CN1812964A - Heterocyclic methyl sulfone derivative - Google Patents
Heterocyclic methyl sulfone derivative Download PDFInfo
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- CN1812964A CN1812964A CN 200480016999 CN200480016999A CN1812964A CN 1812964 A CN1812964 A CN 1812964A CN 200480016999 CN200480016999 CN 200480016999 CN 200480016999 A CN200480016999 A CN 200480016999A CN 1812964 A CN1812964 A CN 1812964A
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Abstract
The invention provides a compound which restrains production and exudation of alpha amyloid. A general formula (1) so represents the compound, oxide of the compound, S-oxide of the compound, salt of the compound and drug which contains the compound, wherein in the formula, R1 represents heterocyclic radical which can be provided with substituent, R2 represents annular alkyl which can be provided with the substituent or the heterocyclic radical which can be provided with the substituent, R3 represents the annular alkyl which can be provided with the substituent or the heterocyclic radical which can be provided with the substituent, R4 represents hydrogen atoms or C1-6 alkyl, and X represents -S-, -SO- or -SO2.
Description
Technical field
The present invention relates to the generations to amyloid beta to secrete inhibited noval chemical compound, and the various diseases as caused by the generation diacrisis of amyloid beta, for example, degenerative brain disorder, Down syndrome, the medicine with the calm related Other diseases of amyloid protein.
Background technique
Degenerative brain disorder be there is neuron degeneration, fall off and the formation of senile plaque as nerve fibril variation pathological characteristics neurodegenerative disease.Degenerative brain disorder causes the dementia symptom of the progressive such as memory, cognition, thinking, judgement damage, until final dead.Currently, not finding the effective method of prevention and treatment to the disease also.
The main protein for being formed in the senile plaque of intracerebral calmness is amyloid beta (amyloid β protein, A β), it is formed by 39~43 amino acid.It is generally acknowledged that amyloid beta shows cell disorders, cause degenerative brain disorder (non-patent literature 1) whereby.Amyloid beta secreted by cell is mainly by 40 or 42 amino acids formed polypeptides, it is especially known stronger by the compendency of 42 amino acids formed amyloid betas, it is calm in intracerebral in early stage, and cytotoxicity is relatively strong (non-patent literature 2).Amyloid beta generates ubiquitously in body, but its original function is also not known.
Amyloid beta is processed by the amyloid precusor protein (APP) as memebrane protein and generates.There is the case of discovery app gene mutation in familial Alzheimer patient.Furthermore it is known that having imported the generation secretory volume of amyloid beta in the cell of the app gene of the mutation increased.It is therefore contemplated that inhibiting the drug of the generation secretion of amyloid beta effective to the prevention or treatment of degenerative brain disorder.
During amyloid precusor protein shearing amyloid beta, as beta-secretase related with the shearing of amyloid beta N-terminal, it was recently reported that aspartic protease BACE (side β APP shears enzyme) (non-patent literature 3) and Asp1 (non-patent literature 4).In addition, for the gamma secretase for shearing C-terminal, strong indication Presenilin constitutes part of it (non-patent literature 5).(non-patent literature 6) is reported to the inhibitor of these beta-secretases and gamma secretase, they are nearly all peptides.
SMITH etc. is disclosed in patent document 1 with sulfonamide backbones, the compound for inhibiting amyloid beta to generate.In addition, BELANGER etc. discloses the compound for bicycloalkyl sulphonamide skeleton, inhibiting gamma secretase in patent document 2.In addition, disclosing the diaryl sulfone compound for inhibiting gamma-secretase in patent document 3,4,5.The thio naphthalene derivatives for inhibiting the agglutination of amyloid protein are disclosed in patent document 6.
Non-patent literature 1:Science, volume 259, page 514 (1993)
Non-patent literature 2:Journal of Biological Chemistry, volume 270, page 7013 (1995)
Non-patent literature 3:Science, volume 286, page 735 (1999)
Non-patent literature 4:Molecular and Cellular Neuroscience, volume 16, page 609 (2000)
Non-patent literature 5:Journal of Medicinal Chemi stry, volume 44, page 2039 (2001)
Patent document 1: No. 00/50391 pamphlet of International Publication No.
Patent document 2: No. 01/70677 pamphlet of International Publication No.
Patent document 3: No. 02/081433 pamphlet of International Publication No.
Patent document 4: No. 02/081435 pamphlet of International Publication No.
Patent document 5: No. 03/18543 pamphlet of International Publication No.
Patent document 6: Japanese Patent Laid-Open 9-95444 bulletin
The announcement of invention
The object of the present invention is to provide it is different from the chemical structure of aforesaid known compound, the generation of amyloid beta is secreted with good inhibiting effect, with the compound as character desired by pharmaceuticals.
Present inventor has found after carrying out various researchs; there is heterocycle methyl mercapto compound, heterocycle first sulfenyl compound and the heterocyclic methyl sulphones indicated with the following general formula (1) good amyloid beta to generate secretion inhibition; they are useful as the medicine for generating various diseases caused by diacrisis as amyloid beta, so as to complete the present invention.
That is, the present invention provides general formula below (1)
The compound of expression, its N- oxide, its S- oxide, its salt or its solvate,
In formula, R1And R3It separately indicates to have the aromatic hydrocarbyl of substituent group or can have the aromatic heterocycle of substituent group, R2Indicate the saturated or unsaturated monocyclic type heteroaromatic base or unsaturated polycyclic heterocycle base that there can be substituent group, R4Indicate hydrogen atom or C1-6Alkyl, X expression-S- ,-SO- or-SO2-。
In addition, the present invention provides compound, its N- oxide, its S- oxide, its salt or its solvate for indicating using above-mentioned general formula (1) as the pharmaceuticals of effective component.
The present invention also provides the medical compositions of the carrier allowed in the compound indicated containing above-mentioned general formula (1), its N- oxide, its S- oxide, its salt or its solvate and pharmacy.
Compound, its N- oxide, its application of S- oxide, its salt or its solvate in the preparation of pharmaceuticals indicated the present invention also provides above-mentioned general formula (1).
Furthermore, the present invention also provides the treatment methods for generating the disease that diacrisis causes by amyloid beta, this method is characterized in, gives compound, its N- oxide, its S- oxide, its salt or its solvate that a effective amount of above-mentioned general formula (1) indicates.
The present invention is capable of providing the generation to amyloid beta and secretes with good inhibiting effect, with the compound as character desired by pharmaceuticals.
The best mode to carry out an invention
The compound that mutual-through type (1) indicates is illustrated.
R1And R3The aromatic hydrocarbyl of expression can enumerate phenyl and naphthalene, preferably phenyl.
R1And R3The aromatic heterocycle of expression can enumerate heteroatomic 5~6 yuan of aromatic heterocycles that nitrogen-atoms, oxygen atom and sulphur atom are selected from 1~4, can specifically enumerate pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, tetrazole radical, thiadiazolyl group, pyrazinyl, pyridazinyl etc..
Wherein, preferably thienyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyl, thiazolyl, thiadiazolyl group, pyridyl group, pyrimidine radicals and pyridazinyl, more preferably thienyl, pyridyl group, pyrimidine radicals and pyridazinyl, particularly preferably thienyl, pyridyl group and pyrimidine radicals.
R2The saturation monocyclic type heteroaromatic base of expression can enumerate heteroatomic 3~7 circle heterocyclic ring base that nitrogen-atoms, oxygen atom and sulphur atom are selected from 1~4, can specifically enumerate pyrrolidinyl, tetrahydrofuran base, oxetanyl, tetrahydro-thienyl, piperidyl, piperazinyl, high piperazine base, morpholinyl, thio-morpholinyl, aziridine base, imidazolidinyl, pyrazolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, dioxolanyl, penta ring group of oxygen thia, hexahydropyrimidine base etc..
Wherein, preferably pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, piperidyl, piperazinyl, high piperazine base, morpholinyl, thio-morpholinyl, imidazolidinyl, pyrazolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, preferably piperidyl, THP trtrahydropyranyl, tetrahydro thiapyran base, hexahydropyrimidine base.
R2The unsaturated monocyclic type heteroaromatic base of expression can be enumerated with 1~4 selected from nitrogen-atoms, heteroatomic 4~7 yuan of the heterocycle of oxygen atom and sulphur atom, pyrrole radicals can specifically be enumerated, furyl, thienyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazine radical, tetrazole radical, thiadiazolyl group, oxadiazoles base, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, oxazoline group, thiazolinyl, isoxazoline base, isothiazoline base, pyranose, dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base, tetrahydro pyridazine base, tetrahydro-pyrimidine base etc..
Wherein, preferably pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl group, pyrimidine radicals, pyrazinyl, triazine radical, tetrazole radical, pyrrolinyl, imidazolinyl, pyrazolinyl, thiadiazolyl group, pyrazinyl, pyridazinyl, tetrahydro pyridyl, dihydro-pyrimidin base, tetrahydro pyridazine base, preferably imidazole radicals, pyridyl group, pyrimidine radicals and thiazolyl.
R2The unsaturated polycyclic heterocycle base of expression can be enumerated with 1~4 selected from nitrogen-atoms, heteroatomic 8~10 yuan of the heterocycle of oxygen atom and sulphur atom, benzofuranyl can specifically be enumerated, benzothiazolyl, indyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzo dioxane base, benzothienyl, benzisothia oxazolyl, benzo isoxazolyl, chromene base, chromanyl, heterochromatic alkenyl, isochroman base, indolinyl, indazolyl, indolizine base, isoindolyl, isoindoline base, quinazinyl, quinoxalinyl, quinazolyl, cinnoline base, benzo pyridazinyl, naphthyridines base, purine radicals, tetrahydro-thiazoles and pyridyl group, imidazopyridyl, triazolo pyridyl, pyrrolopyridinyl, carbazyl, xanthyl, acridine Base, phenazinyl, phenoxazine base, phenothiazinyl, quininuclidinyl etc..
Wherein, preferably benzofuranyl, benzothiazolyl, indyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzo dioxane base, benzothienyl, benzisothia oxazolyl, benzo isoxazolyl, chromene base, chromanyl, heterochromatic alkenyl, isochroman base, indolinyl, indazolyl, indolizine base, quinazinyl, quinoxalinyl, quinazolyl, cinnoline base, benzo pyridazinyl, naphthyridines base, imidazopyridyl and triazolo pyridyl, preferably benzimidazolyl, chromene base, imidazopyridyl and triazolo pyridyl.
R1And R3The aromatic hydrocarbyl or aromatic heterocycle of expression can be selected from halogen atom, C1-6Alkyl, trihalomethyl group, C1-6Alkoxy, C2-6Alkenyl, formoxyl, C2-6Alkanoyl, carboxyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, oxo base, nitro, cyano, amidino groups, C2-6Alkenyloxy, hydroxyl, thio group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio carbamoyl, two (C1-6Alkyl) thiocarbamoyl, sulfydryl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, C6-10Aromatic hydrocarbon-C1-6Identical or different 1~3 group of alkyl replaces.
As substitution R1And R3The aromatic hydrocarbyl of expression or the group of aromatic heterocycle, preferably halogen atom, C1-6Alkyl, trihalomethyl group, C1-6Alkoxy, cyano, amidino groups, hydroxyl, C1-6Alkyl amino, two (C1-6Alkyl) amino, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, preferably halogen atom, C1-6Alkyl, trihalomethyl group, C1-6Alkoxy and cyano, it is special it is good be halogen atom and cyano.In halogen atom, preferably chlorine atom and fluorine atom.
It may replace R2The group of the saturated or unsaturated monocyclic type heteroaromatic base or unsaturated polycyclic heterocycle base that indicate, can enumerate base-Q101-Q102-Q103-Q104-Q105-Q106-Q107, here, Q101Indicate singly-bound, C1-6Alkylidene, C2-6Alkenylene or heterocycle, Q102Indicate singly-bound ,-O- ,-NH- ,-CH=N- ,-C (alkyl)=N- ,-N (alkyl)-or-S-, Q103Indicate singly-bound ,-CO- ,-CS- ,-SO- ,-SO2Or-CONH-, Q104Indicate singly-bound, C1-6Alkylidene, C2-6Alkenylene, C3-8Cycloalkylidene, C4-7Sub- cycloalkenyl, aromatic hydrocarbyl or heterocycle, Q205Indicate singly-bound ,-NH- or-N (alkyl)-, Q106Indicate singly-bound ,-O- ,-CO- ,-CS- ,-SO2,-SO- or-S-, Q107Indicate hydrogen atom, halogen atom, hydroxyl, oxo base, C1-6Alkyl, C2-6Alkenyl, C3-7Naphthenic base, C1-6Alkoxy, C2-6Alkenyloxy, azido, cyano, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, C2-6Alkanoylamino, two (C2-6Alkanoyl) amino, carboxyamino, C1-6Alkoxycarbonyl amino, two (C1-6Alkoxy carbonyl) amino, heterocycle, aromatic hydrocarbyl, C4-7Cycloalkenyl, heterocycle-oxygroup or aromatic hydrocarbon-oxygroup.Here, C1-6Alkylidene or alkyl, C2-6Alkenylene or alkenyl, C3-7Cycloalkylidene or C3-7Naphthenic base, C4-7Sub- cycloalkenyl or C4-7Cycloalkenyl, heterocycle, heterocycle-oxygroup, aromatic hydrocarbyl or aromatic hydrocarbon-oxygroup can be selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, formoxyl, C2-6Alkanoyl, oxo base, nitro, cyano, azido, amidino groups, C2-6Alkenyloxy, hydroxyl, carboxyl, C7-16Aralkyl, thio group, C2-6Alkanoyl, C2-6Thio alkanoyl, thioformyl, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio carbamoyl, two (C1-6Alkyl) thiocarbamoyl, C1-6Alkoxycarbamoyl amino, C1-6Alkoxycarbamoyl (C1-6Alkyl) amino, C2-6Alkanoylamino, C2-6Alkanoyl (C1-6Alkyl) amino, thio C2-6Alkanoylamino, thio C2-6Alkanoyl (C1-6Alkyl) amino, Formylamino, formoxyl (C1-6Alkyl) amino, thioformyl amino, thioformyl (C1-6Alkyl) amino, C2-6Alkanoyloxy, formyloxy, C1-6Alkoxy-carbonyl oxy, carbamoyloxy, C1-6Alkyl carbamoyloxy base, two (C1-6Alkyl) carbamoyloxy, amino carbonyl amino, C1-6Alkyl amino-carbonyl-amino, two (C1-6Alkyl) amino carbonyl amino, amino carbonyl (C1-6Alkyl) amino, C1-6Alkyl amino-carbonyl (C1-6Alkyl) amino, two (C1-6Alkyl) amino carbonyl (C1-6Alkyl) amino, sulfydryl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, amino-sulfonyl, C1-6Alkyl amino sulfonyl, two (C1-6Alkyl) amino-sulfonyl, aminosulfonylamino, C1-6Alkyl amino sulfonyl amino, two (C1-6Alkyl) aminosulfonylamino, amino-sulfonyl (C1-6Alkyl) amino, C1-6Alkyl amino sulfonyl (C1-6Alkyl) amino, two (C1-6Alkyl) amino-sulfonyl (C1-6Alkyl) amino 1~3 group replace.
More specifically, it may replace R2The group of the heterocycle of expression is as described below.
That is, the R2The heterocycle of expression can be selected from halogen atom, cyano, C1-6Alkyl, hydroxyl, C1-6Alkoxy, C2-6Alkenyloxy, carboxyl C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl, heterocyclic-carbonyl C1-6Alkyl, hydroxyl C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfonyl C1-6Alkyl, N, N- dialkyl amino sulfonyl C1-6Alkyl, heterocycle-C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfenyl C1-6Alkyl, azido-C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, hydroxyl C1-6Alkyl amino C1-6Alkyl, C1-6Alkoxy C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkoxy C1-6Alkyl) amino C1-6Alkyl, N- hydroxyl C1-6Alkyl-N-C1-6Alkoxy C1-6Alkyl amino C1-6Alkyl, C2-6Alkanoylamino C1-6Alkyl, two (C2-6Alkanoyl) amino C1-6Alkyl, carboxyamino C1-6Alkyl, two (C1-6Alkyl-carbonyl-amino C1-6Alkyl) amino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, two (C1-6Alkoxy carbonyl) amino C1-6Alkyl, carbamoylamino C1-6Alkyl, N-C1-6Alkyl-carbamoyl amino C1-6Alkyl, (bis- (C of N, N-1-6Alkyl) carbamoyl) amino C1-6Alkyl, aminosulfonylamino C1-6Alkyl, N-C1-6Alkyl sulfonyl-amino C1-6Alkyl, (two (C1-6Alkyl) amino-sulfonyl) amino C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfuryl amino-C2-6Alkanoylamino C1-6Alkyl, amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, N-C1-6Alkyl amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, N, bis- (C of N-1-6Alkyl) amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C2-6Alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-C2-6Alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-carbonylamino C1-6Alkyl, C6-10Aromatic hydrocarbon-thio-carbonyl-amino C1-6Alkyl, heterocyclic-carbonyl amino C1-6Alkyl, C1-6Alkyloxy oxalyl base amino C1-6Alkyl, N- (C6-10Aromatic hydrocarbon-sulfonyl)-N-C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl sulfonyl-amino C1-6Alkyl amino, carbamoyloxy C1-6Alkyl, N-C1-6Alkyl carbamoyloxy base C1-6Alkyl, N, bis- (C of N-1-6Alkyl) carbamoyloxy C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl carbamoyloxy base C1-6Alkyl, C1-6Alkoxy-carbonyl oxy-C1-6Alkyl, C6-10Aromatic hydrocarbon Epoxide carbonyl oxygroup C1-6Alkyl, heterocyclecarbonyl hydrazonomethyl, C6-10Aromatic hydrocarbon carbonyl hydrazonomethyl, C2-6Alkenyl, carboxyl-C2-6Alkenyl, C1-6Alkoxy carbonyl-C2-6Alkenyl, carbamoyl C2-6Alkenyl, heterocycle-C2-6Alkenyl, formoxyl, carboxyl, heterocyclic-carbonyl, C6-10Aromatic hydrocarbon-carbonyl, C1-6Alkoxy carbonyl, carbamoyl, N-C1-6Alkyl-carbamoyl, N, bis- (C of N-1-6Alkyl) carbamoyl, (C3-7Naphthenic base-C1-6Alkyl) carbamoyl, C1-6Alkylthio group C1-6Alkyl-carbamoyl, C1-6Alkyl sulphinyl C1-6Alkyl-carbamoyl, C1-6Alkyl sulphonyl C1-6Alkyl-carbamoyl, hydroxyaminocarbonyl, C1-6Alkoxycarbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy C1-6Alkyl-carbamoyl, amino C1-6Alkyl-carbamoyl, amino C1-6Alkylthio carbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy carbonyl C1-6Alkyl-carbamoyl, (C1-6Alkoxycarbonyl amino) C1-6Alkyl-carbamoyl, (C1-6Alkoxycarbonyl amino) C1-6Alkylthio carbamoyl, heterocycle-carbamoyl, heterocycle-C1-6Alkyl-carbamoyl, C6-10Aromatic hydrocarbon-carbamoyl, Hydrazinocarbonyl, N-C1-6Alkyl hydrazine carbonyl, N '-C1-6Alkyl hydrazine carbonyl, N ', (C of N '-two1-6Alkyl) Hydrazinocarbonyl, N, (the C of N '-two1-6Alkyl) Hydrazinocarbonyl, N, N ', N '-three (C1-6Alkyl) Hydrazinocarbonyl, N '-(heterocyclic-carbonyl)-Hydrazinocarbonyl, amino, C1-6Alkoxy C1-6Alkyl amino, amino C1-6Alkyl amino, (C1-6Alkyl amino C1-6Alkyl) amino, N-C1-6Alkyl amino C1-6Alkyl-N-C1-6Alkyl amino, (C1-6Alkoxycarbonyl amino C1-6Alkyl) amino, (two (C1-6Alkyl) amino C1-6Alkyl) amino, heterocycle-amino C1-6Alkyl amino, carboxyl C1-6Alkyl amino, N- carboxyl C1-6Alkyl-N-C1-6Alkyl amino, heterocycle-C1-6Alkyl amino, N- (heterocycle-C1-6Alkyl)-N-C1-6Alkyl amino, hydroxyl C1-6Alkyl amino, N- hydroxyl C1-6Alkyl-N-C1-6Alkyl amino, (C1-6Alkylthio group C1-6Alkyl) amino, (C1-6Alkyl carbamoyloxy base C1-6Alkyl) amino, N-C1-6Alkyl amino carbonyl oxy C1-6Alkyl-N-C1-6Alkyl amino, C1-6Alkyl sulphinyl C1-6Alkyl amino, C1-6Alkyl sulphonyl C1-6Alkyl amino, general formula-N (R12)SO2R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino) indicate group, hydroxyl C1-6Alkoxy C1-6Alkyl amino, C6-10Aromatic hydrocarbon-C1-6Alkyl amino, heterocyclic-carbonyl amino, C1-6Alkoxycarbonyl amino, heterocycle-C1-6Alkyl-carbonyl-amino, C6-10Aromatic hydrocarbon-carbonylamino, heterocycle-amino, oxyimino, C1-6Alkoximino, oxo base, oxyimino C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl amino, (C2-6Alkanoylamino C1-6Alkyl) amino, C6-10Aromatic hydrocarbyl, heterocycle (here, C6-10Aromatic hydrocarbyl or heterocycle or heterocycle can be selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, formoxyl, C2-6Alkanoyl, carboxyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, oxo base, nitro, cyano, amidino groups, C2-6Alkenyloxy, hydroxyl, thio group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, amino C1-6Alkyl, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio group carbamoyl, two (C1-6Alkyl) thiocarbamoyl, C2-6Alkanoylamino, C2-6Alkanoyl (C1-6Alkyl) amino, thio C2-6Alkanoylamino, thio C2-6Alkanoyl (C1-6Alkyl) amino, Formylamino, formoxyl (C1-6Alkyl) amino, thioformyl amino, thioformyl (C1-6Alkyl) amino, C2-6Alkanoyloxy, formyloxy, sulfydryl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, amino-sulfonyl, C1-6Alkyl amino sulfonyl, two (C1-6Alkyl) amino-sulfonyl, C1-6Alkyl sulfonyl-amino, C1-6Alkyl sulphonyl (C1-6Alkyl) amino, hydroxyl C1-61~3 group of alkyl replaces) 1~3 group replace.
R2The heterocycle of expression is preferably selected from halogen atom, cyano, C1-6Alkyl, hydroxyl, C1-6Alkoxy, C2-6Alkenyloxy, carboxyl C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl, hydroxyl C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfonyl C1-6Alkyl, heterocycle-C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfenyl C1-6Alkyl, azido-C1-6Alkyl, amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, two (C1-6Alkoxy C1-6Alkyl) amino C1-6Alkyl, C2-6Alkanoylamino C1-6Alkyl, two (C2-6Alkanoyl) amino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, two (C1-6Alkoxy carbonyl) amino C1-6Alkyl, (bis- (C of N, N-1-6Alkyl) carbamoyl) amino C1-6Alkyl, N-C1-6Alkyl sulfonyl-amino C1-6Alkyl, (two (C1-6Alkyl) amino-sulfonyl) amino C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfuryl amino-C2-6Alkanoylamino C1-6Alkyl, N, bis- (C of N-1-6Alkyl) amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C2-6Alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-carbonylamino C1-6Alkyl, C6-10Aromatic hydrocarbon-thio-carbonyl-amino C1-6Alkyl, heterocyclic-carbonyl amino C1-6Alkyl, C1-6Alkyloxy oxalyl base amino C1-6Alkyl, N- (C6-10Aromatic hydrocarbon-sulfonyl)-N-C1-6Alkyl amino C1-6Alkyl, C1-6Alkyl sulfonyl-amino C1-6Alkyl amino, N, bis- (C of N-1-6Alkyl) carbamoyloxy C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl carbamoyloxy base C1-6Alkyl, C1-6Alkoxy-carbonyl oxy C1-6Alkyl, C6-10Aromatic hydrocarbon-Epoxide carbonyl oxygroup C1-6Alkyl, carboxyl-C2-6Alkenyl, C1-6Alkoxy carbonyl-C2-6Alkenyl, carbamoyl C2-6Alkenyl, heterocycle-C2-6Alkenyl, formoxyl, carboxyl, heterocyclic-carbonyl, C1-6Alkoxy carbonyl, carbamoyl, N, bis- (C of N-1-6Alkyl) carbamoyl, (C3-7Naphthenic base-C1-6Alkyl) carbamoyl, C1-6Alkylthio group C1-6Alkyl-carbamoyl, C1-6Alkyl sulphinyl C1-6Alkyl-carbamoyl, C1-6Alkyl sulphonyl C1-6Alkyl-carbamoyl, C1-6Alkoxycarbamoyl, amino C1-6Alkyl-carbamoyl, amino C1-6Alkylthio carbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy carbonyl C1-6Alkyl-carbamoyl, (C1-6Alkoxycarbonyl amino) C1-6Alkyl-carbamoyl, (C1-6Alkoxycarbonyl amino) C1-6Alkylthio carbamoyl, heterocycle-carbamoyl, heterocycle-C1-6Alkyl-carbamoyl, the N, (C of N '-two1-6Alkyl) Hydrazinocarbonyl, N '-(heterocyclic-carbonyl)-Hydrazinocarbonyl, amino, C1-6Alkoxy C1-6Alkyl amino, amino C1-6Alkyl amino, C1-6Alkyl amino C1-6Alkyl amino, (C1-6Alkyl amino C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkoxycarbonyl amino C1-6Alkyl amino, two (C1-6Alkyl) amino C1-6Alkyl amino, heterocycle-amino C1-6Alkyl amino, carboxyl C1-6Alkyl amino, (carboxyl C1-6Alkyl) (C1-6Alkyl) amino, heterocycle-C1-6Alkyl amino, (heterocycle-C1-6Alkyl) (C1-6Alkyl) amino, hydroxyl C1-6Alkyl amino, (hydroxyl C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkylthio group C1-6Alkyl amino, C1-6Alkyl amino carbonyl oxy C1-6Alkyl amino, (C1-6Alkyl amino carbonyl oxy C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkyl sulphinyl C1-6Alkyl amino, C1-6Alkyl sulphonyl C1-6Alkyl amino, general formula-N (R12)SO2R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino) indicate group, hydroxyl C1-6Alkoxy C1-6Alkyl amino, C6-10Aromatic hydrocarbon C1-6Alkyl amino, heterocyclic-carbonyl amino, C1-6Alkoxycarbonyl amino, heterocycle-allcyl group carbonylamino, C6-10Aromatic hydrocarbon-carbonylamino, oxo base, oxyimino C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl amino, (C2-6Alkanoylamino C1-6Alkyl) amino, C6-10Aromatic hydrocarbyl, heterocycle (here, C6-10Aromatic hydrocarbyl or heterocycle can be selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkanoyl, oxo base, nitro, cyano, hydroxyl, amino C1-6Alkyl, C1-6Alkoxy carbonyl, Formylamino, hydroxyl C1-61~3 group of alkyl replaces) 1~3 group replace, it is special it is good be to be replaced by 2 groups.
As R2, more preferably general formula
The group of expression, in formula, R10Indicate hydrogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkyl sulphinyl C1-6Alkyl, C1-6Alkyl sulphonyl C1-6Alkyl, carboxyl C1-6Alkyl, heterocycle-C1-6Alkyl or general formula-SO2R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino), R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino, here, R11And R12Can and R11In conjunction with sulphur atom and R12In conjunction with nitrogen-atoms be formed together 5- or 6-membered aliphatic heterocycle, R13Indicate C1-6Alkyl, halogen atom or cyano.
As R2, preferably it is also possible to general formula below
The group of expression, in formula, R13Indicate C1-6Alkyl, halogen atom or cyano, n indicate 0~6 integer.
As R4, particularly preferably hydrogen atom.In addition, as X, in terms of pharmacological effect, preferably-SO2,-SO-, in terms of pharmacological effect, particularly preferably-SO2-。
It may replace above-mentioned R1And R2The aromatic hydrocarbyl of expression or the group of aromatic heterocycle, and may replace R2The group of the saturated or unsaturated monocyclic type heteroaromatic base or unsaturated polycyclic heterocycle base that indicate is described in detail below.
" heterocycle " indicates the ring for having 1~4 hetero atom (N, O, S etc.) as the composition part of ring structure, can be saturation, unsaturation or aromatic ring, and can be the ring of monocycle or polycycle.In addition, polycyclic heterocycle includes hetero ring type spiro-compounds and the heterocyclic compound with caged scaffold.For heterocycle-C1-6" heterocycle " whens alkyl etc. indicates the heterocycle derived from above-mentioned heterocycle.In addition, " heterocycle " indicates the 1 valence group derived from " heterocycle ".
The monocyclic type heteroaromatic base of saturation can be enumerated with 1~4 selected from nitrogen-atoms, the group of heteroatomic 3~7 yuan of saturations ring structure of oxygen atom and sulphur atom, pyrrolidinyl can specifically be enumerated, tetrahydrofuran base, oxetanyl, tetrahydro-thienyl, piperidyl, piperazinyl, high piperazine base, morpholinyl, thio-morpholinyl, oxirane base, tiacyclopentane base, dioxanes base, aziridine base, imidazolidinyl, pyrazolidinyl, THP trtrahydropyranyl, tetrahydro thiapyran base, oxazolidinyl, thiazolidinyl, isoxazolidinyl, dioxolanyl, penta ring group of oxygen thia, hexahydropyrimidine base etc..
Insatiable hunger and/or aromatic monocyclic type heteroaromatic base can be enumerated with 1~4 selected from nitrogen-atoms, heteroatomic 4~7 yuan of the heterocycle of oxygen atom and sulphur atom, pyrrole radicals can specifically be enumerated, furyl, thienyl, pyrazolyl, imidazole radicals, triazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazine radical, tetrazole radical, thiadiazolyl group, oxadiazoles base, pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, isothiazole alkyl, pyranose, dihydropyridine base, tetrahydro pyridyl, dihydrogen dazin base, dihydro-pyrimidin base, tetrahydro pyridazine base, tetrahydro-pyrimidine base etc..
Polycyclic heterocycle base can be enumerated with 1~4 selected from nitrogen-atoms, heteroatomic 8~14 yuan of the heterocycle of oxygen atom and sulphur atom, benzofuranyl can specifically be enumerated, benzothiazolyl, indyl, quinolyl, isoquinolyl, benzopyranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzdioxan base, benzothienyl, benzisothia oxazolyl, benzo isoxazolyl, chromene base, chromanyl, heterochromatic alkenyl, isochroman base, indolinyl, indazolyl, indolizine base, isoindolyl, isoindoline base, quinazinyl, quinoxalinyl, quinazolyl, cinnoline base, benzo pyridazinyl, naphthyridines base, purine radicals, tetrahydro-thiazoles and pyridyl group, imidazopyridyl, pyrrolopyridinyl, carbazyl, xanthyl, acridinyl, phenazinyl, phenoxazine base, phenothiazinyl, Quininuclidinyl etc..
Halogen atom indicates chlorine atom, fluorine atom, bromine atom and iodine atom, preferably chlorine atom and fluorine atom.
C1-6Alkyl indicates C1-6The alkyl of straight or branched, the specific example of the alkyl can enumerate methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, 2- methyl amyl, n-hexyl etc..
C1-6Alkylene basis representation C1-6The alkylidene of straight or branched, the specific example of the alkylidene can enumerate methylene, ethylidene, 1,2- propylidene, 1,3- propylidene, butylidene, pentylidene, hexylidene etc..
C2-6The C of alkene basis representation straight or branched2-6The specific example of alkenyl, the alkenyl can enumerate vinyl, allyl, acrylic, cyclobutenyl, pentenyl etc..
C2-6The C of alkenylene expression straight or branched2-6The specific example of alkenylene, the alkenylene can enumerate ethenylidene, allylidene, butenylidene, inferior pentenyl etc..
C3-7Naphthenic base can enumerate cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl.
C4-7Cycloalkenyl can enumerate cyclopentenyl, cyclohexenyl group etc..
Naphthenic base and the combination example of alkyl can enumerate naphthenic base-alkyl, particularly preferably C3-7Naphthenic base-C1-6Alkyl.
C1-7Alcoxyl basis representation has the alkoxy of abovementioned alkyl or naphthenic base, can enumerate methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, amoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyl oxygroup etc..
C2-6Alkanoyl indicates the C of straight-chain or branched2-6Alkanoyl can enumerate acetyl group, propiono, bytyry, valeryl, caproyl etc..
R1Particularly preferably 2,5- difluorophenyls or the fluoro- 5- cyano-phenyl of 2-.R3Particularly preferably the fluoro- 4- chlorphenyl of 4- chlorphenyl, 4- fluorophenyl, 2,4- difluorophenyl, 3,4- difluorophenyl, 3-, 4- trifluoromethyl, the chloro- 2- thienyl of 5-, 5- chloro-2-pyridyl, 6- chloro-3-pyridyl base, 6- trifluoromethyl -3- pyridyl group.
Stereoisomer or the optical isomer from asymmetric carbon atom may be present in the compound that general formula (1) of the invention indicates, any one of these stereoisomers, optical isomer and their mixture are included in the present invention.In addition, the case where S- oxide of inventive mixture is present in the heterocycle of sulfur atom-containing, which includes any one of monoxide and dioxide.
Salt as the compound that general formula (1) of the invention indicates, as long as the salt that field of medicaments allows, it is not particularly limited, the inorganic acids salt such as hydrochloride, hydrobromate, hydriodate, phosphate, nitrate and sulfate can specifically be enumerated, organic carboxyl acids salt such as organic sulfonic acids salt and benzoate, acetate, propionate, oxalates, malonate, succinate, glutarate, adipate, tartrate, maleate, malate and amygdalate such as mesylate, 2- isethionate and tosilate etc..
In addition, the salt of alkali metal ion or alkaline-earth metal ions can also be formed when the compound that general formula (1) indicates has acidic-group.As solvate, as long as the solvate that field of medicaments allows, is not particularly limited it, can specifically enumerate hydrate, ethanolates etc..
Hereinafter, being illustrated to the preparation method for the compound that general formula (1) of the invention indicates.
Compound, its salt and its solvate of general formula of the invention (1) expression can be prepared by the combination of known general chemical preparation process, be illustrated below to having representative synthetic method.
The representative preparation method of the sulfide (1a) as shown below indicated for general formula (1) of the invention, sulfenyl compound (1b) and sulfonyl compound (1c).
1) preparation method of sulfide (1a)
Sulfide of the invention (1a) can be prepared using the following method.
(in formula, Y indicates leaving group, R1~R4As previously described.)
After forming compound (3) by 01 derivatives (2), make gained compound (3) and mercaptan compound (R in the presence of base3- SH) reaction, sulfide of the invention (1a) can be prepared.In this case, mercaptan compound can be used as alkali metal salt or alkali salt (for example, lithium salts, sodium salt, sylvite) uses.
Compound (3) and mercaptan compound (R3- SH) reaction temperature be usually -20~200 DEG C, preferably room temperature~100 DEG C.According to compound (3) or mercaptan compound (R3- SH) type it is different, preferably reacted in the reaction temperature for being higher than this range, preferably reacted in tube sealing sometimes sometimes.Reaction time is usually 0.5 hour~1 day.
As alkali, can enumerate alkali or alkaline earth metal hydride (such as, lithium hydride, sodium hydride, hydrofining, calcium hydride), alkali or alkaline earth metal amine (such as, amido lithium, amido sodium, lithium diisopropyl amido, dicyclohexyl amido lithium, lithium base amido lithium, lithium base amido sodium, lithium base amido potassium), alkali or alkaline earth metal rudimentary alkoxide (such as, sodium methoxide, sodium ethoxide, potassium tert-butoxide), alkali metal, alkaline-earth metal or silver hydroxide (such as, silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), alkali metal, alkaline-earth metal or silver carbonate (such as, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate), alkali metal bicarbonate (such as, sodium bicarbonate, saleratus), lithium alkylide (such as N-BuLi) or alkyl Grignard reagents (such as, methyl-magnesium-bromide), the inorganic bases such as silver oxide or amine (such as, triethylamine, diisopropylethylamine, N-methylmorpholine), basic heterocycles are (for example, dimethylaminopyridine, pyridine, imidazoles, 2,6- lutidines, trimethylpyridine, 1,11-7- alkene of 8- diazabicylo [5,4,0], 1,5- diazabicylo [4,3,0] nonyl- 5- alkene, Isosorbide-5-Nitrae-diazabicylo [2,2,2] octane) etc. organic bases etc..
As solvent, alcohol series solvent, ether series solvent, halogen-based solvent, aromatic system solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent, water can be enumerated, two or more above can also be used in mixed way.Wherein, preferably methylene chloride, tetrahydrofuran, dimethylformamide etc..
Well known method preparation can be used in 01 derivatives used in above-mentioned preparation process (2), and as there is various examples known to preparation method, wherein an example is as follows.In tetrahydrofuran or ether equal solvent, make R1- C (=O)-R4(that representative is R for the aldehydes or ketones and equivalent of expression or excessive organometallic reagent2The organolithium reagent or R that-Li is indicated2- MgCl or R2The Grignard reagent of the expressions such as-MgBr) reaction, 01 derivatives (2) can be obtained.For example, in R2When for aromatic hydrocarbyl or aromatic heterocycle, J.Org.Chem.16 volumes of the paper of such as H.Gilman, the paper Tetrahedron of 1788-1791 pages (nineteen fifty-one) or F.Trecourt etc., volume 56,1349-1460 pages (2000) etc. are recorded, metal exchange is carried out by the way that alkyl lithium reagents or alkyl Grignard reagents are added in aryl halide or heteroaryl halogen, above-mentioned organometallic reagent can easily be made.
Hydroxyl can be converted to leaving group by well known method by 01 derivatives (2) and is made by the compound (3) with leaving group Y.The leaving group that Y is indicated can enumerate halogen atom (chlorine atom, bromine atom, iodine atom etc.), can be by the C of halogenation1-6Alkylsulfonyloxy (mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy etc.), can have the C of substituent group6-10Aromatic hydrocarbon sulfonyloxy etc..As the substituent group of aromatic hydrocarbon sulfonyloxy, 1~3 halogen atom can be enumerated, can be by the C of halogenation1-6Alkyl, C1-6Alkoxy etc..As the preferable example of leaving group, phenylsulfonyloxy, tolysulfonyl oxygroup, 1- naphthalene sulfonyl oxygroup, 2- naphthalene sulfonyl oxygroup etc. can be enumerated.
In addition, another synthetic method as sulfide (1a), can enumerate 01 derivatives (2) and mercaptan compound (R3- SH) light prolong reaction.Specifically, in solvent the triaryl phosphine of 1~3 equivalent (such as, triphenyl phasphine etc.) or trialkyl phosphine (such as, tributylphosphine) and 1~2 equivalent azodicarboxy acid compound (such as, diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, two piperidine amides of azo-2-carboxylic acid, azo-2-carboxylic acid are bis- (dimethylformamide)) coexisting under, make the mercaptan compound (R of 01 derivatives (2) and 1~3 equivalent3- SH) reaction, compound (1a) can be made.
Reaction temperature is usually -20~150 DEG C, preferably 0 DEG C~80 DEG C.Reaction time is usually 0.5 hour~5 days.As solvent, ether series solvent, halogen-based solvent, aromatic system solvent can be enumerated, two or more that can also be above is used in mixed way.Wherein, preferably tetrahydrofuran.
2) preparation method of sulfenyl compound (1b)
Sulfenyl compound (1b) in the present invention can be as described below, prepares in a solvent through oxidizing from sulfide (1a).
(in formula, R1~R4As previously described.)
Reaction temperature is usually -20 DEG C~200 DEG C, and preferably 0 DEG C~100 DEG C, the reaction time is usually 0.1 hour~7 days, preferably 0.5 hour~2 days.As solvent, alcohol series solvent, ether series solvent, halogen-based solvent, aromatic system solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent and water can be enumerated, two or more above can also be used in mixed way.Wherein, preferably methylene chloride, chloroform, methanol and ethyl alcohol etc..
As oxidant, can enumerate hydrogen peroxide, organic peroxide (such as, peracetic acid, metachloroperbenzoic acid), metaperiodic acid salt of excess (such as, sodium metaperiodate), nitryl, dinitrogen tetroxide, halogen, N- halide (for example, N-chloro-succinimide, N- bromine succinimide), hydroperoxides (such as, tert-butyl hydroperoxide), iodobenzene diacetate ester, dichloride iodobenzene, t-butyl hypochlorate, sulfonic acid chloride, singlet oxygen, ozone, selenium oxide, selenous acid etc..
If enumerating the example of specific reaction condition; then in methylene chloride, tetrahydrofuran-water, methanol equal solvent; about 1 hour~2 days time is spent at 0~100 DEG C; sulfide (1a) is handled with the metachloroperbenzoic acid of 1~2 equivalent, sodium metaperiodate or hydrogen peroxide, sulfenyl compound (1b) can be made.
In addition, as oxidant, titanium tetraisopropylate/optically pure ethyl tartrate/tert-butyl hydroperoxide, titanium tetraisopropylate/optically pure ethyl tartrate/peracetic acid etc. can be used when preparing sulfoxide with optical activation (1b).
3-1) the preparation method of sulfonyl compound (1c)
As described below, by the way that with oxidizing sulfide (1a) or sulfenyl compound (1b), the sulfonyl compound (1c) in the present invention can be made in a solvent.
(in formula, R1~R4As previously described.)
Reaction temperature is usually -20 DEG C~150 DEG C, and preferably 0 DEG C~100 DEG C, the reaction time is usually 0.1 hour~7 days, preferably 1 hour~5 days.
As solvent, alcohol series solvent, ether series solvent, halogen-based solvent, aromatic system solvent, carboxylic acid series solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent and water can be enumerated, two or more that can also be above is used in mixed way.Wherein, preferably methylene chloride, chloroform, methanol, ethyl alcohol, acetic acid, water etc..
As oxidant, hydrogen peroxide can be enumerated, hydrogen peroxide-transition-metal catalyst (such as, ammonium molybdate, ferric trichloride etc.), organic peroxide (such as, peracetic acid, metachloroperbenzoic acid etc.), metaperiodic acid salt of excess (such as, sodium metaperiodate etc.), potassium peroxydisulfate, permanganate (such as, potassium permanganate etc.), sodium perborate, halogen, N- halide (such as, N-chloro-succinimide, N- bromine succinimide etc.), hydroperoxides (such as, tert-butyl hydroperoxide etc.), iodobenzene diacetate ester, dichloride iodobenzene, hypochlorous acid class (such as, sodium hypochlorite, t-butyl hypochlorate etc.), singlet oxygen, ozone, selenium oxide, selenous acid etc..Preferable reaction condition is, in methylene chloride, tetrahydrofuran-water or methanol, react the oxidant (such as metachloroperbenzoic acid, sodium metaperiodate, hydrogen peroxide, hydrogen peroxide-ammonium molybdate etc.) of sulfide (1a) and 2~5 equivalents about 1 hour~5 days.
3-2) the preparation method of sulfonyl compound (1c)
Sulfonyl compound (1c) can also be prepared by the following method.
(in formula, Y1Indicate leaving group or hydroxyl, R1~R4As previously described.)
In the presence of a base, make according to known methods or as the method for the benchmark in this way can made from sulfonyl compound (1d) and electrophilic reagent (R2-Y1) reaction, can be made various has R2The sulfonyl compound (1c) of base.
Specifically, in the presence of equivalent~excessive alkali, make equivalent~excessive R2-Y1It is reacted with compound (1d).Reaction temperature is usually -78 DEG C~200 DEG C, and the reaction time is usually 0.5 hour~1 day.
As solvent, ether series solvent, halogen-based solvent, aromatic system solvent, nitrile series solvent, acid amides series solvent etc. can be used alone or as a mixture.Wherein, preferably tetrahydrofuran, dimethoxy-ethane, ether, dimethylformamide, toluene etc..
As Y1The leaving group of expression can enumerate halogen atom (chlorine atom, bromine atom, iodine atom etc.), can be by the C of halogenation1-6Alkylsulfonyloxy (mesyloxy, ethanesulfonyloxy group, trifluoro-methanesulfonyl oxy etc.), can have the C of substituent group6-10Aromatic hydrocarbon sulfonyloxy etc..As the substituent group of aromatic hydrocarbon sulfonyloxy, 1~3 halogen atom can be enumerated, can be by the C of halogenation1-6Alkyl, C1-6Alkoxy etc..As the C that can have substituent group6-10The specific example of aromatic hydrocarbon sulfonyloxy can enumerate phenylsulfonyloxy, tolysulfonyl oxygroup, 1- naphthalene sulfonyl oxygroup, 2- naphthalene sulfonyl oxygroup etc..
As alkali, can enumerate lithium alkylide (such as, n-BuLi, s-butyl lithium, tert-butyl lithium), alkali or alkaline earth metal hydride (such as, lithium hydride, sodium hydride, hydrofining, calcium hydride), alkali or alkaline earth metal amine (such as, amido lithium, amido sodium, lithium diisopropyl amido, dicyclohexyl amido lithium, lithium base amido lithium, lithium base amido sodium, lithium base amido potassium), alkali or alkaline earth metal rudimentary alkoxide (such as, sodium methoxide, sodium ethoxide, potassium tert-butoxide), alkali metal, alkaline-earth metal or silver hydroxide (such as, silver hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide), alkali metal, alkaline-earth metal or silver carbonate (such as, sodium carbonate, potassium carbonate, cesium carbonate, silver carbonate), the carbonic acid of alkali metal Hydrogen salt (such as sodium bicarbonate, saleratus), silver oxide etc..
3-3) the preparation method of sulfonyl compound (1c)
As described below, by making compound (3) and R3-SO2 -M+(5) alkali metal, alkaline-earth metal or the tetrabutylammonium reactant salt of the sulfinic acid indicated, can also be made the sulfonyl compound (1c) in the present invention.
(in formula, Y indicates leaving group, M+Indicate metal ion, R1~R4As previously described.)
