CN1768031A - Novel hydroxamates as therapeutic agents - Google Patents

Novel hydroxamates as therapeutic agents Download PDF

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Publication number
CN1768031A
CN1768031A CN 200480009225 CN200480009225A CN1768031A CN 1768031 A CN1768031 A CN 1768031A CN 200480009225 CN200480009225 CN 200480009225 CN 200480009225 A CN200480009225 A CN 200480009225A CN 1768031 A CN1768031 A CN 1768031A
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Prior art keywords
hydroxyl
benzamide
oxyethyl group
base
group
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CN 200480009225
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Chinese (zh)
Inventor
埃里克·J·弗纳
马丁·森齐克
奇特拉·鲍什考兰
约瑟夫·J·巴格杰
詹姆士·鲁宾逊
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Axys Pharmaceuticals Inc
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Axys Pharmaceuticals Inc
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Abstract

The present invention is directed to certain hydroxamate derivatives that are useful in the treatment of hepatitis C. These compounds are also inhibitors of histone deacetylase and are therefore useful in the treatment of diseases associated with histone deacetylase activity. Pharmaceutical compositions and processes for preparing these compounds are also disclosed.

Description

Hydroxamic acid ester as therapeutical agent
Background of invention
Invention field
The present invention relates to be used for the treatment of some novel hydroxamic acid esters of hepatitis C.These compounds also are the inhibitor of histone deacetylase, therefore can be used for treatment and the active diseases associated of histone deacetylase.The invention also discloses the method for pharmaceutical composition and these compounds of preparation.
The state of the art
Hepatitis C:
Chronic hepatitis C is a kind of slow PD that M ﹠ M is had material impact.And the patient who much infects hepatitis C will have subclinical or minor ailment, and at least 80% of these HCV infection individualities develop into chronic infectious disease and hepatitis.20-50% among them finally develops into liver cirrhosis, and 1-2% develops into liver cancer (Hoofnagle, J.H.; 1997; Hepatology 26:15S-20S).According to estimates, there are 100,000,000 7 thousand ten thousand HCV carrier in the whole world, and the latter stage hepatopathy relevant with HCV is the one of the main reasons of liver transplantation at present.Singly in the U.S., hepatitis C causes 8000-10000 people's death every year.
At present, the combination therapy of interferon-' alpha ' 2b/ virazole is unique feasible methods of treatment.Those by the curer in the people of about 40-45% occurred the lasting virusology of IFN-α 2b/ virazole combination therapy is replied.To the patient that the combination therapy of interferon-' alpha ' 2b/ virazole was lost efficacy, there is not possible alternative to stop the development of hepatopathy for those at present.Therefore, the alternative medicine that needs the treatment chronic HCV infection.The present invention has satisfied this demand.
Histone deacetylase:
With histone deacetylase (HDAC) is target as study of pharmacy; concern to them concentrates on effect and HDAC the effect (people such as Kramers, commentary in 2001.TrendsEndocrinol.Metab.12:294-300 arranged) in development and enhancement cancer of HDAC in regulating the gene relevant with the cell cycle progress.Several researchs show, treat various clones with hdac inhibitor and cause at G 1Late period or at G 2The highly acetylated effect and the cell cycle arrest of histone during/M conversion.Be subjected to that hdac inhibitor raises, the gene relevant to comprise p21, p27, p53 and cyclin E according to the show with the cell cycle.Reported that cyclin A and cyclin D are reduced by hdac inhibitor.In tumor cell line, several researchs have shown that the treatment that utilizes hdac inhibitor can cause growth-inhibiting, cessation of growth cessation, the end breaks up and/or apoptosis eventually.The interior research of body is verified, can cause tumor growth to suppress and the metastases minimizing with the hdac inhibitor treatment.
The most clearly contact appears in the acute promyelocytic leukemia between unusual HDAC activity and cancer.In this case, chromosomal transposition causes retinoic acid receptor (RAR) RAR α and promyelocytic leukemia (PML) or promyelocytic leukemia zinc to refer to (PLZF) proteic fusion.PML-RAR α and PLZF-RAR α suppress the gene that vitamin A acid is regulated by raising unusually of SMRT-mSin3-HDAC complex compound, thereby promote leukemic progress (people such as Lin, 1998, Nature 391:811-814; People such as Grignani, 1998, Nature 391:815-818).The PML-RARa form of disease can be used retinoic acid therapy, and the PLZF-RAR alpha-form has resistance to this treatment.For the patient who suffers from anti-vitamin A acid form disease, add the hdac inhibitor Sodium propanecarboxylate cause in the dosage clinical completely and plastidogenetic alleviation (people such as Warrell, 1998, J.Natl.Cancer.Inst.90:1621-1625).Also relevant (the people such as Steffan of HDAC with Heng Yandun disease (Huntington ' s disease); Nature 413:739-744, " histone deacetylase inhibitors stops polyglutamic acid amides in the fruit bat-dependency nerve degeneration " (Histonedeacetylase inhibitors arrest polyglutamine-dependent neurodegenerationin Drosophila)).
In a word, the active increase of HDAC helps the pathology and/or the semiotics of numerous disease.Therefore, suppress the active molecule useful as therapeutics of HADC and treat these diseases.
Summary of the invention
In first aspect, the invention provides formula (I) compound or pharmaceutically acceptable salt thereof:
Figure A20048000922500291
Wherein:
R 1Be hydrogen or alkyl;
X is-O-,-NR 2-or-S (O) n-, wherein n is 0-2, R 2Be hydrogen or alkyl;
Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces;
Ar 1Be phenylene or heteroarylidene, wherein said Ar 1Randomly replaced by one or two group, described group is independently selected from alkyl, halogen, hydroxyl, alkoxyl group, halogenated alkoxy or haloalkyl;
R 3Be hydrogen, alkyl, hydroxyalkyl or the optional phenyl that replaces; With
Ar 2Be aryl, aralkyl, arylalkenyl, heteroaryl, heteroaralkyl, impure aromatic ene base, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl.
In second aspect, the present invention relates to a kind of pharmaceutical composition, this pharmaceutical composition comprises formula (I) compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle for the treatment of significant quantity.
In the third aspect, the present invention relates to a kind of method for the treatment of in the animal by the disease of HDAC mediation, this method comprises to animal uses a kind of formula (I) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity and pharmaceutical composition of pharmaceutically acceptable vehicle of comprising.Preferably, described disease is proliferative disease such as cancer and bipolar disorder, and described animal is behaved.Preferably, cancer is prostate cancer, mammary cancer, pulmonary melanoma, cancer of the stomach, neuroblastoma, colorectal carcinoma, carcinoma of the pancreas, ovarian cancer, T-cell lymph gland, or leukemia such as myelomatosis (MM) and acute myelogenous leukemia (AMM).
In fourth aspect, the present invention relates to method for cancer in a kind of treatment animal, this method comprises to animal uses a kind of formula (I) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity and pharmaceutical composition of pharmaceutically acceptable vehicle of comprising, and in conjunction with radiotherapy with randomly in conjunction with one or more compounds, described compound is independently selected from: estrogenic agents, androgen receptor modifier, the retinoid receptor conditioning agent, cytotoxic agent, another kind of antiproliferative, prenyl-protein transferase inhibitor, the HMG-CoA reductase inhibitor, the hiv protease inhibitor, reverse transcriptase inhibitors, angiogenesis inhibitor, or dnmt rna inhibitor.
The applicant finds that also compound of the present invention can be used for treating hepatitis C.Therefore, aspect the 5th, the present invention relates to a kind of method for the treatment of the hepatitis C in the animal, this method comprises to animal uses a kind of formula (I) compound or pharmaceutically acceptable salt thereof for the treatment of significant quantity and pharmaceutical composition of pharmaceutically acceptable vehicle of comprising, randomly in conjunction with one or more other hepatitis C medicaments.Preferably, the hepatitis C medicament is interferon-' alpha ' 2b, virazole and HCV AG14361.
Aspect the 6th, the present invention relates to intermediate or its salt of formula (II):
R wherein 50Be hydrogen or alkyl, and Ar 1, Ar 2, R 3, X and Y such as front be to the definition of formula (I) compound.Preferably, Ar 1, Ar 2, R 3, X and Y in the following preferred embodiment definition.
Aspect the 7th, the present invention relates to the method for a kind of preparation formula (I) compound, this method comprises:
(i) make formula (III) compound:
Figure A20048000922500302
R wherein 51Be hydroxyl, alkoxyl group, halogen or succinimide ester, with formula NH 2OR " azanol reaction, wherein R " is hydrogen, alkyl or oxygen protecting group; Or
(ii) use acid treatment formula (IV) compound:
Figure A20048000922500311
M wherein +Be basic metal; Use NH then 2" after handling, wherein R " is hydrogen, alkyl or oxygen protecting group to OR;
Obtain the formula V compound;
" base obtains formula (I) compound, and wherein R ' is a hydrogen (iii) randomly to remove the R in the compound (V);
The acid salt of the product that (iv) randomly is formed on above-mentioned steps (i), forms in (ii) or (iii);
(the free alkali of the product that v) randomly be formed on above-mentioned steps (i), forms in (ii), (iii) or (iv); Or
(vi) randomly modification in above-mentioned steps (i), (ii), (iii), (iv) or (X, Y, R in the product that forms v) 1, R 2, R 3, Ar 1And Ar 2In the group any one.
In eight aspect, the present invention relates to formula (I) compound or pharmaceutically acceptable salt thereof and be used for the treatment of purposes in the medicine of cancer in preparation.
Aspect the 9th, the present invention relates to formula (I) or (II) compound or pharmaceutically acceptable salt thereof be used for the treatment of purposes in the medicine of hepatitis C in preparation.
Detailed Description Of The Invention
Definition:
Unless otherwise indicated, the following term of using in specification sheets and claims is to define for the application's purpose, has following meanings:
" alkyl " be meant the saturated monovalence alkyl of the straight chain with 1 to 6 carbon atom or have the saturated monovalence alkyl of side chain of 3 to 6 carbon atoms, for example methyl, ethyl, propyl group, 2-propyl group, butyl (comprising all isomeric form), amyl group (comprising all isomeric form) etc.
Unless otherwise indicated, " alkylidene group " is meant saturated bivalent hydrocarbon radical of straight chain with 1 to 6 carbon atom or the saturated bivalent hydrocarbon radical of side chain with 3 to 6 carbon atoms, for example methylene radical, ethylidene, propylidene, 1-methyl propylidene, 2-methyl propylidene, butylidene, pentylidene etc.
" alkenylene " be meant the straight chain bivalent hydrocarbon radical with 2 to 6 carbon atoms or contain the side chain monovalence alkyl with 3 to 6 carbon atoms of one or two pair key, for example vinylidene, propenylidene, 2-propenylidene, crotonylidene (comprising all isomeric form) etc.
" alkylthio " is meant-the SR base, and wherein R is as alkyl defined above, for example methylthio group, ethylmercapto group, rosickyite base (comprising all isomeric form), butylthio (comprising all isomeric form) etc.
" alkyl sulphinyl " is meant-S (O) R base, and wherein R is as alkyl defined above, for example methylsulfinyl, ethyl sulfinyl, propyl group sulfinyl (comprising all isomeric form) etc.
" alkyl sulphonyl " is meant-SO 2The R base, wherein R is as alkyl defined above, for example methyl sulphonyl, ethylsulfonyl etc.
" amino " is meant-NH 2, or its N-oxide derivative or protected derivative, for example-NH → O ,-NHBoc ,-NHCbz etc., preferred-NH 2
" alkylamino " be meant-the NHR base, and wherein R is as alkyl defined above, or its N-oxide derivative, or protected derivative, for example methylamino-, ethylamino, just-third amino, different-third amino; Just-Ding amino, different-Ding amino, uncle-Ding amino, methylamino--N-oxide compound;-N (Boc) CH 3Deng.
" alkoxyl group " is meant-the OR base, and wherein R is as alkyl defined above, for example methoxyl group, oxyethyl group; Propoxy-or 2-propoxy-; Just-butoxy, different-butoxy, uncle-butoxy etc.
" alkoxy carbonyl " is meant-C (O) OR base, and wherein R is as alkyl defined above, for example methoxycarbonyl, ethoxy carbonyl etc.
" alkoxyalkyl " be meant with at least one, preferably the straight chain monovalence alkyl that replaces of one or two alkoxyl group (as top defined) or side chain monovalence alkyl with 3 to 6 carbon atoms with 1 to 6 carbon atom, 2-methoxy ethyl for example, 1-, 2-or 3-methoxy-propyl, 2-ethoxyethyl group etc.
" alkoxyl group alkoxyl group " is meant-the OR base, and wherein R is as alkoxyl group defined above, for example methoxy ethoxy, 2-ethoxy ethoxy etc.
" alkoxy alkoxy alkyl " is meant-(alkylidene group)-R base, and wherein R is as alkoxyl group alkoxyl group defined above, for example methoxy ethoxy methyl, 2-ethoxy ethoxy methyl etc.
" aminoalkyl group " is meant the straight chain monovalence alkyl with 1 to 6 carbon atom or has the side chain monovalence alkyl of 3 to 6 carbon atoms, and it is by at least one, preferably one or two following group replaces :-NRR ', wherein R be hydrogen, alkyl or-COR a, R wherein aBe alkyl, R ' is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, optional heteroaralkyl or the haloalkyl that replaces; Or its N-oxide derivative or protected derivative.Preferably, R and R ' are independently selected from: hydrogen, alkyl or-COR a, R wherein aFor alkyl or N-oxide derivative or protected derivative, for example aminomethyl, methylamino-ethyl, 2-ethylamino-2-methylethyl, 1,3-diamino propyl group, dimethylaminomethyl, diethyl aminoethyl, acetyl aminopropyl, aminomethyl-N-oxide compound etc.
" aminoalkoxy " is meant-the OR base, and wherein R is as aminoalkyl defined above, for example 2-amino ethoxy, 2-dimethylamino propoxy etc.
" aminocarboxyl " be meant-the CONRR base, wherein each R be independently hydrogen or as alkyl defined above, for example-CONH 2, methylamino carbonyl, 2-dimethylamino carbonyl etc.
" amido " is meant-the NHCOR base, and wherein R is as alkyl defined above, for example kharophen, propionamido etc.
" aryl " is meant monovalence monocycle or the bicyclic aromatic alkyl with 6 to 12 annular atomses, for example phenyl, naphthyl or anthryl.Unless otherwise indicated, aromatic ring is randomly by one, two or three substituting groups replace, and described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, alkoxy alkoxy alkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryloxy that replaces, the optional heteroaryl alkoxyl group that replaces, aminoalkyl, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl that replaces, the optional heterocycle alkoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional heterocycle alkoxyl group that replaces,-alkylidene group-S (O) n-R a(wherein n is 0 to 2, R aBe alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) ,-alkylidene group-NHSO 2-R b(R wherein bBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces) ,-alkylidene group-NHCO-R c(R wherein cBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces) or-(alkylidene group) n1-CONR dR e(wherein n1 is 0 or 1, R dAnd R eBe hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl alkyl that replaces independently, or R dAnd R eForm the optional Heterocyclylalkyl that replaces with the nitrogen-atoms that they connected), wherein randomly replaced by one or two fluorine at halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces or the alkyl chain in the aminoalkyl.Preferably, substituting group is independently: methoxyl group, methyl, ethyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-(morpholine-4-yl) oxyethyl group, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-(N, the N-dimethylamino)-and oxyethyl group, methoxymethyl, phenoxymethyl, 2-morpholino-4-base ethyl, morpholino-4-ylmethyl, N, N dimethylaminomethyl, isopropoxy methyl or phenoxymethyl.
" aralkyl " is meant-(alkylidene group)-R base, and wherein R is as aryl defined above.
" arylalkenyl " is meant-(alkenylene)-R base, and wherein R is as aryl defined above.
" cycloalkyl " is meant the saturated monovalence alkyl of the ring-type with 3 to 10 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.The phenyl that cycloalkyl randomly is optionally substituted replaces.
" cycloalkenyl group " is meant the unsaturated monovalence alkyl of the ring-type with 3 to 6 carbon atoms, for example cyclopropenyl radical, cyclobutene base, cyclohexenyl etc.
" cycloalkylalkyl " is meant-(alkylidene group)-R base, and wherein R is as cycloalkyl defined above, for example cyclopropyl methyl, cyclobutylmethyl, cyclopentyl ethyl or cyclohexyl methyl etc.
" cycloalkyloxy " is meant-the OR base, and wherein R is as cycloalkyl defined above, for example encircles propoxy-, cyclohexyloxy etc.
" cyclenes oxygen base " is meant-the OR base, and wherein R is as cycloalkenyl group defined above, for example cyclopropylene oxygen base, tetrahydrobenzene oxygen base etc.
" dialkyl amido " is meant-NRR ' base, wherein R and R ' are as alkyl defined above independently, for example dimethylamino, diethylamino, methyl-propyl amino, methylethyl amino, just-butyl amino, different-butyl amino or tert-butyl amino etc.
" halogen " is meant fluorine, chlorine, bromine, iodine, preferred fluorine or chlorine.
" haloalkyl " is meant the alkyl that is replaced by one or more halogen atoms, preferred 1 to 5 halogen atom, preferred fluorine or chlorine, comprises the alkyl that those are replaced by different halogen atoms, for example-and CH 2Cl ,-CF 3,-CHF 2,-CF 2CF 3,-CF (CH 3) 3Deng.
" halogenated alkoxy " is meant-the OR base, and wherein R is as haloalkyl defined above, for example-and OCF 3,-OCHF 2Deng.
" halogenated alkoxy alkyl " be meant-(alkylidene group)-OR base, and wherein R is as haloalkyl defined above, trifluoromethoxy methyl, 2,2 for example, 2-trifluoro ethoxy methyl, 2-trifluoromethoxy ethyl etc.
" hydroxyalkyl " is meant straight chain monovalence alkyl with 1 to 6 carbon atom that is replaced by one or two hydroxyl or the side chain monovalence alkyl with 3 to 6 carbon atoms, and condition is that if there are two hydroxyls to exist, they are not all on same carbon atom.Its expression property example is including, but not limited to methylol, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(methylol)-2-methyl-propyl, 2-hydroxyl butyl, 3-hydroxyl butyl, 4-hydroxyl butyl, 2,3-dihydroxypropyl, 1-(methylol)-2-hydroxyethyl, 2,3-dihydroxy butyl, 3,4-dihydroxy butyl and 2-(methylol)-3-hydroxypropyl, preferred 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-(methylol)-2-hydroxyethyl.
" hydroxy alkoxy base " is meant-the OR base, and wherein R is as hydroxyalkyl defined above.
" hydroxy alkoxy alkyl " is meant-(alkylidene group)-OR base, and wherein R is as hydroxyalkyl defined above, as hydroxyl methoxymethyl, '-hydroxyethoxy ylmethyl etc.
" Heterocyclylalkyl " is meant the saturated or unsaturated monovalence cyclic group with 3 to 8 annular atomses, and one of them or two annular atomses are heteroatoms, and described heteroatoms is selected from N, O or S (O) n, wherein n is from 0 to 2 integer, the residue ring atom is C.One or two annular atoms can be randomly replaced by-CO-base.More specifically, term " Heterocyclylalkyl " including, but not limited to: pyrrolidino (pyrrolidino), piperidino-(1-position only), morpholino base, Piperazino (piperazino), THP trtrahydropyranyl, tetrahydric quinoline group and thiomorpholine be for base, and derivative (forming when heterocycloalkyl ring is replaced by following substituting group); Protected derivative with its N-oxide compound or quilt.Heterocyclylalkyl randomly is fused to alkyl.Unless otherwise indicated, heterocycloalkyl ring is randomly by one, two or three substituting groups randomly replace, and described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, alkoxy alkoxy alkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, aminoalkyl, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional heterocycle alkoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional heterocycle alkoxyl group that replaces,-alkylidene group-S (O) n-R a(wherein n is 0 to 2, R aBe alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) ,-alkylidene group-NHSO 2-R b(R wherein bBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) ,-alkylidene group-NHCO-R c(R wherein cBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) or-(alkylidene group) n1-CONR dR e(wherein n1 is 0 or 1, R dAnd R eBe independently: hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl alkyl that replaces, or R dAnd R eForm the optional Heterocyclylalkyl that replaces with the nitrogen-atoms that they connected), wherein randomly replaced by one or two fluorine at halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces or the alkyl chain in the aminoalkyl.Preferably, substituting group is independently: methoxyl group, methyl, ethyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-(morpholine-4-yl) oxyethyl group, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-(N, the N-dimethylamino)-and oxyethyl group, methoxymethyl, phenoxymethyl, the basic ethyl of 2-morpholino-4, morpholino-4-ylmethyl, N, N-dimethylamino-methyl, isopropoxy methyl or phenoxymethyl.
" Heterocyclylalkyl alkyl " is meant-(alkylidene group)-R base, and wherein R is as heterocycloalkyl ring defined above, for example furfuryl, piperazine methyl, morpholine ethyl etc.
" heteroaryl " is meant monovalence monocycle or the bicyclic aromatic base with 5 to 10 annular atomses, and wherein one or more annular atomses, preferred one, two or three annular atomses are for being selected from N, OOr SIn heteroatoms, the residue ring atom is CMore specifically, term " heteroaryl " includes but not limited to: pyridyl, pyrryl, imidazolyl, thienyl, furyl, indyl, quinolyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, tetrahydric quinoline group (quinolinyl), isoquinolyl (isoquinolinyl), benzofuryl, benzopyranyl and thiazolyl, and derivative (forming when heterocycloalkyl ring is replaced by following substituting group); Or its N-oxide compound or protected derivative.Unless otherwise indicated, heteroaryl ring is randomly by one, two or three substituting groups replace, and described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, alkoxy alkoxy alkyl, the optional phenyl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces, the optional heteroaryloxy that replaces, the optional assorted aralkoxy that replaces, aminoalkyl, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxy group that replaces, the optional phenyl alkoxyl group that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional heterocycle alkoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional heterocycle alkoxyl group that replaces,-alkylidene group-S (O) n-R a(wherein n is 0 to 2, R aBe alkyl, hydroxyalkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) ,-alkylidene group-NHSO 2-R b(R wherein bBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces) ,-alkylidene group-NHCO-R c(R wherein cBe alkyl, haloalkyl, hydroxyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces) ,-(alkylidene group) n1-CONR dR f(wherein n1 is 0 or 1, R dBe hydrogen or alkyl, R fBe hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl alkyl that replaces), or R dAnd R fForm the optional Heterocyclylalkyl that replaces with the nitrogen-atoms that they connected) ,-alkylidene group-NR e-alkylidene group-CONR cR d(R wherein cAs previously defined, R dAnd R eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl, wherein randomly replaced by one or two fluorine at halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces or the alkyl chain in the aminoalkyl.Preferably, substituting group is independently: methoxyl group, methyl, ethyl, chlorine, trifluoromethyl, fluorine, 2-methoxyethoxy, 2--(morpholine-4-yl) oxyethyl group, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-(N, the N-dimethylamino)-and oxyethyl group, methoxymethyl, phenoxymethyl, 2-morpholino-4-base ethyl, morpholino-4 ylmethyl, N, N-dimethylamino-methyl, isopropoxy methyl or phenoxymethyl.
When heteroaryl ring was divalence, it was known as heteroarylidene in this application.
" heteroaryl amino " is meant the NHR base, and wherein R is as heteroaryl defined above.
" heteroaralkyl " is meant-(alkylidene group)-R base, and wherein R is as heteroaryl defined above.
" impure aromatic ene base " is meant-(alkenylene)-R base, and wherein R is as heteroaryl defined above.
" methylene-dioxy " is meant-O-CH 2-O-.
The present invention also comprises the prodrug of formula (I) compound.Term " prodrug " is used to represent the carrier of covalent bonding, when prodrug is applied to mammalian object, and the activeconstituents of described carrier energy release type (I).The release of activeconstituents takes place in vivo.Prodrug can prepare by the technology that those skilled in the art are familiar with.Appropriate functional group in the given compound of the common modification of these technology.But these modification functional groups are by conventional processing or renewable in vivo initial functional group.The prodrug of formula (I) compound comprises following compound, and wherein hydroxyl, amino, carboxyl or similar group are modified.The example of prodrug includes but not limited to: the carbamate of hydroxyl or amido functional group in ester (for example acetic ester, manthanoate and benzoate derivatives), formula (I) compound (for example N, N-dimethylamino carbonyl), acid amides (for example trifluoroacetamido, kharophen etc.) etc.The prodrug of formula (I) compound also within the scope of the present invention.
The present invention also comprises the N-oxide derivative of formula (I) compound and is protected derivative.For example, when formula (I) when compound comprises oxidable nitrogen-atoms, nitrogen-atoms can change into the N-oxide compound by the method for knowing in this area.When formula (I) compound comprised the group of group such as hydroxyl, carboxyl, thiol or any nitrogen atom, these groups can be protected with suitable protecting group.The comprehensive list of appropriate protection base can be at T.W.Greene, the protecting group in the organic synthesis (ProtectiveGroups in Organic Synthesis), John Wiley﹠amp; Sons finds among the Inc.1981, and its disclosure is incorporated herein by reference in full.The quilt of formula (I) compound protects derivative can be by the method preparation of knowing in this area.
" phenylene " is meant the divalence phenyl.
" pharmacologically acceptable salt " of compound is meant the salt of allowing and have the pharmacological activity of required parent compound on pharmacopedics.This salt comprises:
Acid salt, described salt forms with following acid: use mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid etc.; Or use organic acid, as acetate, propionic acid, caproic acid, cyclopentanepropanoiacid acid, oxyacetic acid, pyruvic acid, lactic acid, propanedioic acid, Succinic Acid, oxysuccinic acid, toxilic acid, fumaric acid, tartrate, citric acid, phenylformic acid, 3-(4-(2-hydroxybenzoyl)) phenylformic acid, styracin, mandelic acid, methylsulfonic acid, ethyl sulfonic acid, 1, the 2-ethylene disulfonic acid, the 2-ethylenehydrinsulfonic acid, Phenylsulfonic acid, the 4-chlorobenzenesulfonic acid, 2-naphthyl sulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid, glucoheptonic acid, 4,4 '-methylene-bis-(3-hydroxyl-2-alkene-1-carboxylic acid), the 3-phenylpropionic acid, trimethylacetic acid, tert.-butylacetic acid, lauryl sulfate, glyconic acid, L-glutamic acid, hydroxynaphthoic acid, Whitfield's ointment, stearic acid, muconic acid etc.; Or
The salt that under following situation, forms: when the acid proton that exists in the parent compound is replaced by metal ion such as alkalimetal ion, alkaline earth ion or aluminum ion; Maybe when coordinations such as this acid proton and organic bases such as thanomin, diethanolamine, trolamine, tromethane, N-methylglucosamine.Should be understood that pharmacologically acceptable salt is nontoxic.Additional Information about suitable pharmacologically acceptable salt can be at Remington ' s Pharmaceutical Sciences, 17th ed, and Mack PublishingCompany, Easton, PA finds in 1985, and the document is introduced into this paper for your guidance.
Compound of the present invention can have asymmetric center.The The compounds of this invention that contains asymmetric replacement atom can separate in optically active form or racemic modification.The well known optically active form that how to prepare is as splitting by material.Unless specifically describe specific stereochemistry or isomeric form, all chiralitys, diastereomeric, racemic forms all within the scope of the invention.
Some compound of formula (I) can be used as tautomer and/or geometrical isomer exists.All possible tautomer and cis and trans-isomer(ide), individuality and composition thereof are all within the scope of the present invention.In addition, as used in this article, term " alkyl " comprises all possible isomeric form of described alkyl, although only listed several examples.In addition, when cyclic group such as aryl, heteroaryl, when Heterocyclylalkyl is substituted, they comprise all positional isomerss, though only listed several examples.In addition, all polymorphic forms of formula (I) compound and hydrate are all within the scope of the invention.
" the optional phenyl that replaces " is meant randomly by one, the phenyl ring that two or three substituting groups replace, described substituting group is independently selected from: alkyl, halogen, alkoxyl group, alkylthio, haloalkyl, halogenated alkoxy, (it is randomly replaced by one or two substituting group heteroaryl, described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, carboxyl, amino, alkylamino or dialkyl amido), (it is randomly replaced by one or two substituting group Heterocyclylalkyl, described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, carboxyl, amino, alkylamino or dialkyl amido), amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, methylene-dioxy, aminocarboxyl, amido, hydroxyalkyl, alkoxy carbonyl, aminoalkyl, or carboxyl, or randomly replaced by five fluorine atoms.
" the optional phenoxy group that replaces " is meant-the OR base that wherein R is the phenyl as optional replacement defined above, for example phenoxy group, chlorophenoxy etc.
" optional replace phenylcarbonyl group amino " is meant-the NHCOR base, and wherein R be the phenyl as optional replacement defined above, for example benzamido etc.
" the optional phenylalkyl that replaces " is meant-(alkylidene group)-R base that wherein R is the phenyl as optional replacement defined above, for example phenmethyl, styroyl etc.
" the optional phenyl alkoxyl group that replaces " is meant-the OR base that wherein R is the phenylalkyl as optional replacement defined above, for example benzyloxy, phenyl ethoxy etc.
" the optional octadecyloxy phenyl sulfenyl that replaces " is meant-S-(alkylidene group)-R base, and wherein R is the phenyl as optional replacement defined above, for example benzylthio-, phenyl ethylmercapto group etc.
" the optional phenylalkyl alkylsulfonyl that replaces " is meant-SO 2-(alkylidene group)-R base, wherein R is the phenyl as optional replacement defined above, for example benzyl alkylsulfonyl, phenylethyl alkylsulfonyl etc.
" the optional phenyl thiazolinyl that replaces " is meant-(alkenylene)-R base that wherein R is randomly replaced, for example styryl, cinnamyl group etc. as previously defined.
" the optional phenoxyalkyl that replaces " is meant-(alkylidene group)-OR base that wherein R is the phenyl as optional replacement defined above, for example phenoxymethyl, phenoxy group ethyl etc.
" the optional heteroaryl that replaces " is meant monovalence monocycle or bicyclic aromatic base with 5 to 10 annular atomses, wherein one or more annular atomses, preferred one, two or three annular atomses are for being selected from N, heteroatoms among O or the S, the residue ring atom is C, it is randomly by one, two or three substituting groups replace, described substituting group is independently selected from: alkyl, halogen, alkoxyl group, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, aminocarboxyl, hydroxyalkyl, alkoxy carbonyl, aminoalkyl, the optional phenyl that replaces, the optional phenoxy group that replaces, carboxyl, or heteroaryl, it is randomly by alkyl, halogen, hydroxyl, alkoxyl group, carboxyl, amino, alkylamino, or dialkyl amido replaces; Heterocyclylalkyl, it is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido; The Heterocyclylalkyl alkyl, it is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido; Or heteroaryl amino, it is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, amino, alkylamino or dialkyl amido.More specifically, term " the optional heteroaryl that replaces " includes but not limited to: pyridyl, pyrryl, imidazolyl, thienyl, furyl, indyl, quinolyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, tetrahydric quinoline group, different tetrahydric quinoline group, benzopyranyl and thiazolyl and derivative thereof (forming when the substituting group of listing above the heteroaryl ring quilt replaces); Or its N-oxide compound or protected derivative.
" the optional heteroaryloxy that replaces " is meant-the OR base that wherein R is the heteroaryl as optional replacement defined above, for example furans oxygen base, pyridyloxy etc.
" the optional assorted aralkoxy that replaces " is meant-the OR base that wherein R is the heteroaralkyl ring as the optional replacement that defines below.
" the optional heteroaryloxy alkyl that replaces " is meant-(alkylidene group)-OR base that wherein R is the heteroaryl ring as optional replacement defined above.
" the optional heteroaralkyl that replaces " is meant-(alkylidene group)-R base that wherein R is the hetero-aromatic ring as optional replacement defined above.
" the optional Heterocyclylalkyl that replaces " is meant the saturated or unsaturated monovalence cyclic group with 3 to 8 annular atomses, and one of them or two annular atomses are for being selected from N, O or S (O) nIn heteroatoms, wherein n is from 0 to 2 integer, the residue ring atom is C.One or two available ring carbon atom is randomly replaced by-CO-base.More specifically, term " Heterocyclylalkyl " includes but not limited to: pyrrolidino, piperidino-(1-position only), morpholino base, Piperazino, THP trtrahydropyranyl and thiomorpholine are for base and derivative (forming when heterocycloalkyl ring is replaced by following substituting group) or its N-oxide compound or protected derivative.Heterocyclylalkyl randomly is fused to aryl, and randomly by one, two or three substituting groups replacements, described substituting group is independently selected from: alkyl, cycloalkyl, halogen, alkoxyl group, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, the optional phenylalkyl that replaces, optional heteroaralkyl, aminocarboxyl, hydroxyalkyl, alkoxy carbonyl, aminoalkyl or the carboxyl that replaces.
" the optional heterocycle alkoxyl group that replaces " is meant-the OR base that wherein R is the heterocycloalkyl ring as optional replacement defined above.
" the optional Heterocyclylalkyl alkyl that replaces " is meant-(alkylidene group)-R base that wherein R is the heterocycloalkyl ring as optional replacement defined above.
" the optional Heterocyclylalkyl alkoxyl group that replaces " is meant-the OR base that wherein R is the Heterocyclylalkyl alkyl ring as optional replacement defined above.
" the optional heterocycle alkoxyalkyl that replaces " is meant-(alkylidene group)-OR base that wherein R is the Heterocyclylalkyl as optional replacement defined above, for example piperidines oxygen ylmethyl, pyrroles's alkoxyethyl etc.
" optional " or " randomly " be meant the incident described subsequently or situation can but be not to occur, this description comprises: the wherein example that takes place of incident or situation and the wherein example that do not take place of time or situation.For example, " randomly being replaced or disubstituted Heterocyclylalkyl " by the alkyl list be meant alkyl can but be not to exist, this description comprises: wherein Heterocyclylalkyl is replaced by the alkyl list or disubstituted situation and Heterocyclylalkyl situation about not replaced by alkyl wherein.
" pharmaceutically acceptable carrier or vehicle " is meant carrier or the vehicle that can be used for pharmaceutical compositions, its normally safety, nontoxic, be not that biology or other aspects are undesirable, comprise the carrier or the vehicle that all allow for veterinary purpose and people's pharmaceutical applications." pharmaceutically acceptable carrier/vehicle " that uses in specification sheets and claims comprises a kind of and more than a kind of such vehicle.
" treatment " of disease comprises:
(1) preventing disease just makes the clinical symptom of disease not develop in Mammals, and described Mammals can be exposed to or tend to suffer from this disease, but does not also suffer or show the symptom of this disease.
(2) suppress disease, just stop or reduce the progress of disease or its clinical symptom; Or
(3) alleviate disease, disease or its clinical symptom are disappeared.
Term " treatment cancer " or " treatment for cancer " are meant the Mammals administration that tormented by cancer, refer to alleviate by kill cancer cell the effect of cancer, also instruct the effect that causes the inhibition of cancer propagation and/or transfer.
" treatment significant quantity " is meant when the Mammals administration during disease, is enough to realize the amount of formula (I) compound of disease treatment with treatment." treatment significant quantity " will be according to compound, disease and severity thereof with by variations such as mammiferous age of treatment, body weight.
The representative compounds of formula (I) is disclosed among the following table I-IV.
Formula (I) compound is as follows:
R wherein 1And R 3Be hydrogen, Ar 1Be phenyl, Ar 2With the definition of the Y I that sees the following form.
