CN1291183A - N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl-3-substituted-alkyl, aryl or heteroarylamides) as matrix metallo protein inhibitors - Google Patents

N-hydroxy-2-(alkyl, aryl or heteroaryl sulfanyl, sulfinyl or sulfonyl-3-substituted-alkyl, aryl or heteroarylamides) as matrix metallo protein inhibitors Download PDF

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CN1291183A
CN1291183A CN98813966A CN98813966A CN1291183A CN 1291183 A CN1291183 A CN 1291183A CN 98813966 A CN98813966 A CN 98813966A CN 98813966 A CN98813966 A CN 98813966A CN 1291183 A CN1291183 A CN 1291183A
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CN1213021C (en
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A·M·文卡特桑
G·T·格罗苏
J·M·达维斯
J·L·巴克尔
J·I·莱文
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Wyeth Holdings LLC
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American Cyanamid Co
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Abstract

Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. TNF-alpha converting enzyme (TACE), a pro-inflammatory cytokine, catalyzes the formation of TNF-alpha from membrane bound TNF-alpha precursor protein. It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. The present invention provides low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-alpha converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection having the formula wherein R2 and R3 form a heterocyclic ring and A is S, S(O), or S(O)2, and R1 and R4 are defined herein.

Description

The alkyl, aryl or the heteroaryl amide that replace as the N-hydroxyl-2-(alkyl, aryl or heteroaryl sulfane base, sulfinyl or alkylsulfonyl) of matrix metallo-proteinase inhibitor-3-
Background of invention
Matrix metalloproteinase (MMP) is one group and destroys relevant enzyme with the pathologic of reticular tissue and basement membrane.These zinciferous endopeptidases are made up of the enzyme of several hypotypes, comprise collagenase, stromelysin and gelatinase.Shown that in these enzymes gelatinase is and growth of tumor and the most closely-related mmp enzyme of diffusion.People known in malignant tumour the gelatinases expression in bovine level raise, and the gelatinase basement membrane of can degrading causes metastases.Prove also that recently the required vasculogenesis of solid tumor growth has the gelatinase component in its pathology.In addition, evidence suggests that the gelatinase spot relevant with atherosclerosis breaks relevant.Other disease by the MMP mediation comprises restenosis, the osteopenia of MMP-mediation, inflammatory disease of central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, keratohelcosis, unusual wound healing, osteopathia, proteinuria, the aortic aneurysm disease, the sex change cartilage that traumatic joint injury causes is lost, the neural system demyelinating disease, liver cirrhosis, renal glomerular disease, breaking in early days of fetal membrane, inflammatory bowel, periodontal disease, the macular degeneration that age is relevant, diabetic retinopathy, proliferative vitreous body retinopathy, retinopathy of prematurity, eye inflammation, keratoconus, the Sjogren Cotard, myopia, ocular tumor, ocular angiogenesis generation/neovascularity generates and corneal graft rejection.Nearest summary, see: (1) matrix metallo-proteinase inhibitor research latest developments, R.P.Beckett, A.H.Davidson, A.H.Drummond, P.Huxley and M.Whittaker, Research Focus, the 1st volume, 16-26, (1996), (2) Curr.Opin.Ther.Patents, (1994) 4 (1): 7-16, (3) Curr.Medicinal Chem. (1995) 2:743-762, (4) Exp.Opin.Ther.Patents, (1995) 5 (2): 1087-110, (5) Exp.Opin.Ther.Patents, (1995) 5 (12): 1287-1196.
TNF-α conversion enzyme (TACE) can form TNF-α by catalytic film bonded TNF-αQian Tidanbai.TNF-α is a pro-inflammatory cytokine, it is believed that it also has effect to this factor in following disease except that its clear and definite antitumor character: rheumatoid arthritis, septic shock, graft-rejection, emaciation, apocleisis, inflammation, congestive heart failure, inflammatory disease of central nervous system, inflammatory bowel, insulin resistance and HIV infect.For example, the formation of carrying out in antagonism TNF-Alpha antibodies and transgenic animal that studies have shown that blocking-up TNF-α can suppress arthritic development.This observation recently also extends to the mankind,
Therefore, people expect that micromolecular MMP and tace inhibitor can be used for the treatment of various diseases.Although determined in the literature and disclose various MMP and tace inhibitor, many be peptide and peptide analogs are arranged in these molecules, they all have bioavailability and pharmacokinetics problem, thereby have limited its clinical effectiveness.Therefore extremely need to be used for the available MMP of low-molecular-weight, effective, long-acting, oral biology and/or the tace inhibitor of the above-mentioned various diseases of effective long-term treatment.
Recently, two pieces of documents (U.S.5,455,258 and european patent application 606,046) disclose the alcohol amide base acid that aromatic yl sodium sulfonamido replaces.These files comprise with CGS 27023A being the compound of example.These are to be to unique disclosed non-peptide matrix inhibitors of metalloproteinase up till now.
Salah etc. are at Liebigs Ann.Chem.195, disclose the alkylsulfonyl N-acetylhydroxylamine derivative that sulfo-that some aryl of general formula 1 replace and aryl replace in (1973).Prepare these compounds with research Mannich reaction.Subsequently, study its Fungicidally active.
Some sulfone carboxylic acid is disclosed in United States Patent (USP) 4,933,367.Verified these compounds have glycopenia activity.
Summary of the invention
The present invention relates to be used for the treatment of that sacroiliitis, metastases, tissue ulcer, unusual wound healing, periodontopathy, osteopathia, diabetes (insulin resistance) and HIV infect is new, lower molecular weight, non-peptide class matrix metalloproteinase (MMP) and TNF-α change enzyme (TACE) inhibitor.
According to the invention provides one group of compound of Formula I and pharmacy acceptable salt thereof: R wherein 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first heteroaryl of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylene dioxo base, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COOC 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit's list or bicyclic heterocycle, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n aryl, wherein n is 0,1 or 2; Or the CO heteroaryl, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO-C 1-C 6Alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO-C 1-C 6Alkyl, CONHSO 2Aryl, aryl or heteroaryl, wherein aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
Or R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein said aryl is a phenyl or naphthyl.
The preferred aspect of the present invention be following general formula (I one group of compound and pharmacy acceptable salt thereof a):
Figure 9881396600291
R wherein 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first heteroaryl of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl; R 5Be H, F, Cl, Br, I, CN, CHO, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylenedioxy group, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; OCOO-C 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COO-C 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl, NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) nAlkyl or aryl, wherein n is 0,1 or 2; Or CO heteroaryl; Wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO-alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2Alkyl, CONHSO 2Aryl, aryl, heteroaryl; C wherein 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or N-R for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein aryl is a phenyl or naphthyl.
Most preferred one group of compound is for having those compounds and the pharmacy acceptable salt thereof of following formula (I b):
Figure 9881396600321
Wherein: R 1Be alkyl or heteroaryl such as pyridyl, thienyl, imidazolyl or the furyl of phenyl, naphthyl, a 1-18 carbon atom, optional by C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 6-C 10Aryloxy, heteroaryl oxygen base, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, halogen replace; Or S (O) n-C 1-C 6Alkyl C 1-C 6Alkoxy aryl or C 1-C 6The alkoxyl group heteroaryl; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylenedioxy group, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COO-C 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit single or two heterocycles, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) nAlkyl or aryl, wherein n is 0,1 or 2; Or CO heteroaryl; Wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2Alkyl, CONHSO 2Aryl, aryl or heteroaryl; Wherein aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The arylalkyl of optional 7-16 the carbon atom that replaces of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
Independently be selected from R by 1 or 2 5The xenyl alkyl of optional 13-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The aromatic yl alkenyl of optional 8-16 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkylalkyl or the bicyclic alkyl alkyl of optional 4-12 the carbon atom that replaces of group;
Contain one and be selected from O, S or NR-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein aryl is a phenyl or naphthyl.
It is following compounds and pharmacy acceptable salt thereof that most preferred matrix metalloproteinase of the present invention and TACE suppress compound: 1-benzyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide; 1-(3; the 4-dichloro benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-naphthalene-2-base-methyl piperidine-4-formic acid oxyamide; 1-xenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl) piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base) piperidines-4-formic acid oxyamide; 1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidines-4-formic acid oxyamide; the 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-encircles octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-methyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-(4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidines-4-formic acid oxyamide; 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide; 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide; 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide; 1-benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide; 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide; 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl] 1-methyl-piperidines-4-formic acid oxyamide; 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl)] 1-ethyl-piperidines-4-formic acid oxyamide; 1-butyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide; 1-benzyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide; 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide; 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide; 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide; 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(4-thiophene-2-base-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidines-4-formic acid oxyamide; 1-(3; the 4-dichloro benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; [4-(4-chloro-benzyl oxygen base)-benzenesulfonyl]-1-methyl piperidine-4-formic acid oxyamide; 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidines-4-formic acid oxyamide; [4-(4-chloro-benzyl oxygen base)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide, 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano group-benzyl)-piperidines-4-formic acid oxyamide and 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidines-4-formic acid oxyamide.
Certainly, work as R 1, R 2, R 3And R 4When containing asymmetric carbon, the definition of formula I, I a and I b compound comprises having active all possible steric isomer discussed below and its mixture.Particularly comprise and have specified active racemic modification and any optically active isomer.Can obtain the optically active isomer of pure form by the standard isolation technique.Except that specifying, term " alkyl " refers to straight or branched C 1-C 6Alkyl, aryl are phenyl or naphthyl.Pharmacy acceptable salt be those by pharmaceutically acceptable organic acid and mineral acid institute deutero-salt, described acid is for example lactic acid, citric acid, acetate, tartrate, succsinic acid, toxilic acid, propanedioic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid and similarly other known acceptable acid.
Therefore the invention provides the medicinal compositions that contains compound of the present invention and pharmaceutically acceptable carrier.Particularly the invention provides the The compounds of this invention that contains significant quantity and the medicinal compositions of pharmaceutically acceptable carrier.
Described composition preferably is fit to oral administration.Yet, also can be with them through other administration, as giving the patient through parenteral.
In order to obtain the consistence of administration, composition of the present invention is preferably unit dosage form.Suitable unit dosage comprises tablet, capsule and the pulvis in folliculus or in the glass tube vial.This type of unit dosage can contain 0.1-100mg compound of the present invention.Can give compound of the present invention with the dosage per os of the about 0.01-100mg of per kilogram.This based composition can give 1-6 time every day, is more typically every day 1-4 time.
Can wait and prepare composition of the present invention with the vehicle of routine such as weighting agent, disintegrating agent, tackiness agent, lubricant, correctives.Can prepare in a usual manner.
According to the present invention, also provide the method for preparation compound of the present invention.
Inventive method
According to one of following universal method, can prepare compound of the present invention.
In the acetone that refluxes, employing salt of wormwood can be with the thiol derivative alkylation that suitably replaces by (flow process I) or unsubstituted (flow process 2) the alpha bromoisobutyric acid ester derivative that replaces as alkali.In methylene dichloride with between-chlorine peroxybenzoic acid or the sulfide derivatives that in methanol, so obtains with the oxone oxidation.The further alkylation of sulfone that said process obtains can be obtained dibasic derivative with various alkylogens, perhaps under room temperature, use sodium hydroxide/methyl alcohol its hydrolysis.If but there are the tert-butyl ester rather than ethyl ester, hydrolysis is then adopted trifluoroacetic acid/dichloromethane and is carried out under room temperature so.Subsequently, by the carboxylic acid derivative that obtains being converted into hydroxamic acid derivs with oxalyl chloride/DMX (catalysis) and azanol/triethylamine reaction.
Flow process 1 is synthetic: A. salt of wormwood/acetone/backflow; B. between-the chlorine peroxybenzoic acid; C. salt of wormwood/18-hat-6/R 3Br/ acetone/backflow/d.NaOH/MeOH/THF/RTe. (COCl) 2/ CH 2Cl 2/ Et 3N/NH 2OHHCl.
Flow process 2 is synthetic:
Figure 9881396600401
A. salt of wormwood/acetone/backflow; B. between-the chlorine peroxybenzoic acid; C. salt of wormwood/18-hat-6/R 3Br/ acetone/backflow/d.R 3Br/10N NaOH/Bz (Et) 3/ CH 2Cl 2/ RTe.NaOH/MeOH/THF/RTf. (COCl) 2/ CH 2Cl 2/ Et 3N/NH 2OHHCl.
Shown in flow process 3, in 0 ℃, can be with the further alkylation of above-mentioned sulfide derivatives in THF with two (trimethylsilyl) lithium amides.With alkylation or mono-substituted compound hydrolysis and be converted into hydroxamic acid derivs.In MeOH solution, can prepare sulfenyl derivant with hydrogen peroxide oxidation sulfide hydroxamic acid derivs.
Flow process 3 is synthetic:
Figure 9881396600411
A. salt of wormwood/acetone/backflow; B.R 3Br/HMDS/THF; C.NaOH/MeOH/THF/RTd. (COCl) 2/ CH 2Cl 2/ Et 3N/NH 2OHHCl.e．MeOH／H 2O 2／RT
By diethanolamine and the alkyl or aryl halogen that suitably replaces is raw material, can prepare that corresponding 1-replaces-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide (flow process 4).With thionyl chloride the ethanolamine derivative that N-replaces is converted into compound of dichloro.In ebullient acetone, in the presence of salt of wormwood/18-hat-6, make the sulphonyl acetic acid ethyl reaction of corresponding dichloride and replacement.Shown in flow process 4, with the 1-that so obtains replace-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate is converted into oxyamide.
Perhaps according to this compounds of preparation and other heterogeneous ring compounds shown in flow process 5 and 6.
Flow process 4 A. salt of wormwood/RBr/ acetone/backflow; B.SOCl 2/ CH 2Cl 2C.R 1SO 2CH 2COOEt/ salt of wormwood/18-is preced with-6/ acetone/backflow d.NaOH/THF/RTe. (COCl) 2/ NH 2OHHCl/Et 3N
Flow process 5 A.RBr/R 1SH/ chloroform/backflow; B. potassium hydrogen persulfate/MeOH; E. (COCl) 2/ NH 2OHHCl/Et 3N
Flow process 6
Figure 9881396600431
A.LiN (TMS) 2/ THF/0 ℃/carbonic acid gas; B. (COCl) 2/ NH 2OHHCl/Et 3N
In addition, flow process 7-11 is depicted as the method for preparing hydroxamic acid compound with solid phase carrier (P).
Flow process 7
Reagent and condition: a) 2-halogenated acid (3.0eq); The I-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1, and the 3-DIC (DIC, 4.0eq); DMF, 25 ℃; 2-16 hour.B) mercaptan (5.0eq.); Sodium iodide (5.0eq.); 1, and 8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 3.0eq.); THF; 25 ℃; 12-16 hour.C) 70% t-butyl hydroperoxide (40eq.); Phenylsulfonic acid (2.0eq.); DCM; 25 ℃; 12-24 hour.D) mCPBA (5.0eq.); DCM; 25 ℃; 12-24 hour.E) TFA: DCM (1: 1); 25 ℃; 1 hour.
Make 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin (azanol resin) and the coupling of 2-halogenated acid, obtain the hydroxamic acid ester resin.This coupled reaction can be in the presence of carbodiimide such as DIC, carry out under room temperature in inert solvent such as DMF.In the presence of alkali such as DBU, in inert solvent such as THF, under room temperature, can replace halogen group with thiol.Can be with sulfide oxidation thing sulfoxide in the presence of acid catalyst such as Phenylsulfonic acid, in inert solvent such as DCM, under room temperature by reacting with oxygenant such as t-butyl hydroperoxide.Perhaps in inert solvent such as DCM, under room temperature by and oxygenant as-chlorine peroxybenzoic acid reaction is a sulfone with sulfide oxidation.Described sulfide, sulfoxide or sulfone all can be handled as trifluoroacetic acid with acid in inert solvent such as DCM, thereby discharge the free hydroxamic acid.
Flow process 8 is depicted as preparation is connected with the hydroxamic acid of alkoxyl group on aromatic ring method.
Flow process 8
Reagent and condition: a) 2-halogenated acid (3.0eq); The I-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1, and the 3-DIC (DIC, 4.0eq); DMF, 25 ℃; 2-16 hour.B) 4-fluorobenzene mercaptan (5.0eq.); Sodium iodide (5.0eq.); 1, and 8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 3.0eq.); THF; 25 ℃; 12-16 hour.C) ethanol (15.0eq.); Sodium hydride (15.0eq.); DMF; 80 ℃; 15 hours.D) 70% t-butyl hydroperoxide (40eq.); Phenylsulfonic acid (2.0eq.); DCM; 25 ℃; 12-24 hour.E) mCPBA (5.0eq.); DCM; 25 ℃; 12-24 hour.F) TFA: DCM (1: 1); 25 ℃; 1 hour.
According to preceding method, make described azanol resin and the coupling of 2-halogenated acid and replace described halo group with fluorobenzene mercaptan.Then can in the presence of alkali such as the sodium hydride, inert solvent as DMF in, in about 80 ℃ replace with alcohol as described in the fluoro group.The back is oxidized to corresponding sulfinyl or sulfonyl hydroxamic acid ester according to preceding method with described alkoxy benzene sulfane base hydroxamic acid ester again.Discharge the free hydroxamic acid according to preceding method.
Flow process 9 be depicted as prepare the two sulfur alkyl aryls of 2--, sulfinyl-and the method for sulfonyl hydroxamic acid.
Flow process 9
Reagent and condition: a) 2-halogenated acid (3.0eq); The I-hydroxybenzotriazole hydrate (HOBt, 6.0eq); 1, and the 3-DIC (DIC, 4.0eq); DMF, 25 ℃; 2-16 hour.B) 4-bromobenzene mercaptan (5.0eq); Sodium iodide (5.0eq); 1, and 8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 3.0eq); THF; 25 ℃; 12-16 hour.C) 70% t-butyl hydroperoxide (40eq); Phenylsulfonic acid (2.0eq); DCM; 25 ℃; 12-24 hour.D) mCPBA (5.0eq); DCM; 25 ℃; 12-24 hour.E) aryl boric acid (2.0eq.); Four (triphenyl phosphine) palladium (O) (0.1eq.); 10% aqueous sodium carbonate (10.0eq); DME; 80 ℃; 8 hours.F) TFA:DCM (1: 1); 25 ℃; 1 hour.
According to preceding method, make described azanol resin and the coupling of 2-halogenated acid and replace the halo group with bromobenzene mercaptan.According to preceding method bromobenzene sulfane base hydroxamic acid ester is oxidized to corresponding sulfinyl or sulfonyl hydroxamic acid ester then.Then catalyzer as four (triphenyl phosphine) palladium (O) and alkali such as yellow soda ash in the presence of, in inert solvent such as DME, about 80 ℃ by with aromatic yl acid reaction, replace the bromo group with aryl.Discharge the free hydroxamic acid according to preceding method then.
Flow process 10 is depicted as preparation is connected with the hydroxamic acid of amine groups on aromatic ring method.
Flow process 10
Figure 9881396600471
Reagent and condition: a) 2-halogenated acid (3.0eq); The I-hydroxybenzotriazole hydrate (HOBt, 6.0eq.); 1, and the 3-DIC (DIC, 4.0eq); DMF, 25 ℃; 2-16 hour.B) 4-bromobenzene mercaptan (5.0eq.); Sodium iodide (5.0eq.); 1, and 8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 3.0eq.); THF; 25 ℃; 12-16 hour.C) amine (20.0eq.); Three (dibenzalacetone)-two palladiums (O) (0.2 eq.); (S)-(-)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((S)-BINAP, 0.8eq.); Sodium tert-butoxide (18.0eq.); Dioxane; 80 ℃, 8 hours; D) TFA: DCM (1: 1); 25 ℃; 1 hour.
According to preceding method, make described azanol resin and the coupling of 2-halogenated acid and replace the halo group with bromobenzene mercaptan.Then catalyzer as three (dibenzalacetone)-two palladiums (O) and ligand as (S)-BINAP and alkali such as sodium tert-butoxide in the presence of, in inert solvent such as dioxane, replace the bromo group with amine at about 80 ℃.Discharge the free hydroxamic acid according to preceding method then.
Flow process 11 is depicted as preparation is connected with the hydroxamic acid of sulfonate ester group on aromatic ring method.
Flow process 11
Figure 9881396600481
Reagent and condition: a) 2-halogenated acid (3.0eq); The I-hydroxybenzotriazole hydrate (HOBt, 6.0eq); 1, and the 3-DIC (DIC, 4.0eq); DMF, 25 ℃, 2-16 hour.B) 4-hydroxybenzene mercaptan (5.0eq); Sodium iodide (5.0eq); 1, and 8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 3.0eq); THF; 25 ℃; 12-16 hour.C) SULPHURYL CHLORIDE (5.0eq); Triethylamine (2.0eq); DCM; 25 ℃; 8 hours.D) 70% t-butyl hydroperoxide (40eq); Phenylsulfonic acid (2.0eq); DCM; 25 ℃; 12-24 hour.E) mCPBA (5.0eq); DCM; 25 ℃; 12-24 hour.F) TFA: DCM (1: 1); 25 ℃; 1 hour.
According to preceding method, make described azanol resin and the coupling of 2-halogenated acid and replace the halo group with hydroxybenzene mercaptan.According to preceding method hydroxyphenyl thio alkylhydroxamic acid ester is oxidized to corresponding sulfinyl or sulfonyl hydroxamic acid ester then.Then in the presence of alkali such as triethylamine, in inert solvent such as DME, under about room temperature by with SULPHURYL CHLORIDE reaction, with the hydroxyl sulfonylation.Discharge the free hydroxamic acid according to preceding method then.
Provide the following example to be not used in and limit it in order to scope of the present invention to be described.HPLC purity according to the compound of bonded method preparation is represented (in the % of nm place) with the area percentage under the specified wavelength.
Embodiment 1
N-hydroxyl-2-(4-methoxyl group-phenyl sulfane base)-2-methyl-3-phenyl-propionic acid amide
(2.8g is 20mmol) and in anhydrous propanone (100ml) stirred solution of Anhydrous potassium carbonate (10g, excessive) to the 4-anisole mercaptan in round-bottomed flask, add 2-bromo-ethyl propionate (3.6g, 20mmol), under fully stirring, this reaction mixture was heated 8 hours down in refluxing.At last, with reactant cooling and filtering sylvite, concentrate above-mentioned reaction mixture.With chloroform extraction residue and water and the washing of 0.5N sodium hydroxide solution.The further thorough washing organic layer of water, dried over mgso is filtered and is concentrated, and obtains 2-(4-methoxyl group-phenyl sulfane the base)-ethyl propionate into faint yellow oily thing.Output 4.5g (94%); MS; 241 (M+H) +
In-4 ℃ to 2-(4-methoxyl group-phenyl sulfane base)-ethyl propionate (2.44g, in THF 10mmol) (100ml) stirred solution, slowly add two (front three is for silylation) lithamides (1M solution, 15ml, 15mmol).Under room temperature this orange reaction mixture was stirred 15 minutes, it is cooled to 0 ℃ then, restir is 1 hour simultaneously.Temperature of reaction is reduced to again-40 ℃, in THF, drip bromotoluene (1.72g, 10mmol).This reactant is warmed to room temperature and stirs spend the night, use the frozen water quenching then, chloroform extraction also washes with water.The dried over mgso organic layer filters and concentrates, and silica gel column chromatography is also used 10% ethyl acetate: the hexane wash-out obtains 2-(4-methoxyl group-phenyl sulfane the base)-2-methyl-3-phenyl-ethyl propionate into colorless oil.Output: 860mg, (26%); MS:331 (M+H) +
(4.12g 12mmol) is dissolved in methyl alcohol (50ml) and add 10N sodium hydroxide (20ml) with 2-(4-methoxyl group-phenyl sulfane base)-2-methyl-3-phenyl-ethyl propionate.Under room temperature, the reactant stirring is spent the night.This reaction mixture is concentrated, and with 1: 1 hexane: ether dilution and water extracted.With ice-cooled water layer and be acidified to pH3.Use the above-mentioned acid of chloroform extraction then, the dried over mgso organic layer filters and concentrates and obtains being low melting point solid 2-(4-methoxyl group-phenyl sulfane base)-2-methyl-3-phenyl-propionic acid.Output: 580mg, 16%; MS:303.2 (M+H) +
In 0 ℃ to 2-(4-methoxyl group-phenyl sulfane base)-2-methyl-3-phenyl-propionic acid (0.5g, 1.65mmol) and drip in methylene dichloride (100ml) stirred solution of DMF (2) oxalyl chloride (1.0g, 8mmol).After dripping end, this reaction mixture was stirred under room temperature 1 hour.Simultaneously, in other flask, in 0 ℃ with oxammonium hydrochloride (2.0g, 29mmol) and triethylamine (5ml, excessive) mixture at THF: water (5: 1, stirred 1 hour in 30ml).After 1 hour, the oxalyl chloride reaction mixture is concentrated, faint yellow residue is dissolved in the 10ml methylene dichloride and in 0 ℃ slowly adds in the above-mentioned azanol.Above-mentioned reaction mixture was stirred under room temperature 24 hours and concentrated.The gained residue is with chloroform extraction and water thorough washing.Products therefrom is with purification by silica gel column chromatography and use eluent ethyl acetate.Separate N-hydroxyl-2-(4-p-methoxy-phenyl sulfane the base)-2-methyl-3-phenyl-propionic acid amide that obtains to colorless solid.Mp88 ℃; Output: 300mg, 57%; MS:318 (M+H) +1H NMR (300MHz, CDCl 3): δ 1.32 (s, 3H), 3.07 (d, J=11Hz, 1H), 3.23 (d, J=11Hz, 1H), 3.79 (s, 3H), 6.83-7.36 (m, 9H).
Embodiment 2
N-hydroxyl-2-(4-methoxyl group-phenyl sulfane base)-2-phenyl-ethanamide
Prepare 2-(4-p-methoxy-phenyl sulfane base)-phenylacetic acid ethyl ester according to embodiment 1 described universal method.(7.18g, 31.4mmol) (4.4g 31.4mmol) as raw material, separates the 8.5g product that obtains to faint yellow oily thing with the 4-methoxybenzenethiol with alpha-brominated phenylacetic acid ethyl ester.Yield 90%; MS:303.1 (M+H) +
At first (3.0g 10mmol) is dissolved in methyl alcohol (50ml) and the 10N sodium hydroxide (20ml), preparation 2-(4-methoxyl group-phenyl sulfane base)-2-phenylacetic acid with 2-(4-methoxyl group-phenyl sulfane base)-phenyl-acetic acid ethyl ester.Handle the gained reaction mixture as embodiment 1.Output 1.9g, 70%.The low melting point solid.MS：273(M+H) +。
(1.05g 3.83mmol) is raw material, according to the described method of embodiment, separates obtaining N-hydroxyl-2-that 154mg is a colorless solid (4-methoxyl group-phenyl sulfane base)-2-phenyl-ethanamide with 2-(4-methoxyl group-phenyl sulfane base)-2-phenylacetic acid.155 ℃ of mp; Yield 14%; MS:290 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 3.72 (s, 3H), 4.68 (s, 1H), 6.86-7.44 (m, 9H).
Embodiment 3
2-(4-methoxyl group-phenyl sulfane base)-2, the 5-dimethyl-oneself-the obtusilic acid oxyamide
Method according to 1 second section of embodiment prepares 2-(4-methoxyl group-phenyl sulfane base)-2, the 5-dimethyl-oneself-the obtusilic acid ethyl ester.(3.5g, 14.3mmol) (2.25g 15mmol) is raw material, separates to obtain the product that 2.2g is an oily matter with the isoprene bromine with (4-methoxyl group-phenyl sulfane base)-ethyl propionate.Yield 50%; MS:310 (M+H) +
At first with 2-(4-methoxyl group-phenyl sulfane base)-2, the 5-dimethyl-oneself-obtusilic acid ethyl ester (2.0g, 6.4mmol) be dissolved in methyl alcohol (50ml) and the 10N sodium hydroxide (20ml), preparation 2-(4-methoxyl group-phenyl sulfane base)-2, the 5-dimethyl-oneself-obtusilic acid.As processing gained reaction mixture as described in the embodiment 1.Low melting point solid output is 1.9g, 99%.MS：280(M+H) +。
With 2-(4-methoxyl group-phenyl sulfane base)-2, the 5-dimethyl-oneself-(1.67g 5.8mmol) is raw material to obtusilic acid, according to the described method of embodiment, separate obtaining the 2-that 1.5g is a colorless solid (4-methoxyl group-phenyl sulfane base)-2, the 5-dimethyl-oneself-the obtusilic acid oxyamide.89 ℃ of mp; Yield 94%; MS:296 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.34 (s, 3H), 1.61 (s, 3H), 1.74 (s, 3H), 2.41-2.58 (m, 2H), 3.80 (s, 3H), 5.17 (t, J=7.5Hz, 1H), 6.86 (d, J=12.4Hz, 2H), 7.35 (d, J=12.4Hz, 2H).
Embodiment 4
N-hydroxyl-2-(4-methoxyl group-phenyl sulfane base)-3-methyl-butyramide
Prepare 2-(4-methoxyl group-phenyl sulfane base)-3-methyl-ethyl butyrate according to embodiment 1 described universal method.(20.9g, 100mmol) (14.0g 100mmol) as raw material, separates obtaining the 30g product with the 4-methoxybenzenethiol with 2-bromo-3 Methylbutanoic acid ethyl ester.Yield 99%; Faint yellow oily thing; MS:271 (M+H) +
At first (5.8g 21.6mmol) is dissolved in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), preparation 2-(4-methoxyl group-phenyl sulfane base)-3-methyl-butyric acid with 2-(4-methoxyl group-phenyl sulfane base)-3-methyl-ethyl butyrate.As processing gained reaction mixture as described in the embodiment 1.Output 5.0g, 99% low melting point solid.MS：242(M+H) +。
(4.39g 18.3mmol) is raw material, according to embodiment 1 described method, separates obtaining N-hydroxyl-2-that 1.5g is a colorless solid (4-methoxyl group-phenyl sulfane base)-3-methyl-butyramide with 2-(4-methoxyl group-phenyl sulfane base)-3-methyl-butyric acid.119 ℃ of mp; Yield 33%; MS:256 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.90-1.07 (m, 6H), 1.84-1.96 (m, 1H), 3.07 (d, J=8.8Hz, 1H), 3.75 (s, 3H), 6.88 (d, J=15Hz, 2H), 7.35 (d, J=15Hz, 2H).
Embodiment 5
N-hydroxyl-2-(4-methoxyl group-benzenesulfinyl)-2-methyl-3-phenyl-propionic acid amide
(400mg, 1.26mmol) (in embodiment 1 preparation) is dissolved in the methyl alcohol (100ml), adds 30% hydrogen peroxide (10ml) with N-hydroxyl-2-(4-methoxyl group-phenyl sulfane base)-2-methyl-3-phenyl-propionic acid amide.This reaction mixture was stirred under room temperature 48 hours, simultaneously it is cooled to 0 ℃ also with the quenching of saturated S-WAT (20ml) solution.It is muddy that this reaction mixture becomes.It was stirred 4 hours, in room-temperature water bath, concentrate then, dilute with water, chloroform extraction also washes with water.The dried over mgso organic layer filters and concentrates.Silica gel column chromatography separates title compound, uses 75% ethyl acetate: the hexane wash-out.The low melting point solid.Output: 220mg (52%); MS:334.1 (M+H) + 1H NMR (300MHz, CDCl 3): d1.11 (s, 2H), 1.22 (s, 3H), 3.84 (s, 3H), 7.00-7.61 (m, 9H).
Embodiment 6
2-(4-methoxyl group-benzenesulfinyl)-2, the 5-dimethyl-oneself-the obtusilic acid oxyamide
With 2-(4-methoxyl group-phenyl sulfane base)-2; the 5-dimethyl-oneself-obtusilic acid oxyamide (900mg; 3.0mmol) (in embodiment 3 preparation) be raw material; according to embodiment 5 described methods; separate the 2-(4-methoxyl group-benzenesulfinyl)-2 that obtains to colorless solid, the 5-dimethyl-oneself-the obtusilic acid oxyamide.Output: 104mg (10%); 108 ℃ of mp; MS:312 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.88 (s, 3H), 1.59 (s, 3H), 1.68 (s, 3H), 2.27-2.80 (m, 2H), 5.02 (t, J=7.5Hz, 1H), 7.09 (d, J=9Hz, 2H), 7.39 (d, J=9Hz, 2H).
Embodiment 7
N-hydroxyl-2-(4-methoxyl group-benzenesulfinyl)-3-methyl-butyramide
N-hydroxyl-2-(4-methoxyl group-phenyl sulfane base)-3-methyl-butyramide (1g with embodiment 4 preparations; 3.9mmol) be raw material; according to embodiment 5 described methods, separate N-hydroxyl-2-(4-methoxyl group-benzenesulfinyl)-3-methyl-butyramide that obtains to colorless solid.Output: 420mg (40%); 163 ℃ of mp; MS:272 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.89-1.12 (m, 6H), 1.63-1.74 (m, 1H), 3.13 (d, J=7Hz, 1H), 3.83 (s, 3H), 6.94-7.65 (m, 4H).
Embodiment 8
N-hydroxyl-2-(4-methoxyl group-benzenesulfinyl)-2-phenyl-ethanamide
N-hydroxyl-2-(4-methoxyl group-phenyl sulfane base)-2-phenyl-ethanamide (240mg with embodiment 2 preparations; 0.83mmol) be raw material; according to embodiment 5 described methods, separate N-hydroxyl-2-(4-methoxyl group-benzenesulfinyl)-2-phenyl-ethanamide that obtains to colorless solid.Output: 100mg (40%); 135 ℃ of mp; MS:304 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 3.75 (s, 3H), 4.38 (s, 1H), 6.92-7.69 (m, 9H).
Embodiment 9
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid amide
In round-bottomed flask, to the 4-methoxybenzenethiol (2.8g, 20mmol) and Anhydrous potassium carbonate (10g, excessive) anhydrous propanone (100ml) stirred solution in, add alpha-brominated ethyl acetate (3.3g, 20mmol), under fully stirring, this reaction mixture was heated 8 hours down in refluxing.Then, with reactant cooling and filtering sylvite, concentrate above-mentioned reaction mixture.With chloroform extraction residue and water and the washing of 0.5N sodium hydroxide solution.The further thorough washing organic layer of water, dried over mgso is filtered and is concentrated.Separate (4-methoxyl group-phenyl sulfane the base)-ethyl acetate that obtains to faint yellow oily thing.Output 4.4g (100%); MS; 227 (M+H) +
(14.0g slowly adds (4-methoxyl group-phenyl sulfane base)-ethyl acetate (4.4g, methylene dichloride 20mmol) (15ml) solution in methylene dichloride 40mmol) (100ml) stirred solution to 60% 3-chloro peroxybenzoic acid in 0 ℃.This reaction mixture becomes muddiness and stirred 6 hours under room temperature.Then this reaction mixture is diluted with hexane (300ml) and stirred 15 minutes.The filtering solid also adds to sodium sulfite solution in the organic layer, stirs after at least 3 hours, uses the chloroform extraction said mixture, washes with water.The dried over mgso organic layer filters and concentrates, and separates (4-methoxyl group-benzenesulfonyl)-ethyl acetate that obtains to colorless oil.Yield: 100%; MS:259.1 (M+H) +
To (4-methoxyl group-benzenesulfonyl)-ethyl acetate (2.5g, 10mmol), (1.8g 10mmol) and in acetone (250ml) stirred solution of 18-hat-6 (500mg) adds salt of wormwood (10g, excessive) to bromotoluene, and this mixture was refluxed 24 hours.Then, above-mentioned reaction mixture is filtered and concentrates the acetone layer.With chloroform extraction gained residue, water thorough washing, anhydrous magnesium sulfate drying, filter and concentrate.Products therefrom is used 30% ethyl acetate through purification by silica gel column chromatography: the hexane wash-out.Separate and obtain being low melting point solid 2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-ethyl propionate.Output: 3.0g, 86%; The low melting point solid; MS:349 (M+H) +
(348mg adds 10N sodium hydroxide (10ml) in methyl alcohol 1mmol) (25ml) stirred solution to 2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-ethyl propionate.Under room temperature, stirred above-mentioned reaction mixture 48 hours.Then, concentrate this reaction mixture, and neutralize carefully with dilute hydrochloric acid.With chloroform extraction gained residue, water thorough washing, dry and concentrated.Products therefrom is used ethyl acetate through purification by silica gel column chromatography: methyl alcohol (95: 5) wash-out obtains 2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid into colorless oil.Output: 250mg, 89%; MS:321 (M+H) +
(200mg 0.625mmol) is raw material, according to embodiment 1 described method, separates obtaining N-hydroxyl-2-that 150mg is a brown solid (4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid amide with 2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid.Yield: 71%; 180 ℃ of mp; MS:336 (M+H) + 1H NMR (300MHz, CDCl 3): δ 3.2 (m, 1H), 3.8 (s, 3H), 4.0-4.2 (m, 2H), 7.0-8.0 (m, 9H).
Embodiment 10
2-(4-methoxyl group-benzenesulfonyl)-caproic acid oxyamide
Prepare 2-(4-methoxyl group-phenyl sulfane base)-ethyl hexanoate according to embodiment 1 described universal method.(7g, 32mmol) (4.2g 30mmol) is raw material, separates to obtain the 8.3g product with the 4-methoxybenzenethiol with the 2-bromide ethyl caproate.Yield 98%; Faint yellow oily thing; MS:283 (M+H) +
(2.8g 10mmol) is raw material, according to the method for embodiment 9, separates obtaining the 2-that 3g is a colorless solid (4-methoxyl group-benzenesulfonyl)-ethyl hexanoate with 2-(4-methoxyl group-phenyl sulfane base)-ethyl hexanoate.Yield 95%; 62 ℃ of mp; MS:314 (M+H) +
(2g 6.3mmol) is raw material, and according to the method for embodiment 9, separation obtains 1.5g (83%) and is the 2-of colorless solid (4-methoxyl group-benzenesulfonyl)-caproic acid with 2-(4-methoxyl group-benzenesulfonyl)-ethyl hexanoate.Mp?116℃；MS：287(M+H) +。
(1.0g 3.1mmol) is raw material, according to the method for embodiment 1, separates obtaining the 2-that 700mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-caproic acid oxyamide with 2-(4-methoxyl group-benzenesulfonyl)-caproic acid.Yield: 60%; 130 ℃ of mp; MS:302 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.786 (t, J=7.2Hz, 3H), 1.1-1.3 (m, 4H), 1.6-1.8 (m, 2H), 3.7 (m, 1H), 3.9 (s, 3H), 7.2 (d, J=11Hz, 2H), 7.8 (d, J=11Hz, 2H), 9.3 (s, 1H), 10.9 (s, 1H).