Specifically, compound (3) are reacted.Usually -20 DEG C of reaction temperature~200 DEG C, preferably room temperature~100 DEG C.Because of the difference of the type of compound (3) or sulfinate (5), preferably reacted under the reaction temperature for being higher than this range sometimes.In addition, preferably being reacted in tube sealing sometimes.Reaction time is usually 0.5 hour~3 days, preferably 0.5 hour~1 day.
As solvent, alcohol series solvent, ether series solvent, halogen-based solvent, aromatic system solvent, nitrile series solvent, acid amides series solvent, ketone series solvent, sulfoxide series solvent, water etc. can be enumerated, they can be used in mixed way.Wherein, preferably butanol, dimethoxy-ethane, N-Methyl pyrrolidone, dimethylformamide etc..
In the preparation method of the compound of the present invention (1) illustrated above; sometimes the substituent groups such as nitrogen-atoms, hydroxyl, carboxyl must be protected; in this case; the well known general protecting group for being suitable for being removed can be used, these protecting groups can be removed by the common method of organic chemistry if necessary.
Utilize the R of sulfide made from the above method (1a), sulfenyl compound (1b) and sulfonyl compound (1c)1~R4In 1 or multiple substituent groups can further change structure.For example, R1~R4Any of there is the substituent group that is replaced by 1,3-dioxolane -2- base in the case where, it, which is hydrolyzed, by well known method can be converted to the compound replaced by formoxyl.In addition, R1~R4Any of there is the substituent group that is replaced by bromine in the case where, the compound replaced by formoxyl can also be converted by well known method.Formoxyl can be exchanged into carboxylic acid, substituted or unsubstituted amino methyl, hydroxymethyl or 2- (alkoxy carbonyl) vinyl etc. by well known method.In addition, the hydroxylic moiety of the hydroxymethyl can be the group of ester, carbonic ester, carbamate, halogen, nitrile or sulphonic acid ester etc. by well known method migration.In addition, these groups can be exchanged into the group of alkoxy, amine, amide, carboxylic acid or sulfide etc..2- (alkoxy carbonyl) vinyl can be the groups such as 2- carboxy ethyl by well known method migration.Such conversion is likely to the various functional groups other than hydroxyl, and conversion method can be carried out by well known technology.Specifically, for example, R2When 4- pyridyl group chloro- for 2-, the various amine such as itself and alkylamine, dialkylamine, benzene methanamine, pyrrolidines, piperidines, morpholine are reacted, the pyridine derivate that 2 chlorine is replaced by these amine can be made.In this case, if using 3,4- dimethoxybenzylamine then can get 3,4- dimethoxy benezene aminopyrazole derivatives, be handled with trifluoroacetic acid or nitric acid diammonium cerium it, then 2-aminopyridine derivative can be made.In addition, if being handled with mesyl chloride 2-aminopyridine derivative in the presence of pyridine, then can be exchanged into 2- methanesulfonamido pyridine derivate.Content known to a person of ordinary skill in the art can be used in the reagent used in these switch process, solvent and reaction condition.
Salt or solvate can be formed as by common method using the compound of the present invention made from the above method (1).
The compound of the present invention (1) has stronger inhibiting effect due to the generation secretion to amyloid beta, so as various diseases caused by the generation diacrisis as amyloid beta, for example, degenerative brain disorder, Down syndrome, the prophylactic treatment medicine of Other diseases related with amyloid protein calmness are useful.
The compound of the present invention as human body pharmaceuticals in use, dosage adult 1 day is 1mg~1g, preferably 10mg~300mg.Dosage as animal pharmaceuticals, because administration purpose (treatment or prevention), the animal that need to be disposed type and size, infection pathogen type and degree it is different and different, it is 0.1mg~200mg, preferably 0.5mg~100mg that 1 day amount, which corresponds generally to 1kg the weight of animals,.1 day amount can be 1 day 1 time, can also divide 2~4 administrations.1 day amount can also be more than above-mentioned amount as needed.
Medical composition containing the compounds of this invention can select preparation appropriate according to medication, can modulate according to the modulator approach of common various preparations.As oral preparations such as the suspensions that tablet, powder, granule, capsule, solution, syrup, elixir, oiliness~aqueous using the compounds of this invention as the dosage form of the medical composition of host agent, can be illustrated.
As injection, stabilizer, preservative and cosolvent can be used in the formulation, after the solution containing these auxiliary agents can also being packed into container, solid pharmaceutical preparation is formed by freeze-drying etc., required preparation is modulated into when in use and reused.In addition, 1 dosage can also be fitted into one container, or multiple dosing amount is fitted into a container.
It, can exemplary solutions agent, suspending agent, emulsion, ointment, gel, creme, lotion, spray and adhesive preparation etc. in addition, as external preparation.
As solid pharmaceutical preparation, containing the additive that the compounds of this invention and pharmaceutical field allow, for example, can select mixed filler class and incremental agent class, adhesive class, disintegrating agent class, chaotropic agent class, wetting agent class, lubricant class etc. then formulation as needed.
As liquid preparation, solution, suspending agent and emulsion etc. can be enumerated, suspending agent and emulsifier etc. can be contained as additive.
Embodiment
The present invention is specifically described hereinafter, enumerating embodiment, but the scope of the present invention is not limited to following embodiments.In embodiment below, no E body, Z body record when, gained compound is either in E body or Z body.
Reference example 1:2- [(4- chlorphenyl) sulfonymethyl]-Isosorbide-5-Nitrae-difluorobenzene
Method 1:1) in 0 DEG C, 2,5- difluorobenzyl alcohol (5.00g, 4- chlorobenzenethiol (5.45g is sequentially added in tetrahydrofuran (150ml) solution 34.7mmol), 38.2mmol), triphenyl phasphine (11.1g, 41.6mmol) and diisopropyl azo-2-carboxylic acid (8.16ml, 41.6mmol).It is concentrated after being stirred 4 days to reaction solution at room temperature.It is residue obtained to be refined with silica gel column chromatography (1% ethylacetate-hexane), obtain 2- [(4- chlorphenyl) sulfidomethyl]-Isosorbide-5-Nitrae-difluorobenzene (2.68g, 29%) in colorless oil.
1H-NMR (400MHz, CDCl3) (4H, the s) of δ: 4.04 (2H, s), 6.85-7.00 (3H, m), 7.23
2) in 0 DEG C, 3- chlorine benzylhydroperoxide (225mg is added in methylene chloride (5ml) solution of 2- [(4- chlorphenyl) sulfidomethyl]-Isosorbide-5-Nitrae-difluorobenzene (271mg, 1.00mmol), after 1.30mmol), stir 15 hours at room temperature.After methylene chloride diluting reaction solution, saturated potassium hydrogen carbonate aqueous solution and saturated common salt water washing are successively used.Dry (MgSO4) be concentrated afterwards.It is dissolved in methylene chloride (5ml) by residue obtained, after 0 DEG C cooling, be added 3- chlorine benzylhydroperoxide (450mg, 2.60mmol), be then stirred at room temperature 15 hours.After methylene chloride diluting reaction solution, with saturated potassium hydrogen carbonate aqueous solution and saturated common salt water washing.Dry (MgSO4) be concentrated afterwards, it is residue obtained to be refined with silica gel column chromatography (9% ethylacetate-hexane), obtain the title compound (210mg, 69%) in colorless solid substance.
1H-NMR (400MHz, CDCl3) 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) in 4- chlorobenzenethiol (3.86g, N 26.6mmol), potassium carbonate (4.00g is added in dinethylformamide (120ml) solution, 29.0mmol) and 2- bromomethyl -1,4- difluorobenzene (5.00g, after 24.2mmol), it is stirred at room temperature 3 hours.It is extracted after saturated ammonium chloride (50ml) and water (20ml) is added in reaction solution with ether.Combining extraction liquid, after water and saturated common salt water washing, dry (MgSO4), concentration is residue obtained to be refined with silica gel column chromatography (1% ethylacetate-hexane), obtains 2- [(4- chlorphenyl) sulfidomethyl]-Isosorbide-5-Nitrae-difluorobenzene (6.41g, 98%) in colorless oil.
2) in 0 DEG C, H is added in methanol (100ml) solution of 2- [(4- chlorphenyl) sulfidomethyl]-Isosorbide-5-Nitrae-difluorobenzene (6.54g, 24.1mmol)2O (16.4ml), 30%H2O2Six ammonium tetrahydrate (425mg, 0.344mmol) of (16.4ml, 145mmol) and seven molybdic acids, stirring are stirred 15 hours at room temperature after 1 hour.The solid that leaching is precipitated, concentrates the filtrate to about half.After obtained aqueous solution is extracted with dichloromethane, previous resulting solid is dissolved in extract liquor, is then successively washed with water and saturated salt solution.Dry (MgSO4) be concentrated afterwards, it is residue obtained to be recrystallized with hexane, obtain the title compound (6.34g, 87%) in colorless needle crystals.
Method 3: it after 2- bromomethyl-Isosorbide-5-Nitrae-difluorobenzene (12.3ml, 95.5mmol) is added in butanol (200ml) suspension of 4- chlorobenzene sulfinic acid sodium (19.0g, 95.5mmol), is heated to reflux 5 hours.The solid that leaching is precipitated uses saturated common salt water washing, dry (MgSO after being dissolved in methylene chloride4).After concentration, obtained solid is recrystallized with hexane, obtains the title compound (12.3g, 43%) in colorless needle crystals.
Reference example 2:4- (4- chlorphenyl sulfonymethyl) pyridine
Under 70 DEG C of heating, to 4- chloromethyl pyridine hydrochloride (1.26g, 7.65mmol), 1- propyl alcohol (50ml) solution of 4- chlorobenzene sulfinic acid sodium (1.52g, 7.65mmol) and potassium acetate (1.50g, 15.3mmol) stirs 8 hours.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.By gained concentrated residue by short column (silica gel, ethyl acetate), eluent is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel column chromatography, to hexane: ethyl acetate (=2: 3) is that the fraction that eluent obtains is concentrated under reduced pressure, and obtains the title compound (1.26g, 62%) of white solid.
1H-NMR (400MHz, CDCl3) (2H, d, the J=6.1Hz) of 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
MS (m/z): 268 (M++H).
Reference example 3:2- [(2,5- difluorophenyl)-hydroxymethyl] pyridine
Under an argon, the hexane solution (1.53M, 3.92ml, 0.6mmol) of n-BuLi is instilled in tetrahydrofuran (10ml) solution of 2- bromopyridine (572 μ l, 6mmol) in -78 DEG C, is stirred 30 minutes.2,5- difluorobenzaldehyde (655 μ l, 6mmol) is instilled in the brown solution, is slowly ramped to room temperature.It is extracted with ethyl acetate in reaction solution plus after water.Lower concentration is depressurized after dry solvent, it is residue obtained to be refined with silica gel chromatography, obtain the title compound (120mg, 9%) of white solid.
1H-NMR (400MHz, CDCl3) (1H, the m) of 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
Mp:65-66 DEG C of
Reference example 4:2- [chloro- (2,5- difluorophenyl) methyl] -3- methyl pyridinium chloride
In argon atmospher, the tetrahydrofuran solution (1.5ml, 3mmol) of isopropyl-magnesium chloride is instilled in tetrahydrofuran (2.0ml) solution of the bromo- 3- picoline (510mg, 3mmol) of 2- under ice-cold, is stirred 60 minutes at room temperature.Under ice cooling, 2,5- difluorobenzaldehyde (328 μ l, 3mmol) is instilled in the brown solution, is slowly ramped to room temperature.After saturated aqueous ammonium chloride is added in reaction solution, it is extracted with ethyl acetate.The lower concentration of decompression after dry solvent, residue obtained with silica gel chromatography, (hexane: ethyl acetate=8: 1) being refined, mixture of the acquisition containing title compound.Thionyl chloride (2.0ml) and 1 drop dimethylformamide are added wherein, stirs 14 hours at room temperature.White precipitate is obtained after boiling off excessive thionyl chloride under decompression.It is developed into (trituration) together with hexane and ether, is obtained title compound (101mg, 12%).
1H-NMR (400MHz, CDCl3) (1H, d, the J=4.9Hz) of 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
Mp:118-119 DEG C of
MS m/z:254 (M++H).
Reference example 5:2- [(2,5- difluorophenyl)-hydroxymethyl] -5- picoline
In argon atmospher, the tetrahydrofuran solution (1.5ml, 3mmol) of isopropyl-magnesium chloride is instilled in tetrahydrofuran (2ml) solution of the bromo- 5- picoline (510mg, 3mmol) of 2- under ice cooling, is stirred 60 minutes at room temperature.Under ice-cold, 2,5- difluorobenzaldehyde (328 μ l, 3mmol) is instilled in the brown solution, is slowly ramped to room temperature.It is extracted with ethyl acetate after saturated aqueous ammonium chloride is added in reaction solution.The lower concentration of decompression after dry solvent, residue obtained with silica gel chromatography, (hexane: ethyl acetate=5: 1) being refined, and acquisition is in the title compound (130mg, 18%) of grease.
1H-NMR (400MHz, CDCl3) (1H, the m) of 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
MS m/z:236 (M++H).
Reference example 6:2- [(2,5- difluorophenyl)-hydroxymethyl] -4- picoline
In argon atmospher, in the bromo- 4- picoline of 2- (334 μ l under ice cooling, the tetrahydrofuran solution (1.5ml, 3mmol) that isopropyl-magnesium chloride is instilled in tetrahydrofuran (2ml) solution 3mmol), is stirred 60 minutes at room temperature.Under ice-cold, 2,5- difluorobenzaldehyde (328 μ l, 3mmol) is instilled in the brown solution, is slowly ramped to room temperature.It is extracted with ethyl acetate after saturated aqueous ammonium chloride is added in reaction solution.The lower concentration of decompression after dry solvent, residue obtained with silica gel chromatography, (hexane: ethyl acetate=5: 1) being refined, and acquisition is in the title compound (456mg, 65%) of acicular crystal.
1H-NMR (400MHz, CDCl3) (1H, the m) of δ: 2.30 (3H, s), 5.48 (1H, br-s), 6.02 (1H, s), 6.83-7.13 (5H, m), 8.38
Mp:105-106 DEG C of
MS m/z:236 (M++H).
The bromo- 3-Methoxy Pyridine of reference example 7:2-
In nitrogen atmosphere, 60% oily sodium hydride (605mg is slowly added into methanol (10ml) under ice cooling, 15.1mmol), dimethylformamide (20ml) solution of the bromo- 3- pyridone (2.5g, 14.4mmol) of 2- is added after twenty minutes.Methanol is boiled off under decompression from mixed liquor, is added methyl iodide (0.94ml, 15.1mmol), is stirred 3 hours at room temperature.Water (50ml) and ether (50ml) is added after being concentrated to dryness in reaction solution.Divide and take organic layer, with saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Extract liquor is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution, and with silica gel chromatography, (hexane: ethyl acetate=8: 1) being refined, and acquisition is in the title compound (1.51g, 56%) of colorless needle crystals.
1H-NMR (400MHz, CDCl3) (1H, the m) of δ: 3.90 (3H, s), 7.12 (1H, m), 7.21 (1H, dd, J=4.8,8.0Hz), 7.97
Mp:34 DEG C of
Reference example 8:3- allyloxy -2- bromopyridine
It is same as the bromo- 3-Methoxy Pyridine of 2- to be synthesized, obtain the title compound (2.35g, 76%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:215 (M++H).
Reference example 9:2- [(2,5- difluorophenyl)-hydroxymethyl] -3-Methoxy Pyridine
In argon atmospher, in the bromo- 3-Methoxy Pyridine (564mg of 2- under ice cooling, the tetrahydrofuran solution (1.5ml, 3mmol) that isopropyl-magnesium chloride is instilled in tetrahydrofuran (2ml) solution 3mmol), is stirred 60 minutes at room temperature.Under ice-cold, 2,5- difluorobenzaldehyde (328 μ l, 3mmol) is instilled in the brown solution, is slowly ramped to room temperature.It is extracted with ethyl acetate after saturated aqueous ammonium chloride is added in reaction solution.Lower concentration is depressurized after dry solvent, and gained acicular crystal is developed with hexane, is obtained title compound (660mg, 88%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:252 (M++H).
Reference example 10:3- allyloxy -2- [(2,5- difluorophenyl)-hydroxymethyl] pyridine
In argon atmospher, 3- allyloxy -2- bromopyridine (the 642mg obtained under ice cooling in reference example 8, the tetrahydrofuran solution (1.5ml, 3mmol) that isopropyl-magnesium chloride is instilled in tetrahydrofuran (2ml) solution 3mmol), is stirred 60 minutes at room temperature.Under ice-cold, 2,5- difluorobenzaldehyde (328 μ l, 3mmol) is instilled in the brown solution, is slowly ramped to room temperature.It is extracted with ethyl acetate after saturated aqueous ammonium chloride is added in reaction solution.Lower concentration is depressurized after dry solvent, (hexane: ethyl acetate=4: 1) refining to residue obtained, and acquisition is in the title compound (375mg, 45%) of grease with silica gel chromatography.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:278 (M++H).
Reference example 11:3- [(2,5- difluorophenyl)-hydroxymethyl] pyridine
In argon atmospher, the tetrahydrofuran solution (1.5ml, 3mmol) of isopropyl-magnesium chloride is instilled in tetrahydrofuran (2ml) solution of 3- bromopyridine (286 μ l, 3mmol) under ice cooling, is stirred 60 minutes at room temperature.Under ice-cold, 2,5- difluorobenzaldehyde (328 μ l, 3mmol) is instilled in the brown solution, is slowly ramped to room temperature.It is extracted with ethyl acetate after saturated aqueous ammonium chloride is added in reaction solution.Lower concentration is depressurized after dry solvent, (hexane: ethyl acetate=1: 1) refining to residue obtained, and acquisition is in the title compound (296mg, 45%) of acicular crystal with silica gel chromatography.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Reference example 12:5- [(2,5- difluorophenyl)-hydroxymethyl] pyrimidine
According to method same as reference example 11, the title compound (117mg, 18%) in grease is obtained by 5- Bromopyrimidine.
1H-NMR (400MHz, CDCl3) (1H, the s) of δ: 6.12 (1H, s), 6.90-7.02 (2H, m), 7.26 (1H, m), 8.70 (2H, s), 9.04
MS m/z:205 (M+-OH)
Reference example 13:2- [(tert-butoxycarbonyl oxygroup)-(2,5- difluorophenyl) methyl] -1- methyl-1 H- benzimidazole
At room temperature, to 2,5- difluorobenzaldehyde (164 μ l, 1.5mmol), 1- tolimidazole (132mg, 1mmol), acetonitrile (3ml) solution of di-tert-butyl dicarbonate (252 μ l, 1.1mmol) stirs 20 hours.The precipitating that leaching generates, develops the precipitating by hexane, obtains the title compound (310mg, 83%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:375 (M++H).
Reference example 14:2- [(tert-butoxycarbonyl oxygroup)-(2,5- difluorophenyl) methyl] -1- methyl-5-chloro -1H- imidazoles
At room temperature, to 2,5- difluorobenzaldehyde (327 μ l, 3mmol), the chloro- 1- methylimidazole of 5- (187 μ g, 2mmol), acetonitrile (6ml) solution of di-tert-butyl dicarbonate (504 μ l, 2.2mmol) stirs 20 hours.The precipitating that leaching generates, develops the precipitating by hexane, obtains the title compound (472mg, 66%) of white solid.
1H-NMR (400MHz, CDCl3) (1H, the m) of δ: 1.48 (9H, s), 3.67 (3H, s), 6.88-7.1 (4H, m), 7.39
Mp:125-126 DEG C of
MS m/z:359 (M++H).
Reference example 15:2- [(2,5- difluorophenyl)-hydroxymethyl] thiazole
In -78 DEG C, in 2- bromo thiazole (180 μ g, hexane solution (the 1.57M of n-BuLi is instilled in tetrahydrofuran (10ml) solution 2mmol), 1.40ml, 2.2mmol), stirring is after ten minutes, it is added 2,5- difluorobenzaldehyde (238 μ l, 2.2mmol), is to slowly warm up to 0 DEG C while stirring.Then, aqueous ammonium chloride solution is added stops reaction, adds ether, dry with anhydrous magnesium sulfate after ether layer water and saturated common salt water washing.Lower concentration filtrate is depressurized after filtering.With silica gel chromatography, (hexane: ethyl acetate=1: 1) being refined to residue obtained, obtains the title compound (358mg, 79%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:228 (M++H).
Reference example 16:2- [(tert-butoxycarbonyl oxygroup)-(2,5- difluorophenyl) methyl] -1- (4- methoxyphenyl) -1H- imidazoles
At room temperature, to 2,5- difluorobenzaldehyde (327 μ l, 3mmol), 1- (4- methoxyphenyl) imidazoles (348mg, 2mmol), acetonitrile (6ml) solution of di-tert-butyl dicarbonate (504 μ l, 2.2mmol) stirs 20 hours.The solution is concentrated, (hexane: ethyl acetate=5: 1~1: 1) being refined, and obtains the title compound (774mg, 93%) in grease with silica gel chromatography.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:417 (M++H).
Reference example 17:5- Chloro-2-Pyridyle mercaptan
After thiocarbamide (152mg, 2.00mmol) is added in ethyl alcohol (4ml) solution of 2,5- dichloropyridine (296mg, 2.00mmol), it is heated to reflux 18 hours.Water (1ml) solution of potassium hydroxide (198mg, 3.00mmol) is added after reaction mixture is cooled to room temperature, is heated to reflux 3 hours.Reaction mixture is cooled to room temperature Hou Jiashui, is washed with methylene chloride.After so that water layer is in acid with acetic acid, it is extracted with dichloromethane.After organic layer is dried, filtered with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure, leaching after obtained solid is washed with ether obtains the title compound (83mg, 0.57mmol, 29%) in yellow powder.
1H-NMR (400MHz, CDCl3) (1H, d, the J=2.4Hz) of δ: 7.35 (1H, dd, J=9.3,2.4Hz), 7.46 (1H, d, J=9.3Hz), 7.64
MS m/z:146 (M++H).
Reference example 18:2,5- difluorophenyl -4- pyridylcarbinol
In -78 DEG C, tetrahydrofuran (30ml) solution of 2,5- difluorobenzene (1.08ml, 9.60mmol) bromo- to 1- is stirred, and the hexane solution (7.32ml, 11.5mmol) of n-BuLi is added.In -78 DEG C, tetrahydrofuran (10ml) solution of 4- pyridine carboxaldehyde (0.764ml, 8.00mmol) is added in the reactive mixture, is stirred 30 minutes at identical temperature.Ether is added after reaction mixture is warming up to room temperature, is washed with saturated sodium bicarbonate aqueous solution.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer, is handled with flashchromatography on silica gel residue obtained.Reduced pressure is by hexane: ethyl acetate=7: the fraction that 3 elution portions obtain, and leaching after obtained solid diisopropyl ether obtains the title compound (1.15g, 5.20mmol, 65%) of white powder.
1H-NMR (400MHz, CDCl3) (2H, d, the J=5.4Hz) of 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
Reference example 19: tetrahydric thiapyran -4- alcohol
Tetrahydric thiapyran-4-ketone (5.00g, 43.0mmol) is dissolved in methanol (100ml), after sodium borohydride (1.6g, 42.3mmol) is added under ice cooling, is stirred 14 hours at room temperature.Reaction mixture is concentrated under reduced pressure, in gained concentrated residue plus water (50ml) is extracted after keeping fluidity weakly acidic with 1N hydrochloric acid with ether.After extract liquor successively uses 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, organic layer is dry with anhydrous magnesium sulfate.Filtrate is concentrated under reduced pressure after filtering, obtains the title compound (4.40g, 37.2mmol, 87%) in khaki solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:119 (M++H).
Bis- bromomethyl -2- of reference example 20:5- (2,5- difluorobenzoyl) pyridine (compound A) and 5- bromomethyl -2- (2,5- difluorobenzoyl) pyridine (compound B)
Compound A compound B
It is heated to reflux down, in the 2- [(2 that reference example 5 obtains, 5- difluorophenyl)-hydroxymethyl] -5- picoline (7.50g, N- bromine succinimide (17.0g is added in carbon tetrachloride (100ml) solution 31.9mmol), 95.7mmol) and 2,2 '-azos two (2- methyl propionitrile) of catalytic amount and stir.Reflux is cooled to room temperature after 24 hours, filters the precipitating of generation.It adds it in sodium thiosulfate solution, is extracted with chloroform.It is dry with sodium sulphate after solution saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Lower concentrate solution is depressurized, residue obtained (hexane: ethyl acetate=10: 1) refining, and acquisition is in the title compound A (3.91g, 31%) and title compound B (3.34g, 34%) of grease with silica gel chromatography.
Compound A
1H-NMR (400MHz, CDCl3) 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)
MS m/z:392 (M++H).
Compound B
1H-NMR (400MHz, CDCl3) 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)
MS m/z:313 (M++H).
Reference example 21: acetic acid [6- (2,5- difluorophenyl carbonyl) pyridin-3-yl] methyl esters
It is heated to reflux down, in the 2- [(2 that reference example 5 obtains, 5- difluorophenyl)-hydroxymethyl] -5- picoline (2.64g, N- bromine succinimide (6.0g is added in carbon tetrachloride (60ml) solution 11.2mmol), 33.6mmol) and 2,2 '-azos two (2- methyl propionitrile) of catalytic amount and stir.Reflux is cooled to room temperature after 7 hours, is added it in sodium thiosulfate solution.It is extracted with ether, it is dry with sodium sulphate after solution water and saturated common salt water washing.Lower concentrate solution is depressurized, toluene is dissolved in by residue obtained, it is concentrated again.
It is dissolved in residue obtained in n,N-Dimethylformamide (20ml).Sodium acetate (4.59g, 56mmol) is added wherein, is stirred 17 hours in 70 DEG C.Ethyl acetate (100ml) is dissolved in after cooling, with water and saturated common salt water washing.Lower concentrate solution is depressurized after solution anhydrous magnesium sulfate drying.It is residue obtained that with silica gel chromatography, (hexane: ethyl acetate=5: 1) being refined, and acquisition is in the title compound (600mg, 18%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:292 (M++H).
Reference example 22:2- [(2,5- difluorophenyl)-hydroxymethyl] -5- (1,3-dioxolane -2- base) pyridine
In the bis- bromomethyl -2- (2 of 5- that reference example 20 obtains, 5- difluorobenzoyl) pyridine (compound A) (3.91g, ethylene glycol (6.2g is added in pyridine solution (60ml) 10mmol), 100mmol), it is stirred while heating 17 hours in 90 DEG C.Lower concentrate solution is depressurized, is dissolved in ether (200ml) for residue obtained.It is dry with anhydrous magnesium sulfate after being washed with water, saturated sodium bicarbonate aqueous solution and saturated salt solution to it.Lower concentrate solution is depressurized, it is residue obtained to be dissolved in ethyl alcohol (60ml).Sodium borohydride (190mg, 5mmol) is added wherein under ice-cooling, is stirred at room temperature 1 hour.It is extracted with ethyl acetate after adding water, with dry with anhydrous magnesium sulfate after saturated common salt water washing solution.Lower concentrate solution is depressurized, residue obtained (hexane: ethyl acetate=5: 1~1: 1) refining, and acquisition is in the title compound (1.52g, 52%) of grease with silica gel chromatography.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:294 (M++H).
The chloro- 4- of reference example 23:3- [(2,5- difluorophenyl)-hydroxymethyl] pyridine
In -78 DEG C, n-BuLi (6.3ml, 1.59M hexane solution) is added in the tetrahydrofuran solution (14ml) of diisopropylamine (1.4ml, 10mmol), 3- chloropyridine (1.13g, 10mmol) is added after ten minutes in stirring.2,5- difluorobenzaldehyde (1.09ml, 10mmol) is added after 30 minutes, is slowly ramped to 0 DEG C, is stirred for 10 minutes.It is diluted after aqueous ammonium chloride solution is added with ethyl acetate (80ml).Organic layer is taken, with drying after saturated common salt water washing.Filtering, depressurizes lower concentrate solution, and the ethyl alcohol development of gained precipitating obtains title compound (1.33g, 52%).
1H-NMR (400MHz, CDCl3) (1H, d, the J=4.8Hz) of 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
Mp:169-170 DEG C of
MS m/z:255 (M+).
The chloro- 4- of reference example 24:2,5- bis- [(2,5- difluorophenyl)-hydroxymethyl] pyridine
In -78 DEG C, n-BuLi (6.3ml is added in the tetrahydrofuran solution (14ml) of diisopropylamine (1.4ml, 10mmol), 1.59M hexane solution), 2,5- dichloropyridine (1.48g, 10mmol) is added in stirring after ten minutes.2,5- difluorobenzaldehyde (1.09ml, 10mmol) is added after 30 minutes, is slowly ramped to 0 DEG C, is stirred for 10 minutes.It is diluted after aqueous ammonium chloride solution is added with ethyl acetate (80ml).Organic layer is taken, with drying after saturated common salt water washing.Filtering, depressurizes lower concentrate solution, and the ethyl alcohol development of gained precipitating obtains title compound (1.93g, 67%).
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
Mp:160-161 DEG C of
MS m/z:289 (M+).
Reference example 25:(3,6- dichloropyridine -2- base) (pyridin-4-yl) methanol
Under -78 DEG C of stirrings, tert-butyl lithium (1.51M pentane solution 4.6ml) is instilled in ether (20ml) solution of 2,5- dichloropyridine (1.02g, 6.89mmol).After -78 DEG C are stirred 2 hours, Pyridine-4-Carboxaldehyde (0.65ml, 6.89mmol) is added in reaction solution, adds water in reaction solution after stirring 1 hour in -78 DEG C, is warming up to room temperature.Filtrate is concentrated under reduced pressure after being dried, filtered after being extracted with dichloromethane with anhydrous sodium sulfate in mixed liquor.Gained concentrated residue is handled with silica gel column chromatography, it is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 50) obtains, leaching after obtained solid is washed with ether obtains the title compound (819mg, 3.21mmol) of white powder.
1H-NMR (400MHz, CDCl3) 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 acids S- (6- chloro-3-pyridyl base) ester O- ethyl ester
5- Amino-2-Chloropyridine (643mg, 3.00mmol) is dissolved in 1N hydrochloric acid (10ml), in water (1ml) solution of -5 DEG C of instillation sodium nitrites (207mg, 3.00mmol).After 60 DEG C are stirred reaction mixture 30 minutes, water (1ml) solution of dithiocarbonic acids O- ethyl ester potassium (481mg, 3.00mmol) is instilled at the same temperature.It is cooled to room temperature after reaction mixture is stirred for 1 hours in 80 DEG C, ethyl acetate is added, is washed with saturated sodium bicarbonate aqueous solution.After organic layer is dried, filtered with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure.Handled with silica gel flash column chromatography residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=49: the fraction that 1 elution portion obtains obtains the title compound (148mg, 0.63mmol, 21%) in yellow oil.
1H-NMR (400MHz, CDCl3) (1H, d, the J=2.4Hz) of 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
MS m/z:234 (M++H).
The chloro- 5- fluorine pyridin-3-yl of reference example 27:(2,6- bis-) methanol
Under ice-cold, ethyl chloroformate (1.32ml, 13.8mmol) is added in toluene (60ml) solution of the chloro- 5- fluorine nicotinic acid (2.76g, 13.1mmol) of 2,6- bis- and triethylamine (1.92ml, 13.8mmol).After stirring 1 hour at room temperature, reaction mixture is concentrated under reduced pressure.
Residue is dissolved in tetrahydrofuran (30ml), in tetrahydrofuran (20ml) suspension of -78 DEG C of instillation lithium aluminium hydride reductions (524mg, 13.8mmol).After reaction mixture is warming up to 0 DEG C, instill 1N sodium hydrate aqueous solution (3.25ml).Filtrate is concentrated under reduced pressure after filtering off precipitate with diatomite.Handled with flashchromatography on silica gel residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains obtains the title compound (1.93g, 9.85mmol, 75%) in orange solids.
1H-NMR (400MHz, CDCl3) (1H, d, the J=7.8Hz) of δ: 2.18 (1H, brs), 4.77 (2H, s), 7.77
Mp:65-67 DEG C of
Reference example 28:3- (t-butyidiphenylsilyl oxygroup methyl) -5- fluorine pyridine
(2 obtained in reference example 27, the chloro- 5- fluorine pyridin-3-yl of 6- bis-) methanol (18.9g, 96.2mmol) and triethylamine (32.2ml, 10% palladium-carbon catalyst (3.20g) is added in ethyl alcohol (650ml) solution 231mmol), stirs 7 hours under a hydrogen atmosphere.Filtrate is concentrated under reduced pressure after filtering off catalyst with diatomite, in residue obtained middle addition saturated sodium bicarbonate aqueous solution, is extracted with chloroform.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
Methylene chloride (600ml) is dissolved in by residue obtained, triethylamine (14.8ml is added, 106mmol) and tertiary butyl chloride diphenyl silane (25.0ml, 96.3mmol), then 4-dimethylaminopyridine (1.18g is added, 9.63mmol), it stirs 14 hours at room temperature.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after reaction mixture is washed with saturated sodium bicarbonate aqueous solution.Handled with flashchromatography on silica gel residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=19: the fraction that 1 elution portion obtains obtains the title compound (30.0g, 81.9mmol, 85%) in colorless oil.
1H-NMR (400MHz, CDCl3) (1H, d, the J=2.4Hz) of 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
MS m/z:366 (M++H).
Reference example 29:[5- (t-butyidiphenylsilyl oxygroup methyl) -3- fluorine pyridine -2- base] (2,5- difluorophenyl) methanol
In -78 DEG C, the hexane solution (30.0ml, 46.8mmol) of n-BuLi is added in ether (250ml), adds N, N, N ', N '-tetramethylethylenediamine (7.06ml, 46.8mmol).After -20 DEG C are stirred reaction mixture 30 minutes, -78 DEG C are cooled to, ether (50ml) solution of 3- (t-butyidiphenylsilyl oxygroup methyl) -5- fluorine pyridine (15.5g, 42.5mmol) is added.It after stirring 30 minutes at the same temperature, is added 2,5- difluorobenzaldehyde (6.04g, 42.5mmol), stirs 2 hours.After first water being added to add saturated sodium bicarbonate aqueous solution in the reactive mixture, extracted with ether, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Handled with flashchromatography on silica gel residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains obtains the title compound (17.0g, 33.5mmol, 79%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:508 (M++H).
Reference example 30:(2,5- difluorophenyl) (the fluoro- 5- hydroxy-methyl pyridine -2- base of 3-) methanol
In [5- (t-butyidiphenylsilyl oxygroup methyl) -3- fluorine pyridine -2- base] (2,5- difluorophenyl) methanol (853mg, tetrahydrofuran solution (the 1.04ml of tetrabutylammonium is added in tetrahydrofuran (7ml) solution 1.68mmol), 1.04mmol), it stirs 5 hours at room temperature.After reaction mixture is concentrated under reduced pressure, it is dissolved in ethyl acetate by residue obtained, is washed with saturated sodium bicarbonate aqueous solution.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Handled with flashchromatography on silica gel residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains the title compound (413mg, 1.53mmol, 91%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:270 (M++H).
Reference example 31:6- (2,5- difluorophenyl) hydroxymethyl -5- fluorine niacinamide
(2 obtained in reference example 30,5- difluorophenyl) (the fluoro- 5- hydroxy-methyl pyridine -2- base of 3-) methanol (406mg, potassium permanganate (795mg is added in acetone (9ml) solution 1.51mmol), water (9ml) solution 7.03mmol), is heated to reflux 4 hours.After filtering off precipitate with diatomite, makes filtrate in acidity with 1N hydrochloric acid, then extracted with methylene chloride.After organic layer is dried, filtered with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure.Leaching after the residue obtained mixed solvent with hexane and methylene chloride washs obtains white solid (367mg).
In the N of obtained solid (240mg), 1H- benzotriazole -1- base oxygroup tripyrrole Wan Ji Phosphonium hexafluorophosphate (666mg is added 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), it stirs 9 hours at room temperature.Ethyl acetate is added in the reactive mixture, after successively being washed with saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and saturated salt solution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.It is handled with flashchromatography on silica gel residue obtained, is concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 4 elution portions obtain.
It is dissolved in ethyl alcohol (8ml) by residue obtained, in 0 DEG C of addition sodium borohydride (30mg, 0.79mmol).Add water after stirring 1 hour to reaction mixture at room temperature, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer, is handled with flashchromatography on silica gel residue obtained.The fraction obtained by ethyl acetate elution portion is concentrated under reduced pressure, obtains the title compound (118mg, 0.42mmol, 42%) of white solid.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
Mp:162-164 DEG C of
MS m/z:283 (M++H).
Reference example 32:2- [(2,5- difluorophenyl) hydroxymethyl] -6- (1,3-dioxolane -2- base) pyridine
In argon atmospher, in the bromo- 6- (1 of 2- under ice-cold, 3- dioxolanes -2- base) pyridine (2.7ml, tetrahydrofuran solution (the 2.0M of isopropyl-magnesium chloride is instilled in tetrahydrofuran (20ml) solution 24.8mmol), 12.4ml, 24.8mmol), it stirs 3 hours at room temperature.Under ice cooling, 2,5- difluorobenzaldehyde (2.7ml, 24.8mmol) is instilled in the brown solution, is slowly ramped to room temperature, is stirred 16 hours.It after saturated aqueous ammonium chloride is added in reaction solution, is extracted with ethyl acetate, then successively uses water, saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Handled with silica gel column chromatography residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (2.90g, 9.89mmol, 40%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:294 (M++H).
Reference example 33:1- [3- (t-butyldimethylsilyloxy base) propyl] piperidines -2- ketone
In 0 DEG C, after sodium hydride (60% oiliness, 2.22g, 55.6mmol) is slowly added into the tetrahydrofuran solution (200ml) of piperidines -2- ketone (5.00g, 50.5mmol), it is stirred at room temperature 3 hours.After (3- bromine propoxyl group)-t-butyldimethyl silane (14.1ml, 60.6mmol) and n,N-Dimethylformamide (20ml) is added in reaction solution, stir 4 days at room temperature.It is extracted with ethyl acetate in reaction solution plus after water.It is dry with magnesium sulfate after extract liquor water and saturated common salt water washing, concentration.Handled with silica gel column chromatography residue obtained, be concentrated by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (6.44g, 23.8mmol, 47%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:272 (M++H).
The bromo- 1- of reference example 34:3- [3- (t-butyldimethylsilyloxy base) propyl] piperidines -2- ketone
Under argon atmospher, in -78 DEG C in 1- [3- (t-butyldimethylsilyloxy base) propyl] piperidines -2- ketone (542mg, tert-butyl lithium (1.50M pentane solution is instilled in tetrahydrofuran solution (5ml) 2.00mmol), 1.40ml, after 2.10mmol), stirred 15 minutes in -78 DEG C.After the tetrahydrofuran solution (5ml) of tetrabutylammonium tribromide (1.16g, 2.40mmol) is added in reaction solution, -40 DEG C are slowly ramped to when stirring 3 hours.Room temperature is warming up in reaction solution plus after water in -40 DEG C.After being extracted with ethyl acetate to gained mixture, extract liquor water and saturated common salt water washing.It is concentrated after being dried with magnesium sulfate, then handled with silica gel flash column chromatography residue obtained, be concentrated by hexane: ethyl acetate=2: the fraction that 3 elution portions obtain obtains the title compound (72.8mg in colorless oil, 0.208mmol, 10%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:350 (M++H).
Embodiment 1:2- [[(4- chlorphenyl) sulfonyl] (cyclohexyl) methyl]-Isosorbide-5-Nitrae-difluorobenzene
The 2- [(4- chlorphenyl) sulfonvlmethvl] -1 that reference example 1 is obtained; 4- difluorobenzene (240mg; 0.793mmol) it is dissolved in toluene (20ml); cyclohexanol (0.11ml is added; 1.0mmol) and three normal-butyl phosphorane (250mg of cyanomethylene; after 1.0mmol), it is heated to reflux under an argon 14 hours.After reaction solution natural cooling, after cyclohexanol (0.22ml, 2.1mmol) and three normal-butyl phosphorane (500mg, 2.08mmol) of cyanomethylene is added, it is heated to reflux under an argon 14 hours.It is concentrated under reduced pressure after reaction solution natural cooling, with silica gel chromatography, (hexane: ethyl acetate=30: 1) refining gained residue, acquisition white solid.After gained white solid is washed with hexane, the title compound (188mg, 62%) of white powder is obtained.
Fusing point: 107~109 DEG C
1H-NMR (400MHz, CDCl3) 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)
Elemental analysis: C19H19ClF2O2S: theoretical value: C 59.29；H 4.98；Cl 9.21；F 9.87；S 8.33. measured value: C 59.11；H 4.93；Cl 9.18；F 9.82；S 8.49.
Embodiment 2:4- [(4- Chlorophenylsulfonyl) (cyclopenta) methyl] pyridine
Under an argon; 4- (the 4- Chlorophenylsulfonyl methyl) pyridine (70mg for obtaining reference example 2; 0.261mmol), cyclopentanol (49 μ l; 0.538mmol) and toluene (5ml) solution of three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene is heated to reflux 3 days.After being cooled to room temperature, cyclopentanol (49 μ l, 0.538mmol) and three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene are added in reaction solution, is then heated to reflux under an argon 22 hours.Reaction solution is concentrated under reduced pressure after being cooled to room temperature.Handled with silica gel flash column chromatography residue obtained, be concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=2: 1) eluent obtains obtains the title compound (77mg, 88%) of white solid.Obtained solid filters after being washed with hexane-ether, obtains the title compound of white solid.
Fusing point: 133~135 DEG C
1H-NMR (400MHz, CDCl3) 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)
Elemental analysis: C17H18ClNO2S: theoretical value: C 60.80；H 5.40；Cl 10.56；N 4.17；S 9.55. measured value: C 60.76；H 5.44；Cl 10.68；N 4.20；S 9.61.
Embodiment 3:4- [(4- Chlorophenylsulfonyl) (tetrahydropyran -4-base) methyl] pyridine
Under an argon; 4- (the 4- Chlorophenylsulfonyl methyl) pyridine (70mg for obtaining reference example 2; 0.261mmol), oxinane -4- alcohol (51 μ l; 0.538mmol) and toluene (5ml) solution of three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene is heated to reflux 3 days.After being cooled to room temperature, oxinane -4- alcohol (51 μ l, 0.538mmol) and three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene are added in reaction solution, is then heated to reflux under an argon 22 hours.Reaction solution is concentrated under reduced pressure after being cooled to room temperature.Handled with silica gel flash column chromatography residue obtained, be concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=1: 2) eluent obtains obtains the title compound (65mg, 71%) of white solid.Obtained solid filters after being washed with hexane-ether, obtains the title compound of white powder.
Fusing point: 208~209 DEG C
1H-NMR (400MHz, CDCl3) 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- benzylpiperidin -4- base) (4- Chlorophenylsulfonyl) methyl] pyridine
Under an argon; 4- (the 4- Chlorophenylsulfonyl methyl) pyridine (70mg for obtaining reference example 2; 0.261mmol), 1- benzylpiperidin -4- alcohol (103mg; 0.538mmol) and toluene (5ml) solution of three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene is heated to reflux 3 days.After being cooled to room temperature, 1- benzylpiperidin -4- alcohol (103mg, 0.538mmol) and three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene are added in reaction solution, is then heated to reflux under an argon 22 hours.Reaction solution is concentrated under reduced pressure after being cooled to room temperature.It is handled with silica gel flash column chromatography residue obtained, is concentrated under reduced pressure by methanol: the fraction that methylene chloride (=1: 10) eluent obtains.It is residue obtained to be refined with high-speed liquid chromatography (using water/acetonitrile/formic acid mixed solvent system), obtain amorphous title compound (40mg, 35%).
1H-NMR (400MHz, CDCl3) 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): C24H26O2N2ClS(M++H)
Theoretical value: 441.1404. measured value: 441.1387
Embodiment 5:4- [(4- Chlorophenylsulfonyl) (1- methyl piperidine -4- base) methyl] pyridine
Under an argon; 4- (the 4- Chlorophenylsulfonyl methyl) pyridine (70mg for obtaining reference example 2; 0.261mmol), 1- methyl piperidine -4- alcohol (62 μ l; 0.538mmol) and toluene (5ml) solution of three normal-butyl phosphorane of cyanomethylene (62 μ l, 0.538mmol) is heated to reflux 3 days.After being cooled to room temperature, 1- methyl piperidine -4- alcohol (62 μ l, 0.538mmol) and three normal-butyl phosphorane (129mg, 0.538mmol) of cyanomethylene are added in reaction solution, is then heated to reflux under an argon 22 hours.Reaction solution is concentrated under reduced pressure after being cooled to room temperature.It is handled with silica gel column chromatography residue obtained, is concentrated under reduced pressure by methanol: the fraction that methylene chloride (=1: 50) eluent obtains.It is residue obtained to be refined with high-speed liquid chromatography (using water/acetonitrile/formic acid mixed solvent system), obtain the title compound (31mg, 33%) as white solid.Obtained solid is washed with hexane-ether, obtains the title compound of white powder.
Fusing point: 176~177 DEG C
1H-NMR (400MHz, CDCl3) 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)
Elemental analysis: C18H21ClN2O2S: theoretical value: C 59.25；H 5.80；Cl 9.72；N 7.68；S 8.79. measured value: C 59.00；H5.76；Cl 9.75；N 7.61；S 8.77.
Embodiment 6:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] pyridine
After 2- [(2,5- difluorophenyl)-hydroxymethyl] pyridine (88mg, 0.40mmol) that reference example 3 obtains is dissolved in thionyl chloride (2.0ml), the dimethylformamide that catalytic amount is added is stirred 15 hours.Reaction solution is concentrated under reduced pressure, dioxanes is added in residue and is concentrated.It is dissolved in dimethylformamide (5ml) by residue obtained, 4- chlorobenzenethiol (79mg, 0.55mmol) and potassium carbonate (226mg, 1.64mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.After reaction solution is cooled to room temperature, it is added ether (50ml), it is washed with water and saturated salt solution.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (128mg, 92%) in grease.
