CN1240429A - The preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors - Google Patents

Abstract

The present invention relates to the discovery of novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF- alpha converting enzyme (TACE, tumor necrosis factor- alpha converting enzyme) which are useful for the treatment of diseases in which these enzymes are implicated such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by formula (I) where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where: A is phenyl or naphthyl, optionally substituted by R<1>, R<2>, R<3> and R<4>; Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R<1>, R<2>, R<3> and R<4>; heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, O and S, and optionally substituted by R<1>, R<2>, R<3> and R<4>; and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R<1>, R<2>, R<3> and R<4>; and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are described in the specification.

Description

It is used as the preparation and use of matrix metalloproteinase and the ortho-sulfonamido aryl hydroxamic acids of tace inhibitor

Background of invention

The present invention relates to matrix metalloproteinase (such as gelatinase, stromelysin and clostridiopetidase A) and TNF-α invertase (TACE, tumor necrosis factor-α convering enzyme) new low molecule amount Nonpeptide inhibitors discovery, the degenerative cartilage that such inhibitor can be used for treating after the disease relevant with these enzymes, such as arthritis, metastases, tissue ulcer, abnormal wound healing, periodontosis, osteopathy, albuminuria, aortic aneurysm, traumatic arthritis is lost, the demyelinating disease and HIV of nervous system.

Matrix metalloproteinase (MMPs) is one group of disease relevant with the pathology destruction of connective tissue and basement membrane [Woessner, J.F., Jr.FASEB J., 1991,5,2145；Birkedal-Hansen, H.；Moore, W.G.I.；Bodden, M.K.；Windsor, L.J.；Birkedal-Hansen, B.；DeCarlo, A.；Engler, J.A.Crit.Rev.OralBiol.Med.1993,4,197；Cawston, T.E.Pharmacol.Ther.1996,70,163；Powell, W.C.；Matrisian, L.M.Cur.Top.Microbiol.andImmunol.1996,213,1].These endopeptidases containing zinc are made up of several hypotypes of enzyme such as clostridiopetidase A, stromelysin and gelatinase.In this several fermentoid, it is growth with tumour and diffusion most closely related MMPs to have shown gelatinase, and clostridiopetidase A [Howell, D.S. relevant with the pathogenesis of osteoarthritis；Pelletier, J.-P.In Arthritis and AlliedConditions；McCarthy, D.J.；Koopman, W.J., Eds.；Lea and Febiger：Philadelphia, 1993；12nd edition, volume 2, page 1723；Dean, D.D.Sem.Arthritis Rheum.1991,20,2；Crawford, H.C；Matrisian, L.M.Invasion Metast.1994-95,14,234；Ray, J.M.；Stetler-Stevenson, W.G.Exp.Opin.Invest.Drugs, 1996,5,323].

The expression rise of the known gelatinase in malignant tumour, and gelatinase can degrade can cause basement membrane [Powell, the W.C. of metastases；Matrisian, L.M.Cur.Top.Microbiol.and Immunol.1996,213,1；Crawford, H.C；Matrisian, L.M.Invasion Metast.1994-95,14,234；Ray, J.M.；Stetler-Stevenson, W.G.Exp.Opin.Invest.Drugs, 1996,5,323；Himelstein, B.P.；Canete-Soler, R.；Bernhard, E.J.；Dilks, D.W.；Muschel, R.J.Invasion Metast.1994-95,14,246；Nuovo, G.J.；MacConnell, P.B.；Simsir, A.；Valea, F.；French, D.L.Cancer Res.1995,55,267-275；Walther, M.M.；Levy, A,；Hurley, K.；Venzon, D.；Linehen, W.M.；Stetler-Stevenson, W.J.Urol.1995,153 (Suppl.4), 403A；Tokuraku, M；Sato, H.；Murakami, S.；Okada, Y.；Watanabe, Y.；Seiki, M.Int.J.Cancer, 1995,64,355；Himelstein, B.；Hua, J.；Bernhard, E.；Muschel, R.J.Proc.Am.Assoc.Cancer Res.Ann.Meet.1996,37,632；Ueda, Y.；Imai, K.；Tsuchiya, H.；Fujimoto, N.；Nakanishi, I.；Katsuda, S.；Seiki., M.；Okada, Y.Am.J.Pathol.1996,148,611；Gress, T.M.；Mueller-Pillasch, F.；Lerch, M.M.；Friess, H.；Buechler, M.；Adler, G.Int.J.Cancer, 1995,62,407；Kawashima, A.；Nakanishi, I.；Tsuchiya, H.；Roessner.A.；Obata, k.；Okada, Y.VirchowsArch., 1994,424,547-552.].Show the angiogenesis needed for implanted solid tumor growth for its teiology recently, it may have gelatin [Crawford, H.C；Matrisian, L.M.Invasion Metast.1994-95,14,234；Ray, J.M.；Stetler-Stevenson, W.G.Exp.Opin.Invest.Drugs, 1996,5,323].Moreover, the prompting gelatinase plaque rupture (plaque rupture) related to atherosclerosis is about [Dollery, C.M. on evidence；McEwan, J.R.；Henney, A.M.Circ.Res.1995,77,863；Zempo, N.；Koyama, N.；Kenagy, R.D.；Lea, H.J.；Clowes, A.W.Arterioscler.Thromb.Vasc.Biol.1996,16,28；Lee, R.T.；Schoen, F.J.；Loree, H.M.；Lark, M.W., Libby, P.Arterioscler.Thromb.Vase.Biol.1996,16,1070.].There is ISR by the MMPs Other diseases mediated, the sclerotin of MMP- mediations is reduced, the inflammation disease of central nervous system, skin aging, tumour growth, osteoarthritis, rheumatoid arthritis, septic arthritis, ulcer of the cornea, abnormal wound healing, osteopathy, albuminuria, aortic aneurysm, degenerative cartilage after traumatic arthritis is lost, the demyelinating disease of nervous system, hepatic sclerosis, renal glomerular disease, the premature rupture (premature rupture) of fetal membrane, inflammatory bowel disease, periodontosis, senile retinal macula lutea is deformed, diabetic retinopathy, Proliferative vetreoretinopathy, Prematurity, inflammation of eye section, keratoconus, Sjogren ' s syndromes, myopia, optic tubercle, Ocular Vessels generation/new vascular generation and corneal allograft rejection.

Since recognizing that these enzymes can be degraded to the collagen and proteoglycans of the principal structural component of cartilage first, it is important medium [Sapolsky, the A.I. for occurring to destroy in arthritic tissues to assume MMPs always for a long time；Keiser, H.；Howell, D.S.；Woessner, J.F., Jr.；J.Clin.Invest.1976,58,1030；Pelletier, J.-P.；Martel-Pelletier, L.；Howell, D.S.；Ghandur-Mnaymneh, L.；Enis, J.E.；Woessner, J.F., Jr., Arthritis Rheum.1983,26,63.], and due to identifying new MMPs, the hypothesis is further developed, for example, clostridiopetidase A -3 (MMP-13) is cloned within 1994 from breast cancer cell, and reports clostridiopetidase A -3 [Freiji, J.M. relevant with arthritis first in nineteen ninety-five；Diez-Itza, I.；Balbin, M.；Sanchez, L.M.；Blasco, R.；Tolivia, J.；Lopez-Otin, C.J.Biol.Chem.1994,269,16766；Flannery, C.R.；Sandy, J.D.102-17,41stAnn.Meet.Orth.Res.Soc.Orlando, FL.1995 13-16 in February days].Increasing evidence prompting MMP-13 is relevant with arthritic pathogenesis.The principal structural component of articular cartilage, i.e. II collagen types, the preferred substrate for being MMP-13, and the enzyme are in terms of II Collagenase Types are cracked substantially than other clostridiopetidase As more effectively [Knauper.V.；Lopez-Otin, C.Smith, B,；Knight, G.；Murphy, G.J.Biol.Chem., 1996,271,1544-1550；Mitchell, P.G.；Magna, H.A.；Reeves, L.M.；Lopresti-Morrow, L.L.；Yocum, S.A.；Rosner, P.J.；Geoghegan, K.F.；Hambor, J.E.J.Clin.Invest.1996,97,761.].MMP-13 is produced by cartilage cell, and MM-13 level rise [Reboul, P. are had found in people's osteo-articular tissues；Pelletier, J-P.；Hambor, J.；Magna, H.；Tardif, G.；Cloutier, J-M.；Martel-Pelletier, J.；Arthritis Rheum.1995,38 (Suppl, 9), S268；Shlopov, B.V.；Mainardi, C.L.；Hasty, K.A.ArthritisRheum.1995,38 (Suppl, 9), S313；Reboul, P.；Pelletier, J-P.；Tardif, G.；Cloutier, J-M.；Martel-Pelletier, J.J.Clin.Invest.1996,97,2011].Although being described to effective MMPs inhibitor before 10 years, the bioavilability of the substrate simulation MMP inhibitor of the peptide of these early detections is poor, and as a result they are excluded outside arthritis animal model.The higher non-peptide MMP inhibitor of bioavilability is preferably used to treat the disease mediated by MMPs.

THF- α conversion enzymatics form THF- α by the THF- αprecursorproteins of film combination.THF- α are a kind of proinflammatory cytokines, it is now recognized that the factor works in rheumatoid arthritis, septic shock, graft-rejection, insulin resistance and HIV and its antitumor properties fully proved for document.For example, the research carried out with anti-THF- Alpha antibodies and transgenic animals is confirmed, arthritic progress [Rankin, E.C. can be suppressed by blocking THF- α formation；Choy, E.H.；Kassimos, D.；Kingsley, G.H.；Sopwith, A.M.；Isenberg, D.A.；Panayi, G.S.Br.J.Rheumatol.1995,34,334；Pharmaprojects, 1996, Therapeutic Updates 17 (Oct.), au 197-M2Z.].This observation is also expanded to people recently.The Other diseases mediated by TNF-α have congestive heart failure, cachexia, low appetite, inflammation, heating, the inflammation disease and inflammatory bowel disease of central nervous system.

Therefore, it is desirable to which small molecule gelatinase and tace inhibitor can effectively treat various morbid states.Although identified in the document and disclose a variety of MMP and tace inhibitor, this most quasi-molecule for peptide or peptide-sample compound, the problem of this kind of compound has bioavilability and pharmacokinetics so that limiting their clinical effectiveness.For the effective long-term treatment of above-mentioned morbid state, thus it is highly desirable to low molecule amount, potent and long-acting, oral bioavailable gelatinase, clostridiopetidase A and/or tace inhibitor.Recently a variety of non-peptide, sulfur-bearing hydroxamic acid has been disclosed, is now listed in down.

United States Patent (USP) 5455258,5506242 and 5552419, and european patent application EP606046A1 and WIPO international application WO96/00214 and WO97/22587 disclose non-peptide matrix metalloproteinase row preparation, wherein using compound CGS27023A as representative.

The discovery of such MMP inhibitor is by MacPherson etc. in J.Med.Chem., and (1997) give further description in 40,2525.The publication of the open MMP inhibitor based on sulfonamides (sulfonamide) of others is european patent application EP-757984-A1 and WIPO international publication WO95/35275, WO95/35276, WO96/27583, WO97/19068 and WO97/27174, and these inhibitor are sulfonamides-Hydroxamates or similar sulfonamides-formic acid esters as shown.

The publication of open compound CGS27023A beta-sulfonamido-Hydroxamates MMP inhibitor analogues includes WIPO international publications WO96/33172 and WO97/20824, in these inhibitor, it is connected, is shown below with sulfonamides nitrogen-atoms on ring with α carbon atoms being connected of hydroxamic acid：

German patent application DE19542189-A1 discloses the example of other ring sulfonamides as MMP inhibitor.In this case, the ring containing sulfonamides condenses to form isoquinolin with phenyl ring.

European patent application EP-780386-A1 and WIPO international publication WO97/24117 discloses the analog of sulfonamides-hydroxamate MMP inhibitor, as shown in following formulas：Wherein carbon atom replaces sulfonamides nitrogen.

Present invention general introduction

The o- sulfonamides aryl hydroxamic acids and its pharmaceutically acceptable salt, optical isomer and diastereomer that the TACE and MMP of the present invention suppresses are expressed from the next：

Here hydroxamic acid groups and sulfamoyl part are connected with group A carbon, here：A is phenyl or naphthyl, optionally by R¹、R²、R³And R⁴Substitution；Z is aryl, heteroaryl or the heteroaryl condensed with phenyl, and aryl is phenyl or naphthyl here, optionally by R¹、R²、R³And R⁴Substitution；Heteroaryl is the heteroatomic 5-6 members hetero-aromatic rings that N, O and S are independently selected from 1-3, and optionally by R¹、R²、R³And R⁴Substitution；And when heteroaryl and phenyl are condensed, any one or two of the ring is optionally by R¹、R²、R³And R⁴Substitution；R¹、R²、R³And R⁴Stand alone as-H ,-COR⁵、-F、-Br、-Cl、-I、-C(O)NR⁵OR⁶、-CN、-OR⁵、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁵(x is 0-2 here) ,-OPO (OR⁵)OR⁶、-PO(OR⁶)OR⁵、-OC(O)NR⁵R⁶、-COOR⁵、-CONR⁵R⁶、-SO₃H、-NR⁵R⁶、-NR⁵COR⁶、-NR⁵COOR⁶、-SO₂NR⁵R⁶、-NO₂、-N(R⁵)SO₂R⁶、-NR⁵CONR⁵R⁶、-NR⁵C (=NR⁶)NR⁵R⁶, be independently selected from 1-3 N, O and S hetero atoms, and optionally there is the 3-6 membered cycloheteroalkyl groups of 1-2 double bond, and be optionally each independently selected from R by 1-3 is individual⁵Substituent group；As defined above aryl or heteroaryl, optionally it is each independently selected from R by 1-4⁴、-SO₂NHCOR⁵Or-CONHSO₂R⁵Substituent group xenyl (R here⁵H),-tetrazolium -5- bases,-SO₂NHCN、-SO₂NHCONR⁵R⁶Or straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group or the-C optionally with 1 or 2 double bond₃-C₆Cycloalkyl, it is each optionally by selected from following substituent group：-COR⁵、-CN、-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group ,-OR⁵、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁵(x is 0-2 here) ,-OC (O) NR⁵R⁶、-COOR⁵、-CONR⁵R⁶、-SO₃H、-NR⁵R⁶、-NR⁵COR⁶、-NR⁵COOR⁶、-SO₂NR⁵R⁶、-NO₂、-N(R⁵)SO₂R⁶、-NR⁵CONR⁵R⁶, as defined above-C₃-C₆Cycloalkyl, 3-6 membered cycloheteroalkyl groups as defined above, aryl or heteroaryl as defined above, xenyl ,-SO₂NHCOR⁵Or-CONHSO₂R⁵(R here⁵H) ,-PO (OR⁵)OR⁶、-PO(OR⁶)OR⁵,-tetrazolium -5- bases,-C (O) NR⁵OR⁶、-NR⁵C (=NR⁶)NR⁵R⁶、-SO₂NHCONR⁵R⁶Or SO₂NHCN；On condition that working as R¹And R²Right, the R on A adjacent carbons¹And R²The saturated or unsaturated heterocycle of 5-7 members or 5-6 member hetero-aromatic rings can be formed together with the carbon that they are connected, it is each with the 1-3 hetero atoms for being independently selected from O, S and N, and each optionally it is each independently selected from R by 1-4⁴Substituent group；Or optionally it is each independently selected from R by 1-4⁴Substituent group the saturated or unsaturated heterocycle of 5-7 members；R⁵And R⁶Stand alone as H, aryl as defined above or heteroaryl, 3-6 members cycloalkyl as defined above, 3-6 membered cycloheteroalkyl groups as defined above ,-C₁-C₄- perfluoroalkyl or straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl or-C₂-C₆Alkynyl group, it is each optionally by selected from following substituent group：-OH、-COR⁸、-CN、-C(O)NR⁸OR⁹、-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group ,-OR⁸、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁸(x is 0-2 here) ,-OPO (OR⁸)OR⁹、-PO(OR⁸)R⁹、-OC(O)NR⁸R⁹、-COOR⁸、-CONR⁸R⁹、-SO₃H、-NR⁸R⁹、-NCOR⁸R⁹、-NR⁸COOR⁹、-SO₂NR⁸R⁹、-NO₂、-N(R⁸)SO₂R⁹、-NR⁸CONR⁸R⁹, as defined above-C₃-C₆Cycloalkyl, 3-6 membered cycloheteroalkyl groups as defined above, aryl or heteroaryl ,-SO as defined above₂NHCOR⁸Or-CONHSO₂R⁸(R here⁸H),-tetrazolium -5- bases,-NR⁸C (=NR⁹)NR⁸R⁹、-SO₂NHCONR⁸R⁹Or SO₂NHCN；R⁷For H, straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl or-C₂-C₆Alkynyl group, it is each optionally by selected from following substituent group：-OH、-COR⁵、-CN、-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group ,-OR⁵、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁵(x is 0-2 here) ,-OPO (OR⁵)OR⁶、-PO(OR⁵)R⁶、-OC(O)NR⁵R⁶、-COOR⁵、-CONR⁵R⁶、-SO₃H、-NR⁵R⁶、-NR⁵COR⁶、-NR⁵COOR⁶、-SO₂NR⁵R⁶、-NO₂、-N(R⁵)SO₂R⁶、-NR⁵CONR⁵R⁶, as defined above-C₃-C₆Cycloalkyl, as defined above-C₃-C₆- cycloheteroalkyl, aryl or heteroaryl ,-SO as defined above₂NHCOR⁵Or-CONHSO₂R⁵(R here⁵H),-tetrazolium -5- bases,-NR⁵C (=NR⁶)NR⁵R⁶、-C(O)NR⁵OR⁶、SO₂NHCONR⁵R⁶Or SO₂NHCN；Or R⁷For phenyl or naphthyl, optionally by R¹、R²、R³And R⁴Substitution, or to be independently selected from N, O and S heteroatomic 5-6 unit's heteroaryls with 1-3 simultaneously optionally by R¹、R²、R³And R⁴Substitution；Or R⁷For-C as defined above₃-C₆Cycloalkyl or 3-6 membered cycloheteroalkyl groups；Or R⁷CH₂- N-A- (here A as defined above) can form the benzo-fused 7-10 circle heterocycles of non-aromatic 1,2-, optionally containing the other hetero atom selected from O, S and N, wherein the heterocycle can optionally with the fusion of another phenyl ring；R⁸And R⁹Respectively H, aryl as defined above or heteroaryl, C as defined above₃-C₇Cycloalkyl or 3-6 membered cycloheteroalkyl groups ,-C₁-C₄- perfluoroalkyl, straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl or-C₂-C₆Alkynyl group, it is each optionally by selected from following substituent group：Hydroxyl, alkoxy, aryloxy group ,-C₁-C₄- perfluoroalkyl, amino, list-and double-C₁-C₆- alkyl amino, carboxylic acid.Carbonylic alkoxy and carbonyl aryloxy group, nitro, cyano group, carbonyl acylamino- (one-level), list-and double-C₁-C₆- alkyl-carbamoyl.

It is preferred that compound be some such compounds, wherein the A neighbouring with being connected the carbon atom of sulfamoyl two carbon atoms have the substituent of non-hydrogen.Further preferably wherein Z is 4- alkoxyl phenyls, 4- aryloxyphenyls or heteroaryloxy phenyl.

In the definition, term " heteroaryl " includes, but are not limited to pyrroles, furans, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, pyrazoles, imidazoles, isothiazole, triazole, isoxazoles He oxazole.Term " 5-7 member saturations or unsaturated heterocycle " includes (but being not limited to) oxazolidines, thiazolidine, imidazolidine, tetrahydrofuran, thiophane, tetramethylene, sulfone, dihydropyran, oxinane, piperidines, pyrrolidines, dioxane, morpholine, azatropylidene and diaza .Term " heteroaryl condensed with phenyl ring " includes but is not limited to benzoxazole, benzoisoxazole, indoles, iso-indoles, benzothiophene, benzofuran, quinoline, quinazoline, quinoxaline, BTA, benzimidazole, benzothiazole, benzopyrazoles and isoquinolin.

Following compounds (1-10) for preparing the compounds of this invention are known, and bibliography is listed below.

Compound 1：A) Meyer, Michael D.；Altenbach, Robert J.；Basha, Fatima Z.；Carroll, William A.；Drizin, Irene；Elmore, Steven W.；Kerwin, Jr James F.；Lebold, Suzanne A.；Lee, Edmund L.；Sippy, KevinB.；Tietje, Karin R.；Cyclosubstituted hexahydro benzo [e] the iso-indoles alpha-1 adrenergic antagonists of Wendt, Michael D. tri-.US 5597823.CAN 126：199575.B) Meyer, Michael D.；Altenbach, Robert J.；Basha, Fatima Z.；Carroll, William A.；Drizin, Irene；Kerwin, James F., Jr.；Lebold, Suzanne A.；Lee, Edmund L.；Elmore, Steven W etc..It is used as the preparation of three cyclosubstituted hexahydro benzo [e] iso-indoles of alpha-1 adrenergic antagonists.PCTInt.Appl WO 9622992 A1 CAN 125：221858.

Compound 2；Troll, Theodor；The preparation and reaction of Schmid, Klaus.2H- pyrrolo- [3,4-b] pyridine and 2H- pyrrolo-es [3,4-b] pyrazine.J.Heterocycl.Chem. (1986), 23 (6), 1641-4.

Compound 3：Meyer, Michael D.；Altenbach, Robert J.；Basha, Fatima Z.；Carroll, William A.；Drizin, Irene；Elmore, Steven W.；Kerwin, Jr James F.；Lebold, Suzanne A.；Lee, Edmund L.；Sippy, KevinB.；Tietje, Karin R.；Cyclosubstituted hexahydro benzo [e] the iso-indoles alpha-1 adrenergic antagonists of Wendt, Michael D. tri-.US 5597823.CAN 126：199575.

Compound 4：A) Meyer, Michael D.；Altenbach, Robert J.；Basha, Fatima Z.；Carroll, William A.；Drizin, Irene；Elmore, Steven W.；Kerwin, Jr James F.；Lebold, Suzanne A.；Lee, Edmund L.；Sippy, KevinB.；Tietje, Karin R.；Cyclosubstituted hexahydro benzo [e] the iso-indoles alpha-1 adrenergic antagonists of Wendt, Michael D. tri-.US 5597823.CAN 126：199575.B) Meyer, Michael D.；Altenbach, Robert J.；Basha, Fatima Z.；Carroll, William A.；Drizin, Irene；Kerwin, James F., Jr.；Lebold, Suzanne A.；Lee, Edmund L.；Elmore, Steven W etc..It is used as the preparation of three cyclosubstituted hexahydro benzo [e] iso-indoles of alpha-1 adrenergic antagonists.PCTInt.Appl WO 9622992 A1 CAN 125：221858.

Compound 5：Geach, Neil；Hawkins, David William；Pearson, Christopher John；Smith, Philip Henry Gaunt；White, Nicolas. as herbicidal isoxazole preparation.Eur.Pat.Appl.EP 636622 A1 CAN 122：290845.

Compound 6：Kotovskaya, S.K.；Mokrushina, G.A.；Suetina, T.A.；Chupakhin, O.N.；Zinchenko, E.Ya.；Lesovaya, Z.I.；Mezentsev, A.S.；Chernyshov, A.I.；The benzimidazolyl derivatives of Samoilova, L.N. penicillin and cynnematin：Synthesis and antibacterial activity.Khim.-Farm.Zh. (1989), 23 (8), 952-6.

Compound 7：Wagner, Klaus. are sterilized and antifungal 4- chloro benzo thiazoles.Ger.Offen.DE2136924 CAN 78：111293.

Compound 8：Eggensperger, Heinz；Diehl, Karl H.；Kloss, Wilfried.2- hydroxyl -4- dodecyloxybenzophenones.Ger.DE 1768599 711223.CAN 76：85557.

Compound 9：Lichtenthaler, Frieder W.；Moser, Alfred. nucleotides 44.Benzo-separated pyrazolopyrimidines：Expeditious syntheses of [3,4-g]-and [3,4-h]-linked pyrazoloquinazolinones.Tetrahedron Lett. (1981), 22 (44), 4397-400.

Compound 10：Terpstra, Jan W.；Van Leusen, Albert M. synthesize the new method of benzo [b] thiophene and benzo [c] thiophene by the ring formation of two substituted thiophenes.J.Org.Chem. (1986), 51 (2), 230-8.

Have shown that the compounds of this invention can inhibitory enzyme MMP-1, MMP-9, MMP-13 and TNF-α invertase (TACE), and suppress the loss of cartilage weight and the loss of internal collagen amount, thus for treatment of arthritis, metastases, tissue ulcer, abnormal wound healing, periodontosis, osteopathy and HIV.

The present invention is described in detail

The compounds of this invention is synthesized using routine techniques known to organic synthesis field technical staff.Flow (flow I) illustrates general reaction sequence used below.Just to the purpose of explanation; wherein group A is phenyl, artificial neroli oil is reacted the N- aryl sulfonamide base esters required for providing with p- Methoxybenzenesulfonyl chloride, the ester is provided N through alkylation; N- disubstituted sulfonamides, are then further converted into corresponding hydroxamic acid through two-step reaction.

Into alkali metal cation such as lithium, sodium, potassium, calcium and aluminium the basic salt of hydroxamic acid can be formed with pharmaceutically acceptable.When substituent contains basic amine group, acid-addition salts can be formed with pharmaceutically acceptable inorganic or organic acid, the acid includes, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, butanedioic acid, lactic acid, malic acid, maleic acid, fumaric acid or methanesulfonic acid.

When required anthranilic acid can not be obtained, some the compounds of this invention can be prepared by the various methods shown in following scheme.In some flows, the explanation of some conversions is not detailed enough, but can be with reference to shown in flow above reaction and understood.In some reaction sequences, substituent R does not indicate label further, but those skilled in the art can readily determine that the meaning of the substituent by reference to the definition of various substituents in above-mentioned formula.

Following flow II shows the 3- trifluoromethyl compounds and route of synthesis for being used to prepare embodiment 125 by the adjacent substitution-fluoro benzonitrile of substitution.

The synthesis of 3- and 5- aryl and heteroaryl analog is completed according to the method shown in flow III and IV.In the two flows, aryl/hetaryl can be added by using Stille or Suzuki palladium chtalysts coupling reaction.As shown in flow IV, the Stille or Suzuki of the palladium chtalyst on the 5- positions of anthranilic acid ring coupling can be carried out before or after the alkylation of sulfonamide nitrogen.

Flow III

Flow IV

As shown in flow V, 5- bromo aryls derivative (such as flow IV preparations) is set to carry out the approach that Stille couplings provide the acquisition anthranilic acid that the 5- with various degrees of functionality replaces with vinyl stannane (vinyl stannane), the degree of functionality includes but is not limited to alkene, alkane, hydroxamic acid, alcohol, halogen and amine.Then whole ester derivatives shown in the flow are converted into required hydroxamic acid.

Flow V

As shown in flow VI, the 5- position functionals of anthranilic acid ring can also be made by using the Heck reactions of palladium chtalyst.Therefore, 5- bromo aryls derivative (being prepared by flow IV Suo Shi) is provided cinnamate derivates with acrylic acid amides, acrylic acid or acrylate reactions, be then processed to by known method and be converted into aryl-hydroxamic acid.These 5- cinnamate derivates can obtain phenylethyl derivatives before aryl-hydroxamic acid is converted into hydrogenated.Many substituents can be subjected to these conversions on anthranilic acid ring, propose that the flow is merely to illustrate that.

Flow VI

Flow VII represents to prepare other approach of the anthranilic acid derivative of 5- substitutions by the coupling of the aryl halide and alkynes of palladium chtalyst.Also illustrate conversion process of the aryl ester to Hydroxamates.

Flow VII

Flow VIII and IX illustrate the approach that preparation has the anthranilic acid derivative of the degree of functionality containing amine in the 3- bit strips of the anthranilic acid ring.Intermediate benzyl bromide a-bromotoluene can also be replaced by malonic acid (malonte) anion or other carbon-base nucleopilic reagent.The 5- substituents of anthranilic acid ester can be handled before or after amino is added to molecule.

Flow VIII

Flow IX

Flow X indicates the approach for synthesizing the dibasic anthranilic acid derivatives of 3,6-.Therefore, by being reduced to alcohol, aldehyde is then progressively oxidized to, reoxidizes as carboxylic acid, the ester can be converted into hydroxamic acid.Then carboxylic acid is converted into by hydroxamic acid by usual way.

Flow X

Flow XI and XII illustrate to be combined into amino into the two methods of the substituent for the sulfonamides nitrogen for being connected to the compounds of this invention.Therefore, in flow XI, make NH- sulphonyl amino-alkylation to provide propinyl sulfonamide with propine bromide.In the presence of one-level or secondary amine and copper chloride, the alkynes is reacted with paraformaldehyde and obtain propinyl amine, required hydroxamic acid can be translated into according to preceding method.

Flow XI

In flow XII, the ester of the p- ethoxycarbonyl benzyl sulfamoyl of selective hydrolysis provides monocarboxylic acid.The acid can change into acid amides (not show), and the anthranilic acid ester then is converted into corresponding Hydroxamates, or be reduced to diborane corresponding alcohol.The alcohol is converted into similar amine by benzyl bromide a-bromotoluene (benzylicbromide), anthranilic acid ester is then converted into corresponding Hydroxamates.

Flow XII

As shown in flow XIII, the amine substituent on hydroxamic acid can also be obtained by 3- nitro anthranilic acids ester derivant.R is added after nitration reaction⁷CH₂- group

Flow XIII

As shown in flow XIV, the coupling of aryl bromide and the palladium chtalyst of required amine can be used for making amino group be attached on the anthranilic acid ester ring.R in flow XIV⁷During for bromo aryl, this method can also be used for generating similar aminoaryl derivatives.

Flow XIV

Flow XV illustrates the process that processing 3- formaldehyde substituent (is prepared) alcohol, ether and ester of generation 3 connections of the anthranilic acid ester as flow VIII Suo Shi.The carboxylic acid product of the sodium chlorite shown in the flow/sulfamic acid oxidation is also just used to synthesize formamide.Method described herein is practically applicable to the substituent of any position of the anthranilic acid ester.

Flow XV

Flow XVI shows the approach (embodiment 34,54-60,101,174) of the alkoxide compound for preparing 3- alkoxies and substitution.

Flow XVI

Flow XVII shows the approach of the benzoic ether intermediate for preparing the compounds of this invention, wherein R⁷- N-A formation non-aromatic heterocyclics.

Flow XVII

The method that flow XVIII-XXI indicates the variant of the different substituents on synthesis sulfonyl aryl.As shown in flow XVIII, the Suzuki on the benzsulfamide that diaryl sulfonyl can be replaced by bromine is coupled to synthesize.The benzsulfamide of raw material bromine substitution can be by commercially available bromo benzene sulfonyl chloride and anthranilic acid Lipase absobed.

Flow XVIII

The method that flow XIX-XXI indicates synthesis sulfonyl aryl ether.In flow XIX, diaryl ether, or aryl heteroaryl ether, it can be synthesized by known sulfonic acid chloride (see for example, ZookSE；Dagnino, R；Deason, ME.Bender, SL；Melnick, MUWO97/20824).

Flow XIX

Or, as shown in flow XX, diaryl ether can be prepared by corresponding boric acid or by sulfonyl phenol.

Flow XX

As shown in flow XXI, aryl ether can also be prepared by the substitution of fluorine by p- fluoro benzsulfamide.Aryl ether or alkyl ether can be prepared with this method.

Flow XXI

The method that flow XXII illustrates synthesis in solid state the compounds of this invention.Therefore, resin-azanol 4 of connection can obtain resin with the reaction of pentafluorophenyl group ester 6-hydroxamic acid 7 being connected.The compound is after sulfonylation, and the then Mitsunobu types alkylation through sulfonamide obtains compound 9, and its pitch shake solution can be come out by being handled by using trifluoroacetic acid.

Flow XXII

The flow XXII continued

Following particular embodiment is in order to for example, not constituting limitation of this disclosure in any way.It is obvious for preparing other methods of the compounds of this invention for the technical staff of organic chemical synthesis field.

Embodiment 1

2- (4- methoxy-benzenesulfonvls amino)-methyl benzoate

3.2ml (0,039mol) pyridine is added to 2.00g (0.013mol) the artificial neroli oils solution for being dissolved in 20ml chloroforms, 2.733g (0.013mol) p- Methoxybenzenesulfonyl chloride is subsequently added into.Reactant mixture is stirred at room temperature 5 hours, then with 3N hydrochloric acid and water washing.Organic matter dried over sodium sulfate, filters and is concentrated in vacuo again.The white solid of generation is washed with ether, vacuum drying provides the sulfonamide needed for 3.7g (87%).CI mass spectrums：322(M+H).

Embodiment 2

3- chloros -2- (4- methoxy-benzenesulfonvls amino)-methyl benzoate

It is white solid using 4.07g (0.022mol) methyl -3- chloros-anthranilic acid ester there is provided the sulfonamide needed for 0.932g (12%) according to the same procedure described in embodiment 1.

Embodiment 3

2- (4- methoxy-benzenesulfonvls amino) -3- methyl-benzoic acid methyl esters

It is white solid using 6.24g (0.038mol) methyl -3- methyl-anthranilic acid ester there is provided the sulfonamide needed for 6.21g (49%) according to the same procedure described in embodiment 1.Electrospray ionization mass spectrum：336.2(M+H).

Embodiment 4

2- (4- methoxy-benzenesulfonvls amino) -4- methyl-benzoic acids

At room temperature, by 4- Methoxybenzenesulfonyl chlorides (2.91g, 14.1mmol) add and containing triethylamine (2.68ml, 20ml dioxane 19.2mmol): in the solution of the 2- amino -4- methyl benzoic acids (1.93g, 12.8mmol) in water (1: 1).The mixture is stirred at room temperature 18 hours.The mixture generated with dchloromethane, with 1N hydrochloric acid, water, salt water washing, is dried and concentrated.Use 16ml ethyl acetate: product needed for hexane (1: 3) grinding provides 2.358g, is white solid (57%).Electrospray ionization mass spectrum：322(M+H).