Table I
Compound number Ar 2 Y
1 Phenyl -CH 2-CH 2-
2 Trans-phenyl-CH=CH- -CH 2-CH 2-
3 Trans-phenycyclopropyl -CH 2-CH 2-
4 Trans-4-MeO-phenyl-CH=CH- -CH 2-CH 2-
5 The 2-phenylethyl -CH 2-CH 2-
6 1H-indol-3-yl methyl -CH 2-CH 2-
7 Thiophene-2-base -CH 2-CH 2-
8 Pyridin-3-yl -CH 2-CH 2-
9 The 4-xenyl -CH 2-CH 2-
10 The 3-xenyl -CH 2-CH 2-
11 5-phenyl thiophene-2-base -CH 2-CH 2-
12 Thiophene-2-ylmethyl -CH 2-CH 2-
13 Naphthalene-2-base -CH 2-CH 2-
14 Quinoline-6-base -CH 2-CH 2-
15 4-phenyl thiazole-2-base -CH 2-CH 2-
16 The 4-tert-butyl-phenyl -CH 2-CH 2-
17 Trans-pyridin-3-yl-CH=CH- -CH 2-CH 2-
18 4-pyrroles-1-base phenyl -CH 2-CH 2-
19 4-(tetrahydrobenzene-3-oxygen)-phenyl -CH 2-CH 2-
20 Benzothiazole-2-base -CH 2-CH 2-
21 Benzoxazoles-2-base -CH 2-CH 2-
22 Octahydro isoquinoline 99.9-2-ylmethyl -CH 2-CH 2-
23 4-pyridin-4-yl-piperazine-1-ylmethyl -CH 2-CH 2-
24 Furans-2-base -CH 2-CH 2-
25 4-(pyridin-3-yl)-phenyl -CH 2-CH 2-
26 4-(pyridine-2-yl)-phenyl -CH 2-CH 2-
27 1H-benzimidazolyl-2 radicals-Ji -CH 2-CH 2-
28 1H-pyrroles-2-base -CH 2-CH 2-
29 4-(benzamido)-phenyl -CH 2-CH 2-
30 4-(pyridin-4-yl)-thiazol-2-yl -CH 2-CH 2-
31 Diamantane-1-base -CH 2-CH 2-
32 The 2,4 difluorobenzene base -CH 2-CH 2-
33 Trans-3,4-methylenedioxyphenyl CH=CH- -CH 2-CH 2-
34 3, the 4-methylenedioxyphenyl -CH 2-CH 2-
35 3, the 4-Dimethoxyphenyl -CH 2-CH 2-
36 3, the 5-Dimethoxyphenyl -CH 2-CH 2-
37 3, the 4-difluorophenyl -CH 2-CH 2-
38 2, the 5-3,5-dimethylphenyl -CH 2-CH 2-
39 2, the 3-dichlorophenyl -CH 2-CH 2-
40 2, the 3-3,5-dimethylphenyl -CH 2-CH 2-
41 4-chloro-2-p-methoxy-phenyl -CH 2-CH 2-
42 The 3-ethoxyl phenenyl -CH 2-CH 2-
43 4-methoxyl group-2-aminomethyl phenyl -CH 2-CH 2-
44 3-fluoro-4-p-methoxy-phenyl -CH 2-CH 2-
45 2-(thiophene-2-ylmethoxy) phenyl -CH 2-CH 2-
46 3-(thiophene-2-ylmethoxy)-phenyl -CH 2-CH 2-
47 The 2-phenyl -CH 2-CH 2-
48 1H-indoles-5-base -CH 2-CH 2-
49 The 1H-indol-3-yl -CH 2-CH 2-
50 Quinoline-3-base -CH 2-CH 2-
51 Quinoline-8-base -CH 2-CH 2-
52 1H-indazole-3-base -CH 2-CH 2-
53 1H-benzotriazole-5-base -CH 2-CH 2-
54 Isoquinolyl-1 -CH 2-CH 2-
55 Isoquinoline 99.9-3-base -CH 2-CH 2-
56 Quinoxaline-2-base -CH 2-CH 2-
57 Naphthalene-1-base -CH 2-CH 2-
58 Quinoline-2-base -CH 2-CH 2-
59 2-pyrroles-1-base-phenyl -CH 2-CH 2-
60 4-fluoronaphthalene-1-base -CH 2-CH 2-
61 1H-benzoglyoxaline-5-base -CH 2-CH 2-
62 1-methyl-indol-3-yl -CH 2-CH 2-
63 4-MeO-quinoline-2-base -CH 2-CH 2-
64 3-MeO-naphthalene-2-base -CH 2-CH 2-
65 2-MeO-naphthalene-1-base -CH 2-CH 2-
66 Quinolyl-4 -CH 2-CH 2-
67 Trans-phenyl-CH=C (CH 3)- -CH 2-CH 2-
68 2-N, N-dimethylaminomethyl cumarone-5-base -CH 2-CH 2-
69 Indoline-1-base -CH 2-CH 2-
70 1,2,3,4-tetrahydroquinoline-1-base -CH 2-CH 2-
71 Trans-the 5-hydroxyl benzofuran-2-base-C (CH 3)＝CH- -(S)-CH(CH 2CH 3)-CH 2-
72 Trans-5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base-C (CH 3)＝CH- -(S)-CH(CH 2CH 3)-CH 2-
73 Cumarone-2-base -(S)-CH (2-phenylethyl)-CH 2-
74 5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base -CH 2-CH 2-
75 5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base -(S)-CH(CH 2CH 3)-CH 2-
76 5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base -(R)-CH 2-CH(CH 3)-
77 5-[1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen] cumarone-2-base -CH 2-CH 2
78 Cumarone-2-base -(R)-CH (benzyl SO 2-methyl)-CH 2-
79 Cumarone-2-base -(R)-CH (benzyl S-methyl)-CH 2-
80 Trans-5-methoxyl group benzo furans-2-base-C (CH 3)＝CH- -CH 2-CH 2-
81 1,2,3,4-tetrahydroisoquinoline-2-base -CH 2-CH 2-
82 Isoindoline-2-base -CH 2-CH 2-
83 Morpholine-4-base -CH 2-CH 2-
84 4-benzyl-piperazine-1-base -CH 2-CH 2-
85 (R)-3-HO-tetramethyleneimine-1-base- -CH 2-CH 2-
86 Piperidines-1-base -CH 2-CH 2-
87 6-CH 3-1,2,3,4-tetrahydroquinoline-1-base -CH 2-CH 2-
88 2-CH 3-indoline-1-base- -CH 2-CH 2-
89 6-F-2-CH 3-1,2,3,4-tetrahydroquinoline-1-base -CH 2-CH 2-
90 Isoindoline-1-base -(S)-CH(CH 2CH 3)-CH 2-
91 Trans-phenyl-CH=CH- -CH 2-CH 2-CH 2-
92 Trans-4-CH 3O-phenyl-CH=CH- -CH 2-CH 2-CH 2-
93 4-phenyl thiazole-2-base -CH 2-CH 2-CH 2-
94 Trans-phenyl-CH=CH- -(S)-CH (methyl)-CH 2-
95 Trans-phenyl-CH=CH- -(R)-CH (methyl)-CH 2-
96 Trans-phenyl-CH=CH- -(S)-CH (isobutyl-)-CH 2-
97 Trans-phenyl-CH=CH- -(S)-CH (cyclohexyl-methyl)-CH 2-
98 Trans-phenyl-CH=CH- -(S)-CH (sec.-propyl)-CH 2-
99 Trans-phenyl-CH=CH- -(S)-CH (benzyl)-CH 2-
100 Trans-phenyl-CH=CH- -(R)-CH (benzyl)-CH 2-
101 Trans-phenyl-CH=CH- -(R)-CH (isobutyl-)-CH 2-
102 Trans-phenyl-CH=CH- -(R)-CH (sec.-propyl)-CH 2-
103 Trans-phenyl-CH=CH- -(RS)-CH (normal-butyl)-CH 2-
104 Trans-phenyl-CH=CH- -(RS)-CH (4-Cl-benzyl)-CH 2-
105 Trans-phenyl-CH=CH- -(S)-CH(CH 2CH 3)-CH 2-
106 Trans-phenyl-CH=CH- -(R)-CH(CH 2CH 3)-CH 2-
107 Trans-phenyl-CH=CH- -(S)-CH (2-MeS-ethyl)-CH 2-
108 Trans-phenyl-CH=CH- -(R)-CH (2-MeS-ethyl)-CH 2-
109 Trans-phenyl-CH=CH- -(S)-CH (phenyl)-CH 2-
110 Trans-phenyl-CH=CH- -(R)-CH (phenyl)-CH 2-
111 Trans-phenyl-CH=CH- -(S)-CH(2-MeSO 2-ethyl)-CH 2-
112 Trans-phenyl-CH=CH- -(R)-CH(2-MeSO 2-second
Base)-CH 2-
113 Trans-phenyl-CH=CH- -(R)-CH (benzyl SO 2-methyl)-CH 2-
114 Thiophene-2-base -(S)-CH(CH 2CH 3)-CH 2-
115 The 4-xenyl -(S)-CH(CH 2CH 3)-CH 2-
116 Naphthalene-2-base -(S)-CH(CH 2CH 3)-CH 2-
117 Trans-phenyl-CH=CH- -(R)-CH (benzyl-S-methyl)-CH 2-
118 Phenyl -(S)-CH(CH 2CH 3)-CH 2-
119 Benzyl -(S)-CH(CH 2CH 3)-CH 2-
120 The 2-phenylethyl -(S)-CH(CH 2CH 3)-CH 2-
121 Trans-phenyl-CH=CH- -(S)-CH (hydroxyl-methyl)-CH 2-
122 4-phenyl thiazole-2-base -(S)-CH(CH 2CH 3)-CH 2-
123 Trans-4-CH 3O-phenyl-CH=CH- -(S)-CH(CH 2CH 3)-CH 2-
124 2-N, N-dimethylaminomethyl-cumarone-5-base- -(S)-CH(CH 2CH 3)-CH 2-
125 Trans-phenyl-CH=CH- -(R)-CH 2-CH(CH 3)-
126 Trans-phenyl-CH=CH- -(S)-CH 2-CH(CH 3)-
127 4-phenyl-thiazol-2-yl -(R)-CH 2-CH(CH 3)-
128 4-phenyl-thiazol-2-yl -(S)-CH 2-CH(CH 3)-
129 The 4-xenyl -(R)-CH 2-CH(CH 3)-
130 Trans-4-CH 3O-phenyl-CH=CH- -(R)-CH 2-CH(CH 3)-
131 4-(2-pyridin-4-yl thiazole-5-yl) phenyl -CH 2-CH 2-
132 7-chloro-4-methyl cumarone-2-base -CH 2-CH 2-
133 4-[2-(4-methylpiperazine-1-yl) thiazole-5-yl]-phenyl -CH 2-CH 2-
134 4-(2-pyridin-4-yl aminothiazole-5-yl) phenyl -CH 2-CH 2-
135 4-(4-methylpiperazine-1-yl) phenyl -CH 2-CH 2-
136 4-(4-hydroxy piperidine-1-yl) phenyl -CH 2-CH 2-
137 4-(4-morpholine-4-ylmethyl thiazol-2-yl) phenyl -CH 2-CH 2-
138 7-fluoro-4-methyl cumarone-2-base -CH 2-CH 2-
139 7-fluoro-4-(2-methoxy ethoxy methyl)-cumarone-2-base -CH 2-CH 2-
140 4-hydroxyquinoline-2-base -CH 2-CH 2-
141 7-fluoro-4-phenoxymethyl cumarone-2-base -CH 2-CH 2-
143 4-[2-(4-methylpiperazine-1-ylmethyl) thiazole-5-yl] phenyl -CH 2-CH 2-
144 Pyridine-2-base -CH 2-CH 2-
145 3-pyridone-2-base -CH 2-CH 2-
146 6-pyridone-2-base -CH 2-CH 2-
147 6-(4-nitrophenoxy) pyridine-2-base -CH 2-CH 2-
148 4-(2-methoxy ethoxy) quinoline-2-base -CH 2-CH 2-
149 4-(2-dimethylamino ethoxy) quinoline-2-base -CH 2-CH 2-
150 6-bromopyridine-2-base -CH 2-CH 2-
151 5-bromopyridine-3-base -CH 2-CH 2-
152 4-methoxy quinoline-2-base -(S)-CH(CH 2CH 3)-CH 2-
153 1-methoxynaphthalene-2-base -CH 2-CH 2-
154 4-methoxy quinoline-2-base -(R)-CH 2-CH(CH 3)-
155 5-phenylpyridine-3-base -CH 2-CH 2-
156 6-benzyloxy pyridine-2-base -CH 2-CH 2-
157 6-(2-methyl propoxy-) pyridine-2-base -CH 2-CH 2-
158 6-(2-phenyl ethoxy) pyridine-2-base -CH 2-CH 2-
159 4-(3,3,3-trifluoro propoxy-) quinoline-2-base -CH 2-CH 2-
160 4-(3,3,3-trifluoro propoxy-) quinoline-2-base -(S)-CH(CH 2CH 3)-CH 2-
161 4-(3,3,3-trifluoro propoxy-) quinoline-2-base -(R)-CH 2-CH(CH 3)-
162 Trans-3-hydroxy phenyl-CH=CH- -CH 2-CH 2-
163 Trans-4-hydroxy phenyl-CH=CH- -CH 2-CH 2-
164 3 '-(2-hydroxyethyl) biphenyl-4-base -CH 2-CH 2-
165 3 '-(2-hydroxyethyl) biphenyl-3-base -CH 2-CH 2-
166 2 '-(2-hydroxyethyl) biphenyl-4-base -CH 2-CH 2-
167 Trans-cumarone-2-base-CH=CH- -CH 2-CH 2-
168 2 '-(2-hydroxyethyl) biphenyl-3-base -CH 2-CH 2-
169 5-thiene-3-yl-pyridin-3-yl -CH 2-CH 2-
170 6-(4-acetylamino phenoxy group) pyridine-2-base -CH 2-CH 2-
171 6-(4-amino-benzene oxygen) pyridine-2-base -CH 2-CH 2-
172 Trans-2-p-methoxy-phenyl-CH=CH- -CH 2-CH 2-
173 Trans-3-p-methoxy-phenyl-CH=CH- -CH 2-CH 2-
174 5-(4-dimethylaminophenyl) pyridin-3-yl -CH 2-CH 2-
175 Trans-5-bromothiophene-2-base-CH=CH- -CH 2-CH 2-
176 Trans-furans-3-base-CH=CH- -CH 2-CH 2-
177 Trans-thiene-3-yl--CH=CH- -CH 2-CH 2-
178 Trans-thiophene-2-base-CH=CH- -CH 2-CH 2-
179 Trans-3-tolyl-CH=CH- -CH 2-CH 2-
180 Trans-4-tolyl-CH=CH- -CH 2-CH 2-
181 Trans-cumarone-2-base-C (CH 3)＝CH- -CH 2-CH 2-
182 Cis-cumarone-2-base-C (CH 3)＝CH- -CH 2-CH 2-
183 Trans-4-dimethylaminophenyl-CH=CH- -CH 2-CH 2-
184 Trans-indol-3-yl-CH=CH- -CH 2-CH 2-
185 Trans-2-tolyl-CH=CH- -CH 2-CH 2-
186 Trans-2-hydroxy phenyl-CH=CH- -CH 2-CH 2-
187 Trans-7-methoxyl group benzo furans-2-base-CH=CH- -CH 2-CH 2-
188 Trans-7-methoxyl group benzo furans-2-base-CH=CH- -(R)-CH(CH 2CH 3)-CH 2-
189 Trans-5-methoxyl group benzo furans-2-base-C (CH 3)＝CH- -(S)-CH(CH 2CH 3)-CH 2-
190 Trans-furans-2-base-CH=CH- -CH 2-CH 2-
191 4-[4-(2-morpholine-4-base ethyl) thiazol-2-yl] phenyl -CH 2-CH 2-
And be named as:
N-hydroxyl-4-(2-phenylcarbamoyl amino-oxyethyl group) benzamide;
N-hydroxyl-4-(2-trans-cinnamoyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-trans-2-phenycyclopropyl carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-trans-4-methoxyl group cinnamoyl amino ethoxy) benzamide;
N-hydroxyl-4-[2-(2-phenylethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indol-3-yl methyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-(2-thiophene-2-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-pyridin-3-yl carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-biphenyl-4-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-biphenyl-3-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-[2-(5-phenyl thiophene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(thiophene-2-ylmethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(naphthalene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-6-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-tert-butyl-phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-pyridin-3-yl acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyrroles-1-base phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-tetrahydrobenzene-3-oxygen phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(benzothiazole-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(benzoxazoles-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(octahydro isoquinoline 99.9-2-ylmethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridin-4-yl piperazine-1-ylmethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(furans-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridin-3-yl phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridine-2-base phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(benzimidazolyl-2 radicals-Ji carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-pyrroles-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-benzamido phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridin-4-yl thiazol-2-yl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(diamantane-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,4 difluorobenzene base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-trans-3,4-methylenedioxyphenyl acryl amino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(3,4-methylenedioxyphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3,4-Dimethoxyphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3,5-Dimethoxyphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3,4-difluorophenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,5-3,5-dimethylphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,3-dichlorophenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,3-3,5-dimethylphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-chloro-2-p-methoxy-phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-ethoxyl phenenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxyl group-2-aminomethyl phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-fluoro-4-p-methoxy-phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-thiophene-2-ylmethoxy phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-thiophene-2-ylmethoxy phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(biphenyl-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indoles-5-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indol-3-yl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-8-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indazole-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-benzotriazole-5-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(isoquinolyl-1 carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(isoquinoline 99.9-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoxaline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(naphthalene-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-pyrroles-1-base phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-fluoronaphthalene-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1-skatole-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxy quinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-methoxynaphthalene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-methoxynaphthalene-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinolyl-4 carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-2-methyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-N, N-dimethylaminomethyl cumarone-5-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-(2-indoline-1-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-[2-(1,2,3,4-tetrahydroquinoline-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2S-[is trans-3-(5-hydroxyl benzofuran-2-yl) but-2-ene acyl amino] and butoxy } benzamide;
N-hydroxyl-4-{2S-[is trans-3-(5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-yl) but-2-ene acyl group-amino] and butoxy } benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-phenyl butoxy] benzamide;
N-hydroxyl-4-{2-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2S-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-butoxy } benzamide;
N-hydroxyl-4-{2-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[5-(1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen) cumarone-2-base carbonyl-amino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2R-(cumarone-2-base carbonylamino)-3-benzyl alkylsulfonyl propoxy-] benzamide;
N-hydroxyl-4-[2R-(cumarone-2-base carbonylamino)-3-benzylthio-propoxy-] benzamide;
N-hydroxyl-4-[2-(trans-3-(5-methoxyl group benzo furans-2-yl) but-2-ene acyl group carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1,2,3,4-tetrahydroisoquinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(isoindoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(morpholine-4-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-benzyl diethylenediamine-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3 (R)-hydroxyl pyrrolidine-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(piperidines-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-1-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(2-methyl indoline-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-fluoro-2-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-1-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2S-(isoindoline-1-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[3-(trans-cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[3-(trans-4-methoxyl group cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[3-(4-phenyl thiazole-2-base carbonylamino) propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methyl pentyloxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-cyclohexyl propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-methyl butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-phenyl propoxy-] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-phenyl propoxy-] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methyl pentyloxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-methyl butoxy] benzamide;
N-hydroxyl-4-[2RS-(trans-cinnamoyl amino) hexyloxy] benzamide;
N-hydroxyl-4-[2RS-(trans-cinnamoyl amino)-3-(4-chloro-phenyl-) propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methylthio group butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methylthio group butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-2-phenyl ethoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-2-phenyl ethoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methyl sulphonyl butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methyl sulphonyl butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-benzyl alkylsulfonyl propoxy-] benzamide;
N-hydroxyl-4-[2S-(thiophene-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(biphenyl-4-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(naphthalene-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-benzylthio-propoxy-] benzamide;
N-hydroxyl-4-[2S-(phenylcarbamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(benzyloxycarbonyl group amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(2-phenylethyl carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-hydroxyl propoxy-] benzamide;
N-hydroxyl-4-[2S-(4-phenyl thiazole-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-4-methoxyl group cinnamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(2-N, N-dimethylaminomethyl cumarone-5-base carbonylamino) butoxy]-benzamide;
N-hydroxyl-4-[2-(trans-cinnamoyl amino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(trans-cinnamoyl amino)-1S-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino)-1S-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(biphenyl-4-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(trans-4-methoxyl group cinnamoyl amino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-{2-[4-(2-pyridine-2-base thiazole-5-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(7-chloro-4-methyl cumarone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[4-(2-(4-methylpiperazine-1-yl) thiazole-5-yl) phenylcarbonyl group amino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(2-pyridin-4-yl aminothiazole-5-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[4-(4-methylpiperazine-1-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(4-hydroxy piperidine-1-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(4-morpholine-4-ylmethyl thiazole-5-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(7-fluoro-4-methyl cumarone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[7-fluoro-4-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(4-hydroxyquinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(7-fluoro-4-phenoxymethyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[4-(2-(4-methylpiperazine-1-ylmethyl) thiazole-5-yl) phenylcarbonyl group-amino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(pyridine-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-pyridone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-pyridone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[6-(4-nitrophenoxy) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(2-methoxy ethoxy) quinoline-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(2-N, N-dimethylamino ethoxy) quinoline-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(6-bromopyridine-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(5-bromopyridine-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2S-(4-methoxy quinoline-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2-(1-methoxynaphthalene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxy quinoline-2-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(5-phenylpyridine-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-benzyloxy pyridine-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl 4-{2-[6-(2-methyl propoxy-) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[6-(2-phenyl ethoxy) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-[2-(trans-3-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-4-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[3 '-(2-hydroxyethyl) biphenyl-4-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3 '-(2-hydroxyethyl) biphenyl-3-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[2 '-(2-hydroxyethyl) biphenyl-4-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-the 2-cumarone-2-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[2 '-(2-hydroxyethyl) biphenyl-3-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[5-(thiene-3-yl-) pyridin-3-yl carbonylamino] oxyethyl group) benzamide;
N-hydroxyl-4-{2-[6-(4-acetylamino phenoxy group) pyridine-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(4-amino-benzene oxygen) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-2-methoxyl group cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-methoxyl group cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[5-(4-dimethylaminophenyl) pyridin-3-yl carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[is trans-3-(5-bromothiophene-2-yl) acryl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-the 3-furans-3-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-thiene-3-yl-acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-thiophene-2-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[is trans-3-methyl cinnamoyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2-[is trans-4-methyl cinnamoyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2-[is trans-3-(cumarone-2-yl) but-2-ene acyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2-[cis-3-(cumarone-2-yl) but-2-ene acyl amino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-4-dimethylamino cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-indol-3-yl acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[is trans-2-methyl cinnamoyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-2-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[is trans-3-(7-methoxyl group benzo furans-2-yl) acryl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2R-[is trans-3-(7-methoxyl group benzo furans-2-yl) acryl amino] and butoxy } benzamide;
N-hydroxyl-4-{2S-[is trans-3-(5-methoxyl group benzo furans-2-yl) but-2-ene acyl amino] and butoxy } benzamide;
N-hydroxyl-4-[2-(trans-the 3-furans-2-base acryl amino) oxyethyl group] benzamide; With
N-hydroxyl-4-{2-[4-(4-(2-morpholine-4-base ethyl) thiazol-2-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;
Formula (I) compound is as follows:
R wherein 1Be hydrogen, Ar 1Be phenyl, R 3, Ar 2With the definition of Y Table II as follows.
Table II
Compound number R 3 Ar 2 Y
1 The 2-HO-ethyl Trans-phenyl-CH=CH- -CH 2-CH 2-
2 Phenyl Trans-phenyl-CH=CH- -CH 2-CH 2-
3 CH 3 Trans-phenyl-CH=CH- -CH 2-CH 2-
4 Sec.-propyl Thionaphthene-2-base -CH 2-CH 2-
5 Sec.-propyl Trans-phenyl-CH=CH- -CH 2-CH 2-
6 CH 3 Trans-phenyl-CH=CH- -CH 2-CH 2-CH 2-
And be named as:
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-hydroxyethyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-phenyl amino oxyethyl group) benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-methyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-N-thionaphthene-2-base-N-sec.-propyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-sec.-propyl amino ethoxy) benzamide; With
N-hydroxyl-4-(3-N-trans-cinnamoyl-N-methylamino propoxy-) benzamide;
Formula (I) compound is as follows:
Figure A20048000922500621
R wherein 1And R 3Be hydrogen, Ar 1Be phenyl, the definition of Z, R and Y is Table II as follows.
Table III
Compound number Z R Y
1 S H -CH 2-CH 2-
2 O H -CH 2-CH 2-
3 NH H -CH 2-CH 2-
4 NMe H -CH 2-CH 2-
5 S H -CH 2-CH 2-CH 2-
6 O H -CH 2-CH 2-CH 2-
7 S H -(S)-CH (sec.-propyl)-CH 2-
8 S H -(S)-CH (ethyl)-CH 2-
9 S H -(S)-CH (methyl)-CH 2-
10 S H -(R)-CH (methyl)-CH 2-
11 O H -(S)-CH (ethyl)-CH 2-
12 S H -(R)-CH 2-CH(CH 3)-
13 S H -(S)-CH 2-CH(CH 3)-
14 O H -(R)-CH 2-CH(CH 3)-
15 S The 6-methoxyl group -CH 2-CH 2-
16 S The 5-methyl -CH 2-CH 2-
17 S 3-chlorine -CH 2-CH 2-
18 O The 5-methyl -CH 2-CH 2-
19 O The 6-methyl -CH 2-CH 2-
20 S 4-CF 3 -CH 2-CH 2-
21 S The 5-fluorine -CH 2-CH 2-
22 S The 5-methoxyl group -CH 2-CH 2-
23 O 5-chlorine -CH 2-CH 2-
24 O The 7-methoxyl group -CH 2-CH 2-
25 O The 5-methoxyl group -CH 2-CH 2-
26 O 5-(2-methoxy ethoxy)- -CH 2-CH 2-
27 O 5-(2-morpholine-4-base oxethyl)- -CH 2-CH 2-
28 O 5-pyridin-3-yl methoxyl group -CH 2-CH 2-
29 O The 3-methyl -CH 2-CH 2-
30 S The 3-methyl -CH 2-CH 2-
31 O 5-(2-hydroxyl-oxethyl)- -CH 2-CH 2-
32 O 5-(2-N, N-dimethylamino ethoxy)- -CH 2-CH 2-
33 O 6-CH 3OCH 2CH 2O -CH 2-CH 2-
34 O 6-(2-morpholine-4-base oxethyl)- -CH 2-CH 2-
35 O 6-pyridin-3-yl methoxyl group- -CH 2-CH 2-
36 O The 3-ethyl -CH 2-CH 2-
37 NH The 5-fluorine -CH 2-CH 2-
38 NH The 5-methoxyl group -CH 2-CH 2-
39 O 3-CH 3OCH 2 -CH 2-CH 2-
40 O The 3-phenoxymethyl -CH 2-CH 2-
41 NH 5, the 6-dimethoxy -CH 2-CH 2-
42 O 3-morpholino-4-ylmethyl -CH 2-CH 2-
43 O 3-N, the N-dimethylaminomethyl -CH 2-CH 2-
44 O 3-isopropoxy methyl -CH 2-CH 2-
45 O The 7-phenoxymethyl -CH 2-CH 2-
46 O 7-CH 3OCH 2 -CH 2-CH 2-
47 O 7-morpholino-4-ylmethyl -CH 2-CH 2-
48 O 7-N, the N-dimethylaminomethyl -CH 2-CH 2-
49 S The 5-methyl -CH 2-CH 2-CH 2-
50 S The 6-methoxyl group -CH 2-CH 2-CH 2-
51 O 7-CH 3OCH 2 -CH 2-CH 2-CH 2-
52 O The 7-phenoxymethyl -CH 2-CH 2-CH 2-
53 O 5-CH 3OCH 2CH 2O -(R)-CH 2-CH(CH 3)-
54 O H (R)-CH(CH 3The S methyl)-CH 2-
55 O H (R)-CH(CH 3SO 2-methyl)-CH 2-
56 O 3-(2-phenylethyl)- -CH 2-CH 2-
57 O 3-(N-methyl-N-benzylamino-methyl)- -CH 2-CH 2-
58 O 3-(N-methyl-N-2-phenylethyl-amino methyl)- -CH 2-CH 2-
59 O 3-(3-hydroxyl rosickyite ylmethyl)- -CH 2-CH 2-
60 O 3-(3-hydroxypropyl sulfinyl methyl)- -CH 2-CH 2-
61 O 3-(3-hydroxypropyl alkylsulfonyl methyl)- -CH 2-CH 2-
62 O 3-(N-methyl-N-2-indol-3-yl-ethylamino methyl)- -CH 2-CH 2-
63 O 3-[2-(3-trifluoromethyl)-ethyl]- -CH 2-CH 2-
64 O 3-[2-(3-Trifluoromethoxyphen-l)-ethyl]- -CH 2-CH 2-
65 O 3-(N-hydroxyl amino carbonyl-methylamino methyl)- -CH 2-CH 2-
66 O 3-(2-carboxy ethyl amino-methyl)- -CH 2-CH 2-
67 O H (RS)-CH 2CH-(phenoxymethyl)-
68 O 3-(3-hydroxyl propoxy-methyl)- -CH 2-CH 2-
69 O 3-(2-fluorophenoxy methyl)- -CH 2-CH 2-
70 O 3-(3-fluorophenoxy methyl)- -CH 2-CH 2-
71 O 3-(4-fluorophenoxy methyl)- -CH 2-CH 2-
72 O 3-(2-methoxy ethoxy methyl)- -CH 2-CH 2-
73 O 3-(pyridin-4-yl oxygen methyl)- -CH 2-CH 2-
74 O 3-(2,4,6-trifluoromethoxy phenoxy ylmethyl)- -CH 2-CH 2-
75 O 3-(2-oxo pyridine-1-ylmethyl)- -CH 2-CH 2-
76 O 3-(2,2,2-trifluoro ethoxy methyl)- -CH 2-CH 2-
77 O 3-(4-imidazoles-1-phenoxyl methyl)- -CH 2-CH 2-
78 O 3-(4-[1.2.4]-triazine-1-phenoxyl-methyl)- -CH 2-CH 2-
79 O 3-(tetramethyleneimine-1-ylmethyl)- -CH 2-CH 2-
80 O 3-(piperidines-1-ylmethyl)- -CH 2-CH 2-
81 O 3-(4-trifluoromethyl piperidin-1-yl methyl)- -CH 2-CH 2-
82 O 3-(4-methylpiperazine-1-base-methyl)- -CH 2-CH 2-
83 O 3-(3,3,3-trifluoro propoxy--methyl)- -CH 2-CH 2-
84 O The 4-methyl -CH 2-CH 2-
85 O 3-(4-fluorobenzene sulfenyl methyl)- -CH 2-CH 2-
86 O 3-(4-fluorophenyl sulfinyl-methyl)- -CH 2-CH 2-
87 O 3-(4-fluorophenyl alkylsulfonyl-methyl)- -CH 2-CH 2-
88 O 3-(2,2,2-trifluoro ethoxy-methyl) -(S)-CH (ethyl)-CH 2-
89 O The 4-hydroxyl -CH 2-CH 2-
90 O 5-chlorine (S)-CH (ethyl)-CH 2-
91 O 5-chlorine (R)-CH 2-CH (methyl)-
92 O 4-pyridin-3-yl methoxyl group-methyl -CH 2-CH 2-
93 O The 4-methoxyl group -CH 2-CH 2-
94 O 4-(2-methoxy ethoxy)- -CH 2-CH 2-
95 O 4-pyridin-3-yl methoxyl group -CH 2-CH 2-
96 NH The 4-methoxyl group -CH 2-CH 2-
97 O 3-(2-methoxy ethoxy methyl)- (S)-CH (ethyl)-CH 2-
98 O 3-(2-methoxy ethoxy methyl)- (R)-CH 2-CH (methyl)-
99 O 3-N, N-diethylamino methyl -CH 2-CH 2-
100 O 5-(2-methoxy ethoxy)- (S)-CH (ethyl)-CH 2
101 O 5-tetrahydropyran-4-base oxygen -CH 2-CH 2-
102 O 5-tetrahydropyran-4-base oxygen (S)-CH (ethyl)-CH 2-
103 O 5-tetrahydropyran-4-base oxygen (R)-CH 2-CH (methyl)-
104 O 5-(2,2, the 2-trifluoro ethoxy)- -CH 2-CH 2-
105 O 5-(2-tetramethyleneimine-1-base oxethyl)- -CH 2-CH 2-
106 O 5-(2-tetramethyleneimine-1-base oxethyl)- (S)-CH (ethyl)-CH 2-
107 O 5-(2-tetramethyleneimine-1-base oxethyl)- (R)-CH 2-CH (methyl)-
108 O 5-(piperidin-4-yl oxygen)- -CH 2-CH 2-
109 O H (S)-CH(2-CH 3The S ethyl)-CH 2-
110 O H (S)-CH(2-CH 3SO 2Ethyl)-CH 2-
And be named as:
N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(1H-indoles-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(1-skatole-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[3-(thionaphthene-2-base carbonylamino) propoxy-]-benzamide;
N-hydroxyl-4-[3-(cumarone-2-base carbonylamino) propoxy-]-benzamide;
N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino)-3-methyl butoxy]-benzamide;
N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino) butoxy]-benzamide;
N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino)-propoxy-]-benzamide;
N-hydroxyl-4-[2R-(thionaphthene-2-base carbonylamino)-propoxy-]-benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino) butoxy]-benzamide;
N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino)-1R-methyl ethoxy]-benzamide;
N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino)-1S-methyl ethoxy]-benzamide;
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-1R-methyl ethoxy]-benzamide;
N-hydroxyl-4-[2-(6-anisole thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methylbenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(3-chloro thiophene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(6-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(4-trifluoromethyl thionaphthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-fluorobenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-anisole thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-chlorobenzene and furans-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(7-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(2-morpholine-4-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(pyridin-3-yl methoxyl group) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(3-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(3-methylbenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[5-(2-hydroxyl-oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(2-N, N-dimethylamino ethoxy) cumarone-2-base carbonylamino]-oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl 4-{2-[6-(2-morpholine-4-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(pyridin-3-yl methoxyl group) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(3-ethyl benzofuran-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-fluoro indole-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methoxyl group indoles-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[3-(methoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(phenoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(5,6-dimethoxy indoles-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[3-(morpholine-4-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(N, N-dimethylaminomethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(isopropoxy methyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[7-(phenoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[7-(methoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[7-(morpholine-4-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[7-(N, N-dimethylaminomethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{3-[5-(methyl) thionaphthene-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{3-[6-(methoxyl group) thionaphthene-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{3-[7-(methoxymethyl) cumarone-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{3-[7-(phenoxymethyl) cumarone-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{2-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-(2R-cumarone-2-base carbonylamino-3-methylthio group propoxy-) benzamide;
N-hydroxyl-4-(2R-cumarone-2-base carbonylamino-3-methyl sulphonyl propoxy-) benzamide;
N-hydroxyl-4-{2-[3-(2-phenylethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-methyl-N-benzylamino-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-methyl-N-2-phenylethyl amino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxyl rosickyite ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxypropyl sulfinyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxypropyl alkylsulfonyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl 4-{2-[3-(N-methyl-N-2-indol-3-yl ethylamino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-(3-trifluoromethyl) ethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-(3-Trifluoromethoxyphen-l) ethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-hydroxyl amino carbonyl methylamino methyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-carboxy ethyl amino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-1RS-phenoxymethyl oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxyl propoxy-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(3-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(4-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(pyridin-4-yl oxygen methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2,4,6-trifluoromethoxy phenoxy ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-oxo pyridine-1-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-imidazoles-1-phenoxyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-[1.2.4]-triazine-1-phenoxyl methyl) cumarone-2-base carbonyl-amino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(tetramethyleneimine-1-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(piperidines-1-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(4-trifluoromethyl piperidines-1-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-methylpiperazine-1-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3,3,3-trifluoropropyl oxygen ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(4-methyl cumarone-2-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-{2-[3-(4-fluorobenzene sulfenyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-fluorophenyl sulfinyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-fluorophenyl alkylsulfonyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2S-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base carbonylamino]-butoxy } benzamide;
N-hydroxyl-4-[2-(4-hydroxyl benzofuran-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2S-(5-chlorobenzene and furans-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2-(5-chlorobenzene and furans-2-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(4-pyridin-3-yl methoxymethyl cumarone-2-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[4-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(4-pyridin-3-yl methoxyl group benzo furans-2-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl 4-[2-(4-methoxyl group indoles-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2S-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-butoxy } benzamide;
N-hydroxyl-4-{2-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[3-(N, N-diethylamino methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[5-(2,2, the 2-trifluoro ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[5-(piperidin-4-yl oxygen) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-methylthio group butoxy] benzamide;
N-hydroxyl 4-[2S-(cumarone-2-base carbonylamino)-4-methyl sulphonyl butoxy] benzamide;
Formula (I) compound is as follows:
Figure A20048000922500721
R wherein 1And R 3Be hydrogen, Ar 1Be isoxzzole-5-base, Ar 2With the definition of Y Table IV as follows.
Table IV
Compound number Ar 2 Y
1 The 4-xenyl (R)-CH 2-CH(CH 3)-
2 The 4-xenyl (S)-CH (ethyl)-CH 2-
3 Cumarone-2-base -CH 2-CH 2-
4 Trans-phenyl-CH=CH- -CH 2-CH 2-
5 4-(2-ethoxyl phenenyl) phenyl -CH 2-CH 2-CH 2-
6 The 3-xenyl -CH 2-CH 2-CH 2-
7 The 4-xenyl -CH 2-CH 2-CH 2-
8 Naphthalene-2-base -CH 2-CH 2-
9 3-methyl diphenyl-4-base -CH 2-CH 2-
10 2 '-ethoxybiphenyl-4-base -CH 2-CH 2-
11 3-methyl diphenyl-4-base -CH 2-CH 2-CH 2-
12 4-phenyl thiazole-2-base -CH 2-CH 2-CH 2-
13 Naphthalene-2-base -CH 2-CH 2-CH 2-
14 Naphthalene-1-base -CH 2-CH 2-CH 2-
15 2-2-(phenylethyl) phenyl -CH 2-CH 2-CH 2-
16 Naphthalene-1-base -CH 2-CH 2-
17 Cumarone-2-base (S)-CH (ethyl)-CH 2-
18 The 3-xenyl (S)-CH (ethyl)-CH 2-
19 Cumarone-2-base (R)-CH 2-CH (methyl)-
20 The 3-xenyl (R)-CH 2-CH (methyl)-
21 The 3-xenyl -CH 2-CH 2-
22 The 4-xenyl -CH 2-CH 2-
23 4-phenyl thiazole-2-base -CH 2-CH 2-
24 2-(2-phenylethyl) phenyl -CH 2-CH 2-
25 The 2-xenyl -CH 2-CH 2-
26 The 2-xenyl -CH 2-CH 2-CH 2-
27 Naphthalene-2-base (S)-CH (ethyl)-CH 2-
28 Naphthalene-1-base (S)-CH (ethyl)-CH 2-
29 Naphthalene-2-base (R)-CH 2-CH (methyl)-
30 Naphthalene-1-base (R)-CH 2-CH (methyl)-
31 Cumarone-2-base -CH 2-CH 2-CH 2-
32 Trans-phenyl CH=CH- -CH 2-CH 2-CH 2-
33 3-(phenoxymethyl) cumarone-2-base -CH 2-CH 2-
And be named as:
N-hydroxyl-3-[2-(biphenyl-4-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(biphenyl-4-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(cumarone-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(trans-cinnamoyl amino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(4-(2-ethoxyl phenenyl) phenylcarbonyl group amino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(biphenyl-3-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(biphenyl-4-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(3-methyl diphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(2 '-ethoxybiphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(3-methyl diphenyl-4-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(4-phenyl thiazole-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(naphthalene-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(naphthalene-1-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-{3-[2-(2-phenylethyl) phenylcarbonyl group amino] propoxy-} isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-1-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(cumarone-2-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(biphenyl-3-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(cumarone-2-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-3-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-3-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(4-phenyl thiazole-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-{2-[2-(2-phenylethyl) phenylcarbonyl group amino] oxyethyl group } isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(biphenyl-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(naphthalene-2-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(naphthalene-1-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-2-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-1-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(cumarone-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(trans-cinnamoyl amino) propoxy-] isoxzzole-5-yl-carboxamides; With
N-hydroxyl-3-[2-(3-phenoxymethyl cumarone-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides.
Preferred embodiment
Although proposed the most extensive definition of the present invention in " summary of the invention ", some compound of formula (I) is preferred.For example:
I. one group of preferred formula (I) compound is, wherein:
R 1Be hydrogen or alkyl;
X is-O-,-NR 2-or-S (O) n, wherein n is 0-2, R 2Be hydrogen or alkyl;
Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces or hydroxyl;
Ar 1Be phenylene or heteroarylidene, wherein said Ar 1Randomly replaced by one or two group, described group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, halogenated alkoxy or haloalkyl;
R 3Be hydrogen, alkyl, hydroxyalkyl or the optional phenyl that replaces; With
Ar 2Be aryl, aralkyl, arylalkenyl, heteroaryl, heteroaralkyl, impure aromatic ene base, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl;
Wherein term " aryl, heteroaryl, Heterocyclylalkyl, the optional phenyl that replaces, the optional heteroaryl that replaces, optional Heterocyclylalkyl and the aminoalkyl group that replaces " or individually or as another term (for example: aralkyl, the optional octadecyloxy phenyl sulfenyl that replaces, aminoalkoxy, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces etc. in the scope of) the involved superincumbent preferred group I of a part, described term has following implication:
" aryl " is meant monovalence monocycle or the double ring arene base with 6 to 12 annular atomses, for example randomly by one, the phenyl that two or three substituting groups replace, naphthyl or anthryl, described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, alkoxy alkoxy alkyl, the optional phenyl that replaces, the optional heteroaryl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryloxy that replaces, the optional assorted aralkoxy that replaces, aminoalkyl group, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional heterocycle alkoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional heterocycle alkoxyl group that replaces,-alkylidene group-S (O) n-R a(wherein n is 0 to 2, R aBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) ,-alkylidene group-NHSO 2-R b(R wherein bBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces) or-alkylidene group-NHCO-R c(R wherein cBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces), wherein randomly replaced by one or two fluorine at halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces or the alkyl chain in the aminoalkyl group.More preferably, aromatic ring is randomly by one, two, or three substituting groups replacements, described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, aminoalkyl group, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional heterocycle alkoxyalkyl that replaces, or the optional heterocycle alkoxyl group that replaces.Preferably, substituting group is independently: methoxyl group, methyl, ethyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-(morpholine-4-yl) oxyethyl group, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-(N, the N-dimethylamino) oxyethyl group, methoxymethyl, phenoxymethyl, 2-morpholino-4-base ethyl, morpholino-4-ylmethyl, N, N-dimethylaminomethyl, isopropoxy methyl or phenoxymethyl;
" Heterocyclylalkyl " is meant the saturated monovalence cyclic group with 3 to 8 annular atomses, and one of them or two annular atomses are heteroatoms, and it is selected from N, O or S (O) n, wherein n is 0 to 2 integer, remaining annular atoms is C.More specifically, term " Heterocyclylalkyl " includes but not limited to: pyrrolidino, piperidino-(1-position only), morpholino base, Piperazino, THP trtrahydropyranyl and thiomorpholine are for basic, as to reach them derivative (forming when heterocycloalkyl ring is replaced by following substituting group); Or its N-oxide compound or protected derivative.Heterocyclylalkyl randomly is fused to aryl, randomly by one, two, or three substituting groups replacements, described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, hydroxyl, amino, alkylamino, dialkyl amido, hydroxyalkyl, the hydroxy alkoxy base, the optional phenyl that replaces, the optional heteroaryl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, aminoalkyl group, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, the optional phenoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, or the optional heterocycle alkoxyl group that replaces.Preferably, substituting group is independently: methoxyl group, methyl, ethyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-(morpholine-4-yl) oxyethyl group, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-(N, the N-dimethylamino) oxyethyl group, methoxymethyl, phenoxymethyl, 2-morpholino-4-base ethyl, morpholino-4-ylmethyl, N, N-dimethylaminomethyl, isopropoxy methyl or phenoxymethyl;
" heteroaryl " is meant monovalence monocycle or the bicyclic aromatic base with 5 to 10 annular atomses, comprises one or more, preferred one, two or three ring hetero atoms, and described heteroatoms is selected from N, O or S, and the residue ring atom is a carbon.More specifically, term " heteroaryl " includes but not limited to: pyridyl, pyrryl, imidazolyl, thienyl, furyl, indyl, quinolyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, tetrahydric quinoline group (quinolinyl), different tetrahydric quinoline group, benzopyranyl and thiazolyl, the derivative (forming when hetero-aromatic ring is replaced by following substituting group) that reaches them or its N-oxide compound or quilt are protected derivative.Hetero-aromatic ring is randomly by one, two, or three substituting groups replacements, described substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, alkoxy alkoxy alkyl, the optional phenyl that replaces, the optional heteroaryl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, aminoalkyl group, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional heterocycle alkoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional heterocycle alkoxyl group that replaces,-alkylidene group-S (O) n-R a(wherein n is 0 to 2, R aBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces or the optional heteroaralkyl that replaces) ,-alkylidene group-NHSO 2-R b(R wherein bBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces) or-alkylidene group-NHCO-R c(R wherein cBe alkyl, haloalkyl, the optional phenyl that replaces, the optional phenylalkyl that replaces, the optional heteroaryl that replaces, the optional heteroaralkyl that replaces or the optional Heterocyclylalkyl that replaces), wherein randomly replaced by one or two fluorine at halogenated alkoxy alkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces or the alkyl chain in the aminoalkyl group.More preferably, substituting group is independently selected from: alkyl, alkoxyl group, halogen, haloalkyl, halogenated alkoxy, amino, alkylamino, dialkyl amido, hydroxyl, hydroxyalkyl, the hydroxy alkoxy base, the optional phenyl that replaces, the optional heteroaryl that replaces, cycloalkyloxy, cyclenes oxygen base, the optional phenylcarbonyl group amino that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, aminoalkyl group, aminoalkoxy, alkoxyalkyl, the alkoxyl group alkoxyl group, methylene-dioxy, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces, the optional heterocycle alkoxyalkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces, or the optional heterocycle alkoxyl group that replaces.Preferably, substituting group is independently: methoxyl group, methyl, ethyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-(morpholine-4-yl) oxyethyl group, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-(N, the N-dimethylamino) oxyethyl group, methoxymethyl, phenoxymethyl, 2-morpholino-4-base ethyl, morpholino-4-ylmethyl, N, N-dimethylaminomethyl, isopropoxy methyl or phenoxymethyl;
" the optional phenyl that replaces " is meant randomly by one, two, or three phenyl ring that substituting group replaces, described substituting group is independently selected from: alkyl, halogen, alkoxyl group, alkylthio, haloalkyl, halogenated alkoxy, (it is randomly replaced by one or two substituting group heteroaryl, described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, carboxyl, amino, alkylamino, or dialkyl amido), (it is randomly replaced by one or two substituting group Heterocyclylalkyl, described substituting group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, carboxyl, amino, alkylamino, or dialkyl amido), amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, methylene-dioxy, aminocarboxyl, hydroxyalkyl, alkoxy carbonyl, aminoalkyl group, or carboxyl, or randomly replaced by five fluorine atoms.More preferably, substituting group is independently selected from: alkyl, halogen, alkoxyl group, alkylthio, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, methylene-dioxy, aminocarboxyl, hydroxyalkyl, alkoxy carbonyl, aminoalkyl group or carboxyl or randomly replaced by five fluorine atoms;
" the optional heteroaryl that replaces " is meant monovalence monocycle or bicyclic aromatic base with 5 to 10 annular atomses, comprise one or more, preferred one, two, or three ring hetero atoms, described heteroatoms is selected from: N, O or S, the residue ring atom is a carbon, it is randomly by one, two, or three substituting groups replace, described substituting group is independently selected from: alkyl, halogen, alkoxyl group, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, aminocarboxyl, hydroxyalkyl, alkoxy carbonyl, aminoalkyl group, the optional phenyl that replaces, the optional phenoxy group that replaces, carboxyl, or heteroaryl, it is randomly by alkyl, halogen, hydroxyl, alkoxyl group, carboxyl, amino, alkylamino, or dialkyl amido replaces.More specifically, term " the optional heteroaryl that replaces " includes but not limited to: pyridyl, pyrryl, imidazolyl, thienyl, furyl, indyl, quinolyl, pyrazinyl, pyrimidyl, pyridazinyl, oxazolyl, isoxazolyl, benzoxazolyl, quinolyl, isoquinolyl, benzopyranyl and thiazolyl reach their derivative (forming) or its N-oxide compound or are protected derivative when hetero-aromatic ring is replaced by following substituting group;
" the optional Heterocyclylalkyl that replaces " is meant the saturated monovalence cyclic group with 3 to 8 annular atomses, and one of them or two annular atomses are heteroatoms, and it is selected from N, O or S (O) n, wherein n is 0 to 2 integer, the residue ring atom is C.Heterocyclylalkyl randomly is fused to aryl, and randomly by one, two or three substituting groups replacements, described substituting group is independently selected from: alkyl, halogen, alkoxyl group, trifluoromethyl, trifluoromethoxy, amino, alkylamino, dialkyl amido, hydroxyl, cyano group, nitro, the optional phenylalkyl that replaces, optional heteroaralkyl, aminocarboxyl, hydroxyalkyl, alkoxy carbonyl, aminoalkyl group or the carboxyl that replaces.More specifically, term " Heterocyclylalkyl " includes but not limited to: pyrrolidino, piperidino-(1-position only), morpholino, Piperazino, THP trtrahydropyranyl and thiomorpholine generation, and their derivative (forming when heterocycloalkyl ring is replaced by following substituting group); Or its N-oxide compound or protected derivative; With
" aminoalkyl group " is meant the straight chain monovalence alkyl with 2 to 6 carbon atoms or has the straight chain monovalence alkyl of 3 to 6 carbon atoms, by at least one, preferably one or two following groups replaces :-NRR ', wherein R and R ' are independently selected from hydrogen, alkyl, or-COR a, R wherein aFor alkyl or N-oxide derivative or protected derivative, for example amino methyl, methylamino ethyl, 2-ethylamino-2-methylethyl, 1,3-diamino propyl group, dimethylaminomethyl, diethylamino ethyl, acetylamino propyl group etc.; With
The definition of other term that comprises in the scope of preferred group I is referring to the application's definitional part.
In group I:
(A) one group of preferred compound is, wherein R 1And R 3Be hydrogen, X is-O-that Y is ethylidene or positive propylidene, preferred ethylidene.
(B) another is organized preferred compound and is, wherein R 1And R 3Be hydrogen, X is-O-that Y is-CH (C 2H 5) CH 2-,-CH (i-C 3H 7) CH 2-or-CH (CH 3) CH 2-, the stereo-formula on chiral carbon is (S).More preferably, Y is-CH (C 2H 5) CH 2-.