1H-NMR (400MHz, CDCl3) (1H, the m) of 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
MS m/z:348 (M++H).
Embodiment 7:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -3- picoline
Under nitrogen atmosphere, in the 2- [chloro- (2 that reference example 4 obtains, 5- difluorophenyl) methyl] -3- methyl pyridinium chloride (94mg, 4- chlorobenzenethiol (70mg is added in dimethylformamide (5ml) solution 0.32mmol), 0.49mmol) and potassium carbonate (265mg, 1.92mmol), it is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (103mg, 89%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:362 (M++H).
Embodiment 8:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -4- picoline
After 2- [(2,5- difluorophenyl)-hydroxymethyl] -4- picoline (235mg, 0.53mmol) that reference example 6 obtains is dissolved in thionyl chloride (2.0ml), the dimethylformamide that catalytic amount is added is stirred 16 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (10ml), 4- chlorobenzenethiol (217mg, 1.5mmol) and potassium carbonate (828mg, 6.0mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (290mg, 80%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:362 (M++H).
Embodiment 9:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -3-Methoxy Pyridine
After 2- [(2,5- difluorophenyl)-hydroxymethyl] -3-Methoxy Pyridine (251mg, 1.0mmol) that reference example 9 obtains is dissolved in thionyl chloride (2.0ml), the dimethylformamide that catalytic amount is added is stirred 16 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (10ml), 4- chlorobenzenethiol (289mg, 2.0mmol) and potassium carbonate (1.10g, 8.0mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (256mg, 58%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:378 (M++H).
Embodiment 10:3- allyloxy -2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] pyridine
3- allyloxy-the 2- [(2 that reference example 10 is obtained, 5- difluorophenyl)-hydroxymethyl] pyridine (370mg, after 1.33mmol) being dissolved in thionyl chloride (2.0ml), the dimethylformamide that catalytic amount is added is stirred 16 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (10ml), 4- chlorobenzenethiol (217mg, 1.5mmol) and potassium carbonate (828mg, 6.0mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (256mg, 68%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:404 (M++H).
Embodiment 11:3- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] pyridine
After 3- [(2,5- difluorophenyl)-hydroxymethyl] pyridine (87mg, 0.39mmol) that reference example 11 obtains is dissolved in thionyl chloride (1.0ml), the dimethylformamide that catalytic amount is added is stirred 14 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (5ml), 4- chlorobenzenethiol (84mg, 0.58mmol) and potassium carbonate (323mg, 2.34mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=1: 1) being handled residue, obtains the title compound (131mg, 96%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:348 (M++H).
Embodiment 12:5- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] pyrimidine
After 5- [(2,5- difluorophenyl)-hydroxymethyl] pyrimidine (111mg, 0.5mmol) that reference example 12 obtains is dissolved in thionyl chloride (1.0ml), the dimethylformamide that catalytic amount is added is stirred 16 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (5ml), 4- chlorobenzenethiol (108mg, 0.75mmol) and potassium carbonate (414mg, 3.0mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=4: 1) being handled residue, obtains the mixture (202mg) of the title compound and non-authenticating compound in grease.
1H-NMR (400MHz, CDCl3) (1H, the s) of δ: 5.66 (1H, s), 6.96 (2H, m), 7.17-7.34 (5H, d), 8.70 (2H, s), 9.09
MS m/z:349 (M++H).
Embodiment 13:2- [[(4- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] pyridine
In 2- [[(4- chlorphenyl) sulfenyl]-(2 that embodiment 6 obtains, 5- difluorophenyl) methyl] pyridine (120mg, seven molybdic acids, six ammonium tetrahydrate (80mg) is added in methanol (12ml) solution 0.345mmol), it adds 30% aquae hydrogenii dioxidi (6ml), stirs 24 hours.The precipitating that leaching generates, recrystallizes it with ethyl alcohol, obtains the title compound (96mg, 73%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:380 (M++H).
Elemental analysis: C18H12ClF2NO2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -3- picoline
Using method similarly to Example 13,2- [[(4- chlorphenyl) sulfenyl]-(2 obtained by embodiment 7,5- difluorophenyl) methyl] synthesis of -3- picoline, (hexane: ethyl acetate=5: 1) is refined with silica gel chromatography again, obtain the title compound (35mg, 35%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H14ClF2NO2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -5- picoline
1) 2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -5- picoline
After 2- [(2,5- difluorophenyl)-hydroxymethyl] -5- picoline (125mg, 0.53mmol) that reference example 5 obtains is dissolved in thionyl chloride (1.0ml), the dimethylformamide that catalytic amount is added is stirred 14 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (5ml), 4- chlorobenzenethiol (115mg, 0.80mmol) and potassium carbonate (438mg, 3.18mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (120mg, 66%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:362 (M++H).
2) 2- [[(4- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -5- picoline
Using method similarly to Example 13, by 2- [[(4- chlorphenyl) sulfenyl]-(2 obtained by above-mentioned reaction, 5- difluorophenyl) methyl] synthesis of -5- picoline, obtain the title compound (91mg, 73%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H14ClF2NO2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -4- picoline
Using method similarly to Example 13,2- [[(4- chlorphenyl) sulfenyl]-(2 obtained by embodiment 8,5- difluorophenyl) methyl] synthesis of -4- picoline, (hexane: ethyl acetate=3: 1) is refined with silica gel chromatography again, obtain the title compound (140mg, 95%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H14ClF2NO2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -3-Methoxy Pyridine
Using method similarly to Example 13,2- [[(4- chlorphenyl) sulfenyl]-(2 obtained by embodiment 9,5- difluorophenyl) methyl] synthesis of -3-Methoxy Pyridine, ethyl alcohol recrystallization is used again, obtain the title compound (71mg, 87%) in colourless column crystallization.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H14ClF2NO3S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] pyridine
Using method similarly to Example 13,3- allyloxy -2- [[(4- chlorphenyl) sulfenyl]-(2 obtained by embodiment 10,5- difluorophenyl) methyl] pyridine synthesis, again with alcohol crystal, obtain the title compound (135mg, 80%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C21H16ClF2NO3S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] pyridine
Using method similarly to Example 13,3- [[(4- chlorphenyl) sulfenyl]-(2 obtained by embodiment 11,5- difluorophenyl) methyl] pyridine synthesis, (hexane: ethyl acetate=4: 1) is refined with silica gel chromatography again, obtain the title compound (118mg, 86%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H12ClF2NO2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] pyridine
After 2, the 5- difluorophenyl -4- pyridylcarbinol (75mg, 0.34mmol) that reference example 18 obtains is dissolved in thionyl chloride (1.0ml), the dimethylformamide that catalytic amount is added is stirred 14 hours.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (5ml), 4- chlorobenzenethiol (74mg, 0.51mmol) and potassium carbonate (281mg, 2.04mmol) are added under nitrogen atmosphere, is stirred 1 hour in 50 DEG C.Ether (50ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel column chromatography, (hexane: ethyl acetate=1: 1) being handled residue, obtains the mixture for containing 4- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] pyridine.
Seven molybdic acids, six ammonium tetrahydrate (60mg) is added in methanol (12ml) solution, adds 30% aqueous hydrogen peroxide solution (6ml), stirs 65 hours.Ethyl acetate (80ml) is added in reaction solution, with water and saturated common salt water washing.After anhydrous magnesium sulfate drying, lower concentrated solvent is depressurized.With silica gel chromatography, (hexane: ethyl acetate=4: 1~1: 1) purification obtains title compound (51mg, 39%) residue.Then, with ethyl alcohol recrystallization, colorless needle crystals are obtained.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H12ClF2NO2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] pyrimidine
Using method similarly to Example 13,5- [[(4- chlorphenyl) sulfenyl]-(2 obtained by embodiment 12,5- difluorophenyl) methyl] pyrimidine synthesized, (hexane: ethyl acetate=5: 1) is refined with silica gel chromatography again, obtain the title compound (71mg in colourless column crystallization, 87%: yield is 2 steps set out by 5- [(2,5- difluorophenyl)-hydroxymethyl] pyrimidine of reference example 12).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C17H11ClF2N2O2S: 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- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -4- hydroxychromen -2- ketone
At room temperature, 2,5- difluorobenzaldehyde (109 μ l, 1mmol), 4 hydroxy coumarin (162mg, 1mmol), glacial acetic acid (60mg, 1mmol) and pyridine (80.5 μ l are added in ethyl alcohol (4ml) solution of 4- chlorothio-phenol (144.6mg, 1mmol), 1mmol), it stirs 24 hours.The precipitating that leaching generates, washs it with a small amount of ethyl alcohol, obtains the title compound (345mg, 80%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:431 (M++H).
Embodiment 23:3- [[(4- chlorphenyl) sulfonyl]-(2; 5- difluorophenyl) methyl] -4- methoxyl group chromen-2-one (compound A) and 3- [[(4- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -2- methoxyl group chromene -4- ketone (compound B)
Compound A compound B
At room temperature, in 3- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -4- hydroxychromen -2- ketone (118mg, hexane solution (the 0.41ml of the trimethylsilyl diazomethane of 2N is slowly added into benzene-methanol (10: 1) solution 0.274mmol), 0.822mmol), it is stirred for 5 minutes.Add acetic acid after solution becomes colorless, depressurizes lower concentration of reaction solution.
It is dissolved in methanol (12ml), 30% aquae hydrogenii dioxidi (6ml) and seven molybdic acids, six ammonium tetrahydrate (60mg) is added, stir 20 hours.Ethyl acetate (50ml) is added in reaction solution, with water and saturated common salt water washing.Lower concentration is depressurized after solution anhydrous magnesium sulfate drying.Residue silica gel chromatography (hexane: ethyl acetate=5: 1~3: 1) purification, the non-polar compound (22mg, 17%) in acicular crystal is obtained, and makes polar compound (9.0mg with hexane, 7%) solidify, obtain white solid.NOE (nuclear Overhauser effect, nuclear Overhauser effect) test result of non-polar compound is to observe NOE between methoxyl group and 5 hydrogen of chromene ketone.Furthermore; NOE is not observed between the hydrogen on the aromatic rings of the chromene ketone of polar compound; but NOE is observed between 6 hydrogen on difluoro phenyl ring; so determining that non-polar compound is 3- [[(4- chlorphenyl) sulfonyl]-(2; 5- difluorophenyl) methyl] -4- methoxyl group chromen-2-one (compound A); polar compound is 3- [[(4- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -2- methoxyl group chromene -4- ketone (compound B).
Compound A
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C23H15ClF2O3S: 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.
Compound B
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:477.0366 (C23H16ClF2O5S, calculated value: 477.0375)
Embodiment 24:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -1- methyl-1 H- benzimidazole
In 2- [(the tert-butoxycarbonyl oxygroup)-(2 that reference example 13 obtains, 5- difluorophenyl) methyl] -1- methyl-1 H- benzimidazole (204mg, trifluoroacetic acid (2.0ml) is added in 0.545mmol), stirs 30 minutes at room temperature.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated under reduced pressure again.The residue is dissolved in thionyl chloride (1.0ml), 1 drop dimethylformamide is added, stirs 16 hours at room temperature.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated under reduced pressure again.Then, residue is dissolved in dimethylformamide (5.0ml), adds 4- chlorobenzenethiol (118mg, 0.82mmol) and potassium carbonate (451mg, 3.27mmol), stirred 2 hours in 50 DEG C.It places to room temperature, is added ether (60ml), it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.With silica gel chromatography, (hexane: ethyl acetate=10: 1~5: 1) refining it, obtains the title compound (195mg, 89%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:401 (M++H).
Embodiment 25:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -1- methyl-5-chloro -1H- imidazoles
In 2- [(the tert-butoxycarbonyl oxygroup)-(2 that reference example 14 obtains, 5- difluorophenyl) methyl] -1- methyl-5-chloro -1H- imidazoles (404mg, trifluoroacetic acid (10ml) is added in 1.13mmol), stirs 3 hours at room temperature.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again under reduced pressure.The residue is dissolved in thionyl chloride (2.0ml), 1 drop dimethylformamide is added, stirs 17 hours at room temperature.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated under reduced pressure again.Then, residue is dissolved in dimethylformamide (5.0ml), adds 4- chlorobenzenethiol (244mg, 1.69mmol) and potassium carbonate (936mg, 6.78mmol), stirred 2 hours in 50 DEG C.It places to room temperature, is added ether (60ml), it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.With silica gel column chromatography, (hexane: ethyl acetate=10: 1~5: 1) refining it, obtains the title compound (195mg, 89%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:386 (M++H).
Embodiment 26:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] thiazole
2- [(2,5- difluorophenyl)-hydroxymethyl] thiazole (348mg, 1.53mmol) that reference example 15 obtains is dissolved in thionyl chloride (1.5ml), 1 drop dimethylformamide is added, stirs 14 hours at room temperature.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again under reduced pressure.The residue is dissolved in dimethylformamide (10.0ml), adds 4- chlorobenzenethiol (332mg, 2.3mmol) and potassium carbonate (845mg, 6.12mmol), is stirred 2 hours in 50 DEG C.It places to room temperature, is added ether (60ml), it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.With silica gel chromatography, (hexane: ethyl acetate=10: 1~6: 1) refining it, obtains the title compound (130mg, 24%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:354 (M++H).
Embodiment 27:2- [[(4- chlorphenyl) sulfenyl]-(2,5- difluorophenyl) methyl] -1- (4- methoxyphenyl) -1H- imidazoles
In 2- [(the tert-butoxycarbonyl oxygroup)-(2 that reference example 16 obtains, 5- difluorophenyl) methyl] -1- (4- methoxyphenyl) -1H- imidazoles (667mg, trifluoroacetic acid (10ml) is added in 1.6mmol), stirs 3 hours at room temperature.Lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again under reduced pressure.The residue is dissolved in thionyl chloride (2.0ml), 1 drop dimethylformamide is added, stirs 17 hours at room temperature.Then, lower concentration of reaction solution is depressurized, dioxanes is added in residue and is concentrated again under reduced pressure.Then, residue is dissolved in dimethylformamide (5.0ml), adds 4- chlorobenzenethiol (347mg, 2.4mmol) and potassium carbonate (1.32g, 9.6mmol), stirred 2 hours in 50 DEG C.It places to room temperature, is added ether (60ml), it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.With silica gel chromatography (hexane: ethyl acetate=10: 1~5: 1) refining it, then with alcohol crystal, obtain be in colorless needle crystals title compound (535mg, 75%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:443 (M++H).
Embodiment 28:2- [[(4- chlorphenyl) sulfonyl]-(2; 5- difluorophenyl) methyl] -1- methyl-1 H- benzimidazole (compound A) and 2- [[(4- chlorphenyl) sulfinyl]-(2,5- difluorophenyl) methyl] -1- methyl-1 H- benzimidazole (compound B)
Compound A compound B
In 2- [[(4- chlorphenyl) sulfenyl]-(2 that embodiment 24 obtains, 5- difluorophenyl) methyl] -1- methyl-1 H- benzimidazole (190mg, seven molybdic acids, six ammonium tetrahydrate (60mg) is added in methanol (12ml) solution 0.474mmol), it is added 30% aquae hydrogenii dioxidi (6ml), stirs 17 hours.Ethyl acetate (60ml) is added in reaction solution, it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.With silica gel chromatography (hexane: ethyl acetate=6: 1~4: 1) purification, obtain non-polar compound (compound A) (48mg as acicular crystal, and the polar compound (compound B) of white solid (23mg, 12%) 23%).
Compound A
1H-NMR (400MHz, CDCl3) 8:3.90 (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 DEG C of
Elemental analysis: C21H15ClF2N2OS: 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.
Compound B
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:477.0646 (C21H16ClF2N2OS, calculated value: 477.0640)
Embodiment 29:2- [[(4- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -1- methyl-5-chloro -1H- imidazoles
In 2- [[(4- chlorphenyl) sulfenyl]-(2 that embodiment 25 obtains, 5- difluorophenyl) methyl] -1- methyl-5-chloro -1H- imidazoles (141mg, seven molybdic acids, six ammonium tetrahydrate (60mg) is added in methanol (12ml) solution 0.37mmol), it adds 30% aquae hydrogenii dioxidi (6ml), stirs 64 hours.Ethyl acetate (60ml) is added in reaction solution, it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.Solution is crystallized with ethyl alcohol, obtains the title compound (103mg, 67%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) (1H, the m) of 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
Mp:179-180 DEG C of
Elemental analysis: C17H12Cl2F2N2O2S: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] thiazole
In 2- [[(4- chlorphenyl) sulfenyl]-(2 that embodiment 26 obtains, 5- difluorophenyl) methyl] thiazole (124mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6.0ml) solution 0.35mmol), it adds 30% aquae hydrogenii dioxidi (3ml), stirs 15 hours.Ethyl acetate (60ml) is added in reaction solution, it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.Solution is crystallized with ethyl alcohol, obtains the title compound (91mg, 67%) in colourless column crystallization.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C16H10ClF2NO2S2: 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- chlorphenyl) sulfonyl]-(2,5- difluorophenyl) methyl] -1- (4- methoxyphenyl) -1H- imidazoles
In 2- [[(4- chlorphenyl) sulfenyl]-(2 that embodiment 27 obtains, 5- difluorophenyl) methyl] -1- (4- methoxyphenyl) -1H- benzimidazole (118mg, seven molybdic acids, six ammonium tetrahydrate (60mg) is added in methanol (12ml) solution 0.27mmol), it adds 30% aquae hydrogenii dioxidi (6ml), stirs 64 hours.Ethyl acetate (60ml) is added in reaction solution, it is washed with water and saturated salt solution.Solution is dry with anhydrous magnesium sulfate, depressurizes lower concentrate solution.Solution is crystallized with ethyl alcohol, obtains the title compound (76mg, 60%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C23H17ClF2N2O3S: 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.
The chloro- 2- of embodiment 32:5- [(2,5- difluorophenyl -4- pyridylmethyl) sulfenyl] pyridine
In 0 DEG C, 2 obtained in reference example 18,5- difluorophenyl -4- pyridylcarbinol (221mg, triethylamine (0.279ml is added in methylene chloride (10ml) solution 1.00mmol), 2.00mmol), mesyl chloride (0.116ml, 1.50mmol) is added, is stirred 3 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.In residue obtained N, the 5- Chloro-2-Pyridyle mercaptan (145mg, 1.00mmol) that reference example 17 obtains is added in dinethylformamide (10ml) solution, adds potassium carbonate (166mg, 1.20mmol), it stirs 2 hours at room temperature.Ethyl acetate is added in the reactive mixture, is washed with water after rear organic layer is dried, filtered with anhydrous sodium sulfate and filtrate is concentrated under reduced pressure.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=17: the fraction that 3 elution portions obtain obtains the title compound (267mg, 0.77mmol, 77%) in yellow solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:349 (M++H).
The chloro- 2- of embodiment 33:5- [(2,5- difluorophenyl -4- pyridylmethyl) sulfonyl] pyridine
In 0 DEG C, oxone (oxone is added in methanol (6ml) solution of the chloro- 2- of 5- [(2,5- difluorophenyl -4- pyridylmethyl) sulfenyl] pyridine (239mg, 0.68mmol), peroxidating-potassium sulfate compound, 2KHSO5·KHSO4·K2SO4) (631mg, 1.03mmol) water (12ml) solution.After being stirred 3 days to reaction mixture at room temperature, methylene chloride is added, is washed with saturated sodium bicarbonate aqueous solution.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue is refined with preparation high-speed liquid chromatography (using water/acetonitrile/formic acid mixed solvent system), and leaching after obtained solid hexane/diisopropyl ether obtains the title compound (67mg, 0.18mmol, 26%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
Elemental analysis: C17H11ClF2N2O2S: 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.
MS m/z:381 (M++H).
Embodiment 34:4- [[(4- chlorphenyl) sulfonyl] (2,5- difluorophenyl) methyl] oxinane
The 2- [(4- chlorphenyl) sulfonymethyl] -1 that reference example 1 is obtained, 4- difluorobenzene (200mg, 0.661mmol) and tetrahydro -4H- pyrans -4- alcohol (0.13ml, 1.36mmol) it is dissolved in toluene (10ml), three normal-butyl phosphorane (330mg of cyanomethylene is added, after 1.37mmol), it is heated to reflux under an argon 14 hours.After reaction solution natural cooling, three normal-butyl phosphorane (200mg, 0.829mmol) of cyanomethylene is added, is heated to reflux under an argon 14 hours.After reaction solution natural cooling, be concentrated under reduced pressure, handled with flashchromatography on silica gel gained residue, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains white solid.Gained white solid is washed with hexane, obtains the title compound (157mg, 0.406mmol, 61%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:387 (M++H).
Elemental analysis: C18H17ClF2O3S: 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- chlorphenyl) sulfonyl] (2,5- difluorophenyl) methyl] tetrahydric thiapyran
The 2- [(4- chlorphenyl) sulfonymethyl] -1 that reference example 1 is obtained, 4- difluorobenzene (500mg, 1.65mmol) and reference example 19 obtain tetrahydric thiapyran -4- alcohol (400mg, 3.38mmol) it is dissolved in toluene (20ml), three normal-butyl phosphorane (800mg of cyanomethylene is added, after 3.31mmol), it is heated to reflux under an argon 14 hours.After reaction solution natural cooling, three normal-butyl phosphorane (400mg, 1.66mmol) of cyanomethylene is added, is heated to reflux under an argon 14 hours.Be concentrated under reduced pressure after reaction solution natural cooling, handled with flashchromatography on silica gel gained residue, is concentrated under reduced pressure by hexane: ethyl acetate=15: the fraction that 1 elution portion obtains obtains white solid.Gained white solid is washed with hexane/diisopropyl ether mixed liquor, obtains the title compound (404mg, 1.00mmol, 61%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:403 (M++H).
Elemental analysis: C18H17ClF2O2S2: 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- chlorphenyl) sulfonyl] (2; 5- difluorophenyl) methyl] tetrahydric thiapyran -1; 1- dioxide (compound A) and 4- [[(4- chlorphenyl) sulfonyl] (2,5- difluorophenyl) methyl] tetrahydric thiapyran -1- oxide (compound B (isomers A) and compound B (isomers B))
Compound A compound B
By 4- [[(4- chlorphenyl) sulfonyl] (2; 5- difluorophenyl) methyl] tetrahydric thiapyran (360mg; after 0.893mmol) being dissolved in methylene chloride (15ml), under ice-cooling plus 3- chlorine benzylhydroperoxide (320mg, 1.85mmol).After stirring 14 hours at room temperature, reaction solution is concentrated under reduced pressure, residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains white solid.Gained white solid is dissolved in methylene chloride, successively with after 1N sodium hydrate aqueous solution and saturated common salt water washing, organic layer is dry with anhydrous magnesium sulfate.Filtrate is concentrated under reduced pressure after filtering, obtains white solid.Gained white solid is washed with ether, obtains the title compound A (187mg, 0.430mmol, 48%) of white powder.Then, be concentrated under reduced pressure by methylene chloride: methanol=50: the fraction that 1 elution portion obtains obtains title compound B (isomers A) and title compound B (isomers B) as white solid.Gained mixture flashchromatography on silica gel (methylene chloride: methanol=80: 1) after separation and purification, gained white solid is washed with ether respectively, obtain title compound B (isomers A) (low polarity) (78mg of white powder, 0.19mmol, 21%), the title compound B (isomers B) (highly polar) (69mg, 0.17mmol, 19%) of white powder.
Compound A
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H17ClF2O4S2: 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.
Compound B (isomers A)
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H17ClF2O3S2: 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.
Compound B (isomers B)
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H17ClF2O3S2: 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- chlorphenyl) sulfonyl] (2,5- difluorophenyl) methyl] -1- piperidinecarboxylate
The 2- [(4- chlorphenyl) sulfonymethyl] -1 that reference example 1 is obtained, 4- difluorobenzene (1.25g, 4.13mmol) and 4- hydroxyl -1- piperidinecarboxylate (1.70g, 8.44mmol) it is dissolved in toluene (50ml), three normal-butyl phosphorane (2.00g of cyanomethylene is added, after 8.29mmol), it is heated to reflux under an argon 14 hours.Be concentrated under reduced pressure after reaction solution natural cooling, handled with flashchromatography on silica gel gained residue, is concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains white solid.Gained white solid is washed with ether, obtains the title compound (1.68g, 3.46mmol, 84%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C23H26ClF2NO4S: 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- chlorphenyl) sulfonyl] (2,5- difluorophenyl) methyl] piperidine hydrochlorate
By 4- [[(4- chlorphenyl) sulfonyl] (2; 5- difluorophenyl) methyl] -1- piperidinecarboxylate (1.56g; it 3.21mmol) is dissolved in methylene chloride (50ml), trifluoroacetic acid (5.0ml) is added dropwise under ice-cooling.Reaction solution is concentrated under reduced pressure after stirring 2 hours to reaction solution at room temperature.It is concentrated under reduced pressure afterwards in residue obtained middle addition methylene chloride (10ml) and 1N ethanol solution hydrochloride (10ml), obtains white solid.Obtained solid is washed with ether, obtains the title compound (1.36g, 3.12mmol, 97%) of white powder.
1H-NMR (400MHz, CD3OD) 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 DEG C of
Elemental analysis: C18H18ClF2NO2S·HCl·0.75H2O: 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- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -5- [(4- chlorophenylsulfanyl) methyl] pyridine
By sodium borohydride (33mg, ethyl alcohol (15ml) suspension 0.88mmol) is cooled to -78 DEG C, it is slowly added into the acetic acid [6- (2 of the acquisition of reference example 21 while stirring, 5- difluorophenyl carbonyl) pyridin-3-yl] methyl esters (510mg, 1.75mmol) ethanol solution (10ml).Aqueous ammonium chloride solution is added in stirring after 30 minutes, place to room temperature.It is extracted with ethyl acetate (100ml), solution water and saturated common salt water washing.With the lower concentrate solution of decompression after anhydrous magnesium sulfate drying.Residue is dissolved in methylene chloride (30ml), triethylamine (270 μ l), mesyl chloride (270 μ l) are added under ice cooling.It stirs 3 days at room temperature.It is extracted after adding water with ethyl acetate (60ml), solution water and saturated common salt water washing.With the lower concentrate solution of decompression after anhydrous magnesium sulfate drying.The residue is dissolved in n,N-Dimethylformamide (25ml), under nitrogen atmosphere plus 4- chlorobenzenethiol (751mg, 5.3mmol) and potassium carbonate (718mg, 5.2mmol), is stirred 1 hour in 60 DEG C.Ether (80ml) is added after being cooled to room temperature in reaction solution, is washed with water and saturated salt solution to it.Organic layer is dry with anhydrous magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=10: 1) being handled residue, obtains the title compound (237mg, 27%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Embodiment 40:2- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -5- [(4- Chlorophenylsulfonyl) methyl] pyridine
In 2- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -5- [(4- chlorophenylsulfanyl) methyl] pyridine (75mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6.0ml) solution 0.15mmol), it adds 30% aquae hydrogenii dioxidi (3ml), stirs 22 hours.Ethyl acetate is added in reaction solution, it is washed with water, sodium thiosulfate solution and saturated salt solution.Lower concentrate solution is depressurized after solution is dry.With silica gel chromatography (20%MeOH/CHCl3) residue is refined, obtain the title compound (70mg, 62%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C25H17Cl2F2NO4S2: 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- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -5- (1,3-dioxolane -2- base) pyridine
In nitrogen atmosphere, the 2- [(2 obtained under ice-cold in reference example 22,5- difluorophenyl)-hydroxymethyl] -5- (1,3- dioxolanes -2- base) pyridine (1.52g, triethylamine (1.08ml is added in dichloromethane solution (30ml) 5.2mmol), 7.8mmol), mesyl chloride (0.52ml, 6.8mmol) is stirred 3 hours at room temperature.It is extracted after saturated sodium bicarbonate aqueous solution is added with ether.Solution saturated common salt water washing, it is dry with anhydrous magnesium sulfate, depressurize lower concentrate solution.Residue is dissolved in dimethylformamide (30ml), adds chlorobenzenethiol (901mg, 6.2mmol) and potassium carbonate (1.08g, 7.8mmol), is stirred 3 hours in 60 DEG C.It after being cooled to room temperature, is diluted with ether, solution water and saturated common salt water washing.Lower concentration is depressurized after solution anhydrous magnesium sulfate drying.With silica gel column chromatography, (hexane: ethyl acetate=5: 1) refining residue, and acquisition is in the title compound (1.56g, 71%) of colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:420 (M++H).
Embodiment 42:2- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -5- (1,3-dioxolane -2- base) pyridine
In 2- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -5- (1,3- dioxolanes -2- base) pyridine (1.54g, seven molybdic acids, six ammonium tetrahydrate (150mg) is added in methanol (30ml) solution 3.67mmol), it adds 30% aquae hydrogenii dioxidi (15ml), stirs 24 hours.After being diluted with ethyl acetate, solution water and saturated common salt water washing.After depressurizing lower concentrate solution, residue is crystallized with ethyl alcohol, obtains the title compound (1.22g, 74%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:452.0544 (C21H17ClF2NO4S, calculated value: 452.0535)
Embodiment 43:2- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -5- (hydroxymethyl) pyridine
In 2- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] -5- (1; 3- dioxolanes -2- base) pyridine (295mg; 0.54mmol) 1; 1N hydrochloric acid (30ml) is added in 4- dioxane (30ml), stirs 18 hours at room temperature.After solution is extracted with ethyl acetate, with water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Lower concentration is depressurized after solution anhydrous magnesium sulfate drying, obtains residue.
Residue is dissolved in ethyl alcohol (10ml), sodium borohydride (10mg, 0.27mmol) is added under ice cooling, is stirred 1 hour.After adding water, mixed liquor to be extracted with ethyl acetate, with water and saturated common salt water washing.After solution anhydrous magnesium sulfate drying, depressurizes lower concentration and obtain residue.It is refined with silica gel chromatography (3% methanol/chloroform), obtains the title compound (205mg, 93%) in acicular crystal.
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:410.0444 (C19H15ClF2NO3S, calculated value: 410.0429)
Embodiment 44:3- [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl acrylate
In 2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 42 obtains; 5- difluorophenyl) methyl] -5- (1; 3- dioxolanes -2- base) pyridine (212mg; 0.47mmol) 1; 1N hydrochloric acid (10ml) is added in 4- dioxane (10ml), stirs 19 hours at room temperature.After solution is extracted with ethyl acetate, with water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Lower concentration is depressurized after solution anhydrous magnesium sulfate drying, obtains residue.
Residue is dissolved in tetrahydrofuran (15ml), triphenylphosphoroanylidene methyl acetate (188mg, 0.56mmol) is added under nitrogen atmosphere, is stirred 17 hours.It depressurizes lower concentrated reaction solution and obtains residue.With silica gel column chromatography, (hexane: ethyl acetate=5: 1) refining residue, obtains the title compound (187mg, 86%) in acicular crystal.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:464 (M++H).
Embodiment 45:3- [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl propionate
By 3- [6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] methyl acrylate (160mg; 0.34mmol) it is dissolved in ethyl alcohol (15ml); it is added palladium carbon (30mg), high degree of agitation 24 hours under the nitrogen atmosphere of 1 air pressure.Lower concentration is depressurized after filtering reacting liquid.With silica gel chromatography, (hexane: ethyl acetate=5: 1) refining residue, and acquisition is in the title compound (94mg, 58%) of acicular crystal.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:466 (M++H).
Embodiment 46:3- [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] propionic acid
By 3- [6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] methyl propionate (92mg; 0.20mmol) it is dissolved in tetrahydrofuran (5ml); the aqueous solution (3ml) that lithium hydroxide (23mg, 0.5mmol) is added stirs 2 hours afterwards.After 10% sodium bisulfate is added in reaction solution, it is extracted with ethyl acetate.Extract liquor water and saturated common salt water washing, then it is dry with anhydrous magnesium sulfate, then the lower concentration of decompression, obtains residue.Residue is crystallized with ethyl alcohol, obtains the title compound (67mg, 75%) in acicular crystal.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:452 (M++H).
Elemental analysis: C21H16ClF2NO4S: 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- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde
In 2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 42 obtains; 5- difluorophenyl) methyl] -5- (1; 3- dioxolanes -2- base) pyridine (602mg; 1.3mmol) 1; 1N hydrochloric acid (30ml) is added in 4- dioxane (30ml), stirs 18 hours at room temperature.After solution is extracted with ethyl acetate, with water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.Lower concentration is depressurized after solution anhydrous magnesium sulfate drying, obtains residue.With silica gel chromatography, (hexane: ethyl acetate=5: 1) refining residue, obtains the title compound (530mg, 98%) in acicular crystal.
1H-NMR (400MHz, CDCl3) 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- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -5- (piperidin-1-yl methyl) pyridine
At room temperature; in [6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (82mg; 0.2mmol) and piperidines (40 μ l; acetic acid (23 μ l are added in dichloromethane solution (5ml) 0.4mmol); 0.4mmol) with sodium triacetoxy borohydride (85mg, 0.4mmol), stir 3 hours.Saturated sodium bicarbonate aqueous solution is added to stop after reacting, is diluted with ethyl acetate (80ml).Divide and take organic layer, with water and saturated common salt water washing.Lower concentrate solution is depressurized after dry solution, obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, then with alcohol crystal, obtains title compound (89mg, 93%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:477 (M++H).
Elemental analysis: C24H23ClF2N2O2S: 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- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] morpholine
At room temperature; in [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 47 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (82mg; 0.2mmol) and morpholine (35 μ l; acetic acid (23 μ l are added in dichloromethane solution (5ml) 0.4mmol); 0.4mmol) with sodium triacetoxy borohydride (85mg, 0.4mmol), stir 3 hours.Saturated sodium bicarbonate aqueous solution is added to stop after reacting, is diluted with ethyl acetate (80ml).Divide and take organic layer, with water and saturated common salt water washing.Lower concentrate solution is depressurized after dry solution, obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, then with alcohol crystal, obtains title compound (90mg, 94%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:479 (M++H).
Elemental analysis: C22H21ClF2N2O3S: 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- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid
At room temperature; in [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 47 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (110mg; 2- methyl-2-butene (143 μ l, 1.35mmol) is added in t-butanol solution (3.0ml) 0.27mmol).The aqueous solution (0.6ml) of sodium dihydrogen phosphate (32.4mg, 0.27mmol) is added in the suspension, adds sodium chlorite (98mg, 1.08mmol), stirs 2 hours.Add water (30ml) and acetic acid (1ml) in reaction solution, is extracted with ethyl acetate (100ml).Extract liquor saturated common salt water washing depressurizes lower retort solution after dry.With ethyl alcohol to residue obtained crystallization, the title compound (71mg, 62%) in colorless needle crystals is obtained.
1H-NMR (400MHz, CDCl3) 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)
230 DEG C of of mp:>
MS m/z:424 (M++H).
Elemental analysis: C19H12ClF2NO4S: 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- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine-N-oxides
At room temperature; in 3- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 19 obtains; 5- difluorophenyl) methyl] pyridine (162mg; 3- chlorine benzylhydroperoxide (81mg is added in methylene chloride (15ml) 0.427mmol); 0.47mmol), it stirs 24 hours.After reaction solution is diluted with ether (60ml), with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing.It is filtered after solution is dry, depressurizes lower concentrate solution, obtain residue.The residue is handled with silica gel chromatography (ethyl acetate), is obtained title compound (68mg, 40%).The compound is crystallized with ethyl alcohol, obtains colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H12ClF2NO3S: 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- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine-N-oxides
In 4- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 20 obtains; 5- difluorophenyl) methyl] pyridine (221mg; 3- chlorine benzylhydroperoxide (100mg is added in methylene chloride (20ml) 0.58mmol); 0.58mmol), it stirs 20 hours.After reaction solution is diluted with ether (60ml), with saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing.It is filtered after solution is dry, depressurizes lower concentrate solution, obtain residue.The residue is handled with silica gel chromatography (ethyl acetate), is obtained title compound (183mg, 80%).The compound is crystallized with ethyl alcohol, obtains colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H12ClF2NO3S: 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.
The chloro- 4- of embodiment 53:3- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine
After the chloro- 4- of 3- [(2,5- difluorophenyl)-hydroxymethyl] pyridine (511mg, 2.0mmol) that reference example 23 obtains is dissolved in thionyl chloride (3.0ml), the dimethylformamide of catalytic amount is added, stirs 17 hours.Lower concentration of reaction solution is depressurized, toluene is added in residue, then be concentrated.
The residue is dissolved in dimethylformamide (10ml), 4- chlorobenzenethiol (375mg, 2.6mmol) and potassium carbonate (414mg, 3mmol) are added under nitrogen atmosphere, is stirred 3 hours in 60 DEG C.Ether (60ml) is added after reaction solution is cooled to room temperature, it is washed with water and saturated salt solution.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ethyl acetate=8: 1) being handled residue, obtains the title compound (196mg, 26%) in solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:382 (M++1).
The chloro- 4- of embodiment 54:2,5- bis- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine
2 that reference example 24 is obtained, after the chloro- 4- of 5- bis- [(2,5- difluorophenyl)-hydroxymethyl] pyridine (580mg, 2.0mmol) is dissolved in thionyl chloride (3.0ml), the dimethylformamide of catalytic amount is added, stirs 17 hours.Lower concentration of reaction solution is depressurized, toluene is added in residue and is concentrated again.The residue is dissolved in dimethylformamide (10ml), 4- chlorobenzenethiol (375mg, 2.6mmol) and potassium carbonate (414mg, 3mmol) are added under nitrogen atmosphere, is stirred 17 hours in 50 DEG C.Ether (60ml) is added after reaction solution is cooled to room temperature, it is washed with water and saturated salt solution.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.With silica gel chromatography, (hexane: ether=10: 1) being handled residue, obtains the title compound (484mg, 58%) in solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:416 (M++1).
The chloro- 4- of embodiment 55:3- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine
In the chloro- 4- of 3- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 53 obtains, 5- difluorophenyl) methyl] pyridine (122mg, seven molybdic acids, six ammonium tetrahydrate (60mg) is added in methanol (12ml) solution 0.32mmol), it adds 30% aquae hydrogenii dioxidi (6ml), stirs 24 hours.After being diluted with ethyl acetate, solution water and saturated common salt water washing.After depressurizing lower concentrate solution, residue is crystallized with ethyl alcohol, obtains the title compound (103mg, 78%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H11Cl2F2NO2S: 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.
The chloro- 4- of embodiment 56:3- [(4- chlorphenyl sulfinyl)-(2,5- difluorophenyl) methyl] pyridine
In the chloro- 4- of 3- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 53 obtains, 5- difluorophenyl) methyl] pyridine (75mg, 3- chlorine benzylhydroperoxide (33mg is added in methylene chloride (10ml) solution 0.20mmol), 0.20mmol), it stirs 3 hours under ice-cooling.After ether (80ml) dilution, solution is washed with water and saturated salt solution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, title compound (48mg, 60%) of the acquisition as non-enantiomer mixture (1: 1).
1H-NMR (400MHz, CDCl3) 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 (C18H12Cl2F2NOS, calculated value: 397.9985)
0.5 hydrate of the chloro- 4- of embodiment 57:2,5- bis- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine
2 obtained in embodiment 54, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (60mg, 3- chlorine benzylhydroperoxide (62mg is added in methylene chloride (3.0ml) solution 0.14mmol), 0.36mmol), it stirs 3 hours at room temperature.After ether (80ml) dilution, solution is washed with saturated sodium bicarbonate aqueous solution and saturated salt solution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=5: 1) refining, then crystallized by hexane residue, acquisition title compound (55mg, 88%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H10Cl3F2NO2S, 0.5H2O: 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- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] morpholine
In 100 DEG C, embodiment 54 is obtained under nitrogen atmosphere 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (100mg, 0.24mmol) stirred 2 days with Isosorbide-5-Nitrae-dioxanes (1.0ml) solution of morpholine (200 μ l).It after being cooled to room temperature, is diluted with ethyl acetate (40ml), solution is washed with water and saturated salt solution.Concentration obtains residue under depressurizing after dry solution, and residue obtained with silica gel chromatography, (hexane: ethyl acetate=5: 1) being refined, and acquisition is in the title compound (100mg, 89%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:467 (M++H).
Embodiment 59:4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] morpholine
In 4- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] morpholine (90mg, seven molybdic acids, six ammonium tetrahydrate (60mg) is added in methanol (12ml) solution 0.19mmol), it adds 30% aquae hydrogenii dioxidi (6ml), stirs 8 hours.After being diluted with ethyl acetate, solution water and saturated common salt water washing.Depressurize after lower concentrate solution residue with silica gel column chromatography (hexane: ethyl acetate=3: 1) being handled, then with alcohol crystal, obtain be in colorless needle crystals title compound (80mg, 83%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C22H18Cl2F2N2O3S: 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- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino-ethyl] morpholine
In 100 DEG C, embodiment 54 is obtained under nitrogen atmosphere 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (100mg, 0.24mmol) stirred 2 days with Isosorbide-5-Nitrae-dioxanes (1.0ml) solution of 4- (2- amino-ethyl) morpholine (200 μ l).It after being cooled to room temperature, is diluted with ethyl acetate (40ml), solution is washed with water and saturated salt solution.Lower be concentrated is depressurized after dry solution obtains residue, it is residue obtained to be refined with silica gel chromatography (30% methanol/chloroform), obtain the title compound (12mg, 10%) in grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:510 (M++H).
Embodiment 61:4- [2- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino-ethyl] methylmorpholine-N-oxide
In 4- [2- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino-ethyl] morpholine (11mg, seven molybdic acids, six ammonium tetrahydrate (10mg) is added in methanol (12ml) solution 0.032mmol), it adds 30% aquae hydrogenii dioxidi (1ml), stirs 8 hours.After being diluted with ethyl acetate, solution water and saturated common salt water washing.Residue is refined with silica gel chromatography (3% methanol, 3% tert-butylamine/chloroformic solution) after depressurizing lower concentrate solution, is obtained title compound (5.0mg, 42%).
1H-NMR (400MHz, CDCl3) 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 (C24H24Cl2F2N3O4S, calculated value: 558.0833)
Embodiment 62:5- azido methyl -2- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine
2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 43 is obtained; 5- difluorophenyl) methyl] -5- (hydroxymethyl) pyridine (471mg; 1.15mmol) it is dissolved in carbon tetrachloride (4ml) and N; in the mixed liquor of dinethylformamide (16ml); sodium azide (112mg is added; 1.72mmol), triphenyl phasphine (451mg, 1.72mmol) is stirred 3 hours in 90 DEG C.Water is added in reaction solution to be extracted with ethyl acetate, then organic layer successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the sodium sulphate drying of gained organic layer.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (244mg, 0.561mmol, 49%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:435 (M++H).
Embodiment 63:[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methylamine
Under argon atmospher; 5- azido methyl -2- [(4- Chlorophenylsulfonyl) (2 is added in ethyl alcohol (10ml); 5- difluorophenyl) methyl] pyridine (77mg; 0.177mmol), it after palladium carbon (14mg) and ethyl acetate (2ml), is stirred 50 minutes under the hydrogen atmosphere gas of 1 air pressure.After filtering reaction mixture, lower concentration filtrate is depressurized.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by methylene chloride: methanol=10: the fraction that 1 elution portion obtains obtains the title compound (28mg, 0.0685mmol, 39%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:409 (M++H).
Embodiment 64:[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] t-butyl carbamate
5- azido methyl -2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 62 obtains is added in the mixed liquor of ethyl acetate (15ml) and ethyl alcohol (15ml); 5- difluorophenyl) methyl] pyridine (230 mg; 0.529mmol) and after palladium carbon (46mg), stirred 45 minutes under the hydrogen atmosphere gas of 1 air pressure.After filtering reaction mixture, lower concentration filtrate is depressurized.By it is residue obtained be dissolved in methylene chloride (5ml) after, triethylamine (70 μ l, 0.499mmol) and dimethyl dicarbonate butyl ester (174mg, 0.996mmol) is added, at room temperature stirring 3 days.Lower concentrated reaction solution is depressurized, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, acquisition are in the title compound (78mg, 0.153mmol, 37%) of colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:509 (M++H).
Embodiment 65:[[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl]-N- (tert-butoxycarbonyl) t-butyl carbamate
Under nitrogen atmosphere; in 2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 43 obtains; 5- difluorophenyl) methyl] -5- (hydroxymethyl) pyridine (178mg; 0.435mmol), iminodicarboxylic acid di tert butyl carbonate (142mg; 0.653mmol), triphenyl phasphine (171mg; diisopropyl azo-2-carboxylic acid (128 μ l are added in tetrahydrofuran (5ml) solution 0.653mmol); 0.653mmol), it stirs 5 hours at room temperature.Add water in reaction solution, is extracted with ethyl acetate, then organic layer successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the sodium sulphate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (78mg, 0.128mmol, 32%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:609 (M++H).
Embodiment 66:[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methylamine hydrochloride
In [[6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] methyl]-N- (tert-butoxycarbonyl) t-butyl carbamate (70mg; concentrated hydrochloric acid (2ml) is added in ethyl alcohol (2ml) solution 0.115mmol), stirs 3 hours at room temperature.Lower concentrated reaction solution is depressurized, is concentrated under reduced pressure in residue obtained middle addition ethyl alcohol, obtains the title compound (51mg, 0.115mmol, 100%) of white powder.
1H-NMR (400MHz, CD3OD) 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)
Elemental analysis: C20H15ClF2N2O2SHCl: 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- acetyl group-N- [[6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] methyl] acetamide (compound A) and N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] acetamide (compound B)
Compound A compound B
Under ice cooling; in [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (40mg; N-methylmorpholine (26 μ l are added in methylene chloride (3ml) solution 0.0978mmol); 0.234mmol), chloroacetic chloride (16 μ l, 0.234mmol) stirs 16 hours at room temperature.In reaction solution plus water is extracted with ethyl acetate, and then organic layer successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the sodium sulphate drying of gained organic layer.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 3 elution portions obtain, obtain title compound A (low polar compound) (15mg of white powder, 0.0304mmol, and the title compound B of white powder (highly polar compound) (12mg 40%), 0.0266mmol, 27%).