Embodiment 5

2- (4- methoxy-benzenesulfonvls amino) -6- methyl-benzoic acids

According to the same procedure described in embodiment 4, by 1.93g 2- amino -6- methyl benzoic acids (12.8mmol) by silica gel chromatography (acetic acid of 2% methanol -0.1%, in dichloromethane) after obtain sulfonamide product needed for 2.24g (55%), be white solid.Electrospray ionization mass spectrum：322(M+H).

Embodiment 6

2- (4- methoxy-benzenesulfonvls amino) -3- methyl-benzoic acids

According to the same procedure described in embodiment 4, using 1.93g 2- amino -3- methyl benzoic acids (12.8mmol), through ethyl acetate: the sulfonamide needed for 2.07g (50%) is obtained after hexane (1: 4) grinding, is white solid.EI is composed：321(M⁺)。

Embodiment 7

2- (4- methoxy-benzenesulfonvls amino) -5- methyl-benzoic acids

According to the same procedure described in embodiment 4, use 1.93g 2- amino -5- methyl benzoic acids (12.8mmol), through dichloromethane: the sulfonamide needed for 2.498g (61%) is obtained after hexane (1: 2) grinding, is white solid.Electrospray ionization mass spectrum：320(M-H).

Embodiment 8

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-Ergols and methyl esters

0.37ml (3.12mmol) benzyl bromide a-bromotoluenes and 3.23g (0.023mol) potassium carbonate are added to solution of 1.00g (3.12mol) products of embodiment 1 in 45ml DMF.Heating response thing adds 1.11ml benzyl bromide a-bromotoluenes to flowing back 24 hours, reheats reactant mixture to flowing back 48 hours, is subsequently cooled to room temperature and is diluted with 400ml water.The mixture of generation is extracted with ether, the organic layer merged with water and salt water washing is dried over sodium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, 0.60g (40%) benzyl ester (CI mass spectrums are provided with ethyl acetate/hexane (1: 10) elution：488 (M+H)), produce white crystal, and 0.57g (44%) methyl esters (CI mass spectrums through triturated under ether：412(M+H)).

Embodiment 9

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- chloros-methyl benzoate

0.127ml (3.165mmol) 60% sodium hydride is added to solution of 0.90g (2.532mol) products of embodiment 2 in 10ml DMF.The mixture of generation is stirred 30 minutes in room temperature, 0.38ml (3.165mmol) benzyl bromide a-bromotoluene is then added.The mixture is stirred at room temperature overnight, is poured into water, is then extracted with ether.The organic layer merged with water and salt water washing, it is dried over sodium sulfate, filter and offer white solid is provided, 0.44g (39%) required product is provided through being recrystallized from ethyl acetate/hexane, is white crystal, CI mass spectrums：466(M+H).

Embodiment 10

5- bromos -2- (4- methoxy-benzenesulfonvls amino) -3- methyl-benzoic acid methyl esters

0.531g (2,985mmol) N-bromosuccinimides and 0.025g AIBN are added to solution of 1.00g (2.985mmol) products of embodiment 3 in 100ml chloroforms.The mixture of generation is heated to flowing back 18 hours, then 0.411g NBS and 0.013g AIBN benzyl bromide a-bromotoluenes are added to the reaction solution.Reactant is flowed back again 5 hours, reactant mixture is cooled to room temperature, diluted with metabisulfite solution and water.Dried with sodium sulphate, filter and be concentrated in vacuo.Residue grinds the required product for providing 0.62g (50%) with ether-hexane, is white solid.CI mass spectrums：413(M⁺)。

Embodiment 11

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -5- bromo -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, use the product of 0.463g (1.118mol) embodiment 10, by silica gel chromatography, 0.514g (91%) required product is afforded with ethyl acetate/hexane (1: 10), is colorless oil.CI mass spectrums：504(M+H).

Embodiment 12

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- methyl-benzoic acid benzyl esters

Sodium hydride (60% suspension in oil, 498mg, 12.5mmol) is added to solution of 1.82g (5.66mmol) products of embodiment 4 in 20ml DMF.Stir the mixture of generation 15 minutes, then add benzyl bromide a-bromotoluene (4.84g, 0.028mmol).Under a nitrogen the agitating and heating mixture to 80-84 DEG C 18 hours.Then the reactant is cooled down to room temperature, is diluted with ether, it is dried over sodium sulfate with water and salt water washing, and be concentrated in vacuo.Residue grinds the required product for providing 2.2g (77%) through ethyl acetate, is white solid.Electrospray ionization mass spectrum：502(M+H)).

Embodiment 13

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -6- methyl-benzoic acid benzyl esters

According to the same procedure described in embodiment 12, the product of 1.45g (4.5mol) embodiment 5, by silica gel chromatography, with ethyl acetate: hexane (1: 9) affords 1.18g (52%) required product, is white solid are used.Electrospray ionization mass spectrum：502(M+H).

Embodiment 14

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -3- methyl-benzoic acid benzyl esters

According to the same procedure described in embodiment 12, use the product of 1.6g (5.00mmol) embodiment 6, by silica gel chromatography, with ethyl acetate: hexane (1: 9) affords 1.269g (50%) required product, is white solid.Electrospray ionization mass spectrum：502(M+H).

Embodiment 15

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -5- methyl-benzoic acid benzyl esters

According to the same procedure described in embodiment 12, use the product of 1.821g (5.66mmol) embodiment 7, by silica gel chromatography, 2.13g (75%) required product is afforded with ethyl acetate/hexane (1: 5), is white solid.Electrospray ionization mass spectrum：502(M+H).

Embodiment 16

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-benzoic acid

To the embodiment 8 being dissolved in 30ml methanol and 30ml THF 0.60g (0.123mmol) benzyl esters and 0.57g (0.139mmol) methyl esters mixture in add 30ml 1N sodium hydroxide solutions.At room temperature, stirring reaction mixture 48 hours, vacuum removes organic matter.The mixture of generation is acidified and is extracted with ethyl acetate with 10% hydrochloric acid.The organic matter merged with water and salt water washing, it is dried over sodium sulfate, filter and be concentrated in vacuo.The residue of generation provides 0.87g (84%) required carboxylic acid with hexanes trituration, is white solid.Mass spectrum：432(M+H).

Embodiment 17

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -3- chloros-benzoic acid

According to the same procedure described in embodiment 16,0.327g (84%) required carboxylic acid is obtained using the product of 0.404g (0.907mmol) embodiment 9, is white solid.Electrospray ionization mass spectrum：432(M+H).

Embodiment 18

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- bromo -3- methyl-benzoic acids

9.3ml 1N sodium hydroxide solutions are added to solution of 0.444g (0.881mmol) products of embodiment 11 in 20ml methanol/THF (1: 1), the mixture is heated to backflow 18 hours.Make that the mixture is cooled to room temperature and vacuum removes organic matter.Remaining solution is acidified and is extracted with ethyl acetate with 10% hydrochloric acid.It is dried over sodium sulfate with water and salt water washing extract, filter and be concentrated in vacuo.Residue provides 0.364g (84%) required carboxylic acid through triturated under ether, is white solid.CI mass spectrums：490(M+H).

Embodiment 19

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- methyl-benzoic acids

7.5ml (0.038mol) 5N sodium hydroxide solutions are added to solution of the product of embodiment 12 in 30ml methanol, the mixture of generation is heated to backflow 66 hours.Make that the reactant is cooled to room temperature and vacuum removes organic matter.The mixture of generation is acidified and is extracted with ethyl acetate with 10% hydrochloric acid.The organic matter merged with water and salt water washing, it is dried over sodium sulfate, filter and be concentrated in vacuo.The residue triturated under ether of generation, filtering provides 0.984g (79%) required carboxylic acid, is white solid.Electrospray ionization mass spectrum：427(M+H).

Embodiment 20

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -6- methyl-benzoic acids

According to the same procedure described in embodiment 19, using the product of 1.043g (2.08mmol) embodiment 13,0.547g (64%) required carboxylic acid is recrystallized to give from ethyl acetate/hexane, is white solid.Electrospray ionization mass spectrum：432(M+H).

Embodiment 21

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -3- methyl-benzoic acids

According to the same procedure described in embodiment 19, using the product of 0.935g (1.864mmol) embodiment 14,0.551g (72%) required carboxylic acid is obtained through hexanes trituration, is white solid.Electrospray ionization mass spectrum：412(M+H).

Embodiment 22

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- methyl-benzoic acids

According to the same procedure described in embodiment 19, but with the product of 1.931g (3.85mmol) embodiment 15, the required carboxylic acid for obtaining 1.19g (70%) is ground through dichloromethane/hexane (2: 1), is white solid.Electrospray ionization mass spectrum：412(M+H).

Embodiment 23

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-benzoyIamides

0.095ml DMF are added to solution of 0.50g (1.26mmol) products of embodiment 16 in 12.5ml dichloromethane, 0.22ml oxalyl chlorides is subsequently added into, the mixture of generation is stirred 1 hour at room temperature.

In another flask, in 0 DEG C of the mixture that 1.05ml (7.5mmol) triethylamine is added to 0.35g (5.04mmol) hydroxylamine hydrochloride in 5.5ml THF and 1.4ml water.After 0 DEG C is stirred the mixture 15 minutes, solution of acid chloride is disposably added to the solution, the solution of generation is warmed to room temperature and is stirred overnight.Then reactant mixture is acidified to pH3 with 10% hydrochloric acid and be extracted with ethyl acetate.The organic layer of merging dried over sodium sulfate, filters and is concentrated in vacuo.Crude residue triturated under ether, there is provided 0.43g (83%) required carboxylic acid, is white solid.CI mass spectrums：413(M+H).

Embodiment 24

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- chloro-N- hydroxy-benzoyIamides

According to the same procedure described in embodiment 23, but it is white solid with the hydroxamic acid needed for the product offer 0.161g (56%) of 0.280g (0.649mol) embodiment 12.Electrospray ionization mass spectrum：446(M+H).

Embodiment 25

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- bromos-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 23, but it is white solid with the hydroxamic acid needed for the product offer 0.164g (53%) of 0.303g (0.618mmol) embodiment 18.Electrospray ionization mass spectrum：505(M+H).

Embodiment 26

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-4-methyls-benzamide

According to the same procedure described in embodiment 23, but with the product of 1.20g (2.91mmol) embodiment 19, the hydroxamic acid needed for 0.984g (79%) is obtained after triturated under ether, is white solid.Electrospray ionization mass spectrum：427(M+H).

Embodiment 27

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -6- methyl-benzamides

According to the same procedure described in embodiment 23, but with the product of 0.537g (1.30mmol) embodiment 20, the hydroxamic acid needed for 0.443g (80%) is obtained after being ground through dichloromethane/hexane (1: 4), is white solid.Electrospray ionization mass spectrum：427(M+H).

Embodiment 28

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 23, but with the product of 0.398g (0.967mmol) embodiment 21, the hydroxamic acid needed for 0.348g (84%) is obtained after being ground through dichloromethane/hexane (1: 4), is white solid.Electrospray ionization mass spectrum：427(M+H).

Embodiment 29

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-5-methyls base-benzamide

According to the same procedure described in embodiment 23, but with the product of 1.00g (2.43mmol) embodiment 22, the hydroxamic acid needed for 0.761g (73%) is obtained after being ground through dichloromethane/hexane (1: 4), is white solid.Electrospray ionization mass spectrum：427(M+H).

Embodiment 30

2- amino -3- hydroxy-benzoic acid methyl esters

5.0mlBF3- methanol complex is added to the solution of the 15ml methanol of 1.0g (6.53mol) 3- hydroxyl anthranilic acids, the solution of generation is heated to backflow 24 hours.It is cooled to after room temperature, reactant mixture is poured into saturated sodium carbonate solution, is then extracted with ether.The organic matter merged with water and salt water washing, it is dried over sodium sulfate, filter and be concentrated in vacuo there is provided 0.90g (83%) required product, be brown solid.Electrospray ionization mass spectrum：167.8(M+H)+.

Embodiment 31

3- hydroxyls -2- (4- methoxy-benzenesulfonvls amino)-methyl benzoate

0.928g (4,48mmol) p- Methoxybenzenesulfonyl chloride is added to the solution of the 10.0ml piperidines of the product of 0.748g (4.48mmol) embodiment 30.Reactant mixture is stirred at room temperature 24 hours, then diluted with chloroform, with 5% hydrochloric acid solution and water washing.Organic matter is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue is ground with ether-hexane, the solid of generation is filtered and the product needed for offer 0.86g (57%) is provided, be brown solid.Electrospray ionization mass spectrum：338.2(M+H)+.

Embodiment 32

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -3- benzyloxies-methyl benzoate

According to the same procedure described in embodiment 9, but the required product of the product offer 0.60g (100%) with 0.50g (1.17mol) embodiment 31, it is colorless oil.Electrospray ionization mass spectrum：518.2(M+H)+.

Embodiment 33

2- [benzyls-(4- methoxy-benzenesulfonvls amino) -3- benzyloxies-benzoic acid

According to the same procedure described in embodiment 18,0.22g (91%) required product is provided using the product of 0.25g (0.484mol) embodiment 32, is white solid.Electrospray ionization mass spectrum：504.2(M+H)+.

Embodiment 34

2- [benzyls-(4- methoxy-benzenesulfonvls amino) -3- benzyloxy-N- hydroxy-benzoyIamides

According to the same procedure described in embodiment 23,0.16g (81%) required product is provided using the product of 0.19g (0.382mmol) embodiment 33, is white solid.Electrospray ionization mass spectrum：519.2(M+H)+.

Embodiment 35

3- (t-butyl-dimethyI-sila base epoxide (silanyloxy) -2- (4- first chloro-benzenesulfonamido-)-methyl benzoates

0.70g (1.03mmol) imidazoles and 0.075g (0.495mmol) tert-butyl dimethylsilyl chlorine are added to the 2.0ml DMF solutions of the product of 0.139g (0.412mol) embodiment 31.Reactant mixture is stirred at room temperature 3 hours, then diluted with 75ml ether.The mixture generated with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo there is provided 0.179g (96%) required product, be white solid.Electrospray ionization mass spectrum：452.2(M+H)+.

Embodiment 36

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (tert-butyl-dimethylsilyl epoxide)-methyl benzoate

According to the same procedure described in embodiment 9,0.088g (64%) required product is provided using the product of 0.114g (0.253mmol) embodiment 33, is colorless oil.Electrospray ionization mass spectrum：542.3(M+H)+.

Embodiment 37

2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -3- hydroxy-benzoic acid methyl esters

16.3ml (16.3mmol) 1M Bu are added to the 50ml THF solutions of the product of 4.42g (8.17mmol) embodiment 36₄NF/THF solution.Reactant mixture is stirred half an hour at room temperature, then diluted with ether.With 5% hydrochloric acid solution, water and salt water washing.The mixture of generation is dried over magnesium sulfate, filters and is concentrated in vacuo, and residue provides 2.81g (81%) required product with triturated under ether, is white solid.Electrospray ionization mass spectrum：428.3(M+H)+.

Embodiment 38

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- t-butoxies carbomethoxy-methyl benzoate

Sodium hydride 60% suspension of the 0.047g (1.171mmol) in mineral oil is added to the 10ml DMF solutions of 0.40g (0.94mmol) product of embodiment 37.The mixture of generation is stirred half an hour at room temperature, it is then disposable to add 0.277ml (1.873mmol) monobromo-acetic acid tert- butyl ester.It is stirred for reactant mixture 18 hours, is then diluted with ether, it is dried over magnesium sulfate with water and salt water washing, filter and be concentrated in vacuo, residue grinds the required product for providing 0.423g (83%) with ether-hexane, is white solid.Electrospray ionization mass spectrum：524.3(M+H)+.

Embodiment 39

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (2,2,2- trifluoro-ethoxy)-methyl benzoate

According to the same procedure described in embodiment 38, use the product and 0.185ml (1.873mmol) 2- iodos -1 of 0.40g (0.937mmol) embodiment 37,1,1- HFC-143a provides 0.231g (48%) required product, is colorless oil.Electrospray ionization mass spectrum：510.3(M+H)+.

Embodiment 40

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (2- Mehtoxy-ethoxies methoxyl group)-methyl benzoate

According to the same procedure described in embodiment 38,0.454g (94%) required product is provided using the product and 0.134ml (1.171mmol) MEM-Cl of 0.40g (0.937mmol) embodiment 37, is colorless oil.Electrospray ionization mass spectrum：516.2(M+H)+.

Embodiment 41

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (4- methoxycarbonyls-benzyloxy)-methyl benzoate

According to the same procedure described in embodiment 38,0.322g (87%) required product is provided using the product and 0.295ml (1.288mmol) 4- (bromomethyl) methyl benzoate of 0.275g (0.644mmol) embodiment 37, is white solid.Electrospray ionization mass spectrum：576.2(M+H)+.

Embodiment 42

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (3- ethoxy carbonyls-propoxyl group)-methyl benzoate

According to the same procedure described in embodiment 38, the required product of 0.530 (84%) is provided using the product and 0.419ml (2.927mmol) 4- bromobutyrates of 0.50g (1.171mmol) embodiment 37, is colorless oil.Electrospray ionization mass spectrum：542.3(M+H)+.

Embodiment 43

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (4- methoxycarbonyls-butoxy)-methyl benzoate

According to the same procedure described in embodiment 38,0.477g (75%) required product is provided using the product and 0.419ml (2.927mmol) 5- bromo pentane acid A esters of 0.50g (1.171mmol) embodiment 37, is white solid.Electrospray ionization mass spectrum：542.3(M+H)+.

Embodiment 44

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- isopropoxies-methyl benzoate

0.26ml (2.81mmol) 2- bromos propane and 1.16g (8.43mmol) potassium carbonate are added into the solution for the product of 0.20g (0.468mmol) embodiment 37 being dissolved in 5.0ml DMF.In 80 DEG C of heating response mixtures 18 hours, room temperature is cooled to, is diluted with ether, it is dried over sodium sulfate with water and salt water washing, filter and be concentrated in vacuo.The residue by silica gel chromatography of generation, the required product for providing 0.198g (90%) is eluted with ethylacetate-hexane (1: 3), is colorless oil.Mass spectrum：470.3(M+H).

Embodiment 45

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- (pyridin-3-yl methoxyl group)-methyl benzoate

0.409ml (2.492mmol) 3- picolyl chloride hydrochlorides and 1.03g (7.477mmol) potassium carbonate are added to the solution for the product of 0.40g (1.187mmo1) embodiment 31 being dissolved in 5.0ml DMF.Stirring reaction mixture 18 hours, are diluted with water at room temperature, are extracted with ether, then with 6N salt acid extraction organic matters, and alkalized aqueous acid layer with 6N sodium hydroxides, is extracted with ether.The ether layer of generation dried over sodium sulfate, filters and is concentrated in vacuo there is provided 0.34g (55%) required product, be brown oil.Mass spectrum：520.2(M+H)+.

Embodiment 46

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- Carboxvmethoxvs-benzoic acid

According to the same procedure described in embodiment 18,0.262g (96%) required product is provided using the product of 0.314g (0.580mmol) embodiment 38, is white solid.Electrospray ionization mass spectrum：472.1(M+H)+.

Embodiment 47

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (2,2,2- trifluoro ethoxy)-benzoic acid

According to the same procedure described in embodiment 18,0.168g (87%) required product is provided using the product of 0.20g (0.393mmol) embodiment 39, is white solid.Electrospray ionization mass spectrum：496.1(M+H)+.

Embodiment 48

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (2- Mehtoxy-ethoxies methoxyl group)-benzoic acid

According to the same procedure described in embodiment 18,0.336g (95%) required product is provided using the product of 0.363g (0.705mmol) embodiment 40, is white foam thing.Electrospray ionization mass spectrum：502.2(M+H)+.

Embodiment 49

Benzyloxy-benzoic acid

According to the same procedure described in embodiment 18,0.245g (91%) required product is provided using the product of 0.283g (0.492mmol) embodiment 41, is white solid.Electrospray ionization mass spectrum：548.1(M+H)+.

Embodiment 50

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (3- carboxyls-propoxyl group)-benzoic acid

According to the same procedure described in embodiment 18,0.260g (78%) required product is provided using the product of 0.363g (0.6710mmol) embodiment 42, is white solid.Electrospray ionization mass spectrum：498.1(M-H)-.

Embodiment 51

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (4- carboxyls-butoxy)-benzoic acid

According to the same procedure described in embodiment 18, the required product of 0.243 (79%) is provided using the product of 0.323g (0.597mmol) embodiment 43, is white solid.Electrospray ionization mass spectrum：512.1(M-H)-.

Embodiment 52

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- isopropoxies-benzoic acid

According to the same procedure described in embodiment 18,0.284g (84%) required product is provided using the product of 0.348g (0.742mmol) embodiment 44, is white solid.Electrospray ionization mass spectrum：456.3(M+H)+.

Embodiment 53

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- (pyridin-3-yl methoxyl group)-benzoic acid

0.050g (1.197mmol) lithium hydroxide monohydrate is added to the 6.0ml THF-MeOH (1: 1) of the product of 0.311g (0.599mmol) embodiment 45 solution.Then heating response mixture is concentrated in vacuo to flowing back 24 hours.With THF wash residuals thing and filter.The lithium salts that filtrate provides 0.277g (91%) title compound is concentrated in vacuo, is brown foam thing.Mass spectrum：506.2(M+H)+.

Embodiment 54

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3- Hydroxycarboamoyl methoxy-b enzamides

According to the same procedure described in embodiment 23,0.085g (75%) required product is provided using the product of 0.110g (0.234mmol) embodiment 46, is white solid.Electrospray ionization mass spectrum：502.2(M+H)+.

Embodiment 55

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (2,2,2- trifluoro ethoxy)-benzamide

According to the same procedure described in embodiment 23,0.092g (68%) required product is provided using the product of 0.131g (0.265mmol) embodiment 47, is white solid.Electrospray ionization mass spectrum：511.1(M+H)+.

Embodiment 56

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (2- Mehtoxy-ethoxies methoxyl group)-benzamide

According to the same procedure described in embodiment 23,0.228g (75%) product for needed for brown glassy is provided using the product of 0.296g (0.591mmol) embodiment 48.Electrospray ionization mass spectrum：517.2(M+H)+.

Embodiment 57

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [4- (hydroxyaminocarbonyl)-benzyloxy]-N- hydroxy-benzoyIamides

According to the same procedure described in embodiment 23,0.20g (92%) required product is provided using the product of 0.207g (0.378mmol) embodiment 49, is white solid.Electrospray ionization mass spectrum：576.0(M-H)-.

Embodiment 58

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (3- Hydroxycarboamoyls propoxyl group)-benzamide

According to the same procedure described in embodiment 23,0.195g (82%) required product is provided using the product of 0.224g (0.449mmol) embodiment 50, is white solid.Electrospray ionization mass spectrum：530.1(M+H)+.

Embodiment 59

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (4- Hydroxycarboamoyls butoxy)-benzamide

According to the same procedure described in embodiment 23,0.208g (98%) required product is provided using the product of 0.20g (0.390mmol) embodiment 51, is brown solid.Electrospray ionization mass spectrum：544.1(M+H)+.

Embodiment 60

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- isopropoxies-benzamide

According to the same procedure described in embodiment 23,0.222g (88%) required product is provided using the product of 0.245g (0.540mmol) embodiment 52, is white solid.Electrospray ionization mass spectrum：471.2(M+H)+.

Embodiment 61

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

0.10ml (1.29mmol) DMF is added in the dichloromethane solution of 0 DEG C of 2M oxalyl chloride to 0.65ml (1.29mmol), the mixture is stirred in 0 DEG C 15 minutes, then warms to room temperature and be stirred for 1 hour.Then solution of the product of 0.220g (0.43mmol) embodiment 53 in 1ml DMF is added in reactant mixture.The reactant is stirred at room temperature 1 hour.

In another flask, in 0 DEG C of the mixture that 1.35ml (9.675mmol) triethylamine is added to 0.448g (6.45mmol) hydroxylamine hydrochloride in 6.8ml THF and 1.8ml water.After 0 DEG C is stirred the mixture 15 minutes, solution of acid chloride is disposably added to the solution, the solution of generation is warmed to room temperature and is stirred overnight.Then washed with dchloromethane reactant mixture and with water and saturated sodium bicarbonate solution.Organic layer dried over sodium sulfate, filters and is concentrated in vacuo.Crude residue triturated under ether, there is provided the hydroxamic acid needed for 0.124g (55%), is white solid.Electrospray ionization mass spectrum：521.2(M+H).

Embodiment 62

2- (4- methoxy-benzenesulfonvls amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 31,11.5g (84%) required product is provided using 7.00g (0.039mol) 3,5- dimethyl artificial neroli oil, is white solid.Electrospray ionization mass spectrum：350.3(M+H)+.

Embodiment 63

2- (4- Fluoro-benzenesulfonyls amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 31, use 2.00g (0.011mol) methyl 2,5- dimethyl anthranilic acid and 2.17g (0.011mol) 4- fluoro benzene sulfonyl chloride provide 3.09g (82%) required product, are white solid.Electrospray ionization mass spectrum：338.3(M+H)+.

Embodiment 64

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9,1.065g (85%) required product is provided using the product of 1.00g (0.2.865mmol) embodiment 62, is white solid.Electrospray ionization mass spectrum：440.3(M+H)+.

Embodiment 65

2- [benzyl-(4- Fluoro-benzenesulfonyls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9,1.084g (85%) required product is provided using the product of 1.00g (0.2.865mmol) embodiment 63, is white solid.Electrospray ionization mass spectrum：428.3(M+H)+.

Embodiment 66

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 18,0.827g (91%) required product is provided using the product of 0.94g (2.141mmol) embodiment 64, is white solid.Electrospray ionization mass spectrum：426.3(M+H)+.

Embodiment 67

2- [benzyl-(4- Fluoro-benzenesulfonyls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 9,0.486g (52%) required product is provided using the product of 0.963g (2.255mmol) embodiment 65, is white solid.Electrospray ionization mass spectrum：414.3(M+H)+.

Embodiment 68

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23,0.436g (62%) required product is provided using the product of 0.683g (1.607mmol) embodiment 66, is white solid.Electrospray ionization mass spectrum：441.3(M+H)+.

Embodiment 69

2- [benzyl-(4- Fluoro-benzenesulfonyls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23,0.364g (83%) required product is provided using the product of 0.423g (1.024mmol) embodiment 67, is white solid.Electrospray ionization mass spectrum：429.3(M+H)+.

Embodiment 70

2- [benzyl-(4- butoxy-benzenesulfonyl)-amino] -3,5- dimethyl-benzoic acid butyl esters

0.429ml (4.684mmol) n-butanols and 0.187g (4.684mmol) 60% sodium hydride are added to the 10ml DMF solutions of the product of embodiment 65.Stirring reaction mixture 18 hours, make reaction all standing with 5% hydrochloric acid solution at room temperature.The mixture of generation is extracted with ether, and the organic matter of merging is washed with water, dried over magnesium sulfate, is filtered and is concentrated in vacuo.Residue by silica gel chromatography, the required product for providing 0.134g (24%) is eluted with ethylacetate-hexane (1: 10), is red oil.Electrospray ionization mass spectrum：524.4(M+H)+.

Embodiment 71

2- [benzyl-(4- butoxy-benzenesulfonyl)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 18,0.115g (97%) required product is provided using the product of 0.134g (0.256mmol) embodiment 70, is white solid.Electrospray ionization mass spectrum：468.3(M+H)+.

Embodiment 72

2- [benzyl-(4- butoxy-benzenesulfonyl)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23,0.105g (73%) required product is provided using the product of 0.139g (0.298mmol) embodiment 71, is yellow colored foam thing.Electrospray ionization mass spectrum：483.3(M+H)+.

Embodiment 73

2- [benzyl-(4- benzyloxies-benzenesulfonyl)-amino] -3,5- dimethyl-benzoic acids

0.485ml (4.684mmol) benzyl alcohols and 0.187g (4.684mmol) 60% sodium hydride are added to the 10ml DMF solutions of the product of 0.50g (1.171mmol) embodiment 65.Stirring reaction mixture 18 hours at room temperature, with 5% hydrochloric acid solution all standing.The mixture of generation is extracted with ether, and the organic matter of merging is washed with water, dried over magnesium sulfate, is filtered and is concentrated in vacuo.Residue is dissolved in 10ml methanol-THF (1: 1), add 4.7ml 1N sodium hydroxide solutions.The mixture of generation is heated to backflow 18 hours.Room temperature is subsequently cooled to, is acidified, is extracted with ethyl acetate with 5% hydrochloric acid.The organic matter merged with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Residue triturated under ether, there is provided 0.432g (74%) required product, is white solid.Electrospray ionization mass spectrum：502.3(M+H)+.

Embodiment 74

2- [benzyl-(4- butoxy-benzenesulfonyl)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23,0.347g (92%) required product is provided using the product of 0.366g (0.731mmol) embodiment 73, is white solid.Electrospray ionization mass spectrum：517.2(M+H)+.

Embodiment 75

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- hex- 1- alkynyl -3- methyl-benzoic acid methyl esters

0.088ml (0.771mmol) 1- hexins, double (triphenyl phasphine) palladium chlorides (II) of 9mg (0.013mmol) and 1.2mg cuprous iodides (I) are added to 2.0ml DMF and the 2.0ml triethylamine solution of the product of 0.324g (0.643mmol) embodiment 11.Then reactant mixture is heated to 65 DEG C 5 hours, other 0.22ml 1- hexins is added to the solution.Then reactant is heated to backflow 6 hours, is cooled to room temperature, is diluted with ether.The organic matter merged with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, the required product for providing 0.198g (61%) is eluted with ethylacetate-hexane (1: 10), is yellow oil.Electrospray ionization mass spectrum：506.3(M+H)+.

Embodiment 76

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- hex- 1- alkynyl -3- methyl-benzoic acids

According to the same procedure described in embodiment 18,0.123g (77%) required product is provided using the product of 0.165g (0.327mmol) embodiment 75, is brown solid.Electrospray ionization mass spectrum：492.2(M+H)+.

Embodiment 77

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- hex- 1- alkynyls-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 23,0.0g7g (82%) required product is provided using the product of 0.115g (0.234mmol) embodiment 76, is brown colored foams thing.Electrospray ionization mass spectrum：507.3(M+H)+.

Embodiment 78

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- acetenyl -3- methyl-benzoic acid methyl esters

0.39ml (0.2.748mmol) trimethylsilanylethyn, double (triphenyl phasphine) palladium chlorides (II) of 19mg (0.027mmol) and 2.6mg cuprous iodides (I) are added to 2.0ml DMF and the 2.0ml triethylamine solution of the product of 0.277g (0.550mmol) embodiment 11.Then reactant mixture is heated to 65 DEG C 2 hours, is cooled to room temperature, is diluted with ether.It is dried over magnesium sulfate with 5% hydrochloric acid, water and salt water washing organic matter, filter and be concentrated in vacuo.Residue is dissolved in 5ml THF, add 1ml 1M tetrabutyl ammonium fluorides-THF solution.The reactant is stirred at room temperature 1 hour, diluted with ether.It is dried over magnesium sulfate with 5% hydrochloric acid, water and salt water washing organic matter, filter and be concentrated in vacuo.Residue by silica gel chromatography, the required product for providing 0.197g (80%) is eluted with ethylacetate-hexane (1: 10), is white foam thing.Electrospray ionization mass spectrum：450.3(M+H)+.

Embodiment 79

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- acetenyl -3- methyl-benzoic acids

According to the same procedure described in embodiment 18,0.161g (94%) required product is provided using the product of 0.177g (0.394mmol) embodiment 78, is brown solid.Electrospray ionization mass spectrum：436.2(M+H)+.

Embodiment 80

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- acetenyls-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 23,0.116g (82%) required product is provided using the product of 0.136g (0.313mmol) embodiment 79, is brown colored foams thing.Electrospray ionization mass spectrum：451.3(M+H)+.

Embodiment 81

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

0.514g (3.134mmol) 3- picolyl chloride hydrochlorides and 1.30g (9.50mmol) potassium carbonate are added to the 7.5ml DMF solutions of the product of 1.00g (2.985mmol) embodiment 3.Stirring reaction mixture 18 hours, then add 0.051g 3- picolyl chloride hydrochlorides and 0.130g potassium carbonate, at room temperature stirring reaction mixture 18 hours at room temperature.The reactant is diluted with water, is extracted with ether.With the organic layer of 6N hydrochloric acid extraction mergings, alkalized aqueous acid layer with 6N sodium hydroxides, is then extracted with ether, the ether layer of generation dried over sodium sulfate, filter and be concentrated in vacuo, 1.058g (83%) required product is provided with triturated under ether residue, is white solid.Electrospray ionization mass spectrum：427.3(M+H)+.

Embodiment 82

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

0.091g (1.197mmol) lithium hydroxide monohydrate is added to the solution of the 10ml THF- water (1: 1) of the product of 0.924g (2.169mmol) embodiment 81.Heating response mixture is subsequently cooled to room temperature, washed with ether to flowing back 48 hours.Then water layer is concentrated in vacuo there is provided the lithium salts of 0.894g (100%) title compound, is white solid.Electrospray ionization mass spectrum：413.2(M+H)+.

Embodiment 83

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

0.307ml (3.966mmol) DMF is added in the dichloromethane solution of 0 DEG C of 2M oxalyl chloride to 1.98ml (3.966mmol), the mixture is stirred in 0 DEG C 15 minutes, then warms to room temperature and be stirred for 1 hour.Then solution of the product of 0.829g (1.983mmol) embodiment 82 in 1ml DMF is added in reactant mixture.The reactant is stirred at room temperature 1 hour.

In another flask, 4.14ml (0.030mol) triethylamine is added in 0 DEG C of the mixture in 19.5ml THF and the 5.6ml water of 1.378g (0.020mmol) hydroxylamine hydrochloride.After 0 DEG C is stirred the mixture 15 minutes, solution of acid chloride is disposably added to the solution, the solution of generation is warmed to room temperature and is stirred overnight.Then washed with dchloromethane reactant mixture and with water and saturated sodium bicarbonate solution.Organic layer dried over sodium sulfate, filters and is concentrated in vacuo.Crude residue is ground there is provided 0.414g (51%) title compound with ethyl acetate-ethyl ether, is white solid.