(C) also one group of preferred compound is, wherein R 1And R 3Be hydrogen, X is-O-that Y is-CH 2CH (CH 3The stereo-formula of)-, on chiral carbon is (R).
(i) in group (A)-(C), one group of preferred compound is, wherein Ar 1Be phenylene, wherein hydroxamic acid ester group and X group toward each other, Ar 2Be aryl.Preferably, Ar 2Be phenyl, randomly replaced by one or two substituting group, described substituting group is independently selected from: methoxyl group, oxyethyl group, phenyl, methyl, the tertiary butyl, pyrroles-1-base, tetrahydrobenzene-3-oxygen, pyridin-3-yl, pyridine-2-base, benzamido, fluorine, chlorine or thiophene-2-ylmethoxy.More preferably, Ar 2Be phenyl, the 4-xenyl, the 3-xenyl, the 4-tert-butyl-phenyl, 4-pyrroles-1-base phenyl, 4-(tetrahydrobenzene-3-oxygen) phenyl, 4-(pyridine-2-yl) phenyl, 4-(pyridin-3-yl)-phenyl, 2, the 4-difluorophenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 3, the 4-difluorophenyl, 2, the 5-3,5-dimethylphenyl, 2, the 3-dichlorophenyl, 2, the 3-3,5-dimethylphenyl, 4-chloro-2-p-methoxy-phenyl, the 3-ethoxyl phenenyl, 4-methoxyl group-2-aminomethyl phenyl, 3-fluoro-4-p-methoxy-phenyl, 2-thiophene-2-ylmethoxy phenyl, 3-thiophene-2-ylmethoxy phenyl, the 2-xenyl, or 2-pyrroles-1-base phenyl.
(ii) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be phenylene, wherein hydroxamic acid ester group and X group toward each other, Ar 2Be trans-aryl-CH=CH-.Preferably, Ar 2Be trans-phenyl-CH=CH-, randomly alkoxy, preferred methoxyl group replace.Preferably, Ar 2Be trans-phenyl-CH=CH-.
(iii) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be phenylene, wherein hydroxamic acid ester group and X group toward each other, Ar 2Be heteroaryl-CH=CH-.Preferably, Ar 2Be pyridyl-CH=CH-.Preferably, Ar 2Be trans-5-bromothiophene-2-base-CH=CH-or trans-indol-3-yl-CH=CH-.
(iv) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be phenylene, wherein hydroxamic acid ester group and X group toward each other, Ar 2Be heteroaryl.Preferably, Ar 2Be pyridin-3-yl, thiophene-2-base, quinoline-6-base, thiazol-2-yl, benzothiazole-2-base, benzoxazoles-2-base, furyl, pyrroles-2-base, indoles-5-base, indol-3-yl, indazole-3-base, quinoline-3-base, quinoline-1-base, quinoline-8-base, benzotriazole-4-base, cumarone-5-base, isoquinolyl-1, isoquinoline 99.9-3-base, quinoxaline-2-base, quinoline-2-base or benzoglyoxaline-5-base, wherein said ring is randomly replaced by phenyl, pyridin-4-yl, methyl, methoxyl group or dimethylaminomethyl.
(v) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be phenylene, wherein hydroxamic acid ester group and X group toward each other, Ar 2Be indoles-2-base, cumarone-2-base or thionaphthene-2-base, they are randomly replaced by alkyl, alkoxyl group, halogen, haloalkyl, alkoxyl group alkoxyl group, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional assorted aralkoxy that replaces, hydroxy alkoxy base, aminoalkyl group, aminoalkoxy, alkoxyl group alkoxyl group, alkoxyalkyl, the optional phenoxyalkyl that replaces or the optional Heterocyclylalkyl alkyl that replaces.Preferably, Ar 2Be cumarone-2-base or thionaphthene-2-base, wherein cumarone-2-base or thionaphthene-2-base is randomly by methoxyl group, methyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-morpholine-4-base oxethyl, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-N, N-dimethylamino ethoxy, ethyl, methoxymethyl, 2-propoxy-methyl, phenoxymethyl, morpholine-4-ylmethyl or N, the N-dimethylaminomethyl replaces, and substituting group is positioned at the 3-position of thionaphthene-2-base or cumarone-2-basic ring or 5-position, preferred 3-position.Even more preferably, Ar 2Be cumarone-2-base, 3-N, N-dimethylaminomethyl cumarone-2-base or 3-phenoxymethyl cumarone-2-base.
(vi) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be phenylene, wherein hydroxamic acid ester group and X group toward each other, Ar 2Be indoles-2-base, cumarone-2-base or thionaphthene-2-base, replaced by the heterocycle alkoxyalkyl of the heteroaryloxy alkyl of phenoxyalkyl, replacement, replacement or halogenated alkoxy alkyl, substituting group is positioned at the 3-position of thionaphthene-2-base and cumarone-2-basic ring.Even more preferably, Ar 2Be 3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base.
(vii) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be heteroarylidene, Ar 2Be aryl.Preferably, Ar 1Be five yuan of assorted inferior aromatic rings, comprise one, two or three heteroatomss, described heteroatoms is independently selected from: N, O or S, more preferably, Ar 1Be isoxazolyl, wherein hydroxamic acid ester group and X group are positioned at the 5-and the 3-position of isoxzzole basic ring, and the intra-annular Sauerstoffatom is at 1-position, Ar 2Be aryl.Preferably, Ar 2Be phenyl, it is randomly replaced by one or two substituting group, and described substituting group is independently selected from: methoxyl group, oxyethyl group, optional by oxyethyl group or methyl substituted phenyl, methyl, the tertiary butyl, pyrroles-1-base, tetrahydrobenzene-3-oxygen, pyridin-3-yl, pyridine-2-base, benzamido, fluorine, chlorine or thiophene-2-ylmethoxy.More preferably, Ar 2Be phenyl, the 4-xenyl, the 3-xenyl, 2-(2-ethoxyl phenenyl) phenyl, 3-methyl diphenyl-4-base, the 4-tert-butyl-phenyl, 4-pyrroles-1-base phenyl, 4-(tetrahydrobenzene-3-oxygen) phenyl, 4-(pyridine-2-yl) phenyl, 4-(pyridin-3-yl)-phenyl, 2, the 4-difluorophenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 3, the 4-difluorophenyl, 2, the 5-3,5-dimethylphenyl, 2, the 3-dichlorophenyl, 2, the 3-3,5-dimethylphenyl, 4-chloro-2-p-methoxy-phenyl, the 3-ethoxyl phenenyl, 4-methoxyl group-2-aminomethyl phenyl, 3-fluoro-4-p-methoxy-phenyl, 2-thiophene-2-ylmethoxy phenyl, 3-thiophene-2-ylmethoxy phenyl, the 2-xenyl, or 2-pyrroles-1-base phenyl.
(viii) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be heteroarylidene, Ar 2Be aryl-CH=CH-.Preferably, Ar 1Be five yuan of assorted inferior aromatic rings, comprise one, two or three heteroatomss, it is independently selected from: N, O or S, more preferably, Ar 1Be isoxazolyl, wherein hydroxamic acid ester group and X group are positioned at the 5-and the 3-position of isoxzzole basic ring, and the intra-annular Sauerstoffatom is at 1-position, Ar 2Be phenyl-CH=CH-, randomly alkoxy replaces.
(ix) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be heteroarylidene, Ar 2Be heteroaryl-CH=CH-.Preferably, Ar 1Be five yuan of assorted inferior aromatic rings, comprise one, two or three heteroatomss, it is independently selected from: N, O or S, more preferably, Ar 1Be isoxazolyl, wherein hydroxamic acid ester group and X group are positioned at the 5-and the 3-position of isoxzzole basic ring, and the intra-annular Sauerstoffatom is at 1-position, Ar 2Be pyridyl CH=CH-.
(x) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be heteroarylidene, Ar 2Be heteroaryl.Preferably, Ar 1Be five yuan of assorted inferior aromatic rings, comprise one, two or three heteroatomss, it is independently selected from: N, O or S, more preferably, Ar 1Be isoxazolyl, wherein hydroxamic acid ester group and X group are positioned at the 5-and the 3-position of isoxzzole basic ring, and the intra-annular Sauerstoffatom is at 1-position, Ar 2Be pyridin-3-yl, thiophene-2-base, quinoline-6-base, thiazol-2-yl, benzothiazole-2-base, benzoxazoles-2-base, furyl, pyrroles-2-base, indoles-5-base, indol-3-yl, indazole-3-base, quinoline-3-base, quinoline-8-base, benzotriazole-4-base, isoquinolyl-1, isoquinoline 99.9-3-base, quinoxaline-2-base, quinoline-2-base or benzoglyoxaline-5-base, wherein said ring is randomly replaced by phenyl, pyridin-4-yl, methyl, methoxyl group or dimethylaminomethyl.
(xi) in group (A)-(C), another is organized preferred compound and is, wherein Ar 1Be heteroarylidene, Ar 2Be indoles-2-base, cumarone-2-base or thionaphthene-2-base, it is randomly replaced by alkyl, alkoxyl group, halogen, haloalkyl, alkoxyl group alkoxyl group, the optional Heterocyclylalkyl alkoxyl group that replaces, the optional assorted aralkoxy that replaces, hydroxy alkoxy base, aminoalkoxy, alkoxyl group alkoxyl group, alkoxyalkyl, the optional phenoxyalkyl that replaces or the optional Heterocyclylalkyl alkyl that replaces.Preferably, Ar 1Be five yuan of assorted inferior aromatic rings, comprise one, two or three heteroatomss, it is independently selected from: N, O or S, more preferably, Ar 1Be isoxazolyl, wherein hydroxamic acid ester group and X group are positioned at the 5-and the 3-position of isoxzzole basic ring, and the intra-annular Sauerstoffatom is at 1-position, Ar 2Be cumarone-2-base and thionaphthene-2-base, it is optional by methoxyl group, methyl, chlorine, trifluoromethyl, fluorine, 2-methoxy ethoxy, 2-morpholine-4-base oxethyl, pyridin-3-yl methoxyl group, 2-hydroxyl-oxethyl, 2-N, N-dimethylamino ethoxy, ethyl, methoxymethyl, phenoxymethyl, morpholine-4-ylmethyl or dimethylaminomethyl replace, and substituting group is positioned at the 3-position of thionaphthene-2-base and cumarone-2-basic ring.Even more preferably, Ar 2Be cumarone-2-base or 3-phenoxymethyl cumarone-2-base.
(xii) in group (A) with (B), another is organized preferred compound and is, wherein Ar 2Alkoxy alkoxyl group, the optional Heterocyclylalkyl alkoxyl group that replaces, hydroxy alkoxy base, aminoalkoxy, alkoxyl group alkoxyl group, alkoxyalkyl, the optional phenoxyalkyl that replaces, the optional heteroaryloxy alkyl that replaces or the optional Heterocyclylalkyl alkyl that replaces replace.In this group, preferred compound is, wherein Ar 1And Ar 2As described in top preferred embodiment.
II. another is organized preferred formula (I) compound and is that wherein X is-O-, R 1And R 3Be hydrogen.
III. also one group of preferred formula (I) compound is that wherein X is-S (O) n-, R 1And R 3Be hydrogen.
In above-mentioned preferred group of II and III, preferred compound is that wherein Y is an alkylidene group.
In above-mentioned preferred group of II and III; another is organized preferred compound and is; wherein Y is an alkylidene group, and it is replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces.
In above-mentioned preferred group of II and III and wherein contained more preferably group, one group even preferred compound be, wherein Ar 1Be phenylene.
In above-mentioned preferred group of II and III and wherein contained more preferably group, another group even preferred compound be, wherein Ar 1Be heteroarylidene.
Above-mentioned preferred group of II and III and wherein contained more preferably and even preferred group in, work as Ar 1During for phenylene, one group of particularly preferred compound is, wherein-and CONHOH and X group be in the 1-and the 4-position of inferior phenyl ring.
IV. also one group of preferred formula (I) compound is, wherein Ar 1Be phenylene, X is-O-R 1And R 3Be hydrogen ,-CONHOH and X group are in the 1-and the 4-position of inferior phenyl ring.
In above-mentioned preferred group of IV, one group of preferred compound is that wherein Y is an alkylidene group.
In above-mentioned preferred group of IV; another is organized preferred compound and is; wherein Y is an alkylidene group, and it is replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces.
(i) in above-mentioned preferred group of II, III and IV and wherein contained preferred even preferred and particularly preferred group, one group of more particularly preferred compound is, wherein Ar 2Be arylalkenyl.Preferably, Ar 2Be aryl (C 2-3) thiazolinyl.More preferably, Ar 2Represent with following formula:
Or
Wherein phenyl is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, alkoxyl group, methylene-dioxy, dialkyl amido or hydroxyl, more preferably alkyl, alkoxyl group, methylene-dioxy or hydroxyl.
Even more preferably, Ar 2Be trans-phenyl-CH=CH-, trans-4-MeO-phenyl-CH=CH-, trans-3,4-methylenedioxyphenyl-CH=CH-, trans-3-hydroxy phenyl-CH=CH-, trans-4-hydroxy phenyl-CH=CH-, trans-2-p-methoxy-phenyl-CH=CH-, trans-3-p-methoxy-phenyl-CH=CH-, trans-3-tolyl-CH=CH-, trans-4-tolyl-CH=CH-, trans-4-dimethylaminophenyl-CH=CH-, trans-2-tolyl-CH=CH-or trans-2-hydroxy phenyl-CH=CH-.
(ii) reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III and IV, another is organized more particularly preferred compound and is, wherein Ar 2Be heteroaryl (C 2-3) thiazolinyl.Preferably, Ar 2Be trans-heteroaryl-CH=CH-or trans-heteroaryl-C (CH 3)=CH-, preferably, hetero-aromatic ring is pyridyl, benzofuryl, thienyl (thiophene), furyl or indyl, and it is chosen wantonly and is replaced by one or two substituting group, and described substituting group is selected from: hydroxyl, alkoxyl group, halogen or the optional heterocycle alkoxyl group that replaces.
More preferably, Ar 2Be trans-pyridin-3-yl-CH=CH-, trans-the 5-hydroxyl benzofuran-2-base-C (CH 3)=CH-, trans-5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base-C (CH 3)=CH-, trans-5-methoxyl group benzo furans-2-base-C (CH 3)=CH-, trans-cumarone-2-base-CH=CH-, trans-5-bromothiophene-2-base-CH=CH-, trans-furans-3-base-CH=CH-, trans-thiene-3-yl--CH=CH-, trans-thiophene-2-base-CH=CH-, trans-cumarone-2-base-C (CH 3)=CH-, cis-cumarone-2-base-C (CH 3)=CH-, trans-indol-3-yl-CH=CH-, trans-7-methoxyl group benzo furans-2-base-CH=CH-, trans-5-methoxyl group benzo furans-2-base-C (CH 3)=CH-or trans-furans-2-base-CH=CH.
(iii) reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III and IV, also one group of more particularly preferred compound is, wherein Ar 2Be aryl.Preferably, the substituting group on the aromatic ring is independently selected from: the optional phenyl that replaces, alkyl, alkoxyl group, halogen, the optional heteroaryl that replaces, the optional cyclenes oxygen base that replaces, the optional assorted aralkoxy that replaces, the optional Heterocyclylalkyl that replaces, optional phenylcarbonyl group amino or the methylene-dioxy that replaces.More preferably, Ar 2Be phenyl, the 4-xenyl, the 3-xenyl, the 4-tert-butyl-phenyl, 4-pyrroles-1-base phenyl, 4-(pyridin-3-yl) phenyl, 4-(pyridine-2-yl) phenyl, 4-(benzamido) phenyl, 2, the 4-difluorophenyl, 3, the 4-methylenedioxyphenyl, 3, the 4-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 3, the 4-difluorophenyl, 2, the 5-3,5-dimethylphenyl, 2, the 3-dichlorophenyl, 2, the 3-3,5-dimethylphenyl, 4-chloro-2-p-methoxy-phenyl, the 3-ethoxyl phenenyl, 4-methoxyl group-2-aminomethyl phenyl, 3-fluoro-4-p-methoxy-phenyl, 2-(thiophene-2-ylmethoxy) phenyl, 3-(thiophene-2-ylmethoxy)-phenyl, the 2-xenyl, naphthalene-1-base, 2-pyrroles-1-base-phenyl, 4-fluoronaphthalene-1-base, 3-MeO-naphthalene-2-base, 2-MeO-naphthalene-1-base, naphthalene-2-base, 4-(2-pyridin-4-yl thiazole-5-yl) phenyl, 4-[2-(4-methylpiperazine-1-yl) thiazole-5-yl]-phenyl, 4-(2-pyridin-4-yl aminothiazole-5-yl) phenyl, 4-(4-methylpiperazine-1-yl) phenyl, 4-(4-hydroxy piperidine-1-yl) phenyl, 4-(4-morpholine-4-ylmethyl thiazol-2-yl) phenyl, 4-[2-(4-methylpiperazine-1-ylmethyl) thiazole-5-yl] phenyl, 1-methoxynaphthalene-2-base, 3 '-(2-hydroxyethyl) biphenyl-4-base, 3 '-(2-hydroxyethyl) biphenyl-3-base, 2 '-(2-hydroxyethyl) biphenyl-4-base, 2 '-(2-hydroxyethyl) biphenyl-3-base or 4-[4-(2-morpholine-4-base-ethyl) thiazol-2-yl] phenyl.
(iv) reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III and IV, also one group of more particularly preferred compound is, wherein Ar 2Be heteroaryl.Preferably, Ar 2Be heteroaryl, its optional one or two substituting group that is substituted replaces, and described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) nR a(wherein n is 0 to 2, R aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR e-alkylidene group CONR cR d(R wherein cBe hydroxyl, R dAnd R eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.
More preferably, Ar 2Be thiophene-2-base, pyridin-3-yl, quinoline-6-base, benzothiazole-2-base, benzoxazoles-2-base, cumarone-2-base, cumarone-5-base, thionaphthene-2-base, furans-2-base, 1H-benzimidazolyl-2 radicals-Ji, 1H-pyrroles-2-base, thiazol-2-yl, 1H-indoles-2-base, 1H-indoles-5-base, the 1H-indol-3-yl, quinoline-3-base, quinoline-8-base, 1H-indazole-3-base, 1H-benzotriazole-5-base, isoquinolyl-1, isoquinoline 99.9-3-base, quinoxaline-2-base, quinoline-2-base, 1H-benzoglyoxaline-5-base, quinoline-1-base, pyridine-2-base, pyridine-2-base, quinoline-2-base, furans-3-base, thiophene-2-base, or thiene-3-yl-, more preferably cumarone-2-base, or thionaphthene-2-base, it is randomly replaced by one or two substituting group that the preceding paragraph is described.
Even more preferably, Ar 2Be cumarone-2-base, replace, or replaced by two that preferably, the substituting group list that cumarone-2-base is described by the preceding paragraph in 3-or 5-position replaces at 4-and 7-position at 3-, 4-or 5-position coverlet.More preferably; substituting group is independently selected from: chlorine; fluorine; trifluoromethyl; methyl; ethyl; methoxyl group; 1-cyclopropyl piperidine-4-base oxygen; 1-(2; 2; the 2-trifluoroethyl) piperidin-4-yl oxygen; N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-methoxy ethoxy methyl; phenoxymethyl; the 2-methoxy ethoxy; 2-morpholine-4-base oxethyl; the pyridin-3-yl methoxyl group; the 2-hydroxyl-oxethyl; 2-N; the N-dimethylamino ethoxy; methoxymethyl; 3-isopropoxy methyl; morpholine-4-ylmethyl; 3-hydroxyl propoxy-methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy-methyl; 3-methoxy propoxy methyl; pyridin-4-yl oxygen methyl; 2; 4; 6-trifluoromethoxy phenoxy ylmethyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy methyl; 4-imidazoles-1-phenoxyl methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3; 3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; the pyridin-3-yl methoxymethyl; tetrahydropyran-4-base oxygen; 2; 2, the 2-trifluoro ethoxy; 2-tetramethyleneimine-1-base oxethyl; piperidin-4-yl oxygen; N-methyl-N-benzylamino-methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl methyl; 3-hydroxypropyl alkylsulfonyl-methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; 2-(3-Trifluoromethoxyphen-l) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 3-(2-carboxy ethyl amino-methyl).
Even more preferably, Ar 2Be cumarone-2-base; it is replaced by following substituting group in the 3-position: N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy methyl; pyridin-4-yl oxygen methyl; 2; 4; 6-trifluoromethoxy phenoxy base-methyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy-methyl; 4-imidazoles-1-phenoxyl-methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; 3-hydroxyl propoxy-methyl; 2-methoxy ethoxy methyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl-piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3,3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; 2-(3-Trifluoromethoxyphen-l ethyl)-; N-methyl-N-benzyl-amino methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl-methyl; 3-hydroxypropyl alkylsulfonyl methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 2-carboxy ethyl amino-methyl.
Even more preferably, Ar 2Be cumarone-2-base, it is replaced by following group in the 5-position: 1-cyclopropyl piperidine-4-base oxygen, piperidin-4-yl oxygen, tetrahydropyran-4-base oxygen, 2,2,2-trifluoro ethoxy, 2-tetramethyleneimine-1-base oxethyl or 1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen.
Even more preferably, Ar 2Be 7-chloro-4-methyl cumarone-2-base, 4-methyl-cumarone-2-base, 7-fluoro-4-methyl cumarone-2-base or 7-fluoro-4-phenoxymethyl cumarone-2-base.
Even more preferably, Ar 2Be thiophene-2-base; pyridin-3-yl; 5-phenyl thiophene-2-base; quinoline-6-base; 4-phenyl thiazole-2-base; benzothiazole-2-base; benzoxazoles-2-base; furans-2-base; 1H-benzimidazolyl-2 radicals-Ji; 1H-pyrroles-2-base; 4-(pyridin-4-yl)-thiazol-2-yl; 1H-indoles-5-base; the 1H-indol-3-yl; quinoline-3-base; quinoline-8-base; 1H-indazole-3-base; 1H-benzotriazole-5-base; isoquinolyl-1; isoquinoline 99.9-3-base; quinoxaline-2-base; quinoline-2-base; 1H-benzoglyoxaline-5-base; 1-methyl-indol-3-yl; 4-MeO-quinoline-2-base; quinolyl-4; 4-hydroxyquinoline-2-base; pyridine-2-base; 3-pyridone-2-base; 6-pyridone-2-base; 6-(4-nitrophenoxy) pyridine-2-base; 4-(2-methoxy ethoxy) quinoline-2-base; 4-(2-dimethylamino ethoxy) quinoline-2-base; 6-bromopyridine-2-base; 5-bromopyridine-3-base; 4-methoxy quinoline-2-base; 5-phenylpyridine-3-base; 6-benzyloxy pyridine-2-base; 6-(2-methyl propoxy-)-pyridine-2-base; 6-(2-phenyl ethoxy) pyridine-2-base; 4-(3; 3,3-trifluoro propoxy-) quinoline-2-base; 5-thiene-3-yl-pyridin-3-yl; 6-(4-acetylamino phenoxy group)-pyridine-2-base; 6-(4-amino-benzene oxygen)-pyridine-2-base; or 5-(4-dimethylaminophenyl) pyridin-3-yl.
V. also one group of preferred formula (I) compound is, wherein Ar 2Be heteroaryl.Preferably, Ar 2Be the heteroaryl that is randomly replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) nR a(wherein n is 0 to 2, R aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR e-alkylidene group CONR cR d(R wherein cBe hydroxyl, R dAnd R eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.
More preferably, Ar 2Be thiophene-2-base, pyridin-3-yl, quinoline-6-base, benzothiazole-2-base, benzoxazoles-2-base, cumarone-2-base, cumarone-5-base, thionaphthene-2-base, furans-2-base, 1H-benzimidazolyl-2 radicals-Ji, 1H-pyrroles-2-base, thiazol-2-yl, 1H-indoles-2-base, 1H-indoles-5-base, the 1H-indol-3-yl, quinoline-3-base, quinoline-8-base, 1H-indazole-3-base, 1H-benzotriazole-5-base, isoquinolyl-1, isoquinoline 99.9-3-base, quinoxaline-2-base, quinoline-2-base, 1H-benzoglyoxaline-5-base, quinoline-1-base, pyridine-2-base, pyridine-2-base, quinoline-2-base, furans-3-base, thiophene-2-base, or thiene-3-yl-, more preferably cumarone-2-base, or thionaphthene-2-base, it is randomly replaced by one or two substituting group that the preceding paragraph is described.
Even more preferably, Ar 2Be cumarone-2-base, replace, or replaced by two that preferably, cumarone-2-base replaces at 3 or 5 substituting group lists of being described by the preceding paragraph at 4-and 7-position at 3-, 4-or 5-position coverlet.More preferably; substituting group is independently selected from: chlorine; fluorine; trifluoromethyl; methyl; ethyl; methoxyl group; 1-cyclopropyl piperidine-4-base oxygen; 1-(2; 2; the 2-trifluoroethyl) piperidin-4-yl oxygen; N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-methoxy ethoxy methyl; phenoxymethyl; the 2-methoxy ethoxy; 2-morpholine-4-base oxethyl; pyridine-3-methoxyl group; the 2-hydroxyl-oxethyl; 2-N; the N-dimethylamino ethoxy; methoxymethyl; 3-isopropoxy methyl; morpholine-4-ylmethyl; 3-hydroxyl propoxy-methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy-methyl; 3-methoxy propoxy methyl; pyridin-4-yl oxygen methyl; 2; 4; 6-trifluoromethoxy phenoxy ylmethyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy methyl; 4-imidazoles-1-phenoxyl methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl piperidines-1-methyl; 4-methylpiperazine-1-ylmethyl; 3; 3; 3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; the pyridin-3-yl methoxymethyl; tetrahydropyran-4-base oxygen; 2; 2, the 2-trifluoro ethoxy; 2-tetramethyleneimine-1-base oxethyl; piperidin-4-yl oxygen; N-methyl-N-benzylamino-methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl methyl; 3-hydroxypropyl alkylsulfonyl-methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; 2-(3-Trifluoromethoxyphen-l) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 3-(2-carboxy ethyl amino-methyl).
Even more preferably, Ar 2Be cumarone-2-base; it is replaced by following substituting group in the 3-position: N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy methyl; pyridin-4-yl oxygen methyl; 2; 4; 6-trifluoromethoxy phenoxy base-methyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy-methyl; 4-imidazoles-1-phenoxyl-methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; 3-hydroxyl propoxy-methyl; 2-methoxy ethoxy methyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl-piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3,3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; 2-(3-Trifluoromethoxyphen-l ethyl)-; N-methyl-N-benzyl-amino methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl-methyl; 3-hydroxypropyl alkylsulfonyl methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 2-carboxy ethyl amino-methyl.
Even more preferably, Ar 2Be cumarone-2-base, it is replaced by following group in the 5-position: 1-cyclopropyl piperidine-4-base oxygen, piperidin-4-yl oxygen, tetrahydropyran-4-base oxygen, 2,2,2-trifluoro ethoxy, 2-tetramethyleneimine-1-base oxethyl or 1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen.
Even more preferably, Ar 2Be 7-chloro-4-methyl cumarone-2-base, 4-methyl-cumarone-2-base, 7-fluoro-4-methyl cumarone-2-base or 7-fluoro-4-phenoxymethyl cumarone-2-base.
Even more preferably, Ar 2Be thiophene-2-base; pyridin-3-yl; 5-phenyl thiophene-2-base; quinoline-6-base; 4-phenyl thiazole-2-base; benzothiazole-2-base; benzoxazoles-2-base; furans-2-base; 1H-benzimidazolyl-2 radicals-Ji; 1H-pyrroles-2-base; 4-(pyridin-4-yl)-thiazol-2-yl; 1H-indoles-5-base; the 1H-indol-3-yl; quinoline-3-base; quinoline-8-base; 1H-indazole-3-base; 1H-benzotriazole-5-base; isoquinolyl-1; isoquinoline 99.9-3-base; quinoxaline-2-base; quinoline-2-base; 1H-benzoglyoxaline-5-base; 1-methyl-indol-3-yl; 4-MeO-quinoline-2-base; quinolyl-4; 4-hydroxyquinoline-2-base; pyridine-2-base; 3-pyridone-2-base; 6-pyridone-2-base; 6-(4-nitrophenoxy) pyridine-2-base; 4-(2-methoxy ethoxy) quinoline-2-base; 4-(2-dimethylamino ethoxy) quinoline-2-base; 6-bromopyridine-2-base; 5-bromopyridine-3-base; 4-methoxy quinoline-2-base; 5-phenylpyridine-3-base; 6-benzyloxy pyridine-2-base; 6-(2-methyl propoxy-)-pyridine-2-base; 6-(2-phenyl ethoxy) pyridine-2-base; 4-(3; 3,3-trifluoro propoxy-) quinoline-2-base; 5-thiene-3-yl-pyridin-3-yl; 6-(4-acetylamino phenoxy group)-pyridine-2-base; 6-(4-amino-benzene oxygen)-pyridine-2-base; or 5-(4-dimethylaminophenyl) pyridin-3-yl.
Reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III, IV and V, one group of most preferred is that wherein Y is a straight-chain alkyl-sub-, preferred ethylidene or positive propylidene, preferred ethylidene.
Reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III, IV and V, also one group of most preferred is that wherein Y is a branched alkylidene, and is preferred-CH (C 2H 5) CH 2-,-CH (i-C 3H 7) CH 2-or-CH (CH 3) CH 2-, the stereo-formula on chiral carbon is (S).More preferably, Y is-CH (C 2H 5) CH 2-.
Reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III, IV and V, also one group of most preferred is that wherein Y is-CH 2CH (CH 3The stereo-formula of)-, on chiral carbon is (R).
Reach in wherein contained preferred even preferred and particularly preferred group at above-mentioned preferred group of II, III, IV and V, also one group of most preferred is that wherein Y is-CH (CH 2R ') CH 2-or-CH (CH 2CH 2R ') CH 2-; wherein R ' is alkylthio, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces, preferred phenyl, phenoxy group, 4-chloro-phenyl-, cyclohexyl, benzylthio-, benzyl alkylsulfonyl, methylthio group, methyl sulphonyl or hydroxyl.
VI. also one group of preferred formula (I) compound is that wherein X is-O-, R 1And R 3Be hydrogen, Ar 1Be phenylene, Ar 2Be arylalkenyl, Y is a branched alkylidene, and-CONHOH and X are in the 1-and the 4-position of inferior phenyl ring.Preferably, Ar 2Be trans-phenyl-CH=CH-, wherein phenyl is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, alkoxyl group, methylene-dioxy or hydroxyl.
The scope of the term that comprises in above-mentioned group of II-VI is as described in the application's the definitional part.
Be meant with reference to the embodiment preferred that proposes above to comprise all combinations concrete and preferred group, unless otherwise indicated.
General synthetic
The compounds of this invention can make by showing the method for describing in the reaction scheme down.
Be used to prepare the starting material of these compounds and reagent from industrial supplier such as AldrichChemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.) or Sigma (St.Louis, Mo.), or by method known to those skilled in the art according to the preparation of the program that proposes in the reference, described reference is for for example: Fieser and Fieser ' s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd ' s Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March ' sAdvanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock ' sComprehensive Organic Transformations (VCH Publishers Inc., 1989).These schemes only be the explanation some can synthesize the method for The compounds of this invention, can carry out various modifications to these schemes, those skilled in the art can expect these modifications with reference to present disclosure.If desired, can use routine techniques to separate starting material and intermediate with purification reaction, described routine techniques includes but not limited to: filtration, distillation, crystallization, chromatography etc.These materials also use usual manner (comprising physical constant and spectroscopic data) to characterize.
Unless opposite explanation is arranged, described herein be reflected under the normal pressure taken place, and temperature range is-78 ℃ to about 150 ℃ approximately, more preferably from about 0 ℃ to about 125 ℃, and room temperature (or envrionment temperature) most preferably from about, for example about 20 ℃.
Formula (I) compound can be by describing in the following option A and the program preparation of explanation, in formula (I), X is-O-or-S (O) n-, wherein n is 0 to 2, other groups are described in " summary of the invention ".
Option A
Figure A20048000922500951
Reaction production 3 compounds of formula 1 compound and formula 2 amino alcohols, in formula 1, R is an alkyl, X is-O-or-S-, Ar 1Described in " summary of the invention ", in formula 2, PG is suitable amido protecting group.In the presence of triphenyl phosphine and diisopropyl azo-2-carboxylic acid, in appropriate organic solvent such as tetrahydrofuran (THF) etc., react.
Formula 1 compound such as 4-methyl hydroxybenzoate, 4-Thiosalicylic acid methyl esters and 3-hydroxyl isoxzzole-5-carboxylate methyl ester are commercially available.Formula 2 compounds can be made as follows by commercially available amino alcohol: amine and suitable amino protecting group such as benzyloxycarbonyl, tert-butoxycarbonyl etc. are reacted under reaction conditions well known in the art.Suitable amino protecting group and preparation can be referring to T.W.Greene with the detailed description of reaction conditions, Protecting Groups in Organic Synthesis, John Wiley ﹠amp; Sons, Inc.1981, its instruction is incorporated herein by reference in full.Amino alcohol such as 2-thanomin, 2-amino-1-propyl alcohol, 2-methylamino ethanol, 2-amino-2-methyl-1-propanol, 2-amino-1-propyl alcohol, 4-amino-2-butanols and 1-amino-2-butanols have commercially available.Perhaps, formula 2 compounds can be made as follows by commercially available amino acid: amino with suitable protecting group protection, under reaction conditions well known in the art, acidic group is reduced to hydroxyl then with appropriate reductant.As shown in the formula (I) compound, wherein X is-5O if desired 2-, (wherein X is-S-) processing such as available oxidant such as OXONE_, metachloroperbenzoic acid so corresponding formula 3 compounds.
The amino protecting group of removing in the formula 3 can obtain formula 4 compounds.Remove the used reaction conditions of amino protecting group and depend on the character of protecting group.For example, if protecting group is a tert-butoxycarbonyl, it is removed under the acid-reaction condition so.Suitable acid has trifluoroacetic acid, hydrochloric acid etc., and they are in appropriate organic solvent such as methyl alcohol, dioxan, tetrahydrofuran (THF) etc.If protecting group is benzyl or benzyloxycarbonyl, it is removed under the catalytic hydrogenation reaction condition so.Appropriate catalyst is palladium-based catalyst and other catalyzer known in the art.Removing other proper reaction conditions that protecting group uses can be referring to T.W.Greene, Protecting Groups in Organic Synthesis, John Wiley ﹠amp; Sons, Inc.1981.Be reflected in inert organic solvents such as methylene dichloride, tetrahydrofuran (THF), the dioxan etc. and carry out.
Formula 4 and formula Ar 2The acid of-COZ (wherein Z is hydroxyl or halogen) or the reaction of acid derivative (for example acyl halide) obtain formula 5 compounds.In addition, used reaction conditions depends on the character of Z group.If Z is a hydroxyl, reaction is typically carried out in the presence of suitable coupling agent so, described coupling agent for for example benzotriazole-1-base oxygen tripyrrole alkane also-phosphorus phosphofluoric acid ester (PyBOP_), O-benzotriazole-1-base-N, N, N ', N '-tetramethyl--urea phosphofluoric acid ester (HBTU), O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl--urea phosphofluoric acid ester (HATU), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl), or 1, randomly there is I-hydroxybenzotriazole hydrate (HOBTH in 3-dicyclohexylcarbodiimide (DCC) 2O) and alkali such as N, N-diisopropylethylamine, triethylamine, N-methylmorpholine etc.Reaction is typically carried out under 20-30 ℃, preferred about 25 ℃, needs finish in 2-24 hour.Suitable reaction solvent is inert organic solvents such as halogenation organic solvent (for example methylene dichloride, chloroform etc.), acetonitrile, N, dinethylformamide, ether solvent such as tetrahydrofuran (THF), dioxan etc.Preferably, reaction HOBtH 2O, EDCHCl carry out in the dinethylformamide at methylene dichloride or N.
Work as Ar 2When COZ is acyl halide, is reflected under the existence of suitable alkali (for example triethylamine, diisopropylethylamine, pyridine etc.) and carries out.Suitable reaction solvent is polar organic solvent such as tetrahydrofuran (THF), acetonitrile, N, the mixture of dinethylformamide (DMF), methylene dichloride or its any appropriate.Acyl halide such as chloride of acid can make by making reactions such as corresponding acid and halogenating agent such as oxalyl chloride, thionyl chloride, phosphoryl chloride.Formula Ar 2The acid of COZ can be by commercially available acquisition, or they can be made by methods known in the art by commercially available starting material.For example, phenylformic acid, styracin, toluylic acid, nicotinic acid, Yi Yansuan, 3-methyl cumarone-2-carboxylic acid and cumarone-2-carboxylic acid have commercially available.Other acid can easily be made by commercially available 3-methyl cumarone-2-carboxylic acid as follows as 3-phenoxymethyl cumarone-2-carboxylic acid: at first it is converted into 2-brooethyl cumarone-2-carboxylic acid (usefulness N-bromine succinimide under condition well known in the art bromination it), makes itself and phenol reactant then.Compound 5 (R wherein 3Be hydrogen) can randomly be converted into corresponding formula 5 compounds (R wherein 3Be not hydrogen): compound 5 and alkylating agent are reacted under condition well known in the art.
By the following method compound 5 is converted into formula (I) compound then: itself and aqueous hydroxylamine are reacted in the presence of alkali such as sodium hydroxide and organic solvent such as tetrahydrofuran (THF) and methanol mixture.Perhaps, acidic group in the compound 5 is at first used suitable coupling agents such as 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCHCl) or 1, randomly there is I-hydroxybenzotriazole hydrate (HOBTH in the activation of 3-and carbodicyclo hexylimide (DCC) 2O), in appropriate organic solvent such as dimethyl formamide etc., carry out above-mentioned activation, then with hydroxylamine hydrochloride at alkali such as N, the existence of N-diisopropylethylamine, triethylamine, N-methylmorpholine etc. is reaction down.Formula (I) compound can also be by compound 5 according to United States Patent (USP) 5,998, the preparation of 412 disclosed methods, and the disclosure of the document is incorporated herein by reference in full.
Formula (I) compound can be converted into other formulas (I) compound then.For example, formula (I) compound (Ar wherein 1Be phenylene, X is-O-that Y is an ethylidene, Ar 2Be 3-dimethylaminomethyl cumarone-2-base, R 1And R 3Be hydrogen) can make by the following method: make formula 4 compounds (Ar wherein 1Be phenylene, X is-O-, and Y is an ethylidene, and R is an alkyl) with 3-methyl cumarone-2-carboxylic acid by reaction as mentioned above, obtain formula 5 compounds (Ar wherein 2Be 3-methyl cumarone-2-yl).Come Diethylaminoethyl with suitable bromizating agent such as N-bromine succinimide, with the dimethylamine reaction, can obtain corresponding 3-dimethylamino cumarone-2-based compound then, under above-mentioned reaction conditions, be translated into required compound then.
Purposes
The compounds of this invention is the inhibitor of histone deacetylase; therefore can be used for treating proliferative disease such as cancer; lung cancer for example; colorectal carcinoma; AML; MML; skin carcinoma; mammary cancer; ovarian cancer; prostate cancer; liver cancer; brain and skin carcinoma; psoriatic; fibroproliferative disease such as liver fibrosis; the proliferation of smooth muscle disease is as atherosclerosis and restenosis; inflammation such as sacroiliitis relate to the disorders such as cancers of vasculogenesis; diabetic retinopathy; hematopoietic disorders such as anemia; fungi infestation; parasitic infection and infectation of bacteria; virus infection; autoimmune disease such as sacroiliitis; multiple sclerosis; lupus; transformation reactions; asthma; rhinallergosis and organ transplantation; and bipolar disorder.In addition, The compounds of this invention can be used for treating hepatitis C infection.
Test
Test in measuring in the external and body that the ability of The compounds of this invention inhibition of histone deacetylase is described in can biological assay embodiment 1 and 2 below.The hcv activity of The compounds of this invention is test in the hcv of Georgetown University replicon is measured.Also can utilize Korner, V.L.et al., Science 1999 Jul 2:285 (5424): the replicon of describing among the 110-3 measures the hcv activity of test compounds.
Administration and pharmaceutical composition
Usually, can accept administering mode arbitrarily, use The compounds of this invention with the treatment significant quantity by what the medicament of performance similar effect was used.The actual amount of The compounds of this invention, promptly activeconstituents will depend on many factors, as the usefulness of severity of disease to be treated, patient's age and relative healthy state, compound used therefor, approach and mode and other factors of administration.
The treatment significant quantity scope of formula (I) compound is about 0.1-50mg/kg receptor's body weight/day, preferably about 0.5-20mg/kg/ days.Therefore, for 70kg people's administration, dosage range most preferably is about 35mg/ days to 1.4g/ days.
Usually, The compounds of this invention is applied by in the following approach any one as pharmaceutical composition: oral, whole body (for example in skin, nose or suppository) or parenteral (for example intramuscular, intravenously or subcutaneous) administration.Preferred administering mode is oral or parenteral, dosage regimen every day easy to use, and this can adjust according to ill degree.Oral compositions can adopt tablet, pill, capsule, semisolid, powder, slow release formulation, solution, suspension, elixir, aerosol or other suitable composition forms arbitrarily.
Various factors such as administering mode (for example, for oral, the formulation of preferred tablet, pill or capsule form) and bioavailability of medicament are depended in the selection of formulation.Recently, based on following principle: can promptly reduce granularity and increase bioavailability by increasing surface-area, develop especially pharmaceutical dosage form at medicine with poor bioavailability.For example, U.S. Patent number 4,107,288 size ranges of having described a kind of pharmaceutical dosage form are 10 to 1,000nm, wherein active substance is loaded on the macromolecular crosslinked matrix.U.S. Patent number 5,145,684 have described a kind of preparation of pharmaceutical preparation, wherein in the presence of surface-modifying agent, medicine is pulverized to nanoparticle (mean particle size is 400nm), is dispersed in the liquid medium then, obtain pharmaceutical preparation, it has very high bioavailability.
Composition is made up of in conjunction with at least a pharmaceutically acceptable vehicle formula (I) compound usually.Pharmaceutically acceptable vehicle is nontoxic, helps administration, can influence the result of treatment of formula (I) compound sharply.This vehicle can be solid, liquid, semisolid arbitrarily, or for aerosol combination, the gaseous state vehicle is obtainable to those skilled in the art usually.
The solid pharmaceutical vehicle comprises: starch, Mierocrystalline cellulose, talcum, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, chalk, silica gel, Magnesium Stearate, sodium stearate, Zerol, sodium-chlor, skim-milk etc.Liquid and semisolid excipient can be selected from: glycerine, propylene glycol, water, ethanol and various oil comprise those oil from oil, animal, plant or synthetic source, for example peanut oil, soya-bean oil, mineral oil, sesame wet goods.Preferred liquid vehicle especially for Injectable solution, comprises water, salt solution, D/W and glycol.
Pressurized gas can be used for disperseing The compounds of this invention with aerosol form.The rare gas element that is applicable to this purpose has nitrogen, carbonic acid gas etc.
Other suitable drug excipients and their formulation are described in Remington ' sPharmaceutical Sciences, edited by E.W.Martin (Mack Publishing Company, 18 ThEd., 1990).