Compound A
1H-NMR (400MHz, CDCl3) 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 DEG C
MS m/z:493 (M++H).
Compound B
1H-NMR (400MHz, CDCl3) δ: 2.03 and 2.04 (3H, rotational isomer), 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 DEG C
MS m/z:451 (M++H).
Embodiment 68:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl]-N ', N '-dimethyl sulfonamide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 66 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine hydrochloride (60mg; N-methylmorpholine (180 μ l are added in methylene chloride (5ml) solution 0.135mmol); 1.62mmol), 4-dimethylaminopyridine (10mg; 0.0819mmol) and N; N- dimethylsufamoyl chloride (66 μ l; 0.609mmol), it stirs 24 hours at room temperature.In reaction solution plus water is extracted with dichloromethane, and then organic layer successively uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain obtains the title compound (48mg, 0.0930mmol, 70%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C
MS m/z:516 (M++H).
Embodiment 69:2- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methylamino] -2- ethyl
Under ice-cold; in [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (30mg; N-methylmorpholine (10 μ l are added in methylene chloride (4ml) solution 0.0734mmol); 0.0881mmol) and glyoxylate ethyl chloride (9 μ l; 0.0807mmol), it stirs 1 hour at room temperature.In reaction solution plus water is extracted with dichloromethane, and then organic layer successively uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain obtains the title compound (28mg, 0.0550mmol, 76%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:509 (M++H).
Embodiment 70:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] -2- (4- methylphenylsulfonyl amino) acetamide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 66 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine hydrochloride (40mg; triethylamine (45 μ l are added in methylene chloride (6ml) solution 0.0898mmol); 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), it stirs 16 hours at room temperature.Reaction solution is diluted with methylene chloride, successively uses water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 3 elution portions obtain obtains the title compound (41mg, 0.0661mmol, 73%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:620 (M++H).
Embodiment 71:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] -2- dimethylamino acetamide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (30mg; triethylamine (12 μ l are added in methylene chloride (5ml) solution 0.0734mmol); 0.0881mmol), 4-dimethylaminopyridine (5mg; 0.0367mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (17mg; 0.0881mmol) and N; N- dimethylglycine (9mg; 0.0881mmol), it stirs 14 hours at room temperature.Reaction solution is diluted with methylene chloride, successively uses water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 4 elution portions obtain obtains the title compound (21mg, 0.0425mmol, 58%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:494 (M++H).
Embodiment 72:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] -4- (carbamoylmethyl amino) benzamide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (50mg; triethylamine (21 μ l are added in methylene chloride (5ml) solution 0.122mmol); 0.147mmol), 4-dimethylaminopyridine (7mg; 0.0610mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (28mg; 0.147mmol) and N- formoxyl -4- (methylamino) benzoic acid (26mg; 0.147mmol), it stirs 2 hours at room temperature.Reaction solution is diluted with methylene chloride, successively uses water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 7 elution portions obtain obtains the title compound (60mg, 0.105mmol, 87%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:570 (M++H).
Embodiment 73:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] -4- (methyl thio Formylamino) thiobenzamide
Under argon atmospher; in N- [[6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] methyl] -4- (carbamoylmethyl amino) benzamide (46mg; Lawson reagent (69mg is added in toluene (5ml) solution 0.0807mmol); after 0.169mmol), it is heated to reflux 12 hours.After being cooled to room temperature, lower concentrated reaction mixture is depressurized.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (40mg, 0.0664mmol, 83%) in Yellow amorphous object.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:602 (M++H).
Embodiment 74:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] -2- (pyridin-3-yl) acetamide
[6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 is obtained; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (30mg; 0.073mmol), 3- pyridylacetic acid hydrochloride (16mg; 0.092mmol), 4- (dimethylamino) pyridine (5mg; 0.04mmol) and triethylamine (0.025ml; 0.18mmol) it is dissolved in methylene chloride (5ml); 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (17mg, 0.089mmol) is added at room temperature.After stirring 14 hours at room temperature, saturated sodium bicarbonate aqueous solution (0.1ml) is added in reaction solution.Reaction mixture is concentrated under reduced pressure, residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by methylene chloride: methanol=30: the fraction that 1 elution portion obtains obtains white solid.Obtained solid is washed with ether, obtains the title compound (35mg, 0.066mmol, 90%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:528 (M++H).
Embodiment 75: dimethyl carbamic acid [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl esters
In 0 DEG C; in 2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 43 obtains; 5- difluorophenyl) methyl] -5- (hydroxymethyl) pyridine (20mg; N-methylmorpholine (0.011ml is added in methylene chloride (0.3ml) solution 0.049mmol); 0.10mmol); p-nitrophenyl chloroformate ester (15mg, 0.074mmol) is added, is stirred 30 minutes at room temperature.Then, N-methylmorpholine (0.033ml, 0.30mmol) and p-nitrophenyl chloroformate ester (15mg, 0.074mmol) are added in the reactive mixture in 0 DEG C, stir 30 minutes at room temperature.Then, dimethylamine hydrochloride (20mg, 0.25mmol) is added in the reactive mixture in 0 DEG C, after stirring 13 hours at room temperature, is washed with saturated aqueous ammonium chloride.Organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering, it is residue obtained to be handled with flashchromatography on silica gel, it is concentrated under reduced pressure by hexane: ethyl acetate=7: the fraction that 3 elution portions obtain, leaching after obtained solid is washed with hexane, obtain the title compound (13mg, 0.027mmol, 55%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:481 (M++H).
Embodiment 76: carbonic acid [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl esters 4- nitro phenyl ester
In 0 DEG C; in 2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 43 obtains; 5- difluorophenyl) methyl] -5- (hydroxymethyl) pyridine (41mg; N-methylmorpholine (0.033ml is added in methylene chloride (0.5ml) solution 0.10mmol); 0.30mmol); chloro-carbonic acid 4- nitro phenyl ester (40mg, 0.20mmol) is added, is stirred 1 hour at room temperature.After reaction mixture is washed with water, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, leaching after obtained solid is washed with hexane obtain the title compound (52mg, 0.090mmol, 90%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:575 (M++H).
Embodiment 77: Benzylamino formic acid [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl esters
In 0 DEG C; carbonic acid [6- (4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) picoline -3- base] methyl esters 4- nitro phenyl ester (51mg; N-methylmorpholine (0.020ml is added in methylene chloride (1ml) solution 0.089mmol); 0.18mmol); benzene methanamine (0.012ml, 0.11mmol) is added, is stirred 20 hours at room temperature.After reaction mixture is washed with saturated aqueous ammonium chloride, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.It is residue obtained to be handled with flashchromatography on silica gel, reduced pressure is by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, and leaching after obtained solid diisopropyl ether obtains the title compound (33mg of white solid, 0.060mmol, 68%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:543 (M++H).
Embodiment 78:N- [6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methyl] -3- cvanobenzenesulfonamide
In 0 DEG C; in [the 6- (4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (28mg; N-methylmorpholine (0.015ml is added in methylene chloride (0.5ml) solution 0.068mmol); 0.14mmol); 3- cyanobenzenesulfonyl chloride (22mg, 0.10mmol) is added, is stirred 6 hours at room temperature.After reaction mixture 1N salt acid elution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=7: the fraction that 3 elution portions obtain, leaching after obtained solid is washed with hexane obtain the title compound (23mg, 0.040mmol, 59%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:574 (M++H).
Embodiment 79:N- [[6- (4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methyl] -3- cyano-N-methyl benzsulfamide
In 0 DEG C; in N- [[6- (4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) picoline -3- base] methyl] -3- cvanobenzenesulfonamide (21mg; methanol (0.003ml is added in tetrahydrofuran (0.5ml) solution 0.037mmol); 0.073mmol), triphenyl phasphine (19mg; 0.073mmol); add diisopropyl azo-2-carboxylic acid (0.014ml; 0.073mmol), it stirs 2 hours at room temperature.Reaction mixture is concentrated under reduced pressure, is refined residue obtained with flashchromatography on silica gel.Be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (13mg, 0.021mmol, 58%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:588 (M++H).
Embodiment 80:3- [[6- (4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methyl] -1,1- dimethyl urea
In 0 DEG C; in [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (31mg; triethylamine (0.032ml is added in methylene chloride (1ml) solution 0.076mmol); 0.23mmol), N, N- dimethylcarbamyl chloride (0.014ml are added; 0.15mmol), it stirs 17 hours at room temperature.Triethylamine (0.032ml, 0.23mmol) and N, N- dimethylcarbamyl chloride (0.014ml, 0.15mmol) are added in the reactive mixture in 0 DEG C, are stirred 29 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.It is residue obtained to be handled with flashchromatography on silica gel, the fraction obtained by ethyl acetate elution portion is concentrated under reduced pressure.Leaching after obtained solid is washed with hexane obtains the title compound (18mg, 0.036mmol, 48%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:480 (M++H).
Embodiment 81:[6- (4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methylene dicarbamate
Using method same as embodiment 80; [the 6- (4- Chlorophenylsulfonyl)-(2 obtained by embodiment 63; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (34mg; 0.082mmol) and methyl-chlorocarbonate (0.019ml; 0.25mmol); obtain the title compound (16mg, 0.034mmol, 42%) in yellow solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:467 (M++H).
Embodiment 82:N- [[6- (4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methyl] Methanesulfomide
Using method same as embodiment 80; [6- [(the 4- Chlorophenylsulfonyl)-(2 obtained by embodiment 63; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (34mg; 0.082mmol) and mesyl chloride (0.019ml; 0.25mmol); obtain the title compound (20mg, 0.040mmol, 49%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:487 (M++H).
Embodiment 83:N- [[6- (4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methyl] -1- acetyl group -4- piperidines carboxylic acid amides
Using method same as embodiment 80; [6- [(the 4- Chlorophenylsulfonyl)-(2 obtained by embodiment 63; 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (34mg; 0.082mmol) and 1- acetyl group -4- piperidine formyl chlorine (56mg; 0.25mmol); obtain the title compound (24mg, 0.043mmol, 52%) in colourless blister substance.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:562 (M++H).
Embodiment 84: methyl carbonic acid [6- (4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) picoline -3- base] methyl esters
In 0 DEG C; in 2- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 43 obtains; 5- difluorophenyl) methyl] -5- (hydroxymethyl) pyridine (50mg; pyridine (0.040ml is added in methylene chloride (2ml) solution 0.12mmol); 0.49mmol); methylchloroformate (0.019ml, 0.24mmol) is added, is stirred 1 hour at room temperature.Then, methylchloroformate (0.019ml, 0.24mmol) is added in the reactive mixture in 0 DEG C, stirred 5 hours at room temperature.After reaction mixture 1N salt acid elution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, leaching after obtained solid is washed with hexane obtain the title compound (50mg, 0.11mmol, 88%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:468 (M++H).
Embodiment 85:[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] formaldoxime (isomers A and isomers B)
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 47 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; N-methylmorpholine (32 μ l are added in methylene chloride (3ml) solution 0.25mmol); 0.29mmol), hydroxylamine hydrochloride (26mg; 0.36mmol), it stirs 3 days at room temperature.After methylene chloride diluting reaction solution, successively washed with water, saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain, obtain title isomers A (low polar compound) (79mg of white powder, 0.19mmol, 72%), the title isomers B (highly polar compound) (17mg, 0.040mmol, 17%) of white powder.
Isomers A
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:423 (M++H).
Isomers B
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:423 (M++H).
Embodiment 86:[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl]-N- cyclohexyl methyl niacinamide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; triethylamine (32 μ l are added in methylene chloride (5ml) solution 0.19mmol); 0.23mmol), 4-dimethylaminopyridine (12mg; 0.095mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (44mg; 0.23mmol) and aminomethyl cyclohexane (30 μ l; 0.23mmol), it stirs 4.5 hours at room temperature.After reaction solution is diluted with methylene chloride, successively washed with water, saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (58mg, 0.11mmol, 59%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:519 (M++H).
Embodiment 87:6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl]-N- (5- chloropyridine -2- base) niacinamide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; triethylamine (32 μ l are added in methylene chloride (5ml) solution 0.19mmol); 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), it stirs 5 hours at room temperature.After reaction solution is diluted with methylene chloride, successively washed with water, saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (27mg, 0.051mmol, 27%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:534 (M++H).
Embodiment 88:6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl]-N ', N '-dimethyl nicotinic acid hydrazide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; triethylamine (32 μ l are added in methylene chloride (5ml) solution 0.19mmol); 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), it stirs 7 hours at room temperature.After reaction solution is diluted with methylene chloride, successively washed with water, saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by methylene chloride: methanol=50: the fraction that 1 elution portion obtains obtains the title compound (60mg, 0.13mmol, 68%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:466 (M++H).
Embodiment 89:6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl]-N '-(furans -2- carbonyl) nicotinic acid hydrazide
In [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (80mg; triethylamine (32 μ l are added in methylene chloride (5ml) solution 0.19mmol); 0.23mmol), 4-dimethylaminopyridine (12mg; 0.095mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (44mg; 0.23mmol) and 2- Furoic hydrazide (29mg; 0.23mmol), it stirs 7.5 hours at room temperature.After reaction solution is diluted with methylene chloride, successively washed with water, saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by methylene chloride: methanol=50: the fraction that 1 elution portion obtains.Obtained solid is recrystallized with dichloromethane/hexane, obtains the title compound (58mg, 0.11mmol, 58%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:532 (M++H).
Embodiment 90:N- [[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] methyl]-(E) -3- (pyridin-4-yl) acrylamide
In 0 DEG C, in [6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 63 obtains, 5- difluorophenyl) methyl] pyridin-3-yl] methylamine (41mg, 0.10mmol), (E) -3- (pyridin-4-yl) acrylic acid (15mg, 0.10mmol), benzotriazole -1- alcohol (14mg, 0.10mmol) and N-methylmorpholine (0.011ml, 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (19mg is added in methylene chloride (1ml) solution 0.10mmol), 0.10mmol), it stirs 19 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, organic layer dries, filters rear filtrate decompression with anhydrous sodium sulfate and is concentrated.It is residue obtained to be handled with flashchromatography on silica gel, the fraction obtained by ethyl acetate elution portion is concentrated under reduced pressure.Obtained solid is washed with ether, leaching, obtains the title compound (35mg, 0.065mmol, 65%) of white solid.
1H-NMR (400MHz, CDCl3) 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), 8.6 4 (2H, d, J=5.9Hz)
MS m/z:540 (M++H).
Embodiment 91:[6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridin-3-yl] (thiomorpholine -4- base) ketone
Using method same as embodiment 90; with [6- [(the 4- Chlorophenylsulfonyl)-(2 of embodiment 50; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (212mg; 0.50mmol) and thiomorpholine (0.047ml; 0.50mmol); obtain the title compound (240mg, 0.47mmol, 94%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:509 (M++H).
Embodiment 92:[6- [(4- Chlorophenylsulfonyl) - (2; 5- difluorophenyl) methyl] pyridin-3-yl] (1; -1 λ 6- thiomorpholine -4- base of 1- dioxo) ketone (compound A) and [6- [(4- Chlorophenylsulfonyl) - (2,5- difluorophenyl) methyl] pyridin-3-yl] (- 1 λ 4- thiomorpholine -4- base of 1- oxo) ketone (compound B)
Compound A compound B
Under ice-cold; in [6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridin-3-yl] (thiomorpholine -4- base) ketone (153mg; 3- chlorine benzylhydroperoxide (96mg is added in methylene chloride (3ml) solution 0.30mmol); 0.36mmol), it stirs 2 hours at room temperature.With methylene chloride diluting reaction solution, 1N sodium hydrate aqueous solution and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 2 elution portions obtain, obtain title compound A (low polar compound) (81mg of white powder, 0.15mmol, 50%) methylene chloride: methanol=10, is concentrated under reduced pressure: the fraction that 1 elution portion obtains obtains title compound B (highly polar compound) (73mg of white powder, 0.14mmol, 46%).
Compound A
1H-NMR (400MHz, CDCl3) 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)
MS m/z:541 (M++H).
Compound B
1H-NMR (400MHz, CDCl3) 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)
MS m/z:525 (M++H).
Embodiment 93:N- (3- methylthio) -6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] niacinamide
Using method same as embodiment 90; with [6- [(the 4- Chlorophenylsulfonyl)-(2 of embodiment 50; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (212mg; 0.50mmol) and 3- methyl mercapto propylamine (0.055ml; 0.50mmol); obtain the title compound (238mg, 0.47mmol, 93%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:511 (M++H).
Embodiment 94:N- (3- methanesulphonylpropyl) -6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] niacinamide (compound A) and N- (3- methanesulphinylpropyl) -6- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] niacinamide (compound B)
Compound A compound B
In 0 DEG C; in N- (3- methylthio) -6- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] niacinamide (153mg; 3- chlorine benzylhydroperoxide (65% or more purity) (96mg is added in methylene chloride (3ml) solution 0.30mmol); 0.36mmol), it stirs 3 hours at room temperature.After 1N sodium hydrate aqueous solution washing reaction mixture, organic layer is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.It is residue obtained to be handled with silica gel flash column chromatography, the fraction obtained by ethyl acetate elution portion is concentrated under reduced pressure, after obtained solid is washed with ether, leaching obtains the title compound A (53mg, 0.098mmol, 32%) of white solid.Then, methylene chloride: methanol=15 is concentrated under reduced pressure: the fraction that 1 elution portion obtains, leaching after obtained solid is washed with ether obtain the title compound B (68mg, 0.13mmol, 43%) of white solid.
Compound A
1H-NMR (400MHz, CDCl3) 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)
MS m/z:543 (M++H).
Compound B
1H-NMR (400MHz, CDCl3) 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 (1 H, d, J=2.2Hz)
MS m/z:527 (M++H).
The chloro- 5- of embodiment 95:2- [(3- chloropyridine -4- base) (2,5- difluorophenyl) methyl mercapto] pyridine
In dithiocarbonic acids S- (6- chloro-3-pyridyl base) the ester O- ethyl ester (164mg that reference example 26 obtains, 1N sodium hydrate aqueous solution (7ml) is added in ethyl alcohol (7ml) solution 0.70mmol), is stirred 3 hours in 80 DEG C.1N hydrochloric acid is added after being cooled to room temperature in reaction mixture, is extracted with dichloromethane.Organic layer dries, filters rear filtrate decompression with anhydrous sodium sulfate and is concentrated, and obtains the 6- chloro-3-pyridyl mercaptan in yellow solid.
In 0 DEG C, in the chloro- 4- [(2 of 3- that reference example 23 obtains, 5- difluorophenyl)-hydroxymethyl] pyridine (153mg, triethylamine (0.167ml is added in methylene chloride (3ml) solution 0.60mmol), 1.20mmol), mesyl chloride (0.070ml, 0.90mmol) is added, is stirred 2 hours at room temperature.After being washed with saturated sodium bicarbonate aqueous solution to reaction mixture, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.N,N-Dimethylformamide (2ml) solution of 6- chloro-3-pyridyl mercaptan is added in residue obtained n,N-Dimethylformamide (3ml) solution, adds potassium carbonate (100mg, 0.72mmol), stirs 18 hours at room temperature.Ethyl acetate is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.Handled with flashchromatography on silica gel residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=17: the fraction that 3 elution portions obtain obtains the title compound (111mg, 0.29mmol, 48%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:383 (M++H).
The chloro- 5- of embodiment 96:2- [(3- chloropyridine -4- base) (2,5- difluorophenyl) methyl sulphonyl] pyridine
In the chloro- 5- of 2- [(3- chloropyridine -4- base) (2,5- difluorophenyl) methyl mercapto] pyridine (109mg, six ammonium tetrahydrate (30mg) of 31% aqueous hydrogen peroxide solution (2ml) and seven molybdic acids is added in methanol (4ml) solution 0.28mmol), stirs 17 hours at room temperature.Ethyl acetate is added in the reactive mixture, after being washed with saturated sodium bicarbonate aqueous solution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: ethyl acetate=17: the fraction that 3 elution portions obtain obtains the title compound (108mg, 0.26mmol, 92%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:415 (M++H).
Embodiment 97:5- [(3- chloropyridine -4- base) (2,5- difluorophenyl) methyl sulphonyl] -2- fluorine pyridine
In the chloro- 5- of 2- [(3- chloropyridine -4- base) (2; 5- difluorophenyl) methyl sulphonyl] pyridine (66mg; potassium fluoride (94mg is added in acetonitrile (2ml) solution 0.16mmol); 1.60mmol) and Xiuization tetraphenylphosphoniphenolate (134mg; 0.32mmol), it is heated to reflux 16 hours.After reaction mixture is cooled to room temperature, methylene chloride is added and is washed with water.Organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: ethyl acetate=17: the fraction that 3 elution portions obtain obtains the title compound (4.5mg, 0.011mmol, 7%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:440 (M++H+MeCN).
Embodiment 98:N '-[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridin-3-yl methylene] -2- thenoyl hydrazine
[6- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 47 is obtained; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; 0.245mmol) and 2- thenoyl hydrazine (41.7mg; it 0.294mmol) is dissolved in ethyl alcohol (3ml), is stirred 3 days at room temperature.The solid that leaching is precipitated, uses ethanol washing.Obtained solid is recrystallized with ethyl alcohol, obtains the title compound (91.0mg, 0.171mmol, 70%) of white solid.
1H-NMR (400MHz, CDCl3/DMSO-d6) 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)
MS m/z:532 (M++H).
Embodiment 99:6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] niacinamide
In [6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; thionyl chloride (1.00ml) and N are added in methylene chloride (4ml) suspension 0.236mmol); after dinethylformamide (1 drop), stir 18 hours at room temperature.Concentration of reaction solution to dry, it is residue obtained be dissolved in methylene chloride (6ml) after, be added 28% ammonium hydroxide (2ml).Make it in acidity with 1N hydrochloric acid after stirring 3 hours to reaction solution at room temperature.Concentration gained mixture, the solid that leaching generates.After obtained solid water and ethanol washing, with ethyl alcohol recrystallization, the title compound (47.9mg, 0.113mmol, 46%) of white solid is obtained.
1H-NMR (400MHz, CDCl3/DMSO-d6) 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)
MS m/z:423 (M++H).
Embodiment 100:6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl]-N- (4- methylcyclohexyl) niacinamide
In [6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; thionyl chloride (1.00ml) and N are added in methylene chloride (4ml) suspension 0.236mmol); after dinethylformamide (1 drop), stir 6 hours at room temperature.Concentration of reaction solution to dry, it is residue obtained be dissolved in methylene chloride (6ml) after, N-methylmorpholine (51.8 μ l, 0.472mmol) and 4- methyl cyclohexylamine (37.4 μ l, 0.283mmol) is added.It is diluted after being stirred 18 hours to reaction solution at room temperature with methylene chloride, then is successively washed with 1N hydrochloric acid, water and saturated salt solution.Then, dry with magnesium sulfate, residue obtained after concentration to be handled with silica gel flash column chromatography, be concentrated by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains white solid.Obtained solid is recrystallized with ethylacetate-hexane, obtains the title compound (70.3mg, 0.135mmol, 57%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:519 (M++H).
Embodiment 101:6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl]-N- methoxyl group niacinamide
In [6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; N-methylmorpholine (77.7 μ l are added in methylene chloride (6ml) suspension 0.236mmol); 0.708mmol), O- methyl hydroxylamine hydrochloride (23.6mg; 0.283mmol) and 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (54.3mg, 0.283mmol).Tetrahydrofuran (1ml) is added after stirring 1 hour to reaction solution at room temperature.It is diluted after being stirred 18 hours to reaction solution at room temperature with methylene chloride, then with water and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains white solid.Obtained solid is washed with ethyl acetate, obtains the title compound (55.1mg, 0.122mmol, 52%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:453 (M++H).
Embodiment 102:N, N- dimethyl-[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridin-3-yl] methylamine
[6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 47 is obtained; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; 0.245mmol), the tetrahydrofuran solution (2.0M of dimethylamine; 0.25ml; 0.50mmol) and after acetic acid (0.029ml, 0.51mmol) is dissolved in 1,2- dichloroethanes (5ml); sodium triacetoxy borohydride (115mg, 0.515mmol) is added at room temperature.After stirring 3 days at room temperature, saturated sodium bicarbonate aqueous solution and ethyl acetate are added in the reactive mixture.After mixture liquid separation, gained organic layer first uses saturated common salt water washing again with saturated sodium bicarbonate aqueous solution, then dry with anhydrous magnesium sulfate.Filtrate is concentrated under reduced pressure after filtering, residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by methylene chloride: methanol=40: the fraction that 1 elution portion obtains obtains white solid.The title compound (88mg, 0.20mmol, 82%) of white powder is obtained after washing obtained solid with hexane.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:437 (M++H).
Embodiment 103:N- [[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridin-3-yl] methyl] bis- (2- methoxy ethyl) amine
[6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 47 is obtained; 5- difluorophenyl) methyl] pyridin-3-yl] formaldehyde (100mg; 0.245mmol), bis- (2- methoxy ethyl) amine (70mg; 0.53mmol) and acetic acid (0.029ml; 0.51mmol) it is dissolved in 1; after 2- dichloroethanes (5ml), sodium triacetoxy borohydride (115mg, 0.515mmol) is added at room temperature.After stirring 3 days at room temperature, saturated sodium bicarbonate aqueous solution and ethyl acetate are added in the reactive mixture.After mixture liquid separation, gained organic layer first uses saturated common salt water washing again with saturated sodium bicarbonate aqueous solution, then dry with anhydrous magnesium sulfate.Filtrate is concentrated under reduced pressure after filtering, residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain obtains white solid.The title compound (101mg, 0.192mmol, 78%) of white powder is obtained after washing obtained solid with hexane.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:525 (M++H).
Embodiment 104:6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl]-N, N- dimethyl nicotinamide
[6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 50 is obtained, 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (90mg, 0.21mmol), tetrahydrofuran solution (the 2.0M of dimethylamine, 0.21ml, 0.42mmol), 4- (dimethylamino) pyridine (15mg, 0.12mmol) and triethylamine (0.045ml, 0.32mmol) it is dissolved in methylene chloride (5ml), at room temperature, 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (61mg is added, after 0.32mmol), it is stirred at room temperature 14 hours.Reaction mixture is concentrated under reduced pressure, it is residue obtained to be handled with flashchromatography on silica gel, then be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (35mg, 0.066mmol, 90%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:451 (M++H).
Embodiment 105:[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridin-3-yl] (4- methylpiperazine-1-yl) ketone
[6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 50 is obtained; 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) it is dissolved in methylene chloride (5ml); 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (61mg, 0.32mmol) is added at room temperature.After being stirred at room temperature 14 hours, N methyl piperazine (0.036ml is added in the reactive mixture, 0.33mmol), triethylamine (0.045ml, 0.32mmol) and 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (61mg, 0.32mmol).Reaction mixture is concentrated under reduced pressure after stirring 14 hours at room temperature, residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by methylene chloride: methanol=25: the fraction that 1 elution portion obtains obtains the title compound (86mg of white powder, 0.17mmol, 80%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:506 (M++H).
Embodiment 106:4- [2- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino-ethyl] morpholine
4- [2- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 61 is obtained; 5- difluorophenyl) methyl] pyridine -2- base] amino-ethyl] methylmorpholine-N-oxide (78mg, 0.14mmol) is dissolved in the in the mixed solvent of acetic acid (2.0ml) and water (2.0ml).It is heated in 60 DEG C, is added iron powder (40mg, 0.72mmol), is stirred 30 minutes.Reaction solution is injected into unsaturated carbonate aqueous solutions of potassium after cooling, is extracted with ethyl acetate (60ml).Solution saturated common salt water washing depressurizes lower concentration after dry.It is residue obtained to be refined with silica gel chromatography (3% methanol/chloroform solution), it obtains title compound (30mg, 40%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:542 (M++H).
Embodiment 107:2- [N- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base]-N- methylamino] ethyl-methyl amino t-butyl formate
Under nitrogen atmosphere, embodiment 54 is obtained in 100 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (78mg, 0.19mmol) and N, Isosorbide-5-Nitrae-dioxanes (2.0ml) solution of N '-dimethyl ethylenediamine (400 μ l) stirs 2 days.It is diluted after being cooled to room temperature with ethyl acetate (40ml), solution water and saturated common salt water washing.Lower concentration is depressurized after dry solution, obtains residue.After residue is dissolved in tetrahydrofuran (10ml), triethylamine (31 μ l, 0.22mmol) and di-tert-butyl dicarbonate (49mg, 0.22mmol) are added at room temperature, stirs 15 hours.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=4: 1) being refined to residue obtained, obtains the title compound (68mg, 64%) in grease.
1H-NMR (400MHz, CDCl3) δ: 1.26 and 1.32 (9H, br-s, rotational isomer), 2.75 and 2.78 (3H, br-s, rotational isomers), 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)
MS m/z:568 (M++H).
Embodiment 108:2- [N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base]-N- methylamino] ethyl-methyl amino t-butyl formate
In 2- [N- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base]-N- methylamino] ethyl-methyl amino t-butyl formate (67mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.12mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.Solution water and saturated common salt water washing after being diluted with ethyl acetate.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, obtains the title compound (64mg, 91%) in grease.
1H-NMR (400MHz, CDCl3) δ: 1.33 and 1.38 (9H, br-s, rotational isomer), 2.87 and 2.89 (3H, br-s, rotational isomers), 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 (C27H29Cl2F2N3O4S, calculated value: 599.1224)
The chloro- 4- of embodiment 109:5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -2- [N- methyl-N- [2- (methylamino) ethyl] amino] pyridine
By 2- [N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine -2- base]-N- methylamino] ethyl-methyl amino t-butyl formate (61mg; 0.10mmol) it is dissolved in methylene chloride (2.0ml); methyl phenyl ethers anisole (40 μ l), trifluoroacetic acid (200 μ l) are added at room temperature, stirs 1 hour.Lower concentration of reaction solution is depressurized, residue obtained to be refined with silica gel chromatography (3% methanol/chloroform to 3% methanol, 3% tert-butylamine/chloroform), acquisition is in the title compound (21mg, 41%) of grease.
1H-NMR (400MHz, CDCl3) 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 (C22H22Cl2F2N3O2S, calculated value: 500.0778)
Embodiment 110:(2 ' S) the chloro- 4- of -5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- [2 '-(hydroxymethyl) pyrrolidines -1 '-yl] pyridine
Under nitrogen atmosphere, embodiment 54 is obtained in 100 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (60mg, 0.14mmol) stirred 3 days with Isosorbide-5-Nitrae-dioxanes (1.0ml) solution of (S) -2- pyrrolidine carbinol (200 μ l).It is diluted after being cooled to room temperature with ethyl acetate (50ml), solution water and saturated common salt water washing.Lower concentration is depressurized after solution is dry, obtains residue.It is residue obtained that with silica gel chromatography, (hexane: ethyl acetate=5: 1) being refined, and acquisition is in the title compound (40mg, 58%) of grease.
1H-NMR (400MHz, CDCl3) 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 and 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)
MS m/z:481 (M++H).
Embodiment 111:(2 ' S) the chloro- 4- of -5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -2- [2 '-(hydroxymethyl) pyrrolidines -1 '-yl] pyridine
In (2 ' S) -5- chloro- 4- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- [2 '-(hydroxymethyl) pyrrolidines -1 '-yl] pyridine (39mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.08mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (60ml) dilution.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (33mg, 79%) of grease after concentrate solution under depressurizing.
1H-NMR (400MHz, CDCl3) 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 isomer)
FAB-MS:513.0627 (C23H21Cl2F2N2O3S, calculated value: 513.0618)
Embodiment 112:[4- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine-2- base] morpholine -2-yl] the methyl carbamic acid tert-butyl ester
Under nitrogen atmosphere, embodiment 54 is obtained in 100 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (60mg, 0.14mmol) stirred 2 days with Isosorbide-5-Nitrae-dioxanes (1.0ml) solution of (morpholine -2-yl) the methyl carbamic acid tert-butyl ester (200mg).It is diluted after being cooled to room temperature with ethyl acetate (50ml), solution water and saturated common salt water washing.Lower concentration is depressurized after solution is dry, obtains residue.It is residue obtained that with silica gel chromatography, (hexane: ether=5: 1) being refined, and acquisition is in the title compound (45mg, 52%) of grease.
1H-NMR (400MHz, CDCl3) 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 isomer), 6.96 and 6.97 (1H, s, rotational isomer), 6.9-7.1 (3H, m), 7.24 (4H, s), 8.11 (1H, s)
MS m/z:596 (M++H).
Embodiment 113:[4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine-2- base] morpholine -2-yl] the methyl carbamic acid tert-butyl ester
In [4- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine-2- base] morpholine -2-yl] the methyl carbamic acid tert-butyl ester (44mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.074mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (60ml) dilution.With silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (31mg, 67%) of grease after concentrate solution under depressurizing.
1H-NMR (400MHz, CDCl3) 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 (C28H30Cl2F2N3O5S, calculated value: 628.1251)
Embodiment 114:2- amino methyl -4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] morpholine
By [4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine-2- base] morpholine -2-yl] the methyl carbamic acid tert-butyl ester (30mg; 0.05mmol) it is dissolved in methylene chloride (1.5ml); methyl phenyl ethers anisole (30 μ l), trifluoroacetic acid (150 μ l) are added at room temperature, stirs 1 hour.Lower concentration of reaction solution is depressurized, residue obtained to be refined with silica gel column chromatography (3% methanol/chloroform to 3% methanol, 3% tert-butylamine/chloroform), acquisition is in the title compound (17mg, 67%) of grease.
1H-NMR (400MHz, CDCl3) 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 (C23H22Cl2F2N3O3S, calculated value: 528.0727)
The chloro- 4- of embodiment 115:5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- (4 '-hydroxy piperidines -1 '-yl) pyridine
Under nitrogen atmosphere, embodiment 54 is obtained in 100 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (60mg, 0.14mmol) stirred 1 day with the Isosorbide-5-Nitrae-dioxanes (1.0ml) of 4- hydroxy piperidine (200mg).It after being cooled to room temperature, is diluted with ether (50ml), solution water and saturated common salt water washing.Lower concentration is depressurized after dry solution, obtains residue.With silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (300mg, 43%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:481 (M++H).
The chloro- 4- of embodiment 116:5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -2- (4 '-hydroxy piperidines -1 '-yl) pyridine
In the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- (4 '-hydroxy piperidines -1 '-yl) pyridine (29mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.06mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (60ml) dilution.Residue is depressurized after lower concentrate solution (hexane: ethyl acetate=2: 1) to be refined with silica gel chromatography, then use crystallizing from ether, obtain the title compound (17mg, 55%) in solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:513.0588 (C23H21Cl2F2N2O3S, calculated value: 513.0618)
The chloro- 2- of embodiment 117:3,6- bis- [(4- Chlorophenylsulfonyl) (pyridin-4-yl) methyl] pyridine
(3 obtained in reference example 25,6- dichloropyridine -2- base) (pyridin-4-yl) methanol (161mg, triethylamine (208 μ l are added in methylene chloride (10ml) solution 0.631mmol), 1.89mmol) and thionyl chloride (138 μ l, 1.89mmol).It is concentrated under reduced pressure after being stirred 4 hours to reaction solution at room temperature.In residue obtained middle addition ethyl acetate, successively with after saturated sodium bicarbonate aqueous solution and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.It is dissolved in residue obtained acetonitrile (10ml), 4- chlorobenzenethiol (137mg, 0.947mmol) and potassium carbonate (131mg, 0.947mmol) is added.Under nitrogen atmosphere, after being stirred 2 days to reaction solution at room temperature, stirred 4 hours in 60 DEG C.Reaction solution is concentrated under reduced pressure after being cooled to room temperature.In residue obtained middle addition ethyl acetate, successively with after water and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.It is residue obtained to be handled with flash chromatography, the fraction obtained by the eluent of 40% ethyl acetate/hexane is concentrated under reduced pressure.It is dissolved in residue obtained methanol (10ml), 30% aquae hydrogenii dioxidi (3ml) and seven molybdic acids, six ammonium tetrahydrate (73mg) is added.Decompression boils off methanol after room temperature stirs reaction solution 5 hours.Saturated sodium bicarbonate aqueous solution is added in acquired solution, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue obtained to be handled with flash chromatography, be concentrated under reduced pressure by methanol: methylene chloride=1: the fraction that 80 eluents obtain obtains the title compound (49mg, 0.118mmol, 19%) of white solid.
1H-NMR (400MHz, CDCl3) 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- Chlorophenylsulfonyl) -1- (2,5- difluorophenyl) ethyl] -5- picoline
Under ice-cold; in 60% oily sodium hydride (30mg; N 0.75mmol); the resulting 2- of embodiment 15 [[(4- chlorphenyl) sulfonyl] (2 is instilled in dinethylformamide (5ml) suspension; 5- difluorophenyl) methyl] -5- picoline (52mg; n,N-Dimethylformamide (5ml) solution 0.132mmol).Under ice-cold, after being stirred 15 minutes to reaction solution, it is added methyl iodide (12 μ l, 0.198mmol).After stirring 1 hour to reaction solution at room temperature, ice-cold lower plus water is concentrated under reduced pressure.In residue obtained plus water, it is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure after being dried, filtered after organic layer saturated common salt water washing with anhydrous sodium sulfate.It is residue obtained to be handled with silica gel column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=8: the fraction that 1 eluent obtains.Residue obtained hexane solidifies, and the title compound (50mg, 0.122mmol, 93%) of white powder is obtained after leaching.
1H-NMR (400MHz, CDCl3) 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).
The chloro- 2- of embodiment 119:3,6- bis- [(6- chloropyridine -3- base sulfenyl) (pyridin-4-yl) methyl] pyridine
In dithiocarbonic acids S- (6- chloro-3-pyridyl base) the ester O- ethyl ester (164mg that reference example 26 obtains, 1N sodium hydrate aqueous solution (7ml) is added in ethyl alcohol (7ml) solution 0.70mmol), is stirred 3 hours in 80 DEG C.After reaction mixture is cooled to room temperature, 1N hydrochloric acid is added, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, obtain the 6- chloro-3-pyridyl mercaptan in yellow solid.
In 0 DEG C, (3 obtained in reference example 25,6- dichloropyridine -2- base) (pyridin-4-yl) methanol (153mg, triethylamine (0.167ml is added in methylene chloride (3ml) solution 0.60mmol), 1.20mmol), mesyl chloride (0.070ml, 0.90mmol) is added, is stirred 2 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after drying, filtering with anhydrous sodium sulfate in organic layer.N,N-Dimethylformamide (2ml) solution of 6- chloro-3-pyridyl mercaptan is added in residue obtained n,N-Dimethylformamide (3ml) solution, adds potassium carbonate (100mg, 0.72mmol), stirs 18 hours at room temperature.Ethyl acetate is added in the reactive mixture, after being washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=7: the fraction that 3 elution portions obtain obtains the title compound (83mg, 0.22mmol, 36%) in yellow oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:382 (M++H).
Embodiment 120:3; the chloro- 2- of 6- bis- [(6- chloropyridine -3- base sulfonyl) (pyridin-4-yl) methyl] pyridine (compound A) and 3, the chloro- 2- of 6- bis- [(6- chloropyridine -3- base sulfinyl) (pyridin-4-yl) methyl] pyridine (compound B (isomers A) and compound B (isomers B))
Compound A compound B
3, the chloro- 2- of 6- bis- [(6- chloropyridine -3- base sulfenyl) (pyridin-4-yl) methyl] pyridine (82mg, six ammonium tetrahydrate (30mg) of 31% aqueous hydrogen peroxide solution (2ml) and seven molybdic acids is added in methanol (4ml) solution 0.24mmol), stirs 2 hours at room temperature.Ethyl acetate is added in the reactive mixture, after being washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue is handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain, obtain the title compound A (41mg of white solid, 0.098mmol, 46%), in addition, it is concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains, title compound B (isomers A) (low polarity) (8mg of white solid is obtained respectively, and title compound B (isomers B) (highly polar) (8mg, 9%) 9%).
Compound A
1H-NMR (400MHz, CDCl3) 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)
MS m/z:414 (M++H).
Compound B (isomers A)
1H-NMR (400MHz, CDCl3) 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)
MS m/z:398 (M++H).
Compound B (isomers B)
1H-NMR (400MHz, CDCl3) 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)
MS m/z:398 (M++H).
Embodiment 121:2- [[(3- chloropyridine -4- base) (2,5- difluorophenyl) methyl] sulfonyl] pyrimidine
In 0 DEG C, in the chloro- 4- [(2 of 3- that reference example 23 obtains, 5- difluorophenyl)-hydroxymethyl] pyridine (102mg, triethylamine (0.112ml is first added in methylene chloride (4ml) solution 0.40mmol), 0.80mmol), mesyl chloride (0.046ml, 0.60mmol) is added, is stirred 17 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
2- pyridinethiol (45mg, 0.40mmol) is added in residue obtained n,N-Dimethylformamide (4ml) solution, adds potassium carbonate (83mg, 0.60mmol), stirs 23 hours at room temperature.Ethyl acetate is added in the reactive mixture, is washed with water after rear organic layer is dried, filtered with anhydrous sodium sulfate and filtrate is concentrated under reduced pressure.In 0 DEG C, the chloro- benzylhydroperoxide of 3- (65% or more purity) (212mg, 0.80mmol) is added in residue obtained methylene chloride (4ml) solution, stirs 3 hours at room temperature.After reaction mixture is washed with 1N sodium hydrate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 3 elution portions obtain obtains the title compound (19mg, 0.049mmol, 12%) in colourless foaming material.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:382 (M++H).
Embodiment 122:6- (4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl -5- fluorine niacinamide
In 0 DEG C, in the 6- (2 that reference example 31 obtains, 5- difluorophenyl) hydroxymethyl -5- fluorine niacinamide (114mg, triethylamine (0.113ml is first added in methylene chloride (4ml) solution 0.40mmol), 0.81mmol), mesyl chloride (0.047ml, 0.61mmol) is added, is stirred 2 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
4- chlorobenzenethiol (70mg, 0.49mmol) is added in residue obtained n,N-Dimethylformamide (6ml) solution, adds potassium carbonate (67mg, 0.49mmol), stirs 15 hours at room temperature.Ethyl acetate is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.Handled, be concentrated under reduced pressure by hexane with flashchromatography on silica gel by residue obtained: ethyl acetate=1: the fraction that 1 elution portion obtains obtains the title compound (120mg, 0.29mmol, 73%) in yellow solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:409 (M++H).
Embodiment 123:6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl -5- fluorine niacinamide (compound A) and 6- (4- chlorphenyl sulfinyl) (2,5- difluorophenyl) methyl -5- fluorine niacinamide (compound B)
Compound A compound B
In 6- (4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl -5- fluorine niacinamide (120mg, six ammonium tetrahydrate (73mg) of 30% aqueous hydrogen peroxide solution (2ml) and seven molybdic acids is added in methanol (3ml) solution 0.29mmol), stirs 3 hours at room temperature.Methylene chloride is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains, obtain the title compound A (33mg of white solid, 0.075mmol, 25%), in addition, it is concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 3 elution portions obtain, obtain the title compound B (39mg, 0.092mmol, 31%) of white solid.
Compound A
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:441 (M++H).
Compound B
1H-NMR (400MHz, CD3OD) 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 DEG C of
Elemental analysis: C19H12ClF3N2O2S: 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- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methanol
At room temperature, in [5- (t-butyidiphenylsilyl oxygroup the methyl) -3- fluorine pyridine -2- base] (2 that reference example 29 obtains, 5- difluorophenyl) methanol (17.0g, triethylamine (7.00ml is added in methylene chloride (180ml) solution 33.5mmol), 50.2mmol) and mesyl chloride (3.11ml, 40.2mmol), it stirs 2 hours.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
4- chlorobenzenethiol (5.33g, 36.8mmol) is added in residue obtained n,N-Dimethylformamide (300ml) solution, adds potassium carbonate (5.55g, 40.2mmol), stirs 18 hours at room temperature.Ethyl acetate is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.It is handled, is concentrated under reduced pressure by hexane with flashchromatography on silica gel by residue obtained: ethyl acetate=30: the fraction that 1 elution portion obtains.
The tetrahydrofuran solution (42.3ml, 42.3mmol) of tetrabutylammonium is added in residue obtained tetrahydrofuran (200ml) solution, stirs 4 hours at room temperature.After reaction mixture is concentrated under reduced pressure, it is dissolved in ethyl acetate by residue obtained, is washed with saturated sodium bicarbonate aqueous solution.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (9.80g, 24.8mmol, 74%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methanol
In [6- (4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methanol (9.80g, six ammonium tetrahydrate (612mg) of 30% aqueous hydrogen peroxide solution (14.0ml) and seven molybdic acids is added in methanol (200ml) solution 24.8mmol), stirs 18 hours at room temperature.30% aqueous hydrogen peroxide solution (14.0ml) is added in the reactive mixture, is stirred 3 days at room temperature.30% aqueous hydrogen peroxide solution (14.0ml) is added in the reactive mixture again, is stirred 5 hours in 50 DEG C.In the reactive mixture plus water, the solid that leaching is precipitated are washed with water, are dried under reduced pressure.Obtained solid is dissolved in ethyl acetate, after being washed with saturated sodium bicarbonate aqueous solution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue ethyl alcohol recrystallization obtains the title compound (6.41g, 15.0mmol, 61%) of white solid.After mother liquor is concentrated under reduced pressure, residue is recrystallized with ethyl alcohol, obtains the title compound (2.14g, 5.00mmol, 20%) of white solid.After mother liquor is concentrated under reduced pressure again, leaching after washing residue with ether obtains the title compound (780mg, 1.82mmol, 7%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:428 (M++H).