In the solution for the room temperature that 0.27ml 4M hydrochloric acid-diethyl ether solution is added to 0.403g (0.976ml) hydroxamic acid in 10ml methylene chloride-methanols (30: 1).Stirring reaction mixture 0.5 hour, is collected by filtration the precipitation of generation, and vacuum drying provides the hydrochloride of 0.439g (100%) title compound, is white solid.Electrospray ionization mass spectrum：428.2(M+H)+.

Embodiment 84

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzoic acid

0.514g (3.134mmol) 3- picolyl chloride hydrochlorides and 1.30g (9.50mmol) potassium carbonate are added to the 7.5ml DMF solutions of the product of 0.958g (2.985mmol) embodiment 1.Stirring reaction mixture 18 hours, then add 0.051g 3- picolyl chloride hydrochlorides and 0.130g potassium carbonate, at room temperature stirring reaction mixture 18 hours at room temperature.The reactant is diluted with water, is extracted with ether.With the organic layer of 6N hydrochloric acid extraction mergings, alkalized aqueous acid layer with 6N sodium hydroxides, is then extracted with ether, the ether layer of generation dried over sodium sulfate, filter and be concentrated in vacuo, the sodium salt of 0.843g (69%) title compound is provided with triturated under ether residue, is pink solid.

0.093g lithium hydroxide monohydrates are added to the solution of the 10ml THF- water (1: 1) of 0.830g (2.015mmol) above-mentioned product.Heating response mixture is subsequently cooled to room temperature to flowing back 48 hours.Reactant mixture is concentrated in vacuo there is provided the lithium salts of 0.813g (100%) title compound, is white solid.Electrospray ionization mass spectrum：399.2(M+H)+.

Embodiment 85

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzamide

According to the same procedure described in embodiment 83, the hydrochloride of 0.450g (62%) title compound is provided using the product of 0.618g (1.530mmol) embodiment 84, is brown solid.Electrospray ionization mass spectrum：414.2(M+H)+.

Embodiment 86

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 81,0.932g (74%) required product is provided using the product of 1.00g (2.865mmol) embodiment 62, is brown solid.Electrospray ionization mass spectrum：441.3(M+H)+.

Embodiment 87

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 82,0.753g (96%) required product is provided using the product of 0.810g (1.841mmol) embodiment 86, is brown colored foams thing.Electrospray ionization mass spectrum：427.3(M+H)+.

Embodiment 88

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 83, the hydrochloride of 0.377g (62%) title compound is provided using the product of 0.645g (1.514mmol) embodiment 87, is white solid.Electrospray ionization mass spectrum：442.3(M+H)+.

Embodiment 89

5- bromos -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 81,0.961g (79%) required product is provided using the product of 1.00g (2.415mmol) embodiment 10, is brown solid.Electrospray ionization mass spectrum：505.2(M+H)+.

Embodiment 90

5- bromos -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

According to the same procedure described in embodiment 82, the lithium salts of 0.837g (100%) title compound is provided using the product of 0.861g (1.708mmol) embodiment 89, is brown solid.Electrospray ionization mass spectrum：491.1(M+H)+.

Embodiment 91

5- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

According to the same procedure described in embodiment 83, the hydrochloride of 0.407g (56%) title compound is provided using the product of 0.767g (1.546mmol) embodiment 90, is white solid.Electrospray ionization mass spectrum：506.2(M+H)+.

Embodiment 92

3- (4- methoxy-benzenesulfonvls amino)-naphthalene -2- formic acid

According to the same procedure described in embodiment 4, with 2.5g (13.4mmol) 3- amino -2- naphthoic acids, the sulfonamide needed for 2.49g (52%) is provided after being ground through ethyl acetate/hexane, is brown solid.Electrospray ionization mass spectrum：358(M+H)+.

Embodiment 93

3- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-naphthalene -2- formic acid

According to the same procedure described in embodiment 12, the product of 1.2g (3.36mmol) embodiment 92 is obtained being dissolved in the brown oil of dioxane (20ml) and handled with 2N sodium hydrate aqueous solutions.The solution of generation is heated in 80 DEG C 3 days.1N aqueous hydrochloric acid solutions are added, is extracted with ethyl acetate, is dried and be concentrated in vacuo with magnesium sulfate, then by silica gel chromatography (hexane/ethyl acetate/HOAc) is obtained as the carboxylic acid (0.81g, 54%) needed for white solid.Electrospray ionization mass spectrum：448(M+H)+.

Embodiment 94

3- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-naphthalene -2- formic acid hydroxy amides

According to the same procedure described in embodiment 23, the hydroxamic acid needed for 0.155g (75%) is provided using the product of 200mg (0.45mmol) embodiment 94, is white powder.Electrospray ionization mass spectrum：463(M+H)+.

Embodiment 95

3- methoxyl groups -2- (4- methoxy-benzenesulfonvls amino)-benzoic acid

According to the same procedure described in embodiment 4, with 2.14g (12.8mmol) 2- amino -3- methoxy benzoic acids, through dichloromethane: the sulfonamide needed for 2.08g (48%) is provided after hexane (1: 2) grinding, is beige solid.CI mass spectrums：338.0(M+H)+.

Embodiment 96

4- chloros -2- (4- methoxy-benzenesulfonvls amino) -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 1, but with 0.5g (2.5mmol) 3- methyl -4- chloroanthranilic acid methyl esters, the sulfonamide needed for 0.56g (61%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：370.2(M+H).

Embodiment 97

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- methoxy-benzoic acid benzyl esters

According to the same procedure described in embodiment 12, with the product of 1.73g (5.14mmol) embodiment 95, by silica gel chromatography, with the product needed for offer 2.01g (75%) after dichloromethane eluent, is white solid.CI mass spectrums：518.1(M+H).

Embodiment 98

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- chloro -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, but with the product of 0.5g (1.35mmol) embodiment 96, the product needed for 0.566g (80%) is provided after hexanes trituration, is white solid.Electrospray ionization mass spectrum：460.2(M+H).

Embodiment 99

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- methoxy-benzoic acids

According to the same procedure described in embodiment 19, with the product of 1.86g (3.6mmol) embodiment 97, through dichloromethane: the carboxylic acid needed for 1.39g (90%) is provided after hexane (1: 4) grinding, is white solid.CI mass spectrums：428.1(M+H).

Embodiment 100

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- chloro -3- methyl-benzoic acids

Methanol is replaced according to the same procedure described in embodiment 19, but with methanol and THF mixture, is white solid by the carboxylic acid needed for offer 0.454g (93%) after the product triturated under ether of 0.506g (1.1mmol) embodiment 98.Electrospray ionization mass spectrum：446.1(M+H).

Embodiment 101

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methoxies-benzamide

According to the same procedure described in embodiment 23, the hydroxamic acid needed for 1.11g (86%) is provided using the product of 1.25g (2.91mmol) embodiment 99, is white solid.CI mass spectrums：443.1(M+H).

Embodiment 102

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- chloros-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 23, but with the product of 0.4g (0.9mmol) embodiment 100, by silica gel chromatography, with ethyl acetate: hexane: the hydroxamic acid needed for 0.273g (66%) is provided after acetic acid (1.0: 1.5: 0.5) elution, is white solid.Electrospray ionization mass spectrum：461.2(M+H).

Embodiment 103

2- [(4- methoxy-benzenesulfonvls)-(3- methyoxy-benzyls)-amino] -3,5- dimethyl-benzoic acid methyl esters

0.096g (2.4mmol) 60% sodium hydride is added to the 5ml DMF solutions of the product of 0.699g (2.0mmol) embodiment 62.The mixture half an hour of generation is stirred at room temperature, then adds 0.376g (2.4mmol) m- methoxy-benzyl chlorine and 0.089g (0.24mmol) tetrabutylammonium iodide.Stirring reaction mixture 18 hours, are poured into water at room temperature, are then extracted with ether, the organic matter merged with water and salt water washing, dried over magnesium sulfate, filter and are concentrated in vacuo.Crude solid provides 0.768g (82%) required product with hexanes trituration, is white solid.Electrospray ionization mass spectrum：470.3(M+H).

Embodiment 104

2- [(4- methoxy-benzenesulfonvls)-(2,3,4,5,6- five fluoro- benzyl)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, with the product and 0626g (2.4mmol) PFBBR bromine of 0.699g (2.0mmol) embodiment 62, through hexanes trituration and preparative TLC, it is white solid with the product needed for offer 1.04g (98%) after dichloromethane eluent.Electrospray ionization mass spectrum：530.1(M+H)+.

Embodiment 105

2- [(4- methoxy-benzenesulfonvls)-propyl-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, with the product and 0.295g (2.4mmol) 1- bromo propane of 0.699g (2.0mmol) embodiment 62, through preparative TLC, with 1: 3 ethyl acetate: the product needed for 0.691g (88%) is provided after Hex, is yellow jelly.Electrospray ionization mass spectrum：392.2(M+H)+.

Embodiment 106

2- [2- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, with the product and 0.6g (2.4mmol) 2- bromobenzyl bromides of 0.699g (2.0mmol) embodiment 62, product needed for 0.761g (73%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：518.1(M+H).

Embodiment 107

2- [3- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, with the product and 0.6g (2.4mmol) m- bromobenzyl bromide of 0.699g (2.0mmol) embodiment 62, product needed for 0.954g (92%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：518.1(M+H).

Embodiment 108

2- [(4- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, with the product and 0.6g (2.4mmol) p- bromobenzyl bromide of 0.699g (2.0mmol) embodiment 62, product needed for 0.896g (86%) is provided after hexane/triturated under ether, is white solid.Electrospray ionization mass spectrum：518.1(M+H).

Embodiment 109

2- [(4- methoxy-benzenesulfonvls)-(3- methyoxy-benzyls)-amino] -3,5- dimethyl-benzoic acids

6.5ml 1N sodium hydroxide solutions are added to the 6.5ml methanol and 6.5ml THF solutions of the product of 0.610g (1.3mmol) embodiment 103.Reaction mixture refluxed 18 hours, vacuum removes organic matter.The mixture of generation is diluted with water, uses 3N acetic acids, is extracted with ethyl acetate.The organic matter merged with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo.The residue triturated under ether of generation, filtering provides 0.417g (79%) required carboxylic acid, is white solid.Electrospray ionization mass spectrum：456.3(M+H).

Embodiment 110

2- [(4- methoxy-benzenesulfonvls)-(2,3,5,6- tetra- fluoro- 4- methyoxy-benzyls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 109, with the product of 0.737g (1.39mmol) embodiment 104, the p- methoxyl group tetrafluorobenzyl derivatives of N- of the carboxylic acid after triturated under ether needed for offer 0.49g (67%).Electrospray ionization mass spectrum：528.1(M+H).

Embodiment 111

2- [(4- methoxy-benzenesulfonvls)-propyl-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 109, with the product of 0.602g (1.54mmol) embodiment 105, the carboxylic acid needed for 0.461g (79%) is provided after being ground through ether/hexane, is white solid.Electrospray ionization mass spectrum：378.2(M+H).

Embodiment 112

2- [(2- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 109, with the product of 0.518g (1.0mmol) embodiment 106, the carboxylic acid needed for 0.4g (79%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：504.0(M+H).

Embodiment 113

2- [(3- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 109, with the product of 0.894g (1.725mmol) embodiment 107, the carboxylic acid needed for 0.61g (70%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：506.0(M+H).

Embodiment 114

2- [(4- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 109, with the product of 0.836g (1.61mmol) embodiment 108, the carboxylic acid needed for 0.584g (72%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：504(M+H).

Embodiment 115

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-(3- methyoxy-benzyls)-amino] -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, with the product of 0.364g (0.8mmol) embodiment 109, the hydroxamic acid needed for 0.245g (65%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：471.3(M+H).

Embodiment 116

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-(2,3,5,6- tetra- fluoro- 4- methyoxy-benzyls)-amino] -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, with the product of 0.369g (0.7mmol) embodiment 110, the hydroxamic acid needed for 0.253g (67%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：543.1(M+H).

Embodiment 117

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-propyl-amino] -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, with the product of 0.377g (1.0mmol) embodiment 111, the hydroxamic acid needed for 0.294g (75%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：393.2(M+H).

Embodiment 118

2- [(2- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, with the product of 0.353g (0.7mmol) embodiment 112, the hydroxamic acid needed for 0.205g (56%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：519.1(M+H).

Embodiment 119

2- [(3- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, with the product of 0.546g (1.08mmol) embodiment 113, the hydroxamic acid needed for 0.397g (71%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：517.0(M+H).

Embodiment 120

2- [(4- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, with the product of 0.521g (1.03mmol) embodiment 114, the hydroxamic acid needed for 0.333g (62%) is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：517.0(M+H).

Embodiment 121

N- benzyl -4- methoxy-benzenesulfonamides

At room temperature, 11.365ml (0.055mol) 4- Methoxybenzenesulfonyl chlorides are slowly added to the 80ml dichloromethane solutions of 5.358g (0.05mol) benzyl amine and 7.755g (0.06mol) DIPEA.Stirring reaction mixture 18 hours, are diluted with water at room temperature.Organic layer is separated, it is dried over magnesium sulfate with sodium acid carbonate, water, salt water washing, filter and concentrate.Make residue in dichloromethane: seethed with excitement in hexane (1: 4), cool down and filter there is provided 11.79g (85%) required product, be Off-white solid.

Embodiment 122

N- benzyls-N- (2- cyano group -6- trifluoromethyl-phenyls) -4- methoxy-benzenesulfonamides

0.484g (12.1mmol) 60% sodium hydride is added to the 15ml DMF solutions of the product of 3.05g (11.0mmol) embodiment 121.The mixture half an hour of generation is stirred at room temperature, 2- fluoro -3- (trifluoromethyl) cyanophenyl (1.89g, 10.0mmol) then added in 2ml DMF.In 90 DEG C of stirring reaction mixtures 18 hours, it is poured into water, is extracted with ether.The organic matter merged with water, salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Crude solid triturated under ether, there is provided 3.33g (75%) required product, is white solid.Electrospray ionization mass spectrum：447.2(M+H).

Embodiment 123

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- triflooromethyl-benzamides

8ml5N sodium hydroxide solution is added to the 30ml n-propanols solution of the product of 1.78g (4.0mmol) embodiment 122.The mixture of generation is set to flow back 66 hours and concentrate.Make residue that the required acid amides for providing 1.725g (93%) is stirred and filtered in water, be white solid.Electrospray ionization mass spectrum：465.2(M+H).

Embodiment 124

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- Trifluoromethyl-benzoic acids

0.068g (0.58mmol) tetrafluoro boric acid Nitrosonium ion is added in the suspension of 2.5ml anhydrous acetonitriles to the product of 0.192g (0.41mmol) embodiment 123.Stir the solution of generation 1 hour, then add the same reagents of 0.040g (0.34mmol) and be stirred for 1 hour.Make reaction all standing with water, filtering provides 0.141g (74%) required carboxylic acid, is white solid.Electrospray ionization mass spectrum：466.2(M+H).

Embodiment 125

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3- triflooromethyl-benzamides

According to the same procedure described in embodiment 23, the hydroxamic acid needed for 0.79g (45%) is provided with the product of 0.17g (0.365mmol) embodiment 124, is Off-white solid.Electrospray ionization mass spectrum：481.1(M+H).

Embodiment 126

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, the product needed for 0.3g (96%) is provided using the product and 0.08ml (1.289mmol) iodomethane of 0.30g (0.860mmol) embodiment 62, is white solid.Electrospray ionization mass spectrum：364.3(M+H).

Embodiment 127

2- [ethyl-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, the product needed for 0.324g (100%) is provided using the product and 0.103ml (1.289mmol) iodic ether of 0.30g (0.860mmol) embodiment 62, is white solid.Electrospray ionization mass spectrum：378.2(M+H).

Embodiment 128

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 18, the product needed for 0.23g (89%) is provided using the product of 0.267g (0.738mmol) embodiment 126, is white solid.Electrospray ionization mass spectrum：350.1(M+H).

Embodiment 129

2- [ethyl-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 18, the product needed for 0.207g (84%) is provided using the product of 0.254g (0.674mmol) embodiment 127, is white solid.Electrospray ionization mass spectrum：364.2(M+H).

Embodiment 130

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethvl-benzamides

It is white solid with the product of 0.194g (0.557mmol) embodiment 128 there is provided the hydroxamic acid needed for 0.140g (69%) according to the same procedure described in embodiment 23.Electrospray ionization mass spectrum：365.3(M+H).

Embodiment 131

2- [ethyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23, the product needed for 0.142g (78%) is provided using the product of 0.175g (0.482mmol) embodiment 129, is white solid.Electrospray ionization mass spectrum：379.2(M+H).

Embodiment 132

2- amino -5- bromo -3- methyl-benzoic acids

1.6g (10mmol) bromine is added into the mixture of the 50ml glacial acetic acid of 1.5g (10mmol) 3- methyl-2-amino benzoic acid benzyl amine.The mixture of generation is stirred at room temperature 5 hours, then reactant mixture is poured into water, filter the solid of precipitation, be brown solid using water washing and the air-dried required product for providing 2.2g (95%).Electrospray ionization mass spectrum：232(M+H).

Embodiment 133

2- amino -5- bromo -3- methyl-benzoic acid methyl esters

To 20ml 50%BF₃The product of 2.3g (10mmol) embodiment 132 is added in-methanol complex.The mixture is heated to backflow 48 hours.Room temperature is subsequently cooled to, is concentrated in vacuo, is diluted with frozen water, is neutralized with 1N sodium hydroxide solutions.The mixture of generation is extracted with chloroform.The organic matter of merging is washed with water, it is dried over magnesium sulfate, filter and be concentrated in vacuo there is provided 2.3g (93%) required product, be brown semi solid.Electrospray ionization mass spectrum：246(M+H).

Embodiment 134

5- bromos -2- (4- methoxy-benzenesulfonvls amino) -3- methyl-benzoic acid methyl esters

21.0g (100mmol) p- Methoxybenzenesulfonyl chloride is added to the agitating solution of the 100ml piperidines of the product of 24.5g (100mmol) embodiment 133, the mixture of generation is heated to 80 DEG C 24 hours.Then reactant mixture is quenched with cold water, is acidified with concentrated hydrochloric acid.The mixture of generation is extracted with chloroform, is washed with water, is dried with magnesium sulfate, filter and be concentrated in vacuo.Triturated under ether residue is used, filters and dries there is provided the product needed for 35g (84%), be brown solid.Electrospray ionization mass spectrum：416(M+H)+.

Embodiment 135

3- bromos -2- (4- methoxy-benzenesulfonvls amino) -5- methyl-benzoic acid methyl esters

2.1g (10mmol) p- Methoxybenzenesulfonyl chloride is added to the solution of the 20ml piperidines of 2.4g (10mmol) 2- amino -3- bromo -5- methyl toluates.Reactant mixture is heated to 70 DEG C 16 hours, is then poured into frozen water, it is 2 that pH is acidified to concentrated hydrochloric acid.The mixture of generation is extracted with chloroform, is washed with water, is dried with anhydrous magnesium sulfate, filter and be concentrated in vacuo.Triturated under ether residue is used, filters and dries there is provided the product needed for 3.8g (92%), be brown solid.m.p.113℃.Electrospray ionization mass spectrum：416(M+H)+.

Embodiment 136

3- bromos -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl-benzoic acid methyl esters

1.0g (10mmol) potassium carbonate and 1.1g (7.2mmol) 3- picolyl chloride hydrochlorides are added to the 20ml DMF of the product of 2.0g (4.8mmol) embodiment 135 agitating solution.Stirring reaction mixture 48 hours, are then diluted with water at room temperature.The mixture of generation is extracted with chloroform, the organic matter of merging is washed with water, it is dried over magnesium sulfate, filter and be concentrated in vacuo, the residue by silica gel chromatography of generation, with ethyl acetate: hexane (1: 1) is eluted, 2.90g (82%) required product is provided, is brown oil.Electrospray ionization mass spectrum：508(M+H).

Embodiment 137

3- bromos -2- [(4- methoxy-benzenesulfonvls-pyridin-3-yl methyl)-amino] -5- methyl-benzoic acids

It is white powder there is provided the product needed for 0.90g (91%) with acetic acid neutralization reaction mixture and after being extracted with ethyl acetate using the product of 1.01g (2mmol) embodiment 136 according to the same procedure described in embodiment 16.m.p.198℃.Electrospray ionization mass spectrum：494(M+H).

Embodiment 138

3- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl-benzamides

According to the same procedure described in embodiment 23, using the product of 0.986g (2mmol) embodiment 137, there is provided the title compound of 0.61g (60%).Corresponding hydrochloride can be prepared with quantitative yield into the solution of the methanolizing of free alkali by blasting hydrogen chloride gas, yellow fluffy shape solid is provided through being concentrated in vacuo reactant mixture after.m.p.87℃.Electrospray ionization mass spectrum：509(M+H).

Embodiment 139

2- (4- methoxy-benzenesulfonvls amino) -3- methyl -5- thiophene -2- bases-methyl benzoate

3.54g (10mmol) 2- thienyls tributyl tin and 0.50g tetra- (triphenyl phasphine) palladium are added to the solution of the 200ml degassed toluenes of the product of 3.0g (7.2mmol) embodiment 134, the mixture of generation is flowed back 16 hours.Then reactant mixture is filtered by diatomite and is concentrated in vacuo filtrate.Residue by silica gel chromatography, uses 30% ethyl acetate: Hex provides 2.5g (83%) required product, is gray solid.m.p.91℃.Electrospray ionization mass spectrum：417(M+H).

Embodiment 140

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- thiophene -2- bases-methyl benzoate

According to the same procedure described in embodiment 136, the product needed for 0.920g (78%) is provided using the product of 0.832g (2.0mmol) embodiment 139, is brown oil.Electrospray ionization mass spectrum：509(M+H).

Embodiment 141

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- thiophene -2- bases-benzoic acid

According to the same procedure described in embodiment 18, the product needed for 0.70g (94%) is provided using the product of 0.800g (1.5mmol) embodiment 140, is white solid.m.p.191℃.Electrospray ionization mass spectrum：495(M+H).

Embodiment 142

2- (4- methoxy-benzenesulfonvls amino) -5- methyl -3- thiophene -2- bases-methyl benzoate

According to the same procedure described in embodiment 39, with the product of 3.0g (7.2mmol) embodiment 135, by silica gel chromatography uses 30% ethyl acetate: Hex, there is provided 2.0g (66%) required product, is gray solid.m.p.141℃.Electrospray ionization mass spectrum：418(M+H).

Embodiment 143

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3- thiophene -2- bases-methyl benzoate

According to the same procedure described in embodiment 136, using the product of 2.0g (4.8mmol) embodiment 142, by silica gel chromatography uses 50% ethyl acetate: Hex, there is provided 2.1g (87%) required product, is brown oil.Electrospray ionization mass spectrum：509(M+H).

Embodiment 144

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3- thiophene -2- bases-benzoic acid

According to the same procedure described in embodiment 16, product using 1.5g (2.9mmol) embodiment 143 is used as raw material, it is white powder through being eluted with acetic acid neutralization reaction mixture and with ethyl acetate there is provided 1.3g (86%) required product.m.p.67℃.Electrospray ionization mass spectrum：495(M+H).

Embodiment 145

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3- thiophene -2- bases-benzamide

According to the same procedure described in embodiment 23, using the product of 1.0g (2.02mmol) embodiment 144, there is provided the title compound of 0.70g (63%).Corresponding hydrochloride can be prepared with quantitative yield into the solution of the methanolizing of free alkali by blasting hydrogen chloride gas, yellow fluffy shape solid is provided through being concentrated in vacuo reactant mixture after.m.p.94℃.Electrospray ionization mass spectrum：547(M+H).

Embodiment 146

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, the product alkylation of 0.30g (0.860mmol) embodiment 62 is obtained 0.30g (96%) required product with methyl iodide, be white solid.Electrospray ionization mass spectrum：364(M+H).

Embodiment 147

2- [ethyl-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acid methyl esters

According to the same procedure described in embodiment 9, the product alkylation of 0.30g (0.860mmol) embodiment 62 is obtained 0.324g (100%) required product with ethyl iodide, be white solid.Electrospray ionization mass spectrum：378(M+H).

Embodiment 148

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 18,0.23g (89%) required product is obtained using the product of 0.267g (0.378mmol) embodiment 146, is white solid.Electrospray ionization mass spectrum：350(M+H).

Embodiment 149

2- [ethyl-(4- methoxy-benzenesulfonvls)-amino] -3,5- dimethyl-benzoic acids

According to the same procedure described in embodiment 18,0.207g (84%) required product is obtained using the product of 0.254g (0.674mmol) embodiment 147, is white solid.Electrospray ionization mass spectrum：364(M+H).

Embodiment 150

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23,0.140g (69%) required product is obtained using the product of 0.194g (0.557mmol) embodiment 148, is pink solid.Electrospray ionization mass spectrum：365(M+H).

Embodiment 151

2- [ethyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the same procedure described in embodiment 23,0.142g (78%) required product is obtained using the product of 0.175g (0.482mmol) embodiment 149, is white solid.Electrospray ionization mass spectrum：379(M+H).

Embodiment 152

3,4,5- trimethoxy -2- (4- methoxy-benzenesulfonvls amino)-methyl benzoate

According to the same procedure described in embodiment 31, using 2.0g (8.289mmol) methyl -3,4,5- trimethyl anthranilic acid esters obtain the required product of 1.945 (57%), are white solid.Electrospray ionization mass spectrum：412(M+H).

Embodiment 153

3,4,5- trimethoxy -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-methyl benzoate

According to the same procedure described in embodiment 45,0.716g (98%) required product is obtained using the product of 0.60g (1.46mmol) embodiment 152, is brown oil.Electrospray ionization mass spectrum：503(M+H).

Embodiment 154

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3,4,5- trimethoxies-methyl benzoate

According to the same procedure described in embodiment 9,0.669g (92%) required product is obtained using the product of 0.60g (1.46mmol) embodiment 152, is white solid.Electrospray ionization mass spectrum：502(M+H).

Embodiment 155

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3,4,5- trimethoxies-benzoic acid

According to the same procedure described in embodiment 18,0.532g (92%) required product is obtained using the product of 0.594g (1.186mmol) embodiment 154, is white solid.Electrospray ionization mass spectrum 488 (M+H).

Embodiment 156

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,4,5- trimethoxy-benzamides

According to the same procedure described in embodiment 23,0.353g (74%) required product is obtained using the product of 0.463g (0.951mmol) embodiment 155, is white solid.Electrospray ionization mass spectrum：503(M+H).

Embodiment 157

3,4,5- trimethoxy -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzoic acid

According to the same procedure described in embodiment 53,0.631g (100%) required product is obtained using the product of 0.640g (1.275mmol) embodiment 153, is brown colored foams thing.Electrospray ionization mass spectrum：489(M+H).

Embodiment 158

N- hydroxyls -3,4,5- trimethoxies -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzamide

According to the same procedure described in embodiment 61,0.395g (71%) required product is obtained using the product of 0.549g (1.109mmol) embodiment 157, is brown foam thing.Electrospray ionization mass spectrum：504(M+H).

Embodiment 159

12- [(4- benzyloxies-benzenesulfonyl) -11,12- dihydro -6H- dibenzo [b, f] [Isosorbide-5-Nitrae] oxazocine-1- methyl formates

0.104g (2.596mmol) 60% sodium hydride is added to the 35ml DMF solutions of the product of 0.350g (1.039mmol) embodiment 31.The solution is stirred at room temperature 15 minutes.Then 0.384g (1.454mmol) a, a '-two bromo-ortho-xylene is added into the mixture of the generation, reactant mixture is heated to 80 DEG C 18 hours, room temperature is cooled to, is diluted with ether, is washed with water, the organic layer of merging dried over magnesium sulfate, filters and is concentrated in vacuo.The residue by silica gel chromatography of generation, the required product for providing 0.358g (79%) is eluted with ethyl acetate/hexane (1: 3), is white solid.Electrospray ionization mass spectrum：440(M+H).

Embodiment 160

Tetrahydrochysene -2H-1, the 6-benzoxazocine-7- methyl formates of 6- (4- methoxy-benzenesulfonvls) -3,4,5,6-

According to the same procedure described in embodiment 159, use the product and 0.198ml (1.662mmol) 1 of 0.400g (1.187mmol) embodiment 31,4- dibromobutanes provide 0.139g (30%) required product, are white solid.Electrospray ionization mass spectrum：392(M+H).

Embodiment 161

5- (4- methoxy-benzenesulfonvls) -2,3,4,5- tetrahydrochysenes-[1,5] benzoxazepine-6- methyl formates

According to the same procedure described in embodiment 159, use the product and 0.127ml (1.246mmol) 1 of 0.300g (0.890mmol) embodiment 31, the bromo propane of 3- bis- provides 0.156g (46%) required product, is colorless oil.Electrospray ionization mass spectrum：378(M+H).

Embodiment 162

Tetrahydrochysene -1, the 5-benzoxazepine-6- formic acid of 5- (4- methoxy-benzenesulfonvls) -2,3,4,5-

According to the same procedure described in embodiment 18,0.133g (79%) required product is provided using the product of 0.174g (0.462mmol) embodiment 161, is white solid.Electrospray ionization mass spectrum：364(M+H).

Embodiment 163

12- (4- methoxy-benzenesulfonvls) -11,12- dihydro -6H- dibenzo [b, f] [Isosorbide-5-Nitrae] oxazocine-1- formic acid

According to the same procedure described in embodiment 18,0.261g (88%) required product is provided using the product of 0.306g (0.697mmol) embodiment 159, is white solid.Electrospray ionization mass spectrum：426(M+H).

Embodiment 164

Tetrahydrochysene -2H-1, the 6-benzoxazocine-7- formic acid of 6- (4- methoxy-benzenesulfonvls) -3,4,5,6-

According to the same procedure described in embodiment 18,0.106g (88%) required product is provided using the product of 0.125g (0.320mmol) embodiment 160, is white solid.Electrospray ionization mass spectrum：378(M+H).

Embodiment 165

Tetrahydrochysene -1, the 5-benzoxazepine-6- formic acid hydroxy amides of 5- (4- methoxy-benzenesulfonvls) -2,3,4,5-

According to the same procedure described in embodiment 23,0.100g (90%) required product is provided using the product of 0.107g (0.295mmol) embodiment 162, is white solid.Electrospray ionization mass spectrum：379(M+H).

Embodiment 166

12- (4- methoxy-benzenesulfonvls) -11,12- dihydro -6H- dibenzo [b, f] [Isosorbide-5-Nitrae] oxazocine-1- formic acid hydroxy amides

According to the same procedure described in embodiment 23,0.192g (81%) required product is provided using the product of 0.230g (0.541mmol) embodiment 163, is white solid.Electrospray ionization mass spectrum：441(M+H).

Embodiment 167

Tetrahydrochysene -2H-1,6-benzoxazocine-7- the formic acid hydroxy amides of 6- (4- methoxy-benzenesulfonvls) -3,4,5,6-

According to the same procedure described in embodiment 23,0.074g (88%) required product is provided using the product of 0.081g (0.215mmol) embodiment 164, is white solid.Electrospray ionization mass spectrum：393(M+H).

Embodiment 168

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- nitro-benzoic acid methyl esters

In 0 DEG C, the mixture of solution dropwise addition 17.5ml acetic anhydrides, 22.5ml 70% nitric acid and the 15.75ml acetic acid of 131ml acetic anhydrides was suspended in the product of 29.5g (0.092mol) embodiment 1 with 1 hour.The reactant is stirred in 0 DEG C 2 hours, be then poured into frozen water.Filtering precipitate is simultaneously washed with ether.Filtrate is transferred to separatory funnel, each layer is separated.Chloroform water layer is used, the organic layer of merging dried over magnesium sulfate is filtered and is concentrated in vacuo.Residue by silica gel chromatography, the nitro-sulfonamide for providing 1.03g (79%) is eluted with ethyl acetate/hexane (1: 10), is yellow solid.

0.250g (0.683mmol) sulfonamide is provided 0.215g (69%) required product with sodium hydride and benzyl bromine reaction according to the same procedure described in embodiment 9, be faint yellow solid.Electrospray ionization mass spectrum：457(M+H).

Embodiment 169

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- Nitro-benzoic acids

According to the same procedure described in embodiment 18,0.172g (89%) required product is provided using the product of 0.199g (0.463mmol) embodiment 168, is faint yellow solid.Electrospray ionization mass spectrum：443(M+H).

Embodiment 170

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3- nitro-benzamides

According to the same procedure described in embodiment 23,0.106g (75%) required product is provided using the product of 0.136g (0.308mmol) embodiment 169, is brown colored foams thing.Electrospray ionization mass spectrum：458(M+H).

Embodiment 171

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [3- (tert-butyl-dimethyl-silanyloxy base)-propoxyl group]-methyl benzoate

According to the same procedure described in embodiment 38,0.355g (72%) required product is provided using the product and 0.290g (1.147mmol) 1- t-butyldimethylsilyi epoxide -3- bromos propane of 0.35g (0.820mmol) embodiment 37, is colorless oil.Electrospray ionization mass spectrum：600(M+H).

Embodiment 172

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [3- hydroxy-propoxies]-benzoic acid

According to the same procedure described in embodiment 18,0.188g (77%) required product is provided using the product of 0.310g (0.518mmol) embodiment 171, is white foam thing.Electrospray ionization mass spectrum：470(M+H).

Embodiment 173

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [3- (tert-butyl-dimethyl-silanyloxy base)-propoxyl group }-benzoic acid

0.105g (1.539mmol) imidazoles and 0.111g (0.739mmol) tert-butyl dimethylsilyl chlorine are added to the 5.0ml DMF solutions of the product of 0.145g (0.308mol) embodiment 172.Reactant is stirred at room temperature 18 hours, then add 0.40ml 1N sodium hydroxide solutions, stir the mixture of generation 1 hour.It is diluted with water.The solution is acidified with 5% hydrochloric acid, is extracted with ethyl acetate, the organic matter of merging is washed with water, it is dried over magnesium sulfate, filter and be concentrated in vacuo, residue by silica gel chromatography, the required product that 0.089g (50%) is provided is eluted with ethyl acetate/hexane, is white foam thing.Electrospray ionization mass spectrum：586(M+H).

Embodiment 174

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls 3- [3- hydroxyl-propyls]-benzamide

According to the same procedure described in embodiment 23,0.038g (62%) required product is provided using the product of 0.073g (0.125mmol) embodiment 173, is white solid.Electrospray ionization mass spectrum：487(M+H).