Embodiment 11
2-(4-methoxyl group-benzenesulfonyl)-tetradecanoic acid oxyamide
Prepare 2-(4-methoxyl group-phenyl sulfane base)-ethyl myristate according to embodiment 1 described universal method.(5.0g, 14.9mmol) (1.9g 13.4mmol) is raw material, separates to obtain the 5.0g product with the 4-methoxybenzenethiol with corresponding 2-bromotetradecane acetoacetic ester.Yield 98%; Faint yellow oily thing; MS:393 (M+H) +
(3.9g 10mmol) is raw material, according to the method for embodiment 9, separates obtaining the 2-that 3.2g is a colorless solid (4-methoxyl group-benzenesulfonyl)-ethyl myristate with 2-(4-methoxyl group-phenyl sulfane base)-ethyl myristate.Yield 76%; Oily matter; MS:425 (M+H) +
(2.5g 5.9mmol) is raw material, and according to the method for embodiment 9, separation obtains 2.0g (85%) and is the 2-of colorless solid (4-methoxyl group-benzenesulfonyl)-tetradecanoic acid with 2-(4-methoxyl group-benzenesulfonyl)-ethyl myristate.mp?82℃；MS：397(M+H) +。
(1.14g 2.9mmol) is raw material, according to the method for embodiment 1, separates obtaining the 2-that 670mg is a pale solid (4-methoxyl group-benzenesulfonyl)-tetradecanoic acid oxyamide with 2-(4-methoxyl group-benzenesulfonyl)-tetradecanoic acid.Yield: 57%; 114 ℃ of mp; MS:414 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.85 (t, J=7Hz, 3H), 1.16-1.27 (m, 20H), 1.66 (m, 2H), 3.62-3.70 (m, 1H), 3.87 (s, 3H), 7.12 (d, J=15Hz, 2H), 7.73 (d, J=15Hz, 2H).
Embodiment 12
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid amide
To 2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-ethyl propionate (1.0g; 3mmol) (embodiment 9), methyl-iodide (1ml; excessive) and acetone (250ml) stirred solution of 18-hat-6 (500mg) in add salt of wormwood (10g, excessive), with this reaction mixture refluxed 24 hours.After the end, filter above-mentioned reaction mixture, concentrate the acetone layer.With chloroform extraction gained residue and water thorough washing, anhydrous magnesium sulfate drying, filter and concentrate.Products therefrom is used 30% ethyl acetate through purification by silica gel column chromatography: the hexane wash-out obtains 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-phenyl-ethyl propionate into colorless oil.Output 1.0g, 98%; MS:349 (M+H) +
(900mg 2.7mmol) is raw material, according to embodiment 9 described methods, separates obtaining 850mg (quantitatively) 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid with 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-phenyl-ethyl propionate.Colorless oil, MS:335 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid (900mg; 2.7mmol) be raw material; according to embodiment 1 described method, separate N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-phenyl-propionic acid amide that obtains to brown solid.Yield: 48%; 58 ℃ of mp; MS:350 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.4 (s, 3H), 3.1 (d, J=9Hz, 1H), 3.6 (d, J=9Hz, 1H), 3.9 (s, 3H), 6.8-7.8 (m, 9H).
Embodiment 13
2-(4-methoxyl group-benzenesulfonyl)-2, the 5-dimethyl-oneself-the obtusilic acid oxyamide
(embodiment 1, and 12g 50mmol) is raw material, according to the method for embodiment 9, separates that to obtain 12g be semi-solid 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate with 2-(4-methoxyl group-phenyl sulfane base)-ethyl propionate.Yield 100%; MS:256.1 (M+H) +
According to embodiment 12 described methods, (1g, 3.6mmol) (1.0g 6mmol) is raw material, preparation 2-(4-methoxyl group-benzenesulfonyl)-2,5-dimethyl-own-obtusilic acid ethyl ester with the isoprene bromine with 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate.Output: 1.0g, 81%; Colorless oil; MS:341 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2; the 5-dimethyl-oneself-(900mg 2.6mmol) is raw material to the obtusilic acid ethyl ester, according to embodiment 9 described methods; it is semisolid 2-(4-anisole alkylsulfonyl)-2 that separation obtains 800mg (96%), the 5-dimethyl-oneself-obtusilic acid.MS：313(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-2; the 5-dimethyl-oneself-(1.0g 3.2mmol) is raw material to obtusilic acid, according to embodiment 1 described method; it is low melting point solid 2-(4-methoxyl group-benzenesulfonyl)-2 that separation obtains 700mg, the 5-dimethyl-oneself-the obtusilic acid oxyamide.Yield 67%; MS:328 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.3 (s, 3H), 1.5 (d, J=6.2Hz, 6H), 2.5-3.0 (m, 2H), 3.9 (s, 3H), 7.0 (d, J=11Hz, 2H), 7.8 (d, J=11Hz, 2H).
Embodiment 14
3-(biphenyl-4-yl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide
Method according to embodiment 12; with (2.7g; 10mmol) (2.5g 12mmol) is raw material, preparation 3-(biphenyl-4-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate for 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate and 4-(chloro methyl) biphenyl.Output 4.0g, 91%; Colorless oil; MS:438 (M+H) +
With 3-(biphenyl-4-yl)-2-(4-methoxyl group-benzenesulfonyl)-2 Methylpropionic acid ethyl ester (3g; 6.8mmol) be raw material; according to embodiment 9 described methods, separation obtains 2.5g (89%) and is the 3-of colorless solid (biphenyl-4-yl)-2-(4-methoxyl group-benzenesulfonyl)-2 Methylpropionic acid.mp?161℃；MS：411(M+H) +。
With 3-(biphenyl-4-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid (2.0g; 4.8mmol) be raw material; according to embodiment 1 described method, separate obtaining the 3-that 1.2g is a colorless solid (biphenyl-4-yl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide.Yield: 58%; 177 ℃ of mp; MS:426 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.4 (s, 3H), 3.2 (d, J=9Hz, 1H), 3.7 (d, J=9Hz, 1H), 3.9 (s, 3H), 7.0-7.8 (m, 13H), 9.7 (bs, 1H).
Embodiment 15
2-(4-methoxyl group-benzenesulfonyl)-2,5,9-trimethylammonium-last of the ten Heavenly stems-4,8-diolefinic acid oxyamide
According to embodiment 12 described methods, with (2.7g, 2-10mmol) (4-methoxyl group-benzenesulfonyl)-ethyl propionate and geranyl bromine (3.0g; 13mmol) be raw material, preparation 2-(4-methoxyl group-benzenesulfonyl)-2,5; 9-trimethylammonium-last of the ten Heavenly stems-4,8-diolefinic acid ethyl ester.Output 4.0g, 98%; Colorless oil; MS:409 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2,5,9-trimethylammonium-last of the ten Heavenly stems-4,8-diolefinic acid ethyl ester (3g; 7.4mmol) be raw material, according to the method for embodiment 9, separation obtains 2.8g (96%) and is the 2-of colorless oil (4-methoxyl group-benzenesulfonyl)-2; 5,9-trimethylammonium-last of the ten Heavenly stems-4,8-diolefinic acid.MS：379(M-H) -。
With 2-(4-methoxyl group-benzenesulfonyl)-2,5,9-trimethylammonium-last of the ten Heavenly stems-4,8-diolefinic acid (2.0g; 5.2mmol) be raw material, according to the method for embodiment 1, separate obtaining the 2-that 1.8g is a colorless oil (4-methoxyl group-benzenesulfonyl)-2; 5,9-trimethylammonium-last of the ten Heavenly stems-4,8-diolefinic acid oxyamide.Yield: 88%; MS:396 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.4 (s, 3H), 1.6 (s, 3H), 1.65 (s, 3H), 1.7 (s, 3H), 2.0-3.1 (m, 6H), 3.9 (s, 3H), 5.5 (m, 2H), 6.98 (d, J=9.0Hz, 2H), 7.7 (d, J=9.0Hz, 2H).
Embodiment 16
3-cyclohexyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide
According to the method for embodiment 12, so that (2.7g, 10mmol) (1.8g 10mmol) is raw material, preparation 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate for 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate and bromo-methylcyclohexane.Output 3.5g, 95%; Yellow oil; MS:369 (M+H) +
With 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate (3g; 8.1mmol) be raw material; according to embodiment 9 described methods, separation obtains 2.5g (90%) and is the 3-cyclohexyl-2-of colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid.mp?116℃；MS：341(M+H) +。
With 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid (2.0g; 5.8mmol) be raw material; according to embodiment 1 described method, separate obtaining 3-cyclohexyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide that 1.1g is a colorless solid.Yield: 55%; 58 ℃ of mp; MS:356 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.4 (s, 3H), 2.3-1.0 (m, 13H), 3.9 (s, 3H), 7.0 (d, 8.8Hz, 2H), 7.69 (d, 9.0Hz, 2H).
Embodiment 17
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-
Phenyl]-propionic acid amide
Method according to embodiment 12; with (2.7g; 10mmol) 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate and 4-(2-piperidines-1-base-oxyethyl group)-benzyl chloride (2.9g 10mmol) is feedstock production 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate.Output 4.8g, 98%; Brown oil; MS:490 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate (4.0g; 7.9mmol) be raw material; according to the method for embodiment 9, separate obtain 3.5g (yield: 94%) be the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid.Mp?106℃；MS：462．5(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid (2.0g; 4.2mmol) be raw material; according to embodiment 1 described method, separate obtaining N-hydroxyl-2-that 1g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid amide.Output: 1g, 48%; 98 ℃ of mp; MS:477 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.2 (s, 3H), 3.5-1.5 (m, 16H), 3.9 (s, 3H), 4.4 (m, 1H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 18
2-[4-(2-azatropylidene ((azepan)-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzene sulfonyl
Base)-the propionic acid oxyamide
Method according to embodiment 12; with (2.7g; 10mmol) 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate and 1-[2-(4-chloro methyl-phenoxy group) ethyl]-azatropylidene (azepane) (3.03g; 10mmol) be raw material, preparation 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate.Output 4.5g, 90%; Brown oil; MS:504 (M+H) +
With 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (4.0g; 7.9mmol) be raw material; according to the method for embodiment 9, separate obtain 3.5g (yield: 94%) be semisolid 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-propionic acid.MS：476(M+H) +。
With 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-propionic acid (2.0g; 4.2mmol) be raw material; according to embodiment 1 described method, separate obtaining the 2-[4-that 1g is a colorless solid (2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-propionic acid oxyamide.Output: 1.8g, 87%; 68 ℃ of mp; MS:491 (M+H) + 1HNMR (300MHz, CDCl 3): δ 1.23 (s, 3H), 3.5-1.7 (m, 18H), 3.8 (s, 3H), 4.2 (m, 1H), 6.4-7.89 (m, 8H), 10.9 (bs, 1H).
Embodiment 19
2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-valeric acid hydroxyl
The base acid amides
Universal method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-Valeric acid ethylester (3.5g; 11.7mmol) and 1-[2-(4-chloro methyl-phenoxy group)-ethyl]-azatropylidene (3.9g; 12.8mmol) be raw material, preparation 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-Valeric acid ethylester.Output 2.58g (42%); Brown oil; MS:532.4 (M+H) +
At first with 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-Valeric acid ethylester (2g; 3.76mmol) be dissolved in methyl alcohol (300ml) and 10N sodium hydroxide (15ml), prepare 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-valeric acid.Method with embodiment 1 is handled the gained mixture.Output 830mg (44%); Brown solid; 55 ℃ of mp; MS:504.4 (M+H) +
With 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-valeric acid (690mg; 1.37mmol) be raw material; according to embodiment 1 described method, separate obtaining the 2-[4-that 240mg is a yellow solid (2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-valeric acid oxyamide.Yield 34%; 85 ℃ of mp; MS:519.2 (M+H) + 1H NMR (300MHz, DMSO-d 6): d0.71 (t, J=7.3Hz, 3H), 0.78-1.77 (m, 16H), 3.04-3.46 (m, 4H), 3.87 (s, 3H), 4.26 (m, 2H), 6.87 (d, J=8.7Hz, 2H), 7.14 (m, 4H), 7.71 (d, J=9Hz, 2H), 9.07 (s, 1H), 10 (s, 1H).
Embodiment 20
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, the N-diisopropylaminoethyl-
Oxyethyl group)-phenyl]-propionic acid amide
Method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (5.4g; 20mmol) and 4-(2-N; N-diisopropylaminoethyl-oxyethyl group)-benzyl chloride (6.1g; 20mmol) be raw material; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diisopropylaminoethyl-oxyethyl group)-phenyl]-ethyl propionate.Output 8.9g, 88%; Yellow oil; MS:506.5 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diisopropylaminoethyl-oxyethyl group)-phenyl]-ethyl propionate (4.0g; 7.9mmol) be raw material; method according to embodiment 9; separate obtain 3.5g (yield: 92%) be the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diisopropylaminoethyl-oxyethyl group)-phenyl]-propionic acid.Mp?68℃；MS：478．6(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diisopropylaminoethyl-oxyethyl group)-phenyl]-propionic acid (2.0g; 4.1mmol) be raw material; according to embodiment 1 described method; separate and obtain the 2-that 1g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diisopropylaminoethyl-oxyethyl group)-phenyl]-propionic acid amide.Output: 1g, 49%; 98 ℃ of mp (hydrochloride); MS:493 (M+H) + 1H NMR (300NHz, CDCl 3): δ 1.2 (s, 3H), 1.3 (d, 6H), 1.4 (d, 6H), 3.5-1.5 (m, 6H), 3.9 (s, 3H), 4.4 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 21
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-second
The oxygen base)-phenyl]-propionic acid amide
Method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (5.4g; 20mmol) and 4-(2-N; N-diethylin-oxyethyl group)-benzyl chloride (5.5g; 20mmol) be raw material; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl]-ethyl propionate.Output 8.5g, 89%; Brown oil; MS:478.6 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-ethyl propionate (3.5g; 7.7mmol) be raw material; method according to embodiment 9; separate obtain 3.0g (yield: 85%) be the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl]-propionic acid.Mp?96-98℃；MS：450．5(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-propionic acid (2.0g; 4.4mmol) be raw material; according to embodiment 1 described method; separate and obtain the 2-that 1g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl]-propionic acid amide.Output: 1g, 48%; Mp 56-59 ℃ (hydrochloride); MS:465.5 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.1 (t, 6H), 1.3 (s, 3H), 3.2-3.9 (m, 8H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 22
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-piperidines-1-base-oxyethyl group)-
Phenyl]-propionic acid amide
Method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (5.2g; 20mmol) and 3-(2-piperidines-1-base-oxyethyl group)-benzyl chloride (6.0g; 20mmol) be raw material, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate.Output 8.2,83%; Brown oil; MS:490 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate (6.0g; 12.2mmol) be raw material; according to the method for embodiment 9, separate obtain 4.9g (yield: 79%) be the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid.Mp?112℃；MS：462．5(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid (3.0g; 6.5mmol) be raw material; according to embodiment 1 described method, separate obtaining the 2-that 1.8g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid amide.Output: 1.8g, 58%; 74 ℃ of mp; MS:477 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.25 (s, 3H), 1.6-1.8 (m, 6H), 2.5-3.7 (m, 8H), 3.9 (s, 3H), 4.4 (t, 2H), 6.7-7.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 23
3-(4-{3-[4-(3-chloro-phenyl)-piperazine-1-yl] propoxy-}-phenyl)-N-hydroxyl-2-(4-first
Oxygen base-benzenesulfonyl)-2-methyl-propionic acid amide
Method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (2.72g; 10mmol) and 1-[2-(4-chloro methyl-phenoxy group)-ethyl]-4-(3-chloro-phenyl)-piperazine (4.2g; 11mmol) be raw material, preparation 3-(4-{3-[4-(3-chloro-phenyl)-piperazine-1-yl] propoxy-}-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate.Output 5.5,89%; Brown oil; MS:616 (M+H) +
With 3-(4-{3-[4-(3-chloro-phenyl)-piperazine-1-yl] propoxy-}-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate (4.0g; 6.5mmol) be raw material; according to the method for embodiment 9, separate obtain 3.0g (yield: 78%) for the 3-of colourless crystallization (4-{3-[4-(3-chloro-phenyl)-piperazine-1-yl]-propoxy--phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid.Mp?196℃；MS：588．1(M+H) +。
With 3-(4-{3-[4-(3-chloro-phenyl)-piperazine-1-yl] propoxy-}-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid (3.0g; 5.1mmol) be raw material; according to embodiment 1 described method, separate obtain the 3-that 1.8g is a faint yellow solid (4-{3-[4-(3-chloro-phenyl)-piperazine-1-yl] propoxy-}-phenyl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide.Output: 1.8g, 55%; 122 ℃ of mp (hydrochloride); MS:640 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.2 (s, 3H), 3.4-1.5 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 6.5-8.2 (m, 12H), 10.3 (bs, 1H).
Embodiment 24
2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-
Oneself-the obtusilic acid oxyamide
To (4-methoxyl group-benzenesulfonyl)-ethyl acetate (5.16g; 20mmol), isoprene bromine (3.0g; 20mmol) and in acetone (250ml) stirred solution of 18-hat-6 (500mg) add salt of wormwood (10g, excessive), with this reaction mixture refluxed 24 hours.After the end, filter above-mentioned reaction mixture, concentrate the acetone layer.With chloroform extraction gained residue and water thorough washing, anhydrous magnesium sulfate drying, filter and concentrate.Products therefrom is used 30% ethyl acetate through purification by silica gel column chromatography: the hexane wash-out.Separate product 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-own-obtusilic acid ethyl ester that obtains to colorless oil.Output 3.0g, 93%.
Method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-own-obtusilic acid ethyl ester (3.26g; 10mmol) and 4-(2-morpholine-1-base-oxyethyl group)-benzyl chloride (3.0g; 11mmol) be raw material, preparation 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-oneself-the obtusilic acid ethyl ester.Output 4.5,82%; Brown oil; MS:546 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-oneself-obtusilic acid ethyl ester (3.0g; 5.5mmol) be raw material; according to the method for embodiment 9, separate obtain 2.1g (yield: 75%) be semisolid 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-oneself-obtusilic acid.MS：518．6(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-oneself-obtusilic acid (1.0g; 1.9mmol) be raw material; according to embodiment 1 described method, separate obtaining the 2-that 450mg is a faint yellow solid (4-methoxyl group-benzenesulfonyl)-5-methyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-oneself-the obtusilic acid oxyamide.Output: 450mg, 45%; Mp92 ℃ (hydrochloride); MS:570 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.3 (d, 3H), 1.65 (d, 2H), 3.5-1.8 (m, 14H), 3.9 (s, 3H), 4.5 (m, 2H), 5.4 (m, 1H), 6.7-7.9 (m, 8H), 11.5 (bs, 1H).
Embodiment 25
N-hydroxyl-2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-second
The oxygen base)-phenyl]-propionic acid amide
To the 4-hydroxythiophenol (12.6g, 100mmol) and triethylamine (15.0g, drip in the stirred solution of chloroform 150mmol) (400ml) the 2-ethyl bromide (18.2g, 100mmol).With this reaction mixture refluxed 1 hour, be cooled to room temperature.Wash above-mentioned reaction mixture with water, dry and concentrated.Separate 2-(4-hydroxyl-phenyl sulfane the base)-ethyl propionate that obtains to colorless oil.Output: 22.0g, 99%, MS:227 (M+H).
(11.3g 50mmol) and in acetone (300ml) stirred solution of salt of wormwood (50g, excessive) adds iodoethane (20ml, excessive), refluxes 8 hours to 2-(4-hydroxyl-phenyl sulfane base)-ethyl propionate.After the end, filter above-mentioned reaction mixture and concentrated.With chloroform extraction gained residue and water thorough washing.Dry and concentrated.Separate product 2-(4-oxyethyl group-phenyl sulfane the base)-ethyl propionate that obtains to colorless oil.Output: 12.0g, 98%; MS:255 (M+H).
According to 9 second sections described methods of embodiment, 2-(4-oxyethyl group-phenyl sulfane base)-ethyl propionate is converted into 2-(4-oxyethyl group-benzenesulfonyl)-ethyl propionate
Method according to embodiment 12; with 2-(4-oxyethyl group-benzenesulfonyl)-ethyl propionate (3.5g; 12.2mmol) and 4-(2-N; N-diethylin-oxyethyl group)-benzyl chloride (3.5g; 12.2mmol) be raw material; preparation 2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl]-ethyl propionate.Output 4.8g, 80%; Brown oil; MS:492.6 (M+H) +
With 2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-ethyl propionate (4.0g; 8.1mmol) be raw material; method according to embodiment 9; separate obtain 3.2g (yield: 80%) be colourless semisolid 2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl]-propionic acid.MS：464．5(M+H) +。
With 2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-propionic acid (2.0g; 4.3mmol) be raw material; according to embodiment 1 described method; it is colourless low melting point solid 2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl that separation obtains 1.2g]-propionic acid amide.Output: 1.2g, 57%; (hydrochloride); MS:478.5 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.9 (t, 3H), 1.1 (t, 6H), 1.3 (s, 3H), 3.2-3.9 (m, 8H), 3.9 (s, 3H), 4.3 (s, 2H), 6.5-7.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 26
(4E)-and 2-(4-methoxyl group-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholine-4-base-ethoxy
Base)-benzyl]-last of the ten Heavenly stems-4,8-diolefinic acid oxyamide
To (4-methoxyl group-benzenesulfonyl)-ethyl acetate (5.16g, 20mmol), (4.2g 20mmol) and in the stirred solution of the acetone (250ml) of 18-hat-6 (500mg) adds salt of wormwood (10g, excessive) to spiceleaf grass bromine, and this reactant was refluxed 24 hours.After the end, above-mentioned reaction mixture is filtered, concentrate the acetone layer.With chloroform extraction gained residue, water thorough washing, anhydrous magnesium sulfate drying, filter and concentrate.Through the purification by silica gel column chromatography products therefrom, use 30% ethyl acetate: the hexane wash-out.Separate the product 2-(4-methoxyl group-benzenesulfonyl)-5 obtain to colorless oil, 9-dimethyl-last of the ten Heavenly stems-4,8-diolefinic acid ethyl ester.Output: 7.0g, 89%.
According to embodiment 12 described methods; with (1.0g; 2.5mmol) 2-(4-methoxyl group-benzenesulfonyl)-5; 9-dimethyl-last of the ten Heavenly stems-4; (800mg 2.5mmol) is raw material to 8-diolefinic acid ethyl ester and 4-(2-morpholine-1-base-oxyethyl group)-benzyl chloride, preparation 2-(4-methoxyl group-benzenesulfonyl)-5; 9-dimethyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-last of the ten Heavenly stems-4,8-diolefinic acid ethyl ester.Output 1.2g, 76%; Brown oil; MS:614 (M+H) +
With 2-(4-methoxyl group-benzenesulfonyl)-5; 9-dimethyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-last of the ten Heavenly stems-4; 8-diolefinic acid ethyl ester (2.0g; 3.2mmol) be raw material; method according to embodiment 9; separate obtain 1.5g (yield: 80%) be semisolid 2-(4-methoxyl group-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-last of the ten Heavenly stems-4, the 8-diolefinic acid.MS：586．6(M+H) +。
With 2-(4-methoxyl group-benzenesulfonyl)-5; 9-dimethyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-last of the ten Heavenly stems-4; 8-diolefinic acid (1.0g; 1.7mmol) be raw material; method according to embodiment 1; separate and obtain (4E)-2-that 550mg is a faint yellow solid (4-methoxyl group-benzenesulfonyl)-5,9-dimethyl-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-last of the ten Heavenly stems-4,8-diolefinic acid oxyamide.Output: 550mg, 53%; 61 ℃ of mp (hydrochloride); MS:638 (M+H) +
Embodiment 27
2-[4-(2-diethylin-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-caproic acid hydroxyl
Acid amides
Universal method according to embodiment 12; with 2-(4-methoxyl group-benzenesulfonyl)-ethyl hexanoate (4g; 12.7mmol) and [2-(4-chloro methyl-phenoxy group)-ethyl]-diethylamine (3.38g; 14mmol) be raw material, preparation 2-[4-(2-diethylin-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-ethyl hexanoate.Output 8.21g crude product (100%); Brown oil; MS:520.4 (M+H) +
At first with 2-[4-(2-diethylin-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-ethyl hexanoate (8g; 15.4mmol) be dissolved in methyl alcohol (200ml) and 10N sodium hydroxide (30ml), prepare 2-[4-(2-diethylin-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-caproic acid.The gained mixture is pressed embodiment 1 described method and is handled.Output: 3.88g crude product (51%); Brown oil; MS:492 (M+H) +
With 2-[4-(2-diethylin-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-caproic acid (3.88g; 7.89mmol) be raw material; according to embodiment 1 described method; separate obtaining 1,800mg is 2-[4-(2-diethylin-oxyethyl group)-benzyl of pale yellow powder]-2-(4-methoxyl group-benzenesulfonyl)-caproic acid oxyamide.Yield 20%; 67 ℃ of mp; MS:507.4 (M+H) + 1HNMR (300MHz, DMSO-d 6): δ 0.75 (t, J=7.1Hz, 3H), 1.05 (m, 2H), 1.23 (t, J=7.2Hz, 6H), 1.37-1.91 (m, 2H), 3.13 (m, 4H), 3.38-3.51 (m, 4H), 3.87 (s, 3H), 4.3 (t, J=4.8Hz, 2H), 6.88 (d, J=8.7Hz, 2H), 7.15 (m, 4H), 7.7 (d, J=9Hz, 2H), 9.07 (s, 1H), 10.1 (s, 1H).
Embodiment 28N-hydroxyl-2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-benzene
Base]-propionic acid amide
Method according to embodiment 12; preparation 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate; adopt (3.1g; 10mmol) 2-(4-n-butoxy-benzenesulfonyl)-ethyl propionate (according to embodiment 27 described methods by the preparation of 2-(4-hydroxyl-phenyl sulfane base)-ethyl propionate and n-butyl bromide) and 4-(2-piperidines-1-base-oxyethyl group)-(3.0g is 10.1mmol) as raw material for benzyl chloride.Output 4.5g, 84%; Brown oil; MS:532.7 (M+H) +
According to embodiment 9 described methods; with 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate (5.0g; 9.4mmol) be raw material, separate to obtain 4.2g (productive rate 88%) and be the 2-of colorless solid (4-just-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid.MS：504．6(M+H) +。
Adopt 2-(4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid (3.0g; 5.9mmol) and according to embodiment 1 described method, separate obtaining the 2-that 1.3g is a colorless solid (4-n-butoxy-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid amide.65 ℃ of MP; Output: 1.3g, 42%; (HCl salt); MS:478.5 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.9 (t, 3H), 1.2 (s, 3H), 1.3-1.9 (m, 10H), 2.8-4.5 (m, 12H), 6.8-7.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 29N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-N, N-diethylin-oxyethyl group)-
Phenyl]-propionic acid amide
Method according to embodiment 12; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-N; N-diethylin-oxyethyl group)-phenyl]-ethyl propionate; adopt (5.0g; 18mmol) 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate and 3-(2-N; N-diethylin-oxyethyl group)-(4.9g is 18mmol) as raw material for benzyl chloride.Output 8.1g, 93%; Brown oil; MS:478.1 (M+H) +
According to embodiment 9 described methods; with 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-N; N-diethylin-oxyethyl group)-phenyl]-ethyl propionate (8.1g; 16.9mmol); it is colourless semisolid 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-N, N-diethylin-oxyethyl group)-phenyl that separation obtains 6.7g (productive rate 88%)]-propionic acid.MP：78-81；MS：450．1(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-N; N-diethylin-oxyethyl group)-phenyl]-propionic acid (6.7g; 15mmol) and according to embodiment 1 described method; it is colourless low melting point solid 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-N, N-diethylin-oxyethyl group)-phenyl that separation obtains 1.5g]-propionic acid amide.Output: 1.5g, 21%; (HCl salt); MS:450.5 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.21 (t, 6H), 1.26 (s, 3H), 3.18-3.24 (m, 2H), 3.38 (m, 4H), 3.43-3.46 (m, 2H), 3.80 (s, 3H), 4.30 (s, 2H), 6.76-6.78 (d, 2H), 6.84-7.2 (m, 6H), 10.3 (bs, 1H).
Embodiment 30N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine-1-base-oxyethyl group)-benzene
Base]-propionic acid amide
Method according to embodiment 12; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine-1-base-oxyethyl group)-phenyl]-ethyl propionate; adopt (5.2g; 20mmol) 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate and 3-(2-morpholine-1-base-oxyethyl group)-(6.0g is 20mmol) as raw material for benzyl chloride.Output 9.1g, 93%; Brown oil; MS:492 (M+H) +
According to embodiment 9 described methods; with 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine-1-base-oxyethyl group)-phenyl]-ethyl propionate (10.0g; 20.3mmol), separation obtains 8.0g (productive rate 86%) and is the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine-1-base-oxyethyl group)-phenyl]-propionic acid.MS：464．5(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine-1-base-oxyethyl group)-phenyl]-propionic acid (4.55g; 9.8mmol) and according to embodiment 1 described method, separate obtaining the 2-that 440mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[3-(2-morpholine-1-base-oxyethyl group)-phenyl]-propionic acid amide.Output: 440mg, 9%; 63 ℃ of mp; MS:479.5 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.26 (s, 3H), 3.18-3.8 (m, 12H), 3.9 (s, 3H), 4.4 (m, 2H), 6.7-8.8 (m, 8H), 10.8 (bs, 1H).
Embodiment 316-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-oneself
The acid oxyamide
Method according to embodiment 9; preparation 6-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl hexanoate; adopt (5.0g; 20mmol) (5.66g is 20mmol) as raw material for 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate and 4-phthalimido (phathalimido) butyl bromide.Output 8.4g, 97%; Colorless oil; MS:474 (M+H).
According to embodiment 9 described methods; with 6-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl hexanoate (8.4g; 17.7mmol); separation obtains 6.95g (productive rate 88%) and is the 6-of colorless oil (1,3-dioxo-1,3-dihydro-isoindole-2-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-caproic acid.MS：446(M-H) -。
Adopt 6-(1; 3-dioxo-1; 3-dihydro-isoindole-2-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-caproic acid (4.9g; 11mmol) and according to embodiment 1 described method; it is light brown solid 6-(1 that separation obtains 3.1g; 3-dioxo-1,3-dihydro-isoindole-2-yl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-caproic acid oxyamide.Productive rate: 46%; Mp 146-148 ℃; MS:461.2 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.55 (s, 3H), 1.61-3.77 (m, 8H), 3.82 (s, 3H), 6.92-8.21 (m, 8H), 10.70 (bs, 1H), 11.20 (bs, 1H).
Embodiment 323-[4-(2-diethylin-oxyethyl group)-phenyl]-2-(4-furans-2-base-benzenesulfonyl)-N-hydroxyl-2-first
Base-propionic acid amide
To the 4-bromobenzene thiophenol that stirs (19.0g, 100mmol) and triethylamine (15.0g, dropping 2-bromoethyl propionic ester in chloroform 150mmol) (400ml) solution (18.2g, 100mmol).With this reaction mixture refluxed 1 hour, be cooled to room temperature then.Wash this reaction mixture with water, dry and concentrated, separate 2-(4-bromo-phenyl sulfane the base)-ethyl propionate that obtains to colorless oil.Output: 28.0g, 99%, MS:290 (M+H).
According to the 2nd section described method of embodiment 9,2-(4-bromo-phenyl sulfane base)-ethyl propionate is converted into 2-(4-bromo-phenyl sulfonyl)-ethyl propionate.
2-(4-bromo-phenyl sulfonyl)-ethyl propionate in the toluene (250mg) of the degassing (6.4g, 20mmol), 2-(tributyl tin alkyl) furans (7.5g, 21mmol) and (Ph 3P) 4Pd (500mg) mixed-liquor return 8 hours.Filter and concentrate by C salt at last.Through the purification by silica gel column chromatography product, use 50% ethyl acetate: the hexane wash-out.Colorless oil.Output: 5.9g, 95%, MS:309 (M+H).
According to embodiment 12 described methods; preparation 2-(4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-ethyl propionate; adopt (3.08; 10.0mmol) 2-(4-(2-furyl-benzenesulfonyl)-ethyl propionate and 4-(2-N; N-diethylin-oxyethyl group)-(3.5g is 12.2mmol) as raw material for benzyl chloride.Output 5.0g, 97%; Brown oil; MS:514.6 (M+H) +
According to embodiment 9 described methods; with 2-(4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-ethyl propionate (5.1g; 10.0mmol); separate obtain 3.8g (productive rate 78%) for the 2-of colorless solid (4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl]-propionic acid.MP：58℃，MS：486．5(M+H) +。
Adopt 2-(4-(2-furyl-benzenesulfonyl)-2-methyl-3-[4-(2-N; N-diethylin-oxyethyl group)-phenyl]-propionic acid (5.0g; 10.3mmol) and according to embodiment 1 described method; it is colourless low melting point solid 2-(4-oxyethyl group-benzenesulfonyl)-2-methyl-3-[4-(2-N, N-diethylin-oxyethyl group)-phenyl that separation obtains 1.2g]-propionic acid amide.Output: 3.2g, 62%; (HCl salt); MS:502 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.23 (t, 6H), 1.4 (s, 2H), 2.8 (q, 4H), 3.0 (t, 2H), 4.1 (t, 2H), 6.5-8.0 (m, 7H).
Embodiment 33N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-butyryl
Amine
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzene sulfane base)-ethyl butyrate.Employing 2-bromo ethyl butyrate (10.71g, 55mmol) (7g 50mmol) is raw material, 5.19g (40%) with the 4-methoxybenzenethiol; Clarification oily matter; MS:255.2 (M+H) +
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-ethyl butyrate.(4-methoxyl group-benzene sulfane base)-(5g 20mmol) is raw material to ethyl butyrate to adopt 2-.Output 5.74g (100%); Clarified oil; MS:287.1 (M+H) +
Method according to embodiment 12; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-ethyl butyrate; adopt (3.5g; 12.2mmol) 2-(4-methoxyl group-benzenesulfonyl)-ethyl butyrate and 4-[2-(chloromethyl-phenoxy group)-ethyl]-(2.34g is 6.7mmol) as raw material for morpholine.Output 5.7g, 100%; Brown oil; MS:506.4 (M+H) +
According to embodiment 9 described methods; with 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-ethyl butyrate (5.54g; 11mmol), separate that to obtain 2.9g (productive rate 55%) be colourless semisolid 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-butyric acid.MS：478，3(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-butyric acid (2.6g; 5.4mmol) and according to embodiment 1 described method, separate obtaining N-hydroxyl-2-that 510mg is a brown solid (4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-butyramide.Productive rate 2%; 51 ℃ of mp; MS:493.3 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.90 (t, J=7.2Hz, 3H), 1.69-1.96 (m, 4H), 2.67 (t, 2H), 3.34 (m, 8H), 3.87 (s, 3H), 4.04 (m, 2H), 6.8 (d, J=8.7Hz, 2H), 7.14 (m, 4H), 7.73 (d, J=4.7Hz, 2H), 9.08 (s, 1H), 10.8 (s, 1H).
Embodiment 34
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-piperidines-1-base-oxyethyl group)
-benzyl]-butyramide
Method according to embodiment 12; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-ethyl butyrate; adopt (1.0g; 3.33mmol) 2-(4-methoxyl group-benzenesulfonyl)-ethyl butyrate and 1-[2-(4-chloromethyl-phenoxy group)-ethyl]-(0.85g is 3.36mmol) as raw material for piperidines.Output 1.07g, 62%; Brown oil; MS:504.4 (M+H) +
According to embodiment 9 described methods; with 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-ethyl butyrate (3.7g; 7.3mmol), it is colourless semisolid 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-piperidines-1-base-oxyethyl group)-benzyl that separation obtains 2.2g (productive rate 63%)]-butyric acid.MS：476(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-butyric acid (2.2g; 4.63mmol) and according to embodiment 1 described method, separate obtaining N-hydroxyl-2-that 360mg is a brown solid (4-methoxyl group-benzenesulfonyl)-2-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-butyramide.Productive rate 16%; 75 ℃ of mp; MS:491.3 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.90 (t, J=7.1Hz, 3H), 1.36-1.96 (m, 4H), and 2.4-2.63 (m, 14H), 3.87 (s, 3H), 4.01 (t, J=5.9Hz, 2H), 6.8 (d, J=8.5Hz, 2H), 7.11 (m, 4H), 7.71 (d, J=8.8Hz, 2H), 9.09 (s, 1H), 10.8 (s, 1H).
Embodiment 352-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-the valeric acid oxyamide
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzene sulfane base)-Valeric acid ethylester.With the 2-bromo pentane acid B ester (8.23g, 39.3mmol) and the 4-methoxybenzenethiol (5g, 35.7mmol) as raw material, 10.46g (100%); Clarified oil; MS:269 (M+H) +
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-Valeric acid ethylester.(4-methoxyl group-benzene sulfane base)-(6.9g is 27.4mmol) as raw material for Valeric acid ethylester with 2-.Output 7.07g (86%); Clarified oil; MS:300.9 (M+H) +
Method according to embodiment 12; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-Valeric acid ethylester; adopt 2-(4-methoxyl group-benzenesulfonyl)-Valeric acid ethylester (3.0g; 10.8mmol) and 4-[2-(chloromethyl-phenoxy group)-ethyl]-(3.45g is 11.9mmol) as raw material for morpholine.Output 3.08g, 62%; Brown oil; MS:520.4 (M+H) +
According to embodiment 9 described methods; with 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-Valeric acid ethylester (2.73g; 5.27mmol), it is colourless semisolid 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl that separation obtains 1.45g (productive rate 56%)]-valeric acid.MS：492．3(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-valeric acid (1.01g; 2.05mmol) and according to embodiment 1 described method, separate obtaining the 2-that 190mg is a brown solid (4-methoxyl group-benzenesulfonyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-benzyl]-the valeric acid oxyamide.Productive rate 18%; 101 ℃ of mp; MS:507.4 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.71 (t, J=7Hz, 3H), 1.58-1.82 (m, 4H), 3.12-3.98 (m, 12H), 3.87 (s, 3H), 4.35 (t, 2H), 6.89 (d, J=8.7Hz, 2H), 7.15 (m, 4H), 7.74 (d, J=8.9Hz, 2H), 9.08 (s, 1H).