Embodiment 126:[6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridin-3-yl] formaldehyde
At room temperature; in [6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methanol (8.46g; 19.8mmol), triethylamine (13.8ml; 98.8mmol) and dimethyl sulfoxide (7.02ml; sulfur trioxide pyridine complex salt (9.44g, 59.3mmol) is added in methylene chloride (100ml) solution 98.9mmol), stirs 16 hours.After reaction mixture saturated common salt water washing, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Residue is handled with flashchromatography on silica gel, and the fraction obtained by dichloromethane eluent portion is concentrated under reduced pressure.It is residue obtained washed with ether after leaching, obtain be in yellow solid title compound (6.33g, 14.9mmol, 75%).
1H-NMR (400MHz, CDCl3) 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5- fluorine nicotinic acid
At room temperature; in [6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- fluorine pyridin-3-yl] formaldehyde (1.28g; 30% aqueous hydrogen peroxide solution (1.02ml is added in formic acid (30ml) solution 3.00mmol); 9.00ml), it stirs 1 hour at room temperature.Then, reaction mixture is stirred 1 hour in 50 DEG C, is cooled to room temperature Hou Jiashui.The solid that leaching is precipitated, is dried under reduced pressure after being washed with water.Obtained solid is dissolved in ethyl acetate, after being washed with saturated aqueous ammonium chloride, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.Leaching after residue ethanol washing obtains the title compound (1.19g, 2.69mmol, 89%) of white solid.
1H-NMR (400MHz, DMSO-d6) 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 DEG C of
Elemental analysis: C19H11ClF3NO4S: 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.
The fluoro- N- thiazol-2-yl niacinamide of embodiment 128:6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5-
At room temperature; in 6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl -5- fluorine nicotinic acid (100mg; thiazol-2-yl amine (25mg is added in methylene chloride (2ml) solution 0.23mmol); 0.25mmol), benzotriazole -1- alcohol (34mg; 0.25mmol), 4- methyl morpholine (0.027ml; 0.25mmol) and 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (48mg; 0.25mmol), it stirs 14 hours at room temperature.Ethyl acetate is added in the reactive mixture, after being washed with saturated sodium bicarbonate aqueous solution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.It is residue obtained to be handled with flashchromatography on silica gel, it is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains.Leaching after residue ethanol washing obtains the title compound (72mg, 0.14mmol, 60%) of white solid.
1H-NMR (400MHz, DMSO-d6) 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 DEG C of
Elemental analysis: C is pressed22H13ClF3N3O3S2It calculates: 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 fluoro- N- isoxazole -3- base niacinamide of embodiment 129:6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5-
According to method same as embodiment 128; the 6- (4- Chlorophenylsulfonyl) (2 obtained using embodiment 127; 5- difluorophenyl) methyl -5- fluorine nicotinic acid (100mg; 0.23mmol) and isoxazole -3- base amine (0.018mol; 0.25mmol); obtain the title compound (43mg, 0.085mmol, 37%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C is pressed22H13ClF3N3O4S is calculated: theoretical value: C, and 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.
The fluoro- N- pyridine -2- ylmethyl niacinamide of embodiment 130:6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5-
According to method same as embodiment 128; the 6- (4- Chlorophenylsulfonyl) (2 obtained using embodiment 127; 5- difluorophenyl) methyl -5- fluorine nicotinic acid (100mg; 0.23mmol) and pyridine -2- base methylamine (0.026ml; 0.25mmol); obtain the title compound (86mg, 0.16mmol, 72%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
Elemental analysis: C is pressed25H17ClF3N3O3S is calculated: theoretical value: C, and 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) -3- [6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methyl acrylate
At room temperature; in [the 6- (4- Chlorophenylsulfonyl) (2 that embodiment 126 obtains; 5- difluorophenyl) methyl] -5- fluorine pyridin-3-yl] formaldehyde (1.70g; triphenylphosphoroanylidene methyl acetate (1.47g is added in tetrahydrofuran (15ml) solution 4.00mmol); 4.40mmol), it stirs 18 hours at room temperature.Reaction mixture is concentrated under reduced pressure, is handled residue obtained with flashchromatography on silica gel.The fraction obtained by dichloromethane eluent portion is concentrated under reduced pressure and obtains the title compound (1.60g, 3.31mmol, 83%) of white solid with the mixed solvent of ethyl alcohol and hexane to leaching after residue obtained wash.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:482 (M++H).
Embodiment 132:3- [6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methyl propionate
First Raney nickel suspension (R-100, day emerging リ カ Co., Ltd.) (1ml) is washed with ethyl alcohol again with water, forms ethyl alcohol (10ml) suspension.In 3- [6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methyl acrylate (1.38g; above-mentioned suspension is added in ethyl alcohol (40ml) solution 2.86mmol), is stirred at room temperature under a hydrogen atmosphere 1 hour.After filtering reaction mixture with diatomite, filtrate is concentrated under reduced pressure, is dissolved in methylene chloride for residue obtained, it is dry with anhydrous sodium sulfate.Filtrate is concentrated under reduced pressure after filtering, obtains the title compound (1.37g, 2.83mmol, 99%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:484 (M++H).
Embodiment 133:3- [6- (4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] propionic acid
In 3- [6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] methyl propionate (387mg; 1N sodium hydrate aqueous solution (4ml) is added in ethyl alcohol (8ml) solution 0.80mmol), stirs 3 hours at room temperature.After so that reaction solution is in acid with 1N hydrochloric acid, then it is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Leaching after the residue obtained mixed solvent with ether and hexane washs obtains the title compound (349mg, 0.74mmol, 93%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:470 (M++H).
Elemental analysis: C21H15ClF3NO4S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] -1- (4- methylpiperazine-1-yl) propane -1- keto hydrochloride
At room temperature; in 3- [6- (4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl -5- fluorine pyridin-3-yl] propionic acid (100mg; 1- methyl piperazine (0.026ml is added in methylene chloride (3ml) solution 0.21mmol); 0.23mmol), benzotriazole -1- alcohol (32mg; 0.23mmol), 4- methyl morpholine (0.026ml; 0.23mmol) and 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (45mg; 0.23mmol), it stirs 16 hours.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, organic layer is dried, filtered with anhydrous sodium sulfate, and filtrate is concentrated under reduced pressure.It is residue obtained to be handled with flashchromatography on silica gel, it is concentrated under reduced pressure by methylene chloride: methanol=19: the fraction that 1 elution portion obtains.It is dissolved in ethyl alcohol (3ml), is added 1N hydrochloric acid (0.224ml) by residue obtained, after stirring 30 minutes at room temperature, reaction mixture is concentrated under reduced pressure.Leaching after residue ethanol washing obtains the title compound (111mg, 0.19mmol, 89%) of white solid.
1H-NMR (400MHz, DMSO-d6) 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 DEG C of
Elemental analysis: C26H25ClF3N3O3SHCl: 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) -3- [6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridin-3-yl] acrylic acid
In (E) -3- [6- [(4- Chlorophenylsulfonyl) (2 that embodiment 44 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] methyl acrylate (460mg; after 1N sodium hydrate aqueous solution (3.0ml) is added in tetrahydrofuran solution (5ml) 0.991mmol), stir 4 hours at room temperature.Reaction solution is extracted with ethyl acetate in after acid with 1N hydrochloric acid.Dry with anhydrous magnesium sulfate after extract liquor water and saturated common salt water washing, concentration quantitatively obtains crude title compound.It is recrystallized with a part of ethylacetate-hexane to obtained solid, obtains the title compound (29.4mg, 0.0653mmol) in colorless solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C21H14ClF2NO4S: 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) -3- [6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridin-3-yl] acrylamide
By (E) -3- [6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridin-3-yl] acrylic acid (370mg; after 0.822mmol) being dissolved in methylene chloride (6ml); thionyl chloride (2.00ml) and N is added; dinethylformamide (1 drop), is stirred 4 hours at room temperature.Reaction solution is concentrated to dryness, by it is residue obtained be dissolved in methylene chloride (6ml) after, be added concentrated ammonia liquor (2.00ml).It is diluted after being stirred 2 hours to reaction solution at room temperature with methylene chloride, with water, 0.1N hydrochloric acid and saturated common salt water washing.It is concentrated after being dried with magnesium sulfate.After being recrystallized with ethyl alcohol to obtained solid, the title compound (250mg, 0.558mmol, 68%) of white solid is obtained.
1H-NMR (400MHz, CDCl3/DMSO-d6) 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 DEG C of
Elemental analysis: C21H15ClF2N2O3S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] nicotinoyl base] glycine ethyl ester
In [6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; triethylamine (80 μ l are added in methylene chloride (5ml) solution 0.236mmol); 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), it stirs 7 hours at room temperature.After methylene chloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the anhydrous magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (95mg, 0.187mmol, 79%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:509 (M++H).
Embodiment 138:[2- [[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -3- carbonyl] amino] ethyl] t-butyl carbamate
In [the 6- (4- Chlorophenylsulfonyl) (2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; triethylamine (40 μ l are added in methylene chloride (5ml) solution 0.236mmol); 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), it stirs 6 hours at room temperature.After methylene chloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains the title compound (57mg, 0.101mmol, 43%) of white powder.
1H-NMR (400MHz, CDCl3) 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=8.6H z), 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)
MS m/z:566 (M++H).
Embodiment 139:N- (2- amino-ethyl) -6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] niacinamide
In [2- [[6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -3- carbonyl] amino] ethyl] t-butyl carbamate (50mg; concentrated hydrochloric acid (2ml) is added in ethyl alcohol (2ml) solution 0.0880mmol), stirs 20 minutes at room temperature.Depressurize lower concentrated reaction solution.Obtained solid is washed with ether, obtains 1.5 hydrochlorides (white powder) (44mg, 0.0880mmol, quantitative) of title compound.
1H-NMR (400MHz, CD3OD) 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)
250 DEG C of mp:> (decomposition)
Elemental analysis: C21H18ClF2N3O3S·1.5H2O1.5HCl: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl]-N- (2- hydroxyethyl) niacinamide
In [the 6- (4- Chlorophenylsulfonyl) (2 that embodiment 50 obtains; 5- difluorophenyl) methyl] pyridin-3-yl] carboxylic acid (100mg; triethylamine (80 μ l are added in methylene chloride (5ml) solution 0.236mmol); 0.566mmol), 4-dimethylaminopyridine (15mg; 0.118mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (54mg; 0.283mmol) and ethanolamine hydrochloric salt (28mg; 0.283mmol), it stirs 17.5 hours at room temperature.After methylene chloride diluting reaction solution, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by methylene chloride: methanol=30: the fraction that 1 elution portion obtains obtains the title compound (69mg, 0.148mmol, 63%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C21H17ClF2N2O4S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -3- thioformyl] amino] ethyl] t-butyl carbamate
Under argon atmospher; in [2- [[6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 138 obtains; 5- difluorophenyl) methyl] pyridine -3- carbonyl] amino] ethyl] t-butyl carbamate (120mg; Lawson reagent (94mg is added in toluene (8ml) solution 0.212mmol); 0.233mmol), it is heated to reflux lower stirring 1.5 hours.Lower concentrated solvent is depressurized after cooling.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains the title compound (84mg, 0.144mmol, 68%) in Yellow amorphous object.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:582 (M++H).
Embodiment 142:N- (2- amino-ethyl) -6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] Thionicotinamide
In [2- [[6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -3- thioformyl] amino] ethyl] t-butyl carbamate (80mg; concentrated hydrochloric acid (2ml) is added in ethyl alcohol (3ml) solution 0.137mmol), stirs 20 minutes at room temperature.Lower concentrated reaction solution is depressurized, in residue obtained middle addition ethyl alcohol, concentration.These operations are carried out 3 times, 1.75 hydrochlorides (yellow powder) (76mg, 0.137mmol, quantitative) of title compound are obtained.
1H-NMR (400MHz, DMSO-d6) 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, dd 8.3,2.4), 9.05 (1H, d, J=2.4Hz), 10.74 (1H, brs)
Mp:164-166 DEG C of
Elemental analysis: C21H18ClF2N3O2S2·0.5H2O1.75HCl: 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- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -6- (1,3-dioxolane -2- base) pyridine
In argon atmospher, the 2- [(2 obtained under ice-cold in reference example 32,5- difluorophenyl) hydroxymethyl] -6- (1,3- dioxolanes -2- base) pyridine (2.48g, triethylamine (1.77ml is added in dichloromethane solution (30ml) 8.46mmol), 12.7mmol), mesyl chloride (851 μ l, 11.0mmol) is stirred 3.5 hours at room temperature.It is extracted after saturated sodium bicarbonate aqueous solution is added in reaction solution with ether.Solution saturated common salt water washing, with the lower concentrate solution of decompression after anhydrous sodium sulfate drying.4- chlorobenzenethiol (1.0g, 6.91mmol), potassium carbonate (1.19g, 8.64mmol) are added in dimethylformamide (20ml) solution of residue (2.14g, 5.76mmol), is stirred 2 hours in 50 DEG C.After being cooled to room temperature, reaction solution is diluted with ether, is successively washed with water and saturated salt solution.It is concentrated under reduced pressure after the sodium sulphate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=5: the fraction that 1 elution portion obtains obtains the title compound (2.12g, 5.05mmol, 88%) in light yellow oil.
1H-NMR (400MHz, CDCl3) 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=7.8H z), 7.44-7.48 (1H, m), 7.69 (1H, t, J=7.8Hz)
MS m/z:420 (M++H).
Embodiment 144:2- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -6- (1,3-dioxolane -2- base) pyridine
In 2- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -6- (1,3- dioxolanes -2- base) pyridine (2.40g, seven molybdic acids, six ammonium tetrahydrate (200mg), 30% aqueous hydrogen peroxide solution (20ml) are added in methanol (40ml) solution 5.72mmol), stirs 5 days.The solid for adding water leaching to be precipitated, residue are washed with water.So that residue is dissolved in ethyl acetate, successively uses water and saturated common salt water washing.After depressurizing lower concentration of organic layers, residue with ethyl acetate washing obtains the title compound (2.09g, 4.63mmol, 81%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:452 (M++H).
Embodiment 145:[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] formaldehyde
In 2- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -6- (1; 3- dioxolanes -2- base) pyridine (2.05g; 4.54mmol) 1; concentrated hydrochloric acid (10ml) is added in 4- dioxanes (40ml) solution, stirs 20 hours at room temperature.After depressurizing lower concentrated solvent, ethyl acetate is added in residue, successively uses water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer, obtains the title compound (1.85g, 4.54mmol, quantitative) of white powder.
1H-NMR (400MHz, CDCl3) 6:6.05 (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)
MS m/z:408 (M++H).
Embodiment 146:6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine carboxylic acid
In [6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] formaldehyde (390mg; 30% aqueous hydrogen peroxide solution (325 μ l are added in formic acid (5ml) solution 0.956mmol); 2.87mmol), it stirs 4 hours at room temperature.In reaction solution plus water filtering, residue are washed with water.Make it is residue obtained be dissolved in ethyl acetate, successively washed with saturated aqueous ammonium chloride, water and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained to be recrystallized with ethyl alcohol, obtain the title compound (310mg, 0.731mmol, 77%) of white powder.
1H-NMR (400MHz, CDCl3) δ: 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 DEG C of
Elemental analysis: C19H12ClF2NO4S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] (4- methylpiperazine-1-yl) ketone
In 6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine carboxylic acid (130mg; N-methylmorpholine (41 μ l are added in methylene chloride (5ml) solution 0.307mmol); 0.368mmol), I-hydroxybenzotriazole (13mg; 0.368mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (71mg; 0.368mmol) and 1- methyl piperazine (40 μ l; 0.368mmol), it stirs 15 hours at room temperature.After reaction solution is diluted with methylene chloride, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Handled with flash column chromatography residue obtained, be concentrated under reduced pressure by methylene chloride: methanol=30: the fraction that 1 elution portion obtains obtains the title compound (40mg, 0.0791mmol, 26%) of white amorphous substance.
1H-NMR (400MHz, CDCl3) 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 (C24H23ClF2N3O3S, calculated value: 506.1117)
Embodiment 148:[6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate
Under argon atmospher; in 6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 146 obtains; 5- difluorophenyl) methyl] pyridine carboxylic acid (600mg; diphenylphosphine amide (428 μ l are added in the mixed solution of butanol (2ml) and toluene (10ml) 1.42mmol); 2.00mmol) and triethylamine (394 μ l; 2.83mmo1), it is heated to reflux lower stirring 23 hours, uses brine It.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Handled with silica gel flash column chromatography residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (380mg, 0.768mmol, 54%) in faint yellow amorphous substance.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:495 (M++H).
Embodiment 149:6- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base amine
In [6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate (370mg; concentrated hydrochloric acid (5ml) is added in ethyl alcohol (5ml) solution 0.748mmol), stirs 6 hours at room temperature.Lower concentrated reaction solution is depressurized successively to be washed in residue obtained middle addition ethyl acetate with saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer, obtains the title compound (210mg, 0.537mmol, 71%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H13ClF2N2O2S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -2- (pyridine -2- base) acetamide
In 6- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base amine (74mg; N-methylmorpholine (90 μ l are added in methylene chloride (5ml) solution 0.187mmol); 0.818mmol), I-hydroxybenzotriazole (11mg; 0.313mmol), 1- ethyl -3- (3- dimethylaminopropyl) carbodiimide hydrochloride (60mg; 0.312mmol) and 2- pyridylacetic acid hydrochloride (54mg; 0.312mmol), it stirs 24 hours at room temperature.After reaction solution is diluted with methylene chloride, water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Handled with silica gel flash column chromatography residue obtained, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (48mg, 0.0934mmol, 50%) of white amorphous substance.
1H-NMR (400MHz, CDCl3) 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=8.5H z), 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 (C25H19ClF2N3O3S, calculated value: 514.0804)
Embodiment 151:(E) -2- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -6- (2- pyridine -2- base vinyl) pyridine
In 6- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 145 obtains; 5- difluorophenyl) methyl] pyridine -2- base] formaldehyde (100mg; 0.245mmol) 1; chlorinated triphenyl base (2- pyridylmethyl) phosphonium salt hydrochlorate (336mg is added in 4- dioxanes (5ml) solution; 0.773mmol), triethylamine (215 μ l; 1.55mmol), it stirs 5 hours at room temperature.Ethyl acetate is added after concentrated reaction solution, successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after organic layer magnesium sulfate drying.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (202mg, 0.418mmol, 81%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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-M S:483.0739 (C25H18ClF2N2O2S, calculated value: 483.0746)
Embodiment 152:2- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -6- (2- pyridine -2- base ethyl) pyridine
In (E) -2- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -6- (2- pyridine -2- base vinyl) pyridine (180mg; ethyl alcohol (5ml) and 1 0.373mmol); the alcohol suspending liquid (1ml) of Raney nickel, high degree of agitation 1.5 hours under the nitrogen atmosphere of 1 air pressure are added in the mixed solution of 4- dioxanes (2ml).It is concentrated under reduced pressure after filtering reacting solution.It is residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain, with hexane: re-crystallizing in ethyl acetate obtains the title compound (110mg of white powder, 0.227mmol, 61%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C25H16ClF2N2O2S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -1- (3- hydroxypropyl) piperidines -2- ketone
Under an argon, in the 2- [(4- chlorphenyl) sulfonymethyl] -1 that -78 DEG C obtain in reference example 1,4- difluorobenzene (63.0mg, 0.208mmol) 1, n-BuLi (1.56M hexane solution is added in 2- dimethoxyethane solution (2ml), 0.140ml, 0.218mmol) after, it is stirred 5 minutes in -78 DEG C.After the bromo- 1- of 3- [3- (t-butyldimethylsilyloxy base) propyl] piperidines -2- ketone (72.8mg, 0.208mmol) that reference example 34 obtains is added, reaction solution is stirred 15 hours in room temperature.Add water after reaction solution is cooled to 0 DEG C, is extracted with ethyl acetate.It is dry with magnesium sulfate after extract liquor water and saturated common salt water washing, concentration.With silica gel flash column chromatography, (hexane: ethyl acetate=4: 1) being refined to residue obtained, obtains low polar silicyl protective (30.0mg) and highly polar silicyl protective (30.0mg) in colorless oil respectively.Resulting highly polar silicyl protective (30.0mg) is dissolved in tetrahydrofuran (3ml), is added hydrogen fluoride-pyridine (0.5ml).It after room temperature stirs reaction solution 3 hours, is diluted with ethyl acetate, then with water and saturated common salt water washing.Dry with magnesium sulfate, after concentration, handled with silica gel column chromatography residue obtained, be concentrated by hexane: ethyl acetate=2: the fraction that 3 elution portion obtains obtains white solid matter.Obtained solid is recrystallized with ethylacetate-hexane, obtains the title compound (11.8mg, 0.0258mmol, 12%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) 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=413.7,9.0,4.6Hz), 3.70-3.78 (1H, m), 5.71-5.73 (1H, m), 6.86 (1H, t d, 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 DEG C of
FAB-MS:458.0966 (C21H23ClF2NO4S, calculated value: 458.1004)
Embodiment 154:3- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propanoic acid tert-butyl ester
Beta-alanine t-butyl ester hydrochloride (1.5g) is dissolved in a small amount of unsaturated carbonate aqueous solutions of potassium, is extracted with dichloromethane.It is dried, is concentrated, obtains the free Beta-alanine tert-butyl ester of 720mg.Under an argon, in the chloro- 4- of 2,5- bis- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine (300mg that 120 DEG C obtain the compound and embodiment 54, Isosorbide-5-Nitrae-dioxanes (2.0ml) solution 0.72mmol) stirs 4 days.It is diluted after being cooled to room temperature with ethyl acetate, solution water and saturated common salt water washing.Lower concentration is depressurized after dry solution, obtains residue.With silica gel column chromatography, (hexane: ethyl acetate=5: 1) being refined to residue obtained, obtains the title compound (79mg, 16%) in grease.
1H-NMR (400MHz, CDCl3) 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- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propionic acid
In 3- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propanoic acid tert-butyl ester (79mg) methanol (6ml) solution in seven molybdic acids, six ammonium tetrahydrate (30mg) is added, it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 16 hours.After ethyl acetate (60ml) dilution, solution water and saturated common salt water washing.Lower concentrate solution is depressurized to stir 1 hour in residue obtained middle addition trifluoroacetic acid (1.0ml).After boiling off trifluoroacetic acid under decompression, residue is dissolved in water-ethanol (1: 1).Addition saturated sodium bicarbonate aqueous solution (0.2ml) wherein makes it be in addition sodium bisulphate solution after alkalinity, mixed liquor ethyl acetate (80ml) extraction, extract liquor saturated common salt water washing, drying.Residue is crystallized in ether after depressurizing lower concentrate solution, obtains 0.5 hydrate of title compound (61mg, 81%).
1H-NMR (400MHz, CDCl3) 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=8.8H z), 7.94 (1H, s)
Mp:200-205 DEG C of
Elemental analysis: C21H16Cl2F2N2O4S·0.5H2O: 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- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] (methyl) amino] ethyl alcohol
Under argon atmospher, embodiment 54 is obtained in 110 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (200mg, 0.48mmol) stirred 3 days with Isosorbide-5-Nitrae-dioxanes (2.0ml) solution of methyl amino ethanol (200 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (164mg, 75%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:455 (M++H).
The chloro- 4- of embodiment 157:5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- [2- (pyridine -2- base) ethylamino] pyridine
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (150mg, 0.36mmol) stirred 5 days with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 2- pyridine -2- base ethamine (400 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (126mg, 70%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:502 (M++H).
The chloro- 4- of embodiment 158:5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- [3- (imidazoles -1- base) propylcarbamic] pyridine
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (200mg, 0.48mmol) stirred 5 days with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 3- (imidazoles -1- base) propylamine (400 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (94mg, 39%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:505 (M++H).
Embodiment 159:2- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] ethyl alcohol
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (180mg, 0.43mmol) stirred 64 hours with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 2- ethylaminoethanol (300 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (106mg, 56%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:441 (M++H).
Embodiment 160:1- [3- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propyl] pyrrolidin-2-one
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (200mg, 0.48mmol) stirred 17 hours with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 1- (3- aminopropyl) pyrrolidin-2-one (400 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (68mg, 27%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:522 (M++H).
Embodiment 161:4- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] piperidines -1- carboxylic acid tert-butyl ester
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (300mg, 0.48mmol) stirred 5 days with Isosorbide-5-Nitrae-dioxanes (2.2ml) solution of 4- amino piperidine -1- carboxylic acid tert-butyl ester (600mg).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (36mg, 9%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:580 (M++H).
Embodiment 162:3- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propylcarbamate
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (300mg, 0.48mmol) stirred 2 days with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 3- (aminopropyl) t-butyl carbamate (400 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (71mg, 27%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:554 (M++H).
The chloro- 4- of embodiment 163:5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] -2- [(2-methylmercaptoethyl) amino] pyridine
Under argon atmospher, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl)-(2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (200mg, 0.48mmol) stirred 2 days with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 2- methyl mercapto ethamine (200 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (29mg, 13%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:471 (M++H).
Embodiment 164:2- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] (methyl) amino] ethyl alcohol
In 2- [[the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 156 obtains, 5- difluorophenyl) methyl] pyridine -2- base] (methyl) amino] ethyl alcohol (160mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.35mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (60ml) dilution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=2: 1) refining, then crystallized with hexane-EtOAc residue, and acquisition is in the title compound (162mg, 95%) of acicular crystal.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C21H18C12F2N2O3S·0.5H2O: 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- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] (methyl) amino] ethyl ester
In 2- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine -2- base] (methyl) amino] ethyl alcohol (73mg; pyridine (0.5ml) is added in methylene chloride (1.0ml) solution 0.15mmol); it adds ethyl isocyanate (100 μ l), stirs 19 hours.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (65mg, 74%) of grease.
1H-NMR (400MHz, CDCl3) 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 (C24H23Cl2F2N3O4S, calculated value: 557.0754)
The chloro- 4- of embodiment 166:5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -2- [2- (pyridine -2- base) ethylamino] pyridine
In the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 157 obtains, 5- difluorophenyl) methyl] -2- [2- (pyridine -2- base) ethylamino] pyridine (120mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.35mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 2 days.With solution water and saturated common salt water washing after ethyl acetate (80ml) dilution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=3: 1) purification obtains amorphous title compound (43mg, 33%) to residue.
1H-NMR (400MHz, CDCl3) 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 (C25H20Cl2F2N3O2S, calculated value: 534.0621)
The chloro- 4- of embodiment 167:5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -2- [3- (imidazoles -1- base) propylcarbamic] pyridine
In the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 158 obtains, 5- difluorophenyl) methyl] -2- [3- (imidazoles -1- base) propylcarbamic] pyridine (94mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.19mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (80ml) dilution.After depressurizing lower concentrate solution, residue is refined with silica gel chromatography (7% methanol-chloroform), obtains the title compound (5mg, 5%) in grease.
1H-NMR (400MHz, CDCl3) 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 (C24H21Cl2F2N4O2S, calculated value: 537.0730)
Embodiment 168:2- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] ethyl alcohol
In 2- [[the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 159 obtains, 5- difluorophenyl) methyl] pyridine -2- base] amino] ethyl alcohol (143mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.33mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (60ml) dilution.After depressurizing lower concentrate solution, residue with silica gel chromatography (hexane: ethyl acetate=1: 1) refining, then with alcohol crystal, obtain be in acicular crystal title compound (98mg, 63%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C20H16Cl2F2N2O3S: 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- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propyl] pyrrolidin-2-one
In 1- [3- [[the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 160 obtains, 5- difluorophenyl) methyl] pyridine -2- base] amino] propyl] pyrrolidin-2-one (143mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.33mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 17 hours.With solution water and saturated common salt water washing after ethyl acetate (60ml) dilution.After depressurizing lower concentrate solution, residue is refined with silica gel chromatography (2% methanol-ethyl acetate), then with crystallizing from ether, obtain be in acicular crystal title compound (42mg, 60%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C25H23Cl2F2N3O3S: 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- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] piperidines -1- carboxylic acid tert-butyl ester
In 4- [[the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 161 obtains, 5- difluorophenyl) methyl] pyridine -2- base] amino] piperidines -1- carboxylic acid tert-butyl ester (41mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.070mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 20 hours.With solution water and saturated common salt water washing after ethyl acetate (80ml) dilution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=4: 1) refining residue, and acquisition is in the title compound (41mg, 95%) of grease.
1H-NMR (400MHz, CDCl3) 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=8.0H z), 7.46 (1H, m), 7.58 (2H, d, J=8.0Hz), 7.96 (1H, s)
MS m/z:612 (M++H).
Embodiment 171:4- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] piperidines dihydrochloride
In 4- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine -2- base] amino] piperidines -1- carboxylic acid tert-butyl ester (41mg; 20% hydrochloric acid-methanol solution is added in 0.067mmol), stirs 2 hours.Lower concentrate solution is depressurized, is dissolved in chloroform for residue obtained, then be concentrated.The lower dry gained of decompression is noncrystal, obtains title compound (34mg, 84%).
1H-NMR (400MHz, CD3OD) 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)
Elemental analysis: C23H21Cl2F2N3O2S·2HCl·H2O: 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- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propylcarbamate
In 3- [[the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 162 obtains, 5- difluorophenyl) methyl] pyridine -2- base] amino propyl amino t-butyl formate (70mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.13mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 20 hours.With solution water and saturated common salt water washing after ethyl acetate (80ml) dilution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=2: 1) refining residue, and acquisition is in the title compound (61mg, 82%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:586 (M++H).
Embodiment 173:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] propyl- 1,3- diamine dihydrochloride
In 3- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine -2- base] amino] propylcarbamate (70mg; 20% hydrochloric acid-methanol solution (2ml) is added in 0.13mmol), stirs 2 hours.Lower concentrate solution is depressurized, makes residue obtained crystallization with ethyl alcohol, obtains the title compound (42mg, 83%) of white solid.
1H-NMR (400MHz, DMSO-d6) 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 DEG C of
Elemental analysis: C21H19Cl2F2N3O2S2HCl: 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- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propyl] acetamide
In N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine -2- base] propyl- 1; 3- diamine dihydrochloride (47mg; pyridine (17 μ l are added in dichloromethane solution (5.0ml) 0.084mmol); 0.34mmol), acetic anhydride (9.5 μ l; 0.10mmol), it stirs 1 hour.Concentration of reaction solution, residue obtained with silica gel chromatography, (ethyl acetate: methanol=10: 1) purification is obtained title compound (35mg, 79%).It is crystallized in ether, is obtained white solid (27mg).
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:528.0740 (C23H22Cl2F2N3O3S, calculated value: 528.0727)
Embodiment 175:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base]-N '-(pyrimidine -2-base) propyl- 1,3- diamines
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 173 obtains; 5- difluorophenyl) methyl] pyridine -2- base] propyl- 1; 3- diamine dihydrochloride (76mg; 0.136mmol) 1; triethylamine (76 μ l are added in 4- dioxane (1.0ml); 0.54mmol), 2- chlorine pyrimidine (23mg, 0.20mmol) is stirred 19 hours in 80 DEG C.After reaction solution cooled to room temperature, diluted with ethyl acetate.With drying after water and saturated common salt water washing.Concentration, residue obtained with silica gel chromatography, (hexane: ethyl acetate=1: 2) purification is obtained title compound (50mg, 65%).It is crystallized in ether, is obtained white solid (36mg).
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:564.0811 (C25H22Cl2F2N5O2S, calculated value: 564.0839)
The chloro- 4- of embodiment 176:5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] -2- [(2- methysulfonylethyl) amino] pyridine
In the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl)-(2 that embodiment 163 obtains, 5- difluorophenyl) methyl] -2- [(2-methylmercaptoethyl) amino] pyridine (29mg, seven molybdic acids, six ammonium tetrahydrate (15mg) is added in methanol (3ml) solution 0.061mmol), it adds 30% aqueous hydrogen peroxide solution (1.5ml), stirs 20 hours.With solution water and saturated common salt water washing after ethyl acetate (80ml) dilution.After depressurizing lower concentrate solution, with silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, then with crystallizing from ether, obtains the title compound (24mg, 73%) of white solid.
1H-NMR (400MHz, CDCl3) 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=8.8H z), 7.45 (1H, m), 7.59 (2H, d, J=8.8Hz), 8.00 (1H, s)
Mp:134-136 DEG C of
Elemental analysis: C21H18Cl2F2N2O4S: 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.
The chloro- 4- of embodiment 177:2,5- bis- [(2,5- difluorophenyl)-(4- chlorophenylthio) methyl] pyridine
2 that reference example 24 is obtained, after the chloro- 4- of 5- bis- [(2,5- difluorophenyl)-hydroxymethyl] pyridine (1.22g, 4.8mmol) is dissolved in thionyl chloride (5.0ml), the dimethylformamide of catalytic amount is added, stirs 4 hours.
Lower concentration of reaction solution is depressurized, Isosorbide-5-Nitrae-dioxanes is added in residue, then be concentrated.The residue is dissolved in dimethylformamide (10ml), 4- fluorobenzenethiol (730mg, 5.7mmol) and potassium carbonate (2.07g, 15mmol) are added under nitrogen atmosphere, is stirred 24 hours at room temperature.Ether (120ml) is added in reaction solution, it is washed with water and saturated salt solution.Lower concentration is depressurized after organic layer magnesium sulfate drying.Residue is crystallized in ethanol, obtains the title compound (950mg, 49%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
Mp:95-97 DEG C of
MS m/z:400 (M++1)
Embodiment 178:2- [[the chloro- 4- of 5- [(2,5- difluorophenyl)-(4- chlorophenylthio) methyl] pyridine -2- base] amino] ethyl alcohol
Under an argon, in 120 DEG C to 2, the chloro- 4- [(2 of 5- bis-, 5- difluorophenyl)-(4- chlorophenylthio) methyl] pyridine (200mg, 0.50mmol) stirred 2 days with Isosorbide-5-Nitrae-dioxanes (1.5ml) solution of 2- ethylaminoethanol (300 μ l).Lower concentration is depressurized after being cooled to room temperature, and obtains residue.With silica gel chromatography, (hexane: ethyl acetate=1: 1) refining residue, and acquisition is in the title compound (120mg, 56%) of grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:425 (M++H).
Embodiment 179:2- [[the chloro- 4- of 5- [(2,5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] amino] ethyl alcohol
In 2- [[the chloro- 4- [(2 of 5-, 5- difluorophenyl)-(4- chlorophenylthio) methyl] pyridine -2- base] amino] ethyl alcohol (119mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.27mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 19 hours.With solution water and saturated common salt water washing after ethyl acetate (80ml) dilution.After depressurizing lower concentrate solution, residue with silica gel chromatography (hexane: ethyl acetate=1: 1) refining, then with crystallizing from ether, obtain be in acicular crystal title compound (65mg, 56%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C20H16ClF3N2O3S: 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.
The chloro- 4- of embodiment 180:5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- [2- (pyridin-4-yl) ethylamino] pyridine
Embodiment 54 is obtained in tube sealing in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] dioxanes (1.5ml) solution of pyridine (220mg, 0.528mmol) and 4- (2- amino-ethyl) pyridine (400 μ l) heats 3 days.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.In residue obtained plus water, it is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure after being dried, filtered after organic layer saturated common salt water washing with anhydrous sodium sulfate.Handled, be concentrated under reduced pressure by methanol with silica gel column chromatography by residue obtained: methylene chloride=1: the fraction that 30 eluent obtains obtains the title compound (114mg, 0.227mmol, 43%) in colorless oil.1H-NMR (400MHz, CDCl3) 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)
MS m/z:501 (M+).
The chloro- 4- of embodiment 181:5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -2- [2- (pyridin-4-yl) ethylamino] pyridine
Under ice-cold, in the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- [2- (pyridin-4-yl) ethylamino] pyridine (110mg, 0.219mmol) methanol (6ml) solution in six ammonium tetrahydrate (34mg) of 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids is added.After stirring 22 hours to reaction solution at room temperature, decompression boils off methanol.In residue obtained middle addition ethyl acetate, successively with after saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 3 eluent obtains obtains the title compound (102mg, 0.191mmol, 87%) in yellowish-white solid.Leaching after obtained solid is washed with diisopropyl ether-hexane obtains the title compound (87mg) of white powder.
1H-NMR (400MHz, CDCl3) 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=8.6H z), 8.03 (1H, s), 8.56 (2H, d, J=5.9Hz)
Mp:148-150 DEG C of
Elemental analysis: C25H19N3O2Cl2F2S: 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- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base amino] ethyoxyl] ethyl alcohol
Embodiment 54 is obtained in tube sealing in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] dioxanes (1.5ml) solution of pyridine (210mg, 0.504mmol) and 2- (2- amino ethoxy) ethyl alcohol (400 μ l) heats 3 days.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.In residue obtained plus water, it is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure after being dried, filtered after organic layer saturated common salt water washing with anhydrous sodium sulfate.It is handled residue obtained with silica gel column chromatography, the fraction obtained by the eluent of 30% ethanol/methylene is concentrated under reduced pressure, obtains the title compound (85mg, 0.175mmol, 35%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base amino] ethyoxyl] ethyl alcohol
Under ice-cold, in 2- [2- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base amino] ethyoxyl] ethyl alcohol (80mg, 0.155mmol) methanol (6ml) solution in six ammonium tetrahydrate (32mg) of 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids is added.After stirring 24 hours to reaction solution at room temperature, decompression boils off methanol.In residue obtained middle addition ethyl acetate, successively with after saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 3 eluent obtains obtains the title compound (70mg, 0.135mmol, 87%) in amorphous substance.Gained non-crystalline material filters after being solidified with ether-hexane, obtains the title compound (55mg) of white powder.
1H-NMR (400MHz, CDCl3) 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) .m p:113-115 DEG C
Elemental analysis: C22H20N2O4Cl2F2S: 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.
The chloro- 4- of embodiment 184:5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- [(3- methoxy-propyl) amino] pyridine
Embodiment 54 is obtained in tube sealing in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] dioxanes (1.5ml) solution of pyridine (216mg, 0.518mmol) and 3 methoxypropyl amine (200 μ l) heats 3 days.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.Handled, be concentrated under reduced pressure by hexane with silica gel column chromatography by residue obtained: the fraction that the eluent of ethyl acetate (=3: 1) obtains obtains the title compound (101mg) in light yellow oil.
Under ice-cold, six ammonium tetrahydrate (41mg) of 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids is added in methanol (6ml) solution of gained light yellow oil (101mg).After stirring 16 hours to reaction solution at room temperature, decompression boils off methanol.In residue obtained middle addition ethyl acetate, successively with after saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 eluent obtains obtains the title compound (90mg, 0.180mmol, 35%) of white solid.Leaching after obtained solid is washed with ether-hexane obtains the title compound (64mg) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C22H20N2O3Cl2F2S: 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.
The chloro- 4- of embodiment 185:5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- (3,4- dimethoxy benezene amino) pyridine
Embodiment 54 is obtained in tube sealing in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (218mg, 0.523mmol) and 3, dioxanes (1.5ml) solution of 4- dimethoxybenzylamine (400 μ l) heats 3 days.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.Handled, be concentrated under reduced pressure by hexane with silica gel column chromatography by residue obtained: ethyl acetate=4: the fraction that 1 eluent obtains obtains the title compound (140mg, 0.256mmol, 49%) in amorphous substance.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:547 (M++H).
The chloro- 4- of embodiment 186:5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -2- (3,4- dimethoxy benezene amino) pyridine
Under ice-cold, in the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- (3,4- dimethoxy benezene amino) pyridine (131mg, 0.239mmol) methanol (6ml) solution in six ammonium tetrahydrate (31mg) of 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids is added.After stirring 16 hours to reaction solution at room temperature, methanol is boiled off under decompression.In residue obtained middle addition ethyl acetate, successively with after saturated sodium bicarbonate, sodium thiosulfate and saturated common salt water washing, is dried, filtered with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure.It is residue obtained to be handled with silica gel flash column chromatography, the fraction obtained by the eluent of 35% ethyl acetate/hexane is concentrated under reduced pressure, obtains the title compound (75mg, 0.129mmol, 54%) of white solid.Leaching after gained white solid is washed with ether-hexane obtains the title compound of white powder.
1H-NMR (400MHz, CDCl3) 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=8.5H z), 8.01 (1H, s)
Mp:204-206 DEG C of
Elemental analysis: C27H22N2O4Cl2F2S: 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.
The chloro- 4- of embodiment 187:5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- [(pyridin-4-yl methyl)] amino] pyridine
Embodiment 54 is obtained in tube sealing in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] dioxanes (1.5ml) solution of pyridine (229mg, 0.550mmol) and 4- aminomethyl pyridine (200 μ l) heats 3 days.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.Handled, be concentrated under reduced pressure by hexane with silica gel column chromatography by residue obtained: ethyl acetate=1: the fraction that 3 eluent obtains obtains the title compound (37mg, 0.076mmol, 14%) in amorphous substance.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:488 (M++H).
The chloro- 4- of embodiment 188:5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -2- [(pyridin-4-yl methyl) amino] pyridine
Under ice-cold, in the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- [(pyridin-4-yl methyl) amino] pyridine (35mg, 0.072mmol) methanol (2ml) solution in six ammonium tetrahydrate (23mg) of 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids is added.After stirring 22 hours to reaction solution at room temperature, decompression boils off methanol.In residue obtained middle addition ethyl acetate, successively with after saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by methanol: methylene chloride=1: the fraction that 30 eluent obtains, obtaining is in faint yellow solid.Leaching after gained faint yellow solid is washed with ether-hexane obtains the title compound (16mg, 0.031mmol, 43%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
FAB-MS:520.0465 (C24H18O2N3Cl2F2S, calculated value: 520.0461)
Embodiment 189:N- [3- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] propyl] Methanesulfomide
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 173 obtains; 5- difluorophenyl) methyl] pyridine -2- base] propyl- 1; 3- diamine dihydrochloride (60mg; triethylamine (70 μ l are added in dichloromethane solution (5.0ml) 0.107mmol); 0.05mmol), mesyl chloride (10 μ l; 0.13mmol), it stirs 20 minutes.It is dry with water and saturated common salt water washing after ether (50ml) is added in reaction solution.Lower concentrate solution is depressurized, residue obtained (hexane: ethyl acetate=2: 1) purification obtains title compound (60mg, 99%) with silica gel chromatography.It is crystallized in ethanol, is obtained white solid (46mg).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C22H21Cl2F2N3O4S2: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] tetrahydropyrimidin-2-ones
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl)-(2 that embodiment 173 obtains; 5- difluorophenyl) methyl] pyridine -2- base] propyl- 1; 3- diamine dihydrochloride (51mg; triethylamine (51 μ l are added in dichloromethane solution (5.0ml) 0.091mmol); 0.36mmol), 1; 1 '-carbonyl dimidazoles (16.2mg, 0.10mmol) stir 17 hours.It is dry with water and saturated common salt water washing after ethyl acetate (80ml) is added in reaction solution.Depressurize lower concentrate solution, it is residue obtained to be dissolved with dimethylformamide (1.0ml), be added potassium carbonate (27.2mg, 0.2mol), in 50 DEG C heating stirring 24 hours.It is cooled to room temperature Hou Jiashui.Organic layer is taken with after ethyl acetate (60ml) dilution points, with saturated common salt water washing.Lower concentration is depressurized after solution is dry, it is residue obtained that silica gel chromatography is used (hexane: ethyl acetate=2: 1) to refine, obtain the title compound (15mg, 99%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:512 (M++H).
230 DEG C of of mp:>
Embodiment 191:2- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] ethylcarbamate
Under an argon, embodiment 54 is obtained in 120 DEG C 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (610mg, 1.46mmol) and (2- amino-ethyl) t-butyl carbamate (700mg, Isosorbide-5-Nitrae-dioxanes (6.0ml) solution 4.38mmol) stirs 4 days.Lower concentration is depressurized after being cooled to room temperature, and obtains residue.By it is residue obtained with silica gel chromatography (hexane: ethyl acetate=4: 1) refining, obtain be in grease title compound (176mg, 22%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:540 (M++H).
Embodiment 192:2- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] ethylcarbamate
In 2- [[the chloro- 4- of 5- [(4- chlorophenylsulfanyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] amino] ethylcarbamate (176mg, seven molybdic acids, six ammonium tetrahydrate (30mg) is added in methanol (6ml) solution 0.32mmol), it adds 30% aqueous hydrogen peroxide solution (3ml), stirs 20 hours.After ethyl acetate (80ml) dilution, solution water and saturated common salt water washing.With silica gel chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the title compound (148mg, 81%) of grease after concentrate solution under depressurizing.
1H-NMR (400MHz, CDCl3) 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=8.8H z), 7.52 (1H, m), 7.61 (2H, d, J=8.8Hz), 7.98 (1H, s)
MS m/z:572 (M++H).
Embodiment 193:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2,5- difluorophenyl) methyl] pyridine -2- base] second -1,2- diamine dihydrochloride
In 2- [[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl)-(2; 5- difluorophenyl) methyl] pyridine -2- base] amino] ethylcarbamate (146mg; 20% hydrochloric acid-methanol solution (1ml) is added in 0.25mmol), stirs 1 hour.Lower concentrate solution is depressurized, makes residue obtained crystallization with ethyl alcohol, obtains title compound (106mg, 76%).
1H-NMR (400MHz, DMSO-d6) 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 DEG C of
Elemental analysis: C20H17Cl2F2N3O2S·2HCl·0.5H2O: 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- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base amino] -2,2- dimethylpropane -1- alcohol
In 120 DEG C, embodiment 54 is obtained in tube sealing 2, chloro- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (191mg, 0.458mmol) and 3- amino -2, dioxanes (1.5ml) solution of 2- dimethyl propylene -1- alcohol (515mg, 5.00mmol) heats 3 days.It is concentrated under reduced pressure after reaction solution is cooled to room temperature.In residue obtained middle addition ethyl acetate, successively with after water and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Handled, be concentrated under reduced pressure by hexane with silica gel column chromatography by residue obtained: ethyl acetate=3: the fraction that 1 eluent obtains obtains the title compound (199mg, 0.412mmol, 90%) in amorphous substance.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:483 (M++H).