The amount of compound can change in the used gamut of those skilled in the art in the formulation.Typically, formulation comprises formula (I) compound of about 0.01-99.99wt% based on the weight percentage (wt%) of total formulation, and surplus is one or more suitable drug excipients.Preferably, the content of compound is about 1-80wt%.The representative drugs formulation that contains formula (I) compound is described hereinafter.
As previously mentioned, The compounds of this invention can be used in conjunction with known anticarcinogen.These known anticarcinogens comprise as follows: estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent, antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors, dnmt rna inhibitor and other angiogenesis inhibitors.The compounds of this invention is useful especially when the associating radiotherapy carries out administration.Preferred angiogenesis inhibitor is selected from: tyrosine kinase inhibitor; the inhibitor of epidermis derivative growth factor; the inhibitor of inoblast derivative growth factor; the inhibitor of Thr6 PDGF BB; MMP (matrix metalloproteinase) inhibitor; the integrin blocking agent; interferon-' alpha '; il-1 2; the piperylene polyethoxy sulfate; cyclooxygenase-2 inhibitors; carboxyl amido triazole; combretastatin A-4; squalamine; 6-O-chloracetyl-carbonyl-aspergillus fumigatus cedrol (fumagillol); Thalidomide; angiostatin; troponin-1; antibody with VEGF.
Preferred estrogenic agents is tamoxifen and raloxifene.
" estrogenic agents " is meant the compound that can disturb or suppress oestrogenic hormon and receptors bind, do not consider its mechanism.The example of estrogenic agents includes but not limited to: tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(piperidino) oxyethyl group] phenyl]-2H-1-chromene-3-yl)-phenyl-2,2-dimethyl propylene acid esters, 4,4 '-dihydroxy benaophenonel-2,4-dinitrophenyl-hydrazone and SH646.
" androgen receptor modifier " is meant the compound that can disturb or suppress male sex hormone and receptors bind, do not consider its mechanism.The example of androgen receptor modifier comprises: finasteride and other 5 inhibitor, Nilutamide, flutamide, bicalutamide, liarozole and Abiraterone acetate.
" retinoid receptor conditioning agent " is meant the compound that can disturb or suppress retinoids and receptors bind, do not consider its mechanism.The example of these retinoid receptor conditioning agents comprises: bexarotene, vitamin A acid, 13-cis-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, ILX23-7553, trans-N-(4 '-hydroxy phenyl) look yellow acid amides (retinamide) and the N-4-carboxyl phenyl is looked yellow acid amides.
" cytotoxic agent " is meant main compound by direct interference cell function or inhibition or interference cell division causing necrocytosis, comprises alkylating agent, tumour necrosis factor, intercalating agent, Antitubulin and topoisomerase enzyme inhibitor.
The example of cytotoxic agent includes but not limited to: Win-59075; sertenef; cachet; ifosfamide; tasonermin; lonidamine; carboplatin; altretamine; prednimustine; mitolactol; ranomustine; fotemustine; S 254; oxaliplatin; Temozolomide; platinum in heptan (heptaplatin); estramustine; the improsulfan tosilate; trofosfamide; nimustine; dibrospidium chloride; pumitepa; Lip river platinum; husky platinum; profiromycin; cis-platinum; irofulven; right ifosfamide (dexifosfamide); cis-amine dichloro (2-methyl-pyridine) platinum; the benzyl guanine; glufosfamide; GPX100; (trans; trans; trans)-two-mu-(hexane-1; the 6-diamines)-and mu-[diamines-platinum (II)] two [diamines (chlorine) platinum (II)]-tetrachlorides; two '-aziridinos (diarizidinyl) spermine; ARSENIC TRI OXIDE 98; 1-(11-dodecyl amino-10-hydroxyl undecyl)-3, the 7-dimethyl xanthine; zorubicin; idarubicin; daunorubicin; bisantrene; mitoxantrone; pirarubicin; pinafide; valrubicin; amrubicin; antineoplaston; 3 '-deaminizating-3 '-morpholino-13-deoxidation generation-10-hydroxyl carminomycin; liposome anthracycline (annamycin); galarubicin; the Nai Fade of Erie; MEN 10755; with 4-demethoxylation-3-deaminizating-3-'-aziridino-4-methyl sulphonyl-daunorubicin (referring to WO 00/50032).
The example of Antitubulin comprises: taxol, vindesine sulfate, 3 ', 4 '-two dehydrogenations-4 '-deoxidation-8 '-NVB (norvincaleukoblastine), docetaxel (docetaxol), root enzyme element, dolastatin, the mivobulin isethionate, auristatin, Cemadotin, RPR109881, BMS184476, Vinflunine, cryptophycin, 2,3,4,5,6-five fluoro-N-(3-fluoro-4-p-methoxy-phenyl) benzsulfamide, anhydrous vinealeucoblastine(VLB), N, N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-propyl group-L-proline(Pro)-tert-butylamides, TDX258, with BMS 188797.
Some examples of topoisomerase enzyme inhibitor are: Hycamtin; hycaptamine; irinotecan; rubitecan; 6-ethoxy-c acyl group-3 '; 4 '-O-is outer-benzylidene-chartreusin; 9-methoxyl group-N; N-dimethyl-5-nitro-pyrrole also [3; 4; 5-kl] acridine-2-(6H) propylamine; 1-amino-9-ethyl-5-fluoro-2; 3-dihydro-9-hydroxy-4-methyl-1H; 12H-benzo [de] pyrans also [3 '; 4 ': b; 7]-indolizino [1; 2b] quinoline-10; 13 (9H; 15H) diketone; lurtotecan (lurtotecan); 7-[2-(N-sec.-propyl amino)-ethyl]-(20S) camptothecine; BNP1350; BNPI1100; BN80915; BN80942; Etoposide phosphoric acid salt; teniposide; sobuzoxane; 2 '-dimethylamino-2 '-deoxidation-Etoposide; GL331; N-[2-(dimethylamino) ethyl]-9-hydroxyl-5; 6-dimethyl-6H-pyrido [4; 3-b] carbazole-1-carboxylic acid amides; asulacrine; (5a; 5aB; 8aa; 9b)-9-[2-[N-[2-(dimethylamino) ethyl]-the N-methylamino] ethyl]-5-[4-hydroxyl-3; the 5-Dimethoxyphenyl]-5; 5a; 6; 8; 8a; 9-six hydrogen furans (hexohydrofuro) (3 '; 4 ': 6; 7) colchic (2; 3-d)-1; 3-dioxole (dioxol)-6-ketone; 2; 3-(methylene-dioxy)-5-methyl-7-hydroxyl-8-methoxyl group benzo [c]-phenanthridines (phenanthridinium); 6; the two different guinoline-5 of [(2-amino-ethyl)-amino] benzo [g] of 9-; the 10-diketone; 5-(3-amino propyl amino)-7; 10-dihydroxyl-2-(2-hydroxyethyl amino methyl)-6H-pyrazolo [4; 5; 1-de] acridine-6-ketone; N-[1-[2-(diethylamino) ethylamino]-7-methoxyl group-9-oxo-9H-thioxanthene-4-ylmethyl] methane amide; N-(2-(dimethylamino) ethyl) acridine-4-carboxylic acid amides; 6-[[2-(dimethylamino) ethyl] amino]-3-hydroxyl-7H-indeno [2,1-c] quinoline-7-ketone; and dimesna.
" antiproliferative " comprising: sense-rna and DNA oligonucleotide; as G3139; ODN698; RVASKRAS; GEM231 and INX3001; with metabolic antagonist such as enocitabine; carmofur; for the first fluorine; pentostatin; doxifluridine; trimetrexate; fludarabine; capecitabine; Galocitabine; arabinosylcytosine; the fosteabine sodium hydrate; Raltitrexed; paltitrexid; emitefur; tiazofurine; the Ta Xita shore; Nolatrexed; pemetrexed; nelzarabine; 2 '-deoxidation-2 '-the methyne cytidine; 2 '-fluorine methylene radical-2 '-Deoxyribose cytidine; N-[5-(2; 3-dihydro-benzofuryl) alkylsulfonyl]-N '-(3; the 4-dichlorophenyl) urea; N6-[4-deoxidation-4-[N2-[2 (E); 4 (E)-tetradecanes, two enoyl-s] glycyl amino]-L-glyceryl-B-L-sweet dew base (manno)-pyrans glycosyl in heptan (heptopyranosyl)]-VITAMIN B4; aplidine; ecteinascidin (ecteinascidin); troxacitabine; 4-[2-amino-4-oxo-4; 6; 7; 8-tetrahydrochysene-3H-Mi Dingbing [5; 4-b] [1; 4] thiazine-6-base-(S)-ethyl]-2; 5-thiophene acyl group (thienoyl)-L-L-glutamic acid; aminopterin; 5-fluor-uracil; alanosin; 11-ethanoyl-8-(carbamoyloxy group methyl)-4-formyl radical-6-methoxyl group-14-oxa--1; 11-diaza Fourth Ring (7.4.1.0.0)-14-2; 4,6-triolefin-9-yl acetate; Tridolgosir; lometrexol; dexrazoxane; methioninase; 2 '-cyano group-2 '-'-deoxy-n 4-palmityl-1-B-D-arabinofuranosyl adenin cytosine(Cyt); with 3-aminopyridine-2-formaldehyde thiosemicarbazone." antiproliferative " also comprises: the monoclonal antibody of somatomedin, except those materials of listing of " angiogenesis inhibitor " part, as trastuzumab and tumor suppressor gene, as p53, they can be sent (for example referring to U.S. Patent number 6 by the transgenosis of recombinant virus mediation, 069,134).
" HMG-CoA reductase inhibitor " is meant the inhibitor of 3-hydroxy-3-methyl glutaryl-CoA reductase enzyme.Compound with HMG-CoA reductase active can easily be identified by measuring method well known in the art.For example, referring to U.S. Patent number 4,231, the measuring method that 938 the 6th hurdle and the 30-33 page or leaf of WO84/02131 are described or quoted.Term " HMG-CoA reductase inhibitor " has identical implication with " inhibitor of HMG-CoA reductase enzyme " when being used for this paper.It is reported (Int.J.Cancer, 20; 97 (6): 746-50,2002), in the Lewis lung cancer model of mouse, with the combination therapy demonstration enhanced antitumous effect of lovastatin (a kind of HMG-CoA reductase inhibitor) and butyric ester (a kind of inducer of apoptosis).
The example of spendable HMG-CoA reductase inhibitor includes but not limited to: lovastatin (MEVACOR_; Referring to U.S. Patent number 4,231,938; 4,294,926; 4,319,039), Simvastatin (ZOCOR_; Referring to U.S. Patent number 4,444,784; 4,820,850; 4,916,239), Pravastatin (PRAVACHOL_; Referring to U.S. Patent number 4,346,227; 4,537,859; 4,410,629; 5,030,447 and 5,180,589), fluvastatin (LESCOL_; Referring to U.S. Patent number 5,354,772; 4,911,165; 4,929,437; 5,189,164; 5,118,853; 5,290,946; 5,356,896), atorvastatin (LIPITOR_; Referring to U.S. Patent number 5,273,995; 4,681,893; 5,489,691; 5,342,952) and Cerivastatin (be also referred to as thunder and cut down his spit of fland (rivastatin) and BAYCHOL_; Referring to U.S. Patent number 5,177,080).The structural formula that can be used for these and the additional HMG-CoA reductase inhibitor of present method is described in M.Yalpani, " Cholesterol Lowering Drugs ", Chemistry ﹠amp; Among the Industry, the 87th page of pp.85-89 (Feb.5,1996) and U.S. Patent number 4,782,084 and 4,885,314.Term used herein " HMG-CoA reductase inhibitor " comprises all pharmaceutically useful lactones and open acid (open-acid) form (promptly, wherein lactonic ring can split to form free acid) and salt and ester-formin with compound of HMG-CoA reductase active, and colchicine, the purposes of these salt, ester, open acid and lactone form is also included within the scope of the present invention.
In the HMG-CoA reductase inhibitor that the open acid form can exist, preferably form salt and ester-formin by open acid, all these forms all is included in the implication of term used herein " HMG-CoA reductase inhibitor ".Preferably, the HMG-CoA reductase inhibitor is selected from: lovastatin and Simvastatin, most preferably Simvastatin.
Herein, be meant the non-toxic salts of compound used therefor of the present invention about the term " pharmacologically acceptable salt " of HMG-CoA reductase inhibitor, it is usually by making free acid and suitable organic or inorganic alkali reaction, especially those are by positively charged ion such as sodium, potassium, aluminium, calcium, lithium, magnesium, those salt that zinc and tetramethyl-ammonium make, and those are by amine such as ammonia, quadrol, the N-methylglucosamine, Methionin, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamin, chloroprocaine, diethanolamine, PROCAINE HCL, PHARMA GRADE, the N-benzyl-1-phenylethylamine, 1-p-chlorobenzyl-2-tetramethyleneimine-1 '-Ji-tolimidazole, diethylamine, piperazine, the salt that makes with three (methylol) aminomethane.Other examples of the salt form of HMG-CoA reductase inhibitor can include but not limited to: acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, calcium hydroxide, camsilate, carbonate, muriate, Clavulanate, Citrate trianion, dihydrochloride, hydroxyl, ethanedisulphonate, estolate, esilate, fumarate, gluceptate, gluconate, glutaminate, bismuth glycolyl arsanilate salt, Sucrets salt (hexylresorcinate), Hai Baming, hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, different thiosulphate, lactic acid salt, Lactobionate, lauroleate, malate, maleate, mandelate, mesylate, Methylsulfate, mucate (mucate), naphthalenesulfonate, nitrate, oleate, oxalate, pamaote, palmitate, pantothenate, phosphoric acid salt/diphosphate, Polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, the teoclate, tosylate, triethiodide (triethiodide), and valerate.
The ester derivative of described HMG-CoA reductase inhibiter compounds can be used as prodrug, when it is absorbed in the blood flow of warm-blooded animal, can split as follows to discharge medicament forms, makes medicine that the result of treatment of improvement is provided.
" prenyl-protein transferase inhibitor " but be the compound of any one or its arbitrary combination in inhibition of isoprenyl base-protein transferase, described enzyme comprises farnesyl-protein transferase (FPTase), geranyl geranyl-protein transferase I type (GGPTase-I) and geranyl geranyl-protein transferase II type (GGPTase-II is also referred to as Rab GGPTase).The example that prenyl-protein transferase suppresses compound comprises: (±)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; (-)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; (+)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; 5 (S)-normal-butyl-1-(2; the 3-3,5-dimethylphenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone; (S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl)-methyl]-2-piperazine ketone; 5 (S)-normal-butyl-1-(2-aminomethyl phenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone; 1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-2-methyl-5-imidazolyl methyl]-2-piperazine ketone; 1-(2; the 2-diphenyl-ethyl)-and 3-[N-(1-(4-cyano group benzyl)-1H-imidazoles-5-base ethyl) carbamyl] piperidines; 4-{5-[4-hydroxymethyl-4-(4-chloropyridine-2-ylmethyl)-piperidines-1-ylmethyl]-glyoxal ethyline-1-ylmethyl } benzonitrile; 4-{5-[4-hydroxymethyl-4-(3-benzyl chloride base)-piperidines-1-ylmethyl]-glyoxal ethyline-1-ylmethyl } benzonitrile; 4-{3-[4-(2-oxo-2H-pyridine-1-yl) benzyl]-3H-imidazol-4 yl methyl } benzonitrile; 4-{3-[4-(5-chloro-2-oxo-2H[1; 2 '] dipyridyl-5 '-ylmethyl)-3H-imidazol-4 yl methyl] benzonitrile; 4-{3-[4-(2-oxo-2H-[1; 2 '] dipyridyl-5 '-ylmethyl)-3H-imidazol-4 yl methyl] benzonitrile; 4-[3-(2-oxo-1-phenyl-1; 2-dihydropyridine-4-ylmethyl)-and 3H-imidazol-4 yl methyl] benzonitrile; 18; 19-dihydro-19-oxo-5H; 17H-6; 10:12; 16-two endo-methylene groups (dimetheno)-1H-imidazo [4; 3-c] [1; 11; 4] two oxa-s-nitrogen heterocyclic 19 carbenes (nonadecine)-9-nitrile; (±)-19; 20-dihydro-19-oxo-5H-18; 21-ethano--12; 14-vinylidene-6; 10-endo-methylene group-22H-benzo [d] imidazo [4; 3-k] [1; 6; 9; 12]-oxa-three azepines-ring vaccenic acid (octadecine)-9-nitrile; 19; 20-dihydro-19-oxo-5H; 17H-18; 21-ethano--6; 10:12; 16-two endo-methylene groups-22H-imidazo [3; 4-h] [1; 8; 11; 14] oxa-three nitrogen heterocyclics-eicosylene (eicosine)-9-nitrile; (±)-19; 20-dihydro-3-methyl isophthalic acid 9-oxo-5H-18; 21-ethano--12; 14-ethano--6; 10-endo-methylene group-22H-benzo [d] imidazo [4; 3-k] [1; 6; 9,12] oxa--three nitrogen heterocyclic vaccenic acid-9-nitrile.
Other example of prenyl-protein transferase inhibitor is referring to following publication and patent: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patent number 5,420,245,5,523,430,5,532,359,5,510,510,5,589,485,5,602,098, European Patent Publication No 0618221, European Patent Publication No 0675112, European Patent Publication No 0604181, European Patent Publication No 0696593, WO 94/19357, WO 95/08542, WO95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Patent number 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Patent number 5,571,792, WO96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, with U.S. Patent number 5,532,359.For prenyl-protein transferase inhibitor to the example of the effect of vasculogenesis referring to J.OfCancer, Vol.35, No.9, pp.1394-1401 (1999).
The example of hiv protease inhibitor comprises: amprenavir, Abacavir, CGP-73547, CGP-61755, DMP-450, Indinavir, viracept see nelfinaivr, tipranavir, ritonavir, Saquinavir, ABT-378, AG 1776 and BMS-232,632.The example of reverse transcriptase inhibitors comprises: Delavirdine, efavirenz, GS-840, HBY097, lamivudine, nevirapine, AZT, 3TC, ddC and ddI.It is reported (Nat.Med.; 8 (3): 225-32,2002), hiv protease inhibitor such as Indinavir or Saquinavir have effective anti-angiogenesis activity and promote disappearing of Kaposi sarcoma (Kaposi Sarcoma).
" angiogenesis inhibitor " is meant the compound that can suppress neovascularization, do not consider its mechanism.The example of angiogenesis inhibitor includes but not limited to: tyrosine kinase inhibitor, inhibitor as tyrosine kinase receptor Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR20), the epidermis deutero-, the inhibitor of inoblast deutero-or platelet-derived somatomedin, MMP (matrix metalloproteinase) inhibitor, integrin inhibitor, interferon-' alpha ', il-1 2, the piperylene polyethoxy sulfate, cyclooxygenase-2 inhibitors, comprise that nonsteroidal anti-inflammatory agent (NSAID) is as acetylsalicylic acid and Ibuprofen BP/EP, and selective cyclooxygenase-2 inhibitor, as celecoxib, Wei Leikao former times (valecoxib) and rofecoxib (PNAS, Vol.89, p.7384 (1992); JNCl, Vol.69, p.475 (1982); Arch.Opthalmol., Vol.108, p.573 (1990); Anat.Rec., Vol.238, p.68 (1994); FEBSLetters, Vol.372, p.83 (1995); Clin., Orthop.Vol.313, p.76 (1995); J.Mol.Endocrinol., Vol.16, p.107 (1996); Jpn.J.Pharmacol., Vol.75, p.105 (1997); Cancer Res., Vol.57, p.1625 (1997); Cell, Vol.93, p.705 (1998); Intl.J.Mol.Med., Vol.2, p.715 (1998); J.Biol.Chem., Vol.274, p.9116 (1999)), carboxyl amido triazole, combretastatin A-4, squalamine, 6-O-chloracetyl-carbonyl-aspergillus fumigatus cedrol, Thalidomide, angiostatin, troponin-1, Angiotensin II antagonist are (referring to Fernandez etal., J.Lab.Clin.Med.105:141-145 (1985)) and the antibody of VEGF (referring to NatureBiotechnology, Vol.17, pp.963-968 (October 1999); Kim et al., Nature, 362,841-844 (1993); WO 00/44777; With WO 00/61186).
As mentioned above, relate to the combination of NSAID and to use NSAID, they are effective cox 2 inhibitors.For the purpose of this specification sheets, if measure according to cell known in the art or microsome measuring method, the NSAID of gained suppresses the IC of COX-2 50Be 1 μ M or littler, this NSAID is effective so.
The present invention also comprises and combination as the NSAID of selective COX-2-2 inhibitor.For the purpose of this specification sheets, be meant that as the NSAID of COX-2 selective depressant those have the specific material that suppresses COX-2 for COX-1, described specificity is by the IC of COX-2 50The IC of relative COX-1 50Ratio measure, this ratio is at least 100 times, IC 50Assess by following public cell or microsome measuring method.This compound includes but not limited to those disclosed materials in following document: U.S. Patent number 5,474,995, invest December 12 nineteen ninety-five; U.S. Patent number 5,861,419 is invested on January 19th, 1999; U.S. Patent number 6,001,843 is invested on December 14th, 1999; U.S. Patent number 6,020,343 is invested on February 1st, 2000; U.S. Patent number 5,409,944 is invested April 25 nineteen ninety-five; U.S. Patent number 5,436,265 is invested July 25 nineteen ninety-five; U.S. Patent number 5,536,752 is invested on July 16th, 1996; U.S. Patent number 5,550,142 is invested on August 27th, 1996; U.S. Patent number 5,604,260 is invested on February 18th, 1997; U.S. Patent number 5,698,584 is invested on December 16th, 1997; U.S. Patent number 5,710,140 is invested on January 20th, 1998; WO 94/15932, is disclosed on July 21st, 1994; U.S. Patent number 5,344,991 is invested on June 6th, 1994; U.S. Patent number 5,134,142 is invested on July 28th, 1992; U.S. Patent number 5,380,738 is invested January 10 nineteen ninety-five; U.S. Patent number 5,393,790 is invested February 20 nineteen ninety-five; U.S. Patent number 5,466,823 is awarded 1114 days nineteen ninety-fives; U.S. Patent number 5,633,272 is invested on May 27th, 1997; With U.S. Patent number 5,932,598, invest on August 3rd, 1999, all these documents all are introduced into this paper for your guidance.Other examples of the concrete inhibitor of COX-2 comprise those at United States Patent (USP) 6,313, disclosed material in 138, and the disclosure of the document is incorporated herein by reference in full.
General and the concrete synthetic method for preparing above-mentioned cox 2 inhibitor compound is invested December 12 nineteen ninety-five referring to U.S. Patent number 5,474,995; U.S. Patent number 5,861,419 is invested on January 19th, 1999; With U.S. Patent number 6,001,843, invest on December 14th, 1999, all these documents all are introduced into this paper for your guidance.
Be described as the concrete inhibitor of COX-2 and therefore can be used for compound of the present invention including but not limited to following:
Or its pharmacologically acceptable salt.
Therefore be described as the concrete inhibitor of COX-2 and can be used for compound of the present invention and synthetic method can be referring to following patent, pending application and publication, they are introduced into this paper for your guidance: WO 94/15932, is disclosed on July 21st, 1994; U.S. Patent number 5,344,991 is invested on June 6th, 1994; U.S. Patent number 5,134,142 is invested on July 28th, 1992; U.S. Patent number 5,380,738 is invested January 10 nineteen ninety-five; U.S. Patent number 5,393,790 is invested February 20 nineteen ninety-five; U.S. Patent number 5,466,823 is invested November 14 nineteen ninety-five; U.S. Patent number 5,633,272 is invested on May 27th, 1997; With U.S. Patent number 5,932,598, invest on August 3rd, 1999.
As the concrete inhibitor of COX-2 and therefore can be used for compound of the present invention and synthetic method can be referring to following patent, pending application and publication, they are introduced into this paper for your guidance: U.S. Patent number 5,474,995, invest December 12 nineteen ninety-five; U.S. Patent number 5,861,419 is invested on January 19th, 1999; U.S. Patent number 6,001,843 is invested on December 14th, 1999; U.S. Patent number 6,020,343 is invested on February 1st, 2000; U.S. Patent number 5,409,944 is invested April 25 nineteen ninety-five; U.S. Patent number 5,436,265 is invested July 25 nineteen ninety-five; U.S. Patent number 5,536,752 is invested on July 16th, 1996; U.S. Patent number 5,550,142 is invested on August 27th, 1996; U.S. Patent number 5,604,260 is invested on February 18th, 1997; U.S. Patent number 5,698,584 is invested on December 16th, 1997; With U.S. Patent number 5,710,140, invest on January 20th, 1998.
Other examples of angiogenesis inhibitor include but not limited to: endostatin; ukrain; ranpirnase; IM862; 5-methoxyl group-4-[2-methyl-3-(3-methyl-2-butene base) Oxyranyle (oxiranyl)]-1-oxaspiro (oxaspiro) [2; 5] suffering-6-base (chloracetyl) carbamate; ethanoyl dinanaline; 5-amino-1-[[3; 5-two chloro-4-(4-chlorobenzoyl) phenyl]-methyl]-1H-1; 2; 3-triazole-4-carboxylic acid amides; CM101; squalamine; combretastatin; RPI4610; NX31838; sulfation sweet dew pentose phosphate; 7; 7-(carbonyl-two [imino--N-methyl-4; 2-pyrrolylcarbonyl-imino-[N-methyl-4; 2-pyrroles]-the carbonyl imino-]-two-(1; the 3-napadisilate); and 3-[(2,4-dimethyl pyrrole-5-yl) methylene radical]-the full ketone (SU5416) of 2-indoline.
Use as top, " integrin inhibitor " is meant alternative antagonism, inhibition or hinders physiology part and α vβ 3The bonded compound of integrin, alternative antagonism, inhibition or obstruction physiology part and α vβ 5But the bonded compound antagonism of integrin, inhibition or obstruction physiology part and α vβ 3Integrin and α vβ 5But the active compound of the specific integrin that both bonded compounds of integrin and antagonism, inhibition or obstruction are expressed on capillary endothelial cell.This term also refers to the antagonistic of following integrin: α vβ 6, α vβ 8, α 1β 1, α 2β 1, α 5β 1, α 6 β 1 and α 6β 4Integrin.This term also refers to the antagonistic of the arbitrary combination of following integrin: α vβ 3, α vβ 5, α vβ 6, α vβ 8, α 1β 1, α 2β 1, α 5β 1, α 6β 1, and α 6β 4Integrin.
Some object lessons of tyrosine kinase inhibitor comprise: N-(trifluoromethyl)-5-methyl isoxzzole-4-carboxylic acid amides, 3-[(2,4-dimethyl pyrrole-5-yl) methyne] Indolin-2-one, 17-(allyl amino)-17-demethoxylation geldanamycin, 4-(3-chloro-4-fluorophenyl amino)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline, N-(3-ethynyl phenyl)-6, two (2-the methoxy ethoxy)-4-quinazoline amine of 7-, BIBX1382,2,3,9,10,11,12-six hydrogen-10-(hydroxymethyl)-10-hydroxyl-9-methyl-9,12-epoxy-1H-diindyl also [1,2,3-fg:3 ', 2 ', 1 '-k1] pyrrolo-[3,4-i] [1,6] benzodiazepine Fang Xin-1-ketone, SH268, genistein, ST1571, CEP2563,4-(3-chloro-phenyl-amino)-5,6-dimethyl-7H-pyrrolo-[2,3-d] the pyrimidine methane sulfonate, 4-(3-bromo-4-hydroxy phenyl) amino-6, the 7-dimethoxyquinazoline, 4-(4 '-hydroxy phenyl) amino-6, the 7-dimethoxyquinazoline, SU6668, SU11248, STI571A, N-4-chloro-phenyl--4-(4-pyridylmethyl)-1-phthalazines amine, and EMD121974.
This compound also can use separately or be used in combination with thrombocyte fibrin original receptor (GP lib/IIIa) antagonist such as Tirofiban, with the transfer of anticancer.Tumour cell can activate thrombocyte in a large number by the generation of zymoplasm.This activation is relevant with the release of VEGF.The release of VEGF is by strengthening transfer (Amirkhosravi, Platelets 10,285-292,1999) increasing to exosmose with blood vessel endothelium bounding point place.Therefore, this compound can be used for suppressing to shift individually or with the combination of GP lib/IIIa antagonist.The example of other fibrinogen receptor antagonists comprises: ReoPro, eptifibatide, SIBRAFIBAN, Lamifiban, lotrafiban, cromofiban and CT50352.
" dnmt rna inhibitor " is meant following compound, and it suppresses methylating of the DNA phonetic heavy stone used as an anchor of base born of the same parents by dnmt rna in the C-5 position of this base.The example of this dnmt rna inhibitor comprises United States Patent (USP) 6,329,412 and 6,268,137 disclosed compounds.Concrete dnmt rna inhibitor comprises 5-azepine cytosine(Cyt) and zebularine_.
If be formulated as fixed dosage, this combination product is used compound of the present invention in above-mentioned dosage range, and uses other forms of pharmacologically active agents with the dosage range of approval.Perhaps, when combination formula was improper, compound of the present invention can use in order with known pharmaceutically acceptable medicament.
Term " administration " and variant (for example, " using " compound) thereof about The compounds of this invention are meant, compound or its prodrug are incorporated in the animal system that needs treatment.When The compounds of this invention or its prodrug with one or more promoting agents (for example cytotoxic agent etc.) when providing, " administration " and variant thereof are interpreted as to comprise and introduce compound or its prodrug and other medicaments simultaneously and sequentially respectively.
Term used herein " composition " is intended to comprise the product of the appointment composition that contains specified amount and any directly or indirectly from the product of the combination of the appointment composition of specified amount.
Compound of the present invention also can be used jointly with other known therapeutical agents, and described therapeutical agent is because it is to by sanatory specific end use and selected.For example, compound of the present invention also can be used jointly with other known cancer therapeutical agents, and described therapeutical agent is because it is to by sanatory specific end use and selected.Being included in has United States Patent (USP) 6,313, a combination of 138 disclosed inhibition of farnesyl protein transferase and antitumour drug in the combination of this therapeutical agent.Should also be understood that this combination of antitumour drug and inhibition of farnesyl protein transferase can unite the method for other treatment cancer and/or tumour (comprising radiotherapy and surgical operation) and use together.
The example of antitumour drug generally includes microtubule and stablizes medicine (as taxol (being also referred to as Taxol_), docetaxel (being also referred to as Taxotere_, esperamicin (epothilone) A, epothilone B, Epothilone C A, Epothilone C B or their derivative); The microtubule medicine that breaks; Alkylating agent; Antimetabolite; Epidophyllotoxin; Antitumor enzyme; Topoisomerase enzyme inhibitor; Procarbazine; Mitoxantrone; Platinum coordination complex; Biological response modifier and growth inhibitor; Hormone/hormone antagonist therapeutical agent and hemopoieticgrowth factor.
The example of all kinds of antitumour drugs comprises: for example anthracyclines medicine, Vinca medicine, mitomycin, bleomycin, cell toxicant nucleosides, taxanes, Macrolide, discodermolide, pteridine class medicine, diynenes and podophyllotoxin.Useful especially member in these classifications comprises: Dx for example, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, two chloro-methotrexates, ametycin, porfiromycin, Herceptino_, Rituxan_, 5 FU 5 fluorouracil, Ismipur, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivative such as colchicine, Etoposide, Etoposide phosphoric acid salt or teniposide, melphalan, vinealeucoblastine(VLB), vincristine(VCR), leurosidine, vindesine, leurosine, taxol etc.Other useful antitumour drugs comprise: estramustine, cis-platinum, carboplatin, endoxan, bleomycin, tamoxifen, ifosfamide, melphalan, altretamine, plug are for group, cytosine arabinoside, idatrexate, trimetrexate, Dacarbazine, altheine enzyme, camptothecine, CPT-11, Hycamtin, ara-C, bicalutamide, flutamide, leuproside, pyrido benzindole derivative, Interferon, rabbit and interleukin.A preferred class antitumour drug is a taxanes, and preferred antitumour drug is a taxol.
Radiotherapy from adding beam or providing by the implantation tiny radioactive source comprises X ray or gamma-radiation, also can unite to make with The compounds of this invention to be used for treating cancer.
Embodiment
Those skilled in the art provide down series preparation and embodiment so that can more be expressly understood and implement the present invention.They should not be regarded as limiting the scope of the invention, and should only think illustrative and representational.
Synthetic embodiment
Embodiment 1
Synthesizing of N-hydroxyl-4-(2-phenylcarbamoyl amino-oxyethyl group) benzamide
Figure A20048000922501121
Step 1
(3.1g adds tert-butoxycarbonyl acid anhydrides (carbonyl anhydride) (10.9g, THF 50mmol) (150ml) solution in THF 50mmol) (10ml) solution to the 2-monoethanolamine.Reaction mixture is stirred 3h, then with the ethyl acetate dilution, with the 0.5M HCl aqueous solution and salt water washing.Use MgSO 4Dry organic layer filters and vacuum concentration, obtains the 2-N-Boc-monoethanolamine, and it can be directly used in next step.
Step 2
To triphenyl phosphine (17.7g, add in anhydrous THF (135ml) solution 67.5mmol) DIAD (13.6g, 67.5mmol).Stirred solution is until forming white depositions (2 to 10min).After passing through 60min again, (7.2g is 45mmol) with 4-methyl hydroxybenzoate (6.8g, THF 45mmol) (25ml) solution, and continuation stirring 5h to add 2-N-Boc-amino-ethanol.With the reaction mixture vacuum concentration,, obtain 4-(2-N-Boc-amino ethoxy) methyl benzoate by flash chromatography method purifying.Perhaps, thick material can be directly used in next step.
Step 3
In methyl alcohol (20ml) solution of thick 4-(2-N-Boc-amino ethoxy) methyl benzoate, add 4MHCl/ dioxan (180ml).After stirring 3h, add diethyl ether (300ml), obtain white depositions.Collect solid, and be suspended in the ethyl acetate, stir 15-20min.Collect solid once more, and dry under high vacuum, obtain 4-(2-amino ethoxy) methyl benzoate hydrochloride 6.3g (60%) through 2 steps.
Step 4
To 4-(2-amino-oxyethyl group) methyl benzoate hydrochloride (0.232g, add in THF 1mmol) (6ml) suspension Benzoyl chloride (0.140g, 1mmol), add then triethylamine (0.121g, 1.2mmol).Reaction mixture is stirred 1h, dilute with ethyl acetate then.The organic layer 0.5M HCl aqueous solution, saturated sodium bicarbonate solution and salt water washing.Organic layer is obtained 4-(2-phenylcarbamoyl amino-oxyethyl group) methyl benzoate by vacuum concentration, and it can be directly used in next step.
Step 5
Add 50wt.% aqueous hydroxylamine (3ml) in THF/ carbinol mixture (20ml) solution of thick 4-(2-phenylcarbamoyl amino-oxyethyl group) methyl benzoate (0.5mmol) at 1: 1, add the 1M NaOH aqueous solution (1ml) subsequently, adjustment pH is 10-11.Reaction mixture is stirred 14h, be neutralized to pH=7-8, vacuum concentration with the 6M HCl aqueous solution.The collecting precipitation thing, and, obtain title compound by the HPLC purifying, be white solid.
1H NMR (DMSO-d 6): δ 8.69 (t, J=5.8Hz, 1H), 7.83 (d, J=7.5Hz, 2H), 7.69 (d, J=9.1Hz, 2H), 7.46 (m, 3H), 6.99 (d, J=9.1Hz, 2H), 4.16 (t, J=5.8Hz, 2H), 3.63 (q, J=5.8Hz, 2H) .EM (calculated value): 300.1; MS (ESI) m/e:301.1 (M-1) +, 299.0 (M+1) -.
Undertaken by step 1-4 in the foregoing description 1 is described, but replace the 2-monoethanolamine, obtain 4-(the amino butoxy of 2S-) methyl benzoate hydrochloride with (S)-(+)-2-amino-1-butanols.
Embodiment 2
N-hydroxyl-4-[2-(cumarone-2-base-carbonylamino)-oxyethyl group]-benzamide synthetic
Figure A20048000922501141
Step 1
With cumarone-2-carboxylic acid (0.162g, 1mmol), EDCHCl (0.268g, 1.4mmol) and HOBTH 2(0.203g, 1.5mmol) mixture in DMF (6ml) stirs 2h to O.Add 4-(2-amino ethoxy) methyl benzoate hydrochloride (0.232g, 1mmol), add subsequently triethylamine (0.121g, 1.2mmol).Reaction mixture is stirred 2h, then with the ethyl acetate dilution, with saturated sodium bicarbonate solution and salt water washing.Organic layer is by vacuum concentration, with thick 4-[2-(cumarone-2-base carbonylamino) oxyethyl group] benzoic ether is converted into as the described title compound of step 5 among the top embodiment 1.
1H NMR (DMSO-d 6) δ 11.05 (s, 1H), 8.92 (t, J=5.6Hz, 1H), 8.88 (s, 1H), 7.76 (d, J=8.0Hz, 1H), 7.70 (d, J=9.2Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=6.8Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.01 (d, J=8.2Hz, 2H), 4.18 (t, J=5.6Hz, 2H), 3.67 (m, 2H) .EM (calculated value): 340.1; MS (ESI) m/e:(M+1H) +: 341.0, (M-1H) -: 339.1.
Embodiment 3
N-hydroxyl-4-[2-(thionaphthene-2-base-carbonylamino)-oxyethyl group]-benzamide synthetic
Figure A20048000922501142
To 4-(2-amino ethoxy) methyl benzoate hydrochloride (0.232g, add in THF 1mmol) (6ml) suspension thionaphthene-2-dicarbonyl chloride (0.150g, 1mmol), add subsequently triethylamine (0.121g, 1.2mmol).Reaction mixture is stirred 1h, with ethyl acetate (50ml) dilution.The organic layer 0.5M HCl aqueous solution, saturated sodium bicarbonate solution and salt water washing.Organic layer is by vacuum concentration, with thick 4-[2-(thionaphthene-2-base-carbonylamino) oxyethyl group] methyl benzoate is converted into as the described title compound of step 5 among the top embodiment 1.
By top embodiment 3 described carrying out, but replace 4-(2-amino ethoxy) methyl benzoate hydrochloride with 4-(the amino butoxy of 2S-) methyl benzoate hydrochloride, replace thionaphthene-2-dicarbonyl chloride with cinnamyl chloride, obtain N-hydroxyl-4-[2S-(trans-cinnyl amino) butoxy] benzamide.
Embodiment 4
N-hydroxyl-4-[2-(3-dimethylamino cumarone-2-base carbonylamino)-oxyethyl group]-benzamide synthetic
Figure A20048000922501151
Step 1
To 3-methyl-cumarone-2-carboxylic acid (0.98g, 5.6mmol) and add in THF (25ml) solution of 5 DMF oxalyl chloride (0.53ml, 6.1mmol).At room temperature behind the stirred solution 1h, add methyl alcohol (20ml) and TEA (7ml).Stir slurries under the room temperature and spend the night, concentrate then and be dissolved in the ethyl acetate (100ml), with rare NaHCO 3(100ml) washing.Organic layer MgSO 4Drying is filtered and is concentrated, and collects 3-methyl cumarone-2-carboxylate methyl ester (1g), is brown solid.Thick methyl esters just need not to be further purified and can use.
Step 2
With 3-methyl cumarone-2-carboxylate methyl ester (1.0g, 5.3mmol), NBS (0.95g, 5.3mmol) and AIBN (87mg, CCl 0.53mmol) 4(40ml) vlil 3h, cool to room temperature and concentrated then.Resistates is dissolved in the ethyl acetate (100ml), water (100ml) washing.Organic layer MgSO 4Drying is filtered and is concentrated, and collects 3-brooethyl cumarone-2-carboxylate methyl ester (1.55g), is brown/yellow solid, and it need not to be further purified and just can be used for next step.
Step 3
With 3-brooethyl cumarone-2-carboxylate methyl ester (269mg 1mmol) is dissolved in dry DMF, and join 2M dimethylamine/THF solution (1.5ml, 3mmol) in.Behind 1-2h, reactant dilutes with EtOAc, uses saturated NaHCO 3The aqueous solution and salt solution washed twice.Organic extract Na 2SO 4Drying, vacuum concentration then.Crude product obtains 3-dimethylaminomethyl cumarone-2-carboxylate methyl ester (131mg) with silicagel column (dichloromethane solution of 5%MeOH) purifying.
Step 4
(131mg adds the 1N NaOH aqueous solution in MeOH solution 0.56mmol), be 13 until pH value of solution to 3-dimethylaminomethyl cumarone-2-carboxylate methyl ester.Reaction mixture is stirred 60-90min.After the end, reaction mixture to pH 3, is concentrated into drying with the HCl acidified aqueous solution, obtains 3-dimethylaminomethyl cumarone-2-carboxylic acid, is hydrochloride, and it need not to be further purified and just can be used for next step.
Step 5
To 3-dimethylaminomethyl cumarone-2-carboxylic acid (140mg, add in 0.56mmol) EDCHCl (150mg, 0.784mmol) and HOBtH 2(114mg is in anhydrous DMF solution 0.84mmol) for O.Reaction mixture is stirred 30-60min, add then (4-(2-amine ethoxylate)) methyl benzoate hydrochloride (130mg, 0.56mmol) and triethylamine (94 μ L, 0.672mmol), reaction stirred is spent the night.Reaction mixture dilutes with EtOAc, uses saturated NaHCO 3The aqueous solution and salt solution washed twice.Organic extract is obtained 4-[2-(3-dimethylamino cumarone-2-base-carbonylamino) oxyethyl group by vacuum concentration] methyl benzoate, it just need not to be further purified and can use.
Step 6
To thick 4-[2-(3-dimethylamino cumarone-2-base-carbonylamino)-oxyethyl group]-add the excessive aqueous hydroxylamine and the NaOH aqueous solution in the MeOH of methyl benzoate and the THF solution, obtain pH10-11.Reaction mixture is stirred and spends the night, then with the hydrochloric acid pH 7-8 that neutralizes, vacuum concentration.Resistates is dissolved in acetonitrile and water, with preparation property HPLC purifying, obtains title compound (107mg).
1H NMR (400MHz, DMSO-d 6) δ 9.88 (m, 1H), 9.31 (t, J=6.0Hz, 1H), 8.04 (d, J=7.6Hz, 1H), 7.70 (m, 3H), 7.57 (t, J=7.6Hz, 1H), 7.45 (t, J=7.6Hz, 1H), 6.99 (d, J=9.2Hz, 2H), 4.76 (d, J=4.8Hz, 2H), 4.23 (t, J=6.0Hz, 2H), 3.71 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H) .EM (calculated value): 397.2; MS (ESI) m/e (M+1H) +: 398.1, (M-1H) -: 396.2.
Embodiment 5
N-hydroxyl-4-{2-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base-
Carbonylamino] oxyethyl group } benzamide synthetic
Step 1
(15mg 0.56mmol) is suspended in the dry DMF, at N with sodium hydride 2(g) stir down.(270 μ L 3.7mmol), behind stirred reaction mixture 15-20min, add 3-brooethyl cumarone-2-carboxylate methyl ester to add 2,2,2 tfifluoroethyl alcohol.Behind the 8h, add the 1N NaOH aqueous solution, reaction mixture is stirred 10-15min.Reaction mixture to pH 3, is used the EtOAc extraction product with hcl acidifying.Organic layer Na 2SO 4Drying, vacuum concentration obtains 3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-carboxylic acid (38mg), and it just need not to be further purified and can use.