Embodiment 175

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- thiophene -2- bases-benzamide

According to the same procedure described in embodiment 23, using the product of 0.600g (1.2mmol) embodiment 141, by silica gel chromatography uses 5% methanol: there is provided 0.520g (79%) required product for ethyl acetate elution.Corresponding hydrochloride can be prepared with quantitative yield into the solution of the methanolizing of free alkali by blasting hydrogen chloride gas, yellow fluffy shape solid is provided through being concentrated in vacuo reactant mixture after.m.p.106℃.Electrospray ionization mass spectrum：547(M+H).

Embodiment 176

3- cyano group -2- (4- methoxy-benzenesulfonvls amino) -5- methyl-benzoic acids

2.0g (22mmol) copper cyanider (I) is added to the 60ml of the product of 4.0g (10mmol) embodiment 135 pyridine solution.The mixture is flowed back 48 hours.Then reactant mixture is made to be cooled to room temperature and be poured into cold water.Stir the mixture of generation 16 hours, be carefully acidified with concentrated hydrochloric acid solution.The sediment of generation is filtered, is washed with water, it is dissolved in chloroform, filter and concentrate.Triturated under ether residue is used, filters and dries there is provided 2.5g (72%) required product, be white solid, m.p.162 DEG C.Electrospray ionization mass spectrum：347(M+H).

Embodiment 177

2- [benzyls-(4- methoxy-benzenesulfonvls amino) -3- cyano group -5- methyl benzoic acids

4g potassium carbonate and 5ml benzyl bromide a-bromotoluenes are added to solution of 1.5g (4.3mol) products of embodiment 176 in 200ml acetone, makes the mixture to backflow 8 hours.Then reactant mixture is filtered, acetone is removed in vacuum.Residue is dissolved in chloroform, fully washed with water.Then organic layer dried over magnesium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, product needed for providing 1.8g (79%) with the elution of 30% ethyl acetate/hexane, is brown oil.Electrospray ionization mass spectrum：527(M+H)).

Embodiment 178

2- [benzyl-(4- methoxy-benzenesulfonvls amino) -3- cyano group -5- methyl]-benzoic acid

Solution into the 100mlTHF: methanol (1: 1) of 1.5g (2.8mmol) product of embodiment 177 adds 10ml 10N sodium hydroxide solutions.At room temperature, stirring reaction mixture 8 hours, and being concentrated in vacuo.Residue neutralizes and made the solid of the separation of generation to be dissolved in chloroform with concentrated hydrochloric acid, is fully washed with water.Organic layer dried over magnesium sulfate, filters and concentrates.The residue triturated under ether of generation, filtering provides 1.1g (91%) required product, is brown solid.Mass spectrum：437(M+H).

Embodiment 179

2- [benzyls-(4- methoxy-benzenesulfonvls amino)-N- hydroxyl -3- cyano group -5- methyl benzamides

According to the same procedure described in embodiment 23,0.70g (67%) required product is provided using the product of 1.0g (2.3mmol) embodiment 178, is white solid.m.p.175℃；Electrospray ionization mass spectrum：452(M+H).

Embodiment 180

5- cyano group -2- (4- Methoxybenzenesulfonylaminos) -3- methyl-benzoic acids

2.0g (22mmol) copper cyanider (I) is added to the 60ml of the product of 4.0g (10mmol) embodiment 10 pyridine solution.The mixture is flowed back 48 hours.Then reactant mixture is made to be cooled to room temperature and be poured into cold water.Stir the mixture of generation 16 hours, be carefully acidified with concentrated hydrochloric acid solution.The sediment of generation is filtered, is washed with water, it is dissolved in chloroform, dried with magnesium sulfate, filter and be concentrated in vacuo.Triturated under ether residue is used, filters and dries there is provided 2.0g (58%) required product, be white solid.m.p.175℃；Electrospray ionization mass spectrum：347(M+H).

Embodiment 181

2- [benzyls-(4- Methoxybenzenesulfonylaminos) -5- cyano group -3- methyl benzoic acids

It is brown solid with the required product that 3.5g (51%) is provided after triturated under ether using the product of 4.5g (13mmol) embodiment 180 and 5ml benzyl bromide a-bromotoluenes according to the same procedure described in embodiment 177.m.p.123℃；Electrospray ionization mass spectrum：527(M+H).

Embodiment 182

2- [benzyls-(4- Methoxybenzenesulfonylaminos) -5- cyano group -3- methyl-benzoic acids

It is brown semi solid using the product of 3.0g (5.7mmol) embodiment 215 there is provided 2.2g (88%) required product according to the same procedure described in embodiment 178.Electrospray ionization mass spectrum：437(M+H).

Embodiment 183

3- furans -2- bases -2- (4- methoxy-benzenesulfonvls amino) -5- methyl-benzoic acid methyl esters

6.0g (16mmol) 2- (tributyl tin) furans and 500mg tetra- (triphenyl phasphine) palladium (0) are added to the solution of the 300ml degassed toluenes of the product of 4.1g (10mmol) embodiment 135, the mixture of generation is flowed back 24 hours.Then reactant mixture is cooled down, is filtered and be concentrated in vacuo by diatomite.The residue triturated under ether of generation, there is provided 3.5g (87%) required product, is gray solid.m.p.133℃.Electrospray ionization mass spectrum：402(M+H).

Embodiment 184

3- furans -2- bases -2- (4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino] -5- methyl-benzoic acid methyl esters

1.64g (10mmol) 3- picolyl chloride hydrochlorides and 4.0g potassium carbonate are added to the 25ml DMF solutions of the product of 3.0g (7.4mmol) embodiment 183, the mixture of generation is stirred at room temperature 72 hours, then reactant mixture is poured into water, extracted with chloroform.Fully washed with water.Organic layer is dried through anhydrous magnesium sulfate, filters and is concentrated in vacuo, residue by silica gel chromatography, product needed for providing 2.5g (68%) with the elution of 50% ethyl acetate/hexane, is brown oil.Electrospray ionization mass spectrum：493(M+H).

Embodiment 185

3- furans -2- bases -2- (4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino] -5- methyl-benzoic acids

It is brown oil using the product of 2.0g (4.0mmol) embodiment 184 there is provided 1.5g (79%) required product according to the same procedure described in embodiment 24.m.p.82℃；Electrospray ionization mass spectrum：479(M+H).

Embodiment 186

3- furans -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino] -5- methyl-benzamides

According to the same procedure described in embodiment 23, using the product of 1.0g (2.01mmol) embodiment 185, by silica gel chromatography is eluted with ethyl acetate/methanol (95: 5), product needed for providing 0.60g (58%), is white solid.m.p.160℃；Electrospray ionization mass spectrum：494(M+H).

Embodiment 187

2- [(4- MethOxybenzenesulfonyls)-methylamino] -3- methyl-benzoic acid methyl esters

0.149g (3.731mmol) 60% sodium hydride is added to the 10ml DMF solutions of the product of 1.0g (2.985mmol) embodiment 3.The mixture half an hour of generation is stirred at room temperature, then adds 0.28ml (4.478mmol) iodomethane.It is stirred for the reactant 18 hours, is then diluted with ether.Organic matter is washed with water, it is dried over magnesium sulfate, filter and offer white solid is provided.The required product that the solid obtains 0.788g (76%) is washed with ethyl acetate/hexane (1: 1), is white solid.Electrospray ionization mass spectrum：350.1(M+H).

Embodiment 188

3- bromomethyls -2- [(4- methoxy-benzenesulfonvls)-methylamino]-methyl benzoate

0.406g (2,279mmol) N-bromosuccinimides and 0.14g dibenzoyl peroxides are added to solution of 0.723g (2.072mmol) products of embodiment 187 in 70ml carbon tetrachloride.The mixture of generation is heated to flowing back 18 hours, room temperature is subsequently cooled to, with sodium bisulfate and water washing.Dried with magnesium sulfate, filter and be concentrated in vacuo.Residue is ground with ether/hexane (1: 1), and then filtering provides 0.504g (57%) required product, is white solid.Electrospray ionization mass spectrum：428(M+H).

Embodiment 189

3- diethylamino methyl -2- [(4- MethOxybenzenesulfonyls)-methylamino]-methyl benzoate

0.242g (1.752mmol) potassium carbonate, 0.066ml (0.643mmol) diethylamine and 2mg tetrabutylammonium iodides are added to the 2.0ml DMF solutions of the product of 0.25g (0.584mmol) embodiment 188.Stirring reaction mixture 5 hours at room temperature, it is diluted with water, extracted with ether, then extracted with 6N hydrochloric acid solutions, alkalized aqueous acid layer with 6N sodium hydroxides, is then extracted with ether, the ether layer of generation is dried with sodium sulphate, filter and be concentrated in vacuo there is provided 0.19g (78%) required product, be colorless oil.Electrospray ionization mass spectrum：421.3(M+H)⁺。

Embodiment 190

3- diethylamino methyl -2- [(4- methoxy-benzenesulfonvls)-methylamino] benzoic acid

0.032g (0.752mmol) lithium hydroxide monohydrate is added to the solution of 4.0ml THF/ water/methanol (1: 1: 0.5) of the product of 0.158g (0.376mmol) embodiment 189, the mixture of generation is heated to flowing back 18 hours, room temperature is cooled to and is concentrated in vacuo.With THF wash residuals thing and filter, then concentrate filtrate, vacuum drying provides the lithium salts of 0.132g (85%) title compound, is white foam thing.Electrospray ionization mass spectrum：407.2(M+H)⁺。

Embodiment 191

3- diethylamino methyl-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-methylamino] benzamide

It is brown foam thing using the product of 0.110g (0.267mmol) embodiment 190 there is provided the hydrochloride of 0.125g (100%) title compound according to the same procedure described in embodiment 61.Electrospray ionization mass spectrum：422.1(M+H)+.

Embodiment 192

2- [(4- MethOxybenzenesulfonyls)-methylamino] -3- (4- methylpiperazine-1-yls methyl)-methyl benzoate

According to the same procedure described in embodiment 189, use the product and 0.143ml (1.285mmol) N methyl piperazine of 0.500g (1.168mmol) embodiment 188,0.368g (70%) required product is provided, is brown solid.Electrospray ionization mass spectrum：448.0(M+H)⁺。

Embodiment 193

2- [(4- MethOxybenzenesulfonyls)-methylamino] -3- (4- methylpiperazine-1-yls methyl)-benzoic acid

It is white foam thing using the product of 0.310g (0.693mmol) embodiment 192 there is provided the lithium salts of 0.305g (100%) title compound according to the same procedure described in embodiment 190.Electrospray ionization mass spectrum：432.1(M-H)^-

Embodiment 194

N- hydroxyls -2- [(4- MethOxybenzenesulfonyls)-methylamino] -3- (4- methylpiperazine-1-yls methyl)-benzamide

It is brown solid using the product of 0.150g (0.334mol) embodiment 193 there is provided the hydrochloride of 0.174g (100%) title compound according to the same procedure described in embodiment 61.Electrospray ionization mass spectrum：448.9(M+H)⁺

Embodiment 195

2- [benzyl-(4- MethOxybenzenesulfonyls) amino] -3- (1- ethoxy carbonyls -1- methyl ethoxies-methyl benzoate

2.42g (17.56mmol) potassium carbonate and 0.86ml (5.854mmol) 2- isobutyl ethyl bromides are added to the 10ml DMF solutions of the product of 0.250g (0.585mmol) embodiment 37.The mixture of generation is heated to 80 DEG C 18 hours, be subsequently cooled to room temperature, diluted with ether, organic matter is washed with water, dried with magnesium sulfate, filter and be concentrated in vacuo there is provided 0.186g (59%) required product, be white solid.Electrospray ionization mass spectrum：442.2(M+H)⁺。

Embodiment 196

2- [benzyl-(4- MethOxybenzenesulfonyls) amino] -3- (1- ethoxy carbonyls -1- methyl ethoxies-benzoic acid

It is white solid using the product of 0.147g (0.272mol) embodiment 195 there is provided 0.107g (79%) required product according to the same procedure described in embodiment 9.Electrospray ionization mass spectrum：500.2(M+H)⁺

Embodiment 197

2- [benzyl-(4- MethOxybenzenesulfonyls) amino] -3- (1- ethoxy carbonyl-N- hydroxyls -1- methyl ethoxies-benzamide

It is white solid using the product of 0.085g (0.170mol) embodiment 196 there is provided 0.052g (58%) required product according to the same procedure described in embodiment 23.Electrospray ionization mass spectrum：530.1(M+H)⁺

Embodiment 198

3- bromos -2- [- (4- MethOxybenzenesulfonyls) amino]-methyl benzoate

0.020 (0.50mmol) 60% sodium hydride is disposably added to the 3ml DMF solutions of 0.096g (0.5mmol) 4- methoxyphenyl sulphonyl amine, in 25 DEG C of reaction stirreds 15 minutes.Then 0.135g (0.58mmol) 3- bromo -2- fluoro henzylate (fluorobenzylate) methyl esters is disposably added in the solution, the mixture generated is stirred then at 90 DEG C (bath temperature) 18 hours, the reactant is set to be cooled to room temperature, it is acidified, is extracted with ethyl acetate with 1N hydrochloric acid.The organic layer of merging dried over magnesium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, with the elution of 30%-50% ethyl acetate/hexanes, there is provided 0.037g (19%) required product.¹HNMR(CDCl₃)：8ppm (s, 1H, NH), 6.8-7.8ppm (m, 7H, Ar), 3.9ppm (s, 1H, OMe), 3.7ppm (s, 1H, OMe).

Embodiment 199

3- bromos -2- [benzyl-(4- MethOxybenzenesulfonyls) amino]-methyl benzoate

0.062 (1.55mmol) 60% sodium hydride is added to the 10ml DMF solutions of the product of 0.413g (1.03mmol) embodiment 198, is continuously stirred in 25 DEG C 15 minutes.Then 0.125ml (1.442mmol) benzyl bromide a-bromotoluene is added, the mixture is stirred then at 55 DEG C 18 hours, the reactant is cooled to room temperature, be then poured into 200ml water and 50ml 1N hydrochloric acid.Then dichloromethane (100ml) and ethyl acetate (100ml) aqueous layer extracted are used.The organic layer of merging dried over magnesium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, with the elution of 10%-20% ethyl acetate/hexanes, there is provided 0.390g (77%) required product.Electrospray ionization mass spectrum：490.0(M+H)

Embodiment 200

3- bromos -2- [benzyl-(4- MethOxybenzenesulfonyls) amino]-benzoic acid

It is white solid using the product of 0.390g (0.80mmol) embodiment 199 there is provided 0.180g (84%) required carboxylic acid according to the same procedure described in embodiment 16.¹HNMR(CDCl₃)：9-10ppm (br, 1H, COOH), 7-8ppm (m, 12H, Ar), 4.5ppm (m, 2H ,-CH₂-), 3.9ppm (s, 1H, OMe).

Embodiment 201

3- bromos -2- [benzyl-(4- MethOxybenzenesulfonyls) amino]-N- hydroxy-benzoyIamides

According to the same procedure described in embodiment 23, using the product of 0.177g (0.372mmol) embodiment 200,0.155g (85%) required hydroxamic acid is obtained, is white solid.Electrospray ionization mass spectrum：491.0(M+H).

Embodiment 202

5- bromos -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

It is white solid there is provided 22.06g (86%) required product after triturated under ether using the product and 4.87ml (78mmol) methyl iodide of 27.0g (65mmol) embodiment 10 according to the same procedure described in embodiment 9.Electrospray ionization mass spectrum：430(M+H).

Embodiment 203

5- (2- t-butoxies carbonyl-ethenyl) -2- [(4- MethOxybenzenesulfonyls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

In 85 DEG C, the mixture of the product of 1.28g (3.0mmol) embodiment 202,1.31ml (9.0mmol) acrylic acid tert- butyl ester, 33.75mg (0.15mmol) palladium diacetate, 1.0g (3.15mmol) tert-butyl ammonium bromides and 1.24g (9.0mmol) potassium carbonate in 10ml DMF is stirred 6 hours.Reactant mixture is poured into water, is extracted with ethyl acetate.The organic matter merged with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Dissolve the residue in 20ml dichloromethane, stirred 20 minutes with 1.0g diatomite and 1.0g silica gel, filter and be concentrated in vacuo.Residue by silica gel chromatography, is white solid with ethyl acetate/hexane (1: 5) elution there is provided 1.26g (88%) required product.Electrospray ionization mass spectrum：476(M+H)+.

Embodiment 204

5- (2- carboxyls-vinyl) -2- [(4- MethOxybenzenesulfonyls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

1ml trifluoroacetic acids are added to the 2ml dichloromethane solutions of the product of 237.8mg (0.5mmol) embodiment 203, the reactant are stirred at room temperature 2 hours.The mixture of generation is concentrated in vacuo, 200mg (95%) required product is provided after being ground through methane/ether (2: 1), is white solid.Electrospray ionization mass spectrum：418(M-H).

Embodiment 205

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-vinyl]-methyl benzoate

Under chlorine, by the 1 of the product of 182.6mg (0.43mmol) embodiment 204,1.83mg molecular sieve and 105.8mg (0.65mmol), mixture of 1 '-dicyclohexyl carbonyl dimidazoles in 4ml THF is stirred 1 hour.The 0.5ml THF solutions of N- methyl octylames are added in the reactant, the mixture are stirred at room temperature 18 hours.The mixture of generation is filtered, filtrate is diluted with ethyl acetate, with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo, residue by silica gel chromatography, it is colorless oil with ethyl acetate/hexane (1: 1) elution there is provided 200mg (84%) required product.Electrospray ionization mass spectrum：545(M+H).

Embodiment 206

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-vinyl]-benzoic acid

It is white solid there is provided 170mg (93%) required carboxylic acid after being ground with ethane/ethyl acetate (2: 1) using the product of 188mg (0.35mmol) embodiment 205 according to the same procedure described in embodiment 18.Electrospray ionization mass spectrum：575.0(M+HCOOH-H).

Embodiment 207

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-vinyl]-benzamide

It is pale solid using the product of 154mg (0.29mmol) embodiment 206 there is provided 45mg (28%) required hydroxamic acid according to the same procedure described in embodiment 23.Electrospray ionization mass spectrum：546(M+H).

Embodiment 208

5- (2- t-butoxies carbonyl-ethyl) -2- [(4- MethOxybenzenesulfonyls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

The mixture of the product of 340mg (0.71mmol) embodiment 203 and 35mg10% palladiums charcoal in 15ml ethanol is hydrogenated 2 hours in Parr shaker.It is colorless gum by the mixture of Celite and Magnesol filtering generations there is provided 325mg (95%) required product.Electrospray ionization mass spectrum：478(M-H).

Embodiment 209

5- (2- CARBOXY-ETHYLs) -2- [(4- MethOxybenzenesulfonyls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

It is colorless gum using the product of 206mg (0.43mmol) embodiment 208 there is provided 181mg (100%) required product according to the same procedure described in embodiment 204.Electrospray ionization mass spectrum：420(M-H).

Embodiment 210

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-ethyl]-methyl benzoate

It is colorless gum using the product of 286mg (0.68mmol) embodiment 209 there is provided 362mg (97%) required product according to the same procedure described in embodiment 205.Electrospray ionization mass spectrum：547(M+H).

Embodiment 211

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-ethyl]-benzoic acid

It is pale yellow crystals solid using the product of 340mg (0.62mmol) embodiment 210 there is provided the carboxylic acid needed for 304mg (92%) according to the same procedure described in embodiment 18.Electrospray ionization mass spectrum：533(M+H).

Embodiment 212

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-ethyl]-benzamide

183mg (0.95mmol) 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides are added into slurry of the product of 300mg (0.56mmol) embodiment 211 and 106mg (0.78mmol) I-hydroxybenzotriazole in 5ml DMF, the reactant are stirred at room temperature 30 minutes.Hydroxylamine hydrochloride (227mg, 3.26mmol) and 0.68ml (4.89mmol) triethylamines and the reactant are stirred 18 hours.The mixture of generation is diluted with water, is extracted with dichloromethane.The organic matter merged with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo, residue by silica gel chromatography, with 2% ethanol/methylene as eluant, eluent there is provided the hydroxamic acid needed for 190mg (62%), is pale solid.Electrospray ionization mass spectrum：548(M+H).

Embodiment 213

5- (2- formyl-dimethylaminos-vinyl) -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 203, use the product and 0.309ml (3.0mmol) N of 428.3mg (1.0mmol) embodiment 202, N- DMAAs, there is provided 418mg (93%) required product, are colorless gum.Electrospray ionization mass spectrum：447(M+H).

Embodiment 214

5- (2- formyl-dimethylaminos-vinyl) -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acids

It is white solid using the product of 418mg (0.94mmol) embodiment 213 there is provided the carboxylic acid needed for 303mg (75%) according to the same procedure described in embodiment 18.Electrospray ionization mass spectrum：447(M+HCOOH-H).

Embodiment 215

5- (2- formyl-dimethylaminos-vinyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides

It is white solid using the product of 303mg (0.70mmol) embodiment 214 there is provided the hydroxamic acid needed for 268mg (85%) according to the same procedure described in embodiment 212.Electrospray ionization mass spectrum：448(M+H).

Embodiment 216

N- Ethyl-N-pyridins -4- ylmethyls-acrylamide

To 0.835ml (6.0mmol) 4- (ethylaminomethyl) pyridines and 1.05ml (7.5mmol) triethylamine 10ml dichloromethane 0 DEG C of solution be added dropwise 0.406ml (5.0mmol) benzene alkene acyl chlorides.Reactant mixture is warmed to room temperature and is stirred 18 hours.The mixture generated with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo, residue by silica gel chromatography, with 3% ethanol/methylene as eluant, eluent there is provided product needed for 651mg (68%), is yellow jelly.Electrospray ionization mass spectrum：191(M+H).

Embodiment 217

5- [2- (EthylPyridine -4- ylmethyl-aminos formoxyl)-vinyl] -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 203, use the product and the product of 456.6mg (2.4mmol) embodiment 216 of 342.6mg (0.80mmol) embodiment 202, product needed for 405mg (94%) is provided, is yellow jelly.Electrospray ionization mass spectrum：538(M+H).

Embodiment 218

5- [2- (EthylPyridine -4- ylmethyl-aminos formoxyl)-vinyl] -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acids

126.4mg (3.01mmol) lithium hydroxide monohydrate is added to the solution of 8ml THF: the methanol: water (2: 1: 1) of the product of 405mg (0.755mmol) embodiment 217.Then heating response mixture is concentrated in vacuo to flowing back 18 hours.Residue diluted with water, is neutralized with 3N hydrochloric acid, is extracted with dichloromethane.The organic matter merged with water and salt water washing, it is dried over magnesium sulfate, filter and be concentrated in vacuo there is provided the carboxylic acid needed for 222mg (56%), be beige solid.Electrospray ionization mass spectrum：524(M+H).

Embodiment 219

5- [2- (EthylPyridine -4- ylmethyl-aminos formoxyl)-vinyl]-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides

According to the same procedure described in embodiment 212, with the product of 214mg (0.408mmol) embodiment 218, hydroxamic acid needed for 156mg (71%) is provided, it is dissolved in 2ml dichloromethane, with 0.32ml (0.32mmol) 1M hydrochloric acid/ether processing.The mixture of generation is stirred at room temperature 1 hour, the hydroxamic acid hydrochloride provided needed for 150mg (64%) is provided, is beige solid.Electrospray ionization mass spectrum：539(M+H).

Embodiment 220

5- (2- t-butoxycarbonyl-vinyls) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

It is brown oil using the product of 1.08g (2.13mmol) embodiment 89 there is provided the product needed for 771mg (65%) according to the same procedure described in embodiment 203.Electrospray ionization mass spectrum：553(M+H).

Embodiment 221

5- (2- carboxyls-vinyl) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 204, using the product of 750mg (1.36mmol) embodiment 220, there is provided the product needed for 500mg (60%).Electrospray ionization mass spectrum：541(M+HCOOH-H).

Embodiment 222

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- (2- methyl-octyls-carbamoyl)-vinyl]-methyl benzoate

It is colorless gum using the product of 270mg (0.54mmol) embodiment 221 there is provided the product needed for 162mg (48%) according to the same procedure described in embodiment 205.Electrospray ionization mass spectrum：622(M+H).

Embodiment 223

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- (2- methoxyl groups-octyl group-carbamoyl)-vinyl]-benzoic acid

It is colorless crystalline solid using the product of 386mg (0.62mmol) embodiment 222 there is provided the product needed for 274mg (73%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：652(M+HCOOH-H).

Embodiment 224

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- (2- methoxyl groups-octyl group-carbamoyl)-vinyl]-benzamide

It is beige solid using the product of 261mg (0.43mmol) embodiment 223 there is provided the product needed for 211mg (75%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：623(M+HCOOH-H).

Embodiment 225

5- (2- formyl-dimethylaminos-vinyl) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 203, use the product and 297.4mg (3.0mmol) N of 550.4mg (1.0mmol) embodiment 89, N- DMAAs, there is provided 419mg (80%) required product, are white solid.Electrospray ionization mass spectrum：524(M+H).

Embodiment 226

5- (2- formyl-dimethylaminos-vinyl) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is faint yellow solid using the product of 404mg (0.77mmol) embodiment 225 there is provided the carboxylic acid needed for 250mg (64%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：508(M-H).

Embodiment 227

5- (2- formyl-dimethylaminos-vinyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is faint yellow solid using the product of 230mg (0.45mmol) embodiment 226 there is provided the carboxylic acid needed for 54mg (20%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：525(M+H).

Embodiment 228

5- [2- (ethyl-phenyl-amino formoxyl)-vinyl] -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

It is brown solid using the product and 425mg (2.43mmol) N- ethylpropionyl base aniline of 550.4mg (1.0mmol) embodiment 89 there is provided the product needed for 392mg (65%) according to the same procedure described in embodiment 203.Electrospray ionization mass spectrum：600(M+H).

Embodiment 229

5- [2- (ethyl-phenyl-amino formoxyl)-vinyl] -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is mustard color solid using the product of 582mg (0.97mmol) embodiment 228 there is provided the carboxylic acid needed for 404.7mg (71%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：584(M+H).

Embodiment 230

5- [2- (ethyl-phenyl-amino formoxyl)-vinyl]-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is beige solid using the product of 402mg (0.69mmol) embodiment 229 there is provided the product needed for 190mg (43%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：601(M+H).

Embodiment 231

5- (2- diallyls carbamoyl-vinyl) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 203, use the product and 453.6mg (3.0mmol) N of 550.4mg (1.0mmol) embodiment 89, N- diallyl acrylamides, there is provided the product needed for 309mg (53%), are yellow jelly.Electrospray ionization mass spectrum：576(M+H).

Embodiment 232

5- (2- diallyls carbamoyl-vinyl) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is beige solid using the product of 276mg (0.48mmol) embodiment 231 there is provided the carboxylic acid needed for 149mg (55%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：562(M+H).

Embodiment 233

5- (2- diallyls carbamoyl-vinyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is brown solid using the product of 188mg (0.34mmol) embodiment 232 there is provided the product needed for 134mg (65%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：577(M+H).

Embodiment 234

5- bromos -2- (dimethylamino-methene amido) -3- methyl-benzoic acid tert-butyl esters

Mixture of the product of 5.0g (21.7mmol) embodiment 132 and 20.8ml (86.9mmol) the DMF di-t-butyl acetal in 30ml toluene is heated to backflow 2 hours.Reactant mixture is cooled down to room temperature, with water and salt water washing, dried over magnesium sulfate and vacuum concentration, there is provided the product needed for 3.61mg (49%), is yellow oil.Electrospray ionization mass spectrum：341(M+H).

Embodiment 235

2- amino -5- bromo -3- methyl-benzoic acid the tert-butyl esters

Mixture of the product of 3.52g (10.3mmol) embodiment 234 and 6.12g (44.94mmol) zinc chloride in 50ml absolute ethyl alcohols is heated to backflow 18 hours.Reactant mixture is concentrated in vacuo, residue dchloromethane is dried over magnesium sulfate with water and salt water washing, filters and is concentrated in vacuo there is provided the product needed for 2.48g (84%), is light brown liquid.Electrospray ionization mass spectrum：286(M+H).

Embodiment 236

5- bromos -2- [(the 4- methoxy-benzenesulfonvl amino -3- methyl-benzoic acid tert-butyl esters

It is pale yellow oil using the product of 2.48g (8.66mmol) embodiment 235 there is provided 3.41g (86%) required product according to the same procedure described in embodiment 1.Electrospray ionization mass spectrum：402(M-t-bu-H).

Embodiment 237

5- bromos -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid tert-butyl esters

It is white solid using the product of 3.15g (6.9mmol) embodiment 235 there is provided 2.6g (69%) required product according to the same procedure described in embodiment 81.Electrospray ionization mass spectrum：547(M+H).

Embodiment 238

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- (3- morpholine -4- base -3- oxo-propenyls)-t-butyl perbenzoate

According to the same procedure described in embodiment 203; use the product and 423mg (3.0mmol) N- acryloyl morpholines of 547.5mg (1.0mmol) embodiment 237; product needed for 542mg (89%) is provided, is faint yellow jelly.Electrospray ionization mass spectrum：608(M+H).

Embodiment 239

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- (3- morpholine -4- base -3- oxo-propenyls)-benzoic acid

It is faint yellow solid using the product of 492mg (0.809mmol) embodiment 238 there is provided the product needed for 464mg (86%) according to the same procedure described in embodiment 204.Electrospray ionization mass spectrum：552(M+H).

Embodiment 240

N- hydroxyls -2- [(4- methoxy-benzenesulfonvl pyridin-3-yls Methyl-amino] -3- methyl -5- (3- morpholine -4- base -3- oxo-propenyls)-benzamide

It is Off-white solid using the product of 150mg (0.27mmol) embodiment 239 there is provided the product needed for 114mg (25%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：567(M+H).

Embodiment 241

2 '-formoxyl -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- methyl formates

Product, 165mg (1.1mmol) 2- formylphenylboronic acids, (triphenyl phasphine) palladiums of 58mg (0.05mmol) four and 1ml (2.0mmol) 2M aqueous sodium carbonates of 505.4mg (1.0mmol) embodiment 89 are added to 5ml degassed ethylene glycols dimethyl ether, the mixture is heated to backflow 18 hours under a nitrogen.The reactant is cooled to room temperature, diluted with ethyl acetate, it is dried over magnesium sulfate with water and salt water washing, filter and be concentrated in vacuo.Residue by silica gel chromatography, is yellow solid with ethyl acetate/hexane (1: 1) as eluant, eluent there is provided 499mg (94%) required product.Electrospray ionization mass spectrum：531(M+H).

Embodiment 242

2 '-formoxyl -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid

It is faint yellow solid using the product of 478mg (0.9mmol) embodiment 241 there is provided the carboxylic acid needed for 392mg (84%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：515(M+H).

Embodiment 243

2 '-(Hydroxyimino-methyl) -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxy amides

It is Off-white solid using the product of 380mg (0.74mmol) embodiment 242 there is provided the product needed for 310mg (53%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：547(M+H).

Embodiment 244

3 '-formoxyl -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- methyl formates

It is light yellow crystal using the product and 165mg (1.1mmol) 3- formylphenylboronic acids of 505.4mg (1.0mmol) embodiment 89 there is provided the product needed for 530mg (100%) according to the same procedure described in embodiment 241.Electrospray ionization mass spectrum：531(M+H).

Embodiment 245

3 '-formoxyl -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid

It is white solid using the product of 500mg (0.96mmol) embodiment 244 there is provided the carboxylic acid needed for 214mg (43%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：515(M+H).

Embodiment 246

3 '-(Hydroxyimino-methyl) -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxy amides

It is Off-white solid using the product of 196mg (0.38mmol) embodiment 245 there is provided the product needed for 176mg (80%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：547(M+H).

Embodiment 247

4 '-formoxyl -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- methyl formates

It is faint yellow solid using the product and 165mg (1.1mmol) 4- formylphenylboronic acids of 505.4mg (1.0mmol) embodiment 89 there is provided the product needed for 519mg (98%) according to the same procedure described in embodiment 241.Electrospray ionization mass spectrum：531(M+H).

Embodiment 248

4 '-formoxyl -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid

It is white solid using the product of 486mg (0.92mmol) embodiment 247 there is provided the product needed for 362mg (76%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：515(M+H).

Embodiment 249

4 '-(Hydroxyimino-methyl) -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxy amides

It is Off-white solid using the product of 320mg (0.62mmol) embodiment 248 there is provided the product needed for 166mg (49%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：547(M+H).

Embodiment 250

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -2 '-Trifluoromethyl-biphenyl -3- methyl formates

According to the same procedure described in embodiment 241, use the product and 244mg (1.1mmol) 2- trifluoromethylbenzene boronic acids of 505.4mg (1.0mmol) embodiment 89, product needed for 559mg (98%) is provided, is faint yellow jelly.Electrospray ionization mass spectrum：571(M+H).

Embodiment 251

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -2 '-Trifluoromethyl-biphenyl -3- formic acid

It is white solid using the product of 541mg (0.95mmol) embodiment 250 there is provided the carboxylic acid needed for 475mg (90%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：557(M+H).

Embodiment 252

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -2 '-Trifluoromethyl-biphenyl -3- formic acid hydroxy amides

According to the same procedure described in embodiment 61, use the product of 447mg (0.803mmol) embodiment 251, product needed for providing, makes it be dissolved in 3ml dichloromethane and 3ml methanol, with 0.76ml (0.76mmol) 1M hydrochloric acid/ether processing.The mixture of generation is stirred at room temperature 1 hour, the product provided needed for 373mg (76%) is provided, is beige solid.Electrospray ionization mass spectrum：572(M+H).

Embodiment 253

5- furans -2- bases -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

It is faint yellow solid using the product and 123mg (1.1mmol) FURAN-2-BORONIC ACIDs of 505.4mg (1.0mmol) embodiment 89 there is provided the product needed for 432mg (88%) according to the same procedure described in embodiment 241.Electrospray ionization mass spectrum：493(M+H).