Embodiment 195:3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base amino] -2,2- dimethyl propylene -1- alcohol
Under ice-cold, in 3- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base amino] -2, six ammonium tetrahydrate (35mg) of 30% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids is added in methanol (6ml) solution of 2- dimethylpropane -1- alcohol (188mg, 0.389mmol).After stirring 13 hours to reaction solution at room temperature, decompression boils off methanol.In residue obtained middle addition ethyl acetate, saturated sodium bicarbonate, sodium thiosulfate solution and saturated common salt water washing are successively used, with filtering after anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 eluent obtains obtains white solid.Gained white solid is solidified with ether-hexane, leaching after washing, obtains the title compound (156mg, 0.303mmol, 78%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C
Elemental analysis: C23H22N2O3Cl2F2S: 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.
The chloro- 4- of embodiment 196:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
Under ice-cold; in the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 186 obtains; 5- difluorophenyl) methyl] -2- (3; 4- dimethoxy benezene amino) pyridine (43mg; nitric acid diammonium cerium (IV) (100mg) is added in acetonitrile (4ml) 0.074mmol)/water (1ml) mixed solution, stirs 1.5 hours.Saturated sodium bicarbonate is added in reaction solution, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.It is residue obtained that with silica gel thin-layer chromatography, (hexane: ethyl acetate=3: 1) being refined, and acquisition is in the title compound (12mg, 0.028mmol, 38%) of yellowish white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:429 (M++H).
Elemental analysis: C18H12N2O2Cl2F2S: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] Methanesulfomide
Under ice-cold; in [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (106mg; mesyl chloride (29 μ l, 0.370mmol) is added in pyridine (2ml) solution 0.247mmol).Reaction solution is stirred 3 days at room temperature, is concentrated under reduced pressure.Ethyl acetate is added in gained concentrated residue, is successively dried, filtered with after saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 eluent obtains obtains the title compound (58mg, 0.114mmol, 46%) of white solid.Leaching after gained white solid is washed with hexane-ether obtains the title compound (28mg) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:507 (M++H).
FAB-MS:506.9824 (C19H15O4N2Cl2F2S2, calculated value: 506.9818)
Elemental analysis: C19H14N2O4Cl2F2S2: 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, 5- amino -2- cyanopyridine (24.5g, 0.206mmol) is added in hydrogen fluoride-pyridine (100ml), stirs 10 minutes.Then, sodium nitrite (15.6g, 0.226mmol) is added, stirs after ten minutes, is stirred 2 hours in 50 DEG C at room temperature.20% sodium hydrate aqueous solution is added in reaction solution, is extracted with ether.It is concentrated under reduced pressure after the sodium sulphate drying of gained organic layer.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (16.0g, 0.131mmol, 64%) in colorless needle crystals
1H-NMR (400MHz, CDCl3) (1H, d, the J=3.1Hz) of δ: 7.57 (1H, ddd, J=8.6,8.6,3.1Hz), 7.77 (1H, dd, J=8.6,4.4Hz), 8.60
IR(ATR)cm-1: 3095,2237,1577,1467,1409,1375,1272,1240,1197,1120,1010.
MS m/z:122 (M+).
EI-MS:122.0293 (C6H3FN2, calculated value: 122.0280)
Reference example 36:2- (1,3-dioxolane -2- base) -5- fluorine pyridine
In -75 DEG C, diisobutylaluminium hydride (1.01M hexane solution, 58ml, 58.9mmol) is instilled in methylene chloride (150ml) solution of 5- fluorine pyridine -2- formonitrile HCN (6.54g, 53.8mmol) under an argon, is stirred 3 hours.Hydrochloric acid (80ml) is added at identical temperature and (concentrated hydrochloric acid: water=1: 3), is warming up to room temperature.After separating dichloromethane layer, sodium bicarbonate is added in water layer, is extracted with ether.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.The dichloromethane layer previously obtained is washed with water, then is concentrated under reduced pressure after being dried with magnesium sulfate.
P-methyl benzenesulfonic acid monohydrate (1.02g, 5.36mmol) and ethylene glycol (30ml, 0.536mol) are added in benzene (150ml) solution of combined residue, is heated to reflux lower stirring 2 hours.Saturated sodium bicarbonate aqueous solution is added after cooling in reaction solution, is extracted with ether, then with saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (3.33g, 19.7mmol, 37%) in brown-red oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:170 (M++H).
Reference example 37:4- [(2,5- difluorophenyl) hydroxymethyl] -2- (1,3-dioxolane -2- base) -5- fluorine pyridine
In -75 DEG C, under an argon in 2- (1,3- dioxolanes -2- base) -5- fluorine pyridine (690mg, lithium diisopropyl amido (1.8M n-heptane solution is added in tetrahydrofuran (100ml) solution 4.08mmol), 12ml, 21.5mmol), it stirs 2 hours.It instills 2,5- difluorobenzaldehyde (2.1ml, 19.5mmol), stirs 2.5 hours in reaction solution.It after water and saturated sodium bicarbonate aqueous solution is added in reaction solution, is extracted with ether, then with saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: the fraction that the elution portion of ethyl acetate (=3: 1) obtains obtains the title compound (2.53g, 8.03mmol, 73%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:312 (M++H).
Embodiment 198:4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- (1,3-dioxolane -2- base) -5- fluorine pyridine
In argon atmospher, in 4- [(2 under ice-cold, 5- difluorophenyl) hydroxymethyl] -2- (1,3- dioxolanes -2- base) -5- fluorine pyridine (2.5g, triethylamine (1.7ml is added in dichloromethane solution (30ml) 8.03mmol), 12.0mmol) with mesyl chloride (850 μ l, 10.4mmol), stir 2 hours at room temperature.It is extracted after saturated sodium bicarbonate aqueous solution is added in reaction solution with ether.Solution saturated common salt water washing, with the lower concentrate solution of decompression after anhydrous sodium sulfate drying.
4- chlorobenzenethiol (1.39g, 9.64mmol), potassium carbonate (1.66g, 12.0mmol) are added in dimethylformamide (20ml) solution of residue, is stirred 3 hours in 50 DEG C.Ether diluting reaction solution is used after being cooled to room temperature, and successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the sodium sulphate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: the fraction that the elution portion of ethyl acetate (=4: 1) obtains obtains the title compound (2.86mg, 5.85mmol, 85%) in yellow oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:438 (M++H).
Embodiment 199:4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -2- (1,3-dioxolane -2- base) -5- fluorine pyridine
In 4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -2- (1,3- dioxolanes -2- base) -5- fluorine pyridine (2.80g, seven molybdic acids, six ammonium tetrahydrate (200mg) and 30% aqueous hydrogen peroxide solution (30ml) are added in methanol (50ml) solution 6.39mmol), stirs 3 hours.Add water, the solid that leaching is precipitated is washed with water.After so that obtained solid is dissolved in ethyl acetate, with water and saturated common salt water washing.Depressurize lower concentration of organic layers.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: the fraction that the elution portion of ethyl acetate (=3: 1) obtains obtains the title compound (1.39g, 2.96mmol, 46%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:470 (M++H).
Embodiment 200:4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] formaldehyde
In 4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -2- (1; 3- dioxolanes -2- base) -5- fluorine pyridine (2.60g; 5.53mmol) 1; concentrated hydrochloric acid (20ml) is added in 4- dioxanes (40ml) solution, stirs 5 hours at room temperature.After depressurizing lower concentrated solvent, ethyl acetate is added in residue, successively uses water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=3: 1) elution portion obtains obtains the title compound (1.86g, 4.37mmol, 79%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:426 (M++H).
Embodiment 201:4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine carboxylic acid
In 4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] formaldehyde (700mg; 30% aqueous hydrogen peroxide solution (562 μ l are added in formic acid (10ml) solution 1.64mmol); 4.93mmol), it stirs 2.5 hours at room temperature.In reaction solution plus water, the solid that leaching is precipitated are washed with water.After so that obtained solid is dissolved in ethyl acetate, saturated aqueous ammonium chloride, water and saturated common salt water washing are successively used.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Make residue obtained recrystallization with ethyl alcohol, obtains the title compound (656mg, 1.48mmol, 91%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:442 (M++H).
Elemental analysis: C19H11ClF3NO4S·0.75H2O: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] t-butyl carbamate
Under argon atmospher; in 4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- fluorine pyridine carboxylic acid (240mg; diphenylphosphoryl azide (162 μ l are added in the mixed solution of the tert-butyl alcohol (2ml) and toluene (5ml) 0.543mmol); 0.762mmol), triethylamine (151 μ l; 1.09mmol), it is heated to reflux lower stirring 15 hours.Ethyl acetate is added after cooling in reaction solution, successively uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=4: 1) elution portion obtains obtains the title compound (181mg, 0.353mmol, 65%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:442 (M+-tBu+2H).
Embodiment 203:[4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] amine
In [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] t-butyl carbamate (170mg; concentrated hydrochloric acid (5ml) is added in ethyl alcohol (5ml) solution 0.331mmol), stirs 2 hours at room temperature.Lower concentrated reaction solution is depressurized to be extracted with ethyl acetate in residue obtained middle addition saturated sodium bicarbonate aqueous solution.Organic layer saturated common salt water washing is concentrated under reduced pressure after being dried with magnesium sulfate.Residue hexane: re-crystallizing in ethyl acetate obtains the title compound (110mg, 0.266mmol, 81%) in lavender powder.
1H-NMR (400MHz, CDCl3) 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: 3645,3174,1631,583,1565,1496,1427,1396,1330,1278,1236,1178,1151,1085,1014.
Mp:181-183 DEG C of
MS m/z:413 (M++H).
Elemental analysis: C18H12ClF3N2O2S: theoretical value: C, 52.37；H, 2.93；Cl, 8.59；F, 13.81；N, 6.79；S, 7.77. measured value: C, 52.09；H, 2.88；Cl, 8.57；F, 13.54；N, 6.90；S, 7.81.
Embodiment 204:N- [4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] Methanesulfomide
Under ice-cold; in [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] amine (54mg; 0.131mmol) and pyridine (16 μ l; mesyl chloride (12 μ l, 0.157mmol) is added in methylene chloride (5ml) solution 0.197mmol).After stirring 7 hours to reaction solution at room temperature, pyridine (16 μ l, 0.197mmol) and mesyl chloride (12 μ l, 0.157mmol) is added.After stirring 17 hours to reaction solution at room temperature, pyridine (16 μ l, 0.197mmol) and mesyl chloride (12 μ l, 0.157mmol) is added.After stirring 2 hours to reaction solution at room temperature, pyridine (16 μ l, 0.197mmol) and mesyl chloride (12 μ l, 0.157mmol) is added.After stirring 21 hours to reaction solution at room temperature, pyridine (16 μ l, 0.197mmol) and mesyl chloride (12 μ l, 0.157mmol) is added.It is concentrated under reduced pressure after being stirred 2 hours to reaction solution at room temperature.Ethyl acetate is added in gained concentrated residue, is washed with saturated sodium bicarbonate aqueous solution, with filtering after anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=2: 1) eluent obtains obtains the title compound (54mg, 0.110mmol, 84%) of white solid.Leaching after washing gained white solid with hexane-ether, obtains the title compound of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:490 (M+).
EI-MS:490.0008 (C19H14O4N2ClF3S2, calculated value: 490.0036)
Elemental analysis: C19H14N2O4ClF3S2: 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.
The bromo- 5- picoline -2- base of reference example 38:(4-) methanol
Under argon atmospher, in bromo- 2, the 5- lutidines -1- oxide (9.8g of 4- under ice-cold, trifluoroacetic anhydride (20.6ml is added in dichloromethane solution (100ml) 48.5mmol), 0.146mol), it stirs 20 minutes, stirs 7.5 hours at room temperature.Depressurize lower concentrated reaction solution.Saturated sodium bicarbonate aqueous solution (100ml) is added in the dichloromethane solution (50ml) of residue, stirs 14 hours.Reaction solution is extracted with dichloromethane, with the lower concentrate solution of decompression after anhydrous sodium sulfate drying.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=1: 1) elution portion obtains obtains the title compound (8.17g, 40.4mmol, 83%) in yellow powder.
1H-NMR (400MHz, CDCl3) (1H, the s) of δ: 2.38 (3H, s), 3.42 (1H, s), 4.71 (2H, s), 7.48 (1H, s), 8.35
MS m/z:202 (M++H).
The bromo- 2- of reference example 39:4- [(t-butyldimethylsilyloxy base) methyl] -5- picoline
Under nitrogen atmosphere, in (the bromo- 5- picoline -2- base of 4-) methanol (7.96g under ice-cold, imidazoles (2.95g is added in dichloromethane solution (100ml) 39.4mmol), 43.3mmol), 4-dimethylaminopyridine (481mg, 3.94mmol) and tertiary butyl chloride dimethylsilane (6.53g, 43.3mmol), it stirs 1 hour at room temperature.Add water in reaction solution, be extracted with dichloromethane, with the lower concentrate solution of decompression after anhydrous sodium sulfate drying.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (12.4g, 39.4mmol, quantitative) in light yellow oil.
1H-NMR (400MHz, CDCl3) (1H, the s) of δ: 0.12 (6H, s), 0.96 (9H, s), 2.36 (3H, s), 4.78 (2H, s), 7.67 (1H, s), 8.29
MS m/z:316 (M++H).
Reference example 40:2- [(t-butyldimethylsilyloxy base) methyl] -4- [(2,5- difluorophenyl) hydroxymethyl] -5- picoline
In -78 DEG C, under an argon in the bromo- 2- of 4- [(t-butyldimethylsilyloxy base) methyl] -5- picoline (200mg, n-BuLi (1.58M hexane solution is added in ether (3ml) solution 0.632mmol), 400 μ l, 0.632mmol), it stirs 1 hour.It instills 2,5- difluorobenzaldehyde (69 μ l, 0.632mmol), stirs 1 hour in reaction solution.It is extracted after water and saturated sodium bicarbonate aqueous solution is added in reaction solution with ether, then with saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (178mg, 0.469mmol, 74%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:380 (M++H).
Embodiment 205:2- [(t-butyldimethylsilyloxy base) methyl] -4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -5- picoline
In argon atmospher, in 2- [(t-butyldimethylsilyloxy base) methyl] -4- [(2 under ice-cold, 5- difluorophenyl) hydroxymethyl] -5- picoline (8.0g, triethylamine (4.41ml is added in dichloromethane solution (100ml) 21.1mmol), 31.7mmol) and mesyl chloride (2.2ml, 27.4mmol), it stirs 50 minutes at room temperature.It is extracted after saturated sodium bicarbonate aqueous solution is added in reaction solution with ether.Solution saturated common salt water washing, with the lower concentrate solution of decompression after anhydrous magnesium sulfate drying
4- chlorobenzenethiol (3.66g, 25.3mmol) and potassium carbonate (4.38g, 31.7mmol) are added in dimethylformamide (100ml) solution of residue, is stirred 1.5 hours in 50 DEG C.Ether diluting reaction solution is used after being cooled to room temperature, and successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Handled, be concentrated under reduced pressure by hexane with silica gel column chromatography by residue obtained: ethyl acetate=5: the fraction that 1 elution portion obtains obtains the title compound (9.3g, 18.4mmol, 87%) in light yellow oil.
1H-NMR (400MHz, CDCl3) δ: 0.04 (3H, s), 0.08 (3H, s), 0.91 (9H, s), 2.33 (3H, s), 4.77 (2H, d, J=4.2H z), 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)
MS m/z:506 (M++H).
Embodiment 206:[4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] methanol
In 2- [(t-butyldimethylsilyloxy base) methyl] -4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -5- picoline (200mg, tetrabutylammonium (1.0M tetrahydrofuran solution is added in tetrahydrofuran solution (3ml) 0.395mmol), 593 μ l, 0.593mmol), it stirs 20 minutes.It is extracted with ethyl acetate in reaction solution plus after water.Organic layer saturated common salt water washing, with the lower concentration of decompression after anhydrous magnesium sulfate drying.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (150mg, 0.384mmol, 97%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:392 (M++H).
Embodiment 207:[4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] methanol
In [4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] methanol (6.5g, seven molybdic acids, six ammonium tetrahydrate (500mg) and 30% aqueous hydrogen peroxide solution (150ml) are added in methanol (150ml) solution 16.6mmol), stirs 23 hours.Add water, the solid that leaching is precipitated is washed with water.Obtained solid is set to be dissolved in ethyl acetate, with water and saturated common salt water washing.Depressurize lower concentration of organic layers.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=1: the fraction that 1 elution portion obtains obtains the title compound (4.0g, 9.44mmol, 57%) of white powder.
1H-NMR (400MHz, CDCl3) 8:2.13 (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 DEG C of
MS m/z:424 (M++H).
Elemental analysis: C20H16ClF2NO3S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] formaldehyde
Under nitrogen atmosphere; in [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- picoline -2- base] methanol (200mg; dimethyl sulfoxide (164 μ l are added in methylene chloride (5ml) solution 0.472mmol); 2.36mmol), triethylamine (329 μ l; 2.36mmol) with sulfur trioxide pyridine complex salt (255mg, 1.42mmol), stir 16 hours at room temperature.Reaction solution is concentrated under reduced pressure, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (160mg, 0.379mmol, 80%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:422 (M++H).
Embodiment 209:[4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- picoline formic acid
In [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- picoline -2- base] formaldehyde (150mg; 30% aqueous hydrogen peroxide solution (121 μ l are added in formic acid (3ml) solution 0.356mmol); 1.07mmol), it stirs 2 hours at room temperature.In reaction solution plus water, the solid that leaching is precipitated are washed with water.So that obtained solid is dissolved in ethyl acetate, is successively washed with water and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Make residue obtained recrystallization with ethyl alcohol, obtains the title compound (140mg, 0.320mmol, 90%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:438 (M++H).
Elemental analysis: C20H14ClF2NO4S·0.75H2O；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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] t-butyl carbamate
In argon atmospher; in [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- picoline formic acid (2.8mg; diphenylphosphoryl azide (2.9ml is added in the mixed solution of the tert-butyl alcohol (20ml) and toluene (40ml) 6.40mmol); 13.6mmol), triethylamine (2.7ml; 19.4mmol), it is heated to reflux lower stirring 16 hours.Ethyl acetate is added after cooling in reaction solution, successively uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained successively to be washed with hexane and ethyl acetate, obtain the title compound (2.60g, 5.11mmol, 80%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:509 (M++H).
Embodiment 211:[4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] amine
In [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- picoline -2- base] t-butyl carbamate (200mg; concentrated hydrochloric acid (6ml) is added in ethyl alcohol (5ml) solution 0.393mmol), stirs 2.5 hours at room temperature.Lower concentrated reaction solution is depressurized to be extracted with ethyl acetate in residue obtained middle addition saturated sodium bicarbonate aqueous solution.Organic layer successively uses water and saturated common salt water washing, is concentrated under reduced pressure after being dried with magnesium sulfate.Residue hexane: re-crystallizing in ethyl acetate obtains the title compound (125mg, 0.306mmol, 78%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H15ClF2N2O2S: 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- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- picoline -2- base] Methanesulfomide
Under ice-cold; in [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- picoline -2- base] amine (133mg; 0.325mmol) and pyridine (39 μ l; mesyl chloride (28 μ l, 0.358mmol) is added in methylene chloride (5ml) solution 0.488mmol).After stirring 2.5 hours to reaction solution at room temperature, pyridine (26 μ l, 0.325mmol) and mesyl chloride (25 μ l, 0.325mmol) is added.After stirring 16 hours to reaction solution at room temperature, pyridine (26 μ l, 0.325mmol) and mesyl chloride (25 μ l, 0.325mmol) is added.It is concentrated under reduced pressure after being stirred 1.5 hours to reaction solution at room temperature.Ethyl acetate is added in gained concentrated residue, successively uses water and saturated common salt water washing, with leaching after anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 eluent obtains obtains the title compound (108mg, 0.222mmol, 68%) of white solid.Leaching after gained white solid is washed with hexane-ether obtains the title compound (67mg) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:486 (M+).
Elemental analysis: C20H17N2O4ClF2S2: 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.
The chloro- 4- of embodiment 213:2,5- bis- [(2,5- difluorophenyl)-(4- chlorophenylthio) methyl] pyridine
2 that reference example 24 is obtained, after the chloro- 4- of 5- bis- [(2,5- difluorophenyl)-hydroxymethyl] pyridine (1.22g, 4.8mmol) is dissolved in thionyl chloride (5.0ml), the dimethylformamide of catalytic amount is added, stirs 4 hours.Lower concentration of reaction solution is depressurized, Isosorbide-5-Nitrae-dioxanes is added in residue, then be concentrated.
After the residue is dissolved in dimethylformamide (10ml), 4- fluorobenzenethiol (730mg, 5.7mmol) and potassium carbonate (2.07g, 15mmol) are added under nitrogen atmosphere, stirs 24 hours at room temperature.Ether (120ml) is added in reaction solution, it is washed with water and saturated salt solution.Organic layer is dry with magnesium sulfate, depressurizes lower concentration.It crystallizes residue in ethanol, obtains the title compound (950mg, 49%) in colorless needle crystals.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
IR(ATR)cm-1: 1571,1489,1329,1222,1157,1109,835.
Mp:95-97 DEG C of
MS m/z:400 (M++H).
The chloro- 4- of embodiment 214:[5- [(2,5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] (3,4- dimethoxy benezene) amine
Under argon atmospher, in 120 DEG C to 2 in tube sealing, the chloro- 4- [(2 of 5- bis-, 5- difluorophenyl)-(4- chlorophenylthio) methyl] pyridine (740mg, 1.85mmol) and 3, Isosorbide-5-Nitrae-dioxanes (3.0ml) solution of 4- dimethoxybenzylamine (836 μ l, 5.55mmol) stirs 3 days.Ethyl acetate (80ml) is added after being cooled to room temperature.Solution saturated common salt water washing depressurizes lower concentration, obtains residue after dry.With silica gel column chromatography, (hexane: ethyl acetate=3: 1) refining residue, and acquisition is in the amine body (235mg) of grease.
The amine body is dissolved in methanol (9.0ml), seven molybdic acids, six ammonium tetrahydrate (30mg) and 30% aqueous hydrogen peroxide solution (3.0ml) is added, is stirred 20 hours at room temperature.After ethyl acetate (80ml) dilution, solution water and saturated common salt water washing.Lower concentrate solution is depressurized after drying, in residue obtained middle addition ethyl alcohol, its crystallization is made to obtain the title compound (159mg, 15%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:563 (M++H).
The chloro- 4- of embodiment 215:[5- [(2,5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] amine
By [the chloro- 4- of 5- [(2; 5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] (3; 4- dimethoxy benezene) amine (157mg; it 0.28mmol) is dissolved in trifluoroacetic acid (5.0ml), is stirred 17 hours in 65 DEG C.Lower concentrate solution is depressurized after cooling.In residue obtained middle addition saturated sodium bicarbonate aqueous solution, it is extracted with ethyl acetate.It is dry after solution saturated common salt water washing, depressurize lower concentration.It is residue obtained that with silica gel chromatography, (hexane: ethyl acetate=3: 1) purification obtains the title compound (114mg, 99%) of white solid.
1H-NMR (400MHz, CDCl3) 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, d d, 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 DEG C of
MS m/z:413 (M++H).
Elemental analysis: C18H12ClF3N2O2S: 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- [the chloro- 4- of 5- [(2,5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] Methanesulfomide
In [the chloro- 4- [(2 of 5-; 5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] amine (114mg; pyridine (440 μ 1 are added in dichloromethane solution (10.0ml) 0.276mmol); 5.5mmol); mesyl chloride (1 day 1 time 77 μ l of addition are added wherein; 3 days 230 μ l, 3.0mmol of total addition), amount to stirring 4 days.Depressurize lower concentrated reaction solution.It is residue obtained that with silica gel chromatography, (hexane: ethyl acetate=2: 1) purification crystallizes it in ether, obtains the title compound (51mg, 38%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:491 (M++H).
IR(ATR)cm-1: 1590,1490,1330,1149,968,852.mp:178-179 DEG C of
Elemental analysis: C19H14ClF3N2O4S2: 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.
The optical resolution (optical isomer A, optical isomer B) of embodiment 217:N- [the chloro- 4- of 5- [(2,5- difluorophenyl) (4- fluorophenylSulphonyl) methyl] pyridine -2- base] Methanesulfomide
By using the supercritical chromatography (Gilson corporation) of chiral (chiral) column; optical resolution is carried out to N- [the chloro- 4- of 5- [(2,5- difluorophenyl)-(4- fluorophenylSulphonyl) methyl] pyridine -2- base] Methanesulfomide that embodiment 216 obtains under the following conditions.
Column: CHIRALPAK AD, 2.0cm φ × 25cm, Dai Saier chemical industry Co. Ltd. system
Mobile phase: 2- propyl alcohol: carbon dioxide=1: 99 → 50: 50 (after 3 minutes, 50: 50)
Flow: 6.0ml/ minutes
Pressure: 14MPa
Temperature: 35 DEG C
Detection: UV (254mm)
The retention time and instrument data of optical isomer are as follows.
Optical isomer A:16.3 minutes
1H-NMR (400MHz, CDCl3) 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)
Optical isomer B:18.4 minutes
1H-NMR (400MHz, CDCl3) 8:3.36 (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 ° of (c=0.5, CHCl3).
The sodium salt of embodiment 218:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] Methanesulfomide
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 197 obtains; 5- difluorophenyl) methyl] pyridine -2- base] and Methanesulfomide (15.1g, 29.8mmol) ethyl alcohol (100ml) solution in be added 1N sodium hydrate aqueous solution (32.8ml) be concentrated under reduced pressure afterwards.2- propyl alcohol is added in gained concentrated residue, dissolves residue while heating, the solid that leaching is precipitated after placing at room temperature obtains title compound (9.10g, 16.6mmol, 56%).
1H-NMR (400MHz, DMSO-d6) δ: 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.
Elemental analysis: C19H13N2O4Cl2F2S2Na·1.0H2O: 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.
The chloro- 4- of embodiment 219:[5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
In 65 DEG C, the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl) (2 that embodiment 185 is obtained, 5- difluorophenyl) methyl] -2- (3,4- dimethoxy benezene amino) pyridine (1.89g, 3.45mmol) trifluoroacetic acid (5ml) solution carry out 2 hours stir.Saturated sodium bicarbonate aqueous solution is added after reaction solution is concentrated under reduced pressure, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Gained concentrated residue is handled with silica gel column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=2: 1) obtains obtains white solid.Leaching after being washed with hexane-ether to gained white solid obtains the title compound (1.06g, 2.67mmol, 77%) of white powder.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:397 (M++H).
Embodiment 220:N- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2; 5- difluorophenyl) methyl] pyridine -2- base]-N- (methyl sulphonyl) Methanesulfomide (compound A) and N- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] Methanesulfomide (compound B)
Compound A compound B
In 0 DEG C, in [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine (575mg, mesyl chloride (0.123ml is added in pyridine (5ml) solution 1.45mmol), 1.59mmol), it stirs 16 hours at room temperature.Mesyl chloride (0.12ml, 1.59mmol) is added in reaction solution in 0 DEG C, stirs 22 hours at room temperature.Pyridine (3ml) is added in reaction solution, in 0 DEG C of addition mesyl chloride (0.123ml, 1.59mmol).It is concentrated under reduced pressure after being stirred 25 hours to reaction solution at room temperature.After being diluted with ethyl acetate to gained concentrated residue, water and saturated common salt water washing are successively used, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=4: 1) elution portion obtains, obtain labeled compound A (low polar compound) (334mg in amorphous substance, 0.603mmol, 42%), obtain the title compound B (highly polar compound) (269mg, 0.566mmol, 39%) of white solid.
Compound A
1H-NMR (400MHz, CDCl3) 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.
MS m/z:552 (M+).
Compound B
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
Mp:149-151 DEG C
IR(ATR)cm-1: 1590,1556,1488,1475,1380,1348,1149,993,962,831,784.
MS m/z:475 (M++H).
FAB-MS:474.9925 (presses C19H15O2N2Cl2F2S2It calculates: 474.9920)
Elemental analysis: C19H14N2O2Cl2F2S2: 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；C1,14.79；F, 7.96；S, 13.61.
Embodiment 221:N- [the chloro- 4- of 5- [(4- chlorphenyl sulfinyl) (2,5- difluorophenyl) methyl] pyridine -2- base] Methanesulfomide
In 0 DEG C, in N- [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] Methanesulfomide (331mg, 3- chlorine benzylhydroperoxide (120mg, 0.696mmol) is added in methylene chloride (10ml) solution 0.696mmol).After 0 DEG C is stirred reaction solution 50 minutes, 3- chlorine benzylhydroperoxide (60mg, 0.348mmol) is added at the same temperature.In 0 DEG C saturated aqueous sodium thiosulfate is added to reaction solution stirring after ten minutes, is extracted with dichloromethane.It is filtered after organic layer anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=2: 1) eluent obtains.Ether is added in gained concentrated residue, the solid that leaching is precipitated obtains the title compound (281mg, 0.572mmol, 82%) of white powder.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:491 (M++H).
FAB-MS:490.9853 (presses C19H15O3N2Cl2F2S2It calculates: 490.9869)
Elemental analysis: C19H14N2O3Cl2F2S2: 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；C1,14.31；F, 7.74；S, 13.02.
The chloro- 4- of embodiment 222:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] hydrazine
2 obtained in embodiment 57; chloro- 4- [(the 4- Chlorophenylsulfonyl) (2 of 5- bis-; 5- difluorophenyl) methyl] pyridine (524mg, 1.17mmol) ethyl alcohol (10ml) solution in be added hydrazine monohydrate (2ml).Reaction solution is heated to reflux 3 hours, is concentrated under reduced pressure after being cooled to room temperature.Gained concentrated residue is handled with silica gel column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=1: 1) obtains obtains light yellow oil.Hexane-ether is added in gained grease, the solid that leaching is precipitated obtains the title compound (95mg, 0.214mmol, 18%) of white powder.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:443 (M+).
Elemental analysis: C18H13N3O2Cl2F2S: 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 '-[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] hydrazine carboxylic acid's tert-butyl ester
[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] hydrazine (166mg; di-tert-butyl dicarbonate (122mg, 0.560mmol) in methylene chloride (5ml) solution 0.374mmol).It is concentrated under reduced pressure after being stirred 16 hours to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=3: 1) obtains obtains the title compound (166mg, 0.305mmol, 82%) of white solid.
1H-NMR (400MHz, CDCl3) 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
MS m/z:544 (M++H).
Embodiment 224:N '-[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base]-N '-sulfonyloxy methyl hydrazine carboxylic acid's tert-butyl ester
In 0 DEG C; in N '-[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] hydrazine carboxylic acid's tert-butyl ester (178mg; 0.327mmol) and triethylamine (43 μ l; mesyl chloride (30 μ l, 0.392mmol) is added in methylene chloride (5ml) solution 0.392mmol).After stirring 16 hours to reaction solution at room temperature, triethylamine (43 μ l, 0.392mmol) and mesyl chloride (30 μ l, 0.392mmol) is added.It is concentrated under reduced pressure after being stirred 3 hours to reaction solution at room temperature.Gained concentrated residue is diluted with ethyl acetate, and filtrate successively is concentrated under reduced pressure with after being dried, filtered after saturated sodium bicarbonate aqueous solution and saturated common salt water washing with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=4: 1) obtains obtains the title compound (174mg, 0.280mmol, 85%) of white solid.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:622 (M++H).
Embodiment 225:1- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -1- sulfonyloxy methyl hydrazine
In N '-[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] and-the N '-sulfonyloxy methyl hydrazine carboxylic acid tert-butyl ester (167mg, 0.268mmol) methylene chloride (5ml) solution in be added trifluoroacetic acid (2.5ml).It is concentrated under reduced pressure after being stirred 21 hours to reaction solution at room temperature.Saturated sodium bicarbonate aqueous solution is added in gained concentrated residue, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered after organic layer separation with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=2: 1) obtains obtains the title compound (91mg, 0.174mmol, 65%) of white solid.Leaching after obtained solid is washed with ether obtains the title compound (60mg) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C
IR(ATR)cm-1: 1583,1490,1361,1319,1149,1079,958,833,754.
MS m/z:522 (M++H).
Elemental analysis: C19H15N3O4Cl2F2S2: 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.
The bromo- 4- of reference example 41:2,5- bis- [(2,5- difluorophenyl) hydroxymethyl] pyridine
In -70 DEG C, n-BuLi (1.59M hexane solution, 76ml, 121mmol) is added in tetrahydrofuran (400ml) solution of diisopropylamine (17ml, 121mmol) under an argon, stirs 1 hour.Tetrahydrofuran (100ml) solution of 2,5- dibromo pyridine is instilled in reaction solution, is stirred 2 hours.It instills 2,5- difluorobenzaldehyde (15ml, 139mmol), stirs 1 hour in reaction solution.It is concentrated under reduced pressure, is extracted with dichloromethane in reaction solution plus after water.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained with methylene chloride: hexane washs, obtain pale yellow powder.Filtrate is handled with silica gel column chromatography, is concentrated under reduced pressure by hexane: ethyl acetate=6: the fraction that 1 elution portion obtains merges with above-mentioned pale yellow powder, obtains the title compound (18.4g, 48.6mmol, 52%) in pale yellow powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:378 (M++H).
The bromo- 4- of embodiment 226:2,5- bis- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine
Under argon atmospher, 2 under ice-cold, the bromo- 4- [(2 of 5- bis-, 5- difluorophenyl) hydroxymethyl] pyridine (9.3g, triethylamine (5.1ml is added in dichloromethane solution (200ml) 24.5mmol), 36.8mmol) with mesyl chloride (2.6ml, 31.9mmol), stir 30 minutes at room temperature.It is concentrated under reduced pressure in reaction solution plus after water, is extracted with ether.Organic layer saturated common salt water washing, with the lower concentrate solution of decompression after anhydrous magnesium sulfate drying.
4- chlorobenzenethiol (4.3g, 29.4mmol) and potassium carbonate (5.1g, 36.8mmol) are added in dimethylformamide (200ml) solution of residue, stirs 17 hours at room temperature.It is extracted in reaction solution plus after water with ether.Organic layer saturated common salt water washing, with the lower concentrate solution of decompression after anhydrous magnesium sulfate drying.It is residue obtained to be washed with hexane, obtain white powder.Filtrate is handled with silica gel flash column chromatography, and the fraction obtained by dichloromethane eluent portion is concentrated under reduced pressure, merges with above-mentioned white powder, obtains the title compound (9.1g, 18.0ml, 73%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:504 (M++H).
The bromo- 4- of embodiment 227:[5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methanol
In -78 DEG C, under an argon 2, bromo- 4- [(the 4- chlorophenylsulfanyl) (2 of 5- bis-, 5- difluorophenyl) methyl] pyridine (200mg, n-BuLi (1.59M hexane solution is added in toluene (10ml) solution 0.396mmol), 0.27ml, 0.435mmol), it stirs 2 hours.Dimethylformamide (40 μ l, 0.514mmol) is instilled in reaction solution, is stirred 1 hour.Methanol (10ml), sodium borohydride (30mg, 0.791mmol) are added in reaction solution, is stirred 1 hour after being warming up to room temperature.It is extracted with ethyl acetate in reaction solution plus after water, then with saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (160mg, 0.350mmol, 89%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:456 (M++H).
The bromo- 4- of embodiment 228:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methanol
In [the bromo- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methanol (550mg, 1.20mmol) methanol (10ml), ethyl acetate (10ml) mixed solution in be added seven molybdic acids, six ammonium tetrahydrate (100mg), 30% aqueous hydrogen peroxide solution (10ml), stir 19 hours.It is extracted with ethyl acetate in reaction solution plus after water, successively uses water, saturated sodium bicarbonate aqueous solution, saturated aqueous sodium thiosulfate and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains, then with hexane: re-crystallizing in ethyl acetate obtains the title compound (506mg of white powder, 1.04mmol, 86%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:488 (M++H).
Elemental analysis: C19H13BrClF2NO3S: 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.
The bromo- 4- of embodiment 229:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] formaldehyde
Under nitrogen atmosphere; in [the bromo- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] methanol (300mg; dimethyl sulfoxide (218 μ l are added in methylene chloride (10ml) solution 0.614mmol); 3.07mmol), triethylamine (428 μ l; 3.07mmol) with sulfur trioxide pyridine complex salt (293mg, 1.84mmol), stir 4 hours at room temperature.Reaction solution is concentrated under reduced pressure, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (227mg, 0.466mmol, 76%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:486 (M++H).
The bromo- 4- of embodiment 230:5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine carboxylic acid
In [the bromo- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] formaldehyde (225mg; 30% aqueous hydrogen peroxide solution (157 μ l are added in formic acid (5ml) solution 0.462mmol); 1.39mmol), it stirs 3 hours at room temperature.Add water in reaction solution, filters the solid of precipitation, solid is washed with water.So that obtained solid is dissolved in ethyl acetate, successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer, obtains the title compound (226mg, 0.461mmol, 97%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:502 (M++H).
The bromo- 4- of embodiment 231:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate
Under argon atmospher; in the bromo- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine carboxylic acid (220mg; diphenylphosphoryl azide (131 μ l are added in the mixed solution of the tert-butyl alcohol (5ml) and toluene (5ml) 0.438mmol); 0.613mmol), triethylamine (122 μ l; 0.875mmol), it is heated to reflux lower stirring 14 hours.Ethyl acetate is added after cooling in residue, is successively washed with saturated sodium bicarbonate aqueous solution and saturated salt solution.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (128mg, 0.223mmol, 51%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:573 (M++H).
The bromo- 4- of embodiment 232:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
In [the bromo- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate (130mg; concentrated hydrochloric acid (2ml) is added in ethyl alcohol (2ml) solution 0.227mmol), stirs 63 hours at room temperature.Lower concentrated reaction solution is depressurized to be extracted with ethyl acetate in residue obtained middle addition saturated sodium bicarbonate.Organic layer saturated common salt water washing is concentrated under reduced pressure after being dried with magnesium sulfate.Residue hexane: re-crystallizing in ethyl acetate obtains the title compound (72mg, 0.152mmol, 67%) in pale yellow powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:473 (M++H).
Elemental analysis: C18H12BrClF2N2O2S: 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 -2- fluorobenzaldehyde
Diisopropylamine (2.80ml, 19.8mmol) is dissolved in tetrahydrofuran (20ml), the hexane solution (1.60M, 11.4ml, 18.2mmol) of n-BuLi is added dropwise in -78 DEG C.After stirring 30 minutes at identical temperature to reaction solution, the tetrahydrofuran solution (20m1) of 4- fluorobenzonitrile (2.00g, 16.5mmol) is added dropwise.After stirring 30 minutes at identical temperature, n,N-Dimethylformamide (1.7m1,21.5mmol) is instilled in reaction solution, is stirred 10 minutes at identical temperature.Acetic acid, saturated aqueous ammonium chloride are added in reaction solution, is extracted with ethyl acetate.With the dry combined organic layer of anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering.Handled with silica gel chromatography gained concentrated residue, be concentrated under reduced pressure by n-hexane: ethyl acetate=10: the fraction that 2 elution portions obtain obtains the title compound (1.83g, 12.3mmol, 74%) in khaki grease.
1H-NMR (400MHz, CD3OD) 8:7.37 (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.
MS m/z:150 (M++H).
Reference example 43:3- [(2,5- dichloropyridine -4- base) hydroxymethyl] -4- fluorobenzonitrile
Diisopropylamine (0.52ml, 3.70mmol) is dissolved in tetrahydrofuran (5ml), the hexane solution (1.54M, 2.20ml, 3.39mmol) of n-BuLi is added dropwise in -78 DEG C.After stirring 30 minutes at identical temperature to reaction solution, the tetrahydrofuran solution (20ml) of 2,5- dichloropyridine (0.46g, 3.08mmol) is added dropwise.After being stirred 1 hour at identical temperature, the tetrahydrofuran solution (5ml) of 5- cyano -2- fluorobenzaldehyde (0.46g, 3.08mmol) is instilled in reaction solution, is stirred 30 minutes at identical temperature.Saturated aqueous ammonium chloride is added in reaction solution, is extracted with ethyl acetate.With the dry combined organic layer of anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering.Handled with silica gel chromatography gained concentrated residue, be concentrated under reduced pressure by n-hexane: ethyl acetate=10: the fraction that 2 elution portions obtain obtains the title compound (0.68g, 2.28mmol, 74%) in khaki grease.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
IR(ATR)cm-1: 3413,1577,1492,1334,1247,1110,829,534.
MS m/z:297 (M++H).
Embodiment 233:3- [(4- Chlorophenylsulfonyl) (2,5- dichloropyridine -4- base) methyl] -4- fluorobenzonitrile
Under ice-cold, in 3- [(2,5- dichloropyridine -4- base) hydroxymethyl] -4- fluorobenzonitrile (677mg, the N of thionyl chloride (3ml) and catalytic amount are added in dichloromethane solution (5ml) 2.28mmol), dinethylformamide stirs 4 hours at room temperature.Add water in reaction solution, is extracted with dichloromethane.With the dry combined organic layer of anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering.
Gained concentrated residue is dissolved in n,N-Dimethylformamide (5ml), adds 4- chlorobenzene sulfinic acid sodium (905mg, 4.56mmol), is stirred 20 hours at room temperature.Add water in reaction solution, is extracted with ethyl acetate.With the dry combined organic layer of anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering.Gained concentrated residue is handled with silica gel chromatography, is concentrated under reduced pressure by n-hexane: ethyl acetate=10: the fraction that 2 elution portions obtain obtains the title compound (170mg, 0.37mmol, 16%) in khaki solid.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:456 (M+).
Embodiment 234:3- [(2- amino -5- chloropyridine -4- base) (4- Chlorophenylsulfonyl) methyl] -4- fluorobenzonitrile
By 3- [(4- Chlorophenylsulfonyl) (2; 5- dichloropyridine -4- base) methyl] -4- fluorobenzonitrile (559mg; 1.23mmol) it is dissolved in N-Methyl pyrrolidone (12ml); it is added 3; 4- dimethoxybenzylamine (0.91ml; 6.13mmol), in 140 DEG C heating stirring 4 hours.In the reactive mixture plus water, it is extracted with ethyl acetate, it is dry with organic layer anhydrous sodium sulfate after saturated common salt water washing.Filtrate is concentrated under reduced pressure after filtering, it is residue obtained to be handled with silica gel chromatography, it is concentrated under reduced pressure by n-hexane: ethyl acetate=2: the fraction that 1 elution portion obtains.
Gained concentrated residue is dissolved in trifluoroacetic acid (5ml), in 70 DEG C heating stirring 2 hours.Reaction mixture is concentrated under reduced pressure, gained concentrated residue is handled with silica gel chromatography, and be concentrated under reduced pressure by n-hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (50mg, 0.11mmol, 9%) of white powder.
1H-NMR (400MHz, CDCl3) 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.
220 DEG C of of mp:>
MS m/z:436 (M++H).
Elemental analysis: C19H12Cl2FN3O2S: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (5- cyano -2- fluorophenyl) methyl] pyridine -2- base]-N- (methyl sulphonyl) Methanesulfomide
By 3- [(2- amino -5- chloropyridine -4- base) (4- Chlorophenylsulfonyl) methyl] -4- fluorobenzonitrile (50mg; after 0.11mmol) being dissolved in methylene chloride (5ml); in 0 DEG C of addition mesyl chloride (27 μ l; 0.39mmol), triethylamine (48 μ l; 0.39mmol) and the 4-dimethylaminopyridine of catalytic amount, it is stirred 30 minutes at identical temperature.Add water in reaction mixture, is extracted with dichloromethane, filtrate is concentrated under reduced pressure after being dried, filtered with organic layer after saturated common salt water washing with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel column chromatography, is concentrated under reduced pressure by n-hexane: ethyl acetate=10: the fraction that 3 elution portions obtain obtains the title compound (80mg, 0.11mmol, 99%) of white powder.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:592 (M++H).
Embodiment 236:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (5- cyano -2- fluorophenyl) methyl] pyridine -2- base] Methanesulfomide
By N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (5- cyano -2- fluorophenyl) methyl] pyridine -2- base]-N- (methyl sulphonyl) Methanesulfomide (80mg; after 0.11mmol) being dissolved in tetrahydrofuran (3ml); tetrahydrofuran solution (the 1.0M of tetrabutylammonium is added in 0 DEG C; 0.15ml, 0.15mmol) it stirs 1 hour at room temperature.Reaction mixture is concentrated under reduced pressure, gained concentrated residue is handled with silica gel column chromatography, and be concentrated under reduced pressure by n-hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains white solid.Resulting white solid is washed with ether, obtains the title compound (32mg, 0.06mmol, 46%) of white powder.
1H-NMR (400MHz, CDCl3) 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), 811 (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 DEG C of
MS m/z:514 (M++H).
Elemental analysis: C20H14Cl2FN3O4S2: 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.
The chloro- 2- of reference example 44:5- (2,2,5,5- tetramethyls -1,2, two silacyclopentan -1- base of 5- azepine) pyridine
In -78 °C, the hexane solution (1.58M, 50.6ml, 80.0mmol) of n-BuLi is added in tetrahydrofuran (350ml) solution of 5- chloropyridine -2- base amine (10.28g, 80.0mmol), stirs 1 hour.Tetrahydrofuran (50ml) solution of bis- (chlorodimethylsilyl) ethane (17.22g, 80.0mmol) of 1,2- is added at the same temperature, stirs 1 hour.Then, the hexane (1.58M, 50.6ml, 80.0mmol) of n-BuLi is added at the same temperature, saturated sodium-chloride water solution is added after 30 minutes in stirring at room temperature.Ether is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after liquid separation.It is evaporated under reduced pressure (120 DEG C/3.0mmHg) to residue obtained, obtains the title compound (12.97g, 47.9mmol, 60%) in colorless needles.
