CN1898234A - Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases - Google Patents

Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases Download PDF

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CN1898234A
CN1898234A CN 200480037188 CN200480037188A CN1898234A CN 1898234 A CN1898234 A CN 1898234A CN 200480037188 CN200480037188 CN 200480037188 CN 200480037188 A CN200480037188 A CN 200480037188A CN 1898234 A CN1898234 A CN 1898234A
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carbonyl
alkyl
hydroxyl
piperidines
amino
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Y·-L·李
J·周
D·博恩斯
W·姚
R·K·亚卢里
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Incyte Corp
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Incyte Corp
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Abstract

The present invention provides compounds of the formula I: its enantiomers, diastereomers, racemic mixtures thereof, prodrugs, crystalline forms, non-crystalline forms, amorphous forms thereof, solvates thereof, metabolites thereof, and pharmaceutically acceptable salts, wherein the ring A substituent groups are fully defined in the following disclosure. The compounds of formula I are inhibitors of metalloproteases such as matrix metalloproteases and sheddases, and are useful in treating diseases such as rheumatoid arthritis, psoriasis, neoplastic diseases, allergies and all those diseases wherein inhibition of MMPs is desirable.

Description

Cyclic hydroxamates as the replacement of matrix metallo-proteinase inhibitor
Invention field
The present invention relates to be used for the treatment of compound with unwanted metal proteinase activity diseases associated, pathological state and obstacle.The invention still further relates to matrix metalloproteinase (MMPS) inhibitor and as the purposes of medicine.The invention still further relates to the medical approaches of new compound and the multiple disease of treatment and other illness (particularly wherein suppressing those illnesss that metal proteinase activity has benefit).More particularly, the present invention relates to cyclic hydroxamates derivative and as MMP ' s inhibitor, particularly sheddase inhibitor with de-connect (ADAMs) purposes of inhibitor of albumen-metalloprotease (metalloprotease-disintegrins).
Background of invention
Many tissues are present in the high modulability running balance, and tissue new in this balance has forms and existing tissue deterioration and elimination.Extracellular matrix (ECM) comprises reticular tissue and basement membrane, is subjected to the influence of the metalloprotease that discharged by the inflammatory cell of reticular tissue and intrusion.The unadjusted activity of the over-drastic of these enzymes can cause undesirable disorganization, and by the activation of the potential proenzyme of control and after translation, by born of the same parents' internal specific supressor (for example TIMP (" tissue depressant of metalloprotease ")) or by more common proteinase inhibitor (as alpha2-macroglobulin) at transcriptional level, regulate their activity.
The metalloprotease of more known structurally associateds (MPs) is playing an important role aspect the destruction of structural protein.These metalloproteases act on the intercellular matrix usually, therefore relate to disorganization and reconstruction.These albumen are called as metalloprotease or MPs always.Through the sequence homology classification, there is the MPs of several different families.Some known MPs family and examples are disclosed in this area.
These MPs comprise matrix-metalloprotease [MMPs], zinc metalloprotein enzyme, multiple membrane-bound metalloprotease, TNF saccharase, angiotensin converting enzyme (ACEs), de-connect albumen, comprise that ADAMs is (referring to Wolfsberg etc., 131 J.Cell Bio.275-78, October 25 nineteen ninety-five) and enkephalinase.But the example of MPs comprises human skin fibroblast collagenase, human skin fibroblast gelatinase, people's saliva collagenase polyprotein glycan and gelatinase, and the molten stromatin enzyme of people.Generally acknowledged that but collagenase, molten stromatin enzyme polyprotein glycan are being important with relevant enzyme aspect the semeiologic mediation of some diseases.
According to the primary structure of their catalytic sites, zinc protease can be segmented again, it comprise gluzincin, metzincin, inuzincin, carboxypeptidase and DD carboxypeptidase hypotype (HooperNM, 1994, FEBS Lett, 354:1-6).The metzincin hypotype can be subdivided into again serralysins, astacin class, stromatin enzyme and echidnotoxin enzyme (Stocker W and Bode W, 1995, Curr Opin Struct Biol, 5:383-390).
The stromatin enzyme comprises matrix metalloproteinase or MMPs.MMPs forms the metalloprotein enzyme that contains zinc of gang's structural similitude, and it relates to the structural remodeling and the degraded of extracellular matrix protein, and both are all as the part of normal physiological processes and pathological state.Relevant commentary is referring to Bode, W etc., 1996, Adv Exp Med Biol, 389:1-11.Reticular tissue, extracellular matrix composition and basement membrane provide toughness, differentiation, attachment site, and in some cases, are used for the elastic biological substance of biosystem.The reticular tissue composition comprises for example collagen protein, elastin, proteoglycans, fibronectin and ln, and they form the support of everyone tissue.Under normal circumstances, the renewal of reticular tissue and/or repair process are controlled and are in the balance.Whatsoever reason has lost described balance, all will cause some diseases.The restraining effect that causes unbalanced enzyme is provided for described histolytic controlling mechanism, and therefore the method for these diseases of treatment is provided.Destructive reticular tissue by the metalloprotease non-controlling is the feature of numerous disease.
Except the effect of regulating extracellular matrix, also have data show the migration of MMPs mediation inflammatory cell enter in the tissue (Moscatelli D and Rifkin DB, 1988, Biochim BiophysActa, 948:67-85).Some reports confirm that also many MMPs can activate some important non-stroma proteins, comprise cytokine class, chemokine class, integrin class and antimicrobial peptide class (referring to Parks WC, 2002, J.Clin Invest, 110:613-4).Many people MMPs overexpression in people's tumour, and with enclose tumor tissues degenerate with shift form relevant.By the preceding territory of rupturing from their proteolytic enzyme structural domain, other critical function of some MMPs is to activate plurality of enzymes, comprises other MMPs.Therefore, some MMPs act on the activity of regulating other MMPs, make the excessive generation of a kind of MMP can cause the excessive proteolysis of extracellular matrix by other MMP.Report has also been arranged, MMPs can cracking and therefore the activity of the endogenous inhibitor of other proteolytic enzyme of inactivation (for example elastoser) (Winyard PG etc., 1991, FEBS Letts, 279:91-94).Therefore, the level of the endogenous inhibitor by regulating them, the MMPs inhibitor can influence other destructive protease activities.In addition, increase or keep endogenous or the level of the serpin that gives, support following treatment of diseases and prevention, for example pulmonary emphysema, lung disease, inflammatory diseases and aging disease, for example skin or organ extensibility and loss of elasticity.Therefore, should only not think MMPs as the catabolic proteolytic enzyme of ECM, and especially as the outer substrate desmoenzyme of the born of the same parents that relate to adjusting cell-cell and cell-ECM signal transition.
Viprinex comprises reprolysins, snake venom metalloproteinase and ADAMs.Described ADAMs (de-connecting albumen and metalloprotease structural domain) the important metalloprotease of gang.They are families of 1 type transmembrane glycoprotein, and described glycoprotein is important in multiple bioprocess (for example the proteolysis of cytoadherence and cell surface receptor discharges)., comprise the member who has determined ADAM family among non-state Bufo (Xenopus), Drosophila (Drosophila) and the Caenorhabditis elegans from Mammals and nonmammalian source.The member of described family have a kind of with metalloprotease exist with integrin receptor be the modular design of feature in conjunction with activity, and cytoplasm domain, it represents to be used for the combining site of multiple signal-transducer in many family members.ADAMs family participates in the release and the cell migration of control, cytokine, somatomedin and growth factor receptors that film merges always, and for example muscle development, fertilization, the neural generation and process that cell fate is determined.The forfeiture of regulating effect can cause disease and pathological state.Shown such as the pathology of sterile, inflammation and cancer relevant with the ADAMs family member.About commenting with reference to Wolfsberg TG and White JM, 1998, ADAM metalloprotein enzyme.Proteolytic ferment handbook (Barrett AJ, Rawlings ND and Woessner JF write) 1310-1313 page or leaf, Academic publishes, London and Seals DF and Courtneidge SA, 2003, Genes and Development, 17:7-30.
Some special examples of important ADAM metalloprotein enzyme comprise TNF α-saccharase, TACE or ADAM17, it is the important target (MossML etc. that are used for anti-inflammatory drug at present, 2001, Drug Discov Today, 6:417-426 and Black RA, 2002Int JBiochem Cell Biol, 34:1-5).Other member of described family also may be the good curing target.Reported that ADAM8 almost is expressed in the immune system cell uniquely, particularly in B-cell, monocyte, eosinophilic granulocyte and the granulocyte.Therefore, a kind of treatment target of ADAM8 representative based on people's Immunological diseases.ADAM15 finds in the huve cell of human aorta unstriated muscle and cultivation.Though ADAM15 does not express in normal blood vessels, but it is detected (Herren B etc. in the atherosclerotic lesion of growing, 1997, FASEB J, shown that 11:173-180), and also showing is incremental adjustments (Bohm BB etc., 1999 in the relation curve of osteoarthritis and normal people's cartilage, ArthritisRheum, 42:1946-1950).Therefore, ADAM15 can play an important role in atherosclerosis and cartilage degradation disease.In addition, compare with the wild-type control group, the mouse that ADAM15 rejects has the neovascularization effect of reduction and less tumour, prompting ADAM15 also may be important (Horiuchi, K et al., 2003 in cancer, Mol Cell Biol, 23:5614-5624).It may have important immunologic function the lymphocyte of ADAM28-specific expressed prompting.
Think that now the excessive generation of IgE is the main medium of allergic effect reaction.CD23, low affinity acceptor for IgE, it is the reason that the pulsating ADAM shaped metal proteolytic enzyme of extracellular soluble exosome-dependence protein hydrolysis discharges, demonstrated the induction that can cause incremental adjustments that IgE produces and inflammatory cytokine (referring to Novak N etc., 2001, Curr OpinImmunol, 13:721-726 and Mayer RJ etc., 2002, Inflamm Res, 51:85-90).The level of having observed solubility CD23 in allergic asthma, chronic B-Lymphocytic leukemia and rheumatoid arthritis increases.Can provide a kind of method for the treatment of various immune-base diseases to the restraining effect that causes the CD23 processive enzyme.Show that also the ADAM metalloprotease undertakes the release of following material or distribute: soluble receptors (for example acceptor of CD30 and TNF), (for example L-selects albumen to adhesion molecule, ICAM-1, fibronectin), somatomedin and cytokine (Fas part for example, TGF-α, EGF, HB-EGF, SCF IL-6, IL-1, TSH and M-CSF), and growth is because of acceptor (ECFR family member for example, as Her-2 and Her-4), its pathogeny relevant (Yarden Y and SliwkowskiMX with dissimilar cancers, 2001, Nature Reviews 2:127-137).For example, Her-2 overexpression in the 25-30% human breast carcinoma, and relevant with the danger increase of recurrence and death (Slamon DJ etc., 1987, Science, 235:177-182).Recently proof ADAM17 for the regularity of Her-4 discharge be crucial (Rio C etc., 2000, J Biol Chem, 275:10379-10387).The proteolytic enzyme that causes the Her-2 spilting of an egg, promptly Her-2sheddases is unknown MMP, it also is the member (Codony-Servat J etc., 1999, Cancer Res59:1196-1201) of ADAM family.Therefore, this active adjusting may have important effect aspect the adjusting of human diseases.About the active commentary of the sheddase of ADAMs referring to Moss ML and Lambert MH, 2002, Essays Biochem, 38:141-153.
Determined that ADAM-TS (being also referred to as ADAMTS) proteolytic enzyme is the ADAM family member.These protein are new protein, and because of structural conservative overseas except some of other ADAM family member, they contain unique thrombospondin (TS) I type motif.Because they lack abundant halfcystine, class-EGF, stride film and cytoplasm domain, also described ADAM-TSs can be made a distinction from ADAMs.Also proved ADAM-TS protein and some pathology or the Human diseases situation relevant.For example, ADAMTS-1 is a kind of tumor-selective gene that is expressed in clone's tumour cell, and also is the relevant protein of a kind of inflammation.Verified recently, people ADAMTS-1 directly has the angiogenesis inhibitor activity to homologue (being called METH-1) and relevant protein METH-2, and these or other ADAMTS family member can play an important role aspect the adjusting vascular development.ADAMTS-2 grows relevant with normal skin.Think that for a long time described enzyme is precollagen N-proteolytic enzyme, be a kind of when I type and II procollagen type class form collagen proteolysis remove the proteolytic enzyme of the peptide class that deaminizes, shown having hereditary connective tissue disease VIIC type dust in syndromic individual's skin, to lack described proteolytic enzyme.But known ADAMTS-4 and ADAMTS-11 are polyprotein glycan-1 and-2, and reason is that they can decompose special site in aggrecan, and aggrecan is a kind of proteoglycan that is keeping the structural performance of cartilage.Aggrecan to carry out sexual involution relevant with IJD (for example rheumatoid arthritis) with degenerative joint disease (for example osteoarthritis) with minimizing.For the summary of ADAM-TS metalloprotease referring to Tang BL, 2001, Int J Biochem Cell Biol, 33:33-44 and Kaushal GP and SV Shah, 2000, J Clin Invest 105:1335-1337.
Metalloprotease is a kind of proteolytic enzyme of old classification, is found in bacterium, fungi and the higher organisms body.Many enzymes contain sequence HEXXH, and it provides two kinds of Histidine parts for zinc, and the third part is L-glutamic acid (thermolysin, neutral molten shortcake, alanyl-amino peptidase) or Histidine (astacin).Other family shows a kind of zinc atom bonded different modes.Therefore from some protokaryons and eucaryon source, isolate metalloprotease.Isolate the tart metalloprotease in leniently banded copperhead and the rattlesnake venom.The neutral metalloprotease, particularly those have optimum active metalloprotease under neutral pH, for example separate from sojae aspergillus.Basic metal proteolytic enzyme is for example separated from Pseudomonas aeruginosa and insect pathogenic bacteria Xenorhabdus luminescens.The restraining effect of microbial metalloproteinases can cause growth-inhibiting and demonstrate germ resistance.The restraining effect of the metalloprotease relevant with snake venom or insect toxicity also can cause producing new methods of treatment.
The potential treatment indication of MP inhibitor is disclosed in the literature.Referring to for example U.S. Patent number 6,500,847 (Bayer Corporation), U.S. Patent number 6,268,379 (DuPont Pharmaceuticals Company), U.S. Patent number 5,968,795 (BayerCorporation), U.S. Patent number 5,892,112 (Glycomed Incorporated and TheUniversity of Florida) and U.S. Patent number 5,872,152 (Britiish BiotechPharmaceuticals Limited).
Matrix metallo-proteinase inhibitor be used for the treatment of because, to small part because the caused disease of decomposition of structural protein.Though prepared many MMP inhibitor in association area, but still need be effective matrix metallo-proteinase inhibitor for being used for the treatment of partly cause at least by the caused disease of decomposition of structural protein.It is effective inhibitors of metalloproteinase that the applicant is surprised to find compound of the present invention.
Goal of the invention
According to aforementioned, the purpose of this invention is to provide and have as the carbocyclic ring of the replacement of formula I therepic use, that a class is new of inhibitors of metalloproteinase and IA or the heterogeneous ring compound of replacement.
Another object of the present invention provides to be had as the carbocyclic ring of the replacement of the formula II of (for the formula I) therepic use, that a group is new of inhibitors of metalloproteinase and IIA or the heterogeneous ring compound of replacement.
Another object of the present invention is to identify and claim has ring-type hydroxamic acid derivs as the replacement of formula III, IIIA, IV and the IVA therepic use, a group new (for formula I and II) of inhibitors of metalloproteinase.
Another object of the present invention is to identify and claim has ring-type hydroxamic acid derivs as the replacement of formula V, VA, VI and the VIA therepic use, a group new (for formula I and II) of inhibitors of metalloproteinase.
Another object of the present invention provides formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI and the VIA compound that has as one or more therepic use of matrix metalloproteinase (MMP) inhibitor, sheddase inhibitor and ADAM inhibitor.
A further object of the present invention provides medicinal compositions, it comprises the inhibitors of metalloproteinase of such formula I, the IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI and the VIA that treat significant quantity, or MMP inhibitor especially, sheddase inhibitor and/or ADAM inhibitor, and one or more pharmaceutically acceptable carrier and/or vehicle.
Another purpose of the present invention provides a kind of treatment and it is characterized by the metalloprotease-related disorders of unwanted metal proteinase activity or the method for illness and morbid state.
Another object of the present invention is to use The compounds of this invention in the method for treatment allergic disease.
Compound and use that another object of the present invention provides the Her-2sheddase inhibition comprise the further embodiment of such Her-2sheddase inhibitor with the composition of treatment tumor disease.
A further object of the present invention provides the compound of the inhibitor of the ADAM10, the ADAM15 that are embodied in anticarcinogen, ADAM28, ADAM33.
Another object of the present invention provides the compound of the inhibitor of the ADAM17/TACE (a.k.a.TNF α transferring enzyme) that is embodied in antiphlogiston, and more specifically is the compound of the inhibitor that is used for the treatment of the ADAM17/TACE (a.k.a.TNF α transferring enzyme) in the method for inflammatory diseases state.
Another purpose of the present invention provides the compound of the inhibitor of the metalloprotease 12 (a.k.a.MMP 12) that is embodied in antiphlogiston, and more specifically is the compound of the inhibitor that is used for the treatment of the metalloprotease 12 (a.k.a.MMP12) in the method for inflammatory diseases state.
In addition, the invention provides new optionally, micromolecular matrix metallo-proteinase inhibitor, it can be used for regulating the progress of potential disease and treatment and excessive MMP-inductive tissue injury diseases associated.
Other purpose of the present invention and embodiment will be discussed hereinafter.Yet, other embodiments of the present invention of not enumerating especially or describing in the following description in addition, and they all fall in the spirit and scope of theme of the present disclosure and appended claims thereof.Those skilled in the art need not to carry out too much experiment can easily understand these other embodiments.
Summary of the invention
The present invention provides the compound with formula IA in its generalized embodiment:
Or its enantiomorph, diastereomer, the mixture that is rich in enantiomorph, raceme mixture, its prodrug, crystalline form, amorphous, amorphous form, its solvate, metabolite and pharmacy acceptable salt thereof, wherein:
Ring A is for comprising carbon atom, a 0-3 carbonyl, 0-4 two keys and individual O, N, NR and the S (O) of being selected from of 0-4 pThe 3-13 unit carbocyclic ring or the heterocycle of ring hetero atom, prerequisite is that ring A does not contain S-S, O-O or S-O key;
N ' is the integer of 1-3;
Z is selected from-COR 5,-CO 2H ,-CH 2CO 2H ,-CO 2R 6,-CONHOH ,-CONHOR 5,-CON (R 6) OH ,-CONHOR 6,-NHR a,-N (OH) C (O) R 5,-N (OH) CHO ,-SH ,-CH 2SH ,-S (O) (=NH) R a,-SN 2H 2R a,-PO (OR g) 2,-PO (OH) NHR a,
Figure A20048003718800881
R gIndependently be selected from H, CH 2OCOR a,
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) O, OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1, NR A1S (O) pAnd NR A1SO 2NR A1
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring, and contain carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) O, OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1, NR A1S (O) pAnd NR A1SO 2NR A1
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R cReplace; Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkylene group)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, Cl, F, Br, I ,-CN, NO 2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M and NR aS (O) 2NR A1(CR dR D1) r-M, (CR dR D1) rP (O) (OR a) 2, (CR dR D1) rP (O) (OR a) (NR dR D1), (CR dR D1) rP (O) (NR aR A1) 2, (CR dR D1) rOP (O) (OR a) 2, (CR dR D1) rOP (O) (OR a) (NR aR A1), (CR dR D1) rOP (O) (NR aR A1) 2, (CR dR D1) rNR aP (O) (OR a) 2, (CR dR D1) rNR aP (O) (OR a) (NR aR A1), (CR dR D1) rNR aP (O) (NR aR A1) 2C (=NR a) NR A1R A2C (=CR dR D1) NR A1R A2By 0-5 R dThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 is selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R dReplace; Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkylene group, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F, Br, I ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3, OCHF 2, by 0-5 R dThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 is selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR A1(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1, (CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2NR A1(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br, I ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3With comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-14 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 13Carbocyclic ring, C 4-C 14Heterocycle, and wherein said C 3-C 13Carbocyclic ring and C 4-C 14Heterocycle is by 1-3 R hAnd CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Perhaps, when two R groups when adjacent ring A atom is connected, then they can connected atom form together and contain carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the unsaturated ring of heteroatomic 3-8 unit, wherein said ring can be benzene-condensed and/or by R dReplace;
Perhaps, when two R groups connected with identical ring A atom, then they can connected carbon atom form together and contain carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the undersaturated spiral shell of heteroatomic 3-8 unit-ring, wherein said spiral shell-ring can be benzene-condensed and/or by R dReplace;
Prerequisite is two or more R or M, M 1Form N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) with the atom debond that is connected with them p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkyl, alkenyl and alkynyl are optional to be replaced by following group: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl (sufonamido) dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-14 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and 5-14 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,=O ,-CN, NO 2, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3And CF 2CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14, C that is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
R D1When occurring, independently be selected from H, by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The optional C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, NR aS (O) pNR jR a, by R cThe C that replaces 1-6Alkyl.
R jWhen occurring, independently be selected from CF at every turn 3, CH 2F, CHF 2, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl; R 3Be H or C 1-6Alkyl OR a, NR aR A1And S (O) pR a
R 4Be selected from H, C 1-6Alkyl, OR a, NR aR A1And S (O) pR a
R 5When occurring, be selected from by 0-2 R at every turn bThe C that replaces 1-10Alkyl and by 0-2 R eThe C that replaces 1-8Alkyl;
R eWhen occurring, be selected from by 0-2 R at every turn bThe phenyl that replaces and by 0-2 R bThe xenyl that replaces;
R 6When occurring, be selected from phenyl, naphthyl, C at every turn 1-10Alkyl-phenyl-C 1-6Alkyl-, C 3-11Cycloalkyl, C 1-6Alkyl-carbonyl oxygen base-C 1-3Alkyl-, C 1-6Alkoxy-carbonyl oxy-C 1-3Alkyl-, C 2-10Alkoxy carbonyl, C 3-6Naphthene base carbonyl oxygen base-C 1-3Alkyl-, C 3-6Cyclo alkoxy carbonyl oxygen base-C 1-3Alkyl-, C 3-6Cyclo alkoxy carbonyl, phenyloxycarbonyl, phenyl oxygen base ketonic oxygen base-C 1-3Alkyl-, phenylcarbonyl group oxygen base-C 1-3Alkyl-, C 1-6Alkoxy-C 1-6Alkyl-carbonyl oxygen base-C 1-3Alkyl-, [5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, [5-(R a)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, (5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl) ,-C 1- 10Alkyl-NR 7R 7a,-CH (R 8) OC (O) R 9With-CH (R 8) OC (O) OR 9Perhaps, R 4And R 6Can form optional together by R cThe 5-10 unit ring that replaces;
R 7Be selected from H, C 1-10Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 1-3Alkyl-and phenyl-C 1-6Alkyl-;
R 7aBe selected from H, C 1-10Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 1-3Alkyl-and phenyl-C 1-6Alkyl-;
R 8Be selected from H and C 1-4Linear alkyl;
R 9Be selected from H, by 1-2 R fThe C that replaces 1-8Alkyl, by 1-2 R fThe C that replaces 3-8Cycloalkyl and by 0-2 R bThe phenyl that replaces;
R fWhen occurring, be selected from H, C at every turn 1-4Alkyl, C 3-8Cycloalkyl, C 1-5Alkoxyl group and by 0-2 R bThe phenyl that replaces;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
As defined above, formula IA refers to the combination of formula I-VI, and embodiment more preferably as described below.Particularly, formula I-VI and other embodiment at large are defined on the ring A and can have 1,2 and 3 substituting group.Therefore, formula IA provides ring A to be replaced by 1,2 or 3 R group.
In another embodiment of the invention, provide formula I compound.Cotype IA compound is the same, and these compounds also have the purposes as inhibitors of metalloproteinase, and preferred purposes as matrix metallo-proteinase inhibitor, sheddase inhibitor and ADAM inhibitors of metalloproteinase.Formula IA compound as cotype I compound, is the carbocyclic ring of replacement with following general formula or the heterogeneous ring compound of replacement:
Figure A20048003718800951
The variable of formula I has as above to the identical meaning of the defined variable of formula IA.Particularly, R, R 1And R 2Definition identical.
In another embodiment of the invention, formula IIA and II compound are provided.This organizes compound, as cotype I compound, also has the purposes as inhibitors of metalloproteinase, and preferred purposes as matrix metallo-proteinase inhibitor, sheddase inhibitor and ADAM inhibitors of metalloproteinase.Formula IIA and II compound as cotype I compound, are the carbocyclic ring of replacement or the heterogeneous ring compound of replacement.Formula IIA compound has following formula;
Figure A20048003718800961
Wherein encircling A is to comprise carbon atom, 0-1 carbonyl group and 0-2 4-10 non-aromatic carbocyclic of unit or heterocycle that is selected from the ring hetero atom of O, N, NR, and prerequisite is that ring A does not contain the O-O key.Variable n ' is 1 or 2.A subgroup of formula IIA compound meets formula II, and it has following structure:
A-ring substituents group R, R 1, P and Z relate in the embodiment preferred hereinafter that more detailed description will be arranged; For the purpose of brief, the definition of each substituting group group is by the definition of the more preferably subgroup of the corresponding substituting group group that formula I compound is defined.
In preferred embodiment of the present invention, ring-type hydroxamic acid compound and/or derivative with effective metalloproteinase inhibitory activity are provided, these compounds have the structure of formula III A or IVA:
Wherein encircling A is to comprise carbon atom, a 0-1 carbonyl group and 0-2 5-7 non-aromatic carbocyclic of unit or heterocycle that is selected from the ring hetero atom of O, N, NR, and prerequisite is that ring A does not contain the O-O key.Variable n ' is 1 or 2.The subgroup of formula III A and IVA compound is respectively the compound of formula III and IV.The structure of these compounds is as follows:
Figure A20048003718800971
A-ring substituents group R, R 1Relate to hereinafter in the embodiment preferred with P more detailed description will be arranged; For the purpose of brief, the definition of each substituting group group is by the definition of the more preferably subgroup of the corresponding substituting group group that formula I compound is defined.
In another preferred embodiment, the invention provides ring-type hydroxamic acid compound and/or derivative with effective metalloproteinase inhibitory activity, these compounds have structural formula VA and VIA
Figure A20048003718800972
Variable n ' is 1 or 2.A compound that subgroup is formula V and VI of formula VA and VIA compound, it has following structure:
Figure A20048003718800973
The present invention also is provided at the method that is used for the treatment of in the mammalian subject with unwanted metal proteinase activity diseases related, and this method comprises the inhibitors of metalloproteinase compound of formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI or the VIA of the described Mammals treatment significant quantity that needs.
The present invention also is provided for treating the method for the disease of being regulated by metalloprotease in the mammalian subject, described disease is selected from sacroiliitis, cancer, cardiovascular disorder, tetter, inflammation and allergic disease, and this method comprises the inhibitors of metalloproteinase compound of formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI or the VIA of the described Mammals treatment significant quantity that needs this kind treatment.
The present invention also provides the method for a kind of inhibition Mammals by the pathological change of high-caliber matrix metalloproteinase (as MMP12) mediation, and this method comprises that the metalloprotease of formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI or the VIA of the described Mammals treatment significant quantity that needs suppresses compound.
The invention still further relates to a kind of being used in the method for mammalian subject treatment with unwanted sheddase activity (as Her-2sheddase, other somatomedin sheddases and cytokine sheddases) diseases associated, this method comprises the sheddase inhibitor compound of formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI or the VIA of the described Mammals treatment significant quantity that needs.
The present invention also provides a kind of and is used in the method for mammalian subject treatment with unwanted TNF-α saccharase and the active diseases associated of ADAM10, and this method comprises the TNF-α converting enzyme inhibitor compound of I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI or the VIA of the described Mammals treatment significant quantity that needs.
In addition, the present invention also provides a kind of medicinal compositions of therepic use, it comprises the The compounds of this invention and at least a pharmaceutically acceptable diluent or carrier for the treatment of significant quantity, and other optional is preparation formulation and the necessary vehicle of suitable route of administration.
The description of preferred embodiment
The invention provides the new compound and the medicinal compositions of quick imbalance obstacle diseases associated that is used for the treatment of with extracellular matrix tissue due to the MMPs (comprising MMP12 and MMP13).Some such diseases comprise rheumatoid arthritis, osteoarthritis, septicemia sacroiliitis, keratohelcosis, epidermis ulcer or stomach ulcer; Periodontal disease, proteinuria, with atherosclerotic plaque come off relevant Coronary thrombosis and osteopathia.New compound of the present invention also is used for the treatment of and also shows active relevant metastases and vascularization with MMP.In addition, because the cycle of tissue injury and reaction is relevant with the deterioration of described morbid state, the tissue injury that the MMP-that causes owing to high-caliber described proteolytic enzyme with specific inhibitor restriction of the present invention causes generally can cause the effective treatment means of weak disease as many these classes.Compound of the present invention also is the inhibitor of TNF α saccharase and sheddases (comprising Her-2sheddase and HB-EGF sheddase and other somatomedin and cytokine sheddases).
The present invention also provides new compound, new composition, their using method and their preparation method, such compound is passing through inhibition or antagonism matrix metalloproteinase usually, metalloprotease, ADAMs, ADAM-TS and/or tumor necrosis factor-alpha (TNF) and in those morbid states of alleviating as the pharmacology purposes of medicine, relate to unusual extracellular matrix degradation on the described nosopathology, cell surface protein ectodomain (ectodomains) come off and/or TNF synthetic, such morbid state comprises sacroiliitis, metastases and diabetes.Aforesaid pharmacological activity is useful in mammiferous treatment.
More particularly, the present invention relates to new anticancer, anti-inflammatory and immunoregulatory ring-type hydroxamic acid bioactive compounds and medicinal compositions, they work by antagonism MMPs, ADAMs, ADAMTS, sheddase (as Her2 sheddase), therefore produce new therapeutic therapeutic regimen (modalities).
The invention still further relates to the compound that suppresses metalloprotease, as MMP12, ADAMs family metalloprotease (comprising TNF α-transferring enzyme), Adam-10 and relevant sheddases (as Her2 sheddase, heparin-bonded EGF sheddase), thereby be used for the treatment of that suffer from can be by suppressing the Mammals of the morbid state that such metal proteinase activity alleviates.
The invention still further relates to the inhibitor of ADAM metalloprotease, they and soluble receptors (for example CD30 and to the acceptor of TNF), adhesion molecule (for example L-selects albumen, ICAM-1, fibronectin), somatomedin and cytokine (for example Fas part, TGF-α, EGF, HB-EGF, SCF IL-6, IL-1, TSH and M-CSF) and growth factor receptors (EGFR family member for example, as Her-2 and Her-4, they are relevant with the pathogeny of dissimilar cancer) release or deviate from relevant.
More particularly, the invention provides new compound with formula IA:
Figure A20048003718801001
Or its enantiomorph, diastereomer, the mixture that is rich in enantiomorph, its raceme mixture, its prodrug, crystalline form, amorphous form, amorphous form, its solvate, metabolite and pharmacy acceptable salt thereof, wherein:
Ring A is for comprising carbon atom, a 0-3 carbonyl, 0-4 two keys and individual O, N, NR and the S (O) of being selected from of 0-4 pThe 3-13 unit carbocyclic ring or the heterocycle of ring hetero atom, prerequisite is that ring A does not contain S-S, O-O or S-O key;
N ' is 1,2 or 3;
Z is selected from-COR 5,-CO 2H ,-CH 2CO 2H ,-CO 2R 6,-CONHOH ,-CONHOR 5,-CON (R 6) OH ,-CONHOR 6,-NHR a,-N (OH) C (O) R 5,-N (OH) CHO ,-SH ,-CH 2SH ,-S (O) (=NH) R a,-SN 2H 2R a,-PO (OR g) 2,-PO (OH) NHR a,
Figure A20048003718801002
R gIndependently be selected from H, CH 2OCOR a,
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) O, OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1, NR A1S (O) pAnd NR A1SO 2NR A1
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring, and contain carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) O, OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1, NR A1S (O) pAnd NR A1SO 2NR A1
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R cReplace; Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkylene group)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, Cl, F, Br, I ,-CN, NO 2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, and NR aS (O) 2NR A1(CR dR D1) r-M, (CR dR D1) rP (O) (OR a) 2, (CR dR D1) rP (O) (OR a) (NR dR D1), (CR dR A1) rP (O) (NR aR A1) 2, (CR dR D1) rOP (O) (OR a) 2, (CR dR D1) rOP (O) (OR a) (NR aR A1), (CR dR D1) rOP (O) (NR aR A1) 2, (CR dR D1) rNR aP (O) (OR a) 2, (CR dR D1) rNR aP (O) (OR a) (NR aR A1), (CR dR D1) rNR aP (O) (NR aR A1) 2C (=NR a) NR A1R A2C (=CR dR D1) NR A1R A2, by 0-5 R dThe C that replaces 3-13Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O, S (O) pThe first heterocycle of heteroatomic 5-14, and described heterocycle is by 0-5 R dReplace; Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkylene group, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F, Br, I ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR A1(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1, (CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2NR A1(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br, I ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatoms 5-14 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 13Carbocyclic ring, C 4-C 14Heterocycle, and wherein said C 3-C 13Carbocyclic ring and C 4-C 14Heterocycle is by 1-3 R hAnd CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Perhaps, when two R groups when adjacent ring A atom is connected, then they can connected atom form together and comprise carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the unsaturated ring of heteroatomic 3-8 unit, wherein said ring can be benzene-condensed and/or by R dReplace;
Perhaps, when two R groups connected with identical ring A atom, then they can connected carbon atom form together and comprise carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the undersaturated spiral shell of heteroatomic 3-8 unit-ring, wherein said spiral shell-ring can be benzene-condensed and/or by R dReplace;
Prerequisite is two or more R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkyl, alkenyl and alkynyl are optional to be replaced by following group: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-16Alkyl; C 3-10Carbocylic radical, and 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and 5-14 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,=O ,-CN, NO 2, NR aR A1And S (O) pR aR cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2C F3 and OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14, C that is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, NR aS (O) pNR jR a, by R cThe C that replaces 1-6Alkyl.
R jWhen occurring, independently be selected from CF at every turn 3, CH 2F, CHF 2, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
R 3Be H or C 1-6Alkyl OR a, NR aR A1And S (O) pR a
R 4Be selected from H, C 1-6Alkyl, OR a, NR aR A1And S (O) pR a
R 5When occurring, be selected from by 0-2 R at every turn bThe C that replaces 1-10Alkyl and by 0-2 R eThe C that replaces 1-8Alkyl;
R eWhen occurring, be selected from by 0-2 R at every turn bThe phenyl that replaces and by 0-2 R bThe xenyl that replaces;
R 6When occurring, be selected from phenyl, naphthyl, C at every turn 1-10Alkyl-phenyl-C 1-6Alkyl-, C 3-11Cycloalkyl, C 1-6Alkyl-carbonyl oxygen base-C 1-3Alkyl-, C 1-6Alkoxy-carbonyl oxy-C 1-3Alkyl-, C 2-10Alkoxy carbonyl, C 3-6Naphthene base carbonyl oxygen base-C 1-3Alkyl-, C 3-6Cyclo alkoxy carbonyl oxygen base-C 1-3Alkyl-, C 3-6Cyclo alkoxy carbonyl, phenyloxycarbonyl, phenyl oxygen base ketonic oxygen base-C 1-3Alkyl-, phenylcarbonyl group oxygen base-C 1-3Alkyl-, C 1-6Alkoxy-C 1-6Alkyl-carbonyl oxygen base-C 1-3Alkyl-, [5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, [5-(R a)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, (5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl) ,-C 1-10Alkyl-NR 7R 7a,-CH (R 8) OC (O) R 9With-CH (R 8) OC (O) OR 9Perhaps, R 4And R 6Can form optional together by R cThe 5-10 unit ring that replaces;
R 7Be selected from H, C 1-10Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 1-3Alkyl-and phenyl-C 1-6Alkyl-;
R 7aBe selected from H, C 1-10Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 1-3Alkyl-and phenyl-C 1-6Alkyl-;
R 8Be selected from H and C 1-4Linear alkyl;
R 9Be selected from H, by 1-2 R fThe C that replaces 1-8Alkyl, by 1-2 R fThe C that replaces 3-8Cycloalkyl and by 0-2 R bThe phenyl that replaces;
R fWhen occurring, be selected from H, C at every turn 1-4Alkyl, C 3-8Cycloalkyl, C 1-5Alkoxyl group and by 0-2 R bThe phenyl that replaces;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
In an embodiment preferred, the invention provides the new compound of a class according to formula IIA;
Figure A20048003718801081
Wherein encircling A is to comprise carbon atom, 0-1 carbonyl group and 0-2 4-10 non-aromatic carbocyclic of unit or heterocycle that is selected from the ring hetero atom of O, N, NR, and prerequisite is that ring A does not contain the O-O key;
N ' is 1 or 2;
Z is selected from-CO 2H ,-CH 2CO 2H ,-CONHOH ,-CONHOR 5,-NHR a,-N (OH) C (O) R 5,-N (OH) CHO ,-SH ,-CH 2SH, and
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1And NR A1S (O) p
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-10Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, S (O) p, S (O) pNR A1And NR A1S (O) p
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R cReplace; Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkylene group)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, Cl, F, Cl ,-CN, NO 2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 heteroatoms is selected from N, O, S (O) p5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkylene group, by 0-3 R B1The C in generation 2-10Alkynylene, OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, 0CHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNNR aC (O) NR A1(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R hAnd CF 3, CF 1CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Perhaps, when two R groups when adjacent ring A atom is connected, then they can connected atom form together and comprise carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the unsaturated ring of heteroatomic 3-8 unit, wherein said ring can be benzene-condensed and/or by R dReplace;
Perhaps, when two R groups connected with identical ring A atom, then they can connected carbon atom form together and comprise carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the undersaturated spiral shell of heteroatomic 3-8 unit-ring, wherein said spiral shell-ring can be benzene-condensed and/or by R dReplace;
Prerequisite is two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkyl, alkenyl and alkynyl are optional to be replaced by following group: O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and 5-10 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,=O ,-CN, NO 2, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F, Br ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F, Br ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace.
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl.
R jWhen occurring, independently be selected from CF at every turn 3, CH 2F, CF 2H, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
R 5When occurring, be selected from by 0-2 R at every turn bThe C that replaces 1-10Alkyl and by 0-2 R eThe C that replaces 1-8Alkyl;
R eWhen occurring, be selected from by 0-2 R at every turn bThe phenyl that replaces is by 0-2 R bThe xenyl that replaces;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
In a more preferred embodiment, the invention provides the effective inhibitors of metalloproteinase of conduct according to the ring-type hydroxamic acid derivs of formula III A or IVA;
Wherein encircling A is to comprise carbon atom, a 0-1 carbonyl group and 0-2 5-7 non-aromatic carbocyclic of unit or heterocycle that is selected from the ring hetero atom of O, N, NR, and prerequisite is that ring A does not contain the O-O key;
N ' is 1 or 2;
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1And NR A1S (O) p
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 5-7Carbocyclic ring and contain carbon atom and 1-4 is selected from N, O and S (O) pHeteroatomic 5-7 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, S (O) p, S (O) pNR A1And NR A1S (O) p
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace; Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkylene group)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkylene group, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR A1(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1, and (CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R h, and CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and 5-10 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,-CN, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace.
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, and OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cReplace C 1-6Alkyl.
R jWhen occurring, independently be selected from CF at every turn 3, CF 2H, CFH 2, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
In a particularly preferred embodiment, described compound has formula VA as follows or VIA
Wherein J, K and W independently are selected from-(CH 2) n-, NH, NR, O, n=1-3, and n '=1 or 2, condition is J and K, and K and W can not be N-N, N-O or O-O;
P is-D-Q-L-Y, wherein
D does not exist or is selected from C (O), C (O) NR A1, NR A1C (O), S (O) p, S (O) pNR A1And NR A1S (O) p
Q does not exist or is selected from by 0-5 R bThe C that replaces 5-7Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-7 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O;
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, Q, L and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R when occurring at every turn, independently be selected from OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on the ring that has J and K or K and W forms group C A=CR dR D1, wherein said atom C ABe the described atom on the ring that has J and K or K and W;
M is selected from H, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R hAnd CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl;
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, be independently selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace.
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, and OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace.
Perhaps, R dAnd R D1The atom that they connect forms together and contains 0-1 the first ring of heteroatomic 4-8 that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl.
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl dialkyl group, alkyl sulphonyl, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl dialkyl group, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl-alkyl, N-amino-alkyl sulfinyl dialkyl group, alkyl sulphonyl, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
Other embodiment relevant with particularly preferred formula III, IIIA, IV, IVA, V, VA, VI or VIA compound comprises the medicinal compositions that comprises formula III, IIIA, IV, IVA, V, VA, VI or VIA compound (comprising aforesaid salt, enantiomorph, diastereomer, prodrug form and other derivative) and at least a pharmaceutically acceptable carrier, and the multiple therapy methods that realizes by these compositions of mammalian subject that need to suppress metalloprotease.
When term " alkyl " uses in independent use or as suffix, comprise the straight or branched structure, as primary alkyl, secondary alkyl and tertiary alkyl.These groups can have 15 at the most, preferably 8 and more preferably 4 carbon atoms at the most at the most.Similarly, term " alkenyl " and " alkynyl " refer to contain for example 2-12, the unsaturated straight or branched structure of preferred 2-6 carbon atom.Cyclic group such as cycloalkyl, cycloalkenyl group and cycloalkynyl radical are similarly in nature, but have at least 3 carbon atoms.The example of saturated hydrocarbyl comprises as methyl, ethyl, n-propyl, sec.-propyl, just-group such as butyl, tert-butyl, isobutyl-, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropyl methyl, and for example homologue and the isomer of n-pentyl, n-hexyl, n-heptyl, n-octyl etc.The example of unsaturated alkyl comprises vinyl, 2-propenyl, crot(on)yl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(1, the 4-pentadienyl), ethynyl, 1-and 3-proyl, 3-butynyl and higher homologue and isomer.In this application, " cycloalkyl " is also intended to comprise adamantyl and other bridge joint compound.Term " alkoxyl group ", " alkylamino " and " alkylthio " (i.e. " thio alkoxy ") use with its conventional meaning, refer to be connected in by Sauerstoffatom, amino or sulphur atom respectively those alkyl of molecule rest part.Therefore, the term such as " alkoxyl group " and " alkylthio " comprises the moieties as defined above that is connected in suitable functional group.
Other the suitable substituents that can be used for many carbocyclic rings of the present invention (such as but not limited to cyclic aliphatic, aromatics, non--aromatic heterocycle or benzyl) comprises, for example-OH, halogen (Br ,-Cl ,-I and-F) ,-O (aromatic group of benzyl, aromatics or the replacement of aliphatic series, the aliphatic series that replaces, benzyl, replacement) ,-CN ,-NO 2,-COOH ,-NH2 ,-NH (aromatic group of the benzyl of the aliphatic series of aliphatic group, replacement, benzyl, replacement, aromatics or replacement) ,-N (aromatic group of the benzyl of the aliphatic series of aliphatic group, replacement, benzyl, replacement, aromatics or replacement) 2,-COO (aromatic group of the benzyl of the aliphatic series of aliphatic group, replacement, benzyl, replacement, aromatics or replacement) ,-CONH 2,-CONH (aromatic group of benzyl, aromatics or the replacement of aliphatic series, the aliphatic group that replaces, benzyl, replacement) ,-SH ,-S (aromatic group of benzyl, aromatics or the replacement of aliphatic series, the aliphatic series that replaces, benzyl, replacement) and-NH-C=NH)-NH2.Non--the aromatic heterocycle, benzyl group or the aromatic group that replace also can have the aliphatic group of aliphatic series or replacement as substituting group.The aromatic group of benzyl, aromatics or replacement that alkyl that replaces or aliphatic group also can have non--aromatic heterocycle, benzyl, replacement is as substituting group.Non--the aromatic heterocycle that replaces also can have=O ,=S ,=NH or=N (aromatic group of aliphatic series, aromatics or replacement) is as substituting group.The aliphatic series, the aromatics of replacement, the non--aromatic heterocycle of replacement or the benzyl of replacement that replace can have more than one substituting group.
Except as otherwise noted, term " halo " or " halogen ", or itself is as other a substituent part, means fluorine, chlorine, bromine or iodine atom.Similarly, term is intended to comprise a haloalkyl and multi-haloalkyl as " haloalkyl ".For example, term " halo (C 1-C 4) alkyl " be intended to comprise trifluoromethyl, 2,2,2-trifluoroethyl, 4-chloro butyl, 3-bromo propyl group etc.
Term " C 3-C 13Carbocylic radical " be intended to comprise the C at the most that is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl 13All cycloaliphatic groups of cyclic group.Reach when appropriate when not having senior loop chain owing to two keys, above cycloaliphatic groups also can have unsaturation.In addition, term " C 3-C 13Carbocylic radical " be also intended to comprise bridge joint and fused rings system, as adamantyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] two cyclodecane, [2.2.2] bicyclooctane, norcamphyl, _ thiazolinyl (menthenyl), fluorenyl, phenyl, naphthyl, indanyl, indenyl, anthryl and hydrogenated derivatives, phenanthryl and hydrogenated derivatives and tetralyl.C as defined above 3-C 13Carbocylic radical also can be replaced by following group :-OH, halogen (Br ,-Cl ,-I and-F) ,-O (aromatic group of benzyl, aromatics or the replacement of aliphatic series, the aliphatic series that replaces, benzyl, replacement) ,-CN ,-NO 2,-COOH ,-NH 2,-NH (aromatic group of the benzyl of the aliphatic series of aliphatic group, replacement, benzyl, replacement, aromatics or replacement) ,-N (aromatic group of the benzyl of the aliphatic series of aliphatic group, replacement, benzyl, replacement, aromatics or replacement) 2,-COO (aromatic group of the benzyl of the aliphatic series of aliphatic group, replacement, benzyl, replacement, aromatics or replacement) ,-CONH 2,-CONH (aromatic group of benzyl, aromatics or the replacement of aliphatic series, the aliphatic group that replaces, benzyl, replacement) ,-SH ,-S (aromatic group of benzyl, aromatics or the replacement of aliphatic series, the aliphatic series that replaces, benzyl, replacement) and-NH-C=NH)-NH2.
Term " contains 0-4 the first heterocyclic ring system of heteroatomic 3-13 " and " containing 1-4 the first heterocyclic ring system of heteroatomic 5-14 " is intended to comprise aromatics and non-aromatic heterocyclic system.Described 3-13 unit heterocycle is intended to comprise 3,4,5,6 or 7-unit's monocycle or two ring or 7,8,9,10,11,12 or 13 yuan of bicyclic heterocycles, its be saturated, part is undersaturated or unsaturated (aromatics), and independently is selected from O, N, NR and S (O) by carbon atom and 1-4 pHeteroatoms form, it comprises the heterocyclic fused in any bicyclic groups of phenyl ring of wherein any above-mentioned definition.Described 5-14 unit heterocyclic ring system is intended to comprise 5,6 or 7-unit's monocycle or two rings or 7,8,9,10,11,12,13 or 14-unit bicyclic heterocycles, its be saturated, part is undersaturated or unsaturated (aromatics), and independently is selected from O, N, NR and S (O) by carbon atom and 1-4 pHeteroatoms form, it comprises the heterocyclic fused in any bicyclic groups of phenyl ring of wherein any above-mentioned definition.Described nitrogen and sulfur heteroatom can be chosen wantonly oxidized.Described heterocycle can be connected with its side group on any heteroatoms or carbon atom and produce stable structure.If the compound that obtains is stable, heterocycle as herein described can be substituted on carbon or nitrogen-atoms.Described assorted nuclear nitrogen can be chosen wantonly by quaternized.
The heterocyclic example comprises, but be not limited to, pyrimidyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl, fen oxathiin base (phenoxathiinyl), fen _ piperazine base, phthalazinyl, piperazinyl, piperidyl, 1,2,3, the 6-tetrahydro pyridyl, piperidone base, the 4-piperidone base, piperonyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido _ azoles, pyridine-imidazole, the pyrido thiazole, pyridyl, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, the 2H-pyrryl, pyrryl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazyl, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thianthrenyl, thiazolyl, thienyl, the thieno-thiazolyl, thieno-_ azoles base, the Thienoimidazole base, thienyl, triazinyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3, the 4-triazolyl, xanthenyl, the octahydro isoquinolyl, _ di azoly, 1,2, the 3-_ di azoly, 1,2, the 4-_ di azoly, 1,2, the 5-_ di azoly, 1,3, the 4-_ di azoly, _ oxazolidinyl, _ azoles base, _ oxazolidinyl, quinazolyl, quinolyl, the 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, acridyl, azocine base (azocinyl), benzimidazolyl-, benzofuryl, benzimidazole thiophanate is for furyl, benzo-thienyl, benzo _ azoles base, benzothiazolyl, the benzotriazole base, the benzo tetrazyl, benzisoxa _ azoles base, the benzisothiazole base, benzimidazolyl-, the methylenedioxyphenyl base, morpholinyl, 1, the 5-phthalazinyl, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran is [2,3-b] tetrahydrofuran (THF) also, furyl, the furazan base, carbazyl, the 4aH-carbazyl, carbolinyl, chromanyl, benzopyranyl, the cinnolines base, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, inferior indyl (indolenyl), indolinyl, the indolizine base, indyl, the 3H-indyl, isobenzofuran-base, the isochroman base, iso indazolyl, iso-dihydro-indole-group, pseudoindoyl, isoquinolyl, isothiazolyl and different _ azoles base.Also comprise and contain for example the above heterocyclic fused rings and spirocyclic compound.
Except as otherwise noted, the compound that is provided in following formula I-IV is intended to comprise its pharmacy acceptable salt, prodrug, enantiomorph, diastereomer, raceme mixture, crystallized form, non--crystallized form, amorphous substance and solvate.
Term " pharmacy acceptable salt " refers to comprise the salt of described active compound, and it is with atoxic relatively acid or alkali, prepares according to the concrete substituting group of compound described herein.When compound of the present invention contains relative tart functional group, the neutral form that can be by making described compound and the required alkali of q.s, perhaps contact obtains base addition salt in pure reactant or in suitable inert solvents.The example of pharmaceutically acceptable base addition salt comprises sodium salt, sylvite, calcium salt, ammonium salt, organic amino salt or magnesium salts, or similar salt.When compound of the present invention contains relatively the functional group of alkalescence, can be by the neutral form and the required acid of q.s that makes described compound, or in pure reactant or in suitable inert solvents, contact and obtain acid salt.The example of pharmaceutically-acceptable acid addition comprises deutero-acid salt from following mineral acid: hydrochloric acid, Hydrogen bromide, nitric acid, carbonic acid, phosphoric acid, part neutral (neutralized) phosphoric acid, sulfuric acid, part neutral sulfuric acid, hydroiodic acid HI or phosphorous acid etc., and derived from following nontoxic relatively organic acid salt: acetate, propionic acid, isopropylformic acid, toxilic acid, propanedioic acid, phenylformic acid, succsinic acid, suberic acid, fumaric acid, amygdalic acid, phthalic acid, Phenylsulfonic acid, right-toluenesulphonic acids, citric acid, tartrate, methylsulfonic acid etc.The salt that also comprises amino acid whose salt (for example arginic acid salt etc.) and organic acid (for example glucuronic acid or galacturonic acid etc.).Some particular compound of the present invention can contain alkalescence and acidic functionality, and they can make described compound change alkali or acid salt into.
Can contact with alkali or acid by making described salt, separate parent compound and the neutral form of the The compounds of this invention of regenerating with ordinary method then.The parent form of described compound for example is different from various salt forms on the solubleness in polar solvent aspect certain physical characteristics, but others, and described salt is equal to the parent form of the described compound that is used for the object of the invention.
As previously discussed, some formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI and VIA compound have chirality or asymmetric carbon atoms (optical center) or two key; Described racemic modification, diastereomer, geometrical isomer and each single optical isomer all are included in the scope of the present invention.
Some formula I, IA, II, IIA, III, IIIA, IV, IVA, V, VA, VI and VIA compound can exist with non-solvent form and solvation form (comprising hydrated form).Usually, described solvation form is equal to the non-solvent form, and is included in the scope of the present invention.Compounds more of the present invention can exist with polycrystal or amorphous form.Usually, all physical form all are identical for the designed purposes of the present invention, and are included in the scope of the present invention.
Except above-mentioned salt form, the present invention also comprises the prodrug form of formula I-VI compound.The prodrug of compound described herein is that those carry out chemical transformation easily and the compound of The compounds of this invention is provided under physiological condition.In addition, under external environment, prodrug can change compound of the present invention into by chemistry or biological method.For example, when placing the transdermal patch bank with suitable enzyme or chemical reagent, prodrug can change compound of the present invention lentamente into.
Can prepare new compound of the present invention with the method known to the skilled in various organic syntheses field.Can use the synthetic together compound of the present invention of method of the known synthetic method of method as described below and synthetic organic chemistry field or its various changes well known by persons skilled in the art.Preferable methods includes, but are not limited to those following methods.Full content at these all reference of quoting is attached to herein by reference.