Embodiment 254

5- furans -2- bases -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

According to the same procedure described in embodiment 218, using the product of 419mg (0.58mmol) embodiment 253, with after triturated under ether there is provided the carboxylic acid needed for 227mg (47%), be white solid.Electrospray ionization mass spectrum：477(M+H).

Embodiment 255

5- furans -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is Off-white solid using the product of 220mg (0.46mmol) embodiment 254 there is provided the product needed for 185mg (76%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：494(M+H).

Embodiment 256

5- (3- fonnyl-thiophen -2- bases) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 241; use the product and 343.2mg (2.2mmol) 3- formylthien -2- boric acid of 505.4mg (1.0mmol) embodiment 89; product needed for 379mg (71%) is provided, is faint yellow solid.Electrospray ionization mass spectrum：537(M+H).

Embodiment 257

5- (3- fonnyl-thiophen -2- bases) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is faint yellow solid using the product of 364mg (0.68mmol) embodiment 256 there is provided the carboxylic acid needed for 229mg (65%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：521(M+H).

Embodiment 258

N- hydroxyls -5- [3- Hydroxyimino-methyls)-thiophene -2- bases] -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is Off-white solid using the product of 220mg (0.42mmol) embodiment 257 there is provided the product needed for 168mg (68%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：553(M+H).

Embodiment 259

5- (5- chloros-thiophene -2- bases) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

It is yellow solid using the product and 357mg (2.2mmol) 5- chloro thiophene -2- boric acid of 505mg (1.0mmol) embodiment 89 there is provided the product needed for 332mg (61%) according to the same procedure described in embodiment 241.Electrospray ionization mass spectrum：543(M+H).

Embodiment 260

5- (5- chloros-thiophene -2- bases) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is faint yellow solid using the product of 312mg (0.58mmol) embodiment 259 there is provided the carboxylic acid needed for 277mg (91%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：527(M+H).

Embodiment 261

5- (5- chloros-thiophene -2- bases)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is faint yellow solid using the product of 277mg (0.524mmol) embodiment 260 there is provided the product needed for 135mg (44%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：544(M+H).

Embodiment 262

5- (5- acetyl group-thiophene -2- bases) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the same procedure described in embodiment 241; use the product and 374mg (2.2mmo1) 5- acetyl thiophene -2- boric acid of 505.4mg (1.0mmol) embodiment 89; product needed for 525mg (95%) is provided, is Off-white solid.Electrospray ionization mass spectrum：551(M+H).

Embodiment 263

5- (5- acetyl group-thiophene -2- bases) -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is faint yellow solid using the product of 500mg (0.9mmol) embodiment 262 there is provided the carboxylic acid needed for 390mg (81%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：535(M-H).

Embodiment 264

5- (5- acetyl group-thiophene -2- bases)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

It is white solid using the product of 400mg (0.75mmol) embodiment 263 there is provided the product needed for 226mg (52%) according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：552(M+H).

Embodiment 265

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- methyl -5- vinyl-benzoic acid methyl esters

It is white solid using the product and 0.552ml (2.0mmol) vinyltributyltins of 728mg (1.44mmol) embodiment 11 there is provided the product needed for 430mg (66%) according to the same procedure described in embodiment 139.Electrospray ionization mass spectrum：452(M+H).

Embodiment 266

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- methyl -5- vinyl-benzoic acids

It is white solid using the product of 160mg (0.35mmol) embodiment 265 there is provided the carboxylic acid needed for 133mg (85%) according to the same procedure described in embodiment 18.Electrospray ionization mass spectrum：436(M-H).

Embodiment 267

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls -5- vinyl-benzamide

It is white solid using the product of 120mg (0.27mmol) embodiment 266 there is provided the hydroxamic acid needed for 63.4mg (51%) according to the same procedure described in embodiment 23.Electrospray ionization mass spectrum：453(M+H).

Embodiment 268

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- formoxyl -3- methyl-benzoic acid methyl esters

To the product of 2.21g (4.89mmol) embodiment 265 in 20ml dioxane: the t-butanol solution of 0.3ml 2.5 (weight) % osmium tetroxide is added in the solution of water (3: 1), the reactant is stirred until solution is changed into dark-brown.Then 2.09g (9.78mmol) sodium peroxide was added by several times with 20 minutes.Stir the mixture of generation 1.5 hours, diluted with ether, it is dried over magnesium sulfate with water and salt water washing, filter and be concentrated in vacuo, be white solid with the required product that 1.73g (78%) is provided after triturated under ether.Electrospray ionization mass spectrum：454(M+H).

Embodiment 269

4- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- methyl-m-phenylene diacid 3- methyl esters

98mg (1.08mmol) sodium chlorite is added in the solution of 40ml water: THF (3: 1) to the product and 102mg (1.05mmol) sulfamic acids of 317mg (0.7mmol) embodiment 268.Stir the mixture of generation 2 hours, diluted with ether, it is dried over magnesium sulfate with water and salt water washing, filter and be concentrated in vacuo there is provided 325mg (99%) required carboxylic acid, be white solid.Electrospray ionization mass spectrum：468(M-H).

Embodiment 270

4- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- methyl-m-phenylene diacid

It is white solid using the product of 325mg (0.7mmol) embodiment 169 there is provided the product needed for 224.3mg (70%) according to the same procedure described in embodiment 18.Electrospray ionization mass spectrum：454(M-H).

Embodiment 271

4- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N (1), N (3)-dihydroxy -5- methyl-m-phenylenes diamides (isophthalamide)

It is Off-white solid using the product of 210mg (0.46mmol) embodiment 270 there is provided the product needed for 160mg (72%) according to the same procedure described in embodiment 23.Electrospray ionization mass spectrum：486(M+H).

Embodiment 272

4- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N (1), N (3)-dihydroxy -5- methyl-m-phenylene diamides disodium salts

0.412ml (.412mmol) 1N sodium hydroxides are added to solution of the product of 100mg (0.206mmol) embodiment 271 in 2ml methanol, the reactant are stirred at room temperature 2 hours.Reactant mixture is concentrated in vacuo, product needed for residue provides 109mg (100%) through triturated under ether, is faint yellow solid.Electrospray ionization mass spectrum：486(M+H)).

Embodiment 273

2- (4- methoxy-benzenesulfonvls amino) -3- methyl -5- vinyl-benzoic acid methyl esters

It is white solid using the product and 0.73ml (2.5mmol) vinyltributyltins of 700mg (1.69mmol) embodiment 10 there is provided 500mg (82%) required product according to the same procedure described in embodiment 139.Electrospray ionization mass spectrum：362(M+H).

Embodiment 274

5- ethyls -2- (4- methoxy-benzenesulfonyls amino) -3- methyl-benzoic acid methyl esters

It is white solid using the product of 479mg (1.33mmol) embodiment 273 there is provided the product needed for 480mg (100%) according to the same procedure described in embodiment 208.Electrospray ionization mass spectrum：364(M+H).

Embodiment 275

5- ethyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

It is pale yellow oil using the product of 455mg (1.25mmol) embodiment 274 there is provided the product needed for 544mg (96%) according to the same procedure described in embodiment 81.Electrospray ionization mass spectrum：455(M+H).

Embodiment 276

5- ethyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acids

It is beige solid using the product of 496mg (1.09mmol) embodiment 275 there is provided the carboxylic acid needed for 345mg (72%) according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：441(M+H).

Embodiment 277

5- ethyl-N-hvdroxvs -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides

According to the same procedure described in embodiment 23, using the product of 320mg (0.73mmol) embodiment 276, there is provided the hydroxamic acid needed for 166mg (50%).The hydroxamic acid is dissolved in 4ml dichloromethane, add 0.1ml methanol and 0.4ml (.4mmol) 1M hydrochloric acid/ether.Stirring reaction mixture 1 hour is simultaneously concentrated in vacuo.Residue, there is provided the hydroxamic acid needed for 177mg (98%), is Off-white solid through triturated under ether.Electrospray ionization mass spectrum：456(M+H).

Embodiment 278

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- methylol -3- methyl-benzoic acid methyl esters

To the product of 907mg (2.0mmol) embodiment 268 sodium borohydride is added in the solution of 50ml methanol: THF (4: 1).Then the reactant half an hour is stirred at room temperature, and is concentrated in vacuo.Dissolve the residue in dichloromethane, it is dried over magnesium sulfate with 5% hydrochloric acid and salt water washing, filter and be concentrated in vacuo there is provided 872mg (96%) required product, be white crystalline solid.Electrospray ionization mass spectrum：456(M+H).

Embodiment 279

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- bromomethyl -3- methyl-benzoic acid methyl esters

To the product and 983mg (2.96mmol) carbon tetrabromides of 1.08mg (2.370mmol) embodiment 278 933mg (3.55mmol) triphenyl phasphine is added in 0 DEG C of solution of 24ml dichloromethane.Stir the mixture of generation 15 minutes, be then concentrated in vacuo.Residue by silica gel chromatography, with ethyl acetate: hexane (1: 6), there is provided 1.1g (96%) required product, is white crystalline solid as eluant, eluent.Electrospray ionization mass spectrum：520(M+H).

Embodiment 280

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- diethylamino methyl -3- methyl-benzoic acid methyl esters

At room temperature, 10 dichloromethane solutions of the product of 518.4mg (1.0mmol) embodiment 279,0.5ml (4.8mmol) diethylamine and 0.172ml (2.0mmol) pyridine are stirred 18 hours.The mixture water and salt water washing of generation, it is dried over magnesium sulfate, filter and be concentrated in vacuo, residue by silica gel chromatography, with 2% ethanol/methylene, as eluant, eluent, there is provided 425mg (83%).Electrospray ionization mass spectrum：511(M+H).

Embodiment 281

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- diethylamino methyl -3- methyl-benzoic acids

It is white solid using the product of 400mg (.78mmol) embodiment 280 there is provided 324mg (85%) required carboxylic acid according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：497(M+H).

Embodiment 282

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- diethylamino methyl-N- hydroxy-3-methyls-benzamide

It is beige solid using the product of 324mg (0.65mmol) embodiment 281 there is provided 162mg (45%) required product according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：512(M+H).

Embodiment 283

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- pyridin-3-yls-methyl benzoate

According to the same procedure described in embodiment 139, use the product and 515mg (1.4mmol) 3- (tributyl tin) pyridine of 505mg (1.0mmol) embodiment 89,437mg (87%) required product is provided, is faint yellow solid.Electrospray ionization mass spectrum：504(M+H).

Embodiment 284

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- pyridin-3-yls-benzoic acid

It is Off-white solid using the product of 422mg (0.84mmol) embodiment 283 there is provided 410mg (100%) required carboxylic acid according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：490(M+H).

Embodiment 285

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- pyridin-3-yls-benzamide

It is pink solid using the product of 420mg (0.85mmol) embodiment 284 there is provided 160mg (33%) required product according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：505(M+H).

Embodiment 286

2- amino -3,6- dimethyl-benzoic acid benzyl esters

940mg (5.73mmol) 2- amino -3,6- dimethyl-benzoic acid, 0.750ml (6.3mmol) benzyl bromide a-bromotoluene, the mixture of 1.04g (7.5mmol) potassium carbonate and 40mg (0.27) sodium iodides in 20ml acetone are heated to backflow 20 hours.Then the mixture of generation is concentrated in vacuo, purified by chromatography, with ethyl acetate/hexane (1: 50) as eluant, eluent there is provided 697mg (48%) required product, is yellow oil.Electrospray ionization mass spectrum：256(M+H)).

Embodiment 287

2- [(4- methoxy-benzenesulfonvls amino) -3,6- dimethyl-benzoic acid benzyl esters

According to the same procedure described in embodiment 1, using the product of 971mg (3.8mmol) embodiment 286,1.415g (87%) required product is provided after being ground through ether/hexane (1: 1), is Off-white solid.Electrospray ionization mass spectrum：426(M+H).

Embodiment 288

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3,6- dimethyl-benzoic acid benzyl esters

According to the same procedure described in embodiment 9, using the product of 321mg (0.754mmol) embodiment 287,356mg (92%) required product is provided after hexanes trituration, is white solid.Electrospray ionization mass spectrum：516(M+H).

Embodiment 289

N- benzyls-N- (2- methylols -3,6- Dimethvl-phenyl) -4- methoxy-benzenesulfonamides

Under a nitrogen, solution of the product of 649mg (1.26mmol) embodiment 288 in the anhydrous THF of 6ml is added dropwise to slurry of 211mg (5.04mmol) lithium aluminium hydride reductions in the anhydrous THF of 6ml.Stirring reaction mixture 3 hours, is then slowly added into sodium sulphate pentahydrate until silk silk sound disappearance, forms thick shape solid.Cross filter solid and be concentrated in vacuo filtrate, be white solid with the required product that 454mg (87%) is provided after hexanes trituration.Electrospray ionization mass spectrum：412(M+H).

Embodiment 290

N- benzyls-N- (2- formoxyls -3,6- Dimethvl-phenyl) -4- methoxy-benzenesulfonamides

5.33ml (10.07mmol) Jones reagents are added to acetone (20ml) solution of the product of 438.7mg embodiments 289, the reactant are stirred at room temperature 18 hours.The mixture of generation is concentrated in vacuo, residue dchloromethane is dried over magnesium sulfate with water and salt water washing, filters and is concentrated in vacuo.396mg (91%) required product is provided after residue hexanes trituration, is white solid.Electrospray ionization mass spectrum：410(M+H).

Embodiment 291

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3,6- dimethyl-benzoic acids

It is white solid using the product of 378mg (0.92mmol) embodiment 290 there is provided 260mg (66%) required product according to the same procedure described in embodiment 269.Electrospray ionization mass spectrum：426(M+H).

Embodiment 292

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3,6- dimethvl-benzamides

It is white solid using the product of 255mg (0.6mmol) embodiment 291 there is provided 206mg (78%) required product according to the same procedure described in embodiment 23.Electrospray ionization mass spectrum：441(M+H).

Embodiment 293

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,6- dimethyl-benzoic acid benzyl esters

According to the same procedure described in embodiment 81, using the product of 1.415g (3.33mmol) embodiment 287,1.02mg (59%) required product is provided after triturated under ether, is white solid.Electrospray ionization mass spectrum：517(M+H).

Embodiment 294

N- (2- hydroxymethyls -3,6- Dimethvl-phenyl) -4- methoxyl group-N- pyridin-3-yl methyl-benzene sulphonamides

It is yellow oil using the product of 933mg (1.92mmol) embodiment 293 there is provided 633mg (80%) required product according to the same procedure described in embodiment 289.Electrospray ionization mass spectrum：413(M+H).

Embodiment 295

N- (2- formoxyls -3,6- Dimethvl-phenyl) -4- methoxyl group-N- pyridin-3-yl methyl-benzene sulphonamides

It is yellow solid using the product of 633mg (1.54mmol) embodiment 294 there is provided 438mg (787%) required product according to the same procedure described in embodiment 290.Electrospray ionization mass spectrum：411(M+H).

Embodiment 296

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,6- dimethyl-benzoic acids

It is pale solid using the product of 438mg (1.07mmol) embodiment 295 there is provided 345mg (76%) required carboxylic acid according to the same procedure described in embodiment 269.Electrospray ionization mass spectrum：425(M+H).

Embodiment 297

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,6- dimethvl-benzamides

According to the same procedure described in embodiment 252, using the product of 130mg (0.31mmol) embodiment 296, there is provided the hydroxamic acid needed for 100mg (74%).235mg (0.53mmol) sample of the product, is Off-white solid with the required hydroxamic acid hydrochloride that 229mg (90%) is provided after triturated under ether.Electrospray ionization mass spectrum：442(M+H).

Embodiment 298

2- (4- methoxy-benzenesulfonvls amino) -3- methyl -5- [3- (5- methyl-ribofuranosyl -2- bases)-isoxazole -5-bases]-methyl benzoate

In room temperature under a nitrogen, 348.2mg (1.09mmol) 5- methyl-ribofuranosyl -2- formaldoximes are added into the 3.0ml chloroformic solutions of 146.6mg (1.1mmol) N-chlorosuccinimides and 0.006ml pyridines.Stirring reaction mixture 30 minutes, it is disposable to add 392mg (1.09mmol) 5- acetenyls -2- (4- methoxy-benzenesulfonyls amino) -3- methyl-benzoic acid methyl esters, 0.16ml (1.15mmol) triethylamine then was added dropwise with 1 hour.The mixture of generation is stirred at room temperature 18 hours, with dchloromethane, with water and salt water washing, is dried with magnesium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is white solid with ethyl acetate/hexane (1: 9) as eluant, eluent there is provided product needed for 313mg (60%).Electrospray ionization mass spectrum：483(M+H).

Embodiment 299

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- [3- (5- methyl-ribofuranosyl -2- bases)-isoxazole -5-bases]-methyl benzoate

It is colorless gum using the product of 305mg (6.3mmol) embodiment 298 there is provided 240mg (66%) required product according to the same procedure described in embodiment 81.Electrospray ionization mass spectrum：574(M+H).

Embodiment 300

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- [3- (5- methyl-ribofuranosyl -2- bases)-isoxazole -5-bases]-benzoic acid

It is faint yellow solid using the product of 234mg (0.408mmol) embodiment 299 there is provided 149mg (65%) required carboxylic acid according to the same procedure described in embodiment 218.Electrospray ionization mass spectrum：560(M+H).

Embodiment 301

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- [3- (5- methyl-ribofuranosyl -2- bases)-isoxazole -5-bases]-benzamide

It is brown solid using the product of 141mg (0.25mmol) embodiment 300 there is provided 30mg (19%) required product according to the same procedure described in embodiment 219.Electrospray ionization mass spectrum：575(M+H).

Embodiment 302

2- [benzyl-(4- ethyoxyls-benzenesulfonyl)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the method for embodiment 73, the product (2.0g, 4.68mmol) and ethanol synthesis for making embodiment 65 obtain the p- ethoxybenzene sulfonamide -ester of 0.461 (21%).

According to the method for embodiment 18, the sulfonamide ester (0.440g, 0.941mmol) hydrolysis is set to obtain 0.318g (77%) carboxylic acid.

According to the method for embodiment 23, the carboxylic acid (0.290g, 0.650mmol) is converted into acyl chlorides, then with azanol reaction, obtain the Hydroxamates of 0.092g (31%).Electrospray ionization mass spectrum：455.3(M+H).

Embodiment 303

2- [benzyl-(4- propoxyl group-benzenesulfonyl)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the method for embodiment 73, the product (1.0g, 2.339mmol) and n-propanol reaction for making embodiment 65 obtain the p- positive propoxy benzsulfamide -ester of 0.456g (46%).

According to the method for embodiment 18, the sulfonamide ester (0.486g, 0.980mmol) hydrolysis is set to obtain 0,217g (49%) carboxylic acid.

According to the method for embodiment 23, the carboxylic acid (0.190g, 0.419mmol) is converted into acyl chlorides, then with azanol reaction, obtain the Hydroxamates of 0.104g (53%).Electrospray ionization mass spectrum：469.0(M+H).

Embodiment 304

2- [benzyl-(4- isopropoxies-benzenesulfonyl)-amino]-N- hydroxyl -3,5- dimethvl-benzamides

According to the method for embodiment 73, the product (2.0g, 4.68mmol) and isopropanol reaction for making embodiment 65 obtain 0.706 (30%) para-n- propoxyl group benzsulfamide -ester.

According to the method for embodiment 18, the sulfonamide ester (0.400g, 0.827mmol) hydrolysis is set to obtain 0.180g (48%) carboxylic acid.

According to the method for embodiment 23, the carboxylic acid (0.113g, 0.331mmol) is converted into acyl chlorides, then with azanol reaction, obtain the Hydroxamates of 0.056g (36%).Electrospray ionization mass spectrum：468.9(M+H)+.

Embodiment 305

5- bromos -2- (4- Fluoro-benzenesulfonyls amino) -3- methyl-benzoic acids

According to the method for embodiment 134,5- bromos -2- (4- fluoro-benzenesulfonamido-) -3- methyl-benzoic acids are provided with the product and 4- fluoro benzene sulfonyl chloride of embodiment 133, are yellow solid, yield 36%.Electrospray ionization mass spectrum：386.0(M-H)-

Embodiment 306

2- [benzyl-(4- Fluoro-benzenesulfonyls)-amino] -5- bromo -3- methyl-benzoic acid benzyl esters

0.23ml (1.923mmol) benzyl bromide a-bromotoluenes and the sodium hydrides of 0.06g (1.511mol) 60% are added to solution of 0.25g (0.687mmol) products of embodiment 305 in 5.0ml DMF.Reactant mixture is stirred at room temperature 18 hours, then diluted, be washed with water with ether, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is colorless oil with ethyl acetate/hexane (1: 10) elution there is provided the product of 0.324g (82%).Electrospray ionization mass spectrum：568.1(M+H)+.

Embodiment 307

2- [benzyl-(4- benzyloxies-benzenesulfonyl)-amino] -5- bromo -3- methyl-benzoic acids

According to the method for embodiment 73,0.185g (66%) required product is obtained with the product of 0.284g (0.493mmol) embodiment 306, is white solid.Electrospray ionization mass spectrum：565.9.(M-H)-

Embodiment 308

2- [benzyl-(4- benzyloxies-benzenesulfonyl)-amino] -5- bromos-N- hydroxy-3-methyls-benzamide

According to the method for embodiment 23,0.131g (76%) required product is obtained with the product of 0.168g (0.297mmol) embodiment 307, is white solid.Electrospray ionization mass spectrum：581.0.(M+H)+

Embodiment 309

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- morpholine -4- ylmethvl-benzamides

According to the method for embodiment 189, with the product (0.50g, 1.168mmol) and morpholine of embodiment 188,0.325g (64%) benzyl amine -ester (benzylic amine-ester) is obtained.

According to the method for embodiment 190,0.291g (0.670mmol) ester hydrolysis is set to obtain 0.286g (100%) carboxylic acid.

According to the method for embodiment 23,0.186g hydroxamic acid is obtained with the carboxylic acid (0.229g, 0.536mmol), is white solid.Hydroxamate is dissolved in 4ml dichloromethane and 0.2ml methanol, add 1.0M hydrochloric acid of the 0.85ml in ether.The reactant being stirred at room temperature 1 hour, being diluted with ether, the solid of generation is collected by filtration, it is vacuum dried to obtain 0.139g hydroxamic acid-amine salt, it is white solid.Electrospray ionization mass spectrum：435.9(M+H)+.

Embodiment 310

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- pyrrolidin-1-yl methyl-benzamides

According to the method for embodiment 189, with the product (0.50g, 1.168mmol) and pyrrolidines of embodiment 188,0.327g (69%) benzyl amine -ester is obtained.

According to the method for embodiment 190,0.307g (0.734mmol) ester hydrolysis is set to obtain 0.302g (100%) carboxylic acid.

According to the method for embodiment 309,0.127g hydroxamic acid-amine salt is obtained with the 0.251g carboxylic acid (0.610mmol), is white solid.Electrospray ionization mass spectrum：419.9(M+H)+.

Embodiment 311

N- hydroxyl -3- imidazole radicals -1- ylmethyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzamide

According to the method for embodiment 189, with the product (0.75g, 1.752mmol) and imidazolidine of embodiment 188,0.441 (61%) benzyl amine -ester is obtained.

According to the method for embodiment 190,0.435g (1.048mmol) ester hydrolysis is set to obtain 0.308g (72%) carboxylic acid.

According to the method for embodiment 309,0.154g hydroxamic acid-amine salt is obtained with the 0.261g carboxylic acid (0.640mmol), is white solid.Electrospray ionization mass spectrum：416.9(M+H)+.

Embodiment 312

5- bromos -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- (4- thyl-piperazin -1- ylmethyl-benzoic acid methyl esters

1.56g (8.76mmol) N-bromosuccinimide is added to solution of the product of 3.0g (7.01 mmol) embodiment 202 in 170ml carbon tetrachloride, the mixture of heating generation uses sun light irradiation 3 hours simultaneously to flowing back.Reactant mixture is cooled down, is washed with water, is dried with magnesium sulfate, filters and is concentrated in vacuo.

Solution of the benzyl bromide a-bromotoluene generated to 0.477g (0.941mmol) in 5.0ml DMF adds 0.115ml (1.035mmol) N methyl piperazines and 0.389g (2.822mmol) potassium carbonate.Then reactant mixture is stirred at room temperature overnight, is diluted with ether, is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is brown oil with methylene chloride/methanol (9: 1) elution there is provided the product of 0.29g (59%).Electrospray ionization mass spectrum：526.1(M+H)+.

Embodiment 313

5- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzamide

According to the method for embodiment 190, with the 0.25g products (0.475mmol) of embodiment 312, the carboxylate needed for 0.475g (100%) is obtained.

According to the method for embodiment 309, the carboxylate is converted into corresponding hydroxamic acid-amine salt, white solid is separated into.Electrospray ionization mass spectrum：527.1(M+H)+.

Embodiment 314

5- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-methylamino] -3- pyrrolidin-1-yl methyl-benzamides

According to the method for embodiment 312, with the product and pyrrolidines of embodiment 202, benzyl amine -ester is obtained.

According to the method for embodiment 190, the ester is converted into corresponding carboxylate.

According to the method for embodiment 309, the carboxylate is converted into corresponding hydroxamic acid-amine salt, is brown solid.Electrospray ionization mass spectrum：498.0(M+H)+.

Embodiment 315

2- [(4- methoxy-benzenesulfonvls)-(t-butoxy carbonyl)-amino] -3- methyl-benzoic acid methyl esters

1.95g (8.955mmol) di-tert-butyl dicarbonates and 0.228g (1.866mmol) 4-dimethylaminopyridine are added to the solution of 10ml DMF and the 6.0ml pyridines of the product of 2.5g (7.463mmol) embodiment 3.The mixture for stirring generation at room temperature is stayed overnight, and is then diluted with ether, is washed with 5% hydrochloric acid solution, water and 1N sodium hydroxide solutions, is then dried organic matter with magnesium sulfate, is filtered and be concentrated in vacuo.Residue is ground with ether/hexane (1: 1), is obtained the product of 3.2g (98%), is white solid.Electrospray ionization mass spectrum：436.0(M+H)+.

Embodiment 316

2- [(4- methoxy-benzenesulfonvls)-(t-butoxy carbonyl)-amino] -3- (pyrrolidin-1-yl methyl)-methyl benzoate

1.498g (8.414mmol) N-bromosuccinimide is added to solution of the product of 3.05g (7.011mmol) embodiment 315 in 165ml carbon tetrachloride, the mixture of heating generation uses sun light irradiation 3 hours simultaneously to flowing back.Reactant mixture is cooled down, is washed with water, is dried with magnesium sulfate, filters and is concentrated in vacuo.

0.644ml (7,71mmol) pyrrolidines and 2.90g potassium carbonate are added to the benzyl bromide solution of the generation in 30.0ml DMF.Then reactant mixture is stirred at room temperature overnight, is diluted with ether, is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is white solid with chloroform/methanol (9: 1) elution there is provided the product of 2.076g (59%).Electrospray ionization mass spectrum：505.2(M+H)+.

Embodiment 317

2- [(4- methoxy-benzenesulfonvls amino) -3- pyrrolidin-1-yl methyl-benzoic acid methyl esters

10.0ml trifluoroacetic acids are added to the 10ml dichloromethane solutions of the product of embodiment 316.The solution of generation is stirred at room temperature 1 hour.Then it is concentrated in vacuo, the residue of generation is diluted with ether, is washed with saturated sodium bicarbonate solution, it is dried over sodium sulfate, filter and be concentrated in vacuo.Residue provides the 0.93g products of (57%) after triturated under ether, is faint yellow solid.Electrospray ionization mass spectrum：405.1(M+H)+.

Embodiment 318

2- [(4- methoxy-benzenesulfonvls)-ylmethyl-amino of pyridine -3] -3- pyrrolidin-1-yl methyl-benzoic acid methyl esters

According to the method for embodiment 45, with 0.80g (1.98mmol) product of embodiment 317, the product of 0.804g (82%) is obtained, is brown solid.Electrospray ionization mass spectrum：496.5(M+H)+.

Embodiment 319

2- [(4- methoxy-benzenesulfonvls)-ylmethyl-amino of pyridine -3] -3- pyrrolidin-1-yl methyl-benzoic acids

7.6ml 1.0N sodium hydroxide solutions are added to 15ml THF/ methanol (1: 1) solution of the product of 0.754 (1.523mmol) embodiment 318.The mixture of generation is heated to backflow 15 hours, is then concentrated in vacuo, the residue of generation is diluted with water, is neutralized, is extracted with dichloromethane with 5% hydrochloric acid solution.Organic matter is dried over sodium sulfate, filters and is concentrated in vacuo there is provided the product of 0.496g (67%), is brown solid.Electrospray ionization mass spectrum：482.5(M+H)+.

Embodiment 320

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-ylmethyl-amino of pyridine -3] -3- pyrrolidin-1-yl methyl-benzamides

According to the method for embodiment 61, with the product of embodiment 319,0.174g hydroxamic acid is obtained, is brown solid.Electrospray ionization mass spectrum：497.5(M+H)+.

Embodiment 321

3- formoxyls -2- [(4- methoxy-benzenesulfonvls amino)-methyl benzoates

0.20g dibenzoyl peroxides 1.168g (6.568mmol) N-bromosuccinimide is added to solution of the product of 1.0g (2.985mmol) embodiment 3 in 100ml carbon tetrachloride; the mixture of generation is flowed back 18 hours; cooling; with sodium hydrogensulfite and water washing; dried with magnesium sulfate, filter and be concentrated in vacuo.Residue is diluted with 10mlTHF and 10ml 1N sodium hydroxide solutions, the mixture is stirred at room temperature 3 hours.Then with 5% hydrochloric acid solution acidified reaction mixture, extracted with ether.Organic matter is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue triturated under ether, there is provided the product of 0.447g (47%), is white solid.Electrospray ionization mass spectrum：350.1(M+H)+.

Embodiment 322

3- formoxyls -2- [(4- methoxy-benzenesulfonvls)-octyl group-amino]-methyl benzoate

0.143g (3.582mmol) 60% sodium hydride is added to solution of the product of 1.0g (2.865mmol) embodiment 321 in 7.5ml DMF, 0.74ml (4.30mmol) n- n-octyl bromide is subsequently added into.The reactant is stirred at room temperature overnight, then diluted with ether, is washed with water, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is white solid with ethyl acetate/hexane (1: 3) elution there is provided the product of 0.592g (49%).Electrospray ionization mass spectrum：462.1(M+H)+.

Embodiment 323

3- methylols -2- [(4- methoxy-benzenesulfonvls)-octyl group-amino]-methyl benzoate

0.045g (1.187mmol) sodium borohydride is added to solution of the product of 0.547g (1.187mmol) embodiment 332 in 10ml methanol and 3ml THF.The reactant being stirred at room temperature 2 hours, being then concentrated in vacuo, residue is diluted with ether, it is dried over magnesium sulfate with 5% hydrochloric acid and water washing, filter and be concentrated in vacuo that there is provided grease colourless 0.549g (100%).Electrospray ionization mass spectrum：464.2(M+H)+.

Embodiment 324

2- [(4- methoxy-benzenesulfonvls)-octyl group-amino] -3- (4- thyl-piperazin -1- ylmethyls)-methyl benzoate

0.438g (1.668mmol) triphenyl phasphines and 0.461g (1.390mmol) carbon tetrachloride are added to the dichloromethane solution of the product of 0.515g (1.112mmol) embodiment 323.The mixture is stirred at room temperature 1 hour, be then concentrated in vacuo.Make residue by silicagel pad, with ethyl acetate: there is provided benzyl bromide a-bromotoluene for hexane (1: 10) elution.

0.136ml (1.224mmol) N methyl piperazines and 0.491g (3.559mmol) potassium carbonate are added to the 6.0ml DMF solutions of the bromide.Reactant mixture is stirred at room temperature to stay overnight, is diluted with ether, is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo the benzyl amine -ester there is provided 0.57g (94%), be white solid.Electrospray ionization mass spectrum：546.2(M+H)+.

Embodiment 325

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-octyl group-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzamide

According to the method for embodiment 18, the product of 0.507g (0.930mmol) embodiment 324 is set to be converted into corresponding carboxylate.

According to the method for embodiment 61,0.343g hydroxamic acid is obtained with the carboxylate, is brown solid.Electrospray ionization mass spectrum：547.7(M+H).

Embodiment 326

3- formoxyls -2- [(4- methoxy-benzenesulfonvls)-thiene-3-yl Methyl-amino]-methyl benzoate

According to the method for embodiment 322, the product and 3- bromomethyls thiophene for making 1.0g (2.865mmol) embodiment 321 are reacted, and by silica gel chromatography is eluted with ethyl acetate/hexane (1: 3), 1.10g (86%) product is obtained, is white solid.Electrospray ionization mass spectrum：446.1(M+H)+.

Embodiment 327

2- [(4- methoxy-benzenesulfonvls)-thiene-3-yl Methyl-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzoic acid

According to the method for embodiment 323, the product of 1.06g (2.3870mmol) embodiment 326 is set to be converted into corresponding alcohol.

According to the method for embodiment 324, the alcohol is converted into corresponding benzyl amine -ester

According to the method for embodiment 319,0.52g carboxylic acid is obtained, is white solid.Electrospray ionization mass spectrum：516.2(M+H).

Embodiment 328

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-thiene-3-yl Methyl-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzamide

0.149g (1.107mmol) HOBT and 0.235g (1.227mmol) EDC are added to the 8.0ml DMF solutions of the product of 0.475g (0.922mmol) embodiment 327.The reactant is stirred at room temperature 1 hour, add 0.28ml (4.612mmol) 50% aqueous hydroxylamine solution.Then reaction stirred is stayed overnight and is concentrated in vacuo.Residue with Ethyl acetate dilutes, and is washed with water and sodium bicarbonate aqueous solution, dried over sodium sulfate, filters and concentrates.Residue is dissolved in 5.0ml dichloromethane, add the diethyl ether solution of 1.8ml 1N hydrochloric acid.The reactant is diluted with ether after 1 hour, solid and the vacuum drying of generation is filtered, obtains 0.242g product, be white solid.Electrospray ionization mass spectrum：531.5(M+H).