Embodiment 36
2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group
-benzenesulfonyl)-sad oxyamide
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzene sulfane base)-ethyl octylate.(11.8g, 47.3mmol) (6g is 43mmol) as raw material with the 4-methoxybenzenethiol with 2-bromo ethyl octylate.Output 7.24g (57%); Clarified oil; MS:311.2 (M+H) +
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-ethyl octylate.(4-methoxyl group-benzene sulfane base)-(4.0g is 13.6mmol) as raw material for ethyl octylate with 2-.Output 3.7g (83%); Clarified oil; MS:343.3 (M+H) +
Method according to embodiment 12; preparation 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-ethyl octylate; adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl octylate (1.69g; 5.18mmol) and 1-[2-(4-chloromethyl-phenoxy group)-ethyl]-(1.73g is 6.0mmol) as raw material for azatropylidene.Output 4.86g, 99%; Brown oil; MS:574.5 (M+H) +
According to embodiment 9 described methods; with 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-ethyl octylate (4.8g; 8.37mmol), it is colourless semisolid 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl that separation obtains 1.55g (productive rate 34%)]-2-(4-methoxyl group-benzenesulfonyl)-sad.MS：551(M+H) +。
Adopt 2-[4-(2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-sad (1.09g; 2.0mmol) and according to embodiment 1 described method, separate obtaining the 2-[4-that 300mg is a yellow solid (2-azatropylidene-1-base-oxyethyl group)-benzyl]-2-(4-methoxyl group-benzenesulfonyl)-sad oxyamide.Productive rate 27%; 65 ℃ of mp; MS:561.6 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.81 (t, J=6.6Hz, 3H), 1.08-1.82 (m, 14H), 3.13-3.51 (m, 12H), 3.87 (s, 3H), 4.33 (t, 2H), 6.88 (d, J=8.7Hz, 2H), 7.14 (m, 4H), 7.7 (d, J=9Hz, 2H), 9.06 (s, 1H), 10.28 (s, 1H).
Embodiment 37
2-(4-methoxyl group-benzene sulfane base)-sad oxyamide
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzene sulfane base)-ethyl octylate.(11.8g, 47.3mmol) (6g is 43mmol) as raw material with the 4-methoxybenzenethiol with 2-bromo ethyl octylate.Output 7.24g (57%); Clarification oily matter; MS:311.2 (M+H) +
According to embodiment 9 described methods, (3.1g 10mmol) as raw material, separates obtaining 2.55g (productive rate 90%) and be colourless semisolid 2-(4-methoxyl group-benzene sulfane base)-sad to adopt 2-(4-methoxyl group-benzene sulfane base)-ethyl octylate.MS：283(M+H) +。
(4.25g 16mmol) as raw material and according to the method for embodiment 1, separates obtaining the 2-that 3.64g is a colorless solid (4-methoxyl group-benzene sulfane base)-sad oxyamide to adopt 2-(4-methoxyl group-benzene sulfane base)-sad.Productive rate 76%; MP:90 ℃; MS:298.2 (M+H).
Embodiment 38
2-(4-fluoro-benzene sulfane base)-sad oxyamide
According to embodiment 9 described universal methods, preparation 2-(4-fluoro-benzene sulfane base)-ethyl octylate.(6.47g, 24.7mmol) (3g is 23.4mmol) as raw material with the 4-fluoro thiophenol with 2-bromo ethyl octylate.Output: 6.31g (90%); Clarification oily matter; MS:299 (M+H) +
According to embodiment 9 described methods, (3.1g 10mmol) as raw material, separates obtaining 2.89g (productive rate 100%) and be colourless semisolid 2-(4-fluoro-benzene sulfane base)-sad to adopt 2-(4-fluoro-benzene sulfane base)-ethyl octylate.MS：268．9(M+H) +。
(2.49g 9.2mmol) as raw material and according to the method for embodiment 1, separates obtaining the 2-that 2.72g is a colorless solid (4-fluoro-benzene sulfane base)-sad oxyamide to adopt 2-(4-fluoro-benzene sulfane base)-sad.Productive rate 99%; MP:58 ℃; MS:284 (M-H).
Embodiment 39
2-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-sad oxyamide
According to embodiment 9 described universal methods, preparation 2-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-ethyl octylate.With 2-bromo ethyl octylate (12.1g, 48mmol) and 1-methyl-2-mercaptoimidazole (5g is 43.8mmol) as raw material.Output: 12g (96%); Clarification oily matter; MS:285 (M+H) +
According to embodiment 9 described methods, adopt 2-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-ethyl octylate (12g, 42.2mmol) as raw material, separate to obtain 10.2g (productive rate 95%) and be the 2-of colorless solid (the basic sulfane base of 1-methyl isophthalic acid H-imidazoles-2-)-sad.MP：95℃，MS：257．1(M+H) +。
(7.84g 30.6mmol) as raw material and according to the method for embodiment 1, separates obtaining the 2-that 2.77g is a colorless solid (1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-sad oxyamide to adopt 2-(1-methyl isophthalic acid H-imidazoles-2-base sulfane base)-sad.Productive rate 33%; MP:125 ℃; MS:272.2 (M+H).
Embodiment 40
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-3-naphthalene-2-base-propionic acid amide
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-3-naphthalene-2-base-ethyl propionate is with (5.0g, 20mmol) (4.4g is 20mmol) as raw material for 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate and 2-brooethyl naphthalene.Output 7.2g, 91%; Colorless oil; MS:399 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-3-naphthalene-2-base-ethyl propionate (3.7g; 9mmol) as raw material, separation obtains 3.3g (productive rate 96%) and is the 2-of colorless oil (4-methoxyl group-benzenesulfonyl)-3-naphthalene-2-base-propionic acid.MS：369．1(M-H) -。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-3-naphthalene-2-base-propionic acid (2.2g; 5.9mmol) as raw material and according to the method for embodiment 1, separate that to obtain 820mg be light brown solid N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-3-naphthalene-2-base-propionic acid amide.Productive rate 36%; Mp 161-163 ℃; MS:385.9 (M+H) + 1H NMR (300MHz, CDCl 3): δ 3.32 (d, J=7.0Hz, 1H), 3.69 (d, J=7.0Hz, 1H), 3.82 (s, 3H), 5.02 (s, 1H), 6.92-7.89 (m, 11H).
Embodiment 41N-hydroxyl-2-(4-methoxyl group-phenyl methanesulfonamide acyl group)-2-methyl-3-phenylpropionic acid oxyamide
In refluxing down, with 4-methoxybenzyl mercaptan (7.0g, 45mmol), the 2-ethyl bromide (8.2g, 46mmol) and the salt of wormwood of powdered oven drying (10g, 150ml acetone mixed solution heating 72mmol) 18 hours.Cool off this mixed solution, filter and concentrated filtrate.Residue is dissolved in the 150ml methylene dichloride, and water (150ml) washing through anhydrous sodium sulfate drying and evaporation, obtains 12g (99%) product; Colourless liquid; MS 255.1 (M+H).With this product without being further purified use.
To the 2-of ice-cooled (5 ℃) (4-methoxyl group-phenyl first sulfane base)-ethyl propionate (5.7g, in 100ml dichloromethane solution 21mmol) by between part adding-(7.2g 42mmol), stirs this mixed solution 1 hour the chlorine peroxybenzoic acid.(500ml) dilutes this reactant with hexane, stirs 30 minutes in 25 ℃.Filter this mixed solution, handle organic layer with saturated aqueous solution of sodium bisulfite (200ml).Wash the hexane solution that contains product with water, dry (sodium sulfate) also concentrates.Output 5.5g (91%); Colorless oil; MS 287.1 (M+H) +
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-phenyl methanesulfonamide acyl group)-2-methyl-3-phenyl-ethyl propionate, adopt 2-(4-methoxyl group-phenyl methanesulfonamide acyl group)-ethyl propionate (2g, 7mmol) and bromotoluene (1.3g is 7.7mmol) as raw material.Output 3.0g, 100%; The low melting point solid; MS:377 (M+H) +
Employing is dissolved in 2-(4-methoxyl group-phenyl methanesulfonamide the acyl group)-2-methyl-3-phenyl-ethyl propionate (3.5g among methyl alcohol (50ml) and the 10N NaOH (30ml); 9.0mmol) as raw material, preparation 2-(4-methoxyl group-phenyl methanesulfonamide acyl group)-2-methyl-3-phenyl-propionic acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 930mg, 31%; Colorless solid, mp:106-108 ℃; MS:347 (M-H) +
Adopt 2-(4-methoxyl group-phenyl methanesulfonamide acyl group)-2-methyl-3-phenyl-propionic acid (2.7; 7.0mmol) as raw material and according to the method for embodiment 1, separate obtaining N-hydroxyl-2-that 266mg is a colorless solid (4-methoxyl group-phenyl methanesulfonamide acyl group)-2-methyl-3-phenyl-propionic acid oxyamide.Productive rate: 10%; Mp 58-59 ℃; MS:364.2 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.28 (s, 3H), 2.84-2.88 (d, 1H), 3.75 (s, 3H), 3.81-3.86 (d, 1H), 4.59-4.63 (d, 1H), 4.69-4.74 (d, 1H), 6.94-6.98 (d, 2H), 7.19 (m, 2H), 7.29-7.33 (d, 4H), 9.24 (s, 1H), 10.88 (s, 1H).
Embodiment 425-methyl-2-(3-methyl-but-2-ene base)-2-(toluene-4-alkylsulfonyl)-oneself-the obtusilic acid oxyamide
Universal method according to embodiment 9 prepares 5-methyl-2-(3-methyl-but-2-ene base)-2-(toluene-4-alkylsulfonyl)-own-obtusilic acid ethyl ester.(2.9g, 10.9mmol) (3.42g is 23mmol) as raw material with 4-bromo-2-methyl butene to adopt α-(ptoluene-sulfonyl) ethyl acetate.Output: 4.6g; Brown oil; MS 379.2 (M+H) +
Universal method according to embodiment 9 prepares 5-methyl-2-(3-methyl-but-2-ene base)-2-(toluene-4-alkylsulfonyl)-own-obtusilic acid.Adopt 5-methyl-2-(3-methyl-but-2-ene base)-2-(toluene-4-alkylsulfonyl)-oneself-the obtusilic acid ethyl ester (4.5g, 11mmol), ethanol (15ml) and 10N sodium hydroxide is as raw material.
Adopt 5-methyl-2-(3-methyl-but-2-ene base)-2-(toluene-4-alkylsulfonyl)-own-obtusilic acid (4.1g, 11mmol) as raw material and according to embodiment 1 described method, separate obtaining 5-methyl-2-that 1.07g is a colorless solid (3-methyl-but-2-ene base)-2-(toluene-4-alkylsulfonyl)-own-obtusilic acid oxyamide; Productive rate: 30%; Mp 108-110 ℃; MS:366.2 (M+H) + 1HNMR (300MHz, DMSO-d 6): δ 1.49 (s, 6H), 1.62 (s, 6H), 2.41 (s, 3H), 2.53-2.63 (m, 4H), 5.00-5.05 (t, 2H), 7.40-7.43 (d, 2H), 7.59-7.62 (d, 2H), 9.04 (s, 1H), 10.80 (s, 1H).
Embodiment 43
2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-phenyl-propionic acid oxyamide
Prepare 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-phenyl-ethyl propionate (by 3-sulfydryl-2-methyl furan preparation) according to embodiment 9 described universal methods.Adopt 2-(2-methyl-furans-3-base sulfane base)-ethyl propionate (2.9g, 11.9mmol), bromotoluene (2.22g, 13mmol) and salt of wormwood (10g) in acetone (75ml), begin to prepare; Productive rate (99%); Amber oily thing; MS 337.1 (M+H) +
Prepare 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-phenyl-propionic acid according to embodiment 9 described universal methods.Employing is dissolved in 2-in ethanol (25ml) and the 10N sodium hydroxide (10ml), and (2-methyl-furans-3-base sulfane base)-(4.8g is 14.3mmol) as raw material for ethyl propionate.Output 3.7g (84%), white solid, MS 307.4 (M-H).
Adopt 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-phenyl-propionic acid (3.58g, 12mmol) as raw material and according to embodiment 1 described method, separate obtaining 2-methyl-2-that 1.078g is an orange solids (2-methyl-furans-3-alkylsulfonyl)-3-phenyl-propionic acid oxyamide; Productive rate: 29%; Mp 68-70 ℃; MS:324 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.27 (s, 3H), 2.81-2.86 (d, 1H), 3.33 (s, 3H), 3.61-3.66 (d, 1H), 6.66 (s, 1H), 7.19-7.25 (m, 5H), 7.76 (s, 1H), 9.09 (s, 1H), 10.81 (s, 1H).
Embodiment 442-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-third
The acid oxyamide
Prepare 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl according to embodiment 9 described universal methods]-ethyl propionate.Adopt 2-(2-methyl-furans-3-alkylsulfonyl)-ethyl propionate (2.4g, 9.8mmol) and 1-[2-(4-chloromethyl phenoxy group)-ethyl]-(2.96g is 10.7mmol) as raw material for piperidines; Output 2.4g (92%); Amber oily thing; MS 464.2 (M+H) +
Prepare 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl according to embodiment 1 described universal method]-propionic acid.Employing is dissolved in 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl in ethanol (20ml) and the 10N sodium hydroxide (10ml)] (2.01g is 4.5mmol) as raw material for ethyl propionate.According to embodiment 9 described methods the mixed solution that produces is handled.Output 2.03g; 66-68 ℃ of amber crystallization mp, MS 434 (M-H).
Adopt 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid (2.03g, 6.0mmol) as raw material and according to embodiment 1 described method, it is amber solid 2-methyl-2-(2-methyl-furans-3-alkylsulfonyl)-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl that separation obtains 1.36g]-the propionic acid oxyamide; Productive rate: 32%; Mp 115-117 ℃; MS:451.1 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.15-1.22 (m, 2H), 1.75 (s, 3H), 1.78 (s, 3H), 2.98-3.03 (m, 2H), 3.42-3.47 (m, 2H), 3.5 (s, 3H), 6.65 (s, 1H), 6.87-6.90 (d, 2H), 7.12-7.17 (d, 2H), 10.35 (s, 1H), 10.60 (s, 1H), 11.70 (s, 1H).
Embodiment 452-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid hydroxyl acyl
Amine
Prepare 2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl-2-(thiophene-2-alkylsulfonyl)-ethyl propionate according to embodiment 9 described universal methods.Adopt 2-(thiophene-2-alkylsulfonyl)-ethyl propionate (by 2-mercapto-thiophene and the preparation of 2 bromopropionic acid ethyl ester) (4.4g, 17.7mmol) and 1-[2-(4-chloromethyl phenoxy group)-ethyl]-(5.3g is 19.5mmol) as raw material for piperidines; Productive rate (96%); Semi-solid; MS 466.
Prepare 2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid according to embodiment 9 described universal methods.Employing is dissolved in 2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl-2-alkylsulfonyl in ethanol (20ml) and the 10N sodium hydroxide (20ml)]-(9.8g is 20mmol) as raw material for ethyl propionate.Handle according to embodiment 1 described mixed solution generation.Output 4.5g (49%); 170-172 ℃ of white solid mp, MS 436.3 (M-H).
Adopt 2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid (3.6g, 8.0mmol) as raw material and according to embodiment 1 described method, separate obtaining 2-methyl-3-[4-that 345mg is a colorless solid (2-piperidines-1-base-oxyethyl group)-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid oxyamide; Productive rate: 10%; Mp 115-118 ℃; MS:451.2 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.29 (s, 3H), 1.66-1.78 (m, 6H), 2.81-2.86 (d, 1H), 2.96-3.99 (m, 4H), 3.39-3.47 (m, 2H), 3.51-3.59 (d, 1H), 4.32 (m, 2H), 6.72-6.74 (d, 1H), 6.87-6.96 (d, 2H), 7.01-7.20 (m, 3H), 7.31-7.33 (m, 1H), 7.69-7.72 (m, 1H), 7.83-7.84 (m, 1H), 8.07-8.08 (dd, 1H), 8.17 (dd, 1H), 9.0 (s, 1H), 10.0 (s, 1H), 10.78 (s, 1H).
Embodiment 46 2-(octane-1-alkylsulfonyl)-3-[4-(2-piperidin-1-yl-oxyethyl group)-phenyl]-the propionic acid oxyamide
Prepare 2-(octane-1-alkylsulfonyl)-3-[4-(2-piperidin-1-yl-oxyethyl group)-phenyl according to embodiment 9 described universal methods]-ethyl propionate.Adopt 2-(octane-1-alkylsulfonyl)-ethyl propionate (5.0g, 18mmol) and 1-[2-(4-chloromethyl phenoxy group)-ethyl]-(5.6g is 19.7mmol) as raw material for piperidines; Output 8.9g (96%); Amber oily thing; MS 495.
Prepare 2-(octane-1-alkylsulfonyl)-3-[4-(2-piperidin-1-yl-oxyethyl group)-phenyl according to embodiment 9 described universal methods]-propionic acid.Adopt 2-(octane-1-alkylsulfonyl)-3-[4-(2-piperidin-1-yl-oxyethyl group)-phenyl]-ethyl propionate (8.9g, 18mmol), ethanol (25ml) and 10N sodium hydroxide (25ml) is as raw material.Output 6.0g (72%).
Adopt 2-(octane-1-alkylsulfonyl)-3-[4-(2-piperidin-1-yl-oxyethyl group)-phenyl]-propionic acid (3.6g, 7.7mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 3.3g is a brown solid (octane-1-alkylsulfonyl)-3-[4-(2-piperidin-1-yl-oxyethyl group)-phenyl]-the propionic acid oxyamide; Productive rate: 89%; Mp 69-70 ℃; MS:483.2 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ .687 (t, 3H), 1.27-1.69 (m, 15H), 2.71-2.75 (d, 1H), 3.51 (s, 3H), 3.65-3.69 (d, 1H), 6.86-6.89 (d, 2H), 7.08-7.11 (d, 2H), 9.16 (s, 1H), 10.70 (s, 1H).
Embodiment 47 3-biphenyl-4-base-2-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-alkylsulfonyl)-propionic acid oxyamide
Prepare 3-biphenyl-4-base-2-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-alkylsulfonyl)-ethyl propionate according to embodiment 9 described universal methods.(3.0g, 12.2mmol) (2.97g is 15mmol) as raw material with 4-chloromethyl biphenyl to adopt 2-methyl-(1-methyl isophthalic acid H-imidazoles alkylsulfonyl)-ethyl propionate (by 1-methyl-2-mercaptoimidazole and the preparation of 2-bromotrifluoromethane propionic ester).Output 5.0g (99%); The low melting point solid; MS 413 (M+H) +
Prepare 3-biphenyl-4-base-2-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-alkylsulfonyl)-propionic acid according to embodiment 9 described universal methods.Adopt 3-biphenyl-4-base-2-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-alkylsulfonyl)-ethyl propionate (5.0g, 11.9mmol), ethanol (15ml) and 10N sodium hydroxide (10ml) is as raw material.Output 2.8g (61%); 119-122 ℃ of brown solid mp; MS 385.2 (M+H).
Adopt 3-biphenyl-4-base-2-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-alkylsulfonyl)-propionic acid (2.8g, 7.0mmol) as raw material and according to embodiment 1 described method, separate obtaining the 3-biphenyl that 112mg is a brown solid-4-base-2-methyl-2-(1-methyl isophthalic acid H-imidazoles-2-alkylsulfonyl)-propionic acid oxyamide; Productive rate: 4%; 112 ℃ of mp; MS:399.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.911 (t, 3H), 3.3 (s, 3H), 3.5 (d, 1H), 4.2 (d, 1H), 6.8 (d, 1H), 6.9 (d, 1H), 7.18-7.66 (m, 5H), 7.30-7.33 (d, 2H), 7.55-7.58 (d, 2H).
Embodiment 48
2-methyl-3-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid oxyamide
Prepare 2-methyl-3-phenyl-2-(thiophene-2-alkylsulfonyl)-ethyl propionate according to embodiment 9 described universal methods.Adopt 2-(thiophene-2-alkylsulfonyl)-ethyl propionate (3.0g, 12mmol) and bromotoluene (2.48g is 15mmol) as raw material; Output 5.2g (%); Brown oil; MS 339.1 (M+H).
Prepare 2-methyl-3-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid according to embodiment 9 described universal methods.Adopt 2-methyl-3-phenyl-2-(thiophene-2-alkylsulfonyl)-ethyl propionate (5.0g, 15mmol), ethanol (30ml) and 10N sodium hydroxide (10ml) is as raw material.Output 5.6g.MS?310．0(M+H)。
(5.0g 16mmol) as raw material and according to embodiment 1 described method, separates obtaining 2-methyl-3-phenyl-2-that 1.8g is a colorless solid (thiophene-2-alkylsulfonyl)-propionic acid oxyamide to adopt 2-methyl-3-phenyl-2-(thiophene-2-alkylsulfonyl)-propionic acid; Productive rate: 40%; Mp 116-117 ℃; MS:325.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.29 (s, 3H), 3.33 (d, 1H), 3.69 (d, 1H), 7.18-7.30 (m, 5H), 7.74 (m, 1H), 8.22 (m, 1H), 9.13 (s, 1H), 10.80 (s, 1H).
Embodiment 49
2-[8-(1-carboxyl-ethylsulfonyl)-octane-1-alkylsulfonyl]-the propionic acid oxyamide
Prepare 2-[8-(1-carboxyl-ethylsulfonyl)-octane-1-alkylsulfonyl according to embodiment 9 described universal methods]-ethyl propionate.Adopt 2-[8 (1-ethoxy carbonyl-second sulfane base)-octyl group sulfane base]-(10.2g, 26mmol) (64g is 104mmol) as raw material with permonosulphuric acid sodium (sodiumperoxymonopersulfate) for ethyl propionate.Output 9.87g (86%); Colourless liquid; MS 422.9 (M+H).
Prepare 2-[8-(1-carboxyl-ethylsulfonyl)-octane-1-alkylsulfonyl according to embodiment 1 described universal method]-propionic acid.Adopt 2-[8-(1-carboxyl-ethylsulfonyl)-octane-1-alkylsulfonyl]-ethyl propionate (3.0g, 6.8mmol), ethanol (15ml) and 10N sodium hydroxide (15ml) is as raw material.Output 2.7g (98%); 99-102 ℃ of white solid mp; MS 387 (M+NH3) +
Adopt 2-[8-(1-carboxyl-ethylsulfonyl)-octane-1-alkylsulfonyl]-propionic acid (2.5g, 6.5mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-[8-that 641mg is amber oily thing (1-carboxyl-ethylsulfonyl)-octane-1-alkylsulfonyl]-the propionic acid oxyamide; Productive rate: 23%; MS:434.0 (M+NH4) + 1H NMR (300MHz, DMSO-d 6): δ 1.27-3.23 (m, 22H), 3.33 (m, 2H), 8.9 (s, 1H), 9.28 (s, 1H).
Embodiment 50
2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]
-propionic acid oxyamide
Prepare 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl according to embodiment 9 described universal methods]-ethyl propionate.Adopt α-(4-bromophenyl-alkylsulfonyl) ethyl acetate (5.0g, 16mmol) and 1-[2-(4-chloromethyl phenoxy group)-ethyl]-(4.97g is 16mmol) as raw material for piperidines.Output 6.1g (71%); Brown oil; MS 541.1 (M+H) +
Prepare 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl according to embodiment 9 described universal methods]-propionic acid.Adopt 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-ethyl propionate (6.5g, 20mmol), ethanol (30ml) and 10N sodium hydroxide (15ml) is as raw material.Output 6.3g (100%); 125-127 ℃ of yellow solid mp; MS 512.5 (M+H) +
Adopt 2-(4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-propionic acid (6.1g, 612mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 1.07g is a faint yellow solid (4-bromo-benzenesulfonyl)-2-methyl-3-[4-(2-piperidines-1-base-oxyethyl group)-phenyl]-the propionic acid oxyamide; Productive rate: 17%; MS:525.4 (M+H) +
Embodiment 51
3-(4-bromo-phenyl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl propanamide
According to embodiment 9 described methods; preparation 3-(4-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate; (3.0g, 11mmol) (3.0g is 12mmol) as raw material with 4-bromo-bromotoluene to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate.Output 4.67g, 96%; Colorless oil; MS:441 (M+H) +
Employing is dissolved in 3-(4-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (4.0g is 9.0mmol) as feedstock production 3-(4-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid.Press the reaction mixture of embodiment 9 described processing gained.Output 3.0g, 78%.The low melting point solid.MS：413(M+H) +。
Adopt 3-(4-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid (2.7g, 6.5mmol) as raw material and according to embodiment 1 described method, separate obtaining the 3-that 2.26g is a colorless solid (4-bromophenyl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide; Productive rate: 81%; Mp 86-88 ℃; MS:429.8 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.42 (s, 3H), 1.77 (bs, 1H), 3.26 (d, J=7.0Hz, 1H), 3.68 (d, J=7.0Hz, 1H), 3.85 (s, 3H), 7.01-7.76 (m, 8H), 9.71-9.88 (bs, 1H).
Embodiment 52
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-naphthalene-2-base-propionic acid amide
According to embodiment 9 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-naphthalene-2-base-ethyl propionate; (5.4g, 20mmol) (4.4g is 20mmol) as raw material with 2-bromo-methylnaphthalene to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate.Output 8.0g, 97%; Clear crystal, mp 182-184 ℃; MS:443 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-naphthalene-2-base-ethyl propionate (4.6g; 11mmol), separate and to obtain 4.2g (98%) and be the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-naphthalene-2-base-propionic acid.mp?144-146℃；MS：384．9(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-naphthalene-2-base-propionic acid (2.4g, 6.2mmol) as raw material and according to embodiment 1 described method, separate obtaining N-hydroxyl-2-that 1.6g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-naphthalene-2-base-propionic acid amide; Productive rate: 64%; Mp 185-187 ℃; MS:400.2 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.56 (s, 3H), 3.28 (d, J=8.0Hz, 1H), 3.81 (d, J=8Hz, 1H), 3.93 (s, 3H), 4.88 (bs, 1H), 7.02-7.92 (m, 11H).
Embodiment 53
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-3-methyl-butyramide
According to embodiment 1 described universal method, preparation 2-(4-methoxyl group-benzene sulfane base)-3-methyl-ethyl butyrate.(20.9g, 100mmol) (14.0g 100mmol) as raw material, separates obtaining 30g 2-(4-methoxyl group-benzene sulfane base)-3-methyl-ethyl butyrate with 4-anisole mercaptan to adopt 2-bromo-3-methyl-ethyl butyrate.Productive rate 99%; Faint yellow oily thing; MS:269 (M+H) +
(2.68g 10mmol) carries out oxidation as raw material and according to embodiment 9 described methods, separates to obtain the 2-that 3g is a colorless solid (4-methoxyl group-benzenesulfonyl)-3-methyl-ethyl butyrate to adopt 2-(4-methoxyl group-benzene sulfane base)-3-methyl-ethyl butyrate.Productive rate 99%; 53 ℃ of mp; MS:273 (M+H) +
According to embodiment 9 described methods, (3g, 10mmol) as raw material, separation obtains 2.7g (96%) and is the 2-of colorless solid (4-methoxyl group-benzenesulfonyl)-3-methyl-butyric acid to adopt 2-(4-methoxyl group-benzenesulfonyl)-3-methyl-ethyl butyrate.Mp?96℃；MS：273(M+H) +。
(2.0g 7.34mmol) as raw material and according to embodiment 9 described methods, separates obtaining N-hydroxyl-2-that 590mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-3-methyl-butyramide to adopt 2-(4-methoxyl group-benzenesulfonyl)-3-methyl-butyric acid.220 ℃ of Mp; Productive rate 28%; MS:288 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.88 (d, J=6.7Hz, 3H), 1.07 (d, J=6.7Hz, 3H), 2.09-2.20 (bs, 1H), 3.53 (d, J=9,1H), 7.12-7.17 (m, 2H), 7.74-7.79 (m, 2H).
Embodiment 54
1-(4-methoxyl group-benzenesulfonyl)-cyclopentane-carboxylic acid oxyamide
According to embodiment 9 described methods, preparation 1-(4-methoxyl group-benzenesulfonyl)-cyclopentane-carboxylic acid ethyl ester, (3.0g, 11.6mmol) with 1, (2.4g is 7.6mmol) as raw material for the 4-dibromobutane to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate.Output 2.4g, 78%; Colorless solid, mp 86-88 ℃; MS:313 (M+H) +
Employing is dissolved in 1-(4-methoxyl group-benzenesulfonyl)-cyclopentane-carboxylic acid ethyl ester in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (2.2g is 7.0mmol) as feedstock production 1-(4-methoxyl group-benzenesulfonyl)-cyclopentane-carboxylic acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 1.66g, 83%.Colorless solid; Mp 112-115 ℃; MS:285 (M+H) +
(442mg 1.5mmol) as raw material and according to embodiment 1 described method, separates obtaining the 1-that 410mg is a colorless solid (4-methoxyl group-benzenesulfonyl) cyclopentane-carboxylic acid oxyamide to adopt 1-(4-methoxyl group-benzenesulfonyl)-cyclopentane-carboxylic acid.Mp 89-91 ℃; Productive rate: 88%; MS:300 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.65-1.82 (m, 4H), 2.17-2.42 (m, 4H), 3.87 (s, 3H), 7.0 (d, J=8Hz, 2H), 7.7 (bs, 1H), 7.72 (d, J=8Hz, 2H), 9.73 (bs, 1H).
Embodiment 55
3-(2-bromo-phenyl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl propanamide
According to embodiment 9 described methods; preparation 3-(2-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate; (2.0g, 7.3mmol) (2.0g is 8mmol) as raw material with the 2-bromo benzyl bromo to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate.Output 3.1g, 87%; Colorless oil; MS:441 (M+H) +
Employing is dissolved in 3-(2-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-ethyl propionate in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (3.0g is 68mmol) as feedstock production 3-(2-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid.According to embodiment 9 described methods the reaction mixture that produces is handled.Output 1.7g, 63%; Waxy solid; MS:414 (M+H) +
Adopt 3-(2-bromo-phenyl)-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid (470mg; 1.1mmol) as raw material and according to embodiment 9 described methods, separate obtaining the 3-that 380mg is a colorless solid (2-bromo-phenyl)-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-propionic acid amide.Mp 93-96 ℃; Productive rate 77%; MS:429 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.3 (s, 3H), 3.32 (d, J=7.0Hz, 1H), 3.69 (d, J=7.0Hz, 1H), 3.82 (s, 3H), 6.92-7.89 (m, 8H).
Embodiment 56
2-(4-methoxyl group-benzenesulfonyl)-2-methyl-5-phenyl-penta-obtusilic acid oxyamide
According to embodiment 9 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-5-phenyl-penta-obtusilic acid ethyl ester; adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (3.0g, 11mmol) and cinnamyl bromide (2.1g is 11mmol) as raw material.Output 3.51g, 82%; Colorless oil; MS:389 (M+H) +
Employing is dissolved in 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-5-phenyl-penta-obtusilic acid ethyl ester in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (3.0g is 11mmol) as feedstock production 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-5-phenyl-penta-obtusilic acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 1.9g, 68%; Little yellow oil; MS:361 (M+H) +
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-5-phenyl-penta-obtusilic acid (440mg; 1.2mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 420mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-5-phenyl-penta-obtusilic acid oxyamide.Mp 162-164 ℃; Productive rate: 92%; MS:376 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.41 (s, 3H), 3.0-3.16 (m, 1H), 3.30 (d, J=11Hz, 2H), 3.92 (s, 3H), 5.9-6.1 (m, 1H), 6.53 (d, J=11Hz, 1H), 7.1-7.72 (m, 9H), 9.12 (bs, 1H).
Embodiment 57
2-(4-methoxyl group-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl group)-valeric acid oxyamide
According to embodiment 9 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl group)-Valeric acid ethylester; (4.0g, 15.8mmol) (6.4g is 32mmol) as raw material with 3-bromopropyl benzene to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate.Output 3.7g, 47%; Colorless oil; MS:495 (M+H) +
Employing is dissolved in 2-(4-methoxyl group-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl group)-Valeric acid ethylester in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (2.0g is 4mmol) as feedstock production 2-(4-methoxyl group-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl group)-valeric acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 1.18g, 63%.Waxy solid; MS:449.2 (M+H-H 2O) +
Adopt 2-(4-methoxyl group-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl group)-valeric acid (600mg; 1.2mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 420mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-5-phenyl-2-(3-phenyl-propyl group)-valeric acid oxyamide.Mp 118-120 ℃; Productive rate: 68%; MS:482 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.52-1.68 (m, 2H), 1.74-1.92 (m, 2H), 1.98-2.20 (m, 4H), 2.58-2.72 (m, 4H), 3.86 (s, 3H), 6.93 (d, J=11Hz, 2H), 7.02-7.63 (m, 10H), 7.81 (d, J=11Hz, 2H).
Embodiment 58
2-allyl group-(4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid oxyamide
According to embodiment 9 described methods, preparation 2-allyl group-2-(4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid ethyl ester, adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate (3.0g, 11.6mmol) and allyl bromide 98 (4ml, excessive) as raw material.Output 3.6g, 92%; Yellow oil; MS:338 (M+H) +
Employing is dissolved in 2-allyl group-2-(4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid ethyl ester in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (2.2g is 6.5mmol) as feedstock production 2-allyl group-2-(4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 1.76g, 87%; Little yellow oil; MS:311 (M+H) +
Adopt 2-allyl group-2-(4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid (1.5g; 4.8mmol) as raw material and according to embodiment 1 described method, separate obtaining 2-allyl group-2-that 1.5g is a colorless solid (4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid oxyamide.Mp 114-116 ℃; Productive rate: 99%; MS:326 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.62 (s, 1H), 2.70-2.80 (m, 4H), 3.9 (s, 3H), 5.16-5.27 (m, 4H), 5.81-5.94 (m, 2H), 7.12 (d, J=8Hz, 2H).
Embodiment 59
2-(4-methoxyl group-benzenesulfonyl)-2-propyl group-valeric acid oxyamide
With 2-allyl group-2-(4-methoxyl group-benzenesulfonyl)-penta-obtusilic acid oxyamide (326mg, 1.0mmol) (embodiment 26) are dissolved in the methyl alcohol (50ml), under room temperature, 49psi pressure through 10%Pd/C (100mg) catalytic hydrogenation 4 hours.Then, filter this reaction mixture, remove methyl alcohol.Make solid crystallization from methyl alcohol of generation.Output 250mg, 75%; MS:330 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.92 (t, J=4.0Hz, 6H), 1.27-1.59 (m, 4H), 1.78-2.02 (m, 4H), 3.86 (s, 3H), 6.04 (bs, 1H), 6.97 (d, J=9Hz, 2H), 7.76 (d, J=9Hz, 2H).
Embodiment 60
2-benzyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid amide
According to embodiment 9 described methods, preparation 2-benzyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-ethyl propionate, adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate (1.0g, 3.8mmol) and bromotoluene (4ml, excessive) as raw material.Output 1.2g, 72%; Yellow oil; MS:439 (M+H) +
Employing is dissolved in 2-benzyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-ethyl propionate in methyl alcohol (50ml) and the 10N sodium hydroxide (30ml), and (1.0g is 2.2mmol) as feedstock production 2-benzyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 580mg, 62%; Waxy solid; MS:409 (M-H) -
Adopt 2-benzyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid (410mg; 1mmol) as raw material and according to embodiment 1 described method, separate obtaining 2-benzyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-propionic acid amide that 225mg is a waxy solid.Productive rate: 52%; MS:426 (M+H) + 1H NMR (300MHz, CDCl 3): δ 3.25 (d, J=14Hz, 2H), 3.52 (d, J=14Hz, 2H), 3.9 (s, 3H), 6.93 (d, J=8Hz, 2H), 7.02-7.26 (m, 9H), 7.61 (d, J=8Hz, 2H), 7.87 (d, J=4Hz, 1H), 9.58 (bs, 1H).
Embodiment 61
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid amide
To 2-(4-methoxyl group-benzenesulfonyl) ethyl propionate (2.7g that stirs; 10mmol), (3.2g adds 10N sodium hydroxide (30ml) 20mmol) and in methylene dichloride (400ml) solution of triethyl benzyl ammonia chloride (1g) to 3-picolyl villaumite hydrochlorate.This reactant is continued 48 hours under room temperature.Then, separate organic layer, the water thorough washing.Dry organic layer filters and concentrates.The crude product product that obtains is through purification by silica gel column chromatography.Use 50% ethyl acetate: hexane wash-out post.Separate 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-ethyl propionate that obtains to brown oil.Output 3.0g, 82%; Brown oil; MS:364 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-ethyl propionate (2.5g; 6.8mmol) as raw material, separation obtains 1.8g (79%) and is the 2-of colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid.mp?58℃；MS：336(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid (410mg; 1mmol) as raw material and according to embodiment 1 described method, separate obtaining N-hydroxyl-2-that 225mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-pyridin-3-yl-propionic acid amide.Productive rate: 52%; 98 ℃ of mp; MS:351 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.4 (s, 3H), 3.1 (d, J=9.0,1H), 3.65 (d, J=9.1,1H), 3.9 (s, 3H), 7-8.5 (m, 8H).
Embodiment 62
2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-capric acid oxyamide
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate (7.5g; 29mmol) (6.7g 35mmol) as raw material, separates compound 2-(4-methoxyl group-benzenesulfonyl)-ethyl decylate that obtains the single octyl groupization of 8g with the 1-bromooctane.Output 8.0g, 74%; MS:370 (M+H) +
According to embodiment 29 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-ethyl decylate; (8.0g, 21.6mmol) (4.1g is 25mmol) as raw material with 3-picolyl villaumite hydrochlorate to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl decylate.Output 6.5g, 68%; Brown oil; MS:462 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-ethyl decylate (5.0g; 11mmol) as raw material, separation obtains 4.5g (91%) and is the 2-of colorless solid (4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-capric acid.Mp?159℃；MS：434(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-capric acid (2.5g; 5.7mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 1.4g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-capric acid oxyamide.Productive rate: 50%; 62 ℃ of mp; MS:448 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.86 (t, 6.9Hz, 3H), 1.25-2.17 (m, 14H), 3.3 (d, J=14Hz, 1H), 3.5 (d, J=14Hz, 1H), 3.9 (s, 3H), 6.8-8.6 (m, 8H).