New compound of the present invention can adopt reaction path as described below and technology preparation.
The compounds of this invention and salt thereof, solvate and prodrug can use the starting raw material that obtains easily to prepare by adopting the existing technology in this area.The illustrative methods of preparation The compounds of this invention is as described below.Except as otherwise noted, in the flow process below, Z, P, R, R 1, R 2, R 3, R 4, D, Q, L, T, X and Y etc. be as indicated above.
Formula I of the present invention and IA compound (wherein Z is the hydroxamic acid base) can prepare by formula 1a compound (wherein Z is a carboxylic acid) and azanol are reacted in the presence of suitable peptide coupling agent.The illustrative examples of suitable coupling agents comprises 1,1 '-carbonyl-diimidazole, N-(dimethylaminopropyl)-N '-ethyl carbodiimide, benzotriazole-1-base oxygen base-three (dimethylamino) _ hexafluoro-phosphoric acid salt (" PyBOP "), or in inert polar solvents the propyl phosphonous acid acid anhydride of (as dimethyl formamide (" DMF ")).
Flow process 1
Figure A20048003718801291
Perhaps; above-mentioned coupled reaction can be with the hydroxylamine compound of formula 1a compound and oxygen-protection (promptly; suitable blocking group well known by persons skilled in the art; as benzyl, tert-butyl, tert-butyl dimetylsilyl or tert-butyl diphenylmethyl silylation; and/or at T.W.Green and P.G.M.Wuts; the blocking group of describing among the Protective Groups in Organic Synthesis (1991)) carries out, obtain formula 2 compounds.Make formula 2 compounds go protection, obtain formula (I) compound.The de-protected suitable method of formula 2 compounds is known in the art, for example at T.W.Green and P.G.M.Wuts, and the method described in the Protectivee Groups in Organic Synthesis (1991).
Formula 1a compound can pass through with suitable alkali aqueous solution, as lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably in homogeneous water-ORGANIC SOLVENT MIXTURES, to corresponding 1b ester (wherein alkyl is suitable group, as methyl, ethyl, allyl group, benzyl-or tert-butyl) carry out alkaline hydrolysis and prepare.Perhaps, these compounds also can under suitable temperature, carry out acid hydrolysis with suitable aqueous acids (example hydrochloric acid) to corresponding ester and prepare by in the dioxane aqueous solution.Other method that is suitable for ester is converted into acid that also can adopt those skilled in the art to approve as with hydrogen and palladium on carbon hydrogenolysis benzyl ester, promotes the cracking of tert-butyl ester with acid under anhydrous condition, and the cracking of palladium-catalytic allyl ester.
Perhaps; formula I compound also can be by known approach in some documents; ester cpds by formula 1b prepares, as under alkaline condition (as KOH or NaOMe), in as methanol solvent; handle ester 1b with azanol; under similar condition,, then carry out the foregoing protection of going by ester 1b being converted into the hydroxamic acid of oxygen-protection; perhaps by using WeinrebShi trimethyl aluminium reaction conditions (J.I.Levin; E.Turos, S.M.Weinreb, Syn.Comm.1982; 12; 989) or two [two (trimethyl silyl) amido] tin reagent (W.-B.Wang, E.J.Roskamp, the J.Org.Chem.1992 of RoskampShi; 57,6101).Have different substituents R, R 1And R 2Formula 1b compound can be according to various document approach, by as described in the flow process 2-5, make the ring A compound of corresponding formula 3 or 16 functionalized come synthetic.In a representative approach shown in the flow process 2 is with suitable metal-hydrogen system known in the art system, as the sodium borohydride in aprotic solvent, the ketone of formula 3 is carried out selective reduction.As at " Comprehensive Organic Transformations; A Guide toFuntional Group Preparations " (R.C.Larock, Wiley-VCH, 1999) described in, under alkaline condition, make the alkylol cpd alkylation of formula 4 with required alkyl halide or alkyl sulfonic ester, obtain the ether compound of formula 5.Perhaps, ether compound 5 can be by Mitsnobu prepared in reaction known in the art.By known several method in the document, also the alkylol cpd of formula 4 can be converted into the carbonic ether of formula 6 or the carbamate of formula 7, react in the presence of alkali as alcohol by making formula 4 and required carbonochloridic acid ester or urea chloride, or, then make active amino manthanoate or the carbonic ether and the required alcohol or the amine reaction of generation by handle the alcohol of formula 4 with carbonyl dimidazoles or right-nitrophenyl carbonochloridic acid ester.
Flow process 2
Perhaps, according to various literature methods, as at " Comprehensive OrganicSynthesis " (B.M.Trost, I.Fleming, Eds.Pergamon, 1991, Vol 8, part 1.2, P25) the middle method of describing, the ketone of formula 3 can be carried out reduction amination with required amine, obtain the amine (flow process 3) of formula 8.Use methods known in the art then, the amine of formula 8 further can be converted into the acid amides of formula 9, the sulphonamide of formula 10, the carbamate of formula 11 or the urea of formula 12.
Flow process 3
Figure A20048003718801321
Perhaps, can be by described in the flow process 4 and at " Comprehensive OrganicTransformations, A Guide to Funtional Group Preparations " (R.C.Larock, Wiley-VCH, 1999) described in, the ketone of formula 3 is carried out the carbonyl homologation.For example, in the presence of tin chloride (II), handle formula 3 compounds with trimethylsilyl cyanide, follow acid hydrolysis (Syn.Commun.1982,12,763), perhaps by with 1,3-dithiane anionic reactive, then through acid catalyzed hydrolysis (Tetrahedron Lett.1988,29,1493) or the catalytic hydrolysis (J.Org.Chem.1991 of mercury salt, 56,4499).When needing, also can be with formula 3 compounds experience Wittig and relevant reaction conditions, then as shown in the flow process 4, reduce two keys of generation through catalytic hydrogenation, obtain formula 13 compounds (ComprehensiveOrganic Synthesis, B.M.Trost, I.Fleming, Eds.Pergamon, 1991, Vol1, Part 3.1, P729).Method described in the available then flow process 1 is converted into the ester of formula 13 acid amides of formula 14.On the other hand, can pass through method known to those skilled in the art, the ester of formula 13 is converted into the aldehyde of formula 15; For example, as by ester as described in the selective hydrolysis, then the acid that produces with borane reduction makes described pure oxidation then to form corresponding alcohol, forms corresponding aldehyde.Can adopt with at the similar reaction method of mode described in flow process 2 and 3, make latter's aldehyde further functionalized.
Flow process 4
Figure A20048003718801331
Perhaps, the ketone of formula 3 can experience Grignard or relevant lithium anionic reactive condition, with generation as at the tertiary alcohol described in the flow process 5.Perhaps, the ketone of formula 3 also can experience the acid catalyzed reaction with allyl trimethyl silane of lewis, generates the corresponding tertiary alcohol.Can be by described in the flow process 2, with the further derivatize of the described tertiary alcohol.Perhaps, the ketone of formula 3 also can experience the Wittig reaction conditions, obtains vinyl compound, and it can be oxidized to epoxide (flow process 5).Described epoxide can pass through HO (CR dR D1) rM or HN (R a) (CR dR D1) rThe M open loop obtains vicinal glycol (vicinal diol) list-ether or vicinal amino alcohol respectively.As (CR dR D1) rWhen M is hydrogen, can described in flow process 2 and 3, the latter further be modified.
Flow process 5
As ring A when being azepine-ring; as shown in the formula in the flow process 6 16; described compound can be converted into formula 17,18,19,20 and 21; for example by under suitable temperature; in suitable solvent, use suitable alkylating agent or acylating agent (as alkyl halide, SULPHURYL CHLORIDE, carbonyl chloride (carboxylic acid chloride), carbonochloridic acid ester or urea chloride) to handle respectively.Perhaps, formula 16 compounds also can be obtained formula 22 by alkylation, then can be as further functionalized at quilt described in the flow process 4.
Flow process 6
Figure A20048003718801351
Formula 3 and 16 ring A compound can be with the methods of summarizing among the flow process 7-15, and the method for its variation of understanding of the known synthetic method in synthetic organic chemistry field or those skilled in the art is synthetic.Preferable methods includes, but is not limited to those following methods.
Formula 30 and 5-oxo-piperidines of 31 can be with the preparations of the method described in the flow process 7.In the presence of DBU, in toluene, handle L-aspartic acid β-tert-butyl ester monohydrate with 2 normal bromotoluenes, obtain one-benzyl amine 23.Make 23 alkylations with 1-chloro-2-chloro methyl isophthalic acid-propylene processing, obtain chlorallylene 24,, be converted into corresponding allyl iodide 25 24 by in acetone, handling with sodium iodide.Make the latter and LiHMDS reaction, obtain piperidine ring compound 26.After 26 benzyl protection changed into Cbz protection, make the alkene 27 experience ozonize (ozonelization) of generation, obtain ketone compound 28.The latter can go by catalytic hydrogenation-protect, and with suitable amine reaction, generates corresponding ketone 30 then.Perhaps, can be in the presence of BOP, make amino acid 29 through with the azanol coupling of benzyl protection, obtain the oxyamide 31 of benzyl protection, be translated into ketone 32 then.
Flow process 7
Formula 40 and 41 pimelinketone can synthesize as shown in Scheme 8.With optically pure (1S, 2R)-the 1-methyl-suitable-1,2,3,6-tetrahydrophthalic acid ester is converted into tert-butyl ester 33, then this methyl ester of hydrolysis obtains corresponding acid 34.Make the latter and uncle-butanols nak response, obtain trans-compound 35.With iodinate 35, obtain lactone 36.After removing iodide with three (trimethyl silyl) silane treatment, handle lactone 37 with benzyl alcohol, obtain different two-esters 38, under the Dess-Martin oxidizing condition or under the Swern oxidizing condition, 38 can oxidizedly obtain ketone 39.Then by go respectively to protect and with required amine coupling, ketone 39 optionally can be converted into ketone 40 or 41, by Wacker oxidation, can directly prepare ketone 39 by corresponding tetrahydrobenzene.
Flow process 8
Formula 46 and 47 cyclopentanone can synthesize described in flow process 9.Can (1S, 2R)-the 1-methyl-suitable-1,2,3,6-tetrahydrophthalic acid ester be converted into trans-isomer 42, then in the presence of sulfuric acid, with the processing of 2-methacrylic, obtains diester 43 with optically pure.Tetrahydrobenzene 43 is oxidized to two-acid, cyclisation is ketone 45 (for a relevant example referring to Gais etc., J.Org.Chem.1989,54,5115) then.Then as shown in Scheme 9, ketone 45 is converted into 46 or 47.
Flow process 9
Figure A20048003718801381
Formula 54 and 55 new tetrahydropyran compound can be as shown in Scheme 10, by (S)-(+)-2, and 2-dimethyl-5-oxo-1, the 3-dioxolane-initial preparation of 4-acetate.Protected be benzyl ester 48 after, with described dioxolane hydrolysis, obtain methyl ester 49.Make 49 under alkaline condition, to react with 1-chloro-2-chloro methyl isophthalic acid-propylene, obtain chlorallylene 50, be translated into iodide 51.Handle 51 with LiHMDS, obtain tetrahydropyrans 52.Then as shown in Scheme 10, make latter's ozonize, obtain ketone 53 and follow-up 54 and 55.
Flow process 10
Figure A20048003718801391
Can be as the tetrahydrofuran-compound of acquisition formula 62 described in the flow process 11 and 63.For silyl ether 56, the latter and allyl group iodate thing are reacted in the presence of KHMDS oxy-compound 49 protections, obtain compound 57 into main diastereomer.After going protection,, obtain 59 with iodinate oxy-compound 58.By alcohol intermediate 60, iodide 59 can be converted into aldehyde 61 then.Then as shown in Scheme 11, make aldehyde 60 and required amine coupling, obtain the tetrahydrofuran-compound of formula 62 and 63.
Flow process 11
Figure A20048003718801401
A series of formula 68 and 69 trans-2,3-tetramethyleneimine dicarboxylic ester can adopt the sequence method preparation shown in the flow process 12.As alkali, with the L-aspartate alkylation that allyl iodide is protected Cbz-, then the diastereomer of two kinds of generations of chromatographic separation obtains required cis-diastereomer 64 with LiHMDS.64 ozone are decomposed and make it be converted into aldehyde 65.Hydrogenation 65 causes closed loop, generates tetramethyleneimine 66.As dicarboxylic acid derivatize as described in make described in the flow process 7, obtain formula 68 and 69 compounds.
Flow process 12
Figure A20048003718801411
Formula 76 and 77 5-carbonyl pyrrolidine compound can obtain as similar method as described in the preparation 5-formyl radical tetrahydrofuran (THF) in the flow process 10, see shown in the flow process 13.
Flow process 13
Figure A20048003718801412
According to the method preparation formula 81 of general introduction in the flow process 14 and a series of compounds of 82.Prepare tetramethyleneimine 79 according to the dipolar addition method of in document (M.Joucla, J.Mortier, Chem.Commun.1985,1566), describing.After the Boc-of tetramethyleneimine protection, compound 80 can be separately converted to the compound of required formula 81 and 82.
Flow process 14
The compound that wherein encircles the formula that A is piperidines (as follows) (I) can prepare according to literature method (C.-B.Xue, X.He, J.Roderick, R.L.Corbertt, C.P.Decicco, J.Org.Chem.2002,67,865).
Should be noted that, can be to synthetic making amendment as implied above, to make up R, R 1And R 2, make ring A and amine coupling then, formation-D-E-G-Q-L-T-X-Y fragment.Can show better activity with other steric isomer comparison one steric isomer of formula (I) compound.Therefore, should think that following stereochemical structure is a part of the present invention.
When needs, by carrying out HPLC with chiral column or by being used in document (S.H.Wilen, " Tables of Resolving Agents and Optical Resolutions; 1972) in the resolving agent (as camphor acyl chlorides camphonic chloride) described or with the bronsted lowry acids and bases bronsted lowry fractionation of enantiomer-pure, can realize the separation of racemic raw material.Also available chiral catalyst of chirality formula (I) compound or chirality aglucon (E.Jacobsen, Acc.Chem.Res.2000,33,421) or with other enantiomorph-and diastereomer-selective reaction and the known reagent of asymmetric synthesis those skilled in the art are directly synthetic.
For example, axial (axial) oxy-compound shown in the flow process 15 can be by also preparing in THF with L-Selectride originally.Obtain axial and calm (equatorial) hydroxyl isomer with 15: 1 ratios.On the other hand, by reducing in methyl alcohol with sodium borohydride, can obtain calm oxy-compound, it is 11: 1 mixtures of separable calm and axial diastereomer.
Flow process 15
Figure A20048003718801431
Under homogeneous phase condition, can with the olefin(e) compound selective reduction in the flow process 16 axial isomer, 92%d.e.
Flow process 16
Figure A20048003718801432
Intermediate of the present invention with formula-Q-Y (P, wherein E, G, L, T and X do not exist) can be synthetic with roughly being divided into following three types strategy: wherein will encircle Q and be connected in the synthetic of ring Y by ring nitrogen; Between two ring texturees, form C-C; And wherein encircle synthetic that Q forms between synthesis phase.This uses aryl piperazines and Arylpiperidine and aryl-pyrrolidine alkane respectively in flow process 15-18 (wherein Q is piperazine, piperidines or pyrroline; With Y be aryl) illustrate as an example.
Aryl piperazines can react (Combs, A.P. by making Boc-piperazine and various boric acid under the catalysis of venus crystals (II); Tadesse, S.; Rafalski, M.; Haque, T.S.; Lam, P.Y.S.Journal of Combinatorial Chemistry 2002,4,179), or by using Hartwig ' s catalyzer, with various aryl halide reaction (Louie, J; Hartwig, J.F.TetrahedronLett.1995,36,3609) prepare.After removing the Boc group, can make compound 90 and the coupling of ring A compound, obtain formula 91 compounds (flow process 17).Should be noted that, aryl piperazines also can be by in the presence of alkali, through the aniline of suitable replacement and the typical closed loop reaction (E.Mishani of two (2-chloro ethyl) amine hydrochlorates, et.al.Tetrahedron Lett.1996,37,319) or direct nucleophilic aromatic substitution reaction (S.M.Dankwardt etc., Tetrahedron Lett.1995 by described piperazine, 36,4923) prepare.
Flow process 17
Figure A20048003718801441
Arylpiperidine (as 36) can synthesize described in flow process 18.Available LDA and N-phenyl trifluoromethanesulfonate Toluidrin are converted into enol triflate 92 with uncle-butoxy carbonyl piperidine-4-ketone.Carry out the coupling of Suzuki-type with aryl boric acid then, obtain aryl tetrahydropyridine 94 (M.G.Bursavich, D.H.Rich, Org.Lett.2001,3,2625).Compound 94 also can be prepared by the Suzuki-type coupling of aryl halide and enol boric acid ester 93.After going protection, compound 95 can be converted into formula 96.When needing, under the catalytic hydrogenation condition, the aryl tetrahydropyridine can be reduced to saturated Arylpiperidine.Should be noted that compound 94 can be a piperidone by the anionic typical directly nucleophilic addition(Adn) of aryl also, the alkylol cpd of generation is dewatered prepare.
Flow process 18
Figure A20048003718801451
Perhaps, by shown in the flow process 19, Arylpiperidine derivatives can be by using Pd (PPh 3) 4As catalyzer, make 4-pyridine bromide and boric acid coupling, then hydrogenation prepares.
Flow process 19
Phenylpyrrolidine 100 can prepare described in flow process 20.Optically pure (R)-phenyl succsinic acid can be reduced to glycol 97, then obtain two-methanesulfonates 98 through methylsulfonylization.In the presence of triethylamine, handle 98 with benzyl amine, obtain tetramethyleneimine 99, hydrogenation after this obtains 100.Perhaps, (R)-phenyl succsinic acid that refluxes in Acetyl Chloride 98Min. obtains corresponding acid anhydrides 102.After refluxing once more with ammonia treatment and in Acetyl Chloride 98Min., obtain imines 103, through the LAH reduction, obtain Phenylpyrrolidine 100 then.Make 100 with the reaction of ring A compound, production 101.Should be noted that the aryl-pyrrolidine hydride compounds also can synthesize through the coupling of Suzuki-type by enol triflate or the enol boric acid ester intermediate described in flow process 16.It can be a pyrrolidone by the anionic typical directly nucleophilic addition(Adn) of aryl also, then makes the alkylol cpd dehydration of generation, carries out the asymmetric hydrogenation preparation then.
Flow process 20
Figure A20048003718801461
Intermediate of the present invention with formula-Q-L-T-Y (P, wherein E, G and X do not exist) can synthesize that (wherein Q is a phenyl, and L is an oxygen, and T is a methylene radical, and Y is toluquinoline (quilonine) as 21 examples of flow process.Starting raw material 2-toluquinoline is converted into alcohol 104, then handles, obtain 105 with thionyl chloride.Make 105 under alkaline condition, to react with phenol 106, obtain 107.The latter can go protection by handling with TFA, obtains aniline 108, is translated into formula 109 intermediates then.
Flow process 21
The available methods known in the art preparation of other possible P group (wherein-D-E-G-Q-L-T-X-Y such as preamble define).Be used to prepare the specific embodiment of method of The compounds of this invention and formula of the present invention (I), (II) and (III) the exemplary preferred embodiment of compound or their pharmaceutically acceptable prodrug, salt or solvate be described below.
Following specific embodiment just illustrates the present invention, and should not think the restriction of the scope of the invention that appended claims is limited.These embodiment comprise the preferred embodiment of The compounds of this invention.
Embodiment
Below employed reagent and solvent can from commercial source for example Aidrich ChemicalCo. (Milwaukee, Wis USA) obtain.With mass ratio record mass spectrum result.In table, be to contain the M+H of common atom isotope (or as indicating M-H) ion with single m/e value reporting.In all cases, the isotropic substance form is corresponding to desired molecular formula.
Embodiment 1
(2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-
The N-hydroxyl-5-[(3R)-3-hydroxyl pyrrolidine-1-yl] piperidines-3-methane amide
Part 1: under 0C, nitrogen, to L-aspartic acid β-tert-butyl ester monohydrate (22g, 106mmol) and bromotoluene (35g, 205mmol) be added dropwise in the mixture in toluene (600mL) DBU (33g, 217mmol).Making this mixture be warmed to room temperature and stir spends the night.Filter crude reaction mixture, concentrating under reduced pressure by glass filter.Residue is through Combiflash purifying (hexane and ethyl acetate: gradient 0-10%, 12 minutes), obtain 12.1g (30.9%) (2S)-benzylamino-succsinic acid 1-benzyl ester 4-tert-butyl ester.MS(ESI)：370(M+H +)。
Part 2: under 81 ℃, with (2S)-benzylamino-succsinic acid 1-benzyl ester 4-tert-butyl ester (12.1g, 32.6mmol), K 2CO 3(3.0g, 20mmol) (5.1g, 40.8mmol) mixture in MeCN (150mL) stirred 16 hours with 1-chloro-2-chloro methyl isophthalic acid-propylene for (14g, 3 equivalents), NaI.After the cooling, filter reaction mixture, concentrating under reduced pressure filtrate.Through Combiflash purifying (hexane and ethyl acetate: gradient 0-8%, 12 minutes), obtain (2S)-[benzyl-(2-chloro methyl-allyl group)-amino]-succsinic acid 1-benzyl ester 4-tert-butyl ester (8.7g, 58%).MS(ESI)：458(M+H +)。
Part 3: with the muriate of above preparation (8.7g, 19.0mmol) and NaI (8.0g, 53.3mmol) mixture in acetone (100mL) stirs under room temperature and spends the night.Filter this out-phase mixture, concentrating under reduced pressure filtrate.Handle residue with methylene dichloride, filter, obtain corresponding iodide compound (9.2g, 88.2%) by silicagel pad.MS(ESI)：550(M+H +)
Part 4: under-78 ℃, nitrogen, (9.2g, in anhydrous THF (50mL) solution 16.76mmol), (1.0M is in THF, 20.2mL) to be added dropwise to LiHMDS to the iodo-compound of above preparation in 30 minutes.Stir these mixtures 1 hour in-78 ℃, be warmed to-30 ℃ with time of 3 hours then.Reaction mixture with 10% citric acid (10mL) quencher, with salt solution (100mL) dilution, is used ethyl acetate (4 * 75mL) extractions.Through MgSO 4The dry organic layer that merges, concentrating under reduced pressure.With residue Combiflash purifying (with hexane and eluent ethyl acetate: gradient 0-5%, 12 minutes), obtain (2S, 3S)-1-benzyl-5-methylene radical-piperidines-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester (3.45g, 48.9%).MS (ESI): 422 (M+H +) part 5: with the N-benzyl piepridine of above preparation (2.3g, 5.46mmol) and the mixture of carbonochloridic acid benzyl ester (3mL) stirred 28 hours in 65 ℃.Excessive carbonochloridic acid benzyl ester is removed through decompression, and residue obtains the piperidine compounds (1.40g, 52.6%) of corresponding N-Cbz protection through Combifiash purifying (hexane and ethyl acetate: gradient 0-10%, 12 minutes).MS(ESI)：488(M+Na +)；366(M+2H +-COO(t-Bu))。
Part 6: in-78 ℃, (6.0g, methylene dichloride 12.9mmol) (250mL) solution keep blue until the color of this solution to make the olefin(e) compound of ozone by above preparation.After adding methyl-sulfide (1.2mL.16.1mmol), make the mixture that obtains be warmed to room temperature and stir and spend the night.This mixture of concentrating under reduced pressure is dissolved in the methylene dichloride once more then, uses the salt water washing.Through MgSO 4After dry organic layer and vacuum are removed volatile matter, crude product through chromatography purification (hexane and ethyl acetate: gradient 0-30%), obtain (2S, 3S)-5-oxo-piperidines-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (5.2g, 86.2%).MS(ESI)：468(M+H +)。
Part 7: with NaBH (OAc) 3(339mg, 1.60mmol) handle (R)-pyrroline alcohol (140mg, 1.60mmol) and the ketone of above preparation (250mg, the 0.53mmol) mixture in methylene dichloride (5mL) stirs under room temperature and spends the night.With the saturated NaHCO of reactant 3Dichloromethane extraction is used in quencher.Merge organic layer, through dried over sodium sulfate.Behind the evaporating solvent, the residue that obtains (is used in CH through the flash chromatography purifying 2Cl 2In the 0-10%MeOH wash-out), obtain (R)-piperidine compounds (115mg, 39.9%) and diastereomer thereof that [(R)-hydroxyl pyrrolidine] replaces, (S)-[(R)-hydroxyl pyrrolidine] mixture of the piperidine compounds (64mg, 22.2%) that replaces.MS(ESI)：539(M+H +)。
Part 8: in the presence of 10%Pd/C, under hydrogen bag pressure power, the isomer that (R) of above preparation-[(R)-hydroxyl pyrrolidine] replaced (230mg, spend the night by the hydrogenation of methyl alcohol 0.43mmol) (5mL) solution.Filter this non-even phase reaction mixture by Celite pad, concentrating under reduced pressure obtains amino acid needed accordingly (133mg, 99%), and it can be directly used in the coupled reaction in the part 13.
Part 9: under-78 ℃, nitrogen, to 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.21g, be added dropwise in anhydrous THF (26mL) solution 26.16mmol) LiHMDS (1.0M in THF, 28.7mL, 28.7mmol).After 20 minutes, (10.0g, THF 27.99mmol) (26mL) solution make reactant be warmed to 0 ℃ and stirred 3 hours gradually to add N-phenyl trifluoromethanesulfonate methylsulfonyl imines (sulfonimide).With the saturated NaHCO of reactant with minute quantity 3The mixture that quencher, concentrating under reduced pressure obtain.At neutral Al 2O 3Last flash chromatography obtains required enol triflate (8.67g, 100%).
Part 10: to one be equipped with hypoboric acid two pinacol esters (3.37g, 13.28mmol), sodium acetate (2.97g, 36.22mmol), [1,1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II)] (PdCl 2Dppf) (0.296g, 0.36mmol), (0.20g 0.36mmol) and 1, feeds nitrogen in the flask of 4-dioxane (30mL) to dppf.In this flask, add described enol triflate (4.0g, 12.07mmol) 1,4-dioxane (30mL) solution spends the night the mixture that obtains in 80 ℃ of stirrings.By dripping entry quencher reactant, use the ethyl acetate extraction water layer.With the organic layer of salt water washing merging, through MgSO 4Drying, concentrating under reduced pressure.Residue is used in the 0-10% eluent ethyl acetate in the hexane through the flash chromatography purifying, obtains boric acid ester, is white waxy solid (3.14g, 84%).MS(ESI)：210(M+2H +-Boc)，332(M+Na +)。
Part 11: to be equipped with above-mentioned boric acid ester (2.0g, 6.47mmol), K 2CO 3(2.68g, 19.40mmol) and PdCl 2(317mg in the flask that purging with nitrogen gas 0.38mmol) is crossed, adds 4-bromo-3-methyl benzonitrile (1.40g, DMF 7.12mmol) (33mL) solution to dppf.With the mixture heating up to 80 that obtains ℃, vigorous stirring is spent the night under nitrogen.Water quencher reactant is used ethyl acetate extraction.Merge organic layer, use the salt water washing, dry (MgSO 4) and concentrating under reduced pressure.Residue is used in the 0-30% eluent ethyl acetate in the hexane through the flash chromatography purifying, obtains required diaryl product (1.5g, 77.7%).
Part 12: under room temperature, (4N 5mL) handles above-mentioned 5,6-tetrahydropyridine compounds (1.3g, 4.36mmol) 1 hour with the HCl/ dioxane solution.This mixture of concentrating under reduced pressure obtains 3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)-benzonitrile HCl salt (1.02g, 100%).MS(ESI)：199(M+H +)。
Part 13: under room temperature, nitrogen, amino acid (the 53mg that will in part 8, prepare, 0.17mmol), 3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl)-and benzonitrile HCl salt (40mg, 0.17mmol) and BOP (82mg, 0.19mmol) (0.065mL 0.37mmol) handled 2 hours with diisopropylethylamine for mixture in DMF (0.2mL).With the saturated NaHCO of reactant 3Ethyl acetate extraction is used in quencher.With the organic layer of salt water washing merging, through MgSO 4Drying, concentrating under reduced pressure then.The residue that obtains need not be further purified and be directly used in next step.MS(ESI)：495(M+H +)。
Part 14: above-claimed cpd is dissolved in CH 2Cl 2(1mL), under room temperature, handled 3 hours with TFA (1mL).This mixture of concentrating under reduced pressure obtains crude product piperidines 3-carboxylic acid, and it need not purifying and is directly used in next step.MS(ESI)：439(M+H +)。
Part 15: under room temperature, nitrogen, above-mentioned crude product piperidines 3-mixture of carboxylic acids is dissolved among the DMF (0.2mL), adds to order wherein: azanol HCl salt (19mg, 0.27mmol), BOP (73mg, 0.16mmol) and diisopropylethylamine (0.072mL, 0.41mmol).After 2 hours, reaction mixture is directly carried out RP-HPLC, obtain title compound, be tfa salt (29mg, 3 steps 35%).MS(ESI)：454.1(M+H +)。
Embodiment 2
(2S, 3S)-2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-5-(2-
{ [2-(dimethylamino) ethyl] amino }-2-oxoethyl)-N-hydroxy piperidine-3-methane amide
Part 1: to (triphenyl phosphine pentylidene) (triphenylphosphoramylidene) methyl acetate (787mg is housed, 2.35mmol) flask in add (1,2S, 3S)-5-oxo-piperidines-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (500mg, toluene 1.07mmol) (5.4mL) solution.Mixture heating up to the backflow and stirring that obtains spent the night.After this compound of reaction was cooled to room temperature, volatile matter was removed in decompression.Through the flash chromatography purifying, be used in the 0-30% eluent ethyl acetate in the hexane, obtain the Wittig product, for separable trans-and cis-mixture (257mg, 45.9%, 7: 1, stereochemistry undetermined).MS(ESI)：546(M+Na +)。
Part 2: in the presence of 10%Pd/C (60mg), under hydrogen bag pressure power, with described alkene mixture (257mg, methyl alcohol 0.49mmol) (3mL) solution hydrogenation 2 hours.Filter this non-even phase mixture by Celite pad, reduce pressure and remove volatile matter, obtain that (5)-methoxycarbonyl methyl-piperidines-(2S 3S)-dicarboxylic acid 3-tert-butyl ester (148mg, 100%), is the mixture of inseparable diastereomer.MS(ESI)：302(M+H +)。
Part 3: press described in the part 13 of embodiment 1, (148mg, 0.49mmol) (1,2,3,6-tetrahydropyridine-4-yl)-(115mg, 0.49mmol) coupling obtain the corresponding amide compound to benzonitrile HCl salt with 3-methyl-4-to make the amino acid of above preparation.MS(ESI)：482(M+H +)。
Part 4: in 0 ℃, to the crude product product of above preparation (115mg, add in THF 0.49mmol) (1mL) solution LiOH solution (3N, 0.049mL, 1.47mmol).The mixture that stirring obtains under room temperature 1 hour adds 3mL 1N HCl in 0 ℃ then.This mixture of freeze-drying obtains (5)-carboxyl methyl-(2S)-[4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidines-(3S)-carboxylic acid tert-butyl ester lithium salts, and it can be directly used in next step.MS(ESI)：468(M+H +)。
Part 5: press described in the part 13 of embodiment 1, (50mg, 0.099mmol) and N, (0.011mL, 0.099mmol) coupling obtain the corresponding amide compound to N '-dimethyl-ethylenediamine to make the lithium salts of above preparation.MS(ESI)：538(M+1 +)。
Part 6: use and the part 14 of embodiment 1 and the similar approach of part 15, above tert-butyl ester is converted into required oxyamide, it is the mixture (3.1mg) of the diastereomer on the C-5 position of inseparable described piperidine ring.MS(ESI)：497(M+1 +)。
Embodiment 3
(2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-
Hydroxyl-5-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl piperidines-3-methane amide and (2S, 3S, 5R)-2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-
The N-hydroxyl-5-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl } piperidines-3-methane amide
Employing prepares this two title compounds with the similar method of method of embodiment 2.Separate described two diastereomers through RP-HPLC.
Embodiment 4
(2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-
Hydroxyl-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide and (2S, 3S, 5R)-2-{[4-(4-
Cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-(2-morpholine-4-
Base-2-oxoethyl) piperidines-3-methane amide
Employing prepares this two title compounds with the similar method of method of embodiment 2.Separate described two diastereomers through RP-HPLC.
Embodiment 5
(2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-
Hydroxyl-5-[2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] piperidines-3-methane amide and (2S, 3S, 5R)-
2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-[2-
(4-hydroxy piperidine-1-yl)-2-oxoethyl] piperidines-3-methane amide
Employing prepares this two title compounds with the similar method of method of embodiment 2.Separate described two diastereomers through RP-HPLC.
Embodiment 6
(2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl }-N-hydroxyl-5-[(first
Oxygen base ethanoyl) (methyl) amino] piperidines-3-methane amide and (2S, 3S, 5S)-2-{[4-(4-cyano group-2-first
The base phenyl) piperazine-1-yl] carbonyl }-N-hydroxyl-5-[(methoxyl group ethanoyl) (methyl) amino] piperidines-3-
Methane amide
Part 1: with NaBH (OAc) 3(680mg, 3.21mmol) handle methylamine hydrochloride (216.6mg, 3.21mmol) and 5-oxo-piperidines-(2S, 3S)-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (500mg, 1.07mmol) 1, the mixture in the 2-ethylene dichloride (3.6mL) stirs under room temperature and spends the night.With the saturated NaHCO of reactant 3Ethyl acetate extraction is used in quencher.Through the organic layer that dried over mgso merges, vacuum concentration obtain (5)-methylamino-piperidines-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester, it can need not to be further purified and be directly used in next step.MS(ESI)：483.1(M+H +)。
Part 2: to the CH of above-mentioned crude product 2Cl 2(3.6ml) add methoxyacetyl chloride and Et in the solution 3N.In the vigorous stirring reaction mixture is after 30 minutes under the room temperature, vacuum is removed volatile matter.Through flash chromatography purifying (0～10% ethyl acetate is in hexane); obtain (5R)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(1; 2S; 3S)-tricarboxylic acid 1; 2-dibenzyl ester 3-tert-butyl ester (190mg) and (5S)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(1,2S, 3S)-tricarboxylic acid 1; 2-dibenzyl ester 3-tert-butyl ester (170mg) is pure diastereomer.Less polar diastereomer is called as (5R)-isomer.And than the diastereomer of high polarity be.MS(ESI)：555.1(M+H +)。
Part 3: in the presence of 10%Pd/C (40mg), under hydrogen bag pressure power, with (5R)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(1; 2S; 3S)-and tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (190mg, methyl alcohol 0.343mmol) (2mL) solution hydrogenation 1 hour.Filter this non-even phase mixture by Celite pad, remove volatile matter, obtain (5R)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(2S, 3S)-dicarboxylic acid 3-tert-butyl ester (102.4mg, 90%), be white solid.MS(ESI)：331.2(M+H +)。
Make in a similar fashion (5S)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(2S, 3S)-dicarboxylic acid 3-tert-butyl ester.
Part 4: in-78 ℃, to the PdCl that contains in THF (5mL) 2Dppf (65.8mg, 0.081mmol), dppf (44.6mg, 0.081mmol) and 4-bromo-3-methyl benzonitrile (631mg, in the flask of purging with nitrogen gas 3.22mmol), be incorporated as solid 1-piperazine carboxylic acid tert-butyl ester (500mg, 2.68mmol).With the mixture heating up to 100 that obtains ℃, vigorous stirring is spent the night under nitrogen.Water quencher reactant is used ethyl acetate extraction.With the organic layer that the salt water washing merges, dry (MgSO 4) and concentrating under reduced pressure.Residue obtains 4-(4-cyano group-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (702mg, 86.9%) through flash chromatography purifying (being used in the 0-30% eluent ethyl acetate in the hexane).MS(ESI)：302.0(M+H +)。
Part 5: (702mg 2.33mmol) is dissolved in CH to make above-mentioned title compound 2Cl 2(2mL), handle with TFA (2mL).After 1 hour, volatile matter is removed in decompression, obtains 4-(4-cyano group-2-methyl-phenyl)-piperazine tfa salt in stirred reaction mixture under the room temperature.
Part 6: under room temperature, nitrogen; with diisopropylethylamine (0.12mL; 0.69mmol) processing (5R)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(2S; 3S)-dicarboxylic acid 3-tert-butyl ester (69mg; 0.21mmol), 4-(4-cyano group-2-methyl-phenyl)-piperazine tfa salt (89.7mg; 0.21mmol) and BOP (102mg, 0.23mmol) mixture in dry DMF (0.4mL) is 2 hours.With the saturated NaHCO of reactant 3Ethyl acetate extraction is used in quencher.With the organic layer of salt water washing merging, through MgSO 4Drying also is evaporated to dried.The residue that obtains need not be further purified and be directly used in next step.MS(ESI)：514.2(M+H +)。
Make in a similar fashion (2S)-[4-(4-cyano group-2-methyl-phenyl)-piperazine-1-carbonyl]-(5S)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(3S)-carboxylic acid tert-butyl ester.
Part 7: make the crude product of above preparation be dissolved in CH 2Cl 2(1.5mL), under room temperature, handled 3 hours with TFA (1.5mL).This mixture is evaporated to drying, obtains piperidines 3-carboxylic acid, it need not purifying and is directly used in next step.MS(ESI)：458.1(M+H +)。
Part 8: under room temperature, nitrogen, with diisopropylethylamine (0.11mL, 0.63mmol) handle above-mentioned crude product piperidines 3-carboxylic acid, oxyamine HCl salt (29mg, 0.42mmol) and BOP (111mg, DMF 0.25mmol) (0.42mL) solution 2 hours.Directly be applied to this reaction mixture on the RP-HPLC; obtain (2S)-[4-(4-cyano group-2-methyl-phenyl)-piperazine-1-carbonyl]-(5R)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(3S)-carboxylic acid hydroxamides; be tfa salt (6.8mg, 3 steps 6.9%).MS(ESI)：473.2(M+H +)。
Make in a similar fashion (2S)-[4-(4-cyano group-2-methyl-phenyl)-piperazine-1-carbonyl]-(5S)-[(2-methoxyl group-ethanoyl)-methyl-amino]-piperidines-(3S)-the carboxylic acid hydroxamides tfa salt.
Embodiment 7
(2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-
Hydroxyl-5-{2-[(2-methoxy ethyl) amino]-the 2-oxoethyl piperidines-3-methane amide and
(2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-
N-hydroxyl-5-{2-[(2-methoxy ethyl) amino]-the 2-oxoethyl } piperidines-3-methane amide
Employing prepares this two title compounds with the similar method of method of embodiment 2.Separate described two diastereomers through RP-HPLC.
Embodiment 8
(2S, 3S, 5S)-2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-{2-oxo-2-[(3R)-tetrahydrofuran (THF)-3-base is amino] ethyl piperidines-3-methane amide and
(2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-{2-oxo-2-[(3R)-tetrahydrofuran (THF)-3-base is amino] ethyl } piperidines-3-methane amide
Employing prepares this two title compounds with the similar method of method of embodiment 2.Separate described two diastereomers through RP-HPLC.
Embodiment 9
(3R, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base carbonic acid methyl ester and (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base carbonic acid methyl ester
Part 1: the suspension of lithium aluminium hydride in 80mL THF in 0 ℃ of cooling, is added dropwise to (R)-phenyl succsinic acid solic by the elasticity of plastics sleeve pipe, and precise control speed makes that not producing too fierce hydrogen takes place.After the adding, make reactant be warmed to room temperature, reflux then and spend the night.Then reactant is cooled to 0 ℃ once more, with ether (80mL) dilution.Water (3.2mL, 30 minutes), the 15%NaOH aqueous solution (3.2mL, 20 minutes) and water (9.6mL, 30 minutes) quencher reactant.Stir this solution 30 minutes, and filtered white precipitate.With ether (3X) washing, merging filtrate is through dried over sodium sulfate and be concentrated into dried with filter cake.Residue is used in the 0-100%EtOAc wash-out in the hexane through silica gel purification, obtains 5.45g (91%) corresponding diol.
In-78 ℃, in the 100mL dry methylene chloride solution of the glycol of above preparation, add triethylamine, then add MsCl.Make this mixture be warmed to room temperature gradually, under room temperature, stir and spend the night.With reactant sodium bicarbonate aqueous solution quencher, use dichloromethane extraction, dry (MgSO 4), be evaporated to dried.Thick residue need not be further purified and be directly used in next step.
Two-methanesulfonates, benzyl amine and triethylamine were refluxed 12 hours in the 120mL dioxane.The vacuum concentration crude mixture is dissolved in the methylene dichloride residue, with 5%HCl washing, drying.Be evaporated to do after, residue is used in the 5%MeOH wash-out in the methylene dichloride through silica gel purification, obtains 1-benzyl-(3R)-Phenylpyrrolidine (6.6g, 2 steps 84.8%) .LCMS (M+H) 238.1.
At 20%Pd (OH) 2Under the existence of/C, in ethanol, with 1-benzyl-(3R)-Phenylpyrrolidine (500mg, 2.11mmol) spend the night under 50psi hydrogen by hydrogenation.Behind the filtration catalizer, filtrate is evaporated to dried, obtains (3R)-Phenylpyrrolidine (310mg, 100%), LCMS (M+H) 148.0.
Part 2: under-78 ℃, nitrogen atmosphere, to 5-oxo-piperidines-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (200mg, MeOH 0.43mmol) (7ml) and CH 2Cl 2(7ml) add NaBH in the solution 4(97mg, 2.6mmol).The mixture that obtains was stirred 1 hour in-78 ℃, use acetone (2ml) quencher then, and be warmed to room temperature gradually through 30 minutes.Volatile matter is removed in decompression, makes the residue that obtains be dissolved in ethyl acetate (10ml), uses the salt water washing, through MgSO 4Dry.Through Combiflash purifying (ethyl acetate in hexane: gradient 0-30%, 25 minutes), obtain 152mg (75.7%) (5R/S)-hydroxy-piperdine-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester.MS(ESI)：492.2(M+Na +)。
Part 3: in 0 ℃, to hydroxy-piperdine (200mg, CH 0.426mmol) of above-mentioned preparation 2Cl 2(48.3mg 0.51mmol), then adds Et (1.4ml) to add the carbonochloridic acid methyl ester in the solution 3N (43mg, 0.43mmol) and DMAP (2.6mg).The mixture stirring that obtains is spent the night, then vacuum concentration.Crude product is through Combiflash purifying (ethyl acetate in hexane: gradient 0-40%, 25 minutes), obtain 49mg (21.8%) (5R/S)-methoxycarbonyl oxygen base-piperidines-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester.MS(ESI)：550.1(M+Na +)。
Part 4:(5R/S)-methoxycarbonyl oxygen base-piperidines-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester and (the 3R)-Phenylpyrrolidine coupling that in part 1, prepares, use then with embodiment 6 in part 3,6,7 and part 8 similar methods, obtain described two title compounds.These two diastereomers separate by RP-HPLC.MS(ESI)：392.2(M+H +)。
Embodiment 10
(2S, 3S)-N, the 5-dihydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
Part 3 similar methods among employing and the embodiment 9, the preparation title compound, it is inseparable mixture (2.4mg) of the diastereomer of C-5 position on the described piperidine ring.MS(ESI)：334.2(M+H +)。
Embodiment 11
(5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-
The ylmethyl carbamate
Part 1: in 0 ℃, to (5R/S)-hydroxy-piperdine-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (200mg, CH 0.426mmol) 2Cl 2(29mg 0.51mmol), then adds Et (1.4ml) to add the isocyanic acid methyl ester in the solution 3N (43mg, 0.43mmol).The mixture that obtains stirred under room temperature spend the night, then vacuum concentration.Crude product is through Combiflash purifying (ethyl acetate in hexane: gradient 0-40%, 25 minutes), obtain 44mg (19.6%) (5R/S)-methylamino formyl radical oxygen base-piperidines-(1,2S, 3S)-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester.
Part 2: part 3 similar methods prepare title compound among employing and the embodiment 9, and it is inseparable mixture (6.7mg) of the diastereomer of 5-position on the described piperidines.MS(ESI)：391.2(M+H +)。
Embodiment 12
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-
Carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
(1a) in 0 ℃, to N-benzyl oxygen base carbonyl-Beta-alanine (11.16g, in anhydrous THF (160mL) 50.00mmol) and the stirred solution of DMF (40mL), slowly add NaH (60% in oil, 6.000g, 150.0mmol).In 0 ℃ stir 15 minutes after, add bromotoluene (9.10mL, 75.00mmol).Stirred reaction mixture is 22 hours under room temperature.Ethyl acetate extraction 3 times are used in water (90mL) and 1N HCl (110mL) quencher in turn.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue obtains 3-{ benzyl [(benzyl oxygen base) carbonyl] amino through Combiflash purifying (40-60%EtOAc/ hexane) } propionic acid, be the faint yellow oily thing of heavy-gravity (14.2g, 91% yield).MS(ESI)：312.0(M-H)。
(1b) in-25 ℃, to 3-{ benzyl [(benzyl oxygen base) carbonyl] amino } propionic acid (13.80g, 44.04mmol) and triethylamine (18.5mL, (6.03mL is 48.44mmol) to forming white precipitate at once slowly to add pivalyl chloride in the stirred solution of anhydrous THF (220mL) 132.1mmol).In-20 ℃ of stirred reaction mixtures 1 hour, order added LiCl and (R)-(+)-4-benzyl-2-_ oxazolidone then.After 16 hours, use saturated NaHCO in stirred reaction mixture under the room temperature 3The aqueous solution (80mL) and water (80mL) quencher reactant.With ethyl acetate extraction water twice, with the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (20-40%EtOAc/ hexane), obtain benzyl-3-[(4R)-benzyl-2-oxo-1,3-_ azoles alkane-3-yl)-3-oxo-propyl group]-the carboxylamine phenylester, be colourless half-solid (17.00g, 82% yield).MS(ESI)：473.1(M+H +)。
(1c) in-78 ℃, to diisopropylamine (5.96mL, add in the stirred solution of anhydrous THF (70mL) 42.16mmol) n-Butyl Lithium (1.6M in hexane, 26.4mL, 42.16mmol).In 0 ℃ stir 30 minutes after, in-78 ℃, by sleeve pipe with LDA join benzyl-3-[(4R)-benzyl-2-oxo-1,3-_ azoles alkane-3-yl)-3-oxo-propyl group]-(16.60g is in anhydrous THF (70mL) solution 35.13mmol) for the carboxylamine phenylester.In-78 ℃ stir 1 hour after, add tert-butylbromo acetate (6.35mL, 42.16mmol).Reaction mixture slowly is warmed to-30 ℃ with 1 hour, stirred 4 hours in-30 ℃.Twice of ethyl acetate extraction used in water (70mL) and saturated aqueous ammonium chloride (70mL) quencher.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (15-35%EtOAc/ hexane), obtain (3R)-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-4-[(4R)-benzyl-2-oxo-1 of 7.547g (37%), 3-_ azoles alkane-3-yl]-4-oxo-butyric acid tert-butyl ester.MS(ESI)：609.2(M+Na +)。
(1d) in 0 ℃, to (3R)-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-4-[(4R)-benzyl-2-oxo-1,3-_ azoles alkane-3-yl]-4-oxo-butyric acid tert-butyl ester (6.703g, 11.43mmol) THF (57mL) and water (37mL) solution in, add 30% hydrogen peroxide (4.67mL, 45.72mmol).In 0 ℃ after following 5 minutes, (559mg, aqueous solution 22.86mmol) (20mL) stir this reaction mixture 1.5 hours in 0 ℃, stir 1 hour under room temperature then to add LiOH.With 10% Sulfothiorine (70mL) quencher reactant, be acidified to pH3 with 1N HCl (30mL), use ethyl acetate extraction 3 times.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (30-60%EtOAc/ hexane), obtain 4.642g (95%) (2R)-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-uncle 4--butoxy-4-ketobutyric acid.MS(ESI)：426.2(M-H +)。(1e) in-78 ℃, to diisopropylamine (3.67mL, in the stirred solution of anhydrous THF (27mL) 26.06mmol), add n-Butyl Lithium (1.6M in hexane, 16.3mL, 26.06mmol).In 0 ℃ stir 30 minutes after, in-78 ℃, by sleeve pipe it is joined that (2R)-({ benzyl [(benzyl oxygen base) carbonyl] amino } (4.642g is in anhydrous THF (27mL) solution 10.86mmol) for methyl-uncle 4--butoxy-4-ketobutyric acid.After 1 hour, (1.32mL 14.12mmol), slowly was warmed to reaction mixture-30 ℃ with 3.5 hours, stirred 2.5 hours in-30 ℃ to add allyl group iodate thing in-78 ℃ of stirrings.Water (50mL) and 1N HCl (50mL) quencher reactant are used ethyl acetate extraction 3 times.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (20-60%EtOAc/ hexane), obtain 3.256g (64%) (2R, 3S)-2-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-4-(uncle-butoxy carbonyl)-5-hexenoic acid.MS(ESI)：466.2(M-H +)。
(1f) under room temperature, to (2R, 3S)-2-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-4-(uncle-butoxy carbonyl)-5-hexenoic acid (2.930g, 6.267mmol) the stirred solution of anhydrous acetonitrile (15mL) in add DBU (1.91mL, 12.53mmol), then add methyl-iodide (0.98mL, 15.67mmol).After stirring 3 hours under the room temperature, water (60mL) quencher reactant is used twice of ethyl acetate extraction.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (10-20%EtOAc/ hexane), obtain 2.523g (84%) (2S, 3R)-and 2-allyl group-3-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl) Succinic Acid 4-methyl ester 1-tert-butyl ester, be colourless thickness oily matter (MS (ESI): 504.2 (M+Na +).
(1g) in-78 ℃, to (2S, 3R)-(2.336g, bubbling feeds ozone to 2-allyl group-3-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl) Succinic Acid 4-methyl ester 1-tert-butyl ester in the stirred solution of methylene dichloride 4.851mmol) (97mL).After this solution changes blueness into, continue bubbling again and fed ozone 15 minutes.Then nitrogen bubble is fed in the mixture and disappear until blueness.(1.78mL, 24.26mmol) quencher reactant stirred this solution 2 hours under room temperature with methyl-sulfide.Solvent is removed through decompression, residue is through Combiflash purifying (15-25%EtOAc/ hexane), obtain 1.853g (79%) (2R, 3S)-2-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-3-(2-oxoethyl) Succinic Acid 1-methyl ester 4-tert-butyl ester, be colourless thickness oily matter (1.853g, 79% yield).MS(ESI)：506.1(M+Na +)。
(1h) to (2R, 3S)-(836mg adds 10% palladium on carbon (251mg) to 2-({ benzyl [(benzyl oxygen base) carbonyl] amino } methyl)-3-(2-oxoethyl) Succinic Acid 1-methyl ester 4-tert-butyl ester in methyl alcohol 1.729mmol) (17mL) solution.Under room temperature, reaction mixture was stirred 15.5 hours under 55psi hydrogen.Reaction mixture is diluted with methyl alcohol, filter, use methanol wash by the Celite pad.Concentrating under reduced pressure filtrate, obtain 417mg (99%) piperidines-(3R, 4S)-3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl ester.MS(ESI)：244.2(M+H +)。
(1i) under room temperature, to piperidines-(3R, 4S) 3,4-dicarboxylic acid 4-tert-butyl ester 3-methyl ester (415mg, 1.706mmol) the stirred solution of anhydrous methylene chloride (11mL) in add 4-methylmorpholine (0.474mL, 4.265mmol) and N-(benzyloxycarbonyloxy) succinimide (651mg, 2.559mmol).After 25 hours, use saturated NaHCO in stirred reaction mixture under the room temperature 3The aqueous solution (30mL) quencher reactant is used twice of ethyl acetate extraction.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (15-25%EtOAc/ hexane), obtains that 490mg (76%) piperidines-(3R, 4R)-1,3,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 3-methyl ester is colorless solid.MS(ESI)：400.0(M+Na +)。
(1j) under room temperature, to piperidines-(3R, 4S)-1,3, (465mg 1.232mmol) adds trifluoroacetic acid (12mL) and water (0.6mL) to 4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 3-methyl ester in the stirred solution of methylene dichloride (12mL).Stirred reaction mixture is 5 hours under room temperature.This reaction mixture of concentrating under reduced pressure, under azeotropic with toluene (3x) wash residual thing, obtain 396mg (100%) piperidines-(3R, 4S)-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester.MS(ESI)：320.1(M-H +)。
(1k) under room temperature, to piperidines-(3R, 4S)-1,3, (208mg adds (3R)-3-phenyl-pyrrolidine hydrochloride (178mg to 4-tricarboxylic acid 1-benzyl ester 3-methyl ester in turn in the stirred solution of dry DMF 0.647mmol) (6mL), 0.971mmol), PyBOP (382mg, 0.712mmol) and diisopropyl ethyl amine (0.566mL, 3.235mmol).Stirred reaction mixture spends the night under room temperature, uses saturated NaHCO then 3The aqueous solution (20mL) quencher reactant is used twice of ethyl acetate extraction.With the organic layer of salt water washing merging, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue is through Combiflash purifying (40-60%EtOAc/ hexane), obtain 200mg (69%) (4S)-[(3R)-3-phenyl-tetramethyleneimine-1-carbonyl]-piperidines-(3R)-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester.MS(ESI)：451.1(M+H +)。
(1l) to (4S)-[(3R)-3-phenyl-tetramethyleneimine-1-carbonyl]-piperidines-(3R)-1, (143mg adds 10% palladium on carbon (29mg) to 3-dicarboxylic acid 1-benzyl ester 3-methyl ester in methyl alcohol 0.317mmol) (8mL) solution.Under room temperature, reaction mixture was stirred 21 hours under the 1atm nitrogen atmosphere.After reaction is finished, use the methyl alcohol diluted reaction mixture, filter, use methanol wash by the Celite pad.Concentrating under reduced pressure filtrate obtain 100mg (100%) (4S)-[(3R)-3-phenyl-tetramethyleneimine-1-carbonyl]-piperidines-(3R)-carboxylic acid 3-methyl ester.MS(ESI)：317.2(M+H +)
(1m) under room temperature, to (4S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-piperidines-(3R)-carboxylic acid 3-methyl ester (23mg, 0.0727mmol) the stirred solution of anhydrous methylene chloride (2mL) in add diisopropyl ethyl amine (0.038mL, 0.218mmol) and carbonic acid 4-nitro-phenylester tetrahydrochysene-pyrans-4-base ester (29mg, 0.109mmol, adopt similar method preparation with embodiment 34 steps 1).Stirred reaction mixture is 22 hours under room temperature, then directly through Combiflash purifying (60-90%EtOAc/ hexane), obtain 27mg (84%) (4S0-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-piperidines-(3R)-1,3-dicarboxylic acid 3-methyl ester 1-(tetrahydrochysene-pyrans-4-yl) ester.MS(ESI)：445.1(M+H +)。
(1n) preparation NH 2OH/NaOMe (the MeOH solution of 1.5M): under room temperature, to hydroxylamine hydrochloride (702mg, add in the stirred solution of anhydrous methanol 10.00mmol) (3mL) NaOMe (25wt% in MeOH, 3.43mL, 15.00mmol).This reaction mixture in 55 ℃ of heating 5 minutes, is warmed to room temperature then gradually, is cooled to 0 ℃ then.Filter crude mixture, obtain clear and bright solution, be estimated as the NH of about 1.5M 2The MeOH solution of OH/NaOMe.