Step 2
To 3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-carboxylic acid (38mg, add in anhydrous DMF solution 0.139mmol) EDCHCl (37mg, 0.195mmol) and HOBtH 2O (26mg, 0.195mmol).Behind 60-90min, add (4-(2-amine ethoxylate)) methyl benzoate hydrochloride (32mg, 0.139mmol) and triethylamine (23 μ L 0.167mmol), stir 1-2h with reaction mixture.Reaction mixture dilutes with EtOAc, and uses saturated NaHCO 3Solution washing twice concentrates organic extract, obtains 4-{2-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base-carbonylamino] oxyethyl group } methyl benzoate, it just need not to be further purified and can use.
Step 3
With 4-{2-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base-carbonylamino]-oxyethyl group }-benzoic ether is dissolved among the MeOH, adds the excessive aqueous hydroxylamine and the NaOH aqueous solution, obtains pH10-11.After stirring is spent the night, with hydrochloric acid with the reaction mixture pH 7-8 that neutralizes.Reaction mixture is obtained solid by vacuum concentration, and it is collected and washes with water, is dissolved in acetonitrile and water then, with preparation property HPLC purifying, obtains title compound (35mg).
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.95 (t, J=5.6Hz, 1H), 8.89 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.63 (d, J=8.8Hz, 1H), 7.50 (t, J=8.8Hz, 1H), 7.36 (t, J=8.0Hz, 1H), 7.00 (d, J=9.2Hz, 2H), 5.25 (s, 2H), 4.18 (m, 4H), 3.67 (m, 2H) EM (calculated value): 452.1; MS (ESI) m/e (M+1H) +: 453.0, (M-1H) -: 451.0.
Embodiment 6
N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-
The base carbonylamino] oxyethyl group } benzamide synthetic
Figure A20048000922501181
Step 1
(5.04g, 26mmol) in the 200ml round-bottomed flask, it is furnished with stirring rod, barrier film and nitrogen inlet to weighing 5-methoxyl group benzo furans-2-carboxylic acid.In nitrogen atmosphere, add anhydrous MeOH (50ml).Cooling solution in ice bath drips thionyl chloride under vigorous stirring.After at room temperature stirring 72h, reaction mixture is poured in the water (150ml), collected white solid.Solid is dissolved in the toluene (100ml), solution 1M NaHCO 3With the salt water washing, use MgSO 4Dry.Remove organic layer, obtain 5-methoxyl group benzo furans-2-carboxylate methyl ester, be white solid (5.15g).
Step 2
In nitrogen atmosphere, (5.15g, anhydrous methylene chloride 25mmol) (15ml) solution is cooled to-40 ℃ with 5-methoxyl group benzo furans-2-carboxylate methyl ester.With the CH of syringe pump with boron tribromide 2Cl 2(27ml 1.0M) adds in 1h solution.Make reaction mixture be warmed up to room temperature.Behind 16h, reaction mixture is cooled off in ice bath, with MeOH (15ml) quenching.Reaction mixture is poured in the salt solution (100ml), extracted with EtOAc.The anhydrous MgSO of organic extract 4Drying is removed with rotatory evaporator and to be desolvated.Resistates grinds with hexane, filters yellow solid, and is dissolved among the anhydrous MeOH (30ml).Solution cools off in ice bath, and the dropping thionyl chloride (1.9ml, 26mmol).Behind the 72h, add entry (100ml), collect solid.At 300cm 3On the silica gel, in 5 * 15cm stopper, use EtOAc purifying crude product, obtain 5-hydroxyl-cumarone-2-carboxylate methyl ester (4.53g).
Step 3
In nitrogen atmosphere, with anhydrous tetrahydro furan (15ml) join 5-hydroxyl benzofuran-2-carboxylate methyl ester (1.10g, 5.7mmol), triphenyl phosphine (1.50g, 5.7mmol) and 1-(2-hydroxyethyl)-tetramethyleneimine (0.66g is in mixture 5.7mmol).At room temperature (1.15ml 5.8mmol) slowly joins in the solution with the diisopropyl azo-2-carboxylic acid.After 2 days, remove and desolvate, resistates is dissolved in Et 2In 2: 1 mixtures (150ml) of O: EtOAC.Solution 1.0M NaOH solution washing.Product is extracted in the 1.0M hydrochloric acid, the acid extraction thing Et of merging 2The O washing.The cooling extract, with the 50%NaOH aqueous solution with the extract pH regulator to pH 12.Use CH 2Cl 2Extract this basic solution, the anhydrous MgSO of organic layer 4Drying concentrates and obtains 5-(2-tetramethyleneimine-1-base-oxyethyl group) cumarone-2-carboxylate methyl ester (0.96g), is amber solid.
Step 4
To ice-cooled 5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-carboxylate methyl ester (960mg, drip in anhydrous ethylene glycol bisthioglycolate methyl esters (10ml) solution 3.3mmol) degassing lithium hydroxide aqueous solution (2.0ml, 2.0M).After at room temperature stirring 4h, cooling solution is 2 with the dioxan solution of 4.0M HCl with pH regulator.Form colloid brown throw out.Remove and desolvate, the gummy residue thing is frozen and freeze-drying.Brown solid is dissolved in the ebullient 2-propyl alcohol (90ml), filtering heat solution, and cooling obtains 5-(2-tetramethyleneimine-1-base-oxyethyl group)-cumarone-2-carboxylic acid then, is beige needles (528mg).From mother liquor, obtain other 153mg.
Step 5
In the 20ml bottle, to 5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-carboxylic acid (156mg, 0.50mmol) and 4-(2-amino ethoxy) methyl benzoate hydrochloride (129mg, add in DMF 0.56mmol) (4.5ml) solution diisopropylethylamine (0.88ml, 5.1mmol).Add O-(7-azepine benzo triazol-1-yl)-1,1,3, (DMF solution 0.61mmol) obtains bright yellow solution to 3-tetramethyl-urea phosphofluoric acid ester for 740 μ L, 0.82M.The bottle purging with nitrogen gas at room temperature stirs 18h.Remove solution, resistates is dissolved among the EtOAc (25ml), uses H 2O, 1.0M K 2CO 3The aqueous solution and salt water washing.The anhydrous MgSO of organic layer 4Drying is removed on rotatory evaporator and is desolvated.On silicagel column, use 93: 5: 2 CH by column chromatography 2Cl 2: MeOH: TEA eluent purifying resistates obtains 4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-carbonylamino]-oxyethyl group }-methyl benzoate, be beige solid (174mg).
Step 6
To 4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-carbonylamino]-oxyethyl group }-methyl benzoate (169mg, 0.37mmol) methyl alcohol (8ml) and tetrahydrofuran (THF) (4ml) solution in add the aqueous solution (2.9ml, 50wt% solution) and the 4.0M aqueous sodium hydroxide solution (0.65ml) of azanol.After stirring 18h, remove organism, the aqueous solution cools off in ice/water-bath, is～8 with 4.4ml 1.0M hydrochloric acid with pH regulator, obtains throw out.Non-homogeneous solution is raised to room temperature, adds acetonitrile and dissolves until throw out.Solution carries out stratographic analysis with the C-18 reversed-phase HPLC.Have at the 214nm place that the fraction of absorption is collected, freezing and freeze-drying, obtain title compound (31mg).
1H NMR (400MHz, DMSO-d 6) δ: 11.05 (s, 1H), 10.4 (s, 1H), 8.91 (s, 2H), 7.70 (d, 2H, J=7.4), 7.59 (dd, 1H, J=3.7,9.1Hz), 7.51 (d, 1H, J=3.7Hz), 7.35 (s, 1H), 7.13 (d, 1H, J=9.0Hz), 7.00 (d, 2H, J=7.4Hz), 4.37 (m, 2H), 4.18 (m, 2H), 3.62 (m, 6H), 3.12 (m, 2H), 2.02 (m, 2H), 1.89 (m, 2H) .EM (calculated value): 453.2; MS (ESI) m/e (M+1H) +: 454.1, (M-1H) -: 452.2.
Embodiment 7
N-hydroxyl-4-[2-(3-dimethylamino cumarone-2-base carbonylamino)-
Oxyethyl group]-benzamide hydrochloride salt synthetic
Step 1
(152.0g, 0.942mol) (174.0g 1.12mol) is dissolved in the tetrahydrofuran (THF) (2000ml), and is cooled to 0-5 ℃ with 4-hydroxy-benzoic acid methyl esters with (2-hydroxyethyl) t-butyl carbamate.(292.8g 1.116mol) joins in the cooling mixture with triphenyl phosphine.(246.0g, tetrahydrofuran (THF) 1.218mol) (400ml) solution remains on below 10 ℃ temperature of charge to drip the diisopropyl azo-2-carboxylic acid through 1-2 hour.After interpolation, allow reactant slowly to be warmed up to room temperature, stirring is spent the night.After reaction finished, underpressure distillation solvent, gained oil were dissolved in ethanol (500ml) and the ethyl acetate (2000ml).(222.0g, 2.826mol), temperature rises to 40 ℃ to dripping acetyl chloride in 15 minutes.Gained suspension finishes until reaction 40 ℃ of stirrings.After reaction finished, the gained crystal filtered on the raw glass material, with ethyl acetate (300ml) washing.Material is obtained 4-(2-amino ethoxy) methyl benzoate hydrochloride (204.1g) by vacuum-drying, is white crystalline solid.
Step 2
(78.90g, 0.340mol) (60.0g 0.340mol) is suspended in the acetonitrile (360ml), and is cooled to 0-5 ℃ with 3-methyl cumarone-2-carboxylic acid with 4-(2-amino ethoxy) methyl benzoate hydrochloride.Quick adding pyridine (137.6ml, 1.702mol).(temperature maintenance is below 20 ℃ for 52.2g, acetonitrile 0.340mol) (60ml) solution to drip phosphorus oxychloride in 30-45 minute.Reaction mixture was stirred one hour, slowly be warmed up to room temperature.After reaction finished, solution joined in the mixture of 0-5 ℃ chlorobenzene (1000ml) of quick stirring and 1N hydrochloric acid (1000ml).Reaction mixture is stirred fast, and makes it be warmed up to room temperature.Organic layer water, 3% potassium hydroxide and other water washing.Chlorobenzene (100ml) is added in the organic layer of washing.Solvent distillation (100ml) under normal pressure reaches 132 ℃ until the jar temperature then.Behind cool to room temperature, with 4-{2-[(3-methyl cumarone-2-carbonyl) amino] oxyethyl group } methyl benzoate is stored in the solution, is used for next step.
Step 3
With 4-{2-[(3-methyl cumarone-2-carbonyl) amino] oxyethyl group } chlorobenzene (1000ml) solution of methyl benzoate (0.340mol) is with 2,2 '-azobis isobutyronitrile (5.60g, 0.017mol) and N-bromine succinimide (75.76g, 0.426mol) processing.The gained mixture is heated to 80 ℃, stirs one hour.After reaction finished, reaction mixture was cooled to room temperature, water, 3% sodium bisulfite and other water washing.Solvent is depressurized distillation, behind the cool to room temperature, adds methylene dichloride, obtains 4-{2-[(3-bromo-methyl cumarone-2-carbonyl) amino] oxyethyl group } methyl benzoate, use it for next step.
Step 4
In 30 minutes, with 4-{2-[(3-brooethyl cumarone-2-carbonyl) amino] oxyethyl group } chlorobenzene (200ml) of methyl benzoate (0.340mol) and the drips of solution of methylene dichloride (800ml) be added to the tetrahydrofuran (THF) (510ml of 0-5 ℃ 2M dimethylamine, 1.022mol) in the solution, temperature is remained on below 20 ℃.The gained mixture is stirred one hour, makes it be warming up to room temperature.After reaction finished, reaction mixture was with 5% salt of wormwood and water washing.Solvent distills under normal pressure, reaches 100 ℃ until the jar temperature.Be cooled to～50 ℃ after, acetonitrile (400ml) and ethyl acetate (400ml) are joined in the jar.Reaction mixture is heated backflow, all dissolves until all solids.Make the reaction mixture cooling, obtain 4-{2-[(3-dimethylaminomethyl-cumarone-2-carbonyl) amino] oxyethyl group } methyl benzoate (76.6g), be pale powder.
Step 5
With 4-{2-[(3-dimethylaminomethyl cumarone-2-carbonyl) amino] oxyethyl group } (70.0g 0.177mol) is suspended in the methyl alcohol (350ml) methyl benzoate.(139.8g, 1.062mol), reaction mixture is heated to 60 ℃, finishes until reaction to add 50% potassium hydroxide.Behind cool to room temperature, the gained crystal filters on the raw glass material, uses methanol wash.Crystal is dry in a vacuum, obtains 4-{2-[(3-dimethylaminomethyl cumarone-2-carbonyl) amino] oxyethyl group } phenylformic acid sylvite (72.0g), be white solid.
Step 6
With 4-{2-[(3-dimethylaminomethyl cumarone-2-carbonyl) amino] oxyethyl group } (20.0g 0.0476mol) is suspended in N to phenylformic acid sylvite, in the dinethylformamide (100ml).(11.9ml, 0.0476mol) solution joins in this suspension with the dioxan of 4mol hydrochloric acid.After at room temperature stirring 30 minutes, by intermediate frit filter reaction mixture.With 1-[3-(dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride (10.94g, 0.0571mol) and I-hydroxybenzotriazole (7.71g 0.0571mol) joins in the solution, and reaction mixture was at room temperature stirred one hour.In separating tank, (13.2g 1.904mol) is suspended in N, and in the dinethylformamide (100ml), (33.1ml 2.380mol) handles with triethylamine with hydroxylamine hydrochloride.Behind stirred reaction mixture 1h, elimination salt, gained solution are added in the above-mentioned active acid solution, at room temperature stir, and finish until reaction.After product begins crystallization, in 30 minutes, slowly add methyl alcohol (150ml).At room temperature reaction mixture is stirred 1h, be cooled to 0-5 ℃ then, and restir hour.Filter crystal, with methyl alcohol (40ml) washing, vacuum-drying then obtains 3-dimethylaminomethyl cumarone-2-carboxylic acid [2-(4-hydroxyl-carbamyl phenoxy group) ethyl] acid amides (11.88g), is white solid.(13.25g 0.033mol) is suspended in N, in the dinethylformamide (80ml), is heated to 100 ℃, obtains solution with thick material.After the cooling, in 30 minutes, drip ethanol (80ml), make gained suspension cooling 1 hour.Filter crystal, with ethanol (40ml) washing, drying obtains pure products (9.82g), is white solid.
Step 7
(22.7g 0.057mol) is suspended in the 2-propyl alcohol (220ml) acid amides with 3-dimethylaminomethyl cumarone-2-carboxylic acid [2-(4-hydroxyl-carbamyl phenoxy group) ethyl].Add a 12MHCl (5.2ml, 0.063mol), reflux gained mixture.Drip water (44ml), until obtaining homogeneous solution.Reaction mixture cooling and crystallization are spent the night.Behind the 1h of cooling below 5 ℃, filter crystal, with the washing of 2-propyl alcohol, vacuum-drying then obtains title compound (22.0g), is white solid.
Embodiment 8
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-ethyl sulfane base] benzamide synthetic
Step 1
Under 0 ℃, to the diisopropyl azo-2-carboxylic acid (DIAD, 4.04g, add in THF 20mmol) (100ml) solution triphenyl phosphine (5.25g, 20mmol).Behind 1h, add Boc-thanomin (3.22g, THF 20mmol) (10ml) solution.Behind 20min, (3.86g, THF 20mmol) (10ml) solution at room temperature stir reaction mixture and to spend the night to add 4-Thiosalicylic acid methyl esters.Concentrated reaction mixture, and add ethyl acetate (150ml).Solution 1M HCl, saturated NaHCO 3MgSO is used in the aqueous solution, salt water washing 4Drying is filtered, and is evaporated to dried.By silica gel plug elution oily yellow residue, (hexane solution of 0-20 ethyl acetate is a moving phase), recrystallized product from ether and hexane obtains 4-(2-tert-butoxycarbonyl amino-ethyl sulfane base) methyl benzoate (4.00g) then.
Step 2
At room temperature, (treatment time is 3h for 1.00g, methylene dichloride 3.21mmol) (8ml) solution to handle 4-(2-tert-butoxycarbonyl amino-ethyl sulfane base) methyl benzoate with the dioxan solution (4M, 8ml, 10 equivalents) of HCl.Add ether (100ml), filtering mixt with the ether washing, and is pumped to driedly, obtains 4-(2-amino-ethyl sulfane base) methyl benzoate hydrochloride.
Step 3
At room temperature, make 4-(2-amino-ethyl sulfane base) methyl benzoate hydrochloride (0.248g, 1.00mmol) with cumarone-2-carboxylic acid (0.162g, 1.00mmol) and HBTU (0.379g, DMF 1.00mmol) (5ml) solution merging.(0.307ml 2.2mmol), at room temperature stirs reaction mixture and spends the night to add triethylamine.Add saturated NaHCO 3The aqueous solution (15ml) obtains throw out, by adding entry (20ml) it is burst apart.Cross filter solid, filter cake is dissolved in the ethyl acetate.Remaining water is removed by transfer pipet, adds hexane, obtains 4-{2-[(cumarone-2-base carbonyl)-amino] ethyl sulfane base } methyl benzoate (0.138g), be glue, it need not to be further purified and just can be used for next step.
Step 4
To 4-{2-[(cumarone-2-base-carbonyl) amino] ethyl sulfane base }-add water (4ml) solution of 50% azanol in THF (2ml) solution of methyl benzoate.Add methyl alcohol (2ml) and 0.1MNaOH (0.1ml).Reaction mixture was at room temperature stirred three days.Evaporating solvent, resistates is crystallization from dichloromethane/ethyl acetate, obtains title compound (46mg).
1H NMR(DMSO-d 6)：3.12(2H，m)；3.5(2H，m)；7.33(1H，t)；7.42(2H，d)；7.45(1H，m *)；7.53(1H，s)；7.62(1H，d)；7.7(2H，d)；7.78(1H，d)；8.96(1H，t)；8.99(1H，b r.s).MS(M+1)：357.
Embodiment 9
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino) ethylsulfonyl] benzamide synthetic
Figure A20048000922501251
Step 1
To 4-(2-tert-butoxycarbonyl amino-ethyl sulfane base)-methyl benzoate (3.00g, methanol 9.63mmol) (1: 1,100ml) add in the solution Oxone_ (13.03g, 21.19mmol).Behind 48h, methyl alcohol is removed in decompression, and resistates is at ethyl acetate (150ml) and saturated NaHCO 3Distribute in the aqueous solution (150ml).Organic phase is used MgSO with salt solution (100ml) washing 4Drying is filtered, vacuum concentration, and resistates is recrystallization from ethyl acetate/hexane, obtains product 4-(2-tert-butoxycarbonyl amino-ethyl alkylsulfonyl) methyl benzoate (2.86g).
Step 2
(2.86g, methylene dichloride 8.33mmol) (20ml) solution is handled 2h with the dioxan solution (20ml) of 4M HCl with 4-(2-tert-butoxycarbonyl amino-ethyl alkylsulfonyl) methyl benzoate.Add ether (200ml), filtering suspension liquid, with ether (2 * 50ml), hexane (50ml) washing; be pumped to dried; obtain 4-(2-amino-ethyl alkylsulfonyl) methyl benzoate hydrochloride (2.23g), it combines with above-mentioned cumarone 2-carboxylic acid, obtains title compound.MS(M+1)：388.
Undertaken by top embodiment 1-3 is described, but use the compound of Table I-IV below the suitable commercially available raw material preparing.
Table 1:
Compound 1
1H NMR (400MHz, DMSO-d 6) δ 8.69 (t, J=5.8Hz, 1H), 7.83 (d, J=7.5Hz, 2H), 7.69 (d, J=9.1Hz, 2H), 7.46 (m, 3H), 6.99 (d, J=9.1Hz, 2H), 4.16 (t, J=5.8Hz, 2H), 3.63 (q, J=5.8Hz, 2H) .EM (calculated value): 300.1; MS (ESI) m/e:301.1 (M-1) +, 299.0 (M+1) -.
Compound 2
1H NMR (400MHz, DMSO-d 6) δ 11.08 (s, 1H), 8.92 (s, 1H), 8.41 (t, J=6Hz, 1H), 7.74 (d, J=8.8Hz, 2H), 7.58 (d, J=6.8Hz, 2H), 7.46 (d, J=15.6Hz, 1H), and 7.45-7.37 (m, 3H), 7.03 (d, J=8.8Hz, 2H), 6.72 (d, J=15.6Hz, 1H), 4.13 (t, J=5.2Hz, 2H), 3.60 (q, J=5.6Hz, 2H) .EM (calculated value): 326.1; MS (ESI) m/e (M+1H) +: 327.1, (M-1H) -: 325.2.
Compound 3
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.42 (t, J=4.8Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 7.27 (t, J=7.2Hz, 2.0Hz), 7.18 (t, J=7.2Hz, 1H), 7.13 (d, J=7.2Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 4.07 (t, J=5.6Hz, 2H), 3.49 (dq, J 1=5.6Hz, J 2=1.6Hz, 2H), 2.28 (ddd, J 1=4.0Hz, J 2=5.6Hz, J 3=9.6Hz, 1H), 1.95 (ddd, J 1=4.1Hz, J 2=5.2Hz, J 3=8.4Hz, 1H), 1.39 (ddd, J 1=4.0Hz, J 2=5.2Hz, J 3=9.2Hz, 1H), 1.24 (ddd, J 1=4.0Hz, J 2=6.4Hz, J 3=10.4Hz, 1H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.2, (M-1H) -: 339.2.
Compound 4
1H NMR (400MHz, DMSO-d 6) δ 11.08 (s, 1H), 8.92 (s, 1H), 8.31 (t, J=5.6Hz, 1H), 7.73 (d, J=9.2Hz, 2H), 7.52 (d, J=9.2Hz, 2H), 7.41 (d, J=15.6Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 6.99 (d, J=8.8Hz, 2H), 6.55 (d, J=15.6Hz, 1H), 4.12 (t, J=5.6Hz, 2H), 3.81 (s, 3H), 3.58 (q, J=5.6Hz, 2H) .EM (calculated value): 356.1; MS (ESI) m/e (M+1H) +: 357.2, (M-1H) -: 355.2.
Compound 5
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.80 (s, 1H), 8.01 (t, J=4.8Hz, 1H), 7.61 (d, J=8.8Hz, 2H), 7.14-7.02 (m, 5H), 6.86 (d, J=8.8Hz, 2H), 3.32 (q, J=5.6Hz, 2H), 2.71 (t, J=7.2,2H), 2.30 (t, J=7.6Hz, 2H) .EM (calculated value): 328.1; MS (ESI) m/e (M+1H) +: 329.2, (M-1H) -: 327.0.
Compound 6
1H NMR (400MHz, DMSO-d 6) δ 11.11 (s, 1H), 10.89 (s, 1H), 8.95 (br s, 1H), 8.22 (t, J=5.6Hz, 1H), 7.76 (d, J=8.8Hz, 2H), 7.56 (d, J=8.0Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 7.22 (d, J=2.0Hz, 1H), 7.08 (t, J=7.6Hz, 1H), 7.02 (d, J=8.4Hz, 2H), 6.93 (t, J=8.4Hz, 1H), 4.09 (false (pseudo) t, J=6.0Hz, 2H), 3.58 (s, 2H), 3.50 (false q, J=5.6Hz, 2H) .EM (calculated value): 353.1; MS (ESI) m/e (M+1H) +: 353.9, (M-1H) -: 252.0.
Compound 7
1H NMR (400MHz, DMSO-d 6) δ 11.11 (s, 1H), 8.80 (t, J=5.6Hz, 1H), 7.82 (d, J=7.6Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.76 (d, J=8.4Hz, 2H), 7.19 (t, J 1=5.2Hz, 1H), 7.06 (d, J=8.8Hz, 2H), 4.21 (false t, J=6.0Hz, 2H), 3.67 (false q, J=5.6Hz, 2H) .EM (calculated value): 306.1; MS (ESI) m/e (M+1H) +: 307.0, (M-1H) -: 304.9.
Compound 8
1H NMR (400MHz, DMSO-d 6) δ 8.98 (s, 1H), 8.9 (t, J=5.4Hz, 1H), 8.67 (d, J=4.6Hz, 1H), 8.16 (d, J=8.1Hz, 1H), 7.69 (d, J=8.9Hz, 2H), 7.48 (m, 1H), 6.99 (d, J=8.9Hz, 2H), 4.17 (t, J=5.4Hz, 2H), 3.65 (m, 2H) .EM (calculated value): 301.11; MS (ESI) m/e (M-1H) -: 300.0.
Compound 9
1H NMR (400MHz, DMSO-d 6) δ 11.03 (1H, s), 8.87 (1H, bs), 8.74 (1H, t, J=5.6Hz), 7.93 (2H, d, J=8.0Hz), 7.75 (2H, d, J=8.0Hz), 7.69 (3H, m), 7.47 (1H, t, J=8.0Hz), 7.39 (2H, m), 6.99 (2H, d, J=8.9Hz), 4.18 (2H, t, J=5.6Hz), 3.66 (2H, m) .EM (calculated value): 376.41; MS (ESI) m/e (M+1H) +: 377.1, (M-1H) -: 375.0.
Compound 10
EM (calculated value): 376.1; MS (ESI) m/e (M+1) +: 376.9, (M-1) -: 375.1.
Compound 11
1H NMR (400MHz, DMSO-d 6) δ 11.11 (s, 1H), 8.95 (s, 1H), 8.84 (t, J=6.0Hz, 1H), 7.83 (d, J=4.0Hz, 1H), 7.77 (d, J=9.2Hz, 2H), 7.75 (d, J=7.2Hz, 2H), 7.59 (d, J=4.0Hz, 1H), 7.49 (false t, J=7.2Hz, 2H), 7.41 (false t, J=7.6Hz, 1H), 7.07 (d, J=8.8Hz, 2H), 4.22 (false t, J=5.6Hz, 2H), 3.69 (false q, J=5.2Hz, 2H) .EM (calculated value): 382.1; MS (ESI) m/e (M+1H) +: 383.1, (M-1H) -: 381.0.
Compound 12
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 10.15 (s, 1H), 8.36 (t, J=5.6Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.32 (m, 1H), 6.97 (d, J=8.8Hz, 2H), 6.92 (m, 1H), 6.88 (m, 1H), 4.04 (t, J=5.6Hz, 2H), 3.66 (s, 2H), 3.45 (m, 2H) .EM (calculated value): 320.1; MS (ESI) m/e (M+1H) +: 320.9, (M-1H) -: 319.0.
Compound 13
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.87 (m, 2H), 8.45 (s, 1H), 7.97 (m, 4H), 7.71 (d, J=8.8Hz, 2H), 7.59 (m, 2H), 7.02 (d, J=8.8Hz, 2H), 4.21 (t, J=5.6Hz, 2H), 3.71 (m, 2H) .EM (calculated value): 350.1; MS (EST) m/e (M+1H) +: 350.9, (M-1H) -: 349.1.
Compound 14
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.98 (m, 2H), 8.52 (m, 2H), 8.19 (d, J=8.8Hz, 1H), 8.08 (d, J=8.8Hz, 1H), 7.71 (d, J=8.8Hz, 2H), 7.62 (m, 1H), 7.02 (d, J=8.8Hz, 2H), 4.22 (t, J=5.6Hz, 2H), 3.72 (m, 2H) .EM (calculated value): 351.1; MS (ESI) m/e (M+1H) +: 351.8, (M-1H) -: 349.9.
Compound 15
EM (calculated value): 383.1; MS (ESI) m/e (M+1) +: 383.9, (M-1) -: 382.2.
Compound 16
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.61 (t, J=4.8Hz, 1H), 7.78 (d, J=8.4Hz, 2H), 7.70 (d, J=8.8Hz, 2H), 7.46 (d, J=8.8Hz, 2H), 6.99 (d, J=8.6Hz, 2H), 4.15 (t, J=5.6Hz, 2H), 3.62 (m, 2H), 1.29 (s, 9H) .EM (calculated value): 356.2; MS (ESI) m/e (M+1H) +: 357.0, (M-1H) -: 355.1.
Compound 17
1H NMR (400MHz, DMSO-d 6) δ 11.06 (s, 1H), 8.95 (s, 1H), 8.72 (d, J=5.2Hz, 1H), 8.56 (t, J=4.8Hz, 1H), 8.40 (d, J=7.6Hz, 1H), 7.80 (m, 1H), 7.71 (d, J=8.8Hz, 2H), 7.55 (d, J=16.0Hz, 1H), 7.00 (d, J=8.8Hz, 2H), 6.90 (d, J=16.0Hz, 1H), 4.12 (t, J=5.6Hz, 2H), 3.59 (m, 2H) .EM (calculated value): 327.1; MS (ESI) m/e (M+1H) +: 328.1, (M-1H) -: 326.1.
Compound 18
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.73 (t, J=5.6Hz, 1H), 7.93 (d, J=9.2Hz, 2H), 7.69 (m, 4H), 7.47 (t, J=2.4Hz, 2H), 7.01 (d, J=9.2Hz, 2H), 6.29 (t, J=2.4Hz, 2H), 4.18 (t, J=5.6Hz, 2H), 3.66 (m, 2H) .EM (calculated value): 365.1; MS (ESI) m/e (M+1H) +: 366.0, (M-1H) -: 364.2.
Compound 19
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.53 (t, J=5.6Hz, 1H), 7.80 (d, J=9.2Hz, 2H), 7.70 (d, J=9.2Hz, 2H), 6.99 (m, 4H), 5.95 (m, 1H), 5.80 (m, 1H), 4.96 (s, 1H), 4.14 (t, J=5.6Hz, 2H), 3.60 (m, 2H), 2.00 (m, 3H), 1.72 (m, 3H) .EM (calculated value): 396.2; MS (ESI) m/e (M+1H) +: 397.1, (M-1H) -: 395.2.
Compound 20
1H NMR (400MHz, DMSO-d 6) δ 11.08 (s, 1H), 9.35 (t, J=5.6Hz, 1H), 8.25 (d, J=7.6Hz, 1H), 8.15 (d, J=8.0Hz, 1H), 7.73 (d, J=8.8Hz, 2H), and 7.68-7.58 (m, 2H), 7.03 (d, J=9.2Hz, 2H), 4.23 (false t, J=6.4Hz, 2H), 3.74 (false q, J=6.0Hz, 2H) .EM (calculated value): 357.1; MS (ESI) m/e (M+1H) +: 358.1, (M-1H) -: 356.0.
Compound 21
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 9.47 (t, J=5.6Hz, 1H), 7.90 (false t, J=9.2Hz, 2H), 7.73 (d, J=8.8Hz, 2H), 4.59 (td, J 1=7.6Hz, J 2=0.8Hz, 1H), 7.52 (td, J 2=8.0Hz, J 2=1.2Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 4.24 (t, J=6.0Hz, 2H), 3.72 (false q, J=6.0Hz, 2H) .EM (calculated value): 341.1; MS (ESI) m/e (M+1H) +: 342.1, (M-1H) -: 340.2.
Compound 22
1H NMR (400MHz, DMSO-d 6) δ 11.08 (s, 1H), 9.70 (s, 1H), 8.91, (t, J=5.6Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 6.97 (d, J=8.4Hz, 2H), 4.10 (m, 2H), 3.93 (m, 2H), 3.54 (m, 2H), 3.27 (m, 2H), 3.08 (m, 2H), 2.21 (m, 1H), 2.01 (m, 1H), 1.51 (m, 10H) .EM (calculated value): 375.2; MS (ESI) m/e (M+1H) +: 376.1, (M-1H) -: 374.1.
Compound 23
1H NMR (400MHz, DMSO-d 6) δ 11.09 (s, 1H), 8.35 (d, J=6.8Hz, 2H), 7.72 (d, J=9.2Hz, 2H), 7.25 (d, J=6.8Hz, 2H), 6.98 (d, J=9.2Hz, 2H), 4.10 (t, J=5.6Hz, 2H), 3.97 (m, 2H), 3.54 (m, 10H) .EM (calculated value): 399.2; MS (ESI) m/e (M+1H) +: 400.1, (M-1H) -: 398.1.
Compound 24
EM (calculated value): 290.1; MS (ESI) m/e (M+1) +: 291.1, (M-1) -: 289.2.
Compound 25
EM (calculated value): 377.1; MS (ESI) m/e (M+1) +: 377.9, (M-1) -: 376.0.
Compound 26
EM (calculated value): 377.1; MS (ESI) m/e (M+1) +: 378.0, (M-1) -: 375.9.
Compound 27
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 9.11 (t, J=5.6Hz, 1H), 7.70 (d, J=9.2Hz, 2H), 7.62 (m, 2H), 7.29 (m, 2H), 7.01 (d, J=9.2Hz, 2H), 4.21 (t, J=5.6Hz, 2H), 3.71 (m, 2H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.0, (M-1H) -: 339.1.
Compound 28
EM (calculated value): 289.1; MS (ESI) m/e (M+1H) +: 290.0, (M-1H) -: 287.8.
Compound 29
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s 1H), 10.43 (s, 1H), 8.62 (t, J=6.0Hz, 1H), 7.94 (d, J=6.4Hz, 2H), 7.853 (m, 4H), 7.70 (d, J=9.2Hz, 2H), 7.60 (m, 1H), 7.52 (m, 2H), 7.00 (d, J=9.2Hz, 2H), 4.16 (t, J=6.0Hz, 2H), 3.63 (dt, J 1=5.6Hz, J 2=6.0Hz, 2H) .EM (calculated value): 419.2; MS (ESI) m/e (M+1H) +: 420.2, (M-1H) -: 418.3.
Compound 30
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 9.23 (t, J=6.0Hz, 1H), 9.01 (s, 1H), 8.89 (d, J=6.8Hz, 2H), 8.38 (d, J=6.4Hz, 2H), 7.70 (d, J=9.2Hz, 2H), 7.00 (d, J=9.2Hz, 2H), 4.22 (t, J=5.6Hz, 2H), 3.71 (m, 2H) .EM (calculated value): 384.1; MS (ESI) m/e (M+1H) +: 384.9, (M-1H) -: 382.9.
Compound 31
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 7.69 (d, J=8.4Hz, 2H), 7.56 (t, J=5.6Hz, 1H), 7.01 (d, J=8.8Hz, 2H), 4.01 (t, J=5.6Hz, 2H), 3.40 (m, 2H), 1.95 (m, 3H), 1.69 (m, 12H) .EM (calculated value): 358.2; MS (ESI) m/e (M+1H) +: 358.9, (M-1H) -: 357.2.
Compound 32
EM (calculated value): 336.09; MS (ESI) m/e (M-1H) -: 335.3.
Compound 33
EM (calculated value): 370.12; MS (ESI) m/e (M-1H) -: 369.0.
Compound 34
EM (calculated value): 344.10; MS (ESI) m/e (M+1H) +: 345.0, (M-1H) -: 343.1.
Compound 35
EM (calculated value): 360.13; MS (ESI) m/e (M-1H) -: 359.1.
Compound 36
EM (calculated value): 344.10; MS (ESI) m/e (M-1H) -: 358.8.
Compound 37
EM (calculated value): 336.09; MS (ESI) m/e (M+1H) +: 337.2, (M-1H) -: 335.0.
Compound 38
EM (calculated value): 328.14; MS (ESI) m/e (M+1H) +: 329.2, (M-1H) -: 327.2.
Compound 39
EM (calculated value): 368.03; MS (ESI) m/e (M-1H) -: 367.0.
Compound 40
EM (calculated value): 328.14; MS (ESI) m/e (M+1H) +: 328.8, (M-1H) -: 327.2.
Compound 41
EM (calculated value): 364.08; MS (ESI) m/e (M+1H) +: 365.1, (M-1H) -: 363.2.
Compound 42
EM (calculated value): 344.14; MS (ESI) m/e (M+1H) +: 345.1, (M-1H) -: 343.1.
Compound 43
EM (calculated value): 344.14; MS (ESI) m/e (M+1H) +: 345.0, (M-1H) -: 343.2.
Compound 44
EM (calculated value): 348.11; MS (ESI) m/e (M+1H) +: 348.8, (M-1H) -: 346.9.
Compound 45
EM (calculated value): 412.11; MS (ESI) m/e (M+1H) +: 413.3, (M-1H) -: 411.0.
Compound 46
EM (calculated value): 412.11; MS (ESI) m/e (M+1H) +: 413.2, (M-1H) -: 411.1.
Compound 47
EM (calculated value): 376.14; MS (ESI) m/e (M+1H) +: 377.0, (M-1H) -: 375.2.
Compound 48
EM (calculated value): 339.12; MS (ESI) m/e (M+1H) +: 340.1, (M-1H) -: 338.3.
Compound 49
1H NMR (400MHz, DMSO-d 6) δ 11.53 (s, 1H), 11.04 (s, 1H), 8.12 (d, J=7.6Hz, 2H), 8.01 (s, 1H), 7.70 (d, J=9.2Hz, 2H), 7.40 (d, J=8.0, Hz, 1H), 7.10 (m, 2H), 7.017 (d, J=8.8Hz, 2H), 4.16 (t, J=5.6Hz, 2H), 3.64 (m, 2H) .EM (calculated value): 339.1; MS (ESI) m/e (M+1H) +: 340.0, (M-1H) -: 338.1.
Compound 50
1H NMR (400MHz, DMSO-d 6) δ 9.37 (s, 1H), 9.21 (t, J=5.2Hz, 1H), 9.02 (s, 1H), 8.15 (t, J=9.2Hz, 2H), 7.94 (m, 1H), 7.74 (m, 3H), 7.02 (d, J=8.8Hz, 2H), 4.24 (t, J=5.6Hz, 2H), 3.75 (m, 2H) .EM (calculated value): 351.1; MS (ESI) m/e (M+1H) +: 352.0, (M-1H) -: 349.9.
Compound 51
1H NMR (400MHz, DMSO-d 6) δ 11.11 (s, and 1H) 9.09 (d, J=4.4Hz, 1H), 8.70 (d, J=7.6Hz, 1H), 8.65 (d, J=7.6Hz, 1H), 8.29 (d, J=8.0Hz, 1H), 7.79 (m, 4H), 7.10 (d, J=8.8Hz, 2H), 4.30 (t, J=5.6Hz, 2H), 3.89 (m, 2H) .EM (calculated value): 351.1; MS (ESI) m/e (M+1H) +: 352.0, (M-1H) -: 349.9.
Compound 52
1H NMR (400MHz, DMSO-d 6) δ 13.57 (s, 1H), 11.04 (s, 1H), 8.88 (s, 1H), 8.53 (t, J=5.6Hz, 1H), 8.16 (d, J=8.0Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.60 (d, J=8.4Hz, 1H), 7.40 (t, J=8.0Hz, 1H), 7.23 (t, J=8.0Hz, 1H), 7.01 (d, J=8.8Hz, 2H), 4.19 (t, J=6.0Hz, 2H), 3.68 (m, 2H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.1, (M-1H) -: 339.2.
Compound 53
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.89 (m, 2H), 8.45 (s, 1H), 7.93 (s, 2H), 7.70 (d, J=8.4Hz, 2H), 7.01 (d, J=8.8Hz, 2H), 4.20 (t, J=5.6Hz, 2H), 3.69 (m, 2H) .EM (calculated value): 341.1; MS (ESI) m/e (M+1H) +: 341.8, (M-1H) -: 340.0.
Compound 54
1H NMR (400MHz, DMSO-d 6) δ 9.07 (s, 1H), 9.24 (d, J=8.0Hz, 1H), 8.53 (m 1H), 8.03 (m, 2H), 7.82 (t, J=6.8Hz, 1H), 7.71 (m, 3H), 7.03 (d, J=8.4Hz, 2H), 4.24 (t, J=4.8Hz, 2H), 3.76 (m, 2H) .EM (calculated value): 351.1; MS (ESI) m/e (M+1H) +: 351.9, (M-1H) -: 350.1.
Compound 55
1H NMR (400MHz, DMSO-d 6) δ 9.39 (s, 1H), 9.11 (s, 1H), 8.59 (s, 1H), 8.25 (m, 1H), 7.87 (m, 2H), 7.70 (m, 2H), 7.02 (m, 2H), 4.23 (s, 2H), 3.76 (s, 2H) .EM (calculated value): 351.1; MS (ESI) m/e (M+1H) +: 3518, (M-1H) -: 349.9.
Compound 56
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 9.47 (m, 1H), 9.23 (m, 1H), 8.19 (m, 2H), 7.98 (m, 2H), 7.70 (d, J=8.8Hz, 2H), 7.02 (d, J=8.4Hz, 2H), 4.25 (t, J=5.2Hz, 2H), 3.78 (m, 2H) .EM (calculated value): 352.1; MS (ESI) m/e (M+1H) +: 352.8, (M-1H) -: 350.9.
Compound 57
EM (calculated value): 350.11; MS (ESI) m/e (M+1H) +: 351.1, (M-1H) -: 349.1.
Compound 58
EM (calculated value): 351.12; MS (ESI) m/e (M+1H) +: 352.2, (M-1H) -: 350.0.
Compound 59
EM (calculated value): 365.14; MS (ESI) m/e (M+1H) +: 366.0, (M-1H) -: 364.2.
Compound 60
EM (calculated value): 368.12; MS (ESI) m/e (M+1H) +: 369.0, (M-1H) -: 367.1.
Compound 61
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.88 (s, 1H), 8.68 (t, J=5.6Hz, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.75 (d, J=8.0Hz, 1H), 7.70 (d, J=8.4Hz, 2H), 7.61 (d, J=8.0Hz, 1H), 7.01 (d, J=8.8Hz, 2H), 4.18 (t, J=6.0Hz, 2H), 3.66 (m, 2H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.0, (M-1H) -: 339.2.
Compound 62
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.11 (m, 2H), 7.98 (s, 1H), 7.70 (d, J=9.2Hz, 2H), 7.47 (d, J=7.6Hz, 1H), 7.20 (t, J=8.4Hz, 1H), 7.13 (t, J=6.8Hz, 1H), 7.01 (d, J=9.2Hz, 2H), 4.15 (t, J=6.0Hz, 2H), 3.82 (s, 3H), 3.62 (m, 2H) .EM (calculated value): 353.1; MS (ESI) m/e (M+1H) +: 354.0, (M-1H) -: 351.9.
Compound 63
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 9.14 (t, J=5.6Hz, 1H), 8.19 (d, J=8.4Hz, 1H), 8.08 (d, J=8.4Hz, 1H), 7.85 (t, J=8.4Hz, 1H), 7.69 (m, 4H), 7.03 (d, J=8.8Hz, 2H), 4.24 (t, J=6.0Hz, 2H), 4.15 (s, 3H), 3.78 (m, 2H) .EM (calculated value): 381.1; MS (ESI) m/e (M+1H) +: 381.9, (M-1H) -: 380.1.
Compound 64
EM (calculated value): 380.14; MS (ESI) m/e (M+1H) +: 381.0, (M-1H) -: 379.0.
Compound 65
EM (calculated value): 380.14; MS (ESI) m/e (M+1H) +: 381.2, (M-1H) -: 378.9.
Compound 66
EM (calculated value): 351.12; MS (ESI) m/e (M+1H) +: 352.0, (M-1H) -: 350.0.