Embodiment 329

N- hydroxyls -2- [[(4- methoxyphenyls) sulfonyl] (phenyl methyl)-amino] -3- (4- methyl isophthalic acids-piperazinyl) methyl]-benzamide

According to the method for embodiment 322, make the product and benzyl bromine reaction of 1.25g (3.582mmol) embodiment 321, obtain N- benzyl sulfonamide

According to the method for embodiment 327 and 328,0.204g hydroxamic acid is obtained with the sulfonamide, is white solid.Electrospray ionization mass spectrum：525.4(M+H)+.

Embodiment 330

2- (4- methoxy-benzenesulfonvls amino) -3- methyl-benzoic acid tert-butyl esters

50ml DMF di-t-butyl acetal is added to solution of the product of 15.0g (0.047mol) embodiment 6 in 45ml toluene, the mixture is then heated to backflow 18 hours.The reactant is cooled down to room temperature, by silica gel chromatography, with ethyl acetate/hexane (1: 3) elution there is provided the product of 8.94g (51%), is white solid.Electrospray ionization mass spectrum：378.1(M+H)+.

Embodiment 331

2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acid tert-butyl esters

According to the same procedure described in embodiment 187, using the product of 2.5g (6.631mmol) embodiment 330,2.59g (100%) N- methylsulfonamides are obtained, are white foam thing.Electrospray ionization mass spectrum：392.4(M+H)+.

Embodiment 332

(2S) -1- { 3- t-butoxy carbonyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzyl }-pyrrolidines -2- methyl formates

Pyrrolidines is replaced according to the method described in embodiment 316, but with L-PROLINE methyl ester hydrochloride, with the product of 2.30g (5.882mmol) embodiment 331, the diester of 1.45g (48%) is obtained, is white solid.Electrospray ionization mass spectrum：519.5(M+H)+.

Embodiment 333

(2S) -1- { 3- carboxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzyl }-pyrrolidines -2- methyl formates

5.0ml trifluoroacetic acids are added to the 5.0ml dichloromethane solutions of the product of 1.39g (2.678mmol) embodiment 332, the reactant is stirred at room temperature 2 hours, is then concentrated in vacuo.Residue by silica gel chromatography, the carboxylic acid of 1.24g (100%) is afforded with chloroform/methanol (9: 1), is white foam thing.Electrospray ionization mass spectrum：463.0(M+H)+.

Embodiment 334

(2S) -1- { 3- Hydroxycarboamoyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzyl }-pyrrolidines -2- methyl formates

According to the method described in embodiment 61, with the product of 1.305g (2.262mmol) embodiment 333,0.285g hydroxamic acid is obtained, is brown solid.Electrospray ionization mass spectrum：478.1(M+H)+.

Embodiment 335

3- formoxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-methyl benzoate

0.099g (0.602mmol) 3- picolyl chloride hydrochlorides and 0.249g (1.805mmol) potassium carbonate are added into the 2.5ml DMF solutions of the product of 0.20g (0.573mmol) embodiment 321, the reactant is stirred at room temperature 18 hours, then reactant is diluted with water, is extracted with ether.The organic matter of merging is washed with water.It is dried over sodium sulfate, filter and be concentrated in vacuo, product needed for residue obtains 0.158g (63%) through triturated under ether, is tan crystals.Electrospray ionization mass spectrum：440.9(M+H)+.

Embodiment 336

3- methylols -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-methyl benzoate

8.6mg sodium borohydrides are added to solution of the product of 0.10g (0.227mmol) embodiment 335 in 5ml methanol and 2.0ml THF.The reactant is stirred at room temperature 1 hour, be then concentrated in vacuo, use dchloromethane residue, it is washed with water, then dries organic matter with sodium sulphate, filter and be concentrated in vacuo, the brown solid of generation is washed with ether, and is dried in vacuo the alcohol for obtaining 0.086g (86%).Electrospray ionization mass spectrum：442.9(M+H)+.

Embodiment 337

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- (ttetrahydro-pyran -2- base epoxides methyl)-methyl benzoate

0.21ml (2.262mmol) dihydropyran and 0.030g toluenesulfonic acid monohydrates are added to solution of the product of 0.500g embodiments 336 in 15ml dichloromethane.The reactant is stirred at room temperature 24 hours, then use dchloromethane.With 1N sodium hydroxide solutions and water washing organic matter, dried with sodium sulphate, filter and be concentrated in vacuo, residue by silica gel chromatography is eluted with ethyl acetate, obtain 0.436g (73%) THP- ethers, be brown foam thing.Electrospray ionization mass spectrum：527.2(M+H)+.

Embodiment 338

2- [[(4- methoxyphenyls) sulfonyl] (3- picolyls) amino] -3- [[(tetrahydrochysene -2H- pyrans -2- bases) epoxide] methyl] benzoic acid

According to the method for embodiment 190,0.370g (100%) carboxylate is obtained with the product of 0.376g (0.715mmol) embodiment 337, is brown foam thing.Electrospray ionization mass spectrum：511.1(M-H)-.

Embodiment 339

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- (ttetrahydro-pyran -2- base epoxides methyl)-benzamide

0.269g (1.995mmol) HOBT (I-hydroxybenzotriazole) and 0.424g (2.211mmol) 1- (3- dimethylaminopropyls) -3- ethyl-carbodiimide hydrochlorides (EDC) are added to the 10.0ml DMF solutions of the product of 0.851g (1.662mmol) embodiment 338.The reactant is stirred at room temperature 1 hour, add 0.578g (8.311mmol) hydroxylamine hydrochloride and 1.73ml triethylamines.Reaction stirred is stayed overnight.Then it is concentrated in vacuo.Residue is diluted with ether, is washed with water and sodium bicarbonate aqueous solution, dried over sodium sulfate, is filtered and is concentrated in vacuo there is provided the hydroxamic acid of 0.635g (72%), is brown colored foams thing.Electrospray ionization mass spectrum：528.1(M+H)+.

Embodiment 340

N- hydroxyl -3- methylols -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzamide

The ethereal solution of 1.3ml 1M hydrochloric acid is added to the 6.5ml dichloromethane and 1.3ml methanol solutions of the product of 0.352g (0.668mmol) embodiment 339.The reactant being stirred at room temperature 5 hours, the precipitation of generation being collected by filtration, is washed with ether, vacuum drying obtains the alcohol of 0.320g (100%), is white solid.Electrospray ionization mass spectrum：444.2(M+H)+.

Embodiment 341

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (2- carboxyls-ethyoxyl)-methyl benzoate

5.0ml trifluoroacetic acids are added to the 20ml dichloromethane solutions of the product of 2.53g (4.677mmol) embodiment 38.The reactant is stirred at room temperature 3 hours, be then concentrated in vacuo.Residue is ground through ether/hexane (1: 1), and the white solid (2.063g) of generation is collected by filtration and is concentrated in vacuo.

Then the carboxylic acid is dissolved in and is cooled to 0 DEG C of anhydrous THF of 40ml, add 19.6ml 1M borines/THF solution.The reactant is set to warm to room temperature and stir 18 hours.Use 10ml hydrochloric acid：The reaction is quenched in water (1: 1), is diluted with water, is extracted with ether.Organic matter is dried with magnesium sulfate, filters and is concentrated in vacuo, residue by silica gel chromatography is eluted with ethyl acetate/hexane, obtains 1.845 alcohol, be white solid electrospray ionization mass spectrums：472.2(M+H)+.

Embodiment 342

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- (2- Hydroxy-ethoxies)-benzoic acid

15.5ml 1N sodium hydroxide solutions are added to 30ml THF/ methanol (1: 1) solution of the product of 1.459g (3.098mmol) embodiment 341, heating response mixture to backflow is stayed overnight.Then the reactant is cooled to room temperature, be acidified, extracted with ether with 5% hydrochloric acid solution.The organic matter merged is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, is white solid with ethyl acetate/hexane (2: 1) elution there is provided 1.22g carboxyl -ol.Electrospray ionization mass spectrum：456.1(M-H)-.

Embodiment 343

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [2- (t-butyl-dimethyI-sila epoxide)-ethyoxyl]-benzoic acid

0.966g (6.407mmol) tert-butyl dimethylsilyl chlorine and 0.908g (0.013mmol) imidazoles are added to the 6.0ml DMF solutions of the product of 1.22g (2.67mmol) embodiment 342.Reactant is stirred at room temperature 5 hours, then diluted with water and 1N sodium hydroxide solutions.It is stirred for 1 hour.Then the reactant is acidified to pH 5, is extracted with ether.The organic matter merged is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, is white solid with ethyl acetate/hexane (1: 3) elution there is provided the carboxylic acid of 1.34g (88%).Electrospray ionization mass spectrum：570.0(M+H)+.

Embodiment 344

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [2- (t-butyl-dimethyI-sila epoxide)-ethyoxyl]-N- hydroxy-benzoyIamides

According to the method described in embodiment 328, with the product of 1.107g (1.939mmol) embodiment 343, the hydroxamic acid of 1.0g (88%) is obtained, is white foam thing.Electrospray ionization mass spectrum：587.6(M+H)+.

Embodiment 345

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (2- Hydroxy-ethoxies)-benzamide

The hydrofluoric acid of 1.5ml 48% is added to the 20ml acetonitrile solutions of the product of 0.957g (1.633mmol) embodiment 344.Reactant is stirred at room temperature 3 hours, then with dchloromethane, be washed with water.The organic matter merged is dried with magnesium sulfate, filters and is concentrated in vacuo there is provided the hydroxamic acid of 0.76g (99%), be white foam thing.Electrospray ionization mass spectrum：473.3(M+H)+.

Embodiment 346

2- { 5- bromos -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- (methoxycarbonyl-benzyl }-dimethyl malenate

0.749g (4.206mmol) N-bromosuccinimides and 0.06g dibenzoyl peroxides are added to solution of the product of 1.50g (3.505mmol) embodiment 202 in 65ml carbon tetrachloride.The reactant is heated to flowing back 15 hours, cooling is washed with water, and dries organic matter with magnesium sulfate, filters and be concentrated in vacuo.Residue by silica gel chromatography, with ethyl acetate/hexane (1: 3) elution, there is provided 1.46g benzyl bromide a-bromotoluene (benzylic bromide).

0.39ml (3.456mmol) dimethyl malenate is added to the benzyl bromide solution in 7.5ml DMF, 0.171g (3.168mmol) sodium methoxide is subsequently added into.Stir the mixture 24 hours at room temperature.Then with 10% hydrochloric acid solution acidified reaction mixture, extracted with ether.Organic matter is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue by silica gel chromatography, is colorless oil with ethyl acetate/hexane (1: 3) elution there is provided 0.766g (48%) three esters.Electrospray ionization mass spectrum：558.0(M+H)+.

Embodiment 347

2- { 5- bromo -3- carboxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzyl }-malonic acid

According to the method described in embodiment 342, with the product of 0.674g (1.208mmol) embodiment 45,0.623g (100%) three acid are obtained, are brown colored foams thing.Electrospray ionization mass spectrum：513.9(M-H)-.

Embodiment 348

5- bromos -3- (2- CARBOXY-ETHYLs) -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzoic acid

The solution of the product of 0.542g (1.050mmol) embodiment 347 in 25ml pyridines is heated to backflow 12 hours, room temperature is subsequently cooled to.The reactant is diluted with water, is acidified with 10% hydrochloric acid solution, ester is extracted with acetic acid.Organic matter is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue triturated under ether, there is provided the diester of 0.339g (48%), is brown solid.Electrospray ionization mass spectrum：470.0(M-H)-.

Embodiment 349

5- bromo-N- hydroxyls -3- [2- (Hydroxycarboamoyl)-ethyl] -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzamide

According to the method described in embodiment 23, with the product of 0.304g (0.644mmol) embodiment 348,0.114g (35%) double-hydroxamic acid is obtained, is white solid.Electrospray ionization mass spectrum：504.0(M+H)+.

Embodiment 350

N- hydroxyls -3- [2- (Hydroxycarboamoyl)-ethyl] -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzamide

According to the method described in embodiment 346-349, with the product of embodiment 188, obtained double-hydroxamic acid, is white foam thing.Electrospray ionization mass spectrum：424.2(M+H)+.

Embodiment 351

5- xenyl -4- ethyl-acetylene bases -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

0.50g (2.804mmol) ethynylbiphenyl, double (triphenyl phasphine) palladium chlorides (II) of 0.033g (0.047mmol), 4.4mg cuprous iodides (I) and 7.5ml triethylamines are added to the 7.5ml DMF solutions of the product of 1.0g (2.336mmol) embodiment 202.The reactant is heated to 80 DEG C 5 hours, diluted with ether.Organic matter is washed with water, 5% hydrochloric acid and sodium bicarbonate solution, it is dried over magnesium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, the alkynes for providing 0.777g (63%) is eluted with ethylacetate-hexane (1: 3), is brown foam thing.Electrospray ionization mass spectrum：526.2(M+H)+.

Embodiment 352

5- xenyl -4- ethyl-acetylene bases -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acids

According to the method described in embodiment 18, with the product of 0.400g (0.762mmol) embodiment 351, the carboxylic acid of 0.383g (98%) is obtained, is brown foam thing.Electrospray ionization mass spectrum：510.1(M+H)+.

Embodiment 353

5- xenyl -4- ethyl-acetylene base-N- hydroxyls 2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides

According to the method described in embodiment 23, with the product of 0.132g (0.258mmol) embodiment 352, the hydroxamic acid of 0.107g (79%) is obtained, is yellow solid.Electrospray ionization mass spectrum：527.1(M+H)+.

Embodiment 354

5- (2- xenyls -4- bases-ethyl) -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acids

The solution of 25ml methanol and 10ml ethyl acetate to the product of 0.20g (0.391mmol) embodiment 352 adds the palladium charcoals of 0.050g 10%.Make mixture hydrogenation 5 hours in Parr devices (30psi hydrogen), then filtered by Celite, then Celite pads are washed with 100ml methanol and 100ml ethyl acetate, it is concentrated in vacuo filtrate, residue triturated under ether, 0.173g (86%) carboxylic acid is provided, is faint yellow solid.Electrospray ionization mass spectrum：514.2(M-H)-.

Embodiment 355

5- (2- xenyls -4- bases-ethyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides

According to the method described in embodiment 23, with the product of 0.138g (0.268mmol) embodiment 354, the hydroxamic acid of 0.091g (64%) is obtained, is yellow solid.Electrospray ionization mass spectrum：531.1(M+H)+.

Embodiment 356

- 1- alkynyls-the 2- of 5- 12 [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the method described in embodiment 351, ethynylbiphenyl is replaced with 1- dodecynes, with the product of 1.0g (2.336mmol) embodiment 202, the alkynes of 0.874g (73%) is obtained, is brown oil.Electrospray ionization mass spectrum：514.4(M+H)+.

Embodiment 357

- 1- alkynyls-the 2- of 5- 12 [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acids

According to the method described in embodiment 18, with the product of 0.808g (1.575mmol) embodiment 356, the carboxylic acid of 0.731g (93%) is obtained, is pale yellow oil.Electrospray ionization mass spectrum：498.2(M-H)-.

Embodiment 358

5- 12-1- alkynyl-N- hydroxyls-2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-3- methyl-benzamides

According to the method described in embodiment 23, with the product of 0.200g (0.401mmol) embodiment 357, the hydroxamic acid of 0.170g (83%) is obtained, is colorless oil.Electrospray ionization mass spectrum：515.2(M+H)+.

Embodiment 359

5- dodecyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzoic acids

According to the method described in embodiment 354, with the product of 0.217g (0.435mmol) embodiment 357, the carboxylic acid of 0.214g (98%) is obtained, is white solid.Electrospray ionization mass spectrum：502.3(M-H)-.

Embodiment 360

5- dodecyl-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides

According to the method described in embodiment 23, with the product of 0.189g (0.376mmol) embodiment 359, the hydroxamic acid of 0.153g (79%) is obtained, is brown oil.Electrospray ionization mass spectrum：519.2(M+H)+.

Embodiment 361

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methoxies-methyl benzoate

0.022g (0.543mmol) 60% sodium hydride is added to the 5.0ml anhydrous THF solutions of the product of 0.20g (0.452mmol) embodiment 336,0.028ml iodomethanes are subsequently added into.The reactant is stirred at room temperature 18 hours, then diluted with ethyl acetate.It is dried over sodium sulfate with water and salt water washing, filter and be concentrated in vacuo.Residue by silica gel chromatography, the methyl ether for providing 0.057g (28%) is eluted with ethyl acetate, is yellow solid.Electrospray ionization mass spectrum：457.3(M+H)+.

Embodiment 362

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3-

According to the method described in embodiment 53, with the product of 0.275g (0.603mmol) embodiment 361, the hydroxamic acid of 0.267g (100%) is obtained, is yellow colored foam thing.Electrospray ionization mass spectrum：443.1(M+H)+.

Embodiment 363

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methoxies-benzamide

According to the method described in embodiment 328, with the product of 0.260g (0.588mmol) embodiment 362,0.151g hydroxamic acid is obtained, is brown solid.Electrospray ionization mass spectrum：456.3(M-H)-.

Embodiment 364

3- formoxyls -2- (4- methoxy-benzenesulfonvls amino)-t-butyl perbenzoate

According to the method described in embodiment 321, with the product of 1.90g (5.04mmol) embodiment 330,1.19g aldehyde is obtained, is faint yellow solid.Electrospray ionization mass spectrum：392.2(M+H)+.

Embodiment 365

3- formoxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-t-butyl perbenzoate

According to the method described in embodiment 335, with the product of 1.106g (2.829mmol) embodiment 364,1.282g (94%) N- picolyl sulfonamide is obtained, is brown oil.Electrospray ionization mass spectrum：483.4(M+H)+.

Embodiment 366

2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-tert-butyl ester of isophthalic acid-one

The solution of 40ml water and 25ml THF to the product of 0.417g (0.865mmol) embodiment 365 adds 0.126g (1.298mmol) sulfamic acid and 0.122g (1.341mmol) sodium chlorite.The reactant is stirred at room temperature to stay overnight, and is then concentrated in vacuo.Residue diluted with water, is extracted with chloroform, organic matter dried over sodium sulfate, is filtered and is concentrated in vacuo.Residue triturated under ether, there is provided the carboxylic acid of 0.080g (77%), is faint yellow solid.Electrospray ionization mass spectrum：499.4(M+H)+.

Embodiment 367

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-isophthalic acid tert- butyl ester

According to the method described in embodiment 328, with the product of 0.354g (0.711mmol) embodiment 366, the hydroxamic acid of 0.063g (17%) is obtained, is brown foam thing.Electrospray ionization mass spectrum：514.3(M+H)+.

Embodiment 368

The methyl esters of 2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-isophthalic acid one

According to the method described in embodiment 366, with the product of 0.10g (0.227mmol) embodiment 335, the carboxylic acid of 0.080g (77%) is obtained, is white solid.Electrospray ionization mass spectrum：457.3(M+H)+.

Embodiment 369

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-isophthalic acid methyl esters

According to the method for embodiment 23, the hydroxamic acid of 0.48g (77%) is obtained with the product of 0.600g (1.316mmol) embodiment 368.Hydroxamate is dissolved in 10.0ml dichloromethane and 0.5ml methanol, add the 2.0ml 1N hydrochloric acid solutions in ether.After 1 hour, the solid of generation is filtered, it is vacuum dried to obtain 0.358g products, it is brown solid.Electrospray ionization mass spectrum：472.2(M+H)+.

Embodiment 370

3- acetoxy-methyl -5- bromos -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-methyl benzoate

0.457g (2.57mmol) N-bromosuccinimide is added to solution of the product of 1.00g (2.336mmol) embodiment 202 in 50ml carbon tetrachloride, reactant is set to be heated within 1 hour backflow in sun light irradiation, cooling, it is washed with water, organic matter is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue is dissolved in 15ml DMF, add 0.958g (0.012mmol) sodium acetate.The reactant is heated to 80 DEG C 4 hours, room temperature is cooled to, is diluted with ether.Organic matter is washed with water, magnesium sulfate is dried, filters and be concentrated in vacuo.Residue by silica gel chromatography, is colorless oil with ethyl acetate/hexane (1: 3) elution there is provided the acetic acid esters of 0.408g (36%).Electrospray ionization mass spectrum：487.8(M+H)+.

Embodiment 371

The methyl esters of 5- bromos -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-isophthalic acid one

0.87ml 1N sodium hydroxide solutions are added to 2.0ml THF/ methanol (1: 1) solution of the product of 0.272g (0.826mmol) embodiment 370, the reactant are stirred at room temperature 3 hours.Then the reactant is extracted with ether.The organic matter merged is dried with magnesium sulfate, filters and is concentrated in vacuo.Residue, there is provided 0.241g alcohol, is white solid through triturated under ether.

The alcohol is dissolved in 1.5ml DMF, 0.366g (0.973mmol) pyridinium dichromate is added, stirs the reactant and stay overnight.Use ether diluted reaction mixture, it is washed with water, it is dried over magnesium sulfate, filter and be concentrated in vacuo, dissolve the residue in 17ml THF and 28ml water, add 0.091g (1.005mmol) sodium chlorites and 0.094g (0.973mmol) sulfamic acid.The reactant is stirred at room temperature to stay overnight, and is concentrated in vacuo, is washed with water, is extracted with chloroform.Organic layer dried over magnesium sulfate, filters and is concentrated in vacuo, and residue, there is provided 0.282g carboxylic acid, is white solid through triturated under ether.Electrospray ionization mass spectrum：456(M-H)-.

Embodiment 372

The methyl esters of 2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-isophthalic acid one

According to the method described in embodiment 370, with the product of 0.50g (1.168mmol) embodiment 188, the acetic acid esters of 0.314g (66%) is obtained.According to the method described in embodiment 371, with 0.287g (0.705mmol) acetic acid esters, the carboxylic acid of 0.152g (66%) is obtained, is white solid.Electrospray ionization mass spectrum：377.9(M-H)-.

Embodiment 373

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls) Methyl-amino]-isophthalamic acid methyl ester

According to the method described in embodiment 23, with the product of 0.126g (0.332mmol) embodiment 372, the hydroxamic acid of 0.116g (89%) is obtained, is white solid.Electrospray ionization mass spectrum：394.8(M+H)+.

Embodiment 374

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-isophthalamic acid

2ml trifluoroacetic acids are added to the solution for the product of 0.235g (0.458mmol) embodiment 367 for being dissolved in 5ml dichloromethane, the reactant is stirred at room temperature 2 hours, then it is concentrated in vacuo, residue triturated under ether, the solid and vacuum concentration of generation is collected by filtration, the hydroxamic acid of 0.178g (65%) is obtained, is brown solid.Electrospray ionization mass spectrum：456.4(M-H)-.

Embodiment 375

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridine -2- ylmethyl-aminos] -3- methyl-benzamides

According to the method for embodiment 45, the product for making 0.750g (2.239mmol) embodiment 3 with 2- picolyl chloride hydrochlorides is alkylated, and obtains 0.916g (96%) N- picolyl sulfonamide.

According to the method for embodiment 53, the ester hydrolysis is set to obtain corresponding carboxylic acid.

According to the method for embodiment 369, the carboxylic acid is converted into hydroxamic acid, obtain 0.180g pyridiniujms, be brown foam thing.Electrospray ionization mass spectrum：428.1(M+H)+.

Embodiment 376

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-4-yl Methyl-amino] -3- methyl-benzamides

According to the method for embodiment 45, the product for making 0.750g (2.239mmol) embodiment 3 with 4- picolyl chloride hydrochlorides is alkylated, and obtains 0.897g (94%) N- picolyl sulfonamide.

According to the method for embodiment 53, the ester hydrolysis is set to obtain corresponding carboxylic acid.

According to the method for embodiment 369, the carboxylic acid is converted into hydroxamic acid, obtain 0.180g pyridiniujms, be brown foam thing.Electrospray ionization mass spectrum：428.1(M+H)+.

Embodiment 377

2- [(4- diethylaminos methyl-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide

According to the method for embodiment 9, the product for making 1.50g (4.478mmol) embodiment 3 with 4- ethoxycarbonyl benzyl bromide a-bromotoluenes is alkylated, obtains the Benzylation sulfonamide of 2.00g (93%), be brown solid.Electrospray ionization mass spectrum：484.2(M+H)+.

The ester is dissolved in 9.0ml methanol/THF (1: 1), add 4.3ml 1.0N sodium hydroxide solutions, the reactant is stirred at room temperature 3 hours, it is acidified with 5% hydrochloric acid solution, it is extracted with ethyl acetate, the organic matter merged is dried with magnesium sulfate, filters and is concentrated in vacuo, the carboxylic acid for white solid is obtained, is washed and dried with grinding.Electrospray ionization mass spectrum：468.5(M-H)-.

Such as the method for be the same as Example 341, reducing the carboxylic acid with borine-THF, there is provided the alcohol for white solid.Electrospray ionization mass spectrum：456.2(M+H)+.

According to the method for embodiment 324, the alcohol is converted into corresponding diethylamine, white solid is separated to obtain.Electrospray ionization mass spectrum：511.5(M+H)+.

According to the method for embodiment 319, benzoic ether is hydrolyzed, be then converted into hydroxamic acid, and according to the method forming salt of embodiment 369, obtain 0.105g Hydroxamates, be white solid.Electrospray ionization mass spectrum：512.1(M+H)+.

Embodiment 378

2- [(4- dimethylaminomethyls-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide

According to the method for embodiment 377, the product of 1.50g (4.478mmol) embodiment 3 is converted into dimethylamine-Hydroxamates, white foam thing is separated to.Electrospray ionization mass spectrum：483.9(M+H)+.

Embodiment 379

2- [(4- methoxy-benzenesulfonvls) -propyl- 2- alkynyl-amino groups] -3- methyl-benzoic acid methyl esters

According to the method for embodiment 9, the product for making 1.50g (4.478mmol) embodiment 3 with propargyl bromide is alkylated, obtains 1.33g (79%) sulfonyl propyl amine, be white solid.Electrospray ionization mass spectrum：374.3(M+H)+.

Embodiment 380

2- [(4- diethylaminos-butyl- 2- alkynyls)-(4- methoxy-benzenesulfonvls)-amino] -3- methyl-benzoic acid methyl esters

The solution of 11ml dioxane and 1.3ml acetic acid to the product of 1.27g (3.61mmol) embodiment 379 adds 0.293g paraformaldehyde, 0.75ml diethylamine and 13mg copper chlorides.The reactant is stirred at room temperature 15 minutes, backflow 1.5 hours is then heated to, reactant color, which has, thereafter green becomes brown.The reactant is cooled down, is then extracted with 10% hydrochloric acid solution.Again with 1N sodium hydroxide solutions alkalization pickle, and extracted with ether.The organic matter of merging dried over sodium sulfate, filters and is concentrated in vacuo, and obtains 1.56g (100%) propylamine, is brown oil.Electrospray ionization mass spectrum：459.5(M+H)+.

Embodiment 381

2- [(4- diethylaminos-butyl- 2- alkynyls)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide

According to the method for embodiment 319, the product of 1.50g (3.275mmol) embodiment 380 is hydrolyzed, the carboxylic acid of 0.86g (59%) is obtained, is brown colored foams thing.Electrospray ionization mass spectrum：443.4(M-H)-.

According to the method described in embodiment 328, with 0.649g (1.462mmol) carboxylic acid, 0.228g hydroxamic acid-amine salt is obtained, is brown solid.Electrospray ionization mass spectrum：460.1(M+H)+.

Embodiment 382

N- hydroxyls -2- { (4- methoxy-benzenesulfonvls)-[4- (4- thyl-piperazin -1- bases)-benzyl] amino } -3- methyl-benzamides

According to the same procedure described in embodiment 9, the product for making 1.50g (4.478mmol) embodiment 3 with 4- bromobenzyl bromides is alkylated, obtains 2.16g (96%) Benzylation sulfonamide, be faint yellow solid.Electrospray ionization mass spectrum：504.0(M+H)+.

0.99ml (8.91mmol) N methyl piperazine, 0.856g (8.91mmol) sodium tert-butoxide, 0.148g (0.162mmol) three-(dibenzalacetone) (dibenzylideneacetone) two palladium and 0.301g (0.486mmol) (R)-(+) -2 are added to the solution of the 60ml toluene of 2.04g (4.048mmol) aryl bromide, 2 '-bis- (diphenylphosphino-l '-binaphthyl (BINAP).Heat generation mixture to 80 DEG C 3 hours, be subsequently cooled to room temperature.Ether diluted reaction mixture is used, is filtered by Celite.Vacuum concentration filtrate, residue by silica gel chromatography, with ethyl acetate elution, there is provided 1.3g aryl piperazines.

According to the method for embodiment 319, aryl piperazines -ester is hydrolyzed, the carboxylic acid of 0.837g (66%) is obtained, is brown foam thing.Electrospray ionization mass spectrum：508.6(M-H)-.

According to the method described in embodiment 328, the acid is converted into 0.432g hydroxamic acid-amine salt, is faint yellow solid.Electrospray ionization mass spectrum：525.1(M+H)+.

Embodiment 383

4- [(2- Hydroxycarboamoyl -6- methylphenyls)-(4- methoxy-benzenesulfonvls)-amino]-ethyl butyrate

According to the method for embodiment 45, the product and bromobutyrate for making 0.750g (1.989mmol) embodiment 330 react, and obtain 0.96g (98%) alkylation sulfonamide, are colorless oil.Electrospray ionization mass spectrum：492.4(M+H)+.

5.0ml trifluoroacetic acids are added to the 5ml dichloromethane solutions of 0.828g (1.686mmol) tert-butyl ester, the reactant is stirred at room temperature 2 hours, then it is concentrated in vacuo, residue is ground with ether/hexane (1: 1), and the solid carboxylic acid (0.653g) of generation is collected by filtration and is dried in vacuo.Electrospray ionization mass spectrum：434.2(M-H)-.

According to the method described in embodiment 23, with 0.603g (1.386mmol) carboxylic acid, the hydroxamic acid of 0.234g (38%) is obtained, is white foam thing.Electrospray ionization mass spectrum：451.4(M+H)+.

Embodiment 384

5- [(2- Hydroxycarboamoyl -6- methylphenyls)-(4- methoxy-benzenesulfonvls)-amino]-ethyl valerate

According to the method for embodiment 45, the product and bromo pentane acid B ester for making 0.750g (1.989mmol) embodiment 330 react, and obtain 0.93g (93%) alkylation sulfonamide, are white solid.Electrospray ionization mass spectrum：506.4(M+H)+.

5.0ml trifluoroacetic acids are added to the 5ml dichloromethane solutions of 0.813g (1.6l0mmol) tert-butyl ester, the reactant is stirred at room temperature 2 hours, then it is concentrated in vacuo, residue is ground with ether/hexane (1: 1), and the solid carboxylic acid (0.693g) of generation is collected by filtration and is dried in vacuo.Electrospray ionization mass spectrum：448.1(M-H)-.

According to the method described in embodiment 23, with 0.631g (1.405mmol) carboxylic acid, the hydroxamic acid of 0.219g (34%) is obtained, is brown glassy thing.Electrospray ionization mass spectrum：465.4(M+H)+.

Embodiment 385

[(2- Hydroxycarboamoyl -6- methylphenyls)-(4- methoxy-benzenesulfonvls)-amino]-benzyl acetate

According to the method for embodiment 9, the product and 2- monobromo-acetic acids benzyl ester for making 1.50g (3.979mmol) embodiment 330 react, and obtain 2.03g (97%) alkylation sulfonamide, are colorless oil.Electrospray ionization mass spectrum：526.3(M+H)+.

5.0ml trifluoroacetic acids are added to the 5ml dichloromethane solutions of 1.00g (1.905mmol) tert-butyl ester, the reactant is stirred at room temperature 1 hour, is then concentrated in vacuo, obtains the carboxylic acid of 0.893g (100%), be white foam thing.Electrospray ionization mass spectrum：468.2(M-H)-.

According to the method described in embodiment 23, with 0.802g (1.71mmol) carboxylic acid, the hydroxamic acid of 0.675g (82%) is obtained, is white foam thing.Electrospray ionization mass spectrum：485.3(M+H)+.

Embodiment 386

N- hydroxyls -2- [[(4- methoxyphenyls) sulfonyl] [2- epoxides -2- [(2- pyridylmethyls) amino] ethyl] amino] -3- methyl benzamides

According to the method for embodiment 9, the product and 2- monobromo-acetic acids benzyl ester for making 4.0g (0.011mmol) embodiment 330 react, and obtain 5.57g (100%) alkylation sulfonamide, are colorless oil.Electrospray ionization mass spectrum：526.3(M+H)+.

3.30g (0.052mol) ammonium formates and the palladium charcoals of 0.550g 10% are added to the solution of the 150ml ethanol of 5.50g (0.010mmol) benzyl ester.The mixture is stirred at room temperature 18 hours, then filtered by diatomite.Filtrate is concentrated in vacuo, is diluted, is washed with water with ethyl acetate, it is dried over magnesium sulfate, filter and concentrate.Residue by silica gel chromatography, is eluted with ethyl acetate/hexane (1: 1), obtains carboxylic acid, be white foam thing.Electrospray ionization mass spectrum：436.2(M+H)+.

0.36mlDMF is added to the 10ml dichloromethane solutions of 1.00g (2.299mmol) carboxylic acid, the dichloromethane solution of 2.3ml 2M oxalyl chlorides is subsequently added into.The reactant is stirred at room temperature 1 hour, be then poured into 0 DEG C of the solution of 0.47ml (4.598mmol) 2- aminomethyl pyridines and 0.96ml triethylamines in 10ml dichloromethane.The reactant is stirred overnight, is then poured into water and is extracted with ether.Organic matter is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is eluted with ethyl acetate, is obtained 1.094g (91%) acid amides, is white foam thing.Electrospray ionization mass spectrum：526.4(M+H)+.

Then, it is bubbled into hydrogen chloride gas 10 minutes to the amide solution for the 0.985g (1.876mmol) being dissolved in 20ml dichloromethane.Stop reaction, be stirred for 1 hour, then diluted with 50ml ether, and stand overnight, solid carboxylic acid and the vacuum drying of generation is collected by filtration.Electrospray ionization mass spectrum：468.1(M-H)-.

According to the method described in embodiment 328, with 0.850g (1.682mmol) carboxylic acid, 0.693g hydroxamic acid-amine salt is obtained, is brown solid.Electrospray ionization mass spectrum：485.3(M+H)+.