Under room temperature, to (4S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-piperidines-(3R)-1, (24mg adds above-mentioned NH to 3-dicarboxylic acid 3-methyl ester 1-(tetrahydrochysene-pyrans-4-yl) ester in the stirred solution of anhydrous methanol 0.054mmol) (1.5mL) 2OH/NaOMe (1.5M in MeOH, 0.72mL, 1.08mmol).After 16 hours,, use twice of ethyl acetate extraction in stirred reaction mixture under the room temperature with 1N HCl (1mL) and saturated aqueous ammonium chloride (10mL) quencher reactant.With the organic layer of salt water washing merging, through Na 2SO 4Drying is filtered concentrating under reduced pressure.Residue is through reversed-phase HPLC purifying (with 5-95% acetonitrile/water (0.05%TFA) wash-out); obtain 6.8mg (28%) (3R)-hydroxyl amino formyl radical-4-[(3R)-phenyl-tetramethyleneimine-1-carbonyl)]-piperidines-1-carboxylic acid tetrahydrochysene-pyrans-4-base ester, be colourless half-solids.MS(ESI)：446.1(M+H +)。
Embodiment 13
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-
Carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 432.1(M+H) +。
Embodiment 14
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-
Carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 432.1(M+H) +。
Embodiment 15
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-
Carboxylic acid 2-methoxy ethyl ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 420.1(M+H) +。
Embodiment 16
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid four
Hydrogen-2H-pyrans-4-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 461.1(M+H) +。
Embodiment 17
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid
(3R)-tetrahydrofuran (THF)-3-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 447.1(M+H) +。
Embodiment 18
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid
(3S)-tetrahydrofuran (THF)-3-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 447.2(M+H) +。
Embodiment 19
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid 2-
The methoxy ethyl ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 435.1(M+H) +。
Embodiment 20
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic acid four
Hydrogen-2H-pyrans-4-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 460.2(M+H) +。
Embodiment 21
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic
Acid (3R)-tetrahydrofuran (THF)-3-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 446.2(M+H) +。
Embodiment 22
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic
Acid (3S)-tetrahydrofuran (THF)-3-base ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 446.2(M+H) +。
Embodiment 23
(3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic
Acid 2-methoxy ethyl ester
Employing prepares title compound with the similar method of method of embodiment 12.ESI MS：m/z 444.2(M+H) +。
Embodiment 24
(1S, 2S, 5S)-and N, the 5-dihydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } hexanaphthene
Methane amide
Part 1: with starting raw material 3a, 4,7,7a-tetrahydrochysene-isobenzofuran-1, (30.4g 0.2mole) is suspended in the methyl alcohol (40mL) the 3-diketone, this mixture is stirred under room temperature spend the night, and forms homogeneous mixture.This reaction mixture is cooled to 0 ℃, is added dropwise to thionyl chloride (14.6ml).After adding is finished, remove cryostat, this mixture was stirred under room temperature 3 hours.Vacuum is removed volatile matter then, the residue that obtains with saturated sodium bicarbonate solution neutralization.Extract product with ethyl acetate (x3), the extract water (x1) of merging, salt solution (x1) washing are through MgSO 4Drying is filtered concentrating under reduced pressure.The residue that obtains obtains 37.06g (93%) pure products through distillation purifying.
(37g, in acetone 187mmole) (127ml) solution, (41 units/mg) (phosphate buffer soln (pH8.0) passes through KH part 2:. at previously prepared phosphate buffer soln (4ml) for 25mg, 1025 units to add LE to the diester that derives from part 1 2PO 4(34.43g, 252mmole) and the solution among the NaOH (9.30g 233mmole) joins preparation in the distilled water (2530ml)).Under room temperature, leniently stir this homogeneous reaction mixture, keep pH between 7 and 8 by adding the NaOH aqueous solution once in a while simultaneously.After 8 days,, be acidified to pH3.0 with HCl solution with saturated this solution of NaCl.This mixture is extracted with EtOAc (600mlx3), with extract water (x1), salt solution (x1) washing that merges, through MgSO 4Drying is filtered and vacuum concentration, obtains required product.
Part 3: under room temperature, with optical purity list acid (25g), 2-methacrylic (100ml), the dense H for preparing above 2SO 4(1.63ml) mixture in methylene dichloride (40ml) stirred 3 days in the reaction vessel of sealing.In this mixture impouring saturated sodium bicarbonate solution, extract with hexane-ether (x2).With extract water (x1), salt solution (x1) washing that merges, through MgSO 4Drying is filtered, and concentrating under reduced pressure obtains 30.3g (91%) and is the required product of oily matter.
Part 4: the tert-butyl ester for preparing above is dissolved in the methyl alcohol (82ml), and is cooled to 0 ℃, slowly add 2N NaOH (NaOH, 13.12g is in 164ml distilled water) then.After 2 days,, extract (x3) in stirred reaction mixture under the room temperature with EtOAc with this mixture of 1N HCl solution acidifying.With extract water (x1), salt solution (x1) washing that merges, through MgSO 4Drying is filtered and vacuum concentration, obtains required product with quantitative yield.
Part 5: slow adding hexamethylene-4-alkene in 0 ℃ KOBu-t solution (10.61mL, 1.0M KOBu-t THF and 6.1mL THF)-(1R, 2S)-dicarboxylic acid-tert-butyl ester (1.6g, THF 7.07mmole) (12.2ml) solution.Reaction mixture in 0 ℃ of stirring 10-15 minute, was stirred 1-2 hour under room temperature then.After reaction is finished, carefully add 1N HCl and be about 2, extract product with EtOAc (x2) until pH.With extract water (x1), salt solution (x1) washing that merges, through MgSO 4Drying is filtered concentrating under reduced pressure.The residue that obtains obtains the required product of 1.56g (97%) through quick column purification.
Part 6: (5.5g, 24.3mmol) order adds I to the epimerization compound of the part 5 in being dissolved in methylene dichloride (60ml) in the solution 2(18.5g, 72.9mmol), KI (24.2g, 145.6mmol) and NaHCO 3(6.1g 72.9mmol), then adds distilled water (90mL).Under room temperature, this mixture lucifuge was stirred 2 days.Add saturated Na this moment 2S 2O 3Solution is used the dichloromethane extraction product.Water (x1), salt solution (x1) washing extract are through MgSO 4Drying is filtered concentrating under reduced pressure.The crude product raw material obtains the required product of 6.21g (82%) through quick column purification.
Part 7: upward Zhi Bei iodo compound (6.6g, add in toluene 18.7mmol) (55mL) solution three (trimethyl silyl) silane (6.94mL, 22.5mmol), then add AIBN (0.31g, 1.87mmol).In 90 ℃ with this mixture heating up 1.5 hours.After the cooling, make this reaction mixture get back to room temperature,, extract with EtOAc with 10% citric acid quencher reactant.With organic phase water (x1), saturated NaHCO 3Solution (x1), water (x1), salt solution (x1) washing are through MgSO 4Drying, vacuum concentration.Residue obtains the required product of 3.42g (80%) through quick column purification.
Part 8: (234mg is 1.59mmol) with 2M AlMe with (R)-3-Phenylpyrrolidine 3Toluene (0.86mL) solution under room temperature, stirred 30 minutes.In this solution, add described lactone compound (300mg, THF 1.33mmol) (0.5ml) solution.Stir this mixture overnight in 40 ℃.After being cooled to room temperature, with EtOAc abstraction reaction mixture.With 10% citric acid (x1), water (x1), salt solution (x1) washing are through MgSO with organic layer 4Drying is filtered and concentrating under reduced pressure.The crude product that obtains obtains the required product of 180mg (36%) through the flash chromatography purifying.
Part 9: with the compound for preparing above at methylene dichloride-TFA-H 2Stirred 3 hours among the O (45: 50: 5).After finishing according to the HPLC analytical reaction, vacuum is removed volatile matter, obtains required product with quantitative yield.
Part 10: under room temperature, with derive from part 9 compound (12mg, 0.038mmol), NH 2OHHCl (7.9mg, 0.113mmol), BOP (17.6mg, 0.039mmol) and DIEA (22.1mg, 0.17mmol) solution stirring in DMF (0.4mL) is 3 hours.This crude reaction mixture obtains the required product of 4mg (32%) through the preparation HPLC direct purification.MS m/z：333.1(M+H +)；687.3(2×M+Na +)。
Embodiment 25
(1S, 2S, 5S)-and N, 5-dihydroxyl-2-{[4-phenyl-3,6-dihydropyridine-1 (2H)-yl] carbonyl } cyclohexane carboxamide
Part 1: the 7-oxo-6-oxa--two that will derive from experiment 24 parts 7 encircles [3.2.1] octane-2-carboxylic acid tert-butyl ester, and (0.92g, 4.07mmol) mixture in methylene dichloride (3ml) and TFA (3mL) stirred 1.5 hours under room temperature.After finishing according to the HPLC analytical reaction, vacuum is removed volatile matter, obtains 0.67 (97%) required product.
Part 2: Zhi Bei acid upward (30mg in 0 ℃ of solution of DMF 0.176mmol) (0.4mL), adds 4-phenyl-1,2,5, the 6-tetrahydropyridine (41mg, 0.212mmol) and BOP (82mg, 0.185mmol).Stir after 5 minutes, and adding DIEA (69mg, 0.529mmol).Making this mixture be warmed to room temperature gradually and stir spends the night.With reactant saturated sodium bicarbonate solution quencher, extract (x3) with EtOAc.With extract water (x1), salt solution (x1) washing that merges, through MgSO 4Drying is filtered, and concentrating under reduced pressure obtains product with quantitative yield.
Part 3: will be by the compound and the LiOHH of part 2 preparations 2O (22mg, THF 0.529mmol) (0.5mL) and H 2O (0.1mL) solution stirred under room temperature 2 hours.After TLC shows the starting raw material completely consumed, carefully add 1N HCl and be about 2 until pH.Reaction mixture is extracted (x3) with EtOAc, with extract water (x1), salt solution (x1) washing that merges, through MgSO 4Drying is filtered, and concentrating under reduced pressure obtains required 5-hydroxyl-2-(phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-hexahydrobenzoic acid.
Part 4: upward Zhi Bei described compound (24mg, 0.07mmol) and NH 2OHH 2Add in the DMF of O (0.4ml) solution BOP (34mg, 0.077mmol).Stir after 5 minutes, and adding DIEA (33mg, 0.255mmol).Under room temperature, stirred this mixture 3 hours.After HPLC analyzed and shows the starting raw material completely consumed, this crude reaction mixture obtained the required product of 16mg (63%) through the preparation HPLC purifying.MS m/z 345.1(M+H +)；367.1(M+Na +)；711.2(2×M+Na +)。
Embodiment 26
(1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexane carboxamide
In methyl alcohol (1mL) solution of (5S)-hydroxyl-(2S)-(4-phenyl-3,6-dihydro-2H-pyridine-1-carbonyl)-hexanaphthene-(1S)-carboxylic acid hydroxamides (5mg), add and be stated from BaSO 4On 5%Pd.Under room temperature, 1atm hydrogen, stirred this mixture 2 hours.After reaction is finished, filter the mixture that obtains by Celite pad, concentrated filtrate obtains the required product of 2.5mg (50%).MS m/z 347.1(M+H +)；369.1(M+Na +)；715.3(2×M+Na +) +。
Embodiment 27
(1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares title compound with the similar method of method of embodiment 25.
Embodiment 28
(1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] cyclohexane carboxamide
Part 1.3-hydroxyl-3-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester
Under room temperature, nitrogen, (1g is added dropwise to phenyl-magnesium-bromide (10.3mL, 3.0M is 6.21mmol in ether) in ether 5.40mmol) (20ml) solution to 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester.This reactant is heated to backflow 15 minutes, is cooled to room temperature then, the saturated NH of impouring 4Among the Cl, with ether extraction (3x).The organic layer that merges is through Na 2SO 4Drying, vacuum concentration.Thick residue obtains required product (700mg, 49.24%) .LCMS (M+H) 264.160 through the rapid column chromatography purifying.
Part 2.3-phenyl-2,5-dihydro-1H-pyrroles
Under room temperature and nitrogen, with 3-hydroxyl-3-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester (0.36g, 0.0014mol) and trifluoroacetic acid (2.0mL, 0.026mol) mixture stirred 1 hour.Vacuum is removed volatile matter, uses twice of toluene evaporates.Residue need not or optional (w/o) be further purified and be used for next step.LCMS：146.1(M+H) +。
Part 3. adopts then and the similar method of method of embodiment 25 prepares title compound.
Embodiment 29
(1S, 2S)-the N-hydroxyl-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl }-5-tetramethyleneimine-1-base
Cyclohexane carboxamide
Step 1: preparation 2-(3-phenyl-tetramethyleneimine-1-carbonyl)-6-oxabicyclo [3.2.1] suffering-7-ketone
In methylene dichloride (3mL) solution of 7-oxo-6-oxa--two ring [3.2.1] octane-2-carboxylic acid tert-butyl ester (500mg), add TFA (3mL).In stirring this mixture under the room temperature after 2 hours, this solution of concentrating under reduced pressure.With residue, it is dissolved among the DMF (3mL) with the washing of methylene dichloride (x3) azeotropic.Add (R)-3-Phenylpyrrolidine in this solution, make the mixture that obtains be cooled to 0 ℃, order adds PyBOP (1.25g) and diisopropylethylamine (0.42ml) then.After stirring this mixture overnight under the room temperature, reaction soln is diluted with EtOAc, use saturated NaHCO 3The aqueous solution (x3), water and salt water washing.Organic phase is through MgSO 4Drying is filtered and concentrating under reduced pressure.Residue is through flash chromatography purifying (being used in 8% methanol-eluted fractions in the methylene dichloride).MS(ESI)：300.1(M+H +)
Step 2: preparation 5-hydroxyl-2-(3-phenyl-tetramethyleneimine-1-carbonyl)-hexanaphthene-carboxylic acid benzyl ester
Add lithium hydroxide (302mg) in THF (4mL) solution of Zhi Bei compound (400mg) upward, then add entry (1mL).After 3 hours, reaction mixture with 1N HCl dilution, is extracted (3 * 30mL) with EtOAc.With organic phase salt water washing, through MgSO 4Drying is filtered concentrating under reduced pressure.Residue need not be further purified and be used for next step.
In acetonitrile (10mL) solution of above-mentioned residue, add bromotoluene (0.41mL), then add DBU (0.51mL).Stirred reaction mixture spends the night under room temperature, with the reaction mixture concentrating under reduced pressure, residue is dissolved among the EtOAc, then with 10% aqueous citric acid solution and salt water washing.Organic phase is through MgSO 4Drying is filtered and concentrating under reduced pressure.Residue is through flash chromatography purifying (being used in 5% methanol-eluted fractions in the methylene dichloride).MS(ESI)：408.2(M+H +)
Step 3: preparation 5-oxo-2-(3-phenyl-tetramethyleneimine-1-carbonyl)-hexanaphthene-carboxylic acid benzyl ester
In the solution of the alkylol cpd that derives from step 2 (400mg), add Dess-Martin reagent (500mg), under room temperature, stirred this mixture 3 hours.After reaction is finished, dilute this mixture, then add the 0.1N NaOH aqueous solution (12mL), continued stir about 20 minutes with methylene dichloride.With organic phase 0.1N NaOH solution, salt water washing, through MgSO 4Dry also concentrating under reduced pressure.Residue is through flash chromatography purifying (being used in 5% methanol-eluted fractions in the methylene dichloride).MS(ESI)：406.1(M+H +)
Step 4: preparation 2-(3-phenyl-tetramethyleneimine-1-carbonyl)-5-tetramethyleneimine-1-base-hexahydrobenzoic acid benzyl ester
Upward 1 of Zhi Bei ketone compound (30mg), add tetramethyleneimine (6 μ L) in the 2-dichloroethane solution.Under room temperature, stir this mixture about 10 minutes, add NaBH (OAc) then 3(24mg).The mixture that obtains was stirred other 1 hour, then with the EtOAc dilution, with saturated NaHCO 3With the salt water washing.Organic phase is through MgSO 4Drying is filtered and is evaporated to dried.MS(ESI)：461.2(M+H +)
Step 5: preparation 2-(3-phenyl-tetramethyleneimine-1-carbonyl)-5-tetramethyleneimine-1-base-hexahydrobenzoic acid oxyamide
Add palladium on carbon (20mg) in methyl alcohol (1mL) solution of Zhi Bei compound (30mg, crude product) upward.Under the hydrogen capsule, this suspension stirring is spent the night.Filter this mixture and vacuum concentration by Celite pad.Residue need not be further purified and be used for next step.MS(ESI)：371.2(M+H +)。
Add azanol (14mg) in the DMF of above-mentioned residue (0.3mL) solution, this mixture is cooled to 0 ℃, order adds PyBOP (34mg) and NMM (18 ì L) then.Under room temperature, stir this mixture about 3 hours, directly be prepared type HPLC then, obtain end product.MS(ESI)：386.2(M+H +)
Embodiment 30
(1S, 2S, 5S)-the N-hydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl }-5-morpholine-4-base
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 29.MS(ESI)：402.2(M+H +)
Embodiment 31
(1S, 2S, 5R)-the N-hydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl }-5-morpholine-4-
Basic ring hexane methane amide
Employing prepares this compound with the similar method of method of embodiment 29.MS(ESI)：402.2(M+H +)
Embodiment 32
(1S, 2S)-the N-hydroxyl-5-[(3R)-3-hydroxyl pyrrolidine-1-yl]-2-{[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl } cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 29.MS(ESI)：402.2(M+H +)
Embodiment 33
(1S, 2S, 5S)-and 2-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-N, 5-dihydroxyl hexamethylene
The alkane methane amide
Step 1: preparation 2-[4-(4-tert-butyl-phenyl)-piperazine-1-carbonyl]-6-oxa--two ring [3.2.1] suffering-7-ketone
Adopt with the similar method of embodiment 29 steps 1 and prepare this compound.MS(ESI)：371.1(M+H +)
Step 2: preparation 2-[4-(4-tert-butyl-phenyl)-piperazine-1-carbonyl]-5-hydroxyl-hexahydrobenzoic acid oxyamide
Add lithium hydroxide (45mg) in THF (2mL) solution of Zhi Bei compound (130mg) upward, then add entry (0.5mL).After stirring 3 hours under the room temperature, reaction mixture with 1N HCl solution dilution, is extracted (3 * 15mL) with EtOAc.With organic phase salt water washing, through MgSO 4Drying is evaporated to dried.Residue need not be further purified and be used for next step.
Thick residue (45mg) is dissolved among the DMF (0.3mL), adds azanol HCl salt (25mg).Make this mixture be cooled to 0 ℃, add PyBOP (68mg), then add DIEA (93 ì L).After 3 hours, crude reaction mixture directly is prepared type HPLC in stirred reaction mixture under the room temperature, obtains end product.MS(ESI)：404.2(M+H +)
Embodiment 34
((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl) methyl carbamic acid (3S)-tetrahydrofuran (THF)-3-base ester
Step 1: preparation carbonic acid 4-nitro-phenylester tetrahydrochysene-furans-3-base ester
In 0 ℃, in the dichloromethane solution of p-nitrophenyl carbonochloridic acid ester (1.21g), add S-(+)-3-hydroxyl tetrahydrofuran (0.51g), then add NMM (0.66mL).In stirring this mixture under the room temperature after 2 hours, volatile matter is removed in decompression, makes the residue that obtains be dissolved in a small amount of methylene dichloride and filtration. and concentrating under reduced pressure filtrate through flash chromatography (being used in 30% eluent ethyl acetate in the methylene dichloride), obtains title compound.
Step 2: preparation 5-methylamino-2-(3-phenyl-tetramethyleneimine-1-carbonyl)-hexahydrobenzoic acid benzyl ester
The similar method of step 4 prepares this compound among employing and the embodiment 29.MS(ESI)：421.2(M+H +)
Step 3: preparation 5-[methyl-(tetrahydrochysene-furans-3-base oxygen base carbonyl)-amino]-2-(3-phenyl-tetramethyleneimine-1-carbonyl)-hexahydrobenzoic acid benzyl ester
Add DIEA (31 μ L) in THF (0.3mL) solution of Zhi Bei compound (37mg) upward, then add THF (0.3mL) solution of carbonic acid 4-nitro-phenylester tetrahydrochysene-furans-3-base ester (25mg).In stirring this mixture under the room temperature after 24 hours, volatile matter is removed in decompression.Residue obtains required product through flash chromatography purifying (being used in 5% methanol-eluted fractions in the methylene dichloride).MS(ESI)：535.2(M+H +)
Step 4: preparation [3-hydroxyl amino formyl radical-4-(3-phenyl-tetramethyleneimine-1-carbonyl)-cyclohexyl]-methyl-carboxylamine tetrahydrochysene-furans-3-base ester
The similar method of step 5 prepares this compound among employing and the embodiment 29.MS(ESI)：460.2(M+H +)
Embodiment 35
((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } ring
Hexyl) methyl carbamic acid (3R)-tetrahydrofuran (THF)-3-base ester
Employing prepares this compound with the similar method of method of embodiment 34.MS(ESI)：460.2(M+H +)
Embodiment 36
((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } ring
Hexyl) methyl carbamic acid tetrahydrochysene-2H-pyrans-4-base ester
Employing prepares this compound with the similar method of method of embodiment 34.MS(ESI)：474.2(M+H +)
Embodiment 37
Tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } cyclohexyl ester
Step 1: preparation 5-(4-nitro-phenyloxycarbonyl oxygen base)-2-(3-phenyl-tetramethyleneimine-1-carbonyl)-hexamethylene-2,3-diene carboxylic acid benzyl ester.
In the dichloromethane solution of right-nitrophenyl carbonochloridic acid ester (181mg), add 5-hydroxyl-2-(3-phenyl-tetramethyleneimine-1-carbonyl)-hexahydrobenzoic acid benzyl ester (183mg), then add NMM (99 μ L).After this reaction conditions stirred 60 hours down, vacuum was removed volatile matter.Residue obtains carbamate compounds through flash chromatography purifying (being used in 5% methanol-eluted fractions in the methylene dichloride).MS(ESI)：573.2(M+H +)
Step 2: preparation tetramethyleneimine-1-carboxylic acid 3-benzyl oxygen base carbonyl-4-(3-phenyl-tetramethyleneimine-1-carbonyl)-cyclohexyl ester
Adopt with the similar method of embodiment 34 steps 3 and prepare this compound.MS(ESI)：505.2(M+H +)。
Step 3: preparation tetramethyleneimine-1-carboxylic acid 3-hydroxyl amino formyl radical-4-(3-phenyl-tetramethyleneimine-1-carbonyl)-cyclohexyl ester
The similar method of step 5 prepares this compound among employing and the embodiment 29.MS(ESI)：430.3(M+H +)315.2(M-114) +
Embodiment 38
Methyl carbamic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：390.2(M+H +)315.2(M-114) +
Embodiment 39
Dimethylamino formic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：404.3(M+H +)315.2(M-114) +
Embodiment 40
Morpholine-4-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：446.2(M+H +)315.2(M-114) +
Embodiment 41
(3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：446.3(M+H +)315.2(M-114) +
Embodiment 42
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }
Piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
Step 1.4-[(trifluoromethyl) alkylsulfonyl] oxygen base-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Under-78 ℃, nitrogen, to 4-oxo-1-piperidine carboxylic acid tert-butyl ester (10.50g, 0.05270mol) tetrahydrofuran (THF) (200.0mL 2.466mol) adds tetrahydrofuran (THF) (55.96mL) solution of 1.00M hexamethyldisilane base Lithium Azide (lithium hexamethyldisilazide) in the solution.In-78 ℃ stir 1 hour after, in the mixture that obtains, add solid N-phenyl two (fluoroform sulfimide) (20.00g, 0.05598mol).This reaction mixture in-78 ℃ of stirrings 2 hours, is warmed to room temperature then gradually, under room temperature, stirs and spend the night.Behind the reduction vaporization THF, residue is diluted with ether.With this mixture 1N HCl, 1N NaOH and salt solution wash in proper order.Dry then organic layer also is evaporated to dried.Residue is applied on the silicagel column, is used in the 0-20% eluent ethyl acetate in the hexane, obtain enol triflate (17.46g, 84%).MS(ESI)：(-Boc)232.0。
Step 2.4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With the 4-[(trifluoromethyl) alkylsulfonyl] oxygen base-3; 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (11.0g; 0.0332mol), (3-isopropyl phenyl) boric acid (5.44g; 0.0332mol) and potassiumphosphate (21.1g; 0.0996mol) tetrahydrofuran (THF) (150.0mL, the mixture degassing in 1.849mol) 15 minutes adds four (triphenyl phosphine) palladium (O) (2g then; 0.002mol), the mixture backflow that obtains is spent the night.After evaporating most of THF,, extract with EtOAc with the residue dilute with water.With the organic layer that the salt water washing merges, drying also is evaporated to dried.Residue is applied on the silicagel column, is used in the 0-20%EtOAc wash-out (9.1g, 91%) in the hexane.MS(ESI)：(M-Bu)246.1。
Step 3:De-Boc
Under room temperature, handle 4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (2.54g, 0.00844mol) 30 minutes with 10mL TFA.Behind the evaporation TFA, residue is exposed under the high vacuum, is directly used in next step then.
Step 4: preparation 2-[4-(3-sec.-propyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidines-3-carboxylic acid tert-butyl ester
To piperidines-2, in 0 ℃ of solution of the DMF (0.6mL) of 3-dicarboxylic acid 3-tert-butyl ester (100mg), order adds 4-(3-sec.-propyl-phenyl)-1,2,3,6-tetrahydrochysene-pyridine (97mg), PyBOP (232mg) and diisopropylethylamine (0.152mL).The mixture that obtains stirred under room temperature spend the night.Reaction soln is diluted with EtOAc, with saturated NaHCO 3Solution (x3), water and salt water washing.Organic layer is through MgSO 4Drying is filtered, and is evaporated to dried.Residue need not be further purified and be used for next step.。MS(ESI)：413.2(M+H +)
Step 5: preparation 2-[4-(3-sec.-propyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidines-3-carboxylic acid benzyl oxygen base-acid amides
Add TFA (3.5mL) in the methylene dichloride of Zhi Bei crude product (1.3mL) solution upward, then add entry (0.3mL).This mixture stirred under room temperature spend the night, be evaporated to dried then.Residue and benzene coevaporation are anhydrated to remove for several times.Make residue be dissolved among the DMF (1mL) and be cooled to 0 ℃, order adds O-benzyl oxyamine (83mg), PyBOP (249mg) and diisopropylethylamine (0.31mL) then.The mixture that obtains stirred under room temperature spend the night.Reaction soln is diluted with EtOAc, with saturated NaHCO 3Solution (x3), water and salt water washing.Organic layer is through MgSO 4Drying is filtered and is evaporated to dried.Residue obtains required product through flash chromatography purifying (being used in 10% methanol-eluted fractions in the methylene dichloride).MS(ESI)：462.2(M+H +)
Step 6: preparation 3-benzyl oxygen base formamyl-2-[4-(3-sec.-propyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-piperidines-1-carboxylic acid tetrahydrochysene-furans-3-base ester
THF (0.5mL) solution that adds DIEA (40 ì L) and carbonic acid 4-nitro-phenylester tetrahydrochysene-furans-3-base ester (30mg) upward in THF (0.5mL) solution of Zhi Bei compound (50mg).After 24 hours, volatile matter is removed in decompression in stirred reaction mixture under the room temperature.Residue obtains title compound through flash chromatography purifying (being used in 7% methanol-eluted fractions in the methylene dichloride).MS(ESI)：576.3(M+H +)
Step 7: preparation 3-hydroxyl amino formyl radical-2-[4-(3-sec.-propyl-phenyl)-piperidines-1-carbonyl]-piperidines-1-carboxylic acid tetrahydrochysene-furans-3-base ester
Add palladium on carbon (20mg) in the methyl alcohol of Zhi Bei compound (1mL) solution upward.Under the hydrogen capsule, this suspension was stirred 3 hours.Filter this mixture, be evaporated to dried.Residue obtains end product through the preparation HPLC purifying.MS(ESI)：488.2(M+H +)
Embodiment 43
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }
Piperidines-1-carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
Employing prepares this compound with the similar method of method of embodiment 42.MS(ESI)：488.2(M+H +)
Embodiment 44
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }
Piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
Employing prepares this compound with the similar method of method of embodiment 42.MS(ESI)：502.2(M+H +)
Embodiment 45
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic
Acid (3R)-tetrahydrofuran (THF)-3-base ester
Employing prepares this compound with the similar method of method of embodiment 42.MS(ESI)：447.2(M+H +)
Embodiment 46
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic
Acid (3S)-tetrahydrofuran (THF)-3-base ester
Employing prepares this compound with the similar method of method of embodiment 42.MS(ESI)：447.2(M+H +)
Embodiment 47
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic
Acid tetrahydrochysene-2H-pyrans-4-base ester
Employing prepares this compound with the similar method of method of embodiment 42.MS(ESI)：461.2(M+H +)
Embodiment 48
5-[({ (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperazine
Pyridine-3-yl } ethanoyl) amino] amyl group } the carboxylamine benzyl ester
Part 1:(2S, 3S)-5-oxo-piperidine-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester.Under nitrogen atmosphere, and the oxalyl chloride of in baking oven-exsiccant is equipped with the conical bottle of 5mL of magnetic stirring bar, packing into (0.080mL, 0.92mmol) and methylene dichloride (0.7mL).Make this solution be cooled to-78 ℃, be added dropwise to methyl-sulphoxide (0.080mL, methylene dichloride 1.13mmol) (0.3mL) solution then.Stir this solution after 45 minutes, be added dropwise to (2S, 3S)-5-hydroxy piperidine-1,2,3-tricarboxylic acid 1, (266mg, methylene dichloride 0.567mmol) (1mL) solution made this solution slowly be warmed to about 0 ℃ with 1.5 hours to 2-dibenzyl ester 3-tert-butyl ester.This reaction mixture is cooled to-78 ℃, and (0.240mL 1.72mmol), continues to stir 3 hours, is warmed to about 0 ℃ gradually simultaneously to be added dropwise to triethylamine then.By being added dropwise to 5% citric acid (2mL) quencher reactant, with methylene dichloride (15mL) dilution.With organic layer with the salt water washing (2 * 5mL), dry (NaSO 4) and vacuum concentration, obtain the required ketone of 264mg (100%), be the thickness yellow oil.LCMS(ESI)：490(M+Na +)
Part 2:(2S, 3S)-5-(2-methoxyl group-2-oxo ethylidene) piperidines-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester: under nitrogen atmosphere, be equipped with in the 25mL round-bottomed flask of magnetic stirring bar to baking oven-exsiccant, and (triphenyl inferior phosphoranyl (phosphoranylidene)) the acetate methyl ester of packing into (199mg, 0.597mmol) and toluene (5mL).In this non-even phase solution, add (2S, 3S)-5-oxo-piperidine-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (93mg, toluene 0.199mmol) (3mL) solution.Reaction mixture is heated to refluxes and stir and spend the night.Vacuum is removed volatile matter then, and this yellow oil obtains 83mg (80%) (2S through Combiflash purifying (the 10-30% ethyl acetate is in hexane), 3S)-5-(2-methoxyl group-2-oxo ethylidene) piperidines-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester.LCMS(ESI)：424(M-CO 2t-Bu+2H +)，468(M-t-Bu+2H +)，524(M+H +)。
Part 3:(2S, 3S)-3-(uncle-butoxy carbonyl)-5-(2-methoxyl group-2-oxoethyl) piperidines-2-carboxylic acid. at 10% palladium on carbon (100mg, 0.094) exist down, under hydrogen bag pressure power, will (2S, 3S)-5-(2-methoxyl group-2-oxo ethylidene) piperidines-1,2,3-tricarboxylic acid 1, methyl alcohol (5mL) the solution hydrogenation of 2-dibenzyl ester 3-tert-butyl ester (98mg, 0.188) is spent the night.The reaction mixture that obtains is filtered by the Celite pad, with methyl alcohol (2 * 5mL) washing precipitates.Vacuum is removed volatile matter, and (2S 3S)-3-(uncle-butoxy carbonyl)-5-(2-methoxyl group-2-oxoethyl) piperidines-2-carboxylic acid, is the thickness amorphous solid, and it need not be further purified and be directly used in the following coupling to obtain 50mg (88%).LCMS(ESI)：246(M-t-Bu+H +)，302(M+H +)。
Part 4:(2S, 3S)-5-(2-methoxyl group-2-oxoethyl)-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-carboxylic acid tert-butyl ester.Under nitrogen atmosphere, being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: (2S, 3S)-3-(uncle-butoxy carbonyl)-5-(2-methoxyl group-2-oxoethyl) piperidines-2-carboxylic acid (50mg, 0.166mmol), dry DMF (2mL), bop reagent (100mg, 0.226mmol), 3-phenyl-tetramethyleneimine (25mg, 0.17mmol) and N, and the N-diisopropylethylamine (0.086mL, 0.49mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4), vacuum concentration obtains the 75mg crude product, it is directly used in the following hydrolysis.LCMS(ESI)：431(M+H)，375(M-t-Bu+2H +)。
Part 5:{[5S, 6S)-5-(uncle-butoxy carbonyl)-6-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-yl } acetate.Will (2S, 3S)-5-(2-methoxyl group-2-oxoethyl)-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] THF (3mL) solution of piperidines-3-carboxylic acid tert-butyl ester is cooled to 0 ℃, add then lithium hydroxide (7mg, 0.16mmol).After being warmed to room temperature, this reaction mixture stirring is spent the night.Vacuum is removed volatile matter, obtains 60mg (87%) { (5S, 6S)-5-(uncle-butoxy carbonyl)-6-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-yl } acetate, is pale solid, and it need not to neutralize and purifying and be used for following coupled reaction.MS(ESI)：417(M+H +)。
Part 6:(2S, 3S)-5-{2-[(5-{[(benzyl oxygen base) carbonyl] amino } amyl group) amino]-the 2-oxoethyl }-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-carboxylic acid tert-butyl ester.Under nitrogen atmosphere, being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: { (5S, 6S)-and 5-(uncle-butoxy carbonyl)-6-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-yl } acetate (60mg, 0.144mmol), dry DMF (2mL), bop reagent (100mg, 0.226mmol), N, N-Cbz-1,5-diamino pentane hydrochloride (45mg, 0.17mmol) and N, and the N-diisopropylethylamine (0.086mL, 0.49mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.Through the Combiflash purifying (dichloromethane solution of 0-10% methyl alcohol, 25 minutes), obtain 56mg (62%) (2S, 3S)-5-{2-[(5-{[(benzyl oxygen base) carbonyl] amino } amyl group) amino]-the 2-oxoethyl }-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-carboxylic acid tert-butyl ester.LCMS(ESI)：635(M+H +)，636(M+2H +)。
Part 7:(2S, 3S)-and 5-{2-[(5-{[(benzyl oxygen base) carbonyl] amino } amyl group) amino]-the 2-oxoethyl }-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-carboxylic acid. to (2S, 3S)-and 5-{2-[(5-{[(benzyl oxygen base) carbonyl] amino } amyl group) amino]-the 2-oxoethyl }-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] (40mg adds 1 and drips and trifluoroacetic acid (4mL) piperidines-3-carboxylic acid tert-butyl ester in methylene dichloride 0.063mmol) (2mL) solution.With this reaction mixture stir spend the night after, vacuum is removed volatile matter, under azeotropic, with benzene (2 * 3mL) and heptane (2 * 3mL) wash residual things.Dry raw product under high vacuum, it need not purifying and is directly used in the following coupled reaction.MS(ESI)：579(M+H)。
Part 8:{5-[({ (5S, 6S)-the 5-[(carbonylamino) carbonyl]-6-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-yl } ethanoyl] amino] amyl group } the carboxylamine benzyl ester.Under nitrogen atmosphere, being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: (2S, 3S)-and 5-{2-[(5-{[(benzyl oxygen base) carbonyl] amino } amyl group) amino]-the 2-oxoethyl }-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-carboxylic acid (0.063mmol), dry DMF (1.5mL), PyBOP reagent (40mg, 0.076mmol), hydroxylamine hydrochloride (20mg, 0.289mmol) and the 4-methylmorpholine (0.046mL, 0.42mmol).After stirring is spent the night; crude reaction mixture directly is applied to purifying on the preparation HPLC; obtain 14mg (38%, 2 step) pure { 7-[5-(S)-hydroxyl amino formyl radical (carbomyl)-6-(R)-(3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-yl]-6-oxo-heptyl }-carboxylamine benzyl ester.LCMS(ESI)：594(M+H +)，595(M+2H +)。
Embodiment 49
(2S, 3S)-the amino amyl group of 5-{2-[(5-) amino]-the 2-oxoethyl }-N-hydroxyl-2-[(3-phenyl
Tetramethyleneimine-1-yl) carbonyl] piperidines-3-methane amide
Under hydrogen bag pressure power; will 7-[5-(S)-hydroxyl amino formyl radical-6-(R)-(3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-yl]-6-oxo-heptyl }-carboxylamine benzyl ester (10mg; 0.0169mmol) methyl alcohol (2mL) solution with being stated from palladium (5%) (10mg, 0.0047mmol) hydrogenation on the barium sulfate.Stir after 4 hours, by the Celite pad filter reaction mixture, (2 * 5mL) wash with methyl alcohol with throw out.Vacuum is removed volatile matter, obtains 6.5mg (84%) 5-(7-amino-2-oxo-heptyl)-2-(R)-(3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-(S)-carboxylic acid hydroxamides.LCMS(ESI)：460(M+H +)。
Embodiment 50
(1S, 2S)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexane carboxamide
Part 1:4-methoxycarbonyl methylene radical-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester 1-(S)-tert-butyl ester.Under nitrogen atmosphere, 4-oxo-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester 1-(S)-tert-butyl ester (470mg packs in baking oven-exsiccant is equipped with the 50mL round-bottomed flask of magnetic stirring bar, 1.42mmol), toluene (35mL) and (triphenyl inferior phosphoranyl) acetate methyl ester (2.4g, 7.2mmol).Should non-even phase mixture be heated to and reflux and stir and spend the night.Vacuum is removed volatile matter then, this yellow oil obtains 496mg (85%) 4-methoxycarbonyl-methylene radical-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester 1-(S)-tert-butyl ester through Combiflash purifying (the 10-30% ethyl acetate is in hexane).LCMS(ESI)：301(M-CO 2(t-Bu)-Me+3H +)，411(M+Na +)。
Part 2:4-methoxycarbonyl methylene radical-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester.(496mg adds number and drips and trifluoroacetic acid (16mL) in methylene dichloride 1.21mmol) (8mL) solution to 4-methoxycarbonyl-methylene radical-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester.After this reaction mixture stirred 3 hours, vacuum was removed volatile matter, under azeotropic, with benzene (2 * 5mL), heptane (2 * 5mL) and toluene (2 * 5mL) wash residual things.Dry raw product under high vacuum, it need not be further purified and be directly used in below the coupled reaction.MS(ESI)：355(M+Na +)。
Part 3:5-methoxycarbonyl methylene radical-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-the carboxylic acid benzyl ester.Under nitrogen atmosphere, being equipped with in the conical bottle of 10mL of magnetic stirring bar order to baking oven-exsiccant packs into: 4-methoxycarbonyl methylene radical-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester (172mg, 0.52mmol), dry DMF (4mL), PyBOP reagent (324mg, 0.62mmol), N-phenylpiperazine (0.10mL, 0.655mmol) and the 4-methylmorpholine (0.220mL, 2.02mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.Through Combiflash purifying (0-10% methyl alcohol in methylene dichloride, 30 minutes), obtain the pure 5-methoxycarbonyl methylene radical-2-(S) of 233mg (94%)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid benzyl ester.LCMS(ESI)：477(M+H +)。
Part 4:5-methoxycarbonyl methylene radical-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid. with 5-methoxycarbonyl methylene radical-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid benzyl ester (233mg, 0.49) methyl alcohol (5mL) solution at 10% palladium on carbon (150mg, 0.14) existence under, hydrogenation is 2 hours under hydrogen bag pressure power.The reaction mixture that obtains is filtered by the Celite pad, and (2 * 5mL) wash with methyl alcohol with throw out.Vacuum is removed volatile matter, obtain 172mg (90%) 5-methoxyl group-carbonyl methylene radical-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid, be thickness oily matter, it is directly used in coupling below and need not be further purified .LCMS (ESI): 389 (M+H +).
Part 5:[3-(S)-benzyloxy formamyl-4-(S)-(4-phenyl-Piperazine-1-carbonyl)-cyclohexyl]-the acetate methyl ester.Under nitrogen atmosphere, being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: 5-methoxycarbonyl-methylene radical-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid (172mg, 0.44mmol), dry DMF (3mL), PyBOP reagent (320mg, 0.61mmol), O-benzyl-hydroxylamine hydrochloride (100mg, 0.627mmol) and the 4-methylmorpholine (0.160mL, 1.47mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.Through Combiflash purifying (0-15% methyl alcohol in methylene dichloride, 30 minutes), obtain pure [3-(S)-benzyloxy formamyl-4-(S)-(4-phenyl-Piperazine-1-carbonyl)-cyclohexyl]-acetate methyl ester of 213mg (98%).LCMS(ESI)：494(M+H +)。
Part 6:[3-(S)-benzyloxy nitrogen base formyl radical-4-(S)-(4-phenyl-Piperazine-1-carbonyl)-cyclohexyl]-acetate. to [3-(S)-benzyloxy formamyl-4-(S)-(4-phenyl-Piperazine-1-carbonyl)-cyclohexyl]-acetate methyl ester (213mg; 0.432mmol) THF (5mL) solution in add entry (3mL) and lithium hydroxide (40mg, 0.95mmol).After stirring 4 hours under the room temperature, this reaction mixture is acidified to about pH5 with 1N HCl.(4 * 5mL) extract, and wash the organic layer that merges with salt solution (5mL), dry (NaSO with ethyl acetate with product 4) and vacuum remove volatile matter, obtain 154mg (87%) [3-(S)-benzyloxy formamyl-4-(S)-(4-phenyl-Piperazine-1-carbonyl)-cyclohexyl]-acetate, be thickness oily matter, it need not be further purified and be used for following coupled reaction.MS(ESI)：480(M+H +)。
Part 7:5-(2-oxo-2-piperidines-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid benzyl oxygen base-acid amides.Under nitrogen atmosphere; being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: [3-(S)-benzyloxy formamyl-4-(S)-(4-phenyl-Piperazine-1-carbonyl)-cyclohexyl]-acetate (16mg; 0.033mmol), dry DMF (1mL), PyBOP reagent (20mg; 0.038mmol), piperidines (0.010mL; 0.101mmol) and the 4-methylmorpholine (0.01mL, 0.092mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.(0-10% methyl alcohol is in methylene dichloride through the Combiflash purifying, 30 minutes), obtain the pure 5-of 17mg (94%) (2-oxo-2-piperidines-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl)-hexanaphthene-(S)-carboxylic acid benzyl oxygen base-acid amides .LCMS (ESI): 547 (M+H +).
Part 8:5-(2-oxo-2-piperidines-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid hydroxamides..With 5-(2-oxo-2-piperidines-1-base-ethyl)-2 (S)-(4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid benzyl oxygen base-acid amides (16mg, 0.029mmol) methyl alcohol (2mL) solution with being stated from palladium (5%) (40mg on the barium sulfate, 0.018mmol), hydrogenation under hydrogen bag pressure power.Stir after 6 hours, by the Celite pad filter reaction mixture, (2 * 5mL) wash with methyl alcohol with throw out.Vacuum is removed volatile matter, (acetonitrile solution of gradient 0-40%0.1%TFA is to the aqueous solution of 0.1%TFA through the preparation HPLC purifying for residue, 30 minutes), obtain that 6mg (46%) 5-(2-oxo-2-piperidines-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid hydroxamides is white solid.LCMS(ESI)：457(M+H +)。
Embodiment 51
(1S, 2S)-N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
The universal method that employing is summarized above prepares title compound.Described acid amides coupling (as described in 7 pairs of similar compounds of part) obtains 18mg (100%) 5-(2-oxo-2-tetramethyleneimine-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl-hexahydrobenzoic acid benzyl oxygen base-acid amides LCMS (ESI): 533 (M+H +).Benzyl (as described in 8 pairs of similar compounds of part) is removed in hydrogenation subsequently, obtain that 7mg (46%) 5-(2-oxo-2-tetramethyleneimine-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid hydroxamides is white solid .LCMS (ESI): 443 (M+H +).
Embodiment 52
(1S, 2S)-the N-hydroxyl-5-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl }-2-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
The universal method that employing is summarized above prepares title compound.Described acid amides coupling (as described in) in 7 pairs of similar compounds of part obtain 13mg (72%) 5-[2-oxo-2-(3-R-hydroxyl pyrrolidine-1-base-ethyl]-2-(S)-(4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid benzyl oxygen base-acid amides LCMS (ESI): 549 (M+H +).Benzyl (as described in 8 pairs of similar compounds of part) is removed in hydrogenation subsequently, obtain that 5mg (45%) 5-[2-oxo-2-(3-(R)-hydroxyl pyrrolidine-1-base-ethyl)-2-(S)-(4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid hydroxamides is white solid .LCMS (ESI): 459 (M+H +).
Embodiment 53
(1S, 2S)-N (2)-hydroxy-n (1)-4-[(2-toluquinoline-4-yl) methoxyl group] phenyl }-4-(2-
Oxo-2-piperidines-1-base ethyl) hexanaphthene-1, the 2-diformamide
Part 1:4-hydroxymethyl-2-toluquinoline is at N 2(g) purify down, order is packed in the 25mL round-bottomed flask that is equipped with magnetic stirring bar: and the 2-toluquinoline (0.57g, 4.0mmol), methyl alcohol (8mL) and water (4mL).This solution is cooled to 0 ℃, and order adds then: the vitriol oil (0.2mL, 4mmol), ferric sulfate (II) heptahydrate (0.33g, 1.2mmol) and iron powder (0.067g, 1.2mmol).Stir this non-even phase mixture after 10 minutes, (1.36g 12mmol), stirs the mixture 6h that obtains, and uses 50%NaOH quencher reactant then, is about 10 until pH to add hydroxylamine-o-sulfonic acid (HOSA).Filter this brown solution by the Celite pad, use dichloromethane extraction (4 * 15mL) then.With organic phase water (20mL), salt solution (15mL) washing that merges, dry (NaSO 4), vacuum concentration obtains brown solid, and it obtains the pure 4-hydroxymethyl of 360mg (52%)-2-toluquinoline .LCMS (ESI): 174 (M+H through Combiflash purifying (0-60% ethyl acetate in hexane, 30 minutes) +).
Part 2:4-chloro methyl-2-toluquinoline. make 4-hydroxymethyl-2-toluquinoline (7.0g, 40mmol) be dissolved in the chloroform (150mL), and being cooled to 0 ℃, the slow thionyl chloride (15.0mL) that adds under room temperature makes reaction mixture be warmed to room temperature then and stirring is spent the night.Solvent removed in vacuo is ground residue with ethylacetate/ether, obtain 9.0g (100%) 4-chloro methyl-2-toluquinoline, is HCl salt.MS(ESI)：191.9(M+H +)。
Part 3:N-(4-hydroxy phenyl) carboxylamine tert-butyl ester.Be equipped with magnetic stirring bar and the N that has diaphragm of rubber to exsiccant 2(g) pack in the 250mL round-bottomed flask of socket the 4-amino-phenol (5.0g, 45.8mmol) and THF (50mL).Make this non-even liquid that mixes be cooled to 0 ℃, add then two carbonic acid, two-tert-butyl ester (12g, 55mmol).Add the fashionable heating that can be observed, muddy solution becomes gets transparent.This solution is warmed to room temperature gradually and stirs spend the night.Vacuum is removed volatile matter, obtains N-(4-hydroxy phenyl) carboxylamine tert-butyl ester (11.3g) .LCMS (ESI): 154 (M-t-Bu+2H +), 232 (M+Na +).
Part 4:[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl]-carboxylamine tert-butyl ester.In the 500mL round-bottomed flask that is equipped with magnetic stirring bar, be enclosed in 4-chloro methyl-2-toluquinoline among the DMSO (150mL) (6.84g, 30.0mmol), N-(4-hydroxy phenyl) carboxylamine tert-butyl ester (6.24g, 30.0mmol), Cs 2CO 3(20.0g, 60.0mmol) and n-Bu 4NI (11.1g, 30.0mmol).Stirred this solution 3 hours in 80 ℃.After being cooled to room temperature, add cold water, with the product ethyl acetate extraction.With extract water, the salt water washing that merges, dry and concentrated.Use CH 2Cl 2/ EtOAc carries out the Combiflash chromatography, obtains the required product of 8.0g (73%).MS(ESI)：365.3(M+H +)。
Part 5:4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amine hydrochloride.(1.5g, dioxane (20mL) solution of adding 4N HCl stirred this mixture 3 hours in ethyl acetate 4.1mmol) (5mL) solution under room temperature to [4-(2-methyl-quinolyl-4 methoxyl group)-phenyl]-carboxylamine tert-butyl ester.Add ether then, filtering precipitate with ether washing, obtains the required unhindered amina of 1.3g, is HCl salt, and it need not be further purified and be used for following reaction.MS(ESI)：265.0(M+H +)。
Part 6:5-methoxycarbonyl methylene radical-2-(S)-[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amino formyl radical]-hexahydrobenzoic acid 1-(S)-benzyl ester.Under nitrogen atmosphere, being equipped with in the conical bottle of 10mL of magnetic stirring bar order to baking oven-exsiccant packs into: 4-methoxycarbonyl methylene radical-hexanaphthene-1-(S), 2-(S)-dicarboxylic acid 2-(S)-benzyl ester (172mg, 0.52mmol), dry DMF (4mL), PyBOP reagent (324mg, 0.62mmol), 4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amine hydrochloride (172mg, 0.655mmol) and the 4-methylmorpholine (0.30mL, 2.76mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.Through Combiflash purifying (0-10% methyl alcohol in methylene dichloride, 30 minutes), obtain 267mg (89%) pure products.LCMS(ESI)：579(M+H +)。
Part 7:5-methoxycarbonyl methyl-2-(S)-[4-(2-toluquinoline-4-ylmethoxy)-phenyl amino formyl radical]-hexanaphthene-(S)-carboxylic acid.Methyl alcohol (5mL) solution of benzyl methyl ester (267mg, 0.46) is existed down at 10% palladium on carbon (150mg, 0.14), and hydrogenation is 2 hours under hydrogen bag pressure power.The reaction mixture that obtains is filtered by the Celite pad, and (2 * 5mL) wash with methyl alcohol with throw out.Vacuum is removed volatile matter, obtains the required carboxylic acid of 212mg (94%), is thickness oily matter, need not be further purified and is directly used in the following coupling.LCMS(ESI)：491(M+H +)。
Part 8:{3-(S)-benzyl oxygen base formamyl-4-(S)-[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amino formyl radical]-cyclohexyl }-the acetate methyl ester.Under nitrogen atmosphere; being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: 5-methoxycarbonyl methyl-2-(S)-[4-(2-toluquinoline-4-ylmethoxy)-phenyl amino formyl radical]-hexanaphthene-(S)-carboxylic acid (212mg; 0.43mmol), dry DMF (3mL), PyBOP reagent (320mg; 0.61mmol), O-benzyl hydroxylamine hydrochloride (100mg; 0.627mmol) and the 4-methylmorpholine (0.160mL, 1.47mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.Through Combiflash purifying (0-15% methyl alcohol in methylene dichloride, 30 minutes), obtain the described pure acid amides .LCMS (ESI) of 238mg (93%): 596 (M+H +).