Compound 67
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 8.26 (t, J=5.6Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.41-7.35 (m, 4H), 7.29 (m, 1H), 7.21 (s, 1H), 7.00 (d, J=9.2,2H), 4.12 (t, J=6.0Hz, 2H), 3.54 (false q, J=6.0Hz, 2H), 2.01 (s, 3H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 340.9, (M-1H) -: 339.2.
Compound 68
1H NMR (400MHz, DMSO-d 6) δ 11.08 (s, 1H), 10.72 (br s, 1H), 8.81 (t, J=5.2Hz, 1H), 7.94 (dd, J 1=8.4Hz, J 2=2.0Hz, 1H), 7.73 (d, J=8.8Hz, 2H), 7.32 (s, 1H), 7.03 (d, J=9.2Hz, 2H), 4.60 (s, 2H), 4.13 (false t, J=5.6Hz, 2H), 3.70 (false q, J=5.2Hz, 2H), 2.83 (s, 6H) .EM (calculated value): 397.2; MS (ESI) m/e (M+1H) +: 398.1, (M-1H) -: 396.0.
Compound 71
1H NMR(DMSO-d 6)：0.92(3H，t，7Hz)；1.53(1H，m)；1.72(1H，m)；2.48(3H，s)；3.94(1H，m)；4.03(2H，m)；6.62(1H，s)；6.78(1H，dd)；6.92(1H，d)；7.01(2H，d)；7.08(1H，s)；7.31(1H，d)；7.7(2H，d)；8.27(2H，d，7Hz)；9.25(1H，s).MS(M+1)：425.
Compound 72
1H NMR(DMSO-d 6)：0.90(2H，dd)；0.91(3H，t，7Hz)；1.1(2H，br.S)；1.52(1H，m)；1.68(1H，m)；1.92(1H，m)；2.0-2.1(3H，m *)；2.25(1H，m)；2.48(3H，s)；3.24(1H，m)；3.37(4H，m)；3.54(1H，m)；3.95(1H，m)；4.03(2H，m)；6.66(1H，s)；6.97(1H，m)；6.99(2H，d，9Hz)；7.07(1H，dd，9，2Hz)；7.12(1H，d，6Hz)：7.28(1H，dd，20，2Hz)；7.45(1H，t，9Hz)，7.7(2H，d，9Hz)；8.29(1H，d，δHz).MS(M+1)：548.
Compound 73
1H NMR(DMS0-d 6)：2.00(2H，m)；2.64(1H，m)；2.75(1H，m)；4.1(1H，m)；4.18(1H，m)；4.39(1H，m)；6.98(2H，d，9Hz)；7.14(1H，m)；7.19-7.28(5H，m)；7.32(1H，t，8Hz)；7.45(1H，m)；7.58(1H，s)；7.65(1H，d，7Hz)；7.68(2H，d，9Hz)；7.76(1H，d，J＝7Hz)8.74(1H，d，7Hz).MS(M-1)：443.
Compound 78
1H NMR(DMSO-d 6)：3.56(2H，m)；4.15(1H，m)；4.23(1H，m)；4.57(2H，s)；4.94(1H，m)；6.99(2H，d，9Hz)；7.33(1H，t，7Hz)；7.38(5H，s)；7.47(1H，t，7Hz)7.58(1H，s)；7.65(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.90(1H，s)；9.0(1H，d，8Hz).MS(M+1)：509.
Compound 79
1H NMR(DMSO-d 6)：2.7-2.81(2H，m)；3.78(2H，s)；4.12(1H，dd，10.5Hz)；4.22(1H，dd，10.7Hz)；4.51(1H，m)；6.97(2H，d，9Hz)；7.22(1H，m)；7.28(2H，m)；7.29(2H，s)；7.33(1H，t，7Hz)；7.46(1H，td，7.1Hz)；7.58(1H，s)；7.65(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(2H，d，8Hz)；8.79(1H，d，8Hz).MS(M+1)：475.
Compound 80
1H NMR(DMSO-d 6)：2.47(3H，d，1Hz)；3.57-3.62(3H，m)；3.77(3H，s)；4.08(1H，t，6Hz)；6.64(1H，s)；6.92(1H，dd，9，3Hz)；6.99(2H，d，9Hz)；7.12-7.15(2H，s+d)；7.42(1H，d，9Hz)；7.7(2H，d，9Hz)；8.49(1H，t，6Hz)；8.88(1H，s).MS(M+1)：411.
Compound 91
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.24 (t, J=5.6Hz, 1H), 7.73 (d, J=9.2Hz, 2H), 7.57 (d, J=6.8Hz, 2H), 7.44 (1H hides (buried) under 7.41 m for d, J=16.0Hz), 7.41 (m, 3H), 7.00 (d, J=8.8Hz, 2H), 6.63 (d, J=16.0Hz, 1H), 4.10 (false t, J=6.0Hz, 2H), 3.37 (false q, J=6.4Hz, 2H), 1.96 (false p, J=6.4Hz, 2H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.2, (M-1H) -: 339.3.
Compound 92
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 8.15 (s, 1H), 7.73 (d, J=8.4Hz, 2H), 7.51 (d, J=8.4Hz, 2H), 7.38 (d, J=15.6Hz, 1H), 6.99 (m, 4H), 6.48 (d, J=15.6Hz, 1H), 4.09 (false t, J=6.0Hz, 2H), 3.80 (s, 3H), 3.35 (false q, J=5.2Hz, 2H), 1.94 (false q, J=6.0Hz, 2H) .EM (calculated value): 370.2; MS (ESI) m/e (M+1H) +: 371.0, (M-1H) -: 368.9.
Compound 93
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.90 (t, J=5.6Hz, 1H), 8.31 (s, 1H), 7.98 (dd, J 1=7.2Hz, J 2=1.6Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.40 (false t, J=7.2Hz, 2H), 7.31 (false tt, J 1=7.2Hz, J 2=2.0Hz, 1H), 6.90 (d, J=9.2Hz, 2H), 4.03 (t, J=5.6Hz, 2H), 3.42 (false q, J=6.0Hz, 2H), 1.98 (false p, J=6.0Hz, 2H) .EM (calculated value): 397.1; MS (ESI) m/e (M+1H) +: 397.9, (M-1H) -: 396.0.
Compound 94
1H NMR (400MHz, DMSO-d 6) δ 11.09 (s, 1H), 8.26 (d, J=7.2Hz, 1H), 7.74 (d, J=8.4Hz, 2H), 7.58 (d, J=7.2Hz, 2H), 7.44 (m, 4H), 7.05 (d, J=8.8Hz, 2H), 6.68 (d, J=16.4Hz, 1H), 4.27 (m, 1H), 4.07 (m, 1H), 3.96 (m, 1H), 1.25 (d, J=6.8Hz, 3H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.1, (M-1H) -: 339.1.
Compound 95
1H NMR (400MHz, DMSO-d 6) δ 11.09 (s, 1H), 8.27 (d, J=8.0Hz, 1H), 7.74 (d, J=8.8Hz, 2H), 7.58 (d, J=7.2Hz, 2H), 7.46 (d, J=16.0Hz, 1H), 7.42 (m, 3H), 7.04 (d, J=9.2Hz, 2H), 6.68 (d, J=16.4Hz, 1H), 4.27 (false p, J=6.8Hz, 1H), 4.07 (dd, J 1=5.6Hz, J 2=10.0Hz, 1H), 3.96 (dd, J 1=5.6Hz, J 2=9.6Hz, 1H), 1.25 (d, J=7.2Hz, 3H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.1, (M-1H) -: 339.1.
Compound 96
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 8.87 (s, 1H), 8.12 (d J=8.0Hz, 1H), 7.67 (dt, J 1=8.8Hz, J 2=2.0Hz, 1H), 7.54 (dd, J 1=8.4Hz, J 2=1.6Hz, 2H), 7.43-7.33 (m, 4H), 6.99 (dt J 1=9.2Hz, J 2=2Hz, 2H), 6.65 (d, J=15.6Hz, 1H), 4.26 (m, 1H), 4.01 (dd, J 1=9.6Hz, J 2=4.8Hz, 1H), 3.94 (dd J 1=9.6Hz, J 2=5.6Hz, 1H), 1.66 (m, 1H), 1.49 (m, 2H), 0.91 (d J=6.8Hz, 3H), 0.87 (d, J=6.4Hz, 3H) .EM (calculated value): 382.2; MS (ESI) m/e (M+1H) +: 383.0, (M-1H) -: 381.1.
Compound 97
1H NMR (400MHz, DMSO-d 6) δ 10.95 (s, 1H), 8.81 (s, 1H), 8.05 (d, J=8.4Hz, 1H), 7.62 (d, J=8.8Hz, 2H), 7.47 (d, J=6.8Hz, 2H), 7.37-7.28 (m, 4H), 6.92 (dt, J 1=8.4Hz, J 2=1.6Hz, 2H), 6.61 (d, J=16Hz, 1H), 4.21 (m, 1H), 3.94 (m, 1H), 3.86 (m, 1H), 1.69 (d.J=12.4Hz, 1H), 1.59-1.52 (m, 4H), 1.42 (t, J=7.2Hz, 2H), 1.28 (m, 1H), 1.15-1.05 (m, 3H), 0.90 (m, 1H), 0.77 (m, 1H) .EM (calculated value): 422.2; MS (ESI) m/e (M+1H) +: 423.2, (M-1H) -: 421.2.
Compound 98
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.88 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.69 (dt, J 1=8.8Hz, J 2=2.8Hz, 2H), 7.432-7.32 (sequence m, 4H), 6.99 (dt, J 1=9.2Hz, J 2=2.4Hz, 2H), 6.73 (d, J=15.6Hz, 1H), 4.05 (s, 3H), 1.98 (m, 1H), 0.95 (d, J=2.4Hz, 3H), 0.93 (d, J=2.4Hz, 3H) .EM (calculated value): 368.2; MS (ESI) m/e (M+1H) +: 368.7, (M-1H) -: 367.1.
Compound 99
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.32 (d, J=8Hz, 1H), 7.69 (d, J=9.2Hz, 2H), 7.53 (m, 2H), 7.43-7.34 (m, 4H), 7.28-7.22 (m, 3H), 7.18 (m, 2H), 6.99 (d, J=9.2Hz, 2H), 6.63 (d, J=16Hz, 1H), 4.38 (m, 1H), 4.02 (d, J=6.4Hz, 2H), 2.99 (m, 1H), 2.88 (m, 1H). lack OH or NH.EM (calculated value): 416.2; MS (ESI) m/e (M+1H) +: 417.3, (M-1H) -: 415.2.
Compound 100
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.78 (s, 1H), 8.32 (d, J=8Hz, 1H), 7.69 (d, J=8.8Hz, 2H), 7.52 (dd, J 1=8.4Hz, J 2=1.6Hz, 2H), 7.41-7.34 (m, 4H), 7.28-7.23 (m, 4H), 7.19-7.15 (m, 1H), 6.99 (d, J=9.2Hz, 2H), 6.63 (d, J=15.6Hz, 1H), 4.38 (m, 1H), 4.01 (d, J=4.4Hz, 2H), 2.99 (dd, J 1=13.6Hz, J 2=6Hz, 1H), 2.88 (dd, J 1=14Hz, J 2=8Hz, 1H) .EM (calculated value): 416.2; MS (ESI) m/e (M+1H) +: 417.2, (M-1H) -: 415.2.
Compound 101
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 8.87 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 7.69 (d, J=8.4Hz, 2H), 7.53 (d, J=7.2Hz, 2H), 7.43-7.33 (m, 4H), 6.99 (d, J=9.2Hz, 2H), 6.65 (d, J=15.6Hz, 1H), 4.25 (m, 1H), 4.01 (dd, J=9.6Hz, 4.8Hz, 1H), 3.94 (dd J 1=9.6Hz, J 2=5.6Hz, 1H), 1.66 (m, 1H), 11.48 (m, 2H), 0.91 (d J=6.8Hz, 3H), 0.87 (d, J=6.4Hz, 3H) .EM (calculated value): 382.2; MS (ESI) m/e (M+1H) +: 383.2, (M-1H) -: 381.2.
Compound 102
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.87 (s, 1H), 8.08 (d, J=8Hz, 1H), 7.69 (d, J=8.8Hz, 2H), 7.55 (d, J=1.2Hz, 2H), 7.43-7.32 (m, 4H), 6.99 (d, J=9.2Hz, 2H), 6.73 (d, J=16Hz, 1H) 4.05 (s, 3H), 1.98 (m, 1H), 0.946 (d, J=2Hz, 3H), 0.93 (d, J=2.4Hz, 3H) .EM (calculated value): 368.2; MS (ESI) m/e (M+1H) +: 369.1, (M-1H) -: 367.1.
Compound 103
1H NMR (400MHz, DMSO-d 6) δ 11.04 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 7.69 (dt, J 1=8.8Hz, J 2=2.8Hz, 2H), 7.54 (dd, J 1=6.8, J 2=1.2Hz, 2H), 7.43-7.32 (m, 4H), 6.99 (dt, J 1=8.8Hz, J 2=3.2Hz, 2H), 6.66 (d, J=15.6Hz, 1H), 4.16 (m, 1H), 4.03 (dd, J 1=10Hz, J 2=5.6Hz, 1H), 3.96 (dd, J 1=10Hz, J 2=5.2Hz, 1H), 1.67 (m, 1H), 1.53 (m, 1H), 1.36-1.27 (m, 4H), 0.87 (t, J=6.4Hz, 3H). lack 1H, NH or OH.EM (calculated value): 382.21; MS (ESI) m/e (M+1H) +: 383.1, (M-1H) -: 381.1.
Compound 104
1H NMR (400MHz, DMSO-d 6) δ 10.97 (s, 1H), 8.25 (d, J=8.4Hz, 1H), 7.64 (dt, J 1=8.8Hz, J 2=2Hz, 2H), 7.46 (dd, J 1=7.6Hz, J 2=2Hz, 2H), 7.34-7.18 (sequence m, 6H), 6.93 (dt, J 1=9.2Hz, J 2=2.8Hz, 2H), 6.54 (d, J=15.6Hz, 1H), 4.31 (m, 1H), 3.95 (d, J=4.8Hz, 2H), 2.93 (dd, J 1=13.6Hz, J 2=5.6Hz, 1H), 2.79 (dd, J 1=13.6Hz, J 2=8.4Hz, 1H) .EM (calculated value): 450.1; MS (ESI) m/e (M+1H) +: 451.2; (M-1H) -: 449.2.
Compound 105
1H NMR (400MHz, DMSO-d 6) δ 10.97 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.62 (dt, J 1=8.8Hz, J 2=2.8Hz, 2H), 7.47 (dd, J 1=8.8Hz, J 2=1.6Hz, 2H), 7.34-7.26 (sequence m, 4H), 6.93 (dt, J 1=8.8Hz, J 2=2.8Hz, 2H), 6.61 (d, J=15.6Hz, 1H), 4.04 (m, 1H), 3.98 (dd, J 1=15.6Hz, J 2=5.6Hz, 1H), 3.90 (dd, J 1=9.2, J 2=5.6Hz, 1H), 1.64 (m, 1H), 1.46 (m, 1H), 0.85 (t, J=6.8Hz, 3H) .EM (calculated value): 354.2; MS (ESI) m/e (M+1H) +: 354.6, (M-1H) -: 353.2.
Compound 106
1H NMR (400MHz, DMSO-d 6) δ 10.97 (s, 1H), 8.07 (d, J=8Hz, 1H), 7.62 (d J=8.8Hz, 2H), 7.47 (dd, J 1=6.8Hz, J 2=1.6Hz, 2H), 7.35-7.62 (sequence m, 4H), 6.93 (dt, J 1=9.2, J 2=2Hz, 2H), 6.61 (d, J=15.6Hz, 1H), 3.98 (dd, J 1=9.6Hz, J 2=5.6Hz, 1H), 3.90 (dd, J 1=9.6, J 2=4.8Hz, 1H), 1.65 (m, 1H), 1.49 (m, 1H), 0.85 (t, J=7.2Hz, 3H) .EM (calculated value): 354.2; MS (ESI) m/e (M+1H) +: 354.8, (M-1H) -: 353.1.
Compound 107
EM (calculated value): 400.49; MS (ESI) m/e (M+1): 401.0, (M-1): 399.0.
Compound 108
EM (calculated value): 400.49; MS (ESI) m/e (M+1): 401.1, (M-1): 399.2.
Compound 109
1H NMR (400MHz, DMSO-d 6) δ 10.97 (s, 1H), 8.80 (br s, 1H), 8.73 (d, J=8.4Hz, 1H), 7.62 (d, J=9.2Hz, 2H), 7.48 (d, J=6.8Hz, 2H), 7.38-7.27 (sequence m, 8H), 7.21 (t, J=7.2Hz, 1H), 6.93 (d, J=8.8,2H), 6.69 (d, J=15.6Hz, 1H), 5.30 (dd, J 1=13.6Hz, J 2=7.6Hz, 1H), 4.19 (d, J=6.4Hz, 2H) .EM (calculated value): 402.2; MS (ESI) m/e (M+1H) +: 403.2, (M-1H) -: 400.9.
Compound 110
1H NMR (400MHz, DMSO-d 6) δ 10.97 (s, 1H), 8.80 (br s, 1H), 8.74 (d, J=8Hz, 1H), 7.62 (dt, J 1=8.8Hz, J 2=2Hz, 2H), 7.48 (dd, J 1=6.4Hz, J 2=1.6Hz, 2H), 7.39-7.27 (sequence m, 8H), 7.21 (tt, J 1=7.6Hz, J 2=1.2Hz, 1H), 6.93 (dt, J 1=9.2Hz, J 2=2.4Hz, 2H), 6.69 (d, J=15.6,1H), 5.29 (dd, J 1=8Hz, J 2=6.4Hz, 1H), 4.18 (d, J=6.4Hz, 2H) .EM (calculated value): 402.2; MS (ESI) m/e (M+1H) +: 402.9, (M-1H) -: 401.2.
Compound 111
1H NMR (400MHz, DMSO-d 6) δ 8.25 (d, J=8Hz, 1H), 7.83 (d, J=8.8Hz, 2H), 7.48 (d, J=6.4Hz, 2H), 7.39-7.27 (sequence m, 4H), 7.01 (d, J=8.8Hz, 2H), 6.58 (d, J=16.4Hz, 1H), 4.25 (m, 1H), 4.03 (m, 2H), 3.73 (s, 3H), 3.12 (m, 2H), 2.06 (m, 1H), 1.93 (m, 1H) .EM (calculated value): 432.1; MS (ESI) m/e (M+1H) +: 433.2, (M-1H) -: 430.0.
Compound 112
1H NMR (400MHz, DMSO-d 6) δ 8.24 (d, J=8Hz, 1H), 7.82 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.84-7.29 (sequence m, 4H), 7.01 (d, J=8.8Hz, 2H), 6.58 (d, J=16.4Hz, 1H), 4.35 (m, 1H), 4.03 (m, 2H), 3.70 (s, 3H), 3.13 (m, 2H), 2.06 (m, 1H), 1.93 (m 1H) .EM (calculated value): 432.1; MS (ESI) m/e (M+1H) +: 432.2, (M-1H) -: 430.2.
Compound 113
1H NMR (400MHz, DMSO-d 6) δ 8.50 (d, J=8.0Hz, 1H), 7.83 (dt, J 1=9.2Hz, J 2=2.8Hz, 2H), 7.48 (dd, J 1=6Hz, J 2=1.6Hz, 2H), 7.39 (d, J=16Hz, 1H), 7.31 (m, 9H), 6.97 (dt, J 1=9.2Hz, J 2=2.4Hz, 2H), 6.57 (d, J=16Hz, 1H), 4.72 (m, 1H), 4.50 (s, 1H), 4.16 (dd, J 1=9.6Hz, J 2=5.2Hz), 1H, 4.08 (dd, J 1=10Hz, J 2=4.8Hz, 1H), 3.45 (dd, J 1=14.4Hz, J 2=5.6Hz, 1H), 3.36 (dd, J 1=14.4Hz, J 2=6.8Hz, 1H) .EM (calculated value): 492.2; MS (ESI) m/e (M+1H) +: 494.3, (M-1H) -: 492.2.
Compound 114
1H NMR (400MHz, DMSO) δ 11.07 (br s, 1H), 8.38 (d, J=7.6Hz, 2H), 7.84 (dd, J 1=3.6Hz, J 2=1.2Hz, 1H), 7.77 (dd, J 1=4.8Hz, J 2=1.2Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 7.16 (dd, J 1=3.6Hz, J 2=5.2Hz, 1H), 7.02 (d, J 1=8.4Hz, 2H), 4.20 (m, 1H), 4.13 (dd, J 1=6.4Hz, J 2=9.6Hz, 1H), 4.04 (dd, J 1=5.2Hz, J 2=9.2Hz, 2H) 1.77 (m 1H), 1.63 (m, 1H), 1.21 (d, J=6.4Hz, 1H), 0.96 (t, J=7.2Hz, 3H) .EM (calculated value): 334.1; MS (ESI) m/e (M+1H) +: 335.0, (M-1H) -: 333.0.
Compound 115
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.37 (d, J=8.0Hz, 1H), 7.94 (d, J=8.4Hz, 2H), 7.72 (m, 6H), 7.48 (m, 2H), 7.39 (m, 1H), 7.00 (d, J=8.4Hz, 2H), 4.24 (m, 1H), 4.06 (m, 2H), 1.74 (m, 2H), 0.95 (t, J=7.2Hz, 3H) .EM (calculated value): 404.2; MS (ESI) m/e (M+1H) +: 405.2, (M-1H) -: 4032.
Compound 116
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.87 (s, 1H), 8.50 (d, J=8.4Hz, 1H), 8.44 (s, 1H), 7.97 (m, 4H), 7.70 (d, J=8.8Hz, 2H), 7.59 (m, 2H), 7.02 (d, J=8.8Hz, 2H), 4.29 (m, 1H), 4.14 (m, 2H), 1.68 (m, 2H), 0.98 (t, J=7.2Hz, 3H) .EM (calculated value): 378.2; MS (ESI) m/e (M+1H) +: 378.9, (M-1H) -: 377.0.
Compound 117
1H NMR (400MHz, DMSO-d 6) δ 10.98 (s, 1H), 8.82 (s, 1H), 8.27 (d, J=8.4Hz, 1H), 7.64 (d, J=9.2Hz, 2H), 7.48 (dd, J 1=6.4Hz, J 2=1.6Hz, 2H), 7.38 (d, J=15.6Hz, 1H), 7.36-7.27 (m, 3H), 7.23-7.19 (m, 4H), 7.14 (m, 1H), 6.92 (d, J=8.8Hz, 2H), 6.61 (d, J=15.6Hz, 1H), 4.29 (m, 1H), 4.08 (dd, J 1=9.6Hz, J 2=5.6Hz, 1H), 3.98 (dd, J 1=9.6Hz, J 2=4.4Hz, 1H), 3.70 (d, J=2.4Hz, 2H), 2.67 (dd, J 1=6.8Hz, J 2=13.6Hz, 1H), 2.58 (dd, J 1=13.2Hz, J 2=7.2Hz, 1H) .EM (calculated value): 460.2; MS (ES1) m/e (M-1H) -: 460.8.
Compound 118
1H NMR (400MHz, DMSO-d 6) δ 11.02 (s, 1H), 8.31 (d, J=8.4Hz, 1H), 7.83 (d, J=7.2Hz, 2H), 7.68 (d, J=8.8Hz, 2H), 7.52-7.42 (m, 3H), 6.99 (d, J=9.2Hz, 2H), 4.22 (m, 1H), 4.11 (dd, J 1=6.4Hz, J 2=10.0Hz, 1H), 4.01 (dd, J 1=6.0Hz, J 2=9.6Hz, 1H), 1.73 (m 1H), 1.62 (m, 1H), 0.93 (t, J=7.6Hz, 3H) .EM (calculated value): 328.1; MS (ESI) m/e (M+1H) +: 329.1. (M-1H) -: 327.0.
Compound 119
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.08 (d, J=7.2Hz, 1H), 7.69 (d, J=8.8Hz, 2H), 7.24 (m, 5H), 6.96 (d, J=9.2Hz, 2H), 3.94 (m3H), 3.43 (s, 2H), 1.64 (m, 1H), 1.47 (m, 1H), 0.86 (t, 7.2Hz, 3H) .EM (calculated value): 342.2; MS (ESI) m/e (M+1H) +: 343.0, (M-1H) -: 341.1.
Compound 120
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.69 (d, J=8.4Hz, 2H), 7.23-7.10 (m, 5H), 6.94 (d, J=9.2Hz, 2H), 3.94 (m, 2H), 3.84 (m, 1H), 2.81 (t, J=7.2Hz, 2H), 2.40 (t, J=7.6Hz, 2H), 1.61 (ddd, J 1=4.4Hz, J 2=7.6Hz, J 3=18.4Hz, 1H), 1.41 (m, 1H), 0.81 (t, J=6.8Hz, 3H) .EM (calculated value): 356.2; MS (ESI) m/e (M+1H) +: 357.1, (M-1H) -: 355.1.
Compound 121
EM (calculated value): 356.38; MS (ESI) m/e (M+1): 357.0, (M-1): 355.1.
Compound 122
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.65 (d, J=8.8Hz, 1H), 8.33 (s, 1H), 8.00 (d, J=7.2Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.39 (false t, J=7.2Hz, 2H), 7.30 (false t, J=7.6Hz, 1H), 6.93 (d, J=9.2Hz, 2H), 4.20 (m, 1H), 4.23 (dd, the lower section, peak 4.20 hides, J 1=9.2Hz, J 2=16.8Hz, 1H), 4.05 (dd, J 1=10.0Hz, J 2=4.8Hz, 1H), 1.69 (m 1H), 1.62 (m, 1H), 0.88 (t, J=7.2Hz, 3H) .EM (calculated value): 411.1; MS (ESI) m/e (M-1H) -: 410.1.
Compound 123
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.03 (d, J=7.6Hz, 1H), 7.69 (d, J=8.8Hz, 2H), 7.48 (d, J=9.2Hz, 2H), 7.36 (d, J=15.6Hz, 1H), 6.99 (d, J=9.2Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 6.52 (d, J=15.6Hz, 1H), 4.09 (m, 1H), 4.04 (dd, J 1=5.2Hz, J 2=9.6Hz, 1H), 3.95 (dd, J 1=5.2Hz, J 2=9.6Hz, 1H), 3.77 (s, 3H), 1.71 (m, 1H), 1.52 (m, 1H), 0.91 (t, J=6.8Hz, 3H) .EM (calculated value): 384.2; MS (ESI) m/e (M+1H) +: 385.0, (M-1H) -: 383.2.
Compound 124
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 10.62 (br s, 1H), 8.43 (d, J=8.0Hz, 1H), 8.28 (d, J=1.6Hz, 1H), 7.94 (dd, J 1=8.4Hz, J 2=2.0Hz, 1H), 7.23 (d, J=8.4Hz, 2H), 7.32 (s, 1H), 7.03 (d, J=8.8Hz, 2H), 4.60 (s, 2H), 4.28 (m, 1H), 4.17 (dd, J 1=10.0Hz, J 2=6.8Hz, 1H), 4.08 (dd, J 1=10.4Hz, J 2=6.0Hz, 1H), 2.84 (s, 6H), 1.80 (m, 1H), 1.65 (m, 1H), 0.98 (t, J=7.6Hz, 3H) .EM (calculated value): 425.2; MS (ESI) m/e (M+1H) +: 426.2, (M-1H) -: 424.1.
Compound 125
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.80 (s, 1H), 8.27 (t, J=5.2Hz, 1H), 7.62 (J=8.8Hz, 2H), 7.46 (d, J=6.8Hz, 2H), 7.36 (d, J=12.8Hz, 1H), 7.33-7.28 (m, 3H), 6.95 (d, J=8.4Hz, 2H), 6.60 (d, J=12.8Hz, 1H), 4.53 (ddd, J=5.6Hz, 1H), 3.40 (m, 1H), 3.29 (m, 1H hides under the water peak), 1.19 (d, J=6.4Hz, 3H) .EM (calculated value): 340.1.
Compound 126
1H NMR (400MHz, DMSO-d 6) δ 11.02 (s, 1H), 8.87 (s, 1H), 8.34 (t, J=5.6Hz, 1H), 7.68 (d, J=8.4Hz, 2H), 7.53 (d, J=8.8Hz, 2H), 7.43 (d, J=13.2Hz, 1H), 7.40-7.35 (m, 3H), 7.02 (d, J=8.8Hz, 2H), 6.67 (d, J=16Hz, 1H), 4.60 (ddd, J 1=6.0Hz, J 2=11.6Hz, J 3=17.6Hz, 1H), 3.47 (m, 1H), 3.36 (m 1H hides under the water peak), 1.26 (d, J=6.0Hz, 3H) .EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.0, (M-1H) -: 339.2.
Compound 127
EM (calculated value): 397.1; MS (ESI) m/e (M-1H) -: 396.1.
Compound 128
EM (calculated value): 397.1; MS (ESI) m/e (M+1H) +: 398.2, (M-1H) -: 396.2.
Compound 129
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.69 (t, J=5.6Hz, 1H), 7.84 (d, J=8.4Hz, 2H), 7.67 (d, J=8.4Hz, 1H), 7.63 (m, 4H), 7.40 (t, J=7.6Hz, 2H), 7.32 (m, 1H), 6.98 (d, J=12.0Hz, 2H), 4.62 (ddd, J 1=6.0Hz, J 2=12.0Hz, J 3=18.0Hz, 1H), 3.52 (ddd, J 1=6.4Hz, J 2=13.6Hz, J 3=19.6Hz, 1H), 3.31 (m, 1H hide under the water peak), 1.23 (d, J=6.0Hz, 3H) .EM (calculated value): 390.2; MS (ESI) m/e (M+1H) +: 391.3, (M-1H) -: 389.0.
Compound 130
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.24 (t, J=5.2Hz, 1H), 7.68 (d, J=8.8Hz, 2H), 7.48 (d, J=8.8Hz, 2H), 7.37 (d, J=15.6Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 6.95 (d, J=8.8Hz, 2H), 6.51 (d, J=15.6Hz, 1H), 4.58 (false q, J=5.6Hz, 1H), 3.77 (s, 3H), 3.46 (ddd, J 1=4.8Hz, J 2=13.2Hz, J 3=19.2Hz, 1H), 3.32 (ddd, J 1=5.2Hz, J 2=10.8Hz, J 3=13.2Hz, 1H), 1.25 (d, J=6.0Hz, 3H) .EM (calculated value): 370.2; MS (ESI) m/e (M+1H) +: 371.0, (M-1H) -: 369.1.
Compound 131
1H NMR(DMSO-d 6)：3.67(q，2H)，4.18(t，2H)，7.01(d，2H)，7.7(d，2H)，7.98(d，2H)，8.12(d，2H)，8.17(d，2H)，8.55(s，1H)，8.79(m，3H)，11.05(s，1H).LC\MS：(M+1) +1461.2，(M-1) -1459.0.
Compound 132
1H NMR (400MHz, DMSO-d 6) δ: 11.08 (s, 1H), 8.94 (m, 2H), 7.75 (m, 3H), 7.47 (d, 1H, J=8.1Hz), 7.16 (d, 1H, J=8.1Hz), 7.04 (d, 2H, J=9.6Hz), 4.22 (t, 2H, J=5.5Hz), 3.71 (t, 2H, J=5.5Hz), 3.36 (s, 3H) .EM (calculated value): 388.08; MS (ESI) m/e (M+1H) +: 388.9, (M-1H) -: 387.1.
Compound 133
1H NMR(DMSO-d 6)：2.85(s，3H)，3.4(s，8H)，3.65(q，2H)，4.17(t，2H)，7.00(d，2H)，7.54(s，1H)，7.7(d，2H)，7.9(dd，4H)，8.74(t，1H)，8.9(s，1H)，10.2(s，1H)，11.05(s，1H).LC\MS：(M+1) +1482.0，(M-1) -1480.2.
Compound 134
1H NMR(DMSO-d 6)：3.66(q，2H)，4.18(t，2H)，7.01(d，2H)，7.69(m，4H)，7.91(d，2H)，8.02(d，3H)，8.33(dd，2H)，8.75(t，1H)，9.16(s，1H)，10.99(s，1H)，11.05(s，1H).LC\MS：(M+1) +1476.1，(M-1) -1474.2.
Compound 135
1H NMR(DMSO-d 6)：2.85(s，3H)，3.01(m，4H)，3.51(d，2H)，3.60(q，2H)，4.00(d，2H)，4.13(t，2H)，6.98(dd，4H)，7.74(dd，4H)，8.48(t，1H)，9.97(s，1H)，11.05(s，1H).LC\MS：(M+1) +1399.3，(M-1) -1397.2.
Compound 136
1H NMR(DMSO-d 6)：1.4(m，2H)，1.8(m，2H)，2.95(m，2H)，3.6(m，5H)，4.12(t，2H)，4.69(s，1H)，6.91(d，2H)，6.99(d，2H)，7.7(dd，4H)，8.36(t，1H)，8.87(s，1H)，11.03(s，1H).LC\MS：(M+1) +1400.2，(M-1) -1398.3.
Compound 138
1H NMR (400MHz, DMSO-d 6) δ: 9.02 (t, 2H, J=5.3Hz), 7.77-7.72 (m, 3H), 7.27 (m, 1H), 7.11 (m, 1H), 7.03 (d, 2H, J=8.8Hz), 4.22 (t, 2H, J=5.3Hz), 3.70 (t, 2H, J=5.3Hz), 2.51 (s, 3H) .EM (calculated value): 372; MS (ESI) m/e (M+1H) +: 373.0, (M-1H) -: 371.0.
Compound 139
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 10.04 (s, 1H), 9.02 (t, 1H, J=5.7Hz), 7.74 (d, 1H, J=2.7Hz), 7.70 (d, 2H, J=8.5Hz), 7.32 (m, 1H), 7.25 (m, 1H), 7.00 (d, 2H, J=8.5Hz), 4.72 (s, 2H), 4.19 (t, 2H, J=5.7Hz), 3.67 (m, 2H), 3.59 (m, 2H), 3.48 (m, 2H), 3.24 (s, 3H) .EM (calculated value): 446.15; MS (ESI) m/e (M+1H) +: 447.4, (M-1H) -: 445.3.
Compound 140
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (br s, 1H), 9.25 (t, 1H, J=5.9Hz), 8.07 (d, 1H, J=8.6Hz), 7.96 (d, 1H, J=8.6Hz), 7.70 (m, 3H), 7.39 (t, 1H, J=7.6Hz), 7.01 (d, 2H, J=9.1Hz), 6.88 (br s, 1H), 4.21 (t, 2H, J=5.9Hz), 3.70 (q, 2H, J=5.9Hz) .EM (calculated value): 367; MS (ES1) m/e (M+1H) +: 368.0, (M-1H) -: 366.2.
Compound 141
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (br s, 1H), 9.04 (t, 1H, J=5.9Hz), 7.80 (d, 1H, J=2.6Hz), 7.70 (d, 1H, J=8.7Hz), 7.40 (m, 2H), 7.28 (t, 1H, J=8.1Hz), 7.05-6.92 (m, 5H), 5.35 (s, 2H), 4.18 (t, 2H, J=5.9Hz), 3.66 (q, 2H, J=5.9Hz) .EM (calculated value): 464; MS (ESI) m/e (M+1H) +: 465.3, (M-1H) -: 463.1.
Compound 143
1H NMR(DMSO-d 6)：2.55(t，3H)，2.80(s，3H)，3.07(d，3H)，3.4(d，2H)，3.65(q，2H)，4.02(s，2H)，4.17(t，2H)，6.99(d，2H)，7.69(d，2H)，7.91(d，2H)，8.01(d，2H)，8.23(s，1H)，8.75(t，1H)，9.6(s，1H)，11.05(s，1H).LC\MS：(M+1) +1496.3，(M-1) -1494.4
Compound 144
MS(ESI)m/e：(M+1H) +：302.0，(M-1H) -：300.2.
Compound 145
MS(ESI)m/e：(M+1H) +：318.1，(M-1H) -：316.1.
Compound 146
MS(ESI)m/e：(M+1H) +：318.1，(M-1H) -：316.2.
Compound 147
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，8.28(m，2H)，8.15(m，1H)，7.94(m，2H)，7.66(m，2H)，7.41(m，3H)，6.89(m，2H)，4.10(m，2H)，3.63(m，2H).MS(ESI)m/e：(M+1H) +：439.2，(M-1H) -：437.2.
Compound 148
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，9.10(t，J＝8.0Hz，1H)，8.18(d，J＝8.0Hz，1H)，8.06(d，J＝8.0Hz，1H)，7.85(t，J＝8.0Hz，1H)，7.67(m，4H)，7.04(d，J＝8.0Hz，2H)，4.45(m，2H)，4.23(t，J＝8.0Hz，2H)，3.84(m，2H)，3.76(m，2H).MS(ESI)m/e：(M+1H) +：426.3，(M-1H) -：424.2.
Compound 149
1H NMR(400MHz，DMSO-d 6)δ11.06(s，1H)，10.31(s，1H)，9.10(t，J＝8.0Hz，1H)，8.40(d，J＝8.0Hz，1H)，8.07(d，J＝8.0Hz，1H)，7.86(t，J＝8.0Hz，1H)，7.69(m，4H)，7.02(d，J＝8.0Hz，2H)，4.74(m，2H)，4.23(t，J＝8.0Hz，2H)，3.77(m，2H)，3.70(m，2H).MS(ESI)m/e：(M+1H) +：439.3，(M-1H) -：437.3.
Compound 150
MS(ESI)m/e：(M+1H) +：379.9，(M-1H) -：379.9.
Compound 151
MS(ESI)m/e：(M+1H) +：379.9，(M-1H) -：379.9.
Compound 152
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (br s, 1H), 8.85 (d, 1H, J=9.0Hz), 8.20 (d, 1H, J=1.2Hz), 8.18 (d, 1H, J=1.2Hz), 7.85 (m, 1H), 7.70-7.65 (m, 4H), 7.01 (t, 2H, J=8.7Hz), 4.32 (m, 1H), 4.25 (m, 1H), 4.15 (s, 3H), 4.13 (m, 1H), 1.77 (m, 2H), 0.95 (t, 3H, J=7.0) .EM (calculated value): 409; MS (ESI) m/e (M+1H) +: 410.2, (M-1H) -: 408.2.
Compound 153
1H NMR (400MHz, DMSO-d 6) δ: 11.05 (s, 1H), 10.17 (s, 1H), 8.65 (m, 1H), 8.14 (m, 1H), 7.95 (m, 1H), 7.88 (d, 1H, J=8.2Hz), 7.73-7.66 (m, 3H), 7.62-7.59 (m, 2H), 7.05 (m, 2H), 4.24 (m, 2H), 3.89 (s, 3H), 3.73 (m, 2H) .EM (calculated value): 380; MS (ESI) m/e (M+1H) +: 381.0, (M-1H) -: 379.1.
Compound 154
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 9.14 (t, 1H, J=6.0Hz), 8.18 (d, 1H, J=7.7Hz), 8.07 (d, 1H, J=8.2Hz), 7.85 (t, 1H, J=7.7Hz), 7.72-7.64 (m, 4H), 7.08 (d, 2H, J=9.1Hz), 4.78 (m, 1H), 4.14 (s, 3H), 3.66 (m, 1H), 3.55 (m, 1H), 1.31 (d, 3H, J=6.1Hz) .EM (calculated value): 395; MS (ESI) m/e (M+1H) +: 396.1, (M-1H) -: 394.2.
Compound 155
MS(ESI)m/e：(M+1H) +：377.9，(M-1H) -：376.1.
Compound 156
MS(ESI)m/e：(M+1H) +：408.3，(M-1H) -：406.2.
Compound 157
MS(ESI)m/e：(M+1H) +：373.9，(M-1H) -：372.1.
Compound 158
MS(ESI)m/e：(M+1H) +：422.3，(M-1H) -：420.3.
Compound 159
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 9.10 (t, 1H, J=5.9Hz), 8.16 (d, 1H, J=8.4Hz), 8.07 (d, 1H, J=8.4Hz), 7.85 (t, 1H, J=7.9Hz), 7.71-7.65 (m, 4H), 7.03 (d, 2H, J=8.9Hz), 4.60 (t, 2H, J=5.9Hz), 4.23 (t, 2H, J=5.1Hz), 3.75 (q, 2H, J=5.9Hz), 3.00 (m, 2H) .EM (calculated value): 463; MS (ESI) m/e (M+1H) +: 464.3, (M-1H) -: 462.2.
Compound 160
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 8.78 (d, 1H, J=9.0Hz), 8.15 (d, 1H, J=8.3Hz), 8.09 (d, 1H, J=8.5Hz), 7.85 (t, 1H, J=6.7Hz), 7.68 (m, 4H), 7.00 (d, 2H, J=9.0Hz), 4.61 (t, 2H, J=5.9Hz), 4.32 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H), 3.00 (m, 2H), 1.76 (m, 2H), 0.95 (t, 3H, J=7.0Hz) .EM (calculated value): 491; MS (ESI) m/e (M+1H) +: 492.1, (M-1H) -: 490.1.
Compound 161
1H NMR (400MHz, DMSO-d 6) δ: 9.13 (t, 1H, J=6.1Hz), 8.15 (d, 1H, J=8.1Hz), 8.07 (d, 1H, J=8.3Hz), 7.86 (t, 1H, J=6.7Hz), and 7.71-7.67 (m, 4H), 7.08 (d, 2H, J=8.7Hz), 4.78 (m, 1H), 4.61 (t, 1H, J=5.5Hz), 3.65 (m, 1H), 3.55 (m, 1H), 3.00 (m, 2H), 1.31 (d, 3H, J=6.0Hz) .EM (calculated value): 477; MS (ESI) m/e (M+1H) +: 477.9, (M-1H) -: 476.1.
Compound 162
1H NMR(DMSO-d 6)：3.56(s，2H)，4.09(t，2H)，6.57(d，1H)，6.77(d，1H)，6.95(m，3H)，7.18(t，1H)，7.32(d，2H)，7.69(d，2H)，8.38(t，1H)，9.6(s，1H)，11.05(s，1H).LC\MS：(M+1) +1343.2，(M-1) -1341.3.
Compound 163
1H NMR(DMSO-d 6)：3.55(s，2H)，4.08(t，2H)，6.4(d，1H)，6.8(d，2H)，7.0(d，2H)，7.35(d，1H)，7.4(d，2H)，7.69(d，2H)，8.25(t，1H)，9.85(s，1H)，11.05(s，1H).LC\MS：(M+1) +1343.1，(M-1) -1341.1.
Compound 164
EM (calculated value): 420.17; MS (ESI) m/e (M+1H) +: 421.2, (M-1H) -: 419.5.
Compound 165
EM (calculated value): 420.17; MS (ESI) m/e (M+1H) +: 421.3, (M-1H) -: 419.3.
Compound 166
EM (calculated value): 420.17; MS (ESI) m/e (M+1H) +: 421.3, (M-1H) -: 419.3.
Compound 167
1H NMR(DMSO-d 6)：δ8.89(1H，s)，8.58(1H，m)，7.71(2H，m)，7.65(1H，d)，7.56(1H，d)，7.41(1H，d)，7.36(1H，t)，7.25(1H，t)，7.21(1H，s)，7.00(2H，d)，6.74(1H，dd)，4.11(2H，t)，3.58(2H，q).
Compound 168
EM (calculated value): 420.17; MS (ESI) m/e (M+1H) +: 421.2, (M-1H) -: 419.3.