Embodiment 632-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-oneself-the obtusilic acid oxyamide
According to embodiment 9 described methods, (6.0g, 23mmol) (3.0g 20mmol) as raw material, prepares 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-own-obtusilic acid ethyl ester with the isoprene bromine to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate.Output 6.52g, 86%; Colorless oil; MS:327 (M+H) +
According to embodiment 29 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-oneself-the obtusilic acid ethyl ester; adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-own-obtusilic acid ethyl ester (4.0g; 12.2mmol) and 3-picolyl villaumite hydrochlorate (2.1g is 13mmol) as raw material.Output 4.14g, 81%; Brown oil; MS:418 (M+H) +
Employing is dissolved in 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-own-obtusilic acid ethyl ester (4.0g among methyl alcohol (50ml) and the 10N NaOH (30ml); 9.5mmol) as raw material, preparation 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-oneself-obtusilic acid.Handle the reaction mixture that produces according to embodiment 9 described methods.Output 3.2g, 87%; Ivory white solid, mp 117-119 ℃; MS:390 (M+H) +
Adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-own-obtusilic acid (2.1g; 5.4mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 1.82g is a colorless solid (4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-own-obtusilic acid oxyamide.Productive rate: 82%; Mp 89-92 ℃; MS:405 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.63 (s, 3H), 1.76 (s, 3H), 2.62-2.78 (m, 2H), 3.3 (d, J=4.0Hz, 1H), 3.63 (d, J=4.0Hz, 1H), 3.82 (s, 3H), 5.26 (m, 1H), 7.12-7.88 (m, 6H), 8.27-8.33 (m, 2H).
Embodiment 64
2-benzyl-4-diisopropylaminoethyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-butyramide
According to embodiment 29 described methods; preparation 2-benzyl-4-diisopropylaminoethyl-2-(4-methoxyl group-benzenesulfonyl)-ethyl butyrate; adopt 2-(4-methoxyl group-benzenesulfonyl)-3-phenyl-ethyl propionate (embodiment 9) (3.0g; 8.5mmol) and 2-diisopropylaminoethyl ethyl chloride hydrochloride (4.0g is 20mmol) as raw material.Output 3.2g, 79%; Ivory white solid, mp 89-91 ℃; MS:476.4 (M+H) +
According to embodiment 9 described methods; adopt 2-benzyl-4-diisopropylaminoethyl-2-(4-methoxyl group-benzenesulfonyl)-ethyl butyrate (3.53g; 7.5mmol) as raw material, separation obtains 2.8g (86%) and is 2-benzyl-4-diisopropylaminoethyl-2-(4-methoxyl group-benzenesulfonyl)-butyric acid of colourless crystallization.Mp?136-138℃；MS：448．5(M+H) +。
Adopt 2-benzyl-4-diisopropylaminoethyl-2-(4-methoxyl group-benzenesulfonyl)-butyric acid (1.85g; 4.1mmol) as raw material and according to embodiment 1 described method, it is low melt wax shape solid 2-benzyl-4-diisopropylaminoethyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-butyramide that separation obtains 1.3g.Productive rate: 68%; MS:463.3 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.98 (d, J=11Hz, 6H), 1.16 (d, J=11Hz, 6H), 1.92 (m, 2H), 2.46 (m, 2H), 2.71 (m, 2H), 3.18 (m, 1H), 3.48 (m, 1H), 3.86 (s, 3H), 6.98 (d, J=8Hz, 2H), and 7.18-7.22 (m, 5H), 7.92 (d, J=8Hz, 2H), 8.12 (s, 1H).
Embodiment 65 3-cyclohexyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-propionic acid amide
According to embodiment 9 described methods, (4.0g, 15mmol) (2.7g 15mmol) as raw material, prepares 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate for 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate and 1-brooethyl hexanaphthene in employing.Output 5.0g, 94%; Colorless oil; MS:355 (M+H) +
According to embodiment 29 described methods; preparation 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-ethyl propionate; adopt 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (1.5g; 4.2mmol) and 3-picolyl chlorine (1.0g is 6mmol) as raw material.Output 1.0g, 38%; Colorless oil; MS:446 (M+H) +
According to embodiment 9 described methods; adopt 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-ethyl propionate (1.3g; 2.9mmol) as raw material, separation obtains 1.0g (83%) and is the 3-cyclohexyl-2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-propionic acid.Mp?92℃；MS：417．5(M+H) +。
Adopt 3-cyclohexyl-2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-propionic acid (1.0g; 2.4mmol) as raw material and according to embodiment 1 described method, separate obtaining 3-cyclohexyl-N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-propionic acid amide that 80mg is colourless hydrochloride.Productive rate: 71%; Mp 57-60 ℃; MS:433 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.8-2.08 (m, 13H), 3.3 (d, J=14Hz, 1H), 3.7 (d, J=14Hz, 1H), 3.9 (s, 3H), 7.0-8.5 (m, 8H).
Embodiment 66
2-(4-methoxyl group-benzenesulfonyl)-4-methyl-2-pyridin-3-yl methyl-valeric acid oxyamide
According to embodiment 9 described methods, (5.0g, 20mmol) (2.6g 20mmol) as raw material, prepares 2-(4-methoxyl group-benzenesulfonyl)-4-methyl-Valeric acid ethylester for 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate and 1-bromo-2-methylpropane in employing.Output 6.0g, 95%; Colorless oil; MS:315 (M+H) +
According to embodiment 29 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-4-methyl-2-pyridin-3-yl methyl-Valeric acid ethylester; adopt 2-(4-methoxyl group-benzenesulfonyl)-4-methylvaleric acid ethyl ester (3.1g; 10mmol) (1.8g is 11mmol) as raw material with 3-picolyl villaumite hydrochlorate.Output 3.0g, 75%; Colorless oil; MS:406 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-4-methyl-2-pyridin-3-yl methyl-Valeric acid ethylester (1.2g; 2.9mmol) as raw material, separation obtains 1.0g (91%) and is the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-4-methyl-2-pyridin-3-yl methyl-valeric acid.Mp?188-186℃；MS：378(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-4-methyl-2-pyridin-3-yl methyl-valeric acid (800mg; 2.1mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 180mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-4-methyl-2-pyridin-3-yl methyl-valeric acid oxyamide.Productive rate: 21%; 78 ℃ of mp; MS:393.4 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.65 (d, 6.3Hz, 3H), 0.89 (d, J=6.2Hz, 3H), 1.7 (m, 1H), 2.06 (m, 2H), 3.85 (s, 3H), 6.8-8.5 (m, 10H).
Embodiment 67
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-quinoline-6-base-propionic acid amide
According to embodiment 29 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-quinoline-6-base-ethyl propionate; (5.2g, 20mmol) (4.4g is 20mmol) as raw material with 7-bromomethyl quinoline to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate.Output 4.5g, 54%; Faint yellow solid; 86 ℃ of mp; MS:414 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-quinoline-6-base-ethyl propionate (3.0g; 7.2mmol) as raw material, separation obtains 2.5g (90%) and is the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-quinoline-6-base-propionic acid.mp?106-108℃；MS：386．4(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-quinoline-6-base-propionic acid (2.0g; 5.2mmol) as raw material and according to embodiment 1 described method, separate obtaining N-hydroxyl-2-that 1.2g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-quinoline-6-base-propionic acid amide.Productive rate: 57%; 206 ℃ of mp; MS:401.4 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.4 (s, 3H), 3.19 (m, 1H), 3.8-4.0 (m, 4H), 7.1-8.95 (m, 12H).
Embodiment 68 2-(4-methoxyl group-benzenesulfonyl)-6-phenoxy group-2-pyridin-3-yl methyl-caproic acid oxyamide
According to embodiment 9 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-6-phenoxy group-ethyl hexanoate; (2.5g, 10mmol) (2.2g is 10mmol) as raw material with 1-bromo-4-phenoxy group butane to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate.Output 3.8g, 93%; Colorless oil; MS:407 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-6-phenoxy group-ethyl hexanoate (3.1g; 10mmol) (1.8g 11mmol) as raw material, prepares 2-(4-methoxyl group-benzenesulfonyl)-6-phenoxy group-2-pyridin-3-yl methyl-ethyl hexanoate with 3-picoline chlorine.Output 3.5g, 71%; Colorless oil; MS:498 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-6-phenoxy group-2-pyridin-3-yl methyl-ethyl hexanoate (3.0g; 6.0mmol) as raw material, separation obtains 2.8g (quantitative yield) and is the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-6-phenoxy group-2-pyridin-3-yl methyl-caproic acid.Mp?148-151℃；MS：470．5(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-6-phenoxy group-2-pyridin-3-yl methyl-caproic acid (2.0g; 4.3mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 1.5g is a colorless solid (4-methoxyl group-benzenesulfonyl)-6-phenoxy group-2-pyridin-3-yl methyl-caproic acid oxyamide.Productive rate: 72%; 68 ℃ of mp; MS:485.5 (M+H) + 1H NMR (300MHz, CDCl 3): δ 1.5-2.5 (m, 8H), 3.4 (bs, 2H), 3.8 (s, 3H), 6.8-8.7 (m, 13H).
Embodiment 69
2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-caproic acid oxyamide
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-5-ethyl hexanoate, (10.0g, 39mmol) (6.0g is 40mmol) as raw material with 1-bromo-3-methylbutane to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate.Output 8.5g, 62%; Colorless oil; MS:329 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-ethyl hexanoate (6.0g; 18mmol) (4.1g 25mmol) as raw material, prepares 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-ethyl hexanoate with the pyrmethyl chloride hydrochloride.Output 4.5g, 60%; Brown oil; MS:420 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-ethyl hexanoate (3.0g; 7.1mmol) as raw material, separation obtains 2.6g (92%) and is the 2-of colorless solid (4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-caproic acid.Mp?173℃；MS：392(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-caproic acid (1.0g; 2.5mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 800mg is a colorless solid (4-methoxyl group-benzenesulfonyl)-5-methyl-2-pyridin-3-yl methyl-caproic acid oxyamide.Productive rate: 72%; 62 ℃ of mp (HCl salt); MS:408 (M+H) + 1H NMR (300MHz, CDCl 3): δ 0.76 (m, 6H), 1.2-2.0 (m, 5H), 3.5 (bq, 2H), 7.1-8.8 (m, 8H), 11.1 (bs, 1H).
Embodiment 70
2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-caproic acid oxyamide
According to embodiment 1 described universal method, preparation (4-methoxyl group-benzene sulfane base)-tert.-butyl acetate.(5.3g, 27mmol) (3.7g 27mmol) as raw material, separates obtaining the 6.4g product with 4-anisole mercaptan to adopt corresponding 1-bromo tertiary butyl acetate.Productive rate 98%; Faint yellow oily thing; MS:255 (M+H) +
According to embodiment 9 described universal methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-tert.-butyl acetate.Adopt 2-(4-methoxyl group-benzene sulfane base)-tert.-butyl acetate (5.0g, 20mmol) and 3-chlorine peroxybenzoic acid (57% (12.0g 40mmol) as raw material, separates obtaining the 5.3g product.Productive rate 92%; Waxy solid; MS:287.1 (M+H) +
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-pyridin-3-yl propionic acid tert-butyl ester.(20.0g, 70.0mmol) (7.28g, 44.4mmol) as raw material, (50% ethyl acetate: hexane) separation obtains the 10.5g product through silica gel column chromatography with 3-picoline chlorine to adopt 2-(4-methoxyl group-benzenesulfonyl)-tert.-butyl acetate.Productive rate 63%; White solid; Mp 93-94 ℃; MS:378.0 (M+H) +
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-hecanoic acid t-butyl ester.Adopt 2-(4-methoxyl group-benzenesulfonyl)-pyridin-3-yl propionic acid tert-butyl ester (2.0g, 5.3mmol) and n-butyl bromide (0.73g, 5.3mmol) as raw material, separation obtaining the 1.20g product.Productive rate 52%; Little yellow jelly; MS:434.3 (M+H) +
Under room temperature, with 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-hecanoic acid t-butyl ester (1.1g, methylene dichloride/trifluoroacetic acid 2.5mmol) (1: 1) mixed solution stir about 2 hours.Evaporating solvent then is through silica gel column chromatography (30% ethanol/methylene) purifying 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-caproic acid.Output 0.90g, 94%; White solid; 70 ℃ of mp; MS:376.1 (M-H) -
According to embodiment 1 described method, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-caproic acid oxyamide.Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-caproic acid (0.31g, 0.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.13g product.Productive rate: 37%; Faint yellow solid; 65 ℃ of mp; MS:392.9 (M+H) + 1HNMR (300MHz, DMSO-d 6): δ 0.80 (t, J=7.2Hz, 3H), 1.10-1.25 (m, 2H), 1.25-1.50 (m, 2H), and 1.70-2.00 (m, 2H), 3.53 (d, J=14.4Hz, 1H), 3.62 (d, J=14.4Hz, 1H), 3.88 (s, 3H), 7.15 (d, J=8.9Hz, 2H), 7.71 (d, J=8.9Hz, 2H), 7.90-8.00 (m, 1H), 8.40-8.45 (m, 1H), 8.70-8.85 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm -1): 3064m, 2958s, 2871m, 1671m.
Embodiment 71
2-(4-methoxyl group-benzenesulfonyl)-2-suffering-2-alkynyl-last of the ten Heavenly stems-4-acetylenic acid oxyamide
According to embodiment 9 described methods, prepare this title compound.(2.86g, 10mmol) (3.80g 20mmol) as raw material, separates obtaining the 4.4g product with 1-bromo-2-octyne to adopt 2-(4-methoxyl group-benzenesulfonyl)-tert.-butyl acetate.Productive rate 100%; Little yellow jelly; MS:446.9 (M+H) +
According to embodiment 70 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-suffering-2-alkynyl-last of the ten Heavenly stems-4-acetylenic acid.Alkynyl-last of the ten Heavenly stems-(4.40g 10.0mmol) as raw material, separates obtaining the 2.0g product to the 4-acetylenic acid tert-butyl ester to adopt 2-(4-methoxyl group-benzenesulfonyl)-2-suffering-2-.Productive rate 49%; White solid; 61 ℃ of mp; MS:345.1 (M-H) -
According to embodiment 1 described method, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-suffering-2-alkynyl-last of the ten Heavenly stems-4-acetylenic acid oxyamide.Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-suffering-2-alkynyl-last of the ten Heavenly stems-4-acetylenic acid (0.36g, 0.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.25g product.Productive rate: 62%; White solid; Mp 83-84 ℃; MS:462.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.82-0.90 (m, 6H), 1.15-1.45 (m, 12H), 1.90-2.05 (m, 4H), 2.86 (brd, J=17.0Hz, 2H), 3.00 (brd, J=17.0Hz, 2H), 3.87 (s, 3H), 7.15 (d, J=10.0Hz, 1H), 7.71 (d, J=10.0Hz, 1H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm -1): 3344s, 3208m, 2930m, 2870m, 1677s, 1592s;
C 25H 35NO 5The analytical calculation value of S: C, 65.05; H, 7.64; N, 3.03;
Measured value: C, 65.26; H, 7.68; N, 2.90.
Embodiment 72
2-(4-methoxyl group-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-4-acetylenic acid oxyamide
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-the 4-acetylenic acid tert-butyl ester.(2.86g, 10mmol) (2.68g 20mmol) as raw material, separates obtaining the 3.50g product with 1-bromo-2-butyne to adopt 2-(4-methoxyl group-benzenesulfonyl)-tert.-butyl acetate.Productive rate 90%; White solid; Mp 85-87 ℃; MS:391.0 (M+H) +
According to embodiment 70 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-the 4-acetylenic acid.(3.0g 7.7mmol) as raw material, separates obtaining the 2.5g product to adopt 2-(4-methoxyl group-benzenesulfonyl)-2-fourth-2-alkynyl-own-4-acetylenic acid tert-butyl ester.Productive rate 97%; White solid; Mp 141-143 ℃; MS:333.1 (M-H) -
According to embodiment 1 described method, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-4-acetylenic acid oxyamide.Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-the 4-acetylenic acid (0.27g, 0.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.23g product.Productive rate: 89%; White solid; Mp 135-137 ℃; MS:349.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.67 (s, 6H), 2.70-3.10 (m, 4H), 3.88 (s, 3H), 7.15 (d, J=10.0Hz, 2H), 7.71 (d, J=10.0Hz, 2H), 9.20 (brs, 1H), 10.90 (brs, 1H); IR (KBr, cm -1): 3301s, 3161m, 2922m, 1640m, 1595s, 1500m.
Embodiment 73
2-(4-methoxyl group-benzenesulfonyl)-2-Propargyl-penta-4-acetylenic acid oxyamide
According to embodiment 9 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-Propargyl-penta-4-acetylenic acid tert-butyl ester.Adopt 2-(4-methoxyl group-benzenesulfonyl)-tert.-butyl acetate (2.0g, 7.0mmol) and propargyl bromide (1.77g, 15mmol) as raw material, separation obtaining the 1.90g product.Productive rate 75%; White solid; Mp 113-115 ℃; MS:362.1 (M+H) +
According to embodiment 70 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-Propargyl-penta-4-acetylenic acid.(1.70g 4.7mmol) as raw material, separates obtaining the 1.30g product to adopt 2-(4-methoxyl group-benzenesulfonyl)-2-Propargyl-penta-4-acetylenic acid tert-butyl ester.Productive rate 90%; White solid; 156 ℃ of mp; MS:305.1 (M-H) -
According to embodiment 1 described method, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-Propargyl-penta-4-acetylenic acid oxyamide.Adopt (4-methoxyl group-benzenesulfonyl)-2-Propargyl-penta-4-acetylenic acid (0.25g, O.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.22g product.Productive rate: 85%; White solid; 156 ℃ of mp; MS:321.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90 (s, 3H), 7.01 (d, J=9.0Hz, 2H), 7.82 (d, J=9.0Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm -1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s.
C 15H 15NO 5The analytical calculation value of S: C, 56.07; H, 4.70; N, 4.36;
Measured value: C, 55.65; H, 4.67; N, 4.10.
Embodiment 74
2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid oxyamide
According to embodiment 38 described methods, prepare this title compound.(2.20g, 5.8mmol) (1.14g 6mmol) as raw material, separates obtaining the 2.60g product with 1-bromo-2-octyne to adopt 2-(4-methoxyl group-benzenesulfonyl)-pyridin-3-yl propionic acid tert-butyl ester.Productive rate 92%; Faint yellow gluey thing; MS:486.0 (M+H) +
Under room temperature, with 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid tert-butyl ester (2.60g, methylene dichloride/trifluoroacetic acid 5.35mmol) (1: 1) mixed solution stir about 2 hours (referring to embodiment 70).Evaporating solvent then is through silica gel column chromatography (about 30% ethanol/methylene) purifying 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid.Output: 2.0g, 87%; White solid; 146 ℃ of mp; MS:428.1 (M-H) -
According to embodiment 1 described method, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid oxyamide.Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid (0.71g, 1.62mmol) and oxammonium hydrochloride (1.39g, 20mmol) as raw material, separation obtaining the 0.48g product.Productive rate: 67%; Pale solid; 65 ℃ of mp; MS:445.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.84 (t, J=6.8Hz, 3H), 1.10-1.40 (m, 6H), 1.85-2.00 (m, 2H), 2.79 (d, J=17.9Hz, 1H), 2.90 (d, J=17.9Hz, 1H), 3.50 (d, J=13.7Hz, 1H), 3.74 (d, J=13.7Hz, 1H), 3.89 (s, 3H), 7.19 (d, J=9.0Hz, 2H), 7.76 (d, J=9.0Hz, 2H), 7.85-7.89 (m, 1H), 8.37-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.0 (brs, 1H); IR (KBr, cm -1): 3157m, 3095m, 2954s, 2932s, 2858m, 1671m, 1593s.
C 23H 28N 2O 5SHCl0.9H 2The analytical calculation value of O: C, 55.56; H, 6.24; N, 5.63; Measured value: C, 55.84; H, 6.19; N, 5.59.
Embodiment 75
2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-penta-4-acetylenic acid oxyamide
According to embodiment 38 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-penta-4-acetylenic acid tert-butyl ester.Adopt 2-(4-methoxyl group-benzenesulfonyl)-pyridin-3-yl propionic acid tert-butyl ester (3.77g, 10mmol) and propargyl bromide (1.74g, 13mmol) as raw material, separation obtaining the 2.50g product.Productive rate 60%; Little yellow solid; Mp 132-133 ℃; MS:416.0 (M+H) +
According to embodiment 70 described methods, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-penta-4-acetylenic acid.(2.0g 4.8mmol) as raw material, separates obtaining the 1.2g product to adopt 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-penta-4-acetylenic acid tert-butyl ester.Productive rate 69%; White solid; Mp 119-121 ℃; MS:358.1 (M-H) -
According to embodiment 1 described method, preparation 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-penta-4-acetylenic acid oxyamide.Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-pyridin-3-yl methyl-penta-4-acetylenic acid (0.29g, 0.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.065g product.Productive rate: 25%; Pale solid; 70 ℃ of mp; MS:375.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.19 (brs, 1H), 2.90-3.00 (m, 2H), 3.55 (d, J=13.8Hz, 1H), 3.67 (d, J=13.8Hz, 1H), 3.89 (s, 3H), 7.18 (d, J=9.0Hz, 2H), 7.75 (d, J=9.0Hz, 2H), 7.80-7.89 (m, 1H), 8.35-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm -1): 3168m, 3095s, 1670m, 1593s.
Embodiment 76
2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-oneself-4-acetylenic acid oxyamide
According to embodiment 1 described method, preparation 2-(4-fluoro-benzene sulfane base)-tert.-butyl acetate.(30.0g, 230mmol) (45.67g 230mmol) as raw material, separates obtaining the 53.4g product with the monobromo-acetic acid tert-butyl ester to adopt the 4-fluoro thiophenol.Productive rate 100%; Faint yellow oily thing; MS:243.1 (M+H) +
According to embodiment 9 described universal methods, preparation 2-(4-fluoro-benzenesulfonyl)-tert.-butyl acetate.(48.4g, 200mmol) (121.3g (57%) 400mmol) as raw material, separates obtaining the 48.0g product with 3-chlorine peroxybenzoic acid to adopt 2-(4-fluoro-benzene sulfane base)-tert.-butyl acetate.Productive rate 88%; Faint yellow oily thing; MS:275.1 (M+H) +
According to embodiment 70 described methods, prepare this title compound.(1.83g, 5.0mmol) (0.67g 5.0mmol) as raw material, separates obtaining the 2.18g product with 1-bromo-2-butyne to adopt 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-yl propionic acid tert-butyl ester.Productive rate 100%; Little yellow jelly; MS:419.2 (M+H) +
According to embodiment 38 described methods, preparation 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-oneself-the 4-acetylenic acid.(2.1g 5.0mmol) as raw material, separates obtaining the 1.20g product to adopt 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-own-4-acetylenic acid tert-butyl ester.Productive rate 67%; Pale solid; 150 ℃ of mp; MS:360.2 (M-H) -
According to embodiment 1 described method, preparation 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-oneself-4-acetylenic acid oxyamide.Adopt 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-oneself-the 4-acetylenic acid (0.29g, 0.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.15g product.Productive rate: 45%; White solid; 190 ℃ of mp; MS:377.2 (M+H) + 1HNMR (300MHz, DMSO-d 6): δ 1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J=13.8Hz, 1H), 3.74 (d, J=13.8Hz, 1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40 (m, 1H), 8.74-8.79 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm -1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s;
C 18H 17FN 2O 4SHCl0.5H 2The analytical calculation value of O: C, 51.24; H, 4.54; N, 6.64; Measured value: C, 51.21; H, 4.35; N, 6.46.
Embodiment 77
2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid oxyamide
According to embodiment 9 described methods, prepare this title compound.(1.83g, 5.0mmol) (0.95g 5.0mmol) as raw material, separates obtaining the 1.80g product with 1-bromo-2-octyne to adopt 2-(4-fluoro-benzenesulfonyl)-3-pyridin-3-yl propionic acid tert-butyl ester.Productive rate 56%; Little yellow jelly; MS:474.3 (M+H) +
According to embodiment 70 described methods, preparation 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid.Methyl-last of the ten Heavenly stems-(1.80g 3.8mmol) as raw material, separates obtaining the 1.40g product to the 4-acetylenic acid tert-butyl ester to adopt 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl.Productive rate 88%; Pale solid; Mp 123-124 ℃; MS:416.3 (M-H) -
According to embodiment 1 described method, preparation 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid oxyamide.Adopt 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-yl methyl-last of the ten Heavenly stems-4-acetylenic acid (0.67g, 1.62mmol) and oxammonium hydrochloride (1.39g, 20mmol) as raw material, separation obtaining the 0.22g product.Productive rate: 29%; White solid; Mp 180-182 ℃; MS:433.2 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.84 (t, J=6.8Hz, 3H), 1.20-1.40 (m, 6H), 1.90-2.05 (m, 2H), 2.75 (d, J=19.9Hz, 1H), 2.94 (d, J=19.9Hz, 1H), 3.54 (d, J=13.7Hz, 1H), 3.75 (d, J=13.7Hz, 1H), 7.40-7.60 (m, 2H), and 7.70-8.00 (m, 3H), 8.30-8.40 (m, 1H), 8.70-8.80 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm -1): 3154m, 3105s, 3067m, 2957s, 2933s, 2873m, 1690s, 1631m;
C 22H 25FN 2O 4The analytical calculation value of SHCl: C, 56.34; H, 5.59; N, 5.97;
Measured value: C, 56.18; H, 5.54; N, 5.76.
Embodiment 78
2-(4-fluoro-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-4-acetylenic acid oxyamide
According to embodiment 9 described methods, preparation 2-(4-fluoro-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-the 4-acetylenic acid tert-butyl ester.(4.87g, 20mmol) (5.36g 40mmol) as raw material, separates obtaining the 6.0g product with 1-bromo-2-butyne to adopt 2-(4-fluoro-benzenesulfonyl)-tert.-butyl acetate.Productive rate 77%; White solid; 85 ℃ of mp; MS:379.1 (M+H) +
According to embodiment 70 described methods; preparation 2-(4-fluoro-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-the 4-acetylenic acid; (3.50g 8.47mmol) as raw material, separates obtaining the 2.35g product to adopt 2-(4-fluoro-benzenesulfonyl)-2-fourth-2-alkynyl-own-4-acetylenic acid tert-butyl ester.Productive rate 79%; White solid; Mp129-131 ℃; MS:642.8 (M-H) -
According to embodiment 1 described method, preparation 2-(4-fluoro-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-4-acetylenic acid oxyamide.Adopt 2-(4-fluoro-benzenesulfonyl)-2-fourth-2-alkynyl-oneself-the 4-acetylenic acid (0.26g, 0.81mmol) and oxammonium hydrochloride (0.70g, 10mmol) as raw material, separation obtaining the 0.21g product.Productive rate: 77%; White solid; Mp 161-163 ℃; MS:338.1 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.67 (s, 6H), 2.80-3.10 (m, 4H), 7.51 (dd, J=9.0,9.0Hz, 2H), 7.87 (m, 2H), 9.26 (brs, 1H), 10.95 (brs, 1H); IR (KBr, cm -1): 3336s, 3245m, 1681s, 1589m, 1493m;
C 16H 16FNO 4The analytical calculation value of S: C, 56.96; H, 4.78; N, 4.15;
Measured value: C, 56.59; H, 4.75; N, 4.04.
Embodiment 792-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-ene base)-oneself-obtusilic acid hydroxyl acyl
Amine
According to embodiment 9 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-ene base)-oneself-the obtusilic acid ethyl ester; (5.0g, 20mmol) (6.0g is 40mmol) as raw material with the prenyl bromine to adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl acetate.Output 7.0g, 88%; Colorless oil; MS:395 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-ene base)-own-obtusilic acid ethyl ester (3.5g; 9mmol) as raw material, it is the 2-of colorless oil (4-methoxyl group-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-ene base)-own-obtusilic acid that separation obtains 3.3g (97%).MS：365(M-H) -。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-ene base)-own-obtusilic acid (2.6g; 7.0mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 1.36g is a colorless solid (4-methoxyl group-benzenesulfonyl)-5-methyl-2-(3-methyl-but-2-ene base)-own-obtusilic acid oxyamide.Productive rate: 67%; Mp 93-96 ℃; MS:383 (M+H) + 1HNMR (300MHz, CDCl 3): δ 1.68 (s, 6H), 1.73 (s, 6H), 2.72 (m, 4H), 3.82 (s, 3H), 5.12 (m, 2H), 6.92 (d, J=8Hz, 2H), 7.33 (bs, 1H), 7.72 (d, J=8Hz, 2H), 9.71 (bs, 1H).
Embodiment 80
2-(4-methoxyl group-phenyl sulfane base)-enanthic acid oxyamide
According to embodiment 1 described universal method, preparation 2-(4-methoxyl group-phenyl sulfane base)-oil of cognac (13.8g, 98%), adopt 2-bromo-oil of cognac (11g, 47mmol) (6g 42.8mmol) as raw material, is yellow oil with the 4-methoxybenzenethiol; MS:297.2 (M+H) +
Employing be dissolved in 2-(4-methoxyl group-phenyl sulfane base)-oil of cognac among methyl alcohol (300ml) and the 10N NaOH (25ml) (4g, 13.5mmol) as raw material, preparation 2-(4-methoxyl group-phenyl sulfane base)-enanthic acid.The reaction mixture that 1 described processing produces according to embodiment.Output 3g (83%).Yellow oil.MS：267．1(M-H) -。
(2.49g 9.32mmol) as raw material and according to embodiment 1 described method, separates obtaining the 2-that 1.83g is a pale solid (4-methoxyl group-phenyl sulfane base)-enanthic acid oxyamide to adopt 2-(4-methoxyl group-phenyl sulfane base)-enanthic acid.Mp 90-95 ℃; Productive rate 70%; MS:284.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.826 (t, J=6.9Hz, 3H), 1.135-1.76 (m, 8H), 3.35 (m, 1H), 3.82 (s, 3H), 6.91-7.49 (m, 4H).
Embodiment 81
(49A) 2R *-(4-methoxyl group-phenyl-S *-sulfinyl)-the enanthic acid oxyamide and
(49B) 2S *-(4-methoxyl group-phenyl-R *-sulfinyl)-the enanthic acid oxyamide
Adopt 2-(4-methoxyl group-phenyl sulfane base)-enanthic acid oxyamide (1.69g; 6mmol) as raw material and according to embodiment 5 described methods; adopt 75% ethyl acetate: the hexane wash-out, silica gel column chromatography separates two diastereomers of 2-(4-methoxyl group-phenyl sulfinyl)-enanthic acid oxyamide.Separate and obtain being the less isomer 2R of the polarity of white powder *-(4-methoxyl group-phenyl-S *-sulfinyl)-the enanthic acid oxyamide.Output: 390mg (22%); 115 ℃ of mp; MS:300.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): 0.828 (t, J=6.2Hz, 3H), 1.18-1.23 (m, 6H), 1.73-1.99 (m, 2H), 3.11-3.15 (m, 1H), 3.82 (s, 3H), 7.09-7.61 (m, 4H).Separate and obtain being the bigger isomer 2S of the polarity of gray solid *-(4-methoxyl group-phenyl-R *-sulfinyl)-the enanthic acid oxyamide.Output: 200mg (11%); 112 ℃ of mp; MS:300.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.754 (t, J=6.9Hz, 3H), 1.014-1.121 (m, 6H), 1.58-1.89 (m, 2H), 3.10-3.15 (m, 1H), 3.834 (s, 3H), 7.13-7.65 (m, 4H).
Embodiment 822-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-morpholine-4-base-oxyethyl group)-phenyl]-the propionic acid hydroxyl
The base amide hydrochloride
According to embodiment 12 described methods; preparation 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-morpholine-1-base-oxyethyl group)-phenyl]-ethyl propionate; adopt 2-(4-methoxyl group-benzenesulfonyl)-ethyl propionate (4.0g; 15mmol) and 4-(morpholine-1-base-oxyethyl group)-(2.9g is 10mmol) as raw material for the benzyl chloride hydrochloride.Output 4.8g, 98%; Brown oil; MS:492 (M+H) +
According to embodiment 9 described methods; adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-morpholine-1-base-oxyethyl group)-phenyl]-ethyl propionate (4.0g; 8.1mmol) as raw material, separation obtains 3.2g (productive rate 84%) and is the 2-of colourless crystallization (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-morpholine-1-base-oxyethyl group)-phenyl]-propionic acid.Mp?171℃；MS：464(M+H) +。
Adopt 2-(4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-morpholine-1-base-oxyethyl group)-phenyl]-propionic acid (4.0g; 8.6mmol) as raw material and according to embodiment 1 described method, separate obtaining the 2-that 2.5g is a colorless solid (4-methoxyl group-benzenesulfonyl)-2-methyl-3-[4-(2-morpholine-1-base-oxyethyl group)-phenyl]-the propionic acid oxyamide.By making described free alkali and methyl alcohol system hydrogenchloride in 0 ℃ of prepared in reaction hydrochloride.Output 2.5g, 60%; 98 ℃ of mp; MS:479 (M+H) + 1H NMR (300MHz, CDCl 3): 1.36 (s, 3H), 3.8-12.6 (m, 16H), 3.9 (s, 3H), 4.1-4.3 (m, 1H), 6.6 (d, J=8Hz, 2H), 6.96 (d, J=9Hz, 2H), 7.1 (d, 8Hz, 2H), 7.84 (d, 9Hz, 2H), 10.8 (bs, 1H).
Embodiment 83
1-benzyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
To the 4-anisole mercaptan (2.8g in round-bottomed flask, 20mmol) and Anhydrous potassium carbonate (10g, excessive) anhydrous propanone (100ml) stirred solution in add alpha-brominated ethylhexoate (3.3g, 20mmol), good stir, reflux under with this reaction mixture heating 8 hours.Then, cool off this reaction mixture, filtering sylvite concentrates this reaction mixture.Use the chloroform extraction residue, water and 0.5N NaOH solution washing.Water thorough washing organic layer through dried over mgso, filters and concentrates again.Separate (4-methoxyl group-phenyl sulfane the base)-ethyl acetate that obtains to faint yellow oily thing.Output 4.4g (100%); MS 277 (M+H) +
In 0 ℃, (14.0g slowly adds (4-methoxyl group-phenyl sulfane base)-ethyl acetate (4.4g, methylene dichloride 20mmol) (15ml) solution in methylene dichloride 40mmol) (100ml) solution to the 60%3-chlorine peroxybenzoic acid that stirs.This reaction mixture becomes muddiness, stirs 6 hours under room temperature.Use hexane (300ml) to dilute this reaction mixture then, stirred 15 minutes.The filtering solid adds to sodium sulfite solution in the organic layer, stirs at least 3 hours, uses chloroform extraction then, washes with water.Through the dried over mgso organic layer, filter and concentrate, separate colourless (4-methoxyl group-benzenesulfonyl)-ethyl acetate that obtains to oily matter.Productive rate: 100%; MS 259.1 (M+H) +
Diethanolamine (10.5g to the stirring in round-bottomed flask, 100mmol) and Anhydrous potassium carbonate (30g, excessive) anhydrous propanone (250ml) solution in add bromotoluene (17.2g, 100mmol), under fully stirring, refluxing with this reaction mixture heating 8 hours.Cool off this reaction mixture then, filtering sylvite concentrates this reaction mixture.Use the chloroform extraction residue, wash with water.Water thorough washing organic layer through dried over mgso, filters and concentrates again.Colorless oil.Output 19.0g, 97%; MS:196 (M+H) +
(9.75g 50mmol) is dissolved in the saturated methyl alcohol salt manufacturing acid and is concentrated into dried with N-benzyl diethanolamine.The hydrochloride that so forms is dissolved in the methylene dichloride (300ml), and thionyl chloride (20g, excessive) stirred 1 hour under room temperature.Then reaction mixture is concentrated into dried, with product two-(2-chloro-ethyl)-benzylamine hydrochloride is used for further conversion without any purifying.Output 13.0g, 97%; MS:232 (M+H) +
Two-(2-chloro-ethyl)-benzylamine hydrochloride (6.6g to the stirring in round-bottomed flask; 24.7mmol), 18-hat-6 (500mg) and Anhydrous potassium carbonate (30g; excessive) anhydrous propanone (250ml) solution in add (4-methoxyl group-benzenesulfonyl)-ethyl acetate (6.12g; 24mmol), under fully stirring, refluxing, this reaction mixture was heated 16 hours.Cool off this reaction mixture then, filtering sylvite concentrates this reaction mixture.Use the chloroform extraction residue, wash with water.Water thorough washing organic layer through dried over mgso, filters and concentrates again.The dark-brown reaction mixture is used 30% ethyl acetate through purification by silica gel column chromatography: the hexane wash-out, separate product 4-(4-methoxyl group-benzenesulfonyl)-1-benzyl-piperidine-4-ethyl formate that obtains to brown oil.Output 6.0g, 60%; MS:418 (M+H).
With 4-(4-methoxyl group-benzenesulfonyl)-1-benzyl-piperidine-4-ethyl formate (5.0g, 11.9mmol) be dissolved in methyl alcohol/tetrahydrofuran (THF) (1: 1,200ml) in, under room temperature, stirred 72 hours.After this concentrated reaction mixture is dissolved in the water (200ml) product with dense HCl neutralization.After the neutralization reaction mixture is concentrated into dried.In solid, add icy water (100ml) and filtration.In 50 ℃ of desciccate 4-(4-methoxyl group-benzenesulfonyl)-1-benzyl-piperidines-4-formic acid, it is used for next step without being further purified.Colorless solid.Output 3.2g, 69%; MS:390 (M+H).
In 0 ℃, to 4-(4-methoxyl group-benzenesulfonyl)-1-benzyl-piperidines-4-formic acid that stirs (2.0g, 5.1mmol) and drip in methylene dichloride (100ml) solution of dimethyl formamide (2) oxalyl chloride (1.0g, 8mmol).After the adding, under room temperature, this reaction mixture was stirred 1 hour.Simultaneously in other flask, with hydroxylamine hydrochloride (2.0g, 29mmol) and triethylamine (5ml, excessive) mixture at tetrahydrofuran (THF): water (5: 1,30ml) in 0 ℃ of stirring 1 hour.After 1 hour, concentrate the oxalyl chloride reaction mixture, faint yellow residue is dissolved in the 10ml methylene dichloride, and slowly adds in the azanol in 0 ℃.Under room temperature, this reaction mixture was stirred 24 hours and concentrated.With the residue that chloroform extraction obtains, water thorough washing.Through the product that purification by silica gel column chromatography obtains, use the chloroform wash-out, separate product 4-(4-methoxyl group-benzenesulfonyl)-1-benzyl-piperidines-4-formic acid oxyamide that obtains to colorless solid.Mp 90-95 ℃; Output 1.2g, 48%; MS:405 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.29 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, 2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).
