1H，s)，6.87-6.93(2H，m)，7.19(2H，d，J＝8.8Hz)，7.27(2H，d，J＝8.8Hz)，7.25-7.33(3H，m)，7.60(1H，m)，7.85(1H，m).
MSm/z：401(M
++H).
Embodiment 25:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-1-methyl-5-chloro-1H-imidazoles
2-[(tert-butoxycarbonyl oxygen base in reference example 14 acquisitions)-(2, the 5-difluorophenyl) methyl]-(404mg, 1.13mmol) the middle trifluoroacetic acid (10ml) that adds stirred 3 hours under the room temperature 1-methyl-5-chloro-1H-imidazoles.Decompression is concentration of reaction solution down, adds two alkane reconcentration under reduced pressure in residue.This residue is dissolved in thionyl chloride (2.0ml), adds 1 dimethyl formamide, stirred 17 hours under the room temperature.Decompression is concentration of reaction solution down, adds two alkane concentrating under reduced pressure again in residue.Then, residue is dissolved in dimethyl formamide (5.0ml), add again 4-chlorobenzene mercaptan (244mg, 1.69mmol) and salt of wormwood (936mg 6.78mmol), stirred 2 hours in 50 ℃.After being placed to room temperature, add ether (60ml), water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.With silica gel column chromatography (hexane: ethyl acetate=10: 1～5: 1) it is made with extra care, obtain to be the title compound (195mg, 89%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：3.57(3H，s)，5.67(1H，s)，6.89-6.95(2H，m)，6.97(1H，s)，7.20(2H，d，J＝8.4Hz)，7.21(2H，d，J＝8.4Hz)，7.54(1H，m).
MSm/z：386(M
++H).
Embodiment 26:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl] thiazole
With the 2-[(2 that reference example 15 obtains, 5-difluorophenyl)-hydroxymethyl] (348mg 1.53mmol) is dissolved in thionyl chloride (1.5ml) to thiazole, adds 1 dimethyl formamide, stirs 14 hours under the room temperature.Decompression is concentration of reaction solution down, adds two alkane reconcentration under reduced pressure in residue.This residue is dissolved in dimethyl formamide (10.0ml), add again 4-chlorobenzene mercaptan (332mg, 2.3mmol) and salt of wormwood (845mg 6.12mmol), stirred 2 hours in 50 ℃.After being placed to room temperature, add ether (60ml), water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.With silica gel chromatography (hexane: ethyl acetate=10: 1～6: 1) it is made with extra care, obtain to be the title compound (130mg, 24%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：6.04(1H，s)，6.90-7.06(2H，m)，7.22(2H，d，J＝8.4Hz)，7.30(2H，d，J＝8.4Hz)，7.15-7.35(2H，m)，7.76(1H，d，J＝3.2Hz).
MSm/z：354(M
++H).
Embodiment 27:2-[[(4-chloro-phenyl-) sulfenyl]-(2, the 5-difluorophenyl) methyl]-1-(4-p-methoxy-phenyl)-1H-imidazoles
2-[(tert-butoxycarbonyl oxygen base in reference example 16 acquisitions)-(2, the 5-difluorophenyl) methyl]-(667mg, 1.6mmol) the middle trifluoroacetic acid (10ml) that adds stirred 3 hours under the room temperature 1-(4-p-methoxy-phenyl)-1H-imidazoles.Decompression is concentration of reaction solution down, adds two alkane reconcentration under reduced pressure in residue.This residue is dissolved in thionyl chloride (2.0ml), adds 1 dimethyl formamide, stirred 17 hours under the room temperature.Then, decompression is concentration of reaction solution down, adds two alkane reconcentration under reduced pressure in residue.Then, residue is dissolved in dimethyl formamide (5.0ml), add again 4-chlorobenzene mercaptan (347mg, 2.4mmol) and salt of wormwood (1.32g 9.6mmol), stirred 2 hours in 50 ℃.After being placed to room temperature, add ether (60ml), water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.With silica gel chromatography (hexane: ethyl acetate=10: 1～5: 1) it is made with extra care, use alcohol crystalization again, obtain to be the title compound (535mg, 75%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：3.86(3H，s)，5.57(1H，s)，6.8-6.9(3H，m)，6.91(2H，d，J＝8.4Hz)，7.00(2H，d，J＝8.4Hz)，7.06(2H，d，J＝6.8Hz)，7.11(2H，d，J＝6.8Hz)，7.16(1H，s)，7.81(1H，m).
MSm/z：443(M
++H).
Embodiment 28:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-1-methyl isophthalic acid H-benzoglyoxaline (compd A) and 2-[[(4-chloro-phenyl-) sulfinyl]-(2, the 5-difluorophenyl) methyl]-1-methyl isophthalic acid H-benzoglyoxaline (compd B)
2-[[(4-chloro-phenyl-in embodiment 24 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl]-1-methyl isophthalic acid H-benzoglyoxaline (190mg, 0.474mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (60mg), add 30% aquae hydrogenii dioxidi (6ml), stirred 17 hours.Add ethyl acetate (60ml) in reaction solution, water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.(hexane: ethyl acetate=6: 1～4: 1) refining, acquisition is as the non-polar compound (compd A) (48mg, 23%) of needle crystal and the solid polar compound (compd B) (23mg, 12%) that is white in color with silica gel chromatography.
Compd A
1H-NMR(400MHz，CDCl
3)δ：3.90(3H，s)，6.14(1H，s)，6.9-7.1(2H，m)，7.26-7.42(3H，m)，7.39(2H，d，J＝8.8Hz)，7.46(2H，d，J＝8.8Hz)，7.81(1H，d，J＝8.0Hz)，8.16(1H，m).
mp：213-214℃.
Ultimate analysis: C
21H
15ClF
2N
2OS: theoretical value: C, 58.27; H, 3.49; N, 6.47; S, 7.41; Cl, 8.19; F, 8.78. measured value: C, 58.08; H, 3.62; N, 6.53; S, 7.35; Cl, 8.10; F, 8.74.
Compd B
1H-NMR(400MHz，CDCl
3)δ：3.35(3/2H，s)，3.78(3/2H，s)，5.52(1/2H，s)，5.57(1/2H，s)，6.78-7.1(2H，m)，7.2-7.4(7H，m)，7.76-7.95(2H，m).
mp：130-131℃.
FAB-MS:477.0646 (C
21H
16ClF
2N
2OS, calculated value: 477.0640).
Embodiment 29:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-1-methyl-5-chloro-1H-imidazoles
2-[[(4-chloro-phenyl-in embodiment 25 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl]-1-methyl-5-chloro-1H-imidazoles (141mg, 0.37mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (60mg), add 30% aquae hydrogenii dioxidi (6ml) again, stirred 64 hours.Add ethyl acetate (60ml) in reaction solution, water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.Make solution crystallizationization with ethanol, obtain to be the title compound (103mg, 67%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：3.71(3H，s)，5.88(1H，s)，6.93-7.08(2H，m)，7.03(1H，s)，7.43(4H，s)，7.98(1H，m).
mp：179-180℃.
Ultimate analysis: C
17H
12C
L2F
2N
2O
2S: theoretical value: C, 48.90; H, 2.93; N, 6.71; S, 7.68; Cl, 16.99; F, 9.11. measured value: C, 48.90; H, 2.93; N, 6.77; S, 7.80; Cl, 17.02; F, 9.19.
Embodiment 30:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2 ,-difluorophenyl) methyl] thiazole
2-[[(4-chloro-phenyl-in embodiment 26 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl] thiazole (124mg, 0.35mmol) methyl alcohol (6.0ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aquae hydrogenii dioxidi (3ml) again, stirred 15 hours.Add ethyl acetate (60ml) in reaction solution, water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.Make solution crystallizationization with ethanol, obtain to be the title compound (91mg, 67%) of colourless column crystallization.
1H-NMR(400MHz，CDCl
3)δ：6.21(1H，s)，6.92-7.08(2H，m)，7.41(2H，d，J＝8.8Hz)，7.45(1H，d，J＝3.6Hz)，7.56(2H，d，J＝8.8Hz)，7.86(1H，d，J＝3.6Hz)，7.94(1H，m).
mp：163-164℃.
Ultimate analysis: C
16H
10ClF
2NO
2S
2: theoretical value: C, 49.81; H, 2.61; N, 3.63; S, 16.62; Cl, 9.19; F, 9.85. measured value: C, 49.98; H, 2.61; N, 3.77; S, 16.60:Cl, 9.25; F, 9.87.
Embodiment 31:2-[[(4-chloro-phenyl-) alkylsulfonyl]-(2, the 5-difluorophenyl) methyl]-1-(4-p-methoxy-phenyl)-1H-imidazoles
2-[[(4-chloro-phenyl-in embodiment 27 acquisitions) sulfenyl]-(2, the 5-difluorophenyl) methyl]-1-(4-p-methoxy-phenyl)-1H-benzoglyoxaline (118mg, 0.27mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (60mg), add 30% aquae hydrogenii dioxidi (6ml) again, stirred 64 hours.Add ethyl acetate (60ml) in reaction solution, water and saturated aqueous common salt wash it.The solution anhydrous magnesium sulfate drying, decompression is concentrated solution down.Make solution crystallizationization with ethanol, obtain to be the title compound (76mg, 60%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：3.89(3H，s)，5.83(1H，s)，6.93-7.05(4H，m)，6.97(2H，d，J＝8.8Hz)，7.01(2H，d，J＝8.8Hz).7.38(2H，d，J＝8.8Hz)，7.41(2H，d，J＝8.8Hz)，8.15(1H，m).
mp：150-151℃.
Ultimate analysis: C
23H
17ClF
2N
2O
3S: theoretical value: C, 58.13; H, 3.61; N, 5.90; S, 6.75; Cl, 7.47; F, 8.00. measured value: C, 58.09; H, 3.51; N, 5.99; S, 6.88; Cl, 7.48; F, 8.06.
Embodiment 32:5-chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl) sulfenyl] pyridine
In 0 ℃, at 2 of reference example 18 acquisitions, 5-difluorophenyl-4-pyridyl methyl alcohol (221mg, 1.00mmol) methylene dichloride (10ml) solution in add triethylamine (0.279ml 2.00mmol), add methylsulfonyl chloride (0.116ml again, 1.50mmol), stirred 3 hours under the room temperature.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.At residue obtained N, (145mg, 1.00mmol), (166mg 1.20mmol), stirred 2 hours under the room temperature 5-chloro-2-pyridine mercaptan that adding reference example 17 obtains in dinethylformamide (10ml) solution to add salt of wormwood again.In reaction mixture, add ethyl acetate, wash back organic layer anhydrous sodium sulfate drying with water, filter back concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=17: 3 wash-out portion obtains obtains to be the title compound (267mg, 0.77mmol, 77%) of yellow solid.
1H-NMR(400MHz，CDCl
3)δ：6.52(1H，s)，6.92-6.98(1H，m)，6.99-7.06(1H，m)，7.48(1H，dd，J＝8.5，0.7Hz)，7.17-7.23(1H，m)，7.34(2H，d，J＝6.1Hz)，7.47(1H，dd，J＝8.5，2.4Hz)，8.33(1H，dd，J＝2.4，0.7Hz)，8.54(2H，d，J＝6.1Hz).
MSm/z：349(M
++H).
Embodiment 33:5-chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl) alkylsulfonyl] pyridine
In 0 ℃, at 5-chloro-2-[(2,5-difluorophenyl-4-pyridylmethyl) sulfenyl] (239mg adds oxone (oxone, peroxidation one vitriolate of tartar mixture, 2KHSO to pyridine in methyl alcohol 0.68mmol) (6ml) solution
5KHSO
4K
2SO
4) (631mg, water 1.03mmol) (12ml) solution.Under the room temperature reaction mixture stirring after 3 days, is added methylene dichloride, wash with saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue is refining with the preparation high speed liquid chromatography mixed solvent of water/acetonitrile/formic acid (make system), and the gained solid is with hexane/diisopropyl ether washing back leaching, the title compound (67mg, 0.18mmol, 26%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.44(1H，s)，6.96-7.08(2H，m)，7.48(2H，d，J＝6.3Hz)，7.70-7.77(1H，m)，7.79(1H，dd，J＝8.3，2.2Hz)，7.84(1H，dd，J＝8.3，0.7Hz)，8.61(2H，d，J＝6.3Hz)，8.67(1H，dd，J＝2.2，0.7Hz).
Ultimate analysis: C
17H
11ClF
2N
2O
2S: theoretical value: C, 53.62; H, 2.91; F, 9.98; N, 7.36; S, 8.42. measured value: C, 53.55; H, 2.87; F, 10.10; N, 7.40; S, 8.55.
MSm/z：381(M
++H).
Embodiment 34:4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl] tetrahydropyrans
2-[(4-chloro-phenyl-with reference example 1 acquisition) sulfonymethyl]-1,4-two fluorobenzene (200mg, 0.661mmol) and tetrahydrochysene-4H-pyrans-4-alcohol (0.13ml, 1.36mmol) be dissolved in toluene (10ml), add cyano group methylene tri normal-butyl phosphorane (330mg, 1.37mmol) after, reflux is 14 hours under argon atmospher.Behind the reaction solution naturally cooling, (200mg, 0.829mmol), reflux is 14 hours under argon atmospher to add cyano group methylene tri normal-butyl phosphorane.Behind the reaction solution naturally cooling, concentrating under reduced pressure is handled the gained residue with the flash chromatography on silica gel method, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains white solid.With hexane wash gained white solid, the title compound (157mg, 0.406mmol, 61%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.28-1.48(2H，m)，1.71(1H，ddd，J＝25.3，11.7，4.3Hz)，2.37(1H，brd，J＝12.7Hz)，2.70-2.88(1H，m)，3.40(1H，td，J＝11.7，2.5Hz)，3.50(1H，td，J＝12.0，2.2Hz)，3.91(1H，dm，J＝11.2Hz)，4.02(1H，dm，J＝11.7Hz)，4.46(1H，d，J＝8.8Hz)，6.68-6.80(1H，m)，6.88-6.98(1H，m)，7.31(2H，d，J＝8.5Hz)，7.36-7.45(1H，m)，7.49(2H，d，J＝8.5Hz).
mp：150-152℃.
MSm/z：387(M
++H).
Ultimate analysis: C
18H
17ClF
2O
3S: theoretical value: C, 55.89; H, 4.43; Cl, 9.16; F, 9.82; S, 8.29. measured value: C, 55.64; H, 4.27; Cl, 9.41; F, 9.89; S, 8.28.
Embodiment 35:4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl] tetrahydric thiapyran
2-[(4-chloro-phenyl-with reference example 1 acquisition) sulfonymethyl]-1,4-two fluorobenzene (500mg, 1.65mmol) and tetrahydric thiapyran-4-alcohol (400mg of obtaining of reference example 19,3.38mmol) be dissolved in toluene (20ml), add cyano group methylene tri normal-butyl phosphorane (800mg, 3.31mmol) after, reflux is 14 hours under argon atmospher.Behind the reaction solution naturally cooling, (400mg, 1.66mmol), reflux is 14 hours under argon atmospher to add cyano group methylene tri normal-butyl phosphorane.Concentrating under reduced pressure behind the reaction solution naturally cooling is handled the gained residue with the flash chromatography on silica gel method, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=15: 1 wash-out portion obtains obtains white solid.With hexane/diisopropyl ether mixed solution washing gained white solid, the title compound (404mg, 1.00mmol, 61%) of the powder that obtains to be white in color
1H-NMR(400MHz，CDCl
3)δ：1.47(1H，ddd，J＝23.4，10.0，3.3Hz)，1.68(1H，ddd，J＝25.0，11.4，3.3Hz)，2.13(1H，dm，J＝11.4Hz)，2.50-2.78(5H，m)，2.82(1H，td，J＝12.8，2.6Hz)，4.47(1H，d，J＝7.3Hz)，6.72-6.82(1H，m)，6.90-7.00(1H，m)，7.31(2H，d，J＝8.8Hz)，7.40-7.60(1H，m)，7.49(2H，d，J＝8.8Hz).
mp：150-152℃.
MSm/z：403(M
++H).
Ultimate analysis: C
18H
17ClF
2O
2S
2: theoretical value: C, 53.66; H, 4.25; Cl, 8.80; F, 9.43; S, 15.92. measured value: C, 53.52; H, 4.21; Cl, 9.00; F, 9.54; S, 15.88.
Embodiment 36:4-[[(4-chloro-phenyl-) alkylsulfonyl] (2; the 5-difluorophenyl) methyl] tetrahydric thiapyran-1; 1-dioxide (compd A) and 4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl] tetrahydric thiapyran-1-oxide compound (compd B (isomer A) and compd B (isomer B))
The compd A compd B
With the 4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl] tetrahydric thiapyran (360mg, 0.893mmol) be dissolved in methylene dichloride (15ml) after, add under ice-cooled 3-chlorine peroxybenzoic acid (320mg, 1.85mmol).Stir under the room temperature after 14 hours, the concentrating under reduced pressure reaction solution is residue obtainedly handled with the flash chromatography on silica gel method, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains, acquisition white solid.The gained white solid is dissolved in methylene dichloride, use 1N aqueous sodium hydroxide solution and saturated common salt water washing successively after, the organic layer anhydrous magnesium sulfate drying.Filter back concentrating under reduced pressure filtrate, obtain white solid.The gained white solid washs with ether, the title compound A (187mg, 0.430mmol, 48%) of the powder that obtains to be white in color.Then, concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=50: 1 wash-out portion obtains obtains title compound B (isomer A) and title compound B (isomer B) as white solid.Gained mixture flash chromatography on silica gel method (methylene dichloride: methyl alcohol=80: 1) behind the separation and purification, respectively with ether washing gained white solid, be white in color title compound B (isomer A) (low the polarity) (78mg of powder of acquisition, 0.19mmol, 21%), the title compound B (isomer B) (high polarity) (69mg, 0.17mmol, 19%) of powder is white in color.
Compd A
1H-NMR(400MHz，CDCl
3)δ：1.85-2.00(1H，m)，2.18-2.35(2H，m)，2.68-2.91(2H，m)，2.98-3.10(2H，m)，3.10-3.28(2H，m)，4.54(1H，brd，J＝7.1Hz)，6.74-6.90(1H，m)，6.94-7.06(1H，m)，7.33(2H，d，J＝8.7Hz)，7.35-7.55(1H，m)，7.49(2H，d，J＝8.7Hz).
mp：245-248℃.
Ultimate analysis: C
18H
17ClF
2O
4S
2: theoretical value: C, 49.71; H, 3.94; Cl, 8.15; F, 8.74; S, 14.75. measured value: C, 49.38; H, 3.87; Cl, 8.50; F, 8.86; S, 14.62.
Compd B (isomer A)
1H-NMR(400MHz，CDCl
3)δ：1.76(1H，brd，J＝13.4Hz)，2.18(1H，ddm，J＝25.4，12.5Hz)，2.32-2.70(4H，m)，2.74-2.90(1H，m)，2.98(1H，dm，J＝14.0Hz)，3.09(1H，dm，J＝14.4Hz)，4.53(1H，d，J＝7.3Hz)，6.72-6.86(1H，m)，6.90-7.02(1H，m)，7.32(2H，d，J＝8.5Hz)，7.40-7.60(1H，m)，7.49(2H，d，J＝8.5Hz).
mp：255-256℃.
Ultimate analysis: C
18H
17ClF
2O
3S
2: theoretical value: C, 51.61; H, 4.09; Cl, 8.46; F, 9.07; S, 15.31. measured value: C, 51.51; H, 4.04; Cl, 8.69; F, 9.15; S, 15.20.
Compd B (isomer B)
1H-NMR(400MHz，CDCl
3)δ：1.42(1H，ddm，J＝22.3，11.7Hz)，1.92(1H，ddm，J＝11.7，11.0Hz)，2.14-2.27(1H，m)，2.66(1H，td，J＝12.2，2.7Hz)，2.70-2.90(3H，m)，3.10-3.24(1H，m)，3.32-3.44(1H，m)，4.49(1H，d，J＝8.1Hz)，6.72-6.85(1H，m)，6.90-7.02(1H，m)，7.32(2H，d，J＝8.5Hz)，7.34-7.50(1H，m)，7.48(2H，d，J＝8.5Hz).
mp：184-187℃.
Ultimate analysis: C
18H
17ClF
2O
3S
2: theoretical value: C, 51.61; H, 4.09; Cl, 8.46; F, 9.07; S, 15.31. measured value: C, 51.82; H, 4.23; Cl, 8.42; F, 9.12; S, 15.07.
Embodiment 37:4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl]-the 1-piperidine carboxylic acid tert-butyl ester
2-[(4-chloro-phenyl-with reference example 1 acquisition) sulfonymethyl]-1,4-two fluorobenzene (1.25g, 4.13mmol) and the 4-hydroxyl-1-piperidine carboxylic acid tert-butyl ester (1.70g, 8.44mmol) be dissolved in toluene (50ml), add cyano group methylene tri normal-butyl phosphorane (2.00g, 8.29mmol) after, reflux is 14 hours under argon atmospher.Concentrating under reduced pressure behind the reaction solution naturally cooling is handled the gained residue with the flash chromatography on silica gel method, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains obtains white solid.With ether washing gained white solid, the title compound (1.68g, 3.46mmol, 84%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.10-1.25(1H，m)，1.40-1.70(2H，m)，1.44(9H，s)，2.30-2.50(1H，m)，2.60-2.95(3H，m)，4.00-4.25(2H，m)，4.45(1H，d，J＝7.8Hz)，6.69-6.80(1H，m)，6.88-6.98(1H，m)，7.31(2H，d，J＝8.6Hz)，7.35-7.50(1H，m)，7.49(2H，d，J＝8.6Hz).
mp：193-196℃.
Ultimate analysis: C
23H
26ClF
2NO
4S: theoretical value: C, 56.84; H, 5.39; Cl, 7.30; F, 7.82; N, 2.88; S, 6.60. measured value: C, 56.41; H, 5.43; Cl, 7.77; F, 7.61; N, 2.99; S, 6.58.
Embodiment 38:4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl] piperidine hydrochlorate
With the 4-[[(4-chloro-phenyl-) alkylsulfonyl] (2, the 5-difluorophenyl) methyl]-(1.56g 3.21mmol) is dissolved in methylene dichloride (50ml) to the 1-piperidine carboxylic acid tert-butyl ester, at the ice-cooled trifluoroacetic acid (5.0ml) that drips down.Under the room temperature reaction solution is stirred concentrating under reduced pressure reaction solution after 2 hours.In residue obtained, add methylene dichloride (10ml) and 1N ethanol solution hydrochloride (10ml) back concentrating under reduced pressure, obtain white solid.With ether washing gained solid, the title compound (1.36g, 3.12mmol, 97%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CD
3OD)δ：1.38-1.52(1H，m)，1.70-1.92(2H，m)，2.73(1H，brd，J＝14.2Hz)，2.86-3.00(1H，m)，3.05(1H，td，J＝12.9，3.1Hz)，3.13(1H，td，J＝13.1，3.1Hz)，3.30-3.40(1H，m)，3.48(1H，dm，J＝13.0Hz)，4.72(1H，d，J＝8.6Hz)，6.82-6.98(1H，m)，7.04-7.12(1H，m)，7.40-7.55(1H，m)，7.44(2H，d，J＝8.6Hz)，7.57(2H，d，J＝8.6Hz).
mp：184-190℃.
Ultimate analysis: C
18H
18ClF
2NO
2SHCl0.75H
2O: theoretical value: C, 49.61; H, 4.74; Cl, 16.27; F, 8.72; N, 3.21; S, 7.36. measured value: C, 49.57; H, 4.75; Cl, 15.79; F, 9.16; N, 3.34; S, 7.25.
Embodiment 39:2-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-5-[(4-chlorobenzene sulfenyl) methyl] pyridine
With sodium borohydride (33mg, 0.88mmol) ethanol (15ml) suspension liquid be cooled to-78 ℃, slowly add acetate [6-(2,5-difluorophenyl carbonyl) pyridin-3-yl] methyl esters (510mg, ethanolic soln 1.75mmol) (10ml) that reference example 21 obtains while stirring.Stir and add aqueous ammonium chloride solution after 30 minutes, be placed to room temperature.(100ml) extracts it with ethyl acetate, solution with water and saturated common salt water washing.With concentrated solution under the decompression behind the anhydrous magnesium sulfate drying.Residue is dissolved in methylene dichloride (30ml), ice-cooled triethylamine (270 μ l), the methylsulfonyl chloride (270 μ l) of adding down.Stirred 3 days under the room temperature.Extract solution with water and saturated common salt water washing with ethyl acetate (60ml) after adding water.With concentrated solution under the decompression behind the anhydrous magnesium sulfate drying.This residue is dissolved in N, dinethylformamide (25ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (751mg, 5.3mmol) and salt of wormwood (718mg 5.2mmol), stirred 1 hour in 60 ℃.Reaction solution adds ether (80ml) after being cooled to room temperature, and water and saturated aqueous common salt wash it.The organic layer anhydrous magnesium sulfate drying, decompression concentrates down.(hexane: ethyl acetate=10: 1) handle, residue obtains to be white in color solid title compound (237mg, 27%) with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.99(2H，s)，5.81(1H，s)，6.90(2H，m)，7.15(2H，d，J＝8.8Hz)，7.16(2H，d，J＝8.8Hz)，7.19(4H，d，J＝8.8Hz)，7.20(1H，d，J＝7.6Hz)，7.38(1H，m)，7.49(1H，dd，J＝2.0，7.6Hz)，8.38(1H，br).
mp：87-88℃.
Embodiment 40:2-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-5-[(4-chloro-phenyl-alkylsulfonyl) methyl] pyridine
At 2-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-5-[(4-chlorobenzene sulfenyl) methyl] pyridine (75mg, 0.15mmol) methyl alcohol (6.0ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aquae hydrogenii dioxidi (3ml) again, stirred 22 hours.Add ethyl acetate in reaction solution, water, sodium thiosulfate solution and saturated aqueous common salt wash it.Concentrated solution under the decompression after the solution drying.With silica gel chromatography (20%MeOH/CHCl
3) residue is made with extra care, obtain to be the title compound (70mg, 62%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：4.29(2H，s)，5.91(1H，s)，6.90-7.08(2H，m)，7.39(2H，dd，J＝1.6，6.8Hz)，7.45(2H，dd，J＝1.6，6.8Hz)，7.51(2H，d，J＝8.8Hz)，7.55(2H，d，J＝8.8Hz)，7.60(1H，d，J＝8.0Hz)，7.65(1H，dd，J＝2.4，8.0Hz)，7.91(1H，m)，8.23(1H，s).
mp：186-187℃.
Ultimate analysis: C
25H
17Cl
2F
2NO
4S
2: theoretical value: C, 52.82; H, 3.01; N, 2.46; S, 11.28; Cl, 12.47; F, 6.68. measured value: C, 52.88; H, 3.10; N, 2.63; S, 11.38; Cl, 12.40; F, 6.83.
Embodiment 41:2-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-5-(1,3-dioxolane-2-yl) pyridine
In nitrogen atmosphere, the ice-cold 2-[(2 that obtains at reference example 22 down, the 5-difluorophenyl)-hydroxymethyl]-5-(1,3-dioxolane-2-yl) pyridine (1.52g, 5.2mmol) dichloromethane solution (30ml) in add triethylamine (1.08ml, 7.8mmol), (0.52ml 6.8mmol), stirred under the room temperature 3 hours methylsulfonyl chloride.Use extracted with diethyl ether after adding saturated sodium bicarbonate aqueous solution.Anhydrous magnesium sulfate drying is used in solution saturated common salt water washing, and decompression is concentrated solution down.Residue is dissolved in dimethyl formamide (30ml), add again chlorobenzene mercaptan (901mg, 6.2mmol) and salt of wormwood (1.08g 7.8mmol), stirred 3 hours in 60 ℃.After being cooled to room temperature, with ether dilution, solution with water and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after decompression concentrate down.(hexane: ethyl acetate=5: 1) refining, acquisition is the title compound (1.56g, 71%) of colourless needle crystal to residue with silica gel column chromatography.
1H-NMR(400MHz，CDCl
3)δ：4.0-4.15(4H，m)，5.84(1H，s)，5.92(1H，s)，6.85-6.96(2H，m)，7.19(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.8Hz)，7.43(1H，d，J＝8.0Hz)，7.43(1H，m)，7.77(1H，dd，J＝2.0，8.0Hz)，8.70(1H，d，J＝2.0Hz).
mp：70-73℃.
MSm/z：420(M
++H).
Embodiment 42:2-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-5-(1,3-dioxolane-2-yl) pyridine
At 2-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-(1.54g adds seven molybdic acids, six ammonium tetrahydrates (150mg) to 5-(1,3-dioxolane-2-yl) pyridine in methyl alcohol 3.67mmol) (30ml) solution, add 30% aquae hydrogenii dioxidi (15ml) again, stirred 24 hours.After the ethyl acetate dilution, solution with water and saturated common salt water washing.Behind the concentrated solution, make the residue crystallization under the decompression, obtain to be the title compound (1.22g, 74%) of colourless needle crystal with ethanol.
1H-NMR(400MHz，CDCl
3)δ：4.02-4.10(4H，m)，5.85(1H，s)，5.97(1H，s)，6.91(1H，m)，6.96(1H，m)，7.38(2H，d，J＝8.4Hz)，7.53(2H，d，J＝8.4Hz)，7.63(1H，d，J＝7.6Hz)，7.82(1H，d，J＝8.0Hz)，7.94(1H，m)，8.67(1H，br-s).
mp：167-168℃.
FAB-MS:452.0544 (C
21H
17ClF
2NO
4S, calculated value: 452.0535).
Embodiment 43:2-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-5-(hydroxymethyl) pyridine
At 2-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-5-(1,3-dioxolane-2-yl) pyridine (295mg, 0.54mmol) 1, add 1N hydrochloric acid (30ml) in the 4-two alkane solution (30ml), stirred 18 hours under the room temperature.Solution with ethyl acetate extraction after, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after decompression concentrate down, obtain residue.
Residue is dissolved in ethanol (10ml), and (10mg 0.27mmol), stirred 1 hour the ice-cooled sodium borohydride of adding down.Add water, mixed solution with ethyl acetate extraction after, water and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after, decompression concentrates down and obtains residue.With silica gel chromatography (3% methyl alcohol/chloroform) it is made with extra care, obtain to be the title compound (205mg, 93%) of needle crystal.
1H-NMR(400MHz，CDCl
3)δ：4.74(2H，s)，5.94(1H，s)，6.91(1H，m)，6.99(1H，m)，7.38(2H，d，J＝8.4Hz)，7.53(2H，d，J＝8.4Hz)，7.62(1H，d，J＝8.0Hz)，7.76(1H，dd，J＝2.0，8.0Hz)，7.98(1H，m)，8.58(1H，d，J＝2.0Hz).
mp：151-152℃.
FAB-MS:410.0444 (C
19H
15ClF
2NO
3S, calculated value: 410.0429).
Embodiment 44:3-[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl acrylate
2-[(4-chloro-phenyl-alkylsulfonyl in embodiment 42 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(1,3-dioxolane-2-yl) pyridine (212mg, 0.47mmol) 1; add 1N hydrochloric acid (10ml) in the 4-two alkane solution (10ml), stirred 19 hours under the room temperature.Solution with ethyl acetate extraction after, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after decompression concentrate down, obtain residue.
Residue is dissolved in tetrahydrofuran (THF) (15ml), and (188mg 0.56mmol), stirred 17 hours to add the inferior phosphoranyl methyl acetate of triphenyl under nitrogen atmosphere.Decompression concentrated reaction solution down obtains residue.With silica gel column chromatography (hexane: ethyl acetate=5: 1) residue is made with extra care, obtained to be the title compound (187mg, 86%) of needle crystal.
1H-NMR(400MHz，CDCl
3)δ：3.80(3H，s)，5.94(1H，s)，6.50(1H，d，J＝16.0Hz)，6.91(1H，m)，6.99(1H，m)，7.38(2H，d，J＝8.8Hz)，7.53(2H，d，J＝8.8Hz)，7.63(1H，d，J＝8.0Hz)，7.63(1H，d，J＝16.0Hz)，7.84(1H，dd，J＝2.0，8.0Hz)，7.98(1H，m)，8.70(1H，d，J＝2.0Hz).
mp：145-146℃.
MSm/z：464(M
++H).
Embodiment 45:3-[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl propionate
With 3-[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] (160mg 0.34mmol) is dissolved in ethanol (15ml) to methyl acrylate, adds palladium carbon (30mg), and high degree of agitation is 24 hours under the nitrogen atmosphere of 1 air pressure.Decompression concentrates down behind the filtering reacting liquid.(hexane: ethyl acetate=5: 1) refining, acquisition is the title compound (94mg, 58%) of needle crystal to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.63(2H，t，J＝7.6Hz)，2.95(2H，t，J＝7.6Hz)，3.65(3H，s)，5.89(1H，s)，6.90(1H，m)，6.97(1H，m)，7.36(2H，d，J＝8.4Hz)，7.53(2H，d，J＝8.4Hz)，7.55(2H，m)，8.00(1H，m)，8.45(1H，d，J＝1.6Hz).
mp：121-123℃.
MSm/z：466(M
++H).
Embodiment 46:3-[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] propionic acid
With 3-[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] (92mg 0.20mmol) is dissolved in tetrahydrofuran (THF) (5ml) to methyl propionate, and (23mg, stirred 2 hours aqueous solution 0.5mmol) (3ml) back to add lithium hydroxide.After in reaction solution, adding 10% sodium pyrosulfate, use ethyl acetate extraction.Anhydrous magnesium sulfate drying is used in extraction liquid water and saturated common salt water washing again, and decompression concentrates down then, obtains residue.To the residue crystallization, obtain to be the title compound (67mg, 75%) of needle crystal with ethanol.
1H-NMR(400MHz，CDCl
3)δ：2.69(2H，t，J＝7.6Hz)，2.96(2H，t，J＝7.6Hz)，5.92(1H，s)，6.90(1H，m)，6.98(1H，m)，7.36(2H，d，J＝8.4Hz)，7.52(2H，d，J＝8.4Hz)，7.56(2H，m)，7.99(1H，m)，8.47(1H，d，J＝2.4Hz).
mp：158-160℃.
MSm/z：452(M
++H).
Ultimate analysis: C
21H
16ClF
2NO
4S: theoretical value: C, 55.82; H, 3.57; N, 3.10; S, 7.10; Cl, 7.85; F, 8.41. measured value: C, 55.70; H, 3.75; N, 3.19; S, 7.12; Cl, 8.64; F, 8.11.
Embodiment 47:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] formaldehyde
2-[(4-chloro-phenyl-alkylsulfonyl in embodiment 42 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(1,3-dioxolane-2-yl) pyridine (602mg, 1.3mmol) 1; add 1N hydrochloric acid (30ml) in the 4-two alkane solution (30ml), stirred 18 hours under the room temperature.Solution with ethyl acetate extraction after, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Solution with anhydrous magnesium sulfate drying after decompression concentrate down, obtain residue.With silica gel chromatography (hexane: ethyl acetate=5: 1) residue is made with extra care, obtained to be the title compound (530mg, 98%) of needle crystal.
1H-NMR(400MHz，CDCl
3)δ：6.01(1H，s)，6.94(1H，m)，7.01(1H，m)，7.40(2H，d，J＝8.4Hz)，7.54(2H，d，J＝8.4Hz)，7.81(1H，d，J＝8.4Hz)，7.97(1H，m)，8.20(1H，dd，J＝2.0，8.4Hz)，9.05(1H，d，J＝2.0Hz)，10.12(1H，s).
Embodiment 48:2-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-5-(piperidines-1-ylmethyl) pyridine
Under the room temperature; [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] formaldehyde (82mg; 0.2mmol) and piperidines (40 μ l; 0.4mmol) dichloromethane solution (5ml) in add acetate (23 μ l; 0.4mmol) and sodium triacetoxy borohydride (85mg 0.4mmol), stirred 3 hours.After adding the saturated sodium bicarbonate aqueous solution stopped reaction, with ethyl acetate (80ml) dilution.Divide and get organic layer, water and saturated common salt water washing.Concentrated solution under the decompression obtains residue after the drying solution.With silica gel chromatography (hexane: ethyl acetate=1: 1) residue is made with extra care, used alcohol crystalization again, obtain title compound (89mg, 93%).
1H-NMR(400MHz，CDCl
3)δ：1.5-1.6(6H，m)，2.3-2.4(4H，m)，3.45(2H，s)，5.91(1H，s)，6.90(1H，m)，6.98(1H，m)，7.35(2H，d，J＝8.4Hz)，7.52(2H，d，J＝8.4Hz)，7.53(1H，m)，7.7(1H，br)，8.02(1H，m)，8.49(1H，d，J＝2.4Hz).
mp：113-114℃.
MSm/z：477(M
++H).
Ultimate analysis: C
24H
23ClF
2N
2O
2S: theoretical value: C, 60.44; H, 4.86; N, 5.87; S, 6.72; Cl, 7.43; F, 7.97. measured value: C, 59.87; H, 4.81; N, 5.83; S, 6.87; Cl, 7.55; F, 8.02.
Embodiment 49:4-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl] morpholine
Under the room temperature; embodiment 47 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] formaldehyde (82mg; 0.2mmol) and morpholine (35 μ l; 0.4mmol) dichloromethane solution (5ml) in add acetate (23 μ l; 0.4mmol) and sodium triacetoxy borohydride (85mg 0.4mmol), stirred 3 hours.After adding the saturated sodium bicarbonate aqueous solution stopped reaction, with ethyl acetate (80ml) dilution.Divide and get organic layer, water and saturated common salt water washing.Concentrated solution under the decompression obtains residue after the drying solution.With silica gel chromatography (hexane: ethyl acetate=1: 1) residue is made with extra care, used alcohol crystalization again, obtain title compound (90mg, 94%).
1H-NMR(400MHz，CDCl
3)δ：2.4(4H，m)，3.49(2H，s)，3.6(4H，m)，5.92(1H，s)，6.90(1H，m)，6.98(1H，m)，7.36(2H，d，J＝8.4Hz)，7.53(2H，d，J＝8.4Hz)，7.57(1H，d，J＝8.0Hz)，7.71(1H，br-d，J＝8.0Hz)，8.02(1H，m)，8.53(1H，d，J＝2.0Hz).
mp：120-121℃.
MSm/z：479(M
++H).
Ultimate analysis: C
22H
21ClF
2N
2O
3S: theoretical value: C, 57.68; H, 4.42; N, 5.85; S, 6.70; Cl, 7.40; F, 7.93. measured value: C, 57.41; H, 4.43; N, 5.90; S, 6.82; Cl, 7.52; F, 7.91.
Embodiment 50:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid
Under the room temperature, [6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl that obtains at embodiment 47] formaldehyde (110mg, add in t-butanol solution 0.27mmol) (3.0ml) the 2-methyl-2-butene (143 μ l, 1.35mmol).((98mg 1.08mmol), stirred 2 hours to add Textone again for 32.4mg, aqueous solution 0.27mmol) (0.6ml) to add SODIUM PHOSPHATE, MONOBASIC in this suspension liquid.Add water (30ml) and acetate (1ml) in reaction solution, (100ml) extracts with ethyl acetate.Extraction liquid saturated common salt water washing, the decompression of dry back is retort solution down.To residue obtained crystallization, obtain to be the title compound (71mg, 62%) of colourless needle crystal with ethanol.
1H-NMR(400MHz，CDCl
3)δ：6.03(1H，s)，6.96(1H，m)，7.03(1H，m)，7.42(2H，d，J＝8.4Hz)，7.56(2H，d，J＝8.4Hz)，7.73(1H，d，J＝8.4Hz)，7.97(1H，m)，8.35(1H，dd，J＝2.0，8.4Hz)，9.20(1H，d，J＝2.0Hz).
mp：＞230℃.
MSm/z：424(M
++H).
Ultimate analysis: C
19H
12ClF
2NO
4S: theoretical value: C, 53.84; H, 2.85; N, 3.30; S, 7.57; Cl, 8.37; F, 8.97. measured value: C, 53.47; H, 2.81; N, 3.46; S, 7.65; Cl, 8.49; F, 9.00.
Embodiment 51:3-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine-N-oxide
Under the room temperature, at the 3-[(4-chloro-phenyl-alkylsulfonyl of embodiment 19 acquisitions)-(2, the 5-difluorophenyl) methyl] ((81mg 0.47mmol), stirred 24 hours pyridine to add 3-chlorine peroxybenzoic acid among the 162mg, methylene dichloride 0.427mmol) (15ml).After reaction solution dilutes with ether (60ml), with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing.The dry after-filtration of solution, decompression is concentrated solution down, obtains residue.This residue is handled with silica gel chromatography (ethyl acetate), obtained title compound (68mg, 40%).Make this compound crystalization with ethanol, obtain colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.58(1H，s)，6.95(1H，m)，7.03(1H，m)，7.29(1H，dd，J＝6.6，8.0Hz)，7.42(2H，d，J＝8.6Hz)，7.57(1H，d，J＝8.0Hz)，7.62(2H，d，J＝8.4Hz)，7.66(1H，m)，8.10(1H，d，J＝6.6Hz)，8.29(1H，s).
mp：183-184℃.
Ultimate analysis: C
18H
12ClF
2NO
3S: theoretical value: C, 54.62; H, 3.06; N, 3.54; S, 8.10; Cl, 8.96; F, 9.60. measured value: C, 54.19; H, 2.99; N, 3.67; S, 8.27; Cl, 8.92; F, 9.53.
Embodiment 52:4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine-N-oxide
4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 20 acquisitions)-and (2, the 5-difluorophenyl) methyl] ((100mg 0.58mmol), stirred 20 hours pyridine to add 3-chlorine peroxybenzoic acid among the 221mg, methylene dichloride 0.58mmol) (20ml).After reaction solution dilutes with ether (60ml), with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing.The dry after-filtration of solution, decompression is concentrated solution down, obtains residue.This residue is handled with silica gel chromatography (ethyl acetate), obtained title compound (183mg, 80%).Make this compound crystalization with ethanol, obtain colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.62(1H，s)，6.97(1H，m)，7.06(1H，m)，7.42(2H，d，J＝7.2Hz)，7.44(2H，d，J＝8.8Hz)，7.60(2H，d，J＝8.8Hz)，7.68(1H，m)，8.17(2H，d，J＝7.2Hz).
mp：211-212℃.
Ultimate analysis: C
18H
12ClF
2NO
3S: theoretical value: C, 54.62; H, 3.06; N, 3.54; S, 8.10; Cl, 8.96; F, 9.60. measured value: C, 54.19; H, 2.92; N, 3.65; S, 8.26; Cl, 8.99; F, 9.61.
Embodiment 53:3-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine
With the 3-chloro-4-[(2 that reference example 23 obtains, 5-difluorophenyl)-hydroxymethyl] pyridine (511mg, 2.0mmol) be dissolved in thionyl chloride (3.0ml) after, add the dimethyl formamide of catalytic amount, stirred 17 hours.Decompression is concentration of reaction solution down, adds toluene in residue, reconcentration.
This residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (375mg, 2.6mmol) and salt of wormwood (414mg, 3mmol), in 60 ℃ of stirrings 3 hours.Add ether (60ml) after reaction solution is cooled to room temperature, water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ethyl acetate=8: 1) handle, acquisition is solid title compound (196mg, 26%) to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：6.07(1H，s)，6.95-7.08(2H，m)，7.18(1H，m)，7.23(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.8Hz)，7.58(1H，d，J＝5.2Hz)，8.51(1H，d，J＝5.2Hz)，8.58(1H，s).
mp：70-72℃.
MSm/z：382(M
++1).
Embodiment 54:2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine
With reference example 24 obtain 2,5-two chloro-4-[(2,5-difluorophenyl)-hydroxymethyl] pyridine (580mg, 2.0mmol) be dissolved in thionyl chloride (3.0ml) after, add the dimethyl formamide of catalytic amount, stirred 17 hours.Decompression is concentration of reaction solution down, adds the toluene reconcentration in residue.This residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-chlorobenzene mercaptan (375mg, 2.6mmol) and salt of wormwood (414mg, 3mmol), in 50 ℃ of stirrings 17 hours.Add ether (60ml) after reaction solution is cooled to room temperature, water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.(hexane: ether=10: 1) handle, acquisition is solid title compound (484mg, 58%) to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：5.96(1H，s)，6.95-7.04(2H，m)，7.01(1H，m)，7.23(2H，d，J＝8.8Hz)，7.26(2H，d，J＝8.8Hz)，7.54(1H，s )，8.33(1H，s).
mp：128-129℃.
MSm/z：416(M
++1).
Embodiment 55:3-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine
3-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 53 acquisitions)-(2, the 5-difluorophenyl) methyl] pyridine (122mg, 0.32mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (60mg), add 30% aquae hydrogenii dioxidi (6ml) again, stirred 24 hours.After the ethyl acetate dilution, solution with water and saturated common salt water washing.Behind the concentrated solution, residue is carried out crystallization under the decompression, obtain to be the title compound (103mg, 78%) of colourless needle crystal with ethanol.
1H-NMR(400MHz，CDCl
3)δ：6.23(1H，s)，6.94(1H，m)，7.06(1H，m)，7.41(2H，d，J＝8.0Hz)，7.53(1H，m)，7.59(2H，d，J＝8.0Hz)，8.11(1H，d，J＝5.2Hz)，8.55(1H，s)，8.60(1H，d，J＝5.2Hz).
mp：160-161℃.
Ultimate analysis: C
18H
11Cl
2F
2NO
2S: theoretical value: C, 52.19; H, 2.68; N, 3.38; S, 7.74; Cl, 17.12; F, 9.17. measured value: C, 52.17; H, 2.69; N, 3.44; S, 7.96; Cl, 17.12; F, 9.00.
Embodiment 56:3-chloro-4-[(4-chloro-phenyl-sulfinyl)-and (2, the 5-difluorophenyl) methyl] pyridine
3-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 53 acquisitions)-and (2, the 5-difluorophenyl) methyl] (75mg, (33mg 0.20mmol), stirred 3 hours down ice-cooled pyridine to add 3-chlorine peroxybenzoic acid in methylene dichloride 0.20mmol) (10ml) solution.After ether (80ml) dilution, solution with water and saturated aqueous common salt wash.Behind the concentrated solution, (hexane: ethyl acetate=3: 1) refining, acquisition is as the title compound (48mg, 60%) of non-enantiomer mixture (1: 1) with silica gel chromatography for residue under the decompression.
1H-NMR(400MHz，CDCl
3)δ：5.53(1/2H，s)，5.66(1/2H，s)，6.83(1/2H，s)，6.95-7.08(3/2H，m)，7.23(1/2H，m)，7.25(1H，d，J＝8.4Hz)，7.26(1H，d，J＝8.4Hz)，7.34(1H，d，J＝8.4Hz)，7.36(1H，d，J＝8.4Hz)，7.37(1/2H，m)，7.76(1/2H，d，J＝5.2Hz)，7.98(1/2H，d，J＝5.2Hz)，8.47(1/2H，s)，8.56(1/2H，d，J＝5.2Hz)，8.60(1/2H，s)，8.61(1/2H，d，J＝5.2Hz).
FAB-MS:397.9992 (C
18H
12Cl
2F
2NOS, calculated value: 397.9985).
Embodiment 57:2,5-two chloro-4-[(4-chloro-phenyl-alkylsulfonyls)-(2, the 5-difluorophenyl) methyl] pyridine 0.5 hydrate
At 2 of embodiment 54 acquisitions, 5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] (60mg, (62mg 0.36mmol), stirred 3 hours under the room temperature pyridine to add 3-chlorine peroxybenzoic acid in methylene dichloride 0.14mmol) (3.0ml) solution.After ether (80ml) dilution, solution washs with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt.Decompression is down behind the concentrated solution, residue with silica gel chromatography (hexane: ethyl acetate=5: 1) refining, again by the hexane crystallization, obtain title compound (55mg, 88%).
1H-NMR(400MHz，CDCl
3)δ：6.15(1H，s)，6.93(1H，m)，7.05(1H，m)，7.44(2H，d，J＝8.8Hz)，7.50(1H，m)，7.59(2H，d，J＝8.8Hz)，8.13(1H，s)，8.55(1H，s)，8.33(1H，s).
mp：147-148℃.
Ultimate analysis: C
18H
10Cl
3F
2NO
2S, 0.5H
2O: theoretical value: C, 47.23; H, 2.42; N, 3.06; S, 7.01; Cl, 23.24; F, 8.30. measured value: C, 47.25; H, 2.24; N, 3.21; S, 7.19; Cl, 23.25; F, 8.32.
Embodiment 58:4-[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine
In 100 ℃, under nitrogen atmosphere to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (100mg, 0.24mmol) and morpholine (200 μ l) 1,4-two alkane (1.0ml) solution stirring 2 days.After being cooled to room temperature, with ethyl acetate (40ml) dilution, solution with water and saturated aqueous common salt wash.Concentrate under the decompression after the drying solution and obtain residue, residue obtained (hexane: ethyl acetate=5: 1) refining, acquisition is the title compound (100mg, 89%) of oily matter with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.48(4H，m)，3.82(4H，m)，6.00(1H，s)，6.94(1H，s)，6.94-7.04(2H，m)，7.09(1H，m)，7.23(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，8.12(1H，s).