1H-NMR (400MHz, CDCl3) (1H, d, the J=2.7Hz) of 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
Reference example 45:(2- amino -5- chloropyridine -4- base) (2,5- difluorophenyl) methanol
In -78 DEG C, diisopropylamine (1.86ml, 13.3mmol) is added in the hexane solution (1.58M, 8.41ml, 13.3mmol) of n-BuLi and the mixture of tetrahydrofuran (40ml).After 0 DEG C carries out stirring in 1 hour to reaction mixture, -78 DEG C are cooled to, the chloro- 2- (2 of 5- is added, 2,5,5- tetramethyls -1,2,5- azepine, two silacyclopentan -1- base) pyridine (3.27g, 12.1mmol) tetrahydrofuran (10ml) solution.After stirring 1 hour at the same temperature, tetrahydrofuran (10ml) solution of 2,5- difluorobenzaldehyde (1.89g, 13.3mmol) is added.After stirring 30 minutes at the same temperature, in 0 DEG C of addition 1N hydrochloric acid (50ml).After 1N sodium hydrate aqueous solution (100ml) is added in the reactive mixture, product is extracted with ether, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.With the mixed solvent of dichloromethane/hexane to leaching after residue obtained wash, the title compound (1.76g, 6.50mmol, 54%) of white solid is obtained.
1H-NMR (400MHz, DMSO-d6) 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)
MS m/z:271 (M++H).
Reference example 46: carbonic acid (2- amino -5- chloropyridine -4- base) (2,5- difluorophenyl) methyl esters tert-butyl ester
Under nitrogen atmosphere, in room temperature in (2- amino -5- chloropyridine -4- base) (2,5- difluorophenyl) methanol (4.50g, di-tert-butyl dicarbonate (3.63g is added in methylene chloride (150ml) solution 16.6mmol), 16.6mmol) and 4-dimethylaminopyridine (203mg, 1.66mmol).Reaction mixture is concentrated under reduced pressure after stirring 2 hours at room temperature, is handled residue obtained with flashchromatography on silica gel.Be concentrated under reduced pressure by methylene chloride: methanol=50: the fraction that 1 elution portion obtains obtains the title compound (5.70g, 15.4mmol, 92%) of white solid.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
MS m/z:371 (M++H).
The chloro- 4- of reference example 47:[5- [(2,5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate
Under nitrogen atmosphere, in 0 DEG C in carbonic acid (2- amino -5- chloropyridine -4- base) (2,5- difluorophenyl) the methyl esters tert-butyl ester (5.70g, tetrahydrofuran solution (the 1M of bis- (trimethyl silyl) amido sodium is added in tetrahydrofuran (80ml) solution 15.4mmol), 33.8mmol, 33.8mmol), tetrahydrofuran (20ml) solution of di-tert-butyl dicarbonate (3.69g, 16.9mmol) is then added.After stirring 30 minutes to reaction mixture at room temperature, saturated aqueous ammonium chloride is added in the reactive mixture, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
By the residue obtained in the mixed solvent for being dissolved in tetrahydrofuran (50ml) and methanol (50ml), 1N sodium hydroxide (50ml) is added at room temperature.It is concentrated under reduced pressure after being stirred 2 hours in 50 DEG C to reaction mixture, product is extracted with dichloromethane.The mixed solvent of residue ethanol/hexane washs, leaching, obtains the title compound (3.49g, 9.41mmol, 61%) of white solid.Be concentrated under reduced pressure filtrate, it is residue obtained washed with ethyl alcohol/ether/hexane mixed solvent after leaching, obtain the title compound (828mg, 2.23mmol, 15%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:371 (M++H).
Reference example 48: dithiocarbonic acids S- (the chloro- 3- methoxyphenyl of 4-) ester 0- ethyl ester
The chloro- 3- aminoanisole (2.77g, 17.6mmol) of 4- is dissolved in 1N hydrochloric acid (80ml), after 0 DEG C is added dropwise water (10ml) solution of sodium nitrite (1.33g, 19.3mmol), is stirred 30 minutes at identical temperature.After reaction mixture is warming up to 60 DEG C, water (30ml) solution of dithiocarbonic acids O- ethyl ester potassium (3.10g, 19.3mmol) is added dropwise at the same temperature.After reaction mixture is warming up to 90 DEG C, stirring 1 hour, it is cooled to room temperature, saturated sodium bicarbonate aqueous solution is added, product is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, residue obtained to be handled with silica gel flash column chromatography.Be concentrated under reduced pressure by hexane: methylene chloride=9: the fraction that 1 elution portion obtains obtains the title compound (1.05g, 4.00mmol, 23%) in yellow oil.
1H-NMR (400MHz, CDCl3) (1H, d, the J=8.1Hz) of 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
MS m/z:263 (M++H).
The chloro- 4- of embodiment 237:[5- [(the chloro- 3- Methoxv-phenylsulfanvl of 4-) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate
1N sodium hydrate aqueous solution (5ml) is added in ethyl alcohol (5ml) solution of dithiocarbonic acids S- (the chloro- 3- methoxyphenyl of 4-) ester O- ethyl ester (394mg, 1.50mmol), is heated to reflux 1 hour.Reaction mixture is cooled to room temperature, after boiling off ethyl alcohol under decompression, is washed with methylene chloride.After so that water layer is in acid with acetic acid, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, obtain the chloro- 3- methoxybenzene thiol of 4- in colorless oil.
In [the chloro- 4- [(2 of 5- that 0 DEG C obtains in reference example 47,5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (371mg, mesyl chloride (0.155ml is added in dichloromethane solution 1.00mmol), 2.00mmol), add triethylamine (0.418ml, 3.00mmol), it stirs 2 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
Under nitrogen atmosphere, in residue obtained N, the N of the chloro- 3- methoxybenzene thiol of the 4- previously obtained is added in dinethylformamide (10ml) solution, dinethylformamide (5ml) solution, add potassium carbonate (207mg, 1.50mmol), it stirs 20 hours at room temperature.Ethyl acetate is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=19: the fraction that 1 elution portion obtains obtains the title compound (354mg, 0.67mmol, 67%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:527 (M++H).
The chloro- 4- of embodiment 238:[5- [(the chloro- 3- methoxy phenylsulfonyl of 4-) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate
In [the chloro- 4- of 5- [(the chloro- 3- Methoxv-phenylsulfanvl of 4-) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate (354mg, methanol (8ml), six ammonium tetrahydrate (166mg of 31% aqueous hydrogen peroxide solution (8ml) and seven molybdic acids are added in ethyl acetate (8ml) solution 0.67mmol), 0.13mmol), it stirs 20 hours at room temperature.In the reactive mixture plus water, saturated sodium bicarbonate aqueous solution is added after ethyl acetate and methanol are boiled off under decompression, product is extracted with dichloromethane.Organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering, it is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains, it is residue obtained washed with the mixed solvent of ether/hexane after leaching, obtain the title compound (308mg, 0.55mmol, 82%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:559 (M++H).
The chloro- 4- of embodiment 239:[5- [(the chloro- 3- methoxy phenylsulfonyl of 4-) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
In 0 DEG C; in [the chloro- 4- of 5- [(the chloro- 3- methoxy phenylsulfonyl of 4-) (2; 5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate (300mg; trifluoroacetic acid (5ml) is added in methylene chloride (5ml) solution 0.54mmol), stirs 2 hours at room temperature.After reaction mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride, is washed with 1N sodium hydrate aqueous solution.Organic layer is concentrated under reduced pressure filtrate after being dried, filtered with anhydrous sodium sulfate, it is residue obtained washed with ether after leaching, obtain the title compound (208mg, 0.45mmol, 84%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H14Cl2F2N2O3S: 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.
MS m/z:459 (M++H).
The chloro- 4- of embodiment 240:[5- [(2,5- difluorophenyl) (4- methoxy phenylsulfonyl) methyl] pyridine -2- base] amine
In 0 DEG C, in [the chloro- 4- [(2 of 5- that reference example 47 obtains, 5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (148mg, mesyl chloride (0.046ml is added in dichloromethane solution 0.40mmol), 0.60mmol), triethylamine (0.167ml, 1.20mmol) is added, is stirred 16 hours at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
Under nitrogen atmosphere, 4- methoxybenzene thiol (56mg, 0.40mmol) is first added in residue obtained n,N-Dimethylformamide (4ml) solution, adds potassium carbonate (66mg, 0.48mmol), stirs 19 hours at room temperature.Ethyl acetate is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.
Methanol (8ml), six ammonium tetrahydrate (99mg, 0.08mmol) of 31% aqueous hydrogen peroxide solution (4ml) and seven molybdic acids are added in residue obtained ethyl acetate (8ml) solution, stirs 20 hours at room temperature.In the reactive mixture plus water, saturated sodium bicarbonate aqueous solution is added after ethyl acetate and methanol are boiled off under decompression, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
In 0 DEG C, trifluoroacetic acid (3ml) is added in residue obtained methylene chloride (3ml) solution, stirs 2 hours at room temperature.After reaction mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride, is washed with saturated sodium bicarbonate aqueous solution.Organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering, it is handled with silica gel flash column chromatography residue obtained, it is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 2 elution portions obtain, it is residue obtained washed with the mixed solvent of ether/hexane after leaching, obtain the title compound (67mg, 0.16mmol, 40%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H15ClF2N2O3S: theoretical value: C, 53.71；H, 3.56；Cl, 8.34；F, 8.94；N, 6.59；S, 7.5
5. measured value: C, 53.53；H, 3.55；Cl, 8.34；F, 9.06；N, 6.31；S, 7.79.
MS m/z:425 (M++H).
The chloro- 4- of embodiment 241:[5- [(5- chloropyridine -2- base sulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
Using method same as embodiment 240, [the chloro- 4- [(2 of 5- obtained with reference example 47,5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (148mg, 0.40mmol) and reference example 17 obtain 5- Chloro-2-Pyridyle mercaptan (58mg, 0.40mmol), obtain the title compound (74mg, 0.17mmol, 43%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C17H11Cl2F2N3O2S: 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.
MS m/z:430 (M++H).
Embodiment 242:N- [the chloro- 4- of 5- [(5- chloropyridine -2- base sulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] Methanesulfomide
Under argon atmospher; in 0 DEG C in [the chloro- 4- of 5- [(5- chloropyridine -2- base sulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] amine (92mg; tetrahydrofuran solution (the 1M of bis- (trimethylsilyl) amido sodium is added in tetrahydrofuran (4ml) solution 0.21mmol); 0.705ml; 0.71mmol), it stirs 30 minutes.Then, mesyl chloride (0.055ml, 0.71mmol) is added, is warming up to room temperature after stirring 2 hours at the same temperature.Saturated aqueous ammonium chloride is added in the reactive mixture, product is extracted with ether.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.It is residue obtained to be handled with silica gel flash column chromatography.Be concentrated under reduced pressure by methylene chloride: ethyl acetate=19: the fraction that 1 elution portion obtains obtains the title compound (27mg, 0.053mmol, 25%) of white solid with the mixed solvent of ethanol/hexane to leaching after residue obtained wash.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H13Cl2F2N3O4S2: 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.
MS m/z:508 (M++H).
Reference example 49:5- chlorothiophene -2- mercaptan
In 75 DEG C, 1N hydrochloric acid (3ml) solution of stannous chloride (3.03g, 16.0mmol) is added in acetic acid (15ml) solution of 5- chlorothiophene -2- sulfonic acid chloride (0.557ml, 4.00mmol).Then, reaction mixture is cooled to room temperature, product after water is added to be extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer, in residue obtained middle addition toluene, is concentrated under reduced pressure again.It is residue obtained washed with ether after leaching, obtain be in yellow solid title compound (89mg, 0.65mmol, 16%).Be concentrated under reduced pressure filtrate, it is residue obtained wash with the mixed solvent of ether/hexane after leaching, obtain in yellow solid title compound (118mg, 0.78mmol, 20%).
1H-NMR (400MHz, CDCl3) δ: 6.81 (1H, d, J=3.9Hz), 6.85 (1H, d, J=3.9Hz)
The chloro- 4- of embodiment 243:[5- [(5- chlorothiophene -2- base sulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
Using method same as embodiment 240, [the chloro- 4- [(2 of 5- obtained with reference example 47,5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (148mg, 0.40mmol) and 5- chlorothiophene -2- mercaptan (90mg, 0.60mmol), obtain the title compound (96mg, 0.22mmol, 55%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C16H10Cl2F2N2O2S2: 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.
MS m/z:435 (M++H).
The chloro- 4- of embodiment 244:[5- [(6- chloropyridine -3- base sulfenyl) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate
Using method same as embodiment 237, dithiocarbonic acids S- (6- chloropyridine -3- base) the ester O- ethyl ester (187mg obtained with reference example 26,0.80mmol) and reference example 47 obtain [the chloro- 4- [(2 of 5-, 5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (151mg, 0.41mmol), obtain the title compound (190mg, 0.38mmol, 94%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:498 (M++H).
The chloro- 4- of embodiment 245:[5- [(6- chloropyridine -3- base sulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
At room temperature, in [the chloro- 4- of 5- [(6- chloropyridine -3- base sulfenyl) (2,5- difluorophenyl) methyl] pyridine -2- base] t-butyl carbamate (187mg, 3- chlorine benzylhydroperoxide (199mg is added in methylene chloride (5ml) solution 0.38mmol), 0.75mmol), it stirs 2 hours.After reaction mixture is washed with 1N sodium hydrate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
It is dissolved in methylene chloride (3ml) by residue obtained, in 0 DEG C of addition trifluoroacetic acid (3ml), is stirred 1 hour at room temperature.After reaction mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride, is washed with 1N sodium hydrate aqueous solution.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, residue obtained to be handled with silica gel flash column chromatography.Be concentrated under reduced pressure by hexane: ethyl acetate=3: 1 elution portion obtain fraction, it is residue obtained washed with the mixed solvent of ethanol/hexane after leaching, obtain the title compound (90mg, 0.21mmol, 55%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C17H11Cl2F2N3O2S: 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.
MS m/z:430 (M++H).
Embodiment 246:4- [(2- amino -5- chloropyridine -4- base) (2,5- difluorophenyl) methyl sulphonyl] benzonitrile
Using method same as embodiment 240, [the chloro- 4- [(2 of 5- obtained with reference example 47,5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (148mg, 0.40mmol) and 4- sulfydryl benzonitrile (56mg, 0.41mmol), obtain the title compound (99mg, 0.24mmol, 59%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C19H12ClF2N3O2S: 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.
MS m/z:420 (M++H).
The chloro- 4- of embodiment 247:[5- [(2,5- difluorophenyl) (3,4- difluorophenyl sulfonyl) methyl] pyridine -2- base] amine
Using method same as embodiment 240, [the chloro- 4- [(2 of 5- obtained with reference example 47,5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (185mg, 0.50mmol) and 3,4- difluoro benzenethiol (84mg, 0.55mmol) obtains the title compound (59mg of white solid, 0.14mmol, 27%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H11ClF4N2O2S: 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.
MS m/z:431 (M++H).
Embodiment 248:N- [the chloro- 4- of 5- [(2,5- difluorophenyl) (3,4- difluorophenyl sulfonyl) methyl] pyridine -2- base]-N- (methyl sulphonyl) Methanesulfomide
Under nitrogen atmosphere; in 0 DEG C in [the chloro- 4- [(2 of 5-; 5- difluorophenyl) (3; 4- difluorophenyl sulfonyl) methyl] pyridine -2- base] amine (63mg; mesyl chloride (0.034ml, 0.44mmol), triethylamine (0.062ml, 0.44mmol) and 4-dimethylaminopyridine (4mg are added in methylene chloride (3ml) solution 0.15mmol); 0.03mmol), it stirs 17 hours at room temperature.After reaction mixture 1N salt acid elution, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains obtains the title compound (73mg, 0.12mmol, 85%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:587 (M++H).
Embodiment 249:N- [the chloro- 4- of 5- [(2,5- difluorophenyl) (3,4- difluorophenyl sulfonyl) methyl] pyridine -2- base] Methanesulfomide
Under nitrogen atmosphere; in N- [the chloro- 4- [(2 of 5-; 5- difluorophenyl) (3; 4- difluorophenyl sulfonyl) methyl] pyridine -2- base]-N- (methyl sulphonyl) Methanesulfomide (72mg; tetrahydrofuran solution (the 1M of tetrabutylammonium is added in tetrahydrofuran (2ml) solution 0.12mmol); 0.147ml, 0.15mmol), it stirs 2 hours at room temperature.After reaction mixture is concentrated under reduced pressure, it is dissolved in ethyl acetate by residue obtained, first uses 1N salt acid elution, then washed with saturated aqueous ammonium chloride.Organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering, it is residue obtained to be handled with flashchromatography on silica gel, it is concentrated under reduced pressure by hexane: ethyl acetate=3: the fraction that 1 elution portion obtains, it is residue obtained washed with the mixed solvent of ether/hexane after leaching, obtain the title compound (53mg, 0.10mmol, 84%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:509 (M++H).
FAB-MS:509.0044 (presses C19H14ClF4N2O4S2It calculates: 509.0020)
Reference example 50: dithiocarbonic acids O- ethyl ester S- (6- trifluoromethyl pyridine -3- base) ester
By 6- trifluoromethyl pyridine -3- base amine (1.00g, 6.02mmol) it is dissolved in 1N hydrochloric acid (15ml) and methanol (3ml), in water (3ml) solution of -10 DEG C of dropwise addition sodium nitrites (506mg, 7.22mmol).Reaction mixture instillation is heated up to water (15ml) solution of 65 DEG C of dithiocarbonic acids O- ethyl ester potassium (1.93g, 12.0mmol), is stirred 30 minutes at identical temperature.After reaction mixture is cooled to room temperature, product is extracted with ethyl acetate, then with saturated common salt water washing.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=100: the fraction that 1 elution portion obtains obtains the title compound (895mg, 3.35mmol, 56%) in yellow oil.
1H-NMR (400MHz, CDCl3) (1H, d, the J=2.0Hz) of 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
MS m/z:268 (M++H).
The chloro- 4- of embodiment 250:[5- [(2,5- difluorophenyl) (6- trifluoromethyl pyridine -3- base sulfonyl) methyl] pyridine -2- base] amine
1N sodium hydrate aqueous solution (2ml) is added in ethyl alcohol (2ml) solution of dithiocarbonic acids O- ethyl ester S- (6- trifluoromethyl pyridine -3- base) ester (160mg, 0.60mmol), is stirred 2 hours in 65 DEG C.Reaction mixture is cooled to room temperature Hou Jiashui, is washed with methylene chloride.After so that water layer is in acid with 1N hydrochloric acid, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, obtain the 6- trifluoromethyl pyridine -3- mercaptan in colorless oil.
At room temperature, in [the chloro- 4- [(2 of 5- that reference example 47 obtains, 5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (185mg, mesyl chloride (0.077ml is first added in dichloromethane solution 0.50mmol), 1.00mmol), triethylamine (0.279ml, 2.00mmol) is added, is stirred 1 hour at room temperature.After reaction mixture is washed with saturated sodium bicarbonate aqueous solution, filtrate is concentrated under reduced pressure after being dried, filtered with colourless sodium sulphate in organic layer.
Under nitrogen atmosphere, in residue obtained N, the N of the 6- trifluoromethyl pyridine -3- mercaptan previously obtained is added in dinethylformamide (5ml) solution, dinethylformamide (5ml) solution, add potassium carbonate (104mg, 0.75mmol), it stirs 15 hours at room temperature.Ethyl acetate is added in the reactive mixture, first uses saturated sodium bicarbonate aqueous solution, then with after saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
Methanol (10ml), six ammonium tetrahydrate (99mg, 0.08mmol) of 31% aqueous hydrogen peroxide solution (5ml) and seven molybdic acids are added in residue obtained ethyl acetate (10ml) solution, is stirred 4 hours in 50 DEG C.After in the reactive mixture plus boiling off ethyl acetate and methanol under water decompression, saturated sodium bicarbonate aqueous solution is added, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains.
In 0 DEG C, trifluoroacetic acid (5ml) is added in residue obtained methylene chloride (5ml) solution, stirs 2 hours at room temperature.After reaction mixture is concentrated under reduced pressure, residue is dissolved in methylene chloride, is washed with saturated sodium bicarbonate aqueous solution.Organic layer is dry with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure after filtering, it is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, it is residue obtained washed with the mixed solvent of ethanol/hexane after leaching, obtain the title compound (75mg, 0.16mmol, 32%) of white solid.
1H-NMR (400MHz, CDCl2) 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 DEG C of
Elemental analysis: C18H11ClF5N3O2S·0.25H2O: 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.
MS m/z:464 (M++H).
Reference example 51: dithiocarbonic acids S- (the chloro- 3- fluorophenyl of 4-) ester O- ethyl ester
The title compound (379mg, 1.51mmol, 38%) in yellow oil is obtained using the chloro- 3- fluoroaniline (582mg, 4.00mmol) of 4- according to method same as reference example 50.
1H-NMR (400MHz, CDCl3) 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)
The chloro- 4- of embodiment 251:[5- [(the chloro- 3- fluorophenylSulphonyl of 4-) (2,5- difluorophenyl) methyl] pyridine -2- base] amine
According to method same as embodiment 250, by dithiocarbonic acids S- (the chloro- 3- fluorophenyl of 4-) O- ethyl ester (150mg, 0.60mmol) and reference example 47 obtain [the chloro- 4- [(2 of 5-, 5- difluorophenyl) (hydroxyl) methyl] pyridine -2- base] t-butyl carbamate (185mg, 0.50mmol), obtain the title compound (78mg, 0.17mmol, 35%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C18H11Cl2F3N2O2S: 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.
MS m/z:447 (M++H).
Embodiment 252:(E) -3- [4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] methyl acrylate
Under argon atmospher; in [4- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 200 obtains; 5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] formaldehyde (300mg; triphenylphosphoroanylidene methyl acetate (259mg is added in tetrahydrofuran (5ml) solution 0.705mmol); 0.775mmol), it stirs 6 hours at room temperature.Reaction solution is concentrated under reduced pressure, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (303mg, 0.629mmol, 89%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:482 (M++H).
Embodiment 253:3- [4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] methyl propionate
First Raney nickel suspension (day emerging リ カ Co., Ltd., R-100) is washed with ethyl alcohol again with water, forms alcohol suspending liquid.(E) -3- [4- [(4- Chlorophenylsulfonyl) (2 is added in gained alcohol suspending liquid (1ml); 5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] methyl acrylate (290mg; ethyl alcohol (6ml) and 1 0.602mmol); in the mixed solution of 4- dioxanes (4ml), high degree of agitation 30 minutes under the nitrogen atmosphere of 1 air pressure.It is concentrated under reduced pressure after filtering reacting solution, is dissolved in methylene chloride for residue obtained, it is dry with anhydrous magnesium sulfate, then it is concentrated under reduced pressure.It is residue obtained to be washed with hexane, obtain the title compound (252mg, 0.521mmol, 87%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:484 (M++H).
Embodiment 254:3- [4- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] propionic acid
In 3- [4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -5- fluorine pyridine -2- base] methyl propionate (150mg; 1N sodium hydrate aqueous solution (2ml) is added in the mixed solution of methanol (2ml) and tetrahydrofuran (2ml) 0.310mmol), stirs 10 minutes at room temperature.1N hydrochloric acid is added in reaction solution to be extracted with dichloromethane after keeping its weakly acidic.It is concentrated under reduced pressure after organic layer magnesium sulfate drying, obtains the title compound (145mg, 0.310mmol, quantitative) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:470 (M++H).
Elemental analysis: C21H15ClF3NO4S·0.75H2O: 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.
The chloro- 4- of the bromo- 5- of reference example 52:2- [(2,5- difluorophenyl) hydroxymethyl] pyridine
In -78 DEG C, under an argon, n-BuLi (1.58M hexane solution, 88ml, 138mmol) is added in tetrahydrofuran (200ml) solution of diisopropylamine (21ml, 150mmol), stirs 1 hour.Tetrahydrofuran (100ml) solution that the bromo- 5- chloropyridine (19g, 98.7mmol) of 2- is instilled in reaction solution, is stirred 1.5 hours.It instills 2,5- difluorobenzaldehyde (16ml, 148mmol), stirs 2 hours in reaction solution.It is concentrated under reduced pressure, is extracted with dichloromethane in reaction solution plus after water.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=6: the fraction that 1 elution portion obtains obtains the title compound (24.8g, 74.1mmol, 75%) in pale yellow powder.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
MS m/z:334 (M++H).
The chloro- 4- of the bromo- 5- of embodiment 255:2- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine
Under argon atmospher, in the chloro- 4- [(2 of the bromo- 5- of 2- under ice-cold, 5- difluorophenyl) hydroxymethyl] pyridine (4.12g, triethylamine (2.6ml is added in dichloromethane solution (80ml) 12.3mmol), 18.5mmol) and mesyl chloride (1.3ml, 16.0mmol), it stirs 1.5 hours at room temperature.It is extracted after saturated sodium bicarbonate aqueous solution is added in reaction solution with ether.Solution saturated common salt water washing, with the lower concentrate solution of decompression after anhydrous magnesium sulfate drying.
4- chlorobenzenethiol (2.1g, 14.8mmol) and potassium carbonate (2.6g, 18.5mmol) are added in dimethylformamide (40ml) solution of residue, is stirred 4 hours in 50 DEG C.After being cooled to room temperature, reaction solution is diluted with ether, successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=10: the fraction that 1 elution portion obtains obtains the title compound (3.3g, 7.16mmol, 58%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:460 (M++H).
The chloro- 4- of embodiment 256:[5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methanol
In -78 DEG C, under an argon, in the bromo- 5- of 2- chloro- 4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine (200mg, n-BuLi (1.58M hexane solution is added in toluene (5ml) solution 0.434mmol), 0.33ml, 0.520mmol), it stirs 2 hours.Dimethylformamide (44 μ l, 0.564mmol) is instilled in reaction solution, is stirred 1 hour.Methanol (5ml) and sodium borohydride (33mg, 0.868mmol) are added in reaction solution, is stirred 2 hours after being warming up to room temperature.It is extracted with ethyl acetate in reaction solution plus after water, then with saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (142mg, 0.344mmol, 80%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:412 (M++H).
The chloro- 4- of embodiment 257:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methanol
In [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methanol (130mg, seven molybdic acids, six ammonium tetrahydrate (20mg), 30% aqueous hydrogen peroxide solution (3ml) are added in methanol (5ml) solution 0.315mmol), stirs 6 hours.It is extracted with ethyl acetate in reaction solution plus after water, successively uses water, saturated sodium bicarbonate aqueous solution, saturated aqueous sodium thiosulfate and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.It is residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains, with hexane: re-crystallizing in ethyl acetate obtains the title compound (10lmg of white powder, 0.227mmol, 72%).
1H-NMR (400MHz, CDCl3) 8.3.22 (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 DEG C of
MS m/z:444 (M++H).
Elemental analysis: C19H13Cl2F2NO3S: 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.
The chloro- 4- of embodiment 258:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] formaldehyde
Under nitrogen atmosphere; in [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] methanol (1.0g; dimethyl sulfoxide (880 μ l are added in methylene chloride (25ml) solution 2.25mmol); 11.3mmol), triethylamine (1.14ml; 11.3mmol), sulfur trioxide pyridine complex salt (1.07g, 6.75mmol) is stirred 18 hours at room temperature.Reaction solution is concentrated under reduced pressure, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains obtains the title compound (770mg, 1.74mmol, 77%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:442 (M++H).
Embodiment 259:(E) -3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methyl acrylate
Under argon atmospher; in [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] formaldehyde (760mg; triphenylphosphoroanylidene methyl acetate (632mg is added in tetrahydrofuran (15ml) solution 1.72mmol); 1.89mmol), it stirs 3 hours at room temperature.Reaction solution is concentrated under reduced pressure, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (776mg, 1.56mmol, 91%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:498 (M++H).
Embodiment 260:3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] methyl propionate
First Raney nickel suspension (day emerging リ カ Co., Ltd., R-100) is washed with ethyl alcohol again with water, forms alcohol suspending liquid.(E) -3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2 is added in gained alcohol suspending liquid (1ml); 5- difluorophenyl) methyl] pyridine -2- base] methyl acrylate (770mg; ethyl alcohol (10ml) and 1 1.55mmol); in the mixed solution of 4- dioxanes (5ml), high degree of agitation 30 minutes under the nitrogen atmosphere of 1 air pressure.It is concentrated under reduced pressure after filtering reacting solution, is dissolved in methylene chloride (15ml) for residue obtained, with being concentrated under reduced pressure after magnesium sulfate drying, obtain the title compound (720mg, 1.44mmol, 93%) of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:500 (M++H).
Embodiment 261:3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] propionic acid
In 3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] methyl propionate (200mg; 1N sodium hydrate aqueous solution (2ml) is added in the mixed solution of methanol (2ml) and tetrahydrofuran (2ml) 0.400mmol), stirs 1 hour at room temperature.1N hydrochloric acid is added in reaction solution, makes to be extracted with dichloromethane after its is weakly acidic.It is concentrated under reduced pressure after organic layer magnesium sulfate drying, with hexane: re-crystallizing in ethyl acetate obtains the title compound (161mg, 0.331mmol, 83%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:486 (M++H).
Elemental analysis: C21H15Cl2F2NO4S: 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.
The chloro- 4- of embodiment 262:5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine carboxylic acid
In [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 258 obtains; 5- difluorophenyl) methyl] pyridine -2- base] formaldehyde (150mg; 30% aqueous hydrogen peroxide solution (115 μ l are added in formic acid (3ml) solution 0.339mmol); 1.02mmol), it stirs 3 hours at room temperature.Add water in reaction solution, filters the solid of precipitation, solid is washed with water.So that obtained solid is dissolved in ethyl acetate, successively uses water and saturated common salt water washing.It is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to use hexane: re-crystallizing in ethyl acetate obtains the title compound (88mg, 0.192mmol, 57%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:458 (M++H).
Elemental analysis: C19H11Cl2F2NO4S: 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.
The chloro- 4- of the bromo- 5- of embodiment 263:2- [(2,5- difluorophenyl) (4- trifluoromethylphenylthio) methyl] pyridine
Under nitrogen atmosphere, in the chloro- 4- [(2 of the bromo- 5- of 2- that reference example 52 obtains, 5- difluorophenyl) hydroxymethyl] pyridine (1.34g, mesyl chloride (0.619ml is added in dichloromethane solution 4.00mmol), 8.00mmol), triethylamine (2.23ml, 16.0mmol) is added, is stirred 1 hour at room temperature.After reaction mixture first uses saturated common salt water washing with water again, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.
Under nitrogen atmosphere, 4- trifluoro benzenethiol (784mg, 4.40mmol) is added in residue obtained n,N-Dimethylformamide (60ml) solution, adds potassium carbonate (663mg, 4.80mmol), stirs 17 hours at room temperature.Ethyl acetate is added in the reactive mixture, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer after being washed with saturated sodium bicarbonate aqueous solution.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=50: the fraction that 1 elution portion obtains obtains the title compound (1.33g, 2.69mmol, 67%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:494,496 (M++H).
Embodiment 264:(E) -3- [the chloro- 4- of 5- [(2,5- difluorophenyl) (4- trifluoromethylphenylthio) methyl] pyridine -2- base] methyl acrylate
Under argon atmospher, in -78 DEG C in the chloro- 4- [(2 of the bromo- 5- of 2-, 5- difluorophenyl) (4- trifluoromethylphenylthio) methyl] pyridine (396mg, hexane solution (the 1.59M of n-BuLi is added in toluene (12ml) solution 0.80mmol), 0.604ml, 0.96mmol), it stirs 30 minutes.N,N-Dimethylformamide (0.081ml, 1.04mmol) is added at the same temperature, stirs 30 minutes.Saturated aqueous ammonium chloride is added in the reactive mixture, adds water, after being warming up to room temperature, product is extracted with ether.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, residue obtained to be handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains obtains aldehyde body (186mg).
Aldehyde body (133mg) is dissolved in tetrahydrofuran (2ml), triphenylphosphoroanylidene methyl acetate (120mg, 0.36mmol) is added at room temperature, is stirred 18 hours at identical temperature.Residue obtained to be handled with silica gel flash column chromatography after reaction mixture is concentrated under reduced pressure, be concentrated under reduced pressure by hexane: ethyl acetate=19: the fraction that 1 elution portion obtains obtains the title compound (132mg, 0.26mmol, 46%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:500 (M++H).
Embodiment 265:(E) -3- [the chloro- 4- of 5- [(2,5- difluorophenyl) (4- trifluoromethyl sulfonyl) methyl] pyridine -2- base] methyl acrylate
In (E) -3- [chloro- 4- [(2 of 5-, 5- difluorophenyl) (4- trifluoromethylphenylthio) methyl] pyridine -2- base] methyl acrylate (118mg, methanol (6ml), six ammonium tetrahydrate (58mg of 31% aqueous hydrogen peroxide solution (6ml) and seven molybdic acids are added in ethyl acetate (6ml) solution 0.24mmol), 0.05mmol), it stirs 11 hours at room temperature.In the reactive mixture plus water, after ethyl acetate and methanol are boiled off under decompression, saturated salt solution is added, product is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, residue obtained to be handled with silica gel flash column chromatography.Be concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains obtains the title compound (111mg, 0.21mmol, 88%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:532 (M++H).
Embodiment 266:3- [the chloro- 4- of 5- [(2,5- difluorophenyl) (4- trifluoromethyl sulfonyl) methyl] pyridine -2- base] methyl propionate
By (E) -3- [chloro- 4- of 5- [(2; 5- difluorophenyl) (4- trifluoromethyl sulfonyl) methyl] pyridine -2- base] methyl acrylate (110mg; 0.21mmol) it is dissolved in the mixed solvent of ethyl acetate (3ml) and methanol (3ml); 10% palladium-carbon catalyst (60mg) is added, is stirred at room temperature under a hydrogen atmosphere 2 hours.With filtrate is concentrated under reduced pressure after diatomite Filtration of catalyst, residue obtained to be handled with silica gel flash column chromatography, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (94mg of white solid, 0.18mmol, 85%).
1H-NMR (400MHz, CDCl3) 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)
MS m/z:534 (M++H).
Embodiment 267:3- [the chloro- 4- of 5- [(2,5- difluorophenyl) (4- trifluoromethyl sulfonyl) methyl] pyridine -2- base] propionic acid
In 0 DEG C; in 3- [the chloro- 4- [(2 of 5-; 5- difluorophenyl) (4- trifluoromethyl sulfonyl) methyl] pyridine -2- base] methyl propionate (92mg; after methanol (2ml) and 1N sodium hydrate aqueous solution (2ml) is added in tetrahydrofuran (2ml) solution 0.17mmol), stir 2 hours at room temperature.1N hydrochloric acid is added in the reactive mixture, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, residue obtained leaching after ethanol washing obtains the title compound (61mg, 0.12mmol, 68%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C of
Elemental analysis: C22H15ClF5NO4S: 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.
MS m/z:520 (M++H).
Embodiment 268:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -1- methyl-1 H- imidazoles -4- sulfonamide
In [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (93mg; 0.217mmol) and pyridine (21 μ l; 1- methyl-1 H- imidazoles -4- sulfonic acid chloride (47mg is added in methylene chloride (5ml) solution 0.260mmol); 0.260mmol), it stirs 18 hours at room temperature.Pyridine (1ml) is added in reaction solution, is concentrated under reduced pressure after stirring 7 hours at room temperature.Ethyl acetate is added in gained concentrated residue, successively uses saturated sodium bicarbonate aqueous solution and saturated common salt water washing, with filtering after anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Gained concentration filtrate is handled with silica gel column chromatography, is concentrated under reduced pressure by methanol: the fraction that methylene chloride (=1: 50) eluent obtains obtains white solid.Leaching after gained white solid ethanol washing obtains the title compound (68mg, 0.119mmol, 55%) of white powder.
1H-NMR (400MHz, DMSO-d6) 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 DEG C
IR(ATR)cm-1: 1594,1562,1494,1382,1332,1159,1118,993,817,755,723.
MS m/z:572 (M+).
EI-MS:571.9962 (presses C22H16O4N4Cl2F2S2It calculates: 571.9958)
Elemental analysis: C22H16N4O4Cl2F2S2: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -1- pyridin-4-yl Methanesulfomide
In [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (104mg; 0.242mmol) and pyridine (74 μ l; (4- pyridylmethyl) sulfonic acid chloride fluoroform sulphonate (91mg is added in methylene chloride (2ml) solution 0.533mmol); 0.266mmol), it stirs 17 hours at room temperature.Pyridine (74 μ l, 0.533mmol) and (4- pyridylmethyl) sulfonic acid chloride fluoroform sulphonate (91mg, 0.266mmol) are added in reaction solution, stirs 19 hours at room temperature.Reaction solution is diluted with ethyl acetate, and after water and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 40) obtains obtains the title compound (66mg, 0.113mmol, 47%) of white solid.
1H-NMR (400MHz, DMSO-d6) 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 DEG C (decomposition)
IR(ATR)cm-1: 1592,1490,1467,1340,1326,1280,1238,1186,1155,1128,1085,1004,966,902,869,823.MS m/z:584 (M++H).
Elemental analysis: C24H17N3O4Cl2F2S2: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] piperidines -1- sulfonamide
In 70 DEG C; [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 is obtained; 5- difluorophenyl) methyl] pyridine -2- base] amine (101mg; 0.235mmol) and pyridine (2ml) solution of piperidines -1- sulfonic acid chloride (48mg, 0.259mmol) stirs 19 hours.Piperidines -1- sulfonic acid chloride (48mg, 0.259mmol) is added in reaction solution, is stirred 4 days in 70 DEG C.The temperature of reaction solution is concentrated under reduced pressure after returning back to room temperature.After gained concentrated residue is diluted with ethyl acetate, with water and saturated common salt water washing, then with anhydrous sodium sulfate it is dry after filter, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=4: 1) obtains obtains white solid.Leaching after obtained solid is washed with hexane-ether obtains the title compound (63mg, 0.109mmol, 47%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C
IR(ATR)cm-1: 1598,1563,1492,1396,1346,1322,1234,1145,1083,998,923,900,833.
MS m/z:576 (M++H).
Elemental analysis: C23H21N3O4Cl2F2S2: 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；C1,12.12；F, 6.66；S, 11.25.
Embodiment 271:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -4- methyl piperidine -1- sulfonamide
[the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 is obtained; 5- difluorophenyl) methyl] pyridine -2- base] amine (101mg; 0.235mmol), 4- methyl piperazine -1- sulfonyl chloride hydrochloride (126mg; 0.534mmol) and acetonitrile (5ml) solution of triethylamine (150 μ l, 1.07mmol) is heated to reflux 23 hours.4- methyl piperazine -1- sulfonyl chloride hydrochloride (126mg, 0.534mmol) and triethylamine (150 μ l, 1.07mmol) are added in reaction solution, is heated to reflux 22 hours.The temperature of reaction solution is concentrated under reduced pressure after returning back to room temperature.Add water in gained concentrated residue, is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure with filtering after anhydrous sodium sulfate drying in organic layer saturated common salt water washing.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 20) obtains obtains the title compound (34mg, 0.057mmol, 16%) in faint yellow solid.
1H-NMR (400MHz, CDCl3) 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 DEG C
IR(ATR)cm-1: 1600,1565,1496,1392,1348,1330,1157,1093,935,835,819.MS m/z:591 (M++H).
Elemental analysis: C23H22N4O4Cl2F2S2: 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.
The chloro- N- of embodiment 272:3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base]-N- (3- chloropropyl sulfonyl) propane -1- sulfonamide
In 0 DEG C; in [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (130mg; 0.303mmol) and triethylamine (42 μ l; the third sulfonic acid chloride of 3- chlorine (37 μ l, 0.303mmol) is added in methylene chloride (5ml) solution 0.303mmol).After stirring 2.5 hours to reaction solution at room temperature, triethylamine (42 μ l, 0.303mmol) and the third sulfonic acid chloride of 3- chlorine (37 μ l, 0.303mmol) are sequentially added in 0 DEG C.Reaction solution is stirred 7 hours at room temperature.Ethyl acetate is added in reaction solution, is washed with saturated sodium bicarbonate aqueous solution, with filtering after anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=5: 1) obtains.Ether is added in gained concentrated residue, the solid that leaching is precipitated obtains the title compound of white powder.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:709,711 (M++H).
The chloro- N- of embodiment 273:3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] propane -1- sulfonamide
In the chloro- N- of 3- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base]-N- (3- chloropropyl sulfonyl) propane -1- sulfonamide (193mg; tetrahydrofuran solution (the 1.0M of tetrabutylammonium is added in tetrahydrofuran (5ml) solution 0.272mmol); 0.28ml; 0.28mmol), it stirs 1 hour at room temperature.Saturated aqueous ammonium chloride is added in reaction solution, is extracted with ethyl acetate.Organic layer saturated common salt water washing, is concentrated under reduced pressure filtrate after being dried, filtered with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=4: 1) obtains obtains the title compound (108mg, 0.190mmol, 70%) of white solid.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:568,570 (M+).
The chloro- 4- of embodiment 274:5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] -2- (- 1 λ of 1,1- dioxo6Isothiazolidine -2- base) pyridine
In 70 DEG C of N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyls) (2 chloro- to 3-; 5- difluorophenyl) methyl] pyridine -2- base] propane -1- sulfonamide (83mg; 0.146mmol) and 1; acetonitrile (5ml) solution of 8- diazabicylo [5.4.0] -7- hendecene (26 μ l, 0.175mmol) stirs 4.5 hours.It is concentrated under reduced pressure after so that the temperature of reaction solution is returned back to room temperature.Gained concentrated residue is diluted with ethyl acetate, and successively with after 1N hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=1: 1) obtains obtains the title compound (75mg, 0.141mmol, 96%) of white solid.
1H-NMR (400MHz, CDCl3) 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 DEG C
IR(ATR)cm-1: 1587,1496,1467,1386,1346,1315,1278,1238,1137,1089,998,831.
MS m/z:532 (M+).
Elemental analysis: C21H16N2O4Cl2F2S2: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base]-N- (trifluoromethyl sulfonyl) trifluoro Methanesulfomide
In 0 DEG C; in [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (103mg; 0.240mmol) and pyridine (19 μ l; trifluoromethanesulfanhydride anhydride (39 μ l, 0.240mmol) is added in methylene chloride (5ml) solution 0.240mmol).After being stirred 3 hours to reaction solution at room temperature, in 0 DEG C of addition pyridine (19 μ l, 0.240mmol) and trifluoromethanesulfanhydride anhydride (39 μ l, 0.240mmol).It is concentrated under reduced pressure after being stirred 15 hours to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=5: 1) obtains obtains the title compound (84mg, 0.120mmol, 50%) of white powder.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
IR(ATR)cm-1: 158l, 1498,1442,1332,1214,1159,1122,1085,997,944,923,865,755.
MS m/z:693 (M++H).
Embodiment 276:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] trifluoro Methanesulfomide
In N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base]-N- (trifluoromethyl sulfonyl) trifluoro Methanesulfomide (77mg; lithium hydroxide monohydrate (5.0mg is added in tetrahydrofuran (5ml) and water (1ml) mixed solution 0.111mmol); 0.111mmol), it stirs 5 hours at room temperature.Saturated aqueous ammonium chloride is added in reaction solution, is extracted with ethyl acetate.Filtrate is concentrated under reduced pressure after being dried, filtered after organic layer saturated common salt water washing with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel column chromatography, and the hexane by containing 0.5% trifluoroacetic acid: the fraction that the eluent of ethyl acetate (=2: 1) obtains is concentrated under reduced pressure.Ether is added in gained concentrated residue, the solid that leaching is precipitated obtains the title compound (39mg, 0.069mmol, 63%) of white powder.
1H-NMR (400MHz, CDCl3) δ: 6.21 (1H, s), 6.95-7.03 (1Hm), 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 DEG C
IR(ATR)cm-1: 1637,1496,1382,1336,1195,1157,1130,1085,1010,923,779,754.
MS m/z:560 (M+).
Elemental analysis: C19H11N2O4Cl2F5S2: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] ethenesulfonamide
In [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (982mg; 2.29mmol) and 2- chloro-ethane-sulfonyl chloride (0.29ml; pyridine (0.44ml, 5.49mmol) is added in methylene chloride (10ml) solution 2.74mmol).After stirring 3.5 hours to reaction solution at room temperature, 2- chloro-ethane-sulfonyl chloride (143 μ l, 1.37mmol) and pyridine (222 μ l, 2.75mmol) is added.Reaction solution is stirred 1 hour at room temperature.Ethyl acetate is added in reaction solution, is washed with saturated sodium bicarbonate aqueous solution, with filtering after anhydrous sodium sulfate drying, filtrate is concentrated under reduced pressure.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=3: 1) obtains obtains the title compound (573mg, 1.10mmol, 48%) of white solid.
1H-NMR (400MHz, CDCl3) 6:6.17-6.25 (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.
MS m/z:519 (M++H).
Embodiment 278:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -2- piperidin-1-yl ethyl sulfonamide
In N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] ethenesulfonamide (34mg; piperidines (10 μ l, 0.098mmol) is added in ethyl alcohol (5ml) solution 0.065mmol).It is concentrated under reduced pressure after being stirred 3 days to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 30) obtains obtains the title compound (35mg, 0.058mmol, 89%) in amorphous substance.Leaching after ethyl alcohol solidifies is added in gained amorphous substance, obtains the title compound of white powder
1H-NMR (400MHz, CDCl3) 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 DEG C
IR(ATR)cm-1: 1600,1571,1492,1390,1332,1141,1083,1002,962,919,811,754.
MS m/z:604 (M++H).
Elemental analysis: C25H25N3O4Cl2F2S2: 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- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -2- (dimethylamino) ethyl sulfonamide
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 277 obtains; 5- difluorophenyl) methyl] pyridine -2- base] ethenesulfonamide (64mg; tetrahydrofuran solution (the 2M of dimethylamine is added in tetrahydrofuran (3ml) solution 0.123mmol); 0.18ml, 0.36mmol).It is concentrated under reduced pressure after being stirred 3 days to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 20) obtains obtains the title compound (67mg, 0.117mmol, 97%) of white solid.Leaching after obtained solid ethanol washing obtains the title compound (43mg) of white powder.