Embodiment 84 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(3-methoxyl group-benzyl)-amino]-ethanol.(3.1g, 29.5mmol) (5g is 31.9mmol) as raw material with 3-methoxy-benzyl chlorine to adopt diethanolamine.Output 9.28g, 99%; Yellow oil; MS:226 (M+H) +
According to embodiment 83 described universal methods, preparation 3-methoxy-benzyl-two-(2-chloro-ethyl)-amine.Methoxyl group-(4.4g is 20mmol) as raw material for the benzyl diethanolamine to adopt 3-.Output 4.5g, 93%; Yellow solid; Mp 86-88 ℃; MS:263 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl)-ethyl acetate (5.0g, 22mmol) and two-(8.0g is 23.5mmol) as raw material for (2-chloro-ethyl)-(3-methoxyl group-benzyl)-amine.Output 2.4g, 24%; The low melting point solid; MS:447.9 (M+H) +
Employing is dissolved in 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidine-4-ethyl formate (2.4g in methyl alcohol (30ml), 10N sodium hydroxide (10ml), the tetrahydrofuran (THF) (20ml); 5.36mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 710mg, 32%; White solid; 199 ℃ of mp, MS:419.9 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid (830mg; 198mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 190mg is a white solid (4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide.130 ℃ of mp; Productive rate 20.4%; MS:435.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.24-2.32 (m, 2H), 2.51 (d, 2H), 2.73-2.83 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 4.32 (s, 2H), 7.01-7.77 (m, 8H), 9.38 (s, 1H), 10.1 (s, 1H).
Embodiment 85
1-(3, the 4-dichloro benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(3, the 4-dichloro benzyl)-amino]-ethanol.(4.84g, 46mmol) with 3, (9.0g is 46mmol) as raw material for the 4-dichlorobenzyl chloride to adopt diethanolamine.Output 13.8g, 99%; Colorless oil; MS:264.3 (M+H) +
According to embodiment 83 described universal methods, preparation 3,4-dichloro benzyl-two-(2-chloro-ethyl)-amine.Adopt 3, (10.7g is 41mmol) as raw material for 4-dichloro benzyl diethanolamine.Productive rate 99%; Yellow solid; Mp 218-220 ℃; MS:301.8 (M+H) +
According to embodiment 83 described universal methods, preparation 1-(3, the 4-dichloro benzyl)-4-(methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.(2.9g, 11mmol) with 3,4-dichloro benzyl-two-(3.4g is 11mmol) as raw material for (2-chloro-ethyl)-amine to adopt 4-(methoxyl group-benzenesulfonyl)-ethyl acetate.Output 5.9g, 60%; Brown oil; MS:494.5 (M+H) +
Employing is dissolved in the 1-(3 in methyl alcohol (50ml), 10N sodium hydroxide (15ml) and the tetrahydrofuran (THF) (75ml); the 4-dichloro benzyl)-4-(methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (5.0g; 10mmol) as raw material; preparation 1-(3, the 4-dichloro benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.94g, 62%; MS:458.3 (M+H) +
Adopt 1-(3; the 4-dichloro benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (2.67g; 5.8mmol) as raw material and according to embodiment 83 described methods; separate and obtain the 1-that .2g is a white solid (3, the 4-dichloro benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Mp 192-195 ℃; Productive rate 10%; MS:472.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.20-2.28 (m, 2H), 2.76-2.79 (m, 2H), 3.43-3.44 (m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, J=.030,2H), and 7.50-7.73 (d, J=.027,1H), 7.65-7.68 (d, J=.029,2H), 7.72-7.75 (d, J=.027,2H), 7.87 (s, 1H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).
Embodiment 86
4-(4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(4-methyl-benzyl)-amino]-ethanol.(4.8g, 46mmol) (8.5g is 46mmol) as raw material with 4-methyl-benzyl chlorine to adopt diethanolamine.Output 9.8g, 99%; MS:209.9 (M+H) +
According to embodiment 83 described universal methods, preparation 4-methyl-benzyl-two-(2-chloro-ethyl)-amine.Methyl-(6g is 20mmol) as raw material for the benzyl diethanolamine to adopt 4-.Output 5.2g, 84%; Yellow solid; Mp 145-147 ℃; MS:245.9 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-ethyl formate.Adopt 4-(4-methoxyl group-benzenesulfonyl)-ethyl acetate (7.0g, 27mmol) and the 4-methyl-two-(5.0g is 17mmol) as raw material for (2-chloro-ethyl)-amine.Output 4.64g, 63%; The low melting point solid; MS:431.9 (M+H) +
Employing is dissolved in 4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (4.3g in methyl alcohol (30ml), 10N sodium hydroxide (10ml), the tetrahydrofuran (THF) (20ml); 9.9mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.6g, 40%; White solid; Mp 207-208 ℃, MS:404.3 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid (1.59g; 3.9mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that .505g is a white solid (4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide.Mp 176-177 ℃; Productive rate 32%; MS:419.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.24-2.32 (m, 2H), 2.51 (t, 3H), 2.73-2.80 (m, 2H), 3.35-3.50 (m, 4H), 3.87 (s, 3H), 4.24 (s, 2H), 7.13-7.17 (d, J=.039,2H), 7.23-7.60 (d, J=.036,2H), 7.38-7.41 (d, J=.025,2H), and 7.65-7.68 (d, J=.039,2H).
Embodiment 87
4-(4-methoxyl group-benzenesulfonyl)-1-naphthalene-2-base-methyl piperidine-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(2-naphthalene-2-ylmethyl)-amino]-ethanol.Adopt diethanolamine (6.18g, 59mmol) and 2-(bromomethyl) naphthalene (10g is 45mmol) as raw material.Output 12.7g, 96%; Yellow solid; Mp 162-164 ℃; MS:246.0 (M+H) +
According to embodiment 83 described universal methods, preparation 2-naphthalene-2-ylmethyl-two-(2-chloro-ethyl)-amine.Naphthalene-ylmethyl-(10g is 36mmol) as raw material for diethanolamine to adopt 2-.Output 9.1g, 79%; Brown solid; Mp 124-126 ℃; MS:281.9 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-naphthalene-ylmethyl-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl)-ethyl acetate (8.4g, 32mmol) and 1-naphthalene-ylmethyl-two-(8.6g is 27mmol) as raw material for (2-chloro-ethyl)-amine.Output 6.5g, 52%; The low melting point solid; MS:440.0 (M+H) +
Employing is dissolved in 4-(4-methoxyl group-benzenesulfonyl)-naphthalene-ylmethyl-piperidine-4-ethyl formate (6.3g in methyl alcohol (30ml), 10N sodium hydroxide (30ml) and the tetrahydrofuran (THF) (30ml); 13mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-naphthalene-ylmethyl-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.3g, 36%; Yellow solid; Mp 226-228 ℃, MS:440.0 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-naphthalene-2-base-methyl piperidine-4-formic acid (2.18g; 5.0mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that .753g is a pale solid (4-methoxyl group-benzenesulfonyl)-1-naphthalene-2-ylmethyl piperidines-4-formic acid oxyamide.Mp 168-170 ℃; Productive rate 31%; MS:455.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.29-2.33 (m, 2H), 2.86-2.89 (m, 2H), 3.42-3.46 (m, 4H), 3.85 (s, 3H), 4.46 (s, 2H), 7.13-7.16 (d, J=.030,2H), 7.56-7.64 (m, 3H), and 7.65-7.68 (d, J=.030,2H), 7.98-8.00 (m, 3H), 8.21 (s, 1H), 10.70 (s, 1H), 11.20 (s, 1H).
Embodiment 88
1-biphenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl) piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(1-biphenyl-4-ylmethyl)-amino]-ethanol.Adopt diethanolamine (5.2g, 49mmol) and 4-(chloro methyl) biphenyl (10g is 49mmol) as raw material.Output 9.98g, 66%; White solid; Mp 160-162 ℃; MS:271.9 (M+H) +According to the embodiment 83 described dihydrochlorides that are translated into.
According to embodiment 83 described universal methods, preparation 1-biphenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(4-methoxyl group-benzenesulfonyl)-ethyl acetate (2.85g, 11mmol) and 1-biphenyl-4-ylmethyl-two-(3.4g is 11mmol) as raw material for (2-chloro-ethyl)-amine.Output 2.1g, 39%; Beige solid; Mp 176-178 ℃; MS:494.1 (M+H) +
Employing is dissolved in 1-biphenyl-4-ylmethyl-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (5.7g in ethanol (20ml), tetrahydrofuran (THF) (20ml) and the 10N sodium hydroxide (10ml); 12mmol) as raw material, preparation 1-biphenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.1g, 39%, MS:465.8 (M+H) +
Adopt 1-biphenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (1.0g; 2.2mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-biphenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl) piperidines-4-formic acid oxyamide that .132g is a brown solid.168 ℃ of mp; Productive rate 20%; MS:440.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.30-2.35 (m, 2H), 2.83-2.87 (m, 2H), 3.35-3.5 (m, 4H), 3.87 (s, 3H), 7.1 5-7.721 (d, J=.059Hz, 2H), 7.49-7.65 (m, 5H), and 7.68-7.74 (d ,=.06Hz, 2H), 9.3 (s, 1H), 10.3 (s, 1H), 11.15 (s, 1H).
Embodiment 89 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base) piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-1-(3-methyl-but-2-ene base)-amino]-ethanol.(4.1g, 39mmol) (6.0g is 40mmol) as raw material with 4-bromo-2-methyl-butylene to adopt diethanolamine.Productive rate 98%; Brown oil; MS:173.8 (M+H) +
According to embodiment 83 described universal methods, preparation 1-(3-methyl-but-2-ene base)-two-(2-chloro-ethyl)-amine.Adopt 2-[(2-hydroxyl-ethyl)-1-(3-methyl-but-2-ene base)-amino]-(10.4g is 50mmol) as raw material for ethanol.Output 10.5g, 99%; Brown solid; MS:210.3 (M+H) +
According to embodiment 1 described universal method, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl)-ethyl acetate (11.32g, 44mmol) and 3-methyl-but-2-ene base-two-(10.4g is 50mmol) as raw material for (2-chloro ethyl)-amine.Output 6.2g, 36%; Brown oil; MS:395.6 (M+H) +
Employing is dissolved in 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base)-piperidine-4-ethyl formate (6.2g in ethanol (15ml), 10N sodium hydroxide (10ml) and the tetrahydrofuran (THF) (75ml); 16mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.2g, 21%; Brown solid; Mp 196-197 ℃, MS:367.9 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base)-piperidines-4-formic acid (1.0g; 3.0mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that .110mg is a yellow solid (4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base)-piperidines-4-formic acid oxyamide.Mp 142-145 ℃; Productive rate 12%; MS:382.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.67 (s, 3H), 1.79 (s, 3H), 2.18-2.23 (m, 2H), and 2.66-2.73 (m, 2H), 3.37-3.46 (m, 2H), 3.67-3.69 (m, 2H), 5.19-5.24 (m, 1H), 7.15-7.18 (d, J=.03,2H), 7.67-7.70 (d, J=.030,2H), 9.34 (s, 1H), 9.88 (s, 1H), 11.15 (s, 1H).
Embodiment 90
1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(4-benzyl bromide)-(2-hydroxyl-ethyl)-amino]-ethanol.(22.5g, 150mmol) (25g is 100mmol) as raw material with the 4-bromobenzyl bromide to adopt diethanolamine.Output 33.66g, 99%; Yellow oil; MS:273.8 (M+H) +
According to embodiment 83 described universal methods, preparation (4-bromo-benzyl)-two-(2-chloro-ethyl)-amine.Adopt the 2-[(4-benzyl bromide)-(2-hydroxyl-ethyl)-amino]-(33.28g is 122mmol) as raw material for ethanol.Output 47g, 99%; Brown solid; 125 ℃ of mp; MS:309.8 (M+H) +
According to embodiment 83 described universal methods, preparation 1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (8.6g, 33.5mmol) and (4-bromo-benzyl)-two-(13.3g is 38.6mmol) as raw material for (2-chloro-ethyl)-amine.Output 17g (44%); Brown oil; MS:497.8 (M+H) +
Employing is dissolved in THF: the 1-in methyl alcohol 3: 1 and the 10N sodium hydroxide (20ml) (4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (16.5g; 33.3mmol) as raw material, preparation 1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 6.18g (40%); Brown solid; 215 ℃ of mp, MS:469.7 (M+H) +
Adopt 1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (1.95g; 4.2mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 1-that 1.29g is a pale solid (4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 60%; 180 ℃ of mp; MS:484.7 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.1 8-2.29 (m, 2H), 2.46 (d, 2H), 2.74-2.89 (m, 2H), 3.39 (d, 2H), 3.87 (s, 3H), 4.28 (s, 2H), 7.18 (d, J=17Hz, 2H), 7.49 (d, J=8.1Hz, 2H), 7.65-7.68 (m, 4H), 9.37 (s, 1H), 10.5 (s, 1H).
Embodiment 91
4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(3-phenyl-propyl group)-amino]-ethanol.(15.8g, 151mmol) (20g is 101mmol) as raw material with 1-bromo-3-phenyl-propane to adopt diethanolamine.Output 21.31g, 95%; Yellow oil; MS:223.9 (M+H) +
According to embodiment 83 described universal methods, prepare two-(2-chloro-ethyl)-(3-phenyl-propyl group)-amine.Adopt 2-[(2-hydroxyl-ethyl)-(3-phenyl-propyl group)-amino]-(20.32g is 90.7mmol) as raw material for ethanol.Output 24.9g, 92%; Brown oil; MS:259.8 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (12g, 46.5mmol) and two-(24.8g is 93.8mmol) as raw material for (2-chloro-ethyl)-(3-phenyl-propyl group)-amine.Output 11.24g, 54%; Brown oil; MS:446 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-methoxyl group-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-(3-phenyl-propyl group)-piperidine-4-ethyl formate (10.74g; 24.13mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.67g, 47%; Pale powder; 203 ℃ of mp, MS:418.2 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidines-4-formic acid (4.37g; 10.4mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.64g is a pale solid (4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidines-4-formic acid oxyamide.Productive rate 37%; 143 ℃ of mp; MS:432.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.92-1.97 (m, 2H), 2.1 8-2.29 (m, 2H), 2.47 (d, 2H), 2.58 (t, J=7.7Hz, 2H), 2.6-2.73 (m, 2H), and 3.0-3.06 (m, 2H), 3.60 (d, J=12.3Hz, 2H), 3.87 (s, 2H), 7.15-7.30 (m, 7H), 7.68 (d, J=9Hz, 2H), 9.3 (s, 1H), 10.1 (s, 1H).
Embodiment 92
The 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, the preparation tertiary butyl-two-(2-chloro-ethyl)-amine.(6g is 37.2mmol) as raw material to adopt the 1-tertiary butyl-diethanolamine.Output 11.15g, 99%; White solid; MS:197.8 (M+H) +
According to embodiment 83 described universal methods, the preparation 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (10g, 38.76mmol) and the tertiary butyl-two-(5.25g is 22.53mmol) as raw material for (2-chloro-ethyl)-amine.Output 5.37g, 62%; Brown oil; MS:384 (M+H) +
Employing is dissolved in the 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (5.37g in methyl alcohol (300ml) and the 10N sodium hydroxide (23ml); 14mmol) as raw material, the preparation 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.52g, 30.6%; White powder; 204 ℃ of mp, MS:356 (M+H) +
Adopt the 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (320mg; 0.9mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 1-tertiary butyl-4-that 190mg is a green solid (4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 52%; 40 ℃ of mp; MS:371.1 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.29 (s, 9H), 1.54 (m, 2H), 1.66 (m, 2H), 2.39 (m, 2H), 2.98 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.67 (d, 2H).
Embodiment 93
1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation butyl-two-(2-chloro-ethyl)-amine.(6g is 37.2mmol) as raw material to adopt N butyl diethanol amine.Output 11.3g, 99%; White powder; 165 ℃ of mp; MS:197.9 (M+H) +
According to embodiment 83 described universal methods, preparation 1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5g, 19.38mmol) and butyl-two-(4.52g is 19.38mmol) as raw material for (2-chloro-ethyl)-amine.Output 6.86g, 93%; Brown oil; MS:384 (M+H) +
Employing is dissolved in 1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (6.42g in methyl alcohol (200ml) and the 10N sodium hydroxide (20ml); 16.8mmol) as raw material, preparation 1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.6g, 27%; White powder; 206 ℃ of mp, MS:356.4 (M+H) +
Adopt 1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (1.51g; 4.3mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-butyl-4-that 200mg is a pale solid (4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 9.3%; 75 ℃ of mp; MS:371.1 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.87 (t, J=7.2Hz, 3H), 1.27 (m, 2H), 1.59 (m, 2H), 2.27 (m, 2H), 2.45 (m, 2H), 2.50 (m, 2H), 2.65 (m, 2H), 2.97 (m, 2H), 3.88 (s, 3H), 7.18 (d, 2H), 7.69 (d, 2H).
Embodiment 94
1-encircles octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation ring octyl group-two-(2-chloro-ethyl)-amine.(6g is 28mmol) as raw material to adopt N-ring octyl group diethanolamine.Output 10g, 99%; Pale solid; 158 ℃ of mp; MS:251.9 (M+H) +
According to embodiment 83 described universal methods, preparation 1-ring octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5g, 19.4mmol) and the ring octyl group-two-(5.57g is 19.4mmol) as raw material for (2-chloro-ethyl)-amine.Output 8.2g, 96%; Brown oil; MS:438 (M+H) +
Employing is dissolved in 1-ring octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (8g in methyl alcohol (200ml) and the 10N sodium hydroxide (25ml); 18.3mmol) as raw material, preparation 1-ring octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.36g, 32%; White powder; 180 ℃ of mp, MS:410 (M+H) +
Adopt 1-ring octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (2.26g; 5.53mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-ring octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide that 570mg is a white powder.Productive rate 22%; Mp＞200 ℃; MS:425 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.42-1.66 (m, 14H), 1.83 (m, 2H), 2.33 (m, 2H), 2.67 (m, 2H), 3.30-3.51 (m, 3H), 3.88 (s, 3H), 7.17 (d, 2H), 7.66 (d, 2H).
Embodiment 95
1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (3g, 11.6mmol) and ethyl-two-(2.39g is 11.6mmol) as raw material for (2-chloro-ethyl)-amine.Output 3.09g, 75%; The low melting point brown solid; MS:356 (M+H) +
Employing is dissolved in 1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (2.42g in methyl alcohol (100ml) and the 10N sodium hydroxide (15ml); 6.8mmol) as raw material, preparation 1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.29g, 58%; White solid; 209 ℃ of mp, MS:328 (M+H) +
Adopt 1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (1.23g; 3.76mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-ethyl-4-that 1.02g is a pale powder (4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 80%; 85 ℃ of mp; MS:343 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.926 (t, J=7.1Hz, 3H), 1.68-1.89 (m, 4H), 2.05-2.24 (m, 4H), 2.73 (q, 2H), 3.85 (s, 3H), 7.07 (d, 2H), 7.64 (d, 2H).
Embodiment 96
1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5.7g, 22.2mmol) and sec.-propyl-two-(4.9g is 22.2mmol) as raw material for (2-chloro-ethyl)-amine.Output 5.64g, 68%; The low melting point brown solid; MS:370 (M+H) +
Employing is dissolved in 1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (5.6g in methyl alcohol (75ml) and the 10N sodium hydroxide (25ml); 15.2mmol) as raw material, preparation 1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.18g, 42%; White powder; 204 ℃ of mp, MS:341.9 (M+H) +
Adopt 1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (2.13g; 6.25mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-sec.-propyl-4-that 590mg is a white powder (4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 2.4%; 75 ℃ of mp; MS:357 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.21 (d, J=6.6Hz, 6H), 2.33-3.53 (m, 9H), 3.88 (s, 3H), 7.16 (d, 2H), 7.66 (d, 2H).
Embodiment 97
1-methyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 1-methyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (3g, 11.6mmol) and methyl-two-(2.2g is 11.6mmol) as raw material for (2-chloro-ethyl)-amine.Output 3.09g, 75%; The low melting point brown solid; MS:342 (M+H) +
Employing is dissolved in 1-methyl-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (8.7g in methyl alcohol (300ml) and the 10N sodium hydroxide (35ml); 25.6mmol) as raw material, preparation 1-methyl-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.23g, 41%; White solid; 204 ℃ of mp, MS:313.9 (M+H) +
Adopt 1-methyl-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (2.0g; 6.38mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-methyl-4-that 1.10g is a yellow powder (4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 53%; 89 ℃ of mp; MS:329 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.67-1.76 (m, 2H), 1.85-1.96 (m, 2H), 2.05 (s, 3H), 2.17 (d, J=11.4Hz, 2H), 2.57 (d, J=10.4Hz, 2H), 3.83 (s, 3H), 7.02 (d, 2H), 7.62 (d, 2H).
Embodiment 98
1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (6g, 20mmol) and two-(10g is 30mmol) as raw material for (2-chloro-ethyl)-benzylamine.Output 5.15g, 56%; Yellow oil; MS:460 (M+H) +
Employing is dissolved in THF: 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate (5.1g in methyl alcohol 3: 1 and the 10N sodium hydroxide (10ml); 11.1mmol) as raw material, preparation 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.66g, 56%; Pale solid; 210 ℃ of mp, MS:432 (M+H) +
Adopt 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid (2.61g; 6.06mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-benzyl-4-that 860mg is a pale powder (4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 32%; Mp144 ℃; MS:446.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.94 (t, J=7.3Hz, 3H), 1.44 (q, J=7.5Hz, 2H), 1.70 (q, 2H), 2.28-2.32 (m, 2H), 2.50 (d, 2H), 2.74-2.83 (m, 2H), 3.35 (d, 2H), 4.08 (t, J=6.3Hz, 2H), 4.34 (s, 2H), 7.13 (d, J=8.7,2H), 7.45 (s, 3H), 7.54 (s, 2H), 7.74 (d, J=8.7,2H), 9.35 (s, 1H), 10.7 (s, 1H).
Embodiment 99
1-(4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 1-(4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (18.8g, 72.8mmol) and (4-fluoro-benzyl)-two-(20.8g is 73mmol) as raw material for (2-chloro-ethyl)-amine.Output 25g, 79%; Brown oil; MS:436.9 (M+H) +
Employing is dissolved in THF: the 1-in methyl alcohol 3: 1 and the 10N sodium hydroxide (40ml) (4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (17.4g; 40mmol) as raw material, preparation 1-(4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 10.8g, 66%; Colorless solid; 154 ℃ of mp, MS:408 (M+H) +
Adopt 1-(4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid (8.14g; 20mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 1-that 4.3g is a pale solid (4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 51%; Mp 176-178 ℃; MS:484.7 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.12-2.20 (m, 2H), 2.64-2.79 (m, 2H), 3.32-3.45 (m, 4H), 3.87 (s, 3H), 4.31 (s, 2H), 7.14-7.19 (d, J=17Hz, 2H), and 7.27-7.33 (d, J=8.1Hz, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.38 (s, 1H), 9.75 (s, 1H).
Embodiment 100
1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate.Adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (6g, 20mmol) and (4-fluoro-benzyl)-two-(4.73g is 20mmol) as raw material for (2-chloro-ethyl)-amine.Output 8.2g, 86%; Yellow oil; MS:478 (M+H) +
Employing is dissolved in THF: the 1-in methyl alcohol 3: 1 and the 10N sodium hydroxide (10ml) (4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate (4.77g; 10mmol) as raw material, preparation 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.5g, 79%; Pale solid; Mp114 ℃, MS:450 (M+H) +
Adopt 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid (2.24g; 5.0mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 1-that 200mg is a pale powder (4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 9%; 112 ℃ of mp; MS:465.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.94 (t, J=7.3Hz, 3H), 1.35-1.50 (m, 2H), 1.68-1.77 (m, 2H), 2.20-2.28 (m, 2H), 2.66-2.77 (m, 2H), and 3.77-3.78 (m, 4H), 4.06-4.10 (m, 2H), 4.19 (s, 2H), 7.14-7.19 (d, J=8.7,2H), 7.27-7.33 (d, 2H), 7.50-7.54 (d, 2H), 7.65-7.68 (d, 2H), 9.34 (s, 1H), 10.55 (s, 1H).
Embodiment 101 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(4-methoxyl group-benzyl)-amino]-ethanol.(12.0g, 114mmol) (14.2g is 100mmol) as raw material with 4-methoxy-benzyl chlorine to adopt diethanolamine.Output 17.5g (77%); Yellow oil; 226 (M+H).
According to embodiment 83 described universal methods, preparation 4-methoxy-benzyl-two-(2-chloro-ethyl)-amine.Methoxyl group-(10g is 44mmol) as raw material for the benzyl diethanolamine to adopt 4-.Output 10g (75%); Yellow solid; 55 ℃ of mp; 263.1 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl)-ethyl acetate (5.0g, 20mmol) and two-(7.0g is 22mmol) as raw material for (2-chloro ethyl)-(4-methoxyl group-benzyl)-amine.Output 5.0g, 56%; The low melting point solid; MS:448.5 (M+H) +
Employing is dissolved in 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidine-4-ethyl formate (4.2g in methyl alcohol (30ml), 10N sodium hydroxide (10ml) and the tetrahydrofuran (THF) (20ml); 10mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.0g, 71%; White solid; 190 ℃ of mp, MS:420.4 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid (2.0g; 4.7mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.2g is a white solid (4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide.175 ℃ of mp (HCl); Output: 1.2g, 59%; MS:433.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.8 (m, 4H), 2.3 (m, 2H), 2.73 (m, 2H), 3.37 (d, 2H), 3.76 (s, 3H), 3.88 (s, 3H), 6.87 (d, 2H), 7.11 (d, 2H), 7.21 (d, 2H), 7.65 (d, 2H), 9.2 (bs, 1H), 10.9 (bs, 1H).
Embodiment 102
4-(4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidines
-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-{ (2-hydroxyl-ethyl)-[2-(4-methoxyl group-phenyl)-ethyl] amino }-ethanol.Adopt diethanolamine (10.0g, excessive) and 1-(2-chloro ethyl)-(8.5g is 50mmol) as raw material for the 4-anisole.Output 11g (92%); Yellow oil; 240 (M+H) +
According to embodiment 83 described universal methods, prepare corresponding dichloride two-(2-chloro-ethyl)-(4-p-methoxy-phenyl-2-ethyl)-amine.Adopt 2-{ (2-hydroxyl-ethyl)-[2-(4-methoxyl group-phenyl)-ethyl]-amino }-(10g is 41.8mmol) as raw material for ethanol.Output 11g (95%); Brown oil; 277.2 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5.0g, 20mmol) and two-(2-chloro-ethyl)-(6.4g is 20mmol) as raw material for (4-p-methoxy-phenyl-2-ethyl)-amine.Output 6.0g, 65%; Brown oil; MS:462.5 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-methoxyl group-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidine-4-ethyl formate (5.0g; 10.8mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.0g, 85%; Pale powder; 205 ℃ of mp, MS:434.5 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidines-4-formic acid (1.5g; 3.46mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 900mg is a pale solid (4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidines-4-formic acid oxyamide.Productive rate 58%; 206 ℃ of mp (HCl); MS:449.5 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m, 4H), 3.60 (d, J=12.3Hz, 2H), 3.77 (s, 3H), 3.99 (s, 3H), 6.9 (d, 2H), 7.1-7.25 (q, 4H), 7.7 (d, 2H), 9.3 (s, 1H), 10.6 (s, 1H).
Embodiment 103
4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(2-phenyl-ethyl)-amino]-ethanol.(9.0g is 48.3mmol) as raw material to adopt diethanolamine (6.0g, 57) and 2-bromo-ethylbenzene.Output 9g (90%); Yellow oil; 210 (M+H) +
According to embodiment 83 described universal methods, prepare two-(2-chloro-ethyl)-(2-phenyl-ethyl)-amine.Adopt 2-[(2-hydroxyl-ethyl)-(2-phenyl-ethyl)-amino]-(8.5g is 40.6mmol) as raw material for ethanol.Output 11g (95%); Brown oil; 247.1 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5.0g, 20mmol) and two-(5.6g is 20mmol) as raw material for (2-chloro-ethyl)-(2-phenyl-ethyl)-amine.Output 5.5g, 63%; Brown oil; MS:432.5 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-methoxyl group-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-(2-phenyl-ethyl)-piperidine-4-ethyl formate (3.0g; 6.9mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.0g, 72%; Pale powder; 208 ℃ of mp, MS:404.5 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidines-4-formic acid (1.5g; 3.7mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 900mg is a pale solid (4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidines-4-formic acid oxyamide.Productive rate 58%; 205 ℃ of mp (HCl); MS:419.4 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.3 (m, 2H), 2.5 (m, 3H), 2.8 (m, 2H), 2.95 (m, 2H), 3.25 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H), 7.22-7.8 (m, 9H), 10.6 (s, 1H), 11.2 (bs, 1H).
Embodiment 104 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 4-(n-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidine-4-ethyl formate.Adopt 4-(n-butoxy-benzenesulfonyl)-ethyl acetate (2.5g, 10mmol) and two-(3.0g is 10mmol) as raw material for (2-chloro ethyl)-(4-methoxyl group-benzyl)-amine.Output 3.5g, 71%; The low melting point solid; MS:490.5 (M+H) +
Employing is dissolved in 4-(4-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidine-4-ethyl formate (3.0g in methyl alcohol (30ml), 10N sodium hydroxide (10ml) and the tetrahydrofuran (THF) (20ml); 6.1mmol) as raw material, preparation 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.5g, 53%; White solid; 207 ℃ of mp, MS:462.5 (M+H) +
Adopt 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid (1.0g; 2.1mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.2g is a white solid (4-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide.173 ℃ of mp (HCl); Output: 800mg, 77%; MS:477.5 (M+H) + 1HNMR (300MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 2H), 2.7 (m, 2H), 3.3 (m, 2H), 3.5 (m, 2H), 4.1 (t, 2H), 4.3 (m, 2H), 6.97 (d, 2H), 7.14 (d, 2H), 7.48 (d, 2H), 7.7 (d, 2H), 9.4 (bs, 1H), 10.9 (bs, 1H).
Embodiment 105 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(3-phenoxy group-propyl group)-amino]-ethanol.(15.8g, 151mmol) (21.5g is 100mmol) as raw material with 3-phenoxy propyl bromine to adopt diethanolamine.Output 21.31g (95%); Yellow oil; 238.1 (M+H) +
According to embodiment 83 described universal methods, prepare two-(2-chloro-ethyl)-(3-phenoxy group-propyl group)-amine.Adopt 2-[(2-hydroxyl-ethyl)-(3-phenoxy group-propyl group)-amino]-(20.0g is 84mmol) as raw material for ethanol.Output 24.0g (91%); Brown oil; 277.8 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5.2g, 20mmol) and two-(7.0g is 22mmol) as raw material for (2-chloro-ethyl)-(3-phenoxy group-propyl group)-amine.Output 6.5g, 70%; Brown oil; MS:462.5 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-methoxyl group-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-(3-phenoxy group-propyl group)-piperidine-4-ethyl formate (4.2g; 9.1mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.0g, 75%; Pale powder; 195 ℃ of mp, MS:434.5 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid (2.5g; 5.77mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.2g is a pale solid (4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide.Productive rate 46%; 101 ℃ of mp; MS:448.5 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.0-3.06 (m, 2H), 3.60 (m, 2H), 3.87 (s, 3H), 4.01 (t, 2H), 6.9-7.7 (m, 9H), 9.33 (bs, 1H), 10.29 (bs, 1H).
Embodiment 106 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidine-4-ethyl formate.Adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (3.0g, 10mmol) and two-(3.0g is 11mmol) as raw material for (2-chloro-ethyl)-(3-phenoxy group-propyl group)-amine.Output 4.5g, 89%; Brown oil; MS:504.6 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-n-butoxy-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-(3-phenoxy group-propyl group)-piperidine-4-ethyl formate (4.0g; 7.9mmol) as raw material, preparation 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.0g, 79%; Pale powder; 191 ℃ of mp, MS:476.5 (M+H) +
Adopt 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid (700mg; 1.4mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 300mg is a pale solid (4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide.Productive rate 43%; 84 ℃ of mp; MS:491.5 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 2.18 (m, 2H), 2.3 (m, 2H), 2.58 (m, 2H), 2.6-2.73 (m, 2H), 3.2 (m, 2H), 3.40 (m, 6H), 3.97 (t, 2H), 4.1 (t, 2H), 6.9-7.7 (m, 9H), 10.7 (bs, 1H), 11.28 (bs, 1H).
Embodiment 107 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 2-[(2-hydroxyl-ethyl)-(2-phenoxy group-ethyl)-amino]-ethanol.(15.6g is 100mmol) as raw material to adopt diethanolamine (15.0g, 150) and 2-chloro-phenetol.Output 18g (80%); Colorless oil; 226 (M+H) +
According to embodiment 83 described universal methods, prepare two-(2-chloro-ethyl)-(2-phenoxy group-propyl group)-amine.Adopt 2-[(2-hydroxyl-ethyl)-(2-phenoxy group-ethyl)-amino]-(20.0g is 88.8mmol) as raw material for ethanol.Output 25g (94%); Brown oil; 263.1 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5.0g, 20mmol) and two-(6.0g is 20mmol) as raw material for (2-chloro-ethyl)-(2-phenoxy group-ethyl)-amine.Output 5.8g, 64%; Brown oil; MS:448.5 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-methoxyl group-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-(2-phenyl-oxyethyl group)-piperidine-4-ethyl formate (5.0g; 11.1mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.0g, 63%; Pale powder; 235 ℃ of mp, MS:420.5 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid (2.5g; 5.9mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.3g is a pale solid (4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide.Productive rate 50%; Mp 168-172 ℃ (HCl); MS:435.5 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.3 (m, 2H), 2.5 (m, 2H), 2.9 (m, 2H), 3.4 (m, 4H), 3.5 (m, 2H), 3.7 (m, 2H), 3.9 (s, 3H), 4.4 (m, 2H), 6.9-7.8 (m, 9H), 9.3 (s, 1H), 10.2 (bs, 1H), 11.3 (s, 1H).
Embodiment 108 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 4-(4-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (2.5g, 10mmol) and two-(2.98g is 10mmol) as raw material for (2-chloro-ethyl)-(2-phenoxy group-ethyl)-amine.Output 3.0g, 69%; Brown oil; MS:490.6 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): the 4-(4-n-butoxy-benzenesulfonyl) in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)-1-(2-phenyl-oxyethyl group)-piperidine-4-ethyl formate (2.5g; 5.76mmol) as raw material, preparation 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.5g, 56%; Pale powder; 204 ℃ of mp, MS:462.5 (M+H) +
Adopt 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid (1.0g; 2.16mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 600mg is a pale solid (4-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide.Productive rate 58%; 112 ℃ of mp (HCl); MS:477.4 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.942 (t, 3H), 1.4 (m, 2H), 1.7 (m, 2H), 2.3 (m, 2H), 2.5 (m, 4H), 2.8 (m, 2H), 2.9-3.4 (m, 4H), 3.3 (m, 4H), 4.2 (t, 2H), 4.4 (m, 2H), 6.9-7.7 (m, 9H), 9.4 (s, 1H), 10.5 (bs, 1H), 11.3 (s, 1H).
Embodiment 1094-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid hydroxyl
The base acid amides
According to embodiment 83 described universal methods, prepare two-(2-chloro-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-amine.Adopt diethanolamine (15.0g, 150) and 4-(2-piperidines-1-base-oxyethyl group)-(5.9g is 20mmol) as raw material for benzyl chloride.Output 5.5g (85%); Brown semisolid; 323 (M+H) +
According to embodiment 83 described universal methods, prepare two-(2-chloro-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-amine.Adopt 2-[(2-hydroxyl-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-(3.22g is 10mmol) as raw material for amine.Output 4.0g (92%); Brown semisolid; MS:361.1 (M+H) +
According to embodiment 83 described universal methods, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidine-4-ethyl formate.Adopt 4-(methoxyl group-benzenesulfonyl) ethyl acetate (5.0g, 20mmol) and two-(2-chloro-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-(8.6g is 20mmol) as raw material for amine.Output 6.0g, 55%; Brown oil; MS:545.7 (M+H) +
Employing is dissolved in tetrahydrofuran (THF): 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl in methyl alcohol (3: 1) and the 10N sodium hydroxide (40ml)]-piperidine-4-ethyl formate (5.4g; 10mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.0g, 77%; Pale powder; 174 ℃ of mp, MS:517.6 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid (3.5g; 6.78mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.8g is a faint yellow solid (4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide.Productive rate 49%; 114 ℃ of mp (HCl); MS:532 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.4-1.6 (m, 4H), 1.9 (m, 2H), 2.3 (m, 2H), 2.8 (m, 2H), 3.4 (m, 4H), 3.9 (s, 3H), 4.2 (m, 1H), 6.9-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).
Embodiment 110
N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-propionic acid amide
Steps A: the coupling of 2-bromo acid and azanol resin
With 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1(2g 1.1meq/g) places in the peptide synthesising container (Chemglass Inc.Part Number CG-1866) and is suspended in dimethyl formamide (20ml).Add the 2-bromo acid (0.6ml, 3.0eq.), the I-hydroxybenzotriazole hydrate (HOBt, 1.8g, 6.0eq.) and 1, the 3-DIC (DIC, 1.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.If showing, test has unhindered amina (it is blue that resin becomes), so then repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins (once washing comprise add solvent, by being blown into nitrogen or jolting 1-5 minute, vacuum filtration then on orbital shaker).Dry described resin under room temperature, in the vacuum.
Under room temperature, carry out the cracking of resin sample (5-20mg) with DCM (0.5ml) and TFA (0.5ml).The filtering reaction thing is with DCM (1 * 1ml) washing resin.Merging filtrate and washings carry out vacuum concentration on Savant SpeedVac Plus.Add methyl alcohol (1ml), enriched mixture.Then through H 1NMR (DMSO-d6) identifies product: δ 4.54 (q, 1H), 1.83 (d, 3H).