Embodiment 387

N- hydroxyls -2- { (4- methoxy-benzenesulfonvls)-[2- (4- thyl-piperazin -1- bases) -2- oxo-ethyls]-amino } -3- methyl-benzamides

According to the method for embodiment 9, the product and 2- monobromo-acetic acids benzyl ester for making 4.0g (0.011mmol) embodiment 330 react, and obtain 5.57g (100%) alkylation sulfonamide, are colorless oil.Electrospray ionization mass spectrum：526.3(M+H)+.

3.30g (0.052mol) ammonium formates and the palladium charcoals of 0.550g 10% are added to the solution of the 150ml ethanol of 5.50g (0.010mmol) benzyl ester.The reactant is stirred at room temperature 18 hours, then filtered by diatomite.Filtrate is concentrated in vacuo, is diluted, is washed with water with ethyl acetate, it is dried over magnesium sulfate, filter and concentrate.Residue by silica gel chromatography, is eluted with ethyl acetate/hexane (1: 1), obtains carboxylic acid, be white foam thing.Electrospray ionization mass spectrum：436.2(M+H)+.

0.36mlDMF is added to the 10ml dichloromethane solutions of 1.00g (2.299mmol) carboxylic acid, the dichloromethane solution of 2.3ml 2M oxalyl chlorides is subsequently added into.The reactant is stirred at room temperature 1 hour, be then poured into 1.3ml (0.011mmol) N methyl piperazine in 0 DEG C of 10ml dichloromethane of solution.The reactant is stirred overnight, is then poured into water and is extracted with ether.Organic matter is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is eluted with ethyl acetate, is obtained 1.19g (100%) acid amides, is white oil thing.Electrospray ionization mass spectrum：518.4(M+H)+.

Then, it is bubbled into hydrogen chloride gas 10 minutes to the amide solution for the 1.10g (2.128mmol) being dissolved in 25ml dichloromethane.Stop reaction, be stirred for 1 hour, then diluted with 50ml ether, and stand overnight, solid carboxylic acid and the vacuum drying of generation is collected by filtration.Electrospray ionization mass spectrum：459.8(M-H)-.

According to the method described in embodiment 328, with 0.927g (1.863mmol) carboxylic acid, 0.350g hydroxamic acid-amine salt is obtained, is white solid.Electrospray ionization mass spectrum：477.3(M+H)+.

Embodiment 388

N- hydroxyls -2- [(2- hydroxy-ethyls]-(4- MethOxybenzenesulfonyls)-amino] -3- methyl-benzamides

According to the method for embodiment 9, the product and Bromo-t-butylacetate for making 2.0g (5.97mmol) embodiment 3 react, and obtain 2.38g (89%) alkylation sulfonamide, are colorless oil.Electrospray ionization mass spectrum：449.9(M+H)+.

5.0ml trifluoroacetic acids are added to the 10ml dichloromethane solutions of 2.20g (4.90mmol) tert-butyl ester, the reactant is stirred at room temperature 2 hours, be then concentrated in vacuo, residue triturated under ether, the white solid carboxylic acid (1.85g) of generation is collected by filtration, is dried in vacuo.Electrospray ionization mass spectrum：392.0(M-H)-.

Such as the method for be the same as Example 341, the carboxylic acid (1.75g, 4.45mmol) is reduced with borine-THF, and there is provided the alcohol that 1.21g is white solid.Electrospray ionization mass spectrum：379.9(M+H)+.

According to the method described in embodiment 337, with 0.812g (2.142mmol) alcohol, the tetrahydropyranyl ethers of 0.910g (92%) is obtained.Then the ether-ester is hydrolyzed according to the method described in embodiment 19, obtains the carboxylic acid of 0.634g (72%), be brown glassy thing.Electrospray ionization mass spectrum：372.2(M+Ha)+.

According to the method described in embodiment 328, with 0.592g (1.318mmol) ether-carboxylate, 0.105g hydroxyl-hydroxamic acid is obtained, is brown solid.Electrospray ionization mass spectrum：381.1(M+H)+.

Embodiment 389

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- dimethylaminos-N- hydroxy-3-methyls-benzamide

0.639ml (3.627mmol) three (dimethylamino) borine, 0.349g (3.627mmol) sodium tert-butoxide, 0.060g (0.066mmol) three-(dibenzylideneacetone) two palladium and 0.123g (0.198mmol) BINAP are added to the 25.0ml toluene solutions of 0.831g (1.649mmol) product of embodiment 11.Heat generation mixture to 80 DEG C 3 hours, be subsequently cooled to room temperature.With ether diluting reaction thing, filtered by Celite.Vacuum concentration filtrate, residue by silica gel chromatography, with ethyl acetate/hexane (1: 3) elution, there is provided 0.342g (44%) DMA ester.

According to the method described in embodiment 53, by 0.356g (0.761mmol) DMA ester hydrolysis, the carboxylic acid of 0.170g (50%) is obtained, is white solid.Electrospray ionization mass spectrum：453.1(M-H)-.

According to the method described in embodiment 369, with 0.225g (0.496mmol) carboxylic acid, 0.159g (69%) hydroxamic acid-aniline salt is obtained, is weak yellow foam thing.Electrospray ionization mass spectrum：469.9(M+H)+.

Embodiment 390

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- dimethylamino-N- hydroxy-benzoyIamides

0.247g (1.096mmol) stannic chloride dihydrate is added to the 10ml ethanol solutions of 0.100g (0.219mmol) product of embodiment 168, heating response mixture extremely flows back 3 hours, it is cooled to after room temperature, is concentrated in vacuo the reactant, is then diluted with ether.It is dried over sodium sulfate with 1N sodium hydroxide solutions and water washing organic matter, filtering and vacuum concentration.Residue triturated under ether, obtains 0.060g aniline, is white solid.Electrospray ionization mass spectrum：426.9(M+H)+.

1.44g (0.011mol) potassium carbonate and 0.66ml iodomethanes are added to the 10ml DMF solutions of 0.455g (1.068mmol) aniline.The reactant is heated to 80 DEG C 18 hours, the reactant is cooled to room temperature, is diluted with ether.Organic matter is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo.Residue by silica gel chromatography, is pink oil with ethyl acetate/hexane (1: 3) elution there is provided 0.44g (91%) DMA ester.Electrospray ionization mass spectrum：454.9(M+H)+.

According to the method described in embodiment 53,0.388g (0.855mmol) DMA -ester is hydrolyzed, 0.314g (82%) DMA-carboxylate is obtained, is white powder foam.Electrospray ionization mass spectrum：439.0(M-H)-.

According to the method described in embodiment 369, with 0.251g (0.563mmol) carboxylate, the hydroxamic acid of 0.226g (88%) is obtained, is pink foam thing.Electrospray ionization mass spectrum：455.9(M+H)+.

Embodiment 391

4- (2- piperidin-1-yls-ethyoxyl)-benzyl chloride

To 4- hydroxy benzaldehydes (12.2g, 0.1mol) with potassium carbonate (25g, the agitating solution of DMF (250ml) excessively) adds the hydrochloride (20.0g, 1.08mol.) of 1- (2- Chloroethyls) piperidines one.Reactant mixture is heated to 80 DEG C 24 hours, room temperature is cooled to.Reactant mixture is quenched with icy water, is extracted with chloroform.Organic matter is washed with water, is dried through anhydrous magnesium sulfate, filters and is concentrated in vacuo.Residue is dissolved in methanol, sodium borohydride (10g, excessive) is slowly added in 0 DEG C.Stirring reaction mixture 2 hours, are then quenched with water at room temperature.Alcohol is extracted with chloroform, organic matter is fully washed with water, is dried with sodium sulphate, excess is simultaneously concentrated in vacuo.

The crude alcohol so obtained is dissolved in THF (200ml), hydrogen chloride gas is passed through 30 minutes in 0 DEG C.Being slowly added to thionyl chloride (30ml, excessive) to the hydrochloric acid salt suspensioning liquid so obtained makes reactant mixture flow back 30 minutes, and is cooled to room temperature.Concentrated reaction mixture is ground to dry with absolute ether, filters the solid of precipitation, is dried in room temperature in vacuo, is obtained the product of 25g (86%), be white solid.m.p.145-148℃.Electrospray ionization mass spectrum：256(M+H).

Embodiment 392

4- (2-N, N- diethyl-ethyoxyl)-benzyl chloride

To 4- hydroxy benzaldehydes (12.2g, 0.1mol) with potassium carbonate (25g, the agitating solution of DMF (250ml) excessively) adds the hydrochloride (20.0g, 1.2mol.) of 2- diethyl-aminoethyls chlorine one.Reactant mixture is heated 24 hours in 80 DEG C, room temperature is cooled to.Make reactant mixture all standing with icy water, extracted with chloroform.Organic matter is washed with water, is dried through anhydrous magnesium sulfate, filters and is concentrated in vacuo.Residue is dissolved in methanol, sodium borohydride (10g, excessive) is slowly added in 0 DEG C.Stirring reaction mixture 2 hours, then use water all standing at room temperature.Alcohol is extracted with chloroform, organic matter is fully washed with water, is dried, excess is simultaneously concentrated in vacuo.

The crude alcohol so obtained is dissolved in THF (200ml), hydrogen chloride gas is passed through 30 minutes in 0 DEG C.Being slowly added to thionyl chloride (30ml, excessive) to the hydrochloric acid salt suspensioning liquid so obtained makes reactant mixture flow back 30 minutes, and is cooled to room temperature.Concentrated reaction mixture is ground to dry with absolute ether, filters the solid of precipitation, is dried in room temperature in vacuo, is obtained the product of 18g (65%), be white solid.m.p.76-79℃.Electrospray ionization mass spectrum：244(M+H).

Embodiment 393

N- hydroxyls -2- [[(4- methoxyphenyls) sulfonyl] [4- [2- (1- piperidyls) ethyoxyl] phenyl] methyl] amino] -3- methyl benzamides

According to the method for embodiment 45, reacted with the product of 1.00g (2.985mmol) embodiment 3 with the product of 0.952g (3.284mmol) embodiment 391, obtain 0.965g (58%) piperidines -ester, colorless oil.Electrospray ionization mass spectrum：553.5(M+H)+.

According to the method for embodiment 319, with 0.889g (1.611mmol) ester, 0.872g carboxylic acid is obtained, is white foam thing.Electrospray ionization mass spectrum：539.2(M+H)+.

According to the method for embodiment 328, with 0.814g (1.513mmol) carboxylic acid, 0.179g hydroxamic acid-amine salt is obtained, is white solid.Electrospray ionization mass spectrum：554.5(M+H)+.

Embodiment 394

2- [[4- (2- diethylamino-ethoxies)-benzyl]-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide

According to the method for embodiment 45, reacted with the product of 1.00g (2.653mmol) embodiment 30 with the product of 0.811g (2.918mmol) embodiment 392, obtain 0.575g (37%) piperidines -ester, be brown colored foams thing.Electrospray ionization mass spectrum：583.1(M+H)+.

According to the method for embodiment 374, with 0.539g (0.926mmol) ester, 0.369g carboxylic acid is obtained, is white solid.Electrospray ionization mass spectrum：525.2(M-H)-.

According to the method for embodiment 369, with 0.328g (0.513mmol) carboxylic acid, 0.194g hydroxamic acid-amine salt is obtained, is white solid.Electrospray ionization mass spectrum：542.3(M+H)+.

Embodiment 395

5- bromo-N- hydroxyls -2- { (4- methoxy-benzenesulfonvls)-[4- (2- piperidin-1-yls-ethyoxyl)-phenyl]-amino } -3- methyl-benzamides

According to the method for embodiment 393, with the product of 1.00g (2.415mmol) embodiment 202,0.470g hydroxamic acid-amine salt is obtained, is faint yellow solid.Electrospray ionization mass spectrum：632.2(M+H)+.

Embodiment 396

N- hydroxyls -2- [[(4- methoxyphenyls) sulfonyl] [4- [[2- (1- piperidyls) ethyl] amino] carbonyl] phenyl] methyl] amino] -3- methyl benzamides

According to the method for embodiment 9, with the product and 0.851g (3.714mmol) para- carbomethoxy benzyl bromine reactions of 1.00g (2.653mmol) embodiment 330, the Benzylation sulfonamide -ester of 1.30g (94%) is obtained, is white foam thing.Electrospray ionization mass spectrum：526.4(M+H)+.

12ml 1N sodium hydroxide solutions are added to 24.0ml THF/ methanol (1: 1) solution of 0.1.249g (2.379mmol) ester, the reactant are stirred at room temperature 3 hours.Then the reactant is acidified, is extracted with ether.The organic matter merged is dried with magnesium sulfate, filters and is concentrated in vacuo.The carboxylic acid of 0.1.08g (89%) is obtained, is white foam thing.Electrospray ionization mass spectrum：512.3(M+H)+.

0.306mlDMF is added to the 10ml dichloromethane solutions of 1.01g (1.977mmol) carboxylic acid, the dichloromethane solution of 2.0ml 2M oxalyl chlorides is subsequently added into.The reactant is stirred at room temperature 1 hour, be then poured into 0.56ml (3.95mmol) aminoethylpiperidine and 0.825ml triethylamines in 0 DEG C of 7ml dichloromethane of solution.The reactant is stirred overnight, is then poured into water and is extracted with ether.Organic matter is washed with water, it is dried over sodium sulfate, filter and be concentrated in vacuo, obtain the acid amides of 1.23g (100%), be white foam thing.Electrospray ionization mass spectrum：622.6(M+H)+.

Then, it is bubbled into hydrogen chloride gas 10 minutes to the amide solution for the 1.167g (1.879mmol) being dissolved in 20ml dichloromethane.Stop reaction, be stirred for 1 hour, then diluted with 50ml ether, and stand overnight, the white solid carboxylic acid of generation is collected by filtration and is dried in vacuo.Electrospray ionization mass spectrum：566.6(M-H)-.

According to the method described in embodiment 328, with 1.023g (1.704mmol) carboxylic acid, 0.177g hydroxamic acid-amine salt is obtained, is white solid.Electrospray ionization mass spectrum：581.0(M+H)+.

Embodiment 397

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts

According to the same procedure described in embodiment 241, the product and phenylboric acid for making embodiment 89 react, and obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：504(M+H)+.

Embodiment 398

- 3 bases of N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- thienyls-benzamide hydrochloride salt

According to the same procedure described in embodiment 241, make the product and thiophene -3- acid reactions of embodiment 89, obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：508.1(M-H)-.

Embodiment 399

4 "-methoxyl group -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl-[1,1 '；4 ', 1 "] terphenyl -3- formic acid hydroxyl amide hydrochloric acid salt

According to the same procedure described in embodiment 241, the product and 4- (4 '-methoxyphenyl) phenylboric acid for making embodiment 89 react, and obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：609.9(M+H)+.

Embodiment 400

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3 '-Nitro-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts

According to the same procedure described in embodiment 241, the product and 3- nitrophenyl boronic acids for making embodiment 89 react, and obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：549.1(M+H)+.

Embodiment 401

4 '-methoxyl group -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts

According to the same procedure described in embodiment 241, the product and 4- methoxyphenyl-boronic acids for making embodiment 89 react, and obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：534.1(M+H)+.

Embodiment 402

5- benzos [b] thiophene -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoyl amine hydrochlorates

According to the same procedure described in embodiment 241, make the product and benzo [b] thiophene -2- acid reactions of embodiment 89, obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：560.1(M+H)+.

Embodiment 403

5- benzos [b] furans benzene -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoyl amine hydrochlorates

According to the method described in embodiment 241, the product and benzo [b] FURAN-2-BORONIC ACID for making embodiment 89 react, and obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：544.3(M+H)+.

Embodiment 404

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -4 '-trifluoromethoxy of -5- methyl-xenyl -3- formic acid hydroxyl amide hydrochloric acid salts

According to the same procedure described in embodiment 241, make the product and 4- Trifluoromethoxyphen-l acid reactions of embodiment 89, obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：588.1(M+H)+.

Embodiment 405

5- benzos [1,3] dioxole -5- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoyl amine hydrochlorates

According to the same procedure described in embodiment 241, the product and 3,4- methylenedioxyphenyl ylboronic acid of embodiment 89 are reacted, corresponding diaryl sulfonamide -ester is obtained.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：548.1(M+H)+.

Embodiment 406

4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3 '-Trifluoromethyl-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts

According to the same procedure described in embodiment 241, make the product and 3- Trifluoromethoxyphen-l acid reactions of embodiment 89, obtain corresponding diaryl sulfonamide -ester.Then according to the method for embodiment 319, it is carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid hydrochloride according to the method for embodiment 369.Electrospray ionization mass spectrum：572.0(M+H)+.

Embodiment 407

2- [(4- chloros-benzyl)-(5- pyridines -2- bases-thiophene -2- sulfonyls)-amino]-N- hydroxy-3-methyls-benzamide

By Wang resins (Wang, S.J.Am.Chem.Soc, 1973,95,1328-1333) (Adbanced ChemTech 200-400 mesh, 1% crosslinking；Load：0.92mmol/g；15.0g, 0.011mol), lithium chloride (1.4g, 0.033mol) and DMF (150ml) mixture magnetic agitation 40 minutes.Collidine (4.0g, 0.033mol) is added, the mixture is cooled down (0-5 DEG C) with ice bath.Methylsufonyl chloride (3.8g, 0.033mol) was added with 5 minutes.After 10 minutes, remove cryostat and continue stirring 68 hours.The mixture is filtered, resin is washed with DMF (250ml), 30% water/DMF (2 × 300ml), DMF (2 × 250ml), ethanol (3 × 250ml), dichloromethane (3 × 300ml) and hexane (2 × 250ml).The resin is dried in vacuo with phosphorus pentoxide, 14.3g is obtained；¹³C NMR(CDCl₃)δ46.22(CH₂Cl)；IR(KBr)cm^-1：2900,1600,1520,1485,1450.

By chloro-Wang resins (1.13mmol/g, 1g),, sodium iodide (169mg, 1.13mmol), cesium carbonate (1.11g, 3.39mmol) 50 DEG C are heated to mixture of the HP (922mg, 5.65mmol) in DMF 16 hours.With DMF/ water (3: 2,4 × 25ml), DMF/ water (9: Isosorbide-5-Nitrae × 25ml), DMF (2 × 25ml), dichloromethane (3 × 25ml) and methanol (2 × 20ml) washing resin after filtering.Then the resin vacuum is dried, obtains product resin (1.1g, 96%).N% theoretical values 1.38%, measured value 1.09%.

THF/ ethanol/NH is used at room temperature₂NH₂The mixture processing phthalimido hydroxylamine resin (10g) of (80ml/80ml/26ml) 18 hours.The mixture is filtered, the resin is washed with methanol (200ml), DMF (200ml), and repeat the process.Then washed with methanol (200ml) and dichloromethane (2 × 150ml).Finally it is dried in vacuo the resin.

With DCC (2.27g, ethyl acetate (20ml) solution processing 2- amino -3- methyl benzoic acids (1.51g 11mmol), 10mmol) with Pentafluorophenol (2g, 11mmol) cold (- 5 DEG C, the ice-salt bath) solution in dry DMF (2ml).By reactant mixture in 0 DEG C of storage over night.It is filtered to remove sediment and is washed with ethyl acetate (about 10ml).Merge washing lotion and filtrate, washed with 5% sodium bicarbonate aqueous solution (2 × 15ml), water (15ml) and dry (sodium sulphate).Removing solvent obtains the product (3.2g, 100%) for solid.

2- amino -3- methyl benzoic acids pentafluorophenyl esters (4.37g, 13.8mmol) are added to the DMF suspension of the azanol (3.05g, 1.13mmol) on Wang resins, 4-dimethylaminopyridine (2.1g, 17.2mmol) is subsequently added into.The mixture of generation is shaken at room temperature 40 hours.Resin is filtered, is washed with DMF (4 × 100ml), dichloromethane (3 × 80ml), methanol (2 × 80ml), dichloromethane (4 × 80ml).The resin is finally dried in vacuo, product resin (3.51g, 100%) is obtained.

Pyridine (2.78ml, 34.4mmol) is added to dichloromethane (20ml) suspension of the 2- amino -3- methyl benzoic acids hydroxy amides (3.51g, 0.98mmol/g) on Wang resins.After 5 minutes, dichloromethane (15ml) solution of 5- (pyridine -2- bases)-thiophene phenol -2- bases-sulfonic acid chloride (4.46g, 17.2mmol) is added in the reactant mixture.The mixture of generation is shaken at room temperature 24 hours, filter resin, washed with DMF (4 × 40ml), dichloromethane (3 × 40ml), methanol (2 × 40ml), dichloromethane (4 × 40ml), vacuum drying, obtains 4.25g (97%) product resin.

To confirm that the reaction is completed, resin (100mg) sample is suspended in TFA/ dichloromethane (1: 1,2ml) and places and stirs 1 hour.Resin is filtered, is washed with dichloromethane (2 × 1.5ml).The filtrate of merging is evaporated to dryness, 24.7mg products are obtained, (5- pyridines -2- bases-thiophene -2- sulfonyls)-amino on Wang resins]-N- hydroxy-3-methyls-benzamide.Mass spectrum：Desired value 389.0504, measured value 389.9.

To (5- pyridines -2- bases-thiophene -2- sulfonyls)-amino on Wang resins] solution of 4- chlorobenzyl alcohol (0.485mmol) of-N- hydroxy-3-methyls-benzamide (100mg, 0.84mmol/g) in THF (1ml) adds THF (1.24ml) solution of triphenyl phasphine (0.485mmol) and diethyl azodiformate (0.485mmol).The mixture of generation is shaken at room temperature 4 hours.Resin is filtered, is washed with THF (4 × 3ml) and dichloromethane (4 × 3ml), is dried in vacuo.Resin is suspended in trifluoroacetic acid/dichloromethane (1: 1,2ml) and placed 1 hour.Resin is filtered, is washed with dichloromethane (2 × 1.5ml).The filtrate of merging is evaporated to dryness, crude product obtains 16.7mg products 2- [(4- chloros-benzyl)-(5- pyridines -2- bases-thiophene -2- sulfonyls)-amino]-N- hydroxy-3-methyls-benzamide through (anti-phase) purifying of solid-phase extraction column.Mass spectrum：Desired value 513.0584, measured value 513.8.

Embodiment 408

2- [(3,4- dimethyl-benzyl)-(5- pyridines -2- bases-thiophene -2- sulfonyls)-amino]-N- hydroxy-3-methyls-benzamide

To (5- pyridines -2- bases-thiophene -2- sulfonyls)-amino on Wang resins]-N- hydroxy-3-methyls-benzamide; that is product (the 100mg of embodiment 407; 0.84mmol/g) solution of 3, the 4- dimethylbenzyl alcohols (0.485mmol) in THF (1ml) adds THF (1.24ml) solution of triphenyl phasphine (0.485mmol) and diethyl azodiformate (0.485mmol).The mixture of generation is shaken at room temperature 4 hours.Resin is filtered, is washed with THF (4 × 3ml) and dichloromethane (4 × 3ml), is dried in vacuo.Resin is suspended in trifluoroacetic acid/dichloromethane (1: 1,2ml) and placed 1 hour.Resin is filtered, is washed with DCM (2 × 1.5ml).The filtrate of merging is evaporated to dryness, crude product obtains 18.1mg product through (anti-phase) purifying of solid-phase extraction column.Mass spectrum：Desired value 507.1286, measured value 507.9.

Embodiment 409

2- [(4- bromos-benzenesulfonyl)-pyridin-3-yl Methyl-amino] -3- methyl-benzoic acid methyl esters

According to the method described in embodiment 1, methyl -3- menthyl anthranilates is reacted with p- bromo benzene sulfonyl chloride there is provided aryl sulfonic acid amides, be white powder.Electrospray ionization mass spectrum：475(M+H)+.

Embodiment 410

N- hydroxy-3-methyls -2- [pyridin-3-yl methyl-(4 '-Trifluoromethyl-biphenyl -4- sulfonyls)-amino]-benzamide

According to the same procedure described in embodiment 241, the product of embodiment 409 is set to be converted into diaryl sulfonamide -ester.Then according to the method for embodiment 190, it is corresponding carboxylic acid by the ester hydrolysis, is then converted into hydroxamic acid according to the method for embodiment 68, is separated to as pale powder.Electrospray ionization mass spectrum：542.1(M+H)+.

Embodiment 411

2- [(2 ', 4 '-dimethoxy-biphenyl base -4- sulfonyls)-pyridin-3-yl Methyl-amino]-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 241, the product of embodiment 409 is set to be converted into diaryl sulfonamide -ester.Then according to the method for embodiment 190, it is corresponding acid by the ester hydrolysis, is then converted into hydroxamic acid according to the method for embodiment 68, is separated to as pale powder.Electrospray ionization mass spectrum：534.0(M+H)+.

Embodiment 412

N- hydroxy-3-methyls -2- [pyridin-3-yl methyl-(4- thiophene -2- bases-benzenesulfonyl)-amino]-benzamide

According to the same procedure described in embodiment 241, the product of embodiment 409 is set to be converted into diaryl sulfonamide -ester.Then according to the method for embodiment 190, it is corresponding acid by the ester hydrolysis, is then converted into hydroxamic acid according to the method for embodiment 68, is separated to as pale powder.Electrospray ionization mass spectrum：480.3(M+H)+.

Embodiment 413

2- [(4- acetenyls-benzenesulfonyl)-pyridin-3-yl Methyl-amino]-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 78, the product of embodiment 409 is set to be converted into alkynyl group-aryl sulfonic acid amides -ester.Then according to the method for embodiment 190, it is corresponding acid by the ester hydrolysis, is then converted into hydroxamic acid according to the method for embodiment 68, is separated to as pale powder.Electrospray ionization mass spectrum：422.3(M+H)+.

Embodiment 414

2- [(4- benzos [b] thiophene -2- bases-benzenesulfonyl)-pyridin-3-yl Methyl-amino]-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 241, the product of embodiment 409 is set to be converted into diaryl sulfonamide -ester.Then according to the method for embodiment 190, it is corresponding acid by the ester hydrolysis, is then converted into hydroxamic acid according to the method for embodiment 68, is separated to as pale powder.Electrospray ionization mass spectrum：530.0(M+H)+.

Embodiment 415

2- [(4- benzos [1,3] dioxole -5- bases-benzenesulfonyl)-pyridin-3-yl Methyl-amino]-N- hydroxy-3-methyls-benzamide

According to the same procedure described in embodiment 241, the product of embodiment 409 is set to be converted into diaryl sulfonamide -ester.Then according to the method for embodiment 190, it is corresponding acid by the ester hydrolysis, is then converted into hydroxamic acid according to the method for embodiment 68, is separated to as pale powder.Electrospray ionization mass spectrum：518(M+H)+.

Embodiment 416

3- methyl -2- [4- (pyridin-4-yl epoxide)-BENZENESUFONYLAMINO]-N- hydroxy-benzoic acid methyl esters

According to the method described in embodiment 1, making the product of embodiment 3, [(pyridin-4-yl) epoxide benzene sulfonyl chloride hydrochloric acid reactant salt, there is provided NH- sulfonamide, is white powder with 4-.Electrospray ionization mass spectrum：399(M+H)+.

Embodiment 417

3- methyl -2- [4- (pyridin-4-yl epoxide)-BENZENESUFONYLAMINO]-N- hydroxy-benzoyIamides

According to the method described in embodiment 9, making the product NH- sulfonamide of embodiment 416, there is provided N- methylsulfonamides -ester with iodomethane reaction.

According to the method for embodiment 190, the ester hydrolysis is obtained corresponding carboxylic acid, the formic acid is then converted into hydroxamic acid according to the method for embodiment 68, pale powder is separated to.Electrospray ionization mass spectrum：414(M+H)+.

Pharmacology

The method for determining MMP-1, MMP-9, and MMP-13 inhibitory action

These measure are with based on matrix metalloproteinase MMP-1, MMP-13 (clostridiopetidase A) or MMP-9 (gelatinase) spilting of an egg (cleavage) sulphur peptide substrates such as Ac-Pro-Leu-Gly (2- sulfydryl -4- methyl-pentanoyls)-Leu-Gly-OEt; its substrate product for causing that chrominance response can be carried out with DTNB (5,5 ｀-two sulphur are double (2- Nitro-benzoic acids)) discharges.Enzymatic activity is determined by the increase of color rate.Sulphur peptide substrates are prepared in 100%DMSO by 20mM stostes are fresh, DTNB is dissolved in 100%DMSO, and dark place is stored at room temperature.Before use, by substrate and DTNB substrate buffer solution (50mM HEPES pH7.5,5mM CaCl₂) both be diluted to 1mM together.By proenzyme liquid assay buffer (50mM HEPES pH7.5,5mM CaCl₂, 0.02%Brij) and it is diluted to the ultimate density of requirement.Assay buffer, enzyme, solvent or inhibitor and DTNB/ substrates are added in 96 hole plates (reaction cumulative volume 200 μ l) in this order, spectrophotometric monitoring color increases by 5 minutes at 405nm on a plate reader, draws linear line of the color increase to the time.

In addition, also using fluorescent peptide substrate.In this measure, the peptide substrates contain fluorophor and quenching group.When cutting off substrate with MMP, with fluorescent quantitation of the fluorimeter plate reader to generation.Measure HCBC assay buffers (50mM HEPES pH7.0,5mM Ca⁺², 0.02%Brij, 0.5% NAC) and people's restructuring MMP-1, MMP-9 or MMP-13 progress.Substrate is dissolved in methanol, with 1mM sample aliquot stored frozens.During measure, substrate and enzyme are diluted to required concentration with HCBC buffer solutions.Compound is added in 96 hole plates containing enzyme, reaction is started by adding substrate.Observation reaction (exciting 340nm, launch 444nm) 10 minutes, draws linear line of the fluorescence increase to the time.

Either sulphur peptide or fluorescent peptide are determined all calculates and represents reactivity with the slope of straight line.Determine the linear (r of reactivity²＞ 0.85).With Dunnett ' s multiple spot contrast experiments, calculate the average (x ± sem) of control rate, and with drug-treated rate comparative statistics meaning (p ＜ 0.05).Dose-effect relationship is drawn with the medicine of multiple dose, the IC with 95%CI is estimated with linear regression₅₀Value.

Internal MMP suppresses

Under anesthesia, matrix metalloproteinase (stromelysin, clostridiopetidase A or gelatinase in 0.5ml buffer solutions) 2cm dialysis tubings (molecular weight cutoff 12-14000 will be contained, the flat width of 10mm) ip or sc implantation rats (Sprague-Dawley, 150-200g) or mouse (CD-1,25-50g) (back).PO, IP, SC give medicine by inserting jugular conduit IV.The drug dose volume given is 0.1-0.25ml/ animals.Collect the content of dialysis tubing and determine enzymatic activity.

Calculate the enzyme reaction rate of each dialysis tubing.Mean value ± sem is calculated with the pipe derived from least 3 different animals.The animal of solvent-processing is determined to the statistical significant difference (P ＜ 0.05) of the animal of drug-treated by variable analysis.(Agents and Actions 21：331,1987.

Determine the method that TACE suppresses

With 96 hole microtiter plates, added per hole by 10 μ l TACE (Immunex, the μ g/mL of ultimate density 1), 70 μ l (pH7.4) contain 10% glycerine Tris buffer solutions (ultimate density 10mM), and 10 μ l testing compounds DMSO solution (1 μM of ultimate density, DMSO concentration ＜ 1%) composition solution, at room temperature be incubated 10 minutes.Add fluorescence peptide based substrate (100 μM of ultimate density) to every hole and start reaction, then shaken 5 seconds in rocker.

Observation reaction (exciting 340nm, launch 420nm) 10 minutes, draws linear line of the fluorescence increase to the time.The slope of straight line is calculated, it represents reactivity.

Determine the linear (r of reactivity²＞ 0.85).With Dunnett ' s multiple spot contrast experiments, calculate the average (x ± sem) of control rate, and with drug-treated rate comparative statistics meaning (p ＜ 0.05).Dose-effect relationship is drawn with the medicine of multiple dose, the IC with 95%CI is estimated with linear regression₅₀Value.