Part 9:{3-(S)-benzyl oxygen base formamyl-4-(S)-[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amino formyl radical]-cyclohexyl }-acetate.To { 3-(S)-benzyl oxygen base formamyl-4-(S)-[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amino formyl radical]-cyclohexyl }-acetate methyl ester (238mg; 0.40mmol) THF (5mL) solution in add entry (3mL) and lithium hydroxide (40mg, 0.95mmol).After stirring 4 hours under the room temperature, use 1N HCl acidified reaction mixture to about pH5.(4 * 5mL) extract, and wash the organic layer that merges with salt solution (5mL), dry (NaSO with ethyl acetate with product 4) and vacuum remove volatile matter, obtain the required carboxylic acid of 210mg (90%), be thickness oily matter, it need not be further purified and be used for following coupled reaction.MS(ESI)：582(M+H +)。
Part 10:4-(2-oxo-2-piperidines-1-base-ethyl)-hexanaphthene-1-(S)-, 2-(S)-dicarboxylic acid 2-(S)-(benzyl oxygen base-acid amides) 1-(S)-{ [4-(2-methyl-quinolyl-4 methoxyl group)-phenyl]-acid amides.Under nitrogen atmosphere; being equipped with in the conical bottle of 5mL of magnetic stirring bar order to baking oven-exsiccant packs into: { 3-(S)-benzyl oxygen base formamyl-4-(S)-[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl amino formyl radical]-cyclohexyl }-acetate (20mg; 0.034mmol), dry DMF (1mL), PyBOP reagent (20mg; 0.038mmol), piperidines (0.010mL; 0.101mmol) and the 4-methylmorpholine (0.01mL, 0.092mmol).With this reaction mixture stir spend the night after, with 5% citric acid (1mL) quencher reactant, reaction mixture is diluted with ethyl acetate (15mL) and water (4mL).With the waterbearing stratum with ethyl acetate (3 * 3mL) extract, with the organic phase that merges with saturated sodium bicarbonate (3 * 5mL), salt solution (5mL) washing, dry (NaSO4) and vacuum concentration.Through Combiflash purifying (0-10% methyl alcohol in methylene dichloride, 30 minutes), obtain the required acid amides of 21mg (95%).LCMS(ESI)：649(M+1H)。
Part 11:4-(2-oxo-2-piperidines-1-base-ethyl)-hexanaphthene-1-(S)-, 2-(S)-dicarboxylic acid 2-(S)-oxyamide 1-{[4-(2-methyl-quinolyl-4 methoxyl group)-phenyl]-acid amides }. with 4-(2-oxo-2-piperidines-1-base-ethyl)-hexanaphthene-1-(S), 2-(S)-dicarboxylic acid 2-(S)-(benzyl oxygen base-acid amides) 1-(S)-{ [4-(2-methyl-quinolyl-4 methoxyl group)-phenyl]-acid amides (18mg, 0.028mmol) methyl alcohol (2mL) solution with being stated from palladium (5%) (40mg on the barium sulfate, 0.018mmol), hydrogenation under hydrogen bag pressure power.Stir after 6 hours, by the Celite pad filter reaction mixture, (2 * 5mL) wash with methyl alcohol with throw out.Vacuum is removed volatile matter, and residue obtains the required hydroxamic acid (hydroxomicacid) of 10mg (64%) through preparation HPLC purifying (acetonitrile solution of gradient 0-40%0.1%TFA to the aqueous solution of 0.1%TFA 30 minutes), is white solid.LCMS(ESI)：559(M+H +)。
Following compound prepares with the method for above-described and example.
Embodiment 54
(2S, 3S, 5R)-and 2-{[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-
N, 5-dihydroxyl piperidines-3-methane amide
(2S, 3S, 5S)-and 2-{[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-
N, 5-dihydroxyl piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 10.MS(ESI)：(M+H) +＝388.3。
Embodiment 55
(2S, 3S, 5R)-and N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
(2S, 3S, 5S)-and N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 10.MS(ESI)：(M+H) +＝349.3.
Embodiment 56
(2S, 3S, 5R)-N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide and (2S, 3S, 5S)-N-hydroxyl-5-(2-morpholine-4-base-2-oxo second
Base)-and 2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝460.3。
Embodiment 57
(2S, 3S, 5S)-and N, 5-dihydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperidines-
The 3-methane amide
(2S, 3S, 5R)-and N, 5-dihydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperazine
Pyridine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 10.MS(ESI)：(M+H) +＝390.2。
Embodiment 58
(2S, 3S, 5R)-and N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide and (2S, 3S, 5S)-N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝501.3。
Embodiment 59
(1S, 2S)-N-hydroxyl-5-[2-(4-methylpiperazine-1-yl)-2-oxoethyl]-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 50.MS(ESI)：(M+H) +＝472.2.
Embodiment 60
(1S, 2S)-N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl)-2-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 50.MS(ESI)：(M+H) +＝459.2.
Embodiment 61
(1S, 2S)-N-hydroxyl-5-{2-[(2-methoxy ethyl) amino]-the 2-oxoethyl }-2-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 50.MS(ESI)：(M+H) +＝447.2。
Embodiment 62
Methyl carbamic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝405.1。
Embodiment 63
Dimethylamino formic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝419.1。
Embodiment 64
Tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝445.1。
Embodiment 65
Piperidines-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝459.2。
Embodiment 66
Morpholine-4-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝461.1。
Embodiment 67
(3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝461.1。
Embodiment 68
The cyclopropyl carboxylamine (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝431.1。
Embodiment 69
(3R, 4S)-N-hydroxyl-1-(morpholine-4-base carbonyl)-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperazine
Pyridine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝445.2。
Embodiment 70
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-the 1-methyl-6-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-base ester and tetramethyleneimine-1-carboxylic acid (3R, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-the 1-methyl-6-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝445.2。
Embodiment 71
(2S, 3S)-2-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-the 3-[(hydroxyl amino) carbonyl]
Piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
Employing prepares this compound with the similar method of method of embodiment 42.MS(ESI)：(M+H) +＝503.3。
Embodiment 72
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } cyclohexyl ester
In-78 ℃, in THF (2mL) solution of 5-oxo-(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-hexanaphthene-(1S)-carboxylic acid benzyl ester (94mg), add THF (1.5mL, 1.0M) solution of L-Selectride.Stirred these solution 30 minutes in-78 ℃, in the impouring frozen water, extract then with ethyl acetate (30mL * 2).With the organic phase MgSO that merges 4Dry.After the removal of solvent under reduced pressure, residue is analyzed through HPLC, is found to be the mixture of 1: 15 ratio of two kinds of isomer.Through silica gel column chromatography, obtain main isomer with 90% yield, find that it is axial-hydroxyl isomer.MS(ESI)：408.1(M+H +)
Adopt the similar method of method with embodiment 37, by pure axially-oxy-compound is initial, prepares these compounds.MS(ESI)：(M+H) +＝430.2。
Embodiment 73
Morpholine-4-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝446.2。
Embodiment 74
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl
Tetramethyleneimine-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝404.2。
Embodiment 75
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝390.2。
Embodiment 76
((1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl }
Cyclohexyl) carboxylamine methyl ester
Part 1: make (4S)-hydroxyl-hexanaphthene-(1S, 2S)-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (320mg) is dissolved among the DCM (5ml).Under room temperature, in the solution that obtains, add triethylamine (1.5eq.0.20ml), then add methylsulfonyl chloride (1.55eq.0.115ml) and DMAP (0.12eq.14mg).Under room temperature, stirred this mixture 3 hours.With the saturated NH of reaction mixture 4The quencher of Cl solution is extracted with ethyl acetate (x2).The extract water, the salt solution that merge are washed in proper order, through MgSO 4Dry.After the filtration, concentrating under reduced pressure filtrate obtains a kind of oily matter, and it is further purified by combi-flash.Obtain quantitative amount of product (400mg).
Part 2: the methanesulfonates compound (390mg) for preparing above is dissolved among the DMF (8.0ml).In this solution, add NaN 3(10eq., 615mg).This mixture in 80 ℃ of heating, is stirred simultaneously and spends the night.After the cooling, with the saturated NaHCO of reactant 3The solution quencher is extracted with ethyl acetate (x2).With extract water (x1), salt solution (x1) washing that merges, through MgSO 4Dry.After the filtration, concentrating under reduced pressure filtrate.The residue that obtains obtains 330mg (95%) trinitride product through the combi-flash purifying.
Part 3: under room temperature, described azide chemical compound (320mg) was stirred 1.5 hours with DCM (2ml)-TFA (2ml) solution.This mixture is concentrated into dried, obtains quantitative corresponding acid.
Part 4: make the acid (100mg) for preparing above be dissolved in DMF (1ml).In this solution, add (R)-3-Phenylpyrrolidine hydrochloride (67mg), then add BOP (153mg).After stirring 5 minutes under the room temperature, in this mixture, add DIEA (0.144ml).The compound of reaction that produces was stirred under room temperature 4 hours.With reactant with saturated KH 2PO 4The solution quencher is extracted with ethyl acetate (x2).With extract water (x1), salt solution (x1) washing that merges; Through MgSO 4Dry.After the filtration, concentrating under reduced pressure filtrate.The residue that obtains is through the combi-flash purifying, obtain 80mg (56%) (5R)-azido--(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-hexanaphthene-(1S)-carboxylic acid benzyl ester.
Part 5: azido cpd (80mg) is dissolved in the mixed solution of methyl alcohol (5ml) and dense HCl (0.1mL) solution.After adding the 10%Pd that is stated from the carbon, under room temperature, nitrogen atmosphere, stirred this mixture 2 hours.Filter reaction mixture, concentrating under reduced pressure obtains corresponding amino acid (60mg) with quantitative yield.
Part 6: acetonitrile (0.4ml) mixture of the amino acid (21mg), carbonochloridic acid methyl ester (6.2mg) and the DIEA (26ul) that prepare above stirred under room temperature spend the night.With 1N HCl solution quencher reactant, use ethyl acetate extraction.With the organic phase salt water washing (x1) that merges, through MgSO 4Dry.After the filtration, concentrating under reduced pressure filtrate obtains (5R)-methoxycarbonyl amino-(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-hexanaphthene-(1S)-carboxylic acid methyl ester.
Part 7: crude product methyl ester and LiOH stirred in THF-water spend the night.Reactant with the acidifying of 1N HCl solution, is used ethyl acetate extraction.With the organic layer (x1) of salt water washing merging, through MgSO 4Dry.After the filtration, concentrating under reduced pressure filtrate obtains the corresponding acid of 14mg (62%, 2 step).
Part 8: the crude acid (14mg), hydroxylamine hydrochloride (8mg), the mixture of BOP (18mg) in DMF (0.2ml) that prepare were above stirred 5 minutes under room temperature.In the mixture that obtains, add DIEA (26ul).Stir after 1.5 hours, reaction mixture generates title compound through the HPLC purifying, is solid (3.1mg, 21%) .MS:M/Z 390.1 (M+H) +801.3 (2M+Na) +357.1 (M-NHOH) +
Embodiment 77
(1S, 2S, 5S)-and N-hydroxyl-5-[(methyl sulphonyl) amino]-2-{[(3R)-the 3-Phenylpyrrolidine-
The 1-yl] carbonyl } cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 76.MS(ESI)：(M+H) +＝410.1。
Embodiment 78
(1S, 2S, 5S)-5-(acetylamino)-N-hydroxyl-2-{[(3R)-3-Phenylpyrrolidine-1-yl]
Carbonyl } cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 76.MS(ESI)：(M+H) +＝374.2。
Embodiment 79
(3R, 4S)-N-hydroxyl-4-[(4-Phenylpiperidine-1-yl) carbonyl]-1-(piperidines-1-base carbonyl) piperazine
Pyridine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝443.2。
Embodiment 80
(3R, 4S)-N-hydroxyl-4-[(4-Phenylpiperidine-1-yl) carbonyl]-1-(tetramethyleneimine-1-base carbonyl)
Piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝429.2。
Embodiment 81
Tetramethyleneimine-1-carboxylic acid (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydro pyrrole
Pyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝443.2。
Embodiment 82
Tetramethyleneimine-1-carboxylic acid (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl) carbonyl
Base] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝445.5。
Embodiment 83
(1S, 2S, 5R)-and N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-oxo-2-piperidines-1-base ethyl) cyclohexane carboxamide and (1S, 2S, 5S)-N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-oxo-2-piperidines-1-base ethyl) cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 50.MS(ESI)：(M+H) +＝498.3。
Embodiment 84
(2S, 3S)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-{[(3R)-3-phenylpyrrole
Alkane-1-yl] carbonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝443.3。
Embodiment 85
(2S, 3S, 5R)-and N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide and (2S, 3S, 5S)-N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝429.3。
Embodiment 86
(2S, 3S)-N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-[(4-phenylpiperazine-1-
Base) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝444.0。
Embodiment 87
(2S, 3S)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝458.2。
Embodiment 88
(2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝472.1。
Embodiment 89
(2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝458.2。
Embodiment 90
(2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-{[(3R)-3-benzene
Base tetramethyleneimine-1-yl] carbonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝457.1。
Embodiment 91
(2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-{[(3R)-3-
Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 2.MS(ESI)：(M+H) +＝443.0。
Embodiment 92
(1S, 2S, 5R)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-
Base) carbonyl] stereoselectivity of cyclohexane carboxamide is synthetic
Under nitrogen atmosphere, being equipped with in the 25mL round-bottomed flask of magnetic stirring bar order to baking oven-exsiccant packs into: (S)-(-)-2,2 '-two (diphenylphosphine)-1,1 '-binaphthylyl bromotoluene (12.5mg, 0.0201mmol), 1, (9.5mg is 0.019mmol) with anhydrous, deoxygenated methyl alcohol (5mL) for 5-cyclooctadiene rhodium chloride (I) dipolymer.The yellow solution that stirring obtains added 4-methoxycarbonyl methylene radical-hexanaphthene-1-(S)-2-(S)-dicarboxylic acid 2-(S)-benzyl ester 1-(S)-tert-butyl ester (135mg, anhydrous, deoxygenated methyl alcohol (3mL) solution 0.348mmol) by sleeve pipe after 1 hour.Use hydrogen purge reaction mixture then, under nitrogen atmosphere, stirred 3 days.Vacuum is removed volatile matter from this non-even phase mixture then, obtains yellow solid.The completely consumed of LCMS data presentation starting raw material forms 30: 70 mixtures of the required product of required product and debenzylation.For required product LCMS (ESI): 413 (M+Na +), 335 (M-t-Bu+2H +), 803 (dipolymer+Na +).Required product LCMS (ESI) for debenzylation: 323 (M+Na +), 227 (M-Ot-Bu), 153 (M-Ot-Bu, CO 2H, OMe ,+2H +), 623 (dipolymer+Na +).
Need not be further purified or analyze, anhydrous acetonitrile (1mL) is joined in this flask, when vigorous stirring, form the out-phase mixture.The dark solid of inferring this suspension is an inorganic byproduct.In this solution, add 1,8-diazabicyclo [5.4.0] 11-7-alkene (50 μ L, 0.33mmol) and bromotoluene (50 μ L, 0.41mmol).The solution that stirring obtains under nitrogen atmosphere 13 hours.Filter this non-even phase mixture by Celite pad, use ethyl acetate (3 * 5mL) washings subsequently.Use then 5% citric acid (2 * 3mL), water (1 * 3mL), salt solution (2 * 3mL) order wash filtrates, dry (Na 2SO 4) and vacuum concentration.Through Combiflash purifying (0-60% ethyl acetate in hexane, 30 minutes), obtain pure product of 91mg (67%) and the pure less important isomer of 10mg (7%).LCMS (ESI): 413 (M+Na +), 335 (M-t-Bu+2H +), 803 (dipolymer+Na +).The chirality HPLC of isomer analyzes and turns out to be optics alcohol, carries out the following NMR experiment absolute stereo chemistry with C4 position that main isomer is described: 1H, COSY, HSQC, HMBC and NOE.
5-(2-oxo-2-piperazine-1-base-ethyl)-2-(S)-(the synthetic residuum of 4-phenyl-Piperazine-1-carbonyl-hexanaphthene-(S)-carboxylic acid hydroxamides carries out according to the universal method of general introduction in above racemic compound (embodiment 50) synthetic.
Embodiment 93
(2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-{[(3R)-the 3-Phenylpyrrolidine-
The 1-yl] carbonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝417.2。
Embodiment 94
(2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(3-phenyl-2,5-dihydro-1H-
Pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝415.2。
Embodiment 95
(2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-phenyl-3, the 6-dihydropyridine-
1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝429.2。
Embodiment 96
(2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-Phenylpiperidine-1-yl) carbonyl
Base] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝431.3。
Embodiment 97
(2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝432.3。
Embodiment 98
(3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-[4-(trifluoro methoxy
Base) benzoyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝506.2。
Embodiment 99
(3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-{[4-(fluoroform
The oxygen base) phenyl] alkylsulfonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝542.0。
Embodiment 100
(3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-[3-(trifluoro methoxy
Base) benzoyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝506.2。
Embodiment 101
(3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-[2-(trifluoro methoxy
Base) benzoyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝506.0。
Embodiment 102
(3R, 4S)-N-hydroxyl-1-[4-(two fluoro methoxyl groups) benzoyl]-4-{[(3S)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 12.MS(ESI)：(M+H) +＝488.2。
Embodiment 103
Tetramethyleneimine-1-carboxylic acid (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-{[(3S)-the 3-Phenylpyrrolidine-
The 1-yl] carbonyl } piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝431.2。
Embodiment 104
Tetramethyleneimine-1-carboxylic acid (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝446.2。
Embodiment 105
Tetramethyleneimine-1-carboxylic acid (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(3-phenyl-2, the 5-dihydro-
1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝429.2。
Embodiment 106
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝487.2。
Embodiment 107
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[(3S)-and 3-Phenylpyrrolidine-1-yl] carbonyl }-5-
[(tetramethyleneimine-1-base carbonyl) oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝489.2。
Embodiment 108
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-Phenylpiperidine-1-yl) carbonyl]-the 5-[(tetramethyleneimine
-1-base carbonyl) oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝503.3。
Embodiment 109
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl
Base]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝501.2。
Embodiment 110
(2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-the 5-[(tetramethyleneimine
-1-base carbonyl) oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝504.3。
Embodiment 111
(2S, 3S)-5-[benzoyl (methyl) amino]-N-hydroxyl-2-[(4-phenyl-3, the 6-dihydropyridine-
1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝463.2。
Embodiment 112
(2S, 3S)-5-[benzoyl (methyl) amino]-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝466.2。
Embodiment 113
(5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-yl }
The methyl carbamic acid isopropyl esters
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝448.3。
Embodiment 114
(5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl)
Carbonyl] piperidines-3-yl } the methyl carbamic acid isopropyl esters
Employing prepares these compounds with the similar method of method of embodiment 6.MS(ESI)：(M+H) +＝445.2。
Embodiment 115
(1S, 2S, 5R)-N, 5-dihydroxyl-2-{[(3R)-3-tetramethyleneimine-1-yl] carbonyl }-5-propyl cyclohexane methane amide and (1S, 2S, 5S)-N, 5-dihydroxyl-2-{[(3R)-3-tetramethyleneimine-1-yl] carbonyl }-5-third
Basic ring hexane methane amide
In 0 ℃, to 5-oxo-(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-hexanaphthene-(1S)-carboxylic acid benzyl ester (120mg, 0.296mMol) dichloromethane solution in add allyl trimethyl silane (0.94mL), (1.48mL, 1.0M is at CH then to be added dropwise to titanium tetrachloride 2Cl 2In).After 20 minutes, make this mixture be warmed to room temperature in 0 ℃ of stir about, stir about is 3 hours under room temperature.In this reactant impouring frozen water, use ethyl acetate extraction.With organic phase water, the salt water washing that merges, then through MgSO 4Dry.After the filtration, concentrating under reduced pressure filtrate.Residue is through the Combiflash purifying, with the methylene dichloride wash-out of 7% methyl alcohol, obtains 5-hydroxyl-(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-5-propyl group-hexanaphthene-(1S)-carboxylic acid benzyl ester, is non-enantiomer mixture (48mg, 37%).
According to the universal method of general introduction in embodiment 25, handle the residuum of synthetic (5R)-5-hydroxyl-(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-5-propyl group-hexanaphthene-(1S)-carboxylic acid hydroxamides and (5S)-5-hydroxyl-(2S)-[(3R)-phenyl-tetramethyleneimine-1-carbonyl]-5-propyl group-hexanaphthene-(1S)-carboxylic acid hydroxamides.Separate this two isomer in final step by HPLC.Ms(ESI)：(M+H) +＝375.2。
Embodiment 116
Methyl carbamic acid (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-
The 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝461.3。
Embodiment 117
Dimethylamino formic acid (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl
Base }-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝475.3。
Embodiment 118
The cyclopropyl carboxylamine (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl
Base }-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝487.3。
Embodiment 119
Tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-
The 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝501.3。
Embodiment 120
(3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-
The 1-yl] carbonyl }-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝517.3。
Embodiment 121
Morpholine-4-carboxylic acid (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-3-
[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝517.3。
Embodiment 122
Piperidines-1-carboxylic acid (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-3-
[(hydroxyl amino) carbonyl] cyclohexyl ester
Employing prepares this compound with the similar method of method of embodiment 37.MS(ESI)：(M+H) +＝515.3。
Embodiment 123
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H +)＝402.1
Embodiment 124
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-two
Pyridinium hydroxide-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H +)＝416.1
Embodiment 125
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H +)＝442.1。
Embodiment 126
(2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Part 1. (S)-2-benzylamino-succsinic acid 1-benzyl ester 4-methyl ester: in 0 ℃, to L-aspartic acid Beta-methyl ester HCl salt (50.00g, 0.2704mol) at acetonitrile (500.00mL, 9.5732mol) in suspension in add 1,8-diazabicyclo [5.4.0] 11-7-alkene (124mL, 0.811mol), follow disposable adding bromotoluene (65.6mL, 0.541mol).Make this reaction mixture be warmed to room temperature, under room temperature, stir and spend the night.The mixture that obtains is concentrated into intimate drying,, removes by filter DBU HCl salt by Celite then with the EtOAc dilution.Concentrating under reduced pressure filtrate.Residue is used in the 0-20%EtOAc wash-out in the hexane through silica gel column chromatography, obtains required product (30.20g, 34.1%).
Part 2. (2S)-2-[benzyl ((2S)-2-hydroxyl-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] Succinic Acid 1-benzyl ester 4-methyl ester: under-78 ℃, nitrogen atmosphere; to (2S)-(+)-glyceryl tosylate (23.0g, toluene (50.4mL) solution of adding 2.00M trimethyl aluminium in 500mL dichloromethane solution 0.101mol).After 10 minutes, in this mixture, add (S)-2-benzylamino-succsinic acid 1-benzyl ester 4-methyl ester (30.0g, 150mL dichloromethane solution 0.0916mol) in-78 ℃ of stirrings.In-78 ℃, the reaction mixture that obtains was stirred 30 minutes.Change the dry ice-propanone bath into ice-water-bath, this mixture is warmed to is up to 0 ℃.Stirred this mixture 30 minutes in 0 ℃.In 0 ℃, in reaction mixture, add Sodium Fluoride (16.2g, 0.385mol), then add entry (10.4mL, 0.577mol).In 0 ℃, the suspension that obtains was stirred 1 hour fast, filter by the diatomite short column, wash post with the 600mL methylene dichloride subsequently.The filtrate that merges is through dried over sodium sulfate, is concentrated into driedly, through column chromatography purification (being used in the 0-20%EtOAc wash-out in the hexane), obtains title compound (46.7g, 91.7%) .MS (ESI): (M+H) +=556.2.
Part 3. (2S)-2-[benzyl ((2S)-2-(1-ethoxy ethoxy)-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] Succinic Acid 1-benzyl ester 4-methyl ester: to 1-benzyl 4-methyl (2S)-2-[benzyl ((2S)-2-hydroxyl-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] succinate (43.0g; 0.0774mol) at methylene dichloride (600.0mL; 9.360mol) in mixture in; add ethyl vinyl ether (14.8mL; 0.155mol); then add right-toluenesulphonic acids pyridine _ (1g, 0.004mol).Under room temperature, stirred this mixture 1 hour, and be concentrated into driedly,, obtain described ether compound (39.7g, 81.7%) through silica gel purification (being used in the 0-20%EtOAc wash-out in the hexane).MS(ESI)：(M+H) +＝628.1。
Part 4. (2S; 3S; 5R)-1-benzyl-5-(1-ethoxy ethoxy) piperidines-2; 3-dicarboxylic acid 2-benzyl ester 3-methyl ester: in-78 ℃; to (2S)-2-[benzyl ((2S)-2-(1-ethoxy ethoxy)-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] Succinic Acid 1-benzyl ester 4-methyl ester (35.7g; 0.0569mol) at tetrahydrofuran (THF) (95.5mL; 1.18mol) and toluene (490mL; 4.6mol) mixed solution in solution in, add tetrahydrofuran (THF) (68.2mL) solution of 1.00M hexamethyldisilane Lithium Azide.Stir these reactants in-78 ℃ and spend the night, be warmed to then and be up to-20 ℃, stirred 3 hours in-20 ℃.After the aqueous ammonium chloride solution quencher, with this mixture ethyl acetate extraction.With the organic layer that the salt water washing merges, drying also is concentrated into dried.Residue is applied on the silicagel column, is used in the 0-20%EtOAc wash-out in the hexane, obtain described product (18.1g, 69.9%).MS(ESI)：(M+H) +＝456.2。Also obtain corresponding diastereomer (4.52g, 17.5%).
Part 5. (2S, 3S, 5R)-1-benzyl-5-hydroxy piperidine-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester: to (2S, 3S, 5R)-1-benzyl-5-(1-ethoxy ethoxy) piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (5.70g, 0.0125mol) 100mL THF solution in add 20mL water, then add 20mL 1N HCl.Under room temperature, stirred this mixture 1 hour.With after the EtOAc dilution,, use the salt water washing, drying with 1N NaOH this mixture that neutralizes.The residue that concentrates the back acquisition is applied on the silica gel, is used in the 0-50%EtOAc wash-out in the hexane, obtain alkylol cpd (4.80g, 89.6%).MS(ESI)：(M+H) +＝384.2。
Part 6. (2S, 3S, 5R)-5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid: with (2S, 3S, 5R)-1-benzyl-5-hydroxy piperidine-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (1.00g, 0.00261mol) mixture in 10mL methyl alcohol is in the presence of 10%Pd/C, and hydrogenation is 3 hours under hydrogen bag pressure power.Behind the filtration catalizer, vacuum concentrated filtrate is directly used in next step to doing.MS(ESI)：(M+H) +＝204.0。
Part 7. (2S, 3S, 5R)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidinyl-1,3-dicarboxylic acid dimethyl esters: in 0 ℃, to (2S, 3S, 5R)-and 5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid (3.140g, 0.01545mol), the 1-phenyl-Piperazine (2.597mL, 0.01700mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (7.518g, 0.01700mol) at N, (10.00mL 0.1291mol) in the mixture in, adds N to dinethylformamide, the N-diisopropylethylamine (3.230mL, 0.01854mol).After stirring under the room temperature was spent the night, (90.0mL, 1.40mol) dilution was cooled to 0 ℃ then with methylene dichloride with reaction mixture.In this mixture, add N, the N-diisopropylethylamine (5.38mL, 0.0309mol), then add the carbonochloridic acid methyl ester (2.39mL, 0.0309mol).Under room temperature, stirred this mixture 2 hours, be concentrated into dried then.With the residue dilute with water, use ethyl acetate extraction.With the organic layer that the salt water washing merges, drying also is concentrated into dried.Residue is used in the 0-100%EtOAc wash-out in the hexane through silica gel purification, obtains title compound (5.20g, 83.0%).MS(ESI)：(M+H) +＝406.1。
Part 8. (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S, 3S, 5R)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (50.0mg, 0.000123mol) tetrahydrofuran (THF) (0.50mL 0.00617mol) in the solution, adds 3-fluoro-phenol (0.0134mL, 0.000148mol), triphenyl phosphine (38.8mg, 0.000148mol), then add azo-2-carboxylic acid's diethyl ester (0.0233mL, 0.000148mol).With this mixture in 70 ℃ of heated overnight.Be concentrated into do after, through this mixture of silica gel purification, be used in the 0-40%EtOAc wash-out in the hexane, to generate phenyl ether compound (27mg, 44%).MS(ESI)：(M+H) +＝500.05。
Part 9. (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (27mg, 0.000054mol) methyl alcohol (0.2189mL, 0.005405mol) in the solution, add methyl alcohol (0.659mL) solution (by corresponding HCl salt and sodium methylate preparation) of 1.640MN-oxyamine.After stirring 1 hour under the room temperature, with this mixture of 1N HCl acidifying.The mixture that obtains directly is applied on the RP-HPLC, obtains product (18mg, 54.5%) into tfa salt.MS(ESI)：(M+H) +＝501.2。
Embodiment 127
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[3-
(trifluoromethyl) phenoxy group] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝551.1。
Embodiment 128
(2S, 3S, 5S)-and 5-(2,4-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝519.0。
Embodiment 129
(2S, 3S, 5S)-and 5-(3-chloro-4-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-benzene
Base piperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝535.0。
Embodiment 130
(2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-the 3-[(hydroxyl amino) carbonyl]-2-[(4-
Phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝518.1。
Embodiment 131
(2S, 3S, 5S)-and 5-(3-bromo phenoxy group)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝561.0。
Embodiment 132
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine
-3-base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝484.1。
Embodiment 133
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline
-6-base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝534.1。
Embodiment 134
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(3-methylphenoxy)-2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝497.1。
Embodiment 135
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(3-methoxyl group phenoxy group)-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝513.1。
Embodiment 136
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-[(6-picoline-2-yl) the oxygen base]-2-[(4-
Phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝498.1。
Embodiment 137
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(4-
Phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝548.15.
Embodiment 138
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝483.2。
Embodiment 139
(2S, 3S, 5S)-and 5-(3-chloro phenoxy group)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝517.0。
Embodiment 140
(2S, 3S, 5S)-and 5-(2,3-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝519.1。
Embodiment 141
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine
-2-base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝484.1。
Embodiment 142
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline
-4-base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝534.1。
Embodiment 143
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine
-4-base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝484.05。
Embodiment 144
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-
Phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝498.2。
Embodiment 145
(2S, 3S, 5S)-and 5-(2-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝501.1。
Embodiment 146
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(2-methylphenoxy)-2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝497.1。
Embodiment 147
(2S, 3S, 5S)-and 5-(4-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝501.1。
Embodiment 148
(2S, 3S, 5S)-and 5-(3,5-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝519.0。
Embodiment 149
(2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝519.0。
Embodiment 150
(2S, 3S, 5S)-and 5-(1,3-benzothiazole-2-base oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-
Phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝540.1。
Embodiment 151
(2S, 3S, 5S)-and 5-(3,4-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝519.0。
Embodiment 152
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl
Base]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide
Part 1. (2S, 3S, 5R)-5-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester: with (2S, 3S, 5R)-5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid (1.851g, 0.009110mol), 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (2.14g, 0.0109mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphates (4.83g, 0.0109mol) at N, dinethylformamide (15.0mL, 0.194mol) in mixture under room temperature, stirred 5 minutes, use N then under room temperature, (3.81mL 0.0219mol) handled 2 hours the N-diisopropylethylamine.(10.0mL 0.156mol) dilutes with methylene dichloride with reaction mixture.The mixture N that obtains then, (3.17mL 0.0182mol) handles the N-diisopropylethylamine, and then (3.98g, 0.0182mol) processing is spent the night with two dimethyl dicarbonate butyl esters under room temperature.With the reactant dilute with water, extract with EtOAc.With the organic layer salt water washing that merges, dry and vacuum concentration is extremely done.Residue is put on the silica gel, be used in the 0-80%EtOAc wash-out in the hexane, obtain title compound (2.10g, 51.9%).MS(ESI)：(M+H-Boc) +＝345.1。
Part 2. (2S, 3S, 5S)-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester: to (2S, 3S, 5R)-5-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (100mg, 0.0002mol) tetrahydrofuran (THF) (0.912mL 0.0112mol) in the solution, adds 4-pyridine alcohol (25.7mg, 0.000270mol), triphenyl phosphine (70.8mg, 0.000270mol), then add azo-2-carboxylic acid's diisopropyl ester (0.0532mL, 0.000270mol).Stir this mixture overnight in 70 ℃.Be concentrated into do after, through this mixture of silica gel purification, be used in the 0-40%EtOAc wash-out in the hexane, obtain required ether compound (56mg, 50%).MS(ESI)：(M+H) +＝522.1。
Part 3. (2S, 3S, 5S)-and 1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-carboxylic acid methyl ester: under room temperature, with trifluoroacetic acid (1.0mL, 0.013mol) processing (2S, 3S, 5S)-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.09g, 0.0002mol) 1 hour.Be concentrated into this mixture dried then.Make the crude product secondary amine for preparing above be dissolved in tetrahydrofuran (THF) (0.80mL, 0.0099mol) and acetonitrile (0.80mL, 0.015mol) in.With this mixture N, (0.061mL 0.00035mol) handles to regulate pH to about 7 the N-diisopropylethylamine then.The aqueous solution (0.071mL) that in the mixture that obtains, adds 12.32M formaldehyde then, then add sodium triacetoxy borohydride (180mg, 0.00087mol).After stirring under the room temperature is spent the night, this mixture vacuum concentration to doing, with the sodium bicarbonate aqueous solution dilution, is extracted with EtOAc.With the organic layer that the salt water washing merges, dry and vacuum-evaporation is extremely done.Residue is exposed in the high vacuum, is directly used in next step then.MS(ESI)：(M+H) +＝436.1。
Part 4. (2S, 3S, 5S)-N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide: to (2S, 3S, 5S)-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-carboxylic acid methyl ester (70mg, 0.0002mol) methyl alcohol (0.6674mL, 0.01648mol) in the solution, add methyl alcohol (2.01mL) solution (by corresponding HCl salt and sodium methylate preparation) of 1.640M N-oxyamine.After stirring 1 hour under the room temperature, with this mixture of 1N HCl acidifying.The mixture that obtains is directly carried out RP-HPLC, obtain product, be tfa salt (56mg, 63.4%).MS(ESI)：(M+H) +＝437.1。
Embodiment 153
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-the 2-[(4-phenyl-
3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝451.1。
Embodiment 154
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-phenoxy group-2-[(4-phenyl-3, the 6-dihydropyridine-
1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝436.0。
Embodiment 155
(2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝454.1。
Embodiment 156
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl
Base]-5-(quinoline-6-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝487.0。
Embodiment 157
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-toluquinoline-4-yl) the oxygen base]-the 2-[(4-phenyl-
3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝501.1。
Embodiment 158
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl
Base]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝437.0。
Embodiment 159
(2S, 3S, 5S)-and 5-(3,5-phenyl-difluoride oxygen base)-N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-two
Pyridinium hydroxide-1 (2H)-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝472.1。
Embodiment 160
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl
Base]-5-(quinolyl-4 oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝486.9.
Embodiment 161
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridine-4-
Base oxygen base) piperidines-3-methane amide (1a).
With (2S, 3S, 5S)-N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide tfa salt (4mg, 0.00001mol) mixture in 1mLMeOH is in the presence of 5%Pd/BaSO4, hydrogenation is 2 hours under hydrogen bag pressure power.Behind the filtration catalizer, filtrate is concentrated into dried, obtains title compound (4mg, 100%).MS(ESI)：(M+H) +＝439.2。
Embodiment 162
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-4-yl) oxygen
Base]-2-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 161.MS(ESI)：(M+H) +＝507.2。
Embodiment 163
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-the 2-[(4-phenyl
Piperidines-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 161.MS(ESI)：(M+H) +＝453.0。
Embodiment 164
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridine-2-
Base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 161.MS(ESI)：(M+H) +＝439.1。
Embodiment 165
(2S, 3S, 5S)-N-hydroxyl-1-(methyl sulphonyl)-5-phenoxy group-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝503.2。
Embodiment 166
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝539.2。
Embodiment 167
(2S, 3S, 5S)-and 5-(2-bromo phenoxy group)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝562.2。
Embodiment 168
(2S, 3S, 5S)-and 5-(2-chloro phenoxy group)-3-[(hydroxyl amino) carbonyl]-the 2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝517.2。
Embodiment 169
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝553.2。
Embodiment 170
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-1-carboxylic acid ethyl ester
Employing prepares these compounds with the similar method of method of embodiment 126.MS(ESI)：(M+H) +＝497.2。
Embodiment 171
(2S, 3S, 5S)-and N-hydroxyl-5-(3-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperazine
Pyridine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝439.1。
Embodiment 172
(2S, 3S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[3-(trifluoromethyl) benzene
The oxygen base] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝493.2。
Embodiment 173
(2S, 3S, 5S)-and 5-(3-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperazine
Pyridine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝459.2。
Embodiment 174
(2S, 3S, 5S)-and N-hydroxyl-5-(3-methoxyl group phenoxy group)-2-[(4-phenylpiperazine-1-yl) carbonyl]
Piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝455.0。
Embodiment 175
(2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperazine
Pyridine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H) +＝443.2。
Embodiment 176
Piperidines-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-
Dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Part 1. (2S)-2-[benzyl ((2R)-2-hydroxyl-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] Succinic Acid 1-benzyl ester 4-methyl ester: under-78 ℃, nitrogen atmosphere; to (2R)-oxyethane-2-ylmethyl 4-toluene sulfonic acide ester (23.0g; 0.101mol) the 500mL dichloromethane solution in, add toluene (50.4mL) solution of 2.000M trimethyl aluminium.Stirred adding (S)-2-benzylamino-succsinic acid 1-benzyl ester 4-methyl ester (30.0g, 150mL dichloromethane solution 0.0916mol) in this mixture 10 minutes in-78 ℃.The reaction mixture that obtains was stirred 30 minutes in-78 ℃.Ice-water-bath is replaced by in the dry ice-propanone bath, this mixture is warmed to is up to 0 ℃.Stirred this mixture 30 minutes in 0 ℃.In reaction mixture, add Sodium Fluoride (16.2g, 0.385mol), then in 0 ℃ add entry (10.4mL, 0.577mol).Stirred fast the suspension that obtains 1 hour in 0 ℃, filter, use 600mL dichloromethane rinse post subsequently by the diatomite short column.The filtrate that merges is through dried over sodium sulfate, is concentrated into driedly, through column chromatography purification (being used in the 0-30%EtOAc wash-out in the hexane), obtains title compound (43.0g, 84.4%).MS(ESI)：(M+H) +＝556.1。
Part 2. (2S)-2-[benzyl ((2R)-2-(1-ethoxy ethoxy)-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino) Succinic Acid 1-benzyl ester 4-methyl ester: to (2S)-2-[benzyl ((2R)-2-hydroxyl-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] Succinic Acid 1-benzyl ester 4-methyl ester (43.0g; 0.0774mol) methylene dichloride (500.0mL; 7.800mol) in the solution; add ethyl vinyl ether (15.0mL; 0.157mol); then add right-toluenesulphonic acids pyridine _ (4.0g, 0.016mol).Under room temperature, stir this mixture 3g.Be concentrated into do after, residue obtains ether compound (38.1g, 78.4%) through silicagel column purifying (being used in the 0-20%EtOAc wash-out in the hexane).MS(ESI)：(M+H) +＝628.1。
Part 3. (2S; 3S; 5S)-1-benzyl-5-(1-ethoxy ethoxy) piperidines-2; 3-dicarboxylic acid 2-benzyl ester 3-methyl ester: in-78 ℃; to (2S)-2-[benzyl ((2R)-2-(1-ethoxy ethoxy)-3-[(4-aminomethyl phenyl) alkylsulfonyl] oxygen base propyl group) amino] Succinic Acid 1-benzyl ester 4-methyl ester (34.30g; 0.05464mol) at tetrahydrofuran (THF) (90.0mL; 1.11mol) and toluene (470.0mL; 4.412mol) mixed solution in solution in, add tetrahydrofuran (THF) (65.6mL) solution of 1.00M hexamethyldisilane base Lithium Azide.The mixture that obtains is spent the night in-78 ℃ of stirrings, be warmed to gradually then and be up to 0 ℃, stirred 30 minutes in 0 ℃.After the aqueous ammonium chloride solution quencher, with this mixture of ethyl acetate extraction.With organic layer water, the salt water washing that merges, dry (sodium sulfate) and be concentrated into dried.Residue is used in the 0-20%EtOAc wash-out in the hexane through purification by silica gel column chromatography, obtains cyclisation product (19.47g, 78.2%).MS(ESI)：(M+H) +＝456.0。
Part 4. (2S, 3S, 5S)-1-benzyl-5-hydroxy piperidine-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester: to (2S, 3S, 5S)-1-benzyl-5-(1-ethoxy ethoxy) piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (3.80g, 0.00834mol) 67mL THF solution in add 13mL water, then add 13mL 1N HCl.Under room temperature, stirred this mixture 1 hour.With after the ethyl acetate dilution,, use the salt water washing, drying with 1N NaOH this mixture that neutralizes.Residue after concentrating is used in the 0-50%EtOAc wash-out in the hexane through column chromatography purification, generates corresponding alkylol cpd (2.90g, 90.6%).MS(ESI)：(M+H) +＝384.1。
Part 5. (2S, 3S, 5S)-5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid: with (2S, 3S, 5S)-1-benzyl-5-hydroxy piperidine-2, (2.00g, 30mL methanol solution 0.00522mol) are in the presence of 10%Pd/C, and hydrogenation is spent the night under hydrogen bag pressure power for 3-dicarboxylic acid 2-benzyl ester 3-methyl ester.Behind the filtration catalizer, filtrate is concentrated into dried, is directly used in next step.
Part 6. (2S, 3S, 5S)-5-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-carboxylic acid methyl ester: with (2S, 3S, 5S)-5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid (0.309g, 0.00152mol), 4-phenyl-1,2,3, and 6-tetrahydropyridine hydrochloride (0.357g, 0.00182mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (0.807g, 0.00182mol) at N, dinethylformamide (2.50mL, 0.0323mol) mixture in stirred under room temperature 5 minutes, used N then under room temperature, (0.636mL 0.00365mol) handled 2 hours the N-diisopropylethylamine.With acetonitrile (5.0mL, 0.096mol) and tetrahydrofuran (THF) (5.0mL, 0.062mol) diluted reaction mixture.The aqueous solution (0.41mL) that in this mixture, adds 12.32M formaldehyde, then add sodium triacetoxy borohydride (1.1g, 0.0051mol).In stir under the room temperature spend the night after, this mixture is concentrated into dried, with the sodium bicarbonate aqueous solution dilution, extract then with EtOAc.With the organic layer that the salt water washing merges, drying also is concentrated into dried.Residue is put on the silica gel, be used in the 0-100%EtOAc wash-out in the hexane, obtain methylamine compound (0.31g, 85%).MS(ESI)：(M+H) +＝358.1。
Part 7. piperidines-1-carboxylic acid (3S, 5S, 6S)-5-(methoxycarbonyl)-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester: under room temperature, use N, (50mg 0.0003mol) handles (2S, 3S to the N-carbonyl dimidazoles, 5S)-5-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] (72mg, (2.0mL, 0.031mol) solution is 2 hours for methylene dichloride 0.00020mol) for piperidines-3-carboxylic acid methyl ester.In this mixture, add piperidines (0.060mL, 0.00060mol).In stir under the room temperature spend the night after, this mixture is concentrated into dried, and be directly used in next step.
Part 8. piperidines-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester: to piperidines-1-carboxylic acid (3S, 5S, 6S)-5-(methoxycarbonyl)-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester (94mg, 0.00020mol) methyl alcohol (0.8109mL, 0.02002mol) in the solution, add the methanol solution (2.44mL) (by corresponding salt and sodium methylate preparation) of 1.640M N-oxyamine.After stirring 1 hour under the room temperature, with this mixture of 1N HCl acidifying.The mixture that obtains is directly carried out RP-HPLC, obtain product (56mg, 48%) as tfa salt.MS(ESI)：(M+H) +＝471.1。
Embodiment 177
(2S)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝487.15。
Embodiment 178
Azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl
-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝485.2。
Embodiment 179
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-benzene
Base-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝443.2。
Embodiment 180
Dimethylamino formic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl
-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝431.1。
Embodiment 181
2,5-dihydro-1H-pyrroles-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-
[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝455.1。
Embodiment 182
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-
3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝457.1。
Embodiment 183
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-benzene
Base piperazine-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝446.2。
Embodiment 184
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(3-benzene
Base-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝429.2。
Embodiment 185
Azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-benzo [e] isoindole-2-base
Carbonyl)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl piperidine-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝453.2。
Embodiment 186
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝460.2。
Embodiment 187
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-the 1-methyl-6-[(3R)-
3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝431.2。
Embodiment 188
Piperidines-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine
-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝474.2。
Embodiment 189
Azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-isoindole-2-base carbonyl)-
The 5-[(hydroxyl amino) carbonyl]-1-methyl piperidine-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝403.2。
Embodiment 190
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(3-phenyl-
2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 176.MS(ESI)：(M+H) +＝443.05.
Embodiment 191
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl piperazine
Pyridine-1-yl) carbonyl] piperidines-3-base ester
With tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester (5.0mg, 0.000011mol) the 1mL MeOH solution of tfa salt is in the presence of 5%Pd/BaSO4, hydrogenation is 2 hours under hydrogen bag pressure power.Behind the filtration catalizer, filtrate is concentrated into dried, obtains product (5.0mg, 100%).MS(ESI)：(M+H) +＝459.15。
Embodiment 192
Azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl
Piperidines-1-yl) carbonyl] piperidines-3-base ester.
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝487.2。
Embodiment 193
(2S)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-
Methyl-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝489.2。
Embodiment 194
Piperidines-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-Phenylpiperidine
-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝473.2。
Embodiment 195
Dimethylamino formic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl
Piperidines-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝433.1。
Embodiment 196
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-([(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl]
The ketonic oxygen base)-and 2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Part 1. (2S, 3S, 5S)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: in 0 ℃, to (2S, 3S, 5S)-5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid (1.10g, 0.00541mol), the 1-phenyl-Piperazine (0.910mL, 0.00595mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (2.63g, 0.00595mol) at N, (6.00mL 0.0775mol) in the mixture in, adds N to dinethylformamide, the N-diisopropylethylamine (1.04mL, 0.00595mol).Under room temperature, stirred this reactant 3 hours.In 0 ℃, in reaction mixture, add methylene dichloride (40.00mL, 0.6240mol), DMAP, the N of catalytic amount, the N-diisopropylethylamine (2.36mL, 0.0135mol), then add the carbonochloridic acid methyl ester (0.836mL, 0.0108mol).The reaction mixture that obtains stirred under room temperature spend the night.After the water quencher, with this mixture of ethyl acetate extraction.With the organic layer that the salt water washing merges, drying also is concentrated into dried.Residue is used in the 0-100%EtOAc wash-out in the hexane through silica gel purification, obtains title compound (1.88g, 85.7%).MS(ESI)：(M+H) +＝406.2。
Part 2. (2S, 3S, 5S)-5-([(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] the ketonic oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S, 3S, 5S)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (0.050g, methylene dichloride (1.00mL 0.00012mol), 0.0156mol) solution in, add N, and the N-carbonyl dimidazoles (0.024g, 0.0001480mol).Under room temperature, stirred this reactant 2 hours.(0.01704mL 0.0001726mol), stirs this reactant and spends the night under room temperature to add L-dried meat ammonia alcohol (prolinol) to the mixture that obtains.This mixture is concentrated into dried, it is directly used in next step.MS(ESI)：(M+H) +＝533.2。
Part 3. (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-([(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] the ketonic oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-5-([(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] the ketonic oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (66mg, 0.00012mol) methyl alcohol (0.57mL, 0.014mol) in the solution, add the methanol solution (1.511mL) (by azanol HCl salt and the preparation of new system sodium methylate) of 1.640M N-oxyamine.Under room temperature, stirred this mixture 1 hour, with 1N HCl acidifying.The mixture that obtains is directly carried out RP-HPLC, obtain required compound (61mg, 76%).MS(ESI)：(M+H) +＝534.2。
Embodiment 197
(2S, 3S, 5S)-and 2-(1,3-dihydro-2H-isoindole-2-base carbonyl)-3-[(hydroxyl amino) carbonyl]-
5-[(tetramethyleneimine-1-base carbonyl) oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 196.MS(ESI)：(M+H) +＝461.2。
Embodiment 198
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-the 5-[(piperazine
Pyridine-1-base carbonyl) oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 196.MS(ESI)：(M+H) +＝518.15。
Embodiment 199
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-the 5-[(pyrrole
Cough up alkane-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 196.MS(ESI)：(M+H) +＝504.2。
Embodiment 200
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(3-Phenylpyrrolidine-1-yl) carbonyl]-
5-[(tetramethyleneimine-1-base carbonyl) oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 196.MS(ESI)：(M+H) +＝489.2。
Embodiment 201
(2S, 3S, 5S)-and the 5-[(dimethylamino) carbonyl] oxygen base-3-[(hydroxyl amino) carbonyl]-2-[(4-
Phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 196.MS(ESI)：(M+H) +＝478.1。
Embodiment 202
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl)
Carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 196.MS(ESI)：(M+H) +＝501.2。
Embodiment 203
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-Phenylpiperidine-1-yl) carbonyl]-the 5-[(pyrrole
Cough up alkane-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝503.2。
Embodiment 204
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Part 1. (2S, 3S, 5S)-and 1-benzyl-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester: to (2S, 3S, 5S)-1-benzyl-5-hydroxy piperidine-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (144mg, (2.0mL 0.031mol) adds N to methylene dichloride 0.000376mol) in the solution, the N-carbonyl dimidazoles (73.1mg, 0.000451mol).Under room temperature, stirred this reactant 2 hours.(0.0470mL 0.000563mol), stirs this reactant and spends the night under room temperature to add tetramethyleneimine in the mixture that obtains.With the quencher of reactant carbonic acid hydrogen sodium water solution, use dichloromethane extraction.The dry organic layer that merges through silica gel purification (being used in the 0-40%EtOAc wash-out in the hexane), obtains carbamate compounds (160mg, 88.7%).MS(ESI)：(M+H) +＝481.2。
Part 2. (2S, 3S, 5S)-and 3-(methoxycarbonyl)-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-2-carboxylic acid: with (2S, 3S, 5S)-and 1-benzyl-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (144mg, methyl alcohol (3.0mL 0.000300mol), 0.074mol) solution is in the presence of 10%Pd/C, hydrogenation is spent the night under hydrogen bag pressure power.Behind the filtration catalizer, filtrate is concentrated into dried, obtains the crude product product, it is directly used in next step.
Part 3. (2S, 3S, 5S)-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-3-carboxylic acid methyl ester: under room temperature, to (2S, 3S, 5S)-and 3-(methoxycarbonyl)-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-2-carboxylic acid (90.1mg, 0.000300mol) and 4-phenyl-1,2,3,6-tetrahydropyridine (64.6mg, 0.000330mol) HCl salt, benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphates (146mg, 0.000330mol) at N, dinethylformamide (0.44mL, 0.0057mol) in mixture in, add N, and the N-diisopropylethylamine (0.115mL, 0.000660mol).Under room temperature, stir this mixture overnight, use the sodium bicarbonate aqueous solution quencher then.After separating organic layer, extract water layer with EtOAc.With the organic layer that the salt water washing merges, dry and be concentrated into dried.The crude product raw material is directly used in next step.
Part 4. tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester: with N-hydroxy amine hydrochloric acid salt (1.20g, 0.0173mol) mixture heating up to 55 in 4.5mL methyl alcohol ℃.Add the sodium methylate (methanol solution of 25wt.% (5.925mL, 0.06506mol)).The mixture that obtains was stirred 5 minutes in 55 ℃, be cooled to room temperature then, be cooled to 0 ℃ then.Remove by filter insolubles, obtain settled solution, be estimated as the MeOH solution of about 1.64M oxyamine.Preparing this solution and new system uses.