MSm/z：467(M
++H).
Embodiment 59:4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine
At 4-[5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine (90mg, 0.19mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (60mg), add 30% aquae hydrogenii dioxidi (6ml) again, stirred 8 hours.After the ethyl acetate dilution, solution with water and saturated common salt water washing.(hexane: ethyl acetate=3: 1) handle, use alcohol crystalization again, acquisition is the title compound (80mg, 83%) of colourless needle crystal to residue with silica gel column chromatography behind the following concentrated solution of decompression.
1H-NMR(400MHz，CDCl
3)δ：3.54(4H，m)，3.84(4H，m)，6.12(1H，s)，6.90(1H，m)，7.02(1H，m)，7.42(2H，d，J＝8.4Hz)，7.45(1H，s)，7.46(1H，m)，7.58(2H，d，J＝8.4Hz)，8.06(1H，s).
mp：180-181℃.
Ultimate analysis: C
22H
18Cl
2F
2N
2O
3S: theoretical value: C, 52.92; H, 3.63; N, 5.61; S, 6.42; Cl, 14.20; F, 7.61. measured value: C, 52.68; H, 3.56; N, 5.69; S, 6.70; Cl, 14.32; F, 7.97.
Embodiment 60:4-[2-[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino-ethyl] morpholine
In 100 ℃, under nitrogen atmosphere to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (100mg, 0.24mmol) and 4-(2-amino-ethyl) morpholine (200 μ l) 1,4-two alkane (1.0ml) solution stirring 2 days.After being cooled to room temperature, with ethyl acetate (40ml) dilution, solution with water and saturated aqueous common salt wash.Decompression concentrates down and obtains residue after the drying solution, and is residue obtained refining with silica gel chromatography (30% methyl alcohol/chloroform), obtains to be the title compound (12mg, 10%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：2.42(4H，m)，2.54(2H，d，J＝6.0Hz)，3.27(2H，q，J＝6.0Hz)，3.67(4H，m)，5.12(br，1H)，5.90(1H，s)，6.61(1H，s)，6.86-7.0(2H，m)，7.06(1H，m)，7.15(2H，d，J＝8.4Hz)，7.16(2H，d，J＝8.4Hz)，7.95(1H，s).
MSm/z：510(M
++H).
Embodiment 61:4-[2-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino-ethyl] morpholine-N-oxide compound
At 4-[2-[5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino-ethyl] morpholine (11mg, 0.032mmol) methyl alcohol (12ml) solution in add seven molybdic acids, six ammonium tetrahydrates (10mg), add 30% aquae hydrogenii dioxidi (1ml) again, stirred 8 hours.After the ethyl acetate dilution, solution with water and saturated common salt water washing.Decompression down behind the concentrated solution residue refining with silica gel chromatography (3% methyl alcohol, 3% TERTIARY BUTYL AMINE/chloroformic solution), obtain title compound (5.0mg, 42%).
1H-NMR(400MHz，CDCl
3)δ：3.2-3.4(4H，m)，3.54(2H，m)，3.81(2H，m)，3.91(2H，m)，4.44(2H，m)，6.09(1H，s)，6.88(1H，m)，6.98(1H，m)，7.22(1H，s)，7.40(2H，d，J＝8.4Hz)，7.51(1H，m)，7.60(2H，d，J＝8.4Hz)，7.94(1H，s).
FAB-MS:558.0837 (C
24H
24Cl
2F
2N
3O
4S, calculated value: 558.0833).
Embodiment 62:5-azido methyl-2-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine
2-[(4-chloro-phenyl-alkylsulfonyl with embodiment 43 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(hydroxymethyl) pyridine (471mg; 1.15mmol) be dissolved in tetracol phenixin (4ml) and N; in the mixed solution of dinethylformamide (16ml); add sodiumazide (112mg; 1.72mmol), (451mg 1.72mmol), stirred 3 hours in 90 ℃ triphenyl phosphine.In reaction soln, add the entry ethyl acetate extraction, organic layer water and saturated common salt water washing successively then.The gained organic layer with dried over sodium sulfate after concentrating under reduced pressure.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be the title compound (244mg, 0.561mmol, 49%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：4.42(2H，s)，5.96(1H，s)，6.94(1H，m)，6.99-7.05(1H，m)，7.40(2H，d，J＝8.8Hz)，7.55(2H，d，J＝8.8Hz)，7.60(1H，d，J＝8.1Hz)，7.72(1H，dd，J＝8.1，2.0Hz)，8.02(1H，m)，8.57(1H，d，J＝2.0Hz).
MSm/z：435(M
++H).
Embodiment 63:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine
Under the argon atmospher; in ethanol (10ml), add 5-azido methyl-2-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] and pyridine (77mg, 0.177mmol), after palladium carbon (14mg) and the ethyl acetate (2ml), under the hydrogen atmosphere gas of 1 air pressure, stirred 50 minutes.After the filtering reaction mixed solution, decompression is concentrated filtrate down.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=10: 1 wash-out portion obtains, the title compound (28mg, 0.0685mmol, 39%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.84(2H，brs)，3.92(2H，s)，5.94(1H，s)，6.92(1H，m)，7.03-6.98(1H，m)，7.39(2H，d，J＝8.3Hz)，7.56(2H，d，J＝8.3Hz)，7.60(1H，d，J＝8.1Hz)，7.74(1H，d，J＝8.1Hz)，8.01(1H，m)，8.57(1H，s).
MSm/z：409(M
++H).
Embodiment 64:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl] t-butyl carbamate
In the mixed solution of ethyl acetate (15ml) and ethanol (15ml), add 5-azido methyl-2-[(4-chloro-phenyl-alkylsulfonyl that embodiment 62 obtains)-(2; the 5-difluorophenyl) methyl] pyridine (230mg; 0.529mmol) and palladium carbon (46mg) after, under the hydrogen atmosphere gas of 1 air pressure, stirred 45 minutes.Behind the filter reaction mixture, decompression is concentrated filtrate down.With residue obtained be dissolved in methylene dichloride (5ml) after, add triethylamine (70 μ l, 0.499mmol) and the dimethyl dicarbonate butyl ester (174mg 0.996mmol), stirred 3 days under the room temperature.Decompression is concentrated reaction solution down, residue obtainedly handles with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, acquisition is the title compound (78mg, 0.153mmol, 37%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：1.45(9H，s)，4.34(2H，d，J＝5.6Hz)，4.91(1H，brs)，5.93(1H，s)，6.91(1H，m)，6.98-7.04(1H，m)，7.39(2H，d，J＝8.8Hz)，7.54(2H，d，J＝8.8Hz)，7.59(1H，d，J＝7.8Hz)，7.67(1H，dd，J＝7.8，2.2Hz)，7.99(1H，m)，8.53(1H，d，J＝2.2Hz).
MSm/z：509(M
++H).
Embodiment 65:[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-N-(tert-butoxycarbonyl) t-butyl carbamate
Under nitrogen atmosphere; 2-[(4-chloro-phenyl-alkylsulfonyl in embodiment 43 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(hydroxymethyl) pyridine (178mg; 0.435mmol), iminodicarboxylic acid di tert butyl carbonate (142mg; 0.653mmol), triphenyl phosphine (171mg; 0.653mmol) tetrahydrofuran (THF) (5m1) solution in add the diisopropyl azo-2-carboxylic acid (128 μ l 0.653mmol), stirred under the room temperature 5 hours.In reaction soln, add water, use ethyl acetate extraction, organic layer water and saturated common salt water washing successively then.The gained organic layer with dried over sodium sulfate after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be the title compound (78mg, 0.128mmol, 32%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：1.48(18H，s)，4.78(2H，s)，5.94(1H，s)，6.93(1H，td，J＝9.0，4.4Hz)，6.98-7.04(1H，m)，7.38(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，7.58(1H，d，J＝8.1Hz)，7.71(1H，dd，J＝8.1，2.4Hz)，7.96-8.00(1H，m)，8.57(1H，d，J＝2.4Hz).
MSm/z：609(M
++H).
Embodiment 66:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine hydrochloride
[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-N-(tert-butoxycarbonyl) t-butyl carbamate (70mg; 0.115mmol) ethanol (2ml) solution in add concentrated hydrochloric acid (2ml), stirred under the room temperature 3 hours.Decompression is concentrated reaction solution down, adds the ethanol concentrating under reduced pressure in residue obtained, the be white in color title compound (51mg, 0.115mmol, 100%) of powder of acquisition.
1H-NMR(400MHz，CD
3OD)δ：4.18(2H，s)，6.22(1H，s)，7.03(1H，td，J＝9.3，4.4Hz)，7.11-7.17(1H，m)，7.52(2H，d，J＝8.8Hz)，7.64(2H，d，J＝8.8Hz)，7.79(1H，d，J＝8.3Hz)，7.92(1H，dd，J＝8.3，2.2Hz)，8.05-8.09(1H，m)，8.71(1H，d，J＝2.2Hz).
Ultimate analysis: C
20H
15ClF
2N
2O
2SHCl: theoretical value: C, 51.25; H, 3.62; Cl, 15.92; F, 8.53; N, 6.29. measured value: C, 51.11; H, 3.57; Cl, 15.50; F, 8.39; N, 5.83.
Embodiment 67:N-ethanoyl-N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methyl] ethanamide (compd A) and N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl] ethanamide (compd B)
The compd A compd B
Under ice-cooled; embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (40mg; 0.0978mmol) methylene dichloride (3ml) solution in add N-methylmorpholine (26 μ l; 0.234mmol), (16 μ l 0.234mmol) stirred under the room temperature 16 hours Acetyl Chloride 98Min..In reaction soln, add the water ethyl acetate extraction, organic layer water and saturated common salt water washing successively then.The gained organic layer with dried over sodium sulfate after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 3 wash-out portion obtains, be white in color title compound A (low the polar compound) (15mg of powder of acquisition, 0.0304mmol, 40%) and the title compound B of the powder that is white in color (high polar compound) (12mg, 0.0266mmol, 27%).
Compd A
1H-NMR(400MHz，CDCl
3)δ：2.43(6H，s)，4.96(2H，s)，5.93(1H，s)，6.91(1H，m)，6.98-7.03(1H，m)，7.39(2H，d，J＝8.5Hz)，7.54-7.61(2H，m)，7.55(2H，d，J＝8.5Hz)，8.02(1H，m)，8.51(1H，d，J＝1.7Hz).
mp：60-64℃
MSm/z：493(M
++H).
Compd B
1H-NMR (400MHz, CDCl
3) δ: 2.03 and 2.04 (3H, rotational isomers), 4.42-4.50 (2H, m), 5.89 (1H, brs), 5.93 (1H, s), 6.92 (1H, td, J=9.1,4.4Hz), 6.97-7.02 (1H, m), 7.41 (2H, d, J=8.1Hz), 7.57 (2H, d, J=8.1Hz), 7.61 (1H, d, J=8.1Hz), 7.71 (1H, d, J=8.1Hz), 7.98-8.03 (1H, m), 8.54 (1H, s).
mp：177-178℃
MSm/z：451(M
++H).
Embodiment 68:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-N ', N '-dimethyl methyl acid amides
Embodiment 66 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine hydrochloride (60mg; 0.135mmol) methylene dichloride (5ml) solution in add N-methylmorpholine (180 μ l; 1.62mmol), 4-dimethylaminopyridine (10mg; 0.0819mmol) and N; (66 μ l 0.609mmol), stirred 24 hours under the room temperature N-dimethylamino SULPHURYL CHLORIDE.Add the water dichloromethane extraction in reaction soln, organic layer is used saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively then.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, the title compound (48mg, 0.0930mmol, 70%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.76(6H，s)，4.29(2H，d，J＝6.4Hz)，4.43(1H，t，J＝6.4Hz)，5.94(1H，s)，6.92(1H，m)，6.98-7.04(1H，m)，7.41(2H，d，J＝8.6Hz)，7.58(2H，d，J＝8.6Hz)，7.66(1H，d，J＝8.1Hz)，7.79(1H，dd，J＝8.1，2.5Hz)，8.02(1H，m)，8.61(1H，d，J＝2.5Hz).
mp：177-178℃
MSm/z：516(M
++H).
Embodiment 69:2-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methylamino]-2-oxo ethyl acetate
Under ice-cold; embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (30mg; 0.0734mmol) methylene dichloride (4ml) solution in add N-methylmorpholine (10 μ l; 0.0881mmol) and glyoxylate ethyl chloride (9 μ l; 0.0807mmol), stirred 1 hour under the room temperature.Add the water dichloromethane extraction in reaction soln, organic layer is used saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively then.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, the title compound (28mg, 0.0550mmol, 76%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.39(3H，t，J＝7.1Hz)，4.37(2H，q，J＝7.1Hz)，4.55(2H，d，J＝5.9Hz)，5.94(1H，s)，6.89-6.94(1H，m)，6.98-7.05(1H，m)，7.40(2H，d，J＝8.3Hz)，7.56(2H，d，J＝8.3Hz)，7.53(1H，brs)，7.62(1H，d，J＝8.1Hz)，7.72(1H，d，J＝8.1Hz)，7.97-8.03(1H，m)，8.58(1H，s).
mp：193-194℃.
MSm/z：509(M
++H).
Embodiment 70:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-2-(4-aminomethyl phenyl sulfuryl amino) ethanamide
Embodiment 66 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine hydrochloride (40mg; 0.0898mmol) methylene dichloride (6ml) solution in add triethylamine (45 μ l; 0.324mmol), 4-dimethylaminopyridine (5mg; 0.0499mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (21mg; 0.108mmol) and N-p-toluenesulfonyl glycine (25mg; 0.108mmol), stirred 16 hours under the room temperature.Reaction soln dilutes with methylene dichloride, successively water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 3 wash-out portion obtains, the title compound (41mg, 0.0661mmol, 73%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.44(3H，s)，3.59(2H，d，J＝6.4Hz)，4.44(2H，dd，J＝6.1，2.8Hz)，5.42(1H，t，J＝6.1Hz)，5.95(1H，s)，6.91(1H，m)，6.96-7.03(2H，m)，7.33(2H，d，J＝8.3Hz)，7.41(2H，d.J＝8.6Hz)，7.57(2H，d，J＝8.6Hz)，7.58(1H，d，J＝8.1Hz)，7.66(1H，dd，J＝8.1，2.4Hz)，7.74(2H，d，J＝8.3Hz)，8.01(1H，m)，8.49(1H，d，J＝2.4Hz).
mp：217-218℃.
MSm/z：620(M
++H).
Embodiment 71:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-2-dimethylamino ethanamide
Embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (30mg; 0.0734mmol) methylene dichloride (5ml) solution in add triethylamine (12 μ l; 0.0881mmol), 4-dimethylaminopyridine (5mg; 0.0367mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (17mg, 0.0881mmol) and N, N-N-methylsarcosine (9mg; 0.0881mmol), stirred 14 hours under the room temperature.Reaction soln dilutes with methylene dichloride, successively water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 4 wash-out portion obtains, the title compound (21mg, 0.0425mmol, 58%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.30(6H，s)，3.01(2H，s)，4.50(2H，d，J＝6.1Hz)，5.93(1H，s)，6.91(1H，m)，6.98-7.04(1H，m)，7.40(2H，d，J＝8.6Hz)，7.55(2H，d，J＝8.6Hz)，7.60(1H，d，J＝8.1Hz)，7.62(1H，brs)，7.69(1H，dd，J＝8.1，2.4Hz)，8.02(1H，m)，8.56(1H，d，J＝2.4Hz).
mp：177-179℃.
MSm/z：494(M
++H).
Embodiment 72:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-4-(formyl radical methylamino) benzamide
Embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (50mg; 0.122mmol) methylene dichloride (5ml) solution in add triethylamine (21 μ l; 0.147mmol), 4-dimethylaminopyridine (7mg; 0.0610mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (28mg; 0.147mmol) and N-formyl radical-4-(methylamino) phenylformic acid (26mg; 0.147mmol), stirred 2 hours under the room temperature.Reaction soln dilutes with methylene dichloride, successively water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 7 wash-out portion obtains obtains to be the title compound (60mg, 0.105mmol, 87%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.35(3H，s)，4.67-4.71(2H，m)，5.94(1H，s)，6.53(1H，brs)，6.90(1H，m)，6.97-7.03(1H，m)，7.25(2H，d，J＝8.6Hz)，7.40(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，7.63(1H，d，J＝8.1Hz)，7.78(1H，dd，J＝8.1，2.2Hz)，7.86(2H，d，J＝8.6Hz)，8.03(1H，m)，8.61(1H，s)，8.64(1H，d，J＝2.2Hz).
MSm/z：570(M
++H).
Embodiment 73:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-4-(methyl thioformyl amino) thiobenzamide
Under the argon atmospher; at N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-4-(formyl radical methylamino) benzamide (46mg; 0.0807mmol) toluene (5ml) solution in add Lawson reagent (69mg; 0.169mmol) after, reflux 12 hours.After being cooled to room temperature, decompression is concentrated reaction mixture down.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be the title compound (40mg, 0.0664mmol, 83%) of yellow amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.72(3H，s)，5.08(2H，d，J＝4.4Hz)，5.92(1H，s)，6.89(1H，td，J＝9.0，4.4Hz)，6.98-7.05(1H，m)，7.25(2H，d，J＝8.6Hz)，7.40(2H，d，J＝8.6Hz)，7.55(2H，d，J＝8.6Hz)，7.60(1H，d，J＝8.1Hz)，7.81(1H，d，J＝8.1Hz)，7.87(2H，d，J＝8.6Hz)，8.02-8.06(1H，m)，8.20(1H，brs)，8.62(1H，s)，9.70(1H，s).
MSm/z：602(M
++H).
Embodiment 74:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-2-(pyridin-3-yl) ethanamide
With embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (30mg; 0.073mmol), 3-pyridyl acetic acid hydrochloride (16mg; 0.092mmol), 4-(dimethylamino) pyridine (5mg; 0.04mmol) and triethylamine (0.025ml; 0.18mmol) be dissolved in methylene dichloride (5ml), and adding 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride under the room temperature (17mg, 0.089mmol).Stir after 14 hours under the room temperature, in reaction solution, add saturated sodium bicarbonate aqueous solution (0.1ml).The concentrating under reduced pressure reaction mixture is residue obtainedly handled with the flash chromatography on silica gel method, and concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=30: 1 wash-out portion obtains obtains white solid.The gained solid washs with ether, the title compound (35mg, 0.066mmol, 90%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.59(2H，s)，4.45(2H，dd，J＝5.9，1.5Hz)，5.92(1H，s)，5.96-6.10(1H，m)，6.86-6.98(1H，m)，6.99-7.05(1H，m)，7.24-7.35(1H，m)，7.39(2H，d，J＝8.8Hz)，7.55-7.60(3H，m)，7.60-7.71(2H，m)，7.96-8.06(1H，m)，8.50(2H，d，J＝1.6Hz)，8.55(1H，d，J＝4.8，1.6Hz).
MSm/z：528(M
++H).
Embodiment 75: dimethylamino formic acid [6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl esters
In 0 ℃; 2-[(4-chloro-phenyl-alkylsulfonyl in embodiment 43 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(hydroxymethyl) pyridine (20mg; 0.049mmol) methylene dichloride (0.3ml) solution in add N-methylmorpholine (0.011ml; 0.10mmol); (15mg 0.074mmol), stirred 30 minutes under the room temperature to add p-nitrophenyl chloroformate ester again.Then, in 0 ℃ in reaction mixture, append N-methylmorpholine (0.033ml, 0.30mmol) and p-nitrophenyl chloroformate ester (15mg 0.074mmol), stirred under the room temperature 30 minutes.Then, (20mg 0.25mmol), stirs after 13 hours under the room temperature, washs with saturated aqueous ammonium chloride to add dimethylamine hydrochloride in 0 ℃ in reaction mixture.The organic layer anhydrous sodium sulfate drying, filter back concentrating under reduced pressure filtrate, residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=7: 3 wash-out portion obtains, the gained solid with hexane wash after leaching, the acquisition solid title compound (13mg, 0.027mmol, 55%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：2.94(6H，s)，5.14(2H，s)，5.94(1H，s)，6.87-7.07(2H，m)，7.39(2H，d，J＝8.5Hz)，7.55(2H，d，J＝8.5Hz)，7.62(1H，d，J＝7.8Hz)，7.75(1H，dd，J＝7.8，2.0Hz)，7.99-8.07(1H，m)，8.63(1H，d，J＝2.0Hz).
MSm/z：481(M
++H).
Embodiment 76: carbonic acid [6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl esters 4-nitro phenyl ester
In 0 ℃; 2-[(4-chloro-phenyl-alkylsulfonyl in embodiment 43 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(hydroxymethyl) pyridine (41mg; 0.10mmol) methylene dichloride (0.5ml) solution in add N-methylmorpholine (0.033ml; 0.30mmol); (40mg 0.20mmol), stirred 1 hour under the room temperature to add chloroformic acid 4-nitro phenyl ester again.After reaction mixture washed with water, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, gained solid with hexane wash after leaching, obtain to be white in color solid title compound (52mg, 0.090mmol, 90%).
1H-NMR(400MHz，CDCl
3)δ：5.33(2H，s)，5.97(1H，s)，6.87-6.95(1H，m)，6.98-7.06(1H，m)，7.39(2H，d，J＝9.0Hz)，7.40(2H，d，J＝8.5Hz)，7.57(2H，d，J＝8.5Hz)，7.71(1H，d，J＝7.6Hz)，7.85(1H，dd，J＝7.6，2.0Hz)，7.97-8.05(1H，m)，8.29(2H，d，J＝9.0Hz)，8.72(1H，d，J＝2.0Hz).
MSm/z：575(M
++H).
Embodiment 77: the phenmethyl carboxylamine [6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl esters
In 0 ℃; carbonic acid [6-(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) picoline-3-yl] methyl esters 4-nitro phenyl ester (51mg; 0.089mmol) methylene dichloride (1ml) solution in add N-methylmorpholine (0.020ml; 0.18mmol); (0.012ml 0.11mmol), stirred 20 hours under the room temperature to add benzene methanamine again.After reaction mixture washed with saturated aqueous ammonium chloride, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, the gained solid obtains to be white in color solid title compound (33mg, 0.060mmol, 68%) with diisopropyl ether washing back leaching.
1H-NMR(400MHz，CDCl
3)δ：4.38(2H，brd，J＝5.4Hz)，5.06(1H，brs)，5.16(2H，s)，5.94(1H，s)，6.87-7.04(2H，m)，7.22-7.38(5H，m)，7.39(2H，d，J＝8.3Hz)，7.54(2H，d，J＝8.3Hz)，7.62(1H，d，J＝8.3Hz)，7.74(1H，d，J＝8.3Hz)，7.96-8.03(1H，m)，8.61(1H，s).
MSm/z：543(M
++H).
Embodiment 78:N-[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methyl]-3-cyano group benzsulfamide
In 0 ℃; [6-(4-chloro-phenyl-alkylsulfonyl)-(2 in embodiment 63 acquisitions; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (28mg; 0.068mmol) methylene dichloride (0.5ml) solution in add N-methylmorpholine (0.015ml; 0.14mmol); (22mg 0.10mmol), stirred 6 hours under the room temperature to add 3-cyano group benzene sulfonyl chloride again.After reaction mixture was used 1N salt acid elution, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=7: 3 wash-out portion obtains, gained solid with hexane wash after leaching, obtain to be white in color solid title compound (23mg, 0.040mmol, 59%).
1H-NMR(400MHz，CDCl
3)δ：4.26(2H，d，J＝6.4Hz)，5.08(1H，t，J＝6.4Hz)，5.91(1H，s)，6.86-7.06(2H，m)，7.40(2H，d，J＝8.1Hz)，7.55(2H，d，J＝8.1Hz)，7.57-7.70(3H，m)，7.81(1H，d，J＝7.4Hz)，7.94-8.05(2H，m)，8.11(1H，s)，8.46(1H，s).
MSm/z：574(M
++H).
Embodiment 79:N-[[6-(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methyl]-3-cyano group-N-methyl benzenesulfonamide
In 0 ℃; at N-[[6-(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) picoline-3-yl] methyl]-3-cyano group benzsulfamide (21mg; 0.037mmol) tetrahydrofuran (THF) (0.5ml) solution in add methyl alcohol (0.003ml; 0.073mmol), (19mg 0.073mmol), adds diisopropyl azo-2-carboxylic acid (0.014ml to triphenyl phosphine again; 0.073mmol), stirred 2 hours under the room temperature.The concentrating under reduced pressure reaction mixture is with residue obtained refining with the flash chromatography on silica gel method.Concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains obtains to be white in color solid title compound (13mg, 0.021mmol, 58%).
1H-NMR(400MHz，CDCl
3)δ：2.70(3H，s)，4.25(2H，d，J＝6.4Hz)，5.95(1H，s)，6.87-7.05(2H，m)，7.40(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.66(1H，d，J＝8.1Hz)，7.73(1H，t，J＝7.8Hz)，7.81(1H，dd，J＝8.1，2.2Hz)，7.91(1H，d，J＝7.8Hz)，7.99-8.09(2H，m)，8.12(1H，s)，8.53(1H，t，J＝2.2Hz).
MSm/z：588(M
++H).
Embodiment 80:3-[[6-(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methyl]-1, the 1-dimethyl urea
In 0 ℃; embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (31mg; 0.076mmol) methylene dichloride (1ml) solution in add triethylamine (0.032ml; 0.23mmol), add N again, N-dimethylcarbamyl chloride (0.014ml; 0.15mmol), stirred 17 hours under the room temperature.(0.032ml, 0.23mmol) and N, (0.014ml 0.15mmol), stirred 29 hours under the room temperature N-dimethylcarbamyl chloride to append triethylamine in 0 ℃ in reaction mixture.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue obtainedly handle the cut that concentrating under reduced pressure is obtained by eluent ethyl acetate portion with the flash chromatography on silica gel method.The gained solid with hexane wash after leaching, solid title compound (18mg, 0.036mmol, 48%) obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.93(6H，s)，4.44(2H，d，J＝4.2Hz)，4.76(1H，t，J＝4.2Hz)，5.93(1H，s)，6.85-7.04(2H，m)，7.39(2H，d，J＝8.3Hz)，7.56(2H，d，J＝8.3Hz)，7.58(1H，d，J＝8.5Hz)，7.74(1H，dd，J＝8.5，2.0Hz)，7.98-8.06(1H，m)，8.57(1H，d，J＝2.0Hz).
MSm/z：480(M
++H).
Embodiment 81:[6-(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methylene dicarbamate
Adopt the method same with embodiment 80; [6-(4-chloro-phenyl-alkylsulfonyl)-(2 by embodiment 63 acquisitions; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (34mg; 0.082mmol) and methyl-chlorocarbonate (0.019ml; 0.25mmol); acquisition is the title compound (16mg, 0.034mmol, 42%) of yellow solid.
1H-NMR(400MHz，CDCl
3)δ：3.71(3H，s)，4.40(2H，d，J＝6.1Hz)，5.07(1H，brs)，5.93(1H，s)，6.87-7.04(2H，m)，7.39(2H，d，J＝8.5Hz)，7.55(2H，d，J＝8.5Hz)，7.60(1H，d，J＝7.8Hz)，7.70(1H，d，J＝7.8Hz)，7.97-8.04(1H，m)，8.55(1H，s).
MSm/z：467(M
++H).
Embodiment 82:N-[[6-(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methyl] Toluidrin
Adopt the method same with embodiment 80; by embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (34mg; 0.082mmol) and methylsulfonyl chloride (0.019ml; 0.25mmol); the acquisition solid title compound (20mg, 0.040mmol, 49%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：2.97(3H，s)，4.37(2H，d，J＝6.1Hz)，4.70(1H，brs)，5.95(1H，s)，6.88-7.07(2H，m)，7.40(2H，d，J＝8.3Hz)，7.56(2H，d，J＝8.3Hz)，7.65(1H，d，J＝8.1Hz)，7.80(1H，d，J＝8.1Hz)，7.97-8.07(1H，m)，8.61(1H，s).
MSm/z：487(M
++H).
Embodiment 83:N-[[6-(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methyl]-1-ethanoyl-4-piperidines carboxylic acid amides
Adopt the method same with embodiment 80; by embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (34mg; 0.082mmol) and 1-ethanoyl-4-piperidine formyl chlorine (56mg; 0.25mmol); acquisition is the title compound (24mg, 0.043mmol, 52%) of colourless blister material.
1H-NMR(400MHz，CDCl
3)δ：1.58-1.79(2H，m)，1.82-1.95(2H，m)，2.09(3H，s)，2.30-2.41(1H，m)，2.59-2.70(1H，m)，3.03-3.13(1H，m)，3.82-3.92(1H，m)，4.41-4.53(2H，m)，4.55-4.63(1H，m)，5.90-5.98(2H，m)，6.85-6.94(1H，m)，6.97-7.04(1H，m)，7.40(2H，d，J＝8.5Hz)，7.55(2H，d，J＝8.5Hz)，7.60(1H，d，J＝8.1Hz)，7.66(1H，d，J＝8.1Hz)，7.98-8.05(1H，m)，8.53(1H，s).
MSm/z：562(M
++H).
Embodiment 84: methyl carbonic acid [6-(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) picoline-3-yl] methyl esters
In 0 ℃; 2-[(4-chloro-phenyl-alkylsulfonyl in embodiment 43 acquisitions)-(2; the 5-difluorophenyl) methyl]-5-(hydroxymethyl) pyridine (50mg; 0.12mmol) methylene dichloride (2ml) solution in add pyridine (0.040ml; 0.49mmol); (0.019ml 0.24mmol), stirred 1 hour under the room temperature to add methyl-chloroformate again.Then, (0.019ml 0.24mmol), stirred 5 hours under the room temperature to append methyl-chloroformate in 0 ℃ in reaction mixture.After reaction mixture was used 1N salt acid elution, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, gained solid with hexane wash after leaching, obtain to be white in color solid title compound (50mg, 0.11mmol, 88%).
1H-NMR(400MHz，CDCl
3)δ：3.81(3H，s)，5.18(2H，s)，5.95(1H，s)，6.89-7.04(2H，m)，7.40(2H，d，J＝8.5Hz)，7.55(2H，d，J＝8.5Hz)，7.65(1H，d，J＝8.1Hz)，7.78(1H，dd，J＝8.1，2.2Hz)，7.97-8.03(1H，m)，8.64(1H，d，J＝2.2Hz).
MSm/z：468(M
++H).
Embodiment 85:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] formoxime (isomer A and isomer B)
Embodiment 47 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; 0.25mmol) methylene dichloride (3ml) solution in add N-methylmorpholine (32 μ l; 0.29mmol), oxammonium hydrochloride (26mg; 0.36mmol), stirred 3 days under the room temperature.Behind methylene dichloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt wash successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, be white in color title isomer A (low the polar compound) (79mg of powder of acquisition, 0.19mmol, 72%), the title isomer B (high polar compound) (17mg, 0.040mmol, 17%) of powder is white in color.
Isomer A
1H-NMR(400MHz，CDCl
3)δ：5.97(1H，s)，6.91-6.96(1H，m)，6.99-7.05(1H，m)，7.40(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，7.66(1H，d，J＝8.1Hz)，7.78(1H，s)，7.96-8.02(2H，m)，8.14(1H，s)，8.75(1H，d，J＝1.7Hz).
mp：187-188℃.
MSm/z：423(M
++H).
Isomer B
1H-NMR(400MHz，CDCl
3)δ：5.98(1H，s)，6.91-6.97(1H，m)，7.00-7.06(1H，m)，7.40(1H，s)，7.41(2H，d，J＝8.6Hz)，7.57(2H，d，J＝8.6Hz)，7.71(1H，d，J＝8.3Hz)，7.90-8.02(2H，m)，8.41(1H，dd，J＝8.3，2.1Hz)，9.00(1H，s).
mp：194-196℃.
MSm/z：423(M
++H).
Embodiment 86:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-N-cyclohexyl methyl niacinamide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; 0.19mmol) methylene dichloride (5ml) solution in add triethylamine (32 μ l; 0.23mmol), 4-dimethylaminopyridine (12mg; 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (44mg; 0.23mmol) and the amino methyl hexanaphthene (30 μ l 0.23mmol), stirred under the room temperature 4.5 hours.After reaction soln diluted with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt washed successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains, the title compound (58mg, 0.11mmol, 59%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：0.95-1.80(11H，m)，3.32(2H，d，J＝6.4Hz)，5.98(1H，s)，6.13-6.16(1H，m)，6.90-6.96(1H，m)，7.00-706(1H，m)，7.40(2H，d，J＝8.6Hz)，7.55(2H，d，J＝8.6Hz)，7.69(1H，d，J＝8.3Hz)，7.97-8.02(1H，m)，8.13(1H，dd，J＝8.3，2.2Hz)，8.94(1H，d，J＝2.2Hz).
MSm/z：519(M
++H).
Embodiment 87:6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-N-(5-chloropyridine-2-yl) niacinamide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; 0.19mmol) methylene dichloride (5ml) solution in add triethylamine (32 μ l; 0.23mmol), 4-dimethylaminopyridine (12mg; 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (44mg; 0.23mmol) and 2-amino-5-chloropyridine (29mg 0.23mmol), stirred under the room temperature 5 hours.After reaction soln diluted with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt washed successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains, the title compound (27mg, 0.051mmol, 27%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.04(1H，s)，6.92-6.97(1H，m)，7.01-707(1H，m)，7.42(2H，d，J＝8.6Hz)，7.57(2H，d，J＝8.6Hz)，7.75(1H，dd，J＝9.1，2.4Hz)，7.80(1H，d，J＝8.1Hz)，7.97-8.01(1H，m)，8.26(1H，dd，J＝8.1，2.2Hz)，8.28(1H，d，J＝2.4Hz)8.33(1H，d，J＝9.1Hz)，8.51(1H，s)，9.12(1H，d，J＝2.2Hz).
MSm/z：534(M
++H).
Embodiment 88:6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-N ', N '-dimethyl nicotinic acid hydrazide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; 0.19mmol) methylene dichloride (5ml) solution in add triethylamine (32 μ l; 0.23mmol), 4-dimethylaminopyridine (12mg; 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (44mg, 0.23mmol) and 1,1-dimethylhydrazine (21 μ l; 0.23mmol), stirred 7 hours under the room temperature.After reaction soln diluted with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt washed successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=50: 1 wash-out portion obtains obtains to be the title compound (60mg, 0.13mmol, 68%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：2.57(0.9H，s)，2.72(5.1H，s)，5.98(1H，s)，6.48(0.15H，s)，6.90-7.06(2.85H，m)，7.41(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，7.68(1H，d，J＝8.1Hz)，7.97-8.04(1H，m)，8.13-8.17(1H，m)，8.94(0.85H，s)，9.07(0.15H，s).
MSm/z：466(M
++H).
Embodiment 89:6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-N '-(furans-2-carbonyl) nicotinic acid hydrazide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; 0.19mmol) methylene dichloride (5ml) solution in add triethylamine (32 μ l; 0.23mmol), 4-dimethylaminopyridine (12mg; 0.095mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (44mg; 0.23mmol) and 2-furans hydrazides (29mg 0.23mmol), stirred under the room temperature 7.5 hours.After reaction soln diluted with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and saturated aqueous common salt washed successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=50: 1 wash-out portion obtains.With methylene dichloride-hexane the gained solid is carried out recrystallization, the title compound (58mg, 0.11mmol, 58%) of the powder that obtains to be white in color
1H-NMR(400MHz，CDCl
3)δ：6.01(0.7H，s)，6.02(0.3H，s)，6.55(0.7H，dd，J＝3.4，1.7Hz)，6.91-6.96(1H，m)，6.99-7.04(1H，m)，7.21(0.7H，d，J＝3.4Hz)，7.41(2H，d，J＝8.6Hz)，7.53(0.3H，dd，J＝1.7，0.7Hz)，7.56-7.60(3H，m)，7.74(1H，d，J＝8.3Hz)，7.77(0.3H，d，J＝8.8Hz)，7.95-7.99(1H，m)，8.15-8.19(1H，m)，8.99(0.3H，s)，9.03(1H，d，J＝2.2Hz)，9.14(0.7H，brs)，9.67(0.7H，brs)，9.98(0.3H，brs).
MSm/z：532(M
++H).
Embodiment 90:N-[[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl]-(E)-3-(pyridin-4-yl) acrylamide
In 0 ℃; embodiment 63 obtain [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine (41mg; 0.10mmol), (E)-3-(pyridin-4-yl) vinylformic acid (15mg; 0.10mmol), benzotriazole-1-alcohol (14mg; 0.10mmol) and N-methylmorpholine (0.011ml; 0.10mmol) methylene dichloride (1ml) solution in add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (19mg; 0.10mmol), stirred 19 hours under the room temperature.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered the rear filtrate concentrating under reduced pressure.Residue obtainedly handle the cut that concentrating under reduced pressure is obtained by eluent ethyl acetate portion with the flash chromatography on silica gel method.With ether the gained solid is washed, leaching obtains to be white in color solid title compound (35mg, 0.065mmol, 65%).
1H-NMR(400MHz，CDCl
3)δ：4.53-4.66(2H，m)，5.93(1H，s)，6.09-6.17(1H，m)，6.57(1H，d，J＝15.6Hz)，6.86-6.93(1H，m)，6.96-7.04(1H，m)，7.34(2H，d，J＝5.9Hz)，7.40(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.60(1H，d，J＝15.6Hz)，7.61(1H，d，J＝8.1Hz)，7.74(1H，dd，J＝8.1，2.2Hz)，7.99-8.06(1H，m)，8.59(1H，d，J＝2.2Hz)，8.64(2H，d，J＝5.9Hz).
MSm/z：540(M
++H).
Embodiment 91:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] (thiomorpholine-4-yl) ketone
Adopt the method same with embodiment 90; with embodiment 50 [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (212mg; 0.50mmol) and thiomorpholine (0.047ml; 0.50mmol); the acquisition solid title compound (240mg, 0.47mmol, 94%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：2.61(2H，brs)，2.74(2H，brs)，3.69(2H，brs)，4.04(2H，brs)，5.97(1H，s)，6.88-6.95(1H，m)，6.98-7.06(1H，m)，7.41(2H，d，J＝8.5Hz)，7.57(2H，d，J＝8.5Hz)，7.73(1H，d，J＝8.1Hz)，7.79(1H，dd，J＝8.1，2.2Hz)，7.95-8.02(1H，m)，8.64(1H，d，J＝2.2Hz).
MSm/z：509(M
++H).
Embodiment 92:[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] (1,1-dioxo-1 λ
6-thiomorpholine-4-yl) ketone (compd A) and [6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] (1-oxo-1 λ
4-thiomorpholine-4-yl) ketone (compd B)
The compd A compd B
Under ice-cold; [6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl] (153mg adds 3-chlorine peroxybenzoic acid (96mg to (thiomorpholine-4-yl) ketone in methylene dichloride 0.30mmol) (3ml) solution; 0.36mmol), stirred 2 hours under the room temperature.With methylene dichloride diluting reaction solution, use 1N aqueous sodium hydroxide solution and saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 2 wash-out portion obtains, be white in color title compound A (low the polar compound) (81mg of powder of acquisition, 0.15mmol, 50%) concentrating under reduced pressure methylene dichloride: the cut that methyl alcohol=10: 1 wash-out portion obtains, title compound B (high the polar compound) (73mg of the powder that obtains to be white in color, 0.14mmol, 46%).
Compd A
1H-NMR(400MHz，CDCl
3)δ：3.10(4H，brs)，4.13(4H，brs)，5.99(1H，s)，6.88-6.93(1H，m)，7.00-7.06(1H，m)，7.42(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz)，7.79(1H，d，J＝8.1Hz)，7.86(1H，dd，J＝8.1，1.7Hz)，7.97-8.02(1H，m)，8.71(1H，d，J＝1.7Hz).
MSm/z：541(M
++H).
Compd B
1H-NMR(400MHz，CDCl
3)δ：2.70-3.00(4H，m)，3.74(1H，brs)，4.10(2H，brs)，4.63(1H，brs)，5.98(1H，s)，6.88-6.94(1H，m)，7.00-7.06(1H，m)，7.42(2H，d，J＝8.6Hz)，7.58(2H，d，J＝8.6Hz)，7.77(1H，d，J＝8.1Hz)，7.84(1H，dd，J＝8.1，2.2Hz)，7.98-8.02(1H，m)，8.70(1H，d，J＝2.2Hz).
MSm/z：525(M
++H).
Embodiment 93:N-(3-methylthio group propyl group)-6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] niacinamide
Adopt the method same with embodiment 90; with embodiment 50 [6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (212mg; 0.50mmol) and 3-methylthio group propylamine (0.055ml; 0.50mmol); the acquisition solid title compound (238mg, 0.47mmol, 93%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：1.92-2.01(2H，m)，2.14(3H，s)，2.63(2H，t，J＝6.8Hz)，3.58-3.64(2H，m)，5.99(1H，s)，6.57-6.64(1H，m)，6.90-6.97(1H，m)，6.99-7.06(1H，m)，7.41(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.71(1H，d，J＝8.1Hz)，7.96-8.03(1H，m)，8.16(1H，dd，J＝8.1，2.2Hz)，8.96(1H，d，J＝2.2Hz).
MSm/z：511(M
++H).
Embodiment 94:N-(3-methyl sulphonyl propyl group)-6-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] niacinamide (compd A) and N-(3-methylsulfinyl propyl group)-6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] niacinamide (compd B)
The compd A compd B
In 0 ℃; at N-(3-methylthio group propyl group)-6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] (153mg adds 3-chlorine peroxybenzoic acid (purity is more than 65%) (96mg to niacinamide in methylene dichloride 0.30mmol) (3ml) solution; 0.36mmol), stirred 3 hours under the room temperature.After washing reaction mixture with the 1N aqueous sodium hydroxide washes, the organic layer anhydrous sodium sulfate drying filters the back concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, the cut that concentrating under reduced pressure is obtained by eluent ethyl acetate portion, gained solid with the ether washing after, leaching obtains to be white in color solid title compound A (53mg, 0.098mmol, 32%).Then, concentrating under reduced pressure methylene dichloride: the cut of methyl alcohol=wash-out portion acquisition in 15: 1, the gained solid obtains to be white in color solid title compound B (68mg, 0.13mmol, 43%) with ether washing back leaching.
Compd A
1H-NMR(400MHz，CDCl
3)δ：2.20-2.30(2H，m)，2.98(3H，s)，3.17(2H，t，J＝6.8Hz)，3.65-3.72(2H，m)，5.99(1H，s)，6.82-6.88(1H，m)，6.90-6.97(1H，m)，6.99-7.06(1H，m)，7.41(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.72(1H，d，J＝8.1Hz)，7.96-8.02(1H，m)，8.16(1H，dd，J＝8.1，2.2Hz)，9.00(1H，d，J＝2.2Hz).
MSm/z：543(M
++H).
Compd B
1H-NMR(400MHz，CDCl
3)δ：2.11-2.23(1H，m)，2.26-2.37(1H，m)，2.63(3H，s)，2.78-2.86(1H，m)，2.92-3.00(1H，m)，3.51-3.61(1H，m)，3.66-3.75(1H，m)，5.99(1H，s)，6.90-6.98(1H，m)，6.99-7.06(1H，m)，7.40(2H，d，J＝8.5Hz)，7.55(2H，d，J＝8.5Hz)，7.69(1H，d，J＝8.1Hz)，7.88-8.01(2H，m)，8.22(1H，dd，J＝8.1，2.2Hz)，9.08(1H，d，J＝2.2Hz).
MSm/z：527(M
++H).
Embodiment 95:2-chloro-5-[(3-chloropyridine-4-yl) (2, the 5-difluorophenyl) methylthio group] pyridine
(164mg adds 1N aqueous sodium hydroxide solution (7ml) to dithiocarbonic acid S-(6-chloro-3-pyridyl) the ester O-ethyl ester that obtains at reference example 26 in ethanol 0.70mmol) (7ml) solution, stirred 3 hours in 80 ℃.Reaction mixture adds 1N hydrochloric acid after being cooled to room temperature, uses dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters the rear filtrate concentrating under reduced pressure, obtains to be the 6-chloro-3-pyridine mercaptan of yellow solid.
In 0 ℃, at the 3-chloro-4-[(2 that reference example 23 obtains, 5-difluorophenyl)-hydroxymethyl] pyridine (153mg, 0.60mmol) methylene dichloride (3ml) solution in add triethylamine (0.167ml 1.20mmol), add methylsulfonyl chloride (0.070ml again, 0.90mmol), stirred 2 hours under the room temperature.After with saturated sodium bicarbonate aqueous solution reaction mixture being washed, the organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.At residue obtained N, add the N of 6-chloro-3-pyridine mercaptan in dinethylformamide (3ml) solution, dinethylformamide (2ml) solution, (100mg 0.72mmol), stirred 18 hours under the room temperature to add salt of wormwood again.In reaction mixture, add ethyl acetate,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Handle residue obtained with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=17: 3 wash-out portion obtains obtains to be white in color solid title compound (111mg, 0.29mmol, 48%).
1H-NMR(400MHz，CDCl
3)δ：6.04(1H，s)，6.95-7.05(2H，m)，7.10-7.20(1H，m)，7.25(1H，d，J＝8.1Hz)，7.57(1H，d，J＝5.1Hz)，7.60(1H，dd，J＝8.1，2.5Hz)，8.31(1H，d，J＝2.5Hz)，8.54(1H，d，J＝5.1Hz)，8.59(1H，s).
MSm/z：383(M
++H).
Embodiment 96:2-chloro-5-[(3-chloropyridine-4-yl) (2, the 5-difluorophenyl) methyl sulphonyl] pyridine
At 2-chloro-5-[(3-chloropyridine-4-yl) (2, the 5-difluorophenyl) methylthio group] pyridine (109mg, 0.28mmol) methyl alcohol (4ml) solution in add 31% aqueous hydrogen peroxide solution (2ml) and seven molybdic acids, six ammonium tetrahydrates (30mg), stirred 17 hours under the room temperature.Add ethyl acetate in reaction mixture, after the saturated sodium bicarbonate aqueous solution washing, the organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.Residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=17: 3 wash-out portion obtains obtains to be white in color solid title compound (108mg, 0.26mmol, 92%).
1H-NMR(400MHz，CDCl
3)δ：6.26(1H，s)，6.94-7.03(1H，m)，7.06-7.15(1H，m)，7.44(1H，d，J＝8.3Hz)，7.50-7.56(1H，m)，7.89(1H，dd，J＝8.3，2.7Hz)，8.12(1H，d，J＝5.1Hz)，8.59(1H，d，J＝2.7Hz)，8.61(1H，s)，8.66(1H，d，J＝5.1Hz).
MSm/z：415(M
++H).
Embodiment 97:5-[(3-chloropyridine-4-yl) (2, the 5-difluorophenyl) methyl sulphonyl]-2-fluorine pyridine
At 2-chloro-5-[(3-chloropyridine-4-yl) (2; the 5-difluorophenyl) methyl sulphonyl] pyridine (66mg, add in acetonitrile 0.16mmol) (2ml) solution Potassium monofluoride (94mg, 1.60mmol) and tetraphenylphosphonibromide bromide (134mg; 0.32mmol), reflux 16 hours.After reaction mixture is cooled to room temperature, adds methylene dichloride and wash with water.The organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.Residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=17: 3 wash-out portion obtains obtains to be white in color solid title compound (4.5mg, 0.011mmol, 7%).
1H-NMR(400MHz，CDCl
3)δ：6.26(1H，s)，6.93-7.13(3H，m)，7.50-7.56(1H，m)，8.01-8.08(1H，m)，8.13(1H，d，J＝5.1Hz)，8.48(1H，d，J＝2.2Hz)，8.60(1H，s)，8.66(1H，d，J＝5.1Hz).
MSm/z：440(M
++H+MeCN).
Embodiment 98:N '-[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] the pyridin-3-yl methylene radical]-2-thenoyl hydrazine
[6-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridin-3-yl that embodiment 47 is obtained] formaldehyde (100mg, 0.245mmol) and 2-thenoyl hydrazine (41.7mg 0.294mmol) is dissolved in ethanol (3ml), stirs 3 days under room temperature.The solid that leaching is separated out is used washing with alcohol.With ethanol the gained solid is carried out recrystallization, obtain to be white in color solid title compound (91.0mg, 0.171mmol, 70%).
1H-NMR(400MHz，CDCl
3/DMSO-d
6)δ：5.98(1H，s)，6.93-7.01(1H，m)，7.02-7.09(1H，m)，7.14-7.20(1H，brm)，7.42(2H，d，J＝8.5Hz)，7.57(2H，d，J＝8.5Hz)，7.62-7.73(2H，brm)，8.02-8.20(3H，m)，8.95(1H，s)，11.5(1H，s).
MSm/z：532(M
++H).