The pharmacological results of above in vitro and in vivo matrix metalloproteinase inhibitory action and TACE inhibitory action are given in Table I below.Table I .MMP and TACE inhibitory action

Internal embodiment MMP-1¹   MMP-9¹   MMP-13¹    MMP²                 TACE¹23 639 650 555 ＞ 1,000 24 398 31 1,000 25 32% (100),The ＞ 1,000 28 115 23 50 460 29 553 353 728 1,000 34 281 28 69 31.6 (100) of 1,000 26 884 346 982 ＞ of ip ＞ 1,000 27 1,573 440 717,The ＞ 1,000 60 152 7 15 232 61 34 33 46 (20) of 1,000 57 ＞ of ip ＞ 1,000 54 24 34 55 670 29 216 ＞, 1,000 56 ＞, 1,000 57 138 ＞ 500 12 33 1,000 58 244 5 36 682 59 242 8 34,po              289

                                        59(50),The ＞ 1,000 88 132 15 11 50 91 24 20 55 (100) of 1,000 144 137 377 74 ＞ of po 68 82 21 15 239 69 153 874 1370 ＞, 1,000 72 ＞ 1,000 554 959 429 77 131 80 109 21 18 134 83 34 32 85 663,The ＞ 1,000 11 20 173 116 201 13 14 271 117 114 10 10 28.3 (100) of 94 1,000 276 209 ＞ of po 1,000 101 267 23 138 422 102 314 29 162 115,The Table I of 154 118 248 345 229 ＞ of ip 1000 continue

Internal embodiment MMP-1¹      MMP-9¹      MMP-13¹  MMP²   TACE¹119, , , 223, , , 27, , , 14, , , , 252120, , , 238, , , 18, , , 39, , , , 310125, , , ＞, 1000, , , 27, , , 134, , , , 300130, , , 213, , , 4, , , 13, , , , , 76131, , , 212, , , 54, , , 48, , , , , 80138, , , 258, , , 77, , , 57, , , , 215145, , , 55, , , 7, , , 3, , , , 158150, , , 213, , , 4, , , 13, , , , , 76151, , , 212, , , 54, , , 48, , , , , 80156, , , ＞, 1000, , , 104, , , 134158, , , ＞, 1000, , , 11, , , 62165, , , , , , 286, , , 350166, , , , , , 203, , , ＞, 300167, , , , , , , 42, , , 178170, , , 347, , , 12, , , 39, , , , 176174, , , 323, , , 16, , , 71, , , , 50%175, , , 90, , , 7, , , 4, , , , 57179, , , 680, , , 40, , , 53, , , , 64%186, , , 37, , , 13, , , 1.4, , , , 61191, , , 1239, , , 10, , , 67, , , , 210194, , , 306, , , , , , 12, , , , 154197, , , 711, , , 5, , , 6, , , , 32%201, , , 104, , , 11, , , 27, , , , 1000207, , , 1117, , , 2.0, , , 2.5, , , , 375212, , , 415, , , 5.2, , , 11, , , , 314214, , , 423, , , 6.4, , , 19, , , , 232219, , , 290, , , 6.7, , , 5.8, , , , 548224, , , 957, , , 11, , , 14, , , , 715227, , , 193, , , 3.1, , , 4.1, , , , 446230, , , 20, , , 2.4, , , 1.9, , , 47%, (, 1, ), 233, , , 32, , , 2.3, , , 1.8, , , , 450240, , , 86, , , 3.5, , , 1.6, , , , 548243, , , 528, , , 6.6, , , 3.1, , , , , 66246, , , 106, , , 6.0, , , 3.6, , , , , 56 Table I continue

Internal embodiment MMP-1¹   MMP-9¹   MMP-13¹   MMP²    TACE¹249, , , 231, , 2.8, , 6.0, , , , , 100252, , , 652, , 15, , 10, , , , , 346255, , , 48, , 7.1, , 3.2, , , , , 65258, , , 169, , 8.0, , 7.0, , , , , 110261, , , 247, , 1.3, , 2.8, , , , , 54264, , , 159, , 3.7, , 6.4, , , , , 77267, , , 59, , 3.0, , 13, , , , , 136272, , , 66, , 0.5, , 6.0, , , , , 311277, , , 56, , 4.0, , 4.0, , , , , 34282, , 1050, , 5.0, , 113, , , , 44%, (, 1, ), 285, , , 312, , 6.0, , 9.8, , , , , 61292, , , 184, , 8.0, , 29, , , , 7%, (, 1, ), 297, , , 297, , 9.0, , 14, , , , 58%, (, 1, ), 301, , , 211, , 6.9, , 8.7, , , , 1484302, , , 291, , , , , 24, , , , , 173303, , 2782, , 64, , 104, , , 218%, (, 1, ), 304, , 4100, , , , , 305, , , , 25%, (, 1, ), 308, , 10%, (, 1, ), , 45%, (, 1, ), , 36%, (, 1, ), , , , , 285309, , , 608, , , 5, , 14, , , , , 174310, , 4800, , 21, , 101, , , , , 154311, , , 781, , 10, , 43, , , , , 157313, , , 180, , 1.4, , 6.3, , , , , 26314, , , 954, , 8.4, , 13, , , , , 27320, , 2188, , 46, , 150, , , , , 142325, , 15%, (, 1, ), , 49%, (, 1, ), , 60%, (, 1, ), , , , , 1640325, , , 20, , 2.4, , 1.9, , , , 47%, (, 1, ), 328, , , 326, , 4.9, , 13, , , , , 263329, , , 319, , 6.1, , 23, , , , , 173339, , , 216, , 5.2, , 5.7, , , , , 564340, , , 522, , 11, , 30, , , , , 110344, , 1173, , 69, , 320, , , , , 529345, , 1158, , 31, , 134, , , , , 523349, , , 396, , , 8, , , 9, , , , , 32350, , , 450, , , 5, , 21, , , , , 373

Table I continues

Internal embodiment MMP-1¹        MMP-9¹         MMP-13¹       MMP²             TACE¹353, , , , 23%, (, 1, ), , , 61, , , , 141, , , , , , , , 780355, , , , 701, , , , 28, , , , 20, , , , , , , , 288358, , , , 25%, (, 10, ), , , 101, , , 107, , , , , , , , 1054360, , , , 14%, (, 10, ), , , 525, , , 1260, , , , , , , 1405363, , , , 449, , , , 20, , , , 54, , , , , , , , 137367, , , , 597, , , , 12, , , , 13, , , , , , , , 2700369, , , , 207, , , , 6.4, , , 3.8, , , , , , , , 38373, , , , 1280, , , 26, , , , 59, , , , , , , , 539374, , , , 56%, (, 10, ), , , 36%, (, 1, ), , , 17%, (, 1, ), , , , , , , 29%, (, 1, ), 375, , , , 329, , , , 7.1, , , 18, , , , , , , , 356376, , , , 391, , , , 8.4, , , 18, , , , , , , , 645377, , , , 123, , , , 4.7, , , 15, , , , , , , , 258378, , , , 213, , , , 2.9, , , 11, , , , , , , , 243381, , , , 470, , , , 11, , , , 19, , , , , , , , 218382, , , , 142, , , , 6.5, , , 20, , , , , , , , 146383, , , , 34%, (, 1, ), , , 87%, (, 1, ), , , 48%, (, 1, ), , , , , , , 45%, (, 1, ), 384, , , , 48%, (, 1, ), , , 52%, (, 1, ), , , 61%, (, 1, ), , , , , , , 55%, (, 1, ), 385, , , , 25%, (, 1, ), , , 65%, (, 1, ), , , 66%, (, 1, ), , , , , , , 56%, (, 1, ), 386, , , , 21%, (, 1, ), , , 16%, (, .1, ), , , 11%, (, .1, ), , , , , , , 46%, (, 1, ), 387, , , , 2715, , , 96, , , , 307, , , , , , , , 38%, (, 1, ), 388, , , , 66%, (, 10, ), , , 47%, (, 1, ), , , 39%, (, 1, ), , , , , , , 35%, (, 1, ), 389, , , , 63, , , , 2, , , , 39, , , , , , , , 633390, , , , 19%, (, 1, ), , , 64, , , , 531, , , , , , , , 39%, (, 1, ), 393, , , , 176, , , , 6.9, , , 56, , , , , , , , 277394, , , , 96, , , , 2.3, , , 8.8, , , , , , , , 215395, , , , 35, , , , 2.3, , , 3.1, , , , , , , , 108396, , , , 184, , , , 6.3, , , 35, , , , , , , , 363397, , , , 195, , , , 3.0, , , 3.7, , , , , , , , 64398, , , , 85, , , , 2.0, , , 3.7, , , , , , , , 56399, , , , 2197, , , 45, , , , 41, , , , , , , , 25%, (, 1, ), 400, , , , 295, , , , 6.0, , , 4.9, , , , , , , , 231401, , , , 176, , , , 1.4, , , 2.8, , , , , , , , 146402, , , , 543, , , , 2.6, , , 8.5, , , , , , , , 639404, , , , 1800, , , 5.9, , , 9.5, , , , , , , , 54%, (, 1, ),

Table I continues

Internal embodiment MMP-1¹      MMP-9¹       MMP-13¹      MMP²      TACE¹405 176 4.1 5.8 151406 542 1.1 1.6 294407 1690 199 35408 3450 731 148410 47％ ( 10 ) 28％ ( 1 ) 40％ ( .1 ) 2％ ( 1 ) 411 32％ ( 10 ) 39％ ( 1 ) 44％ ( 1 ) 9％ ( 1 ) 412 69％ ( 10 ) 44％ ( 1 ) 42％ ( .1 ) 3％ ( 1 ) 413 529 55 75 43％ ( 1 ) 414 29％ ( 10 ) 68％ ( 1 ) 38 6％ ( 1 ) 415 37％ ( 10 ) 43％ ( 1 ) 26 9％ ( 1 ) 417 3245 6.8 3.7

1.IC₅₀The suppression percentage of nM or 1 μM of concentration

2. in couple MMP-9 (dosage, mg/kg) suppression percentage, ip=strands of films, po=is oral.

The cartilage degradation of rat

20mg cartilage slices are obtained from the knee for the ox just butchered.Cutting diameter is 6mm cellulose sponge disk, in the existing 2mm apertures in sponge center.The 100 μ l sterile suspensions containing Mycobacterium tuberculosis heat-killed 1mg are applied on sponge.After air dried overnight, it is placed in by sponge autoclaving and by cartilage slices in the hole of sponge cutting.Aseptically, cartilage-sponge section is placed in anesthetized rat (Lewis kinds, 200-250g) dorsal sc.Otch is closed with pin, rat is come to life from anesthesia.About after sponge is implanted into 5 days, aseptically, peritonaeum is implanted into the isotonic micropump (Alza Corp., Palo Alto, CA) of the compound containing research or solvent.After 19 days, make rat painless lethal by using carbon dioxide asphyxia, the granuloma containing implantation sponge is removed from the tissue of surrounding.

The weight of the cartilage piece reclaimed from sponge is recorded, the content of the collagen of cartilage is determined.Determine the cartilage weight and the average of collagen content of solvent group and medicine-treatment group.By the way that the compound is compared with vehicle treated rat, determine it to cartilage weight and the inhibitory action of collagen content.The animal of solvent-processing is determined to the statistical significant difference (P ＜ 0.05) of the animal of drug-treated by variable analysis.

As a result：

The average daily dose cartilage weight of processing loses Cartilage collagen

(mg/kg) suppress % and lose suppression % embodiments 83 50 44.6 51.2^*Embodiment 313 50 45.5 28.0^*

                         ^*=p ＜ 0.05 are relative to vehicle treated rat

Bibliography：Bishop J., Greenham AK., Lewis EJ.Anovel in vivomodel for the study of cartilage degradation.J.Pharmacol.Toxicol.Methods, 30：19-25,1993

Pharmaceutical composition

The compounds of this invention can individually or together with pharmaceutical carrier to required patient be taken.Pharmaceutical carrier can be solid or liquid.

Solid carrier used may include one or more materials, and it also is used as flavouring agent, lubricant, cosolvent, supensoid agent, filler, slides agent, pressing aid agent, binder or tablet disintegrant or encapsulating substance.In powder agent, carrier is to disperse sufficient solid, and it is mixed with well dispersed active component.In tablet, active component is mixed with the carrier with compacting property of proper proportion, is compressed by required shape and size.Powder agent and tablet preferably comprise up to 99% active component.Appropriate solid carrier includes, e.g., calcium phosphate, magnesium stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melt wax and ion exchange resin.

Liquid-carrier can be used in and prepare in solution, suspension, emulsion, syrup and elixir.The active component of the present invention can be dissolved or is suspended in pharmaceutically acceptable liquid-carrier such as water, organic solvent, the two mixture or pharmaceutically acceptable oils or grease.Liquid-carrier can contain other appropriate pharmacy additive such as cosolvent, emulsifying agent, buffer, protective agent, sweetener, flavouring agent, supensoid agent, intensifier, colouring agent, viscosity-controlling agent, stabilizer or osmotic pressure regulators.The appropriate liquid-carrier embodiment of oral and parenterai administration includes water (the partly additive containing the above, such as cellulose derivative, preferably carboxymethyl cellulose sodium solution), alcohols (including single hydroxyl alcohol and polyhydroxy-alcohol, such as ethylene glycol) and its derivative and oils (coconut oil and peanut oil of such as rectifying).The carrier of parenterai administration can also be grease such as ethyl oleate and tetradecanoic acid.Sterile liquid carrier can be used in the composition of the sterile liquid form of parenterai administration.

Using the liquid pharmaceutical composition progress such as intramuscular, intraperitoneal or hypodermic injection for being sterile solution or suspension.Also intravenous administration can be carried out with sterile solution.The form of liquid or solid composition can be used by being administered orally.

The suppository form rectally that the compound of the present invention can also be commonly used.For sucking or being blown into administration in nasal cavity or in bronchus, the compounds of this invention can be made to water or partially aqueous solution, the form of its aerosol is then utilized.The compounds of this invention also can be by using the percutaneous plaster cutaneous penetration containing active component and carrier, and the carrier is to active component inertia, nontoxic to skin and enhancing transport can be entered into blood systemic Absorption by skin.The carrier can be using various forms such as missible oil and paste, paste, gel and adsorbent equipment.Missible oil and paste can be the viscous liquid or semisolid emulsions of oil-in-water or water-in-oil type.The paste being made up of the absorption powder being dispersed in the oil containing active component or hydrophilic petroleum is also suitable.Active component can be discharged into blood with various adsorbent equipments, such as be covered with the pellicle of a reservoir containing active component and with or without carrier, or the basement membrane containing active component.Other adsorbent equipments are known in the literature.

Dosage used in individual patient of the treatment with the affiliated diseases of MMP or TACE must be determined by doctor in charge's subjectivity.Variable factor includes seriousness, stature, age, the reaction mode of dysfunction.Treatment is general since less than the low dose of the compound dose,optimum.Then incremental dose is until reach optimum efficiency.Accurately oral, non-bowel, nasal cavity or intrabronchial dosage will be determined by the doctor in charge according to individual treated experience and standard medical principle.

It is preferred that Pharmaceutical composition be unit dosage form, such as tablet or capsule.Again in these forms, composition Asia is divided into the unit dosage form containing appropriate active component；The unit dosage form can be packaged into composition, such as the powder of packing, the bottle containing liquid, ampoule, the syringe or sachet being full of in advance.Unit dosage form can be, such as capsule or tablet in itself, or these any compositions appropriate packaged form.

Claims (11)

1. the optical isomer and diastereomer of the compound with following formula, its pharmaceutically acceptable salt that can be formed, and its presence：

Wherein hydroxamic acid groups and sulfamoyl part are connected with the carbon on group A phenyl ring or naphthalene nucleus, wherein：A is phenyl or naphthyl, optionally by R¹、R²、R³And R⁴Substitution；Z is aryl, heteroaryl or the heteroaryl condensed with phenyl, and wherein aryl is phenyl or naphthyl, optionally by R¹、R²、R³And R⁴Substitution；Heteroaryl is the heteroatomic 5-6 members hetero-aromatic rings that N, O and S are independently selected from 1-3, and optionally by R¹、R²、R³And R⁴Substitution；And when heteroaryl and phenyl are condensed, any one or two of the ring is optionally by R¹、R²、R³And R⁴Substitution；R¹、R²、R³And R⁴Stand alone as-H ,-COR⁵、-F、-Br、-Cl、-I、-C(O)NR⁵OR⁶、-CN、-OR⁵、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁵(wherein x is 0-2) ,-OPO (OR⁵)OR⁶、-PO(OR⁶)OR⁵、-OC(O)NR⁵R⁶、-COOR⁵、-CONR⁵R⁶、-SO₃H、-NR⁵R⁶、-NR⁵COR⁶、-NR⁵COOR⁶、-SO₂NR⁵R⁶、-NO₂、-N(R⁵)SO₂R⁶、-NR⁵CONR⁵R⁶、-NR⁵C (=NR⁶)NR⁵R⁶, be independently selected from 1-3 N, O and S hetero atoms, and optionally there is the 3-6 membered cycloheteroalkyl groups of 1-2 double bond, and be optionally each independently selected from R by 1-3 is individual⁵Substituent group；As defined above aryl or heteroaryl, optionally it is each independently selected from R by 1-4⁴、-SO₂NHCOR⁵Or-CONHSO₂R⁵Substituent group xenyl (wherein R⁵H),-tetrazolium -5- bases,-SO₂NHCN、-SO₂NHCONR⁵R⁶Or straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group or the-C optionally with 1 or 2 double bond₃-C₆Cycloalkyl, it is each optionally by selected from following substituent group：-COR⁵、-CN、-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group ,-OR⁵、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁵(wherein x is 0-2) ,-OC (O) NR⁵R⁶、-COOR⁵、-CONR⁵R⁶、-SO₃H、-NR⁵R⁶、-NR⁵COR⁶、-NR⁵COOR⁶、-SO₂NR⁵R⁶、-NO₂、-N(R⁵)SO₂R⁶、-NR⁵CONR⁵R⁶, as defined above-C₃-C₆Cycloalkyl, 3-6 membered cycloheteroalkyl groups as defined above, aryl or heteroaryl as defined above, xenyl ,-SO₂NHCOR⁵Or-CONHSO₂R⁵(wherein R⁵H) ,-PO (OR⁵)OR⁶、-PO(OR⁶)OR⁵,-tetrazolium -5- bases,-C (O) NR⁵OR⁶、-NR⁵C (=NR⁶)NR⁵R⁶、-SO₂NHCONR⁵R⁶Or SO₂NHCN；On condition that working as R¹And R²When on A adjacent carbons, R¹And R²The saturated or unsaturated heterocycle of 5-7 members or 5-6 member hetero-aromatic rings can be formed together with the carbon that they are connected, it is each with the 1-3 hetero atoms for being independently selected from O, S or N, and each optionally it is each independently selected from R by 1-4⁴Substituent group；Or optionally it is each independently selected from R by 1-4⁴Substituent group the saturated or unsaturated carbocyclic ring of 5-7 members；R⁵And R⁶Stand alone as H, aryl as defined above or heteroaryl, as defined above-C₃-C₆- cycloalkyl ,-C as defined above₃-C₆Cycloheteroalkyl ,-C₁-C₄- perfluoroalkyl or straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl or-C₂-C₆Alkynyl group, it is each optionally by selected from following substituent group：-OH、-COR⁸、-CN、-C(O)NR⁸OR⁹、-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group ,-OR⁸、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁸(wherein x is 0-2) ,-OPO (OR⁸)OR⁹、-PO(OR⁸)R⁹、-OC(O)NR⁸R⁹、-COOR⁸、-CONR⁸R⁹、-SO₃H、-NR⁸R⁹、-NCOR⁸R⁹、-NR⁸COOR⁹、-SO₂NR⁸R⁹、-NO₂、-N(R⁸)SO₂R⁹、-NR⁸CONR⁸R⁹, as defined above-C₃-C₆Cycloalkyl, 3-6 membered cycloheteroalkyl groups as defined above, aryl or heteroaryl ,-SO as defined above₂NHCOR⁸Or-CONHSO₂R⁸(wherein R⁸H),-tetrazolium -5- bases,-NR⁸C (=NR⁹)NR⁸R⁹、-SO₂NHCONR⁸R⁹Or SO₂NHCN；R⁷For H, straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl or-C₂-C₆Alkynyl group, it is each optionally by selected from following substituent group：-OH、-COR⁵、-CN、-C₂-C₆Alkenyl ,-C₂-C₆Alkynyl group ,-OR⁵、-C₁-C₄- perfluoroalkyl ,-S (O)_xR⁵(wherein x is 0-2) ,-OPO (OR⁵)OR⁶、-PO(OR⁵)R⁶、-OC(O)NR⁵R⁶、-COOR⁵、-CONR⁵R⁶、-SO₃H、-NR⁵R⁶、-NR⁵COR⁶、-NR⁵COOR⁶、-SO₂NR⁵R⁶、-NO₂、-N(R⁵)SO₂R⁶、-NR⁵CONR⁵R⁶, as defined above-C₃-C₆Cycloalkyl, as defined above-C₃-C₆- cycloheteroalkyl, aryl or heteroaryl ,-SO as defined above₂NHCOR⁵Or-CONHSO₂R⁵(wherein R⁵H),-tetrazolium -5- bases,-NR⁵C (=NR⁶)NR⁵R⁶、-C(O)NR⁵OR⁶、-SO₂NHCONR⁵R⁶Or SO₂NHCN；Or R⁷For phenyl or naphthyl, optionally by R¹、R²、R³And R⁴Substitution, or to be independently selected from N, O and S heteroatomic 5-6 unit's heteroaryls with 1-3 simultaneously optionally by R¹、R²、R³And R⁴Substitution；Or R⁷For-C as defined above₃-C₆Cycloalkyl or 3-6 membered cycloheteroalkyl groups；Or R⁷CH₂- N-A- (wherein A is as defined above) can form the benzo-fused 7-10 circle heterocycles of non-aromatic 1,2-, optionally containing the other hetero atom selected from O, S and N, wherein the heterocycle can be condensed optionally with another phenyl ring；R⁸And R⁹Respectively H, aryl as defined above or heteroaryl, as defined above-C₃-C₇Cycloalkyl or 3-6 membered cycloheteroalkyl groups ,-C₁-C₄- perfluoroalkyl, straight or branched-C₁-C₆- alkyl ,-C₂-C₆Alkenyl or-C₂-C₆Alkynyl group, it is each optionally by selected from following substituent group：Hydroxyl, alkoxy, aryloxy group ,-C₁-C₄- perfluoroalkyl, amino, list-and double-C₁-C₆- alkyl amino, carboxylic acid.Carbonylic alkoxy and carbonyl aryloxy group, nitro, cyano group, carbonyl acylamino- (one-level), list-and double-C₁-C₆- alkyl-carbamoyl.

2. compound according to claim 1, wherein the A adjacent with being connected with sulfonamido carbon phase two carbon all have the substituent of non-hydrogen.

3. compound according to claim 2, wherein Z group are palkoxy benzene bases, to aryloxyphenyl or to heteroaryloxy phenyl.

4. compound according to claim 3, it is selected from：

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- chloro-N- Hydroxy-benzoyIcarbamos

Amine,

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- bromo-N- hydroxy-3-methyls -

Benzamide.

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzoyl

Amine,

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- benzyloxy-N- hydroxy-benzoyIamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- Hydroxycarboamoyls-methoxy-b enzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (2,2,2- trifluoro ethoxies)-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (2- Mehtoxy-ethoxies methoxyl group)-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [4- (hydroxyl amino-carbonyl)-benzyloxy]-N- hydroxy-benzoyIamides 2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (3- Hydroxycarboamoyls-propoxyl group)-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (4- Hydroxycarboamoyls-butoxy)-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- isopropoxies-benzamide N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- Fluoro-benzenesulfonyls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- butoxy-benzenesulfonyl)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- benzyloxies-benzenesulfonyl)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- hex- 1- alkynyls-N- hydroxy-3-methyls-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- acetenyls-N- hydroxy-3-methyls-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,5- dimethvl-benzamides,5- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methoxies-benzamide 2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -4- chloros-N- hydroxy-3-methyls-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-(3- methyoxy-benzyls)-amino] -3,5- dimethvl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-(2,3,5,The fluoro- 4- methyoxy-benzyls of 6- tetra-)-amino] -3,5- dimethvl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-propyl-amino] -3,5- dimethvl-benzamides 2- [(2- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [(3- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [(4- bromos-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3- triflooromethyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3,5- dimethvl-benzamides,2- [ethyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,3- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3- thiophene -2- bases-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3.5- dimethvl-benzamides,2- [ethyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,4,5- trimethoxy-benzamides,N- hydroxyls -3,4,5- trimethoxies -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzamide,5- (4- methoxy-benzenesulfonvls) -2,3,4,5- tetrahydrochysenes -1,5-benzoxazepine-6- formic acid hydroxy amides,12- [(4- methoxy-benzenesulfonvls) -11,12- dihydro -6H- dibenzo [b,f][1,4] oxazocine-1- formic acid hydroxy amide,6- (4- methoxy-benzenesulfonvls) -3,4,5,6- tetrahydrochysenes -2H-1,6-benzoxazocine-7- formic acid hydroxy amides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -3- nitro-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (3- hydroxy-propoxies)-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- thiophene -2- yl-benzamides,2- [benzyls-(4- methoxy-benzenesulfonvls amino)-N- hydroxyl -3- cyano group -5- methyl-benzamides,3- furans -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl-benzamides,3- Diethylaminomethyl-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-methylamino] benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-methylamino] -3- (4- methylpiperazine-1-yls methyl)-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls) amino] -3- (1- ethoxy carbonyl-N- hydroxyls -1- methyl ethoxies-benzamide,3- bromos -2- [benzyl-(4- MethOxybenzenesulfonyls) amino]-N- hydroxy-benzoyIamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-vinyl]-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-ethyl]-benzamide,5- (2- formyl-dimethylaminos-vinyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides,5- [2- (EthylPyridine -4- ylmethyl-aminos formoxyl)-vinyl]-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- [2- (methyl-octyl-carbamoyl)-vinyl]-benzamide,5- (2- formyl-dimethylaminos-vinyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,5- [2- (ethyl-phenyl-amino formoxyl)-vinyl]-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,5- (2- diallyls carbamoyl-vinyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- (3- morpholine -4- base -3- oxo-propenyls)-benzamide,2 '-(Hydroxyimino-methyl) -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyls -3- formic acid-hydroxy amide,3 '-(Hydroxyimino-methyl) -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyls -3- formic acid-hydroxy amide,4 '-(Hydroxyimino-methyl) -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyls -3- formic acid-hydroxy amide,4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- -2 '-Trifluoromethyl-biphenyl of methyl -3- formic acid-hydroxy amide,5- furans -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,N- hydroxyls -5- [3- (the Hydroxyimino-methyl)-base of thiophene -2] -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,5- (5- chloros-thiophene -2- bases)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,5- (5- acetyl group-thiophene -2- bases)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls -5- vinyl-benzamide,4- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N (1),N (3)-dihydroxy -5- methyl-m-phenylenes diamides (isophthalamide) disodium salt,5- ethyl-N-hvdroxvs -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- diethylamino methyl-N- hydroxy-3-methyls-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- pyridin-3-yls-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3,6- dimethvl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3,6- dimethvl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- [3- (5- methyl-ribofuranosyl -2- bases)-isoxazole -5-bases]-benzamide,2- [benzyl-(4- ethyoxyls-benzenesulfonyl)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- propoxyl group-benzenesulfonyl)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- isopropoxies-benzenesulfonyl)-amino]-N- hydroxyls -3,5- dimethvl-benzamides,2- [benzyl-(4- benzyloxies-benzenesulfonyl)-amino] -5- bromos-N- hydroxy-3-methyls-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- morpholine -4- ylmethvl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- pyrrolidin-1-yl methyl-benzamides,N- hydroxyl -3- imidazoles -1- ylmethyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzamide,5- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls amino)-Methyl-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzamide,5- bromo-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls amino)-Methyl-amino] -3- pyrrolidin-1-yl methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- pyrrolidin-1-yl methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-octyl group-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-thiene-3-yl Methyl-amino] -3- (4- thyl-piperazin -1- ylmethyls)-benzamide,N- hydroxyls -2- [(4- methoxyphenyls) sulfonyl) (phenyl methyl)-amino] -3- (4- methyl isophthalic acids-piperazinyl) methyl] benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- (ttetrahydro-pyran -2- base epoxides methyl)-benzamide,N- hydroxyl -3- methylols -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- [2- (t-butyl-dimethyI-sila epoxide)-ethyoxyl]-N- hydroxy-benzoyIamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyls -3- (2- Hydroxy-ethoxies)-benzamide,5- bromo-N- hydroxyls -3- [2- (Hydroxycarboamoyl)-ethyl] -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzamide,N- hydroxyls -3- [2- (Hydroxycarboamoyl)-ethyl] -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-benzamide,5- xenyl -4- ethyl-acetylene base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides,5- (2- xenyl -4- bases ethyl)-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides,5- 12-1- alkynyl-N- hydroxyls-2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-3- methyl-benzamides,5- dodecyl-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino] -3- methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methoxies-benzamide,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-isophthalic acid tert- butyl ester,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-isophthalic acid methyl esters,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-Methyl-amino]-isophthalic acid methyl esters,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl methylamino]-isophthalic acid,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridine -2- ylmethyl-aminos] -3- methyl-benzamides,N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-4-yl Methyl-amino] -3- methyl-benzamides,2- [(4- diethylaminos methyl-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide,2- [(4- dimethylaminomethyls-benzyl)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide,2- [(4- diethylaminos-butyl- 2- alkynyls)-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-methyl benzoate,N- hydroxyls -2- { (4- methoxy-benzenesulfonvls)-[4- (4- thyl-piperazin -1- bases)-benzyl]-amino } -3- methyl-benzamides,4- [(2- Hydroxycarboamoyl -6- methylphenyls)-(4- methoxy-benzenesulfonvls)-amino]-ethyl butyrate,5- [(2- Hydroxycarboamoyl -6- methylphenyls)-(4- methoxy-benzenesulfonvls)-amino]-ethyl valerate,[(2- Hydroxycarboamoyl -6- methylphenyls)-(4- methoxy-benzenesulfonvls)-amino]-benzyl acetate,N- hydroxyls -2- [[(4- methoxy-benzyls) sulfonyl] [2- oxos -2- (2- picolyls) amino] ethyl] amino] -3- methyl-benzamides,N- hydroxyls -2- { (4- methoxy-benzenesulfonvls)-[2- (4- thyl-piperazin -1- bases) -2- oxo-ethyls]-amino } -3- methyl-benzamides,N- hydroxyls -2- [(2- hydroxy-ethyls)-(4- methoxy-benzenesulfonvls)-amino] -3- methyl-benzamides,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -5- dimethylaminos-N- hydroxy-3-methyls-benzamide,2- [benzyl-(4- methoxy-benzenesulfonvls)-amino] -3- dimethylamino-N- hydroxy-benzoyIamides,N- hydroxyls -2- [[(4- methoxyphenyls) sulfonyl] [[[4- [2- (1- piperidyls) ethyoxyl] phenyl] methyl] amino] -3- methyl benzamides,2- [[4- (2- diethylamino-ethoxies)-benzyl]-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-3-methyls-benzamide,5- bromo-N- hydroxyls -2- { (4- methoxy-benzenesulfonvls)-[4- (2- piperidin-1-yls-ethyoxyl)-benzyl]-amino } -3- methyl-benzamides,N- hydroxyls -2- [[(4- methoxyphenyls) sulfonyl] [[4- [2- (1- piperidyls) ethyl] amino] carbamoyl] phenyl] methyl] amino] -3- methyl benzamides,4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts,- 3 bases of N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl -5- thiophene-benzamide hydrochloride salt,4 "-methoxyl group -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl-[1,1’；4 ', 1 " ] triphenyl -3- formic acid hydroxyl amide hydrochloric acid salts, 4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3 '-Nitro-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts, 4 '-methoxyl group -4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- Methvl-biphenyl -3- formic acid hydroxyl amide hydrochloric acid salts, 5- benzos [b] thiophene -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoyl amine hydrochlorates, 5- benzos [b] furans benzene -2- base-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoyl amine hydrochlorates, 4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -4 '-trifluoromethoxy of -5- methyl-xenyl -3- formic acid hydroxyl amide hydrochloric acid salts, 5- benzos [1, 3] dioxole -5- bases-N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -3- methyl-benzoyl amine hydrochlorates, '-three of 4- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino] -5- methyl -3

Methyl fluoride-xenyl -3- formic acid hydroxyl amide hydrochloric acid salts,

2- [(4- chloros-benzyl)-(5- pyridines -2- bases-thiophene -2- sulfonyls)-amino]-N- hydroxyls

Base -3- methyl-benzamides,

2- [(3,4- dimethyl-benzyl)-(5- pyridines -2- bases-thiophene -2- sulfonyls)-amino] -

N- hydroxy-3-methyls-benzamide,

N- hydroxy-3-methyls -2- [pyridin-3-yl methyl-(4 '-Trifluoromethyl-biphenyl) -4- sulphurs

Acyl group)-amino]-benzamide,

2- [(2 ', 4 '-dimethoxy-biphenyl base -4- sulfonyls)-pyridin-3-yl Methyl-amino] -

N- hydroxy-3-methyls-benzamide,

N- hydroxy-3-methyls -2- [pyridin-3-yl methyl-(4- thiophene -2- bases-benzenesulfonyl)-ammonia

Base]-benzamide,

2- [(4- acetenyls-benzenesulfonyl)-pyridin-3-yl Methyl-amino]-N- hydroxy-3-methyls

- benzamide,

2- [(4- benzos [b] thiophene -2- bases-benzenesulfonyl)-pyridin-3-yl Methyl-amino]-N-

Hydroxy-3-methyl-benzamide,

2- [(4- benzos [1,3] dioxole -5- bases-benzenesulfonyl)-pyridin-3-yl first

Base-amino]-N- hydroxy-3-methyls-benzamide,

3- methyl -2- [4- (pyridin-4-yl epoxide)-BENZENESUFONYLAMINO]-N- Hydroxy-benzoyIcarbamos

Amine.

5. compound according to claim 1, it is selected from：

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-benzoyIamides,

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-4-methyls-benzamide,

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxyl -6- methyl-benzamides,

2- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-N- hydroxy-5-methyls base-benzamide,

N- hydroxyls -2- [(4- methoxy-benzenesulfonvls)-pyridin-3-yl Methyl-amino]-benzamide, and

3- [benzyl-(4- methoxy-benzenesulfonvls)-amino]-naphthalene -2- formic acid hydroxy amides.

6. suppressing the method for the pathological change that mammal is mediated by matrix metalloproteinase, it includes giving the compound according to claim 1 for suppressing matrix metalloproteinase of this mammalian therapeutic effective dose treated of needs.

7. method according to claim 6, the illness wherein treated is atherosclerosis, atherosclerosis Plaque Formation, the coronary thrombus as caused by atherosclerosis plaque rupture is formed, the osteoporosis that MMP- induces, the inflammatory disease of central nervous system, skin aging, angiogenesis, metastases, tumour growth, osteoarthritis, rheumatoid arthritis, septic arthritis, ulcer of the cornea, aberrant wound heals, osteopathy, albuminuria, aortic aneurysm, degenerative cartilage after traumatic joint injury is lost, neurologic demyelinating disease, hepatic sclerosis, renal glomerular disease, the too early rupture (premature rupture) of fetal membrane, inflammatory bowel disease or periodontosis.

8. method according to claim 6, wherein the illness treated is the deformation of senile retinal macula lutea, diabetic retinopathy, Proliferative vetreoretinopathy, Prematurity, inflammation of eye section, keratoconus, Sjogren ' s syndromes, myopia, optic tubercle, Ocular Vessels generation/new vascular generation and corneal allograft rejection.

9. suppress the method for pathological change that mammal mediate by TNF-α invertase (TACE), it includes giving the suppression TACE of needs this mammalian therapeutic effective dosies treated compound according to claim 1.

10. method according to claim 9, wherein the symptom treated is rheumatoid arthritis, graft-rejection, cachexia, apositia, inflammation, heating, insulin resistance, septic shock, congestive heart failure, the inflammatory disease of central nervous system and inflammatory bowel disease or HIV.

11. Pharmaceutical composition, it includes pharmaceutical carrier and the suppression matrix metalloproteinase or TACE compound according to claim 1 of therapeutically effective amount.