The solution of the above-mentioned preparation of 1.90mL is joined crude product (2S, 3S, 5S)-and 2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] (132.5mg is 0.0003001mol) in the mixture in 1.43mL methyl alcohol for piperidines-3-carboxylic acid methyl ester.Under room temperature, stirred 1 hour, this mixture is adjusted to pH7 with 1N HCl (about 1.9mL).The mixture that obtains is directly carried out RP-HPLC, obtain target product (65mg, 39%).MS(ESI)：(M+H) +＝443.2。
Embodiment 205
Azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-benzo [e] isoindole-2-base
Carbonyl)-and the 5-[(hydroxyl amino) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)：(M+H) +＝439.2。
Embodiment 206
Azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-isoindole-2-base carbonyl)-
The 5-[(hydroxyl amino) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)：(M+H) +＝389.2。
Embodiment 207
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-
Dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)：(M+H) +＝429.2。
Embodiment 208
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(3R)-the 3-phenyl
Tetramethyleneimine-1-yl] carbonyl piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)：(M+H) +＝417.2。
Embodiment 209
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-the 6-[(4-phenylpiperazine
-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)：(M+H) +＝432.2。
Embodiment 210
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(3-phenyl-2,5-
Dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)：(M+H) +＝415.2。
Embodiment 211
Azetidine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-the 6-[(4-Phenylpiperidine
-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝431.3。
Embodiment 212
Tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl)
Carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝445.2。
Embodiment 213
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(2-oxo-2-tetramethyleneimine-1-base oxethyl)-
2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
Part 1. (2S, 3S, 5S)-and 5-(uncle 2--butoxy-2-oxo oxyethyl group)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S, 3S, 5S)-5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (50.0mg, 0.000123mol) tetrahydrofuran (THF) (0.50mL 0.0062mol) adds tetrahydrofuran (THF) (0.150mL) solution of uncle 1.00M-butanols potassium in the solution.Under room temperature, stirred 30 minutes, in this mixture, add bromo-acetate 1, and 1-dimethyl ethyl ester (0.0228mL, 0.000154mol).The mixture that obtains stirred under room temperature spend the night, be concentrated into dried then.
Part 2. ((3S, 5S, 6S)-1, two (methoxycarbonyl)-6-[(4-phenylpiperazines of 5--1-yl) carbonyl] piperidines-3-base oxygen base) acetate: under room temperature, the crude mixture for preparing above with 1mL TFA processing 30 minutes.Be concentrated into do after, thick residue can be directly used in next step.
Part 3. (2S, 3S, 5S)-and 5-(2-oxo-2-tetramethyleneimine-1-base oxethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to ((3S, 5S, 6S)-1, two (the methoxycarbonyl)-6-[(4-phenylpiperazines of 5--1-yl) carbonyl] piperidines-3-base oxygen base) acetate (57mg, 0.00012mol), tetramethyleneimine (0.0308mL, 0.000369mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (163mg, 0.000369mol) N, (0.50mL 0.0064mol) in the mixture in, adds N to dinethylformamide, the N-diisopropylethylamine (0.0857mL, 0.000492mol).Under room temperature, stirred this mixture 2 hours, then with the ethyl acetate dilution, water, salt water washing and dry.Be concentrated into do after, residue can be directly used in next step.
Part 4. (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(2-oxo-2-tetramethyleneimine-1-base oxethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-and 5-(2-oxo-2-tetramethyleneimine-1-base oxethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (64mg, 0.00012mol) at methyl alcohol (0.5018mL, 0.01239mol) reaction mixture in, add the methanol solution (1.51mL) (by corresponding salt and sodium methylate preparation) of 1.640M N-oxyamine.After stirring 1 hour under the room temperature, with this mixture of 1N HCl acidifying.The mixture that obtains is directly carried out RP-HPLC, obtain product (14mg, 18%) as tfa salt.MS(ESI)：(M+H) +＝518.2。
Embodiment 214
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(benzene sulphur
Base) piperidines-1-carboxylic acid methyl ester
Part 1. (2S; 3S, 5R)-the 5-[(methyl sulphonyl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S; 3S; 5R)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (1.00g, 0.00247mol) and triethylamine (0.412mL; 0.00296mol) methylene dichloride (20.00mL; 0.3120mol) stirred solution in, add methylsulfonyl chloride (0.210mL, 0.00271mol).Under room temperature, stir this mixture overnight.After the MeOH quencher, this mixture vacuum-evaporation to doing, is diluted with ethyl acetate.With organic layer water, salt water washing and dry, be concentrated into dried.Residue is used in the 0-80%EtOAc wash-out in the hexane through the silica gel column chromatography purifying, generates methanesulfonates compound (0.98g, 82%).MS(ESI)：(M+H) +＝484.1。
Part 2. (2S; 3S; 5S)-and 2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(thiophenyl) piperidines-1; 3-dicarboxylic acid dimethyl esters: to (2S; 3S; 5R)-and the 5-[(methyl sulphonyl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1; 3-dicarboxylic acid dimethyl esters (50.0mg; 0.000103mol) and thiophenol (0.0149mL; 0.000145mol) at tetrahydrofuran (THF) (0.50mL; 0.0062mol) in mixture in, add the tetrahydrofuran solution (0.150mL) of uncle 1.00M-butanols potassium.Under room temperature, stir the mixture and spend the night.This reaction mixture is directly used in next step.
Part 3. (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(thiophenyl) piperidines-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-and 2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(thiophenyl) piperidines-1, (51mg is 0.00010mol) at tetrahydrofuran (THF) (0.50mL for 3-dicarboxylic acid dimethyl esters, 0.0062mol) reaction mixture in, add the methanol solution (1.25mL) (by corresponding salt and sodium methylate preparation) of 1.640M N-oxyamine.Under room temperature, stirred 1 hour, with this mixture of 1N HCl acidifying.The mixture that obtains is directly carried out RP-HPLC, obtain product (39mg, 63%) as tfa salt.MS(ESI)：(M+H) +＝499.1。
Embodiment 215
(2S, 3S, 5S)-and 5-(allyl group oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-
Base) carbonyl] piperidines-1-carboxylic acid methyl ester
Part 1. (2S, 3S, 5S)-and 5-[(allyl group oxygen base) carbonyl] oxygen base-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S, 3S, 5S)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (0.1000g, 0.0002466mol) methylene dichloride (1.00mL, 0.0156mol) in the solution, add triethylamine (0.04469mL, 0.0003206mol), the DAMP of catalytic amount, then add the carbonochloridic acid allyl ester (0.03146mL, 0.0002960mol).Under room temperature, stir this mixture overnight, use the sodium bicarbonate aqueous solution quencher then, use dichloromethane extraction.The dry organic layer that merges also is concentrated into dried.Residue is purifying on post, is used in the 0-100%EtOAc wash-out in the hexane, obtains corresponding carbonic ether (0.11g, 91%).MS(ESI)：(M+H) +＝490.2。
Part 2. (2S, 3S, 5S)-and 5-(allyl group oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: will (2S, 3S, 5S)-and 5-[(allyl group oxygen base) carbonyl] oxygen base-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (100mg, 0.0002mol) and four (triphenyl phosphine) palladium (O) (24mg, 0.000020mol) (5.00mL, the mixture in 0.0616mol) refluxed 2 hours at tetrahydrofuran (THF).This mixture is concentrated into dried, is directly used in next step.
Part 3. (2S, 3S, 5S)-and 5-(allyl group oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-and 5-(allyl group oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (80mg, 0.0002mol) methyl alcohol (0.79mL, 0.020mol) in the solution, add methyl alcohol (2mL) solution (by handle corresponding azanol HCl salt preparation with sodium methylate) of 1.640M N-oxyamine.Under room temperature, stirred this mixture 1 hour, use 1N HCl acidifying then, directly carry out RP-HPLC, obtain title compound, be tfa salt (23mg, 23%).MS(ESI)：(M+H) +＝447.1。
Embodiment 216
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-third oxygen
Phenylpiperidines-1-carboxylic acid methyl ester
Employing prepares these compounds with the similar method of method of embodiment 191.MS(ESI)：(M+H) +＝449.2。
Embodiment 217
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] piperidines-1-carboxylic acid methyl ester
Part 1. (2S, 3S, 5S)-1-benzyl-5-methoxyl group piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester: preparation diazomethane (deriving from 5g Diazald), then with ether distill (2S, 3S, 5S)-1-benzyl-5-hydroxy piperidine-2, (0.60g is 0.0016mol) and in the mixture in the 10mL ether of about 1g silica gel for 3-dicarboxylic acid 2-benzyl ester 3-methyl ester.After the distillation, this mixture stirred under room temperature spend the night.Mixture is diluted with methylene dichloride, remove by filter silica gel.Filtrate is concentrated into dried, the residue that obtains is put on the post, be used in the 0-40%EtOAc wash-out in the hexane, obtain methyl etherified compound (20mg, 3.2%).MS(ESI)：(M+H) +＝398.1。
Part 2. (2S, 3S, 5S)-5-methoxyl group-3-(methoxycarbonyl) piperidines-2-carboxylic acid: with (2S, 3S, 5S)-1-benzyl-5-methoxyl group piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (30.0mg, 2mL MeOH solution 0.0000755mol) is in the presence of 10%Pd/C, and hydrogenation is 1 hour under hydrogen bag pressure power.Remove by filter catalyzer, filtrate is concentrated into dried.Residue is directly used in next step (16mg, 97.6%).MS(ESI)：(M+H) +＝218.0。
Part 3. (2S, 3S, 5S)-and 5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-carboxylic acid methyl ester: to (2S, 3S, 5S)-5-methoxyl group-3-(methoxycarbonyl) piperidines-2-carboxylic acid (14.0mg, 0.0000644mol), 1-phenyl-Piperazine (0.01231mL, 8.056E-5mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (35.63mg, 8.056E-5mol) at N, (0.20mL 0.0026mol) in the mixture in, adds N to dinethylformamide, the N-diisopropylethylamine (0.01403mL, 8.056E-5mol).Under room temperature, stirred this mixture 2 hours.After the water quencher, with this mixture of ethyl acetate extraction.With the organic layer salt water washing that merges, drying also is concentrated into dried.Residue need not be further purified, and is directly used in next step.MS(ESI)：(M+H) +＝362.1。
Part 4. (2S, 3S, 5S)-and 5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S, 3S, 5S)-and 5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-carboxylic acid methyl ester (0.0233g, 0.0000645mol) and 4-dimethylaminopyridine (0.0118g, 0.0000967mol) (1.00mL is 0.0156mol) in the mixture at methylene dichloride, adding carbonochloridic acid methyl ester (0.00648mL, 0.0000838mol).Stirring this reactant under room temperature spends the night.After the sodium bicarbonate aqueous solution quencher, with the reactant ethyl acetate extraction.With the organic layer that the salt water washing merges, dry, be concentrated into dried.The residue that obtains is directly used in next step.MS(ESI)：(M+H) +＝420.2。
Part 5. (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidinyl-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-and 5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (0.027g, methyl alcohol (0.30mL 0.000064mol), 0.0074mol) in the solution, add methyl alcohol (0.7850mL) solution (corresponding azanol HCl salt and sodium methylate prepared fresh are arranged) of 1.640M N-oxyamine.Under room temperature, stir this mixture 1 hour, use 1N HCl acidifying then.Crude mixture is directly carried out RP-HPLC, obtain product (23mg, 68%) as tfa salt.MS(ESI)：(M+H) +＝421.2。
Embodiment 218
(2S, 3S, 5S)-and uncle 5--butoxy-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-
Methane amide
Part 1. (2S, 3S, 5S)-1-benzyl-uncle 5--butoxy piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester: in-78 ℃ collect iso-butylenes (2.96mL, 0.0313mol).In cold iso-butylene, add (2S, 3S, 5S)-1-benzyl-5-hydroxy piperidine-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (0.60g, 0.0016mol), tetrahydrofuran (THF) (3.00mL, 0.0370mol), sulfuric acid (0.021mL, 0.00039mol).Sealed reactor makes to be warmed to room temperature, stirs under room temperature and spends the night.Mixture is cooled to once more-78 ℃.Replace closure with the barrier film that is connected with air bag.Then reactant is warmed to room temperature gradually, to evaporate excessive iso-butylene.Residue is diluted with EtOAc, neutralize with aqueous sodium hydroxide solution.With organic layer salt water washing, drying.Residue is used in the 0-30%EtOAc wash-out in the hexane through silica gel purification, obtains described tert-butyl ether (0.35g, 51%).MS(ESI)：(M+H) +＝440.25。
Part 2. (2S, 3S, 5S)-uncle 5--butoxy-3-(methoxycarbonyl) piperidines-2-carboxylic acid: with (2S, 3S, 5S)-1-benzyl-uncle 5--butoxy piperidines-2,3-dicarboxylic acid 2-benzyl ester 3-methyl ester (80.0mg, 5mL MeOH solution 0.000182mol) is in the presence of 10%Pd/C, and hydrogenation is spent the night under hydrogen bag pressure power.Behind the filtration catalizer, filtrate is concentrated into dried, it is directly used in next step (43mg, 91.1%).MS(ESI)：(M+H) +＝260.1。
Part 3. (2S, 3S, 5S)-and uncle 5--butoxy-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-carboxylic acid methyl ester: to (2S, 3S, 5S)-uncle 5--butoxy-3-(methoxycarbonyl) piperidines-2-carboxylic acid (43.0mg, 0.000166mol), 1-phenyl-Piperazine (0.03166mL, 0.0002073mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (0.09168g, 0.0002073mol) at N, (0.40mL 0.0052mol) in the mixture in, adds N to dinethylformamide, the N-diisopropylethylamine (0.03611mL, 0.0002073mol).Under room temperature, stirred this reactant 2 hours, water quencher then.With the mixture ethyl acetate extraction.With the organic layer that the salt water washing merges, drying also is concentrated into dried.Residue is directly used in next step.MS(ESI)：(M+H) +＝404.2。
Part 4. (2S, 3S, 5S)-and uncle 5--butoxy-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide (3a): to (2S, 3S, 5S)-and uncle 5--butoxy-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-carboxylic acid methyl ester (0.03345g, 8.290E-5mol) methyl alcohol (0.30mL 0.0074mol) adds methyl alcohol (1.011mL) solution (by corresponding HCl salt and sodium methylate prepared fresh) of 1.640MN-oxyamine in the solution.Under room temperature, stir this mixture 1 hour, use 1N HCl acidifying then.The mixture that obtains is directly carried out RP-HPLC, obtain product (21mg, 49%) as tfa salt.MS(ESI)：(M+H) +＝405.1。
Embodiment 219
(2S, 3S, 5S)-and uncle 5--butoxy-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-1-carboxylic acid methyl ester
Part 1. (2S, 3S, 5S)-and uncle 5--butoxy-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters: to (2S, 3S, 5S)-and uncle 5--butoxy-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-carboxylic acid methyl ester (0.03345g, 8.290E-5mol) and 4-dimethylaminopyridine (0.0152g, 0.000124mol) methylene dichloride (1.50mL, 0.0234mol) add in the mixture in the carbonochloridic acid methyl ester (0.00833mL, 0.000108mol).Stirring this reactant under room temperature spends the night.After the sodium bicarbonate aqueous solution quencher, with the reactant ethyl acetate extraction.With the organic layer that the salt water washing merges, dry, be concentrated into dried.The residue that obtains is directly used in next step.MS(ESI)：(M+H) +＝462.2。
Part 2. (2S, 3S, 5S)-and uncle 5--butoxy-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester: to (2S, 3S, 5S)-and uncle 5--butoxy-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1,3-dicarboxylic acid dimethyl esters (0.038g, methyl alcohol 0.000082mol) (0.30mL, 0.0074mol) methyl alcohol (1.004mL) solution (by corresponding azanol HCl salt and sodium methylate prepared fresh) of adding 1.640M N-oxyamine in the solution.Under room temperature, stir this mixture 1 hour, use 1N HCl acidifying then.The mixture that obtains is directly carried out RP-HPLC, obtain target product (10mg, 45%) as tfa salt.MS(ESI)：(M+H) +＝463.2。
Embodiment 220
(3R, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-the N-hydroxyl-4-[(3R)-
3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Part 1. (3R, 4S)-1-[(Z)-(cyanoimino) (phenoxy group) methyl]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester: under room temperature, to (3R, 4S)-4-((R)-3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-carboxylic acid methyl ester (654mg, 0.00207mol) anhydrous acetonitrile (11.0mL, 0.211mol) stirred solution in, add triethylamine (0.579mL, 0.00413mol) and phenylbenzene cyano group carbon imidate (762mg, 0.00310mol).Reaction mixture is heated to backflow (oil bath temperature: 85 ℃) 18 hours.The vacuum concentration reaction mixture.Residue is used the 40-90%EtOAc/Hex wash-out through the Combiflash purifying, obtains product, is colorless solid (841mg, 88% yield).MS(ESI)：(M+H) +＝461.1。
Part 2. (3R, 4S)-1-[(E)-cyanoimino]-tetramethyleneimine-1-base-methyl-4-(R)-3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-carboxylic acid methyl ester: to (3R, 4S)-1-[(Z)-(cyanoimino) (phenoxy group) methyl]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester (112mg, 0.000243mol) anhydrous isopropyl alcohol (3.00mL, 0.0392mol) stirred solution in, the adding tetramethyleneimine (61.5uL, 0.000730mol).Reaction mixture is heated to backflow (oil bath temperature: 85 ℃) 18 hours.The vacuum concentration reaction mixture.Residue is used 0-5%MeOH/CH through the Combiflash purifying 2Cl 2Wash-out obtains the product (90mg, 85% yield) into colorless solid.MS(ESI)：(M+H) +＝438.2。
Part 3. (3S, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide: the 1.50MNH of preparation in MeOH 2OH/NaOMe: under room temperature, to hydroxylamine hydrochloride (2.106g, 0.03000mol) methyl alcohol (10.3mL) solution of adding 4.37M sodium methylate in the suspension of the stirring in anhydrous methanol (9.0mL).In 55 ℃ of heating this reaction mixtures 5 minutes, be cooled to room temperature, be cooled to 0 ℃ then.Filtration obtains settled solution, is estimated as the methanol solution of about 1.50M.
Under room temperature, to (3R, 4S)-1-[(E)-cyanoimino]-tetramethyleneimine-1-base-methyl-4-((R)-3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-carboxylic acid methyl ester (90.0mg, 0.000206mol) anhydrous methanol (1.5mL, 0.037mol) stirred solution in, add methyl alcohol (2.74mL) solution of above-mentioned 1.50M azanol.Stirred reaction mixture is 1 hour 15 minutes under room temperature.LCMS demonstration reaction is finished.Use saturated NH 4The Cl aqueous solution (20mL) quencher reactant extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2O (0.05%NH 4OH) wash-out obtains the clean product (57.2mg, 63% yield) into colorless solid.MS(ESI)：(M+H) +＝439.2。
Embodiment 221
(3R, 4S)-1-[(E)-azetidine-1-base (the inferior cyano group of cyano group) methyl]-N-hydroxyl-4-
[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝425.2。
Embodiment 222
(3R, 4S)-1-[(E)-(cyanoimino) (dimethylamino) methyl]-the N-hydroxyl-4-[(3R)-
3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝413.2。
Embodiment 223
(3R, 4S)-1-[(E)-(cyanoimino) (cyclopropyl amino) methyl]-the N-hydroxyl-4-[(3R)-
3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝425.2。
Embodiment 224
(3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-
Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝453.3。
Embodiment 225 (3R, 4S)-1-[(Z)-(cyanoimino) (morpholine-4-yl) methyl]-the N-hydroxyl-4-[(3R)-3-
Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝455.3。
Embodiment 226
(3R, 4S)-1-[(Z)-(cyanoimino) (hydroxyl amino) methyl]-the N-hydroxyl-4-[(3R)-3-
Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝401.2。
Embodiment 227
(3R, 4S)-1-[(E)-aza-heptane-1-base (cyanoimino) methyl]-the N-hydroxyl-4-[(3R)-
3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝467.3。
Embodiment 228
(3R, 4S)-1-[(Z)-(cyanoimino) (4-methylpiperazine-1-yl) methyl]-N-hydroxyl-4-
[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝468.2。
Embodiment 229
(3R, 4S)-1-[(Z)-(cyanoimino) (parathiazan-4-yl) methyl]-the N-hydroxyl-4-[(3R)-
3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝471.1。
Embodiment 230
(3R, 4S)-1-[(E)-(cyanoimino) (4-methyl piperidine-1-yl) methyl]-N-hydroxyl-4-
[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝467.2。
Embodiment 231
(3R, 4S)-1-[(Z)-(cyanoimino) (2,5-dihydro-1H-pyrroles-1-yl) methyl]-the N-hydroxyl
Base-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝437.2。
Embodiment 232
(3R, 4S)-1-[(Z)-(cyanoimino) (1,3-dihydro-2H-isoindole-2-yl) methyl]-N-
Hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝487.1。
Embodiment 233
(3R, 4S)-1-[(Z)-(cyanoimino) (3,4-dihydro-isoquinoline-2 (1H)-yl) methyl]-N-
Hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 220.
MS(ESI)：(M+H) +＝501.1。
Embodiment 234
(3R, 4S)-the N-hydroxyl-1-[(Z)-1-(hydroxyl amino)-2-nitroethylene base]-4-[(3R)-3-benzene
Base tetramethyleneimine-1-yl] carbonyl piperidines-3-methane amide
Part 1. (3S, 4S)-1-[(Z)-1-(methylthio group)-2-nitroethylene base]-4-[(3R) 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester: under room temperature, to (3R, 4S)-4-(R)-3-phenyl-tetramethyleneimine-1-carbonyl)-piperidines-3-carboxylic acid methyl ester (3.10E2mg, 0.000980mol) anhydrous acetonitrile (9.8mL, 0.19mol) stirred solution in, add triethylamine (274uL, 0.00196mol) and 1, two (the methylthio group)-2-nitroethylenes of 1-(248mg, 0.00147mol).This reaction mixture is heated to backflow (oil bath temperature: 85 ℃) 19 hours.The vacuum concentration reaction mixture.Residue is used the 40-95%EtOAc/Hex wash-out through the Combiflash purifying, obtains the product (227mg, 53% yield) into yellow thickness oily matter.MS(ESI)：(M+H) +＝434.1。
Part 2. (3R, 4S)-1-[(E)-2-nitro-1-piperidines-1-base vinyl]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester: to (3R, 4S)-1-[(Z)-1-(methylthio group)-2-nitroethylene base]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester (81.0mg, 0.000187mol) ethanol (3.0mL, 0.051mol) stirred solution in, the adding piperidines (92.8uL, 0.000934mol).This reaction mixture is heated to backflow (oil bath temperature: 85 ℃) 17 hours 45 minutes.The vacuum concentration reaction mixture.Residue is used 0-8%MeOH/CH through the Combiflash purifying 2Cl 2Wash-out obtains product, is yellow solid (62mg, 71% yield).MS(ESI)：(M+H) +＝471.1。
Part 3. (3S, 4S)-the N-hydroxyl-1-[(Z)-1-(hydroxyl amino)-2-nitroethylene base]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide: to (3R, 4S)-1-[(E)-2-nitro-1-piperidines-1-base vinyl]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester (62.0mg, 0.000132mol) anhydrous methanol (1.0mL, 0.025mol) stirred solution in, add methyl alcohol (1.76mL) solution of 1.50M azanol.Stirred reaction mixture is 2 hours under room temperature.With the saturated NH of reactant 4The Cl aqueous solution (20mL) quencher is extracted (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2The O wash-out obtains pure products, is colorless solid (14.3mg, 26% yield).MS(ESI)：(M+Na) +＝442.2。
Embodiment 235
(3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-methyl
Phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Part 1. (3R, 4S)-and 4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester: to (3R, 4S)-piperidines-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester (0.554g, 0.00172mol) N, (8.500mL in stirred solution 0.1098mol), adds 3-methyl-4-piperazine-1-base benzonitrile dihydrochloride (0.6146g to dinethylformamide, 0.002241mol), (benzotriazole-1-base oxygen base) tripyrrole alkane subbase _ hexafluorophosphate (1.017g, 0.001896mol) and N, and the N-diisopropylethylamine (1.509mL, 0.008620mol).Under room temperature, this compound of reaction stirring is spent the night.Use KH 2PO 4(saturated solution) quencher reactant.Separate each layer, extract water layer with ethyl acetate (3X).With organic layer salt water washing, through dried over mgso.Filter and concentrate.Residue is used the 40-70%EtOAc/Hex wash-out through the Combiflash purifying, obtains product (75% yield).MS(ESI)：(M+H) +＝505。
Part 2. (3R, 4S)-and 4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester: under room temperature, to (3R, 4S)-and 4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (0.5265g, 0.001043mol) methyl alcohol (11.00mL, 0.2716mol) add in the solution 10% palladium be stated from the carbon (93.9mg, 0.0000883mol).This compound of reaction stirred under 1atm air pressure hydrogen spend the night.After stirring was spent the night, filter reaction mixture concentrated the product that obtains quantitative yield.MS(ESI)：(M+H) +＝371。
Part 3. (3R, 4S)-1-[(Z)-(cyanoimino) (phenoxy group) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester: under room temperature, to (3R, 4S)-and 4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester (386.500mg, 1.04334E-3mol) anhydrous acetonitrile (6.000mL, 0.1149mol) stirred solution in, add triethylamine (0.2923mL, 0.002087mol) and phenylbenzene cyano group carbon imido-ester (384.4mg, 0.001565mol).This reaction mixture is heated to backflow (oil bath temperature: 85 ℃) 5 hours.The vacuum concentration reaction mixture.Residue is used the 40-90%EtOAc/Hex wash-out through the Combiflash purifying, obtains product (60% yield).MS(ESI)：(M+H) +＝515。
Part 4. (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl)-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester: to (3R, 4S)-1-[(Z)-(cyanoimino) (phenoxy group) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester (52mg, 0.00010mol) acetonitrile (2.006mL, 0.03840mol) stirred solution in, the adding piperidines (0.200mL, 0.00202mol).Reaction mixture refluxed (in 85 ℃ of oil baths).After reaction is finished, vacuum concentrated mixture.Residue with 0-5% ethanol/methylene wash-out, obtains product (53.3mg, 98% yield) through the Combiflash purifying.MS(ESI)：(M+H) +＝506.
Part 5. (3R, 4S)-1-[(E)-(cyanoimino) (methyl of piperidinyl-1-yl)]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide: the 1.50M NH of preparation in MeOH 2OH/NaOMe: under room temperature, (1.56573g 0.0223062mol) in the stirred suspension in anhydrous methanol (6.0mL), adds methyl alcohol (7.64mL) solution of 4.37M sodium methylate to hydroxylamine hydrochloride.In 55 ℃, with this reaction mixture heating 5 minutes, be cooled to room temperature, be cooled to 0 ℃ then.Filtration obtains settled solution, is estimated as the methanol solution of about 1.50M.
Under room temperature, to (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl piperidines-3-carboxylic acid methyl ester (53.30mg, 0.0001054mol) anhydrous methanol (1.110mL, 0.02740mol) stirred solution in, add methyl alcohol (1.40mL) solution of above-mentioned 1.50M azanol.Stirred reaction mixture is 2 hours under room temperature.LCMS demonstration reaction is finished.With saturated NH 4Cl aqueous solution quencher reactant extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2The O wash-out obtains product.MS(ESI)：(M+H) +＝507。
Embodiment 236
(3R, 4S)-1-[(E)-(cyanoimino) (dimethylamino) methyl]-4-[4-(4-cyano group-2-first
The base phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 235.
MS(ESI)：(M+H) +＝467。
Embodiment 237
(3R, 4S)-1-[(E)-aza-heptane-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-2-
Aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 235.
MS(ESI)：(M+H) +＝521。
Embodiment 238
(3R, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-4-[4-(4-cyano group-2-first
The base phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 235.
MS(ESI)：(M+H) +＝493。
Embodiment 239
(3R, 4S)-1-[(E)-(cyanoimino) (cyclopropyl amino) methyl]-4-[4-(4-cyano group-2-first
The base phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 235.
MS(ESI)：(M+H) +＝479。
Embodiment 240
(3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-
The 2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 235.
MS(ESD：(M+H) +＝479。
Embodiment 241
(1S, 2S, 5E)-and 5-benzylidene-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] the hexanaphthene first
Acid amides trifluoroacetate (salt)
Part 1. (1S, 2S)-and 5-oxo-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene-carboxylic acid methyl ester: under room temperature, to (1S, 2S)-2-(methoxycarbonyl)-4-oxo hexahydrobenzoic acid (1.014g, 0.005065mol) anhydrous N, dinethylformamide (20.0mL, 0.258mol) stirred solution in, add (benzotriazole-1-base oxygen base) tripyrrole alkane subbase _ hexafluorophosphate (2.989g, 0.005572mol), (1.17mL 0.00760mol), then adds N to the 1-phenylpiperazine, the N-diisopropylethylamine (2.66mL, 0.0152mol).Stirred reaction mixture is 15 hours under room temperature.Water quencher reactant (40mL) extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over mgso, filters and vacuum concentration.Residue is used the 40-70%EtOAc/Hex. wash-out through the Combiflash purifying, obtains the product (1.299g, 74% yield) into colorless solid.MS(ESI)：(M+H) +＝345.1。
Part 2. (1S, 2S, 5E)-and 5-benzylidene-2-[(4-phenylpiperazine-1-yl) carbonyl]-the hexahydrobenzoic acid methyl ester: under room temperature, to bromination benzyl triphenyl _ (0.397g, 0.000880mol) in anhydrous THF (3.0mL) suspension, be added dropwise to tetrahydrofuran (THF) (0.880mL) solution of two (trimethyl silyl) ammonification sodium of 1.00M.The orange suspension that obtains was stirred under room temperature 1 hour, adds (1S, 2S)-5-oxo-2-[(4-phenylpiperazine-1-yl) carbonyl by sleeve pipe then] hexahydrobenzoic acid methyl ester (202mg, anhydrous THF (3.0mL) solution 0.000586mol).Stirred reaction mixture is 18 hours under room temperature.Water quencher reactant (20mL) extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used the 20-60%EtOAc/Hex wash-out through the Combiflash purifying, obtains product (141mg, 57% yield) and S.M. (50mg reclaims 25% S.M.).MS(ESI)：(M+H) +＝419.2。
Part 3. (1S, 2S, 5E)-and 5-benzylidene-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide trifluoroacetate (salt): the 1.50MNH of preparation in MeOH 2OH/NaOMe: under room temperature, (1.404g in the suspension of the stirring of anhydrous methanol 0.02000mol) (6.0mL), adds methyl alcohol (6.86mL) solution of 4.37M sodium methylate to hydroxylamine hydrochloride.This reaction mixture in 55 ℃ of heating 5 minutes, is cooled to room temperature, is cooled to 0 ℃ then.Filtration obtains settled solution, is estimated as the methanol solution of about 1.50M.
Under room temperature, to (1S, 2S, 5E)-and 5-benzylidene-2-[(4-phenylpiperazine-1-yl) carbonyl] hexahydrobenzoic acid methyl ester (30.0mg, 0.0000717mol) anhydrous tetrahydro furan (2.0mL 0.025mol) in the solution, adds the methanol solution (1.43mL) of the azanol of above-mentioned 1.50M.Stirred reaction mixture is 17 hours under room temperature.Use saturated NH 4The Cl aqueous solution (15mL) quencher reactant extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2(contain 0.05%TFA, pH=2.5) wash-out obtains pure products to O, is colorless solid (18.3mg, 48% yield).MS(ESI)：(M+H) +＝420.1。
Embodiment 242
(1S, 2S, 5E)-and 5-(cyclopropyl methylene radical)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares title compound with the similar method of method of embodiment 241.
MS(ESI)：(M+H) +＝384.1。
Embodiment 243
(1S, 2S, 5S)-and 5-benzyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene
Methane amide
Part 1. (1S, 2S, 5E)-and 5-benzylidene-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene-carboxylic acid: under room temperature, to (1S, 2S, 5E)-and 5-benzylidene-2-[(4-phenylpiperazine-1-yl) carbonyl] hexahydrobenzoic acid methyl ester (116mg, 0.000277mol) tetrahydrofuran (THF) (6.0mL in stirred solution 0.074mol), adds lithium hydroxide (102mg, 0.00416mol) water (2.0mL, 0.11mol) solution.The turbid solution that obtains was stirred under room temperature 17 hours.LCMS shows only has 40% to transform.Make reaction mixture be cooled to 0 ℃, add then hydrogen peroxide (0.113mL, 0.00111mol).In 0 ℃, this compound of reaction was stirred 2 hours.LCMS shows the change that only has seldom.Then reaction mixture was stirred weekend under room temperature.LCMS demonstration reaction is finished.Use 10%Na 2S 2O 3(10mL) quencher reactant is acidified to pH=4 with 1N HCl (5mL), extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over mgso, filters and vacuum concentration, obtains required product, is colorless solid. and (112mg, 100% yield).MS(ESI)：(M+H) +＝405.1。
Part 2. (1S, 2S, 5S)-5-[(S)-iodo (phenyl) methyl]-2-[4-(4-iodine substituted phenyl) piperazine-1-yl] carbonyl-6-oxabicyclo [3.2.1] suffering-7-ketone: under room temperature, to (1S, 2S, 5E)-and 5-benzylidene-2-[(4-phenylpiperazine-1-yl) carbonyl] hexahydrobenzoic acid (112mg, 0.000277mol) methylene dichloride (5.0mL in stirred solution 0.078mol), adds sodium bicarbonate (69.8mg, 0.000831mol) and iodine (211mg, 0.000831mol).Stirred reaction mixture is 24 hours under room temperature.LCMS demonstration reaction is not finished.(3.0mL, 0.17mol), stirred reaction mixture is other 18 hours under room temperature to add entry then.Use 10%Na 2S 2O 3(20mL) quencher reactant extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over mgso, filters and vacuum concentration.Residue is used the 20-60%EtOAc/Hex wash-out through the Combiflash purifying, obtains required product.(49.5mg, 27% yield).MS(ESI)：(M+H) +＝656.9。
Part 3. (1S, 2S, 5S)-and 5-benzyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-6-oxabicyclo [3.2.1]-Xin-7-ketone: to (the 1S in the Parr bottle, 2S, 5S)-5-[(S)-iodo (phenyl) methyl]-2-[4-(4-iodine substituted phenyl) piperazine-1-yl] carbonyl-6-oxabicyclo [3.2.1] suffering-7-ketone (49.0mg, 0.0000747mol) ethyl acetate (5.0mL, 0.051mol) in the solution, add lime carbonate (15mg, 0.00015mol) and palladium (20mg, 0.00002mol) (as 10%Pd/C).This compound of reaction was stirred 18 hours under 55psi hydrogen.Reaction mixture is diluted with EtOAc, filter, wash with EtOAc by the Celite pad.Vacuum concentrated filtrate obtains crude product product (30mg, 100% yield).MS(ESI)：(M+H) +＝405.1。
Part 4. (1S, 2S, 5S)-and 5-benzyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide: the 1.50M NH of preparation in MeOH 2OH/NaOMe: under room temperature, to (1.404g 0.02000mol) in the suspension of the stirring in anhydrous methanol (6.0mL), adds methyl alcohol (6.86mL) solution of 4.37M sodium methylate at hydroxylamine hydrochloride.This reaction mixture in 55 ℃ of heating 5 minutes, is cooled to room temperature, is cooled to 0 ℃ then.Filtration obtains settled solution, is estimated as the methanol solution of about 1.50M.
Under room temperature, to (1S, 2S, 5S)-and 5-benzyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-6-oxabicyclo [3.2.1]-Xin-7-ketone (8.0mg, 0.020mmol) anhydrous methanol (1.0mL in stirred solution 0.025mol), adds methyl alcohol (0.396mL) solution of 1.50M azanol.Stirred reaction mixture is 3 hours under room temperature.With reactant with saturated NH 4The Cl aqueous solution (15mL) quencher is extracted (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2O (containing 0.05%TFA) wash-out obtains pure products, is colorless solid (2.3mg, 26% yield).MS(ESI)：(M+H) +＝438.1。
Embodiment 244
(1S, 2S, 5R)-and N, 5-dihydroxyl-5-phenyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide trifluoroacetate (salt)
Part 1. (1S, 2S)-and 5-hydroxyl-5-phenyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-the hexahydrobenzoic acid methyl ester: in-78 ℃, to (1S, 2S)-and 5-oxo-2-[(4-phenylpiperazine-1-yl) carbonyl]-hexahydrobenzoic acid methyl ester (130.0mg, 0.0003775mol) anhydrous tetrahydro furan (4.0mL, 0.049mol) stirred solution in, add tetrahydrofuran (THF) (0.755mL) solution of 1.00M phenyl-magnesium-bromide.This reaction mixture in-78 ℃ of stirrings 1 hour, slowly was warmed to-35 ℃ with 3 hours then.With the saturated NH of reactant 4The Cl aqueous solution (20mL) quencher is extracted (2x) with EtOAc.Organic layer with the salt water washing merges through dried over mgso, filters and vacuum concentration.Residue is used the 30-80%EtOAc/Hex wash-out through the Combiflash purifying, obtains the product (123mg, 62% yield) into colorless solid.MS(ESI)：(M+H) +＝423.1。
Part 2. (1S, 2S, 5R)-and N, 5-dihydroxyl-5-phenyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide trifluoroacetate (salt): the 1.50MNH of preparation in MeOH 2OH/NaOMe: under room temperature, (1.404g, 0.02000mol) (6.0mL 0.15mol) in the suspension of the stirring in, adds methyl alcohol (6.86mL) solution of 4.37M sodium methylate at anhydrous methanol to hydroxylamine hydrochloride.Stirred reaction mixture is 15 minutes under room temperature.Filtration obtains settled solution, is estimated as the methanol solution of about 1.50M.
Under room temperature, to (1S, 2S, 5R)-and 5-hydroxyl-5-phenyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexahydrobenzoic acid methyl ester (120.0mg, 0.0002272mol) anhydrous tetrahydro furan (1.0mL, 0.012mol) stirred solution in, add methyl alcohol (3.03mL) solution of 1.50M azanol.Stirred reaction mixture is 3 hours under room temperature.Use saturated NH 4The Cl aqueous solution (15mL) quencher reactant extracts (2x) with EtOAc.Organic layer with the salt water washing merges through dried over sodium sulfate, filters and vacuum concentration.Residue is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2O (pH=2 contains 0.05%TFA) wash-out obtains pure products, is colorless solid (69.2mg, 56% yield).MS(ESI)：(M+H) +＝424.1。
Embodiment 245
(1S, 2S, 5R)-and 5-benzyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares title compound with the similar method of method of embodiment 244.
MS(ESI)：(M+H) +＝438.1。
Embodiment 246
(1S, 2S, 5R)-and N, 5-dihydroxyl-5-sec.-propyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares title compound with the similar method of method of embodiment 244.
MS(ESI)：(M+H) +＝390.1。
Embodiment 247
(1S, 2S, 5R)-and 5-cyclopropyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares title compound with the similar method of method of embodiment 244.
MS(ESI)：(M+H) +＝388.1。
Embodiment 248
(2S, 3S, 5R)-and 2-[4-cyano group-2-aminomethyl phenyl) piperidines-1-yl] carbonyl-N-hydroxyl-5-(2-
Oxo-2-tetramethyleneimine-1-base ethyl) piperidines-3-methane amide
Employing prepares title compound with the similar method of method of embodiment 11.MS(ESI)：(M+H) +＝482.1。
Embodiment 249
(5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base
The methyl carbamic acid isopropyl esters
Employing prepares title compound with the similar method of method of embodiment 11.。MS(ESI)：(M+H) +＝447.1。
Embodiment 250
(1S, 2S)-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyrroles
Alkane-1-base carbonyl) cyclohexane carboxamide
Part 1. (1S, 2S, 4S)-and 4-hydroxyl hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: make (1S, 2S, 5S)-(5.65g 25.0mmol) is suspended in the methyl alcohol (20mL) 7-oxo-6-oxabicyclo [3.2.1] octane-2-carboxylic acid tert-butyl ester.Add methyl alcohol (52mL) solution of 25wt% sodium methylate in this suspension, stirred reaction mixture is 2 hours under room temperature.In ice-water-bath, cool off then, be neutralized to pH6 with 4MHCl solution.After removing volatile matter, add salt solution (50mL), (3 * 40mL) extract this solution with ethyl acetate.Through MgSO 4The dry organic layer that merges filters and concentrates, and obtains required product (5.70g, 88.4% yield).LCMS：m/z 281.1(M+Na) +。
(1S, 2S)-4-oxo hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: (6.54g 25.3mmol) is dissolved in the acetone (65mL) and is cooled to 0 ℃ part 2. will to derive from the product of part 1.(2.07g is 20.7mmol) in water-soluble (6mL), to wherein being added dropwise to sulfuric acid (1.74mL) to make chromic oxide (VI).This solution is cooled to 0 ℃, and is added drop-wise in the above-mentioned solution with 10 minutes time.Stirred reaction mixture is 30 minutes under room temperature.Add Virahol (11mL) then, continue again to stir other 5 minutes.Filter the mixture (using the acetone wash-out) that obtains by silicagel pad.Concentrate subsequently, add ether (60mL), water (2 * 50mL) and salt solution (50mL) wash this solution in proper order.Organic phase is through MgSO 4Drying is filtered and is concentrated, and obtains required product, is white solid (5.75g, 88.6% yield).
Part 3. (1S, 2S, 4E)-4-(methoxyl group methylene radical) hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: make that (2.00g 7.80mmol) is dissolved among the THF for product from part 2.In addition, (4.01g 11.7mmol) is dissolved among the THF, is cooled to 0 ℃ to make chloro (methoxymethyl) triphenyl phosphorane.In this solution, add THF (11.7mL) solution of 1.00M NaHMDS, this reaction mixture was stirred 15 minutes.In 0 ℃,, this Witting reagent is joined in the aforementioned solution with 25 minutes time.Stir after 30 minutes, with reaction mixture with ethyl acetate (50mL) dilution, water (2 * 100mL) and salt solution (1 * 100mL) order is washed.Organic phase is through MgSO 4Drying is filtered and is concentrated.Residue is through flash chromatography (silica gel, hexane: EtOAc, 12: 1-10: 1-8: 1-6: 1), obtain required product, be yellow oil (1.43g, 64.6% yield).
Part 4. (1S; 2S)-and 4-formyl radical hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: make that (0.510g 1.79mmol) is dissolved in acetonitrile (18.0mL) and the water (4.5mL) for product from part 3; (2.29g 7.17mmol) handles with mercuric acetate (II).Should non-even phase reaction mixture under room temperature, stir and spend the night.It is diluted with saturated potassium iodide aqueous solution, extract with EtOAc subsequently.With organic phase salt water washing, through MgSO 4Drying is filtered and is concentrated.Residue through flash chromatography (silica gel, hexane: EtOAc, 5: 1-3: 1-1: 1), obtain required aldehyde (0.456g, 94% yield), be two kinds of mixture of isomers (calm: axially, 3.5: 1, based on 1H NMR).
Part 5. (3S, 4S)-4-(uncle-butoxy carbonyl)-3-(methoxycarbonyl) hexahydrobenzoic acid: (52mg 0.192mmol) is dissolved among the DMF (1.9mL) feasible product from part 4, and (118mg 0.192mmol) handles with oxone.Stirred reaction mixture is 4.5 hours under room temperature.With a small amount of 0.1N HCl solution dilution, then with EtOAc and water dilution.Separate each layer, organic layer is through MgSO 4Drying is filtered and is concentrated, and obtains required product, is yellow oil (52mg, 94.4% yield).LCMS：m/z 309.0(M+Na) +。
Part 6. (1S, 2S)-and 4-(tetramethyleneimine-1-base carbonyl) hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: make that (0.265g 0.925mmol) is dissolved among the DMF (9.3mL) for product from part 5, (0.491g 1.11mmol) handles with bop reagent.Stir after 10 minutes, the adding tetramethyleneimine (81.1 μ L 0.971mmol), then add N, and the N-diisopropylethylamine (322 μ L, 1.85mmol).This reaction mixture stirred under room temperature spend the night.With the saturated NaHCO of its impouring 3In the aqueous solution, extract with EtOAc.With organic phase water (2x) and salt water washing, through MgSO 4Drying is filtered and is concentrated.Residue is through flash chromatography (silica gel, hexane: EtOAc, 5: 1-4: 1-3: 1), obtain required product (0.265g, 84.4% yield).LCMS：m/z 340.1(M+H) +。
Part 7. (1S, 2S)-2-(methoxycarbonyl)-4-(tetramethyleneimine-1-base carbonyl) hexahydrobenzoic acid: (0.260g 0.766mmol) is dissolved in the methylene dichloride (2.7mL) feasible product from part 6, is cooled to 0 ℃, handles with TFA (2.74mL).Stirred reaction mixture is 2 hours under room temperature.Add entry, then add other methylene dichloride, separate each layer.Organic phase is through MgSO 4Drying is filtered and is concentrated.With residue and methylbenzene azeotropic (3x), dry under the high vacuum, obtain required product (217mg, 100% yield).LCMS：m/z 284.2(M+H) +。
Part 8. (1S, 2S)-2-[(4-Phenylpiperidine-1-carbonyl]-5-(tetramethyleneimine-1-base carbonyl) hexahydrobenzoic acid methyl ester: feasible product (0.112g from part 7,0.395mmol) be dissolved among the DMF (4.0mL), (0.210g 0.474mmol) handles with bop reagent.Stir after 10 minutes, add 4-phenyl-1,2,3, the HCl salt of 6-tetrahydropyridine (81mg 0.415mmol), then adds N, and the N-diisopropylethylamine (206 μ L, 1.18mmol).This reaction mixture stirred under room temperature spend the night.With the saturated NaHCO of its impouring 3In the aqueous solution, extract with EtOAc.With organic phase water (2x) and salt water washing, through MgSO 4Drying is filtered and is concentrated.Residue is through flash chromatography (silica gel, hexane: EtOAc, 5: 1-4: 1-3: 1), obtain required product (0.126g, 79.7% yield).LCMS：m/z 425.2(M+H) +。
Part 9. (1S, 2S)-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(tetramethyleneimine-1-base carboxyl) cyclohexane carboxamide: make that (89mg 0.210mmol) is dissolved in methyl alcohol (2.1mL), uses 1.5M NH for product from part 8 2The methyl alcohol of OH/NaOMe (2.8mL) solution-treated (preparation 1.5MNH 2The methanol solution of OH/NaOMe: under room temperature, (1.404g in the suspension of the stirring of anhydrous methanol 20.20mmol) (6mL), adds methyl alcohol (6.86mL) solution of the sodium methylate of 4.37M to hydroxylamine hydrochloride.In 55 ℃, with this reaction mixture heating 5 minutes, be cooled to room temperature more earlier, be cooled to 0 ℃ then.Logical filtering plug filters, and obtains settled solution, is estimated as the methanol solution of about 1.50M).Monitor this reaction by LCMS, when reaction is finished, be poured into saturated NH 4In the Cl solution, extract twice with EtOAc.The organic extraction that merges is through MgSO 4Drying is filtered and is concentrated.(anti-phase, 5%MeCN-95%MeCN 35 minutes, pH=2.5), obtains required hydroxamic acid (36mg, 40.4% yield) to residue through the preparation HPLC purifying.LCMS：m/z 426.2(M+H) +。
Embodiment 251
N-cyclopropyl-N-((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexyl) methyl) morpholine-4-methane amide
Part 1. (1S, 2S)-and 4-[(cyclopropyl amino) methyl] hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: make from the product of embodiment 250 parts 4 (174mg, 0.644mmol) and cyclopropylamine (35.6mg 0.611mmol) is dissolved in the methyl alcohol (6.0mL).(38.4mg 0.611mmol) handles this solution with acetate (0.209mL) and sodium cyanoborohydride.This reaction mixture stirred under room temperature spend the night.It is concentrated,, use saturated NaHCO with the ethyl acetate dilution 3Solution washing.Organic layer is through MgSO 4Drying is filtered and is concentrated.Residue is through flash chromatography (silica gel, 5%-6%-10%MeOH/CH 2Cl 2), obtain required product, be colorless oil (131mg, 68.8% yield).LCMS：m/z 312.2(M+H) +。
Part 2. (1S, 2S)-4-{[cyclopropyl (morpholine-4-base carbonyl) amino] methyl hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester: make from part 1 (131mg 0.421mmol) is dissolved in the methylene dichloride (4.2mL) and is cooled to 0 ℃.Use N, and the N-diisopropylethylamine (0.146mL, 0.841mmol) and morpholine-4-carbonyl chlorine (54 μ L, 0.463mmol) this solution of subsequent treatment.Stirred reaction mixture is 36 hours under room temperature.It is diluted with methylene dichloride, then in the impouring 0.1M HCl solution.Separate each layer, organic phase is through MgSO 4Drying is filtered and is concentrated.Residue is through flash chromatography (silica gel, 2%MeOH/CH 2Cl 2), obtain required product, be colorless oil (0.148g, 82.9% yield).LCMS：m/z 425.2(M+H) +。
Part 3. (1S, 2S)-4-{[cyclopropyl (morpholine-4-base carbonyl) amino] methyl }-2-(methoxycarbonyl) hexahydrobenzoic acid: according to method described in embodiment 250 parts 7, obtain required carboxylic acid (0.124g, 96.5% yield).LCMS：m/z 369.1(M+H) +。
Part 4. (1S, 2S)-and 5-{[cyclopropyl (morpholine-4-base carbonyl) amino] methyl }-2-[(4-phenylpiperazine-1-yl) carbonyl } the hexahydrobenzoic acid methyl ester: according to method described in embodiment 250 parts 8, use the 1-phenylpiperazine, obtain required product (0.140g, 81.1% yield).LCMS：m/z513.3(M+H) +。
Part 5.N-cyclopropyl-N-({ (3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl } methyl) morpholine-4-methane amide: adopt method described in embodiment 250 parts 9,, obtain required product (56mg, 46% yield).LCMS：m/z 514.3(M+H) +。
Embodiment 252
(1S, 2S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(piperidines-1-base carbonyl)
Cyclohexane carboxamide
According to embodiment 250 these compounds of preparation.LCMS：m/z 443.1(M+H) +。
Embodiment 253
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(piperidines-1-base carbonyl)
Cyclohexane carboxamide
According to embodiment 250 these compounds of preparation.LCMS：m/z 443.1(M+H) +。
Embodiment 254
(1S, 2S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(tetramethyleneimine-1-base carbonyl
Base) cyclohexane carboxamide
According to embodiment 250 these compounds of preparation.LCMS：m/z 429.1(M+H) +。
Embodiment 255
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(tetramethyleneimine-1-base carbonyl
Base) cyclohexane carboxamide
According to embodiment 250 these compounds of preparation.LCMS：m/z 429.1(M+H) +。
Embodiment 256
(1S, 2S)-N-hydroxyl-5-(morpholine-4-base carbonyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] hexamethylene
The alkane methane amide
According to embodiment 250 preparation title compounds.LCMS：m/z 445.2(M+H) +。
Embodiment 257
N-cyclopentyl-N-((3S, 4S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl } methyl) piperidines-1-methane amide
According to embodiment 251 preparation title compounds.LCMS：m/z 540.2(M+H) +。
Embodiment 258
N-cyclopentyl-N-((3S, 4S, 5R)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl } methyl) piperidines-1-methane amide
According to embodiment 251 preparation title compounds.LCMS：m/z 540.2(M+H) +。
Embodiment 259
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝430.1。
Embodiment 260
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl
Tetramethyleneimine-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝404.1。
Embodiment 261
Morpholine-4-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydro pyrrole
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS (ESI)：(M+H) +＝458.1。
Embodiment 262
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝442.1。
Embodiment 263
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝402.1。
Embodiment 264
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-two
Pyridinium hydroxide-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝416.1。
Embodiment 265
(1S, 2S, 5R)-and N, the 5-dihydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } hexanaphthene
Methane amide
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝333.1。
Embodiment 266
Dimethylamino formic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-two
Pyridinium hydroxide-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝416.1。
Embodiment 267
Tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝442.1。
Embodiment 268
Methyl carbamic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝402.1。
Embodiment 269
Morpholine-4-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydro pyrrole
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝458.1。
Embodiment 270
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝390.1。
Embodiment 271
Morpholine-4-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl } cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝446.1。
Embodiment 272
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝444.2。
Embodiment 273
Piperidines-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝459.2。
Embodiment 274
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝445.2。
Embodiment 275
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝419.2。
Embodiment 276
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS (ESI)：(M+H) +＝405.2。
Embodiment 277
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝442.2。
Embodiment 278
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝402.1。
Embodiment 279
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-two
Pyridinium hydroxide-1 (2H)-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝416.1。
Embodiment 280
Dimethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝418.2
Embodiment 281
Piperidines-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝458.2
Embodiment 282
(1S, 2S, 5R)-and N, 5-dihydroxyl-5-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene
Methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝362.1。
Embodiment 283
(1S, 2S, 5S)-and N, 5-dihydroxyl-5-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl)
Carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝359.1。
Embodiment 284
(3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1R, 3R, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝461.2。
Embodiment 285
N-{ (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] ring
Hexyl }-N-methyl azetidine-1-methane amide
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝430.2。
Embodiment 286
Diethylamino formic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.MS(ESI)：(M+H) +＝447.2。
Embodiment 287
(1S, 2S, 5R)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-
Base) carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝385.2。
Embodiment 288
(1S, 2S, 5R)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexamethylene
The alkane methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝388.2。
Embodiment 289
(1S, 2S, 5S)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-
Base) carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝385.2。
Embodiment 290
(1S, 2S, 5S)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexamethylene
The alkane methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝388.2。
Embodiment 291
(1S, 2S, 5R)-and N, 5-dihydroxyl-5-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] hexanaphthene
Methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝361.2。
Embodiment 292
(1S, 2S, 5S)-and N, 5-dihydroxyl-5-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] hexanaphthene
Methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝361.2。
Embodiment 293
(1S, 2S, 5S)-and N, 5-dihydroxyl-5-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene
Methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝362.2。
Embodiment 294
(1S, 2S, 5R)-and N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-
5-propyl cyclohexane methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝369.2。
Embodiment 295
(1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-
5-propyl cyclohexane methane amide
Employing prepares these compounds with the similar method of method of embodiment 243.MS(ESI)：(M+H) +＝369.2。
Embodiment 296
(1S, 2S, 5R)-and N-hydroxyl-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] the hexanaphthene first
Acid amides
Part 1. (1S, 2S, 5S)-and 2-[(4-phenylpiperazine-1-yl) carbonyl]-6-oxabicyclo [3.2.1] suffering-7-ketone.In 0 ℃, with benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (7.0g, 0.016mol) join (1S, 2S, 5S)-(14.4mmol is 0.0144mol) with 1-phenylpiperazine (2.4mL, N 0.016mol) for 7-oxo-6-oxabicyclo [3.2.1] octane-2-carboxylic acid, (30mL is 0.4mol) in the solution for dinethylformamide.After 5 minutes, in 0 ℃ of adding N, the N-diisopropylethylamine (7.5mL, 0.043mol).Under room temperature, stir this mixture overnight.Product is through the silicagel column flash chromatography (ethyl acetate in hexane: 60%).