Step B: with 4-anisole mercaptan replace bromine
(0.35g 1.1meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the N-hydroxyl-2-bromo-propionic acid amide of steps A preparation.Add 4-anisole mercaptan (0.23ml, 5.0eq), sodium iodide (288mg, 5.0eq) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.17ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(175mg 1.1meq/g) is suspended among the DCM (3.0ml) N-hydroxyl-2-(4-methyl-benzene sulfane base)-propionic acid amide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (1.0ml) and Phenylsulfonic acid (50mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(175mg 1.1meq/g) is suspended among the DCM (30ml) N-hydroxyl-2-(4-methoxyl group-benzene sulfane base)-propionic acid amide resin that step B is prepared, and adds mCPBA (180mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-propionic acid amide from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) N-hydroxyl-2-(4-methoxyl group-benzenesulfonyl)-propionic acid amide resin that step D is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.
In 215nm place, 84%; 1H NMR (DMSO d-6): δ 10.75 (brs, 1H), 7.95 (brs, 1H), 7.71 (dd, 2H), 7.16 (dd, 2H), 3.87 (s, 3H), 3.83 (q, 1H), 1.26 (d, 3H).
Adopt suitable raw material and according to the step of embodiment 110, the hydroxamic acid compound of synthetic embodiment 111-113.
Embodiment 111
N-hydroxyl-2-(4-methoxyl group-benzene sulfane base)-propionic acid amide is in 215nm place, 72%.
N-hydroxyl-2-(4-methoxyl group-phenylsulfinyl alkyl)-propionic acid amide.In 215nm place, 76%; 1HNMR (DMSO d-6): δ 10.90 ﹠amp; 10.60 (brs, 1H), 7.95 (brs, 1H), 7.61 ﹠amp; 7.52 (dd, 2H), 7.15 ﹠amp; 7.10 (dd, 2H), 3.83 ﹠amp; 3.82 (s, 3H), 3.42 ﹠amp; 3.28 (q, 1H), 1.23 ﹠amp; 0.97 (d, 3H).
Embodiment 112
N-hydroxyl-2-(3-methyl-butane-1-sulfane base)-propionic acid amide is in 215nm place, 74%.
N-hydroxyl-2-(3-methyl-butane-1-sulfinyl)-propionic acid amide. 1H?NMR(DMSO?d-6)：δ10．8(brs，1H)，7．95(brs，1H)，3．45?&?3．31(q，1H)，2．71-2．50(m，2H)，1．71-1．46(m，3H)，1．33?&?1．25(d，3H)，0．94-0．82(m，6H)。
Embodiment 113
N-hydroxyl-2-(3-methyl-butane-1-alkylsulfonyl)-propionic acid amide is in 215nm place, 84%.
Embodiment 114
N-hydroxy-3-methyl-2-(naphthalene-2-base sulfane base)-butyramide
Steps A: the coupling of 2-bromo-3-methyl-butyric acid and azanol resin
With 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1(5g 1.1meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml).Add 2-bromo-3-methyl-butyric acid (9.96g, 10.0eq) and DIC (9.04ml, 10.5eq).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 2-thionaphthol replace bromine
(0.15g 1.1meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add the 2-thionaphthol (138mg, 5.0eq), sodium iodide (129mg, 5.0eq) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.078ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(175mg 1.1meq/g) is suspended among the DCM (30ml) 2-(2-naphthalene sulfane base)-N-hydroxyl propionic acid amide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (1.0ml) and Phenylsulfonic acid (50mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(175mg 1.1meq/g) is suspended among the DCM (30ml) 2-(2-naphthalene sulfane base)-N-hydroxyl propionic acid amide resin that step B is prepared, and adds mCPBA (180mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking N-hydroxy-3-methyl-2-from the resin (naphthalene-2-base sulfane base)-butyramide
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 2-(2-naphthalene sulfane base)-N-hydroxyl propionic acid amide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.
In 215nm place, 83%; LCMS (API-electron spray(ES)) m/z 276 (M+H) + 1HNMR (DMSO d-6): δ 10.7 (brs, 1H), 7.91 (brs, 1H), 7.91-7.81 (m, 4H), 7.55-7.45 (m, 3H), 3.41 (d, 1H), 2.09-1.97 (m, 1H), 1.05 (d, 3H), 0.97 (d, 3H).
Adopt suitable raw material and according to the step of embodiment 114, the hydroxamic acid compound of synthetic embodiment 115-118.
Embodiment 115N-hydroxy-3-methyl-2-(naphthalene-2-base sulfinyl)-butyramide.In 215nm place, 67%.
Embodiment 116N-hydroxy-3-methyl-2-(naphthalene-2-base alkylsulfonyl)-butyramide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 308 (M+H) +
Embodiment 117N-hydroxy-3-methyl-2-styroyl sulfinyl-butyramide.In 215nm place, 93%; LCMS (API-electron spray(ES)) m/z 254 (M+H) +
Embodiment 118
N-hydroxy-3-methyl-2-styroyl alkylsulfonyl-butyramide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 286 (M+H) +
Embodiment 119
(1-hydroxyl amino formyl radical-propane-1-sulfane base)-methyl acetate
Steps A: the coupling of 2-bromo butyric acid and azanol resin
With 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1% Vinylstyrene)-resin 1(5g 1.1meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml).Add 2-bromo butyric acid (3.0g, 3.0eq), HOBt (4.86g, 6.0eq) and DIC (3.75ml, 4.0eq).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with thiol methyl acetate replace bromine
(0.45g 1.1meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add the thiol methyl acetate (286mg, 5.0eq), sodium iodide (404mg, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.24ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml, DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(150mg 1.1meq/g) is suspended among the DCM (30ml) (1-hydroxyl amino formyl radical-propane-1-sulfane base)-methyl acetate resin that step B is prepared, and adds 70% t-butyl hydroperoxide (1.0ml) and Phenylsulfonic acid (50mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(150mg 1.1meq/g) is suspended among the DCM (30ml) (1-hydroxyl amino formyl radical-propane-1-sulfane base)-methyl acetate resin that step B is prepared, and adds mCPBA (180mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking (1-hydroxyl amino formyl radical-propane-1-sulfane base)-methyl acetate from the resin
(150mg 1.2meq/g) is suspended among the DCM (1.0ml) (1-hydroxyl amino formyl radical-propane-1-sulfane base)-methyl acetate resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.LCMS (API-electronic spraying) m/z 228 (M+Na) +
Adopt suitable raw material and according to the step of embodiment 119, the hydroxamic acid compound of synthetic embodiment 120-124.
Embodiment 120 (1-hydroxyl amino formyl radical-propane-1-alkylsulfonyl)-acetate oxyamide.LCMS (API-electron spray(ES)) m/z 224 (M+H) +
Embodiment 121 (1-hydroxyl amino formyl radical-propane-1-sulfinyl)-acetate oxyamide.In 220nm place, 100%; LCMS (API-electron spray(ES)) m/z 240 (M+H) +
Embodiment 122
(1-hydroxyl amino formyl radical-propane-1-sulfane base)-propionic acid oxyamide. 1H NMR (DMSO d-6) δ 10.7 (brs, 1H), 4.03 (t, 2H), 2.95 (q, 1H), 2.75-2.70 (m, 1H), 2.60-2.54 (m, 1H), 1.74-1.66 (m, 2H), and 1.58-1.50 (m, 4H), 1.32 (sextet, 2H), 0.88 (t, 3H), 0.85 (t, 3H); LCMS (API-electron spray(ES)) m/z 264 (M+H) +
Embodiment 123 (1-hydroxyl amino formyl radical-propane-1-sulfinyl)-propionic acid oxyamide.In 220nm place, 83%; LCMS (API-electron spray(ES)) m/z 280 (M+H) +
Embodiment 124 (1-hydroxyl amino formyl radical-propane-1-alkylsulfonyl)-propionic acid oxyamide.In 220nm place, 100%.
Embodiment 125
2-(4-hydroxyphenyl thio alkyl)-N-hydroxyl-3-phenyl-propionic acid amide
Steps A: the coupling of 2-bromo-3-phenyl-propionic acid and azanol resin
(5g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml) with 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1.Add 2-bromo-3-phenyl-propionic acid (3.5g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 4-hydroxythiophenol replace bromine
(0.33g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add the 4-hydroxythiophenol (250mg, 5.0eq.), sodium iodide (297mg, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.18ml, 3.0eq.).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(110mg 1.1meq/g) is suspended among the DCM (3.0ml) 2-(4-hydroxyphenyl thio alkyl)-N-hydroxyl-3-phenyl-propionic acid amide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (0.73ml) and Phenylsulfonic acid (36mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(110mg 1.1meq/g) is suspended among the DCM (3.0ml) 2-(4-hydroxyphenyl thio alkyl)-N-hydroxyl-3-phenyl-propionic acid amide resin that step B is prepared, and adds mCPBA (132mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(4-hydroxyphenyl thio alkyl)-N-hydroxyl-3-phenyl-propionic acid amide from the resin
(110mg 1.2meq/g) is suspended in DCM (1.0ml) to 2-(4-hydroxyphenyl thio alkyl)-N-hydroxyl-3-phenyl-propionic acid amide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 84%; 1H NMR (DMSO d-6) δ 10.41 (brs, 1H), 7.95 (brs, 1H), 7.30-7.15 (m, 5H), 7.10 (dd, 2H), 6.75 (dd, 2H), 3.53 (q, 1H), 3.05 (dd, 1H), 2.79 (dd, 1H).
Adopt suitable raw material and according to the step of embodiment 125, the hydroxamic acid compound of synthetic embodiment 126-130.
Embodiment 1262-(4-hydroxybenzene sulfinyl)-N-hydroxyl-3-phenyl-propionic acid amide.In 215nm place, 73%.
Embodiment 1272-(4-hydroxybenzene alkylsulfonyl)-N-hydroxyl-3-phenyl-propionic acid amide.In 215nm place, 77%. 1HNMR(DMSO?d-6)δ10．50(brs，1H)，7．95(brs，1H)，7．68-7．57(m，2H)，7．28-7．17(m，3H)，7．08-7．98(m，2H)，6．95-6．87(m，2H)，3．96(t，1H)，3．02(d，2H)。
Embodiment 1282-(4-acetylaminohydroxyphenylarsonic acid benzene sulfane base)-N-hydroxyl-3-phenyl-propionic acid amide.In 215nm place, 86%; 1HNMR (DMSO d-6) δ 10.50 (brs, 1H), 10.03 (brs, 1H), 8.13 (brs, 1H), 7.56-7.12 (m, 9H), 3.67 (q, 1H), 3.08 (dd, 1H), 2.84 (dd, 1H), 2.04 (s, 3H).
Embodiment 1292-(4-acetylaminohydroxyphenylarsonic acid benzenesulfinyl)-N-hydroxyl-3-phenyl-propionic acid amide.In 215nm place, 73%.
Embodiment 1302-(4-acetylaminohydroxyphenylarsonic acid benzenesulfonyl)-N-hydroxyl-3-phenyl-propionic acid amide.In 215nm place, 95%.
Embodiment 131
4-hydroxyl amino formyl radical-4-(4-first sulphur alkyl-phenyl sulfane base)-methyl-butyrate
Steps A: the coupling of 2-bromo-5-methylglutaric acid and azanol resin
With 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1(4.5g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml).Add S-2-bromo-5-methylglutaric acid ester (3.87g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 4-hydroxythiophenol replace bromine
(0.22g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add 4-methylthio phenyl thiophenol (206mg, 5.0eq.), sodium iodide (197mg, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.12ml, 3.0eq.).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(4-first sulphur alkyl-phenyl sulfane base)-(73mg 1.1meq/g) is suspended among the DCM (1.5ml) the methyl-butyrate resin 4-hydroxyl amino formyl radical-4-that step B is prepared, and adds 70% t-butyl hydroperoxide (0.49ml) and Phenylsulfonic acid (24mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 4-hydroxyl amino formyl radical-4-(4-first sulphur alkyl-phenyl sulfane base)-methyl-butyrate resin that step B is prepared, and adds mCPBA (87mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 4-hydroxyl amino formyl radical-4-(4-first sulphur alkyl-phenyl sulfane base)-methyl-butyrate from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 4-hydroxyl amino formyl radical-4-(4-first sulphur alkyl-phenyl sulfane base)-methyl-butyrate resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 77%; LCMS (API-electron spray(ES)) m/z 316 (M+H) +
Adopt suitable raw material and according to the step of embodiment 131, the hydroxamic acid compound of synthetic embodiment 132-139.
Embodiment 1324-hydroxyl amino formyl radical-4-(4-methanesulfinyl-phenyl sulfinyl)-butyric acid oxyamide.In 215nm place, 79%; LCMS (API-electron spray(ES)) m/z 348 (M+H) +
Embodiment 1334-hydroxyl amino formyl radical-4-(4-methylsulfonyl-phenyl sulfonyl)-butyric acid oxyamide.In 215nm place, 78%; LCMS (API-electron spray(ES)) m/z 380 (M+H) +
Embodiment 1344-hydroxyl amino formyl radical-4-(4-bromo-benzene sulfane base)-butyric acid oxyamide.In 215nm place, 93%.
Embodiment 1354-hydroxyl amino formyl radical-4-(4-bromo-benzenesulfinyl)-butyric acid oxyamide.In 215nm place, 80%.
Embodiment 1364-hydroxyl amino formyl radical-4-(4-bromo-benzenesulfonyl)-butyric acid oxyamide.In 215nm place, 77%.
Embodiment 1374-hydroxyl amino formyl radical-4-(2-trifluoromethyl-benzene sulfane base)-butyric acid oxyamide.In 215nm place, 93%.
Embodiment 1384-hydroxyl amino formyl radical-4-(2-trifluoromethyl-benzenesulfinyl)-butyric acid oxyamide.In 215nm place, 72%.
Embodiment 1394-hydroxyl amino formyl radical-4-(2-trifluoromethyl-benzenesulfonyl)-butyric acid oxyamide.In 215nm place, 90%.
Embodiment 140
2-(3-methoxyl group-benzene sulfane base) capric acid oxyamide
Steps A: the coupling of 2-bromo-capric acid and azanol resin
(4.5g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml) with 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1.Add 2-bromo-capric acid (4.07g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 3-methoxyl group-benzenethiol replace bromine
(0.22g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add 3-methoxyl group-benzenethiol (185mg, 5.0eq.), sodium iodide (197mg, 5.0eq) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.12ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 2-(3-methoxyl group-benzene sulfane base) the capric acid oxyamide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (0.49ml) and Phenylsulfonic acid (24mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 2-(3-methoxyl group-benzene sulfane base) the capric acid oxyamide resin that step B is prepared, and adds mCPBA (87mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(3-methoxyl group-benzene sulfane base) capric acid oxyamide from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 2-(3-methoxyl group-benzene sulfane base) the capric acid oxyamide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 89%.
Adopt suitable raw material and according to the step of embodiment 140, the hydroxamic acid compound of synthetic embodiment 141-145.
Embodiment 1412-(3-methoxyl group-benzenesulfinyl) capric acid oxyamide.In 215nm place, 96%.
Embodiment 1422-(3-methoxyl group-benzenesulfonyl) capric acid oxyamide.In 215nm place, 96%.
Embodiment 1432-(4-first sulfane base-benzene sulfane base) capric acid oxyamide.In 215nm place, 85%; LCMS (API-electron spray(ES)) m/z 342 (M+H) +
Embodiment 1442-(4-methanesulfinyl-benzenesulfinyl) capric acid oxyamide.In 215nm place, 86%; LCMS (API-electron spray(ES)) m/z 374 (M+H) +
Embodiment 1452-(4-methylsulfonyl-benzenesulfonyl) capric acid oxyamide.In 215nm place, 92%.
Embodiment 146
3-benzyloxy-N-hydroxyl-2-(4-first sulfane base-benzene sulfane base)-propionic acid amide
Steps A: the coupling of 2-bromo-3-benzyloxy-propionic acid and azanol resin
With 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1(4.5g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml).Add S-2-bromo-3-benzyloxy-propionic acid (4.2g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 4-methylthio phenyl thiophenol replace bromine
(0.22g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add 4-methylthio phenyl thiophenol (206mg, 5.0eq), sodium iodide (197mg, 5.0eq) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.12ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 3-benzyloxy-N-hydroxyl-2-(4-first sulfane base-benzene sulfane base)-propionic acid amide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (0.49ml) and Phenylsulfonic acid (24mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 3-benzyloxy-N-hydroxyl-2-(4-first sulfane base-benzene sulfane base)-propionic acid amide resin that step B is prepared, and adds mCPBA (87mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 3-benzyloxy-N-hydroxyl-2-(4-first sulfane base-benzene sulfane base)-propionic acid amide from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 3-benzyloxy-N-hydroxyl-2-(4-first sulfane base-benzene sulfane base)-propionic acid amide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 76%; LCMS (API-electron spray(ES)) m/z 350 (M+H) +
Adopt suitable raw material and according to the step of embodiment 146, the hydroxamic acid compound of synthetic embodiment 147-152.
Embodiment 1473-benzyloxy-N-hydroxyl-2-(4-methanesulfinyl-benzenesulfinyl)-propionic acid amide.In 215nm place, 70%; LCMS (API-electron spray(ES)) m/z 382 (M+H) +
Embodiment 1483-benzyloxy-N-hydroxyl-2-(4-methylsulfonyl-benzenesulfonyl)-propionic acid amide.In 215nm place, 63%; LCMS (API-electron spray(ES)) m/z 414 (M+H) +
Embodiment 1493-benzyloxy-N-hydroxyl-2-(2-chloro-dibenzylsulfide alkyl)-propionic acid amide.In 215nm place, 90%.
Embodiment 1503-benzyloxy-N-hydroxyl-2-(2-chloro-benzyl sulfinyl)-propionic acid amide.In 215nm place, 70%.
Embodiment 1513-benzyloxy-N-hydroxyl-2-(2-chloro-benzyl alkylsulfonyl)-propionic acid amide.In 215nm place, 72%.
Embodiment 152
2-(2-bromo-benzene sulfane base)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide
Steps A: the coupling of 2-bromo-3-(3H-imidazol-4 yl)-propionic acid and azanol resin
(4.5g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml) with 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1.Add S-2-bromo-3-(3H-imidazol-4 yl)-propionic acid (3.55g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 2-bromobenzene thiophenol replace bromine
(0.22g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add 2-bromobenzene thiophenol (249mg, 5.0eq), sodium iodide (197mg, 5.0eq) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.12ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 2-(2-bromo-benzene sulfane base)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (0.49ml) and Phenylsulfonic acid (24mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 2-(2-bromo-benzene sulfane base)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide resin that step B is prepared, and adds mCPBA (87mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(2-bromo-benzene sulfane base)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 2-(2-bromo-benzene sulfane base)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 86%.
Adopt suitable raw material and according to the step of embodiment 152, the hydroxamic acid compound of synthetic embodiment 153-154.
Embodiment 1532-(4-bromo-benzenesulfinyl)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide.In 215nm place, 69%.
Embodiment 1542-(4-chloro-benzenesulfonyl)-N-hydroxyl-3-(3H-imidazol-4 yl)-propionic acid amide.
Embodiment 155
2-(3-fluorobenzene sulfane base)-5-guanidine radicals-valeric acid oxyamide
Steps A: the coupling of 2-bromo-5-guanidine radicals-valeric acid and azanol resin
(4.5g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (40ml) with 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1.Add S-2-bromo-5-guanidine radicals-valeric acid (3.85g, 3.0eq.), HOBt (4.4g, 6.0eq.) and DIC (3.4ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiset test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 3-fluorobenzene thiophenol replace bromine
(0.22g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (2ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add 3-fluorobenzene thiophenol (169mg, 5.0eq), sodium iodide (197mg, 5.0eq) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.12ml, 3.0eq).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 2-(3-fluorobenzene sulfane base)-5-guanidine radicals-valeric acid oxyamide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (0.49ml) and Phenylsulfonic acid (24mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(73mg 1.1meq/g) is suspended among the DCM (1.5ml) 2-(3-fluorobenzene sulfane base)-5-guanidine radicals-valeric acid oxyamide resin that step B is prepared, and adds mCPBA (87mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(3-fluorobenzene sulfane base)-5-guanidine radicals-valeric acid oxyamide from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 2-(3-fluorobenzene sulfane base)-5-guanidine radicals-valeric acid oxyamide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 93%.
Adopt suitable raw material and according to the step of embodiment 155, the hydroxamic acid compound of synthetic embodiment 156-159.
Embodiment 1562-(3-fluorobenzene sulfinyl)-5-guanidine radicals-valeric acid oxyamide.In 220nm place, 80%; LCMS (API-electron spray(ES)) m/z 317 (M+H) +
Embodiment 1572-(2-bromo sulfane base)-5-guanidine radicals-valeric acid oxyamide.In 220nm place, 92%; 1H NMR (DMSO d-6) δ 10.90 (brs, 2H), 10.41 (brs, 1H), 7.95 (brs, 1H), 7.66-7.14 (m, 5H), 3.72 (q, 1H), 3.13 (q, 2H), 1.90-1.66 (m, 2H), 1.58-1.43 (2H).
Embodiment 1582-(2-bromo sulfinyl)-5-guanidine radicals-valeric acid oxyamide.In 220nm place, 79%; LCMS (API-electron spray(ES)) m/z 379 (M+H) +
Embodiment 1592-(2-bromo alkylsulfonyl)-5-guanidine radicals-valeric acid oxyamide. 1H?NMR(DMSO?d-6)δ8．03-7．45(m，5H)，4．52(q，1H)，3．16(q，2H)，2．07-1．90(m，2H)，1．66-1．59(2H)。
Embodiment 160
2-(2,5-dichlorobenzene sulfane base)-sad oxyamide
Steps A: the coupling of 2-bromo-sad and azanol resin
(10.0g 1.2meq/g) places in the peptide synthesising container and is suspended in dimethyl formamide (80ml) with 4-O-methyl hydroxylamine-phenoxymethyl-copolymerization (vinylbenzene-1%-Vinylstyrene)-resin 1.Add 2-bromo-sad (8.4g, 3.0eq.), HOBt (8.8g, 6.0eq.) and DIC (7.2ml, 4.0eq.).Under room temperature with this reactant on orbital shaker jolting 2-16 hour.Filter this reactant and use dimethyl formamide (3 * 20ml) washings.Take out resin sample and carry out the Kaiser test.Have unhindered amina (it is blue that resin becomes) if test shows, so then to repeat above-mentioned coupled reaction, otherwise with DCM (3 * 20ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washing resins.Dry described resin under room temperature, in the vacuum.
Step B: with 2,5-thiophenol dichlorobenzene replace bromine
(0.45g 1.2meq/g) places in the 20ml scintillation vial and is suspended in tetrahydrofuran (THF) (6ml) with the 2-bromo hydroxamic acid ester resin of steps A preparation.Add 2, the 5-thiophenol dichlorobenzene (483mg, 5.0eq.), sodium iodide (404mg, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 0.24ml, 3.0eq.).Under room temperature, with this reactant jolting 12-16 hour.Reaction mixture is inclined to the polypropylene syringe with polypropylene filter plate, filter and with DMF (2 * 2ml), DMF: water 9: 1 (2 * 2ml), DMF (2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
With step B preparation 2-(2,5-dichlorobenzene sulfane base)-(150mg 1.1meq/g) is suspended among the DCM (3.0ml) sad oxyamide resin, adds 70% t-butyl hydroperoxide (1.0ml) and Phenylsulfonic acid (50mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(150mg 1.1meq/g) is suspended among the DCM (3.0ml) 2-(2,5-dichlorobenzene sulfane base)-sad oxyamide resin that step B is prepared, and adds mCPBA (180mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(2,5-dichlorobenzene sulfane base)-sad oxyamide from the resin
(73mg 1.2meq/g) is suspended among the DCM (1.0ml) 2-(2,5-dichlorobenzene sulfane base)-sad oxyamide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.In 215nm place, 92%; 1HNMR (DMSO d-6) δ 10.96 (brs, 1H), 9.26 (brs, 1H), 7.93-7.76 (m, 3H), 4.07 (q, 1H), 2.04-1.95 (m, 1H), 1.78-1.64 (m, 1H), 1.32-1.09 (m, 8H), 0.81 (t, 3H).
Adopt suitable raw material and according to the step of embodiment 160, the hydroxamic acid compound of synthetic embodiment 161-167.
Embodiment 1612-(2,5-dichlorobenzene alkylsulfonyl)-sad oxyamide.In 215nm place, 96%.
Embodiment 1622-(3-anisole sulfane base)-sad oxyamide.In 220nm place, 86%; LCMS (API-electron spray(ES)) m/z 298 (M+H) +
Embodiment 1632-(3-anisole sulfinyl)-sad oxyamide.In 220nm place, 96%.
Embodiment 1642-(3-anisole alkylsulfonyl)-sad oxyamide.In 220nm place, 83%.
Embodiment 1652-(3,4-dimethoxy benzene sulfane base)-sad oxyamide.In 215nm place, 87%; LCMS (API-electron spray(ES)) m/z 328 (M+H) +
Embodiment 1662-(3,4-dimethoxy benzenesulfinyl)-sad oxyamide.In 215nm place, 90%.
Embodiment 1672-(3,4-dimethoxy benzenesulfonyl)-sad oxyamide.In 215nm place, 87%.
Adopt suitable raw material and according to the step of embodiment 160, the hydroxamic acid compound of synthetic embodiment 168-198.The crude product product is dissolved in DMSO: methyl alcohol (1: 1,2ml) in, under the following conditions through the reversed-phase HPLC purifying:
Post: ODS-A, 20mm * 50mm, 5 μ m granular sizes (YMC, Inc.Wilmington, North Carolina)
Solvent gradient time water-acetonitrile
0．0????95????5
25min???5?????95
Flow velocity: 15ml/min
Embodiment 168
2-(2-benzimidazolyl-2 radicals-Ji sulfane base)-sad oxyamide.In 215nm place, 81%; LCMS (API-electron spray(ES)) m/z 308 (M+H) +
Embodiment 169
2-(2-benzoxazole-2-base sulfane base)-sad oxyamide.In 215nm place, 72%; LCMS (API-electron spray(ES)) m/z 309 (M+H) +
Embodiment 170
2-(2-[4-morpholinodithio-2-base sulfane base)-sad oxyamide.In 215nm place, 72%; LCMS (API-electron spray(ES)) m/z 325 (M+H) +
Embodiment 171
2-(2-pyridine-2-sulfane base)-sad oxyamide.In 215nm place, 76%; LCMS (API-electron spray(ES)) m/z 269 (M+H) +
Embodiment 172
2-(4-phenyl-thiazole-2-sulfane base)-sad oxyamide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 336 (M+H) +
Embodiment 173
2-(2-pyridine-2-base-ethyl sulfane base)-sad oxyamide.In 215nm place, 84%; LCMS (API-electron spray(ES)) m/z 297 (M+H) +
Embodiment 174
2-(2-phenyl-5H-tetrazolium-5-base sulfane base)-sad oxyamide.In 215nm place, 67%; LCMS (API-electron spray(ES)) m/z 338 (M+H) +
Embodiment 175
2-(2-pyrazine-2-base-ethyl sulfane base)-sad oxyamide.In 215nm place, 98%; LCMS (API-electron spray(ES)) m/z 298 (M+H) +
Embodiment 176
2-(1-methyl isophthalic acid H-tetrazolium-5-base sulfane base)-sad oxyamide.In 215nm place, 66%; LCMS (API-electron spray(ES)) m/z 274 (M+H) +
Embodiment 177
2-(2-benzimidazolyl-2 radicals-Ji sulfane base)-sad oxyamide.In 215nm place, 81%.
Embodiment 178
2-(2-pyridine-2-sulfinyl)-sad oxyamide.In 215nm place, 76%.
Embodiment 179
2-(4-phenyl-thiazole-2-sulfinyl)-sad oxyamide.In 215nm place, 78%.
Embodiment 180
2-(2-pyrazine-2-base-ethyl sulfinyl)-sad oxyamide.In 215nm place, 96%; LCMS (API-electron spray(ES)) m/z 314 (M+H) +
Embodiment 181
2-(3-Oxy-1 H-benzothiazole-2-alkylsulfonyl)-sad oxyamide.In 215nm place, 63%; LCMS (API-electron spray(ES)) m/z 356 (M+H) +
Embodiment 182
2-(4-phenyl-thiazole-2-alkylsulfonyl)-sad oxyamide.In 215nm place, 70%; LCMS (API-electron spray(ES)) m/z 383 (M+H) +
Embodiment 183
2-[2-(1-oxygen base-pyridine-2-yl)-ethylsulfonyl]-sad oxyamide.In 215nm place, 77%; LCMS (API-electron spray(ES)) m/z 345 (M+H) +
Embodiment 184
3-(1-hydroxyl amino formyl radical-heptan sulfane base)-phenylformic acid oxyamide.In 220nm place, 100%; LCMS (API-electron spray(ES)) m/z 312 (M+H) +
Embodiment 185
3-[4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-phenyl]-the propionic acid oxyamide.In 220nm place, 90%; LCMS (API-electron spray(ES)) m/z 340 (M+H) +
Embodiment 186
2-(thiazol-2-yl sulfane base)-sad oxyamide.In 215nm place, 75%; LCMS (API-electron spray(ES)) m/z 275 (M+H) +
Embodiment 187
2-(2,5-dioxo-imidazolidine-4-ylmethyl sulfane base)-sad oxyamide.In 215nm place, 98%; LCMS (API-electron spray(ES)) m/z 304 (M+H) +
Embodiment 188
3-(1-hydroxyl amino formyl radical-heptyl sulfinyl)-phenylformic acid oxyamide.In 220nm place, 84%; LCMS (API-electron spray(ES)) m/z 328 (M+H) +
Embodiment 189
3-[4-(1-hydroxyl amino formyl radical-heptyl sulfinyl)-phenyl]-the propionic acid oxyamide.In 220nm place, 78%; LCMS (API-electron spray(ES)) m/z 356 (M+H) +
Embodiment 190
2-(quinoline-8-sulfinyl)-sad oxyamide.In 220nm place, 87%; LCMS (API-electron spray(ES)) m/z 335 (M+H) +
Embodiment 191
2-(naphthalene-2-base formamyl methanesulfinyl)-sad oxyamide.In 220nm place, 83%; LCMS (API-electron spray(ES)) m/z 391 (M+H) +
Embodiment 192
3-(1-hydroxyl amino formyl radical-heptyl alkylsulfonyl)-phenylformic acid oxyamide.In 215nm place, 72%.
Embodiment 193
3-[4-(1-hydroxyl amino formyl radical-heptyl alkylsulfonyl)-phenyl]-the propionic acid oxyamide.In 215nm place, 67%.
Embodiment 194
2-(1H-imidazoles-2-alkylsulfonyl)-sad oxyamide.In 215nm place, 95%; LCMS (API-electron spray(ES)) m/z 290 (M+H) +
Embodiment 195
2-(thiazol-2-yl alkylsulfonyl)-sad oxyamide.In 215nm place, 91%; LCMS (API-electron spray(ES)) m/z 307 (M+H) +
Embodiment 196
2-(quinoline-8-alkylsulfonyl)-sad oxyamide.In 220nm place, 94%; LCMS (API-electron spray(ES)) m/z 351 (M+H) +
Embodiment 197
2-(naphthalene-2-base formamyl methylsulfonyl)-sad oxyamide.In 220nm place, 79%; LCMS (API-electron spray(ES)) m/z 407 (M+H) +
Embodiment 198
2-(2,5-dioxo-imidazolidine-4-base methylsulfonyl)-sad oxyamide.In 215nm place, 97%.
Embodiment 199
Steps A: with 4-fluorobenzene thiophenol replace bromine
(9.4g 1.2meq/g) places in the peptide synthesising container 2-bromo hydroxamic acid ester resin that embodiment 160 steps A are prepared, and is suspended in the tetrahydrofuran (THF) (50ml).Add 4-fluorobenzene thiophenol (6.6g, 5.0eq.), sodium iodide (7.7g, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 4.6ml, 3.0eq.).Under room temperature, with this reactant jolting 12-16 hour, filter then and with DMF (2 * 30ml), DMF: water 9: 1 (2 * 30ml), DMF (30ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washings.Dry this resin under room temperature, in the vacuum.
The coupling of step B:2-(4-fluorobenzene sulfane base)-sad oxyamide resin and benzylalcohol
With 2-(4-fluorobenzene sulfane the base)-sad oxyamide resin of steps A preparation (330mg 1.1meq/g) is suspended in the dimethyl formamide (2.0ml), add benzylalcohol (731mg, 15eq.) and sodium hydride (237mg, 15eq.).With this reactant be heated to 80 ℃ 15 hours, jolting on orbital shaker simultaneously.After being cooled to room temperature, filter this mixture, with DMF (2 * 2ml), DMF: water 9: 1 (2 * 3ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(110mg 1.1meq/g) is suspended among the DCM (2.2ml) 2-(4-benzyloxy-phenyl sulfane base)-sad oxyamide resin that step B is prepared, and adds 70% t-butyl hydroperoxide (0.73ml) and Phenylsulfonic acid (36mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(110mg 1.1meq/g) is suspended among the DCM (2.2ml) 2-(4-benzyloxy-phenyl sulfane base)-sad oxyamide resin that step B is prepared, and adds mCPBA (132mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 2ml), DMF (2 * 2ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(4-benzyloxy-benzene sulfane base)-sad oxyamide from the resin
(110mg 1.2meq/g) is suspended among the DCM (1.0ml) 2-(4-benzyloxy-phenyl sulfane base)-sad oxyamide resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.The crude product product is dissolved in dimethyl sulfoxide (DMSO): methyl alcohol (1: 1,2ml) in, under the following conditions through the reversed-phase HPLC purifying:
Post: ODS-A, 20mm * 50mm, 5 μ m granular sizes (YMC, Inc.Wilmington, North Carolina)
Solvent gradient time water-acetonitrile
0．0????95????5
25min???5?????95
Flow velocity: 15ml/min.
2-(4-benzyloxy-phenyl sulfane base)-sad oxyamide.In 215nm place, 100%; LCMS (API-electron spray(ES)) m/z 374 (M+H) +
Adopt suitable raw material and, synthesize the hydroxamic acid compound of embodiment 200-220 according to embodiment 199 described steps.
Embodiment 200
2-(4-butoxy-benzene sulfane base-sad oxyamide.In 215nm place, 100%; LCMS (API-electron spray(ES)) m/z 374 (M+H) +
Embodiment 201
2-[4-(2-piperazine-1-base-oxyethyl group)-benzene sulfane base]-sad oxyamide.In 215nm place, 98%; LCMS (API-electron spray(ES)) m/z 370 (M+H) +
Embodiment 202
2-[4-(5-hydroxyl-pentyloxy-phenyl sulfane base]-sad oxyamide.In 215nm place, 65%; LCMS (API-electron spray(ES)) m/z 370 (M+H) +
Embodiment 203
2-[4-(3-pyridine-2-base-propoxy-)-benzene sulfane base]-sad oxyamide.In 215nm place, 95%; LCMS (API-electron spray(ES)) m/z 403 (M+H) +
Embodiment 204
2-(4-benzyloxy-benzenesulfinyl)-sad oxyamide.In 215nm place, 100%.
Embodiment 205
2-(4-butoxy-benzenesulfinyl)-sad oxyamide.In 215nm place, 98%.
Embodiment 206
2-[4-(2-piperazine-1-base-oxyethyl group)-benzenesulfinyl]-sad oxyamide.In 215nm place, 98%.
Embodiment 207
2-[4-(3-pyridine-2-base-propoxy-)-benzenesulfinyl]-sad oxyamide.In 215nm place, 99%.
Embodiment 208
2-(4-benzyloxy-benzenesulfonyl)-sad oxyamide.In 215nm place, 100%.
Embodiment 209
2-(4-butoxy-benzenesulfonyl)-sad oxyamide.In 215nm place, 100%.
Embodiment 210
2-[4-(2-piperazine-1-base-oxyethyl group)-benzenesulfonyl]-sad oxyamide.In 215nm place, 97%.
Embodiment 211
2-[4-(3-pyridine-2-base-propoxy-)-benzenesulfonyl]-sad oxyamide.In 215nm place, 100%.
Embodiment 212
2-[4-(1-methyl-tetramethyleneimine-3-base oxygen base)-benzene sulfane base]-sad oxyamide.In 215nm place, 91%; LCMS (API-electron spray(ES)) m/z 367 (M+H) +
Embodiment 213
2-[4-(1-ethyl-propoxy-)-benzene sulfane base]-sad oxyamide.In 215nm place, 100%; LCMS (API-electron spray(ES)) m/z 354 (M+H) +
Embodiment 214
2-[4-(tetrahydrochysene-pyrans-4-base oxygen base)-benzene sulfane base]-sad oxyamide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 368 (M+H) +
Embodiment 215
2-[4-(1-methyl-tetramethyleneimine-3-base oxygen base)-benzenesulfinyl]-sad oxyamide.In 215nm place, 96%.
Embodiment 216
2-[4-(1-ethyl-propoxy-)-benzenesulfinyl]-sad oxyamide.In 215nm place, 97%.
Embodiment 217
2-[4-(tetrahydrochysene-pyrans-4-base oxygen base)-benzenesulfinyl]-the aprylic acid oxyamide.In 215nm place, 97%.
Embodiment 218
2-[4-(1-methyl-tetramethyleneimine-3-base oxygen base)-benzenesulfonyl]-sad oxyamide.In 215nm place, 96%.
Embodiment 219
2-[4-(1-ethyl-propoxy-)-benzenesulfonyl]-sad oxyamide.In 215nm place, 100%.
Embodiment 220
2-[4-(tetrahydrochysene-pyrans-4-base oxygen base)-benzenesulfonyl]-sad oxyamide.In 215nm place, 100%.
Embodiment 221
Steps A: with 4-bromobenzene thiophenol replace bromine
(5.0g 1.1meq/g) places in the peptide synthesising container 2-bromo-sad hydroxamic acid ester resin that embodiment 160 steps A are prepared, and is suspended in the tetrahydrofuran (THF) (60ml).Add 4-bromobenzene thiophenol (5.2g, 5.0eq.), sodium iodide (4.1g, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 2.5ml, 3.0eq.).Under room temperature, with this reactant jolting 12-16 hour, filter then and with DMF (2 * 30ml), DMF: water 9: 1 (2 * 30ml), DMF (30ml), MeOH (2 * 20ml) and DCM (2 * 20ml) washings.Dry this resin under room temperature, in the vacuum.