1H-NMR (400MHz, CD3OD) 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.
MS m/z:564 (M++H).
FAB-MS:564.0399 (presses C22H22O4N3Cl2F2S2It calculates: 564.0397)
Embodiment 280:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -2- morpholine -4- base ethyl sulfonamide
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 277 obtains; 5- difluorophenyl) methyl] pyridine -2- base] ethenesulfonamide (53mg; morpholine (18 μ l, 0.204mmol) is added in ethyl alcohol (3ml) solution 0.102mmol).It is concentrated under reduced pressure after being stirred 3 days to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 40) obtains.Ether is added in resulting concentrated residue, the solid that leaching is precipitated obtains the title compound (45mg, 0.074mmol, 73%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C
IR(ATR)cm-1: 1602,1565,1492,1388,1321,1286,1238,1147,1116,1083,998
MS m/z:606 (M++H).
FAB-MS:606.0499 (presses C24H24O5N3Cl2F2S2It calculates: 606.0503)
Elemental analysis: C24H23N3O5Cl2F2S2: 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- [[[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] ethyl] piperazine -1- carboxylic acid tert-butyl ester
In N- [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 277 obtains; 5- difluorophenyl) methyl] pyridine -2- base] ethenesulfonamide (59mg; 1- (tert-butoxycarbonyl) piperazine (32mg, 0.170mmol) is added in ethyl alcohol (3ml) solution 0.114mmol).It is concentrated under reduced pressure after being stirred 3 days to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 40) obtains obtains the title compound (75mg, 0.106mmol, 93%) in amorphous substance.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:705 (M++H).
Embodiment 282:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -2- piperazine -1- base ethyl sulfonamide
In 4- [2- [[[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] ethyl] piperazine -1- carboxylic acid tert-butyl ester (72mg, 0.102mmol) ethyl alcohol (5ml) solution in be added concentrated hydrochloric acid (1ml).It is concentrated under reduced pressure after being stirred 2 days to gained reaction solution at room temperature.Saturated sodium bicarbonate aqueous solution is added in gained concentrated residue, is extracted with dichloromethane.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in organic layer.Gained concentrated residue is washed with ether, obtains the title compound (23mg, 0.038mmol, 37%) of white powder.
1H-NMR (400MHz, DMSO-d6) 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)
MS m/z:605 (M++H).
The chloro- 4- of embodiment 283:[[[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] ethyl acetate
In 0 DEG C; in [the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 196 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amine (331mg; 0.771mmol) and pyridine (94 μ l; methylene chloride (2ml) solution of chlorine sulphonyl ethyl acetate (216mg, 1.16mmol) is added in methylene chloride (10ml) solution 1.16mmol).After stirring 12 hours to reaction solution at room temperature, methylene chloride (2ml) solution of pyridine (94 μ l, 1.16mmol), chlorine sulphonyl ethyl acetate (216mg, 1.16mmol) is sequentially added in 0 DEG C.It is concentrated under reduced pressure after being stirred 9 hours to reaction solution at room temperature.Ethyl acetate is added in gained concentrated residue, filtrate successively is concentrated under reduced pressure with after being dried, filtered after saturated sodium bicarbonate aqueous solution and saturated common salt water washing with anhydrous sodium sulfate.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that the eluent of ethyl acetate (=3: 1) obtains obtains the title compound (239mg, 0.412mmol, 53%) of white solid.
1H-NMR (400MHz, CDCl3) 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.
MS m/z:579 (M++H).
Embodiment 284:N- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] -2- hydroxyl ethyl sulfonamide
In 0 DEG C; in [[[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] and ethyl acetate (67mg, 0.116mmol) tetrahydrofuran (5ml) solution in be added 1M lithium aluminium hydride reduction diethyl ether solution (0.18ml).Reaction solution is stirred in 0 DEG C, after reaction with TLC confirmation, saturated aqueous ammonium chloride is added.Mixed solution is filtered with diatomite.Filtrate is concentrated under reduced pressure after being dried, filtered with anhydrous sodium sulfate in filtrate.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by hexane: the fraction that ethyl acetate (=2: 1) eluent obtains obtains the title compound (39mg, 0.073mmol, 63%) of white solid.1H-NMR (400MHz, DMSO-d6) 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 DEG C
IR(ATR)cm-1: 3093,2867,1600,1565,1492,1392,1322,1139,1083,813,754.MS m/z:536 (M+).
EI-MS.535.9835(C20H16O5N2Cl2F2S2, calculated value: 535.9846)
Elemental analysis: C20H16N2O5Cl2F2S2·0.5H2O: 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- [[[the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] acetamide
[[[chloro- [(the 4- Chlorophenylsulfonyl) (2 of 5- that embodiment 283 obtains is added in the methanol solution (5ml) of 7N ammonium hydroxide; 5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] ethyl acetate (78mg, 0.135mmol).It is concentrated under reduced pressure after being stirred 3 days to reaction solution at room temperature.Gained concentrated residue is handled with silica gel flash column chromatography, is concentrated under reduced pressure by methanol: the fraction that the eluent of methylene chloride (=1: 25) obtains obtains the title compound (66mg, 0.120mmol, 89%) of white solid.
1H-NMR (400MHz, DMSO-d6) 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.
MS m/z:550 (M++H).
Elemental analysis: C20H15N3O5Cl2F2S2·0.5H2O: 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.
The chloro- 4- of embodiment 286:[[[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] acetic acid
In [[[the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 283 obtains; 5- difluorophenyl) methyl] pyridine -2- base] amino] sulfonyl] ethyl acetate (60mg; lithium hydroxide monohydrate (9.1mg, 0.218mmol) is added in tetrahydrofuran (5ml) and water (1ml) mixed solution 0.104mmol).1N hydrochloric acid is added after stirring 2 hours to reaction solution at room temperature.Filtrate is concentrated under reduced pressure after being dried, filtered after being extracted with dichloromethane with anhydrous sodium sulfate in mixed solution.Gained concentrated residue is handled with silica gel column chromatography, the methanol by containing 0.5% trifluoroacetic acid: the fraction that the eluent of methylene chloride (=1: 30) obtains is concentrated under reduced pressure, obtain the title compound (54mg, 0.098mmol, 94%) of white solid
1H-NMR (400MHz, DMSO-d6) 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)
MS m/z:551 (M++H).
Embodiment 287:(Z) the chloro- 4- of -5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -2- (3- [1; 3] dioxolanes -2- base acrylic) pyridine (isomers 287-A) and (E) -5- chloro- 4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -2- (3- [1,3] dioxolanes -2- base acrylic) pyridine (isomers 287-B)
Isomers 287-A isomers 287-B
In -78 DEG C, in bromination 2- (1 under argon atmospher, 3- dioxolanes -2- base) Yi base triphenyl phosphonium (738mg, n-BuLi (1.59M hexane solution is added in tetrahydrofuran (30ml) solution 1.99mmol), 1.3ml, 1.99mmol), it stirs 1 hour.[the chloro- 4- of 5- [(the 4- Chlorophenylsulfonyl) (2 that embodiment 258 obtains is added in reaction solution; 5- difluorophenyl) methyl] pyridine -2- base] formaldehyde (400mg; after 0.904mmol), stirred 4 hours after being warming up to room temperature.It is extracted with dichloromethane after saturated aqueous ammonium chloride is added in reaction solution.It is concentrated under reduced pressure after organic layer magnesium sulfate drying.It is residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, obtain isomers 287-A (low polarity) (140mg in colorless amorphous, 0.266mmol, 29%) and in colorless amorphous isomers 287-B (highly polar) (170mg, 0.323mmol, 36%).
Isomers 287-A
1H-NMR (400MHz, CDCl3) 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)
MS m/z:526 (M++H).
Isomers 287-B
1H-NMR (400MHz, CDCl3) 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)
MS m/z:526 (M++H).
Embodiment 288:4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] butyraldehyde
After first being washed again with ethyl alcohol to Raney nickel suspension (day emerging リ カ Co., Ltd., R-100) with water, ethyl alcohol is added and forms alcohol suspending liquid.In (Z) and (E) -5- chloro- 4- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] -2- (3- [1; 3] dioxolanes -2- base acrylic) pyridine (80mg; ethyl alcohol (5ml) and 1 0.152mmol); the alcohol suspending liquid (1ml) is added in the mixed solution of 4- dioxanes (3ml), in high degree of agitation 30 minutes under the nitrogen atmosphere of 1 air pressure.It is concentrated under reduced pressure after filtering reacting solution.
Concentrated hydrochloric acid (1ml) is added in Isosorbide-5-Nitrae-dioxanes (4ml) solution of gained concentrated residue, stirs 1 hour at room temperature.After depressurizing lower concentrated solvent, saturated sodium bicarbonate aqueous solution is added in residue, is extracted with ethyl acetate.Organic layer saturated common salt water washing is concentrated under reduced pressure after the magnesium sulfate drying of gained organic layer.Residue obtained to be handled with flashchromatography on silica gel, be concentrated under reduced pressure by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains obtains the title compound (44mg, 0.0908mmol, 59%) in colorless amorphous.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:484 (M++H).
Embodiment 289:4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] butyric acid
In 4- [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] butyraldehyde (40mg; 30% aqueous hydrogen peroxide solution (84 μ l are added in formic acid (1ml) solution 0.0828mmol); 0.745mmol), it stirs 9 hours at room temperature.Add water in reaction solution, is extracted with ethyl acetate.Organic layer successively uses water and saturated common salt water washing, is concentrated under reduced pressure after organic layer magnesium sulfate drying.Residue obtained to use hexane: re-crystallizing in ethyl acetate obtains the title compound (13mg, 0.0260mmol, 32%) of white powder.
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:500 (M++H).
The chloro- 4- of embodiment 290:2- bromomethyl -5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine
In 0 DEG C, in [the chloro- 4- of 5- [(the 4- chlorophenylsulfanyl) (2 that embodiment 256 obtains, 5- difluorophenyl) methyl] pyridine -2- base] methanol (582mg, carbon tetrabromide (936mg is added in methylene chloride (15ml) solution 1.41mmol), 2.82mmol), add triphenylphosphine (407mg, 1.55mmol).Reaction mixture is concentrated under reduced pressure after stirring 15 hours at room temperature, it is residue obtained to be handled with silica gel flash column chromatography.Be concentrated under reduced pressure by hexane: ethyl acetate=20: the fraction that 1 elution portion obtains obtains the title compound (518mg, 1.09mmol, 77%) in colorless oil.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:474,476 (M++H).
The chloro- 4- of embodiment 291:[5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] acetonitrile
Under argon atmospher, in room temperature in 2- bromomethyl -5- chloro- 4- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine (516mg, trimethylsilyl nitrile (0.226ml is added in acetonitrile (10ml) solution 1.09mmol), 1.63mmol), tetrahydrofuran solution (1M, the 1.63ml of tetrabutylammonium are added, 1.63mmol), it stirs 30 minutes.Reaction mixture is concentrated under reduced pressure, it is residue obtained to be handled with silica gel flash column chromatography.Be concentrated under reduced pressure by hexane: ethyl acetate=9: the fraction that 1 elution portion obtains obtains the title compound (390mg, 0.93mmol, 85%) of brown grease.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:421 (M++H).
The chloro- 4- of embodiment 292:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] acetonitrile
In [the chloro- 4- of 5- [(4- chlorophenylsulfanyl) (2,5- difluorophenyl) methyl] pyridine -2- base] acetonitrile (387mg, methanol (5ml), six ammonium tetrahydrate (227mg of 31% aqueous hydrogen peroxide solution (3ml) and seven molybdic acids are added in ethyl acetate (5ml) solution 0.92mmol), 0.18mmol), it stirs 2 hours at room temperature.In the reactive mixture plus water, saturated sodium bicarbonate aqueous solution is added after ethyl acetate and methanol are boiled off under decompression, product is extracted with dichloromethane.Filtrate is concentrated under reduced pressure in organic layer after being dried, filtered with anhydrous sodium sulfate, residue obtained to be handled with silica gel flash column chromatography, it is concentrated under reduced pressure by hexane: ethyl acetate=17: the fraction that 3 elution portions obtain, obtain the title compound (364mg, 0.80mmol, 87%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:453 (M++H).
The chloro- 4- of embodiment 293:[5- [(4- Chlorophenylsulfonyl) (2,5- difluorophenyl) methyl] pyridine -2- base] acetic acid
At room temperature; in [the chloro- 4- of 5- [(4- Chlorophenylsulfonyl) (2; 5- difluorophenyl) methyl] pyridine -2- base] acetonitrile (113mg; the mixture of water (2ml) and the concentrated sulfuric acid (2ml) is added in acetic acid (2ml) solution 0.25mmol), is stirred 2 hours in 100 DEG C.Reaction mixture is cooled to room temperature Hou Jiashui, is extracted with dichloromethane.Organic layer is concentrated under reduced pressure filtrate after being dried, filtered with anhydrous sodium sulfate, it is residue obtained washed with the mixed solvent of ether/hexane after leaching, obtain the title compound (101mg, 0.21mmol, 86%) of white solid.
1H-NMR (400MHz, CDCl3) 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)
MS m/z:472 (M++H).
The chloro- 4- pyridyl group of reference example 53:(2,5- bis-) (2,6- difluorophenyl) methanol
Under argon atmospher, after n-BuLi (1.60M hexane solution, 2.33ml, 3.72mmol) is added in -78 DEG C of tetrahydrofuran solutions (12ml) in diisopropylamine (0.520ml, 3.72mmol), stirred 30 minutes in -78 DEG C.After the tetrahydrofuran solution (2ml) of 2,5- dichloropyridine (500mg, 3.38mmol) is added in reaction solution, stirred 1 hour in -78 DEG C.Then, the tetrahydrofuran solution (2ml) of 2,6- difluorobenzaldehyde (395mg, 3.72mmol) is added, is stirred 2 hours in -78 DEG C.After 1N hydrochloric acid (7ml) is added in reaction solution, it is warming up to room temperature.Reaction solution uses water and saturated common salt water washing after being diluted with ethyl acetate.With being concentrated after magnesium sulfate drying, obtained solid is washed with methylene chloride, obtains the title compound (746mg, 2.57mmol, 76%) of white solid.
1H-NMR (400MHz, CDCl3) (1H, the s) of 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
MS m/z:290 (M++H).
The chloro- 4- of embodiment 294:2,5- bis- [(4- Chlorophenylsulfonyl) (2,6- difluorophenyl) methyl] pyridine
Make (2 that reference example 53 obtains, the chloro- 4- pyridyl group of 5- bis-) (2,6- difluorophenyl) methanol (744mg, 2.57mmol) it is suspended in methylene chloride (6ml), after thionyl chloride (0.5ml) and dimethylformamide (1 drop) is added, stir 5 hours at room temperature.It is stirred at room temperature 24 hours after adding thionyl chloride (1.0ml).Concentration of reaction solution, with saturated sodium bicarbonate aqueous solution to being extracted with dichloromethane after residue obtained neutralize.It is dry with magnesium sulfate after extract liquor water and saturated common salt water washing, concentration.It is dissolved in residue obtained dimethylformamide (10ml), after 4- chlorobenzene sulfinic acid sodium (613mg, 3.08mmol) is added, heats in 50 DEG C 5 hours, then heated 3 hours at 80 DEG C.Reaction solution is diluted with ethyl acetate, with water and saturated common salt water washing.With being concentrated after magnesium sulfate drying, residue obtained to be handled with silica gel flash column chromatography, concentration is by hexane: ethyl acetate=4: the fraction that 1 elution portion obtains, obtained solid is recrystallized with ether-hexane, obtain the title compound (761mg, 1.69mmol, 66%) of white solid.
1H-NMR (400MHz, CDCl3) 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=8.5H z), 8.35 (1H, s), 8.43-8.46 (1H, m)
MS m/z:448 (M++H).
The chloro- 4- of embodiment 295:5- [(4- Chlorophenylsulfonyl) (2,6- difluorophenyl) methyl] -2- (3,4- dimethoxy benezene amino) pyridine
Under argon atmospher; 2 obtained in embodiment 294; chloro- 4- [(the 4- Chlorophenylsulfonyl) (2 of 5- bis-; 6- difluorophenyl) methyl] pyridine (755mg; 3 are added in n-methyl-2-pyrrolidone solution (20ml) 1.68mmol); 4- dimethoxybenzylamine (0.745ml, 5.04mmol) heats 5 hours in 150 DEG C.Reacting liquid temperature is diluted after being back to room temperature with ethyl acetate, then uses saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution, water and saturated common salt water washing.With being concentrated after magnesium sulfate drying, residue obtained to be handled with silica gel flash column chromatography, hexane: ethyl acetate=2 is concentrated: the fraction that 1 elution portion obtains obtains the title compound (295mg, 0.509mmol, 30%) of white amorphous substance.
1H-NMR(400MHz CDCl3) δ: 3.89 (3H, s), 3.90 (3H, s), 4.48 (2H, d, J=5.6Hz), 5.06 (1H, t, J=5.6H z), 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)
MS m/z:579 (M++H).
The chloro- 4- of embodiment 296:5- [(4- Chlorophenylsulfonyl) (2,6- difluorophenyl) methyl] pyridine -2- base amine
The chloro- 4- of the 5- that embodiment 295 is obtained [(4- Chlorophenylsulfonyl) (2; 6- difluorophenyl) methyl] -2- (3; 4- dimethoxy benezene amino) pyridine (293mg; it 0.506mmol) is dissolved in trifluoroacetic acid (4ml), is heated 2 hours in 65 DEG C.Concentration of reaction solution, with saturated sodium bicarbonate aqueous solution make it is residue obtained in alkalinity after be extracted with ethyl acetate.Extract liquor water and saturated common salt water washing are concentrated after being dried with magnesium sulfate.It is residue obtained to be handled with silica gel flash column chromatography, be concentrated by hexane: ethyl acetate=2: the fraction that 1 elution portion obtains recrystallizes obtained solid with ethylacetate-hexane, obtains the title compound (147mg of white solid, 0.343mmol, 68%).
1H-NMR (400MHz, CDCl3) 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 DEG C of
MS m/z:429 (M++H).
Elemental analysis: C18H12Cl2F2N2O2S: 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.
Test example
The measuring method of the inhibiting substances of the generation secretion of amyloid beta
By the following method, inhibitory activity is generated to the amyloid beta of embodiment compound and is tested.
The APP751 gene as people's wild-type beta amyloid precursor protein gene is imported in human glioma cell's (H4 cell), and E35 cell is made.
E35 cell inoculation is cultivated in 37 DEG C of incubator in 96 orifice plates using the improved Eagle culture medium (10%FBS-DMEM) of the Dulbecco of 10% fetal calf serum containing inactivation.After inoculation 24 hours, 2000 times of the DMSO that will have been dissolved tested compound its concentration is made to reach ultimate density adds 1/2000 capacity of culture solution in each hole.Culture supernatant is recycled after being further cultured for 24 hours, is quantified by amount of sandwich type Enzyme-linked Immunosorbent Assay (ELISA) method to secreted amyloid beta (A β) in culture supernatant.That is, the monoclonal antibody 25-1 of the A β 25-35 immobilization in 96 hole ELISA plates will be identified, heat preservation in 16~20 hours is carried out in 4 DEG C.After being washed with phosphoric acid buffer agent (pH7.4) (PBS) to it, the monoclonal antibody MA32-40 of the A β 1-8 of biotin labeling is added, stands 2 hours in 4 DEG C.Supernatant is removed, after the abundant washing hole of PBS, the streptavidin for combining alkaline phosphatase is added, then add the Blue Phos (KPL company) as substrate, measures absorbance.The A β amount for including in culture supernatant is found out with the standard curve in addition made using the A β of known concentration.Make comparisons with the A β amount for the control cell for being only added to DMSO, it will be observed that 50% A β the compound concentration that is suppressed of generation as IC50。
In addition, finding out the cytotoxicity of tested compound according to the following steps.As described above, the tested compound for being dissolved in DMSO is added in the H4 cell for being incubated at 10%FBS-DMEM.After culture 72 hours, Survival Cells number is measured using Alamar Blue (BIOSOURCE company).Concentration when Survival Cells number to be reached to 80% or less the control cell for being only added to DMSO is defined as cytotoxicity and shows concentration.
By IC50The compound that the compound for showing 10 times of deviation of concentration or more with cytotoxicity is judged to that there is the secretion of amyloid beta matter to generate inhibitory activity.
The compound of the present invention is shown in table 1 using the result that said determination method is evaluated.In table 1, by IC50It is denoted as in 5nM compound below +++, the compound of 5~50nM is denoted as ++, the compound of 50~500nM is denoted as+.
Table 1
| Compound | Activity | Compound | Activity |
| 1 | + | 220(B) | + |
| 19 | + | 221 | +++ |
| 20 | + | 222 | ++ |
| 23 (compound A) | ++ | 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 | +++ |
Table 1
| Compound | Activity | Compound | Activity |
| 1 | + | 220(B) | + |
| 19 | + | 221 | +++ |
| 20 | + | 222 | ++ |
| 23 (compound A) | ++ | 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 (22)
1. general formula (1)
The compound of expression, its N- oxide, its S- oxide, its salt or its solvate,
In formula, R1And R3It separately indicates to have the aromatic hydrocarbyl of substituent group or can have the aromatic heterocycle of substituent group, R2Indicate the saturated or unsaturated monocyclic type heteroaromatic base or unsaturated polycyclic heterocycle base that there can be substituent group, R4Indicate hydrogen atom or C1-6Alkyl, X expression-S- ,-SO- or-SO2-。
2. compound, its N- oxide, its S- oxide, its salt or its solvate as described in claim 1, wherein R1And R3It is each independently the phenyl that there can be substituent group.
3. compound as described in claim 1, its N- oxide, its S- oxide, its salt or its solvate, wherein R1And R3Being each independently can have selected from halogen atom, C1-6Alkyl, trihalomethyl group, C1-6Alkoxy, formoxyl, C2-6Alkanoyl, carboxyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, oxo base, nitro, cyano, amidino groups, C2-6Alkenyloxy, hydroxyl, thio group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio carbamoyl, two (C1-6Alkyl) thiocarbamoyl, sulfydryl, C1-6Alkyl sulfenyl, C1-6Alkyl sulphinyl and C1-6The aromatic hydrocarbyl or aromatic heterocycle of 1~3 substituent group of alkyl sulphonyl.
4. compound as described in claim 1, its N- oxide, its S- oxide, its salt or its solvate, wherein R1And R3Being each independently can have selected from halogen atom, C1-6Alkyl, trihalomethyl group, C1-6Alkoxy, formoxyl, C2-6Alkanoyl, carboxyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, oxo base, nitro, cyano, amidino groups, C2-6Alkenyloxy, hydroxyl, thio group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio carbamoyl, two (C1-6Alkyl) thiocarbamoyl, sulfydryl, C1-6Alkylthio group, C1-6Alkyl sulphinyl and C1-6The phenyl of 1~3 substituent group of alkyl sulphonyl.
5. compound as described in any one of claims 1 to 4, its N- oxide, its S- oxide, its salt or its solvate, wherein R2For that can have the pyridyl group of substituent group.
6. compound as described in any one of claims 1 to 4, its N- oxide, its S- oxide, its salt or its solvate, wherein R2For halogen atom, cyano, C can be selected from1-6Alkyl, hydroxyl, C1-6Alkoxy, C2-6Alkenyloxy, carboxyl C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl, heterocyclic-carbonyl C1-6Alkyl, hydroxyl C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfonyl C1-6Alkyl, N, N- dialkyl amino sulfonyl C1-6Alkyl, heterocycle-C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl, C6-10The thio C of aromatic hydrocarbon-1-6Alkyl, azido-C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, hydroxyl C1-6Alkyl amino C1-8Alkyl, C1-6Alkoxy C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkoxy C1-6Alkyl) amino C1-6Alkyl, (hydroxyl C1-6Alkyl) (C1-6Alkoxy C1-6Alkyl) amino C1-6Alkyl, C2-6Alkanoylamino C1-6Alkyl, two (C2-6Alkanoyl) amino C1-6Alkyl, carboxyamino C1-6Alkyl, two (C1-6Alkyl-carbonyl-amino C1-6Alkyl) amino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, two (C1-6Alkoxy carbonyl) amino C1-6Alkyl, carbamoylamino C1-6Alkyl, N-C1-6Alkyl-carbamoyl amino C1-6Alkyl, N, bis- (C of N-1-6Alkyl) carbamoylamino C1-6Alkyl, aminosulfonylamino C1-6Alkyl, N-C1-6Alkyl sulfonyl-amino C1-6Alkyl, two (C1-6Alkyl) aminosulfonylamino C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfuryl amino-C1-6Alkanoylamino C1-6Alkyl, amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, N-C1-6Alkyl amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, N, bis- (C of N-1-6Alkyl) amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C2-6Alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-carbonylamino C1-6Alkyl, C6-10Aromatic hydrocarbon-thio-carbonyl-amino C1-6Alkyl, heterocyclic-carbonyl amino C1-6Alkyl, C1-6Alkyloxy oxalyl base amino C1-6Alkyl, (C6-10Aromatic hydrocarbon-sulfonyl) (C1-6Alkyl) amino C1-6Alkyl, C1-6Alkyl sulfonyl-amino C1-6Alkyl, C1-6Alkyl sulfonyl-amino C1-6Alkyl, carbamoyloxy C1-6Alkyl, N-C1-6Alkyl carbamoyloxy base C1-6Alkyl, N, bis- (C of N-1-6Alkyl) carbamoyloxy C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl carbamoyloxy base C1-6Alkyl, C1-6Alkoxy-carbonyl oxy-C1-6Alkyl, C6-10Aromatic hydrocarbon-Epoxide carbonyl oxygroup C1-6Alkyl, heterocyclecarbonyl hydrazonomethyl, C6-10Aromatic hydrocarbon-carbonyl hydrazonomethyl, C2-6Alkenyl, carboxyl-C2-6Alkenyl, C1-6Alkoxy carbonyl-C2-6Alkenyl, carbamoyl C2-6Alkenyl, heterocycle-alkenyl, formoxyl, carboxyl, heterocyclic-carbonyl, C6-10Aromatic hydrocarbon-carbonyl, C1-6Alkoxy carbonyl, carbamoyl, N-C1-6Alkyl-carbamoyl, N, bis- (C of N-1-6Alkyl) carbamoyl, C3-8Naphthenic base-C1-6Alkyl-carbamoyl, C1-6Alkylthio group C1-6Alkyl-carbamoyl, C1-6Alkyl sulphinyl C1-6Alkyl-carbamoyl, C1-6Alkyl sulphonyl C1-6Alkyl-carbamoyl, hydroxyaminocarbonyl, C1-6Alkoxycarbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy C1-6Alkyl-carbamoyl, amino C1-6Alkyl-carbamoyl, amino C1-6Alkylthio carbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy carbonyl C1-6Alkyl-carbamoyl, C1-6Alkoxycarbonyl amino C1-6Alkyl-carbamoyl, C1-6Alkoxycarbonyl amino C1-6Alkylthio carbamoyl, heterocycle-carbamoyl, heterocycle-C1-6Alkyl-carbamoyl, C6-10Aromatic hydrocarbon-carbamoyl, Hydrazinocarbonyl, N-C1-6Alkyl hydrazine carbonyl, N '-C1-6Alkyl hydrazine carbonyl, N ', (C of N '-two1-6Alkyl) Hydrazinocarbonyl, N, (the C of N '-two1-6Alkyl) Hydrazinocarbonyl, N, N ', N '-three (C1-6Alkyl) Hydrazinocarbonyl, N '-(heterocyclic-carbonyl)-Hydrazinocarbonyl, amino, C1-6Alkoxy C1-6Alkyl amino, amino C1-6Alkyl amino, C1-6Alkyl amino C1-6Alkyl amino, (C1-6Alkyl amino C1-6Alkyl) (C1-6Alkyl) amino, (C1-6Alkyl-carbonyl-amino C1-6Alkyl) amino, (C1-6Alkyl sulfonyl-amino C1-6Alkyl) amino, C1-6Alkoxycarbonyl amino C1-6Alkyl amino, two (C1-6Alkyl) amino C1-6Alkyl amino, heterocycle-amino C1-6Alkyl amino, carboxyl C1-6Alkyl amino, (carboxyl C1-6Alkyl) (C1-6Alkyl) amino, heterocycle-C1-6Alkyl amino, (heterocycle-C1-6Alkyl) (C1-6Alkyl) amino, hydroxyl C1-6Alkyl amino, (hydroxyl C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkylthio group C1-6Alkyl amino, C1-6Alkyl amino carbonyl oxy C1-6Alkyl amino, (C1-6Alkyl amino carbonyl oxy C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkyl sulphinyl C1-6Alkyl amino, C1-6Alkyl sulphonyl C1-6Alkyl amino, general formula-N (R12)SO2R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino) indicate group, hydroxyl C1-6Alkoxy C1-6Alkyl amino, C6-10Aromatic hydrocarbon-C1-6Alkyl amino, heterocyclic-carbonyl amino, C1-6Alkoxycarbonyl amino, heterocycle-C1-6Alkyl-carbonyl-amino, C6-10Aromatic hydrocarbon-carbonylamino, heterocycle-amino, oxyimino, C1-6Alkoximino, oxo base, oxyimino C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl amino, (C2-6Alkanoylamino C1-6Alkyl) amino, C6-10Aromatic hydrocarbyl and heterocycle (here, C6-10Aromatic hydrocarbyl or heterocycle or heterocycle can be selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, formoxyl, C2-6Alkanoyl, carboxyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, oxo base, nitro, cyano, amidino groups, C2-6Alkenyloxy, hydroxyl, thio group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, amino C1-6Alkyl, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio carbamoyl, two (C1-6Alkyl) thiocarbamoyl, C2-6Alkanoylamino, C2-6Alkanoyl (C1-6Alkyl) amino, thio C2-6Alkanoylamino, thio C2-6Alkanoyl (C1-6Alkyl) amino, Formylamino, formoxyl (C1-6Alkyl) amino, thioformyl amino, thioformyl (C1-6Alkyl) amino, C2-6Alkanoyloxy, formyloxy, sulfydryl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, amino-sulfonyl, C1-6Alkyl amino sulfonyl, two (C1-6Alkyl) amino-sulfonyl, C1-6Alkyl sulfonyl-amino and C1-6Alkyl sulphonyl (C1-6Alkyl) amino 1~3 group replace) 1~3 group replace monocyclic or polycyclic heterocycle base.
7. compound as claimed in claim 5, its N- oxide, its S- oxide, its salt or its solvate, wherein R2For halogen atom, cyano, C can be selected from1-6Alkyl, hydroxyl, C1-6Alkoxy, C2-6Alkenyloxy, carboxyl C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl, heterocyclic-carbonyl C1-6Alkyl, hydroxyl C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfonyl C1-6Alkyl, N, bis- (C of N-1-6Alkyl) amino-sulfonyl C1-6Alkyl, heterocycle-C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfenyl C1-6Alkyl, azido-C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, hydroxyl C1-6Alkyl amino C1-6Alkyl, C1-6Alkoxy C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkoxy C1-6Alkyl) amino C1-6Alkyl, (hydroxyl C1-6Alkyl) (C1-6Alkoxy C1-6Alkyl) amino C1-6Alkyl, C2-6Alkanoylamino C1-6Alkyl, two (C2-6Alkanoyl) amino C1-6Alkyl, carboxyamino C1-6Alkyl, two (C1-6Alkyl-carbonyl-amino C1-6Alkyl) amino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, two (C1-6Alkoxy carbonyl) amino C1-6Alkyl, carbamoylamino C1-6Alkyl, N-C1-6Alkyl-carbamoyl amino C1-6Alkyl, N, bis- (C of N-1-6Alkyl) carbamoylamino C1-6Alkyl, aminosulfonylamino C1-6Alkyl, N-C1-6Alkyl sulfonyl-amino C1-6Alkyl, two (C1-6Alkyl) aminosulfonylamino C1-6Alkyl, C6-10Aromatic hydrocarbon-sulfuryl amino-C2-6Alkanoylamino C1-6Alkyl, amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, N-C1-6Alkyl amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, N, bis- (C of N-1-6Alkyl) amino C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C1-6Alkyl-carbonyl-amino C1-6Alkyl, heterocycle-C2-6Alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-C2-6Alkenyl carbonyl amino C1-6Alkyl, C6-10Aromatic hydrocarbon-carbonylamino C1-6Alkyl, C6-10Aromatic hydrocarbon-thio-carbonyl-amino C1-6Alkyl, heterocyclic-carbonyl amino C1-6Alkyl, C1-6Alkyloxy oxalyl base amino C1-6Alkyl, (C6-10Aromatic hydrocarbon-sulfonyl) (C1-6Alkyl) amino C1-6Alkyl, C1-6Alkyl sulfonyl-amino C1-6Alkyl, C1-6Alkyl sulfonyl-amino C1-6Alkyl, carbamoyloxy C1-6Alkyl, N-C1-6Alkyl carbamoyloxy base C1-6Alkyl, N, bis- (C of N-1-6Alkyl) carbamoyloxy C1-6Alkyl, C6-10Aromatic hydrocarbon-C1-6Alkyl carbamoyloxy base C1-6Alkyl, C1-6Alkoxy-carbonyl oxy-C1-6Alkyl, C6-10Aromatic hydrocarbon-Epoxide carbonyl oxygroup C1-6Alkyl, heterocyclecarbonyl hydrazonomethyl, C6-10Aromatic hydrocarbon carbonyl hydrazonomethyl, C2-6Alkenyl, carboxyl-C2-6Alkenyl, C1-6Alkoxy carbonyl-C2-6Alkenyl, carbamoyl C2-6Alkenyl, heterocycle-C2-6Alkenyl, formoxyl, carboxyl, heterocyclic-carbonyl, C6-10Aromatic hydrocarbon-carbonyl, C1-6Alkoxy carbonyl, carbamoyl, N-C1-6Alkyl-carbamoyl, N, bis- (C of N-1-6Alkyl) carbamoyl, C3-8Naphthenic base-C1-6Alkyl-carbamoyl, C1-6Alkylthio C1-6Alkyl-carbamoyl, C1-6Alkyl sulphinyl C1-6Alkyl-carbamoyl, C1-6Alkyl sulphonyl C1-6Alkyl-carbamoyl, hydroxyaminocarbonyl, C1-6Alkoxycarbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy C1-6Alkyl-carbamoyl, amino C1-6Alkyl-carbamoyl, amino C1-6Alkylthio carbamoyl, hydroxyl C1-6Alkyl-carbamoyl, C1-6Alkoxy carbonyl C1-6Alkyl-carbamoyl, C1-6Alkoxycarbonyl amino C1-6Alkyl-carbamoyl, C1-6Alkoxycarbonyl amino C1-6Alkylthio carbamoyl, heterocycle-carbamoyl, heterocycle-C1-6Alkyl-carbamoyl, C6-10Aromatic hydrocarbon-carbamoyl, Hydrazinocarbonyl, N-C1-6Alkyl hydrazine carbonyl, N '-C1-6Alkyl hydrazine carbonyl, N ', (C of N '-two1-6Alkyl) Hydrazinocarbonyl, N, (the C of N '-two1-6Alkyl) Hydrazinocarbonyl, N, N ', N '-three (C1-6Alkyl) Hydrazinocarbonyl, N '-(heterocyclic-carbonyl)-Hydrazinocarbonyl, amino, C1-6Alkoxy C1-6Alkyl amino, amino C1-6Alkyl amino, C1-6Alkyl amino C1-6Alkyl amino, (C1-6Alkyl amino C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkoxycarbonyl amino C1-6Alkyl amino, two (C1-6Alkyl) amino C1-6Alkyl amino, heterocycle-amino C1-6Alkyl amino, carboxyl C1-6Alkyl amino, (carboxyl C1-6Alkyl) (C1-6Alkyl) amino, heterocycle-C1-6Alkyl amino, (heterocycle-C1-6Alkyl) (C1-6Alkyl) amino, hydroxyl C1-6Alkyl amino, (hydroxyl C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkylthio group C1-6Alkyl amino, C1-6Alkyl amino carbonyl oxy C1-6Alkyl amino, (C1-6Alkyl amino carbonyl oxy C1-6Alkyl) (C1-6Alkyl) amino, C1-6Alkyl sulphinyl C1-6Alkyl amino, C1-6Alkyl sulphonyl C1-6Alkyl amino, general formula-N (R12)SO2R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino) indicate group, hydroxyl C1-6Alkoxy C1-6Alkyl amino, C6-10Aromatic hydrocarbon-C1-6Alkyl amino, heterocyclic-carbonyl amino, C1-6Alkoxycarbonyl amino, heterocycle-C1-6Alkyl-carbonyl-amino, C6-10Aromatic hydrocarbon-carbonylamino, heterocycle-amino, oxyimino, C1-6Alkoximino, oxo base, oxyimino C1-6Alkyl, C1-6Alkoxy carbonyl C1-6Alkyl amino, (C2-6Alkanoylamino C1-6Alkyl) amino, C6-10Aromatic hydrocarbyl and heterocycle (here, C6-10Aromatic hydrocarbyl or heterocycle can be selected from halogen atom, C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, formoxyl, C2-6Alkanoyl, carboxyl, carboxyamino C1-6Alkyl, C1-6Alkoxycarbonyl amino C1-6Alkyl, oxo base, nitro, cyano, amidino groups, C2-6Alkenyloxy, hydroxyl, thio group, amino, C1-6Alkyl amino, two (C1-6Alkyl) amino, amino C1-6Alkyl, C1-6Alkoxy carbonyl, carbamoyl, C1-6Alkyl-carbamoyl, two (C1-6Alkyl) carbamoyl, thiocarbamoyl, C1-6Alkylthio carbamoyl, two (C1-6Alkyl) thiocarbamoyl, C2-6Alkanoylamino, C2-6Alkanoyl (C1-6Alkyl) amino, thio C2-6Alkanoylamino, thio C2-6Alkanoyl (C1-6Alkyl) amino, Formylamino, formoxyl (C1-6Alkyl) amino, thioformyl amino, thioformyl (C1-6Alkyl) amino, C2-6Alkanoyloxy, formyloxy, sulfydryl, C1-6Alkylthio group, C1-6Alkyl sulphinyl, C1-6Alkyl sulphonyl, amino-sulfonyl, C1-6Alkyl amino sulfonyl, two (C1-6Alkyl) amino-sulfonyl, C1-6Alkyl sulfonyl-amino and C1-6Alkyl sulphonyl (C1-6Alkyl) amino 1~3 group replace) 1~3 group replace pyridyl group.
8. compound as claimed in claim 5, its N- oxide, its S- oxide, its salt or its solvate, wherein R2By general formula
It indicates, in formula, R10For hydrogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkyl sulphinyl C1-6Alkyl, C1-6Alkyl sulphonyl C1-6Alkyl, carboxyl C1-6Alkyl, heterocycle-C1-6Alkyl or general formula-SO2-R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino) indicate group, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino, here, R11And R12Can and R11In conjunction with sulphur atom and R12In conjunction with nitrogen-atoms-rise form 5- or 6-membered aliphatic heterocycle, R12Indicate C1-6Alkyl, halogen atom or cyano.
9. compound as claimed in claim 5, its N- oxide, its S- oxide, its salt or its solvate, wherein R2For general formula
The group of expression, in formula, R10By-SO2-R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino) it indicates, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino, here, R11And R12Can and R11In conjunction with sulphur atom and R12In conjunction with nitrogen-atoms be formed together 5- or 6-membered aliphatic heterocycle, R13Indicate C1-6Alkyl, halogen atom or cyano.
10. compound as claimed in claim 5, its N- oxide, its S- oxide, its salt or its solvate, wherein R2By general formula
It indicates, in formula, R13Indicate C1-6Alkyl, halogen atom or cyano, n indicate 0~6 integer.
11. compound as described in claim 1, its N- oxide, its S- oxide, its salt or its solvate, wherein R1For 2,5- difluorophenyl or the fluoro- 5- cyano-phenyl of 2-, R3For 4- chlorphenyl, 4- fluorophenyl, 2,4- difluorophenyl, 3,4- difluorophenyl, the fluoro- 4- chlorphenyl of 3-, 4- trifluoromethyl, the chloro- 2- thienyl of 5-, 5- chloro-2-pyridyl, 6- chloro-3-pyridyl base or 6- trifluoromethyl -3- pyridyl group, R2By general formula
It indicates, in formula, R10For hydrogen atom, C1-6Alkyl, hydroxyl C1-6Alkyl, C1-6Alkyl sulphinyl C1-6Alkyl, C1-6Alkyl sulphonyl C1-6Alkyl, carboxyl C1-6Alkyl, heterocycle-C1-6Alkyl or general formula-SO2-R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, carboxyl C1-6Alkyl, carbamoyl C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino) indicate group, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino, here, R11And R12Can and R11In conjunction with sulphur atom and R12In conjunction with nitrogen-atoms be formed together 5- or 6-membered aliphatic heterocycle, R13Indicate C1-6Alkyl, halogen atom or cyano.
12. compound as described in claim 1, its N- oxide, its S- oxide, its salt or its solvate, wherein R1For 2,5- difluorophenyl or the fluoro- 5- cyano-phenyl of 2-, R3For 4- chlorphenyl, 4- fluorophenyl, 2,4- difluorophenyl, 3,4- difluorophenyl, the fluoro- 4- chlorphenyl of 3-, 4- trifluoromethyl, the chloro- 2- thienyl of 5-, 5- chloro-2-pyridyl, 6- chloro-3-pyridyl base or 6- trifluoromethyl -3- pyridyl group, R2For general formula
The group of expression, in formula, R10By-SO2-R11(in formula, R11Indicate C1-6Alkyl, heterocycle, C1-6Alkyl-heterocyclyl groups, heterocycle-C1-6Alkyl, hydroxyl C1-6Alkyl, amino C1-6Alkyl, C1-6Alkyl amino C1-6Alkyl, two (C1-6Alkyl) amino C1-6Alkyl, trifluoromethyl, difluoromethyl, methyl fluoride, amino, C1-6Alkyl amino or two (C1-6Alkyl) amino) it indicates, R12Indicate hydrogen atom, C1-6Alkyl, hydroxyl or amino, here, R11And R12Can and R11In conjunction with sulphur atom and R12In conjunction with nitrogen-atoms be formed together 5- or 6-membered aliphatic heterocycle, R13Indicate C1-6Alkyl, halogen atom or cyano.
13. compound as described in claim 1, its N- oxide, its S- oxide, its salt or its solvate, wherein R1For 2,5- difluorophenyl or the fluoro- 5- cyano-phenyl of 2-, R3For 4- chlorphenyl, 4- fluorophenyl, 2,4- difluorophenyl, 3,4- difluorophenyl, the fluoro- 4- chlorphenyl of 3-, 4- trifluoromethyl, the chloro- 2- thienyl of 5-, 5- chloro-2-pyridyl, 6- chloro-3-pyridyl base or 6- trifluoromethyl -3- pyridyl group, R2By general formula
It indicates, in formula, R13Indicate C1-6Alkyl, halogen atom or cyano, n indicate 0~6 integer.
14. pharmaceuticals, which is characterized in that using compound described in any one of claim 1~13, its N- oxide, its S- oxide, its salt or its solvate as effective component.
15. pharmaceuticals as claimed in claim 14, it is further characterized in that, the prevention for the disease that the pharmaceuticals are caused by the generation of amyloid beta, diacrisis or medicine.
16. pharmaceuticals as claimed in claim 15, it is further characterized in that, the disease that the generation of amyloid beta, diacrisis are caused is degenerative brain disorder or Down syndrome.
17. medical composition, which is characterized in that contain the carrier allowed in compound described in any one of claim 1~13, its N- oxide, its S- oxide, its salt or its solvate and pharmacy.
18. appointing compound, its N- oxide, its application of S- oxide, its salt or its solvate in the preparation of pharmaceuticals of-Xiang Suoshu in claim 1~13.
19. application as claimed in claim 18, it is further characterized in that, the prevention for the disease that the pharmaceuticals are caused by the generation of amyloid beta, diacrisis or medicine.
20. application as claimed in claim 19, it is further characterized in that, the disease that the generation of amyloid beta, diacrisis are caused is degenerative brain disorder or Down syndrome.
21. the treatment method for the disease that the generation of amyloid beta, diacrisis are caused, which is characterized in that give compound described in any one of a effective amount of claim 1~13, its N- oxide, its S- oxide, its salt or its solvate.
22. treatment method as claimed in claim 21, it is further characterized in that, the disease that the generation of amyloid beta, diacrisis are caused is degenerative brain disorder or Down syndrome.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP187796/2003 | 2003-06-30 | ||
| JP2003187796 | 2003-06-30 | ||
| JP099151/2004 | 2004-03-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1812964A true CN1812964A (en) | 2006-08-02 |
| CN100378072C CN100378072C (en) | 2008-04-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800169993A Expired - Fee Related CN100378072C (en) | 2003-06-30 | 2004-06-29 | Heterocyclic methyl sulfone derivative |
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| Country | Link |
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| CN (1) | CN100378072C (en) |
| ZA (1) | ZA200509613B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109071902A (en) * | 2016-03-30 | 2018-12-21 | 株式会社尼康 | Curable compositions, cured article and optical component |
Family Cites Families (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 |
| ZA794030B (en) * | 1978-08-08 | 1980-07-30 | Sterling Drug Inc | Aryl sulfinic acid derivatives of aliphatic,aromatic or heterocyclic compounds |
| 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 |
| DE19521355A1 (en) * | 1995-06-12 | 1996-12-19 | Hoechst Schering Agrevo Gmbh | Sulfonamides, processes for their preparation and their use as herbicides and plant growth regulators |
| GB0108592D0 (en) * | 2001-04-05 | 2001-05-23 | Merck Sharp & Dohme | Therapeutic agents |
-
2004
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| CN109071902A (en) * | 2016-03-30 | 2018-12-21 | 株式会社尼康 | Curable compositions, cured article and optical component |
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| Publication number | Publication date |
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| CN100378072C (en) | 2008-04-02 |
| ZA200509613B (en) | 2007-05-30 |
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