Part 2. (1S, 2S, 5R)-and 5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene-carboxylic acid methyl ester.Under room temperature, nitrogen, with triphenyl phosphine (150mg, 0.00058mol) join (1S, 2S, 5S)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene-carboxylic acid methyl ester (100.0mg, 0.00029mol) and phenol (54mg is in tetrahydrofuran (THF) 0.00058mol) (2.0mL) solution.Add azo-2-carboxylic acid's diethyl ester (91uL, tetrahydrofuran (THF) 0.00058mol) (2.0mL) solution.This reaction mixture stirred under room temperature spend the night.Product is through the silicagel column flash chromatography purifying (ethyl acetate in hexane: 30%).
Part 3. (1S, 2S, 5R)-and N-hydroxyl-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] ring-hexane methane amide.Under room temperature, with the MeOH of oxyamine (1.5M, 0.75ml) solution join (1S, 2S, 5R)-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] (0.29mmol is in MeOH 0.00029mol) (0.5mL) solution for hexanaphthene-carboxylic acid methyl ester.The mixture that obtains was stirred under room temperature 2 hours, be adjusted to pH=2.0,, obtain required product then through the Prep-HPLC purifying with TFA.LCMS：(M+H) +＝424.2。
Embodiment 297
(1S, 2S, 5R)-and N-hydroxyl-5-[(6-picoline-3-yl) the oxygen base]-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝439.2。
Embodiment 298
(1S, 2S, 5R)-and N-hydroxyl-5-(4-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝438.1。
Embodiment 299
(1S, 2S, 5R)-and 5-(2,3-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝460.2。
Embodiment 300
(1S, 2S, 5R)-and N-hydroxyl-5-[(6-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝439.2。
Embodiment 301
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[(2-toluquinoline-4-
Base) oxygen base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝489.2。
Embodiment 302
(1S, 2S, 5R)-and 5-(3,4-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝460.2。
Embodiment 303
(1S, 2S, 5R)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-N-hydroxyl-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝459.1/461.1。
Embodiment 304
(1S, 2S, 5R)-and N-hydroxyl-5-[1-(methyl sulphonyl) piperidin-4-yl] oxygen base-2-[(4-phenyl
Piperazine-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝509.0
Embodiment 305
(1S, 2S, 5R)-and 5-(2,4-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝492.1/494.1。
Embodiment 306
4-((1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] hexamethylene
Base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝489.1。
Embodiment 307
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-3-yl oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝425.1。
Embodiment 308
(1S, 2S, 5R)-and 5-(4-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝442.2。
Embodiment 309
(1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝459.2。
Embodiment 310
(1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(3-phenyl-2,5-two
Hydrogen-1H-pyrroles-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝442.2
Embodiment 311
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2。
Embodiment 312
(1S, 2S, 5R)-and 5-(2,3-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝492.0/494.0。
Embodiment 313
(1S, 2S, 5R)-and 5-(benzyl oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexamethylene
The alkane methane amide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝438.2。
Embodiment 314
(1S, 2S, 5R)-and N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝439.2。
Embodiment 315
(1S, 2S, 5R)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝442.2。
Embodiment 316
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝425.2。
Embodiment 317
(1S, 2S, 5R)-and 5-[(1-ethanoyl piperidin-4-yl) the oxygen base]-N-hydroxyl-2-[(4-phenylpiperazine-
The 1-yl) carbonyl] cyclohexane carboxamide
Under room temperature, (2.0E3mg 0.0077mol) joins (1S with triphenyl phosphine, 2S, 4S)-4-hydroxyl hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.0g, 0.0039mol) and 4-pyridine alcohol (730mg, (10.0mL is 0.123mol) in the solution for tetrahydrofuran (THF) 0.0076mol).Add azo-2-carboxylic acid's diethyl ester (1200uL, tetrahydrofuran (THF) 0.0077mol) (10.0mL, 0.123mol) solution.This reaction mixture stirred under room temperature spend the night.Reactant is through the combiflash chromatography (ethyl acetate in hexane: 80%), obtain that (4R)-4-(pyridin-4-yl oxygen base) hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (is mixed with a small amount of Ph for 1S, 2S 3PO), it is used for next step.
The black diethyl ether solution with 1mL 1M HCl of 20mg Pd is joined (1S, 2S, 4R)-and 4-(pyridin-4-yl oxygen base) hexanaphthene-1, (0.1g, (50mL is 1mol) in the solution for methyl alcohol 0.0003mol) for 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.This reactant (60Psi) under nitrogen atmosphere jolted spend the night.LCMS demonstration reaction is finished.
In 22 ℃, with Acetyl Chloride 98Min. (24uL, 0.00033mol) 0.5ml CAN solution join the (1S of above preparation, 2S, 4R)-and 4-(piperidin-4-yl oxygen base) hexanaphthene-1, (50mg is 0.0001mol) with 4-methylmorpholine (44uL for 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester hydrochloride, 0.00040mol) acetonitrile (1.5mL is 0.029mol) in the solution.Stirred 30 minutes under room temperature, water quencher is then extracted with EA, and concentrated obtaining (1S, 2S, 4R)-and 4-[(1-ethanoyl piperidin-4-yl) the oxygen base] hexanaphthene-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.
2mL TFA is joined (1S, 2S, 4R)-and 4-[(1-ethanoyl piperidin-4-yl) the oxygen base] hexanaphthene-1, (0.1mmol is in methylene dichloride 0.0001mol) (2ml) solution for 2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.Stirring is spent the night and is concentrated under room temperature, obtains being used for the corresponding tfa salt of next step.
Under room temperature; with benzotriazole-1-base oxygen base three (dimethylaminos)-_ hexafluorophosphate (49mg; 0.00011mol) join (1S of above preparation; 2S; 4R)-and 4-[(1-ethanoyl piperidin-4-yl) the oxygen base]-(0.1mmol is 0.0001mol) with 1-phenylpiperazine (17uL, N 0.00011mol) for 2-(methoxycarbonyl) hexahydrobenzoic acid; (0.5mL is 0.006mol) in the solution for dinethylformamide.After 5 minutes, in 0 ℃ of adding N, the N-diisopropylethylamine (52uL, 0.00030mol).Under room temperature, stir and spend the night.Reactant is through the combiflash chromatography (ethyl acetate in hexane: 100%).
With 1.5M H 2The MeOH solution (0.75ml) of NOH join (1S, 2S, 5R)-5-[(1-ethanoyl piperidin-4-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] (0.1mmol is in 0.5ml MeOH solution 0.0001mol) for hexanaphthene-carboxylic acid methyl ester.Under room temperature, stirred 2 hours.Make it through the Prep-HPLC purifying.LCMS：(M+H) +＝473.1。
Embodiment 318
(1S, 2S, 5R)-and N-hydroxyl-5-[(2-picoline-3-yl) the oxygen base]-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝439.2。
Embodiment 319
(1S, 2S, 5R)-and 5-[3, two (trifluoromethyl) phenoxy groups of 5-]-N-hydroxyl-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝560.2。
Embodiment 320
(1S, 2S, 5R)-and 5-(2-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝458.1/460.1。
Embodiment 321
(1S, 2S, 5R)-and 5-(4-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝458.2/460.1。
Embodiment 322
(1S, 2S, 5R)-and 5-(3-bromo phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝502.1/504.1。
Embodiment 323
(1S, 2S, 5R)-5-(1,3-benzothiazole-2-base oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝481.1。
Embodiment 324
(1S, 2S, 5R)-and 5-(3-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝543.2。
Embodiment 325
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyrimidine-2-yloxy)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝426.2。
Embodiment 326
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[3-(trifluoromethyl) benzene
The oxygen base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝492.1。
Embodiment 327
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinolyl-4 oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2。
Embodiment 328
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(thieno-[3,2-b] pyrrole
Pyridine-7-base oxygen base) cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝481.2。
Embodiment 329
(1S, 2S, 5R)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝431.3
Embodiment 330
The cyclopropyl carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝430.2
Embodiment 331
Ethyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝418.1
Embodiment 332
Methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝404.1
Embodiment 333
The sec.-propyl carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝432.1
Embodiment 334
Third-2-alkynes-1-aminocarbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-the 4-[(4-phenyl
Piperidines-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝428.1
Embodiment 335
Piperidines-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl)
Carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝460.1
Embodiment 336
4-methylpiperazine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-the 4-[(4-Phenylpiperidine
-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝473.2
Embodiment 337
Carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl
Base] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝390.2
Embodiment 338
(1-methyl piperidine-4-yl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝488.3
Embodiment 339
Isobutyl-(methyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-the 4-[(4-phenyl
Piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝461.2
Embodiment 340
Methyl (3-phenyl propyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝523.3
Embodiment 341
Cyclohexyl (methyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-((4-phenyl
Piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝487.3
Embodiment 342
(4-p-methoxy-phenyl) methyl carbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝511.3
Embodiment 343
Indoline-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝493.2
Embodiment 344
1,3-dihydro-2H-isoindole-2-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝493.2
Embodiment 345
(2-phenycyclopropyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝507.3
Embodiment 346
The cyclobutyl carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝445.2
Embodiment 347
4-{[({ (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] ring
Hexyl } the oxygen base) carbonyl] amino } piperidines-1-carboxylic acid ethyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝546.3
Embodiment 348
Tetrahydrofuran (THF)-3-aminocarbamic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-the 4-[(4-phenyl
Piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝461.2
Embodiment 349
(4-hydroxy-cyclohexyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝489.2
Embodiment 350
(2-methoxy ethyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝449.2
Embodiment 351
(pyridine-2-ylmethyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝482.2
Embodiment 352
(pyridin-3-yl methyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝482.2
Embodiment 353
(pyridin-4-yl methyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝482.2
Embodiment 354
2,5-dihydro-1H-pyrroles-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-benzene
Base piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝442.2
Embodiment 355
The cyclopentyl carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝459.2
Embodiment 356
The cyclohexyl carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝473.3
Embodiment 357
(1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl
Piperazine-1,4-dicarboxylic acid ethyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝532.3
Embodiment 358
4-{2-[methyl (phenyl) amino]-the 2-oxoethyl } and piperazine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl
Base is amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝607.3
Embodiment 359
4-hydroxy piperidine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-the 4-[(4-phenylpiperazine
-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝475.2
Embodiment 360
(3R)-and 3-(acetylamino) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl
Base]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝502.3
Embodiment 361
(3S)-and 3-(acetylamino) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl
Base]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝502.2
Embodiment 362
(2R)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-
4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝475.2
Embodiment 363
(2S)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝475.2
Embodiment 364
[1-(hydroxymethyl) cyclopentyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝489.3
Embodiment 365
[(1R, 2R)-2-hydroxycyclopent base] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-
4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝475.2
Embodiment 366
[2-(hydroxymethyl) cyclohexyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝503.3
Embodiment 367
[(2R)-the 2-hydroxy-cyclohexyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝489.3
Embodiment 368
[(1R)-2-hydroxyl-1-phenylethyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl
Base]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝511.2
Embodiment 369
[(1R)-2-hydroxyl-1-methylethyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl
Base]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝449.2
Embodiment 370
[(1R)-1-(hydroxymethyl) propyl group] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-
4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝463.2
Embodiment 371
[(1R)-1-(hydroxymethyl)-2-methyl-propyl] carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino)
Carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝477.2
Embodiment 372
[(2R)-the 2-hydroxypropyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝449.2
Embodiment 373
(3-hydroxyl-1-phenyl propyl) carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝525.3
Embodiment 374
[(1R)-1-(hydroxymethyl)-3-methyl butyl] carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino)
Carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝491.2
Embodiment 375
4-formyl piperazine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl piperazine
Piperazine-1-yl) carbonyl] cyclohexyl ester
Employing prepares these compounds with the similar method of method of embodiment 72.LCMS：(M+H) +＝488.2
Embodiment 376
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-3-yl methoxy
Base) cyclohexane carboxamide
In 0 ℃, the tetrahydrofuran (THF) (o.212ml) of uncle 1.00M-butanols potassium is joined (1S, 2S, 5R)-and 5-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexahydrobenzoic acid methyl ester (36.8mg, 0.000106mol) and 4-(chloro methyl) pyridine hydrochloride (17.4mg, 0.106mmol) tetrahydrofuran (THF) (1.0mL is 0.012mol) in the solution.After 10 minutes, be added in the 3-chloro picoline among the THF.Under room temperature, stirred 1 hour, then through the HPLC purifying.
(0.7ml) joins (1S for preparing above with the 1.5M hydroxylamine solutions, 2S, 5R)-and 2-[(4-phenylpiperazine-1-yl) carbonyl]-(0.075mmol, (0.5mL is 0.01mol) in the solution for methyl alcohol 0.000075mol) for 5-(pyridin-3-yl methoxyl group) hexahydrobenzoic acid methyl ester.Under room temperature, stirred 2 hours, then through the Prep-HPLC purifying.LCMS：(M+H) +＝439.3
Embodiment 377
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝425.2
Embodiment 378
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 379
(1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(4-phenyl-3,6-two
Pyridinium hydroxide-1 (2H)-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝459.2
Embodiment 380
(1S, 2S, 5R)-and N-hydroxyl-5-(4-hydroxyphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝440.1
Embodiment 381
(1S, 2S, 5R)-and N-hydroxyl-5-[(4-methoxyl group cyclohexyl) the oxygen base]-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝460.2
Embodiment 382
(1S, 2S, 5R)-and N-hydroxyl-5-(4-methoxyl group phenoxy group)-2-[(4-phenyl-3, the 6-dihydropyridine-
1 (2H)-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝437.1
Embodiment 383
(1S, 2S, 5R)-and N-hydroxyl-5-[(4-methoxyl group cyclohexyl) the oxygen base]-2-[(4-phenyl-3, the 6-dihydro
Pyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝457.2
Embodiment 384
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-{[2-(trifluoromethyl) quinoline
Quinoline-4-yl] the oxygen base } cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝543.2
Embodiment 385
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-2-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 386
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-3-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.1
Embodiment 387
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-5-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.1
Embodiment 388
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-7-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 389
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-8-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.1
Embodiment 390
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyrrole
Pyridine-2-base oxygen base) cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝422.1
Embodiment 391
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyrrole
Pyridine-4-base oxygen base) cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝422.1
Embodiment 392
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(quinoline
Quinoline-6-base oxygen base) cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝472.1
Embodiment 393
(1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(4-Phenylpiperidine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 317.LCMS：(M+H) +＝458.3
Embodiment 394
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝424.2
Embodiment 395
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝424.2
Embodiment 396
(1S, 2S, 5R)-and N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base)
Cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝474.2
Embodiment 397
(1S, 2S, 5R)-and 5-(3-chloro phenoxy group)-N-hydroxyl-2-[(4-phenyl-3, the 6-dihydropyridine-
1 (2H)-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝455.1，457.1
Embodiment 398
(1S, 2S, 5R)-and 5-(3,4-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenyl-3, the 6-dihydropyridine
-1 (2H)-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝457.1
Embodiment 399
(1S, 2S, 5R)-and 5-(2,3-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenyl-3, the 6-dihydropyridine
-1 (2H)-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝457.1
Embodiment 400
(1S, 2S, 5R)-and N-hydroxyl-5-(isoquinolyl-1 oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 401
(1S, 2S, 5R)-and N-hydroxyl-5-(isoquinoline 99.9-3-base oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 402
(1S, 2S, 5R)-and N-hydroxyl-5-(isoquinoline 99.9-5-base oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 403
(1S, 2S, 5R)-and N-hydroxyl-5-(isoquinoline 99.9-7-base oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝475.2
Embodiment 404
(1S, 2S, 5R)-and N-hydroxyl-5-(2-naphthyl oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] ring
The hexane methane amide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝474.2
Embodiment 405
(1S, 2S, 5R)-and 5-(2,4-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝460.1
Embodiment 406
(1S, 2S, 5R)-and 5-(3,5-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝460.1
Embodiment 407
(1S, 2S, 5R)-5-(3-chloro-4-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl)
Carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝476.1，478.1
Embodiment 408
(1S, 2S, 5R)-and 5-(3,4-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝492.1，494.1
Embodiment 409
(1S, 2S, 5R)-and 5-(3,5-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl
Base] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝492.1，494.1
Embodiment 410
(1S, 2S, 5R)-5-(2,5-dioxo tetramethyleneimine-1-yl)-N-hydroxyl-2-[(4-phenylpiperazine-1-
Base) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝429.2
Embodiment 411
(1S, 2S, 5R)-5-(5,5-dimethyl-2,4-dioxo-1,3-_ azoles alkane-3-yl)-N-hydroxyl-2-
[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝459.2
Embodiment 412
(1S, 2S, 5R)-N-hydroxyl-5-(3-methyl-2,5-dioxo alkyl imidazole-1-yl)-2-[(4-phenyl
Piperazine-1-yl) carbonyl] cyclohexane carboxamide
Employing prepares this compound with the similar method of method of embodiment 296.LCMS：(M+H) +＝442.1
Embodiment 413
(3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl]
Piperidines-3-base 2,5-dihydro-1H-pyrroles-1-carboxylicesters
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)(M+H)458.1。
Embodiment 414
(3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl]
Piperidines-3-base azepine ring-1-in heptan carboxylicesters
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)(M+H)488.1
Embodiment 415
Dimethylamino formic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)(M+H)434.1
Embodiment 416
Aza-octane-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)(M+H)502.2
Embodiment 417
(2S, 3S, 5S)-5-(2-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)457.2。
Embodiment 418
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(6-picoline-2-yl) the oxygen base]-the 2-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)454.2。
Embodiment 419
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-4-
Base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)440.1。
Embodiment 420
(2S, 3S, 5S)-5-(3-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)457.2。
Embodiment 421
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-
Base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)440.2。
Embodiment 422
(2S, 3S, 5S)-5-(1,3-benzothiazole-2-base oxygen base)-N-hydroxyl-1-methyl-2-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)469.1。
Embodiment 423
(2S, 3S, 5S)-N-hydroxyl-1-methyl-5-(3-methylphenoxy)-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)453.2。
Embodiment 424
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-the 2-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)454.2。
Embodiment 425
(2S, 3S, 5S)-5-(3,4-phenyl-difluoride oxygen base)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-
The 1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)475.1。
Embodiment 426
(2S, 3S, 5S)-5-(2-chloro phenoxy group)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl)
Carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)473.2。
Embodiment 427
3,3-two fluoropyrrolidines-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-
[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.MS(ESI)(M+H)：496.1。
Embodiment 428
(2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline
-6-base oxygen base) piperidines-1-carboxylic acid methyl ester
Employing prepares these compounds .ESI (MS) with the similar method of method of embodiment 126: (M+H) 534.2.
Embodiment 429
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base]-5-(pyridin-3-yl oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)423.1。
Embodiment 430
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)423.0。
Embodiment 431
(2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(3-phenyl-2, the 5-dihydro-
1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)440.1。
Embodiment 432
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-phenoxy group-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-
The 1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(ESI)：(M+H)422.1。
Embodiment 433
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(ESI)：(M+H)423.1。
Embodiment 434
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-the 2-[(3-phenyl-
2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)437.1。
Embodiment 435
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(6-picoline-2-yl) the oxygen base]-the 2-[(3-phenyl-
2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)437.1。
Embodiment 436
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-
Base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)440.2。
Embodiment 437
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-3-
Base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)440.1。
Embodiment 438
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-toluquinoline-4-yl) the oxygen base]-the 2-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)504.2。
Embodiment 439
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-toluquinoline-4-yl) the oxygen base]-the 2-[(3-phenyl-
2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)487.2。
Embodiment 440
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-4-
Base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)490.3。
Embodiment 441
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base]-5-(quinoline-6-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)473.1。
Embodiment 442
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base]-5-(quinolyl-4 oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)473.1。
Embodiment 443
(2S, 3S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base)
Piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)426.1。
Embodiment 444
(2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-the 2-[(4-phenyl
Piperazine-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.MS(ESI)：(M+H)454.2。
Embodiment 445
(2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-2-[4-(4-cyano group-3,5-dimethyl benzene
Base)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Part 1.4-[(trifluoromethyl) alkylsulfonyl] oxygen base-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Under-78 ℃, nitrogen, (10.50g adds the tetrahydrofuran solution (55.96mL) of 1.00M hexamethyldisilane base Lithium Azide in tetrahydrofuran (THF) 0.05270mol) (200.0mL) solution to 4-oxo-1-piperidine carboxylic acid tert-butyl ester.In-78 ℃ stir 1 hour after, in the mixture that obtains, add solid N-phenyl two (fluoroform sulfimide) (20.00g, 0.05598mol).This reaction mixture in-78 ℃ of stirrings 2 hours, is warmed to room temperature then gradually, under room temperature, stirs and spend the night.Behind the reduction vaporization THF, residue is diluted with ether.With mixture 1NHCl, 1N NaOH and salt solution continuous washing.Then that organic layer is dry and be evaporated to dried.Residue is applied on the silicagel column, is used in the 0-20% eluent ethyl acetate in the hexane, obtain enol triflate (14.60g, 83.6%).MS(ESI)：(M+2-Boc)232.0。
Part 2.4-(4-hydroxyl-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Nitrogen bubble is fed the 4-[(trifluoromethyl) alkylsulfonyl] oxygen base-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (5.80g, 0.0175mol), 2; 6-dimethyl-4-(4; 4,5,5-tetramethyl--1; 3; the 2-two oxa-boron penta ring-2-base (dioxaborolan-2-yl) of mixing) phenol (4.82g, 0.0194mol) and salt of wormwood (7.26g is 0.0525mol) at N; dinethylformamide (50.0mL, 0.646mol) in the mixture in 10 minutes.In this reaction mixture, add then [1,1 '-two (diphenylphosphine) ferrocene]-complex compound of palladium chloride (II) and methylene dichloride (1: 1) (0.8g, 0.001mol).With the mixture that obtains in 80 ℃ of heated overnight.After the water quencher,, use ethyl acetate extraction with 1N HCl this mixture that neutralizes.With organic layer water, the salt water washing that merges, drying also is evaporated to dried.Residue is put on the post, be used in the 0-50%EtOAc wash-out in the hexane, obtain required product (4.36g, 82.09%).MS(ESI)：(M-Boc+2)204.0。
Part 3.4-(3,5-dimethyl-4-[(trifluoromethyl) alkylsulfonyl] oxygen base phenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
In-78 ℃, to 4-(4-hydroxyl-3, the 5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (2.30g, 0.00758mol) methylene dichloride (50.0mL, 0.780mol) add in the solution triethylamine (3.17mL, 0.0227mol), then add trifluoromethanesulfanhydride anhydride (1.40mL, 0.00834mol).Made reaction mixture slowly be warmed to room temperature with 1.5 hours.With saturated aqueous ammonium chloride quencher reactant, use ethyl acetate extraction.With the organic layer that the salt water washing merges, dry (sodium sulfate) also concentrates then.The residue that obtains obtains triflate through flash chromatography (with 0-10%EtOAc/ hexane wash-out), is yellow oil (3.10g, 93.91%).MS(ESI)：(M-Bu+1)：380.0。
Part 4.4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With 4-(3; 5-dimethyl-4-[(trifluoromethyl) alkylsulfonyl] oxygen base phenyl)-3; 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (2.80g; 0.00643mol) and zinc cyanide (1.51g; 0.0128mol) at N; (15.0mL, 0.194mol) mixture in outgased 15 minutes with nitrogen dinethylformamide.In this mixture, add four (triphenyl phosphine) palladium (O) (0.74g, 0.00064mol).This reaction mixture was heated 4 hours in 100 ℃.Mixture is diluted with ether, with sodium bicarbonate aqueous solution, salt water washing, through dried over mgso and vacuum-evaporation.Residue is used in the 0-10%EtOAc wash-out in the hexane through silica gel purification, to generate title compound (1.08g, 53.66%).LCMS(M+H)313.1
Part 5. (2S, 3S, 5R)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5-hydroxy piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester
(1) under room temperature, with 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3, (0.88g 0.0028mol) handled 1 hour with 5mL TFA 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester.Be evaporated to do after, the tfa salt of generation is directly used in next step.
(2) in 0 ℃, to (2S, 3S, 5R)-5-hydroxyl-3-(methoxycarbonyl) piperidines-2-carboxylic acid (0.477g, 0.00235mol) and the tfa salt for preparing above at N, (2.38mL 0.0308mol) in the mixture in, adds benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (1.24g to dinethylformamide, 0.00282mol), then add N, and the N-diisopropylethylamine (0.981mL, 0.00563mol).The mixture that stirring obtains under room temperature 3 hours.After the sodium bicarbonate aqueous solution quencher, with this mixture of dichloromethane extraction.Dry organic layer and the reduction vaporization that merges.
(3) (4.77mL 0.0744mol) dilutes residue, uses N, and (0.818mL 0.00469mol) handles the N-diisopropylethylamine, and then (1.02g, 0.00469mol) processing is spent the night with two dimethyl dicarbonate butyl esters under room temperature to use methylene dichloride then.With sodium bicarbonate aqueous solution diluting reaction thing, use ethyl acetate extraction.The dry organic layer that merges is used the salt water washing, and dry and vacuum-evaporation is extremely done.Residue is put on the silica gel, be used in the 0-100%EtOAc wash-out in the hexane, obtain required product (790mg, 67.64%).MS(ESI)：(M-Boc+2H)398.1。
Part 6. (2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester
To (2S, 3S, 5R)-2-[4-(4-cyano group-3, the 5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5-hydroxy piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (100mg, tetrahydrofuran (THF) (0.912mL 0.0002mol), 0.0112mol) in the solution, add 5-chloro-pyridine-3-alcohol (35.0mg, 0.000270mol), triphenyl phosphine (70.8mg, 0.000270mol), then add azo-2-carboxylic acid's diisopropyl ester (0.0532mL, 0.000270mol).In 70 ℃, this mixture heating up is spent the night.Be concentrated into do after, through this mixture of silica gel purification, be used in the 0-40%EtOAc wash-out in the hexane, obtain required product (45mg, 32.84%).MS(ESI)(M+H)609.1。
Part 7. adopts the similar method of method with embodiment 152, methanol solution with azanol is handled (2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-2-[4-(4-cyano group-3, the 5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl piperidines-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester obtains title product.ESI MS：(M+H)510.1。
Embodiment 446
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-[(6-picoline-2-yl) oxygen base] piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 445.ESI MS：(M+H)490.1。
Embodiment 447
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-[(4-picoline-2-yl) oxygen base] piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 445.ESI MS：(M+H)490.2。
Embodiment 448
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-(pyridine-2-base oxygen base) piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 445.ES IMS：(M+H)476.2。
Embodiment 449
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-Phenoxypiperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 445.ES IMS：(M+H)475.2。
Embodiment 450
(2S, 3S, 5S)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyrrole
Pyridine-2-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds .ES IMS:(M+H with the similar method of method of embodiment 152) 423.1.
Embodiment 451
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-[(3-methyl isophthalic acid H-pyrazoles-5-yl) oxygen base] piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 445.ESI MS：(M+H)497.1。
Embodiment 452
(2S, 3S, 5S)-and N-hydroxyl-5-[(5-methyl is different _ azoles-3-yl) and the oxygen base]-2-[(3R)-the 3-phenyl pyrazoline
Cough up alkane-1-yl] carbonyl piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 415.1.
Embodiment 453
(2S, 3S, 5S)-and N-hydroxyl-5-[(3-methyl isophthalic acid H-pyrazoles-5-yl) the oxygen base]-2-[(3R)-the 3-phenyl
Tetramethyleneimine-1-yl] carbonyl piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 414.1.
Embodiment 454
(2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-the N-hydroxyl-2-[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 445.1.
Embodiment 455
(2S, 3S, 5S)-and N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 425.0.
Embodiment 456
(2S, 3S, 5S)-the N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl-5-(pyridine-2-base
The oxygen base) piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 411.1.
Embodiment 457
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-5-(3,4-phenyl-difluoride oxygen base)-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 511.1.
Embodiment 458
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-[(5-methyl is different _ azoles-3-yl) and the oxygen base] piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 480.1.
Embodiment 459
(2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-N-hydroxyl-5-[(2-toluquinoline-4-yl) oxygen base] piperidines-3-methane amide
Employing prepares these compounds .ESI MS:(M+H with the similar method of method of embodiment 152) 540.1.
Embodiment 460
(2S, 3S, 5S)-and N-hydroxyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(3R)-the 3-phenylpyrrole
Alkane-1-yl] carbonyl piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 296.ESI MS：(M+H)475.1。
Embodiment 461
(2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl
Base-5,5-two fluoro-N-hydroxyls-1-methyl piperidine-3-methane amide
Part 1. (2S, 3S)-5,5-difluoro piperidines-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester
Under room temperature, with 2-methoxyl group-N-(2-methoxy ethyl)-N-(three fluoro-＜λ〉(4)-sulfane base) ethamine (1.25mL, 0.00680mol) (the 2S of processing in being equipped with the teflon bottle of nitrogen inlet tube and stirring rod, 3S)-5-oxo-piperidine-1,2,3-tricarboxylic acid 1,2-dibenzyl ester 3-tert-butyl ester (1.87g, 0.00400mol) methylene dichloride (3.00mL, 0.0468mol) solution.(0.047mL 0.00080mol), stirs this mixture and to spend the night under room temperature to add ethanol.After finishing, this solution is poured in the saturated sodium bicarbonate, uses dichloromethane extraction, dry and vacuum-evaporation.Flash chromatography on silica gel through with 0-10%EtOAc/ hexane wash-out obtains pure product (370mg, 18.9%).MS(ESI)：(M+Na)512.1。Product is mixed with on a small quantity the corresponding vinyl of (inseparable) and fluoridizes thing (M+Na) 493.1.
Part 2. (2S, 3S)-3-(uncle-butoxy carbonyl)-5,5-difluoro piperidines-2-carboxylic acid
Will (2S, 3S)-5,5-difluoro piperidines-1,2,3-tricarboxylic acid 1, (0.370g, EtOH 0.000756mol) (7.0mL) solution are in the presence of 10%Pd/C, and hydrogenation is 2 hours under hydrogen bag pressure power for 2-dibenzyl ester 3-tert-butyl ester.Behind the filtration catalizer, evaporated filtrate is to doing.Residue is directly used in next step (190mg, 94.77%) .LC MS (M-Bu+1) 210.0.
Part 3. (2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5,5-difluoro piperidines-3-carboxylic acid tert-butyl ester
To (2S, 3S)-3-(uncle-butoxy carbonyl)-5,5-difluoro piperidines-2-carboxylic acid (48mg, 0.00018mol) and 2,6-dimethyl-4-(1,2,3,6-tetrahydropyridine-4-yl) benzonitrile hydrochloride (84.7mg, 0.000217mol) tfa salt is at N, (0.406mL 0.00524mol) in the mixture in, adds benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (96.0mg to dinethylformamide, 0.000217mol), then add N, and the N-diisopropylethylamine (0.0756mL, 0.000434mol).Under room temperature, stir this mixture overnight, use the sodium bicarbonate aqueous solution quencher then.Mixture is extracted with EtOAc.With organic layer water, the salt water washing that merges, dry and be evaporated to dried.Residue is directly used in next step and need not be further purified.LCMS(M+H)460.2。
Part 4 (2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5,5-two fluoro-1-methyl piperidines-3-carboxylic acid tert-butyl ester
With the crude reaction mixture that derives from 3256-82 with acetonitrile (0.64mL, 0.012mol) and tetrahydrofuran (THF) (0.64mL 0.0078mol) dilutes.The aqueous solution (0.035mL) that in this mixture, adds 12.32M formaldehyde, then add sodium triacetoxy borohydride (92mg, 0.00044mol).In stir under the room temperature spend the night after, this mixture is evaporated to dried, with the sodium bicarbonate aqueous solution dilution, extract with EtOAc.With organic layer water, the salt water washing and dry that merges.Be evaporated to do after, residue is directly used in next step.LCMS(M+H)474.2。
Part 5. (2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5,5-two fluoro-N-hydroxyls-1-methyl piperidine-3-methane amide
(1) under room temperature, handle (2S, 3S)-5,5-two fluoro-2-[(4-[(2-toluquinoline-4-yls) methoxyl group with 0.5mL TFA] phenyl amino)-carbonyl] piperidines-3-carboxylic acid tert-butyl ester 30 minutes.Behind the evaporation TFA, residue is exposed in the high vacuum, is directly used in next step then.
(2) the crude product tfa salt for preparing upward is at N, dinethylformamide (0.20mL, 0.0025mol) in mixture in, add N-hydroxy amine hydrochloric acid salt (7.44mg, 0.000107mol) and benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphates (47.4mg, 0.000107mol).Stir after 10 minutes, in this mixture, add N, and the N-diisopropylethylamine (0.0373mL, 0.000214mol).The mixture that obtains stirred under room temperature spend the night.Crude mixture directly is applied on the RP-HPLC, generates required product, be tfa salt.LC MS(M+H)433.1。
Embodiment 462
(2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl
Base-5,5-two fluoro-N-hydroxy piperidine-3-methane amides
Employing prepares this compound with the similar method of method of embodiment 461.LC MS(M+H)419.1。
Embodiment 463
(2S, 3S)-5,5-two fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3, the 6-dihydropyridine-
1 (2H)-yl] carbonyl-1-methyl piperidine-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 461.LC MS(M+H)422.2。
Embodiment 464
(2S, 3S)-5,5-two fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3, the 6-dihydropyridine-
1 (2H)-yl] carbonyl piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 461.LC MS(M+H)408.15.
Embodiment 465
(2S, 3S)-5,5-two fluoro-N (3)-hydroxyls-1-methyl-N (2)-4-[(2-toluquinoline-4-yl) first
The oxygen base] Phenylpiperidine-2, the 3-diformamide
Employing prepares this compound with the similar method of method of embodiment 461.LC MS(M+H)485.1。
Embodiment 466
(2S, 3S)-5,5-two fluoro-N (3)-hydroxy-n (2)-4-[(2-toluquinoline-4-yl) methoxyl group] benzene
Phenylpiperidines-2, the 3-diformamide
Employing prepares this compound with the similar method of method of embodiment 461.LC MS(M+H)471.1。
Embodiment 467
Azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-[(4-[(2-methyl quinoline
Quinoline-4-yl) methoxyl group] phenyl amino) carbonyl] piperidines-3-base ester
Employing prepares these compounds .LC MS (M+H) 576.2 with the similar method of method of embodiment 204.
Embodiment 468
(2S, 3S, 5R)-and 5-fluoro-N (3)-hydroxy-n (2)-4-[(2-toluquinoline-4-yl) methoxyl group] benzene
Phenylpiperidines-2, the 3-diformamide
Step 1: make (2S, 3S, 5S)-1-benzyl-5-hydroxy piperidine-2,3-dicarboxylic acid 2-benzyl 3-methyl ester (1.89g, 0.00493mol) be dissolved in methylene dichloride (2.7mL, 0.042mol) in, be cooled to-78 ℃, (0.650mL, 0.00492mol) (DAST) handles to use the diethylamino sulfur trifluoride then.Make the reaction mixture that obtains be warmed to room temperature, under room temperature, stirred 18 hours.The reaction mixture impouring is contained NaHCO 3Frozen water in, use CH 2Cl 2(3x) extract.Organic layer is through Na 2SO 4Drying concentrates and (is used in CH through silica gel purification 2Cl 2In 0～5%MeOH wash-out).Must measure: 1.73g, 91.24%.LCMS(M+H)386.1
Step 2: (1.73g, (20mL 0.5mol) adds 0.34g Pd/C (10%wt is stated from the activated carbon, wet product) to methyl alcohol 0.00449mol) to Zhi Bei product in the solution, under 43psi hydrogen, hydrogenation is 3 hours in the par electromagnetic shaker then upward.After the filtration, concentrating under reduced pressure filtrate, dry under high vacuum, obtain (2S, 3S, 5R)-and 5-fluoro-3-(methoxycarbonyl) piperidines-2-carboxylic acid, be white solid.LC-MS (M+H)206.1
Step 3: to (2S, 3S, 5R)-5-fluoro-3-(methoxycarbonyl) piperidines-2-carboxylic acid (75.0mg, 0.000366mol) and 4-[(2-toluquinoline-4-yl) methoxyl group] aniline dihydrochloride (148mg, 0.000439mol) at N, dinethylformamide (0.56mL, 0.0073mol) in mixture in, add benzotriazole-1-base oxygen base three (dimethylamino) _ hexafluorophosphate (194mg, 0.000439mol), then add N, and the N-diisopropylethylamine (0.229mL, 0.00132mol).Under room temperature, stirred 2 hours,, extract with EtOAc with reactant sodium bicarbonate aqueous solution quencher.With the organic layer that the salt water washing merges, dry and reduction vaporization is extremely done.Residue is directly used in next step.LCMS(M+H)452.1。
Step 4: under room temperature, methyl alcohol (2.161mL) solution (by azanol HCl salt and sodium methylate preparation) with 1.640M N-oxyamine is handled (2S, 3S, 5R)-and 5-fluoro-2-[(4-[(2-toluquinoline-4-yl) methoxyl group]-phenyl amino) carbonyl] piperidines-3-carboxylic acid methyl ester (80.0mg, 0.000177mol) 2 hours.After the acidifying of 1: 1 TFA/ water, mixture is directly carried out RP-HPLC, obtain product, be tfa salt.LC MS(M+H)453.0。
Embodiment 469
Azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-[(2-
Toluquinoline-4-yl) methoxyl group] phenyl amino) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.LCMS(M+H)＝590.2。
Embodiment 470
Azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-and 6-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-two
Pyridinium hydroxide-1 (2H)-yl] carbonyl-5-[(hydroxyl amino) carbonyl] piperidines-3-base ester
Employing prepares these compounds with the similar method of method of embodiment 204.LCMS(M+H)524.2。
Embodiment 471
(2S, 3S, 5R)-5-fluoro-N-hydroxyl-1-methyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl
Piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 468.LCMS(M+H)350.1。
Embodiment 472
(2S, 3S, 5R)-5-fluoro-N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-
Methane amide
Employing prepares this compound with the similar method of method of embodiment 468.LCMS(M+H)336.1。
Embodiment 473
(2S, 3S, 5S)-and N-hydroxyl-5-phenoxy group-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl
Base] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)408.2。
Embodiment 474
(2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyrrole
Pyridine-2-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)409.2，(M+Na)431.2
Embodiment 475
(2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyrrole
Pyridine-4-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)409.2，(M+Na)431.2
Embodiment 476
(2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyrrole
Pyridine-3-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)409.2，(M+Na)431.2
Embodiment 477
(2S, 3S, 5S)-and N-hydroxyl-5-[(6-picoline-2-yl) the oxygen base]-2-[(3-phenyl-2, the 5-dihydro
-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)423.2
Embodiment 478
(2S, 3S, 5S)-and N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(3-phenyl-2, the 5-dihydro
-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)423.2
Embodiment 479
(2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles
-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)426.2
Embodiment 480
(2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinoline
Quinoline-6-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)459.2
Embodiment 481
(2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinoline
Quinoline-7-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)459.2
Embodiment 482
(2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinoline
Quinoline-4-base oxygen base) piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)459.2
Embodiment 483
(2S, 3S, 5S)-and N-hydroxyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(3-phenyl-2, the 5-dihydro
-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 152.LCMS(M+H)473.2.
Embodiment 484
(2S, 3S, 5R)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-5-fluoro-N-hydroxy piperidine-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 468. and (M+H) 401.2.
Embodiment 485
(2S, 3S, 5R)-and 5-fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-
Base] carbonyl piperidines-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 468. and (M+H) 390.2.
Embodiment 486
(2S, 3S, 5R)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl]
Carbonyl-5-fluoro-N-hydroxyl-1-methyl piperidine-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 468. and (M+H) 415.2.
Embodiment 487
(2S, 3S, 5R)-and 5-fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-
Base] carbonyl-1-methyl piperidine-3-methane amide
Employing prepares this compound with the similar method of method of embodiment 468.LCMS (M+H) 404.2 (alkali)
Embodiment 488
(1S, 2S, 5E)-and 5-benzylidene-2-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxyl cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 241.The crude product product is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2(contain 0.05%TFA, pH=2.5) wash-out obtains the trans product [peak 1,3.6mg, 14% yield, (M+H)=459.2] into colorless solid and is the cis-product [peak 2,1.9mg, 7% yield, (M+H)=459.2] of colorless solid O.
Embodiment 489
(1S, 2S, 5E)-and 2-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-5-(cyclopropyl methylene radical)-N-hydroxyl cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 241.The crude product product is used 5-95%MeCN/H through the reversed-phase HPLC purifying 2O (containing 0.05%TFA) wash-out, obtain into colorless solid trans product [peak 1,12.0mg, 20% yield, (M+H)=423.2] and as the cis-product of colorless solid [peak 2,6.4mg, 11% yield, (M+H)=423.2].
Embodiment 490
(1S, 2S, 5E)-5-benzylidene-N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] the carbonyl ring
The hexane methane amide
Employing prepares these compounds with the similar method of method of embodiment 241.The crude product product is through the reversed-phase HPLC purifying, (contain 0.05%TFA with 5-95%MeCN/H2O, pH=2) wash-out, obtain trans product [peak 1,20.5mg, 48% yield for colorless solid, ] and be the cis-product [peak 2 of colorless solid (M+H)=405.1,9.4mg, 22% yield, (M+H)=405.2].
Embodiment 491
(1S, 2S, 5S)-and N, 5-dihydroxyl-5-isobutyl--2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-
Base) carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 244.LCMS(M+Na)＝423.2。
Embodiment 492
(1S, 2S, 5S)-and 5-butyl-N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl)
Carbonyl] cyclohexane carboxamide
Employing prepares these compounds with the similar method of method of embodiment 243.LCMS(M+H)＝401.2。
Embodiment 493
Azetidine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-1-methyl-4-[(4-
Phenylpiperazine-1-yl) carbonyl] cyclohexyl ester trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 204.LCMS(M+H)＝445.2。
Embodiment 494
Tetramethyleneimine-1-carboxylicesters (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-1-methyl-4-[(4-phenyl
Piperazine-1-yl) carbonyl] cyclohexyl trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 204.LCMS(M+Na)＝481.2。
Embodiment 495
(1S, 2S, 5S)-and N, 5-dihydroxyl-5-isobutyl--2-[(4-phenylpiperazine-1-yl) carbonyl] hexamethylene
Alkane methane amide trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 244.LCMS(M+H)＝404.0。
Embodiment 496
(1S, 2S, 5R)-and 5-(cyclopropyl methyl)-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]
Cyclohexane carboxamide trifluoroacetate (salt)
Employing prepares these compounds .LC MS (M+H)=402.1 with the similar method of method of embodiment 243.
Embodiment 497
(1S, 2S, 5R)-and 5-butyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene
Methane amide trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 244.The crude product product is through the reversed-phase HPLC purifying, with 5-95%MeCN/H2O (containing 0.05%TFA) wash-out, obtain for the ax of colorless solid axially-OH product [peak 2,9.1mg, 5% yield, two steps, (M+H)=404.2] and be the eq of colorless solid calm-OH product [peak 1,1.5mg, 1% liang of step yield, (M+H)=404.2].
Embodiment 498
Tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-1-methyl-4-[(4-phenyl
Piperazine-1-yl) carbonyl] cyclohexyl ester trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 204.LCMS(M+H)＝459.2。
Embodiment 499
(1S, 2S, 5E)-5-(cyclopropyl methylene radical)-N-hydroxyl-2-[(3R)-3-Phenylpyrrolidine-1-yl]
The carbonyl-cyclohexane methane amide
Employing prepares these compounds with the similar method of method of embodiment 241.The crude product material with 5-95%MeCN/H2O (containing 0.05%TFA) wash-out, obtains peak 1[9.8mg through the reversed-phase HPLC purifying, 33% yield, (M+H)=369.2], be colorless solid, and peak 2[7.6mg, 25% yield, (M+H)=369.2], be colorless solid.
Embodiment 500
(1S, 2S, 5R)-and 5-ethyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] hexanaphthene
Methane amide trifluoroacetate (salt)
Employing prepares these compounds with the similar method of method of embodiment 244.The crude product raw material is through the reversed-phase HPLC purifying, with 5-95%MeCN/H2O (containing 0.05%TFA) wash-out, obtain axial ax-OH product [peak 2 for colorless solid, 39.1mg, 22% liang of step yield, (M+H)=376.2] and be calm eq-OH product [peak 1, the 25.0mg of colorless solid, 14% liang of step yield, (M+H)=376.2].
Embodiment 501
(3R, 4S)-1-[(E)-(cyanoimino) (cyclopropyl amino) methyl]-4-[4-(4-cyano group-2-first
The base phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)＝476.2。
Embodiment 502
(3R, 4S)-1-[(E)-(cyanoimino) (dimethylamino) methyl]-4-[4-(4-cyano group-2-first
The base phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)＝464.2。
Embodiment 503
(3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-methyl
Phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)507.2。
Embodiment 504
(3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-
The 2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)476.1。
Embodiment 505
(3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-
The 2-aminomethyl phenyl) piperidines-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)478.1。
Embodiment 506
(3R, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-4-[4-(4-cyano group-2-first
The base phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)＝490.2
Embodiment 507
(3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-methyl
Phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)504.2。
Embodiment 508
(3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-methyl
Phenyl) piperidines-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
Employing prepares these compounds with the similar method of method of embodiment 220.LCMS(M+H)＝506.2。
More than illustrational All new compounds feature be summarized in the table 1-table 7.