Embodiment 99:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] niacinamide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; 0.236mmol) methylene dichloride (4ml) suspension liquid in add thionyl chloride (1.00ml) and N, behind the dinethylformamide (1), stirred under the room temperature 18 hours.Concentration of reaction solution is to doing, residue obtained be dissolved in methylene dichloride (6ml) after, add 28% ammoniacal liquor (2ml).Make it be acid with 1N hydrochloric acid to the reaction solution stirring after 3 hours under the room temperature.Concentrate the gained mixture, the solid that leaching generates.After gained solid water and the washing with alcohol, use ethyl alcohol recrystallization, obtain to be white in color solid title compound (47.9mg, 0.113mmol, 46%).
1H-NMR(400MHz，CDCl
3/DMSO-d
6)δ：6.00(1H，s)，6.38(1H，brs)，6.94-6.99(1H，m)，7.02-7.08(1H，m)，7.43(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.67(1H，d，J＝7.6Hz)，7.65-7.75(1H，brm)，7.99-8.04(1H，m)，8.26(1H，dd，J＝8.1，2.4Hz)，9.12(1H，d，J＝1.7Hz).
MSm/z：423(M
++H).
Embodiment 100:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-N-(4-methylcyclohexyl) niacinamide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; 0.236mmol) methylene dichloride (4ml) suspension liquid in add thionyl chloride (1.00ml) and N, behind the dinethylformamide (1), stirred under the room temperature 6 hours.Concentration of reaction solution is to doing, residue obtained be dissolved in methylene dichloride (6ml) after, add N-methylmorpholine (51.8 μ l, 0.472mmol) and the 4-methyl cyclohexylamine (37.4 μ l, 0.283mmol).Under the room temperature reaction solution is stirred after 18 hours with the methylene dichloride dilution, wash successively with 1N hydrochloric acid, water and saturated aqueous common salt again.Then, use dried over mgso, concentrated back is residue obtained handles with the silica gel flash column chromatography, concentrates by hexane: the cut of ethyl acetate=wash-out portion acquisition in 3: 1 obtains white solid.The gained solid is with ethyl acetate-hexane recrystallization, the title compound (70.3mg, 0.135mmo1,57%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：0.92(1.8H，d，J＝6.6Hz)，0.96(1.2H，d，J＝6.4Hz)，1.05-1.30(3H，m)，1.32-1.43(0.6H，m)，1.55-1.83(4.4H，m)，2.03-2.12(1H，m)，3.86-3.97(0.6H，m)，4.20-4.28(0.4H，m)，5.88(0.6H，d，J＝7.1Hz)，5.98(1H，s)，6.18(0.4H，d，J＝7.3Hz)，6.90-6.96(1H，m)，6.98-7.06(1H，m)，7.41(1.2H，d，J＝8.1Hz)，7.41(0.8H，d，J＝8.1Hz)，7.56(1.2H，d，J＝8.1Hz)，7.57(0.8H，d，J＝8.1Hz)，7.67-7.72(1H，m)，7.97-8.05(1H，m)，8.10-8.18(1H，m)，8.93(0.6H，d，J＝2.2Hz)，8.96(0.4H，d，J＝2.2Hz).
MSm/z：519(M
++H).
Embodiment 101:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-N-methoxyl group niacinamide
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; 0.236mmol) methylene dichloride (6ml) suspension liquid in add N-methylmorpholine (77.7 μ l; 0.708mmol), O-methyl hydroxylamine hydrochloride (23.6mg; 0.283mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (54.3mg, 0.283mmol).Stirring added tetrahydrofuran (THF) (1ml) after 1 hour to reaction solution under the room temperature.Under the room temperature reaction solution is stirred after 18 hours with methylene dichloride dilution, water and saturated common salt water washing again.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrate by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains obtains white solid.The gained solid washs with ethyl acetate, the title compound (55.1mg, 0.122mmol, 52%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.90(2.4H，s)，3.97(0.6H，s)，5.97(0.2H，s)，5.98(0.8H，s)，6.90-7.07(2H，m)，7.39-7.46(2H，m)，7.54-7.59(2H，m)，7.63(0.2H，d，J＝8.3Hz)，7.73(0.8H，d，J＝8.1Hz)，7.94-8.00(1H，m)，8.10-8.15(1H，m)，8.76(1H，brs)，8.92(0.8H，d，J＝1.7Hz)，9.01(0.2H，d，J＝1.5Hz).
MSm/z：453(M
++H).
Embodiment 102:N, the N-dimethyl-[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridin-3-yl] methylamine
With embodiment 47 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; 0.245mmol), the tetrahydrofuran solution (2.0M of dimethylamine; 0.25ml; 0.50mmol) and acetate (0.029ml 0.51mmol) is dissolved in 1, behind the 2-ethylene dichloride (5ml); add under the room temperature sodium triacetoxy borohydride (115mg, 0.515mmol).Stir under the room temperature after 3 days, in reaction mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.Behind the mixture separatory, the gained organic layer is used the saturated common salt water washing again with saturated sodium bicarbonate aqueous solution earlier, uses anhydrous magnesium sulfate drying then.Filter back concentrating under reduced pressure filtrate, residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=40: 1 wash-out portion obtains, acquisition white solid.Title compound (88mg, 0.20mmol, 82%) with the powder that obtains behind the hexane wash gained solid to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.23(6H，s)，3.43(2H，s)，5.94(1H，s)，6.88-6.98(1H，m)，6.98-7.06(1H，m)，7.38(2H，d，J＝8.6Hz)，7.52-7.62(3H，m)，7.71(1H，dd，J＝8.1，2.1Hz)，7.98-8.08(1H，m)，8.51(1H，d，J＝2.1Hz).
MSm/z：437(M
++H).
Embodiment 103:N-[[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridin-3-yl] methyl] two (2-methoxy ethyl) amine
With embodiment 47 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; 0.245mmol), two (2-methoxy ethyl) amine (70mg; 0.53mmol) and acetate (0.029ml; 0.51mmol) be dissolved in 1; behind the 2-ethylene dichloride (5ml), add under the room temperature sodium triacetoxy borohydride (115mg, 0.515mmol).Stir under the room temperature after 3 days, in reaction mixture, add saturated sodium bicarbonate aqueous solution and ethyl acetate.Behind the mixture separatory, the gained organic layer is used the saturated common salt water washing again with saturated sodium bicarbonate aqueous solution earlier, uses anhydrous magnesium sulfate drying then.Filter back concentrating under reduced pressure filtrate, residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, acquisition white solid.Title compound (101mg, 0.192mmol, 78%) with the powder that obtains behind the hexane wash gained solid to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.73(4H，t，J＝5.8Hz)，3.31(6H，s)，3.47(4H，d，J＝5.8Hz)，3.75(2H，s)，5.93(1H，s)，6.88-6.97(1H，m)，6.97-7.07(1H，m)，7.38(2H，d，J＝8.8Hz)，7.50-7.60(3H，m)，7.76(1H，dd，J＝8.1，2.0Hz)，7.98-8.08(1H，m)，8.54(1H，d，J＝2.0Hz).
MSm/z：525(M
++H).
Embodiment 104:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-N, the N-dimethyl nicotinamide
With embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (90mg; 0.21mmol), the tetrahydrofuran solution (2.0M of dimethylamine; 0.21ml; 0.42mmol), 4-(dimethylamino) pyridine (15mg; 0.12mmol) and triethylamine (0.045ml; 0.32mmol) be dissolved in methylene dichloride (5ml); under the room temperature; add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (61mg; 0.32mmol) after, in stirring at room 14 hours.The concentrating under reduced pressure reaction mixture is residue obtainedly handled with the flash chromatography on silica gel method, and concentrating under reduced pressure is by hexane again: the cut that ethyl acetate=2: 1 wash-out portion obtains, the title compound (35mg, 0.066mmol, 90%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.01(3H，s)，3.14(3H，s)，5.97(1H，s)，6.88-6.99(1H，m)，6.99-7.08(1H，m)，7.40(2H，d，J＝8.7Hz)，7.57(2H，d，J＝8.7Hz)，7.70(1H，dd，J＝8.0，0.7Hz)，7.82(1H，dd，J＝8.0，2.2Hz)，7.93-8.04(1H，m)，8.68(1H，dd，J＝2.2，0.7Hz).
MSm/z：451(M
++H).
Embodiment 105:[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridin-3-yl] (4-methylpiperazine-1-yl) ketone
With embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (90mg; 0.21mmol), N methyl piperazine (0.036ml; 0.33mmol), 4-(dimethylamino) pyridine (15mg; 0.12mmol) and triethylamine (0.045ml; 0.32mmol) be dissolved in methylene dichloride (5ml), and adding 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride under the room temperature (61mg, 0.32mmol).In stirring at room after 14 hours, in reaction mixture, append N methyl piperazine (0.036ml, 0.33mmol), triethylamine (0.045ml, 0.32mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (61mg, 0.32mmol).Stir concentrating under reduced pressure reaction mixture after 14 hours under the room temperature, residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=25: 1 wash-out portion obtains, the title compound (86mg of the powder that obtains to be white in color, 0.17mmol, 80%).
1H-NMR(400MHz，CDCl
3)δ：2.33(3H，s)，2.38(2H，brs)，2.50(2H，brs)，3.44(2H，brs)，3.81(2H，brs)，5.97(1H，s)，6.87-6.98(1H，m)，6.98-7.08(1H，m)，7.40(2H，d，J＝8.8Hz)，7.57(2H，d，J＝8.8Hz)，7.71(1H，dd，J＝8.1，0.7Hz)，7.81(1H，dd，J＝8.1，2.2Hz)，7.94-8.04(1H，m)，8.66(1H，dd，J＝2.2，0.7Hz).
MSm/z：506(M
++H).
Embodiment 106:4-[2-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino-ethyl] morpholine
4-[2-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl with embodiment 61 acquisitions)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino-ethyl] (78mg 0.14mmol) is dissolved in the mixed solvent of acetate (2.0ml) and water (2.0ml) morpholine-N-oxide compound.It is heated in 60 ℃, (40mg 0.72mmol), stirred 30 minutes to add iron powder.After the cooling reaction solution is injected the unsaturated carbonate aqueous solutions of potassium, with ethyl acetate (60ml) extraction.Solution saturated common salt water washing, the decompression of dry back concentrates down.Residue obtained refining with silica gel chromatography (3% methanol), obtain title compound (30mg, 40%).
1H-NMR(400MHz，CDCl
3)δ：2.5-2.8(6H，m)，3.59(2H，br)，3.81(4H，br)，5.45(1H，br)，6.10(1H，s)，6.88(1H，m)，7.01(1H，m)，7.25(1H，s)，7.42(2H，d，J＝8.8Hz)，7.49(1H，m)，7.60(2H，d，J＝8.4Hz)，7.97(1H，s).
MSm/z：542(M
++H).
Embodiment 107:2-[N-[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-the N-methylamino] ethyl-methyl carbamic acid tert-butyl ester
Under the nitrogen atmosphere, in 100 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (78mg, 0.19mmol) and N, 1 of N '-dimethyl-ethylenediamine (400 μ l), 4-two alkane (2.0ml) solution stirring 2 days.Dilute solution with water and saturated common salt water washing with ethyl acetate (40ml) after being cooled to room temperature.Decompression concentrates down after the drying solution, obtains residue.After residue is dissolved in tetrahydrofuran (THF) (10ml), add under the room temperature triethylamine (31 μ l, 0.22mmol) and tert-Butyl dicarbonate (49mg 0.22mmol), stirred 15 hours.Behind the concentrated solution, (hexane: ethyl acetate=4: 1) make with extra care residue obtained, acquisition is the title compound (68mg, 64%) of oily matter with silica gel chromatography under the decompression.
1H-NMR (400MHz, CDCl
3) δ: 1.26 and 1.32 (9H, br-s, rotational isomers), 2.75 and 2.78 (3H, br-s, rotational isomer), 2.95 (3H, br-s), 3.30 (2H, m), 3.65 (2H, m), 5.92 (1H, s), 6.6-6.8 (1H, m), 6.84-6.97 (2H, m), 7.05 (1H, m), 7.14 (2H, d, J=8.8Hz), 7.17 (2H, d, J=8.4Hz), 7.98 (1H, s).
MSm/z：568(M
++H).
Embodiment 108:2-[N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-the N-methylamino] ethyl-methyl carbamic acid tert-butyl ester
At 2-[N-[5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl]-the N-methylamino] ethyl-methyl carbamic acid tert-butyl ester (67mg, 0.12mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, (hexane: ethyl acetate=3: 1) residue is made with extra care, acquisition is the title compound (64mg, 91%) of oily matter with silica gel chromatography under the decompression.
1H-NMR (400MHz, CDCl
3) δ: 1.33 and 1.38 (9H, br-s, rotational isomers), 2.87 and 2.89 (3H, br-s, rotational isomer), 3.11 (3H, br-s), 3.3-3.4 (2H, m), 3.6-3.9 (2H, m), 6.12 (1H, s), 6.89 (1H, m), 7.00 (1H, m), 7.26 (1H, m), 7.41 (2H, d, J=8.4Hz), 7.53 (1H, m), 7.59 (2H, d, J=8.4Hz), 8.00 (1H, s).
EI-MS:599.1204 (C
27H
29Cl
2F
2N
3O
4S, calculated value: 599.1224).
Embodiment 109:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-2-[N-methyl-N-[2-(methylamino) ethyl] amino] pyridine
With 2-[N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl]-the N-methylamino] ethyl-methyl carbamic acid tert-butyl ester (61mg; 0.10mmol) be dissolved in methylene dichloride (2.0ml); add methyl-phenoxide (40 μ l), trifluoroacetic acid (200 μ l) under the room temperature, stirred 1 hour.Decompression is concentration of reaction solution down, and is residue obtained refining with silica gel chromatography (3% methyl alcohol/chloroform to 3% methyl alcohol, 3% TERTIARY BUTYL AMINE/chloroform), obtains to be the title compound (21mg, 41%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：2.51(3H，s)，2.90(2H，d，J＝6.0Hz)，3.14(3H，s)，3.72(2H，m)，6.13(1H，s)，6.89(1H，m)，7.00(1H，m)，7.36(1H，m)，7.41(2H，d，J＝8.4Hz)，7.52(1H，m)，7.60(2H，d，J＝8.4Hz)，8.00(1H，s).
FAB-MS:500.0770 (C
22H
22Cl
2F
2N
3O
2S, calculated value: 500.0778).
Embodiment 110:(2 ' S)-5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-2-[2 '-(hydroxymethyl) tetramethyleneimine-1 '-yl] pyridine
Under the nitrogen atmosphere, in 100 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (60mg, 0.14mmol) and (S)-2-pyrrolidine carbinol (200 μ l) 1,4-two alkane (1.0ml) solution stirring 3 days.Dilute solution with water and saturated common salt water washing with ethyl acetate (50ml) after being cooled to room temperature.Decompression concentrates down after the solution drying, obtains residue.It is residue obtained that (hexane: ethyl acetate=5: 1) refining, acquisition is the title compound (40mg, 58%) of oily matter with silica gel chromatography.
1H-NMR (400MHz, CDCl
3) δ: 1.78 (1H, m), 2.06 (3H, m), 3.29 (1H, m), 3.50 (1H, m), 3.66 (1H, m), 3.72 (1H, m), 4.33 (1H, m), 5.97 with 5.98 (1H, s, rotational isomers), 6.73 and 6.77 (1H, s, rotational isomer), 6.92-7.15 (3H, m), 7.25 (4H, m), 7.98 (1H, s).
MSm/z：481(M
++H).
Embodiment 111:(2 ' S)-5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-2-[2 '-(hydroxymethyl) tetramethyleneimine-1 '-yl] pyridine
At (2 ' S)-5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-2-[2 '-(hydroxymethyl) tetramethyleneimine-1 '-yl] pyridine (39mg, 0.08mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (60ml) dilution back solution with water and saturated common salt water washing.Residue silica gel chromatography (hexane: ethyl acetate=1: 1) make with extra care, obtain to be the title compound (33mg, 79%) of oily matter behind the concentrated solution under the decompression.
1H-NMR (400MHz, CDCl
3) δ: 1.75 (1H, m), 2.02 (3H, m), 3.3-3.5 (1H, m), 3.52-3.75 (3H, m), 4.2-4.35 (1H, m), 6.05 (1H, br-s), 6.84 (1H, m), 6.96 (1H, m), 7.36 (1H, s), 7.36 and 7.37 (2H, d, J=8.8Hz, rotational isomer), 7.43 (1H, m), 7.53 and 7.54 (2H, d, J=8.8Hz, rotational isomer), 7.89 and 7.90 (1H, s, rotational isomers).
FAB-MS:513.0627 (C
23H
21Cl
2F
2N
2O
3S, calculated value: 513.0618).
Embodiment 112:[4-[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine-2-yl] the methyl carbamic acid tert-butyl ester
Under the nitrogen atmosphere, in 100 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (60mg, 0.14mmol) and (1 of the methyl carbamic acid tert-butyl ester (200mg) of morpholine-2-yl), 4-two alkane (1.0ml) solution stirring 2 days.Dilute solution with water and saturated common salt water washing with ethyl acetate (50ml) after being cooled to room temperature.Decompression concentrates down after the solution drying, obtains residue.It is residue obtained that (hexane: ether=5: 1) refining, acquisition is the title compound (45mg, 52%) of oily matter with silica gel chromatography.
1H-NMR (400MHz, CDCl
3) δ: 1.46 (9H, s), 2.72 (1H, m), 3.00 (1H, m), 3.22 (1H, m), 3.44 (1H, m), 3.6-3.75 (2H, m), 3.9-4.1 (3H, m), 4.95 (1H, br), 5.99 and 6.00 (1H, s, rotational isomers), 6.96 and 6.97 (1H, s, rotational isomer), 6.9-7.1 (3H, m), 7.24 (4H, s), 8.11 (1H, s).
MSm/z：596(M
++H).
Embodiment 113:[4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine-2-yl] the methyl carbamic acid tert-butyl ester
[4-[5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine-2-yl] the methyl carbamic acid tert-butyl ester (44mg, 0.074mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (60ml) dilution back solution with water and saturated common salt water washing.Residue silica gel chromatography (hexane: ethyl acetate=3: 1) make with extra care, obtain to be the title compound (31mg, 67%) of oily matter behind the concentrated solution under the decompression.
1H-NMR(400MHz，CDCl
3)δ：1.40(9H，s)，2.69(1H，m)，3.02(1H，m)，3.18(1H，m)，3.41(1H，br)，3.6-3.75(2H，m)，3.92(1H，m)，4.02(1H，m)，4.13(1H，m)，4.91(1H，br)，6.07(1H，s)，6.85(1H，m)，6.99(1H，m)，7.37(2H，d，J＝8.4Hz)，7.35-7.45(2H，m)，7.53(2H，d，J＝8.4Hz)，8.17(1H，s).
FAB-MS:628.1255 (C
28H
30Cl
2F
2N
3O
5S, calculated value: 628.1251)
Embodiment 114:2-amino methyl-4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine
Will [4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl] morpholine-2-yl] the methyl carbamic acid tert-butyl ester (30mg; 0.05mmol) be dissolved in methylene dichloride (1.5ml); add methyl-phenoxide (30 μ l), trifluoroacetic acid (150 μ l) under the room temperature, stirred 1 hour.Decompression is concentration of reaction solution down, and is residue obtained refining with silica gel column chromatography (3% methyl alcohol/chloroform to 3% methyl alcohol, 3% TERTIARY BUTYL AMINE/chloroform), obtains to be the title compound (17mg, 67%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：2.77(1H，m)，2.9-3.3(2H，m)，3.5-3.85(3H，m)，3.97(1H，m)，4.04-4.25(2H，m)，6.12(1H，s)，6.90(1H，m)，7.02(1H，m)，7.42(2H，d，J＝8.4Hz)，7.4-7.55(2H，m)，7.58(2H，d，J＝8.4Hz)，8.05(1H，s).
FAB-MS:528.0695 (C
23H
22Cl
2F
2N
3O
3S, calculated value: 528.0727)
Embodiment 115:5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-2-(pyridine of 4 '-hydroxy piperidine-1 '-yl)
Under the nitrogen atmosphere, in 100 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (60mg, 0.14mmol) and 4-hydroxy piperidine (200mg) 1,4-two alkane (1.0ml) stirred 1 day.After being cooled to room temperature, with ether (50ml) dilution, solution with water and saturated common salt water washing.Decompression concentrates down after the drying solution, obtains residue.(hexane: ethyl acetate=3: 1) refining, acquisition is the title compound (300mg, 43%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：1.62(2H，m)，2.05(2H，m)，3.30(2H，m)，3.98(3H，m)，5.97(1H，s)，6.96-7.12(3H，m)，7.23(4H，m)，7.26(1H，s)，8.10(1H，s).
MSm/z：481(M
++H).
Embodiment 116:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-2-(pyridine of 4 '-hydroxy piperidine-1 '-yl)
At 5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-2-(pyridine (29mg of 4 '-hydroxy piperidine-1 '-yl), 0.06mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (60ml) dilution back solution with water and saturated common salt water washing.Residue silica gel chromatography (hexane: ethyl acetate=2: 1) make with extra care, use the ether crystallization again, obtain to be solid title compound (17mg, 55%) behind the concentrated solution under the decompression.
1H-NMR(400MHz，CDCl
3)δ：1.64(2H，m)，2.02(2H，m)，3.33(2H，m)，3.98(1H，m)，4.08(2H，m)，6.11(1H，s)，6.92(1H，m)，7.02(1H，m)，7.42(2H，d，J＝8.8Hz)，7.45(1H，m)，7.53(1H，s)，7.58(2H，d，J＝8.8Hz)，8.05(1H，s).
mp：146-148℃.
FAB-MS:513.0588 (C
23H
21Cl
2F
2N
2O
3S, calculated value: 513.0618).
Embodiment 117:3,6-two chloro-2-[(4-chloro-phenyl-alkylsulfonyls) (pyridin-4-yl) methyl] pyridine
(3,6-dichloropyridine-2-yl) (pyridin-4-yl) methyl alcohol that obtains at reference example 25 (161mg, add in methylene dichloride 0.631mmol) (10ml) solution triethylamine (208 μ l, 1.89mmol) and thionyl chloride (138 μ l, 1.89mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 4 hours.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate afterwards.With the residue obtained acetonitrile (10ml) that is dissolved in, add 4-chlorobenzene mercaptan (137mg, 0.947mmol) and salt of wormwood (131mg, 0.947mmol).Under the nitrogen atmosphere, under the room temperature reaction solution stirring after 2 days, being stirred 4 hours in 60 ℃.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.In residue obtained, add ethyl acetate, after water and the saturated common salt water washing, use anhydrous sodium sulfate drying successively, filter back concentrating under reduced pressure filtrate.Residue obtainedly handle the cut that concentrating under reduced pressure is obtained by the elutriant of 40% ethyl acetate/hexane with flash chromatography.With the residue obtained methyl alcohol (10ml) that is dissolved in, add 30% aquae hydrogenii dioxidi (3ml) and seven molybdic acids, six ammonium tetrahydrates (73mg).Room temperature stirs pressure reducing and steaming methyl alcohol after 5 hours to reaction solution.In gained solution, add saturated sodium bicarbonate aqueous solution, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with flash chromatography, concentrating under reduced pressure is by methyl alcohol: the cut that methylene dichloride=1: 80 elutriant obtains obtains to be white in color solid title compound (49mg, 0.118mmol, 19%).
1H-NMR(400MHz，CDCl
3)δ：6.08(1H，s)，7.31(1H，d，J＝8.3Hz)，7.41(2H，d，J＝8.8Hz)，7.45(2H，d，J＝6.0Hz)，7.51(2H，d，J＝8.8Hz)，7.69(1H，d，J＝8.3Hz)，8.58(2H，d，J＝6.0Hz).
MS(m/z)：413，415(M
++H).
Embodiment 118:2-[1-(4-chloro-phenyl-alkylsulfonyl)-1-(2, the 5-difluorophenyl) ethyl]-the 5-picoline
Under ice-cold; at 60% oily sodium hydride (30mg; 0.75mmol) N; splash into the 2-[[(4-chloro-phenyl-of embodiment 15 gained in dinethylformamide (5ml) suspension liquid) alkylsulfonyl] (2; the 5-difluorophenyl) methyl]-5-picoline (52mg; 0.132mmol) N, dinethylformamide (5ml) solution.Ice-cold down, reaction solution stirred 15 minutes after, add methyl-iodide (12 μ l, 0.198mmol).After under the room temperature reaction solution being stirred 1 hour, add water, concentrating under reduced pressure under ice-cold.In residue obtained, add water, use ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=8: 1 elutriant obtains.Residue obtainedly solidify the title compound (50mg, 0.122mmol, 93%) of the powder that obtains after the leaching to be white in color with hexane.
1H-NMR(400MHz，CDCl
3)δ：2.14(3H，s)，2.33(3H，s)，6.80-7.10(2H，m)，7.23-7.34(4H，m)，7.39-7.51(2H，m)，7.88-8.00(1H，m)，8.15(1H，s).
MS(m/z)：408(M
++H).
Embodiment 119:3,6-two chloro-2-[(6-chloropyridines-3-base sulfenyl) (pyridin-4-yl) methyl] pyridine
(164mg adds 1N aqueous sodium hydroxide solution (7ml) to dithiocarbonic acid S-(6-chloro-3-pyridyl) the ester O-ethyl ester that obtains at reference example 26 in ethanol 0.70mmol) (7ml) solution, stirred 3 hours in 80 ℃.After reaction mixture is cooled to room temperature, add 1N hydrochloric acid, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, obtains to be the 6-chloro-3-pyridine mercaptan of yellow solid.
In 0 ℃, at (3,6-dichloropyridine-2-yl) (pyridin-4-yl) methyl alcohol (153mg of reference example 25 acquisitions, 0.60mmol) methylene dichloride (3ml) solution in add triethylamine (0.167ml 1.20mmol), add methylsulfonyl chloride (0.070ml again, 0.90mmol), stirred 2 hours under the room temperature.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, organic layer filtered back concentrating under reduced pressure filtrate with anhydrous sodium sulfate drying.At residue obtained N, add the N of 6-chloro-3-pyridine mercaptan in dinethylformamide (3ml) solution, dinethylformamide (2ml) solution, (100mg 0.72mmol), stirred 18 hours under the room temperature to add salt of wormwood again.Add ethyl acetate in reaction mixture, after the saturated sodium bicarbonate aqueous solution washing, the organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=7: 3 wash-out portion obtains obtains to be the title compound (83mg, 0.22mmol, 36%) of yellow oil.
1H-NMR(400MHz，CDCl
3)δ：5.69(1H，s)，7.20(1H，d，J＝8.3Hz)，7.24(1H，d，J＝8.3Hz)，7.35(2H，d，J＝6.1Hz)，7.52(1H，dd，J＝8.3，2.4Hz)，7.62(1H，d，J＝8.3Hz)，8.32(1H，d，J＝2.4Hz)，8.55(2H，d，J＝6.1Hz).
MSm/z：382(M
++H).
Embodiment 120:3; 6-two chloro-2-[(6-chloropyridines-3-base alkylsulfonyl) (pyridin-4-yl) methyl] pyridine (compd A) and 3,6-two chloro-2-[(6-chloropyridines-3-base sulfinyl) (pyridin-4-yl) methyl] pyridine (compd B (isomer A) and compd B (isomer B))
The compd A compd B
3,6-two chloro-2-[(6-chloropyridines-3-base sulfenyl) (pyridin-4-yl) methyl] pyridine (82mg, 0.24mmol) methyl alcohol (4ml) solution in add 31% aqueous hydrogen peroxide solution (2ml) and seven molybdic acids, six ammonium tetrahydrates (30mg), stirred 2 hours under the room temperature.Add ethyl acetate in reaction mixture, after the saturated sodium bicarbonate aqueous solution washing, the organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue is handled with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, the acquisition solid title compound A (41mg that is white in color, 0.098mmol, 46%), in addition, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=1: 1 obtains, solid title compound B (isomer A) (low polarity) (8mg, 9%) and title compound B (isomer B) (high polarity) (8mg, 9%) obtain respectively to be white in color.
Compd A
1H-NMR(400MHz，CDCl
3)δ：6.11(1H，s)，7.35(1H，d，J＝8.3Hz)，7.36(2H，d，J＝6.1Hz)，7.40(1H，d，J＝8.3Hz)，7.73(1H，d，J＝8.3Hz)，7.78(1H，dd，J＝8.3，2.4Hz)，8.48(1H，d，J＝2.4Hz)，8.61(2H，d，J＝6.1Hz).
MSm/z：414(M
++H).
Compd B (isomer A)
1H-NMR(400MHz，CDCl
3)δ：5.54(1H，s)，6.99(2H，d，J＝6.1Hz)，7.27(1H，d，J＝8.3Hz)，7.37(1H，d，J＝8.3Hz)，7.55(1H，dd，J＝8.3，2.2Hz)，7.73(1H，d，J＝8.3Hz)，8.47(1H，d，J＝2.2Hz)，8.51(2H，d，J＝6.1Hz).
MSm/z：398(M
++H).
Compd B (isomer B)
1H-NMR(400MHz，CDCl
3)δ：5.40(1H，s)，7.26(1H，d，J＝8.5Hz)，7.42(1H，d，J＝8.3Hz)，7.53(2H，d，J＝6.1Hz)，7.57(1H，d，J＝8.5Hz)，7.96(1H，dd，J＝8.3，2.4Hz)，8.34(1H，d，J＝2.4Hz)，8.68(2H，d，J＝6.1Hz).
MSm/z：398(M
++H).
Embodiment 121:2-[[(3-chloropyridine-4-yl) (2, the 5-difluorophenyl) methyl] alkylsulfonyl] pyrimidine
In 0 ℃, 3-chloro-4-[(2 in reference example 23 acquisitions, the 5-difluorophenyl)-and hydroxymethyl] pyridine (102mg, 0.40mmol) methylene dichloride (4ml) solution in add earlier triethylamine (0.112ml, 0.80mmol), (0.046ml 0.60mmol), stirred 17 hours under the room temperature to add methylsulfonyl chloride again.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
At residue obtained N, (45mg, 0.40mmol), (83mg 0.60mmol), stirred 23 hours under the room temperature to add salt of wormwood again to add 2-pyrimidine mercaptan in dinethylformamide (4ml) solution.In reaction mixture, add ethyl acetate, wash back organic layer anhydrous sodium sulfate drying with water, filter back concentrating under reduced pressure filtrate.In 0 ℃, (212mg 0.80mmol), stirred 3 hours under the room temperature to add 3-chloro-peroxybenzoic acid (purity is more than 65%) in residue obtained methylene dichloride (4ml) solution.After reaction mixture was washed with the 1N aqueous sodium hydroxide washes, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 3 wash-out portion obtains obtains to be the title compound (19mg, 0.049mmol, 12%) of colourless foaming material.
1H-NMR(400MHz，CDCl
3)δ：6.26(1H，s)，6.93-7.13(3H，m)，7.50-7.56(1H，m)，8.01-8.08(1H，m)，8.13(1H，d，J＝5.1Hz)，8.48(1H，d，J＝2.2Hz)，8.60(1H，s)，8.66(1H，d，J＝5.1Hz).
MSm/z：382(M
++H).
Embodiment 122:6-(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl-5-fluorine niacinamide
In 0 ℃, 6-(2 in reference example 31 acquisitions, the 5-difluorophenyl) hydroxymethyl-5-fluorine niacinamide (114mg, 0.40mmol) methylene dichloride (4ml) solution in add earlier triethylamine (0.113ml, 0.81mmol), (0.047ml 0.61mmol), stirred 2 hours under the room temperature to add methylsulfonyl chloride again.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
At residue obtained N, (70mg, 0.49mmol), (67mg 0.49mmol), stirred 15 hours under the room temperature to add salt of wormwood again to add 4-chlorobenzene mercaptan in dinethylformamide (6ml) solution.In reaction mixture, add ethyl acetate,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Handle with the flash chromatography on silica gel method residue obtained, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains obtains to be the title compound (120mg, 0.29mmol, 73%) of yellow solid.
1H-NMR(400MHz，CDCl
3)δ：6.14(1H，s)，6.88-6.96(2H，m)，7.21(2H，d，J＝8.5Hz)，7.28(2H，d，J＝8.5Hz)，7.58-7.74(1H，m)，7.85(1H，dd，J＝9.4，1.6Hz)，8.80(1H，s).
MSm/z：409(M
++H).
Embodiment 123:6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine niacinamide (compd A) and 6-(4-chloro-phenyl-sulfinyl) (2, the 5-difluorophenyl) methyl-5-fluorine niacinamide (compd B)
The compd A compd B
(120mg adds 30% aqueous hydrogen peroxide solution (2ml) and seven molybdic acids, six ammonium tetrahydrates (73mg) in methyl alcohol 0.29mmol) (3ml) solution, stirred 3 hours under the room temperature at 6-(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl-5-fluorine niacinamide.In reaction mixture, add methylene dichloride,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains, the acquisition solid title compound A (33mg that is white in color, 0.075mmol, 25%), in addition, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 3 wash-out portion obtains, the acquisition solid title compound B (39mg, 0.092mmol, 31%) that is white in color.
Compd A
1H-NMR(400MHz，CDCl
3)δ：6.37(1H，s)，6.90-6.97(1H，m)，7.01-7.08(1H，m)，7.43(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz)，7.94(1H，dd，J＝9.2，1.8Hz)，8.17-8.22(1H，m)，8.91(1H，s).
mp：222-224℃.
MSm/z：441(M
++H).
Compd B
1H-NMR(400MHz，CD
3OD)δ：5.86(1H，s)，6.94-7.02(1H，m)，7.06-7.14(1H，m)，7.44(2H，d，J＝8.8Hz)，7.48(2H，d，J＝8.8Hz)，7.66-7.71(1H，m)，8.07(1H，dd.J＝9.8，1.7Hz)，9.09(1H，s).
mp：171-173℃.
Ultimate analysis: C
19H
12ClF
3N
2O
2S: theoretical value: C, 53.72; H, 2.85; Cl, 8.35; F, 13.42; N, 6.59; S, 7.55. measured value: C, 53.44; H, 2.96; Cl, 8.37; F, 13.34; N, 6.66; S, 7.54.
Embodiment 124:[6-(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl alcohol
Under the room temperature, [5-(tert-butyl diphenyl siloxy-methyl)-3-fluorine pyridine-2-yl] (2 in reference example 29 acquisitions, the 5-difluorophenyl) methyl alcohol (17.0g, 33.5mmol) methylene dichloride (180ml) solution in add triethylamine (7.00ml, 50.2mmol) and methylsulfonyl chloride (3.11ml, 40.2mmol), stirred 2 hours.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
At residue obtained N, (5.33g, 36.8mmol), (5.55g 40.2mmol), stirred 18 hours under the room temperature to add salt of wormwood again to add 4-chlorobenzene mercaptan in dinethylformamide (300ml) solution.In reaction mixture, add ethyl acetate,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Handle with the flash chromatography on silica gel method residue obtained, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=30: 1 wash-out portion obtains.
(42.3ml 42.3mmol), stirred 4 hours under the room temperature tetrahydrofuran solution of adding tetrabutylammonium in residue obtained tetrahydrofuran (THF) (200ml) solution.Behind the concentrating under reduced pressure reaction mixture,, wash with saturated sodium bicarbonate aqueous solution with the residue obtained ethyl acetate that is dissolved in.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be the title compound (9.80g, 24.8mmol, 74%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.76(2H，s)，6.13(1H，s)，6.84-6.96(2H，m)，7.20(2H，d，J＝8.7Hz)，7.27(2H，d，J＝8.7Hz)，7.43(1H，d，J＝9.8Hz)，7.57-7.64(1H，m)，8.43(1H，s).
Embodiment 125:[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl alcohol
At [6-(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl alcohol (9.80g, 24.8mmol) methyl alcohol (200ml) solution in add 30% aqueous hydrogen peroxide solution (14.0ml) and seven molybdic acids, six ammonium tetrahydrates (612mg), stirred 18 hours under the room temperature.In reaction mixture, append 30% aqueous hydrogen peroxide solution (14.0ml), stirred 3 days under the room temperature.In reaction mixture, append 30% aqueous hydrogen peroxide solution (14.0ml) once more, stirred 5 hours in 50 ℃.Add water in reaction mixture, the solid that leaching is separated out washes with water, drying under reduced pressure.The gained solid is dissolved in ethyl acetate, and after the saturated sodium bicarbonate aqueous solution washing, the organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.The residue ethyl alcohol recrystallization obtains to be white in color solid title compound (6.41g, 15.0mmol, 61%).Behind the concentrating under reduced pressure mother liquor, residue is carried out recrystallization, obtain to be white in color solid title compound (2.14g, 5.00mmol, 20%) with ethanol.To behind the mother liquor concentrating under reduced pressure,, obtain to be white in color solid title compound (780mg, 1.82mmol, 7%) once more with leaching behind the ether washing residue.
1H-NMR(400MHz，CDCl
3)δ：1.90(1H，t，J＝5.6Hz)，4.80(2H，d，J＝5.6Hz)，6.32(1H，s)，6.89-6.97(1H，m)，6.99-7.06(1H，m)，7.41(2H，d，J＝8.8Hz)，7.49(1H，d，J＝9.8Hz)，7.57(2H，d，J＝8.8Hz)，8.18-8.24(1H，m)，8.52(1H，s).
mp：181-183℃.
MSm/z：428(M
++H).
Embodiment 126:[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridin-3-yl] formaldehyde
Under the room temperature; at [6-(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl alcohol (8.46g; 19.8mmol), triethylamine (13.8ml; 98.8mmol) and methyl-sulphoxide (7.02ml; 98.9mmol) methylene dichloride (100ml) solution in add sulphur trioxide pyridine complex salt (9.44g 59.3mmol), stirred 16 hours.After reaction mixture was used the saturated common salt water washing, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue is handled with the flash chromatography on silica gel method, the cut that concentrating under reduced pressure is obtained by methylene dichloride wash-out portion.Residue obtained with ether washing back leaching, obtain to be the title compound (6.33g, 14.9mmol, 75%) of yellow solid.
1H-NMR(400MHz，CDCl
3)δ：6.40(1H，s)，6.91-6.98(1H，m)，7.02-7.09(1H，m)，7.43(2H，d，J＝8.6Hz)，7.59(2H，d，J＝8.6Hz)，7.89(1H，dd，J＝8.6，1.7Hz)，8.17-8.23(1H，m)，9.02(1H，s)，10.15(1H，d，J＝2.2Hz).
Embodiment 127:6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine nicotinic acid
Under the room temperature; at [6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridin-3-yl] (1.28g adds 30% aqueous hydrogen peroxide solution (1.02ml to formaldehyde in formic acid 3.00mmol) (30ml) solution; 9.00ml), stirred 1 hour under the room temperature.Then, reaction mixture was stirred 1 hour, add water after being cooled to room temperature in 50 ℃.The solid that leaching is separated out washes the back drying under reduced pressure with water.The gained solid is dissolved in ethyl acetate, and after the saturated aqueous ammonium chloride washing, the organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.Residue with washing with alcohol after leaching, solid title compound (1.19g, 2.69mmol, 89%) obtains to be white in color.
1H-NMR(400MHz，DMSO-d
6)δ：6.37(1H，s)，7.27-7.42(2H，m)，7.64(2H，d，J＝8.8Hz)，7.67(2H，d，J＝8.8Hz)，8.01-8.07(1H，m)，8.17(1H，dd，J＝9.6，1.7Hz)，9.04(1H，s).
mp：249-251℃.
Ultimate analysis: C
19H
11ClF
3NO
4S: theoretical value: C, 51.65; H, 2.51; Cl, 8.02; F, 12.90; N, 3.17; S, 7.26. measured value: C, 51.70; H, 2.73; Cl, 7.96; F, 12.81; N, 3.36; S, 7.39.
Embodiment 128:6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluoro-N-thiazol-2-yl niacinamide
Under the room temperature; at 6-(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl-5-fluorine nicotinic acid (100mg; 0.23mmol) methylene dichloride (2ml) solution in add thiazol-2-yl amine (25mg; 0.25mmol), benzotriazole-1-alcohol (34mg, 0.25mmol), the 4-methylmorpholine (0.027ml, 0.25mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (48mg; 0.25mmol), stirred 14 hours under the room temperature.Add ethyl acetate in reaction mixture, after the saturated sodium bicarbonate aqueous solution washing, the organic layer anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains.Residue with washing with alcohol after leaching, solid title compound (72mg, 0.14mmol, 60%) obtains to be white in color.
1H-NMR(400MHz，DMSO-d
6)δ：6.38(1H，s)，7.24-7.42(2H，m)，7.60(1H，d，J＝3.7Hz)，7.65(2H，d，J＝9.1Hz)，7.68(2H，d，J＝9.1Hz)，8.03-8.10(1H，m)，8.38(1H，d，J＝9.6Hz)，9.17(1H，s)，13.00(1H，s).
mp：243-245℃.
Ultimate analysis: press C
22H
13ClF
3N
3O
3S
2Calculate: theoretical value: C, 50.43; H, 2.50; Cl, 6.77; F, 10.88; N, 8.02; S, 12.24. measured value: C, 50.34; H, 2.48; Cl, 6.93; F, 10.82; N, 8.11; S, 12.29.
The different azoles of embodiment 129:6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluoro-N--3-base niacinamide
According to the method same with embodiment 128; the 6-(4-chloro-phenyl-alkylsulfonyl) (2 that adopts embodiment 127 to obtain; the 5-difluorophenyl) methyl-5-fluorine nicotinic acid (100mg; 0.23mmol) and different azoles-3-base amine (0.018mol; 0.25mmol); the acquisition solid title compound (43mg, 0.085mmol, 37%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：6.41(1H，s)，6.92-7.00(1H，m)，7.03-7.11(1H，m)，7.25(1H，d，J＝1.7Hz)，7.44(2H，d，J＝8.6Hz)，7.60(2H，d，J＝8.6Hz)，8.05(1H，dd，J＝9.1，2.0Hz)，8.20-8.26(1H，m)，8.40(1H，d，J＝1.7Hz)，9.14(1H，d，J＝1.5Hz)，10.25(1H，s).
mp：200-202℃.
Ultimate analysis: press C
22H
13ClF
3N
3O
4S calculates: theoretical value: C, 52.03; H, 2.58; Cl, 6.98; F, 11.22; N, 8.27; S, 6.31. measured value: C, 51.84; H, 2.55; Cl, 7.36; F, 11.19; N, 8.36; S, 6.46.
Embodiment 130:6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluoro-N-pyridine-2-ylmethyl niacinamide
According to the method same with embodiment 128; the 6-(4-chloro-phenyl-alkylsulfonyl) (2 that adopts embodiment 127 to obtain; the 5-difluorophenyl) methyl-5-fluorine nicotinic acid (100mg; 0.23mmol) and pyridine-2-base methylamine (0.026ml; 0.25mmol); acquisition is the title compound (86mg, 0.16mmol, 72%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：4.77(2H，d，J＝4.4Hz)，6.37(1H，s)，6.91-7.09(2H，m)，7.25-7.34(2H，m)，7.43(2H，d，J＝8.8Hz)，7.58(2H，d，J＝8.8Hz)，7.72(1H，td，J＝7.6，1.7Hz)，7.94(1H，s)，7.96(1H，dd，J＝9.3，2.0Hz)，8.19-8.25(1H，m)，8.59(1H，d，J＝4.4Hz)，9.03(1H，s).
Ultimate analysis: press C
25H
17ClF
3N
3O
3S calculates: theoretical value: C, 56.45; H, 3.22; Cl, 6.66; F, 10.71; N, 7.90; S, 6.03. measured value: C, 56.32; H, 3.30; Cl, 6.63; F, 10.61; N, 7.88; S, 6.14.
Embodiment 131:(E)-and 3-[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl acrylate
Under the room temperature; [6-(4-chloro-phenyl-alkylsulfonyl) (2 in embodiment 126 acquisitions; the 5-difluorophenyl) methyl]-5-fluorine pyridin-3-yl] formaldehyde (1.70g; 4.00mmol) tetrahydrofuran (THF) (15ml) solution in add the inferior phosphoranyl methyl acetate of triphenyl (1.47g; 4.40mmol), stirred 18 hours under the room temperature.The concentrating under reduced pressure reaction mixture is handled with the flash chromatography on silica gel method residue obtained.The cut that concentrating under reduced pressure is obtained by methylene dichloride wash-out portion washs the back leaching with the mixed solvent of ethanol and hexane to residue obtained, obtains to be white in color solid title compound (1.60g, 3.31mmol, 83%).
1H-NMR(400MHz，CDCl
3)δ：3.84(3H，s)，6.33(1H，s)，6.53(1H，d，J＝16.7Hz)，6.89-6.97(1H，m)，6.99-7.08(1H，m)，7.42(2H，d，J＝8.3Hz)，7.55(1H，d，J＝9.6，1.5Hz)，7.58(2H，d，J＝8.3Hz)，7.65(1H，d，J＝16.7Hz)，8.18-8.24(1H，m)，8.67(1H，s).
MSm/z：482(M
++H).
Embodiment 132:3-[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl propionate
Elder generation's water (1ml) washs drawing Buddhist nun's nickel suspension liquid (R-100, emerging リ カ of day Co., Ltd.) with ethanol again, forms ethanol (10ml) suspension liquid.At 3-[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] methyl acrylate (1.38g adds above-mentioned suspension liquid in ethanol 2.86mmol) (40ml) solution, under nitrogen atmosphere in stirring at room 1 hour.Behind the diatomite filtration reaction mixture, concentrating under reduced pressure filtrate with the residue obtained methylene dichloride that is dissolved in, is used anhydrous sodium sulfate drying.Filter back concentrating under reduced pressure filtrate, obtain to be white in color solid title compound (1.37g, 2.83mmol, 99%).
1H-NMR(400MHz，CDCl
3)δ：2.66(2H，t，J＝7.4Hz)，3.00(2H，t，J＝7.4Hz)，3.69(3H，s)，6.29(1H，s)，6.88-6.96(1H，m)，6.98-7.06(1H，m)，7.29(1H，dd，J＝10.1，1.5Hz)，7.40(2H，d，J＝8.3Hz)，7.56(2H，d，J＝8.3Hz)，8.20-8.26(1H，m)，8.42(1H，s).
MSm/z：484(M
++H).
Embodiment 133:3-[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] propionic acid
At 3-[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] (387mg adds 1N aqueous sodium hydroxide solution (4ml) to methyl propionate in ethanol 0.80mmol) (8ml) solution, stirred 3 hours under the room temperature.After making reaction solution be acidity with 1N hydrochloric acid, use dichloromethane extraction again.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtained mixed solvent washing back leaching with ether and hexane obtains to be white in color solid title compound (349mg, 0.74mmol, 93%).
1H-NMR(400MHz，CDCl
3)δ：2.73(2H，t，J＝7.4Hz)，3.01(2H，t，J＝7.4Hz)，6.29(1H，s)，6.89-6.96(1H，m)，6.99-7.06(1H，m)，7.30(1H，dd，J＝9.8，1.7Hz)，7.40(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，8.19-8.26(1H，m)，8.44(1H，s).
mp：174-176℃.
MSm/z：470(M
++H).
Ultimate analysis: C
21H
15ClF
3NO
4S: theoretical value: C, 53.68; H, 3.22; Cl, 7.55; F, 12.13; N, 2.98; S, 6.82. measured value: C, 53.68; H, 3.35; Cl, 7.42; F, 12.09; N, 3.16; S, 6.92.
Embodiment 134:3-[6-(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl]-1-(4-methylpiperazine-1-yl) propane-1-keto hydrochloride
Under the room temperature; at 3-[6-(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl-5-fluorine pyridin-3-yl] propionic acid (100mg; 0.21mmol) methylene dichloride (3ml) solution in add 1-methylpiperazine (0.026ml; 0.23mmol), benzotriazole-1-alcohol (32mg, 0.23mmol), the 4-methylmorpholine (0.026ml, 0.23mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (45mg; 0.23mmol), stirred 16 hours.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered concentrating under reduced pressure filtrate.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by methylene dichloride: the cut that the wash-out portion of methyl alcohol=19: 1 obtains.With the residue obtained ethanol (3ml) that is dissolved in, add 1N hydrochloric acid (0.224ml), stir after 30 minutes the concentrating under reduced pressure reaction mixture under the room temperature.Residue with washing with alcohol after leaching, solid title compound (111mg, 0.19mmol, 89%) obtains to be white in color.
1H-NMR(400MHz，DMSO-d
6)δ：2.40-3.08(6H，m)，2.75(3H，s)，2.90(2H，t，J＝7.1Hz)，3.19-3.50(2H，m)，3.92-4.17(1H，m)，4.29-4.52(1H，m)，6.23(1H，s)，7.24-7.39(2H，m)，7.61(2H，d，J＝8.8Hz)，7.66(2H，d，J＝8.8Hz)，7.75(1H，dd，J＝10.8，1.5Hz)，8.10-8.16(1H，m)，8.53(1H，s)，10.70(1H，s).
mp：243-245℃.
Ultimate analysis: C
26H
25ClF
3N
3O
3SHCl: theoretical value: C, 53.07; H, 4.45; Cl, 12.05; F, 9.69; N, 7.14; S, 5.45. measured value: C, 52.81; H, 4.51; Cl, 11.74; F, 9.48; N, 7.09; S, 5.50.