Step B: sulfide oxidation is a sulfoxide
(4.4g 1.1meq/g) is suspended among the DCM (60ml) 2-(4-bromobenzene sulfane base)-sad oxyamide resin that steps A is prepared, and adds 70% t-butyl hydroperoxide (30ml) and Phenylsulfonic acid (1.5g).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 30ml), DMF (2 * 30ml), MeOH (2 * 30ml) and DCM (2 * 30ml) wash.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfone
(4.4g 1.1meq/g) is suspended among the DCM (60ml) 2-(4-bromobenzene sulfane base)-sad oxyamide resin that step B is prepared, and adds mCPBA (5.2g).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 30ml), DMF (2 * 30ml), MeOH (2 * 30ml) and DCM (2 * 30ml) wash.Dry this resin under room temperature, in the vacuum.
The coupling of step D:2-(4-bromobenzene sulfinyl)-sad oxyamide resin and 4-chlorinated benzene boric acid
(150mg 1.1meq/g) is suspended in the dimethyl formamide (2.0ml) 2-(4-bromobenzene sulfinyl)-sad oxyamide resin that step B is prepared, and is blown into nitrogen 1-2 minute in this suspension.Add 4-chlorinated benzene boric acid (51.6mg, 2eq.), four (triphenyl phosphine) palladium (0) (19.07mg, 0.1eq.) and yellow soda ash (2M solution, 0.825ml, 10eq.).With this reactant be heated to 80 ℃ 8 hours, jolting on orbital shaker simultaneously.After being cooled to room temperature, filter this mixture, with DMF (2 * 2ml), DMF: water 9: 1 (2 * 3ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking 2-(4 '-chloro-xenyl-4-sulfinyl)-sad oxyamide from the resin
(150mg 1.1meq/g) is suspended among the DCM (1.0ml) 2-(4 '-chloro-xenyl-4-sulfinyl)-sad oxyamide resin that step D is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.The crude product product is dissolved in dimethyl sulfoxide (DMSO): methyl alcohol (1: 1,2ml) in, under the following conditions through the reversed-phase HPLC purifying:
Post: ODS-A, 20mm * 50mm, 5 μ m granular sizes (YMC, Inc.Wilmington, North Carolina)
Solvent gradient time water-acetonitrile
0．0????95????5
25min???5?????95
Flow velocity: 15ml/min.
2-(4 '-chloro-xenyl-4-sulfinyl)-sad oxyamide.In 215nm place, 96%; LCMS (API-electron spray(ES)) m/z 394 (M+H) +
Adopt suitable raw material and, synthesize the hydroxamic acid compound of embodiment 222-224 according to embodiment 221 described steps.
Embodiment 222
2-[4-(5-chloro-benzene sulphur-2-yl)-benzenesulfinyl]-sad oxyamide.In 215nm place, 100%; LCMS (API-electron spray(ES)) m/z 400 (M+H) +
Embodiment 223
2-(4 ,-chloro-xenyl-4-alkylsulfonyl)-sad oxyamide.In 215nm place, 94%; LCMS (API-electron spray(ES)) m/z 410 (M+H) +
Embodiment 224
2-[4-(5-chloro-benzene sulphur-2-yl)-benzenesulfonyl]-sad oxyamide.In 215nm place, 85%; LCMS (API-electron spray(ES)) m/z 416 (M+H) +
Embodiment 225
The coupling of steps A: 2-(4-bromobenzene sulfane base)-sad oxyamide resin and N-(3-aminopropyl)-morpholine
With embodiment 199 steps A preparations 2-(4-bromobenzene sulfane base)-(100mg 1.1meq/g) is suspended in the dioxane (2.0ml) sad oxyamide resin, is blown into nitrogen 1-2 minute in this suspension.Add N-(3-aminopropyl)-morpholine (346mg, 20eq.), three (dibenzalacetone)-two palladium (O) (22mg, 0.2eq.), (S)-(-)-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene ((S)-BINAP, 60mg, 0.8eq.) and sodium tert-butoxide (207mg, 18eq.).With this reactant be heated to 80 ℃ 8 hours, jolting on orbital shaker simultaneously.After being cooled to room temperature, filter this mixture, with DMF (2 * 2ml), DMF: water 9: 1 (2 * 3ml), MeOH (2 * 2ml) and DCM (2 * 2ml) wash.Dry this resin under room temperature, in the vacuum.
Step B: cracking 2-[4-(3-morpholine-4-base-third amino)-phenyl sulfane base from the resin]-sad oxyamide
2-[4-(3-morpholine-4-base-third amino)-phenyl sulfane base with the steps A preparation]-(100mg 1.1meq/g) is suspended among the DCM (1.0ml) sad oxyamide resin, adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.The crude product product is dissolved in dimethyl sulfoxide (DMSO): methyl alcohol (1: 1,2ml) in, under the following conditions through the reversed-phase HPLC purifying:
Post: ODS-A, 20mm * 50mm, 5 μ m granular sizes (YMC, Inc.Wilmington, North Carolina)
Solvent gradient time water-acetonitrile
0．0????95????5
25min???5?????95
Flow velocity: 15ml/min.
2-[4-(3-morpholine-4-base-third amino)-phenyl sulfane base]-sad oxyamide.In 215nm place, 88%; LCMS (API-electron spray(ES)) m/z 410 (M+H) +
Adopt suitable raw material and according to the step of this embodiment, the hydroxamic acid compound of synthetic embodiment 226-231.
Embodiment 226
2-[4-(biphenyl-4-base is amino)-phenyl sulfane base]-sad oxyamide.In 215nm place, 95%; LCMS (API-electron spray(ES)) m/z 435 (M+H) +
Embodiment 227
2-[4-(pyridin-4-yl amino)-phenyl sulfane base]-sad oxyamide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 360 (M+H) +
Embodiment 228
2-(4-cyclopentyl amino-phenyl sulfane base)-sad oxyamide.In 215nm place, 77%; LCMS (API-electron spray(ES)) m/z 351 (M+H) +
Embodiment 229
2-(4-methylamino--phenyl sulfane base)-sad oxyamide.In 215nm place, 99%; LCMS (API-electron spray(ES)) m/z 297 (M+H) +
Embodiment 230
2-(4-piperidines-1-base-phenyl sulfane base)-sad oxyamide.In 215nm place, 72%; LCMS (API-electron spray(ES)) m/z 351 (M+H) +
Embodiment 231
2-(4-piperazine-1-base-benzene sulfane base)-sad oxyamide.In 215nm place, 74%; LCMS (API-electron spray(ES)) m/z 352 (M+H) +
Embodiment 232
Steps A: with 4-hydroxythiophenol replace bromine
(15.0g 1.1meq/g) places in the peptide synthesising container 2-bromo-sad hydroxamic acid ester resin that embodiment 160 steps A are prepared, and is suspended in the tetrahydrofuran (THF) (120ml).Add the 4-hydroxythiophenol (11.3g, 5.0eq.), sodium iodide (13.5g, 5.0eq.) and 1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU, 8.1ml, 3.0eq.).Under room temperature, with this reactant jolting 12-16 hour, filter then and with DMF (2 * 60ml), DMF: water 9: 1 (2 * 60ml), DMF (60ml), MeOH (2 * 60ml) and DCM (2 * 60ml) washings.Dry this resin under room temperature, in the vacuum.
The coupling of step B:2-(4-hydroxyphenyl thio alkyl)-sad oxyamide resin and benzene sulfonyl chloride
(240mg 1.2meq/g) is suspended among the DCM (3.0ml) 2-(4-hydroxyphenyl thio alkyl)-sad oxyamide resin that steps A is prepared.Add benzene sulfonyl chloride (225mg, 5eq.) and triethylamine (0.06ml, 2eq.).Under room temperature with the jolting 8 hours on orbital shaker of this reactant, filter then and with DME (2 * 2ml), DMF: water 9: 1 (2 * 3ml), MeOH (2 * 2ml) and DCM (2 * 2ml) washings.Dry this resin under room temperature, in the vacuum.
Step C: sulfide oxidation is a sulfoxide
(80mg 1.2meq/g) is suspended among the DCM (3ml) Phenylsulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-phenylester resin that step B is prepared, and adds 70% t-butyl hydroperoxide (1ml) and Phenylsulfonic acid (23mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 3ml), DMF (2 * 3ml), MeOH (2 * 3ml) and DCM (2 * 3ml) wash.Dry this resin under room temperature, in the vacuum.
Step D: sulfide oxidation is a sulfone
(80mg 1.2meq/g) is suspended among the DCM (3ml) Phenylsulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-phenylester resin that step B is prepared, and adds mCPBA (84mg).Under room temperature, on orbital shaker with this reaction mixture jolting 12-24 hour.Filter this reactant, with DCM (2 * 3ml), DMF (2 * 3ml), MeOH (2 * 3ml) and DCM (2 * 3ml) wash.Dry this resin under room temperature, in the vacuum.
Step e: cracking Phenylsulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-phenylester resin
(80mg 1.2meq/g) is suspended among the DCM (1.0ml) Phenylsulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-phenylester resin that step B is prepared, and adds TFA (1.0ml).Under room temperature with this reactant jolting 1 hour.Filter this reactant, with DCM (2 * 1ml) washing resins.Merging filtrate and washings are concentrated into dried on Savant SpeedVac Plus.Add methyl alcohol (1ml), concentrate this mixture.The crude product product is dissolved in dimethyl sulfoxide (DMSO): methyl alcohol (1: 1,2ml) in, under the following conditions through the reversed-phase HPLC purifying:
Post: ODS-A, 20mm * 50mm, 5 μ m granular sizes (YMC, Inc.Wilmington, North Carolina)
Solvent gradient time water-acetonitrile
0．0????95????5
25min???5?????95
Flow velocity: 15ml/min.
Phenylsulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-phenylester.In 215nm place, 91%; LCMS (API-electron spray(ES)) m/z 424 (M+H) +
Adopt suitable raw material and, synthesize the hydroxamic acid compound of embodiment 233-240 according to embodiment 232 described steps.
Embodiment 233
2,5-dichloro--thiophene-3-sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-oxyamide.In 215nm place, 98%; LCMS (API-electron spray(ES)) m/z 498 (M+H) +
Embodiment 234
Ethyl sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfane base)-oxyamide.In 215nm place, 72%; LCMS (API-electron spray(ES)) m/z 376 (M+H) +
Embodiment 235
5-chloro-1,3-dimethyl-1H-pyrazoles-4-sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfinyl)-oxyamide.In 215nm place, 99%; LCMS (API-electron spray(ES)) m/z 492 (M+H) +
Embodiment 236
2,5-dichloro--thiophene-3-sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfinyl)-oxyamide.In 215nm place, 96%; LCMS (API-electron spray(ES)) m/z 514 (M+H) +
Embodiment 237
5-pyridine-2-base-thiophene-2-sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl sulfinyl)-oxyamide.In 215nm place, 96%; LCMS (API-electron spray(ES)) m/z 523 (M+H) +
Embodiment 238
2-nitro-Phenylsulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl alkylsulfonyl)-oxyamide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 501 (M+H) +
Embodiment 239
3-bromo-2-chloro-thiophene-2-sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl alkylsulfonyl)-oxyamide.In 215nm place, 97%; LCMS (API-electron spray(ES)) m/z 576 (M+H) +
Embodiment 240
Benzo [1,2,5] thiadiazoles-4-sulfonic acid 4-(1-hydroxyl amino formyl radical-heptyl alkylsulfonyl)-oxyamide.In 215nm place, 83%; LCMS (API-electron spray(ES)) m/z 514 (M+H) +
Embodiment 241
1-benzyl-4-(4-benzyloxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
To the 4-of the stirring in round-bottomed flask anisole mercaptan (2.8g, 20mmol) and Anhydrous potassium carbonate (10g, excessive) anhydrous propanone (100ml) solution in add alpha-brominated ethylhexoate (3.3g, 20mmol), under fully stirring, refluxing with this reaction mixture heating 8 hours.Cool off this reaction mixture then, filtering sylvite concentrates this reaction mixture.Use the chloroform extraction residue, water and 0.5N NaOH solution washing.Water thorough washing organic layer through dried over mgso, filters and concentrates again.Separate (4-methoxyl group-phenyl sulfane the base)-ethyl acetate that obtains to faint yellow oily thing.Output 4.4g, 100%; MS:227 (M+H).
To (4-methoxyl group-phenyl sulfane the base)-ethyl acetate that stirs (4.4g, 20mmol), (3.5g 20mmol), refluxed 4 hours to add bromotoluene in anhydrous propanone (100ml) solution of Anhydrous potassium carbonate (10g, excessive).Filter this reaction mixture then, concentrate, use the chloroform extraction residue.The water thorough washing, dry and concentrated.According to embodiment 83 described methods by the crude product product of gained being converted into (4-benzyloxy-benzenesulfonyl)-ethyl acetate with the m-chloro benzoic acid oxidation.The low melting point solid.Output 6.6g, 97%; MS:335 (M+1).
Two-(2-chloro-ethyl)-benzylamine hydrochloride (6.6g to the stirring in round-bottomed flask; 24.7mmol), 18-hat-6 (500mg) and Anhydrous potassium carbonate (30g; excessive) anhydrous propanone (250ml) solution in add (4-benzyloxy-benzenesulfonyl)-ethyl acetate (8.01g; 24mmol), under fully stirring, refluxing, this reaction mixture was heated 16 hours.Cool off this reaction mixture then, filtering sylvite concentrates this reaction mixture.Use the chloroform extraction residue, wash with water.Water thorough washing organic layer through dried over mgso, filters and concentrates again.The dark-brown reaction mixture is used 30% ethyl acetate through purification by silica gel column chromatography: the hexane wash-out, separate product 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-ethyl formate that obtains to brown oil.Output 6.5g, 55%; MS:494 (M+H).
With 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidine-4-ethyl formate (5.0g, 10.1mmol) be dissolved in methyl alcohol/tetrahydrofuran (THF) (1: 1,200ml) in, under room temperature, stirred 72 hours.After this concentrated reaction mixture is dissolved in the water (200ml) product with dense HCl neutralization.After the neutralization reaction mixture is concentrated into dried.In solid, add icy water (100ml) and filtration.In 50 ℃ of desciccate 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidines-4-formic acid, it is used for next step without being further purified.Colorless solid.MP:66-68 ℃; Output 4.3g, 91%; MS:466 (M+H).Adopt 4-(4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidines-4-formic acid (4.65g; 10.0mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 1.1g is a colorless solid (4-benzyloxy-benzenesulfonyl)-1-benzyl-piperidines-4-formic acid oxyamide.Productive rate 21%; 89 ℃ of mp; MS:481.1 1H NMR (300MHz, DMSO-d 6): δ 2.27 (m, 3H), 2.76-2.79 (m, 2H), 3.43 (m, 4H), 4.30 (s, 2H), 7.14-7.17 (d, 2H), 7.50-7.73 (m, 5H), 9.37 (s, 1H), 10.53 (s, 1H), 11.18 (s, 1H).
Embodiment 2424-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid hydroxyl
The base acid amides
According to embodiment 83 described universal methods, adopt diethanolamine (15.0g, 150) and 4-(2-piperidines-1-base-oxyethyl group)-benzyl chloride (5.9g, 20mmol) as raw material, preparation 2-[(2-hydroxyl-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-amine.Output 5.5g, 85%; Brown semisolid; MS:323 (M+H) +
According to embodiment 83 described universal methods, adopt 2-[(2-hydroxyl-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-amine (3.22g, 10mmol) as raw material, prepare two-(2-chloro-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-amine.Output 4.0g, 92%; Brown semisolid; MS:361.1 (M+H) +
According to embodiment 83 described universal methods; adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (6.0g; 20mmol) with two-(2-chloro-ethyl)-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-amine (8.6g; 20mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidine-4-ethyl formate.Output 8.0g, 68%; Brown oil; MS:587.7 (M+H) +
Employing is dissolved in THF: 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl in methyl alcohol 3: 1 and the 10N sodium hydroxide (40ml)]-piperidine-4-ethyl formate (5.8g; 10mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.8g, 86%; Spongy brown solid; 98 ℃ of mp, MS:559.6 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid (5.5g; 10mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 2.4g is a faint yellow solid (4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide.Productive rate 41%; 155 ℃ of mp (HCl); MS:574 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.1-1.8 (m, 6H), 1.9 (m, 4H), 2.3 (m, 4H), 2.8 (m, 6H), 3.2-3.6 (m, 8H), 4.2 (m, 2H), 6.9-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).
Embodiment 2434-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid hydroxyl
The base acid amides
According to embodiment 83 described universal methods, adopt diethanolamine (15.0g, 150) and 3-(2-morpholine-1-base-oxyethyl group)-benzyl chloride (5.9g, 20mmol) as raw material, preparation is two-(2-hydroxyl-ethyl)-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-amine.Output 6.2g, 95%; Brown semisolid; MS:325 (M+H) +
According to embodiment 83 described universal methods, adopt two-(2-hydroxyl-ethyl)-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-amine (3.24g, 10mmol) as raw material, prepare two-(2-chloro-ethyl)-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-amine.Output 4.0g, 92%; Brown semisolid; MS:363.1 (M+H) +
According to embodiment 83 described universal methods; adopt 4-(butoxy-benzenesulfonyl)-ethyl acetate (6.0g; 20mmol) with two-(2-chloro-ethyl)-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-amine (8.6g; 20mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-piperidine-4-ethyl formate.Output 8.5g, 72%; Brown oil; MS:589.7 (M+H) +
Employing is dissolved in THF: 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine-1-base-oxyethyl group)-benzyl in methyl alcohol 3: 1 and the 10N sodium hydroxide (40ml)]-piperidine-4-ethyl formate (5.8g; 10mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.8g, 85%; Spongy brown solid; 98 ℃ of mp, MS:561.6 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid (5.6g; 10mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 4.02g is a faint yellow solid (4-butoxy-benzenesulfonyl)-1-[3-(2-morpholine-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide.Productive rate 62%; 123 ℃ of mp; MS:576 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.4 (m, 2H), 1.8 (t, 2H), 2.3-4.7 (m, 24H), 7.0-7.8 (m, 8H), 9.1 (s, 1H), 10.8 (bs, 1H).
Embodiment 244
1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (3g; 10mmol) and methyl-two-(2-chloro-ethyl)-amine (2.2g, 11.6mmol) as raw material, the preparation 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate.Output 4.0g, 98%; The low melting point brown solid; MS:384 (M+H) +
Employing is dissolved in 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate (7.6g in methyl alcohol (300ml) and the 10N sodium hydroxide (35ml); 20mmol) as raw material, preparation 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 6.0g, 84%; White solid; 195 ℃ of mp, MS:356.4 (M+H) +
Adopt 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid (4.0g; 11.2mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-methyl-4-that 3.9g is a yellow powder (4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 85%; 118 ℃ of mp; MS:371 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.45 (q, 2H), 1.8 (q, 2H), 2.1 (s, 3H), 2.3 (d, J=11.4Hz, 2H), 2.5-3.7 (m, 8H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H).
Embodiment 245
1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (3g; 10mmol) and ethyl-two-(2-chloro-ethyl)-amine (2.2g, 10.6mmol) as raw material, the preparation 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate.Output 3.5g, 88%; The low melting point brown solid; MS:398 (M+H) +
Employing is dissolved in 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate (7.94g in methyl alcohol (300ml) and the 10N sodium hydroxide (35ml); 20mmol) as raw material, preparation 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 6.5g, 88%; White solid; 162 ℃ of mp, MS:370 (M+H) +
Adopt 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid (3.7g; 10mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-ethyl-4-that 3.2g is a yellow powder (4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 76%; 98 ℃ of mp; MS:385 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.9 (t, 3H), 1.2 (t, 3H), 1.46 (q, 2H), 1.9 (q, 2H), 2.3 (d, J=11.4Hz, 2H), 2.5-3.6 (m, 10H), 4.1 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H).
Embodiment 246
1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(butoxy-benzenesulfonyl) ethyl acetate (3g; 10mmol) and normal-butyl-two-(2-chloro-ethyl)-amine (2.0g, 10.1mmol) as raw material, the preparation 1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate.Output 3.8g, 89%; The low melting point brown solid; MS:426 (M+H) +
Employing is dissolved in 1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-ethyl formate (8.5g in methyl alcohol (300ml) and the 10N sodium hydroxide (35ml); 20mmol) as raw material, preparation 1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 7.5g, 88%; White solid; 182 ℃ of mp, MS:398 (M+H) +
Adopt 1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid (3.9g; 10mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-normal-butyl-4-that 1.8g is a yellow powder (4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 40%; Mp121 ℃; MS:413 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.9-1.0 (m, 6H), 1.2-1.8 (m, 8H), 2.2-2.8 (m, 8H), 3.0-3.6 (m, 4H), 4.2 (t, 2H), 7.16 (d, 2H), 7.67 (d, 2H), 9.3 (bs, 1H), 10.3 (bs, 1H), 11.1 (bs, 1H).
Embodiment 247
[4-(4-chloro-phenoxy group)-phenyl sulfane base]-ethyl acetate
With 4-bromo chlorinated benzene (1.92g, 10mmol), (4-hydroxyl-phenyl sulfane base)-ethyl acetate (2.12g, 10mmol), sodium hydride (460mg, 10mmol) and cupric chloride (II) (500mg) in anhydrous pyridine (50ml), refluxed 12 hours.Carefully the concentrated hydrochloric acid acidifying is also used in above-mentioned reaction mixture quenching with icy water.Use the chloroform extraction product, the water thorough washing, dry and concentrated.With the product purification by silica gel column chromatography, use 30% ethyl acetate: the hexane wash-out.Output 2.5g (77%); Colourless low melting point solid; MS:323 (M+H) +Also can prepare title compound with 4-(4-chloro-phenoxy group)-benzenethiol and bromoethyl acetate as described in the embodiment 83.
Embodiment 248
[4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl acetate
According to embodiment 83 described universal methods, adopt [4-(4-chloro-phenoxy group)-phenyl sulfane base]-ethyl acetate (3.23g, 10mmol) and oxone (10g) be raw material, prepare [4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl acetate.Output 3.5g, 99%; Oil; MS:356 EI (M+H) +
Embodiment 249
4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-methyl-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl acetate (2.0g; 5.6mmol) and mustine hydrochlcride (Aldrich) (1.9g; 10mmol) as raw material, preparation [4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-methyl-piperidine-4-ethyl formate.Output 2g, 81%; Brown oil; MS:438 (M+H) +
Employing is dissolved in THF: [4-(4-chloro-phenoxy group)-the benzenesulfonyl]-1-methyl-piperidine-4-ethyl formate (4.3g in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (100ml); 10mmol) as raw material, preparation 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-methyl-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.5g, 86%; White solid; Mp185 ℃, MS:410 (M+H) +
Adopt 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-methyl-piperidines-4-formic acid (1.0g; 2.4mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-[4-that 460mg is hydrochloride, white powder (4-chloro-phenoxy group)-benzenesulfonyl]-1-methyl-piperidines-4-formic acid oxyamide.Productive rate 41%; 52 ℃ of mp; MS:426 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.3 (s, 3H), 2.2-2.9 (m, 6H), 3.5 (bd, 2H), 7.2-7.9 (m, 8H), 8.1 (s, 1H), 11.0 (bs, 1H).
Embodiment 250
4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl acetate (4g; 11.3mmol) and ethyl-two-(2-chloro-ethyl)-amine (2.32g; 16.9mmol) as raw material, preparation 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-ethyl-piperidine-4-ethyl formate.Output 3.36g, 66%; Brown oil; MS:452.0 (M+H) +
Employing is dissolved in THF: the 4-[4-in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (20ml) (4-chloro-phenoxy group)-benzenesulfonyl]-1-ethyl-piperidine-4-ethyl formate (3.02g; 6.7mmol) as raw material, preparation 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-ethyl-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 185g, 65%; White solid; 184 ℃ of mp, MS:423.9 (M+H) +
Adopt 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-1-ethyl-piperidines-4-formic acid (1.75g; 4.14mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-[4-that 650mg is hydrochloride, white powder (4-chloro-phenoxy group)-benzenesulfonyl]-1-ethyl-piperidines-4-formic acid oxyamide.Productive rate 33%; 158 ℃ of mp; MS:438.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 1.78 (t, J=7.23Hz, 3H), 2.23-2.27 (m, 2H), and 2.51-2.73 (m, 4H), 3.04 (m, 2H), 3.81 (d, J=24Hz, 2H), 7.16-7.27 (m, 4H), 7.50-7.57 (m, 2H), 7.76 (d, J=7Hz, 2H), 9.34 (s, 1H), 9.85 (s, 1H).
Embodiment 251
1-butyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl acetate (6g; 18.3mmol) and butyl-two-(2-chloro-ethyl)-amine (5.2g; 22mmol) as raw material, preparation 1-butyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidine-4-ethyl formate.Output 3.3g, 38%; Yellow oil; MS:480 (M+H) +
Employing is dissolved in THF: the 1-butyl-4-[4-in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (25ml) (4-chloro-phenoxy group)-benzenesulfonyl]-piperidine-4-ethyl formate (3.3g; 6.9mmol) as raw material, preparation 1-butyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 2.08g, 67%; White solid; Mp201 ℃, MS:451.9 (M+H) +
Adopt 1-butyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid (2g; 4.43mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-butyl-4-[4-that 630mg is hydrochloride, white solid (4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide.Productive rate 31%; 212 ℃ of mp; MS:466.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.87 (t, J=7.3Hz, 3H), 1.32 (m, 2H), 1.60 (m, 2H), 2.21 (m, 2H), 2.50 (m, 2H), 2.70 (q, 2H), 3.00 (m, 2H), 3.57 (d, 2H), 7.16-7.26 (m, 4H), 7.49-7.56 (m, 2H), 7.77 (d, J=9Hz, 2H), 9.34 (s, 1H), 10.13 (s, 1H).
Embodiment 252
1-benzyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(4-chloro-phenoxy group)-benzenesulfonyl]-ethyl acetate (6g; 16.9mmol) and two-(2-chloro-ethyl)-benzyl amine (6.44g; 24mmol) as raw material, preparation 1-benzyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidine-4-ethyl formate.Output 2.21g, 25%; Yellow oil; MS:513.9 (M+H) +
Employing is dissolved in THF: the 1-benzyl-4-[4-in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (20ml) (4-chloro-phenoxy group)-benzenesulfonyl]-piperidine-4-ethyl formate (2.11g; 4.1mmol) as raw material, preparation 1-benzyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.11g, 56%; White solid; Mp201 ℃, MS:485.9 (M+H) +
Adopt 1-benzyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid (1g; 2.06mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-benzyl-4-[4-that 430mg is hydrochloride, pale solid (4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide.Productive rate 39%; 90.4 ℃ of mp; MS:500.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.18-2.30 (m, 2H), 2.73-2.81 (m, 4H), 3.36 (d, 2H), 4.28 (d, J=4.5Hz, 2H), and 7.15-7.25 (m, 4H), 7.43-7.48 (m, 3H), and 7.51-7.56 (m, 4H), 7.74 (d, J=9Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).
Embodiment 253
[4-(3-methyl-butoxy)-phenyl sulfane base]-ethyl acetate
To (4-hydroxyl-phenyl sulfane base)-ethyl acetate (2.12g, 10mmol), salt of wormwood (anhydrous, 10g) and in the solution that stirs of 1-bromo-3-methylbutane (3g, excessive) add ebullient acetone.With above-mentioned reaction mixture refluxed 24 hours and be cooled to room temperature.Reaction mixture is filtered and concentrates.The gained residue is through chloroform extraction; The water thorough washing also concentrates.The gained crude product is not purified to be used for next step reaction.Output 2.7g (94%); MS:(M+H) +283.
Embodiment 254
[4-(3-methyl-butoxy)-benzenesulfonyl]-ethyl acetate
According to embodiment 83 described universal methods, adopt [4-(3-methyl-butoxy)-phenyl sulfane base]-ethyl acetate (2.8g, 10mmol) and oxone (10g) be raw material, prepare [4-(3-methyl-butoxy)-benzenesulfonyl]-ethyl acetate.Output 3.0g, 99%; Oily matter; MS:314 EI (M+H) +
Embodiment 255
1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(3-methyl-butoxy)-benzenesulfonyl]-ethyl acetate (6.2g; 20mmol) with two-(2-chloro-ethyl)-benzyl amine (6.44g; 24mmol) as raw material, preparation 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-ethyl formate.Output 8g, 84%; Yellow oil; MS:474 (M+H) +
Employing is dissolved in THF: 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (20ml)]-piperidine-4-ethyl formate (4.7g; 10mmol) as raw material, preparation 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3g, 67%; White solid; Mp182 ℃, MS:446 (M+H) +
Adopt 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid (2.2g; 5mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-benzyl-4-[4-that 1.82g is hydrochloride, pale solid (3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide.Productive rate 73%; 106 ℃ of mp; MS:498 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.8 (d, 6H), 1.5 (m, 1H), 1.6-2.0 (m, 6H), 2.73-2.81 (m, 4H), 3.5 (d, 2H), 4.28 (d, J=4.5Hz, 2H), 7.15-7.25 (m, 4H), and 7.43-7.48 (m, 3H), 7.51-7.56 (m, 4H), 7.74 (d, J=9Hz, 2H), 9.53 (s, 1H), 10.47 (s, 1H).
Embodiment 256
1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(3-methyl-butoxy)-benzenesulfonyl]-ethyl acetate (6.2g; 20mmol) and butyl-two-(2-chloro-ethyl)-amine (5.2g; 22mmol) as raw material, preparation 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidine-4-ethyl formate.Output 7g, 79%; Yellow oil; MS:440 (M+H) +
Employing is dissolved in THF: 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (20ml)]-piperidine-4-ethyl formate (4.4g; 10mmol) as raw material, preparation 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 3.2g, 77%; White solid; 188 ℃ of mp, MS:412 (M+H) +
Adopt 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid (2.0g; 5mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-butyl-4-[4-that 1.6g is hydrochloride, pale solid (3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide.Productive rate 69%; 201 ℃ of mp; MS:464 (M+H) +
Embodiment 257
[4-(2-ethyl-butoxy)-phenyl sulfane base]-ethyl acetate
To (4-hydroxyl-phenyl sulfane base)-ethyl acetate (2.12g, 10mmol), salt of wormwood (anhydrous, 10g) and in the solution that stirs of 1-bromo-2-ethyl butane (3g, excessive) add ebullient acetone.With above-mentioned reaction mixture refluxed 24 hours and be cooled to room temperature.Reaction mixture is filtered and concentrates.The gained residue is through chloroform extraction; The water thorough washing also concentrates.The gained crude product is not purified to be used for next step reaction.Output 2.8g (94%); MS:(M+H) +297.
Embodiment 258
[4-(2-ethyl-butoxy)-benzenesulfonyl]-ethyl acetate
According to embodiment 83 described universal methods; adopt [4-(2-ethyl-butoxy)-phenyl sulfane base]-ethyl acetate (2.96g; 10mmol) and oxone (10g) be raw material, the preparation [4-(2-ethyl-butoxy)-benzenesulfonyl]-ethyl acetate.Output 3.1g, 99%; Oily matter; MS:329 EI (M+H) +
Embodiment 259
1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(2-ethyl-butoxy)-benzenesulfonyl]-ethyl acetate (6.4g; 20mmol) with two-(2-chloro-ethyl)-benzyl amine (6.44g; 24mmol) as raw material, preparation 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-ethyl formate.Output 8g, 82%; Yellow oil; MS:488 (M+H) +
Employing is dissolved in THF: 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (20ml)]-piperidine-4-ethyl formate (4.8g; 10mmol) as raw material, preparation 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4g, 87%; Semi-solid; MS:460 (M+H) +
Adopt 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid (2.2g; 5mmol) as raw material and according to embodiment 83 described methods, separate obtaining 1-benzyl-4-[4-that 1.02g is hydrochloride, pale solid (2-ethyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide.Productive rate 40%; 114 ℃ of mp; MS:512 (M+H) +
Embodiment 260
4-(4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (20g; 77.5mmol) and two-(2-chloro-ethyl)-(3-methoxyl group-benzyl)-amine (34g; 116mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidine-4-ethyl formate.Output 9.53g, 25%; Brown oil; MS:490.2 (M+H) +
Employing is dissolved in THF: the 4-(4-methoxyl group-benzenesulfonyl) in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (15ml)-1-(3-methoxyl group-benzyl)-piperidine-4-ethyl formate (2.61g; 5.34mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1g, 41%; Brown solid; 175 ℃ of mp; MS:462.0 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid (900mg; 1.95mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 200mg is hydrochloride, brown ceramic powder (4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide.Productive rate 20%; 137 ℃ of mp; MS:477.0 (M+H) + 1HNMR (300MHz, DMSO-d 6): δ 0.96 (t, J=7.11Hz, 3H), 1.48 (m, 2H), 1.73 (m, 2H), 2.27 (m, 2H), 2.47 (m, 2H), 2.78 (m, 2H), 3.35 (m, 2H), 3.77 (s, 2H), 4.08 (t, J=6.3Hz, 3H), 4.32 (s, 2H), 7.03 (t, 2H), 7.15 (m, 3H), 7.36 (t, J=7.8Hz, 1H), 7.64 (d, J=9Hz, 2H), 9.36 (s, 1H), 10.22 (s, 1H).
Embodiment 261
4-(4-methoxyl group-benzenesulfonyl)-1-(4-benzene sulphur-2-base-benzyl)-piperidines-4-formic acid oxyamide
In the presence of four palladiums (O), in ebullient toluene; adopt 1-(4-bromo-benzyl)-4-(methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (3g; 6.05mmol) and 2-(tributyl stannyl)-thiophene (6.8g; 18.14mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-benzene sulphur-2-base-benzyl)-piperidine-4-ethyl formate.Output 1.58g, 52%; Brown solid; 130 ℃ of mp; MS:500 (M+H) +
Employing is dissolved in THF: 4-(4-methoxyl group-benzenesulfonyl)-1-(the 4-benzene sulphur-2-base-benzyl)-piperidine-4-ethyl formate (1.3g in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (20ml); 2.61mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-benzene sulphur-2-base-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 950mg, 77%; Brown solid; 235 ℃ of mp, MS:471.8 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(4-benzene sulphur-2-base-benzyl)-piperidines-4-formic acid (920mg; 1.95mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 510mg is hydrochloride, brown solid (4-methoxyl group-benzenesulfonyl)-1-(4-benzene sulphur-2-base-benzyl)-piperidines-4-formic acid oxyamide.Productive rate 50%; 166 ℃ of mp; MS:486.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.12-2.21 (m, 2H), 2.50 (m, 2H), 2.78 (m, 2H), 3.39 (m, 2H), 3.87 (s, 3H), 4.29 (d, 2H), 7.17 (m, 3H), 7.54-7.75 (m, 8H), 9.36 (s, 1H), 10.07 (s, 1H).
Embodiment 262
4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 261 described universal methods; adopt 1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidine-4-ethyl formate (4.65g; 9.38mmol) and 2-(tributyl stannyl)-pyridine (12.08g; 32.8mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidine-4-ethyl formate.Output 2.79g, 60%; Brown oil; MS:495.1 (M+H) +
Employing is dissolved in THF: 4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidine-4-ethyl formate (1.83g in methyl alcohol (3: 1 150ml) and the 10N sodium hydroxide (10ml); 3.7mmol) as raw material, preparation 4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.38g, 80%; Pale solid; 217 ℃ of mp, MS:466.9 (M+H) +
Adopt 4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidines-4-formic acid (1.32g; 2.83mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 480mg is hydrochloride, white powder (4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidines-4-formic acid oxyamide.Productive rate 33%; 214 ℃ of mp; MS:482.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.30 (m, 2H), 2.80 (m, 2H), 3.42 (d, J=12.5Hz, 2H), 3.75 (m, 2H), 3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, J=8.9Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, J=8.1Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17 (s, 1H).
Embodiment 263
1-(3, the 4-dichloro benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods, preparation 4-(4-butoxy-benzenesulfonyl)-1-(3, the 4-dichloro benzyl)-piperidine-4-ethyl formate.Adopt (4-butoxy-benzenesulfonyl) ethyl acetate (13.2g, 44mmol) and (3, the 4-dichloro benzyl)-two-(14.3g is mmol) as raw material for (2-chloro-ethyl)-amine.Output 14.1g, 60%; White solid, 86 ℃ of MP; MS:527.9 (M+H) +
Employing is dissolved in THF: methyl alcohol (100: 50ml) and 10N sodium hydroxide (20ml) in 4-(4-butoxy-benzenesulfonyl)-1-(3; 4-two chloro-benzyls)-piperidine-4-ethyl formate (14.0g; 26.5mmol) as raw material; preparation 1-(3, the 4-dichloro benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 7.87g, 60%; Pale solid; 239 ℃ of mp, MS:501.9 (M+H) +
Adopt 1-(3; the 4-dichloro benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid (7.7g; 15.5mmol) as raw material and according to embodiment 83 described methods; separate and obtain the 1-that 4.05g is hydrochloride, white solid (3, the 4-dichloro benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide.Productive rate 48%; 256.8 ℃ of mp; MS:514.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.94 (t, 3H), 1.38-1.48 (q, 2H), 1.68-1.75 (q, 2H), 2.27 (m, 4H), 2.72 (m, 2H), 4.10 (t, 2h), 4.24 (s, 2H), 7.12-7.15 (d, J=8.9,2H), 7.51-7.53 (d, J=8.1,1H), 7.63-7.65 (d, J=8.8,2H), 7.72-7.75 (d, J=9.9,2H), 7.87 (s, 1H), 9.36 (s, 1H), 10.5 (s, 1H), 11.2 (s, 1H).
Embodiment 264
[4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methyl piperidine-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [4-(4-chloro-benzyloxy)-benzenesulfonyl] ethyl acetate (13.97g; 37mmol) and 4-(4-chloro-benzyloxy)-two-(2-chloro-ethyl)-amine (8.7g; 45mmol) as raw material, preparation [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methyl piperidine-4-ethyl formate.Output 10.9g, 65%; Brown oil; MS:451.9 (M+H) +
Employing is dissolved in THF: methyl alcohol (75: 75ml) and 10N sodium hydroxide (20ml) in [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methyl piperidine-4-ethyl formate (10.7g; 24mmol) as raw material, preparation [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methyl piperidine-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.9g, 50%; Pale solid; MS:426.2 (M+H) +
Adopt [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methyl piperidine-4-formic acid (4.9g; 12mmol) as raw material and according to embodiment 83 described methods, separate obtaining [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-methyl piperidine-4-formic acid oxyamide that 1.2g is hydrochloride, pale solid.Productive rate 24%; 117.8 ℃ of mp; MS:438.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 2.2 (m, 2H), 2.49 (m, 4H), 2.5 (s, 3H), 2.6 (m, 2H), 5.2 (s, 2H), 7.25-7.23 (d, t=8.7,2H), 7.5 (d, t=2.7,4H), 7.68-7.71 (d, t=9.6,2H), 9.33 (s, 1H), 10.11 (s, 1H).