Table 1
Figure A20048003718803211
Ex. R QY MS
42 Tetrahydrofuran (THF)-(3S)-Ji oxo-carbonyl 4-(3-sec.-propyl-phenyl)-piperidyl 488.2
43 Tetrahydrofuran (THF)-(3R)-Ji oxo-carbonyl 4-(3-sec.-propyl-phenyl)-piperidyl 488.2
44 Tetrahydropyran-4-base oxo-carbonyl 4-(3-sec.-propyl-phenyl)-piperidyl 502.2
45 Tetrahydrofuran (THF)-(3R)-Ji oxo-carbonyl 4-phenyl-Piperazine base 447.2
46 Tetrahydrofuran (THF)-(3S)-Ji oxo-carbonyl The 4-phenyl-Piperazine 447.2
47 Tetrahydropyran-4-base oxo-carbonyl The 4-phenyl-Piperazine 461.2
71 Tetrahydrofuran (THF)-(3S)-Ji oxo-carbonyl 4-(4-tert-butyl-phenyl)-piperazinyl 503.3
Table 2
Figure A20048003718803212
Ex. R R 1/R 2 QY MS
1 H (R)-[(3R)-hydroxyl-pyrroline-1-yl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 454.1
2 H (RS)-[(2-dimethylamino-ethylamino formyl radical)-methyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 497
3 H (R)-{ [2-(3R)-hydroxyl-tetramethyleneimine-1-yl]-2-oxo-ethyl } 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 496.2
3 H (S)-{ [2-(3R)-hydroxyl-tetramethyleneimine-1-yl]-2-oxo-ethyl } 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 496.2
4 H (S)-(2-morpholine-4-base-2-oxo-ethyl) 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 496.2
4 H (R)-(2-morpholine-4-base-2-oxo-ethyl) 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 496.2
5 H (R)-[2-(4-hydroxy-piperdine-1-yl)-2-oxo-ethyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 510.3
5 H (S)-[2-(4-hydroxy-piperdine-1-yl)-2-oxo-ethyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 510.3
6 H (R)-[(2-methoxyl group-ethanoyl)-methyl-amino] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 473.2
6 H (S)-[(2-methoxyl group-ethanoyl)-methyl-amino] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 473.2
7 H (S)-[(2-methoxyl group-ethylamino formyl radical)-methyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 484.2
7 H (R)-[(2-methoxyl group-ethylamino formyl radical)-methyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 484.2
8 H (S)-[(tetrahydrochysene-furans-(3R)-the Ji formamyl)-methyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 496.2
8 H (R)-[(tetrahydrochysene-furans-(3R)-the Ji formamyl)-methyl] 4-(4-cyano group-2-methyl-phenyl)-3,6-dihydro-2H-pyridyl 496.2
9 H (R)-[methoxyl group-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 392.2
9 H (S)-[methoxyl group-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 392.2
10 H (RS)-hydroxyl (3R)-phenyl-pyrrolidyl 334.2
11 H (RS)-[methylamino-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 391.2
48 H (RS)-the amino amyl group of 2-[(5-Cbz-) amino]-the 2-oxoethyl } (3RS)-phenyl-pyrrolidyl 594
49 H (RS)-(2-[(5-amino amyl group) amino]-the 2-oxoethyl } (3RS)-phenyl-pyrrolidyl 460
54 H (R)-hydroxyl 4-(3-sec.-propyl-phenyl)-3,6-dihydro-2H-pyridyl 388.3
54 H (S)-hydroxyl 4-(3-sec.-propyl-phenyl)-3,6-dihydro-2H-pyridyl 388.3
55 H (R)-hydroxyl 4-phenyl-Piperazine base 349.3
55 H (S)-hydroxyl 4-phenyl-Piperazine base 349.3
56 H (R)-(2-morpholine-4-base-2-oxo-ethyl) 4-phenyl-Piperazine base 460.3
56 H (S)-(2-morpholine-4-base-2-oxo-ethyl) 4-phenyl-Piperazine base 460.3
57 H (R)-hydroxyl 4-(3-sec.-propyl-phenyl)-piperidyl 390.2
57 H (S)-hydroxyl 4-(3-sec.-propyl-phenyl)-piperidyl 390.2
58 H (S)-(2-morpholine-4-base-2-oxo-ethyl) 4-(3-sec.-propyl-phenyl)-piperidyl 501.3
58 H (S)-(2-morpholine-4-base-2-oxo-ethyl) 4-(3-sec.-propyl-phenyl)-piperidyl 501.3
70 Me (R)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 445.2
70 Me (S)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 445.2
81 H (R)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-3,6-dihydro-2H-pyridyl 443.2
82 H (R)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-piperidyl 445.5
84 H (S)-(2-oxo-2-piperidines-1-base-ethyl) (3R)-phenyl-pyrrolidyl 443.3
85 H (R)-(2-oxo-2-tetramethyleneimine-1-base-ethyl) (3R)-phenyl-pyrrolidyl 429.3
85 H (S)-(2-oxo-2-tetramethyleneimine-1-base-ethyl) (3R)-phenyl-pyrrolidyl 429.3
86 H (RS)-(2-oxo-2-tetramethyleneimine-1-base-ethyl) 4-phenyl-Piperazine base 444.0
87 H (RS)-(2-oxo-2-piperidines-1-base-ethyl) 4-phenyl-Piperazine base 458.2
88 Me (RS)-(2-oxo-2-piperidines-1-base-ethyl) 4-phenyl-Piperazine base 472.1
89 Me (RS)-(2-oxo-2-tetramethyleneimine-1-base-ethyl) 4-phenyl-Piperazine base 458.2
90 Me (RS)-(2-oxo-2-piperidines-1-base-ethyl) (3R)-phenyl-pyrrolidyl 457.1
91 Me (RS)-(2-oxo-2-tetramethyleneimine-1-base-ethyl) (3R)-phenyl-pyrrolidyl 443.0
93 H (RS)-(isobutyryl-methyl-amino) (3R)-phenyl-pyrrolidyl 417.2
94 H (RS)-(isobutyryl-methyl-amino) 3-phenyl-2,5-dihydro-pyrryl 415.2
95 H (RS)-(isobutyryl-methyl-amino) 4-phenyl-3,6-dihydro-2H-pyridyl 429.2
96 H (RS)-(isobutyryl-methyl-amino) 4-phenyl-piperidyl 431.3
97 H (RS)-(isobutyryl-methyl-amino) 4-phenyl-Piperazine base 432.3
103 H (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 431.2
104 H (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-Piperazine base 446.2
105 H (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 3-phenyl-2,5-dihydro-pyrryl 429.2
106 CO 2Me (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 3-phenyl-2,5-dihydro-pyrryl 487.2
107 CO 2Me (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 489.2
108 CO 2Me (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-piperidyl 503.3
109 CO 2Me (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-3,6-dihydro-2H-pyridyl 501.2
110 CO 2Me (RS)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-Piperazine base 504.3
111 H (RS)-(benzoyl-methyl-amino) 4-phenyl-3,6-dihydro-2H-pyridyl 463.2
112 H (RS)-(benzoyl-methyl-amino) 4-phenyl-Piperazine base 466.2
113 H (RS)-[sec.-propyl-oxo carbonyl-(methyl) amino] 4-phenyl-Piperazine base 448.3
461 Me 5, the 5-difluoro 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 433.1
462 H 5, the 5-difluoro 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 419.1
463 Me 5, the 5-difluoro 4-(3-isopropyl phenyl-3,6-dihydropyridine-1 (2H)-Ji 422.2
464 H 5, the 5-difluoro 4-(3-isopropyl phenyl-3,6-dihydropyridine-1 (2H)-Ji 408.2
465 Me 5, the 5-difluoro 4-[(2-toluquinoline-4-yl) methoxyl group] phenyl amino 485.1
466 H 5, the 5-difluoro 4-[(2-toluquinoline-4-yl) methoxyl group] phenyl amino 471.1
468 H (5R)-F 4-[(2-toluquinoline-4-yl) methoxyl group] phenyl amino 453.0
471 Me (5R)-F (3R)-Phenylpyrrolidine-1-base 350.1
472 H (5R)-F (3R)-Phenylpyrrolidine-1-base 336.1
484 H (5R)-F 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 401.2
485 H (5R)-F 4-(3-isopropyl phenyl-3,6-dihydropyridine-1 (2H)-Ji 390.2
486 Me (5R)-F 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 415.2
487 Me (5R)-F 4-(3-isopropyl phenyl-3,6-dihydropyridine-1 (2H)-Ji 404.2
Table 3
Figure A20048003718803251
Ex. R R 1 QY MS
24 H (S)-hydroxyl (3R)-phenyl-pyrrolidyl 333.1
25 H (S)-hydroxyl 4-phenyl-3,6-dihydro-2H-pyridyl 345.1
26 H (S)-hydroxyl 4-phenyl-piperidyl 347.1
27 H (S)-hydroxyl 4-phenyl-Piperazine base 348.1
28 H (S)-hydroxyl 3-phenyl-2,5-dihydro-pyrryl 331.1
29 H (RS)-tetramethyleneimine 1-base (3R)-phenyl-pyrrolidyl 386.2
30 H (R)-[morpholine-4-yl] (3R)-phenyl-pyrrolidyl 402.2
31 H (S)-[morpholine-4-yl] (3R)-phenyl-pyrrolidyl 402.2
32 H (RS)-[(3R)-hydroxyl-tetramethyleneimine-1-yl] (3R)-phenyl-pyrrolidyl 402.2
33 H (S)-hydroxyl [4-(4-tert-butyl-phenyl)-piperazinyl 404.2
34 H (RS)-[tetrahydrochysene-furans-(3S)-Ji oxo carbonyl (methyl) amino] (3R)-phenyl-pyrrolidyl 460.2
35 H (RS)-[tetrahydrochysene-furans-(3R)-Ji oxo carbonyl (methyl) amino] (3R)-phenyl-pyrrolidyl 460.2
36 H (RS)-[tetrahydrochysene-pyrans-4-base oxo carbonyl (methyl) amino] (3R)-phenyl-pyrrolidyl 474.2
37 H (S)-[tetramethyleneimine-1-base ketonic oxygen base] (3R)-phenyl-pyrrolidyl 430.3
38 H (S)-[methylamino-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 390.2
39 H (S)-[dimethylamino-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 404.3
40 H (S)-[(morpholine-4-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 446.2
41 H (S)-[(3R)-hydroxyl-tetramethyleneimine-1-yl]-the ketonic oxygen base (3R)-phenyl-pyrrolidyl 446.3
50 H (RS)-(2-oxo-2-piperidines-1-base-ethyl) 4-phenyl-Piperazine base 457
51 H (RS)-(2-oxo-2-tetramethyleneimine-1-base-ethyl) 4-phenyl-Piperazine base 443
52 H (RS)-the 2-oxo-2-[(3R)-hydroxyl pyrrolidine-1-yl]-ethyl } 4-phenyl-Piperazine base 459
53 H (RS)-(2-oxo-2-piperidines-1-base-ethyl) [4-(2-methyl-quinolyl-4 methoxyl group)-phenyl]-amino 559
59 H (RS)-[2-(4-methyl-piperazine-1-yl)-2-oxo-ethyl] 4-phenyl-Piperazine base 472.2
60 H (RS)-(2-morpholine-4-base-2-oxo-ethyl) 4-phenyl-Piperazine base 459.2
61 H (RS)-[(2-methoxyl group-ethylamino formyl radical)-methyl] 4-phenyl-Piperazine base 447.2
62 H (S)-[methylamino-ketonic oxygen base] 4-phenyl-Piperazine base 405.1
63 H (S)-[dimethylamino-ketonic oxygen base] 4-phenyl-Piperazine base 419.1
64 H (S)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] 4-phenyl-Piperazine base 445.1
65 H (S)-[(piperidines-1-yl)-ketonic oxygen base] 4-phenyl-Piperazine base 459.2
66 H (S)-[(morpholine-4-yl)-ketonic oxygen base] 4-phenyl-Piperazine base 461.1
67 H (S)-[(3R)-hydroxyl-tetramethyleneimine-1-yl]-the ketonic oxygen base } 4-phenyl-Piperazine base 461.1
68 H (S)-[cyclopropyl amino-ketonic oxygen base] 4-phenyl-Piperazine base 431.1
72 H (R)-[(tetramethyleneimine-1-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 430.2
73 H (R)-[(morpholine-4-yl)-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 446.2
74 H (R)-[dimethylamino-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 404.2
75 H (R)-[methylamino-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 390.2
76 H (S)-[methylamino-ketonic oxygen base] (3R)-phenyl-pyrrolidyl 390.1
77 H (R)-methylsulfonyl amino (3R)-phenyl-pyrrolidyl 410.1
78 H (R)-acetylamino (3R)-phenyl-pyrrolidyl 374.2
83 H (S)-(2-oxo-2-piperidines-1-base-ethyl) 4-(3-sec.-propyl-phenyl)-piperidyl 498.3
83 H (R)-(2-oxo-2-piperidines-1-base-ethyl) 4-(3-sec.-propyl-phenyl)-piperidyl 498.3
92 H (RS)-(2-oxo-2-piperidines-1-base-ethyl) 4-phenyl-Piperazine base 457
115 n-Pr (S)-hydroxyl (3R)-phenyl-pyrrolidyl 375.2
115 n-Pr (R)-hydroxyl (3R)-phenyl-pyrrolidyl 375.2
116 H (S)-methylamino-ketonic oxygen base 4-(4-tert-butyl-phenyl)-piperazinyl 461.3
117 H (S)-dimethylamino-ketonic oxygen base 4-(4-tert-butyl-phenyl)-piperazinyl 475.3
118 H (S)-cyclopropyl amino-ketonic oxygen base 4-(4-tert-butyl-phenyl)-piperazinyl 487.3
119 H (S)-(tetramethyleneimine-1-base ketonic oxygen base) 4-(4-tert-butyl-phenyl)-piperazinyl 501.3
120 H (S)-[(3R)-hydroxyl pyrrolidine-1-base ketonic oxygen base] 4-(4-tert-butyl-phenyl)-piperazinyl 517.3
121 H (S)-(morpholine-4-base ketonic oxygen base) 4-(4-tert-butyl-phenyl)-piperazinyl 517.3
122 H (S)-(piperidines-1-base ketonic oxygen base) 4-(4-tert-butyl-phenyl)-piperazinyl 515.3
123 H (R)-methylamino-ketonic oxygen base 4-phenyl-3,6-dihydro-2H-pyridyl 402.1
124 H (R)-dimethylamino-ketonic oxygen base 4-phenyl-3,6-dihydro-2H-pyridyl 416.1
125 H (R)-(tetramethyleneimine-1-base ketonic oxygen base) 4-phenyl-3,6-dihydro-2H-pyridyl 442.1
Table 4
Ex. R QY MS
12 [tetrahydrochysene-pyrans-4-yl]-oxo-carbonyl (3R)-phenyl-pyrrolidyl 446.1
13 [(3R)-tetrahydrochysene-furans-3-yl]-oxygen base-carbonyl (3R)-phenyl-pyrrolidyl 432.1
14 [(3S)-tetrahydrochysene-furans-3-yl]-oxygen base-carbonyl (3R)-phenyl-pyrrolidyl 432.1
15 2-methoxyl group-ethyl oxygen base-carbonyl (3R)-phenyl-pyrrolidyl 420.1
16 [tetrahydrochysene-pyrans-4-yl]-oxo-carbonyl 4-phenyl-Piperazine base 461.2
17 [(3R)-tetrahydrochysene-furans-3-yl]-oxo-carbonyl 4-phenyl-Piperazine base 447.1
18 [(3S)-tetrahydrochysene-furans-3-yl]-oxo-carbonyl 4-phenyl-Piperazine base 447.2
19 2-methoxyl group-ethyl oxygen base-carbonyl 4-phenyl-Piperazine base 435.1
20 [tetrahydrochysene-pyrans-4-yl]-oxo-carbonyl 4-phenyl-piperidyl 460.2
21 [(3R)-tetrahydrochysene-furans-3-yl]-oxo-carbonyl 4-phenyl-piperidyl 446.2
22 [(3S)-tetrahydrochysene-furans-3-yl]-oxo-carbonyl 4-phenyl-piperidyl 446.2
23 2-methoxyl group-ethyl oxygen base-carbonyl 4-phenyl-piperidyl 444.2
69 Morpholine-4-carbonyl 4-phenyl-piperidyl 445.2
79 Piperidines-1-carbonyl 4-phenyl-piperidyl 443.2
80 Tetramethyleneimine-1-carbonyl 4-phenyl-piperidyl 429.2
98 4-trifluoromethoxy-benzoyl (3R)-phenyl-pyrrolidyl 506.2
99 4-trifluoromethoxy-benzenesulfonyl (3R)-phenyl-pyrrolidyl 542.0
100 3-trifluoromethoxy-benzoyl (3R)-phenyl-pyrrolidyl 506.2
101 2-trifluoromethoxy-benzoyl (3R)-phenyl-pyrrolidyl 506.0
102 4-difluoro-methoxy-benzoyl (3R)-phenyl-pyrrolidyl 488.2
Table 5
Figure A20048003718803291
Ex. R R 1 QY MS
126 CO 2Me The 3-fluorinated phenoxy 4-phenylpiperazine-1-base 501.2
127 CO 2Me 3-(trifluoromethyl) phenoxy group 4-phenylpiperazine-1-base 551.1
128 CO 2Me 2,4 difluorobenzene oxygen base 4-phenylpiperazine-1-base 519.0
129 CO 2Me 3-chloro-4-fluorinated phenoxy 4-phenylpiperazine-1-base 535.0
130 CO 2Me 5-chloro-pyridine-3-yl) oxygen base 4-phenylpiperazine-1-base 518.1
131 CO 2Me 3-bromo phenoxy group 4-phenylpiperazine-1-base 561.0
132 CO 2Me Pyridin-3-yl oxygen base 4-phenylpiperazine-1-base 484.1
133 CO 2Me Quinoline-6-base oxygen base 4-phenylpiperazine-1-base 534.1
134 CO 2Me The 3-methylphenoxy 4-phenylpiperazine-1-base 497.1
135 CO 2Me 3-methoxyl group phenoxy group 4-phenylpiperazine-1-base 513.1
136 CO 2Me (5-picoline-2-yl) oxygen base 4-phenylpiperazine-1-base 498.1
137 CO 2Me (2-toluquinoline-4-yl) oxygen base 4-phenylpiperazine-1-base 548.1 5
138 CO 2Me Phenoxy group 4-phenylpiperazine-1-base 438.2
139 CO 2Me 3-chloro phenoxy group 4-phenylpiperazine-1-base 517.0
140 CO 2Me 2,3-two fluorophenoxies 4-phenylpiperazine-1-base 519.1
141 CO 2Me Pyridine-2-base oxygen base 4-phenylpiperazine-1-base 484.1
142 CO 2Me Quinolyl-4 oxygen base 4-phenylpiperazine-1-base 534.1
143 CO 2Me Pyridin-4-yl oxygen base 4-phenylpiperazine-1-base 484.0 5
144 CO 2Me (4-picoline-2-yl) oxygen base 4-phenylpiperazine-1-base 498.2
145 CO 2Me The 2-fluorinated phenoxy 4-phenylpiperazine-1-base 501.1
146 CO 2Me The 2-methylphenoxy 4-phenylpiperazine-1-base 497.1
147 CO 2Me The 4-fluorinated phenoxy 4-phenylpiperazine-1-base 501.1
148 CO 2Me 3,5-two fluorophenoxies 4-phenylpiperazine-1-base 519.0
149 CO 2Me The 3-fluorinated phenoxy 4-phenylpiperazine-1-base 519.0
150 CO 2Me 1,3-benzothiazole-2-base 4-phenylpiperazine-1-base 540.1
151 CO 2Me 3,4-two fluorophenoxies 4-phenylpiperazine-1-base 519.0
152 Me Pyridin-4-yl oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 437.1
153 Me (4-picoline-2-yl) oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 451.1
154 Me Phenoxy group 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 436.0
155 Me The 3-fluorinated phenoxy 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 454.1
156 Me Quinoline-6-base oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 487.0
157 Me (2-toluquinoline-4-yl) oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 501.1
158 Me Pyridine-2-base oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 437.0
159 Me 3,5-two fluorophenoxies 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 472.1
160 Me Quinolyl-4 oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 486.9
161 Me Pyridin-4-yl oxygen base 4-Phenylpiperidine-1-base 439.2
162 Me (2-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-4-yl) oxygen base 4-Phenylpiperidine-1-base 507.2
163 Me (4-picoline-2-yl) oxygen base 4-Phenylpiperidine-1-base 453.0
164 Me Pyridine-2-base oxygen base 4-Phenylpiperidine-1-base 439.1
165 MeSO 2 Phenoxy group 4-phenylpiperazine-1-base 503.2
Base -2-base
186 Me (tetramethyleneimine-1-base carbonyl) oxygen base 4-phenylpiperazine-1-base 460.2
187 Me Azetidine-1-base-ketonic oxygen base (3R)-3-Phenylpyrrolidine-1-base 431.2
188 Me (piperidines-1-base carbonyl) oxygen base 4-phenylpiperazine-1-base 474.2
189 Me Azetidine-1-base-ketonic oxygen base 1,3-dihydro-2H-isoindole-2-base 402.2
190 Me (tetramethyleneimine-1-base carbonyl) oxygen base 3-phenyl-2,5-dihydro-1H-pyrroles-1-base 443.0 5
191 Me (tetramethyleneimine-1-base carbonyl) oxygen base 4-Phenylpiperidine-1-base 459.1 5
192 Me Azepine ring-1-in heptan base-ketonic oxygen base 4-Phenylpiperidine-1-base 487.2
193 Me [(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl]-the ketonic oxygen base 4-Phenylpiperidine-1-base 489.2
194 Me (piperidines-1-base carbonyl) oxygen base 4-Phenylpiperidine-1-base 473.2
195 Me [(dimethylamino) carbonyl] oxygen base 4-Phenylpiperidine-1-base 433.1
196 CO 2Me [(2S)-2-(hydroxymethyl) tetramethyleneimine-1-yl]-the ketonic oxygen base 4-phenylpiperazine-1-base 534.2
197 CO 2Me (tetramethyleneimine-1-base carbonyl) oxygen base 1,3-dihydro-2H-isoindole-2-base 461.2
198 CO 2Me (piperidines-1-base carbonyl) oxygen base 4-phenylpiperazine-1-base 518.1 5
199 CO 2Me (tetramethyleneimine-1-base carbonyl) oxygen base 4-phenylpiperazine-1-base 504.2
200 CO 2Me (tetramethyleneimine-1-base carbonyl) oxygen base (3R)-3-Phenylpyrrolidine-1-base 489.2
201 CO 2Me [(dimethylamino) carbonyl] oxygen base 4-phenylpiperazine-1-base 478.1
202 CO 2Me (tetramethyleneimine-1-base carbonyl) oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 501.2
203 CO 2Me (tetramethyleneimine-1-base carbonyl) oxygen base 4-Phenylpiperidine-1-base 503.2
204 H (tetramethyleneimine-1-base carbonyl) oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 443.2
205 H Azetidine-1-base-ketonic oxygen base 1,3-dihydro-2H-benzo [e] isoindole-2-base 439.2
206 H Azetidine-1-base-ketonic oxygen base 1,3-dihydro-2H-isoindole-2-base 389.2
Figure A20048003718803331
Figure A20048003718803341
440 Me Quinolyl-4 oxygen base 4-phenylpiperazine-1-base 490.3
441 Me Quinoline-6-base oxygen base 3-phenyl-2,5-dihydro-1H-pyrroles-1-base 473.1
442 Me Quinolyl-4 oxygen base 3-phenyl-2,5-dihydro-1H-pyrroles-1-base 473.1
443 H Pyridine-2-base oxygen base 4-phenylpiperazine-1-base 426.1
444 Me (4-picoline-2-yl) oxygen base 4-phenylpiperazine-1-base 454.2
445 H (5-chloro-pyridine-3-yl) oxygen base 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 510.1
446 H (6-picoline-2-yl) oxygen base 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 490.1
447 H (4-picoline-2-yl) oxygen base 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 490.2
448 H Pyridine-2-base oxygen base 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6--pyridinium hydroxide-1 (2H)-Ji 476.2
449 H Phenoxy group 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 475.2
450 H Pyridine-2-base oxygen base 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 423.1
451 H (3-methyl isophthalic acid H-pyrazoles-5-yl) oxygen base 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 497.1
452 H (5-methyl different _ azoles-3-yl) oxygen base (3R)-Phenylpyrrolidine-1-base 415.1
453 H (3-methyl isophthalic acid H-pyrazoles-5-yl) oxygen base (3R)-Phenylpyrrolidine-1-base 414.1
454 H (5-chloro-pyridine-3-yl) oxygen base (3R)-Phenylpyrrolidine-1-base 445.1
455 H (4-picoline-2-yl) oxygen base (3R)-Phenylpyrrolidine-1-base 425.0
456 H Pyridine-2-base oxygen base (3R)-Phenylpyrrolidine-1-base 411.1
457 H 3,4-two fluorophenoxies 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 511.1
458 H (5-methyl different _ azoles-3-yl) oxygen base 4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-Ji 480.1
Figure A20048003718803361
The 1-base
Table 6
Figure A20048003718803371
Ex. R QY MS
220 (E)-(cyanoimino) methyl tetramethyleneimine-1-yl) (3R)-Phenylpyrrolidine-1-base 439.2
221 (E)-azetidine-1-base (cyanoimino) methyl (3R)-Phenylpyrrolidine-1-base 425.2
222 (E)-(cyanoimino) (dimethylamino) methyl (3R)-Phenylpyrrolidine-1-base 413.2
223 (E)-(cyanoimino) (cyclopropyl amino) methyl (3R)-Phenylpyrrolidine-1-base 425.2
224 (E)-(cyanoimino) (piperidines-1-yl) methyl (3R)-Phenylpyrrolidine-1-base 453.3
225 (Z)-(cyanoimino) (morpholine-4-yl) methyl (3R)-Phenylpyrrolidine-1-base 455.3
226 (Z)-(cyanoimino) (hydroxyl amino) methyl (3R)-Phenylpyrrolidine-1-base 401.1
227 (E)-aza-heptane-1-base (cyanoimino) methyl (3R)-Phenylpyrrolidine-1-base 467.3
228 (Z)-(cyanoimino) (4-methylpiperazine-1-yl) methyl (3R)-Phenylpyrrolidine-1-base 468.2
229 (Z)-and cyanoimino) (parathiazan-4-yl) methyl (3R)-Phenylpyrrolidine-1-base 471.1
230 (E)-(cyanoimino) (4-methyl piperidine-1-yl) methyl (3R)-Phenylpyrrolidine-1-base 467.2
231 (Z)-(cyanoimino) (2,5-dihydro-1H-pyrroles-1-yl) methyl (3R)-Phenylpyrrolidine-1-base 437.2
232 (Z)-(cyanoimino) (1,3-dihydro-2H-isoindole-2-yl) methyl (3R)-Phenylpyrrolidine-1-base 487.1
233 (Z)-(cyanoimino) (3,4-dihydro-isoquinoline-2 (1H)-yl) methyl (3R)-Phenylpyrrolidine-1-base 487.1
234 (Z)-1-(hydroxyl amino)-2-nitroethylene base (3R)-Phenylpyrrolidine-1-base 442.2
235 (E)-(cyanoimino) (piperidines-1-yl) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl) 507
236 (E)-(cyanoimino) (dimethylamino) methyl 4-(4-cyano group-2-aminomethyl phenyl) 467
Piperazine-1-yl)
237 (E)-aza-heptane-1-base (cyanoimino) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl) 521
238 (E)-(cyanoimino) methyl tetramethyleneimine-1-yl) 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl) 493
239 (E)-(cyanoimino) (cyclopropyl amino) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl) 479
240 (E)-azetidine-1-base (cyanoimino) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl) 479
501 (E)-(cyanoimino) (cyclopropyl amino) methyl 4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-Ji 476.2
502 (E)-(cyanoimino) (dimethylamino) methyl 4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-Ji 464.2
503 (E)-(cyanoimino) (piperidines-1-yl) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl) 507.2
504 (E)-azetidine-1-base (cyanoimino) methyl 4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-Ji 476.1
505 (E)-azetidine-1-base (cyanoimino) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base 478.1
506 (E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl 4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-Ji 490.2
507 (E)-(cyanoimino) (piperidines-1-yl) methyl 4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-Ji 504.2
508 (E)-(cyanoimino) (piperidines-1-yl) methyl 4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base 506.2
Table 7
Figure A20048003718803392
Figure A20048003718803401
Figure A20048003718803411
Figure A20048003718803421
Figure A20048003718803441
Figure A20048003718803451
Figure A20048003718803461
Figure A20048003718803471
Figure A20048003718803481
Figure A20048003718803491
Base }
385 (5R)-(quinoline-2-base oxygen base) H 4-phenylpiperazine-1-base 475.2
386 (5R)-(quinoline-3-base oxygen base) H 4-phenylpiperazine-1-base 475.1
387 (5R)-(quinoline-5-base oxygen base) H 4-phenylpiperazine-1-base 475.1
388 (5R)-(quinoline-7-base oxygen base) H 4-phenylpiperazine-1-base 475.2
389 (5R)-(quinoline-8-base oxygen base) H 4-phenylpiperazine-1-base 475.1
390 (5R)-(pyridine-2-base oxygen base) H 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 422.1
391 (5R)-(pyridin-4-yl oxygen base) H 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 422.1
392 (5R)-(quinoline-6-base oxygen base) H 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 472.1
393 (5R)-[(1-ethyl piperidine-4-yl) oxygen base] H 4-Phenylpiperidine-1-base 458.3
394 (5R)-(pyridine-2-base oxygen base) H 4-Phenylpiperidine-1-base 424.2
395 (5R)-(pyridin-4-yl oxygen base) H 4-Phenylpiperidine-1-base 424.2
396 (5R)-(quinoline-6-base oxygen base) H 4-Phenylpiperidine-1-base 474.2
397 (5R)-(3-chloro phenoxy group) H 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 455.1
398 (5R)-(3,4-phenyl-difluoride oxygen base) H 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 457.1
399 (5R)-(2,3-phenyl-difluoride oxygen base) H 4-phenyl-3,6-dihydropyridine-1 (2H)-Ji 457.1
400 (5R)-(isoquinolyl-1 oxygen base) H 4-phenylpiperazine-1-base 475.2
401 (5R)-(isoquinoline 99.9-3-base oxygen base) H 4-phenylpiperazine-1-base 475.2
402 (5R)-(isoquinoline 99.9-5-base oxygen base) H 4-phenylpiperazine-1-base 475.2
403 (5R)-(isoquinoline 99.9-7-base oxygen base) H 4-phenylpiperazine-1-base 475.2
404 (5R)-(2-naphthyl oxygen base) H 4-phenylpiperazine-1-base 474.2
405 (5R)-(2,4-phenyl-difluoride oxygen base) H 4-phenylpiperazine-1-base 460.1
406 (5R)-(3,5-phenyl-difluoride oxygen base) H 4-phenylpiperazine-1-base 460.1
407 (5R)-(3-chloro-4-fluorinated phenoxy) H 4-phenylpiperazine-1-base 476.1
408 (5R)-(3,4-dichloro-phenoxy group) H 4-phenylpiperazine-1-base 492.1
409 (5R)-(3,5-dichloro-phenoxy group) H 4-phenylpiperazine-1-base 492.1
410 (5R)-(2,5-dioxo tetramethyleneimine-1-yl) H 4-phenylpiperazine-1-base 429.2
Biological experimental method
Can use suitable screening method (for example high-throughput test) to determine that new compound of the present invention suppresses the ability of TNF α or inhibition MMP function (promptly suppressing sheddase).For example, can check medicine in conjunction with test or chemotaxis test at the test of extracellular acidifying test, calcium current amount, part.For example, can use following method to determine the ability of general formula (I) compound as the inhibitor that produces TNF α.At 37 ℃, 5%CO 2Under the atmosphere, the solution of the described inhibitor that 100 μ M are verified or its diluent with 1 * 10 6/ ml cell density also is suspended in THP-1 cell (person monocytic cell) incubation together in RPM11640 medium and the 20 μ M beta-mercaptoethanols with what LPS stimulated.After 18 hours, use can be bought the TNF alpha levels of the ELISA test kit test supernatant liquor that obtains.To be present in the activity of 0.1mM inhibitor or its diluent and the activity contrast of the control group that does not have inhibitor, the result will be represented with 50% inhibitor concentration that effectively suppresses TNF α generation effect.
Embodiment 509
PBMC test determination TNF alpha active
From normally not containing medicine (not being acetylsalicylic acid, Ibuprofen BP/EP, NSAIDs) etc.) donor (Biological Specialties, Colmar PA) obtain white corpuscle and move (leukophoresis).50mL taper pipe (VWR, NJ) in, add 20mL blood and 20mL 0.9% Sterile Saline (Baxter Healthcare, Dearfield, IL) and thorough mixing.Put in its lower section 10mL do not have endotoxic Ficoll-Paque (Pharmacia, Uppsala, Sweden), centrifugal 30 minutes then with 3000RPM.Remove leukocytic cream, with 50mls 0.9% salt water washing.Counting cells, with 2 * 106c/ml, be dissolved in 0.250mL in RPMI 1640 media (Gibco BRL) join in 96 orifice plates (Costar/Corning VWR, NJ).Add compound and with cell preincubation 10 minutes, then with 5 hours with 1 μ g/ml adding LPS (Calbiochem, CA).Collect supernatant liquor and pass through standard sandwich ELISA (R﹠amp; DSystems, Minneapolis, MN) generation of mensuration TNF α.Determine with respect to the independent LPS cultured cells of using, the restraining effect of compound.
Embodiment 510
The active mensuration of Her-2 Sheddase
96 orifice plates (Costar/Corning VWR, NJ) in, 100 μ L contain 10% foetal calf serum (Hyclone, Lenexa, RPMI 1640 media KS) (In Vitrogen, Carlsbad, CA) in, with 2 * 10 4Individual cells/well inoculation human breast cell cancer pedigree BT474 (ATCC, Manassas, Va), and at 37 ℃, 5%CO 2Under be incubated overnight.In second day morning, remove medium and add fresh medium with 100 μ L/ holes.Add compound with suitable concentration, with cell at 37 ℃, 5%CO 2Following incubation 72 hours.Remove supernatant liquor then, and test immediately or be placed under-20 ℃ until testing.(CA), the extent of dilution check supernatant liquor with 1/20 is for the restraining effect of Her-2 Sheddase for Oncogene Research, San Diego by buying the ELISA that obtains.Determine cell, the restraining effect of compound with respect to single culture.
Embodiment 512
MMP2 measures
Preparation 5mM compound stoste in DMSO.500uM begins by maximum concentration, carries out 2-times of serial dilution according to the 11-point curve, obtains the compound flat board.The 1.0 μ L compounds that will be dissolved among the DMSO are transferred on the test panel from the compound flat board.In assay buffer, press 10ng/50 μ L prepared at concentrations enzyme solution.The substrate solution of preparation 20 μ M concentration in assay buffer.The enzyme solution of 50 μ L is joined on the test panel.With test panel incubation 5 minutes.Substrate solution with 50 μ L joins on the test panel then.With described plate lucifuge and incubation reaction thing 1 hour at room temperature.Make reaction terminating by adding 10 μ L 500mM EDTA solution.With flat board reading on the plate reader of 320nm excitation wavelength and 405nm emission wavelength.
Embodiment 513
MMP3 measures
Preparation 5mM compound stoste in DMSO.500uM begins by maximum concentration, carries out 2-times of serial dilution according to the 11-point curve, preparation compound flat board.The 1 μ L compound that will be dissolved among the DMSO is transferred on the test panel from the compound flat board.In assay buffer, press 10ng/50 μ L prepared at concentrations enzyme solution.The substrate solution of preparation 20 μ M concentration in assay buffer.The enzyme solution of 50 μ L is joined on the test panel.With test panel incubation 5 minutes.10ul 500mM EDTA is joined in background (Background) hole.Substrate solution with 50 μ L joins on the test panel then.With described plate lucifuge, and incubation reaction thing 1 hour at room temperature.Make reaction terminating by adding 10 μ L 500mM EDTA solution.With flat board reading on the plate reader of 320nm excitation wavelength and 405nm emission wavelength.
Embodiment 514
MMP12 measures
Preparation 5mM compound stoste in DMSO.500uM begins by maximum concentration, carries out 2-times of serial dilution according to the 11-point curve, preparation compound flat board.The 1 μ L compound that will be dissolved among the DMSO is transferred on the test panel from the compound flat board.In assay buffer, press 10ng/50 μ L prepared at concentrations enzyme solution.The substrate of preparation 20 μ M concentration in assay buffer ((ayapanin-4-yl) ethanoyl-Pro-Leu-Gly-Leu-(3-[2,4-dinitrophenyl]-L-2,3-diamino propionyl)-Ala-Arg-NH 2) solution.The enzyme solution of 50 μ L is joined on the test panel.With test panel incubation 5 minutes.10ul 500mM EDTA is joined in background (Background) hole.Substrate solution with 50 μ L joins on the test panel then.With described plate lucifuge, and incubation reaction thing 1 hour at room temperature.Make reaction terminating by adding 10 μ L 500mMEDTA solution.With flat board reading on the plate reader of 320nm excitation wavelength and 405nm emission wavelength.
Embodiment 515
ADAM10 measures
Preparation 5mM compound stoste in DMSO.500uM begins by maximum concentration, carries out 2-times of serial dilution according to the 11-point curve and obtains the compound flat board.The 1 μ L compound that will be dissolved among the DMSO is transferred on the test panel from the compound flat board.In assay buffer, press 100ng/50 μ L prepared at concentrations enzyme solution.The substrate of preparation 20 μ M concentration in assay buffer ((ayapanin-4-yl)-ethanoyl-Pro-Leu-Ala-Gln-Ala-Val-(3-[2,4-dinitrophenyl]-L-2,3-diamino propionyl)-Arg-Ser-Ser-Ser-Arg-NH 2) solution.The enzyme solution of 50 μ L is joined on the test panel.With test panel incubation 5 minutes.Substrate solution with 50 μ L joins on the test panel then.With described plate lucifuge, and 37 ℃ of following incubation reaction things 4 hours.Make reaction terminating by adding 10 μ L 500mM EDTA solution.With flat board reading on the plate reader of 320nm excitation wavelength and 405nm emission wavelength.
When adopting the said determination scheme, compound of the present invention has the IC of the about 10 μ M scopes of about 10nM-to Her2 sheddase restraining effect, TNF-α restraining effect and MMP2, MMP12 and MMP3 restraining effect 50
Medicinal compositions of the present invention and uses thereof
The compounds of this invention can be given Mammals (for example people) takes, but also can give other Mammals, the animal that for example needs veterinary treatment, the animal of for example raising and train (for example dog, cat etc.), agricultural animal (for example ox, sheep, pig, horse etc.) and laboratory animal (for example rat, mouse, cavy etc.).The Mammals that the inventive method is treated is its male or female Mammals that need regulate matrix metal proteinase activity.Antagonistic action, agonism, partial antagonism and/or part agonism contained in term " adjusting ".
In specification sheets of the present invention, that term " treatment significant quantity " expression gives is that the amount of this compound is confirmed by researchist, animal doctor, doctor or other clinician, can tissue, system, animal or human produce biology or medical effect.
Can give compound of the present invention to treat for example disease of rheumatoid arthritis with the treatment significant quantity.The treatment significant quantity of compound is that one or more that can cause suppressing by the MMPs mediation in the patient who suffers from unusual metal proteinase activity diseases related are planted the amount of diseases.Perhaps, the treatment significant quantity of compound is to reach the required amount that treats and/or prevents effect, for example causes preventing or alleviates and the amount of the symptom of the active diseases related of unusual MMP.
Can comprise with disease or the illness of MMP depressant of functions of the present invention or modulators for treatment people or other animal, but be not limited to: inflammation or allergic disease and illness, comprise the respiratory tract allergic disease, for example asthma, rhinallergosis, the supersensitivity lung disease, hypersensitivity pneumonitis, eosinophilic cellulitis's (for example Well ' s syndrome), acidophilia pneumonia (Loeffler ' s syndrome for example, the chronic eosinophilic pneumonia), eosinophilic fasciitis's (for example Shulman ' s syndrome), delayed-type hypersensitivity, between matter lung disease (ILD) (for example idiopathic pulmonary fibrosis or and rheumatoid arthritis, systemic lupus erythematous, the ankylosis rachitis, systemic scleroderma, Sjogren ' s syndrome, the ILD that polymyositis or dermatomyositis are relevant); Systemic anaphylaxis or allergy are replied, drug allergy (for example to penicillin, cephalosporins allergy), because eosinophilia-muscle pain syndrome, the sting transformation reactions that the tryptophane that take in to pollute causes; Autoimmune disorder, for example rheumatoid arthritis, psoriasis arthropathica, multiple sclerosis, systemic lupus erythematous, myasthenia gravis, juvenile diabetes; Glomerulonephritis, autoimmune thyroiditis, Behcet ' s disease; Transplant rejection (for example repulsion in transplantation) comprises homograft rejection or graft-antagonism-host disease; Inflammatory bowel disease, for example Crohn ' s disease and ulcerative colitis; SpA; Scleroderma; Psoriatic (comprising the psoriatic that T-is cell-mediated) and inflammatory dermatosis, for example dermatitis, eczema, atopic dermatitis, contact dermatitis, urticaria; Vasculitis (for example gangrenosum acne, skin and allergic angiitis); Oxyphie myositis, eosinophilic fasciitis; The leukocyte infiltration cancer of ND and skin or organ.Treatable other disease or illness (wherein can suppress bad inflammatory response) include, but are not limited to poisoning (for example septic shock, endotoxin shock), polymyositis and the dermatomyositis of reperfusion injury, atherosclerosis, some hematologic malignancies, cytokine-mediation.
Can be with the oral dosage form form administration of the compound of representing by formula I, II and III of the present invention with tablet, capsule (its comprise separately continue to discharge or time release formulation), pill, powder, granule, elixir, tincture, suspension agent, syrup and emulsifying agent.They also can intravenously (heavy dose or infusion), intraperitoneal, subcutaneous or intramuscular form administration, and the formulation of all uses all is that the those of ordinary skill of pharmaceutical field is known.Can they are individually dosed, but carry out administration with selected pharmaceutical carrier on based on route of administration and standard pharmaceutical practical basis usually.
Certainly, the dosage specification of The compounds of this invention can change according to known factor, for example the pharmaco-kinetic properties of certain drug and its administering mode and the approach of administration; Metabolic stability, discharge rate, drug regimen, and the time length of described compound effects, patient's species, age, sex, healthy state, medical conditions and body weight; The nature and extent of symptom; The kind of existing methods of treatment; The number of times of treatment; The particular approach of administration, patient's the kidney and the function of liver and required curative effect.Doctor or animal doctor can determine and determine the medicine effective quantity of the process of the particular disorder that required prevention, antagonism or inhibition need be treated.
Usually, the day oral dosage of each activeconstituents when being used for required effect, can approximately change in the 0.0001-1000mg/kg weight range, and preferred every day is approximately between the 0.001-100mg/kg body weight, more preferably approximately between 0.1-20mg/kg/ days.Use for intravenously, during the constant speed injection, most preferably be the about 10mg/kg/ of about 0.1-minute scope.For oral administration, described composition is preferably with the tablet administration, described tablet contains the 1.0-1000mg activeconstituents, preferably contain 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and the activeconstituents of 1000.0mg, so that for the adjustment dosage of treatment patient symptom.Described compound can be by scheme administration every day 1-4 time, and be administered once or twice preferred every day.
The compounds of this invention also can use the interior medium of suitable nose with form administration in the nose by the part, or by through the skin approach, uses the transdermal patch administration.With when the form administration of skin delivery system, in whole dosage, described dosage yes successive rather than discontinuity.
The compounds of this invention Chang Yiyu is according to the mixture administration that is fit to selected suitable medicinal diluent, vehicle or the carrier (being called pharmaceutical carrier herein together) of required form of medication, described form of medication is oral tablet, capsule, elixir, syrup etc., and is consistent with the conventional pharmaceutical regulation.
For example, tablet or capsule formulation for oral administration, described active medicine component and oral, non-toxicity, pharmaceutically acceptable, inert support can be combined, for example lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, calcium sulfate, mannitol, sorbyl alcohol etc.For the liquid dosage form of oral administration, can for example ethanol, glycerine, water etc. combine with any oral, non-toxicity, pharmaceutically acceptable inert support with described oral pharmaceutical component.On the other hand, when needs or must the time, also suitable binder, lubricant, disintegrating agent and tinting material can be mixed in the described mixture.Suitable binder comprises starch, gelatin, natural sugar (for example glucose or beta lactose), corn sweetener, natural and synthetic is gummy (for example gum arabic, tragacanth gum or sodium alginate), carboxy methyl cellulose, polyoxyethylene glycol, paraffin etc.The lubricant that uses in these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Disintegrating agent includes but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum etc.
Also The compounds of this invention can be offered patient with liposome delivery system form, for example small-sized unilamellar vesicle, large-scale unilamellar vesicle and multilamellar vesicle.Liposome can for example cholesterol, stearylamine or Yelkin TTS form by various phosphatide.
The compounds of this invention also can with the soluble polymer coupling as the target pharmaceutical carrier.Described polymkeric substance can comprise polyvinylpyrrolidone, pyrans interpolymer, poly-hydroxy propyl methyl acid amides-phenol, poly-hydroxy ethyl asparagine phenol or the polyethylene oxide-polylysin that is replaced by the palmityl residue.In addition, The compounds of this invention can with the crosslinked or amphiphilic block copolymer of the interpolymer of for example poly-acetate, polyoxyethylene glycol acid, lactic acid and polyoxyethylene glycol acid, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe class, polyacetals, poly-dihydroxyl pyrans class and hydrogel is arranged in a series of Biodegradable polymeric couplings that reach control drug release.
The formulation that is fit to the The compounds of this invention of administration can every dose unit contains the activeconstituents from about 0.1mg to about 100mg.In these medicinal compositionss, the amount that activeconstituents exists usually is the weight based on about 0.5-95% of described composition total weight.
Also can use gelatine capsule as dosage form, it can contain activeconstituents and powder carrier, for example lactose, starch, derivatived cellulose, Magnesium Stearate, stearic acid etc.Can use similar thinner to form compressed tablet.Tablet and capsule can be prepared into slow release product, and persistence discharges medicine in several hours to be provided at.Compressed tablet dressing sugar or film coating so that shelter any unacceptable taste and avoid tablet to be exposed in the air, or can be packed enteric coating to be used for selectivity in the gi tract disintegration.
When using the liquid dosage form of oral administration, described formulation can contain tinting material and seasonings to increase patient's acceptance.
In general, water, suitable oil, salt solution, dextrose (glucose) aqueous solution and relevant sugar soln and glycols (for example propylene glycol or polyoxyethylene glycol) are the suitable carriers that is used for the parenteral solution.The solution that is used for parenteral admin preferably contains water-soluble salt, the suitable stabilizers of activeconstituents, and if desired, contains buffer reagent.Antioxidant, for example sodium bisulfite, sodium pyrosulfate or xitix (single or combination) are suitable stabilizers.Also can use citric acid and its salt and EDTA sodium as stablizer.In addition, parenteral solution can contain sanitas, for example benzalkonium chloride, methyl-or propyl group-p-Hydroxybenzoate and chlorobutanol.Suitable pharmaceutical carrier is narrated among the MackPublishing Company at Remington ' s Plarmaceutical Sciences, and this book is the canonical reference book in the pharmaceutical field.
Medicinal compositions of the present invention also can be an oil-in-water emulsion.Described oil phase can be vegetables oil (for example sweet oil or peanut oil) or mineral oil (for example Liquid Paraffin) or its mixture.Suitable emulsifying agent can be naturally occurring natural gum (for example Sudan Gum-arabic or tragacanth gum), naturally occurring phospholipid (for example soybean lecithin) and by lipid acid and hexitol dehydrate deutero-ester or partial ester, the for example condensation product of sorbitan monooleate and described partial ester and oxyethane, for example polyoxyethylene sorbitan monoleate.Emulsion also can contain sweeting agent and correctives.
The compounds of this invention also can be to be used for the suppository form administration of rectal administration.Can be by described medicine and suitable non--pungency mixed with excipients be prepared these compositions, described vehicle is solid at normal temperatures, but is liquid under rectal temperature, therefore fusing and discharge medicine in rectum.Described material is theobroma oil and polyoxyethylene glycol.
Use for the part, can use emulsifiable paste, ointment, gel, solution or the suspension etc. that contain The compounds of this invention." the local use " used herein also expression comprises the use of mouth wass and collut.
Except the compound of formula I of the present invention, II and III, medicinal compositions of the present invention and method can also comprise other therapeutical active compound of using usually in the above pathologic conditions of treatment, prerequisite is that such being combined in do not cause disadvantageous reaction or do not make the active reduction of described inhibitors of metalloproteinase among the patient to be treated.
The representational useful pharmaceutical dosage form that is used to give The compounds of this invention can illustrate as follows:
Capsule
By the powdered activated composition of 50mg, 100mg lactose, 25mg fiber and 3mg Magnesium Stearate are filled in two-Jie hard gelatin capsule of every standard, can prepare the capsule of a large amount of unitary doses.
Gelseal
Can prepare the mixture of active principles that is dissolved in digestible oil (for example soybean oil, oleum gossypii seminis or sweet oil), enter in the gelatin by the volumetric pump injection then, form the soft gelatin capsule that contains the 75mg activeconstituents.Should be with this capsule washing and dry.
Tablet
Can prepare tablet by ordinary method, make dose unit contain 75mg activeconstituents, 0.15mg colloidal silica, 4mg Magnesium Stearate, 250mg Microcrystalline Cellulose, 9mg starch and 75mg lactose.Can use suitable dressing well known to those skilled in the art absorbs to increase palatability or to postpone.
Injection
Stir in the 8% volumetrical propylene glycol and water by activeconstituents, can prepare the parenteral composition that is suitable for drug administration by injection 1.0% (weight).Should its grade of described solution be oozed with sodium-chlor, then sterilization.
Suspension
Can prepare and be used for oral aq suspension, make every 5mL contain the pulverizing activeconstituents of 75mg, 150mg Xylo-Mucine, 3.75mg Sodium Benzoate, 0.75g Sorbitol Solution USP U.S.P. and 0.015mL Vanillin.
All patents, patent application and the publication of quoting in this application done as a whole being attached to by reference herein as a reference at this, and as quoting each single patent separately, patent application or publication are the same.
Though below disclose many embodiments of the present invention, and these embodiments comprise at present preferred scheme, many other embodiments and variant may be present in scope of the present invention and reach in the additional thereafter claim.Therefore, the details of preferred embodiment that is provided and embodiment does not constitute a kind of qualification.Should be appreciated that term as used herein only is that explanation rather than conduct limit, and in the spirit or scope that do not break away from the present invention for required protection, can make the different change of many equivalents.