Embodiment 135:(E)-and 3-[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridin-3-yl] vinylformic acid
(E)-3-[6-[(4-chloro-phenyl-alkylsulfonyl in embodiment 44 acquisitions) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] methyl acrylate (460mg; 0.991mmol) tetrahydrofuran solution (5m1) in add 1N aqueous sodium hydroxide solution (3.0ml) after, stirred 4 hours under the room temperature.Use ethyl acetate extraction after making reaction solution be acidity with 1N hydrochloric acid.Use anhydrous magnesium sulfate drying after extraction liquid water and the saturated common salt water washing, concentrate, obtain rough title compound quantitatively.With ethyl acetate-hexane a gained solid part is carried out recrystallization, obtain to be colorless solid title compound (29.4mg, 0.0653mmol).
1H-NMR(400MHz，CDCl
3)δ：5.96(1H，s)，6.52(1H，d，J＝16.1Hz)，6.94(1H，td，J＝9.0，4.6Hz)，6.99-7.06(1H，m)，7.41(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，7.64(1H，d，J＝16.1Hz)，7.64(1H，d，J＝8.1Hz)，7.88(1H，dd，J＝8.1，2.2Hz)，8.01(1H，ddd，J＝9.0，5.6，3.4Hz)，8.72(1H，d，J＝2.2Hz).
mp：236-238℃.
Ultimate analysis: C
21H
14ClF
2NO
4S: theoretical value: C, 56.07; H, 3.14; Cl, 7.88; F, 8.45; N, 3.11; S, 7.13. measured value: C, 55.98; H, 3.21; Cl, 7.90; F, 8.45; N, 3.21; S, 7.12.
Embodiment 136:(E)-and 3-[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridin-3-yl] acrylamide
With (E)-3-[6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] vinylformic acid (and 370mg, 0.822mmol) be dissolved in methylene dichloride (6ml) after, add thionyl chloride (2.00ml) and N; dinethylformamide (1) stirred 4 hours under the room temperature.Reaction solution is concentrated into dried, with residue obtained be dissolved in methylene dichloride (6ml) after, add strong aqua (2.00ml).Under the room temperature reaction solution is stirred after 2 hours with methylene dichloride dilution, water, 0.1N hydrochloric acid and saturated common salt water washing.With concentrating after the dried over mgso.After with ethanol the gained solid being carried out recrystallization, obtain to be white in color solid title compound (250mg, 0.558mmol, 68%).
1H-NMR(400MHz，CDCl
3/DMSO-d
6)δ：5.79(1H，brs)，5.95(1H，s)，6.42(1H，brs)，6.63(1H，d，J＝15.9Hz)，6.94(1H，td，J＝9.0，4.4Hz)，7.00-7.07(1H，m)，7.41(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.62(1H，d，J＝15.9Hz)，7.64(1H，d，J＝8.1Hz)，7.85(1H，dd，J＝8.1，2.2Hz)，8.02(1H，ddd，J＝9.0，5.4，3.2Hz)，8.74(1H，d，J＝2.2Hz).
mp：219-220℃.
Ultimate analysis: C
21H
15ClF
2N
2O
3S: theoretical value: C, 56.19; H, 3.37; Cl, 7.90; F, 8.46; N, 6.24; S, 7.14. measured value: C, 55.98; H, 3.34; Cl, 8.03; F, 8.45; N, 6.39; S, 7.23.
Embodiment 137:N-[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] nicotinoyl] glycine ethyl ester
Embodiment 50 obtain [6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; 0.236mmol) methylene dichloride (5ml) solution in add triethylamine (80 μ l; 0.566mmol), 4-dimethylaminopyridine (14mg; 0.118mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (54mg; 0.283mmol) and glycine ethyl ester hydrochloride (40mg 0.283mmol), stirred under the room temperature 7 hours.Behind methylene dichloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.The gained organic layer with anhydrous magnesium sulfate drying after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=2: 1 obtains obtains to be the title compound (95mg, 0.187mmol, 79%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：1.33(3H，t，J＝7.1Hz)，4.25(2H，d，J＝5.1Hz)，4.28(2H，q，J＝7.1Hz)，6.00(1H，s)，6.99(1H，brs)，6.91-6.97(1H，m)，7.00-7.06(1H，m)，7.42(2H，d，J＝8.5Hz)，7.56(2H，d，J＝8.5Hz)，7.73(1H，d，J＝8.3Hz)，7.96-8.00(1H，m)，8.18(1H，dd，J＝8.3，2.2Hz)，9.01(1H，d，J＝2.2Hz).
MSm/z：509(M
++H).
Embodiment 138:[2-[[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-3-carbonyl] amino] ethyl] t-butyl carbamate
[6-(4-chloro-phenyl-alkylsulfonyl) (2 in embodiment 50 acquisitions; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; 0.236mmol) methylene dichloride (5ml) solution in add triethylamine (40 μ l; 0.283mmol), 4-dimethylaminopyridine (14mg; 0.118mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (54mg; 0.283mmol) and N-(2-amino-ethyl) t-butyl carbamate (45 μ l; 0.283mmol), stirred 6 hours under the room temperature.Behind methylene dichloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=1: 1 obtains, the title compound (57mg, 0.101mmol, 43%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.44(9H，s)，3.37-3.43(2H，m)，3.55-3.59(2H，m)，4.97(1H，brs)，6.00(1H，s)，6.92-7.05(2H，m)，7.40(2H，d，J＝8.6Hz)，7.55(2H，d，J＝8.6Hz)，7.60(1H，brs)，7.70(1H，d，J＝8.3Hz)，7.92-7.97(1H，m)，8.17(1H，dd，J＝8.3，2.4Hz)，9.03(1H，d，J＝2.4Hz).
MSm/z：566(M
++H).
Embodiment 139:N-(2-amino-ethyl)-6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] niacinamide
[2-[[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-3-carbonyl] amino] ethyl] (50mg adds concentrated hydrochloric acid (2ml) in ethanol 0.0880mmol) (2ml) solution to t-butyl carbamate, stirs 20 minutes under the room temperature.Decompression is concentrated reaction solution down.The gained solid washs with ether, and 1.5 hydrochlorides (white powder) of acquisition title compound (44mg, 0.0880mmol, quantitatively).
1H-NMR(400MHz，CD
3OD)δ：3.19(2H，t，J＝5.9Hz)，3.69(2H，d，J＝5.9Hz)，6.27(1H，s)，7.03-7.09(1H，m)，7.12-7.18(1H，m)，7.54(2H，d，J＝8.6Hz)，7.66(2H，d，J＝8.6Hz)，7.83(1H，d，J＝8.3Hz)，8.06-8.10(1H，m)，8.27(1H，dd，J＝8.3，2.4Hz)，9.08(1H，d，J＝2.4Hz).
Mp:＞250 ℃ (decomposition).
Ultimate analysis: C
21H
18ClF
2N
3O
3S1.5H
2O1.5HCl: theoretical value: C, 46.06; H, 4.14; Cl, 16.18; F, 6.94; N, 7.67; S, 5.86. measured value: C, 46.39; H, 3.93; Cl, 16.58; F, 6.84; N, 7.74; S, 5.94
Embodiment 140:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-N-(2-hydroxyethyl) niacinamide
[6-(4-chloro-phenyl-alkylsulfonyl) (2 in embodiment 50 acquisitions; the 5-difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; 0.236mmol) methylene dichloride (5ml) solution in add triethylamine (80 μ l; 0.566mmol), 4-dimethylaminopyridine (15mg; 0.118mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (54mg; 0.283mmol) and ethanolamine hydrochloric salt (28mg 0.283mmol), stirred under the room temperature 17.5 hours.Behind methylene dichloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by methylene dichloride: the cut that the wash-out portion of methyl alcohol=30: 1 obtains, the title compound (69mg, 0.148mmol, 63%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.38(1H，t，J＝4.9Hz)，3.65(2H，td，J＝5.4，4.9Hz)，3.85(2H，q，J＝4.6Hz)，5.99(1H，s)，6.77(1H，brs)，6.90-6.96(1H，m)，7.00-7.06(1H，m)，7.42(2H，d，J＝8.6Hz)，7.56(2H，d，J＝8.6Hz)，7.70(1H，d，J＝8.1Hz)，7.97-8.01(1H，m)，8.15(1H，dd，J＝8.1，2.2Hz)，8.99(1H，d，J＝2.2Hz)H，m)，.
mp：179-181℃.
Ultimate analysis: C
21H
17ClF
2N
2O
4S: theoretical value: C, 54.02; H, 3.67; Cl, 7.59; F, 8.14; N, 6.00; S, 6.87. measured value: C, 53.83; H, 3.63; Cl, 7.72; F, 8.14; N, 6.06; S, 7.02.
Embodiment 141:[2-[[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-3-thioformyl] amino] ethyl] t-butyl carbamate
Under the argon atmospher; embodiment 138 obtain [2-[[6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-3-carbonyl] amino] ethyl] t-butyl carbamate (120mg; 0.212mmol) toluene (8ml) solution in add Lawson reagent (94mg; 0.233mmol), stirred 1.5 hours under the reflux.The decompression of cooling back is concentrated solvent down.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=1: 1 obtains obtains to be the title compound (84mg, 0.144mmol, 68%) of yellow amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：1.46(9H，s)，3.52-3.57(2H，m)，3.82-3.86(2H，m)，5.09(1H，brs)，5.99(1H，s)，6.92-6.98(1H，m)，6.99-7.05(1H，m)，7.41(2H，d，J＝8.6Hz)，7.55(2H，d，J＝8.6Hz)，7.63(1H，d，J＝8.3Hz)，7.89-7.94(1H，m)，8.21(1H，dd，J＝8.3，2.2Hz)，9.06(1H，d，J＝2.2Hz)，9.61(1H，brs).
MSm/z：582(M
++H).
Embodiment 142:N-(2-amino-ethyl)-6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] Thionicotinamide
[2-[[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-3-thioformyl] amino] ethyl] (80mg adds concentrated hydrochloric acid (2ml) in ethanol 0.137mmol) (3ml) solution to t-butyl carbamate, stirs 20 minutes under the room temperature.Decompression is concentrated reaction solution down, adds ethanol in residue obtained, concentrates.These operations are carried out 3 times, and 1.75 hydrochlorides (yellow powder) of acquisition title compound (76mg, 0.137mmol, quantitatively).
1H-NMR(400MHz，DMSO-d
6)δ：3.07-3.12(2H，m)，3.93-3.97(2H，m)，6.46(1H，s)，7.20-7.26(1H，m)，7.28-7.34(1H，m)，7.66(2H，d，J＝9.0Hz)，7.69(2H，d，J＝9.0Hz)，7.88(1H，d，J＝8.3Hz)，8.05-8.12(1H，m)，8.14(2H，brs)，8.24(1H，dd8.3，2.4)，9.05(1H，d，J＝2.4Hz)，10.74(1H，brs).
mp：164-166℃.
Ultimate analysis: C
21H
18ClF
2N
3O
2S
20.5H
2O1.75HCl: theoretical value: C, 45.46; H, 3.77; Cl, 17.57; F, 6.85; N, 7.57; S, 11.56. measured value: C, 45.02; H, 3.83; Cl, 17.37; F, 6.36; N, 7.54; S, 11.36.
Embodiment 143:2-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-6-(1,3-dioxolane-2-yl) pyridine
In the argon atmospher, in the ice-cold 2-[(2 that obtains at reference example 32 down, the 5-difluorophenyl) hydroxymethyl]-6-(1,3-dioxolane-2-yl) pyridine (2.48g, 8.46mmol) dichloromethane solution (30ml) in add triethylamine (1.77ml, 12.7mmol), (851 μ l 11.0mmol), stirred under the room temperature 3.5 hours methylsulfonyl chloride.Use extracted with diethyl ether after in reaction solution, adding saturated sodium bicarbonate aqueous solution.Solution saturated common salt water washing is with concentrated solution under the decompression behind the anhydrous sodium sulfate drying.Residue (2.14g, add in dimethyl formamide 5.76mmol) (20ml) solution 4-chlorobenzene mercaptan (1.0g, 6.91mmol), (1.19g 8.64mmol), stirred 2 hours in 50 ℃ salt of wormwood.After being cooled to room temperature, with ether reaction soln is diluted, water and saturated aqueous common salt wash successively.The gained organic layer with dried over sodium sulfate after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=5: 1 obtains obtains to be the title compound (2.12g, 5.05mmol, 88%) of faint yellow oily thing.
1H-NMR(400MHz，CDCl
3)δ：4.06-4.20(4H，m)，5.84(1H，s)，5.89(1H，s)，6.86-6.96(2H，m)，7.17(2H，d，J＝8.8Hz)，7.23(2H，d，J＝8.8Hz)，7.38(1H，d，J＝7.8Hz)，7.43(1H，d，J＝7.8Hz)，7.44-7.48(1H，m)，7.69(1H，t，J＝7.8Hz).
MSm/z：420(M
++H).
Embodiment 144:2-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-6-(1,3-dioxolane-2-yl) pyridine
At 2-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-6-(1,3-dioxolane-2-yl) (2.40g adds seven molybdic acids, six ammonium tetrahydrates (200mg), 30% aqueous hydrogen peroxide solution (20ml) to pyridine in methyl alcohol 5.72mmol) (40ml) solution, stirred 5 days.Add the solid that the water leaching is separated out, the residue water washs.Make residue be dissolved in ethyl acetate, successively water and saturated common salt water washing.Down behind the concentrated organic layer, residue washs with ethyl acetate in decompression, the title compound (2.09g, 4.63mmol, 81%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.05-4.17(4H，m)，5.73(1H，s)，5.98(1H，s)，6.93-7.05(2H，m)，7.41(2H，d，J＝8.8Hz)，7.52(2H，d，J＝8.8Hz)，7.50-7.53(1H，m)，7.64(1H，dd，J＝7.6，1.0Hz)，7.80(1H，t，J＝7.6Hz)，7.91-7.95(1H，m).
MSm/z：452(M
++H).
Embodiment 145:[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] formaldehyde
At 2-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-6-(1,3-dioxolane-2-yl) pyridine (2.05g, 4.54mmol) 1, add concentrated hydrochloric acid (10ml) in 4-two alkane (40ml) solution, stirred under the room temperature 20 hours.Behind the concentrated solvent, in residue, add ethyl acetate, successively water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing under the decompression.The gained organic layer with dried over mgso after concentrating under reduced pressure, the title compound of the powder that obtains to be white in color (1.85g, 4.54mmol, quantitatively).
1H-NMR(400MHz，CDCl
3)δ：6.05(1H，s)，6.92-6.98(1H，m)，7.02-7.08(1H，m)，7.43(2H，d，J＝8.8Hz)，7.58(2H，d，J＝8.8Hz)，7.90(1H，dd，J＝7.1，2.0Hz)，7.93-7.99(2H，m)，8.04-8.09(1H，m)，10.00(1H，s).
MSm/z：408(M
++H).
Embodiment 146:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine carboxylic acid
[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (390mg, (325 μ l 2.87mmol), stirred 4 hours under the room temperature formaldehyde to add 30% aqueous hydrogen peroxide solution in formic acid 0.956mmol) (5ml) solution.Add water filtration in reaction soln, the residue water washs.Make the residue obtained ethyl acetate that is dissolved in, wash with saturated aqueous ammonium chloride, water and saturated aqueous common salt successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly carry out recrystallization, the title compound (310mg, 0.731mmol, 77%) of the powder that obtains to be white in color with ethanol.
1H-NMR(400MHz，CDCl
3)8：6.01(1H，s)，6.93-6.99(1H，m)，7.04-7.10(1H，m)，7.44(2H，d，J＝8.6Hz)，7.61(2H，d，J＝8.6Hz)，7.78-7.82(1H，m)，7.99(1H，d，J＝7.8Hz)，8.06(1H，t，J＝7.8Hz)，8.26(1H，d，J＝7.8Hz).
mp：200-201℃.
Ultimate analysis: C
19H
12ClF
2NO
4S: theoretical value: C, 53.84; H, 2.85; Cl, 8.37; F, 8.97; N, 3.30; S, 7.57. measured value: C, 53.55; H, 2.80; Cl, 8.23; F, 9.00; N, 3.55; S, 7.68.
Embodiment 147:[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (4-methylpiperazine-1-yl) ketone
At 6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine carboxylic acid (130mg; 0.307mmol) methylene dichloride (5ml) solution in add N-methylmorpholine (41 μ l; 0.368mmol), I-hydroxybenzotriazole (13mg; 0.368mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (71mg; 0.368mmol) and the 1-methylpiperazine (40 μ l 0.368mmol), stirred under the room temperature 15 hours.After reaction soln dilutes with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Handle residue obtained with flash column chromatography, concentrating under reduced pressure is by methylene dichloride: the cut that the wash-out portion of methyl alcohol=30: 1 obtains, the title compound (40mg, 0.0791mmol, 26%) of the amorphous substance that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.36(3H，s)，2.44-2.65(4H，m)，3.48-4.00(4H，m)，5.91(1H，s)，6.87-6.94(1H，m)，6.98-7.05(1H，m)，7.41(2H，d，J＝7.8Hz)，7.55-7.60(3H，m)，7.74(1H，d，J＝7.3Hz)，7.85(1H，t，J＝7.6Hz)，8.06-8.13(1H，m).
FAB-MS:506.1085 (C
24H
23ClF
2N
3O
3S, calculated value: 506.1117).
Embodiment 148:[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] t-butyl carbamate
Under the argon atmospher; 6-[(4-chloro-phenyl-alkylsulfonyl in embodiment 146 acquisitions) (2; the 5-difluorophenyl) methyl] pyridine carboxylic acid (600mg; 1.42mmol) butanols (2ml) and the mixing solutions of toluene (10ml) in add diphenylphosphine acid amides (428 μ l; 2.00mmol) and triethylamine (394 μ l; 2.83mmol), stirred 23 hours under the reflux, wash with salt solution.The gained organic layer with dried over mgso after concentrating under reduced pressure.Handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=4: 1 obtains obtains to be the title compound (380mg, 0.768mmol, 54%) of faint yellow amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：1.54(9H，s)，5.76(1H，s)，6.90-6.95(1H，m)，6.99-7.05(1H，m)，7.14(1H，d，J＝7.3Hz)，7.19(1H，brs)，7.40(2H，d，J＝8.8Hz)，7.55(2H，d，J＝8.8Hz)，7.65(1H，dd，J＝8.3，7.3Hz)，7.95(1H，d，J＝8.3Hz)，8.01-8.05(1H，m).
MSm/z：495(M
++H).
Embodiment 149:6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amine
[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (370mg adds concentrated hydrochloric acid (5ml) in ethanol 0.748mmol) (5ml) solution to t-butyl carbamate, stirs 6 hours under the room temperature.Decompression is concentrated reaction solution down, adds ethyl acetate in residue obtained, washs successively with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt.The gained organic layer with dried over mgso after concentrating under reduced pressure, the title compound (210mg, 0.537mmol, 71%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.46(2H，brs)，5.72(1H，s)，6.45(1H，d，J＝8.1Hz)，6.88(1H，d，J＝7.3Hz)，6.91-7.03(2H，m)，7.39(2H，d，J＝8.6Hz)，7.39-7.43(1H，m)，7.56(2H，d，J＝8.6Hz)，7.98-8.03(1H，m).
mp：183-184℃.
Ultimate analysis: C
18H
13ClF
2N
2O
2S: theoretical value: C, 54.76; H, 3.32; Cl, 8.98; F, 9.62; N, 7.10; S, 8.12. measured value: C, 54.46; H, 3.22; Cl, 8.82; F, 9.55; N, 7.07; S, 8.11.
Embodiment 150:N-[6-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-2-(pyridine-2-yl) ethanamide
At 6-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-base amine (74mg; 0.187mmol) methylene dichloride (5ml) solution in add N-methylmorpholine (90 μ l; 0.818mmol), I-hydroxybenzotriazole (11mg; 0.313mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (60mg; 0.312mmol) and 2-pyridyl acetic acid hydrochloride (54mg 0.312mmol), stirred under the room temperature 24 hours.After reaction soln dilutes with methylene dichloride, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=4: 1 obtains, the title compound (48mg, 0.0934mmol, 50%) of the amorphous substance that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.86(1H，d，J＝15.9Hz)，3.95(1H，d，J＝15.9Hz)，5.82(1H，s)，6.92-6.96(1H，m)，6.98-7.08(1H，m)，7.21(1H，d，J＝7.6Hz)，7.25-7.33(3H，m)，7.39(2H，d，J＝8.5Hz)，7.54(2H，d，J＝8.5Hz)，7.66-7.73(2H，m)，8.07-8.11(1H，m)，8.20(1H，d，J＝8.6Hz)，8.69(1H，d，J＝4.4Hz).
FAB-MS:514.0800 (C
25H
19ClF
2N
3O
3S, calculated value: 514.0804).
Embodiment 151:(E)-and 2-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-6-(2-pyridine-2-base vinyl) pyridine
6-[(4-chloro-phenyl-alkylsulfonyl in embodiment 145 acquisitions) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] formaldehyde (100mg; 0.245mmol) 1; add chlorinated triphenyl base (2-pyridylmethyl) hydrochloride (336mg in 4-two alkane (5ml) solution; 0.773mmol), triethylamine (215 μ l; 1.55mmol), stirred 5 hours under the room temperature.Add ethyl acetate behind the concentrated reaction solution, successively water and saturated common salt water washing.Organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=4: 1 obtains obtains to be the title compound (202mg, 0.418mmol, 81%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：5.99(1H，s)，6.98-7.08(2H，m)，7.21-7.25(1H，m)，7.37-7.48(6H，m)，7.54(2H，d，J＝8.1Hz)，7.64(1H，d，J＝15.4Hz)，7.69-7.75(2H，m)，8.04-8.09(1H，m)，8.65(1H，d，J＝4.4Hz).
FAB-MS:483.0739 (C
25H
18ClF
2N
2O
2S, calculated value: 483.0746).
Embodiment 152:2-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-6-(2-pyridine-2-base ethyl) pyridine
At (E)-2-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-6-(2-pyridine-2-base vinyl) pyridine (180mg; 0.373mmol) ethanol (5ml) and 1; add the alcohol suspending liquid (1ml) that draws Buddhist nun's nickel in the mixing solutions of 4-two alkane (2ml), high degree of agitation is 1.5 hours under the nitrogen atmosphere of 1 air pressure.Concentrating under reduced pressure behind the filtering reacting solution.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, use hexane: the be white in color title compound (110mg, 0.227mmol, 61%) of powder of re-crystallizing in ethyl acetate, acquisition.
1H-NMR(400MHz，CDCl
3)δ：3.13-3.23(4H，m)，5.92(1H，s)，6.93-7.06(2H，m)，7.07-7.12(3H，m)，7.37-7.40(3H，m)，7.52-7.60(4H，m)，8.05-8.09(1H，m)，8.52(1H，d，J＝3.7Hz).
mp：88-89℃.
Ultimate analysis: C
25H
19ClF
2N
2O
2S: theoretical value: C, 61.92; H, 3.95; Cl, 7.31; F, 7.84; N, 5.78; S, 6.61. measured value: C, 61.84; H, 4.08; Cl, 7.26; F, 7.69; N, 5.90; S, 6.75.
Embodiment 153:3-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-1-(3-hydroxypropyl) piperidines-2-ketone
Under argon atmospher, in-78 ℃ of 2-[(4-chloro-phenyl-s that obtain at reference example 1) sulfonymethyl]-1,4-two fluorobenzene (63.0mg, 0.208mmol) 1, add n-Butyl Lithium (1.56M hexane solution in the 2-glycol dimethyl ether solution (2ml), 0.140ml, 0.218mmol) after, stirred 5 minutes in-78 ℃.Add 3-bromo-1-[3-(t-butyldimethylsilyloxy base) propyl group that reference example 34 obtains] piperidines-2-ketone (72.8mg, 0.208mmol) after, in room temperature reaction solution was stirred 15 hours.Add water after reaction solution is cooled to 0 ℃, use ethyl acetate extraction.Use dried over mgso after extraction liquid water and the saturated common salt water washing, concentrate.With silica gel flash column chromatography (hexane: ethyl acetate=4: 1) make with extra care, obtain to be the low polar silyl protective (30.0mg) and the high polar silyl protective (30.0mg) of colorless oil respectively to residue obtained.The high polar silyl protective (30.0mg) of gained is dissolved in tetrahydrofuran (THF) (3ml), adds hydrogen fluoride-pyridine (0.5ml).After room temperature stirs 3 hours to reaction solution, with ethyl acetate dilution, water and saturated common salt water washing again.Use dried over mgso, after concentrating, handle residue obtained with silica gel column chromatography, concentrate by hexane: the cut that the wash-out portion of ethyl acetate=2: 3 obtains obtains white solid matter.The gained solid is the title compound (11.8mg, 0.0258mmol, 12%) of colourless needle crystal with ethyl acetate-hexane recrystallization, acquisition.
1H-NMR(400MHz，CDCl
3)δ：1.50-1.60(2H，m)，1.88-2.08(3H，m)，2.70-2.77(1H，m)，2.86-2.93(1H，m)，3.20-3.36(5H，m)，3.62(1H，ddd，J＝13.7，9.0，4.6Hz)，3.70-3.78(1H，m)，5.71-5.73(1H，m)，6.86(1H，td，J＝9.0，4.6Hz)，6.96-7.02(1H，m)，7.37(2H，d，J＝8.8Hz)，7.55-7.62(3H，m).
mp：120-121℃.
FAB-MS:458.0966 (C
21H
23ClF
2NO
4S, calculated value: 458.1004).
Embodiment 154:3-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the propionic acid tert-butyl ester
Beta-alanine tert-butyl ester hydrochloride (1.5g) is dissolved in a spot of unsaturated carbonate aqueous solutions of potassium, uses dichloromethane extraction.It is carried out drying, concentrate, obtain the free Beta-alanine tert-butyl ester of 720mg.Under argon atmospher, in 120 ℃ to this compound and embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (300mg, 0.72mmol) 1,4-two alkane (2.0ml) solution stirring 4 days.Dilute solution with water and saturated common salt water washing with ethyl acetate after being cooled to room temperature.Decompression concentrates down after the drying solution, obtains residue.With silica gel column chromatography (hexane: ethyl acetate=5: 1) make with extra care, obtain to be the title compound (79mg, 16%) of oily matter to residue obtained.
1H-NMR(400MHz，CDCl
3)δ：1.46(9H，s)，2.52(2H，t，J＝6.0Hz)，3.58(2H，q，J＝6.0Hz)，4.95(1H，br)，5.96(1H，s)，6.68(1H，s)，6.9-7.05(2H，m)，7.11(1H，m)，7.22(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，8.02(1H，s).
MS：525(M
++H).
Embodiment 155:3-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] propionic acid
At 3-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] add seven molybdic acids, six ammonium tetrahydrates (30mg) in methyl alcohol (6ml) solution of the propionic acid tert-butyl ester (79mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 16 hours.After ethyl acetate (60ml) dilution, solution with water and saturated common salt water washing.Decompression is concentrated solution down, adds trifluoroacetic acid (1.0ml) in residue obtained, stirs 1 hour.After boiling off trifluoroacetic acid under the decompression, residue is dissolved in water-ethanol (1: 1).Add therein after saturated sodium bicarbonate aqueous solution (0.2ml) makes it be alkalescence, add the sodium pyrosulfate aqueous solution, mixed solution is with ethyl acetate (80ml) extraction, extraction liquid saturated common salt water washing, drying.Decompression makes the residue crystallization behind the concentrated solution down in ether, obtain 0.5 hydrate of title compound (61mg, 81%).
1H-NMR(400MHz，CDCl
3)δ：2.76(2H，m)，3.72(2H，m)，6.11(1H，s)，6.92(1H，m)，7.04(1H，m)，7.44(2H，d，J＝8.8Hz)，7.46(1H，s)，7.48(1H，m)，7.61(2H，d，J＝8.8Hz)，7.94(1H，s).
mp：200-205℃.
Ultimate analysis: C
21H
16Cl
2F
2N
2O
4S0.5H
2O: theoretical value: C, 49.42; H, 3.36; N, 5.49; S, 6.28; Cl, 13.89; F, 7.44. measured value: C, 49.51; H, 3.28; N, 5.52; S, 6.35; Cl, 13.75; F, 7.77.
Embodiment 156:2-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (methyl) amino] ethanol
Under the argon atmospher, in 110 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (200mg, 0.48mmol) and methylamino ethanol (200 μ l) 1,4-two alkane (2.0ml) solution stirring 3 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=3: 1) refining, acquisition is the title compound (164mg, 75%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.07(3H，s)，3.73(2H，d，J＝4.8Hz)，3.85(2H，d，J＝4.8Hz)，5.99(1H，s)，6.86(1H，s)，6.91-7.12(3H，m)，7.23(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.8Hz)，8.00(1H，s).
MSm/z：455(M
++H).
Embodiment 157:5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-2-[2-(pyridine-2-yl) ethylamino] pyridine
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (150mg, 0.36mmol) and 2-pyridine-2-base ethamine (400 μ l) 1,4-two alkane (1.5ml) solution stirring 5 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=1: 1) refining, acquisition is the title compound (126mg, 70%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.07(2H，d，J＝6.4Hz)，3.71(2H，q，J＝6.4Hz)，5.24(1H，br)，5.96(1H，s)，6.69(1H，s)，6.93-7.30(9H，m)，7.61(1H，dt，J＝2.0，7.6Hz)，8.01(1H，s)，8.56(1H，m).
MSm/z：502(M
++H).
Embodiment 158:5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-2-[3-(imidazoles-1-yl) propyl group amino] pyridine
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (200mg, 0.48mmol) and 3-(imidazoles-1-yl) propylamine (400 μ l) 1,4-two alkane (1.5ml) solution stirring 5 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=1: 1) refining, acquisition is the title compound (94mg, 39%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.11(2H，m)，3.35(2H，m)，4.11(2H，d，J＝6.8Hz)，4.86(1H，m)，5.94(1H，s)，6.69(1H，s)，6.96(1H，s)，6.95-7.26(3H，m)，7.12(1H，s)，7.21(2H，d，J＝8.8Hz)，7.23(2H，d，J＝8.8Hz)，7.92(1H，m)，8.02(1H，s)
MSm/z：505(M
++H).
Embodiment 159:2-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] ethanol
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (180mg, 0.43mmol) and 2-monoethanolamine (300 μ l) 1,4-two alkane (1.5ml) solution stirring 64 hours.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=1: 1) refining, acquisition is the title compound (106mg, 56%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.00(1H，br)，3.51(2H，br)，3.81(2H，d，J＝4.8Hz)，5.05(1H，br)，5.95(1H，s)，6.74(1H，s)，6.92-7.06(2H，m)，7.13(1H，m)，7.23(4H，s)，7.99(1H，s).
MSm/z：441(M
++H).
Embodiment 160:1-[3-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] propyl group] pyrrolidin-2-one
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (200mg, 0.48mmol) and 1-(3-aminopropyl) pyrrolidin-2-one (400 μ l) 1,4-two alkane (1.5ml) solution stirring 17 hours.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=1: 1) refining, acquisition is the title compound (68mg, 27%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：1.77(2H，m)，2.04(2H，m)，2.41(2H，m)，3.30-3.40(6H，m)，5.53(1H，br)，5.94(1H，s)，6.72(1H，s)，6.90-7.03(2H，m)，7.13(1H，m)，7.22(2H，d，J＝8.0Hz)，7.25(2H，d，J＝8.0Hz)，7.99(1H，s).
MSm/z：522(M
++H).
Embodiment 161:4-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] piperidines-1-carboxylic acid tert-butyl ester
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (300mg, 0.48mmol) and 4-amino piperidine-1-carboxylic acid tert-butyl ester (600mg) 1,4-two alkane (2.2ml) solution stirring 5 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=3: 1) refining, acquisition is the title compound (36mg, 9%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：1.34(2H，m)，1.47(9H，s)，1.98(2H，m)，2.94(2H，m)，3.79(1H，m)，4.11(2H，m)，4.58(1H，br)，5.95(1H，s)，6.63(1H，s)，6.93-7.04(2H，m)，7.12(1H，m)，7.22(4H，s)，8.01(1H，s).
MSm/z：580(M
++H).
Embodiment 162:3-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the propyl carbamic acid tert-butyl ester
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (300mg, 0.48mmol) and 3-(aminopropyl) t-butyl carbamate (400 μ l) 1,4-two alkane (1.5ml) solution stirring 2 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=1: 1) refining, acquisition is the title compound (71mg, 27%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：1.45(9H，s)，1.73(2H，m)，3.21(2H，m)，3.38(2H，m)，4.85(1H，br)，5.10(1H，br)，5.95(1H，s)，6.96-7.04(2H，m)，7.12(1H，m)，7.22(2H，d，J＝8.8Hz)，7.24(2H，d，J＝8.8Hz)，8.00(1H，s).
MSm/z：554(M
++H).
Embodiment 163:5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl]-the 2-[(2-methylmercaptoethyl) amino] pyridine
Under the argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls)-(2, the 5-difluorophenyl) methyl] pyridine (200mg, 0.48mmol) and 2-methylthio group ethamine (200 μ l) 1,4-two alkane (1.5ml) solution stirring 2 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=3: 1) refining, acquisition is the title compound (29mg, 13%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：2.12(3H，s)，2.74(2H，d，J＝6.4Hz)，3.52(2H，m)，4.98(1H，br)，5.96(1H，s)，6.69(1H，s)，6.92-7.05(2H，m)，7.13(1H，m)，7.23(4H，m)，8.02(1H，s).
MSm/z：471(M
++H).
Embodiment 164:2-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (methyl) amino] ethanol
2-[[5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 156 acquisitions)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] (methyl) amino] ethanol (160mg, 0.35mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (60ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, (hexane: ethyl acetate=2: 1) make with extra care, use hexane-alcohol crystalization again, acquisition is the title compound (162mg, 95%) of needle crystal to residue with silica gel chromatography under the decompression.
1H-NMR(400MHz，CDCl
3)δ：3.20(3H，s)，3.7-3.85(2H，m)，3.89(2H，m)，6.14(1H，s)，6.94(1H，m)，7.04(1H，m)，7.42(1H，br)，7.44(2H，d，J＝8.8Hz)，7.52(1H，m)，7.62(2H，d，J＝8.8Hz)，7.99(1H，s).
mp：88-89℃.
Ultimate analysis: C
21H
18C
12F
2N
2O
3S0.5H
2O: theoretical value: C, 50.82; H, 3.86; N, 5.64; S, 6.46; Cl, 14.29; F, 7.66. measured value: C, 51.16; H, 3.66; N, 5.78; S, 6.62; Cl, 14.32; F, 7.73.
Embodiment 165: ethyl carbamic acid 2-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] (methyl) amino] ethyl ester
At 2-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl] (methyl) amino] ethanol (73mg; 0.15mmol) methylene dichloride (1.0ml) solution in add pyridine (0.5ml), add ethyl isocyanate (100 μ l) again, stirred 19 hours.Behind the concentrated solution, (hexane: ethyl acetate=3: 1) refining, acquisition is the title compound (65mg, 74%) of oily matter to residue with silica gel chromatography under the decompression.
1H-NMR(400MHz，CDCl
3)δ：1.06(3H，t，J＝7.2Hz)，3.19(3H，s)，3.20(2H，m)，3.68(1H，m)，3.91(1H，m)，4.25(1H，m)，4.40(1H，m)，5.15(1H，br)，6.16(1H，s)，6.92(1H，m)，7.03(1H，m)，7.45(2H，d，J＝8.4Hz)，7.49(1H，s)，7.55(1H，m)，7.60(2H，d，J＝8.4Hz)，8.03(1H，s).
EI-MS:557.0714 (C
24H
23Cl
2F
2N
3O
4S, calculated value: 557.0754).
Embodiment 166:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-2-[2-(pyridine-2-yl) ethylamino] pyridine
5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 157 acquisitions)-(2, the 5-difluorophenyl) methyl]-2-[2-(pyridine-2-yl) ethylamino] pyridine (120mg, 0.35mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 2 days.With ethyl acetate (80ml) dilution back solution with water and saturated common salt water washing.Behind the following concentrated solution of decompression, and the residue silica gel chromatography (hexane: ethyl acetate=3: 1) refining, obtain amorphous title compound (43mg, 33%).
1H-NMR(400MHz，CDCl
3)δ：3.19(2H，t，J＝5.2Hz)，3.81(2H，m)，5.51(1H，br)，6.13(1H，s)，6.91(1H，m)，7.03(1H，m)，7.20-7.30(3H，m)，7.43(2H，d，J＝8.8Hz)，7.50(1H，m)，7.62(2H，d，J＝8.8Hz)，7.68(1H，s)，7.98(1H，s)，8.60(1H，m).
FAB-MS:534.0651 (C
25H
20Cl
2F
2N
3O
2S, calculated value: 534.0621).
Embodiment 167:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-2-[3-(imidazoles-1-yl) propyl group amino] pyridine
5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 158 acquisitions)-(2, the 5-difluorophenyl) methyl]-2-[3-(imidazoles-1-yl) propyl group amino] pyridine (94mg, 0.19mmol) methyl alcohol (6m1) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (80ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, residue is refining with silica gel chromatography (7% methyl alcohol-chloroform) under the decompression, obtains to be the title compound (5mg, 5%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：2.20(2H，m)，3.44(2H，m)，4.32(2H，m)，5.77(1H，br)，6.13(1H，s)，6.91(1H，m)，7.02(1H，m)，7.10(1H，s)，7.30(1H，s)，7.40(1H，s)，7.44(2H，d，J＝8.4Hz)，7.54(1H，m)，7.65(2H，d，J＝8.4Hz)，7.97(s，1H)，8.05(1H，s)，8.89(1H，s).
FAB-MS:537.0737 (C
24H
21Cl
2F
2N
4O
2S, calculated value: 537.0730).
Embodiment 168:2-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] ethanol
2-[[5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 159 acquisitions)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] ethanol (143mg, 0.33mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (60ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, (hexane: ethyl acetate=1: 1) make with extra care, use alcohol crystalization again, acquisition is the title compound (98mg, 63%) of needle crystal to residue with silica gel chromatography under the decompression.
1H-NMR(400MHz，CDCl
3)δ：3.60(2H，m)，3.87(2H，m)，5.53(1H，br)，6.11(1H，s)，6.92(1H，m)，7.03(1H，m)，7.40(1H，s)，7.45(2H，d，J＝8.8Hz)，7.48(1H，m)，7.61(2H，d，J＝8.8Hz)，7.96(1H，s).mp：168-169℃.
Ultimate analysis: C
20H
16Cl
2F
2N
2O
3S: theoretical value: C, 50.75; H, 3.41; N, 5.92; S, 6.77; Cl, 14.98; F, 8.03. measured value: C, 50.33; H, 3.40; N, 5.95; S, 6.90; Cl, 14.93; F, 8.04.
Embodiment 169:1-[3-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] propyl group] pyrrolidin-2-one
1-[3-[[5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 160 acquisitions)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] propyl group] pyrrolidin-2-one (143mg, 0.33mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 17 hours.With ethyl acetate (60ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, residue is refining with silica gel chromatography (2% methyl alcohol-ethyl acetate), uses the ether crystallization again under the decompression, obtains to be the title compound (42mg, 60%) of needle crystal.
1H-NMR(400MHz，CDCl
3)δ：1.82(2H，m)，2.05(2H，m)，2.43(2H，m)，3.35-3.50(6H，m)，5.53(1H，br)，6.12(1H，s)，6.92(1H，m)，7.02(1H，m)，7.23(1H，s)，7.42(2H，d，J＝8.4Hz)，7.53(1H，m)，7.62(2H，d，J＝8.4Hz)，7.96(1H，s).
mp：78-80℃.
Ultimate analysis: C
25H
23Cl
2F
2N
3O
3S: theoretical value: C, 54.16; H, 4.18; N, 7.58; S, 5.78; Cl, 12.79; F, 6.85. measured value: C, 54.15; H, 4.37; N, 7.39; S, 5.60; Cl, 12.20; F, 6.64.
Embodiment 170:4-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] piperidines-1-carboxylic acid tert-butyl ester
4-[[5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 161 acquisitions)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] piperidines-1-carboxylic acid tert-butyl ester (41mg, 0.070mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 20 hours.With ethyl acetate (80ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, (hexane: ethyl acetate=4: 1) refining, acquisition is the title compound (41mg, 95%) of oily matter to residue with silica gel chromatography under the decompression.
1H-NMR(400MHz，CDCl
3)δ：1.43(2H，m)，1.47(9H，s)，2.04(2H，m)，2.97(2H，m)，3.88(1H，m)，4.08(2H，m)，6.08(1H，s)，6.89(1H，m)，7.02(1H，m)，7.25(1H，s)，7.43(2H，d，J＝8.0Hz)，7.46(1H，m)，7.58(2H，d，J＝8.0Hz)，7.96(1H，s).
MSm/z：612(M
++H).
Embodiment 171:4-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the piperidines dihydrochloride
At 4-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] (41mg, 0.067mmol) the middle 20% hydrochloric acid-methanol solution that adds stirred 2 hours piperidines-1-carboxylic acid tert-butyl ester.Decompression is concentrated solution down, with the residue obtained chloroform that is dissolved in, and reconcentration.Dry gained is noncrystal down in decompression, obtains title compound (34mg, 84%).
1H-NMR(400MHz，CD
3OD)δ：1.90(2H，m)，2.33(2H，m)，3.22(2H，m)，3.52(2H，m)，4.10(1H，m)，6.28(1H，s)，7.09(1H，m)，7.23(1H，m)，7.53(1H，m)，7.61(2H，d，J＝6.4Hz)，7.75(2H，d，J＝6.4Hz)，7.89(1H，s)，8.05(1H，s).
Ultimate analysis: C
23H
21Cl
2F
2N
3O
2S2HClH
2O: theoretical value: C, 45.79; H, 4.18; N, 6.96; S, 5.31; Cl, 23.50; F, 6.30. measured value: C, 45.48; H, 4.17; N, 7.2; S, 5.24; Cl, 22.82; F, 6.02.
Embodiment 173:3-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the propyl carbamic acid tert-butyl ester
3-[[5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 162 acquisitions)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino propyl amino t-butyl formate (70mg, 0.13mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 20 hours.With ethyl acetate (80ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, (hexane: ethyl acetate=2: 1) refining, acquisition is the title compound (61mg, 82%) of oily matter to residue with silica gel chromatography under the decompression.
1H-NMR(400MHz，CDCl
3)δ：1.45(9H，s)，1.77(2H，m)，3.23(2H，m)，3.42(2H，m)，4.89(1H，br)，5.36(1H，br)，6.10(1H，s)，6.90(1H，m)，7.02(1H，m)，7.24(1H，s)，7.42(2H，d，J＝8.8Hz)，7.49(1H，m)，7.59(2H，d，J＝8.8Hz)，7.95(1H，s)
MSm/z：586(M
++H).
Embodiment 173:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] the third-1,3-diamines dihydrochloride
At 3-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] (70mg, 0.13mmol) the middle 20% hydrochloric acid-methanol solution (2ml) that adds stirred 2 hours the propyl carbamic acid tert-butyl ester.Decompression is concentrated solution down, makes residue obtained crystallization with ethanol, obtains to be white in color solid title compound (42mg, 83%).
1H-NMR(400MHz，DMSO-d
6)δ：1.83(2H，m)，2.87(2H，m)，3.33(2H，m)，6.16(1H，s)，7.28(1H，m)，7.36(1H，s)，7.38(1H，m)，7.52(1H，m)，7.69(2H，d，J＝8.4Hz)，7.74(2H，d，J＝8.4Hz)，8.05(1H，s).
mp：193-195℃.
Ultimate analysis: C
21H
19Cl
2F
2N
3O
2S2HCl: theoretical value: C, 45.10; H, 3.78; N, 7.51; S, 5.73; Cl, 25.36; F, 6.79. measured value: C, 44.55; H, 3.74; N, 7.52; S, 5.73; Cl, 25.09; F, 6.73.
Embodiment 174:N-[3-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] propyl group] ethanamide
At N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl] the third-1; 3-diamines dihydrochloride (47mg; 0.084mmol) dichloromethane solution (5.0ml) in add pyridine (17 μ l; 0.34mmol), diacetyl oxide (9.5 μ l; 0.10mmol), stirred 1 hour.Concentration of reaction solution, residue obtained with silica gel chromatography (ethyl acetate: methyl alcohol=10: 1) make with extra care, obtain title compound (35mg, 79%).With its crystallization in ether, obtain white solid (27mg).
1H-NMR(400MHz，CDCl
3)δ：1.80(2H，m)，2.02(3H，s)，3.36(2H，m)，3.45(2H，m)，5.25(1H，br)，6.12(1H，s)，6.15(1H，m)，6.93(1H，m)，7.04(1H，m)，7.44(2H，d，J＝8.8Hz)，7.50(1H，m)，7.62(2H，d，J＝8.8Hz)，7.97(1H，s).
mp：103-105℃.
FAB-MS:528.0740 (C
23H
22Cl
2F
2N
3O
3S, calculated value: 528.0727).
Embodiment 175:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-N '-(pyrimidine-2-base) the third-1, the 3-diamines
N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 173 acquisitions)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl] the third-1; 3-diamines dihydrochloride (76mg; 0.136mmol) 1; add triethylamine (76 μ l in the 4-two alkane solution (1.0ml); 0.54mmol), (23mg 0.20mmol), stirred 19 hours in 80 ℃ the 2-chloropyrimide.After reaction solution naturally cooled to room temperature, dilute with ethyl acetate.Water and saturated common salt water washing after drying.Concentrate, residue obtained with silica gel chromatography (hexane: ethyl acetate=1: 2) make with extra care, obtain title compound (50mg, 65%).With its crystallization in ether, obtain white solid (36mg).
1H-NMR(400MHz，CDCl
3)δ：1.94(2H，m)，3.48(2H，m)，3.59(2H，m)，5.33(1H，br)，5.60(1H，br)，6.12(1H，s)，6.56(1H，t，J＝4.8Hz)，6.92(1H，m)，7.03(1H，m)，7.24(1H，s)，7.44(2H，d，J＝8.0Hz)，7.51(1H，m)，7.61(2H，d，J＝8.0Hz)，8.00(1H，s)，8.32(1H，d，J＝4.8Hz).
mp：176-178℃.
FAB-MS:564.0811 (C
25H
22Cl
2F
2N
5O
2S, calculated value: 564.0839).
Embodiment 176:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl]-2-[(2-methyl sulphonyl ethyl) amino] pyridine
5-chloro-4-[(4-chlorobenzene sulfenyl in embodiment 163 acquisitions)-(2, the 5-difluorophenyl) methyl]-the 2-[(2-methylmercaptoethyl) amino] pyridine (29mg, 0.061mmol) methyl alcohol (3ml) solution in add seven molybdic acids, six ammonium tetrahydrates (15mg), add 30% aqueous hydrogen peroxide solution (1.5ml) again, stirred 20 hours.With ethyl acetate (80ml) dilution back solution with water and saturated common salt water washing.Decompression is down behind the concentrated solution, residue with silica gel chromatography (hexane: ethyl acetate=1: 1) refining, use the ether crystallization again, obtain to be white in color solid title compound (24mg, 73%).
1H-NMR(400MHz，CDCl
3)δ：2.98(3H，s)，3.37(2H，t，J＝6.0Hz)，3.94(2H，m)，5.38(1H，m)，6.10(1H，s)，6.90(1H，m)，7.01(1H，m)，7.32(1H，s)，7.42(2H，d，J＝8.8Hz)，7.45(1H，m)，7.59(2H，d，J＝8.8Hz)，8.00(1H，s).
mp：134-136℃.
Ultimate analysis: C
21H
18Cl
2F
2N
2O
4S: theoretical value: C, 47.11; H, 3.39; N, 5.23; S, 11.98. measured value: C, 46.80; H, 3.35; N, 5.30; S, 11.84.
Embodiment 177:2,5-two chloro-4-[(2,5-difluorophenyl)-(4-fluorobenzene sulfenyl) methyl] pyridine
With reference example 24 obtain 2,5-two chloro-4-[(2,5-difluorophenyl)-hydroxymethyl] pyridine (1.22g, 4.8mmol) be dissolved in thionyl chloride (5.0ml) after, add the dimethyl formamide of catalytic amount, stirred 4 hours.
Decompression is concentration of reaction solution down, adds 1 in residue, 4-two alkane, reconcentration.This residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-fluorobenzene mercaptan (730mg, 5.7mmol) and salt of wormwood (2.07g, 15mmol), stirring is 24 hours under the room temperature.Add ether (120ml) in reaction solution, water and saturated aqueous common salt wash it.Organic layer with dried over mgso after decompression concentrate down.In ethanol, make the residue crystallization, obtain to be the title compound (950mg, 49%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.92(1H，s)，6.94-7.04(4H，m)，7.19(1H，m)，7.33-7.4(2H，m)，7.57(1H，s)，8.33(1H，s).
mp：95-97℃.