Embodiment 265
4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (10.1g; 34mmol) and 1-(3-phenoxy group-benzyl)-two-(2-chloro-ethyl)-amine (18g; 50mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidine-4-ethyl formate.Output 8.9,49%; Brown oil; MS:552.1 (M+H) +
Employing is dissolved in THF: methyl alcohol (75: 50ml) and 10N sodium hydroxide (20ml) in 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidine-4-ethyl formate (10.7g; 24mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 5.0g, 76%; Pale solid; MS:524.3 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidines-4-formic acid (5.9g; 11mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 0.39g is hydrochloride, brown solid (4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidines-4-formic acid oxyamide.Productive rate 11%; 92.5 ℃ of mp; MS:539.1 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.93-0.97 (t, J=3.6,3H), 1.49 (m, 2H), 1.73 (m, 2H), 2.51 (m, 4H), 4.09 (t, 2H), 4.29 (bs, 2H), 7.06-7.10 (d, J=12,2H), 7.13-7.15 (m, 3H), 7.39-7.42 (d, 2H), 7.63-7.66 (d, 2H), 9.50 (s, 1H), 9.98 (s, 1H).
Embodiment 266
[4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt [1-(4-chloro-benzyloxy)-benzenesulfonyl]-ethyl acetate (5.47g; 15mmol) and 1-(4-methyl-benzyl)-two-(2-chloro-ethyl)-amine (5.23g; 18mmol) as raw material, preparation [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidine-4-ethyl formate.Output 8.0g, 96%; Brown oil; MS:542.0 (M+H) +
Employing is dissolved in THF: methyl alcohol (50: 50ml) and 10N sodium hydroxide (20ml) in [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidine-4-ethyl formate (7.9g; 124mmol) as raw material, preparation [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 4.6g, 61%; Pale solid, 204 ℃ of mp; MS:514.2 (M+H) +
Adopt [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidines-4-formic acid (4.2g; 8mol) as raw material and according to embodiment 83 described methods, separate obtaining [4-(4-chloro-benzyloxy)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide that 1.3g is hydrochloride, yellow solid.Productive rate 24%; 172 ℃ of mp; MS:528.9 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ
Embodiment 267
4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (5.47g; 15mmol) and 1-(4-methyl-benzyl)-two-(2-chloro-ethyl)-amine (15.3g; 51mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-ethyl formate.Output 10.1g, 57%; White solid, 93 ℃ of MP; MS:474.1 (M+H) +
Employing is dissolved in THF: methyl alcohol (50: 50ml) and 10N sodium hydroxide (20ml) in 4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidine-4-ethyl formate (10.0g; 22mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 7.2g, 72%; Pale solid, 244 ℃ of mp; MS:446.3 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid (6.6g; 1.5mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 2.06g is hydrochloride, yellow solid (4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide.Productive rate 28%; 137 ℃ of mp; MS:461.3 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ 0.91-0.964 (t, J=7.3,3H), 1.41 (m, 2H), 1.70 (m, 4H), 1.79 (t, s, 3H), 2.52 (m, 2H), 2.76 (m, 2H), 3.33 (bd, 2H), 4.10 (t, 2H), 4.22 (d, 2H), 7.12-7.14 (d, J=8.7,2H), 7.25-7.28 (d, J=8.1,2H), 7.42-7.45 (d, J=7.8,2H), 7.63-7.65 (d, J=8.7,2H), 10.31 (s, 1H), 10.75 (bs, 1H).
Embodiment 2684-(4-butoxy-benzenesulfonyl)-1-(4-cyano group-benzyl)-piperidines-4-oxyamide formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(4-butoxy-benzenesulfonyl) ethyl acetate (5.29g; 17.6mmol) and 1-(4-cyano group-benzyl)-two-(2-chloro-ethyl)-amine (6.19g; 21mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano group-benzyl)-piperidine-4-ethyl formate.Output 6.8g, 80%; Brown oil; MS:485.0 (M+H) +
Employing is dissolved in THF: methyl alcohol (75: 50ml) and 10N sodium hydroxide (20ml) in 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano group-benzyl)-piperidine-4-ethyl formate (10.0g; 124mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano group benzyl)-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 7g, 11%; Pale solid; MS:456.0 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano group benzyl)-piperidines-4-formic acid (600g; 1.2mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 21g is hydrochloride, pale solid (4-butoxy-benzenesulfonyl)-1-(4-cyano group-benzyl)-piperidines-4-formic acid oxyamide.Productive rate 34%; 241.6 ℃ of mp; MS:472.0 (M+H) + 1H NMR (300MHz, DMSO-d 6): δ .915-.964 (t, J=7.2,3H), 1.51 (q, 2H), 1.75 (q, 2H), 2.27 (m, 2H), 2.49 (m, 4H), 4.11-4.19 (t, 2H), 4.37 (s, 1H), 7.12-7.15 (d, J=8.7,2H), 7.63-7.66 (d, J=9,2H), and 7.72-7.74 (d, J=7.8,2H), 9.36 (s, 1H), 10.23 (s, 1H), 11.16 (s, 1H).
Embodiment 269
4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidines-4-formic acid oxyamide
According to embodiment 83 described universal methods; adopt 4-(4-butoxy-benzenesulfonyl)-ethyl acetate (6.0g; 20.0mmol) and pyridin-4-yl methyl-two-(2-chloro-ethyl)-amine (4.89g; 21mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidine-4-ethyl formate.Output 4.5g, 48%; Brown oil; MS:461.0 (M+H) +
Employing is dissolved in THF: methyl alcohol (75: 50ml) and 10N sodium hydroxide (20ml) in 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidine-4-ethyl formate (3.0g; 6.5mmol) as raw material, preparation 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidines-4-formic acid.The reaction mixture that 83 described processing produce according to embodiment.Output 1.2g, 42%; Pale solid; MS:433.0 (M+H) +
Adopt 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidines-4-formic acid (0.864mg; 2.0mmol) as raw material and according to embodiment 83 described methods, separate obtaining the 4-that 600mg is hydrochloride, pale solid (4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidines-4-formic acid oxyamide.Productive rate 67%; 118 ℃ of mp; MS:447.9 (M+H) + 1HNMR (300MHz, DMSO-d 6): d 0.94 (t, 3H), 1.11 (t, 1H), 1.23 (t, 1H), 1.44 (m, 1H), 1.73 (m, 1H), 2.34 (m, 2H), 2.78 (m, 2H), 3.10 (m, 2H), 3.38 (m, 2H), 4.08 (t, 2H), 4.42 (br s, 2H), 7.13 (d, 2H), 7.64 (d, 2H), 7.94 (d, 2H), 8.82 (d, 2H), 11.2 (br s, 2H), 11.4 (br s, 1H).
Reference:
1．Rickter，L．S．；Desai，M．C．Tetrahedron?Letters，1997，38，321-322。
Biological activity according to following method test The compounds of this invention.
External gelatinase is measured
This mensuration is based on gelatinase to sulphur peptide substrates ((Ac-Pro-Leu-Gly (2-sulfydryl-4-methyl-pentanoyl)-Leu-Gly-OEt); derive from Bachem Bioscience) cracking; thereby release can ((5,5 '-dithio-two (2-nitro-phenylformic acid)) produce the substrate product of color reaction with DTNB.Advance the speed according to color and to measure described enzymic activity.
Described sulphur peptide substrates is mixed with the fresh storing solution of 20mM with 100%DMSO, DTNB is dissolved in be mixed with the 100mM storing solution among the 100%DMSO and store in the dark place under room temperature.Before using described substrate and DTNB one are reinstated substrate buffer solution (50mM HEPES, pH7.5,5mM calcium chloride) dilution and be 1mM.With measure damping fluid (50mM HEPES, pH7.5,5mM calcium chloride, 0.02%Brij) people's neutrophilic granulocyte gelatinase B being diluted to final concentration is 0.15nM.
To measure damping fluid, enzyme, DTNB/ substrate (final concentration is 500 μ M) and solvent or inhibitor and add to 96 orifice plates (total reaction volume is 200 μ l), read to increase by 5 minutes in 405nm punishment light luminosity monitoring color on the plate instrument.
With OD 405Increase mapping and calculate gained collinear slope, slope is represented speed of reaction.
Confirm that this speed of reaction is linear (r 2＞0.85).The average of calculating contrast speed (x ± sem), and according to the significance,statistical (p＜0.05) of the multinomial comparing check comparison of DunnettShi with drug treating group speed.Obtain dose-response relationship with a plurality of drug doses, according to linear regression (IPRED, HTB) IC of estimation 95% CI 50Value.
Reference: Weingarten, H and Feder, J " Spectrophotometric Assayfor Vertebrate Collegenase ", Anal.Biochem 147:437-440, (1985).
External collagenase is measured
This mensuration is based on collagenase to peptide substrates ((Dnp-Pro-Cha-Gly-Cys (Me)-His-Ala-Lys (NMa)-NH 2), derive from Peptide International, cracking Inc.), thus produce fluorescence NMa group, with photofluorometer this group is carried out quantitatively.The fluorescence of NMa in the complete substrate of Dnp quencher.This is determined in the HCBC mensuration damping fluid (50mM HEPES, pH7.0,5mM calcium ion, 0.02%Brij, 0.5% halfcystine) that contains recombinant human fibroblast cell glue protoenzyme (brachymemma, mw=18,828, WAR Radnor) and carries out.Be dissolved in described substrate in the methyl alcohol and with 1mM equal portions refrigerated storage.With collagenase in damping fluid with 25 μ m equal portions refrigerated storage.When measuring, with described substrate be dissolved in the HCBC damping fluid to final concentration be 10 μ M and the final concentration of collagenase is 5nM.Testing compound is dissolved among methyl alcohol, DMSO or the HCBC.With HCBC dilution methyl alcohol and DMSO to＜1.0%.Described compound is added in 96 orifice plates that contain enzyme, and add substrate startup reaction.
Read reaction 10 minutes (excite, in 444nm emission) in 340nm, with fluorescence increase in time with linear mapping.Calculate this collinear slope of representing speed of reaction.
Confirm that this speed of reaction is linear (r 2＞0.85).The average of calculating contrast speed (x ± sem), and according to the significance,statistical (p＜0.05) of the multinomial comparing check comparison of DunnettShi with drug treating group speed.Obtain dose-response relationship with a plurality of drug doses, according to linear regression (IPRED, HTB) IC of estimation 95% CI 50Value.
Reference: Bickett, D.M. wait at " A High Throughput FluorogenicSubstrate for Interstitial Collagenase (MMP-1) and Gelatinase (MMP-9) ", Anal.Biochem.212:58-64, (1993).
Measure the method that TACE suppresses
(final concentration is 1 μ M to add the solution contain following material: 10 μ l TACE (deriving from Immunex) (final concentration is 1 μ g/mL), 70 μ l Tris damping fluids (pH7.4 also contains 10% the glycerine that final concentration is 10mM) and the DMSO solution of 10 μ l test-compounds in each hole of 96 hole black microtiter plates, DMSO concentration＜1%), under room temperature with titer plate incubation 10 minutes.In each hole, add fluorescence peptide substrate (final concentration is 100 μ M) and shake startup reaction in 5 seconds at wobbler simultaneously.
Read reaction 10 minutes (exciting in 340nm), fluorescence is increased in time with linear mapping in the 420nm emission.Calculate this collinear slope of representing speed of reaction.
Confirm that this speed of reaction is linear (r 2＞0.85).The average of calculating contrast speed (x ± sem), and according to the significance,statistical (p＜0.05) of the multinomial comparing check comparison of DunnettShi with drug treating group speed.Obtain dose-response relationship with a plurality of drug doses, estimate the IC of 95% CI according to linear regression 50Value.
Providing the result that these standard test testing method obtain in the tabulation down.
IC 50(nM or 1 μ M or 10 μ M (*) time inhibition %), embodiment, MMP1, MMP9, MMP13, TACE, 1, NT, 559.6, 193.3, 31.62%, 2, NT, 10.50%, 0%, 403, 3, NT, 308.9, 169.4, 27.43%, 4, 371, 22.20%, 17.10%, 21%, 5, NT, 7.7, 4.7, 25%, 6, 267, 21.4, 15.6, 40.43%, 7, 844, 72.9, 42.1, 33%, 8, NT, 346, 307.9, 47%, 9, 313, 107, NT, 20.30%, 10, 8%, 128, 64, 54.75%, 11, 18.80%, 2925, 319, 942, 12, 100, 10.8, 11, 15.50%, 13, 239, 11, 14, 626, 14, 158, 23, 8, 17.18%, 15, 285, 17, 4, 137, 16, 325, 9, 24, 180, 17, 238.6, 8.9, 1.4, 41.00%, 18, 540, 18.9, 11.5, 29.2%, 19, 446, 95.8, 4.8, 33.1%, 20, 423, 14.6, 18.7, 31%, 21, 318, 13.2, 15.3, 39%, 22, 219, 3.2, 2.5, 30%, 23, 593, 7.9, 4.0, 40.6%, 24, 413, 20.9, 31.3, 47.5, 25, 262, 26.7, 8.0, NT, 26, 304.6, 6.3, 3.2, 34.6, 27, 629, 106, 30.1, NT, 28, 761, 3.1, 2.0, 30.6%, 29, 297, 4.3, 3.6, 41%, 30, 397, 8.1, 5.7, 25.2%, 31, 162, 15.2, 5.7, 688, 32, 13.7, 3.7, 1.0, NT, 33, 318, 53.9, 18.4, 23.9%, 34, 519.8, 34.7, 26.1, 28.1%, 35, 455.8, 233.6, 48.2, 44.9, 36, 622, 83.8, 20.7, 826, 37, 9%, 31.6%, 14.3%, 87, 38, 48.3%, 1.7%, 5.8%, 55.1%, 39, 29.4%, 35.2%, 26.6%, 69.4, 40, 583, 197, 14, 160, 41, 100, 10.8, 11, 15.50%, 42, 262, 50.9, 6.2, 36.5, 43, 66.1%, 34.7%, 55.5%, 46.6%, 44, 47.1%, 36.9%, 39.5%, 14.9%, embodiment, MMP1, MMP9, MMP13, TACE, 45, 49%, 48.6%, 36.7%, 20.4%, 46, 78.9%, 79.12%, 84.7%, 1.4%, 47, 17.1%, 12.9%, 7.12%, 3.3%, 48, 99.1%, 79.1%, 85.4%, 51.1%, 49, 10.1%, 23.7%, 54.6%, NT, 50, 51.1, 58.4, 10.6, NT, 51, 178.1, 10.4, 13.1, 48.14%, 52, 139.3, 7.9, 9.1, NT, 53, 647.9, 27.80%, 188, 52.57%, 54, 110, 66, 21, 55.10%, 55, 303, 10, 7, 21.70%, 56, 299, 16, 12, 65%, 57, 258, 332, 191, 16.57%, 58, 211, 35, 39, 7.70%, 59, 30.20%, 447, 141, 24.86%, 60, NT, 184, NT, 23.60%, 61, 258, 38, 22, 17.21%, 62, 522, 174, 43, 669, 63, 156, 9, 3, 203, 64, 40.90%, 25.60%, 36.70%, 29.70%, 65, 1000, 63, 13, 42.21%, 66, 1600, 131, 226, 42.33%, 67, 364, 2.3, 43.7, 690, 68, 297, 29, 27, 522, 69, 574.5, 120.2, 90, 41.32%, 70, 1139, 88.80%, 127, 764, 71, 1000, 63, 13, 42.21%, 72, 117, 11, 1, 51.64%, 73, 300, 141, 12, 20.17%, 74, 138.1, 9.2, 4.3, 47.86%, 75, 672.3, 83.4, 32.7, 23.77%, 76, 805, NT, 500, NT, 77, 205.5, NT, 170, NT, 78, 262, 560, 34, 24.58%, 79, 25, 0.54, 0.4, 805, 80, 22.1%, 26%, 63.6%, 191, 81a, 2036, 230.9, 43.9, 27.1, 81b, 3765, 154, 15.7, 228, 82, 237.6, 19.4, 5.1, 34.5%, 83, 492, 10.2, 2.0, 229, 84, 519, 8.8, 2.0, 213, 85, 450, 5.8, 1.5, 115, 86, 494, 16.8, 1.5, 222, embodiment, MMP1, MMP9, MMP13, TACE, 89, 1389, 38.6, 7.0, 49%, 90, 598, 10.3, 2.2, 71.9, 91, 1929, 13.3, 10.8, 503, 92, 59.6%, 649, 148, 9.7, 93, 56.3%, 452, 38, 15.8%, 94, 2640, 138, 28.6, 22.9, 95, 3681, 364, 33.1, 25.4%, 96, 4437, 374, 33.8, 18.1, 97, 5109, 484, 43.7, 20.20%, 98, 2383, 3.8, 1.2, 154, 99, 656, 16.2, 2.4, 250, 100, 4729, 19.1, 5.3, 39.5%, 101, 642, 12.3, 2.1, 197, 102, 662, 33.7, 1.9, 53%, 103, 1306, 45.1, 8.8, 470, 104, 2610, 3.1, 1.4, 208, 105, 1214, 44.2, 4.1, 50.2%, 106, 3788, 5.1, 0.9, 631, 107, 629, 26.8, 2.5, 293, 108, 2896, 5.4, 1.7, 270, 109, 393, 2.7, 2.5, 386, 241, 48.2%* 2．7     15．8      277  242      1950     2         1．3      581  243      2181     1．9      1．5      506  244      3417     9．8      1．5      594  245      7062     43．4     2．2    51．95％ *  246    50．30％ *28．3     2．4      880  249      1412     2         1．6      270  250      1717     1．6      0．8      413  251      1067     0．8      0．9      301  252       801     1．1      0．9      278  255      2558     3．6      1．5      565  256     10000     7．2      2．9    43．01％ *  259      3160     14．3     5．3      39％ *  260      1495     2．9      1．3      272  261       513     10．9     2．7      273  262       422     6．1      2．3      298  263      3669     20．3     5．2    57．70％ *The compound data of the synthetic preparation of 264 4,293 2.9 3.1 182 265 1,944 9.3 7.8 1,037 266 4,746 6 5.7 421 267 3,620 5.4 2.3 508 268 2,292 2.8 1.1 278 269 2,071 2.2 1.4 296 solid phases: embodiment 110-240 embodiment sequence number MMP1 MMP9 MMP13 MMP13 TACE
When 0.2 μ M when 0.2 μ M during at 1mM
The inhibition % of inhibition % of inhibition %
(HTS), (manual), 110, 75, 17.6, 111, 10, 40.4, 112, 50, 33.7, 113, 0, 13.1, 114, 0, 0, 115, 0, 0, 116, 0, 9.1, 117, 7, 8.1, 118, 24, 16.7, 119, 0, 7.8, 120, 31, 19.9, 121, 0, 6.1, 122, 0, 3.1, 123, 0, 2.5, 124, 0, 0, 125, 5, 2.3, 126, 25, 10.4, 127, 47, 29.2, 128, 1.9mM, 213nM, 91, 255nM, 19.31, 129, 90, 32.77, 130, 28, 27.9, 131, 71, 20.73, 132, 71, 20.76, 133, 53, 22.04, 134, 25,-9.31, 135, 79, 42.67, 136, 89, 42.69, 137, 83, 13.35, 138, 20, 5.284, 139, 8, 28.05, 140, 29,-4.22, 141, 32, 11.76, 142, 69, 54.27, 143, 53, 43.9, 144, 38, 19.7, 145, 45, 2.5, 146, 68, 7.317, 147, 73, 11.95, 148, 15, 43.46, 149, 13, 4.408, 150, 54, 1.818, 151, 6, 5.927, 152, 9, 10.03, 153, 12, 11.8, 154, 89, 13.14, 155, 31, 18.62, 156, 23,-2.09 embodiment sequence numbers, MMP1, MMP9, MMP13, MMP13, TACE
When 0.2 μ M when 0.2 μ M during at 1mM
The inhibition % of inhibition % of inhibition %
(HTS) (manual) 157 19 13.7 158 33-7.48 159 49 5.852 160 14-3.57 161 0 12.7 162 13 0 163 84 9.515 164 74 62.69 165 71 73.7 166 9 4.16 167 27 8.961 168 21 3.688 embodiment sequence number MMP13 MMP13 MMP13 TACE TACE
When 36nM at 0.36mM at 3.6mM IC 50NM is when 1mM
Inhibition % the time inhibition % the time the inhibition % of inhibition %
(HTS)??????(HTS)??????(HTS)???169???????28??????????40????????72????????????????41．7???170???????32??????????49????????90????????????????25．5???171???????31??????????38????????48????????????????16．6???172???????34??????????32????????42????????????????29．4???173???????18??????????46????????56????????????????25．5???174???????10??????????19????????40????????????????27．7???175???????16??????????20????????37????????????????32．9???176???????6???????????5?????????16????????????????26．6???177???????5???????????1?????????9?????????????????38．5???178??????-10??????????74????????39????????????????26???179???????12??????????32????????60????????????????42．7???180???????14??????????19????????45????????????????34．4???181???????6???????????35????????62????????????????15．7???182??????-9??????????-8?????????7?????????????????28．6???183??????-6???????????12????????70????????????????34．6???184???????16??????????24????????44????????????????24．8???185???????9???????????0?????????23?????????????????7．21???186??????-14?????????-4?????????35????????????????19．5???187??????-14?????????-12????????20????????????????85．5
Figure 9881396601981
Medicinal compositions
Can compound of the present invention be needed the patient with pure product or with pharmaceutical carrier.Described pharmaceutical carrier can be solid or liquid.
The solid carrier that is suitable for comprises one or more materials, and they also can be used as correctives, lubricant, solubility promoter, suspension agent, weighting agent, glidant, compression aids, tackiness agent or tablet disintegrant or packing material.When being powder, described carrier is the solid of segmentation, its active substance with segmentation can be mixed.During for tablet, described active substance can be mixed and is compressed to required shape and size with suitable proportion with the carrier with the compressing tablet character that needs.Powder and tablet preferably contain and are up to 99% active ingredient.Suitable solid carrier comprises as calcium phosphate, Magnesium Stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Liquid vehicle can be used to prepare solution, suspension, emulsion, syrup and elixir.Can with solubilization of active ingredient of the present invention in or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, both mixture or pharmaceutically acceptable oil or fat.Liquid vehicle also can contain other suitable medicinal additive such as solubility promoter, emulsifying agent, buffer reagent, sanitas, sweeting agent, correctives, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or osmotic pressure regulator.The suitable example of the liquid vehicle of per os and parenteral admin comprises water (can contain above-mentioned additive such as derivatived cellulose especially, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol such as dibasic alcohol) and their derivative and oil (as fractionated coconut oil and peanut oil).During parenteral admin, described carrier also can be grease such as ethyl oleate and Wickenol 101.Sterile liquid carrier can be used for the composition of the sterile liquid form of parenteral admin.
Sterile solution or suspension liquid pharmaceutical composition can be through using as intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can be through intravenously administrable.Oral administration can be the liquid or solid composition forms.
Compound of the present invention can be with the administration of conventional suppository form per rectum.Suck in the nose or in the tracheae or when being blown into administration, compound of the present invention can be formulated as the aqueous solution or partially aqueous solution, use with aerosol form then.Compound of the present invention also can by employing contain described active compound and carrier through skin patch form transdermal administration, described carrier is inert to described active compound, to skin is atoxic, and can make this medicine enter blood flow through the integumentary system absorption.This carrier can take various forms, as creme and paste, paste, gelifying agent and closing device (occlusive device).Creme and paste can be viscous liquid or semi-solid oil-in-water or water-in-oil emulsion.Also be suitable for by being scattered in the paste that the oil that contains described active ingredient or the absorptivity powder in the hydrophilic petroleum forms.Can adopt various closing devices that described active ingredient is released in the blood flow, closing device such as covering contain active ingredient bank (having or carrier free) or contain the semi-permeable membranes of the matrix of active ingredient.Other closing device by document as can be known.
The dosage that is used for the treatment of the concrete patient who suffers from the disease that relates to MMP and TACE or illness must be determined by the attending doctor.Included variable comprises the severity of disease and this patient's build size, age and reaction type.Treatment is generally begun by the low dose that is lower than the compound optimal dose.After this increase dosage gradually to till obtaining best effect under these factors.In the per os, parenteral, nose or the accurate dosage of administration in the tracheae decide according to concrete patient who is treated and standard medical principle by being responsible for the doctor.
Medicinal compositions is preferably unit dosage, as tablet or capsule.When being these forms, described composition can be further divided into the unitary dose of the active ingredient that contains appropriate amount; Described unit dosage can be packaged composition, as packaged powders, the glass tube vial that contains liquid, ampoule, pre-syringe or sachet of filling.Described unit dosage can perhaps be the packaged form of this based composition of proper number for as capsule or tablet itself.

Claims (42)

1. formula 1 compound or its pharmacy acceptable salt: R wherein 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first heteroaryl of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylene dioxo base, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COOC 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit's list or bicyclic heterocycle, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; Or the CO heteroaryl, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO-C 1-C 6Alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO-C 1-C 6Alkyl, CONHSO 2Aryl, aryl or heteroaryl, wherein aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
Or R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein said aryl is a phenyl or naphthyl.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein: R 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first group of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl; R 5Be H, F, Cl, Br, I, CN, CHO, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylenedioxy group, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COO-C 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) nAlkyl or aryl, wherein n is 0,1 or 2; Or CO heteroaryl; Wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2Alkyl, CONHSO 2Aryl, aryl, heteroaryl, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or N-R for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein aryl is a phenyl or naphthyl.
3. the compound of claim 2 or its pharmacy acceptable salt, wherein: R 1Be alkyl or heteroaryl such as pyridyl, thienyl, imidazolyl or the furyl of phenyl, naphthyl, a 1-18 carbon atom, optional by C 1-C 6Alkyl, C 1-C 6Alkoxyl group, C 6-C 10Aryloxy, heteroaryl oxygen base, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, halogen replace; Or S (O) n-C 1-C 6Alkyl C 1-C 6Alkoxy aryl or C 1-C 6The alkoxyl group heteroaryl; A is-S-,-SO-or-SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylenedioxy group, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCCNR 6, COOH, COOC 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit single or two heterocycles, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) nAlkyl or aryl, wherein n is 0,1 or 2; Or CO heteroaryl; Wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2Alkyl, CONHSO 2Aryl, aryl or heteroaryl; Wherein aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The arylalkyl of optional 7-16 the carbon atom that replaces of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
Independently be selected from R by 1 or 2 5The xenyl alkyl of optional 13-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The aromatic yl alkenyl of optional 8-16 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkylalkyl or the bicyclic alkyl alkyl of optional 4-12 the carbon atom that replaces of group;
Contain one and be selected from O, S or NR-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein aryl is a phenyl or naphthyl.
4. the compound of claim 1, it is 1-benzyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
5. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
6. the compound of claim 1, it is 1-(3, the 4-dichloro benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
7. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
8. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-naphthalene-2-base-methyl piperidine-4-formic acid oxyamide or its pharmacy acceptable salt.
9. the compound of claim 1, it is 1-xenyl-4-ylmethyl-4-(4-methoxyl group-benzenesulfonyl) piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
10. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-(3-methyl-but-2-ene base) piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
11. the compound of claim 1, it is 1-(4-bromo-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
12. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
13. the compound of claim 1, it is 1-benzyl-4-(4-benzyl oxygen base-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
14. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
15. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-[3-(2-morpholinyl-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
16. the compound of claim 1, it is 1-methyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
17. the compound of claim 1, it is 1-ethyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
18. the compound of claim 1, it is 1-normal-butyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
19. the compound of claim 1, it is 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl] 1-methyl-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
20. the compound of claim 1, it is 4-[4-(4-chloro-phenoxy group)-benzenesulfonyl] 1-ethyl-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
21. the compound of claim 1, it is 1-butyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
22. the compound of claim 1, it is 1-benzyl-4-[4-(4-chloro-phenoxy group)-benzenesulfonyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
23. the compound of claim 1, it is 1-benzyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
24. the compound of claim 1, it is 1-butyl-4-[4-(3-methyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
25. the compound of claim 1, it is 1-benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
26. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-(3-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
27. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-(4-thiophene-2-base-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
28. the compound of claim 1, it is 4-(4-methoxyl group-benzenesulfonyl)-1-(4-pyridine-2-base-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
29. the compound of claim 1, it is 1-(3, the 4-dichloro benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
30. the compound of claim 1, it is [4-(4-chloro-benzyl oxygen base)-benzenesulfonyl]-1-methyl piperidine-4-formic acid oxyamide or its pharmacy acceptable salt.
31. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-(3-phenoxy group-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
32. the compound of claim 1, it is [4-(4-chloro-benzyl oxygen base)-benzenesulfonyl]-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
33. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-(4-methyl-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
34. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-(4-cyano group-benzyl)-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
35. the compound of claim 1, it is 4-(4-butoxy-benzenesulfonyl)-1-pyridin-4-yl methyl-piperidines-4-formic acid oxyamide or its pharmacy acceptable salt.
36. the compound of claim 1 or its pharmacy acceptable salt; it is selected from: 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenyl-propyl group)-piperidines-4-formic acid oxyamide; the 1-tertiary butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-butyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-encircles octyl group-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-ethyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-sec.-propyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-methyl-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-benzyl-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-(4-fluoro-benzyl)-4-(4-methoxyl group-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 1-(4-fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-[2-(4-p-methoxy-phenyl)-ethyl]-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidines-4-formic acid oxyamide; 4-(4-n-butoxy-benzenesulfonyl)-1-(4-methoxyl group-benzyl)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide; 4-(4-n-butoxy-benzenesulfonyl)-1-(3-phenoxy group-propyl group)-piperidines-4-formic acid oxyamide; 4-(4-methoxyl group-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide, 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenoxy group-ethyl)-piperidines-4-formic acid oxyamide and 4-(4-methoxyl group-benzenesulfonyl)-1-[4-(2-piperidines-1-base-oxyethyl group)-benzyl]-piperidines-4-formic acid oxyamide.
37. suppress the method for Mammals by the pathological change of matrix metalloproteinase mediation, this method comprises that the matrix metalloproteinase of the following formula of the Mammals treatment significant quantity that gives its needs suppresses compound or its pharmacy acceptable salt: R wherein 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first heteroaryl of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylene dioxo base, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COOC 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit's list or bicyclic heterocycle, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; Or the CO heteroaryl, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6-alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO-C 1-C 6-alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO-C 1-C 6-alkyl, CONHSO 2Aryl, aryl or heteroaryl, wherein aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein said cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
Or R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein said aryl is a phenyl or naphthyl.
38. the method for claim 37, wherein the illness of being treated is an atherosclerosis, atherosclerotic plaque formation, the minimizing of the Coronary thrombosis that causes by atherosclerotic plaque rupture, restenosis, the osteopenia of MMP-mediation, inflammatory disease of central nervous system, skin aging, blood vessel takes place, metastases, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, keratohelcosis, unusual wound healing, osteopathia, proteinuria, the aortic aneurysm disease, the sex change cartilage that traumatic joint injury causes is lost, the neural system demyelinating disease, liver cirrhosis, renal glomerular disease, breaking in early days of fetal membrane, inflammatory bowel or periodontal disease.
39. the method for claim 37, wherein the illness of being treated is relevant macular degeneration of age, diabetic retinopathy, proliferative vitreous body retinopathy, retinopathy of prematurity, eye inflammation, keratoconus, Sjogren Cotard, myopia, ocular tumor, the generation of ocular angiogenesis generation/neovascularity and corneal graft rejection.
40. suppress the method for Mammals by the pathological change of TNF-α conversion enzyme (TACE) mediation, this method comprises that giving it needs the TACE of the following formula of Mammals treatment significant quantity to suppress compound or its pharmacy acceptable salt:
Figure 9881396600171
R wherein 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first heteroaryl of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylene dioxo base, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COOC 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit's list or bicyclic heterocycle, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; Or the CO heteroaryl, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6-alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO-C 1-C 6-alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO-C 1-C 6Alkyl, CONHSO 2Aryl, aryl or heteroaryl, wherein aryl is for independently to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein said cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
Or R 8R 9N-C 1-C 6-alkoxy aryl-C 1-C 6Alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein said aryl is a phenyl or naphthyl.
41. the method for claim 40, wherein the illness of being treated is that rheumatoid arthritis, graft-rejection, emaciation, apocleisis, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of central nervous system, inflammatory bowel or HIV infect.
42. medicinal compositions, matrix metalloproteinase or TACE that it contains the following formula of pharmaceutical carrier and treatment significant quantity suppress compound or its pharmacy acceptable salt:
Figure 9881396600201
R wherein 1For independently being selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The aryl of optional 6-10 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The cycloalkyl of optional 3-8 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit;
Or heteroaryl-(CH 2) 0-6-, wherein said heteroaryl is to have 1 or 2 first heteroaryl of heteroatomic 5-6 that independently is selected from O, S and N, and can independently be selected from R by 1 or 2 5Optional replacement of group; A is-S-,-SO-or SO 2-; R 2And R 3Form with the carbon atom that it connected and to contain O, S or N-R 7And optional 5-7 unit heterocycle with 1 or 2 two key; R 4Be hydrogen,
Independently be selected from R by 1 or 2 5The alkyl of optional 1-6 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
Independently be selected from R by 1 or 2 5The optional phenyl or naphthyl that replaces of group;
Independently be selected from R by 1 or 2 5The optional C that replaces of group 3-C 8Cycloalkyl or bicyclic alkyl;
Independently be selected from R by 1 or 2 5Optional containing one and being selected from O, S or NR of replacing of group 7The single or two heterocycles of heteroatomic saturated or unsaturated 5-10 unit; R 5Be H, C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Alkyl, C 2-C 12Alkenyl, C 2-C 12Alkynyl, F, Cl, Br, I, CN, CHO, C 1-C 6Alkoxyl group, aryloxy, heteroaryloxy, C 3-C 6Alkenyl oxy, C 3-C 6Alkynyloxy base, C 1-C 6Alkoxy aryl, C 1-C 6Alkoxyl group heteroaryl, C 1-C 6Alkylamino-C 1-C 6Alkoxyl group, C 1-C 2Alkylene dioxo base, aryloxy-C 1-C 6Alkylamine, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; OCOOC 1-C 6Alkyl, OCOO aryl, OCONR 6, COOH, COOC 1-C 6Alkyl, COO aryl, CONR 6R 6, CONHOH, NR 6R 6, SO 2NR 6R 6, NR 6SO 2Aryl ,-NR 6CONR 6R 6, NHSO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, SO 2NHCO aryl, CONHSO 2-C 1-C 6Alkyl, CONHSO 2Aryl, NH 2, OH, aryl, heteroaryl, C 3-C 8Cycloalkyl; Or contain one and be selected from O, S or NR 7Heteroatomic saturated or unsaturated 5-10 unit's list or bicyclic heterocycle, wherein C 1-C 6Alkyl is a straight or branched, and heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 6Be H, the optional C that replaces by OH 1-C 18Alkyl; C 3-C 6Alkenyl, C 3-C 6Alkynyl, C 1-C 6Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) nAryl, wherein n is 0,1 or 2; Or the CO heteroaryl, wherein heteroaryl independently is selected from O, S or NR for containing 1-3 7Heteroatomic 5-10 unit's list or bicyclic heteroaryl, and aryl is for to be selected from halogen, cyano group, amino, nitro, C by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; R 7Be C 7-C 11Aroyl, C 2-C 6Alkanoyl, C 1-C 12Perfluoroalkyl, S (O) n-C 1-C 6Alkyl, S (O) n-aryl, wherein n is 0,1 or 2; COO-C 1-C 6Alkyl, COO aryl, CONHR 6, CONR 6R 6, CONHOH, SO 2NR 6R 6, SO 2CF 3, SO 2NH heteroaryl, SO 2NHCO aryl, CONHSO-C 1-C 6Alkyl, CONHSO 2Aryl, aryl or heteroaryl, wherein aryl is for to be selected from halogen, cyano group, amino, nitro, C alone by 1 or 2 1-C 6Alkyl, C 1-C 6The optional phenyl or naphthyl that replaces of the group of alkoxyl group or hydroxyl; Heteroaryl independently is selected from O, S or N-C for containing 1-3 1-C 6The heteroatomic 5-10 unit's list or the bicyclic heteroaryl of alkyl;
Independently be selected from R by 1 or 2 5The alkyl of optional 1-18 the carbon atom that replaces of group;
Independently be selected from R by 1 or 2 5The alkenyl of optional 3-18 the carbon atom that replaces of group with 1-3 two keys;
Independently be selected from R by 1 or 2 5The optional alkynyl that replaces of group with 1-3 triple-linked 3-18 carbon atom;
The arylalkyl of 7-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
Heteroarylalkyl, wherein alkyl contains 1-6 carbon atom, and heteroaryl contains 1 or 2 heteroatoms that is selected from O, S or N and optionally independently is selected from R by 1 or 2 5Group replace;
The xenyl alkyl of 13-18 carbon atom, wherein xenyl independently is selected from R by 1 or 2 5Optional replacement of group;
The aromatic yl alkenyl of 8-16 carbon atom, wherein aryl independently is selected from R by 1 or 2 5Optional replacement of group;
The cycloalkylalkyl of 4-12 carbon atom or bicyclic alkyl alkyl, wherein said cycloalkyl or bicyclic alkyl independently are selected from R by 1 or 2 5Optional replacement of group;
Contain one and be selected from O, S or N-C 1-C 6The heteroatoms of alkyl also independently is selected from R by 1 or 2 5Optional saturated or unsaturated list or the bicyclic heterocycle that replaces of group;
Or R 8R 9N-C 1-C 6Alkoxy aryl-C 1-C 6-alkyl, wherein R 8And R 9Independently be selected from C 1-C 6Alkyl, perhaps R 8And R 9With form the optional 5-7 unit saturated heterocyclic that contains Sauerstoffatom between the nitrogen between the two, wherein said aryl is a phenyl or naphthyl.
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