Compound 169
1H NMR(400MHz，DMSO-d 6)δ11.07(s，1H)，9.14(s，1H)，9.11(t，J＝8.0Hz，1H)，8.93(s，1H)，8.63(t，J＝4.0Hz，1H)，8.17(m，1H)，7.72(m，4H)，7.00(d，J＝8.0Hz，2H)，4.20(t，J＝8.0Hz，2H)，3.71(m，2H).MS(ESI)m/e：(M+1H) +：384.1，(M-1H) -：382.0.
Compound 170
MS(ESI)m/e：(M+1H) +：451.0，(M-1H) -：449.2.
Compound 171
MS(ESI)m/e：(M+1H) +：409.3，(M-1H) -：407.2.
Compound 172
1H NMR(DMSO-d 6)：3.54(q，2H)，3.84(s，3H)，4.08(t，2H)，6.6(d，1H)，6.98(m，4H)，7.35(t，1H)，7.5(d，1H)，7.65(d，1H)，7.69(d，2H)，8.36(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1) +1356.9，(M-1) -1355.2.
Compound 173
1H NMR(DMSO-d 6)：3.56(q，2H)，3.77(s，3H)，4.09(t，2H)，6.66(d，1H)，6.93(m，2H)，6.99(d，2H)，7.1(d，2H)，7.29(t，1H)，7.39(d，1H)，7.70(d，2H)，7.87(d，1H)，8.36(t，1H)，8.9(s，1H)，11.05(s，1H).LC\MS：(M+1) +1357.1，(M-1) -1355.1.
Compound 174
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，9.21(t，J＝8.0Hz，1H)，9.07(s，1H)，8.92(s，1H)，8.67(s，1H)，7.70(m，4H)，7.01(d，J＝8.0Hz，2H)，6.92(m，1H)，4.21(t，J＝8.0Hz，2H)，3.71(m，2H).MS(ESI)m/e：(M+1H) +：421.2，(M-1H) -：419.4.
Compound 175
1H NMR(DMSO-d 6)：δ8.91(1H，s)，8.44(1H，t)，7.73(2H，d)，7.72(1H，s)，7.57(1H，d)，7.44(1H，d)，7.02(2H，d)，6.50(1H，d)，4.11(2H，t)，3.58(2H，q).LC/MS，(M+1)：413.1.
Compound 176
1H NMR(DMSO-d 6)：3.54(q，2H)，4.07(t，2H)，6.36(d，1H)，6.68(s，1H)，6.98(d，2H)，7.32(d，1H)，7.69(m，3H)，7.98(s，1H)，8.27(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1) +1316.9，(M-1) -1315.3.
Compound 177
1H NMR(DMSO-d 6)：3.55(q，2H)，4.08(t，2H)，6.47(d，1H)，6.98(d，2H)，7.31(d，1H)，7.42(d，1H)，7.58(m，1H)，7.69(d，2H)，7.78(s，1H)，8.30(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1) +1333.0，(M-1) -1331.0.
Compound 178
1H NMR(DMSO-d 6)：δ8.91(1H，s)，8.40(1H，t)，7.73(2H，d)，7.61(2H，m)，7.38(1H，d)，7.11(1H，dd)，7.01(2H，d)，6.43(1H，d)，4.11(2H，t)，3.57(2H，q).LC/MS，(M+1)：333.0.
Compound 179
1H NMR(DMSO-d 6)：2.31(s，3H)，3.55(q，2H)，4.09(t，2H)，6.6(d，1H)，6.99(d，2H)，7.2-7.4(m，6H)，7.70(d，2H)，8.33(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1) +1341.1，(M-1) -1339.1.
Compound 180
1H NMR(DMSO-d 6)：2.31(s，3H)，3.55(q，2H)，4.09(t，2H)，6.6(d，1H)，6.99(d，2H)，7.2(d，2H)，7.38(d，1H)，7.42(d，2H)，7.69(d，2H)，8.33(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1) +1341.2，(M-1) -1339.2.
Compound 181
1H NMR(DMSO-d 6)：δ8.87(1H，s)，8.52(1H，t)，7.70(2H，d)，7.64(1H，d)，7.52(1H，d)，7.34(1H，m)，7.24(1H，t)，7.22(1H，s)，6.99(2H，d)，6.67(1H，m)，4.09(2H，t)，3.52(2H，q)，2.48(3H，m).LC/MS，(M+1)：381.0.
Compound 182
1H NMR(DMSO-d 6)：δ8.88(1H，s)，8.33(1H，t)，7.68(2H，d)，7.54(1H，m)，7.41(1H，d)，7.28(1H，s)，7.24(1H，m)，7.19(1H，m)，6.95(2H，d)，6.07(1H，m)，4.11(2H，t)，3.52(2H，q)，2.15(3H，m).LC/MS，(M+1)：381.1.
Compound 183
1H NMR(DMSO-d 6)：2.94(s，6H)，3.54(q，2H)，4.07(t，2H)，6.38(d，1H)，6.69(d，2H)，6.98(d，2H)，7.29(d，1H)，7.35(d，2H)，7.69(d，2H)，8.15(t，1H)，8.87(s，1H)，11.04(s，1H).LC\MS：(M+1) +1370.1，(M-1) -1368.3.
Compound 184
1H NMR(DMSO-d 6)：3.57(q，2H)，4.10(t，2H)，6.65(d，1H)，7.0(d，2H)，7.14(m，2H)，7.42(m，1H)，7.6(d，1H)，7.72(m，3H)，7.87(d，1H)，8.149(t，1H)，8.87(s，1H)，11.04(s，1H)，11.52(s，1H).LC\MS：(M+1) +1366.2，(M-1) -1364.4.
Compound 185
1H NMR(DMSO-d 6)：2.36(s，3H)，3.56(q，2H)，4.10(t，2H)，6.56(d，1H)，7.00(d，2H)，7.23(m，3H)，7.5(d，1H)，7.65(d，1H)，7.7(d，2H)，8.4(t，1H)，8.87(s，1H)，11.04(s，1H).LC\MS：(M+1) +1341.2，(M-1) -1339.3.
Compound 186
1H NMR(DMSO-d 6)：3.55(q，2H)，3.93(s，3H)，4.08(t，2H)，6.66(d，1H)，6.79(t，1H)，6.86(d，1H)，6.98(d，2H)，7.15(m，1H)，7.4(d，1H)，7.65(d，1H)，7.7(d，2H)，8.31(t，1H)，10.0(s，1H)，11.04(s，1H).LC\MS：(M+1) +1343.1，(M-1) -1340.9.
Compound 187
1H NMR(DMSO-d 6)：3.57(q，2H)，3.93(s，3H)，4.09(t，2H)，6.75(d，1H)，6.98(m，3H)，7.18(m，3H)，7.38(d，1H)，7.7(d，2H)，8.5(t，1H)，8.87(s，1H)，11.04(s，1H).LC\MS：(M+1H) +1396.7，(M-1) -1395.0.
Compound 188
1H NMR(DMSO-d 6)：0.922(t，3H)，1.5-1.8(m，2H)，3.93(s，3H)，3.95-4.07(m，3H)，6.8(d，1H)，6.98(m，3H)，7.19(m，3H)，7.36(d，1H)，7.69(d，2H)，8.3(d，1H)，11.03(s，1H).LC\MS：(M+1) +1425.2，(M-1) -1423.2.
Compound 189
1H NMR(DMSO-d 6)：0.95(3H，t，7Hz)；1.53(1H，m)；1.72(1H，m)；2.52(3H，s)；3.79(3H，s)；3.94(1H，m)；4.06(2H，m)；6.66(1H，s)；6.93(1H，dd)；7.02(2H，d)；7.15(2H，m)；7.42(1H，d)；7.7(2H，d)；8.27(2H，d，7Hz)；8.87(1H，d，2Hz).MS(M+1)：439.
Compound 190
1H NMR(DMSO-d 6)：3.54(q，2H)，4.08(t，2H)，6.44(d，1H)，6.56(s，1H)，6.75(s，1H)，6.98(d，2H)，7.23(d，1H)，7.70(d，2H)，7.75(s，1H)，8.41(t，1H)，8.9(s，1H)，11.04(s，1H).LC\MS：(M+1) +1317.0，(M-1) -1315.2.
Compound 191
1H NMR(DMSO-d 6)：3.5-4.05(m，14H)，4.18(t，2H)，6.99(d，2H)，7.69(d，2H)，7.93(d，2H)，8.02(d，2H)，8.2(s，1H)，8.76(t，1H)，8.97(s，1H)，11.05(s，1H).LC\MS：(M+1) +1497.4，(M-1) -1495.4.
Table 2:
Compound 1
EM (calculated value): 370.2; MS (ESI) m/e (M+1) +: 371.1, (M-1) -: 369.2.
Compound 2
1H NMR (400MHz, DMSO-d 6) δ 11.03 (s, 1H), 8.88 (s, 1H), 7.67 (d, J=9.2Hz, 2H), 7.51 (m, 3H), 7.36 (m, 8H), 6.92 (d, J=9.2Hz, 2H), 6.27 (d, J=15.2Hz, 1H), 4.16 (m, 4H) .EM (calculated value): 402.2; MS (ESI) m/e (M+1H) +: 403.1, (M-1H) -: 401.1.
Compound 3
EM (calculated value): 340.1; MS (ESI) m/e (M+1H) +: 341.0, (M-1H) -: 339.4.
Compound 4
EM (calculated value): 398.13; MS (ESI) m/e (M+1H) +: 399.0, (M-1H) -: 397.1.
Compound 5
EM (calculated value): 368.17; MS (ESI) m/e (M+1H) +: 368.8, (M-1H) -: 367.2.
Compound 6
EM (calculated value): 354.1; MS (ESI) m/e (M+1H) +: 354.8, (M-1H) -: 353.2.
Table 3:
Compound 1
1H NMR (400MHz, DMSO-d 6) δ 11.11 (s, 1H), 9.07 (t, J=5.2Hz, 1H), 8.94 (s, 1H), 8.16 (s, 1H), 8.07 (dd, J 1=2.4Hz, J 2=8.4Hz, 1H), 7.99 (dd, J 1=2.4Hz, J 2=6.8Hz, 1H), 7.77 (d, J=9.2Hz, 2H), 7.50 (m.2H), 7.08 (d, J=8.8Hz, 2H), 4.25 (false t, J=5.6Hz, 2H), 3.73 (false q, J=5.2Hz, 2H) .EM (calculated value): 358.1; MS (ESI) m/e (M+1H) +: 357.0, (M-1H) -: 355.1.
Compound 2
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 8.92 (t, J=5.6Hz, 1H), 8.88 (s, 1H), 7.76 (d, J=8.0Hz, 1H), 7.70 (d, J=9.2Hz, 2H), 7.64 (d, J=8.0Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=6.8Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 7.01 (d, J=8.2Hz, 2H), 4.18 (t, J=5.6Hz, 2H), 3.67 (m, 2H) .EM (calculated value): 340.1; MS (ESI) m/e:(M+1H) +: 341.0, (M-1H) -: 339.1.
Compound 3
1H NMR (400MHz, DMSO-d 6) δ: 11.57 (s, 1H), 11.04 (s, 1H), 8.71 (t, J=5.6Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.59 (d, J=8.4Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.16 (t, J=8.4Hz, 1H), 7.12 (m, 1H), 7.00 (m, 3H), 4.18 (t, J=5.6Hz, 2H), 3.68 (m, 2H) .EM (calculated value): 339.1; MS (ESI) m/e (M+1H) +: 340.1, (M-1H) -: 338.3.
Compound 4
EM (calculated value): 353.1; MS (ESI) m/e (M+1) +: 354.1, (M-1) -: 352.2.
Compound 5
1H NMR (400MHz, DMSO-d 6) δ 8.84 (t, J=5.6Hz, 1H), 8.05 (s, 1H), 7.99 (dd, J 1=6.0Hz, J 2=2.0Hz, 1H), 7.91 (dd, J 1=6.4Hz, J 2=2.0Hz, 1H), 7.65 (d, J=8.8Hz, 2H), 7.42 (m, 2H), 6.88 (d, J=8.4Hz, 2H), 4.06 (t, J=6.0Hz, 2H), 3.43 (false q, J=5.6Hz, 2H), 2.00 (false p, J=6.0Hz, 2H) .EM (calculated value): 370.1; MS (ESI) m/e (M+1H) +: 371.1, (M-1H) -: 369.0.
Compound 6
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.74 (t, J=6.0Hz, 1H), 7.67 (d, J=7.6Hz, 1H), 7.62 (d, J=8.4Hz, 2H), 7.44 (s, 1H), 7.55 (dd, J 1=8.4Hz, J 2=0.8Hz, 1H), 7.43 (d, J=0.8Hz, 1H), 7.37 (td, J 1=7.2Hz, J 2=1.2Hz, 1H), 7.241 (td, J 1=8.0HZ, J 2=0.8Hz, 1H), 6.89 (d, J=8.8Hz, 2H), 4.01 (t, J=6.4Hz, 2H), 3.37 (false q, J=6.0Hz, 2H), 1.94 (false p, J=6.0Hz, 2H) .EM (calculated value): 354.1; MS (ESI) m/e (M+1H) +: 355.2, (M-1H) -: 353.1.
Compound 7
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.65 (br d, J=7.2Hz, 1H), 8.20 (s, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.72 (d, J=8.4Hz, 2H), 7.46 (m, 2H), 7.03 (d, J=8.8Hz, 2H), 4.20 (m, 3H), 2.08 (m, 1H), 1.02 (d, J=6.8Hz, 6H) .EM (calculated value): 398.1; MS (ESI) m/e (M+1H) +: 399.0, (M-1H) -: 397.1.
Compound 8
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 8.91 (s, 1H), 8.68 (d, J=8.0Hz, 1H), 8.17 (s, 1H), 8.03 (dd, J 1=2.0Hz, J 2=6.4Hz, 1H), 7.96 (dd, J 1=4.0Hz, J 2=6.8Hz, 1H), 7.73 (d, J=8.8Hz, 2H), 7.46 (m, 4H), 7.04 (d, J=9.2Hz, 2H), 4.24 (m, 1H), 4.18 (dd, J 1=6.8Hz, J 2=10.0Hz, 1H), 4.09 (dd, J 1=5.2Hz, J 2=9.6Hz), 1.81 (m, 1H), 1.67 (m, 1H), 0.99 (t, J=7.6Hz, 3H) .EM (calculated value): 384.1; MS (ESI) m/e (M+1H) +: 385.0, (M-1H) -: 383.1.
Compound 9
1H NMR (400MHz, DMSO-d 6) δ 11.11 (s, 1H), 8.95 (br s, 1H), 8.80 (d, J=8.0Hz, 1H), 8.19 (s, 1H), 8.06 (dd, J 1=5.6Hz, J 2=1.6Hz, 1H), 7.98 (dd, J 1=6.8Hz, J 2=1.6Hz, 1H), 7.76 (d, J=8.4Hz, 2H), 7.49 (m, 2H), 7.08 (d, J=8.8Hz, 2H), 4.42 (p, J=6.4Hz, 1H), 4.20 (dd, J 1=9.6Hz, J 2=6.4Hz, 1H), 4.07 (dd, J 1=9.6Hz, J 2=5.6Hz, 1H), 1.36 (d, J=6.8Hz, 3H) .EM (calculated value): 370.1; MS (ESI) m/e (M+1H) +: 371.0, (M-1H) -: 368.9.
Compound 10
1H NMR (400MHz, DMSO-d 6) δ 10.95 (s, 1H), 8.65 (d, J=7.6Hz, 1H), 8.04 (s, 1H), 7.91 (d, J=7.2Hz, 1H), 7.83 (d, J=6.4Hz, 1H), 7.61 (d, J=8.8Hz, 2H), 7.34 (m, 2H), 6.93 (d, J=8.8Hz, 2H), 4.27 (p.J=6.4Hz, 1H), 4.05 (dd, J 1=6.8Hz, J 2=10.0Hz, 1H), 3.92 (dd, J 1=10.0Hz, J 2=6.0Hz, 1H), 1.21 (d, J=5.2Hz, 3H) .EM (calculated value): 370.1; MS (ESI) m/e (M+1H) +: 370.9, (M-1H) -: 369.0.
Compound 11
1H NMR (400MHz, DMSO-d 6) δ 10.96 (s, 1H), 8.54 (d, J=8.4Hz, 1H), 7.68 (d, J=7.6Hz, 1H), 7.61 (d, J=8.4Hz, 2H), 7.58 (d, J=8.4Hz, 1H), 7.48 (d, J=0.8Hz, 1H), 7.38 (td, J 1=8.0Hz, J 2=0.8Hz, 1H), 7.25 (td, J 1=7.2Hz, J 2=0.8Hz, 1H), 6.92 (d, J=8.8Hz, 2H), 4.19 (m, 1H), 4.07 (dd, J 1=10.4Hz, J 2=6.4Hz, 1H), 3.99 (dd, J 1=10.0Hz, J 2=5.6Hz, 1H), 1.68 (m, 1H), 1.55 (m, 1H), 0.86 (t, J=7.2Hz, 3H) .EM (calculated value): 368.1; MS (ESI) m/e (M-1H) -: 367.1.
Compound 12
1H NMR (400MHz, DMSO-d 6) δ 11.06 (s, 1H), 9.03 (t, J=6.0Hz, 1H), 8.11 (s, 1H), 8.03 (d, J=7.2Hz, 1H), 7.94 (d, J=6.4Hz, 1H), 7.72 (d, J=8.8Hz, 2H), 7.46 (m, 2H), 7.07 (d, J=9.2Hz, 2H), 4.72 (false q, J=5.6Hz, 1H), 3.62 (m, 1H), 3.42 (m, 1H), 1.34 (d, J=6.4Hz, 3H) .EM (calculated value): 370.1; MS (ESI) m/e (M+1H) +: 371.0, (M-1H) -: 369.1.
Compound 13
1H NMR (400MHz, DMSO-d 6) δ 11.06 (s, 1H), 9.03 (t, J=5.6Hz, 1H), 8.11 (s, 1H), 8.03 (d, J=6.8Hz, 1H), 7.94 (d, J=7.2Hz, 1H), 7.72 (d, J=8.4Hz, 2H), 7.46 (false p, J=5.6Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 4.74 (false q, J=5.6Hz, 1H), 3.63 (m, 1H), 3.42 (m, 1H), 1.34 (d, J=6.0Hz, 3H) .EM (calculated value): 370.1; MS (ESI) m/e (M+1H) +: 371.0, (M-1H) -: 369.1.
Compound 14
1H NMR (400MHz, DMSO-d 6) δ 11.02 (s, 1H), 8.92 (t, J=6.0Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.68 (d, J=8.8Hz, 2H), 7.54 (d, J=0.8Hz, 1H), 7.44 (td, J 1=7.2Hz, J 2=0.8Hz, 1H), 7.31 (td, J=7.6Hz, J 2=0.8Hz, 1H), 7.03 (d, J=9.2Hz, 2H), 4.69 (false q, J=6.4Hz, 1H), 3.59 (ddd, J 1=6.4Hz, J 2=13.6Hz, J 3=19.6Hz, 1H), 3.39 (ddd, J 1=6.0Hz, J 2=12.4Hz, J 3=19.6Hz, 1H), 1.29 (d, J=6.4Hz, 3H) .EM (calculated value): 354.1; MS (ESI) m/e (M+1H) +: 354.7, (M-1H) -: 353.1.
Compound 15
EM (calculated value): 386.09; MS (ESI) m/e (M-1H) -: 384.7.
Compound 16
EM (calculated value): 370.10; MS (ESI) m/e (M-1H) -: 369.0.
Compound 17
EM (calculated value): 390.0; MS (ESI) m/e (M+1H) +: 391.2.
Compound 18
EM (calculated value): 354.12; MS (ESI) m/e (M-1H) -: 353.2.
Compound 19
EM (calculated value): 354.12; MS (ESI) m/e (M-1H) -: 353.1.
Compound 20
EM (calculated value): 424.07; MS (ESI) m/e (M-1H) -: 423.9.
Compound 21
EM (calculated value): 374.0; MS (ESI) m/e (M+1) +: 375.0, (M-1) -: 373.0.
Compound 22
EM (calculated value): 386.1; MS (ESI) m/e (M+1) +: 387.1, (M-1) -: 384.7.
Compound 23
EM (calculated value): 374.1; MS (ESI) m/e (M+1) +: 374.9, (M-1) -: 372.9.
Compound 24
EM (calculated value): 370.1; MS (ESI) m/e (M+1) +: 370.8, (M-1) -: 369.0.
Compound 25
EM (calculated value): 370.1; MS (ESI) m/e (M+1) +: 371.0, (M-1) -: 369.1.
Compound 26
EM (calculated value): 414.14; MS (ESI) m/e (M+1H) +: 415.2, (M-1H) -: 413.2.
Compound 27
EM (calculated value): 469.18; MS (ESI) m/e (M+1H) +: 470.1, (M-1H) -: 468.4.
Compound 28
EM (calculated value): 447.14; MS (ESI) m/e (M+1H) +: 448.1, (M-1H) -: 446.2.
Compound 29
EM (calculated value): 354.1; MS (ESI) m/e (M+1) +: 355.1, (M-1) -: 353.1.
Compound 30
EM (calculated value): 370.1; MS (ESI) m/e (M+1) +: 371.0, (M-1) -: 368.9.
Compound 31
EM (calculated value): 400.1; MS (ESI) m/e (M+1H) +: 401.0, (M-1H) -: 399.2.
Compound 32
EM (calculated value): 427.1; MS (ESI) m/e (M+1H) +: 428.2, (M-1H) -: 426.2.
Compound 33
EM (calculated value): 414.1; MS (ESI) m/e (M+1) +: 415.4, (M-1) -: 413.2.
Compound 34
EM (calculated value): 469.2; MS (ESI) m/e (M+1) +: 470.1, (M-1) -: 468.3.
Compound 35
EM (calculated value): 447.1; MS (ESI) m/e (M+1) +: 448.2, (M-1) -: 446.5.
Compound 36
EM (calculated value): 368.1; MS (ESI) m/e (M+1) +: 369.0, (M-1) -: 367.2.
Compound 37
1H NMR (400MHz, DMSO-d 6) δ 11.69 (s, 1H), 11.04 (s, 1H), 8.77 (t, J=5.6Hz, 1H), 7.70 (d, J=8.4Hz, 2H), 7.39 (m, 2H), 7.11 (s, 1H), 7.05 (m, 1H), 7.01 (d, J=8.4Hz, 2H), 4.18 (t, J=6.0Hz, 2H), 3.67 (m, 2H) .EM (calculated value): 357.1; MS (ESI) m/e (M+1H) +: 357.8, (M-1H) -: 356.2.
Compound 38
1H NMR (400MHz, DMSO-d 6) δ 11.42 (s, 1H), 11.05 (s, 1H), 8.66, (t, J=5.6Hz, 1H), 7.70 (d, J=9.2Hz, 2H), 7.29 (d, J=8.4Hz, 1H), 7.03 (m, 4H), 6.81 (m, 1H), 4.17 (t, J=5.6Hz, 2H), 3.75 (s, 3H), 3.66 (m, 2H) .EM (calculated value): 369.1; MS (ESI) m/e (M+1H) +: 369.9, (M-1H) -: 368.2.
Compound 39
EM (calculated value): 384.13; MS (ESI) m/e (M+1H) +: 384.9, (M-1H) -: 383.2.
Compound 40
EM (calculated value): 446.15; MS (ESI) m/e (M+1H) +: 447.2, (M-1H) -: 445.4.
Compound 41
1H NMR (400MHz, DMSO-d 6) δ 11.28 (s, 1H), 11.04 (s, 1H), 8.53 (t, J=5.6Hz, 1H), 7.70 (d, J=9.2Hz, 2H), 7.02 (m, 4H), 6.86 (s, 1H), 4.16 (t, J=5.6Hz, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.63 (m, 2H) .EM (calculated value): 399.1; MS (ESI) m/e (M+1H) +: 400.0, (M-1H) -: 398.1.
Compound 42
1H NMR (400MHz, DMSO-d 6) δ 11.09 (bs, 1H), 10.60 (bs, 1H), 9.29 (t, J=6.0Hz, 1H), 8.08 (d, J=8.0Hz; 1H), 7.70 (m, 3H), 7.57 (t, J=7.2Hz, 1H), 7.45 (t, J=7.2Hz, 1H), 7.00 (d, J=9.2Hz, 2H), 4.83 (m, 2H), 4.23 (t, J=6.0Hz, 2H), 3.94 (m, 2H), 3.73 (m, 4H), 3.44 (m, 2H), 3.27 (m, 2H) .EM (calculated value): 439.2; MS (ESI) e (M+1H) +: 439.8, (M-1H) -: 438.2.
Compound 44
EM (calculated value): 412.16; MS (ESI) m/e (M+1H) +: 413.1, (M-1H) -: 411.3.
Compound 45
1H NMR (400MHz, DMSO-d 6) δ 11.05 (s, 1H), 8.92 (t, J=5.2Hz, 1H), 7.74 (d, J=7.6Hz, 1H), 7.70 (d, J=8.8Hz, 2H), 7.59 (s, 1H), 7.55 (d, J=6.8HZ, 1H), 7.32 (m, 3H), 7.06 (d, J=7.6Hz, 2H), 7.00 (d, J=9.2Hz, 2H), 6.95 (t, J=7.2Hz, 1H), 5.44 (s, 2H), 4.19 (t, J=6.0Hz, 2H), 3.69 (m, 2H) .EM (calculated value): 446.2; MS (ESI) m/e (M+1H) +: 447.2, (M-1H) -: 445.3.
Compound 46
1H NMR (400MHz, DMSO-d 6) δ 11.08 (s, 1H), 8.91 (t, J=5.6Hz, 1H), 7.71 (m, 3H), 7.58 (s, 1H), 7.44 (d, J=7.6Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 4.78 (s, 2H), 4.20 (t, J=6.0Hz, 2H), 3.69 (m, 2H), 3.36 (s, 3H) .EM (calculated value): 384.1; MS (ESI) m/e (M+1H) +: 385.9, (M-1H) -: 383.2.
Compound 47
1H NMR (400MHz, DMSO-d 6) δ 11.33 (s, 1H), 11.09 (s, 1H), 9.32 (t, J=5.6Hz, 1H), 7.88 (d, J=8.4Hz, 1H), 7.71 (m, 3H), 7.61 (s, 1H), 7.43 (t, J=7.6Hz, 1H), 7.03 (d, J=8.8Hz, 1H), 4.68 (s, 2H), 4.23 (t, J=5.6Hz, 2H), 3.83 (m, 6H), 3.37 (m, 2H), 3.20 (m, 2H) .EM (calculated value): 439.2; MS (ESI) m/e (M+1H) +: 440.2, (M-1H) -: 438.4.
Compound 48
1H NMR (400MHz, DMSO-d 6) δ 11.09 (s, 1H) 10.74 (s, 1H), 9.31 (t, J=5.6Hz, 1H), 7.88 (d, J=8.0Hz, 1H), 7.72 (d, J=8.6Hz, 2H), 7.65 (d, J=7.2Hz, 1H), 7.62 (s, 1H), 7.42 (t, J=8.0Hz, 1H), 7.02 (d, J=8.8Hz, 2H), 4.63 (d, J=5.2Hz, 2H), 4.23 (t, J=6.0Hz, 2H), 3.70 (m, 2H), 2.78 (s, 3H), 2.770 (s, 3H) .EM (calculated value): 397.2; MS (ESI) m/e (M+1H) +: 398.0, (M-1H) -: 396.1.
Compound 49
EM (calculated value): 384.1; MS (ESI) m/e (M-1) -: 382.9.
Compound 50
EM (calculated value): 400.1; MS (ESI) m/e (M-1) -: 398.7.
Compound 51
1H NMR (400MHz, DMSO-d 6) δ 11.07 (s, 1H), 8.78 (t, J=6.0Hz, 1H), 7.71 (m, 3H), 7.54 (s, 1H), 7.43 (d, J=7.2Hz, 1H), 7.32 (d, J=7.6Hz, 1H), 6.99 (d, J=8.4Hz, 2H), 4.77 (s, 2H), 4.10 (t, J=6.0Hz, 2H), 3.47 (m, 2H), 3.36 (s, 3H), 2.02 (m, 2H) .EM (calculated value): 398.2; MS (ESI) m/e (M+1H) +: 399.1, (M-1H) -: 397.1.
Compound 52
1H NMR (400MHz, DMSO-d 6) δ 8.82 (t, J=5.6Hz, 1H), 7.71 (m, 3H), 7.54 (m, 2H), 7.31 (m, 3H), 7.06 (d, J=8.0Hz, 2H), 6.95 (m, 3H), 5.43 (s, 2H), 4.09 (t, J=6.0Hz, 2H), 3.47 (m, 2H), 2.02 (m, 2H) .EM (calculated value): 460.2; MS (ESI) m/e (M+1H) +: 461.0, (M-1H) -: 459.1.
Compound 53
EM (calculated value): 428.16; MS (ESI) m/e (M+1H) +: 428.9, (M-1H) -: 427.1.
Compound 54
1H NMR(DMSO-d 6)：2.11(3H，s)；2.78(1H，dd，14，8Hz)；2.86(1H，dd，14，5Hz)；4.17(1H，dd，10，4Hz)；4.23(1H，dd，10，6Hz)；4.49(1H，m)；7.00(2H，d，9Hz)；7.32(1H，t，7Hz)；7.46(1H，td，8，1Hz)；7.56(1H，s)；7.64(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.77(1H，d，8Hz)；8.88(1H，s).MS(M+1)：401.
Compound 55
1H NMR(DMSO-d 6)：3.31(3H，s)；3.53(1H，dd，13，3.5Hz)；3.66(1H，dd，13，8Hz)；4.16(1H，dd，9，6Hz)；4.24(1H，dd，9，8Hz)；4.87(1H，m)；7.00(2H，d，9Hz)；7.33(1H，t，7Hz)；7.47(1H，t，8Hz)；7.57(1H，s)；7.65(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.89(1H，s)；9.0(1H，d，8Hz).MS(M-1)：431.
Compound 56
1H NMR (400MHz, DMSO-d 6) δ: 7.92 (br s, 1H), 8.76 (t, 1H, J=5.9Hz), 7.75 (m, 3H), 7.60 (d, 1H, J=7.6Hz), 7.48 (t, 1H, J=8.0Hz), 7.32 (t, 1H, J=8.0Hz), 7.27 (m, 5H), 7.17 (m, 1H), 7.04 (m, 2H), 4.21 (t, 2H, J=5.9Hz), 3.69 (m, 2H) 3.39 (m, 2H), 2.96 (t, 2H, J=8.3Hz) .EM (calculated value): 444; MS (ESI) m/e (M+1H) +: 445.3, (M-1H) -: 443.3.
Compound 57
1H NMR(400MHz，DMSO-d 6)δ11.07(s，1H)，9.38(s，1H)，8.90(s，1H)，7.94(d，J＝8.0Hz，1H)，7.57(m，10H)，6.97(d，J＝8.0Hz，2H)，4.80(m，2H)，4.20(s，2H)，3.70(m，2H)，3.31(m，3H)，2.66(m，2H).MS(ESI)m/e：(M+1H) +：474.4，(M-1H) -：472.1.
Compound 58
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，9.73(m，1H)，8.89(s，1H)，7.75(d，J＝8.0Hz，2H)，7.70(t，J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，1H)，7.43(t，8.0Hz，1H)，7.18(m，6H)，6.98(d，J＝8.0Hz，2H)，4.13(t，J＝8.0Hz，2H)，3.95(m，2H)，3.58(m，2H)，2.78(m，2H)，2.65(m，2H)，1.24(s，3H).MS(ES1)m/e：(M+1H) +：487.9，(M-1H) -：486.1.
Compound 59
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，8.88(s，1H)，8.84(t，J＝8.0Hz，1H)，7.82(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.59(d，J＝8.0Hz，1H)，7.48(t，J＝8.0Hz，1H)，7.34(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.31(s，2H)，4.18(t，J＝8.0Hz，2H)，3.66(m，2H)，3.38(m，2H)，2.45(t，J＝8.0Hz，2H)，1.65(m，2H).MS(ESI)m/e：(M+1H) +：445.2，(M-1H) -：443.1.
Compound 60
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，9.04(t，J＝8.0Hz，1H)，7.86(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.63(d，J＝8.0Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.36(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.57(m，2H)，4.18(t，J＝8.0Hz，2H)，3.65(m，2H)，3.46(t，J＝8.0Hz，2H)，2.77(m，2H)，1.80(m，2H).MS(ESI)m/e：(M+1H) +：461.0，(M-1H) -：459.1.
Compound 61
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，9.05(t，J＝8.0Hz，1H)，7.87(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.64(d，J＝8.0Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.11(s，2H)，4.19(t，J＝8.0Hz，2H)，3.68(m，2H)，3.44(t，J＝8.0Hz，2H)，3.13(m，2H)，1.83(m，2H).MS(ESI)m/e：(M+1H) +：477.0，(M-1H) -：475.0.
Compound 62
MS(ESI)m/e：(M+1H) +：527.6，(M-1H) -：525.5.
Compound 63
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 8.88 (br s, 1H), 8.73 (t, 1H, J=5.9Hz), 7.75-7.69 (m, 3H), 7.57-7.42 (m, 6H), 7.28 (t, 1H, J=7.7Hz), 7.00 (d, 2H, J=8.7Hz), 4.17 (t, 2H, J=5.9Hz), 3.65 (q, 2H, J=5.9Hz) 3.40 (t, 2H, J=6.9Hz), 3.04 (t, 2H, J=6.9Hz) .EM (calculated value): 512; MS (ESI) m/e (M+1H) +: 513.3, (M-1H) -: 511.2.
Compound 64
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 8.87 (br s, 1H), 8.83 (t, 1H, J=5.9Hz), 7.70 (m, 3H), 7.55 (d, 1H, J=8.3Hz), 7.43 (t, 1H, J=7.4Hz), 7.34 (t, 1H, J=8.0Hz), 7.28-7.20 (m, 3H), 7.11 (d, 1H, 8.0Hz), 7.00 (d, 2H, J=8.6Hz), 4.17 (t, 2H, J=5.9Hz), 3.65 (q, 2H, J=5.9Hz) 3.38 (t, 2H, J=8.3Hz), 3.00 (t, 2H, J=8.3Hz) .EM (calculated value): 528; MS (ESI) m/e (M+1H) +: 529.4, (M-1H) -: 527.5.
Compound 65
1H NMR(400MHz，DMSO-d 6)δ11.06(s，1H)，10.93(s，1H)，9.32(m，2H)，9.23(s，1H)，8.89(s，1H)，7.96(d，J＝8.0Hz，1H)，7.70(m，3H)，7.56(t，J＝8.0Hz，1H)，7.44(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.64(s，2H)，4.23(t，J＝8.0Hz，2H)，3.71(m，4H).MS(ESI)m/e：(M+1H) +：443.4，(M-1H) -：441.4.
Compound 66
1H NMR(400MHz，DMSO-d 6)δ11.06(s，1H)，9.33(t，J＝8.0Hz，1H)，8.89(s，1H)，8.00(d，J＝8.0Hz，1H)，7.71(m，3H)，7.56(t，J＝8.0Hz，1H)，7.43(t，J＝8.0Hz，3H)，7.00(d，J＝8.0Hz，2H)，4.60(s，2H)，4.23(t，J＝8.0Hz，2H)，3.71(m，2H)，3.20(t，J＝8.0Hz，2H)，2.72(t，J＝8.0Hz，2H).MS(ESI)m/e：(M+1H) +：442.3，(M-1H) -：440.1.
Compound 67
1H NMR (400MHz, DMSO-d 6) δ: 9.11 (t, 1H, J=6.0Hz), 7.82 (d, 1H, J=7.7Hz), 7.76 (d, 2H, J=8.5Hz), 7.69 (d, 1H, J=8.5Hz), 7.62 (s, 1H), 7.51 (t, 1H, J=8.5Hz), 7.40-7.30 (m, 3H), 7.21 (d, 2H, J=8.5Hz), 7.00-6.97 (m, 3H), 4.99 (m, 1H), 4.35 (m, 1H), 4.27 (m, 1H), 3.78 (m, 1H), 3.70 (m, 1H) .EM (calculated value): 446.15; MS (ESI) m/e (M+1H) +: 447.4, (M-1H) -: 445.3.
Compound 68
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，8.86(t，J＝4.0Hz，1H)，7.83(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0HZ，1H)，7.47(t，J＝8.0Hz，1H)，7.33(t，J＝4.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.02(s，2H)，4.18(t，J＝8.0Hz，2H)，3.65(m，2H)，3.52(t，J＝8.0Hz，2H)，3.44(t，J＝8.0Hz，2H)，1.68(m，2H).MS(ESI)m/e：(M+1H) +：429.1，(M-1H) -：426.9.
Compound 69
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 9.03 (t, 1H, J=5.9Hz), 7.86 (d, 1H, J=9.2Hz), 7.70 (d, 2H, J=8.3Hz), 7.63 (d, 1H, J=8.3Hz), 7.49 (t, 1H, J=8.8Hz), 7.36 (t, 1H, J=7.0Hz), 7.29 (t, 1H, J=8.8Hz), 7.18 (m, 1H), 7.07 (t, 1H, J=7.0Hz), 7.00 (d, 1H, J=8.3Hz), 6.91 (m, 1H), 5.78 (s, 2H), 4.20 (t, 2H, J=5.9Hz), 3.68 (q, 2H, J=5.9Hz) .EM (calculated value): 464; MS (ESI) m/e (M+1H) +: 465.1, (M-1H) -: 463.1.
Compound 70
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 9.04 (t, 1H, J=5.9Hz), 9.00 (br s, 1H), 7.84 (d, 1H, J=7.3Hz), 7.70 (d, 2H, J=9.2Hz), 7.63 (d, 1H, J=8.1Hz), 7.49 (t, 1H, J=8.6Hz), 7.35 (t, 1H, J=7.7Hz), 7.27 (m, 1H), 7.18 (m, 1H), 7.00 (d, 1H, J=9.2Hz), 6.95 (m, 1H), 6.87 (m, 1H), 6.74 (m, 1H), 5.71 (s, 2H), 4.21 (t, 2H, J=5.9Hz), 3.69 (q, 2H, J=5.9Hz) .EM (calculated value): 464; MS (ESI) m/e (M+1H) +: 465.0, (M-1H) -: 463.1.
Compound 71
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 9.00 (t, 1H, J=5.9Hz), 7.84 (d, 1H, J=8.4Hz), 7.70 (d, 2H, J=9.2Hz), 7.62 (d, 1H, J=8.8Hz), 7.48 (t, 1H, J=8.4Hz), 7.34 (t, 1H, J=7.3Hz), 7.10-7.00 (m, 6H), 5.67 (s, 2H), 4.20 (t, 2H, J=5.9Hz), 3.68 (q, 2H, J=5.9Hz) .EM (calculated value): 464; MS (ESI) m/e (M+1H) +: 464.9, (M-1H) -: 463.0.
Compound 72
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，8.88(m，2H)，7.86(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0HZ，1H)，7.47(t，J＝8.0Hz，1H)，7.33(t，J＝4.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.05(s，2H)，4.19(t，J＝8.0Hz，2H)，3.65(m，2H)，3.59(m，2H)，3.47(m，2H)，3.23(s，3H).MS(ESI)m/e：(M+1H) +：428.9，(M-1H) -：426.9.
Compound 73
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，9.20(t，J＝4.0Hz，1H)，8.83(d，J＝8.0Hz，2H)，7.86(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，2H)，7.66(d，J＝8.0Hz，1H)，7.51(t，J＝8.0Hz，1H)，7.38(t，J＝8.0Hz，1H)，7.25(d，J＝8.0Hz，2H)，6.98(d，J＝8.0Hz，2H)，6.07(s，2H)，4.21(t，J＝8.0Hz，2H)，3.70(m，2H).MS(ESI)m/e：(M+1H) +：448.0，(M-1H) -：446.4.
Compound 74
1H NMR (400MHz, DMSO-d 6) δ: 8.86 (m, 1H), 8.81 (br s, 1H), 7.80 (d, 1H, J=8.2Hz), 7.63 (d, 2H, J=9.4Hz), 7.57 (d, 1H, J=8.2Hz), 7.44 (t, 1H, J=7.8Hz), 7.32 (t, 1H, J=7.0Hz), 7.12 (t, 1H, J=9.0Hz), 6.91 (t, 1H, J=8.6Hz), 5.64 (s, 2H), 4.06 (t, 2H, J=6.0Hz), 3.54 (t, 2H, J=6.0Hz) .EM (calculated value): 500.13; MS (ESI) m/e (M+1H) +: 501.5, (M-1H) -: 499.3.
Compound 75
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，9.14(t，J＝4.0Hz，1H)，7.89(m，1H)，7.70(m，3H)，7.61(d，J＝8.0Hz，1H)，7.46(m，1H)，7.40(m，ITI)，7.29(t，J＝4.0Hz，1H)，7.02(d，J＝8.0Hz，2H)，6.43(d，J＝8.0Hz，1H)，6.23(t，J＝4.0Hz，1H)，5.62(s，2H)，4.23(t，J＝4.0Hz，2H)，3.72(m，2H).MS(ESI)m/e：(M+1H) +：448.2，(M-1H) -：446.4.
Compound 76
1H NMR(400MHz，DMSO-d 6)δ11.04(s，1H)，8.96(t，J＝4.0Hz，1H)，8.88(s，1H)，7.82(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.63(d，J＝8.0Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.36(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.24(s，2H)，4.18(m，4H)，3.66(m，2H).MS(ESI)m/e：(M+1H) +：453.3，(M-1H) -：451.1.
Compound 77
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，9.04(t，J＝4.0Hz，1H)，8.89(s，1H)，8.09(s，1H)，7.87(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.63(d，J＝8.0Hz，1H)，7.89(m，1H)，7.50(m，3H)，7.35(t，J＝8.0Hz，1H)，7.17(d，J＝8.0Hz，2H)，7.03(m，3H)，5.77(s，2H)，4.22(t，J＝8.0Hz，2H)，3.70(m，2H).MS(ESI)m/e：(M+1H) +：513.1，(M-1H) -：511.1.
Compound 78
1H NMR (400MHz, DMSO-d 6) δ: 9.05 (s, 1H), 8.97 (t, 1H, J=5.9Hz), 8.81 (s, 1H), 8.08 (s, 1H), 7.80 (d, 1H, J=7.6Hz), 7.66-7.62 (m, 4H), 7.56 (d, 1H, J=8.6Hz), 7.42 (t, 1H, J=8.1Hz), 7.28 (t, 1H, J=7.6Hz), 7.15 (m, 2H), 6.94 (d, 2H, J=8.6Hz), 5.70 (s, 2H), 4.15 (t, 2H, J=5.9Hz), 3.64 (t, 2H, J=5.9Hz) .EM (calculated value): 513.16; MS (ESI) m/e (M+1H) +: 514.2, (M-1H) -: 512.2.
Compound 79
1H NMR(400MHz，DMSO-d 6)δ11.08(s，1H)，10.33(s，1H)，9.25(t，J＝4.0Hz，1H)，8.11(d，J＝8.0Hz，1H)，7.70(m，3H)，7.53(t，J＝8.0Hz，1H)，7.44(t，J＝8.0Hz，1H)，6.99(d，J＝8.0Hz，2H)，4.84(d，J＝4.0Hz，2H)，4.23(t，J＝8.0Hz，2H)，3.70(m，2H)，3.48(m，2H)，3.23(m，2H)，2.04(m，2H)，1.90(m，2H).MS(ESI)m/e：(M+1H) +：424.1，(M-1H) -：422.3.