MSm/z：400(M
++1)
Embodiment 178:2-[[5-chloro-4-[(2, the 5-difluorophenyl)-(4-fluorobenzene sulfenyl) methyl] pyridine-2-yl] amino] ethanol
Under argon atmospher, in 120 ℃ to 2,5-two chloro-4-[(2,5-difluorophenyl)-(4-fluorobenzene sulfenyl) methyl] pyridine (200mg, 0.50mmol) and 2-monoethanolamine (300 μ l) 1,4-two alkane (1.5ml) solution stirring 2 days.Decompression concentrates down after being cooled to room temperature, obtains residue.(hexane: ethyl acetate=1: 1) refining, acquisition is the title compound (120mg, 56%) of oily matter to residue with silica gel chromatography.
1H-NMR(400MHz，CDCl
3)δ：3.53(2H，m)，3.82(2H，m)，4.95(1H，br)，5.89(1H，s)，6.74(1H，s)，6.90-7.00(4H，m)，7.16(1H，m)，7.31-7.36(2H，m)，7.99(1H，s).
MSm/z：425(M
++H).
Embodiment 179:2-[[5-chloro-4-[(2, the 5-difluorophenyl)-(4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] amino] ethanol
At 2-[[5-chloro-4-[(2, the 5-difluorophenyl)-(4-fluorobenzene sulfenyl) methyl] pyridine-2-yl] amino] ethanol (119mg, 0.27mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 19 hours.With ethyl acetate (80ml) dilution back solution with water and saturated common salt water washing.Behind the concentrated solution, (hexane: ethyl acetate=1: 1) make with extra care, use the ether crystallization again, acquisition is the title compound (65mg, 56%) of needle crystal to residue with silica gel chromatography under the decompression.
1H-NMR(400MHz，CDCl
3)δ：3.61(2H，m)，3.88(2H，d，J＝4.8Hz)，6.09(1H，s)，6.90(1H，m)，7.04(1H，m)，7.10-7.18(2H，m)，7.42(1H，s)，7.49(1H，m)，7.66-7.71(2H，m)，7.95(1H，s).
mp：157-158℃.
Ultimate analysis: C
20H
16ClF
3N
2O
3S: theoretical value: C, 52.58; H, 3.53; N, 6.13; S, 7.02; Cl, 7.76; F, 12.48. measured value: C, 52.18; H, 3.51; N, 6.19; S, 7.10; Cl, 7.82; F, 12.38.
Embodiment 180:5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-[2-(pyridin-4-yl) ethylamino] pyridine
In 120 ℃ in tube sealing to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (and 220mg, 0.528mmol) and two alkane (1.5ml) solution of 4-(2-amino-ethyl) pyridine (400 μ l) heating 3 days.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.In residue obtained, add water, use ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, filters back concentrating under reduced pressure filtrate.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure is by methyl alcohol: the cut that the elutriant of methylene dichloride=1: 30 obtains obtains to be the title compound (114mg, 0.227mmol, 43%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：2.90(2H，t，J＝7.1Hz)，3.54-3.65(2H，m)，4.70-4.81(1H，m)，5.96(1H，s)，6.64(1H，s)，6.90-7.03(2H，m)，7.05-7.16(3H，m)，7.22(4H，s)，8.03(1H，s)，8.53(2H，d，J＝6.1Hz).
MSm/z：501(M
+).
Embodiment 181:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-2-[2-(pyridin-4-yl) ethylamino] pyridine
Under ice-cold, at 5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-[2-(pyridin-4-yl) ethylamino] (110mg adds 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrates (34mg) to pyridine in methyl alcohol 0.219mmol) (6ml) solution.After under the room temperature reaction solution being stirred 22 hours, pressure reducing and steaming methyl alcohol.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate afterwards.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=2: 3 obtains obtains to be yellowish white solid title compound (102mg, 0.191mmol, 87%).The gained solid is with leaching after diisopropyl ether-hexane wash, the title compound (87mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.96(2H，t，J＝7.1Hz)，3.68(2H，q，J＝6.8Hz)，4.72(1H，t，J＝6.1Hz)，6.12(1H，s)，6.89-6.96(1H，m)，6.98-7.08(1H，m)，7.20(2H，d，J＝5.9Hz)，7.24(1H，s)，7.40-7.50(3H，m)，7.60(2H，d，J＝8.6Hz)，8.03(1H，s)，8.56(2H，d，J＝5.9Hz).
mp：148-150℃.
Ultimate analysis: C
25H
19N
3O
2Cl
2F
2S: theoretical value: C, 56.19; H, 3.58; N, 7.86; Cl, 13.27; F, 7.11; S, 6.00. measured value: C, 56.01; H, 3.57; N, 7.93; Cl, 13.27; F, 7.04; S, 6.16.
Embodiment 182:2-[2-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amino] oxyethyl group] ethanol
In 120 ℃ in tube sealing to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (and 210mg, 0.504mmol) and two alkane (1.5ml) solution of 2-(2-amino ethoxy) ethanol (400 μ l) heating 3 days.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.In residue obtained, add water, use ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, filters back concentrating under reduced pressure filtrate.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure obtains to be the title compound (85mg, 0.175mmol, 35%) of colorless oil by the cut of the elutriant acquisition of 30% ethanol/methylene.
1H-NMR(400MHz，CDCl
3)δ：2.11(1H，brs)，3.53(2H，q，J＝5.3Hz)，3.61(2H，t，J＝4.4Hz)，3.70(2H，t，J＝5.1Hz)，3.72-3.80(2H，m)，4.95(1H，t，J＝5.6Hz)，5.97(1H，s)，6.71(1H，s)，6.80-7.03(2H，s)，7.08-7.17(1H，m)，7.18-7.30(4H，m)，8.03(1H，s).
MS(m/z)：484(M
+).
Embodiment 183:2-[2-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amino] oxyethyl group] ethanol
Under ice-cold, at 2-[2-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amino] oxyethyl group] (80mg adds 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrates (32mg) to ethanol in methyl alcohol 0.155mmol) (6ml) solution.After under the room temperature reaction solution being stirred 24 hours, pressure reducing and steaming methyl alcohol.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate afterwards.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=2: 3 obtains obtains to be the title compound (70mg, 0.135mmol, 87%) of amorphous substance.The gained amorphous material is solidified after-filtration with ether-hexane, the title compound (55mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.11(1H，brs)，3.55-3.63(2H，m)，3.66(2H，t，J＝4.5Hz)，3.74(2H，t，J＝5.1Hz)，3.78-3.85(2H，m)，5.03-5.13(1H，m)，6.13(1H，s)，6.89-6.97(1H，m)，6.98-7.08(1H，m)，7.30(1H，s)，7.45(2H，d，J＝8.5Hz)，7.48-7.56(1H，m)，7.62(2H，d，J＝8.5Hz)，8.00(1H，s).mp：113-115℃.
Ultimate analysis: C
22H
20N
2O
4Cl
2F
2S: theoretical value: C, 51.07; H, 3.90; N, 5.41; Cl, 13.70; F, 7.34; S, 6.20. measured value: C, 50.81; H, 3.83; N, 5.49; Cl, 13.64; F, 7.46; S, 6.34.
Embodiment 184:5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-the 2-[(3-methoxy-propyl) amino] pyridine
In 120 ℃ in tube sealing to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (and 216mg, 0.518mmol) and two alkane (1.5ml) solution of 3 methoxypropyl amine (200 μ l) heating 3 days.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure is by hexane: (=3: the cut that elutriant 1) obtains obtains to be the title compound (101mg) of faint yellow oily thing to ethyl acetate.
Under ice-cold, in methyl alcohol (6ml) solution of the faint yellow oily thing of gained (101mg), add 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrates (41mg).After under the room temperature reaction solution being stirred 16 hours, pressure reducing and steaming methyl alcohol.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate afterwards.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=3: 1 obtains obtains to be white in color solid title compound (90mg, 0.180mmol, 35%).The gained solid is with leaching after ether-hexane wash, the title compound (64mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.87-1.98(2H，m)，3.39(3H，s)，3.46(2H，q，J＝6.1Hz)，3.55(2H，t，J＝5.8Hz)，5.09(1H，brt，J＝5.3Hz)，6.13(1H，s)，6.88-6.96(1H，m)，6.98-7.08(1H，m)，7.20(1H，s)，7.43(2H，d，J＝8.7Hz)，7.50-7.57(1H，m)，7.62(2H，d，J＝8.7Hz)，7.98(1H，s).
mp：146-148℃.
Ultimate analysis: C
22H
20N
2O
3Cl
2F
2S: theoretical value: C, 52.70; H, 4.02; N, 5.59; Cl, 14.14; F, 7.58; S, 6.40. measured value: C, 52.72; H, 3.95; N, 5.78; Cl, 14.14; F, 7.75; S, 6.54.
Embodiment 185:5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-(3,4-dimethoxy benzene methylamino) pyridine
In 120 ℃ in tube sealing to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (and 218mg, 0.523mmol) and 3, two alkane (1.5ml) the solution heating of 4-dimethoxy benzene methanamine (400 μ l) 3 days.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=4: 1 obtains obtains to be the title compound (140mg, 0.256mmol, 49%) of amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.86(3H，s)，3.88(3H，s)，4.42(2H，d，J＝5.6Hz)，4.99(1H，t，J＝5.6Hz)，5.95(1H，s)，6.68(1H，s)，6.80-7.02(6H，m)，7.12-7.21(4H，m)，8.05(1H，s).
MSm/z：547(M
++H).
Embodiment 186:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-2-(3,4-dimethoxy benzene methylamino) pyridine
Under ice-cold, at 5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-(131mg adds 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrates (31mg) to 2-(3,4-dimethoxy benzene methylamino) pyridine in methyl alcohol 0.239mmol) (6ml) solution.Under the room temperature reaction solution stirring after 16 hours, is boiled off methyl alcohol under the decompression.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate, Sulfothiorine and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure filtrate.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure obtains to be white in color solid title compound (75mg, 0.129mmol, 54%) by the cut that the elutriant of 35% ethyl acetate/hexane obtains.The gained white solid is with leaching after ether-hexane wash, the title compound of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.89(6H，s)，4.48-4.51(2H，m)，5.08-5.15(1H，m)，6.12(1H，s)，6.85-7.05(5H，m)，7.24(1H，s)，7.28-7.35(1H，m)，7.40(2H，d，J＝8.5Hz)，7.55(2H，d，J＝8.5Hz)，8.01(1H，s).
mp：204-206℃.
Ultimate analysis: C
27H
22N
2O
4Cl
2F
2S: theoretical value: C, 55.97; H, 3.83; N, 4.83; Cl, 12.24; F, 6.56; S, 5.53. measured value: C, 56.05; H, 3.82; N, 4.87; Cl, 12.30; F, 6.60; S, 5.73.
Embodiment 187:5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-[(pyridin-4-yl methyl)] amino] pyridine
In 120 ℃ in tube sealing to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (and 229mg, 0.550mmol) and two alkane (1.5ml) solution of 4-aminomethyl pyridine (200 μ l) heating 3 days.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=1: 3 obtains obtains to be the title compound (37mg, 0.076mmol, 14%) of amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：4.55(2H，d，J＝6.1Hz)，5.06(1H，t，J＝6.0Hz)，5.94(1H，s)，6.61(1H，s)，6.90-7.09(3H，m)，7.13-7.30(6H，m)，8.05(1H，s)，8.55(2H，d，J＝6.1Hz).
MSm/z：488(M
++H).
Embodiment 188:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-2-[(pyridin-4-yl methyl) amino] pyridine
Under ice-cold, at 5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-[(pyridin-4-yl methyl) amino] (35mg adds 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrates (23mg) to pyridine in methyl alcohol 0.072mmol) (2ml) solution.After under the room temperature reaction solution being stirred 22 hours, pressure reducing and steaming methyl alcohol.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filter concentrating under reduced pressure filtrate afterwards.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by methyl alcohol: the cut that the elutriant of methylene dichloride=1: 30 obtains obtains to be faint yellow solid.With leaching after gained pale yellow colored solid body and function ether-hexane wash, the title compound (16mg, 0.031mmol, 43%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.63(2H，dd，J＝6.1，2.9Hz)，5.20(1H，t，J＝6.4Hz)，6.11(1H，s)，6.87-6.95(1H，m)，6.99-7.08(1H，m)，7.25(1H，s)，7.30(2H，d，J＝6.0Hz)，7.35-7.40(1H，m)，7.42(2H，d，J＝8.9Hz)，7.56(2H，d，J＝8.9Hz)，8.02(1H，s)，8.59(2H，d，J＝6.0Hz).
mp：141-142℃.
FAB-MS:520.0465 (C
24H
18O
2N
3Cl
2F
2S, calculated value: 520.0461).
Embodiment 189:N-[3-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] propyl group] Toluidrin
N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 173 acquisitions)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl] the third-1; 3-diamines dihydrochloride (60mg; 0.107mmol) dichloromethane solution (5.0ml) in add triethylamine (70 μ l; 0.05mmol), methylsulfonyl chloride (10 μ l; 0.13mmol), stirred 20 minutes.After in reaction solution, adding ether (50ml), water and saturated common salt water washing, drying.Decompression is concentrated solution down, and is residue obtained with silica gel chromatography (hexane: ethyl acetate=2: 1) make with extra care, obtain title compound (60mg, 99%).With its crystallization in ethanol, obtain white solid (46mg).
1H-NMR(400MHz，CDCl
3)δ：1.86(2H，quint，J＝6.0Hz)，2.95(3H，s)，3.21(2H，q，J＝6.0Hz)，3.55(2H，q，J＝6.0Hz)，4.99(1H，br)，5.65(1H，br)，6.11(1H，s)，6.91(1H，m)，7.03(1H，m)，7.29(1H，s)，7.44(2H，d，J＝8.8Hz)，7.49(1H，m)，7.60(2H，d，J＝8.8Hz)，8.00(1H，s).
mp：138-139℃.
Ultimate analysis: C
22H
21Cl
2F
2N
3O
4S
2: theoretical value: C, 46.81; H, 3.75; N, 7.44; S, 11.36.; F, 6.73; Cl, 12.56; Measured value: C, 46.81; H, 3.72; N, 7.43; S, 11.39; F, 6.80; Cl, 12.41
Embodiment 190:1-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] tetrahydropyrimidine-2-ketone
N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 173 acquisitions)-(2; the 5-difluorophenyl) methyl] pyridine-2-yl] the third-1; 3-diamines dihydrochloride (51mg; 0.091mmol) dichloromethane solution (5.0ml) in add triethylamine (51 μ l; 0.36mmol), 1; (16.2mg 0.10mmol), stirred 17 hours 1 '-carbonyl dimidazoles.After in reaction solution, adding ethyl acetate (80ml), water and saturated common salt water washing, drying.Decompression is concentrated solution down, and is residue obtained with dimethyl formamide (1.0ml) dissolving, add salt of wormwood (27.2mg, 0.2mol), in 50 ℃ of heated and stirred 24 hours.Add water after being cooled to room temperature.Get organic layer with ethyl acetate (60ml) dilution back branch, use the saturated common salt water washing.Decompression concentrates down after the solution drying, and is residue obtained with silica gel chromatography (hexane: ethyl acetate=2: 1) make with extra care, obtain to be white in color solid title compound (15mg, 99%).
1H-NMR(400MHz，CDCl
3)δ：2.12(2H，m)，3.46(2H，m)，3.99(2H，m)，5.22(1H，br)，6.26(1H，s)，6.96(1H，m)，7.03(1H，m)，7.43(2H，d，J＝8.8Hz)，7.68(1H，m)，7.76(2H，d，J＝8.8Hz)，8.23(1H，s)，8.93(1H，s).
MSm/z：512(M
++H).
mp：＞230℃.
Embodiment 191:2-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the ethyl carbamic acid tert-butyl ester
Under argon atmospher, in 120 ℃ to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (610mg, 1.46mmol) and (2-amino-ethyl) t-butyl carbamate (700mg, 4.38mmol) 1,4-two alkane (6.0ml) solution stirring 4 days.Decompression concentrates down after being cooled to room temperature, obtains residue.With residue obtained with silica gel chromatography (hexane: ethyl acetate=4: 1) make with extra care, obtain to be the title compound (176mg, 22%) of oily matter.
1H-NMR(400MHz，CDCl
3)δ：1.43(9H，s)，3.36(2H，m)，3.42(2H，m)，5.01(1H，br)，5.12(1H，br)，5.95(1H，s)，6.90-7.04(2H，m)，7.13(1H，m)，7.21(2H，d，J＝8.4Hz)，7.23(2H，d，J＝8.4Hz)，8.00(1H，s).
MSm/z：540(M
++H).
Embodiment 192:2-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the ethyl carbamic acid tert-butyl ester
At 2-[[5-chloro-4-[(4-chlorobenzene sulfenyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] the ethyl carbamic acid tert-butyl ester (176mg, 0.32mmol) methyl alcohol (6ml) solution in add seven molybdic acids, six ammonium tetrahydrates (30mg), add 30% aqueous hydrogen peroxide solution (3ml) again, stirred 20 hours.After ethyl acetate (80ml) dilution, solution with water and saturated common salt water washing.Residue silica gel chromatography (hexane: ethyl acetate=3: 1) make with extra care, obtain to be the title compound (148mg, 81%) of oily matter behind the concentrated solution under the decompression.
1H-NMR(400MHz，CDCl
3)δ：1.45(9H，s)，3.39(2H，m)，3.49(2H，m)，5.03(1H，br)，5.29(1H，br)，6.12(1H，s)，6.91(1H，m)，7.03(1H，m)，7.24(1H，s)，7.43(2H，d，J＝8.8Hz)，7.52(1H，m)，7.61(2H，d，J＝8.8Hz)，7.98(1H，s).
MSm/z：572(M
++H).
Embodiment 193:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-and (2, the 5-difluorophenyl) methyl] pyridine-2-yl] second-1,2-diamines dihydrochloride
At 2-[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl)-(2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] (146mg, 0.25mmol) the middle 20% hydrochloric acid-methanol solution (1ml) that adds stirred 1 hour the ethyl carbamic acid tert-butyl ester.Decompression is concentrated solution down, makes residue obtained crystallization with ethanol, obtains title compound (106mg, 76%).
1H-NMR(400MHz，DMSO-d
6)δ：2.99(2H，m)，3.51(2H，m)，6.17(1H，s)，7.28(1H，m)，7.38(1H，m)，7.39(1H，s)，7.52(1H，m)，7.69(2H，d，J＝8.8Hz)，7.75(2H，d，J＝8.8Hz)，8.04(1H，s).
mp：163-166℃.
Ultimate analysis: C
20H
17Cl
2F
2N
3O
2S2HCl0.5H
2O: theoretical value: C, 43.34; H, 3.64; N, 7.58; S, 5.78; Cl, 25.59; F, 6.86. measured value: C, 43.32; H, 3.55; N, 7.67; S, 5.83; Cl, 25.84; F, 6.87.
Embodiment 194:3-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amino]-2,2-dimethylpropane-1-alcohol
In 120 ℃, in tube sealing to embodiment 54 obtain 2,5-two chloro-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine (191mg, 0.458mmol) and 3-amino-2,2-dimethyl propylene-1-alcohol (515mg, two alkane (1.5ml) solution heating 5.00mmol) 3 days.Reaction solution is cooled to concentrating under reduced pressure after the room temperature.In residue obtained, add ethyl acetate, after water and the saturated common salt water washing, use anhydrous sodium sulfate drying successively, filter back concentrating under reduced pressure filtrate.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=3: 1 obtains obtains to be the title compound (199mg, 0.412mmol, 90%) of amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：0.91(6H，s)，3.12-3.28(4H，m)，4.73(1H，t，J＝6.4Hz)，4.87(1H，brs)，5.92(1H，s)，6.62(1H，s)，6.92-7.07(2H，m)，7.16-7.32(5H，m)，7.96(1H，m).
MSm/z：483(M
++H).
Embodiment 195:3-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amino]-2,2-dimethyl propylene-1-alcohol
Under ice-cold, at 3-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-base amino]-2, (188mg adds 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrates (35mg) to 2-dimethylpropane-1-alcohol in methyl alcohol 0.389mmol) (6ml) solution.After under the room temperature reaction solution being stirred 13 hours, pressure reducing and steaming methyl alcohol.In residue obtained, add ethyl acetate, use saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing successively, use the anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure filtrate.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=3: 1 obtains obtains white solid.The gained white solid solidifies with ether-hexane, washing back leaching, the title compound (156mg, 0.303mmol, 78%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：0.94(3H，s)，0.95(3H，s)，3.20(2H，d，J＝6.6Hz)，3.27(2H，d，J＝7.1Hz)，4.68(1H，brs)，4.94(1H，t，J＝6.9Hz)，6.09(1H，s)，6.86-6.95(1H，m)，7.00-7.09(1H，m)，7.29(1H，s)，7.40-7.52(3H，m)，7.60(2H，d，J＝8.6Hz)，7.94(1H，s).
mp：176-178℃
Ultimate analysis: C
23H
22N
2O
3Cl
2F
2S: theoretical value: C, 53.60; H, 4.30; N, 5.44; Cl, 13.76; F, 7.37; S, 6.22. measured value: C, 53.50; H, 4.26; N, 5.44; Cl, 13.78; F, 7.31; S, 6.30.
Embodiment 196:[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
Under ice-cold; 5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 186 acquisitions) (2; the 5-difluorophenyl) methyl]-2-(3; 4-dimethoxy benzene methylamino) pyridine (43mg; 0.074mmol) acetonitrile (4ml)/water (1ml) mixing solutions in add nitric acid two ammonium ceriums (IV) (100mg), stirred 1.5 hours.In reaction soln, add saturated sodium bicarbonate, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.It is residue obtained that (hexane: ethyl acetate=3: 1) refining, acquisition is the title compound (12mg, 0.028mmol, 38%) of yellowish white powder with silica gel thin-layer chromatography.
1H-NMR(400MHz，CDCl
3)δ：4.65(2H，brs)，6.13(1H，s)，6.89-6.98(1H，m)，7.00-7.09(1H，m)，7.33(1H，s)，7.44(2H，d，J＝8.8Hz)，7.49-7.57(1H，m)，7.62(2H，d，J＝8.8Hz)，7.99(1H，s).
mp：147-150℃.
MSm/z：429(M
++H).
Ultimate analysis: C
18H
12N
2O
2Cl
2F
2S: theoretical value: C, 50.36; H, 2.82; N, 6.53; Cl, 16.52; F, 8.85; S, 7.47. measured value: C, 50.46; H, 2.68; N, 6.63; Cl, 16.42; F, 9.00; S, 7.66.
Embodiment 197:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] Toluidrin
Ice-cold down, [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl that obtains at embodiment 196] amine (106mg, add in pyridine 0.247mmol) (2ml) solution methylsulfonyl chloride (29 μ l, 0.370mmol).Under the room temperature reaction soln was stirred 3 days concentrating under reduced pressure.In the gained concentrated residue, add ethyl acetate, use anhydrous sodium sulfate drying with after saturated sodium bicarbonate aqueous solution, water and the saturated common salt water washing successively, filter concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 elutriant obtains obtains to be white in color solid title compound (58mg, 0.114mmol, 46%).The gained white solid is with hexane-ether washing back leaching, the title compound (28mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.35(3H，s)，6.19(1H，s)，6.90-6.99(1H，m)，7.01-7.10(1H，m)，7.42-7.53(3H，m)，7.60-7.70(3H，m)，7.97(1H，s)，8.32(1H，s).
mp：220-222℃.
MSm/z：507(M
++H).
FAB-MS:506.9824 (C
19H
15O
4N
2Cl
2F
2S
2, calculated value: 506.9818).
Ultimate analysis: C
19H
14N
2O
4Cl
2F
2S
2: theoretical value: C, 44.98; H, 2.78; N, 5.52; Cl, 13.98; F, 7.49; S, 12.64. measured value: C, 45.35; H, 2.85; N, 5.63; Cl, 13.49; F, 7.34; S, 12.69.
Reference example 35:5-fluorine pyridine-2-formonitrile HCN
Under ice-cold, amino-(24.5g 0.206mmol), stirred 10 minutes the 2-cyanopyridine to add 5-in hydrogen fluoride-pyridine (100ml).Then, (15.6g 0.226mmol), stirs under the room temperature after 10 minutes, stirs 2 hours in 50 ℃ to add Sodium Nitrite.In reaction soln, add 20% aqueous sodium hydroxide solution, use extracted with diethyl ether.The gained organic layer with dried over sodium sulfate after concentrating under reduced pressure.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be the title compound (16.0g, 0.131mmol, 64%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：7.57(1H，ddd，J＝8.6，8.6，3.1Hz)，7.77(1H，dd，J＝8.6，4.4Hz)，8.60(1H，d，J＝3.1Hz).
IR(ATR)cm
-1：3095，2237，1577，1467，1409，1375，1272，1240，1197，1120，1010.
MSm/z：122(M
+).
EI-MS:122.0293 (C
6H
3FN
2, calculated value: 122.0280).
Reference example 36:2-(1,3-dioxolane-2-yl)-5-fluorine pyridine
In-75 ℃, (6.54g, (1.01M hexane solution, 58ml 58.9mmol), stirred 3 hours to splash into diisobutylaluminium hydride in methylene dichloride 53.8mmol) (150ml) solution at 5-fluorine pyridine-2-formonitrile HCN under argon atmospher.Uniform temp adds hydrochloric acid (80ml) (concentrated hydrochloric acid: water=1: 3), be warming up to room temperature down.Behind the separate dichloromethane layer, add sodium bicarbonate, use extracted with diethyl ether at water layer.The gained organic layer with dried over mgso after concentrating under reduced pressure.Wash the dichloromethane layer of previous acquisition with water, again with concentrating under reduced pressure after the dried over mgso.
In benzene (150ml) solution of the residue that merges, add tosic acid-hydrate (1.02g, 5.36mmol) and ethylene glycol (30ml 0.536mol), stirred 2 hours under the reflux.The cooling back adds saturated sodium bicarbonate aqueous solution in reaction soln, use extracted with diethyl ether, uses the saturated common salt water washing again.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that the wash-out portion of ethyl acetate=4: 1 obtains obtains to be the title compound (3.33g, 19.7mmol, 37%) of sorrel oily matter.
1H-NMR(400MHz，CDCl
3)δ：4.02-4.21(4H，m)，5.85(1H，s)，7.45(1H，ddd，J＝8.3，8.3，2.9Hz)，7.57(1H，dd，J＝8.3，4.5Hz)，8.48(1H，d，J＝2.9Hz).
MSm/z：170(M
++H).
Reference example 37:4-[(2, the 5-difluorophenyl) hydroxymethyl]-2-(1,3-dioxolane-2-yl)-5-fluorine pyridine
In-75 ℃, (690mg, (1.8M n-heptane solution, 12ml 21.5mmol), stirred 2 hours to add lithium diisopropyl amido in tetrahydrofuran (THF) 4.08mmol) (100ml) solution at 2-(1,3-dioxolane-2-yl)-5-fluorine pyridine under argon atmospher.Splash into 2 in reaction soln, (2.1ml 19.5mmol), stirred 2.5 hours the 5-difluorobenzaldehyde.After in reaction solution, adding entry and saturated sodium bicarbonate aqueous solution, use extracted with diethyl ether, use the saturated common salt water washing again.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: ethyl acetate (=3: the cut that wash-out portion 1) obtains, the title compound (2.53g, 8.03mmol, 73%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.65(1H，d，J＝4.6Hz)，4.05-4.21(4H，m)，5.84(1H，s)，6.35(1H，d，J＝4.6Hz)，6.96-7.05(2H，m)，7.09-7.26(1H，m)，7.76(1H，d，J＝5.9Hz)，8.40(1H，d，J＝1.5Hz).
MSm/z：312(M
++H).
Embodiment 198:4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-(1,3-dioxolane-2-yl)-5-fluorine pyridine
In the argon atmospher, in ice-cold following at 4-[(2, the 5-difluorophenyl) hydroxymethyl]-2-(1,3-dioxolane-2-yl)-5-fluorine pyridine (2.5g, 8.03mmol) dichloromethane solution (30ml) in add triethylamine (1.7ml, 12.0mmol) and methylsulfonyl chloride (850 μ l 10.4mmol), stirred under the room temperature 2 hours.Use extracted with diethyl ether after in reaction soln, adding saturated sodium bicarbonate aqueous solution.Solution saturated common salt water washing is with concentrated solution under the decompression behind the anhydrous sodium sulfate drying.
In dimethyl formamide (20ml) solution of residue, add 4-chlorobenzene mercaptan (1.39g, 9.64mmol), (1.66g 12.0mmol), stirred 3 hours in 50 ℃ salt of wormwood.Use ether diluting reaction solution, water and saturated common salt water washing successively after being cooled to room temperature.The gained organic layer with dried over sodium sulfate after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: (=4: the cut that wash-out portion 1) obtains obtains to be the title compound (2.86mg, 5.85mmol, 85%) of yellow oil to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：4.06-4.18(4H，m)，5.82(1H，s)，5.94(1H，s)，6.96-7.03(2H，m)，7.20-7.28(5H，m)，7.71(1H，d，J＝5.9Hz)，8.38(1H，d，J＝1.2Hz).
MSm/z：438(M
++H).
Embodiment 199:4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-2-(1,3-dioxolane-2-yl)-5-fluorine pyridine
At 4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-2-(1,3-dioxolane-2-yl)-(2.80g adds seven molybdic acids, six ammonium tetrahydrates (200mg) and 30% aqueous hydrogen peroxide solution (30ml) to 5-fluorine pyridine in methyl alcohol 6.39mmol) (50ml) solution, stirred 3 hours.Add water, the solid that leaching is separated out washes with water.After making the gained solid be dissolved in ethyl acetate, water and saturated common salt water washing.Decompression is concentrated organic layer down.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: ethyl acetate (=3: the cut that wash-out portion 1) obtains, the title compound (1.39g, 2.96mmol, 46%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.08-4.28(4H，m)，4.08-4.28(4H，m)，5.88(1H，s)，6.10(1H，s)，6.94-7.00(1H，m)，7.03-7.10(1H，m)，7.43(2H，d，J＝8.3Hz)，7.62(2H，d，J＝8.3Hz)，7.66-7.70(1H，m)，8.17(1H，d，J＝5.9Hz)，8.41(1H，s)
MSm/z：470(M
++H).
Embodiment 200:4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] formaldehyde
At 4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-2-(1,3-dioxolane-2-yl)-5-fluorine pyridine (2.60g, 5.53mmol) 1, add concentrated hydrochloric acid (20ml) in 4-two alkane (40ml) solution, stirred under the room temperature 5 hours.Behind the concentrated solvent, in residue, add ethyl acetate, successively water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing under the decompression.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: ethyl acetate (=3: the 1) cut that obtains of wash-out portion, the title compound (1.86g, 4.37mmol, 79%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.13(1H，s)，6.93-6.99(1H，m)，7.05-7.10(1H，m)，7.45(2H，d，J＝7.8Hz)，7.65(2H，d，J＝7.8Hz)，7.70-7.75(1H，m)，8.59(1H，s)，8.60(1H，s)，10.06(1H，s).
MSm/z：426(M
++H).
Embodiment 201:4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine carboxylic acid
At 4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] (700mg, (562 μ l 4.93mmol), stirred 2.5 hours under the room temperature formaldehyde to add 30% aqueous hydrogen peroxide solution in formic acid 1.64mmol) (10ml) solution.Add water in reaction soln, the solid that leaching is separated out washes with water.After making the gained solid be dissolved in ethyl acetate, use saturated aqueous ammonium chloride, water and saturated common salt water washing successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Make residue obtained recrystallization with ethanol, the title compound (656mg, 1.48mmol, 91%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.14(1H，s)，6.93-7.00(1H，m)，7.05-7.11(1H，m)，7.46(2H，d，J＝8.6Hz)，7.67(2H，d，J＝8.6Hz)，7.75-7.79(1H，m)，8.47(1H，s)，8.85(1H，d，J＝5.6Hz).
IR(ATR)cm
-1：3288，2942，1751，1722，1693，1608，1575，1492，1398，1326，1290，1241，1182，1147，1089，1043，1014)
mp：208-209℃.
MSm/z：442(M
++H).
Ultimate analysis: C
19H
11ClF
3NO
4S0.75H
2O: theoretical value: C, 50.12; H, 2.77; Cl, 7.79; F, 12.52; N, 3.08; S, 7.04. measured value: C, 50.49; H, 2.97; Cl, 7.53; F, 12.02; N, 3.11, S, 6.89.
Embodiment 202:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] t-butyl carbamate
Under the argon atmospher; at 4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-5-fluorine pyridine carboxylic acid (240mg; 0.543mmol) the trimethyl carbinol (2ml) and the mixing solutions of toluene (5ml) in add diphenylphosphine acylazide (162 μ l; 0.762mmol), triethylamine (151 μ l; 1.09mmol), stirred 15 hours under the reflux.The cooling back adds ethyl acetate in reaction solution, successively with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: ethyl acetate (=4: the 1) cut that obtains of wash-out portion, the title compound (181mg, 0.353mmol, 65%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.57(9H，s)，6.07(1H，s)，6.93-6.99(1H，m)，7.02-7.08(1H，m)，7.43(2H，d，J＝8.6Hz)，7.49(1H，brs)，7.70(2H，d，J＝8.6Hz)，7.71-7.75(1H，m)，8.04(1H，s)，8.65(1H，d，J＝4.9Hz).
MSm/z：442(M
+-tBu+2H).
Embodiment 203:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] amine
[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] (170mg adds concentrated hydrochloric acid (5ml) in ethanol 0.331mmol) (5ml) solution to t-butyl carbamate, stirs 2 hours under the room temperature.Decompression is concentrated reaction solution down, adds saturated sodium bicarbonate aqueous solution in residue obtained, uses ethyl acetate extraction.Organic layer saturated common salt water washing is with concentrating under reduced pressure after the dried over mgso.The residue hexane: re-crystallizing in ethyl acetate, acquisition is the title compound (110mg, 0.266mmol, 81%) of lavender powder.
1H-NMR(400MHz，CDCl
3)δ：4.51(2H，s)，5.99(1H，s)，6.92-6.97(1H，m)，7.02-7.08(1H，m)，7.16(1H，d，J＝4.6Hz)，7.44(2H，d，J＝8.6Hz)，7.61-7.65(1H，m)，7.63(2H，d，J＝8.6Hz)，7.86(1H，s).IR(ATR)cm
-1：3645，3174，1631，583，1565，1496，1427，1396，1330，1278，1236，1178，1151，108
5，1014.
mp：181-183℃.
MSm/z：413(M
++H).
Ultimate analysis: C
18H
12ClF
3N
2O
2S: theoretical value: C, 52.37; H, 2.93; Cl, 8.59; F, 13.81; N, 6.79; S, the real side value of 7.77.: C, 52.09; H, 2.88; Cl, 8.57; F, 13.54; N, 6.90; S, 7.81.
Embodiment 204:N-[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] Toluidrin
Under ice-cold; at [4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] and amine (54mg, 0.131mmol) and pyridine (16 μ l; 0.197mmol) methylene dichloride (5ml) solution in add methylsulfonyl chloride (12 μ l, 0.157mmol).After under the room temperature reaction solution being stirred 7 hours, add pyridine (16 μ l, 0.197mmol) and methylsulfonyl chloride (12 μ l, 0.157mmol).After under the room temperature reaction solution being stirred 17 hours, add pyridine (16 μ l, 0.197mmol) and methylsulfonyl chloride (12 μ l, 0.157mmol).After under the room temperature reaction solution being stirred 2 hours, add pyridine (16 μ l, 0.197mmol) and methylsulfonyl chloride (12 μ l, 0.157mmol).After under the room temperature reaction solution being stirred 21 hours, add pyridine (16 μ l, 0.197mmol) and methylsulfonyl chloride (12 μ l, 0.157mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 2 hours.In the gained concentrated residue, add ethyl acetate,, use the anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure filtrate with the saturated sodium bicarbonate aqueous solution washing.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=2: the 1) cut that obtains of elutriant obtains to be white in color solid title compound (54mg, 0.110mmol, 84%) to ethyl acetate.With leaching behind the hexane-ether washing gained white solid, the title compound of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.30(3H，s)，6.06(1H，s)，6.90-6.99(1H，m)，7.02-7.10(1H，m)，7.46(2H，d，8.8Hz)，7.58-7.69(3H，m)，7.83-7.91(2H，m)，8.21(1H，s).
mp：217-219℃.
MSm/z：490(M
+).
EI-MS:490.0008 (C
19H
14O
4N
2ClF
3S
2, calculated value: 490.0036).
Ultimate analysis: C
19H
14N
2O
4ClF
3S
2: theoretical value: C, 46.49; H, 2.87; N, 5.71; Cl, 7.22; F, 11.61; S, 13.06. measured value: C, 46.90; H, 2.95; N, 5.78; Cl, 7.33; F, 11.56; S, 13.04.
Reference example 38:(4-bromo-5-picoline-2-yl) methyl alcohol
Under the argon atmospher, down at 4-bromo-2, ((20.6ml 0.146mol), stirred 20 minutes 5-lutidine-1-oxide compound, stirred 7.5 hours under the room temperature to add trifluoroacetic anhydride among the 9.8g, dichloromethane solution 48.5mmol) (100ml) in ice-cold.Decompression is concentrated reaction solution down.In the dichloromethane solution (50ml) of residue, add saturated sodium bicarbonate aqueous solution (100ml), stirred 14 hours.The reaction soln dichloromethane extraction is with concentrated solution under the decompression behind the anhydrous sodium sulfate drying.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: (=1: the 1) cut that obtains of wash-out portion obtains to be the title compound (8.17g, 40.4mmol, 83%) of yellow powder to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：2.38(3H，s)，3.42(1H，s)，4.71(2H，s)，7.48(1H，s)，8.35(1H，s).
MSm/z：202(M
++H).
Reference example 39:4-bromo-2-[(t-butyldimethylsilyloxy base) methyl]-the 5-picoline
Under nitrogen atmosphere, in ice-cold following at (4-bromo-5-picoline-2-yl) methyl alcohol (7.96g, 39.4mmol) dichloromethane solution (100ml) in add imidazoles (2.95g, 43.3mmol), 4-dimethylaminopyridine (481mg, 3.94mmol) and tertiary butyl chloride dimethylsilane (6.53g, 43.3mmol), stirred 1 hour under the room temperature.In reaction soln, add water, use dichloromethane extraction, with concentrated solution under the decompression behind the anhydrous sodium sulfate drying.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, obtain to be faint yellow oily thing title compound (12.4g, 39.4mmol, quantitatively).
1H-NMR(400MHz，CDCl
3)δ：0.12(6H，s)，0.96(9H，s)，2.36(3H，s)，4.78(2H，s)，7.67(1H，s)，8.29(1H，s).
MSm/z：316(M
++H).
Reference example 40:2-[(t-butyldimethylsilyloxy base) methyl]-4-[(2, the 5-difluorophenyl) hydroxymethyl]-the 5-picoline
In-78 ℃, under argon atmospher at 4-bromo-2-[(t-butyldimethylsilyloxy base) methyl]-(200mg adds n-Butyl Lithium (1.58M hexane solution, 400 μ l to the 5-picoline in ether 0.632mmol) (3ml) solution, 0.632mmol), stirred 1 hour.Splash into 2 in reaction soln, (69 μ l 0.632mmol), stirred 1 hour the 5-difluorobenzaldehyde.Use extracted with diethyl ether after in reaction solution, adding entry and saturated sodium bicarbonate aqueous solution, use the saturated common salt water washing again.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains, the title compound (178mg, 0.469mmol, 74%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：0.06(3H，s)，0.09(3H，s)，0.91(9H，s)，2.26(3H，s)，2.52(1H，brs)，4.79(2H，s)，6.24(1H，s)，6.95-7.10(3H，m)，7.58(1H，s)，8.27(1H，s).
MSm/z：380(M
++H).
Embodiment 205:2-[(t-butyldimethylsilyloxy base) methyl]-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-the 5-picoline
In the argon atmospher, in ice-cold following at 2-[(t-butyldimethylsilyloxy base) methyl]-4-[(2, the 5-difluorophenyl) hydroxymethyl]-5-picoline (8.0g, 21.1mmol) dichloromethane solution (100ml) in add triethylamine (4.41ml, 31.7mmol) and methylsulfonyl chloride (2.2ml, 27.4mmol), stirred 50 minutes under the room temperature.Use extracted with diethyl ether after in reaction soln, adding saturated sodium bicarbonate aqueous solution.Solution saturated common salt water washing is with concentrated solution under the decompression behind the anhydrous magnesium sulfate drying
In dimethyl formamide (100ml) solution of residue, add 4-chlorobenzene mercaptan (3.66g, 25.3mmol) and salt of wormwood (4.38g, 31.7mmol), in 50 ℃ of stirrings 1.5 hours.Use ether diluting reaction solution, water and saturated common salt water washing successively after being cooled to room temperature.The gained organic layer with dried over mgso after concentrating under reduced pressure.Handle with silica gel column chromatography residue obtained, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=5: 1 wash-out portion obtains obtains to be the title compound (9.3g, 18.4mmol, 87%) of faint yellow oily thing.
1H-NMR(400MHz，CDCl
3)δ：0.04(3H，s)，0.08(3H，s)、0.91(9H，s)，2.33(3H，s)，4.77(2H，d，J＝4.2Hz)，5.83(1H，s)，6.92-7.00(2H，m)，7.20(4H，s)，7.33-7.38(1H，m)，7.56(1H，s)，8.29(1H，s).
MSm/z：506(M
++H).
Embodiment 206:[4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] methyl alcohol
At 2-[(t-butyldimethylsilyloxy base) methyl]-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-5-picoline (200mg, 0.395mmol) tetrahydrofuran solution (3ml) in add tetrabutylammonium (1.0M tetrahydrofuran solution, 593 μ l, 0.593mmol), stirred 20 minutes.Use ethyl acetate extraction after in reaction soln, adding water.Organic layer saturated common salt water washing concentrates down with decompression behind the anhydrous magnesium sulfate drying.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be the title compound (150mg, 0.384mmol, 97%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：2.31(3H，s)，3.54(1H，brs)，4.72(2H，s)，5.81(1H，s)，6.94-7.03(2H，m)，7.20(4H，s)，7.22-7.28(1H，m)，7.33(1H，s)，8.35(1H，s).
MSm/z：392(M
++H).
Embodiment 207:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] methyl alcohol
[4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] methyl alcohol (6.5g, 16.6mmol) methyl alcohol (150ml) solution in add seven molybdic acids, six ammonium tetrahydrates (500mg) and 30% aqueous hydrogen peroxide solution (150ml), stirred 23 hours.Add water, the solid that leaching is separated out washes with water.Make the gained solid be dissolved in ethyl acetate, water and saturated common salt water washing.Decompression is concentrated organic layer down.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=1: 1 wash-out portion obtains, the title compound (4.0g, 9.44mmol, 57%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.13(3H，s)，3.53(1H，brs)，4.80(1H，d，J＝14.4Hz)，4.85(1H，d，J＝14.4Hz)，5.88(1H，s)，6.90-6.96(1H，m)，7.01-7.07(1H，m)，7.43(2H，d，J＝8.8Hz)，7.60(2H，d，J＝8.8Hz)，7.60(2H，d，J＝8.8Hz)，7.63-7.67(1H，m)，7.93(1H，s)，8.36(1H，s).
IR(ATR)cm
-1：3179，1604，1573，1492，1427，1394，1349，1322，1280，1234，1151，1085，039，1010.
mp：196-198℃.
MSm/z：424(M
++H).
Ultimate analysis: C
20H
16ClF
2NO
3S: theoretical value: C, 56.67; H, 3.80; Cl, 8.36; F, 8.96; N, 3.30; S, 7.56. measured value: C, 56.41; H, 3.83; Cl, 8.28; F, 8.89; N, 3.31; S, 7.67.
Embodiment 208:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] formaldehyde
Under the nitrogen atmosphere; [4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-5-picoline-2-yl] methyl alcohol (200mg; 0.472mmol) methylene dichloride (5ml) solution in add methyl-sulphoxide (164 μ l; 2.36mmol), triethylamine (329 μ l; 2.36mmol) and sulphur trioxide pyridine complex salt (255mg 1.42mmol), stirred under the room temperature 16 hours.The concentrating under reduced pressure reaction solution is residue obtainedly handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains, the title compound (160mg, 0.379mmol, 80%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.29(3H，s)，5.94(1H，s)，6.92-6.97(1H，m)，7.02-7.08(1H，m)，7.43(2H，d，J＝8.8Hz)，7.62(2H，d，J＝8.8Hz)，7.70-7.75(1H，m)，8.57(1H，s)，8.59(1H，s)，10.08(1H，s).
MSm/z：422(M
++H).
Embodiment 209:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline formic acid
[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] (150mg, (121 μ l 1.07mmol), stirred 2 hours under the room temperature formaldehyde to add 30% aqueous hydrogen peroxide solution in formic acid 0.356mmol) (3ml) solution.Add water in reaction soln, the solid that leaching is separated out washes with water.Make the gained solid be dissolved in ethyl acetate, water and saturated aqueous common salt wash successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Make residue obtained recrystallization with ethanol, the title compound (140mg, 0.320mmol, 90%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.33(3H，s)，5.96(1H，s)，6.92-6.98(1H，m)，7.02-7.08(1H，s)，7.44(2H，d，J＝8.6Hz)，7.64(2H，d，J＝8.6)，7.74-7.78(1H，m)，8.45(1H，s)，8.81(1H，s).
IR(ATR)cm
-1：1922，1683，1598，1488，1450，1428，1396，1375，1326，1290，1236，1174，47，1085，1047，1014.
mp：105-107℃.
MSm/z：438(M
++H).
Ultimate analysis: C
20H
14ClF
2NO
4S0.75H
2O: theoretical value: C, 53.22; H, 3.46; Cl, 7.85; F, 8.42; N, 3.10; S, 7.10. measured value: C, 53.44; H, 3.90; Cl, 7.47; F, 8.06; N, 3.07; S, 6.95
Embodiment 210:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] t-butyl carbamate
In the argon atmospher; [4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-5-picoline formic acid (2.8mg; 6.40mmol) the trimethyl carbinol (20ml) and the mixing solutions of toluene (40ml) in add diphenylphosphine acylazide (2.9ml; 13.6mmol), triethylamine (2.7ml; 19.4mmol), stirred 16 hours under the reflux.The cooling back adds ethyl acetate in reaction solution, successively with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtained successively with the washing of hexane and ethyl acetate, the title compound (2.60g, 5.11mmol, 80%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.58(9H，s)，2.07(3H，s)，5.88(1H，s)，6.92-6.98(1H，m)，7.00-7.06(1H，m)，7.42(2H，d，J＝8.8Hz)，7.42(2H，d，J＝8.8Hz)，7.57(1H，brs)，7.67-7.72(1H，m)，7.71(2H，d，J＝8.8Hz)，8.02(1H，s)，8.67(1H，s).
MSm/z：509(M
++H).
Embodiment 211:[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] amine
[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] (200mg adds concentrated hydrochloric acid (6ml) in ethanol 0.393mmol) (5ml) solution to t-butyl carbamate, stirs 2.5 hours under the room temperature.Decompression is concentrated reaction solution down, adds saturated sodium bicarbonate aqueous solution in residue obtained, uses ethyl acetate extraction.Organic layer is water and saturated common salt water washing successively, with concentrating under reduced pressure after the dried over mgso.Residue hexane: re-crystallizing in ethyl acetate, the title compound (125mg, 0.306mmol, 78%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.89(3H，s)，5.95-5.96(3H，m)，7.12(1H，s)，7.22-7.34(2H，m)，7.51-7.55(1H，m)，7.65(2H，d，J＝8.8Hz)，7.69(1H，s)，7.78(2H，d，J＝8.8Hz).
IR(ATR)cm
-1：3424，1637，1554，1492，1457，1411，1309，1276，1230，1151，1089，1039，1008.
mp：188-189℃.
Ultimate analysis: C
19H
15ClF
2N
2O
2S: theoretical value: C, 55.82; H, 3.70; Cl, 8.67; F, 9.29; N, 6.85; S, 7.84. measured value: C, 55.58; H, 3.95; Cl, 8.61; F, 9.13; N, 6.91; S, 7.89.
Embodiment 212:N-[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] Toluidrin
Under ice-cold; at [4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-picoline-2-yl] and amine (133mg, 0.325mmol) and pyridine (39 μ l; 0.488mmol) methylene dichloride (5ml) solution in add methylsulfonyl chloride (28 μ l, 0.358mmol).After under the room temperature reaction solution being stirred 2.5 hours, add pyridine (26 μ l, 0.325mmol) and methylsulfonyl chloride (25 μ l, 0.325mmol).After under the room temperature reaction solution being stirred 16 hours, add pyridine (26 μ l, 0.325mmol) and methylsulfonyl chloride (25 μ l, 0.325mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 1.5 hours.In the gained concentrated residue, add ethyl acetate, water and saturated common salt water washing successively, with leaching behind the anhydrous sodium sulfate drying, concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that the elutriant of ethyl acetate=3: 2 obtains obtains to be white in color solid title compound (108mg, 0.222mmol, 68%).The gained white solid is with hexane-ether washing back leaching, the title compound (67mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.13(3H，s)，3.29(3H，s)，5.85(1H，s)，6.89-6.99(1H，m)，7.01-7.10(1H，m)，7.45(2H，d，J＝8.3Hz)，7.59-7.69(3H，m)，7.90(1H，s)，8.12(1H，s).
mp：214-217℃.