Claims (24)

1. the compound of a formula IA:
Figure A2004800371880002C1
Or its enantiomorph, diastereomer, the mixture that is rich in enantiomorph, raceme mixture, its prodrug, crystalline form, amorphous, amorphous form, its solvate, metabolite and pharmacy acceptable salt thereof, wherein:
Ring A is for comprising carbon atom, a 0-3 carbonyl, 0-4 two keys and individual O, N, NR and the S (O) of being selected from of 0-4 pThe 3-13 unit carbocyclic ring or the heterocycle of ring hetero atom, prerequisite is that ring A does not contain S-S, O-O or S-O key;
N ' is the integer of 1-3;
Z is selected from-COR 5,-CO 2H ,-CH 2CO 2H ,-CO 2R 6,-CONHOH ,-CONHOR 5,-CON (R 6) OH ,-CONHOR 6,-NHR a,-N (OH) C (O) R 5,-N (OH) CHO ,-SH ,-CH 2SH ,-S (O) (=NH) R a,-SN 2H 2R a,-PO (OR g) 2,-PO (OH) NHR a,
R gIndependently be selected from H, CH 2OCOR a,
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) O, OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1, NR A1S (O) pAnd NR A1SO 2NR A1
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkenylene and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring, and contain carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-14 unit's heterocycle and described heterocycle by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) O, OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1, NR A1S (O) pAnd NR A1SO 2NR A1
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkenylene and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkenylene)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, Cl, F, Br, I ,-CN, NO 2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M and NR aS (O) 2NR A1(CR dR D1) r-M, (CR dR D1) rP (O) (OR a) 2, (CR dR D1) rP (O) (OR a) (NR dR D1), (CR dR D1) rP (O) (NR aR A1) 2, (CR dR D1) rOP (O) (OR a) 2, (CR dR D1) rOP (O) (OR a) (NR aR A1), (CR dR D1) rOP (O) (NR aR A1) 2, (CR dR D1) rNR aP (O) (OR a) 2, (CR dR D1) rNR aP (O) (OR a) (NR aR A1), (CR dR D1) rNR aP (O) (NR aR A1) 2C (=NR a) NR A1R A2C (=CR dR D1) NR A1R A2By 0-5 R dThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 is selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkenylene, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F, Br, I ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3, OCHF 2, by 0-5 R dThe C that replaces 3-13Carbocyclic ring, and contain carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from (CR at every turn when occurring dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR A1(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1, (CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2NR A1(CR dR D1) r-M 1
M 1Be selected from C 1-10Alkylidene group-M 1, C 2-10Alkenylene-M 1, C 2-10Alkynylene-M 1, OR a, Cl, F, Br, I ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3With comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-14 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 13Carbocyclic ring, C 4-C 14Heterocycle, and wherein said C 3-C 13Carbocyclic ring and C 4-C 14Heterocycle is by 1-3 R h, and CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Perhaps, when two R groups when adjacent ring A atom is connected, then they can connected atom form together and contain carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the unsaturated ring of heteroatomic 3-8 unit, wherein said ring can be benzene-condensed and/or by R dReplace;
Perhaps, when two R groups connected with identical ring A atom, then they can connected carbon atom form together and contain carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the undersaturated spiral shell of heteroatomic 3-8 unit-ring, wherein said spiral shell-ring can be benzene-condensed and/or by R dReplace;
Prerequisite is two or more R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkyl, alkenyl and alkynyl are optional to be replaced by following group: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-14 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl, and 5-14 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,=O ,-CN, NO 2, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl, and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3And CF 2CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14, C that is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl, and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, by R at every turn C1, OR a, Cl, F, Br, I ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A1, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3The optional C that replaces 1-6Alkyl; C 3-10Carbocylic radical, and contain 1-4 the first heterocyclic ring system of heteroatomic 5-14 that is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, NR aS (O) pNR jR a, by R cThe C that replaces 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CFH 2, CF 2CF 3, the C that replaces by following group 1-C 8Alkyl: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br, I ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCF 2CF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
R 3Be H or C 1-6Alkyl OR a, NR aR A1And S (O) pR a
R 4Be selected from H, C 1-6Alkyl, OR a, NR aR A1And S (O) pR a
R 5When occurring, be selected from by 0-2 R at every turn bThe C that replaces 1-10Alkyl and by 0-2 R eThe C that replaces 1-8Alkyl;
R eWhen occurring, be selected from by 0-2 R at every turn bThe phenyl that replaces and by 0-2 R bThe xenyl that replaces;
R 6When occurring, be selected from phenyl, naphthyl, C at every turn 1-10Alkyl-phenyl-C 1-6Alkyl-, C 3-11Cycloalkyl, C 1-6Alkyl-carbonyl oxygen base-C 1-3Alkyl-, C 1-6Alkoxy-carbonyl oxy-C 1-3Alkyl-, C 2-10Alkoxy carbonyl, C 3-6Naphthene base carbonyl oxygen base-C 1-3Alkyl-, C 3-6Cyclo alkoxy carbonyl oxygen base-C 1-3Alkyl-, C 3-6Cyclo alkoxy carbonyl, phenyloxycarbonyl, phenyl oxygen base ketonic oxygen base-C 1-3Alkyl-, phenylcarbonyl group oxygen base-C 1-3Alkyl-, C 1-6Alkoxy-C 1-6Alkyl-carbonyl oxygen base-C 1-3Alkyl-, [5-(C 1-C 5Alkyl)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, [5-(R a)-1,3-two oxa-s-cyclopentenes-2-ketone-yl] methyl, (5-aryl-1, the methyl of 3-two oxa-s-cyclopentenes-2-ketone-yl) ,-C 1-10Alkyl-NR 7R 7a,-CH (R 8) OC (O) R 9With-CH (R 8) OC (O) OR 9
Perhaps, R 4And R 6Can form optional together by R cThe 5-10 unit ring that replaces;
R 7Be selected from H, C 1-10Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 1-3Alkyl-and phenyl-C 1-6Alkyl-;
R 7aBe selected from H, C 1-10Alkyl, C 2-6Alkenyl, C 3-6Cycloalkyl-C 1-3Alkyl-and phenyl-C 1-6Alkyl-;
R 8Be selected from H and C 1-4Linear alkyl;
R 9Be selected from H, by 1-2 R fThe C that replaces 1-8Alkyl, by 1-2 R fThe C that replaces 3-8Cycloalkyl and by 0-2 R bThe phenyl that replaces;
R fWhen occurring, be selected from H, C at every turn 1-4Alkyl, C 3-8Cycloalkyl, C 1-5Alkoxyl group and by 0-2 R bThe phenyl that replaces;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
2. the compound of a claim 1, wherein said compound has formula IIA:
Figure A2004800371880010C1
Wherein encircling A is to comprise carbon atom, 0-1 carbonyl group and 0-2 4-10 non-aromatic carbocyclic of unit or heterocycle that is selected from the ring hetero atom of O, N, NR, and prerequisite is that ring A does not contain the O-O key;
N ' is 1 or 2;
Z is selected from-CO 2H ,-CH 2CO 2H ,-CONHOH ,-CONHOR 5,-NHR a,-N (OH) C (O) R 5,-N (OH) CHO ,-SH ,-CH 2SH, and
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1And NR A1S (O) p
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group, and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) O, OC (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, S (O) p, S (O) pNR A1And NR A1S (O) p
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R cReplace; Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkylene group)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, Cl, F, Cl ,-CN, NO 2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkylene group, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR A1(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And comprise carbon atom and 1-4 and be selected from N, O, S (O) pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R h, and CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Perhaps, when two R groups when adjacent ring A atom is connected, then they can connected atom form together and comprise carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the unsaturated ring of heteroatomic 3-8 unit, wherein said ring can be benzene-condensed and/or by R dReplace;
Perhaps, when two R groups connected with identical ring A atom, then they can connected carbon atom form together and comprise carbon atom and 0-3 and be selected from N, NR a, O and S (O) pSaturated, fractional saturation or the undersaturated spiral shell of heteroatomic 3-8 unit-ring, wherein said spiral shell-ring can be benzene-condensed and/or by R dReplace;
Prerequisite is or two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkyl, alkenyl and alkynyl are optional to be replaced by following group: O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F, Br ,=O ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; alkyl-carbonyl; aromatic alkyl carbonyl; aryl carbonyl; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphinyl; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and 5-10 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,=O ,-CN, NO 2, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F, Br ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F, Br ,=O ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3- 10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
R 5When occurring, be selected from by 0-2 R at every turn bThe C that replaces 1-10Alkyl and by 0-2 R eThe C that replaces 1-8Alkyl;
R eWhen occurring, be selected from by 0-2 R at every turn bThe phenyl that replaces is by 0-2 R bThe xenyl that replaces;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
3. the compound of a claim 2, wherein said compound is selected from formula III A or IVA:
Figure A2004800371880016C1
Wherein encircling A is to comprise carbon atom, a 0-1 carbonyl group and 0-2 5-7 non-aromatic carbocyclic of unit or heterocycle that is selected from the ring hetero atom of O, N, NR, and prerequisite is that ring A does not contain the O-O key;
N ' is 1 or 2;
P is-D-E-G-Q-L-T-X-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, NR A1C (O) NR A1, S (O) p, S (O) pNR A1And NR A1S (O) p
E does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group, and C 2-10Alkynylene;
G does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 is selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) NR A1, NR A1C (O), OC (O) NR A1, NR A1C (O) O, S (O) p, S (O) pNR A1And NR A1S (O) p
T does not exist or is selected from C 1-10Alkylidene group, C 2-10Alkylene group and C 2-10Alkynylene;
X does not exist or is selected from O, NR A1, S (O) pAnd C (O);
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, E, G, Q, L, T, X and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkylene group)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkylene group, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R h, and CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is or two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and 5-10 unit heterocyclic radical-(C 1-8) alkyl, and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,-CN, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cReplace C 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
4. the compound of a claim 3, wherein said compound has formula III wherein:
Ring A is selected from O for comprising carbon atom and 1-2, N, and the 5-7 unit of the ring hetero atom of NR is non--aromatic carbocyclic or heterocycle, prerequisite is to encircle A not contain the O-O key;
P is-D-Q-L-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) NR A1, NR A1C (O), S (O) p, S (O) pNR aAnd NR A1S (O) p
Q do not exist or be selected from replacement by 0-5 R bThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 is selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) NR A1, S (O) p, S (O) pNR A1And NR A1S (O) p
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, Q, L and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-M, (by 1-3 R B1The C that replaces 2-10Alkenylene)-M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on A forms group C A=CR dR D1, wherein said atom C ABe the described atom on the A;
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkenylene, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkenylene-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3With comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R hAnd CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is or two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that they connect with it forms and contains 0-1 the first ring of other heteroatomic 3-8 that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and 5-10 unit heterocyclic radical-(C 1-8) alkyl and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,-CN, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3And CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl group are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
5. the compound of claim 2, wherein said compound has formula VA
Figure A2004800371880026C1
Wherein J and K independently are selected from-(CH 2) n-, NH, NR, O and n=1-3; Condition is that J and K can not be N-N, O-O or N-O;
N ' is 1 or 2;
P is-D-Q-L-Y, wherein
D does not exist or is selected from C (O), C (O) NR A1, NR A1C (O), S (O) p, S (O) pNR A1And NR A1S (O) p
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O;
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, Q, L and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R when occurring at every turn, independently be selected from OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on the ring that has J and K forms group C A=CR dR D1, wherein said atom C ABe the described atom on the ring that has J and K;
M is selected from H, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R A1NC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R h, and CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is or two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl;
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl dialkyl group, alkyl sulphonyl, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl dialkyl group, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl-alkyl, N-amino-alkyl sulfinyl dialkyl group, alkyl sulphonyl, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
6. the compound of a claim 2, wherein said compound has formula VIA
Figure A2004800371880030C1
Wherein K and W independently are selected from-(CH 2) n-, NH, NR, O and n=1-3, condition is that K and W can not be N-N, N-O or O-O;
N ' is 1 or 2;
P is-D-Q-L-Y, wherein
D does not exist or is selected from C (O), C (O) NR A1, NR A1C (O), S (O) p, S (O) pNR A1And NR A1S (O) p
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O;
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, Q, L and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R when occurring at every turn, independently be selected from OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, the carbon atom of two R on the ring that has K and W forms group C A=CR dR D1, wherein said atom C ABe the described atom on the ring that has K and W; M is selected from H, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1,
C 2-10Alkylene group-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) NR A1R A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R h, and CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is or two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup, or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that connects with their forms and contains 0-1 other heteroatomic 3-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from optional by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl;
R cWhen occurring, independently be selected from optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, by O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl dialkyl group, alkyl sulphonyl, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-C 8Alkyl; C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl dialkyl group, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10Carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, alkylamino, dialkyl amido, alkaryl amino, arylamino, alkyl amido, dialkyl group amido, formamyl alkyl, formamyl dialkyl group, alkyl-carbamoyl, sulfonamido alkyl, sulfonamido dialkyl group, N-amino-alkyl sulfinyl alkyl, N-amino-alkyl sulfinyl-alkyl, N-amino-alkyl sulfinyl dialkyl group, alkyl sulphonyl, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
7. claim 5 or 6 compound, wherein said compound i is selected from:
Figure A2004800371880034C2
Wherein:
P is-D-Q-L-Y, wherein
D does not exist or is selected from O, NR A1, C (O), C (O) NR A1, NR A1C (O), S (O) p, S (O) pNR A1And NR A1S (O) p
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring, and contain carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace;
L does not exist or is selected from O, NR A1, C (O), C (O) NR A1, S (O) p, S (O) pNR A1And NR A1S (O) p
Y is selected from H, by 0-5 R cThe C that replaces 5-7Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-6 unit heterocycle, and described heterocycle is by 0-5 R cReplace;
Prerequisite is that D, Q, L and Y debond form N-N, N-O, O-N, O-O, S (O) p-O, O-S (O) pOr S (O) p-S (O) pGroup;
R independently is selected from (by 1-3 R when occurring at every turn B1The C that replaces 1-10Alkylidene group)-and M, (by 1-3 R B1The C that replaces 2-10Alkenylene)-and M, (by 1-3 R B1The C that replaces 2-10Alkynylene)-M, OH, F, Cl ,-CN, NO 2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, O (CR dR D1) r-M, NR a(CR dR D1) r-M, OC (O) (CR dR D1) r-M, NR aC (O) (CR dR D1) r-M, OC (O) O (CR dR D1) r-M, OC (O) NR a(CR dR D1) r-M, NR aC (O) O (CR dR D1) r-M, NR aC (O) NR A1(CR dR D1) r-M, S (O) p(CR dR D1) r-M, S (O) 2NR a(CR dR D1) r-M, NR aS (O) 2(CR dR D1) r-M, C (=NCN) NR A1R A2C (=C (H) (NO 2)) NR A1R A2By 0-5 R dThe C that replaces 3-10Carbocyclic ring, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, when two R were positioned on the identical carbon atom, these two R formed group C with the carbon atom that they connect A=CR dR D1
M is selected from H, by 0-3 R B1The C that replaces 2-10Alkenylene, by 0-3 R B1The C that replaces 2-10Alkynylene, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, NR aC (O) OR a, NR aC (O) R a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, by 0-5 R dThe C that replaces 3-10Carbocyclic ring, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace;
Perhaps, R independently is selected from C at every turn when occurring 1-10Alkylidene group-M 1, C 2-10Alkenylene-M 1, C 2-10Alkynylene-M 1, (CR dR D1) rO (CR dR D1) r-M 1, (CR dR D1) rNR a(CR dR D1) r-M 1, (CR dR D1) rC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) (CR dR D1) r-M 1, (CR dR D1) rC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) (CR dR D1) r-M 1, (CR dR D1) rOC (O) O (CR dR D1) r-M 1, (CR dR D1) rOC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rNR aC (O) O (CR dR D1) r-M 1, (CR dR D1) rNR aC (O) NR a(CR dR D1) r-M 1, (CR dR D1) rS (O) p(CR dR D1) r-M 1, (CR dR D1) rS (O) 2NR a(CR dR D1) r-M 1(CR dR D1) rNR aS (O) 2(CR dR D1) r-M 1
M 1Be selected from OR a, Cl, F, Br ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-10 unit non-aromatic heterocyclic, and described heterocycle is by 0-5 R dReplace; C 3-C 10Carbocyclic ring, C 5-C 10Heterocycle, and wherein said C 3-C 10Carbocyclic ring and C 5-C 10Heterocycle is by 1-3 R hAnd CF 3, CF 2CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2, OCF 2CF 3And OCH 2CF 3Replace;
Prerequisite is or two R or M, M 1The atom debond that is connected with them forms N-N, N-O, O-N, O-O, N-halogen, O-halogen, S-halogen, S (O) p-O, O-S (O) p, S (O) p-S (O) pGroup or C (O) F, C (O) Cl, C (O) Br or C (O) I reactive group;
R a, R A1And R A2When occurring, independently be selected from H, C at every turn 1-C 8Alkyl, C 2-C 8Alkenyl, C 2-C 8Alkynyl; C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10The carbocylic radical alkyl, the heterocyclic radical alkyl;
Perhaps, R aAnd R A1The nitrogen-atoms that they connect with it forms and contains 0-1 the first ring of other heteroatomic 3-8 that is selected from N, O and S, and wherein said ring can be by R dReplace;
R bWhen occurring, independently be selected from by R at every turn C1, O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) O R A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, OS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and 5-10 unit heterocyclic radical-(C 1-8) alkyl and described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R B1When occurring, independently be selected from OR at every turn a, F ,-CN, NR aR A1And S (O) pR a
R cWhen occurring, independently be selected from by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, NR aS (O) 2NR aR A1, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
R C1When occurring, independently be selected from C at every turn 1-6Alkyl, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, OC (O) NR aR A1, R aNC (O) OR a, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3And CH 2F and CHF 2
R dWhen occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NO 2, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain heteroatomic 5-10 unit heterocyclic ring system, the C that 1-4 is selected from N, O and S 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl is optional by R C1Replace;
R D1When occurring, independently be selected from H, optional by R at every turn C1, OR a, Cl, F ,-CN, NR aR A1, C (O) R a, C (O) OR a, C (O) NR aR A1, R aNC (O) NR aR a, OC (O) NR aR A1, R aNC (O) OR A1, S (O) 2NR aR A1, NR aS (O) 2R A2, S (O) pR A2, CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3The C that replaces 1-6Alkyl; C 3-10Carbocylic radical and contain the heteroatomic 5-10 unit heterocyclic ring system that 1-4 is selected from N, O and S, C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-10 unit 1-8) alkyl; Described C 3-10Carbocylic radical, heterocyclic ring system C 3-C 10Carbocylic radical (C 1-8) alkyl and the heterocyclic radical (C of 5-14 unit 1-8) alkyl is optional by R C1Replace;
Perhaps, R dAnd R D1The atom that connects with their forms and contains 0-1 heteroatomic 4-8 unit ring that is selected from N, O and S, and wherein said ring can be by R dReplace;
R hWhen occurring, independently be selected from OR at every turn j, NR jR a, COR j, C (O) OR j, C (O) NR jR a, NR aC (O) NR jR A1, OC (O) NR jR a, S (O) pNR jR A1, NR aS (O) pR j, by R cThe C that replaces 1-6Alkyl;
R jWhen occurring, independently be selected from CF at every turn 3, CHF 2, CH 2F, CF 2CF 3, the C that replaces by following group 1-C 8Alkyl: O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 2-C 8Alkenyl, C 2-C 8Alkynyl, wherein said alkenyl and alkynyl group are optional to be replaced by following group: C 1-C 8Alkyl, O (primary, the second month in a season or uncle) C 1-C 8OH; Cl; F;-CN; alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3, OCHF 2And OCH 2CF 3C 3-C 10Carbocyclic ring, 5-10 unit heterocycle, C 3-C 10The carbocylic radical alkyl, heterocyclic radical alkyl, and wherein said C 3-C 10Carbocyclic ring, heterocycle, C 3-C 10Carbocylic radical alkyl and heterocyclic radical alkyl can be chosen wantonly by being selected from following one or more substituting groups and replace: O (primary, the second month in a season or uncle) C 1-C 8, OH, Cl, F ,-CN, NO 2Alkylamino; dialkyl amido; alkaryl amino; arylamino; carboxyl; the alkyl carboxylic acid root; alkyl amido; the dialkyl group amido; alkyl urea groups alkyl; alkyl urea groups dialkyl group; the formamyl alkyl; the formamyl dialkyl group; alkyl-carbamoyl; the sulfonamido alkyl; the sulfonamido dialkyl group; N-amino-alkyl sulfinyl alkyl; N-amino-alkyl sulfinyl-alkyl; N-amino-alkyl sulfinyl dialkyl group; the alkyl amido sulfonate radical; dialkyl group amido sulfonate radical; alkyl sulphonyl; CF 3, CH 2F, CHF 2, CF 2CH 3, C (CH 3) 2F, OCF 3And OCH 2CF 3, condition is described C 3-C 10Carbocyclic ring can not be a phenyl, and C 3-C 10The carbocylic radical alkyl can not be a benzyl;
P is 0,1 and 2 when occurring at every turn; With
R is 0 or the integer of 1-10 when occurring at every turn.
8. the compound of a claim 7, wherein said compound is selected from:
9. the compound of a claim 8, wherein said compound is selected from:
Figure A2004800371880039C2
Wherein:
M is selected from by 0-5 R dThe C that replaces 3-10Carbocyclic ring and comprise carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-10 unit heterocycle, and described heterocycle is by 0-5 R dReplace.
10. the compound of a claim 9, wherein said compound is:
Wherein:
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring, and contain carbon atom and individual N, O and the S (O) of being selected from of 1-4 pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace; With
Y is by 0-5 R bThe aryl that replaces.
11. the compound of a claim 9, wherein said compound is:
Figure A2004800371880040C2
Wherein:
Q does not exist or is selected from by 0-5 R bThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R bReplace; With
Y is by 0-5 R cThe C that replaces 3-13Carbocyclic ring and contain carbon atom and 1-4 and be selected from N, O and S (O) pHeteroatomic 5-14 unit heterocycle, and described heterocycle is by 0-5 R cReplace.
12. the compound of a claim 7, wherein said compound is selected from:
Figure A2004800371880041C1
13. the compound of claim 1, wherein said compound exists with the form of single enantiomorph or diastereomer.
14. one kind is used for the treatment of mammalian subject and method unwanted metal proteinase activity diseases related, this method comprises the inhibitors of metalloproteinase compound of the claim 1 of the described Mammals significant quantity that needs are arranged.
15. method that is used for the treatment of the disease that mediates by metalloprotease in the mammalian subject, wherein said disease is selected from sacroiliitis, cancer, cardiovascular disorder, tetter, inflammation and allergic disease, and this method comprises the inhibitors of metalloproteinase of the claim 1 of the described Mammals treatment significant quantity that needs this kind treatment.
16. a method that is used to suppress mammiferous pathological change by high-caliber matrix metalloproteinase mediation, this method comprise that the described Mammals that needs are arranged treats the matrix metallo-proteinase inhibitor compound of the claim 1 of significant quantity.
17. one kind is used in the method for mammalian subject treatment with the active diseases related of unwanted sheddase, this method comprises the sheddase inhibitor compound of the claim 1 of the described Mammals significant quantity that needs are arranged.
18. one kind is used in the method for mammalian subject treatment with unwanted TNF-α invertase activity diseases related, this method comprises the TNF-α converting enzyme inhibitor compound of the claim 1 of the described Mammals treatment significant quantity that needs are arranged.
19. one kind is used in the method for mammalian subject treatment with unwanted metal proteinase activity diseases related, wherein said metalloprotease is selected from MMP12, MMP13, MMP3, MMP2, MMP9, and this method comprises the inhibitors of metalloproteinase compound of the claim 1 of the described Mammals significant quantity that needs are arranged.
20. one kind is used in the method for mammalian subject treatment with unwanted Her2 sheddase active growth factor and cytokine sheddases diseases related, this method comprises the sheddase inhibitor compound of the claim 1 of the described Mammals significant quantity that needs are arranged.
21. one kind is used in the method for mammalian subject treatment with the active diseases related of unwanted ADAM, wherein said ADAM is selected from ADAM10, ADAM15, ADAM28, ADAM33, and this method comprises the sheddase inhibitor compound of the claim 1 of the described Mammals significant quantity that needs are arranged.
22. a medicinal compositions that is used for the treatment of, it comprises the compound and the pharmaceutically acceptable diluent or carrier of claim 1.
23. the compound of a claim 1, described compound is selected from:
1) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-the N-hydroxyl-5-[(3R)-3-hydroxyl pyrrolidine-1-yl] piperidines-3-methane amide
2) (2S, 3S)-2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-5-(2-{[2-(dimethylamino) ethyl] amino }-the 2-oxoethyl)-N-hydroxy piperidine-3-methane amide
3) (2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-the N-hydroxyl-5-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl } piperidines-3-methane amide
4) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-the N-hydroxyl-5-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl } piperidines-3-methane amide
5) (2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide
6) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide
7) (2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-[2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] piperidines-3-methane amide
8) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-[2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] piperidines-3-methane amide
9) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl }-N-hydroxyl-5-[(methoxyl group ethanoyl) (methyl) amino] piperidines-3-methane amide
10) (2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl }-N-hydroxyl-5-[(methoxyl group ethanoyl) (methyl) amino] piperidines-3-methane amide
11) (2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-{2-[(2-methoxy ethyl) amino]-the 2-oxoethyl } piperidines-3-methane amide
12) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-{2-[(2-methoxy ethyl) amino]-the 2-oxoethyl } piperidines-3-methane amide
13) (2S, 3S, 5S)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-{2-oxo-2-[(3R)-tetrahydrofuran (THF)-3-base is amino] ethyl } piperidines-3-methane amide
14) (2S, 3S, 5R)-and 2-{[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N-hydroxyl-5-{2-oxo-2-[(3R)-tetrahydrofuran (THF)-3-base is amino] ethyl } piperidines-3-methane amide
15) (3R, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-base carbonic acid methyl ester
16) (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-6-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-base carbonic acid methyl ester
17) (2S, 3S)-N, the 5-dihydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
18) (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-base ester
19) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
20) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
21) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
22) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-1-carboxylic acid 2-methoxy ethyl ester
23) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
24) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
25) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
26) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid 2-methoxy ethyl ester
27) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
28) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
29) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
30) (3R, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-1-carboxylic acid 2-methoxy ethyl ester
31) (1S, 2S, 5S)-and N, the 5-dihydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexane carboxamide
32) (1S, 2S, 5S)-and N, 5-dihydroxyl-2-{[4-phenyl-3,6-dihydropyridine-1 (2H)-yl] carbonyl } cyclohexane carboxamide
33) (1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexane carboxamide
34) (1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
35) (1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] cyclohexane carboxamide
36) (1S, 2S)-the N-hydroxyl-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl }-5-tetramethyleneimine-1-basic ring hexane methane amide
37) (1S, 2S, 5S)-the N-hydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl }-5-morpholine-4-basic ring hexane methane amide
38) (1S, 2S, 5R)-the N-hydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl }-5-morpholine-4-basic ring hexane methane amide
39) (1S, 2S)-the N-hydroxyl-5-[(3R)-3-hydroxyl pyrrolidine-1-yl]-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexane carboxamide
40) (1S, 2S, 5S)-and 2-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-N, 5-dihydroxyl cyclohexane carboxamide
41) ((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl) methyl carbamic acid (3S)-tetrahydrofuran (THF)-3-base ester
42) ((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl) methyl carbamic acid (3R)-tetrahydrofuran (THF)-3-base ester
43) ((3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl) methyl carbamic acid tetrahydrochysene-2H-pyrans-4-base ester
44) tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
45) methyl carbamic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
46) dimethylamino formic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
47) morpholine-4-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
48) (3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl ester
49) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
50) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperidines-1-carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
51) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
52) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid (3R)-tetrahydrofuran (THF)-3-base ester
53) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
54) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
55) 5-[({ (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-yl } ethanoyl) amino] amyl group } the carboxylamine benzyl ester
56) (2S, 3S)-the amino amyl group of 5-{2-[(5-) amino]-the 2-oxoethyl }-N-hydroxyl-2-[(3-Phenylpyrrolidine-1-yl) carbonyl] piperidines-3-methane amide
57) (1S, 2S)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
58) (1S, 2S)-N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
59) (1S, 2S)-the N-hydroxyl-5-{2-[(3R)-3-hydroxyl pyrrolidine-1-yl]-the 2-oxoethyl }-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
60) (1S, 2S)-N (2)-hydroxy-n (1)-4-[(2-toluquinoline-4-yl) methoxyl group] phenyl }-4-(2-oxo-2-piperidines-1-base ethyl) hexanaphthene-1, the 2-diformamide
61) (2S, 3S, 5R)-and 2-{[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N, 5-dihydroxyl piperidines-3-methane amide
62) (2S, 3S, 5S)-and 2-{[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl }-N, 5-dihydroxyl piperidines-3-methane amide
63) (2S, 3S, 5R)-and N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
64) (2S, 3S, 5S)-and N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
65) (2S, 3S, 5R)-and N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
66) (2S, 3S, 5S)-and N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
67) (2S, 3S, 5S)-and N, 5-dihydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperidines-3-methane amide
68) (2S, 3S, 5R)-and N, 5-dihydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl } piperidines-3-methane amide
69) (2S, 3S, 5R)-and N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide
70) (2S, 3S, 5S)-and N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-morpholine-4-base-2-oxoethyl) piperidines-3-methane amide
71) (1S, 2S)-N-hydroxyl-5-[2-(4-methylpiperazine-1-yl)-2-oxoethyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
72) (1S, 2S)-N-hydroxyl-5-(2-morpholine-4-base-2-oxoethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
73) (1S, 2S)-N-hydroxyl-5-{2-[(2-methoxy ethyl) amino]-the 2-oxoethyl }-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
74) methyl carbamic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
75) dimethylamino formic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
76) tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
77) piperidines-1-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
78) morpholine-4-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
79) (3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
80) the cyclopropyl carboxylamine (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
81) (3R, 4S)-N-hydroxyl-1-(morpholine-4-base carbonyl)-4-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-methane amide
82) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base ester
83) tetramethyleneimine-1-carboxylic acid (3R, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base ester
84) (2S, 3S)-2-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-the 3-[(hydroxyl amino) carbonyl] piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
85) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
86) morpholine-4-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
87) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
88) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
89) ((1S, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexyl) the carboxylamine methyl ester
90) (1S, 2S, 5S)-and N-hydroxyl-5-[(methyl sulphonyl) amino]-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexane carboxamide
91) (1S, 2S, 5S)-5-(acetylamino)-N-hydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexane carboxamide
92) (3R, 4S)-N-hydroxyl-4-[(4-Phenylpiperidine-1-yl) carbonyl]-1-(piperidines-1-base carbonyl) piperidines-3-methane amide
93) (3R, 4S)-N-hydroxyl-4-[(4-Phenylpiperidine-1-yl) carbonyl]-1-(tetramethyleneimine-1-base carbonyl) piperidines-3-methane amide
94) tetramethyleneimine-1-carboxylic acid (5S, 6S)-5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
95) tetramethyleneimine-1-carboxylic acid (5S, 6S)-5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
96) (1S, 2S, 5R)-and N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-oxo-2-piperidines-1-base ethyl) cyclohexane carboxamide
97) (1S, 2S, 5S)-and N-hydroxyl-2-{[4-(3-isopropyl phenyl) piperidines-1-yl] carbonyl }-5-(2-oxo-2-piperidines-1-base ethyl) cyclohexane carboxamide
98) (2S, 3S)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
99) (2S, 3S, 5R)-and N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
100) (2S, 3S, 5S)-and N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
101) (2S, 3S)-N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
102) (2S, 3S)-N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
103) (2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
104) (2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
105) (2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
106) (2S, 3S)-N-hydroxyl-1-methyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl)-2-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
107) (1S, 2S, 5R)-and N-hydroxyl-5-(2-oxo-2-piperidines-1-base ethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
108) (2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
109) (2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide
110) (2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
111) (2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-methane amide
112) (2S, 3S)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
113) (3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-[4-(trifluoromethoxy) benzoyl] piperidines-3-methane amide
114) (3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-{[4-(trifluoromethoxy) phenyl] alkylsulfonyl } piperidines-3-methane amide
115) (3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-[3-(trifluoromethoxy) benzoyl] piperidines-3-methane amide
116) (3R, 4S)-the N-hydroxyl-4-{[(3S)-3-Phenylpyrrolidine-1-yl] carbonyl }-1-[2-(trifluoromethoxy) benzoyl] piperidines-3-methane amide
117) (3R, 4S)-N-hydroxyl-1-[4-(two fluoro methoxyl groups) benzoyl]-4-{[(3S)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-methane amide
118) tetramethyleneimine-1-carboxylic acid (5S, 6S)-5-[(hydroxyl amino) carbonyl]-6-{[(3S)-and 3-Phenylpyrrolidine-1-yl] carbonyl } piperidines-3-base ester
119) tetramethyleneimine-1-carboxylic acid (5S, 6S)-5-[(hydroxyl amino) carbonyl]-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester
120) tetramethyleneimine-1-carboxylic acid (5S, 6S)-5-[(hydroxyl amino) carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
121) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
122) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-{[(3S)-and 3-Phenylpyrrolidine-1-yl] carbonyl }-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
123) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
124) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
125) (2S, 3S)-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
126) (2S, 3S)-5-[benzoyl (methyl) amino]-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
127) (2S, 3S)-5-[benzoyl (methyl) amino]-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
128) (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-yl } the methyl carbamic acid isopropyl esters
129) (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-yl } the methyl carbamic acid isopropyl esters
130) (1S, 2S, 5R)-and N, the 5-dihydroxyl-2-{[(3R)-and 3-tetramethyleneimine-1-yl] carbonyl }-5-propyl cyclohexane methane amide
131) (1S, 2S, 5S)-and N, the 5-dihydroxyl-2-{[(3R)-and 3-tetramethyleneimine-1-yl] carbonyl }-5-propyl cyclohexane methane amide
132) methyl carbamic acid (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
133) dimethylamino formic acid (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
134) the cyclopropyl carboxylamine (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
135) tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
136) (3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1S, 3S, 4S)-and 4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl }-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
137) morpholine-4-carboxylic acid (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
138) piperidines-1-carboxylic acid (1S, 3S, 4S)-4-{[4-(4-tert-butyl phenyl) piperazine-1-yl] carbonyl-the 3-[(hydroxyl amino) carbonyl] cyclohexyl ester
139) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
140) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
141) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
142) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
143) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[3-(trifluoromethyl) phenoxy group] piperidines-1-carboxylic acid methyl ester
144) (2S, 3S, 5S)-and 5-(2,4-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
145) (2S, 3S, 5S)-and 5-(3-chloro-4-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
146) (2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
147) (2S, 3S, 5S)-and 5-(3-bromo phenoxy group)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
148) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-3-yl oxygen base) piperidines-1-carboxylic acid methyl ester
149) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) piperidines-1-carboxylic acid methyl ester
150) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(3-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
151) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(3-methoxyl group phenoxy group)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
152) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-[(6-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
153) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
154) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
155) (2S, 3S, 5S)-and 5-(3-chloro phenoxy group)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
156) (2S, 3S, 5S)-and 5-(2,3-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
157) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-1-carboxylic acid methyl ester
158) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinolyl-4 oxygen base) piperidines-1-carboxylic acid methyl ester
159) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-1-carboxylic acid methyl ester
160) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
161) (2S, 3S, 5S)-and 5-(2-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
162) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(2-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
163) (2S, 3S, 5S)-and 5-(4-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
164) (2S, 3S, 5S)-and 5-(3,5-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
165) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
166) (2S, 3S, 5S)-and 5-(1,3-benzothiazole-2-base oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
167) (2S, 3S, 5S)-and 5-(3,4-phenyl-difluoride oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
168) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide
169) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
170 (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-phenoxy group-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
171) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
172) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(quinoline-6-base oxygen base) piperidines-3-methane amide
173) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
174) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide
175) (2S, 3S, 5S)-and 5-(3,5-phenyl-difluoride oxygen base)-N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-methane amide
176) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(quinolyl-4 oxygen base) piperidines-3-methane amide
177) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide
178) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-4-yl) the oxygen base]-2-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-methane amide
179) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-methane amide
180) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide
181) (2S, 3S, 5S)-and N-hydroxyl-1-(methyl sulphonyl)-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
182) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid (3S)-tetrahydrofuran (THF)-3-base ester
183) (2S, 3S, 5S)-and 5-(2-bromo phenoxy group)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
184) (2S, 3S, 5S)-and 5-(2-chloro phenoxy group)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
185) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid tetrahydrochysene-2H-pyrans-4-base ester
186) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid ethyl ester
187) (2S, 3S, 5S)-and N-hydroxyl-5-(3-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
188) (2S, 3S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[3-(trifluoromethyl) phenoxy group] piperidines-3-methane amide
189) (2S, 3S, 5S)-and 5-(3-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
190) (2S, 3S, 5S)-and N-hydroxyl-5-(3-methoxyl group phenoxy group)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
191) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
192) piperidines-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
193) (2S)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
194) azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
195) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
196) dimethylamino formic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
197) 2,5-dihydro-1H-pyrroles-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
198) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
199) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester
200) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
201) azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-benzo [e] isoindole-2-base carbonyl)-5-[(hydroxyl amino) carbonyl]-1-methyl piperidine-3-base ester
202) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester
203) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base ester
204) piperidines-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester
205) azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-isoindole-2-base carbonyl)-5-[(hydroxyl amino) carbonyl]-1-methyl piperidine-3-base ester
206) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
207) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
208) azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
209) (2S)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
210) piperidines-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
211) dimethylamino formic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
212) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-([(2S)-and 2-(hydroxymethyl) tetramethyleneimine-1-yl] the ketonic oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
213) (2S, 3S, 5S)-and 2-(1,3-dihydro-2H-isoindole-2-base carbonyl)-3-[(hydroxyl amino) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
214) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[(piperidines-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
215) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
216) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(3-Phenylpyrrolidine-1-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
217) (2S, 3S, 5S)-and the 5-[(dimethylamino) carbonyl] oxygen base-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
218) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
219) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-[(tetramethyleneimine-1-base carbonyl) the oxygen base] piperidines-1-carboxylic acid methyl ester
220) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
221) azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-benzo [e] isoindole-2-base carbonyl)-5-[(hydroxyl amino) carbonyl] piperidines-3-base ester
222) azetidine-1-carboxylic acid (3S, 5S, 6S)-6-(1,3-dihydro-2H-isoindole-2-base carbonyl)-5-[(hydroxyl amino) carbonyl] piperidines-3-base ester
223) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] piperidines-3-base ester
224) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-base ester
225) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester
226) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-base ester
227) azetidine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
228) tetramethyleneimine-1-carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-base ester
229) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-(2-oxo-2-tetramethyleneimine-1-base oxethyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
230) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(thiophenyl) piperidines-1-carboxylic acid methyl ester
231) (2S, 3S, 5S)-and 5-(allyl group oxygen base)-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
232) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-Phenoxypiperidines-1-carboxylic acid methyl ester
233) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-5-methoxyl group-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
234) (2S, 3S, 5S)-and uncle 5--butoxy-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide
235) (2S, 3S, 5S)-and uncle 5--butoxy-3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-1-carboxylic acid methyl ester
236) (3R, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
237) (3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
238) (3R, 4S)-1-[(E)-(cyanoimino) (dimethylamino) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
239) (3R, 4S)-1-[(E)-(cyanoimino) (cyclopropyl amino) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
240) (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
241) (3R, 4S)-1-[(Z)-(cyanoimino) (morpholine-4-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
242) (3R, 4S)-1-[(Z)-(cyanoimino) (hydroxyl amino) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
243) (3R, 4S)-1-[(E)-aza-heptane-1-base (cyanoimino) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
244) (3R, 4S)-1-[(Z)-(cyanoimino) (4-methylpiperazine-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
245) (3R, 4S)-1-[(Z)-(cyanoimino) (parathiazan-4-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
246) (3R, 4S)-1-[(E)-(cyanoimino) (4-methyl piperidine-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
247) (3R, 4S)-1-[(Z)-(cyanoimino) (2,5-dihydro-1H-pyrroles-1-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
248) (3R, 4S)-1-[(Z)-(cyanoimino) (1,3-dihydro-2H-isoindole-2-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
249) (3R, 4S)-1-[(Z)-(cyanoimino) (3,4-dihydro-isoquinoline-2 (1H)-yl) methyl]-the N-hydroxyl-4-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
250) (3R, 4S)-the N-hydroxyl-1-[(Z)-1-(hydroxyl amino)-2-nitroethylene base]-4-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide
251) (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
252) (3R, 4S)-1-[(E)-(cyanoimino) (dimethylamino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
253) (3R, 4S)-1-[(E)-aza-heptane-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
254) (3R, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
255) (3R, 4S)-1-[(E)-(cyanoimino) (cyclopropyl amino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
256) (3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide
257) (1S, 2S, 5E)-and 5-benzylidene-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexane carboxamide trifluoroacetate
258) (1S, 2S, 5E)-and 5-(cyclopropyl methylene radical)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexane carboxamide trifluoroacetate
259) (1S, 2S, 5S)-and 5-benzyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
260) (1S, 2S, 5R)-and N, 5-dihydroxyl-5-phenyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-the cyclohexane carboxamide trifluoroacetate
261) (1S, 2S, 5R)-and 5-benzyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-the cyclohexane carboxamide trifluoroacetate
262) (1S, 2S, 5R)-and N, 5-dihydroxyl-5-sec.-propyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-the cyclohexane carboxamide trifluoroacetate
263) (1S, 2S, 5R)-and 5-cyclopropyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-the cyclohexane carboxamide trifluoroacetate
264) (2S, 3S, 5R)-and 2-[4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-yl] carbonyl-N-hydroxyl-5-(2-oxo-2-tetramethyleneimine-1-base ethyl) piperidines-3-methane amide
265) (5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-Phenylpiperidine-1-yl) carbonyl] piperidines-3-ylmethyl carboxylamine isopropyl esters
266) (1S, 2S)-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(tetramethyleneimine-1-base carbonyl) cyclohexane carboxamide
267) N-cyclopropyl-N-({ (3S, 4S)-3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl } methyl) morpholine-4-methane amide
268) (1S, 2S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(piperidines-1-base carbonyl) cyclohexane carboxamide
269) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(piperidines-1-base carbonyl) cyclohexane carboxamide
270) (1S, 2S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(tetramethyleneimine-1-base carbonyl) cyclohexane carboxamide
271) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(tetramethyleneimine-1-base carbonyl) cyclohexane carboxamide
272) (1S, 2S)-N-hydroxyl-5-(morpholine-4-base carbonyl)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
273) N-cyclopentyl-N-((3S, 4S, 5S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl methyl) piperidines-1-methane amide
274) N-cyclopentyl-N-((3S, 4S, 5R)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl methyl) piperidines-1-methane amide
275) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
276) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
277) piperidines-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester
278) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
279) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
280) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
281) (1S, 2S, 5R)-and N, the 5-dihydroxyl-2-{[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl } cyclohexane carboxamide
282) dimethylamino formic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
283) tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
284) methyl carbamic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
285) morpholine-4-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
286) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
287) morpholine-4-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-{[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl cyclohexyl ester
288) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester
289) piperidines-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
290) N-{ (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl-N-methyl azetidine-1-methane amide
291) diethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
292) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
293) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
294) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
295) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
296) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester
297) morpholine-4-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexyl ester
298) (1S, 2S, 5R)-and N, 5-dihydroxyl-5-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
299) (1S, 2S, 5S)-and N, 5-dihydroxyl-5-methyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide
300) (3R)-3-hydroxyl pyrrolidine-1-carboxylic acid (1R, 3R, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
301) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
302) dimethylamino formic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester
303) (1S, 2S, 5R)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide
304) (1S, 2S, 5R)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
305) (1S, 2S, 5S)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide
306) (1S, 2S, 5S)-and 5-allyl group-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
307) (1S, 2S, 5R)-and N, 5-dihydroxyl-5-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexane carboxamide
308) (1S, 2S, 5S)-and N, 5-dihydroxyl-5-methyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexane carboxamide
309) (1S, 2S, 5S)-and N, 5-dihydroxyl-5-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
310) (1S, 2S, 5R)-and N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-propyl cyclohexane methane amide
311) (1S, 2S, 5S)-and N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-propyl cyclohexane methane amide
312) (1S, 2S, 5R)-and N-hydroxyl-5-phenoxy group-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
313) (1S, 2S, 5R)-and N-hydroxyl-5-[(6-picoline-3-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
314) (1S, 2S, 5R)-and N-hydroxyl-5-(4-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
315) (1S, 2S, 5R)-and 5-(2,3-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
316) (1S, 2S, 5R)-and N-hydroxyl-5-[(6-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
317) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[(2-toluquinoline-4-yl) the oxygen base] cyclohexane carboxamide
318) (1S, 2S, 5R)-and 5-(3,4-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
319) (1S, 2S, 5R)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
320) (1S, 2S, 5R)-and N-hydroxyl-5-[1-(methyl sulphonyl) piperidin-4-yl] oxygen base-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
321) (1S, 2S, 5R)-and 5-(2,4-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
322) 4-((1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl oxygen base) piperidines-1-carboxylic acid methyl ester
323) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-3-yl oxygen base) cyclohexane carboxamide
324) (1S, 2S, 5R)-and 5-(4-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
325) (1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
326) (1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] cyclohexane carboxamide
327) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) cyclohexane carboxamide
328) (1S, 2S, 5R)-and 5-(2,3-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
329) (1S, 2S, 5R)-and 5-(benzyl oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
330) (1S, 2S, 5R)-and N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
331) (1S, 2S, 5R)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
332) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) cyclohexane carboxamide
333) (1S, 2S, 5R)-and 5-[(1-ethanoyl piperidin-4-yl) the oxygen base]-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
334) (1S, 2S, 5R)-and N-hydroxyl-5-[(2-picoline-3-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
335) (1S, 2S, 5R)-and 5-[3, two (trifluoromethyl) phenoxy groups of 5-]-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
336) (1S, 2S, 5R)-and 5-(2-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
337) (1S, 2S, 5R)-and 5-(4-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
338) (1S, 2S, 5R)-and 5-(3-bromo phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
339) (1S, 2S, 5R)-and 5-(1,3-benzothiazole-2-base oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
340) (1S, 2S, 5R)-and 5-(3-chloro phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide
341) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyrimidine-2-yloxy) cyclohexane carboxamide
342) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-[3-(trifluoromethyl) phenoxy group] cyclohexane carboxamide
343) (1S, 2S, 5R)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinolyl-4 oxygen base) cyclohexane carboxamide and
344) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(thieno-[3,2-b] pyridine-7-base oxygen base) cyclohexane carboxamide.
24. the compound of a claim 1, described compound is selected from:
1) (1S, 2S, 5R)-N-hydroxyl-5-[isobutyryl (methyl) amino]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
2) the cyclopropyl carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
3) ethyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
4) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
5) the sec.-propyl carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
6) third-2-alkynes-1-aminocarbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
7) piperidines-1-carboxylic acid (] R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
8) 4-methylpiperazine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
9) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexyl ester,
10) (1-methyl piperidine-4-yl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
11) isobutyl-(methyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
12) methyl (3-phenyl propyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
13) cyclohexyl (methyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
14) (4-p-methoxy-phenyl) methyl carbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
15) indoline-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
16) 1,3-dihydro-2H-isoindole-2-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
17) (2-phenycyclopropyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
18) the cyclobutyl carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
19) 4-{[({ (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl the oxygen base) carbonyl] amino piperidines-1-carboxylic acid ethyl ester,
20) tetrahydrofuran (THF)-3-aminocarbamic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
21) (4-hydroxy-cyclohexyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
22) (2-methoxy ethyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
23) (pyridine-2-ylmethyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
24) (pyridin-3-yl methyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
25) (pyridin-4-yl methyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
26) 2,5-dihydro-1H-pyrroles-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
27) the cyclopentyl carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
28) the cyclohexyl carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
29) piperazine-1,4-dicarboxylic acid ethyl ester (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
30) 4-{2-[methyl (phenyl) amino]-the 2-oxoethyl } piperazine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
31) 4-hydroxy piperidine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
32) (3R)-3-(acetylamino) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
33) (3S)-3-(acetylamino) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
34) (2R)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
35) (2S)-2-(hydroxymethyl) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
36) [1-(hydroxymethyl) cyclopentyl] carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
37) [(1R, 2R)-2-hydroxycyclopent base] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
38) [2-(hydroxymethyl) cyclohexyl] carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
39) [(2R)-the 2-hydroxy-cyclohexyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
40) [(1R)-2-hydroxyl-1-phenylethyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
41) [(1R)-2-hydroxyl-1-methylethyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
42) [(1R)-1-(hydroxymethyl) propyl group] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
43) [(1R)-1-(hydroxymethyl)-2-methyl-propyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
44) [(2R)-the 2-hydroxypropyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
45) (3-hydroxyl-1-phenyl propyl) carboxylamine (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
46) [(1R)-1-(hydroxymethyl)-3-methyl butyl] carboxylamine (1R, 3S, 4S)-and the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
47) 4-formyl piperazine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-4-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexyl ester,
48) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-3-yl methoxyl group) cyclohexane carboxamide,
49) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) cyclohexane carboxamide,
50) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) cyclohexane carboxamide,
51) (1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
52) (1S, 2S, 5R)-and N-hydroxyl-5-(4-hydroxyphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
53) (1S, 2S, 5R)-and N-hydroxyl-5-[(4-methoxyl group cyclohexyl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
54) (1S, 2S, 5R)-and N-hydroxyl-5-(4-methoxyl group phenoxy group)-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
55) (1S, 2S, 5R)-and N-hydroxyl-5-[(4-methoxyl group cyclohexyl) the oxygen base]-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
56) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-{[2-(trifluoromethyl) quinolyl-4] the oxygen base } cyclohexane carboxamide,
57) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-2-base oxygen base) cyclohexane carboxamide,
58) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-3-base oxygen base) cyclohexane carboxamide,
59) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-5-base oxygen base) cyclohexane carboxamide,
60) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-7-base oxygen base) cyclohexane carboxamide,
61) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-8-base oxygen base) cyclohexane carboxamide,
62) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridine-2-base oxygen base) cyclohexane carboxamide,
63) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridin-4-yl oxygen base) cyclohexane carboxamide,
64) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(quinoline-6-base oxygen base) cyclohexane carboxamide,
65) (1S, 2S, 5R)-and 5-[(1-ethyl piperidine-4-yl) the oxygen base]-N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl] cyclohexane carboxamide,
66) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) cyclohexane carboxamide,
67) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) cyclohexane carboxamide,
68) (1S, 2S, 5R)-and N-hydroxyl-2-[(4-Phenylpiperidine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) cyclohexane carboxamide,
69) (1S, 2S, 5R)-and 5-(3-chloro phenoxy group)-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
70) (1S, 2S, 5R)-and 5-(3,4-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
71) (1S, 2S, 5R)-and 5-(2,3-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
72) (1S, 2S, 5R)-and N-hydroxyl-5-(isoquinolyl-1 oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
73) (1S, 2S, 5R)-and N-hydroxyl-5-(isoquinoline 99.9-3-base oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
74) (1S, 2S, 5R)-and N-hydroxyl-5-(isoquinoline 99.9-5-base oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
75) (1S, 2S, 5R)-and N-hydroxyl-5-(isoquinoline 99.9-7-base oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
76) (1S, 2S, 5R)-and N-hydroxyl-5-(2-naphthyl oxygen base)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
77) (1S, 2S, 5R)-and 5-(2,4-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
78) (1S, 2S, 5R)-and 5-(3,5-phenyl-difluoride oxygen base)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
79) (1S, 2S, 5R)-and 5-(3-chloro-4-fluorinated phenoxy)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
80) (1S, 2S, 5R)-and 5-(3,4-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
81) (1S, 2S, 5R)-and 5-(3,5-dichloro-phenoxy group)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
82) (1S, 2S, 5R)-and 5-(2,5-dioxo tetramethyleneimine-1-yl)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
83) (1S, 2S, 5R)-and 5-(5,5-dimethyl-2,4-dioxo-1,3-_ azoles alkane-3-yl)-N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
84) (1S, 2S, 5R)-and N-hydroxyl-5-(3-methyl-2,5-dioxo alkyl imidazole-1-yl)-2-[(4-phenylpiperazine-1-yl) carbonyl] cyclohexane carboxamide,
85) 2,5-dihydro-1H-pyrroles-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester,
86) azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester,
87) dimethylamino formic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester,
88) the hot ring-1-carboxylic acid of azepine (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] the basic ester of piperidines-3-,
89) (2S, 3S, 5S)-and 5-(2-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
90) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(6-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
91) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide,
92) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
93) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
94) (2S, 3S, 5S)-and 5-(1,3-benzothiazole-2-base oxygen base)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
95) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-(3-methylphenoxy)-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
96) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
97) (2S, 3S, 5S)-and 5-(3,4-phenyl-difluoride oxygen base)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
98) (2S, 3S, 5S)-and 5-(2-chloro phenoxy group)-N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
99) 3,3-two fluoropyrrolidines-1-carboxylic acid (3S, 5S, 6S)-and the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-base ester,
100) (2S, 3S, 5S)-and the 3-[(hydroxyl amino) carbonyl]-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) piperidines-1-carboxylic acid methyl ester,
101) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyridin-3-yl oxygen base) piperidines-3-methane amide,
102) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide,
103) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
104) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-phenoxy group-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
105) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
106) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
107) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(6-picoline-2-yl) the oxygen base]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
108) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
109) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridin-3-yl oxygen base) piperidines-3-methane amide,
110) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
111) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
112) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(quinolyl-4 oxygen base) piperidines-3-methane amide,
113) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) piperidines-3-methane amide,
114) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinolyl-4 oxygen base) piperidines-3-methane amide,
115) (2S, 3S, 5S)-and N-hydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
116) (2S, 3S, 5S)-and N-hydroxyl-1-methyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(4-phenylpiperazine-1-yl) carbonyl] piperidines-3-methane amide,
117) (2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
118) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-[(6-picoline-2-yl) the oxygen base] piperidines-3-methane amide,
119) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base] piperidines-3-methane amide,
120) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
121) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-Phenoxypiperidines-3-methane amide,
122) (2S, 3S, 5S)-and N-hydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
123) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-[(3-methyl isophthalic acid H-pyrazoles-5-yl) the oxygen base] piperidines-3-methane amide,
124) (2S, 3S, 5S)-and N-hydroxyl-5-[(5-methyl is different _ azoles-3-yl) and the oxygen base]-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
125) (2S, 3S, 5S)-and N-hydroxyl-5-[(3-methyl isophthalic acid H-pyrazoles-5-yl) the oxygen base]-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
126) (2S, 3S, 5S)-and 5-[(5-chloro-pyridine-3-yl) the oxygen base]-the N-hydroxyl-2-[(3R)-3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
127) (2S, 3S, 5S)-and N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
128) (2S, 3S, 5S)-the N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
129) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5-(3,4-phenyl-difluoride oxygen base)-N-hydroxy piperidine-3-methane amide,
130) (2S, 3S, 5S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-[(5-methyl is different _ azoles-3-yl) the oxygen base] piperidines-3-methane amide,
131) (2S, 3S, 5S)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxyl-5-[(2-toluquinoline-4-yl) the oxygen base] piperidines-3-methane amide,
132) (2S, 3S, 5S)-and N-hydroxyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
133) (2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5,5-two fluoro-N-hydroxyls-1-methyl piperidine-3-methane amide,
134) (2S, 3S)-2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5,5-two fluoro-N-hydroxy piperidine-3-methane amides,
135) (2S, 3S)-5,5-two fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-1-methyl piperidine-3-methane amide,
136) (2S, 3S)-5,5-two fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl piperidines-3-methane amide,
137) (2S, 3S)-5,5-two fluoro-N (3)-hydroxyls-1-methyl-N (2)-4-[(2-toluquinoline-4-yl) methoxyl group] Phenylpiperidine-2, the 3-diformamide,
138) (2S, 3S)-5,5-two fluoro-N (3)-hydroxy-n (2)-4-[(2-toluquinoline-4-yl) methoxyl group] Phenylpiperidine-2, the 3-diformamide,
139) azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-6-[(4-[(2-toluquinoline-4-yl) methoxyl group] phenyl amino) carbonyl] piperidines-3-base ester,
140) (2S, 3S, 5R)-and 5-fluoro-N (3)-hydroxy-n (2)-4-[(2-toluquinoline-4-yl) methoxyl group] Phenylpiperidine-2, the 3-diformamide,
141) azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-the 5-[(hydroxyl amino) carbonyl]-1-methyl-6-[(4-[(2-toluquinoline-4-yl) methoxyl group] phenyl amino) carbonyl] piperidines-3-base ester,
142) azepine ring-1-in heptan carboxylic acid (3S, 5S, 6S)-6-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5-[(hydroxyl amino) carbonyl] piperidines-3-base ester,
143) (2S, 3S, 5R)-5-fluoro-N-hydroxyl-1-methyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
144) (2S, 3S, 5R)-5-fluoro-N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] carbonyl piperidines-3-methane amide,
145) (2S, 3S, 5S)-and N-hydroxyl-5-phenoxy group-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
146) (2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyridine-2-base oxygen base) piperidines-3-methane amide,
147) (2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyridin-4-yl oxygen base) piperidines-3-methane amide,
148) (2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(pyridin-3-yl oxygen base) piperidines-3-methane amide,
149) (2S, 3S, 5S)-and N-hydroxyl-5-[(6-picoline-2-yl) the oxygen base]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
150) (2S, 3S, 5S)-and N-hydroxyl-5-[(4-picoline-2-yl) the oxygen base]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
151) (2S, 3S, 5S)-and 5-(3-fluorinated phenoxy)-N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
152) (2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinoline-6-base oxygen base) piperidines-3-methane amide,
153) (2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinoline-7-base oxygen base) piperidines-3-methane amide,
154) (2S, 3S, 5S)-and N-hydroxyl-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl]-5-(quinolyl-4 oxygen base) piperidines-3-methane amide,
155) (2S, 3S, 5S)-and N-hydroxyl-5-[(2-toluquinoline-4-yl) the oxygen base]-2-[(3-phenyl-2,5-dihydro-1H-pyrroles-1-yl) carbonyl] piperidines-3-methane amide,
156) (2S, 3S, 5R)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5-fluoro-N-hydroxy piperidine-3-methane amide,
157) (2S, 3S, 5R)-and 5-fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl piperidines-3-methane amide,
158) (2S, 3S, 5R)-and 2-[4-(4-cyano group-3,5-3,5-dimethylphenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-5-fluoro-N-hydroxyl-1-methyl piperidine-3-methane amide,
159) (2S, 3S, 5R)-and 5-fluoro-N-hydroxyl-2-[4-(3-isopropyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-1-methyl piperidine-3-methane amide,
160) (1S, 2S, 5E)-and 5-benzylidene-2-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxyl cyclohexane carboxamide trifluoroacetate,
161) (1S, 2S, 5E)-and 2-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-5-(cyclopropyl methylene radical)-N-hydroxyl cyclohexane carboxamide trifluoroacetate,
162) (1S, 2S, 5E)-5-benzylidene-N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] the carbonyl-cyclohexane methane amide,
163) (1S, 2S, 5S)-and N, 5-dihydroxyl-5-isobutyl--2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
164) (1S, 2S, 5S)-and 5-butyl-N, 5-dihydroxyl-2-[(4-phenyl-3,6-dihydropyridine-1 (2H)-yl) carbonyl] cyclohexane carboxamide,
165) azetidine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-1-methyl-4-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexyl ester trifluoroacetate,
166) tetramethyleneimine-1-carboxylic acid (1S, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-1-methyl-4-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexyl ester trifluoroacetate,
167) (1S, 2S, 5S)-and N, 5-dihydroxyl-5-isobutyl--2-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexane carboxamide trifluoroacetate,
168) (1S, 2S, 5R)-and 5-(cyclopropyl methyl)-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexane carboxamide trifluoroacetate,
169) (1S, 2S, 5R)-and 5-butyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexane carboxamide trifluoroacetate,
170) tetramethyleneimine-1-carboxylic acid (1R, 3S, 4S)-the 3-[(hydroxyl amino) carbonyl]-1-methyl-4-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexyl ester trifluoroacetate,
171) (1S, 2S, 5E)-5-(cyclopropyl methylene radical)-N-hydroxyl-2-[(3R)-and 3-Phenylpyrrolidine-1-yl] the carbonyl-cyclohexane methane amide,
172) (1S, 2S, 5R)-and 5-ethyl-N, 5-dihydroxyl-2-[(4-phenylpiperazine-1-yl) carbonyl] the cyclohexane carboxamide trifluoroacetate,
173) (3R, 4S)-1-[(E)-(cyanoimino) (cyclopropyl amino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
174) (3R, 4S)-1-[(E)-(cyanoimino) (dimethylamino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
175) (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
176) (3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
177) (3R, 4S)-1-[(E)-azetidine-1-base (cyanoimino) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
178) (3R, 4S)-1-[(E)-(cyanoimino) (tetramethyleneimine-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide,
179) (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl)-3,6-dihydropyridine-1 (2H)-yl] carbonyl-N-hydroxy piperidine-3-methane amide and
180) (3R, 4S)-1-[(E)-(cyanoimino) (piperidines-1-yl) methyl]-4-[4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-yl] carbonyl-N-hydroxy piperidine-3-methane amide.
CN 200480037188 2003-10-17 2004-10-15 Substituted cyclic hydroxamates as inhibitors of matrix metalloproteinases Pending CN1898234A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101497878B (en) * 2008-01-30 2012-11-07 房学迅 Polypeptide of specific efficient affinity membrane type I substrate metal protease (MT1-MMP), protein and use

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101497878B (en) * 2008-01-30 2012-11-07 房学迅 Polypeptide of specific efficient affinity membrane type I substrate metal protease (MT1-MMP), protein and use

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