MSm/z：486(M
+).
Ultimate analysis: C
20H
17N
2O
4ClF
2S
2: theoretical value: C, 49.33; H, 3.52; N, 5.75; Cl, 7.28; F, 7.80; S, 13.17. measured value: C, 49.18; H, 3.45; N, 5.82; Cl, 7.18; F, 7.98; S, 13.14.
Embodiment 213:2,5-two chloro-4-[(2,5-difluorophenyl)-(4-fluorobenzene sulfenyl) methyl] pyridine
With reference example 24 obtain 2,5-two chloro-4-[(2,5-difluorophenyl)-hydroxymethyl] pyridine (1.22g, 4.8mmol) be dissolved in thionyl chloride (5.0ml) after, add the dimethyl formamide of catalytic amount, stirred 4 hours.Decompression is concentration of reaction solution down, adds 1 in residue, 4-two alkane, reconcentration.
After this residue is dissolved in dimethyl formamide (10ml), under nitrogen atmosphere, add 4-fluorobenzene mercaptan (730mg, 5.7mmol) and salt of wormwood (2.07g, 15mmol), stirring is 24 hours under the room temperature.Add ether (120ml) in reaction solution, water and saturated aqueous common salt wash it.The organic layer dried over mgso, decompression concentrates down.Make residue crystallization in ethanol, obtain to be the title compound (950mg, 49%) of colourless needle crystal.
1H-NMR(400MHz，CDCl
3)δ：5.92(1H，s)，6.94-7.04(4H，m)，7.19(1H，m)，7.33-7.4(2H，m)，7.57(1H，s)，8.33(1H，s).
IR(ATR)cm
-1：1571，1489，1329，1222，1157，1109，835.
mp：95-97℃.
MSm/z：400(M
++H).
Embodiment 214:[5-chloro-4-[(2, the 5-difluorophenyl)-(4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] (3,4-dimethoxy phenmethyl) amine
Under the argon atmospher, in tube sealing in 120 ℃ to 2,5-two chloro-4-[(2, the 5-difluorophenyl)-(4-fluorobenzene sulfenyl) methyl] and pyridine (740mg, 1.85mmol) and 3,4-dimethoxy benzene methanamine (836 μ l, 5.55mmol) 1,4-two alkane (3.0ml) solution stirring 3 days.Add ethyl acetate (80ml) after being cooled to room temperature.Solution saturated common salt water washing, the decompression of dry back concentrates down, obtains residue.(hexane: ethyl acetate=3: 1) refining, acquisition is the amine body (235mg) of oily matter to residue with silica gel column chromatography.
This amine body is dissolved in methyl alcohol (9.0ml), adds seven molybdic acids, six ammonium tetrahydrates (30mg) and 30% aqueous hydrogen peroxide solution (3.0ml), stirred 20 hours under the room temperature.After ethyl acetate (80ml) dilution, solution with water and saturated common salt water washing.The decompression of dry back is concentrated solution down, adds ethanol in residue obtained, makes its crystallization obtain to be white in color solid title compound (159mg, 15%).
1H-NMR(400MHz，CDCl
3)δ：3.89(6H，s)，4.50(2H，m)，6.10(1H，s)，6.85-7.05(5H，m)，7.11(2H，t，J＝8.4Hz)，7.25-7.35(1H，m)，7.29(1H，s)，7.61(2H，dd，J＝5.2，8.4)，7.99(1H，s).
IR(ATR)cm
-1：3249，1589，1490，1236，1147，817.
mp：158-159℃.
MSm/z：563(M
++H).
Embodiment 215:[5-chloro-4-[(2, the 5-difluorophenyl)-(4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] amine
Will [5-chloro-4-[(2,5-difluorophenyl)-(4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] (157mg 0.28mmol) is dissolved in trifluoroacetic acid (5.0ml) to (3,4-dimethoxy phenmethyl) amine, stirs 17 hours in 65 ℃.The decompression of cooling back is concentrated solution down.In residue obtained, add saturated sodium bicarbonate aqueous solution, use ethyl acetate extraction.Solution concentrates down with saturated common salt water washing after drying, decompression.Residue obtained with silica gel chromatography (hexane: ethyl acetate=3: 1) make with extra care, obtain to be white in color solid title compound (114mg, 99%).
1H-NMR(400MHz，CDCl
3)δ：4.76(2H，br)，6.12(1H，s)，6.91(1H，m)，7.06(1H，m)，7.14(2H，t，J＝8.4)，7.37(1H，s)，7.53(1H，m)，7.69(2H，dd，J＝4.8，8.4Hz)，7.98(1H，s).
IR(ATR)cm
-1：3456，3167，1639，1591，1491，1417，1327，1238，1140，1084.
mp：157-159℃.
MSm/z：413(M
++H).
Ultimate analysis: C
18H
12ClF
3N
2O
2S: theoretical value: C, 52.37; H, 2.93; Cl, 8.59; F, 13.81; N, 6.79; S, 7.77. measured value: C, 52.45; H, 2.96; Cl, 8.62; F, 13.69; N, 6.82; S, 7.83.
Embodiment 216:N-[5-chloro-4-[(2, the 5-difluorophenyl)-(4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] Toluidrin
At [5-chloro-4-[(2; the 5-difluorophenyl)-(4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] amine (114mg; 0.276mmol) dichloromethane solution (10.0ml) in add pyridine (440 μ l; 5.5mmol); add methylsulfonyl chloride (1 day 1 time adding 77 μ l therein; added 230 μ l in 3 days altogether, 3.0mmol), amount to and stirred 4 days.Decompression is concentrated reaction solution down.Residue obtained with silica gel chromatography (hexane: ethyl acetate=2: 1) make with extra care, make its crystallization in ether, obtain to be white in color solid title compound (51mg, 38%).
1H-NMR(400MHz，CDCl
3)δ：3.35(3H，s)，6.19(1H，s)，6.92(1H，m)，7.08(1H，m)，7.15(2H，t，J＝8.8Hz)，7.50(1H，m)，7.73(2H，m)，8.00(1H，s)，8.32(1H，s)，
MSm/z：491(M
++H).
IR(ATR)cm
-1：1590，1490，1330，1149，968，852.mp：178-179℃.
Ultimate analysis: C
19H
14ClF
3N
2O
4S
2: theoretical value: C, 46.49; H, 2.87; N, 5.71; S, 13.06; Cl, 7.22; F, 11.61. measured value: C, 46.55; H, 2.96; N, 5.73; S, 13.02; Cl, 7.13; F, 11.39.
Embodiment 217:N-[5-chloro-4-[(2,5-difluorophenyl) (4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] optical resolution (optically active isomer A, optically active isomer B) of Toluidrin
By having used the supercritical chromatography (Gilson corporate system) of chirality (chiral) post; the N-[5-chloro-4-[(2 that embodiment 216 is obtained under the following conditions, 5-difluorophenyl)-and (4-fluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] Toluidrin carries out optical resolution.
Post: CHIRALPAK AD, 2.0cm φ * 25cm, Dai Saier chemical industry Co., Ltd. system
Moving phase: 2-propyl alcohol: carbonic acid gas=1: 99 → 50: 50 (after 3 minutes, 50: 50)
Flow: 6.0ml/ minute
Pressure: 14MPa
Temperature: 35 ℃
Detect: UV (254mm)
The retention time and the instrument data of optically active isomer are as follows.
Optically active isomer A:16.3 minute
1H-NMR(400MHz，CDCl
3)δ：3.35(3H，s)，6.18(1H，s)，6.89-6.97(1H，m)，7.02-7.10(1H，m)，7.12-7.20(2H，m)，7.47-7.54(1H，m)，7.69-7.76(2H，m)，7.83(1H，brs)，7.98(1H，s)，8.32(1H，s).
Optically active isomer B:18.4 minute
1H-NMR(400MHz，CDCl
3)δ：3.36(3H，s)，6.18(1H，s)，6.89-6.96(1H，m)，7.02-7.10(1H，m)，7.12-7.20(2H，m)，7.46-7.54(1H，m)，7.69-7.76(2H，m)，7.99(1H，s)，8.32(1H，s).
[α]
D 25：+102.6°(c＝0.5，CHCl
3).
Embodiment 218:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] sodium salt of Toluidrin
N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 197 acquisitions) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] (15.1g adds 1N aqueous sodium hydroxide solution (32.8ml) back concentrating under reduced pressure to Toluidrin in ethanol 29.8mmol) (100ml) solution.In the gained concentrated residue, add the 2-propyl alcohol, make the residue dissolving, at room temperature place the solid that the back leaching is separated out, obtain title compound (9.10g, 16.6mmol, 56%) while heat.
1H-NMR(400MHz，DMSO-d
6)6：2.79(3H，s)，6.10(1H，s)，7.14(1H，s)，7.23-7.40(2H，m)，7.48-7.57(1H，m)，7.68(2H，d，J＝8.8Hz)，7.75(2H，d，J＝8.8Hz)，7.89(1H，s).
IR(ATR)cm
-1：1583，1494，1463，1384，1326，1230，1151，1108，1089，1012，813，755.
Ultimate analysis: C
19H
13N
2O
4Cl
2F
2S
2Na1.0H
2O: theoretical value: C, 41.69; H, 2.76; N, 5.12; Cl, 12.95; F, 6.94; S, 11.72. measured value: C, 41.77; H, 2.66; N, 5.18; Cl, 13.02; F, 7.03; S, 11.78.
Embodiment 219:[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
In 65 ℃, to the 5-chloro-4-[(4-chlorobenzene sulfenyl of embodiment 185 acquisitions) (2, the 5-difluorophenyl) methyl]-(1.89g, trifluoroacetic acid 3.45mmol) (5ml) solution carry out stirring in 2 hours 2-(3,4-dimethoxy benzene methylamino) pyridine.Add saturated sodium bicarbonate aqueous solution behind the concentrating under reduced pressure reaction solution, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by hexane: (=2: the cut that elutriant 1) obtains obtains white solid to ethyl acetate.With hexane-ether the gained white solid is washed the back leaching, the title compound (1.06g, 2.67mmol, 77%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.50(2H，s)，5.96(1H，s)，6.76(1H，s)，6.90-7.10(2H，m)，7.12-7.35(5H，m)，8.02(1H，s).
IR(ATR)cm
-1：3129，1635，1602，1540，1490，1469，1415，1093，1012，819，728.
MSm/z：397(M
++H).
Embodiment 220:N-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl]-N-(methyl sulphonyl) Toluidrin (compd A) and N-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] Toluidrin (compd B)
The compd A compd B
In 0 ℃, [5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (575mg, (0.123ml 1.59mmol), stirred 16 hours under the room temperature amine to add methylsulfonyl chloride in pyridine 1.45mmol) (5ml) solution.(0.12ml 1.59mmol), stirred 22 hours under the room temperature to add methylsulfonyl chloride in 0 ℃ in reaction solution.In reaction solution, add pyridine (3ml), in 0 ℃ add methylsulfonyl chloride (0.123ml, 1.59mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 25 hours.To after the gained concentrated residue dilution, anhydrous sodium sulfate drying use in water and saturated common salt water washing successively with ethyl acetate, filters concentrating under reduced pressure filtrate afterwards.The gained concentrated residue is handled with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: ethyl acetate (=4: the 1) cut that obtains of wash-out portion, acquisition is tagged compound A (low the polar compound) (334mg of amorphous substance, 0.603mmol, 42%), the acquisition solid title compound B (high polar compound) (269mg, 0.566mmol, 39%) that is white in color.
Compd A
1H-NMR(400MHz，CDCl
3)δ：3.56(6H，s)，5.97(1H，s)，6.95-7.09(3H，m)，7.20-7.31(4H，m)，7.76(1H，s)，8.45(1H，s).
IR(ATR)cm
-1：1583，1492，1367，1321，1159，1093，1006，962，931，821，759.
MSm/z：552(M
+).
Compd B
1H-NMR(400MHz，CDCl
3)δ：3.15(3H，s)，6.02(1H，s)，6.94-7.13(3H，m)，7.20-7.35(4H，m)，7.59(1H，s)，8.07(1H，brs)，8.30(1H，s).
mp：149-151℃
IR(ATR)cm
-1：1590，1556，1488，1475，1380，1348，1149，993，962，831，784.
MSm/z：475(M
++H).
FAB-MS:474.9925 (presses C
19H
15O
2N
2Cl
2F
2S
2Calculate: 474.9920).
Ultimate analysis: C
19H
14N
2O
2Cl
2F
2S
2: theoretical value: C, 48.01; H, 2.97; N, 5.89; Cl, 14.92; F, 7.99; S, 13.49. measured value: C, 48.27; H, 2.95; N, 5.91; Cl, 14.79; F, 7.96; S, 13.61.
Embodiment 221:N-[5-chloro-4-[(4-chloro-phenyl-sulfinyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] Toluidrin
In 0 ℃, at N-[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] Toluidrin (331mg, and adding 3-chlorine peroxybenzoic acid in methylene dichloride 0.696mmol) (10ml) solution (120mg, 0.696mmol).In 0 ℃ reaction solution stirred 50 minutes after, under uniform temp, add 3-chlorine peroxybenzoic acid (60mg, 0.348mmol).Stirring added saturated aqueous sodium thiosulfate after 10 minutes to reaction solution in 0 ℃, used dichloromethane extraction.Organic layer anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: ethyl acetate (=2: the 1) cut that obtains of elutriant.In the gained concentrated residue, add ether, the solid that leaching is separated out, the title compound (281mg, 0.572mmol, 82%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.36(3H，s)，5.48(0.5H，s)，5.66(0.5H，s)，6.79-6.88(0.5H，m)，6.95-7.09(1.5H，m)，7.18-7.44(5H，m)，7.64(0.5H，s)，7.83(0.5H，s)，8.23(0.5H，s)，8.36(0.5H，s)，8.70(1H，brs).
IR(ATR)cm
-1：3124，3081，1594，1492，1463，1334，1143，964，871，821，742.
MSm/z：491(M
++H).
FAB-MS:490.9853 (presses C
19H
15O
3N
2Cl
2F
2S
2Calculate: 490.9869).
Ultimate analysis: C
19H
14N
2O
3Cl
2F
2S
2: theoretical value: C, 46.44; H, 2.87; N, 5.70; Cl, 14.43; F, 7.73; S, 13.05. measured value: C, 46.64; H, 3.02; N, 5.64; Cl, 14.31; F, 7.74; S, 13.02.
Embodiment 222:[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] hydrazine
At 2 of embodiment 57 acquisitions, 5-two chloro-4-[(4-chloro-phenyl-alkylsulfonyls) (2, the 5-difluorophenyl) methyl] (524mg adds hydrazine monohydrate (2ml) to pyridine in ethanol 1.17mmol) (10ml) solution.Reaction solution reflux 3 hours is cooled to concentrating under reduced pressure after the room temperature.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by hexane: (=1: the cut that elutriant 1) obtains obtains faint yellow oily thing to ethyl acetate.In gained oily matter, add hexane-ether, the solid that leaching is separated out, the title compound (95mg, 0.214mmol, 18%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.89(2H，s)，6.03(1H，s)，6.16(1H，s)，6.89-6.97(1H，m)，7.00-7.09(1H，m)，7.44(2H，d，J＝8.8Hz)，7.50-7.58(1H，m)，7.60-7.68(3H，m)，8.03(1H，s).
IR(ATR)cm
-1：3249，1590，1550，1492，1413，1315，1174，1149，1083，811，754.
MSm/z：443(M
+).
Ultimate analysis: C
18H
13N
3O
2Cl
2F
2S: theoretical value: C, 48.66; H, 2.95; N, 9.46; Cl, 15.96; F, 8.55; S, 7.22. measured value: C, 48.48; H, 2.81; N, 9.40; Cl, 15.80; F, 8.59; S, 7.23.
Embodiment 223:N '-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] hydrazine carboxylic acid's tert-butyl ester
[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] hydrazine (166mg, and tert-Butyl dicarbonate in methylene dichloride 0.374mmol) (5ml) solution (122mg, 0.560mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 16 hours.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=3: the cut that elutriant 1) obtains obtains to be white in color solid title compound (166mg, 0.305mmol, 82%) to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：1.51(9H，s)，6.19(1H，s)，6.42(1H，s)，6.59(1H，brs)，6.91-7.09(2H，m)，7.43(2H，d，J＝8.8Hz)，7.50-7.56(1H，m)，7.57(1H，s)，7.63(2H，d，J＝8.8Hz)，8.06(1H，s).
IR(ATR)cm
-1：3336，3295，1681，1596，1558，1496，1477，1321，1151，1091，809.
MSm/z：544(M
++H).
Embodiment 224:N '-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-N '-sulfonyloxy methyl hydrazine carboxylic acid tert-butyl ester
In 0 ℃; at N '-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] and hydrazine carboxylic acid's tert-butyl ester (178mg, 0.327mmol) and triethylamine (43 μ l; 0.392mmol) methylene dichloride (5ml) solution in add methylsulfonyl chloride (30 μ l, 0.392mmol).After under the room temperature reaction solution being stirred 16 hours, add triethylamine (43 μ l, 0.392mmol) and methylsulfonyl chloride (30 μ l, 0.392mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 3 hours.The gained concentrated residue dilutes with ethyl acetate, successively with using anhydrous sodium sulfate drying after saturated sodium bicarbonate aqueous solution and the saturated common salt water washing, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=4: the cut that elutriant 1) obtains obtains to be white in color solid title compound (174mg, 0.280mmol, 85%) to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：1.52(9H，s)，3.56(3H，s)，6.21(1H，s)，6.92-7.10(2H，m)，7.31(1H，brs)，7.44(2H，d，J＝8.7Hz)，7.47-7.54(1H，m)，7.63(2H，d，J＝8.7Hz)，8.05(1H，s)，8.28(1H，s).
IR(ATR)cm
-1：3320，1731，1583，1494，1353，1326，1236，1149，1091，958，754，728.
MSm/z：622(M
++H).
Embodiment 225:1-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-1-sulfonyloxy methyl hydrazine
At N '-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-(167mg adds trifluoroacetic acid (2.5ml) in methylene dichloride 0.268mmol) (5ml) solution to N '-sulfonyloxy methyl hydrazine carboxylic acid tert-butyl ester.Under the room temperature reaction solution is stirred concentrating under reduced pressure after 21 hours.In the gained concentrated residue, add saturated sodium bicarbonate aqueous solution, use dichloromethane extraction.Organic layer separates the back anhydrous sodium sulfate drying, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=2: the cut that elutriant 1) obtains obtains to be white in color solid title compound (91mg, 0.174mmol, 65%) to ethyl acetate.The gained solid is with the leaching of ether washing back, the title compound (60mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.25(3H，s)，4.80(2H，brs)，6.25(1H，s)，6.90-7.10(2H，m)，7.44(2H，d，J＝8.6Hz)，7.53-7.61(1H，m)，7.68(2H，d，J＝8.6Hz)，8.32(1H，s)，8.44(1H，s).
mp：152-154℃
IR(ATR)cm
-1：1583，1490，1361，1319，1149，1079，958，833，754.
MSm/z：522(M
++H).
Ultimate analysis: C
19H
15N
3O
4Cl
2F
2S
2: theoretical value: C, 43.69; H, 2.89; N, 8.04; Cl, 13.57; F, 7.27; S, 12.28. measured value: C, 43.86; H, 2.93; N, 7.91; Cl, 13.19; F, 7.31; S, 12.28.
Reference example 41:2,5-two bromo-4-[(2,5-difluorophenyl) hydroxymethyl] pyridine
In-70 ℃, (17ml, (1.59M hexane solution, 76ml 121mmol), stirred 1 hour to add n-Butyl Lithium in tetrahydrofuran (THF) 121mmol) (400ml) solution at Diisopropylamine under argon atmospher.Splash into 2 in reaction soln, the tetrahydrofuran (THF) of 5-dibromo pyridine (100ml) solution stirred 2 hours.Splash into 2 in reaction soln, (15ml 139mmol), stirred 1 hour the 5-difluorobenzaldehyde.In reaction solution, add concentrating under reduced pressure behind the water, use dichloromethane extraction.The gained organic layer with dried over mgso after concentrating under reduced pressure.The residue obtained methylene dichloride of using: hexane wash obtains pale yellow powder.Filtrate is handled with silica gel column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=6: 1 wash-out portion obtains, merge with above-mentioned pale yellow powder, and obtain to be the title compound (18.4g, 48.6mmol, 52%) of pale yellow powder.
1H-NMR(400MHz，CDCl
3)δ：2.62(1H，s)，6.24(1H，s)，6.85-6.89(1H，m)，7.00-7.10(2H，m)，7.79(1H，s)，8.43(1H，s)
MSm/z：378(M
++H).
Embodiment 226:2,5-two bromo-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] pyridine
Under the argon atmospher, in ice-cold following 2,5-two bromo-4-[(2, the 5-difluorophenyl) hydroxymethyl] pyridine (9.3g, add in dichloromethane solution 24.5mmol) (200ml) triethylamine (5.1ml, 36.8mmol) and methylsulfonyl chloride (2.6ml, 31.9mmol), stirred 30 minutes under the room temperature.In reaction solution, add concentrating under reduced pressure behind the water, use extracted with diethyl ether.Organic layer saturated common salt water washing is with concentrated solution under the decompression behind the anhydrous magnesium sulfate drying.
In dimethyl formamide (200ml) solution of residue, add 4-chlorobenzene mercaptan (4.3g, 29.4mmol) and salt of wormwood (5.1g, 36.8mmol), stirring is 17 hours under the room temperature.Use extracted with diethyl ether after in reaction solution, adding water.Organic layer saturated common salt water washing is with concentrated solution under the decompression behind the anhydrous magnesium sulfate drying.The residue obtained hexane wash of using obtains white powder.Filtrate is handled with the silica gel flash column chromatography, and the cut that concentrating under reduced pressure is obtained by methylene dichloride wash-out portion merges with above-mentioned white powder, the title compound (9.1g, 18.0ml, 73%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：5.94(1H，s)，7.00-7.05(2H，m)，7.15-7.20(1H，m)，7.25(2H，d，J＝8.6Hz)，7.29(2H，d，J＝8.6Hz)，7.68(1H，s)，8.45(1H，s).
MSm/z：504(M
++H).
Embodiment 227:[5-bromo-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol
In-78 ℃, under argon atmospher 2,5-two bromo-4-[(4-chlorobenzene sulfenyls) (2, the 5-difluorophenyl) methyl] (200mg adds n-Butyl Lithium (1.59M hexane solution, 0.27ml in toluene 0.396mmol) (10ml) solution to pyridine, 0.435mmol), stirred 2 hours.(40 μ l 0.514mmol), stirred 1 hour to splash into dimethyl formamide in reaction soln.(30mg 0.791mmol), stirred 1 hour after being warming up to room temperature to add methyl alcohol (10ml), sodium borohydride in reaction soln.Use ethyl acetate extraction after in reaction solution, adding water, use the saturated common salt water washing again.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be the title compound (160mg, 0.350mmol, 89%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.18(1H，t，J＝5.2Hz)，4.72(2H，d，J＝5.2Hz)，6.04(1H，s)，6.95-7.05(2H，m)，7.16-7.21(1H，m)，7.22(2H，d，J＝7.8Hz)，7.25(2H，d，J＝7.8Hz)，7.51(1H，s)，8.64(1H，s).
MSm/z：456(M
++H).
Embodiment 228:[5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol
[5-bromo-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol (550mg, 1.20mmol) the mixing solutions of methyl alcohol (10ml), ethyl acetate (10ml) in add seven molybdic acids, six ammonium tetrahydrates (100mg), 30% aqueous hydrogen peroxide solution (10ml), stirred 19 hours.Use ethyl acetate extraction after in reaction solution, adding water, successively water, saturated sodium bicarbonate aqueous solution, saturated aqueous sodium thiosulfate and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains, use hexane again: re-crystallizing in ethyl acetate, the title compound (506mg, 1.04mmol, 86%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.18(1H，t，J＝5.0Hz)，4.79-4.88(2H，m)，6.24(1H，s)，6.92-6.97(1H，m)，7.03-7.09(1H，m)，7.45(2H，d，J＝8.6Hz)，7.51-7.55(1H，m)，7.61(2H，d，J＝8.6Hz)，8.11(1H，s)，8.65(1H，s).
IR(ATR)cm
-1：3262，1583，1492，1427，1392，1330，1280，1236，1157，1083，1033.
mp：172-173℃.
MSm/z：488(M
++H).
Ultimate analysis: C
19H
13BrClF
2NO
3S: theoretical value: C, 46.69; H, 2.68; Br, 16.35; Cl, 7.25; F, 7.77; N, 2.87; S, 6.56. measured value: C, 46.59; H, 2.55; Br, 16.31; Cl, 7.05; F, 7.78; N, 2.89; S, 6.70.
Embodiment 229:[5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] formaldehyde
Under the nitrogen atmosphere; [5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol (300mg; 0.614mmol) methylene dichloride (10ml) solution in add methyl-sulphoxide (218 μ l; 3.07mmol), triethylamine (428 μ l; 3.07mmol) and sulphur trioxide pyridine complex salt (293mg 1.84mmol), stirred under the room temperature 4 hours.The concentrating under reduced pressure reaction solution is residue obtainedly handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be the title compound (227mg, 0.466mmol, 76%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：6.29(1H，s)，6.93-7.00(1H，m)，7.04-7.10(1H，m)，7.44(2H，d，J＝8.8Hz)，7.57-7.62(1H，m)，7.62(2H，d，J＝8.8Hz)，8.68(1H，s)，8.88(1H，s)，10.09(1H，s).
MSm/z：486(M
++H).
Embodiment 230:5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine carboxylic acid
[5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (225mg, (157 μ l 1.39mmol), stirred 3 hours under the room temperature formaldehyde to add 30% aqueous hydrogen peroxide solution in formic acid 0.462mmol) (5ml) solution.In reaction soln, add water, filter the solid of separating out, wash solid with water.Make the gained solid be dissolved in ethyl acetate, successively water and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure, the title compound (226mg, 0.461mmol, 97%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.30(1H，s)，6.94-6.99(1H，m)，7.05-7.11(1H，m)，7.46(2H，d，J＝8.8Hz)，7.61-7.66(1H，m)，7.65(2H，d，J＝8.8Hz)，8.75(1H，s)，8.94(1H，s).
MSm/z：502(M
++H).
Embodiment 231:[5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] t-butyl carbamate
Under the argon atmospher; at 5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine carboxylic acid (220mg; 0.438mmol) the trimethyl carbinol (5ml) and the mixing solutions of toluene (5ml) in add diphenylphosphine acylazide (131 μ l; 0.613mmol), triethylamine (122 μ l; 0.875mmol), stirred 14 hours under the reflux.The cooling back adds ethyl acetate in residue, wash with saturated sodium bicarbonate aqueous solution and saturated aqueous common salt successively.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, the title compound (128mg, 0.223mmol, 51%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.59(9H，s)，6.23(1H，s)，6.92-7.00(1H，m)，7.02-7.08(1H，m)，7.33(1H，brs)，7.43(2H，d，J＝8.4Hz)，7.57-7.62(1H，m)，7.71(2H，d，J＝8.4Hz)，8.28(1H，s)，8.86(1H，s).
MSm/z：573(M
++H).
Embodiment 232:[5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
[5-bromo-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (130mg adds concentrated hydrochloric acid (2ml) in ethanol 0.227mmol) (2ml) solution to t-butyl carbamate, stirs 63 hours under the room temperature.Decompression is concentrated reaction solution down, adds saturated sodium bicarbonate in residue obtained, uses ethyl acetate extraction.Organic layer saturated common salt water washing is with concentrating under reduced pressure after the dried over mgso.The residue hexane: re-crystallizing in ethyl acetate, acquisition is the title compound (72mg, 0.152mmol, 67%) of pale yellow powder.
1H-NMR(400MHz，CDCl
3)δ：4.67(2H，s)，6.12(1H，s)，6.91-6.97(1H，m)，7.02-7.08(1H，m)，7.36(1H，s)，7.45(2H，d，J＝8.6Hz)，7.48-7.54(1H，m)，7.62(2H，d，J＝8.6Hz)，8.11(1H，s).
IR(ATR)cm
-1：3467，3372，1617，1585，1540，1492，1475，1413，1330，1311，1280，1238，1178，1151，1081，1033，1012.
mp：204-206℃.
MSm/z：473(M
++H).
Ultimate analysis: C
18H
12BrClF
2N
2O
2S: theoretical value: C, 45.64; H, 2.55; Br, 16.87; Cl, 7.48; F, 8.02; N, 5.91; S, 6.77. measured value: C, 45.87; H, 2.58; Br, 16.61; Cl, 7.56; F, 8.05; N, 5.90; S, 6.90.
Reference example 42:5-cyano group-2-fluorobenzaldehyde
With Diisopropylamine (2.80ml 19.8mmol) is dissolved in tetrahydrofuran (THF) (20ml), in-78 ℃ of hexane solutions that drip n-Butyl Lithiums (1.60M, 11.4ml, 18.2mmol).Under the uniform temp reaction solution stirring after 30 minutes, is dripped 4-fluorobenzonitrile (2.00g, tetrahydrofuran solution 16.5mmol) (20ml).Uniform temp stirs after 30 minutes down, splashes into N in reaction solution, and (1.7ml, 21.5mmol), uniform temp stirred 10 minutes down dinethylformamide.In reaction solution, add acetate, saturated aqueous ammonium chloride, use ethyl acetate extraction.With the organic layer that anhydrous sodium sulfate drying merges, filter back concentrating under reduced pressure filtrate.With silica gel chromatography the gained concentrated residue is handled, concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=10: 2 wash-out portion obtains obtains to be the title compound (1.83g, 12.3mmol, 74%) of khaki oily matter.
1H-NMR(400MHz，CD
3OD)δ：7.37(1H，t，J＝9.0Hz)，7.92(1H，ddd，J＝9.0，6.4，2.2Hz)，8.21(1H，dd，J＝6.4，2.2Hz)，10.4(1H，s).
IR(ATR)cm
-1：1953，1695，1600，1482，1236，1105，846，624，580.
MSm/z：150(M
++H).
Reference example 43:3-[(2,5-dichloropyridine-4-yl) hydroxymethyl]-the 4-fluorobenzonitrile
With Diisopropylamine (0.52ml 3.70mmol) is dissolved in tetrahydrofuran (THF) (5ml), in-78 ℃ of hexane solutions that drip n-Butyl Lithiums (1.54M, 2.20ml, 3.39mmol).Under the uniform temp reaction solution stirring after 30 minutes, is dripped 2,5-dichloropyridine (0.46g, tetrahydrofuran solution 3.08mmol) (20ml).Uniform temp stirs after 1 hour down, and (uniform temp stirred 30 minutes down for 0.46g, tetrahydrofuran solution 3.08mmol) (5ml) to splash into 5-cyano group-2-fluorobenzaldehyde in reaction solution.In reaction solution, add saturated aqueous ammonium chloride, use ethyl acetate extraction.With the organic layer that anhydrous sodium sulfate drying merges, filter back concentrating under reduced pressure filtrate.With silica gel chromatography the gained concentrated residue is handled, concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=10: 2 wash-out portion obtains obtains to be the title compound (0.68g, 2.28mmol, 74%) of khaki oily matter.
1H-NMR(400MHz，CDCl
3)δ：6.33(1H，s)，7.22(1H，t，J＝8.3Hz)，7.60(1H，dd，J＝6.6，2.2Hz)，7.66(1H，s)，7.66-7.69(1H，m)，8.34(1H，s).
IR(ATR)cm
-1：3413，1577，1492，1334，1247，1110，829，534.
MSm/z：297(M
++H).
Embodiment 233:3-[(4-chloro-phenyl-alkylsulfonyl) (2,5-dichloropyridine-4-yl) methyl]-the 4-fluorobenzonitrile
Under ice-cold, at 3-[(2,5-dichloropyridine-4-yl) hydroxymethyl]-(N that adds thionyl chloride (3ml) and catalytic amount among the 677mg, dichloromethane solution 2.28mmol) (5ml), dinethylformamide stirred 4 hours under the room temperature 4-fluorobenzonitrile.In reaction solution, add water, use dichloromethane extraction.With the organic layer that anhydrous sodium sulfate drying merges, filter back concentrating under reduced pressure filtrate.
The gained concentrated residue is dissolved in N, dinethylformamide (5ml), (905mg 4.56mmol), stirred 20 hours under the room temperature to add 4-chlorobenzene-sulfinic acid sodium again.In reaction solution, add water, use ethyl acetate extraction.With the organic layer that anhydrous sodium sulfate drying merges, filter back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with silica gel chromatography, and concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=10: 2 wash-out portion obtains obtains to be khaki solid title compound (170mg, 0.37mmol, 16%).
1H-NMR(400MHz，CDCl
3)δ：6.19(1H，s)，7.15(1H，t，J＝8.5Hz)，7.48(2H，d，J＝8.5Hz)，7.62(2H，d，J＝8.5Hz)，7.72(1H，ddd，J＝8.5，5.4，2.4Hz)，8.12(1H，dd，J＝5.4，2.4Hz)，8.13(1H，s)，8.36(1H，s).
IR(ATR)cm
-1：1569，1494，1315，1257，1120，1081，752，617，570，536.
MSm/z：456(M
+).
Embodiment 234:3-[(2-amino-5-chloropyridine-4-yl) (4-chloro-phenyl-alkylsulfonyl) methyl]-the 4-fluorobenzonitrile
With 3-[(4-chloro-phenyl-alkylsulfonyl) (2,5-dichloropyridine-4-yl) methyl]-(559mg 1.23mmol) is dissolved in N-Methyl pyrrolidone (12ml) to the 4-fluorobenzonitrile; add 3; 4-dimethoxy benzene methanamine (0.91ml, 6.13mmol), in 140 ℃ of heated and stirred 4 hours.In reaction mixture, add water, use ethyl acetate extraction, with organic layer anhydrous sodium sulfate drying after the saturated common salt water washing.Filter back concentrating under reduced pressure filtrate, residue obtainedly handle with silica gel chromatography, concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains.
The gained concentrated residue is dissolved in trifluoroacetic acid (5ml), in 70 ℃ of heated and stirred 2 hours.The concentrating under reduced pressure reaction mixture, the gained concentrated residue is handled with silica gel chromatography, and concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains, the title compound (50mg, 0.11mmol, 9%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：4.74(2H，s)，6.16(1H，s)，7.12(1H，t，J＝8.8Hz)，7.32(1H，s)，7.48(2H，d，J＝8.5Hz)，7.62(2H，d，J＝8.5Hz)，7.98(1H，s)，8.15(1H，dd，J＝8.8，2.0Hz)，8.55(1H，d，J＝2.0Hz).
IR(ATR)cm
-1：1614，1475，1411，1311，1259，1145，1091，755，642，620，561，543，460.
mp：＞220℃.
MSm/z：436(M
++H).
Ultimate analysis: C
19H
12Cl
2FN
3O
2S: theoretical value: C, 52.31; H, 2.77; Cl, 16.25; F, 4.35; N, 9.63; S, 7.35. measured value: C, 52.17; H, 2.85; Cl, 16.50; F, 4.32; N, 9.40; S, 7.30.
Embodiment 235:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (5-cyano group-2-fluorophenyl) methyl] pyridine-2-yl]-N-(methyl sulphonyl) Toluidrin
With 3-[(2-amino-5-chloropyridine-4-yl) (4-chloro-phenyl-alkylsulfonyl) methyl]-4-fluorobenzonitrile (50mg; 0.11mmol) be dissolved in methylene dichloride (5ml) after; add methylsulfonyl chloride (27 μ l in 0 ℃; 0.39mmol), triethylamine (48 μ l; 0.39mmol) and the 4-dimethylaminopyridine of catalytic amount, uniform temp stirred 30 minutes down.In reaction mixture, add water, use dichloromethane extraction,, filter back concentrating under reduced pressure filtrate with organic layer anhydrous sodium sulfate drying after the saturated common salt water washing.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=10: 3 wash-out portion obtains, the title compound (80mg, 0.11mmol, 99%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.65(6H，s)，6.25(1H，s)，7.24(1H，t，J＝8.8Hz)，7.45(2H，d，J＝8.5Hz)，7.66(2H，d，J＝8.5Hz)，7.75(1H，ddd，J＝8.8，6.6，2.0Hz)，8.16(1H，s)，8.19(1H，dd，J＝6.6，2.0Hz)，8.43(1H，s).
IR(ATR)cm
-1：1725，1583，1492，1369，1326，1164，931，835，757，628，551，505，460.
MSm/z：592(M
++H).
Embodiment 236:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (5-cyano group-2-fluorophenyl) methyl] pyridine-2-yl] Toluidrin
With N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (5-cyano group-2-fluorophenyl) methyl] pyridine-2-yl]-N-(methyl sulphonyl) Toluidrin (80mg; 0.11mmol) be dissolved in tetrahydrofuran (THF) (3ml) after; in 0 ℃ of tetrahydrofuran solution (1.0M that adds tetrabutylammonium; 0.15ml, 0.15mmol) stirred 1 hour under the room temperature.The concentrating under reduced pressure reaction mixture, the gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by normal hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains obtains white solid.With the white solid of ether washing gained, the title compound (32mg, 0.06mmol, 46%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：3.37(3H，s)，6.20(1H，s)，7.14(1H，d，J＝8.8Hz)，7.48(2H，d，J＝8.5Hz)，7.62(2H，d，J＝8.5Hz)，7.68-7.72(1H，m)，7.92(1H，s)，8.11(1H，dd，J＝6.6，2.0Hz)，8.34(1H，s).
IR(ATR)cm
-1：1596，1494，1473，1328，1151，1089，755，636，541，516.
mp：118-120℃.
MSm/z：514(M
++H).
Ultimate analysis: C
20H
14Cl
2FN
3O
4S
2: theoretical value: C, 46.70; H, 2.74; Cl, 13.78; F, 3.69; N, 8.17; S, 12.47. measured value: C, 47.00; H, 2.94; Cl, 13.64; F, 3.58; N, 8.15; S, 12.44.
Reference example 44:5-chloro-2-(2,2,5,5-tetramethyl--1,2,5-azepine two silas pentamethylene-1-yl) pyridine
In-78 ℃, (10.28g, (1.58M, 50.6ml 80.0mmol), stirred 1 hour the hexane solution of adding n-Butyl Lithium in tetrahydrofuran (THF) 80.0mmol) (350ml) solution at 5-chloropyridine-2-base amine.Add 1 under uniform temp, (17.22g, tetrahydrofuran (THF) 80.0mmol) (50ml) solution stirred 1 hour two (Chlorodimethyl silyl) ethane of 2-.Then, (1.58M, 50.6ml 80.0mmol), stir and add saturated sodium-chloride water solution under the room temperature after 30 minutes to add the hexane of n-Butyl Lithium under uniform temp.Add ether in reaction mixture, organic layer anhydrous sodium sulfate drying behind the separatory filters back concentrating under reduced pressure filtrate.Carry out (120 ℃/3.0mmHg), obtain to be the title compound (12.97g, 47.9mmol, 60%) of colourless spicule of underpressure distillation to residue obtained.
1H-NMR(400MHz，CDCl
3)δ：0.29(12H，s)，0.82(4H，s)，6.50(1H，d，J＝8.8Hz)，7.34(1H，dd，J＝8.8，2.7Hz)，8.05(1H，d，J＝2.7Hz).
Reference example 45:(2-amino-5-chloropyridine-4-yl) (2, the 5-difluorophenyl) methyl alcohol
In-78 ℃, the hexane solution of n-Butyl Lithium (1.58M, 8.41ml, 13.3mmol) and add in the mixture of tetrahydrofuran (THF) (40ml) Diisopropylamine (1.86ml, 13.3mmol).In 0 ℃ reaction mixture carried out stirred in 1 hour after, be cooled to-78 ℃, add 5-chloro-2-(2,2,5,5-tetramethyl--1,2,5-azepine two silas pentamethylene-1-yl) pyridine (3.27g, tetrahydrofuran (THF) 12.1mmol) (10ml) solution.Under uniform temp, stir after 1 hour, add 2,5-difluorobenzaldehyde (1.89g, tetrahydrofuran (THF) 13.3mmol) (10ml) solution.Under uniform temp, stir after 30 minutes, add 1N hydrochloric acid (50ml) in 0 ℃.Add 1N aqueous sodium hydroxide solution (100ml) in reaction mixture after, use the extracted with diethyl ether resultant, the organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Wash the back leaching with the mixed solvent of dichloromethane/hexane to residue obtained, obtain to be white in color solid title compound (1.76g, 6.50mmol, 54%).
1H-NMR(400MHz，DMSO-d
6)δ：5.96(1H，d，J＝4.9Hz)，6.17(2H，s)，6.31(1H，d，J＝4.9Hz)，6.68(1H，s)，6.97-7.04(1H，m)，7.15-7.29(2H，m)，7.82(1H，s).
MSm/z：271(M
++H).
Reference example 46: carbonic acid (2-amino-5-chloropyridine-4-yl) (2, the 5-difluorophenyl) the methyl esters tert-butyl ester
Under the nitrogen atmosphere, (4.50g adds tert-Butyl dicarbonate (3.63g in methylene dichloride 16.6mmol) (150ml) solution at (2-amino-5-chloropyridine-4-yl) (2, the 5-difluorophenyl) methyl alcohol in room temperature, 16.6mmol) and 4-dimethylaminopyridine (203mg, 1.66mmol).Stir concentrating under reduced pressure reaction mixture after 2 hours under the room temperature, handle with the flash chromatography on silica gel method residue obtained.Concentrating under reduced pressure is by methylene dichloride: the cut that methyl alcohol=50: 1 wash-out portion obtains obtains to be white in color solid title compound (5.70g, 15.4mmol, 92%).
1H-NMR(400MHz，CDCl
3)δ：1.49(9H，s)，4.53(2H，s)，6.66(1H，s)，6.89-6.95(1H，m)，6.99-7.09(2H，m)，7.00(1H，s)，8.01(1H，s).
MSm/z：371(M
++H).
Reference example 47:[5-chloro-4-[(2, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate
Under the nitrogen atmosphere, in 0 ℃ at carbonic acid (2-amino-5-chloropyridine-4-yl) (2, the 5-difluorophenyl) the methyl esters tert-butyl ester (5.70g, 15.4mmol) tetrahydrofuran (THF) (80ml) solution in add the tetrahydrofuran solution (1M of two (trimethyl silyl) amido sodium, 33.8mmol, 33.8mmol), add tert-Butyl dicarbonate (3.69g, tetrahydrofuran (THF) 16.9mmol) (20ml) solution then.Under the room temperature reaction mixture stirring after 30 minutes, is added saturated aqueous ammonium chloride, the resultant dichloromethane extraction in reaction mixture.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.
In the residue obtained mixed solvent that is dissolved in tetrahydrofuran (THF) (50ml) and methyl alcohol (50ml), add 1N sodium hydroxide (50ml) under the room temperature.In 50 ℃ reaction mixture stirred 2 hours after concentrating under reduced pressure, the resultant dichloromethane extraction.Residue washs with the mixed solvent of ethanol/hexane, and leaching obtains to be white in color solid title compound (3.49g, 9.41mmol, 61%).Concentrating under reduced pressure filtrate, residue obtained mixed solvent washing back leaching with ethanol/ether/hexane obtains to be white in color solid title compound (828mg, 2.23mmol, 15%).
1H-NMR(400MHz，CDCl
3)δ：1.54(9H，s)，2.69(1H，d，J＝4.9Hz)，6.32(1H，d，J＝4.9Hz)，6.88-7.08(3H，m)，7.81(1H，s)，8.17(1H，s)，8.33(1H，s).
MSm/z：371(M
++H).
Reference example 48: dithiocarbonic acid S-(4-chloro-3-p-methoxy-phenyl) ester O-ethyl ester
(2.77g 17.6mmol) is dissolved in 1N hydrochloric acid (80ml), and (1.33g, behind water 19.3mmol) (10ml) solution, uniform temp stirred 30 minutes down to drip Sodium Nitrite in 0 ℃ with 4-chloro-3-anisidine.After reaction mixture is warming up to 60 ℃, under uniform temp, drip dithiocarbonic acid O-ethyl ester potassium (3.10g, water 19.3mmol) (30ml) solution.Reaction mixture is warming up to 90 ℃, stirs after 1 hour, be cooled to room temperature, add saturated sodium bicarbonate aqueous solution, the resultant ethyl acetate extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, residue obtainedly handles with the silica gel flash column chromatography.Concentrating under reduced pressure is by hexane: the cut that methylene dichloride=9: 1 wash-out portion obtains obtains to be the title compound (1.05g, 4.00mmol, 23%) of yellow oil.
1H-NMR(400MHz，CDCl
3)δ：1.35(3H，t，J＝7.1Hz)，3.91(3H，s)，4.62(2H，q，J＝7.1Hz)，7.03-7.08(2H，m)，7.41(1H，d，J＝8.1Hz).
MSm/z：263(M
++H).
Embodiment 237:[5-chloro-4-[(4-chloro-3-anisole sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] t-butyl carbamate
(394mg adds 1N aqueous sodium hydroxide solution (5ml), reflux 1 hour in ethanol 1.50mmol) (5ml) solution at dithiocarbonic acid S-(4-chloro-3-p-methoxy-phenyl) ester O-ethyl ester.Reaction mixture is cooled to room temperature, the decompression under boil off ethanol after, use washed with dichloromethane.After making water layer be acidity with acetate, the resultant dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, obtains to be the 4-chloro-3-anisole mercaptan of colorless oil.
In 0 ℃ of [5-chloro-4-[(2 that obtains at reference example 47, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (371mg, 1.00mmol) dichloromethane solution in add methylsulfonyl chloride (0.155ml, 2.00mmol), add triethylamine (0.418ml again, 3.00mmol), stirred 2 hours under the room temperature.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
Under the nitrogen atmosphere,, add the N of the previous 4-chloro-3-anisole mercaptan that obtains in dinethylformamide (10ml) solution at residue obtained N, dinethylformamide (5ml) solution, (207mg 1.50mmol), stirred 20 hours under the room temperature to add salt of wormwood again.In reaction mixture, add ethyl acetate,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=19: 1 wash-out portion obtains obtains to be white in color solid title compound (354mg, 0.67mmol, 67%).
1H-NMR(400MHz，CDCl
3)δ：1.55(9H，s)，3.81(3H，s)，6.07(1H，s)，6.91-7.08(3H，m)，6.97(1H，dd，J＝7.8，2.0Hz)，7.00(1H，d，J＝2.0Hz)，7.23(1H，d，J＝7.8Hz)，7.86(1H，s)，8.18(1H，s)，8.55(1H，s).
MSm/z：527(M
++H).
Embodiment 238:[5-chloro-4-[(4-chloro-3-p-methoxy-phenyl alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] t-butyl carbamate
[5-chloro-4-[(4-chloro-3-anisole sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] t-butyl carbamate (354mg, 0.67mmol) ethyl acetate (8ml) solution in add methyl alcohol (8ml), 31% aqueous hydrogen peroxide solution (8ml) and seven molybdic acids, six ammonium tetrahydrate (166mg, 0.13mmol), stirred 20 hours under the room temperature.In reaction mixture, add water, add saturated sodium bicarbonate aqueous solution, the resultant dichloromethane extraction after boiling off ethyl acetate and methyl alcohol under the decompression.The organic layer anhydrous sodium sulfate drying, filter back concentrating under reduced pressure filtrate, residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains, residue obtained mixed solvent with ether/hexane washs the back leaching, the acquisition solid title compound (308mg, 0.55mmol, 82%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：1.58(9H，s)，3.82(3H，s)，6.27(1H，s)，6.94-7.09(2H，m)，7.24(1H，d，J＝2.0Hz)，7.36(1H，dd，J＝8.3，2.0Hz)，7.46(1H，d，J＝8.3Hz)，7.56-7.62(2H，s)，8.18(1H，s)，8.89(1H，s).
MSm/z：559(M
++H).
Embodiment 239:[5-chloro-4-[(4-chloro-3-p-methoxy-phenyl alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
In 0 ℃; [5-chloro-4-[(4-chloro-3-p-methoxy-phenyl alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] (300mg adds trifluoroacetic acid (5ml) in methylene dichloride 0.54mmol) (5ml) solution to t-butyl carbamate, stirs 2 hours under the room temperature.Behind the concentrating under reduced pressure reaction mixture, residue is dissolved in methylene dichloride, washs with the 1N aqueous sodium hydroxide solution.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, and is residue obtained with ether washing back leaching, obtains to be white in color solid title compound (208mg, 0.45mmol, 84%).
1H-NMR(400MHz，CDCl
3)δ：3.82(3H，s)，4.66(2H，s)，6.14(1H，s)，6.91-6.98(1H，m)，7.02-7.09(1H，m)，7.09(1H，d，J＝2.0Hz)，7.25(1H，dd，J＝8.3，2.0Hz)，7.34(1H，s)，7.46(1H，d，J＝8.3Hz)，7.51-7.57(1H，s)，7.99(1H，s).
IR(ATR)cm
-1：3151，1645，1595，1481，1414，1390，1325，1254，1140，1055，1026.
mp：198-200℃.
Ultimate analysis: C
19H
14Cl
2F
2N
2O
3S: theoretical value: C, 49.69; H, 3.07; Cl, 15.44; F, 8.27; N, 6.10; S, 6.98. measured value: C, 49.56; H, 3.03; Cl, 15.29; F, 8.58; N, 6.08; S, 7.07.
MSm/z：459(M
++H).
Embodiment 240:[5-chloro-4-[(2, the 5-difluorophenyl) (4-p-methoxy-phenyl alkylsulfonyl) methyl] pyridine-2-yl] amine
In 0 ℃, [5-chloro-4-[(2 in reference example 47 acquisitions, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (148mg, 0.40mmol) dichloromethane solution in add methylsulfonyl chloride (0.046ml, 0.60mmol), (0.167ml 1.20mmol), stirred 16 hours under the room temperature to add triethylamine again.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
Under the nitrogen atmosphere, at residue obtained N, (56mg, 0.40mmol), (66mg 0.48mmol), stirred 19 hours under the room temperature to add salt of wormwood again to add 4-anisole mercaptan in dinethylformamide (4ml) solution earlier.In reaction mixture, add ethyl acetate,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.
(99mg 0.08mmol), stirred 20 hours under the room temperature to add methyl alcohol (8ml), 31% aqueous hydrogen peroxide solution (4ml) and seven molybdic acids, six ammonium tetrahydrates in residue obtained ethyl acetate (8ml) solution.In reaction mixture, add water, add saturated sodium bicarbonate aqueous solution, the resultant dichloromethane extraction after boiling off ethyl acetate and methyl alcohol under the decompression.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.
In 0 ℃, in residue obtained methylene dichloride (3ml) solution, add trifluoroacetic acid (3ml), stirred 2 hours under the room temperature.Behind the reaction mixture concentrating under reduced pressure, residue is dissolved in methylene dichloride, wash with saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying, filter back concentrating under reduced pressure filtrate, handle residue obtained with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 2 wash-out portion obtains, residue obtained mixed solvent washing back leaching with ether/hexane, the acquisition solid title compound (67mg, 0.16mmol, 40%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：3.87(3H，s)，4.63(2H，s)，6.10(1H，s)，6.87-6.94(1H，m)，6.90(2H，d，J＝8.8Hz)，6.98-7.06(1H，m)，7.31(1H，s)，7.51-7.57(1H，m)，7.59(2H，d，J＝8.8Hz)，7.97(1H，s).
IR(ATR)cm
-1：3469，3294，3172，1630，1593，1491，1419，1327，1261，1244，1230，1142，1092.
mp：153-155℃.
Ultimate analysis: C
19H
15ClF
2N
2O
3S: theoretical value: C, 53.71; H, 3.56; Cl, 8.34; F, 8.94; N, 6.59; S, 7.55. measured value: C, 53.53; H, 3.55; Cl, 8.34; F, 9.06; N, 6.31; S, 7.79.
MSm/z：425(M
++H).
Embodiment 241:[5-chloro-4-[(5-chloropyridine-2-base alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
Adopt the method same with embodiment 240, [5-chloro-4-[(2 with reference example 47 acquisitions, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (148mg, 0.40mmol) and the 5-chloro-2-pyridine mercaptan (58mg that obtains of reference example 17,0.40mmol), the acquisition solid title compound (74mg, 0.17mmol, 43%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.62(2H，s)，6.77(1H，s)，6.95-7.08(2H，m)，7.28(1H，s)，7.40-7.47(1H，m)，7.82-7.84(2H，m)，8.00(1H，s)，8.68-8.70(1H，m).
IR(ATR)cm
-1：3427，3317，3199，1635，1491，1477，1327，1238，1163，1113，1018.
mp：187-189℃.
Ultimate analysis: C
17H
11Cl
2F
2N
3O
2S: theoretical value: C, 47.46; H, 2.58; Cl, 16.48; F, 8.83; N, 9.77; S, 7.45. measured value: C, 47.43; H, 2.64; Cl, 16.52; F, 8.98; N, 9.69; S, 7.71.
MSm/z：430(M
++H).
Embodiment 242:N-[5-chloro-4-[(5-chloropyridine-2-base alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] Toluidrin
Under the argon atmospher; in 0 ℃ [5-chloro-4-[(5-chloropyridine-2-base alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (92mg; 0.21mmol) tetrahydrofuran (THF) (4ml) solution in add the tetrahydrofuran solution (1M of two (trimethylsilyl) amido sodium; 0.705ml; 0.71mmol), stirred 30 minutes.Then, (0.055ml 0.71mmol), stirs after 2 hours under uniform temp and is warming up to room temperature to add methylsulfonyl oxygen.In reaction mixture, add saturated aqueous ammonium chloride, the resultant extracted with diethyl ether.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with the silica gel flash column chromatography.Concentrating under reduced pressure is by methylene dichloride: the cut that ethyl acetate=19: 1 wash-out portion obtains, wash the back leaching with the mixed solvent of ethanol/hexane to residue obtained, the acquisition solid title compound (27mg, 0.053mmol, 25%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：3.32(3H，s)，6.86(1H，s)，6.98-7.09(2H，m)，7.36-7.43(1H，m)，7.75(1H，s)，7.85(1H，dd，J＝8.3，2.2Hz)，7.90(1H，d，J＝8.3Hz)，7.93(1H，s)，8.32(1H，s)，8.67(1H，d，J＝2.2Hz).
IR(ATR)cm
-1：1603，1568，1493，1389，1329，1240，1144，1109.
mp：214-216℃.
Ultimate analysis: C
18H
13Cl
2F
2N
3O
4S
2: theoretical value: C, 42.53; H, 2.58; Cl, 13.95; F, 7.47; N, 8.27; S, 12.62. measured value: C, 42.56; H, 2.56; Cl, 14.03; F, 7.54; N, 8.23; S, 12.58.
MSm/z：508(M
++H).
Reference example 49:5-chlorothiophene-2-mercaptan
In 75 ℃, (0.557ml adds tin protochloride (3.03g, 1N hydrochloric acid (3ml) solution 16.0mmol) in acetate 4.00mmol) (15ml) solution in 5-chlorothiophene-2-SULPHURYL CHLORIDE.Then, reaction mixture is cooled to room temperature, adds resultant dichloromethane extraction behind the water.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, adds toluene, concentrating under reduced pressure once more in residue obtained.Residue obtained with ether washing back leaching, obtain to be the title compound (89mg, 0.65mmol, 16%) of yellow solid.Concentrating under reduced pressure filtrate, residue obtained mixed solvent washing back leaching with ether/hexane, acquisition is the title compound (118mg, 0.78mmol, 20%) of yellow solid.
1H-NMR(400MHz，CDCl
3)δ：6.81(1H，d，J＝3.9Hz)，6.85(1H，d，J＝3.9Hz).
Embodiment 243:[5-chloro-4-[(5-chlorothiophene-2-base alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
Adopt the method same with embodiment 240, [5-chloro-4-[(2 with reference example 47 acquisitions, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (148mg, 0.40mmol) and 5-chlorothiophene-2-mercaptan (90mg, 0.60mmol), the acquisition solid title compound (96mg, 0.22mmol, 55%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.66(2H，s)，6.25(1H，s)，6.93(1H，d，J＝4.2Hz)，6.97-7.11(2H，m)，7.28(1H，s)，7.29(1H，d，J＝4.2Hz)，7.47-7.53(1H，m)，8.02(1H，s).
IR(ATR)cm
-1：3438，3180，1643，1595，1543，1485，1404，1315，1242，1138，993.
mp：170-171℃.
Ultimate analysis: C
16H
10Cl
2F
2N
2O
2S
2: theoretical value: C, 44.15; H, 2.32; Cl, 16.29; F, 8.73; N, 6.44; S, 14.73. measured value: C, 44.22; H, 2.41; Cl, 16.00; F, 8.77; N, 6.46; S, 14.81.
MSm/z：435(M
++H).
Embodiment 244:[5-chloro-4-[(6-chloropyridine-3-base sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] t-butyl carbamate
Adopt the method same with embodiment 237, dithiocarbonic acid S-(6-chloropyridine-3-yl) ester O-ethyl ester (187mg with reference example 26 acquisitions, 0.80mmol) and [the 5-chloro-4-[(2 that obtains of reference example 47, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (151mg, 0.41mmol), the acquisition solid title compound (190mg, 0.38mmol, 94%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：1.56(9H，s)，6.01(1H，s)，6.93-7.08(3H，m)，7.22(1H，d，J＝8.3Hz)，7.42(1H，s)，7.71(1H，dd，J＝8.3，2.5Hz)，8.16(1H，s)，8.37(1H，d，J＝2.5Hz)，8.50(1H，s).
MSm/z：498(M
++H).
Embodiment 245:[5-chloro-4-[(6-chloropyridine-3-base alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
Under the room temperature, [5-chloro-4-[(6-chloropyridine-3-base sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (187mg adds 3-chlorine peroxybenzoic acid (199mg to t-butyl carbamate in methylene dichloride 0.38mmol) (5ml) solution, 0.75mmol), stirred 2 hours.After reaction mixture was washed with the 1N aqueous sodium hydroxide washes, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
With the residue obtained methylene dichloride (3ml) that is dissolved in,, stirred 1 hour under the room temperature in 0 ℃ of adding trifluoroacetic acid (3ml).Behind the concentrating under reduced pressure reaction mixture, residue is dissolved in methylene dichloride, washs with the 1N aqueous sodium hydroxide washes.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, residue obtainedly handles with the silica gel flash column chromatography.Concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains, residue obtained mixed solvent with ethanol/hexane washs the back leaching, the acquisition solid title compound (90mg, 0.21mmol, 55%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.68(2H，s)，6.15(1H，s)，6.93-7.00(1H，m)，7.05-7.12(1H，m)，7.29(1H，s)，7.44(1H，d，J＝8.3Hz)，7.48-7.54(1H，m)，7.91(1H，dd，J＝8.3，2.4Hz)，8.01(1H，s)，8.58(1H，d，J＝2.4Hz).
IR(ATR)cm
-1：3342，3167，1495，1479，1331，1240，1161，1115.
mp：157-158℃.
Ultimate analysis: C
17H
11Cl
2F
2N
3O
2S: theoretical value: C, 47.46; H, 2.58; Cl, 16.48; F, 8.83; N, 9.77; S, 7.45. measured value: C, 47.24; H, 2.59; Cl, 16.50; F, 8.80; N, 9.82; S, 7.61.
MSm/z：430(M
++H).
Embodiment 246:4-[(2-amino-5-chloropyridine-4-yl) (2, the 5-difluorophenyl) methyl sulphonyl] cyanobenzene
Adopt the method same with embodiment 240, [5-chloro-4-[(2 with reference example 47 acquisitions, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (148mg, 0.40mmol) and 4-sulfydryl cyanobenzene (56mg, 0.41mmol), the acquisition solid title compound (99mg, 0.24mmol, 59%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.68(2H，s)，6.15(1H，s)，6.89-6.96(1H，m)，7.03-7.10(1H，m)，7.31(1H，s)，7.49-7.55(1H，m)，7.76(2H，d，J＝8.5Hz)，7.81(2H，d，J＝8.5Hz)，7.99(1H，s).
IR(ATR)cm
-1：3388，1618，1495，1415，1331，1149.
mp：233-235℃.
Ultimate analysis: C
19H
12ClF
2N
3O
2S: theoretical value: C, 54.36; H, 2.88; Cl, 8.44; F, 9.05; N, 10.01; S, 7.64. measured value: C, 54.41; H, 2.93; Cl, 8.41; F, 8.92; N, 9.92; S, 7.69.
MSm/z：420(M
++H).
Embodiment 247:[5-chloro-4-[(2, the 5-difluorophenyl) (3,4-difluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] amine
Adopt the method same with embodiment 240, [5-chloro-4-[(2 with reference example 47 acquisitions, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (185mg, 0.50mmol) and 3, (84mg 0.55mmol), obtains to be white in color solid title compound (59mg to 4-difluoro benzenethiol, 0.14mmol, 27%).
1H-NMR(400MHz，CDCl
3)δ：4.67(2H，s)，6.13(1H，s)，6.91-6.98(1H，m)，7.03-7.10(1H，m)，7.23-7.31(1H，m)，7.31(1H，s)，7.45-7.55(3H，m)，8.00(1H，s).
IR(ATR)cm
-1：3452，3168，1635，1599，1493，1415，1325，1281，1244，1144，1120.
mp：140-141℃.
Ultimate analysis: C
18H
11ClF
4N
2O
2S: theoretical value: C, 50.18; H, 2.57; Cl, 8.23; F, 17.64; N, 6.50; S, 7.44. measured value: C, 50.12; H, 2.60; Cl, 8.25; F, 17.35; N, 6.51; S, 7.58.
MSm/z：431(M
++H).
Embodiment 248:N-[5-chloro-4-[(2, the 5-difluorophenyl) (3,4-difluorophenyl alkylsulfonyl) methyl] pyridine-2-yl]-N-(methyl sulphonyl) Toluidrin
Under the nitrogen atmosphere; in 0 ℃ at [5-chloro-4-[(2; the 5-difluorophenyl) (3; 4-difluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] amine (63mg; 0.15mmol) methylene dichloride (3ml) solution in add methylsulfonyl chloride (0.034ml, 0.44mmol), triethylamine (0.062ml, 0.44mmol) and 4-dimethylaminopyridine (4mg; 0.03mmol), stirred 17 hours under the room temperature.After reaction mixture was used 1N salt acid elution, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains obtains to be white in color solid title compound (73mg, 0.12mmol, 85%).
1H-NMR(400MHz，CDCl
3)δ：3.63(6H，s)，6.22(1H，s)，7.02-7.16(2H，m)，7.22-7.31(1H，m)，7.45-7.51(2H，m)，7.56-7.62(1H，m)，8.17(1H，s)，8.45(1H，s).
MSm/z：587(M
++H).
Embodiment 249:N-[5-chloro-4-[(2, the 5-difluorophenyl) (3,4-difluorophenyl alkylsulfonyl) methyl] pyridine-2-yl] Toluidrin
Under the nitrogen atmosphere; at N-[5-chloro-4-[(2; the 5-difluorophenyl) (3; 4-difluorophenyl alkylsulfonyl) methyl] pyridine-2-yl]-N-(methyl sulphonyl) Toluidrin (72mg; 0.12mmol) tetrahydrofuran (THF) (2ml) solution in add the tetrahydrofuran solution (1M of tetrabutylammonium; 0.147ml, 0.15mmol), stirred 2 hours under the room temperature.Behind the concentrating under reduced pressure reaction mixture,, with 1N salt acid elution, wash with saturated aqueous ammonium chloride more earlier the residue obtained ethyl acetate that is dissolved in.The organic layer anhydrous sodium sulfate drying, filter back concentrating under reduced pressure filtrate, residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=3: 1 wash-out portion obtains, residue obtained mixed solvent with ether/hexane washs the back leaching, the acquisition solid title compound (53mg, 0.10mmol, 84%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：3.35(3H，s)，6.19(1H，s)，6.92-6.99(1H，m)，7.04-7.12(1H，m)，7.25-7.32(1H，m)，7.44-7.60(3H，m)，7.98(1H，s)，7.99(1H，s)，8.34(1H，s).
IR(ATR)cm
-1：1599，1495，1468，1333，1281，1146，1003，970.
mp：118-120℃.
MSm/z：509(M
++H).
FAB-MS:509.0044 (presses C
19H
14ClF
4N
2O
4S
2Calculate: 509.0020).
Reference example 50: dithiocarbonic acid O-ethyl ester S-(6-5-flumethiazine-3-yl) ester
With the 6-5-flumethiazine-(1.00g 6.02mmol) is dissolved in 1N hydrochloric acid (15ml) and methyl alcohol (3ml) to 3-base amine, drips Sodium Nitrite (506mg, water 7.22mmol) (3ml) solution in-10 ℃.Reaction mixture is splashed into the dithiocarbonic acid O-ethyl ester potassium of heating to 65 ℃, and (uniform temp stirred 30 minutes down for 1.93g, water 12.0mmol) (15ml) solution.After reaction mixture was cooled to room temperature, the resultant ethyl acetate extraction was used the saturated common salt water washing again.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=100: 1 wash-out portion obtains obtains to be the title compound (895mg, 3.35mmol, 56%) of yellow oil.
1H-NMR(400MHz，CDCl
3)δ：1.38(3H，t，J＝7.1Hz)，4.65(2H，q，J＝7.1Hz)，7.76(1H，d，J＝8.1Hz)，8.01(1H，dd，J＝8.1，2.0Hz)，8.79(1H，d，J＝2.0Hz).
MSm/z：268(M
++H).
Embodiment 250:[5-chloro-4-[(2, the 5-difluorophenyl) (6-5-flumethiazine-3-base alkylsulfonyl) methyl] pyridine-2-yl] amine
(160mg adds 1N aqueous sodium hydroxide solution (2ml) in ethanol 0.60mmol) (2ml) solution, stirred 2 hours in 65 ℃ at dithiocarbonic acid O-ethyl ester S-(6-5-flumethiazine-3-yl) ester.Add water after reaction mixture is cooled to room temperature, use washed with dichloromethane.After making water layer be acidity with 1N hydrochloric acid, the resultant dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, obtains to be the 6-5-flumethiazine-3-mercaptan of colorless oil.
Under the room temperature, [5-chloro-4-[(2 in reference example 47 acquisitions, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (185mg, 0.50mmol) dichloromethane solution in add earlier methylsulfonyl chloride (0.077ml, 1.00mmol), (0.279ml 2.00mmol), stirred 1 hour under the room temperature to add triethylamine again.After reaction mixture washed with saturated sodium bicarbonate aqueous solution, the colourless dried over sodium sulfate of organic layer was filtered back concentrating under reduced pressure filtrate.
Under the nitrogen atmosphere,, add the N of the previous 6-5-flumethiazine-3-mercaptan that obtains in dinethylformamide (5ml) solution at residue obtained N, dinethylformamide (5ml) solution, (104mg 0.75mmol), stirred 15 hours under the room temperature to add salt of wormwood again.In reaction mixture, add ethyl acetate, earlier use saturated sodium bicarbonate aqueous solution, use the saturated common salt water washing again after, the organic layer anhydrous sodium sulfate drying, filtration is concentrating under reduced pressure filtrate afterwards.
(99mg 0.08mmol), stirred 4 hours in 50 ℃ to add methyl alcohol (10ml), 31% aqueous hydrogen peroxide solution (5ml) and seven molybdic acids, six ammonium tetrahydrates in residue obtained ethyl acetate (10ml) solution.In reaction mixture, add boil off ethyl acetate and methyl alcohol under the water decompression after, add saturated sodium bicarbonate aqueous solution, the resultant dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains.
In 0 ℃, in residue obtained methylene dichloride (5ml) solution, add trifluoroacetic acid (5ml), stirred 2 hours under the room temperature.Behind the concentrating under reduced pressure reaction mixture, residue is dissolved in methylene dichloride, washs with saturated sodium bicarbonate aqueous solution.The organic layer anhydrous sodium sulfate drying, filter back concentrating under reduced pressure filtrate, residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, residue obtained mixed solvent washing back leaching with ethanol/hexane, the acquisition solid title compound (75mg, 0.16mmol, 32%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.71(2H，s)，6.18(1H，s)，6.91-6.99(1H，m)，7.06-7.14(1H，m)，7.30(1H，s)，7.50-7.56(1H，m)，7.81(1H，d，J＝8.1Hz)，8.01(1H，s)，8.20(1H，dd，J＝8.1，2.0Hz)，8.90(1H，d，J＝2.0Hz).
IR(ATR)cm
-1：3446，3157，1649，1601，1485，1419，1325，1147，1101，1076.
mp：201-202℃.
Ultimate analysis: C
18H
11ClF
5N
3O
2S0.25H
2O: theoretical value: C, 46.16; H, 2.48; Cl, 7.57; F, 20.28; N, 8.97; S, 6.85. measured value: C, 46.30; H, 2.36; Cl, 7.61; F, 19.96; N, 8.93; S, 7.12.
MSm/z：464(M
++H).
Reference example 51: dithiocarbonic acid S-(4-chloro-3-fluorophenyl) ester O-ethyl ester
According to the method same with reference example 50, (582mg 4.00mmol), obtains to be the title compound (379mg, 1.51mmol, 38%) of yellow oil to adopt 4-chloro-3-fluoroaniline.
1H-NMR(400MHz，CDCl
3)δ：1.36(3H，t，J＝7.1Hz)，4.63(2H，q，J＝7.1Hz)，7.22-7.25(1H，m)，7.30-7.35(1H，m)，7.43-7.49(1H，m).
Embodiment 251:[5-chloro-4-[(4-chloro-3-fluorophenyl alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amine
According to the method same with embodiment 250, by dithiocarbonic acid S-(4-chloro-3-fluorophenyl) O-ethyl ester (150mg, 0.60mmol) and [the 5-chloro-4-[(2 that obtains of reference example 47, the 5-difluorophenyl) (hydroxyl) methyl] pyridine-2-yl] t-butyl carbamate (185mg, 0.50mmol), the acquisition solid title compound (78mg, 0.17mmol, 35%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.68(2H，s)，6.14(1H，s)，6.92-6.99(1H，m)，7.03-7.10(1H，m)，7.31(1H，s)，7.40-7.55(4H，m)，8.00(1H，s).
IR(ATR)cm
-1：3159，1628，1543，1495，1473，1408，1335，1238，1149，1055.
mp：159-160℃.
Ultimate analysis: C
18H
11Cl
2F
3N
2O
2S: theoretical value: C, 48.34; H, 2.48; Cl, 15.85; F, 12.74; N, 6.26; S, 7.17. measured value: C, 48.22; H, 2.47; Cl, 15.89; F, 12.75; N, 6.24; S, 7.34.
MSm/z：447(M
++H).
Embodiment 252:(E)-and 3-[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] methyl acrylate
Under the argon atmospher; embodiment 200 obtain [4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] formaldehyde (300mg; 0.705mmol) tetrahydrofuran (THF) (5ml) solution in add the inferior phosphoranyl methyl acetate of triphenyl (259mg; 0.775mmol), stirred 6 hours under the room temperature.The concentrating under reduced pressure reaction soln is residue obtainedly handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be the title compound (303mg, 0.629mmol, 89%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.84(3H，s)，6.07(1H，s)，6.92(1H，d，J＝15.6Hz)，6.94-6.99(1H，m)，7.05-7.11(1H，m)，7.45(2H，d，J＝8.3Hz)，7.63(2H，d，J＝8.3Hz)，7.65-7.69(1H，m)，7.73(1H，d，J＝15.6Hz)，8.05(1H，d，J＝5.6Hz)，8.44(1H，s).
MSm/z：482(M
++H).
Embodiment 253:3-[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] methyl propionate
With ethanol to draw Buddhist nun nickel suspension liquid (R-100) wash, form alcohol suspending liquid again by emerging リ カ of day Co., Ltd. for elder generation's water.Gained alcohol suspending liquid (1ml) is added (E)-3-[4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] methyl acrylate (290mg; 0.602mmol) ethanol (6ml) and 1; in the mixing solutions of 4-two alkane (4ml), high degree of agitation is 30 minutes under the nitrogen atmosphere of 1 air pressure.Concentrating under reduced pressure behind the filtering reacting solution with the residue obtained methylene dichloride that is dissolved in, is used anhydrous magnesium sulfate drying, then concentrating under reduced pressure.The residue obtained hexane wash of using, the title compound (252mg, 0.521mmol, 87%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.83(2H，t，J＝7.1Hz)，3.19(2H，t，J＝7.1Hz)，3.71(3H，s)，6.06(1H，s)，6.93-6.99(1H，m)，7.03-7.09(1H，m)，7.44(2H，d，J＝8.6Hz)，7.63(2H，d，J＝8.6Hz)，7.64-7.69(1H，m)，7.88(1H，d，J＝5.4Hz)，8.31(1H，s).
MSm/z：484(M
++H).
Embodiment 254:3-[4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] propionic acid
At 3-[4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-5-fluorine pyridine-2-yl] methyl propionate (150mg; 0.310mmol) methyl alcohol (2ml) and the mixing solutions of tetrahydrofuran (THF) (2ml) in add 1N aqueous sodium hydroxide solution (2ml), stirred 10 minutes under the room temperature.In reaction soln, add 1N hydrochloric acid, make it be slightly acidic after, use dichloromethane extraction.Organic layer with dried over mgso after concentrating under reduced pressure, the title compound of the powder that obtains to be white in color (145mg, 0.310mmol, quantitatively).
1H-NMR(400MHz，CDCl
3)δ：2.88(2H，t，J＝6.6Hz)，3.21-3.25(2H，m)，6.07(1H，s)，6.93-6.99(1H，m)，7.04-7.10(1H，m)，7.45(2H，d，J＝8.6Hz)，7.62(2H，d，J＝8.6Hz)，7.63-7.67(1H，m)，7.92(1H，d，J＝5.4Hz)，8.33(1H，s).
IR(ATR)cm
-1：3453，1716，1664，1614，1571，1496，1430，1394，1330，1284，1238，1187，1151，1089，1010.
mp：89-91℃.
MSm/z：470(M
++H).
Ultimate analysis: C
21H
15ClF
3NO
4S0.75H
2O: theoretical value: C, 52.18; H, 3.44; Cl, 7.33; F, 11.79; N, 2.90; S, 6.63. measured value: C, 52.20; H, 3.65; Cl, 7.11; F, 11.43; N, 2.99; S, 6.58.
Reference example 52:2-bromo-5-chloro-4-[(2, the 5-difluorophenyl) hydroxymethyl] pyridine
In-78 ℃, under argon atmospher, (21ml, (1.58M hexane solution, 88ml 138mmol), stirred 1 hour to add n-Butyl Lithium in tetrahydrofuran (THF) 150mmol) (200ml) solution at Diisopropylamine.(19g, tetrahydrofuran (THF) 98.7mmol) (100ml) solution stirred 1.5 hours to splash into 2-bromo-5-chloropyridine in reaction soln.Splash into 2 in reaction soln, (16ml 148mmol), stirred 2 hours the 5-difluorobenzaldehyde.In reaction solution, add concentrating under reduced pressure behind the water, use dichloromethane extraction.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with silica gel column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=6: 1 wash-out portion obtains obtains to be the title compound (24.8g, 74.1mmol, 75%) of pale yellow powder.
1H-NMR(400MHz，CDCl
3)δ：2.65(1H，d，J＝4.2Hz)，6.20(1H，d，J＝4.2Hz)，6.88-6.92(1H，m)，7.01-7.27(2H，m)，7.81(1H，s)，8.30(1H，s).
MSm/z：334(M
++H).
Embodiment 255:2-bromo-5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine
Under the argon atmospher, in ice-cold following at 2-bromo-5-chloro-4-[(2, the 5-difluorophenyl) hydroxymethyl] pyridine (4.12g, 12.3mmol) dichloromethane solution (80ml) in add triethylamine (2.6ml, 18.5mmol) and methylsulfonyl chloride (1.3ml 16.0mmol), stirred under the room temperature 1.5 hours.Use extracted with diethyl ether after in reaction soln, adding saturated sodium bicarbonate aqueous solution.Solution saturated common salt water washing is with concentrated solution under the decompression behind the anhydrous magnesium sulfate drying.
In dimethyl formamide (40ml) solution of residue, add 4-chlorobenzene mercaptan (2.1g, 14.8mmol) and salt of wormwood (2.6g, 18.5mmol), in 50 ℃ of stirrings 4 hours.After being cooled to room temperature, reaction soln dilutes with ether, successively water and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=10: 1 wash-out portion obtains, the title compound (3.3g, 7.16mmol, 58%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：5.96(1H，s)，6.99-7.06(2H，m)，7.15-7.20(1H，m)，7.25(2H，d，J＝8.8Hz)，7.28(2H，d，J＝8.8Hz)，7.69(1H，s)，8.32(1H，s).
MSm/z：460(M
++H).
Embodiment 256:[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol
In-78 ℃, under argon atmospher, at 2-bromo-5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] (200mg adds n-Butyl Lithium (1.58M hexane solution, 0.33ml in toluene 0.434mmol) (5ml) solution to pyridine, 0.520mmol), stirred 2 hours.(44 μ l 0.564mmol), stirred 1 hour to splash into dimethyl formamide in reaction soln.(33mg 0.868mmol), is warming up to after the room temperature and stirred 2 hours to add methyl alcohol (5ml) and sodium borohydride in reaction soln.Use ethyl acetate extraction after in reaction solution, adding water, use the saturated common salt water washing again.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains obtains to be the title compound (142mg, 0.344mmol, 80%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.19(1H，t，J＝5.4Hz)，4.75(2H，d，J＝5.4Hz)，6.06(1H，s)，6.96-7.04(2H，m)，7.16-7.21(1H，m)，7.22(2H，d，J＝8.8Hz)，7.25(2H，d，J＝8.8Hz)，7.52(1H，s)，8.51(1H，s).
MSm/z：412(M
++H).
Embodiment 257:[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol
[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol (130mg, 0.315mmol) methyl alcohol (5ml) solution in add seven molybdic acids, six ammonium tetrahydrates (20mg), 30% aqueous hydrogen peroxide solution (3ml), stirred 6 hours.Use ethyl acetate extraction after in reaction solution, adding water, successively water, saturated sodium bicarbonate aqueous solution, saturated aqueous sodium thiosulfate and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains, use hexane: the be white in color title compound (101mg, 0.227mmol, 72%) of powder of re-crystallizing in ethyl acetate, acquisition.
1H-NMR(400MHz，CDCl
3)δ：3.22(1H，t，J＝5.4Hz)，4.86(2H，dd，J＝5.4，2.0Hz)，6.24(1H，s)，6.91-6.97(1H，m)，7.02-7.09(1H，m)，7.45(2H，d，J＝8.8Hz)，7.52-7.57(1H，m)，7.61(2H，d，J＝8.8Hz)，8.10(1H，s)，8.52(1H，s).
IR(ATR)cm
-1：3255，1583，1492，1428，1394，1330，1280，1236，1159，1085，1035.
mp：164-165℃.
MSm/z：444(M
++H).
Ultimate analysis: C
19H
13Cl
2F
2NO
3S: theoretical value: C, 51.36; H, 2.95; Cl, 15.96; F, 8.55; N, 3.15; S, 7.22. measured value: C, 51.26; H, 2.91; Cl, 15.97; F, 8.72; N, 3.11; S, 7.45.
Embodiment 258:[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] formaldehyde
Under the nitrogen atmosphere; [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol (1.0g; 2.25mmol) methylene dichloride (25ml) solution in add methyl-sulphoxide (880 μ l; 11.3mmol), triethylamine (1.14ml; 11.3mmol), (1.07g 6.75mmol), stirred under the room temperature 18 hours sulphur trioxide pyridine complex salt.The concentrating under reduced pressure reaction solution is residue obtainedly handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=2: 1 wash-out portion obtains obtains to be the title compound (770mg, 1.74mmol, 77%) of colourless amorphous substance
1H-NMR(400MHz，CDCl
3)δ：6.23(1H，s)，6.93-6.99(1H，m)，7.04-7.10(1H，m)，7.44(2H，d，J＝8.8Hz)，7.59-7.64(1H，m)，7.62(2H，d，J＝8.8Hz)，8.69(1H，s)，8.73(1H，s)，10.09(1H，s).
MSm/z：442(M
++H).
Embodiment 259:(E)-and 3-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl acrylate
Under the argon atmospher; [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (760mg adds the inferior phosphoranyl methyl acetate of triphenyl (632mg to formaldehyde in tetrahydrofuran (THF) 1.72mmol) (15ml) solution; 1.89mmol), stirred 3 hours under the room temperature.The concentrating under reduced pressure reaction soln is residue obtainedly handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be the title compound (776mg, 1.56mmol, 91%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：3.85(3H，s)，6.22(1H，s)，6.93-6.98(1H，m)，6.99(1H，d，J＝15.6Hz)，7.03-7.10(1H，m)，7.44(2H，d，J＝8.6Hz)，7.54-7.58(1H，m)，7.60(2H，d，J＝8.6Hz)，7.73(1H，d，J＝15.6Hz)，8.17(1H，s)，8.56(1H，s).
MSm/z：498(M
++H).
Embodiment 260:3-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl propionate
With ethanol to draw Buddhist nun nickel suspension liquid (R-100) wash, form alcohol suspending liquid again by emerging リ カ of day Co., Ltd. for elder generation's water.Gained alcohol suspending liquid (1ml) is added (E)-3-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] methyl acrylate (770mg; 1.55mmol) ethanol (10ml) and 1; in the mixing solutions of 4-two alkane (5ml), high degree of agitation is 30 minutes under the nitrogen atmosphere of 1 air pressure.Concentrating under reduced pressure behind the filtering reacting solution, with the residue obtained methylene dichloride (15ml) that is dissolved in, with concentrating under reduced pressure after the dried over mgso, the title compound (720mg, 1.44mmol, 93%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.84(2H，t，J＝7.1Hz)，3.20(2H，t，J＝7.1Hz)，3.70(3H，s)，6.22(1H，s)，6.92-6.97(1H，m)，7.02-7.08(1H，m)，7.43(2H，d，J＝8.6Hz)，7.53-7.58(1H，m)，7.61(2H，d，J＝8.6Hz)，8.03(1H，s)，8.44(1H，s).
MSm/z：500(M
++H).
Embodiment 261:3-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] propionic acid
At 3-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] methyl propionate (200mg; 0.400mmol) methyl alcohol (2ml) and the mixing solutions of tetrahydrofuran (THF) (2ml) in add 1N aqueous sodium hydroxide solution (2ml), stirred 1 hour under the room temperature.In reaction soln, add 1N hydrochloric acid, use dichloromethane extraction after making it be slightly acidic.Organic layer with dried over mgso after concentrating under reduced pressure, use hexane: re-crystallizing in ethyl acetate, the title compound (161mg, 0.331mmol, 83%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.90(2H，t，J＝6.7Hz)，3.24(2H，t，J＝6.7Hz)，6.21(1H，s)，6.92-6.97(1H，m)，7.03-7.08(1H，m)，7.44(2H，d，J＝8.6Hz)，7.51-7.56(1H，m)，7.61(2H，d，J＝8.6Hz)，8.06(1H，s)，8.47(1H，s).
IR(ATR)cm
-1：1718，1587，1496，1423，1396，1365，1321，1280，1240，1205，1174，1083，1054，1014.
mp：194-196℃.
MSm/z：486(M
++H).
Ultimate analysis: C
21H
15Cl
2F
2NO
4S: theoretical value: C, 51.86; H, 3.11; Cl, 14.58; F, 7.81; N, 2.88; S, 6.59. measured value: C, 51.87; H, 3.07; Cl, 14.37; F, 7.77; N, 2.95; S, 6.75.
Embodiment 262:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine carboxylic acid
Embodiment 258 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] formaldehyde (150mg; 0.339mmol) formic acid (3ml) solution in add 30% aqueous hydrogen peroxide solution (115 μ l 1.02mmol), stirred 3 hours under the room temperature.Add water in reaction soln, filter the solid of separating out, solid washes with water.Make the gained solid be dissolved in ethyl acetate, successively water and saturated common salt water washing.The gained organic layer with dried over mgso after concentrating under reduced pressure.The residue obtained hexane of using: re-crystallizing in ethyl acetate, the title compound (88mg, 0.192mmol, 57%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.30(1H，s)，6.93-7.00(1H，m)，7.05-7.11(1H，m)，7.45(2H，d，J＝8.8Hz)，7.62-7.66(1H，m)，7.64(2H，d，J＝8.8Hz)，8.95(1H，s)，9.24(1H，s).
IR(ATR)cm
-1：1758，1712，1583，1542，1494，1425，1396，1328，1280，1228，1153，1085，1054，1014.
mp：94-96℃.
MSm/z：458(M
++H).
Ultimate analysis: C
19H
11Cl
2F
2NO
4S: theoretical value: C, 49.80; H, 2.42; Cl, 15.47; F, 8.29; N, 3.06; S, 7.00. measured value: C, 50.05; H, 2.58; Cl, 15.17; F, 8.28; N, 3.06; S, 7.05.
Embodiment 263:2-bromo-5-chloro-4-[(2, the 5-difluorophenyl) (4-trifluoromethyl thiophenyl) methyl] pyridine
Under the nitrogen atmosphere, at the 2-bromo-5-chloro-4-[(2 that reference example 52 obtains, 5-difluorophenyl) hydroxymethyl] pyridine (1.34g, 4.00mmol) dichloromethane solution in add methylsulfonyl chloride (0.619ml 8.00mmol), add triethylamine (2.23ml again, 16.0mmol), stirred 1 hour under the room temperature.After reaction mixture elder generation water was used the saturated common salt water washing again, the organic layer anhydrous sodium sulfate drying filtered back concentrating under reduced pressure filtrate.
Under the nitrogen atmosphere, at residue obtained N, (784mg, 4.40mmol), (663mg 4.80mmol), stirred 17 hours under the room temperature to add salt of wormwood again to add 4-trifluoro-benzene mercaptan in dinethylformamide (60ml) solution.In reaction mixture, add ethyl acetate,, filter back concentrating under reduced pressure filtrate with saturated sodium bicarbonate aqueous solution washing back organic layer anhydrous sodium sulfate drying.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=50: 1 wash-out portion obtains obtains to be white in color solid title compound (1.33g, 2.69mmol, 67%).
1H-NMR(400MHz，CDCl
3)δ：6.10(1H，s)，6.99-7.11(2H，m)，7.14-7.20(1H，m)，7.36(2H，d，J＝8.1Hz)，7.52(2H，d，J＝8.1Hz)，7.69(1H，s)，8.36(1H，s).
MSm/z：494，496(M
++H).
Embodiment 264:(E)-and 3-[5-chloro-4-[(2, the 5-difluorophenyl) (4-trifluoromethyl thiophenyl) methyl] pyridine-2-yl] methyl acrylate
Under the argon atmospher, in-78 ℃ at 2-bromo-5-chloro-4-[(2,5-difluorophenyl) (4-trifluoromethyl thiophenyl) methyl] pyridine (396mg, 0.80mmol) toluene (12ml) solution in add the hexane solution (1.59M of n-Butyl Lithium, 0.604ml, 0.96mmol), stirred 30 minutes.Add N under uniform temp, (0.081ml 1.04mmol), stirred 30 minutes dinethylformamide.In reaction mixture, add saturated aqueous ammonium chloride, add water again, be warming up to room temperature after, with ether resultant is extracted.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, residue obtainedly handles with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains, acquisition aldehyde body (186mg).
Aldehyde body (133mg) is dissolved in tetrahydrofuran (THF) (2ml), and (120mg, 0.36mmol), uniform temp stirred 18 hours down to add the inferior phosphoranyl methyl acetate of triphenyl under the room temperature.Behind the reaction mixture concentrating under reduced pressure, residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=19: 1 wash-out portion obtains obtains to be white in color solid title compound (132mg, 0.26mmol, 46%).
1H-NMR(400MHz，CDCl
3)δ：3.82(3H，s)，6.17(1H，s)，6.92(1H，d，J＝15.7Hz)，6.99-7.09(2H，m)，7.13-7.18(1H，m)，7.35(2H，d，J＝8.1Hz)，7.50(2H，d，J＝8.1Hz)，7.61(1H，s)，7.61(1H，d，J＝15.7Hz)，8.59(1H，s).
MSm/z：500(M
++H).
Embodiment 265:(E)-and 3-[5-chloro-4-[(2, the 5-difluorophenyl) (4-trifluoromethyl alkylsulfonyl) methyl] pyridine-2-yl] methyl acrylate
At (E)-3-[5-chloro-4-[(2, the 5-difluorophenyl) (4-trifluoromethyl thiophenyl) methyl] pyridine-2-yl] methyl acrylate (118mg, 0.24mmol) ethyl acetate (6ml) solution in add methyl alcohol (6ml), 31% aqueous hydrogen peroxide solution (6ml) and seven molybdic acids, six ammonium tetrahydrate (58mg, 0.05mmol), stirred 11 hours under the room temperature.In reaction mixture, add water, after decompression down boils off ethyl acetate and methyl alcohol, adding saturated aqueous common salt, resultant ethyl acetate extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, residue obtainedly handles with the silica gel flash column chromatography.Concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains obtains to be white in color solid title compound (111mg, 0.21mmol, 88%).
1H-NMR(400MHz，CDCl
3)δ：3.86(3H，s)，6.25(1H，s)，6.91-6.98(1H，m)，7.01(1H，d，J＝15.7Hz)，7.04-7.11(1H，m)，7.53-7.59(1H，m)，7.74(1H，d，J＝15.7Hz)，7.74(2H，d，J＝8.3Hz)，7.83(2H，d，J＝8.3Hz)，8.18(1H，s)，8.56(1H，s).
MSm/z：532(M
++H).
Embodiment 266:3-[5-chloro-4-[(2, the 5-difluorophenyl) (4-trifluoromethyl alkylsulfonyl) methyl] pyridine-2-yl] methyl propionate
With (E)-3-[5-chloro-4-[(2; the 5-difluorophenyl) (4-trifluoromethyl alkylsulfonyl) methyl] pyridine-2-yl] methyl acrylate (110mg; 0.21mmol) be dissolved in the mixed solvent of ethyl acetate (3ml) and methyl alcohol (3ml); add 10% palladium-carbon catalyst (60mg), under nitrogen atmosphere in stirring at room 2 hours.Remove concentrating under reduced pressure filtrate behind the catalyzer with diatomite filtration, residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be white in color solid title compound (94mg, 0.18mmol, 85%).
1H-NMR(400MHz，CDCl
3)δ：2.82-2.89(2H，m)，3.21(2H，t，J＝7.1Hz)，3.70(3H，s)，6.25(1H，s)，6.90-6.97(1H，m)，7.03-7.10(1H，m)，7.54-7.60(1H，m)，7.73(2H，d，J＝8.3Hz)，7.84(2H，d，J＝8.3Hz)，8.04(1H，s)，8.44(1H，s).
MSm/z：534(M
++H).
Embodiment 267:3-[5-chloro-4-[(2, the 5-difluorophenyl) (4-trifluoromethyl alkylsulfonyl) methyl] pyridine-2-yl] propionic acid
In 0 ℃; at 3-[5-chloro-4-[(2; the 5-difluorophenyl) (4-trifluoromethyl alkylsulfonyl) methyl] pyridine-2-yl] methyl propionate (and 92mg, add methyl alcohol (2ml) and 1N aqueous sodium hydroxide solution (2ml) in tetrahydrofuran (THF) 0.17mmol) (2ml) solution after, stirred under the room temperature 2 hours.In reaction mixture, add 1N hydrochloric acid, resultant dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, and is residue obtained with leaching after the washing with alcohol, obtains to be white in color solid title compound (61mg, 0.12mmol, 68%).
1H-NMR(400MHz，CDCl
3)δ：2.90(2H，t，J＝6.7Hz)，3.18-3.31(2H，m)，6.25(1H，s)，6.90-6.97(1H，m)，7.03-7.10(1H，m)，7.51-7.57(1H，m)，7.74(2H，d，J＝8.3Hz)，7.82(2H，d，J＝8.3Hz)，8.07(1H，s)，8.47(1H，s).
IR(ATR)cm
-1：1707，1495，1408，1321，1244，1174，1159，1124，1063.
mp：166-167℃.
Ultimate analysis: C
22H
15ClF
5NO
4S: theoretical value: C, 50.83; H, 2.91; Cl, 6.82; F, 18.27; N, 2.69; S, 6.17. measured value: C, 50.66; H, 2.93; Cl, 6.87; F, 17.83; N, 2.75; S, 6.28.
MSm/z：520(M
++H).
Embodiment 268:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-1-methyl isophthalic acid H-imidazoles-4-sulphonamide
Embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (93mg; 0.217mmol) and pyridine (21 μ l; 0.260mmol) methylene dichloride (5ml) solution in add 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE (47mg; 0.260mmol), stirred 18 hours under the room temperature.In reaction solution, add pyridine (1ml), stir concentrating under reduced pressure after 7 hours under the room temperature.In the gained concentrated residue, add ethyl acetate, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing, use the anhydrous sodium sulfate drying after-filtration successively, concentrating under reduced pressure filtrate.The gained concentrated filtrate is handled with silica gel column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the 50) cut that obtains of elutriant obtains white solid to methylene dichloride.The gained white solid with washing with alcohol after leaching, the title compound (68mg, 0.119mmol, 55%) of the powder that obtains to be white in color.
1H-NMR(400MHz，DMSO-d
6)δ：3.69(3H，s)，6.25(1H，s)，7.29-7.45(2H，m)，7.47-7.54(1H，m)，7.68(2H，d，J＝8.8Hz)，7.75(2H，d，J＝8.8Hz)，7.77(1H，s)，7.94(1H，s)，8.10(1H，s)，8.26(1H，s)，11.40(1H，brs).
mp：294-296℃
IR(ATR)cm
-1：1594，1562，1494，1382，1332，1159，1118，993，817，755，723.
MSm/z：572(M
+).
EI-MS:571.9962 (presses C
22H
16O
4N
4Cl
2F
2S
2Calculate: 571.9958).
Ultimate analysis: C
22H
16N
4O
4Cl
2F
2S
2: theoretical value: C, 46.08; H, 2.81; N, 9.77; Cl, 12.37; F, 6.63; S, 11.18. measured value: C, 46.04; H, 2.77; N, 9.74; Cl, 12.46; F, 6.90; S, 11.21.
Embodiment 269:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-1-pyridin-4-yl Toluidrin
Embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (104mg; 0.242mmol) and pyridine (74 μ l; 0.533mmol) methylene dichloride (2ml) solution in add (4-pyridylmethyl) SULPHURYL CHLORIDE fluoroform sulphonate (91mg; 0.266mmol), stirred 17 hours under the room temperature.(74 μ l, (91mg 0.266mmol), stirred 19 hours under the room temperature 0.533mmol) to reach (4-pyridylmethyl) SULPHURYL CHLORIDE fluoroform sulphonate to add pyridine in reaction solution.Reaction solution dilutes with ethyl acetate, after water and the saturated common salt water washing, uses anhydrous sodium sulfate drying, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the cut that elutriant 40) obtains obtains to be white in color solid title compound (66mg, 0.113mmol, 47%) to methylene dichloride.
1H-NMR(400MHz，DMSO-d
6)δ：4.88(2H，s)，6.30(1H，s)，7.27(2H，d，J＝6.0Hz)，7.29-7.49(3H，m)，7.70(2H，d，J＝8.8Hz)，7.74(1H，s)，7.79(2H，d，J＝8.8Hz)，8.45(1H，s)，8.53(2H，d，J＝6.0Hz)，11.00(1H，brs).
Mp:257 ℃ (decomposition)
IR(ATR)cm
-1：1592，1490，1467，1340，1326，1280，1238，1186，1155，1128，1085，1004，966，902，869，823.
MSm/z：584(M
++H).
Ultimate analysis: C
24H
17N
3O
4Cl
2F
2S
2: theoretical value: C, 49.32; H, 2.93; N, 7.19; Cl, 12.13; F, 6.50; S, 10.97. measured value: C, 49.35; H, 3.12; N, 7.17; Cl, 12.05; F, 6.43; S, 10.93.
Embodiment 270:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] piperidines-1-sulphonamide
In 70 ℃; to embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (101mg, 0.235mmol) and piperidines-1-SULPHURYL CHLORIDE (48mg, pyridine 0.259mmol) (2ml) solution stirring 19 hours.(48mg 0.259mmol), stirred 4 days in 70 ℃ to add piperidines-1-SULPHURYL CHLORIDE in reaction solution.The temperature retrieval of reaction solution concentrating under reduced pressure to the room temperature.After the gained concentrated residue diluted with ethyl acetate, the anhydrous sodium sulfate drying after-filtration was used in water and saturated common salt water washing again, concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=4: the cut that elutriant 1) obtains obtains white solid to ethyl acetate.The gained solid is with hexane-ether washing back leaching, the title compound (63mg, 0.109mmol, 47%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.51-1.61(2H，m)，1.65-1.75(4H，m)，3.38(4H，t，J＝4.6Hz)，6.21(1H，s)，6.94-7.10(2H，m)，7.41-7.52(3H，m)，7.70(2H，d，J＝8.6Hz)，8.24(1H，s)，8.29(1H，s)，8.71(1H，brs).
mp：192-194℃
IR(ATR)cm
-1：1598，1563，1492，1396，1346，1322，1234，1145，1083，998，923，900，833.
MSm/z：576(M
++H).
Ultimate analysis: C
23H
21N
3O
4Cl
2F
2S
2: theoretical value: C, 47.92; H, 3.67; N, 7.29; Cl, 12.30; F, 6.59; S, 11.12. measured value: C, 47.87; H, 3.66; N, 7.33; Cl, 12.12; F, 6.66; S, 11.25.
Embodiment 271:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-4-methyl piperidine-1-sulphonamide
To embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (101mg; 0.235mmol), 4-methylpiperazine-1-SULPHURYL CHLORIDE hydrochloride (126mg; 0.534mmol) and triethylamine (150 μ l, acetonitrile 1.07mmol) (5ml) vlil 23 hours.In reaction solution, add 4-methylpiperazine-1-SULPHURYL CHLORIDE hydrochloride (126mg, 0.534mmol) and triethylamine (150 μ l, 1.07mmol), reflux 22 hours.The temperature retrieval of reaction solution concentrating under reduced pressure to the room temperature.In the gained concentrated residue, add water, use ethyl acetate extraction.The anhydrous sodium sulfate drying after-filtration is used in organic layer saturated common salt water washing, concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the cut that elutriant 20) obtains obtains to be the title compound (34mg, 0.057mmol, 16%) of faint yellow solid to methylene dichloride.
1H-NMR(400MHz，CDCl
3)δ：2.31(3H，s)，2.45-2.60(4H，m)，3.38-3.52(4H，m)，6.20(1H，s)，6.95-7.10(2H，m)，7.41-7.50(3H，m)，7.69(2H，d，J＝8.8Hz)，8.24(1H，s)，8.26(1H，s).
mp：215-218℃
IR(ATR)cm
-1：1600，1565，1496，1392，1348，1330，1157，1093，935，835，819.
MSm/z：591(M
++H).
Ultimate analysis: C
23H
22N
4O
4Cl
2F
2S
2: theoretical value: C, 46.70; H, 3.75; N, 9.47; Cl, 11.99; F, 6.42; S, 10.84. measured value: C, 46.89; H, 3.76; N, 9.40; Cl, 11.78; F, 6.42; S, 10.72.
Embodiment 272:3-chloro-N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-N-(3-chloropropyl alkylsulfonyl) propane-1-sulphonamide
In 0 ℃; embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (130mg; 0.303mmol) and triethylamine (42 μ l; 0.303mmol) methylene dichloride (5ml) solution in add 3-chlorine third SULPHURYL CHLORIDE (37 μ l, 0.303mmol).After under the room temperature reaction solution being stirred 2.5 hours, in 0 ℃ add successively triethylamine (42 μ l, 0.303mmol) and 3-chlorine third SULPHURYL CHLORIDE (37 μ l, 0.303mmol).Under the room temperature reaction solution was stirred 7 hours.In reaction solution, add ethyl acetate,, use the anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure filtrate with the saturated sodium bicarbonate aqueous solution washing.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by hexane: ethyl acetate (=5: the cut that elutriant 1) obtains.In the gained concentrated residue, add ether, the solid that leaching is separated out, the title compound of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.47-2.57(4H，m)，3.74(4H，t，J＝6.1Hz)，3.96-4.05(4H，m)，6.20(1H，s)，6.98-7.15(2H，m)，7.40-7.53(3H，m)，7.62(2H，d，J＝8.3Hz)，8.22(1H，s)，8.64(1H，s).
MSm/z：709，711(M
++H).
Embodiment 273:3-chloro-N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] propane-1-sulphonamide
At 3-chloro-N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl]-N-(3-chloropropyl alkylsulfonyl) propane-1-sulphonamide (193mg; 0.272mmol) tetrahydrofuran (THF) (5ml) solution in add the tetrahydrofuran solution (1.0M of tetrabutylammonium; 0.28ml; 0.28mmol), stirred 1 hour under the room temperature.In reaction solution, add saturated aqueous ammonium chloride, use ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer saturated common salt water washing, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by hexane: (=4: the cut that elutriant 1) obtains obtains to be white in color solid title compound (108mg, 0.190mmol, 70%) to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：2.35-2.44(2H，m)，3.61-3.67(2H，m)，3.70(2H，t，J＝6.1Hz)，6.19(1H，s)，6.90-6.99(1H，m)，7.02-7.10(1H，m)，7.42-7.53(3H，m)，7.64(2H，d，J＝8.3Hz)，7.84(1H，brs)，8.01(1H，s)，8.31(1H，s).
IR(ATR)cm
-1：1596，1560，1488，1384，1336，1234，1145，1083，997，925，844.
MSm/z：568，570(M
+).
Embodiment 274:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl]-2-(1,1-dioxo-1 λ
6-isothiazolidine-2-yl) pyridine
In 70 ℃ to 3-chloro-N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] propane-1-sulphonamide (83mg; 0.146mmol) and 1; 8-diazabicylo [5.4.0]-7-hendecene (26 μ l, acetonitrile 0.175mmol) (5ml) solution stirring 4.5 hours.The temperature retrieval that makes reaction solution concentrating under reduced pressure to the room temperature.The gained concentrated residue dilutes with ethyl acetate, use 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively after, use anhydrous sodium sulfate drying, filter back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=1: the cut that elutriant 1) obtains obtains to be white in color solid title compound (75mg, 0.141mmol, 96%) to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：2.52-2.62(2H，m)，3.47(2H，t，J＝7.6Hz)，4.02(2H，t，J＝6.6Hz)，6.24(1H，s)，6.95-7.10(2H，m)，7.44(2H，d，J＝8.6Hz)，7.49-7.56(1H，m)，7.74(2H，d，J＝8.6Hz)，8.13(1H，s)，8.24(1H，s).
mp：219-221℃
IR(ATR)cm
-1：1587，1496，1467，1386，1346，1315，1278，1238，1137，1089，998，831.
MSm/z：532(M
+).
Ultimate analysis: C
21H
16N
2O
4Cl
2F
2S
2: theoretical value: C, 47.29; H, 3.02; N, 5.25; Cl, 13.29; F, 7.12; S, 12.02. measured value: C, 47.39; H, 3.02; N, 5.37; Cl, 13.32; F, 7.24; S, 11.95.
Embodiment 275:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-N-(trifluoromethyl sulfonyl) fluoroform sulphonamide
In 0 ℃; embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (103mg; 0.240mmol) and pyridine (19 μ l; 0.240mmol) methylene dichloride (5ml) solution in add trifluoromethanesulfanhydride anhydride (39 μ l, 0.240mmol).After under the room temperature reaction solution being stirred 3 hours, in 0 ℃ add pyridine (19 μ l, 0.240mmol) and trifluoromethanesulfanhydride anhydride (39 μ l, 0.240mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 15 hours.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: ethyl acetate (=5: the cut that elutriant 1) obtains, the title compound (84mg, 0.120mmol, 50%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.23(1H，s)，6.99-7.15(2H，m)，7.38-7.48(3H，m)，7.62(2H，d，J＝8.8Hz)，8.36(1H，s)，8.53(1H，s).
IR(ATR)cm
-1：1581，1498，1442，1332，1214，1159，1122，1085，997，944，923，865，755.
MSm/z：693(M
++H).
Embodiment 276:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] the fluoroform sulphonamide
At N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl]-N-(trifluoromethyl sulfonyl) fluoroform sulphonamide (77mg; 0.111mmol) tetrahydrofuran (THF) (5ml) and water (1ml) mixing solutions in add lithium hydroxide monohydrate (5.0mg; 0.111mmol), stirred 5 hours under the room temperature.In reaction solution, add saturated aqueous ammonium chloride, use ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying after using the saturated common salt water washing, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by the hexane that contains 0.5% trifluoroacetic acid: ethyl acetate (=2: the cut that elutriant 1) obtains.In the gained concentrated residue, add ether, the solid that leaching is separated out, the title compound (39mg, 0.069mmol, 63%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：6.21(1H，s)，6.95-7.03(1H m)，7.06-7.15(1H，m)，7.42-7.52(3H，m)，7.71(2H，d，J＝8.8Hz)，8.23(1H，s)，8.71(1H，s).
mp：221-223℃
IR(ATR)cm
-1：1637，1496，1382，1336，1195，1157，1130，1085，1010，923，779，754.
MSm/z：560(M
+).
Ultimate analysis: C
19H
11N
2O
4Cl
2F
5S
2: theoretical value: C, 40.65; H, 1.98; N, 4.99; Cl, 12.63; F, 16.92; S, 11.42. measured value: C, 40.68; H, 1.94; N, 5.06; Cl, 12.46; F, 16.91; S, 11.47.
Embodiment 277:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] the ethene sulphonamide
Embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (982mg; 2.29mmol) and the 2-chloro-ethane-sulfonyl chloride (0.29ml, add in methylene dichloride 2.74mmol) (10ml) solution pyridine (0.44ml, 5.49mmol).After under the room temperature reaction solution being stirred 3.5 hours, add the 2-chloro-ethane-sulfonyl chloride (143 μ l, 1.37mmol) and pyridine (222 μ l, 2.75mmol).Under the room temperature reaction solution was stirred 1 hour.In reaction solution, add ethyl acetate,, use the anhydrous sodium sulfate drying after-filtration, concentrating under reduced pressure filtrate with the saturated sodium bicarbonate aqueous solution washing.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=3: the cut that elutriant 1) obtains obtains to be white in color solid title compound (573mg, 1.10mmol, 48%) to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：6.17-6.25(2H，m)，6.65-6.70(2H，m)，6.91-7.10(2H，m)，7.41-7.49(3H，m)，7.66(2H，d，J＝8.6Hz)，8.16(1H，s)，8.33(1H，s).
IR(ATR)cm
-1：1600，1565，1492，1388，1349，1322，1147，1081，998，916，821，757.
MSm/z：519(M
++H).
Embodiment 278:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-2-piperidines-1-base ethyl sulfonamide
At N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] the ethene sulphonamide (34mg, add in ethanol 0.065mmol) (5ml) solution piperidines (10 μ l, 0.098mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 3 days.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the cut that elutriant 30) obtains obtains to be the title compound (35mg, 0.058mmol, 89%) of amorphous substance to methylene dichloride.In the gained amorphous substance, add ethanol and solidify the back leaching, the title compound of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：1.45-1.76(6H，m)，2.50-2.65(4H，m)，2.97(2H，t，J＝5.9Hz)，3.30-3.38(2H，m)，6.21(1H，s)，6.92-7.10(2H，m)，7.44(2H，d，J＝8.6Hz)，7.52-7.59(1H，m)，7.69(2H，d，J＝8.6Hz)，8.06(1H，s)，8.22(1H，s).
mp：200-203℃
IR(ATR)cm
-1：1600，1571，1492，1390，1332，1141，1083，1002，962，919，811，754.
MSm/z：604(M
++H).
Ultimate analysis: C
25H
25N
3O
4Cl
2F
2S
2: theoretical value: C, 49.67; H, 4.17; N, 6.95; Cl, 11.73; F, 6.29; S, 10.61. measured value: C, 49.90; H, 4.13; N, 6.88; Cl, 11.64; F, 6.17; S, 10.52.
Embodiment 279:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-2-(dimethylamino) ethyl sulfonamide
N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 277 acquisitions) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] ethene sulphonamide (64mg; 0.123mmol) tetrahydrofuran (THF) (3ml) solution in add dimethylamine tetrahydrofuran solution (2M, 0.18ml, 0.36mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 3 days.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the cut that elutriant 20) obtains obtains to be white in color solid title compound (67mg, 0.117mmol, 97%) to methylene dichloride.The gained solid with washing with alcohol after leaching, the title compound (43mg) of the powder that obtains to be white in color.
1H-NMR(400MHz，CD
3OD)δ：2.73(6H，s)，3.37(2H，t，J＝7.0Hz)，3.82(2H，t，J＝7.0Hz)，6.31(1H，s)，7.16-7.26(2H，m)，7.53-7.65(3H，m)，7.75(2H，d，J＝8.8Hz)，7.84(1H，s)，8.24(1H，s).
IR(ATR)cm
-1：1587，1494，1455，1321，1151，1087，998，757.
MSm/z：564(M
++H).
FAB-MS:564.0399 (presses C
22H
22O
4N
3Cl
2F
2S
2Calculate: 564.0397).
Embodiment 280:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-2-morpholine-4-base ethyl sulfonamide
The N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl that obtains at embodiment 277) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] the ethene sulphonamide (and 53mg, add in ethanol 0.102mmol) (3ml) solution morpholine (18 μ l, 0.204mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 3 days.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by methyl alcohol: methylene dichloride (=1: the cut that elutriant 40) obtains.In the concentrated residue of gained, add ether, the solid that leaching is separated out, the title compound (45mg, 0.074mmol, 73%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.51-2.60(4H，m)，2.96(2H，t，J＝6.1Hz)，3.36-3.45(2H，m)，3.70-3.80(4H，m)，6.22(1H，s)，6.90-7.10(2H，m)，7.45(2H，d，J＝8.8Hz)，7.50-7.59(1H，m)，7.68(2H，d，J＝8.8Hz)，8.19(1H，s)，8.24(1H，s).
mp：219-221℃
IR(ATR)cm
-1：1602，1565，1492，1388，1321，1286，1238，1147，1116，1083，998.
MSm/z：606(M
++H).
FAB-MS:606.0499 (presses C
24H
24O
5N
3Cl
2F
2S
2Calculate: 606.0503).
Ultimate analysis: C
24H
23N
3O
5Cl
2F
2S
2: theoretical value: C, 47.53; H, 3.82; N, 6.93; Cl, 11.69; F, 6.27; S, 10.57. measured value: C, 47.73; H, 3.84; N, 6.97; Cl, 11.72; F, 6.25; S, 10.72.
Embodiment 281:4-[2-[[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethyl] piperazine-1-carboxylic acid tert-butyl ester
N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl in embodiment 277 acquisitions) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] ethene sulphonamide (59mg; 0.114mmol) ethanol (3ml) solution in add 1-(tert-butoxycarbonyl) piperazine (32mg, 0.170mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 3 days.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the cut that elutriant 40) obtains obtains to be the title compound (75mg, 0.106mmol, 93%) of amorphous substance to methylene dichloride.
1H-NMR(400MHz，CDCl
3)δ：1.46(9H，s)，2.50(4H，t，J＝5.0Hz)，2.97(2H，t，J＝6.0Hz)，3.35-3.42(2H，m)，3.44-3.54(4H，m)，6.22(1H，s)，6.90-7.10(2H，m)，7.45(2H，d，J＝8.8Hz)，7.50-7.58(1H，m)，7.68(2H，d，J＝8.8Hz)，8.19(1H，s)，8.24(1H，s).
IR(ATR)cm
-1：1691，1592，1494，1330，1240，1147，1083，998，755.
MSm/z：705(M
++H).
Embodiment 282:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-2-piperazine-1-base ethyl sulfonamide
At 4-[2-[[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethyl] (72mg adds concentrated hydrochloric acid (1ml) in ethanol 0.102mmol) (5ml) solution to piperazine-1-carboxylic acid tert-butyl ester.Under the room temperature gained reaction solution is stirred concentrating under reduced pressure after 2 days.In the gained concentrated residue, add saturated sodium bicarbonate aqueous solution, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate.The gained concentrated residue washs with ether, the title compound (23mg, 0.038mmol, 37%) of the powder that obtains to be white in color.
1H-NMR(400MHz，DMSO-d
6)δ：2.40-2.47(4H，m)，2.62-2.70(2H，m)，2.83-2.90(4H，m)，6.15(1H，s)，7.25-7.42(3H，m)，7.47-7.55(1H，m)，7.68(2H，d，J＝8.7Hz)，7.77(2H，d，J＝8.7Hz)，8.03(1H，s).
MSm/z：605(M
++H).
Embodiment 283:[[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethyl acetate
In 0 ℃; embodiment 196 obtain [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amine (331mg; 0.771mmol) and pyridine (94 μ l; 1.16mmol) methylene dichloride (10ml) solution in add chlorine sulphonyl ethyl acetate (216mg, methylene dichloride 1.16mmol) (2ml) solution.After under the room temperature reaction solution being stirred 12 hours, in 0 ℃ add successively pyridine (94 μ l, 1.16mmol), chlorine sulphonyl ethyl acetate (216mg, methylene dichloride 1.16mmol) (2ml) solution.Under the room temperature reaction solution is stirred concentrating under reduced pressure after 9 hours.In the gained concentrated residue, add ethyl acetate,, filter back concentrating under reduced pressure filtrate successively with using anhydrous sodium sulfate drying after saturated sodium bicarbonate aqueous solution and the saturated common salt water washing.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=3: the cut that elutriant 1) obtains obtains to be white in color solid title compound (239mg, 0.412mmol, 53%) to ethyl acetate.
1H-NMR(400MHz，CDCl
3)δ：1.29(3H，t，J＝7.2Hz)，4.25(2H，q，J＝7.2Hz)，4.37(2H，s)，6.21(1H，s)，6.91-7.10(2H，m)，7.45(2H，d，J＝8.6Hz)，7.50-7.58(1H，m)，7.66(2H，d，J＝8.6Hz)，8.09(1H，s)，8.30(1H，s).
IR(ATR)cm
-1：1745，1600，1567，1496，1386，1355，1317，1280，1232，1147，1081.
MSm/z：579(M
++H).
Embodiment 284:N-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl]-2-hydroxyl ethyl sulfonamide
In 0 ℃; [[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethyl acetate (67mg, the diethyl ether solution (0.18ml) of adding 1M lithium aluminum hydride in tetrahydrofuran (THF) 0.116mmol) (5ml) solution.Reaction solution is stirred in 0 ℃, confirm that with TLC reaction finishes after, add saturated aqueous ammonium chloride.Use the diatomite filtration mixing solutions.Filtrate is used anhydrous sodium sulfate drying, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by hexane: (=2: the 1) cut that obtains of elutriant obtains to be white in color solid title compound (39mg, 0.073mmol, 63%) to ethyl acetate.
1H-NMR(400MHz，DMSO-d
6)δ：3.63(2H，t，J＝6.3Hz)，3.75-3.85(2H，m)，4.94(1H，brs)，6.28(1H，s)，7.28-7.55(3H，m)，7.70(2H，d，J＝8.7Hz)，7.80(2H，d，J＝8.7Hz)，7.81(1H，s)，8.37(1H，s)，10.91(1H，brs).
mp：155-158℃
IR(ATR)cm
-1：3093，2867，1600，1565，1492，1392，1322，1139，1083，813，754.
MSm/z：536(M
+).
EI-MS:535.9835 (C
20H
16O
5N
2Cl
2F
2S
2, Meter calculation value: 535.9846).
Ultimate analysis: C
20H
16N
2O
5Cl
2F
2S
20.5H
2O: theoretical value: C, 43.96; H, 3.14; N, 5.13; Cl, 12.98; F, 6.95; S, 11.74. measured value: C, 44.22; H, 3.07; N, 5.13; Cl, 12.89; F, 7.10; S, 11.65.
Embodiment 285:2-[[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethanamide
[[[5-chloro-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethyl acetate that adding embodiment 283 obtains in the methanol solution (5ml) of 7N ammoniacal liquor (78mg, 0.135mmol).Under the room temperature reaction solution is stirred concentrating under reduced pressure after 3 days.The gained concentrated residue is handled with the silica gel flash column chromatography, and concentrating under reduced pressure is by methyl alcohol: (=1: the cut that elutriant 25) obtains obtains to be white in color solid title compound (66mg, 0.120mmol, 89%) to methylene dichloride.
1H-NMR(400MHz，DMSO-d
6)δ：4.33(2H，s)，6.29(1H，s)，7.29-7.56(4H，m)，7.64-7.72(3H，m)，7.76-7.84(3H，m)，8.35(1H，s)，11.16(1H，brs).
IR(ATR)cm
-1：1691，1596，1565，1492，1382，1322，1238，1149，1083，995，966，811.
MSm/z：550(M
++H).
Ultimate analysis: C
20H
15N
3O
5Cl
2F
2S
20.5H
2O: theoretical value: C, 42.94; H, 2.88; N, 7.51; Cl, 12.68; F, 6.79; S, 11.46. measured value: C, 42.64; H, 2.73; N, 7.46; Cl, 12.57; F, 6.97; S, 11.48.
Embodiment 286:[[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] acetate
Embodiment 283 obtain [[[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl] pyridine-2-yl] amino] alkylsulfonyl] ethyl acetate (60mg; 0.104mmol) tetrahydrofuran (THF) (5ml) and water (1ml) mixing solutions in add lithium hydroxide monohydrate (9.1mg, 0.218mmol).Under the room temperature reaction solution stirring is added 1N hydrochloric acid after 2 hours.Mixing solutions is used anhydrous sodium sulfate drying after with dichloromethane extraction, filters back concentrating under reduced pressure filtrate.The gained concentrated residue is handled with silica gel column chromatography, and concentrating under reduced pressure is by the methyl alcohol that contains 0.5% trifluoroacetic acid: (=1: the cut that elutriant 30) obtains obtains to be white in color solid title compound (54mg, 0.098mmol, 94%) to methylene dichloride.
1H-NMR(400MHz，DMSO-d
6)δ：4.45-4.60(2H，m)，6.29(1H，s)，7.29-7.55(3H，m)，7.69(2H，d，J＝8.9Hz)，7.80(2H，d，J＝8.9Hz)，7.81(1H，s)，8.38(1H，s).
MSm/z：551(M
++H).
Embodiment 287:(Z)-and 5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-2-(3-[1; 3] dioxolane-2-base propenyl) pyridine (isomer 287-A) reaches (E)-5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2; the 5-difluorophenyl) methyl]-2-(3-[1,3] dioxolane-2-base propenyl) pyridine (isomer 287-B)
Isomer 287-A isomer 287-B
In-78 ℃, (738mg, (1.59M hexane solution, 1.3ml 1.99mmol), stirred 1 hour to add n-Butyl Lithium in tetrahydrofuran (THF) 1.99mmol) (30ml) solution at bromination 2-(1,3-dioxolane-2-yl) ethyl triphenyl under the argon atmospher.[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl that adds in reaction soln that embodiment 258 obtains] formaldehyde (400mg, 0.904mmol) after, stirred 4 hours after being warming up to room temperature.Use dichloromethane extraction after in reaction soln, adding saturated aqueous ammonium chloride.Organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains, acquisition is isomer 287-A (low the polarity) (140mg of colourless amorphous substance, 0.266mmol, 29%) and be isomer 287-B (high the polarity) (170mg of colourless amorphous substance, 0.323mmol, 36%).
Isomer 287-A
1H-NMR(400MHz，CDCl
3)δ：3.03-3.17(2H，m)，3.88-4.10(4H，m)，5.11(1H，t，J＝4.3Hz)，6.10(1H，dt，J＝12.0，7.6Hz)，6.25(1H，s)，6.65(1H，d，J＝12.0Hz)，6.93-6.99(1H，m)，7.03-7.09(1H，m)，7.44(2H，d，J＝8.6Hz)，7.61(2H，d，J＝8.6Hz)，7.67-7.71(1H，m)，8.10(1H，s)，8.49(1H，s).
MSm/z：526(M
++H).
Isomer 287-B
1H-NMR(400MHz，CDCl
3)δ：2.67-2.71(2H，m)，3.88-4.08(4H，m)，5.07(1H，t，J＝4.6Hz)，6.20(1H，s)，6.68(1H，d，J＝15.9Hz)，6.85-7.00(2H，m)，7.02-7.08(1H，m)，7.44(2H，d，J＝8.1Hz)，7.55-7.62(1H，m)，7.61(2H，d，J＝8.1Hz)，7.96(1H，s)，8.43(1H，s).
MSm/z：526(M
++H).
Embodiment 288:4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] butyraldehyde
Elder generation's water again with ethanol to draw Buddhist nun's nickel suspension liquid (day emerging リ カ Co., Ltd., R-100) wash after, add ethanol and form alcohol suspending liquid.Reach (E)-5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl at (Z)) (2; the 5-difluorophenyl) methyl]-2-(3-[1; 3] pyridine (80mg dioxolane-2-base propenyl); 0.152mmol) ethanol (5ml) and 1; add this alcohol suspending liquid (1ml) in the mixing solutions of 4-two alkane (3ml), under the nitrogen atmosphere of 1 air pressure in high degree of agitation 30 minutes.Concentrating under reduced pressure behind the filtering reacting solution.
At 1 of gained concentrated residue, add concentrated hydrochloric acid (1ml) in 4-two alkane (4ml) solution, stirred 1 hour under the room temperature.Behind the concentrated solvent, in residue, add saturated sodium bicarbonate aqueous solution under the decompression, use ethyl acetate extraction.Organic layer saturated common salt water washing, gained organic layer with dried over mgso after concentrating under reduced pressure.Residue obtainedly handle with the flash chromatography on silica gel method, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=4: 1 wash-out portion obtains obtains to be the title compound (44mg, 0.0908mmol, 59%) of colourless amorphous substance.
1H-NMR(400MHz，CDCl
3)δ：2.09-2.17(2H，m)，2.56(2H，td，J＝7.3，1.5Hz)，2.92(2H，t，J＝7.7Hz)，6.21(1H，s)，6.92-6.97(1H，m)，7.03-7.08(1H，m)，7.45(2H，d，J＝8.6Hz)，7.51-7.55(1H，m)，7.61(2H，d，J＝8.6Hz)，7.95(1H，s)，8.47(1H，s)，9.81(1H，t，J＝1.5Hz).
MSm/z：484(M
++H).
Embodiment 289:4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] butyric acid
At 4-[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (40mg, (84 μ l 0.745mmol), stirred 9 hours under the room temperature butyraldehyde to add 30% aqueous hydrogen peroxide solution in formic acid 0.0828mmol) (1ml) solution.In reaction soln, add water, use ethyl acetate extraction.Organic layer is water and saturated common salt water washing successively, organic layer with dried over mgso after concentrating under reduced pressure.The residue obtained hexane of using: re-crystallizing in ethyl acetate, the title compound (13mg, 0.0260mmol, 32%) of the powder that obtains to be white in color.
1H-NMR(400MHz，CDCl
3)δ：2.16-2.18(2H，m)，2.46(2H，t，J＝7.2Hz)，2.99(2H，t，J＝7.5Hz)，6.22(1H，s)，6.92-6.98(1H，m)，7.03-7.08(1H，m)，7.45(2H，d，J＝8.6Hz)，7.51-7.56(1H，m)，7.61(2H，d，J＝8.6Hz)，8.00(1H，s)，8.49(1H，s).
mp：147-148℃.
MSm/z：500(M
++H).
Embodiment 290:2-brooethyl-5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine
In 0 ℃, embodiment 256 obtain [5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] methyl alcohol (582mg, 1.41mmol) methylene dichloride (15ml) solution in add carbon tetrabromide (936mg, 2.82mmol), add again triphenylphosphine (407mg, 1.55mmol).Stir concentrating under reduced pressure reaction mixture after 15 hours under the room temperature, residue obtainedly handle with the silica gel flash column chromatography.Concentrating under reduced pressure is by hexane: the cut that ethyl acetate=20: 1 wash-out portion obtains obtains to be the title compound (518mg, 1.09mmol, 77%) of colorless oil.
1H-NMR(400MHz，CDCl
3)δ：4.51(1H，d，J＝10.5Hz)，4.54(1H，d，J＝10.5Hz)，6.03(1H，s)，6.94-7.06(2H，m)，7.10-7.16(1H，m)，7.23(2H，d，J＝8.5Hz)，7.28(2H，d，J＝8.5Hz)，7.73(1H，s)，8.49(1H，s).
MSm/z：474，476(M
++H).
Embodiment 291:[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] acetonitrile
Under the argon atmospher, in room temperature at 2-brooethyl-5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine (516mg, 1.09mmol) acetonitrile (10ml) solution in add trimethylsilyl nitrile (0.226ml, 1.63mmol), add tetrahydrofuran solution (1M, the 1.63ml of tetrabutylammonium again, 1.63mmol), stirred 30 minutes.The concentrating under reduced pressure reaction mixture is residue obtainedly handled with the silica gel flash column chromatography.Concentrating under reduced pressure is by hexane: the cut that ethyl acetate=9: 1 wash-out portion obtains obtains to be the title compound (390mg, 0.93mmol, 85%) of brown oil.
1H-NMR(400MHz，CDCl
3)δ：3.90(1H，d，J＝19.0Hz)，3.95(1H，d，J＝19.0Hz)，6.04(1H，s)，6.96-7.07(2H，m)，7.12-7.18(1H，m)，7.24(2H，d，J＝8.8Hz)，7.29(2H，d，J＝8.8Hz)，7.67(1H，s)，8.52(1H，s).
MSm/z：421(M
++H).
Embodiment 292:[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] acetonitrile
[5-chloro-4-[(4-chlorobenzene sulfenyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] acetonitrile (387mg, 0.92mmol) ethyl acetate (5ml) solution in add methyl alcohol (5ml), 31% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids, six ammonium tetrahydrate (227mg, 0.18mmol), stirred 2 hours under the room temperature.In reaction mixture, add water, add saturated sodium bicarbonate aqueous solution after boiling off ethyl acetate and methyl alcohol under the decompression, use the dichloromethane extraction resultant.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, residue obtainedly handles with the silica gel flash column chromatography, concentrating under reduced pressure is by hexane: the cut that ethyl acetate=17: 3 wash-out portion obtains, the acquisition solid title compound (364mg, 0.80mmol, 87%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：4.02(2H，s)，6.22(1H，s)，6.92-6.99(1H，m)，7.04-7.11(1H，m)，7.46(2H，d，J＝8.6Hz)，7.48-7.54(1H，m)，7.62(2H，d，J＝8.6Hz)，8.15(1H，s)，8.56(1H，s).
MSm/z：453(M
++H).
Embodiment 293:[5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] acetate
Under the room temperature, at [5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 5-difluorophenyl) methyl] pyridine-2-yl] (113mg adds the mixture of the entry (2ml) and the vitriol oil (2ml) to acetonitrile in acetate 0.25mmol) (2ml) solution, stirred 2 hours in 100 ℃.Add water after reaction mixture is cooled to room temperature, use dichloromethane extraction.The organic layer anhydrous sodium sulfate drying filters back concentrating under reduced pressure filtrate, and residue obtained mixed solvent washing back leaching with ether/hexane obtains to be white in color solid title compound (101mg, 0.21mmol, 86%).
1H-NMR(400MHz，CDCl
3)δ：1.74(1H，brs)，4.00(1H，d，J＝17.9Hz)，4.05(1H，d，J＝17.9Hz)，6.23(1H，s)，6.92-6.99(1H，m)，7.04-7.11(1H，m)，7.45(2H，d，J＝8.6Hz)，7.48-7.54(1H，m)，7.62(2H，d，J＝8.6Hz)，8.12(1H，s)，8.52(1H，s)
MSm/z：472(M
++H).
Reference example 53:(2,5-two chloro-4-pyridyl) (2, the 6-difluorophenyl) methyl alcohol
Under the argon atmospher, in-78 ℃ Diisopropylamine (0.520ml, add in tetrahydrofuran solution 3.72mmol) (12ml) n-Butyl Lithium (the 1.60M hexane solution, 2.33ml, 3.72mmol) after, stirred 30 minutes in-78 ℃.Add 2 in reaction solution, (500mg behind tetrahydrofuran solution 3.38mmol) (2ml), stirred 1 hour in-78 ℃ the 5-dichloropyridine.Then, add 2, (395mg, tetrahydrofuran solution 3.72mmol) (2ml) stirred 2 hours in-78 ℃ the 6-difluorobenzaldehyde.After in reaction solution, adding 1N hydrochloric acid (7ml), be warming up to room temperature.Reaction solution dilutes back water and saturated common salt water washing with ethyl acetate.With concentrating after the dried over mgso, gained solid washed with dichloromethane obtains to be white in color solid title compound (746mg, 2.57mmol, 76%).
1H-NMR(400MHz，CDCl
3)δ：2.62(1H，brd，J＝3.7Hz)，6.30(1H，brs)，6.87-6.93(2H，m)，7.28-7.37(1H，m)，7.91(1H，s)，8.25(1H，s).
MSm/z：290(M
++H).
Embodiment 294:2,5-two chloro-4-[(4-chloro-phenyl-alkylsulfonyls) (2, the 6-difluorophenyl) methyl] pyridine
Make (2,5-two chloro-4-pyridyl) (2, the 6-difluorophenyl) methyl alcohol that reference example 53 obtains (744mg 2.57mmol) is suspended in methylene dichloride (6ml), add thionyl chloride (0.5ml) and dimethyl formamide (1) after, stirred 5 hours under the room temperature.Add again under the room temperature of thionyl chloride (1.0ml) back and stirred 24 hours.Concentration of reaction solution is used dichloromethane extraction with saturated sodium bicarbonate aqueous solution after to residue obtained the neutralization.Use dried over mgso after extraction liquid water and the saturated common salt water washing, concentrate.With the residue obtained dimethyl formamide (10ml) that is dissolved in, add 4-chlorobenzene-sulfinic acid sodium (613mg, 3.08mmol) after, in 50 ℃ of heating 5 hours, then 80 ℃ of heating 3 hours.Reaction solution dilutes with ethyl acetate, water and saturated common salt water washing.With concentrating after the dried over mgso, residue obtainedly handle with the silica gel flash column chromatography, concentrate by hexane: the cut of ethyl acetate=wash-out portion acquisition in 4: 1, gained solid ether-hexane recrystallization, the acquisition solid title compound (761mg, 1.69mmol, 66%) that is white in color.
1H-NMR(400MHz，CDCl
3)δ：6.02(1H，s)，6.84-6.90(2H，m)，7.32-7.40(1H，m)，7.46(2H，d，J＝8.5Hz)，7.65(2H，d，J＝8.5Hz)，8.35(1H，s)，8.43-8.46(1H，m)
MSm/z：448(M
++H).
Embodiment 295:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 6-difluorophenyl) methyl]-2-(3,4-dimethoxy benzene methylamino) pyridine
Under the argon atmospher; in 2 of embodiment 294 acquisitions; 5-two chloro-4-[(4-chloro-phenyl-alkylsulfonyls) (2; the 6-difluorophenyl) methyl] pyridine (755mg; 1.68mmol) N-N-methyl-2-2-pyrrolidone N-solution (20ml) in add 3; 4-dimethoxy benzene methanamine (0.745ml, 5.04mmol), in 150 ℃ of heating 5 hours.Reacting liquid temperature dilutes with ethyl acetate after being back to room temperature, uses saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing then.With concentrating after the dried over mgso, residue obtainedly handle with the silica gel flash column chromatography, concentrate hexane: the be white in color title compound (295mg, 0.509mmol, 30%) of amorphous substance of the cut that ethyl acetate=2: 1 wash-out portion obtains, acquisition.
1H-NMR(400MHz CDCl
3)δ：3.89(3H，s)，3.90(3H，s)，4.48(2H，d，J＝5.6Hz)，5.06(1H，t，J＝5.6Hz)，6.02(1H，s)，6.81-6.88(3H，m)，6.93-7.00(2H，m)，7.28-7.36(1H，m)，7.40(2H，d，J＝8.3Hz)，7.51(1H，s)，7.56(2，d，J＝8.3Hz)，8.00(1H，s).
MSm/z：579(M
++H).
Embodiment 296:5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl) (2, the 6-difluorophenyl) methyl] pyridine-2-base amine
5-chloro-4-[(4-chloro-phenyl-alkylsulfonyl with embodiment 295 acquisitions) (2, the 6-difluorophenyl) methyl]-(293mg 0.506mmol) was dissolved in trifluoroacetic acid (4ml) to 2-(3,4-dimethoxy benzene methylamino) pyridine, in 65 ℃ of heating 2 hours.Concentration of reaction solution makes with saturated sodium bicarbonate aqueous solution and residue obtainedly to use ethyl acetate extraction after being alkalescence.Extraction liquid water and saturated common salt water washing are with concentrating after the dried over mgso.Residue obtainedly handle with the silica gel flash column chromatography, concentrate by hexane: the cut of ethyl acetate=wash-out portion acquisition in 2: 1, with ethyl acetate-hexane the gained solid is carried out recrystallization, obtain to be white in color solid title compound (147mg, 0.343mmol, 68%).
1H-NMR(400MHz，CDCl
3)δ：4.62(2H，s)，6.01(1H，s)，6.82-6.89(2H，m)，7.29-7.38(1H，m)，7.44(2H，d，J＝8.5Hz)，7.59(1H，brs)，7.65(2H，d，J＝8.5Hz)，7.99(1H，s).
IR(ATR)cm
-1：3502，3400，1620，1603，1545，1471，1412，1333，1279，1230，1151，1084，993，928，891，829，795，756，623，559，513，459.
mp：179-181℃.
MSm/z：429(M
++H).
Ultimate analysis: C
18H
12Cl
2F
2N
2O
2S: theoretical value: C, 50.36; H, 2.82; Cl, 16.52; F, 8.85; N, 6.53; S, 7.47. measured value: C, 50.36; H, 2.83; Cl, 16.39; F, 8.88; N, 6.48; S, 7.56.
The test example
The measuring method of the generation excretory inhibitory substance of amyloid beta
By following method, the amyloid beta generation inhibition activity of embodiment compound is tested.
In human glioma cell's (H4 cell), import APP751 gene, make the E35 cell as people's wild-type beta amyloid precursor protein gene.
The E35 cell inoculation in 96 orifice plates, is adopted the improved Eagle substratum of Dulbecco (10%FBS-DMEM) of 10% foetal calf serum that contains deactivation, in 37 ℃ incubator, cultivate.Inoculate after 24 hours, make its concentration reach 2000 times DMSO of ultimate density with having dissolved tested compound, 1/2000 capacity that adds nutrient solution is in each hole.Cultivate again after 24 hours and reclaim culture supernatant, the amount of amyloid beta secreted in culture supernatant (A β) is carried out quantitatively by sandwich type enzyme linked immunological absorption (ELISA) method.That is, will discern the monoclonal antibody 25-1 of A β 25-35 at 96 hole ELISA immobilization in the plate, in 4 ℃ of insulations of carrying out 16～20 hours.With phosphoric acid buffer agent (pH7.4) (PBS) it is washed after, add the monoclonal antibody MA32-40 of biotin labeled A β 1-8, left standstill 2 hours in 4 ℃.Remove supernatant liquor, behind PBS thorough washing hole, add the streptavidin that combines alkaline phosphatase, add Blue Phos (KPL company) again, measure absorbancy as substrate.Adopt the A β of concentration known,, obtain the A β amount that comprises in the culture supernatant with the typical curve of making in addition.Make comparisons with the A β of the control cells of only having added DMSO amount, the compound concentration that the generation of 50% the A β that observes is suppressed is as IC
50
In addition, obtain the cytotoxicity of tested compound according to following steps.With above-mentioned same, in being incubated at the H4 cell of 10%FBS-DMEM, add the tested compound that is dissolved in DMSO.Cultivate after 72 hours, adopt Alamar Blue (BIOSOURCE company) to measure the existence cell count.80% concentration when following that the existence cell count is reached the control cells of only having added DMSO is defined as cytotoxicity and manifests concentration.
With IC
50Manifesting the compound of deviation of concentration more than 10 times with cytotoxicity is judged to be and has amyloid beta matter secretion and generate and suppress active compound.
Compound of the present invention utilizes the table 1 that the results are shown in that the said determination method estimates.In the table 1, with IC
50Compound below 5nM is designated as +++, the compound of 5～50nM is designated as ++, the change thing of 50～500nM is designated as+.
Table 1
| Compound | Active | Compound | Active |
| 1 | + | 220(B) | + |
| 19 | + | 221 | +++ |
| 20 | + | 222 | ++ |
| 23 (compd As) | ++ | 225 | ++ |
| 42 | + | 234 | +++ |
| 43 | + | 236 | +++ |
| 46 | + | 239 | + |
| 55 | ++ | 240 | ++ |
| 56 | ++ | 241 | ++ |
| 57 | ++ | 242 | + |
| 59 | ++ | 243 | ++ |
| 61 | +++ | 245 | ++ |
| 82 | + | 246 | ++ |
| 84 | + | 247 | +++ |
| 106 | +++ | 249 | +++ |
| 109 | ++ | 250 | ++ |
| 111 | ++ | 251 | +++ |
| 114 | ++ | 254 | + |
| 115 | +++ | 261 | ++ |
| 116 | ++ | 267 | ++ |
| 164 | +++ | 268 | +++ |
| 168 | +++ | 269 | +++ |
| 176 | +++ | 270 | ++ |
| 196 | +++ | 271 | +++ |
| 197 | +++ | 274 | ++ |
| 203 | ++ | 276 | ++ |
| 211 | +++ | 278 | +++ |
| 215 | +++ | 279 | +++ |
| 216 | +++ | 280 | +++ |
Claims (14)
1. general formula (1)
Compound, its salt or its solvate of expression,
In the formula,
R
1Expression has 1-3 substituent phenyl that is selected from halogen atom and cyano group;
R
3Expression has 1-2 substituent phenyl that is selected from halogen atom and trihalomethyl group;
R
4The expression hydrogen atom; With
X represents-SO
2-.
2. compound as claimed in claim 1, its salt or its solvate, wherein, R
2By general formula (2)
Expression, in the formula, R
10Be hydrogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkyl sulphinyl C
1-6Alkyl, C
1-6Alkyl sulphonyl C
1-6Alkyl, carboxyl C
1-6Alkyl, heterocycle-C
1-6Alkyl or general formula-SO
2-R
11The group of expression, in the formula, R
11Expression C
1-6Alkyl, heterocyclic radical, C
1-6Alkyl-heterocyclic radical, heterocycle-C
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkylamino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, carboxyl C
1-6Alkyl, formamyl C
1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino, R
12Expression hydrogen atom, C
1-6Alkyl, hydroxyl or amino, here, R
11And R
12Can and R
11Bonded sulphur atom and R
12The bonded nitrogen-atoms forms the aliphatics heterocycle of 5 yuan or 6 yuan, R together
13Expression C
1-6Alkyl, halogen atom or cyano group.
3. compound as claimed in claim 1, its salt or its solvate, wherein, R
2Be general formula (3)
The group of expression, in the formula, R
10By-SO
2-R
11Expression, in the formula, R
11Expression C
1-6Alkyl, heterocyclic radical, C
1-6Alkyl-heterocyclic radical, heterocycle-C
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkylamino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, carboxyl C
1-6Alkyl, formamyl C
1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino, R
12Expression hydrogen atom, C
1-6Alkyl, hydroxyl or amino, here, R
11And R
12Can and R
11Bonded sulphur atom and R
12The bonded nitrogen-atoms forms the aliphatics heterocycle of 5 yuan or 6 yuan, R together
13Expression C
1-6Alkyl, halogen atom or cyano group.
4. compound as claimed in claim 1, its salt or its solvate, wherein, R
2By general formula (4)
Expression, in the formula, R
13Expression C
1-6Alkyl, halogen atom or cyano group, n are represented 0～6 integer.
5. compound as claimed in claim 1, its salt or its solvate,
Wherein, R
1Be 2,5-difluorophenyl or 2-fluoro-5-cyano-phenyl, R
3Be 4-chloro-phenyl-, 4-fluorophenyl, 2,4 difluorobenzene base, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl-, 4-trifluoromethyl, 5-chloro-2-thienyl, 5-chloro-2-pyridyl, 6-chloro-3-pyridyl or 6-trifluoromethyl-3-pyridyl, R
2By general formula (5)
Expression, in the formula, R
10Be hydrogen atom, C
1-6Alkyl, hydroxyl C
1-6Alkyl, C
1-6Alkyl sulphinyl C
1-6Alkyl, C
1-6Alkyl sulphonyl C
1-6Alkyl, carboxyl C
1-6Alkyl, heterocycle-C
1-6Alkyl or general formula-SO
2-R
11The group of expression, in the formula, R
11Expression C
1-6Alkyl, heterocyclic radical, C
1-6Alkyl-heterocyclic radical, heterocycle-C
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkylamino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, carboxyl C
1-6Alkyl, formamyl C
1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino, R
12Expression hydrogen atom, C
1-6Alkyl, hydroxyl or amino, here, R
11And R
12Can and R
11Bonded sulphur atom and R
12The bonded nitrogen-atoms forms the aliphatics heterocycle of 5 yuan or 6 yuan, R together
13Expression C
1-6Alkyl, halogen atom or cyano group.
6. compound as claimed in claim 1, its salt or its solvate,
Wherein, R
1Be 2,5-difluorophenyl or 2-fluoro-5-cyano-phenyl, R
3Be 4-chloro-phenyl-, 4-fluorophenyl, 2,4 difluorobenzene base, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl-, 4-trifluoromethyl, 5-chloro-2-thienyl, 5-chloro-2-pyridyl, 6-chloro-3-pyridyl or 6-trifluoromethyl-3-pyridyl, R
2Be general formula (6)
The group of expression, in the formula, R
10By-SO
2-R
11Expression, in the formula, R
11Expression C
1-6Alkyl, heterocyclic radical, C
1-6Alkyl-heterocyclic radical, heterocycle-C
1-6Alkyl, hydroxyl C
1-6Alkyl, amino C
1-6Alkyl, C
1-6Alkylamino C
1-6Alkyl, two (C
1-6Alkyl) amino C
1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C
1-6Alkylamino or two (C
1-6Alkyl) amino, R
12Expression hydrogen atom, C
1-6Alkyl, hydroxyl or amino, here, R
11And R
12Can and R
11Bonded sulphur atom and R
12The bonded nitrogen-atoms forms the aliphatics heterocycle of 5 yuan or 6 yuan, R together
13Expression C
1-6Alkyl, halogen atom or cyano group.
7. compound as claimed in claim 1, its salt or its solvate, wherein, R
1Be 2,5-difluorophenyl or 2-fluoro-5-cyano-phenyl, R
3Be 4-chloro-phenyl-, 4-fluorophenyl, 2,4 difluorobenzene base, 3,4-difluorophenyl, 3-fluoro-4-chloro-phenyl-, 4-trifluoromethyl, 5-chloro-2-thienyl, 5-chloro-2-pyridyl, 6-chloro-3-pyridyl or 6-trifluoromethyl-3-pyridyl, R
2By general formula (7)
Expression, in the formula, R
13Expression C
1-6Alkyl, halogen atom or cyano group, n are represented 0～6 integer.
8. pharmaceuticals is characterized in that, described pharmaceuticals comprise that the described compound of claim 1, its salt or its solvate are as effective constituent.
9. pharmaceuticals as claimed in claim 8, its feature also are, described pharmaceuticals are the generation of amyloid beta, the prevention or the curative of disease that diacrisis caused.
10. pharmaceuticals as claimed in claim 9, its feature are that also the generation of amyloid beta, the disease that diacrisis caused are degenerative brain disorder or mongolism.
11. medical composition is characterized in that, contains the carrier that allows in the described compound of claim 1, its salt or its solvate and the pharmacy.
12. the described compound of claim 1, its salt or the application of its solvate in the preparation of pharmaceuticals.
13. application as claimed in claim 12, its feature also be, described pharmaceuticals are the generation of amyloid beta, the prevention or the curative of disease that diacrisis caused.
14. application as claimed in claim 13, its feature are that also the generation of amyloid beta, the disease that diacrisis caused are degenerative brain disorder or mongolism.
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|---|---|---|---|
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Citations (6)
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|---|---|---|---|---|
| US4116665A (en) * | 1976-04-02 | 1978-09-26 | Eli Lilly And Company | Method of regulating the growth of aquatic weeds with pyridine derivatives |
| JPS5533473A (en) * | 1978-08-08 | 1980-03-08 | Sterling Drug Inc | Substituted *phenylsulfonyl*methanes and their manufacture |
| JPH0625168A (en) * | 1992-07-10 | 1994-02-01 | Nippon Bayeragrochem Kk | Fungicidal benzylpyridines |
| JPH0656780A (en) * | 1992-08-01 | 1994-03-01 | Nippon Bayeragrochem Kk | Fungicidal alpha-substituted benzylpyridines |
| WO1996041799A1 (en) * | 1995-06-12 | 1996-12-27 | Hoechst Schering Agrevo Gmbh | Sulphonamides as herbicides and plant-growth regulators |
| WO2002081433A1 (en) * | 2001-04-05 | 2002-10-17 | Merck Sharp & Dohme Limited | Sulphones which modulate the action of gamma secretase |
-
2004
- 2004-06-29 ZA ZA200509613A patent/ZA200509613B/en unknown
- 2004-06-29 CN CNB2004800169993A patent/CN100378072C/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4116665A (en) * | 1976-04-02 | 1978-09-26 | Eli Lilly And Company | Method of regulating the growth of aquatic weeds with pyridine derivatives |
| JPS5533473A (en) * | 1978-08-08 | 1980-03-08 | Sterling Drug Inc | Substituted *phenylsulfonyl*methanes and their manufacture |
| JPH0625168A (en) * | 1992-07-10 | 1994-02-01 | Nippon Bayeragrochem Kk | Fungicidal benzylpyridines |
| JPH0656780A (en) * | 1992-08-01 | 1994-03-01 | Nippon Bayeragrochem Kk | Fungicidal alpha-substituted benzylpyridines |
| WO1996041799A1 (en) * | 1995-06-12 | 1996-12-27 | Hoechst Schering Agrevo Gmbh | Sulphonamides as herbicides and plant-growth regulators |
| WO2002081433A1 (en) * | 2001-04-05 | 2002-10-17 | Merck Sharp & Dohme Limited | Sulphones which modulate the action of gamma secretase |
Non-Patent Citations (1)
| Title |
|---|
| 'The alkylation of coumarin at C-3 of 4-hydroxycoumarin'. TABAKOVIC I. ET AL.ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL,Vol.29 No.2. 1997 * |
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| CN1812964A (en) | 2006-08-02 |
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