Compound 80
1H NMR(400MHz，DMSO-d 6)δ11.06(s，1H)，9.87(s，1H)，9.29(t，J＝4.0Hz，1H)，8.03(d，J＝8.0Hz，1H)，7.71(m，3H)，7.57(t，J＝8.0Hz，1H)，7.45(t，J＝8.0Hz，1H)，6.99(d，J＝8.0Hz，2H)，4.77(s，2H)，4.23(t，J＝8.0Hz，2H)，3.70(m，2H)，3.48(m，2H)，3.04(m，2H)，1.73(m，5H)，1.38(m，1H).MS(ESI)m/e：(M+1H) +：438.0，(M-1H) -：436.3.
Compound 81
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，9.55(t，J＝4.0Hz，1H)，8.89(s，1H)，7.89(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，1H)，7.45(t，J＝8.0Hz，1H)，7.33(t，J＝8.0Hz，1H)，6.99(d，J＝8.0Hz，2H)，4.19(t，J＝8.0Hz，2H)，3.96(s，2H)，3.68(m，2H)，2.95(m，2H)，2.28(m，1H)，2.09(m，2H)，1.78(m，2H)，1.44(m，2H).MS(ESI)m/e：(M+1H) +：506.1，(M-1H) -：504.2.
Compound 82
1H NMR(400MHz，DMSO-d 6)δ11.07(s，1H)，9.18(s，1H)，8.04(s，1H)，7.70(m，3H)，7.53(t，J＝8.0Hz，1H)，7.39(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，4.21(t，J＝8.0Hz，2H)，3.70(m，12H)，2.76(s，3H).MS(ESI)m/e：(M+1H) +：453.0，(M-1H) -：451.1.
Compound 83
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，8.90(m，2H)，7.83(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，2H)，7.61(d，J＝8.0Hz，1H)，7.48(t，J＝8.0Hz，1H)，7.34(t，J＝8.0Hz，1H)，7.00(d，J＝8.0Hz，2H)，5.08(s，2H)，4.19(t，J＝8.0Hz，2H)，3.68(m，4H)，2.58(m，2H).MS(ESI)m/e：(M+1H) +：467.0，(M-1H) -：465.1.
Compound 84
1H NMR (400MHz, DMSO-d 6) δ: 11.07 (s, 1H), 8.91 (m, 2H), 7.73 (d, 2H, J=9.0Hz), 7.66 (s, 1H), 7.47 (d, 1H, J=8.7Hz), 7.37 (t, 1H, J=8.4Hz), 7.15 (d, 1H, J=7.4Hz), 7.04 (d, 2H, J=9.0Hz), 4.21 (t, 1H, J=5.7Hz), 3.69 (t, 2H, J=5.7Hz), 3.36 (s, 3H) .EM (calculated value): 354.12; MS (ESI) m/e (M+1H) +: 354.7, (M-1H) -: 353.1.
Compound 85
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，8.88(s，1H)，8.80(t，J＝8.0Hz，1H)，7.76(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，2H)，7.57(d，J＝8.0Hz，1H)，7.46(t，J＝8.0Hz，1H)，7.32(m，3H)，7.03(m，4H)，4.76(s，2H)，4.15(t，J＝8.0Hz，2H)，3.62(m，2H).MS(ESI)m/e：(M+1H) +：481.1，(M-1H) -：479.0.
Compound 86
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，8.88(m，2H)，7.71(d，J＝8.0Hz，2H)，7.55(m，4H)，7.46(t，J＝8.0Hz，1H)，7.28(m，3H)，7.00(d，J＝8.0Hz，2H)，4.77(s，2H)，4.15(t，J＝8.0Hz，2H)，3.60(m，2H).MS(ESI)m/e：(M+1H) +：497.3，(M-1H) -：495.1.
Compound 87
1H NMR(400MHz，DMSO-d 6)δ11.05(s，1H)，8.89(s，1H)，8.82(t，J＝8.0Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.71(d，J＝8.0Hz，2H)，7.63(m，3H)，7.50(t，J＝8.0Hz，1H)，7.34(m，3H)，7.00(d，J＝8.0Hz，2H)，5.32(s，2H)，4.06(t，J＝8.0Hz，2H)，3.49(m，2H).MS(ESI)m/e：(M+1H) +：513.2，(M-1H) -：511.2.
Compound 88
1H NMR(400MHz，DMSO-d 6)δ11.03(s，1H)，8.88(s，1H)，8.68(d，J＝8.0Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.69(d，J＝8.0Hz，2H)，7.64(d，J＝8.0Hz，1H)，7.50(t，J＝8.0Hz，1H)，7.36(t，J＝8.0Hz，1H)，6.98(d，J＝8.0Hz，2H)，5.25(s，2H)，4.18(m，5H)，1.72(m，2H)，0.94(t，J＝8.0Hz，3H).MS(ESI)m/e：(M+1H) +：481.2，(M-1H) -：479.2.
Compound 89
1H NMR (400MHz, DMSO-d 6) δ: 11.94 (s, 1H), 11.04 (m, 1H), 9.36 (m, 1H), 8.88 (br s, 1H), 8.63 (s, 1H), 7.71 (d, 2H, J=8.5Hz), 7.22 (t, 1H, J=8.1Hz), 7.07 (dd, 1H, J=8.1,1.7Hz), 7.02 (d, 2H, J=8.5Hz), 6.65 (dd, 1H, J=7.6,1.6Hz), 4.21 (t, 2H, J=5.6Hz), 3.73 (2H, q, J=5.2Hz) .EM (calculated value): 356; MS (ESI) m/e (M+1H) +: 357.2, (M-1H) -: 354.9.
Compound 90
1H NMR (400MHz, DMSO-d 6) δ: 11.03 (s, 1H), 8.69 (d, 1H, J=8.3Hz), 7.86 (d, 1H, J=2.1Hz), 7.69 (m, 3H), 7.54 (s, 1H), 7.47 (dd, 1H, J=8.5Hz, 2.5Hz), 6.98 (d, 2H, J=8.6Hz), 4.24 (m, 1H), 4.13 (m, 1H), 4.06 (m, 1H), 1.75 (m, 1H), 1.62 (m, 1H), 0.93 (t, 3H, J=7.3Hz) .EM (calculated value): 402; MS (ES1) m/e (M+1H) +: 403.0, (M-1H) -: 400.9.
Compound 91
1H NMR (400MHz, DMSO-d 6) δ: 11.02 (s, 1H), 9.00 (t, 1H, J=5.8Hz), 7.85 (d, 1H, J=1.9Hz), 7.68 (m, 3H), 7.52 (s, 1H), 7.46 (dd, 1H, J=8.5Hz, 1.9Hz), 7.03 (d, 2H, J=8.5Hz), 4.69 (m, 1H), 3.57 (m, 1H), 3.40 (m, 1H), 1.32 (d, 3H, J=5.9Hz) .EM (calculated value): 388; MS (ESI) m/e (M+1H) +: 389.1, (M-1H) -: 387.0.
Compound 92
1H NMR (400MHz, DMSO-d 6) δ: 11.05 (br s, 1H), 8.96 (t, 1H, J=5.6Hz), 8.80 (d, 1H, J=2.0Hz), 8.75 (dd, 1H, J=5.6,0.8Hz), 8.35 (d, 1H, J=8.0 Hz), 7.87 (dd, 1H, J=7.6,5.6Hz), 7.71 (m, 3H), 7.61 (d, 1H, J=8.0Hz), 7.45 (t, 1H, J=6.8Hz), 7.34 (d, 1H, J=7.2Hz), 7.00 (m, 2H), 4.91 (s, 2H), 4.75 (s, 2H), 4.18 (t, 2H, J=5.6Hz), 3.66 (q, 2H, J=6.0Hz) .EM (calculated value): 461; MS (ESI) m/e (M+1H) +: 462.2, (M-1H) -: 460.3.
Compound 93
1H NMR (400MHz, DMSO-d 6) δ: 11.00 (s, 1H), 8.82 (m, 1H), 8.37 (s, 1H), 7.67 (dd, 2H, J=6.8,1.6Hz), 7.32-7.24 (m, 2H), 7.01 (d, 2H, J=9.6Hz), 6.90 (d, 1H, J=8.0Hz), 4.17 (t, 2H, J=5.2Hz), 3.89 (s, 3H), 3.69 (m, 2H) .EM (calculated value): 370; MS (ESI) m/e (M+1H) +: 371.2, (M-1H) -: 369.1.
Compound 94
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (s, 1H), 8.96 (t, 1H, J=5.6Hz), 8.45 (s, 1H), 7.70 (d, 2H, J=8.4Hz), 7.37-7.30 (m, 2H), 7.02 (d, 2H, J=8.4Hz), 6.98 (dd, 1H, J=7.6,0.8Hz), 4.37 (m, 2H), 4.17 (t, 2H, J=5.6Hz), 3.82 (m, 2H), 3.69 (q, 2H, J=6.0Hz), 3.34 (s, 3H) .EM (calculated value): 414; MS (ESI) m/e (M+1H) +: 415.2, (M-1H) -: 413.3.
Compound 95
1H NMR (400MHz, DMSO-d 6) δ: 11.04 (br s, 1H), 8.86 (m, 1H), 8.65 (t, 1H, 5.6Hz), 8.61 (dd, 1H, J=4.8,1.6Hz), 8.37 (s, 1H), 8.13 (m, 1H), 7.67 (m, 2H), 7.54 (m, 1H), and 7.38-7.31 (m, 2H), 7.07 (dd, 1H, J=7.6,0.8 Hz), 6.88 (m, 2H), 5.40 (s, 2H), 3.91 (t, 2H, J=6.0Hz), 3.40 (m, 2H) .EM (calculated value): 447; MS (ESI) m/e (M+1H) +: 448.2, (M-1H) -: 446.1.
Compound 96
1H NMR (400MHz, DMSO-d 6) δ: 11.57 (s, 1H), 8.65 (t, 1H, J=4.5Hz), 7.69 (d, 2H, J=8.5Hz), 7.20 (s, 1H), 7.09-6.98 (m, 4H), 6.48 (d, 1H, J=7.9Hz), 4.17 (m, 2H), 3.85 (s, 3H), 3.65 (m, 2H) .EM (calculated value): 369; MS (ESI) m/e (M+1H) +: 370.1, (M-1H) -: 368.2.
Compound 97
1H NMR (400MHz, DMSO-d 6) δ: 11.06 (s, 1H), 8.62 (d, 1H, J=8.7Hz), 7.88 (d, 1H, J=7.6Hz), 7.72 (d, 2H, J=8.5Hz), 7.65 (d, 1H, J=8.5Hz), 7.50 (t, 1H, J=8.5Hz), 7.36 (t, 1H, J=8.5Hz), 7.02 (d, 2H, J=8.5Hz), 5.08 (s, 2H), 4.29 (m, 1H), 4.18 (m, 1H), 4.10 (m, 1H), 3.62 (m, 2H), 3.51 (m, 2H), 3.26 (s, 3H), 1.77 (m, 1H), 1.67 (m, 1H), 0.97 (t, 3H, J=7.3Hz) .EM (calculated value): 456; MS (ESI) m/e (M+1H) +: 457.1, (M-1H) -: 455.2.
Compound 98
1H NMR (400MHz, DMSO-d 6) δ: 11.05 (s, 1H), 8.91 (t, 1H, J=6.1Hz), 7.88 (d, 1H, J=7.5Hz), 7.72 (d, 2H, J=8.4Hz), 7.63 (d, 1H, J=8.4Hz), 7.50 (t, 1H, J=8.5Hz), 7.36 (t, 1H, J=8.5Hz), 7.07 (d, 2H, J=8.4Hz), 5.07 (s, 2H), 4.74 (q, 1H, J=6.0Hz), 3.60 (m, 2H), 3.50 (m, 2H), 3.45 (m, 2H), 3.26 (s, 3H), 1.32 (d, 3H, J=6.1Hz) .EM (calculated value): 442; MS (ESI) m/e (M+1H) +: 443.1, (M-1H) -: 441.5.
Compound 99
1H NMR (400MHz, DMSO-d 6) δ: 11.09 (s, 1H), 9.54 (s, 1H), 9.40 (t, 1H, J=5.6Hz), 8.04 (d, 1H, J=7.8Hz), 7.74 (d, 2H, J=8.3Hz), 7.61 (t, 1H, J=7.3Hz), 7.49 (t, 1H, J=7.3Hz), 7.03 (d, 2H, J=8.5Hz), 4.82 (s, 2H), 4.26 (t, 2H, J=5.6Hz), 3.75 (q, 2H, J=5.6Hz), 3.50 (m, 2H), 3.25 (m, 4H), 1.32 (t, 6H, J=7.4Hz) .EM (calculated value): 425; MS (ESI) m/e (M+1H) +: 426.1, (M-1H) -: 424.2.
Compound 109
1H NMR(DMSO-d 6)：1.95(2H，m)；2.05(3H，s)；2.48-2.62(2H，.m)；4.08(1H，dd，11，6Hz)；4.16(1h，dd，11，7Hz)；4.45(1H，m)；6.99(2H，d，9Hz)；7.32(1H，t，7Hz)；7.45(1H，td，8，1Hz)；7.55(1H，d，1Hz)；7.64(1H，d，8Hz)；7.69(2H，d，9Hz)；7.76(1H，d，8Hz)；8.7(1H，d，8Hz)；8.87(1H，s).MS(M+1)：415.
Compound 110
1H NMR(DMSO-d 6)：2.03-2.21(2H，m)；2.991H，s，3H)；3.22(2H，t，7Hz)；4.12(1H，dd，11，6Hz)；4.19(1H，dd，11，7Hz)；4.46(1H，m)；7.00(2H，d，9Hz)；7.33(1H，t，7Hz)；7.46(1H，td，8，1Hz)；7.57(1H，d，1Hz)；7.64(1H，d，8Hz)；7.70(2H，d，9Hz)；7.77(1H，d，8Hz)；8.79(1H，d，8Hz)；8.88(1H，s).MS(M+1)：447.
Table 4:
Compound 1
EM (calculated value): 381.13; MS (ESI) m/e (M+1H) +: 382.3, (M-1H) -: 380.2.
Compound 2
EM (calculated value): 395.15; MS (ESI) m/e (M+1H) +: 396.1, (M-1H) -: 394.2.
Compound 3
EM (calculated value): 331.08; MS (ESI) m/e (M+1H) +: 331.7, (M-1H) -: 330.1.
Compound 4
EM (calculated value): 317.10; MS (ESI) m/e (M+1H) +: 318.10, (M-1H) -: 315.9.
Compound 5
EM (calculated value): 425.2; MS (ESI) m/e (M+1) +: 426.1, (M-1) -: 424.1.
Compound 6
EM (calculated value): 381.1; MS (ESI) m/e (M+1) +: 382.0, (M-1) -: 380.1.
Compound 7
EM (calculated value): 381.1; MS (ESI) m/e (M+1) +: 382.0, (M-1) -: 380.2.
Compound 8
EM (calculated value): 341.1; MS (ESI) m/e (M+1) +: 341.9, (M-1) -: 340.1.
Compound 9
EM (calculated value): 381.1; MS (ESI) m/e (M+1) +: 381.8, (M-1) -: 380.0.
Compound 10
EM (calculated value): 411.1; MS (ESI) m/e (M+1) +: 412.0, (M-1) -: 410.3.
Compound 11
EM (calculated value): 395.2; MS (ESI) m/e (M+1) +: 396.0, (M-1) -: 394.2.
Compound 12
EM (calculated value): 388.1; MS (ESI) m/e (M+1) +: 389.1, (M-1) -: 387.0.
Compound 13
EM (calculated value): 355.12; MS (ESI) m/e (M+1) +: 355.9, (M-1) -: 354.1.
Compound 14
EM (calculated value): 355.1; MS (ESI) m/e (M+1) +: 355.9, (M-1) -: 353.8.
Compound 15
EM (calculated value): 409.2; MS (ESI) m/e (M+1) +: 410.2, (M-1) -: 408.3.
Compound 16
EM (calculated value): 341.1; MS (ESI) m/e (M+1) +: 341.8, (M-1) -: 340.2.
Compound 17
1H NMR (400MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.66 (d, J=8.0Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.64 (d, J=8.0Hz, 1H), 7.55 (s, 1H), 7.46 (t, J=8.4Hz, 1H), 7.32 (t, J=8.0Hz, 1H), 6.72 (s, 1H), 4.30 (m, 3H), 1.67 (m, 2H), 0.92 (t, J=7.2Hz, 3H) .EM (calculated value): 359.1; MS (ESI) m/e:(M+1H) +: 359.8, (M-1H) -: 358.1.
Compound 18
1H NMR (400MHz, DMSO-d 6) δ 11.64 (s, 1H), 9.48 (s, 1H), 8.47 (d, J=8.0Hz, 1H), 8.09 (m, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.55 (t, J=8.0Hz, 1H), 7.49 (m, 2H), 7.39 (m, 1H), 4.30 (m, 3H), 1.69 (m, 2H), 0.94 (t, J=7.2Hz, 3H) .EM (calculated value): 395.2; MS (ESI) m/e:(M+1H) +: 395.8, (M-1H) -: 394.0.
Compound 19
1H NMR (400MHz, DMSO-d 6) δ 11.63 (s, 1H), 8.93 (t, J=5.6Hz, 1H), 7.75 (d, J=7.6Hz, 1H), 7.63 (d, J=7.6Hz, 1H), 7.54 (s, 1H), 7.45 (t, J=7.6Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 6.72 (s, 1H), 4.90 (m, 1H), 3.56 (m, 2H), 0.35 (d, J=7.2Hz, 3H) .EM (calculated value): 345.1; MS (ESI) m/e:(M+1H) +: 345.8, (M-1H) -: 344.0.
Compound 20
1H NMR (400MHz, DMSO-d 6) δ 11.64 (s, 1H), 9.480 (s, 1H), 8.83 (t, J=5.6Hz, 1H), 7.07 (m, 1H), 7.80 (d, J=7.6Hz, 1H), 7.70 (d, J=7.6Hz, 1H), 7.53 (t, J=7.6Hz, 1H), 7.48 (m, 2H), 7.39 (m, 1H), 6.72 (s, 1H), 4.91 (m, 1H), 3.58 (m, 2H), 1.36 (d, J=7.0Hz, 3H) .EM (calculated value): 381.1; MS (ESI) m/e:(M+1H) +: 382.0, (M-1H) -: 380.0.
Compound 21
EM (calculated value): 367.1; MS (ESI) m/e (M+1) +: 367.8, (M-1) -: 366.2.
Compound 22
EM (calculated value): 367.12; MS (ESI) m/e (M+1H) +: 368.0, (M-1H) -: 366.1.
Compound 23
EM (calculated value): 374.0; MS (ESI) m/e (M+1) +: 374.7, (M-1) -: 372.9.
Compound 24
EM (calculated value): 395.2; MS (ESI) m/e (M+1) +: 396.1. (M-1) -: 394.1.
Compound 25
EM (calculated value): 367.1; MS (ESI) m/e (M+1) +: 368.1, (M-1) -: 366.2.
Compound 26
EM (calculated value): 381.1; MS (ESI) m/e (M+1) +: 382.0, (M-1) -: 380.1.
Compound 27
1H NMR (400MHz, DMSO-d 6) δ 11.62 (s, 1H), 9.45 (s, 1H), 8.54 (d, J=7.6Hz, 1H), 8.43 (s, 1H), 7.97 (m, 4H), 7.60 (m, 2H), 6.73 (s, 1H), 4.33 (m, 3H), 1.70 (m, 2H), 0.96 (t, J=7.6Hz, 3H) .EM (calculated value): 369.1; MS (ESI) m/e:(M+1H) +: 369.9, (M-1H) -: 368.0.
Compound 28
1H NMR (400MHz, DMSO-d 6) δ 11.66 (s, 1H), 9.50 (s, 1H), 8.53 (d, J=7.6Hz, 1H), 8.11 (m, 1H), 7.96 (m, 2H), 7.55 (m, 4H), 6.78 (s, 1H), 4.33 (m, 3H), 1.68 (m, 2H), 1.01 (t, J=7.2Hz, 3H) .EM (calculated value): 369.1; MS (ESI) m/e:(M+1H) +: 370.0, (M-1H) -: 368.2.
Compound 29
1H NMR (400MHz, DMSO-d 6) δ 11.64 (s, 1H), 8.86 (t, J=5.6Hz, 1H), 8.40 (s, 1H), 7.90 (m, 4H), 7.59 (m, 2H), 6.73 (s, 1H), 4.94 (m, 1H), 3.60 (m, 2H), 1.38 (d, J=6.0Hz, 3H) .EM (calculated value): 355.1; MS (ESI) m/e:(M+1H) +: 355.9, (M-1H) -: 353.9.
Compound 30
1H NMR (400MHz, DMSO-d 6) δ 11.66 (s, 1H), 8.78 (t, J=5.6Hz, 1H), 8.09 (d, J=7.6Hz, 1H), 7.96 (m, 2H), 7.50 (m, 4H), 6.74 (s, 1H), 4.97 (m, 1H), 3.61 (m, 2H), 1.41 (d, J=6.4Hz, 3H) .EM (calculated value): 355.1; MS (ESI) m/e:(M+1H) +: 356.1, (M-1H) -: 353.9.
Compound 31
EM (calculated value): 345.1; MS (ESI) m/e (M+1) +: 345.8, (M-1) -: 344.0.
Compound 32
EM (calculated value): 331.1; MS (ESI) m/e (M+1) +: 331.9, (M-1) -: 330.2.
Compound 33
EM (calculated value): 437.12; MS (ESI) m/e (M+1H) +: 438.0, (M-1H) -: 436.2.
Embodiment 4
(N-ethanoyl-Lys)-AMC's is synthetic for ethanoyl-Gly-Ala-
(N-ethanoyl-Lys)-AMC (445mg, 1mmol is available from Bachem) is dissolved in the dioxan solution of 4M HCl, and (N-ethanoyl-Lys)-AMC is white solid to obtain H-with uncle Boc.Use PyBOP (520mg, 1mmol), HOBt (135mg, 1mmol) and NMM (0.296ml, 2mmol), to H-(adding Ac-Gly-Ala-OH in the DMF solution (5ml) of N-ethanoyl-Lys)-AMC (and 188mg, 1mmol).Reaction mixture is stirred 1h, by the MS/LC monitoring H-(existence of N-ethanoyl-Lys)-AMC.Add additional content PyBOP (260mg, 0.5mmol), HOBt (70mg, 0.5mmol) and NMM (0.146ml 1mmol), continues stirring 4h, more then with the quantitative yield separated product.
Biological Examples
The inhibition of embodiment 1 external HDAC
The compounds of this invention suppresses active in following mensuration at external HDAC.
Use 96 hole identification plates in 100 μ L reaction volumes, to measure.Make reaction cushion (the 50mM HEPES of HDAC-1 (200pM ultimate density); 100mM KCl; 0.001%Tween-20; 5%DMSO; pH 7.4) inhibitor mixed of solution and different concns; cultivated 30 minutes, (N-ethanoyl-Lys)-AMC is respectively 50nM and 25 μ M to ultimate density, with initiation reaction to add trypsinase and ethanoyl-Gly-Ala-then.Do not having under the situation of inhibitor, repeating negative control reaction 8 times.
Monitoring reaction in the fluorescent plate reader.After 30 minute retardation time, after 30 minute retardation time, use the excitation wavelength of 355nm, the detection wavelength of 460nm to measure fluorescence.Fluorescence increase in time is used as measuring of speed of reaction.Use BatchKi program (Kuzmicet al.Anal.Biochem.2000,286, the 45-50) constant that is inhibited.The Ki of most The compounds of this invention is less than 40nm.
The cell proliferating determining that embodiment 2 is external
Formula (I) compound is pressed following mensuration in the ability of extracorporeal suppression tumor cell growth.
Under 37 ℃, 5%CO 2In the humidification atmosphere, the stock culture of colon carcinoma cell line is remained in the RPMI substratum 1640, it comprises ketone acid sodium, 50 units/ml penicillin and 50 μ g/ml Streptomycin sulphates in 10% (v/v) fetal bovine serum, 2mM L-glutaminate, the 1mM.Cell is at 75-cm 2Cultivate in the culturing bottle, set up the branch training, and converged in every 3-4 days in order to avoid make cell surpass 90%.
Results HCT116 cell, (0.05% trypsinase/0.53mMEDTA) carry out proliferation assay, washed twice in substratum are suspended in the substratum of appropriate volume once more, use the hematimeter counting then by trypsin treatment.The cell sowing is in the hole of round bottom 96 orifice plates, and density is 5,000 cells/100 μ l holes.Under 37 ℃, make cell attachment 1.5-2 hour.
Compound is diluted to the DMSO from the 10mM liquid storage.In containing the substratum of 0.6%DMSO, in the hole of 96 hole U-base plates (three parts), begin with 60 μ M solution, carry out continuous 3-and doubly dilute.After dilution finishes, every kind of diluted chemical compound liquid of 100 μ l (three parts) to be transferred in three times of holes of appointment of 96-orifice plate, described 96-orifice plate comprises 100 μ l culture medium solutions of cell.The ultimate density scope of the dose response of compound is 0.12 to 30 μ M in identification plate.Control wells (cell that does not have processing) is accepted the culture medium solution of 100 μ l 0.6%DMSO.The hole that contains substratum but do not have a cell is as the background hole.CO at humidification 2In the incubator, under 37 ℃, with compound culturing cell 48 and 72 hours.
Adding fluorescence oxidation-reduction indicator Alamar Blue TM(BioSourceInternational) after, assess cell proliferation by measuring fluorescence.Finish preceding 3 to 4 hours in the incubation period, with 10 μ l Alamar Blue TMAdd in each hole of 96-orifice plate.At fluorescent plate reader (excitation wavelength, 530nM; Emission wavelength is read identification plate in 620nM).By contrasting the logarithm mapping of fluorescence percentage ratio and compound concentration, can determine the G of compound 150Value (growth of tumour cell is suppressed 50% o'clock concentration).The compounds of this invention has suppressed the growth of tumour cell.
Pharmaceutical composition embodiment
Be the representative drugs prescription that contains formula (I) compound below.
Tablet formulation
The uniform mixing following ingredients is even, and is pressed into single Divide-Tab.
Amount in each tablet of composition, mg
The compounds of this invention 400
W-Gum 50
Cross-linked carboxymethyl cellulose sodium 25
Lactose 120
Magnesium Stearate 5
Capsule formula
The uniform mixing following ingredients, and be encased in the duricrust gelatine capsule.
Amount in each capsule of composition, mg
The compounds of this invention 200
Lactose, spray-dired 148
Magnesium Stearate 2
The suspensoid prescription
Mix following ingredients to form suspensoid for oral use.
Become component
The compounds of this invention 1.0g
Fumaric acid 0.5g
Sodium-chlor 2.0g
Para methyl paraben 0.15g
Propylparaben 0.05g
Granulated sugar 25.5g
Sorbitol Powder (70% solution) 12.85g
Veegum K(Vanderbilt Co.) 1.0g
Seasonings 0.035ml
Tinting material 0.5mg
Water is in right amount to 100ml
The injection prescription
Mix following ingredients to form the injection prescription.
Become component
The compounds of this invention 1.2g
Lactate buffer, 0.1M 10.0ml
HCl (1N) or NaOH (1N) are an amount of to suitable pH
Salt solution (optional) is an amount of to suitable osmolarity
Water (distillation, aseptic) is in right amount to 20ml
Compound (1.2g) and 0.1M lactate buffer (10ml) are merged, and mix gently.If desired, apply several times supersound process to form solution.Add an amount of acid or alkali to reach suitable pH (preferred pH 4).Add enough water then to 20ml.
The suppository prescription
With The compounds of this invention and Witepsol TMH-15 (the triglyceride level of saturated vegetable fatty acid; Riches-Nelson, Inc., New York) mix making suppository, gross weight 2.5g, it has following composition:
The compounds of this invention 500mg
Witepsol TMThe H-15 surplus
In order to be aware and understand, with some details foregoing invention has been described by explanation and embodiment.It should be apparent to those skilled in the art that and to implement within the scope of the appended claims to change and revise.Therefore, so should understand above-mentioned illustrative purposes illustrative and nonrestrictive.Therefore, scope of the present invention should not determine according to the above description, and should determine according to the four corner of the Equivalent of appended claims and these claims.All patents, patent application and the publication quoted are in this application introduced for your guidance in full at this, are used for all purposes with following degree, are represented separately as each independent patent, patent application or publication.

Claims (41)

1. compound or pharmaceutically acceptable salt thereof with following formula (I):
Wherein:
R 1Be hydrogen or alkyl;
X is-O-,-NR 2-or-S (O) n-, wherein n is 0-2, R 2Be hydrogen or alkyl;
Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces;
Ar 1Be phenylene or heteroarylidene, wherein said Ar 1Randomly replaced by one or two group, described group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, halogenated alkoxy or haloalkyl;
R 3Be hydrogen, alkyl, hydroxyalkyl or the optional phenyl that replaces; With
Ar 2Be aryl, aralkyl, arylalkenyl, heteroaryl, heteroaralkyl, impure aromatic ene base, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl.
2. compound as claimed in claim 1, wherein X is-O-, R 1And R 3Be hydrogen.
3. compound as claimed in claim 1, wherein X is-S (O) n-, R 1And R 3Be hydrogen.
4. as claim 2 or 3 described compounds, wherein Y is an alkylidene group.
5. as claim 2 or 3 described compounds; wherein Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces.
6. compound as claimed in claim 1, wherein Ar 1Be phenylene, X is-O-R 1And R 3Be hydrogen ,-CONHOR 1With 1-and the 4-position of X group at the phenylene ring.
7. as each described compound, wherein Ar among the claim 2-5 1Be heteroarylidene.
8. as each described compound, wherein Ar among the claim 2-5 1Be phenylene.
9. as each described compound, wherein Ar among the claim 2-8 2Be aryl or arylalkenyl.
10. as each described compound, wherein Ar among the claim 2-5,7 and 8 2Be heteroaryl.
11. compound as claimed in claim 6, wherein Ar 2Be heteroaryl.
12. compound as claimed in claim 1, wherein Ar 2Be the heteroaryl that is randomly replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) nR a(wherein n is 0 to 2, R aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR e-alkylidene group CONR cR d(R wherein cBe hydroxyl, R dAnd R eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.
13. compound as claimed in claim 10, wherein Ar 2Be the heteroaryl that is randomly replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) nR a(wherein n is 0 to 2, R aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR e-alkylidene group CONR cR d(R wherein cBe hydroxyl, R dAnd R eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.
14. compound as claimed in claim 10, wherein Ar 2Be cumarone-2-base; and replace at the 3-position of cumarone-2-basic ring coverlet; wherein substituting group is N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy-methyl; hydroxyl-4-yloxymethyl; 2; 4; 6-trifluoromethoxy phenoxy base-methyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy-methyl; 4-imidazoles-1-phenoxyl-methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; 3-hydroxyl propoxy-methyl; 2-methoxy ethoxy methyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3,3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; 2-(3-Trifluoromethoxyphen-l ethyl); N-methyl-N-benzylamino-methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl-methyl; 3-hydroxypropyl alkylsulfonyl methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 2-carboxy ethyl amino methyl.
15. compound as claimed in claim 11, wherein Ar 2Be the optional heteroaryl that is replaced by one or two substituting group, described substituting group is independently selected from: alkyl, halogen, haloalkyl, alkoxyl group, alkoxyalkyl, the hydroxy alkoxy base, hydroxy alkoxy alkyl, the alkoxyl group alkoxyl group, alkoxy alkoxy alkyl, aminoalkyl group, aminoalkoxy, halogenated alkoxy, halogenated alkoxy alkyl, the optional phenylalkyl that replaces, the optional phenoxyalkyl that replaces, the optional heteroaryl that replaces, the optional assorted aralkoxy that replaces, the optional heteroaryloxy alkyl that replaces, the optional Heterocyclylalkyl alkyl that replaces, the optional heterocycle alkoxyl group that replaces, the optional Heterocyclylalkyl alkoxyl group that replaces,-alkylidene group-S (O) nR a(wherein n is 0 to 2, R aBe hydroxyalkyl or the optional phenyl that replaces) ,-alkylidene group-NR e-alkylidene group CONR cR d(R wherein cBe hydroxyl, R dAnd R eBe hydrogen or alkyl independently) or the carboxyalkyl aminoalkyl group.
16. compound as claimed in claim 11, wherein Ar 2Be cumarone-2-base; and coverlet replaces on the 3-position of cumarone-2-basic ring; wherein substituting group is N; the N-dimethylaminomethyl; N; N-diethylamino methyl; 2-fluorophenoxy methyl; 3-fluorophenoxy methyl; 4-fluorophenoxy methyl; hydroxyl-4-yloxymethyl; 2; 4; 6-trifluoromethoxy phenoxy base-methyl; 2-oxo pyridine-1-ylmethyl; 2; 2; 2-trifluoro ethoxy-methyl; 4-imidazoles-1-phenoxyl-methyl; 4-[1.2.4]-triazine-1-base-phenoxymethyl; the 2-phenylethyl; 3-hydroxyl propoxy-methyl; 2-methoxy ethoxy methyl; tetramethyleneimine-1-ylmethyl; piperidines-1-ylmethyl; 4-trifluoromethyl piperidines-1-ylmethyl; 4-methylpiperazine-1-ylmethyl; 3; 3,3-trifluoropropyl oxygen ylmethyl; 4-fluorobenzene sulfenyl methyl; 4-fluorophenyl sulfinyl methyl; 4-fluorophenyl alkylsulfonyl methyl; 2-(3-Trifluoromethoxyphen-l ethyl); N-methyl-N-benzylamino-methyl; N-methyl-N-2-phenylethyl amino methyl; 3-hydroxyl rosickyite ylmethyl; 3-hydroxypropyl sulfinyl-methyl; 3-hydroxypropyl alkylsulfonyl methyl; N-methyl-N-2-indol-3-yl ethylamino methyl; 2-(4-trifluoromethyl) ethyl; N-hydroxyl amino carbonyl-methylamino methyl; or 2-carboxy ethyl amino methyl.
17. compound as claimed in claim 11, wherein Ar 2Be cumarone-2-base, and coverlet replaces on the 5-position of cumarone-2-basic ring.
18. compound as claimed in claim 11, wherein Ar 2Be cumarone-2-base, and coverlet replaces on the 5-position of cumarone-2-basic ring, wherein substituting group is: cyclopropyl piperidine-4-base oxygen, piperidin-4-yl oxygen, tetrahydropyran-4-base oxygen, 2,2,2-trifluoro ethoxy, 2-tetramethyleneimine-1-base oxethyl or 1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen.
19. as each described compound among the claim 15-18, wherein Y is an ethylidene.
20. as each described compound, wherein Ar among the claim 2-8 2Be arylalkenyl.
21. compound as claimed in claim 1, wherein X is-O-, R 1And R 3Be hydrogen, Ar 1Be phenylene, Ar 2Be arylalkenyl, Y is a branched alkylidene, and-CONHOH and X are in the 1-and the 4-position of phenylene ring.
22. compound as claimed in claim 21, wherein Ar 2Be trans-phenyl CH=CH-, wherein phenyl is randomly replaced by one or two substituting group, and described substituting group is independently selected from: alkyl, alkoxyl group, methylene-dioxy or hydroxyl.
23. a compound or pharmaceutically acceptable salt thereof, described compound is selected from:
N-hydroxyl-4-(2-phenylcarbamoyl amino-oxyethyl group) benzamide;
N-hydroxyl-4-(2-trans-cinnamoyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-trans-2-phenycyclopropyl carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-trans-4-methoxyl group cinnamoyl amino ethoxy) benzamide;
N-hydroxyl-4-[2-(2-phenylethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indol-3-yl methyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-(2-thiophene-2-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-pyridin-3-yl carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-biphenyl-4-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-(2-biphenyl-3-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-[2-(5-phenyl thiophene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(thiophene-2-ylmethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(naphthalene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-6-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-tert-butyl-phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-pyridin-3-yl acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyrroles-1-base phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-tetrahydrobenzene-3-oxygen phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(benzothiazole-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(benzoxazoles-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(octahydro isoquinoline 99.9-2-ylmethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridin-4-yl piperazine-1-ylmethyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(furans-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridin-3-yl phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridine-2-base phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(benzimidazolyl-2 radicals-Ji carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-pyrroles-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-benzamido phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-pyridin-4-yl thiazol-2-yl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(diamantane-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,4 difluorobenzene base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-trans-3,4-methylenedioxyphenyl acryl amino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(3,4-methylenedioxyphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3,4-Dimethoxyphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3,5-Dimethoxyphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3,4-difluorophenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,5-3,5-dimethylphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,3-dichlorophenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2,3-3,5-dimethylphenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-chloro-2-p-methoxy-phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-ethoxyl phenenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxyl group-2-aminomethyl phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-fluoro-4-p-methoxy-phenyl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-thiophene-2-ylmethoxy phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-thiophene-2-ylmethoxy phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(biphenyl-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indoles-5-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indol-3-yl carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-8-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-indazole-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-benzotriazole-5-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(isoquinolyl-1 carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(isoquinoline 99.9-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoxaline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(naphthalene-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-pyrroles-1-base phenylcarbonyl group amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-fluoronaphthalene-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1H-benzoglyoxaline-5-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1-skatole-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxy quinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-methoxynaphthalene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-methoxynaphthalene-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(quinolyl-4 carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-2-methyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(2-N, N-dimethylaminomethyl cumarone-5-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-(2-indoline-1-base carbonylamino oxyethyl group) benzamide;
N-hydroxyl-4-[2-(1,2,3,4-tetrahydroquinoline-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2S-[is trans-3-(5-hydroxyl benzofuran-2-yl) but-2-ene acyl amino] and butoxy } benzamide;
N-hydroxyl-4-{2S-[is trans-3-(5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-yl) but-2-ene acyl group-amino] and butoxy } benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-phenyl butoxy] benzamide;
N-hydroxyl-4-{2-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2S-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-butoxy } benzamide;
N-hydroxyl-4-{2-[5-(1-cyclopropyl piperidine-4-base oxygen) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[5-(1-(2,2, the 2-trifluoroethyl) piperidin-4-yl oxygen) cumarone-2-base carbonyl-amino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2R-(cumarone-2-base carbonylamino)-3-benzyl alkylsulfonyl propoxy-] benzamide;
N-hydroxyl-4-[2R-(cumarone-2-base carbonylamino)-3-benzylthio-propoxy-] benzamide;
N-hydroxyl-4-[2-(trans-3-(5-methoxyl group benzo furans-2-yl) but-2-ene acyl group carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2-(1,2,3,4-tetrahydroisoquinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(isoindoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(morpholine-4-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-benzyl diethylenediamine-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3 (R)-hydroxyl pyrrolidine-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(piperidines-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-1-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(2-methyl indoline-1-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-fluoro-2-methyl isophthalic acid, 2,3,4-tetrahydroquinoline-1-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2S-(isoindoline-1-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[3-(trans-cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[3-(trans-4-methoxyl group cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[3-(4-phenyl thiazole-2-base carbonylamino) propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino) propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methyl pentyloxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-cyclohexyl propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-methyl butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-phenyl propoxy-] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-phenyl propoxy-] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methyl pentyloxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-methyl butoxy] benzamide;
N-hydroxyl-4-[2RS-(trans-cinnamoyl amino) hexyloxy] benzamide;
N-hydroxyl-4-[2RS-(trans-cinnamoyl amino)-3-(4-chloro-phenyl-) propoxy-] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methylthio group butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methylthio group butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-2-phenyl ethoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-2-phenyl ethoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-4-methyl sulphonyl butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-4-methyl sulphonyl butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-benzyl alkylsulfonyl propoxy-] benzamide;
N-hydroxyl-4-[2S-(thiophene-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(biphenyl-4-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(naphthalene-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2R-(trans-cinnamoyl amino)-3-benzylthio-propoxy-] benzamide;
N-hydroxyl-4-[2S-(phenylcarbamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(benzyloxycarbonyl group amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(2-phenylethyl carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-cinnamoyl amino)-3-hydroxyl propoxy-] benzamide;
N-hydroxyl-4-[2S-(4-phenyl thiazole-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2S-(trans-4-methoxyl group cinnamoyl amino) butoxy] benzamide;
N-hydroxyl-4-[2S-(2-N, N-dimethylaminomethyl cumarone-5-base carbonylamino) butoxy]-benzamide;
N-hydroxyl-4-[2-(trans-cinnamoyl amino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(trans-cinnamoyl amino)-1S-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(4-phenyl thiazole-2-base carbonylamino)-1S-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(biphenyl-4-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(trans-4-methoxyl group cinnamoyl amino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-{2-[4-(2-pyridine-2-base thiazole-5-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(7-chloro-4-methyl cumarone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[4-(2-(4-methylpiperazine-1-yl) thiazole-5-yl) phenylcarbonyl group amino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(2-pyridin-4-yl aminothiazole-5-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[4-(4-methylpiperazine-1-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(4-hydroxy piperidine-1-yl) phenylcarbonyl group amino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(4-morpholine-4-ylmethyl thiazole-5-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(7-fluoro-4-methyl cumarone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[7-fluoro-4-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(4-hydroxyquinoline-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(7-fluoro-4-phenoxymethyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[4-(2-(4-methylpiperazine-1-ylmethyl) thiazol-2-yl) phenylcarbonyl group-amino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(pyridine-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(3-pyridone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-pyridone-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[6-(4-nitrophenoxy) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(2-methoxy ethoxy) quinoline-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(2-N, N-dimethylamino ethoxy) quinoline-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(6-bromopyridine-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(5-bromopyridine-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2S-(4-methoxy quinoline-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2-(1-methoxynaphthalene-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxy quinoline-2-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(5-phenylpyridine-3-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(6-benzyloxy pyridine-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[6-(2-methyl propoxy-) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[6-(2-phenyl ethoxy) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[4-(3,3,3-trifluoro propoxy-) quinoline-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-[2-(trans-3-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-4-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[3 '-(2-hydroxyethyl) biphenyl-4-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3 '-(2-hydroxyethyl) biphenyl-3-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[2 '-(2-hydroxyethyl) biphenyl-4-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-the 2-cumarone-2-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[2 '-(2-hydroxyethyl) biphenyl-3-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[5-(thiene-3-yl-) pyridin-3-yl carbonylamino] oxyethyl group) benzamide;
N-hydroxyl-4-{2-[6-(4-acetylamino phenoxy group) pyridine-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(4-amino-benzene oxygen) pyridine-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-2-methoxyl group cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-methoxyl group cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[5-(4-dimethylaminophenyl) pyridin-3-yl carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[is trans-3-(5-bromothiophene-2-yl) acryl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-the 3-furans-3-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-thiene-3-yl-acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-thiophene-2-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[is trans-3-methyl cinnamoyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2-[is trans-4-methyl cinnamoyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2-[is trans-3-(cumarone-2-yl) but-2-ene acyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2-[cis-3-(cumarone-2-yl) but-2-ene acyl amino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-4-dimethylamino cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-[2-(trans-3-indol-3-yl acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[is trans-2-methyl cinnamoyl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-[2-(trans-2-hydroxyl cinnamoyl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[is trans-3-(7-methoxyl group benzo furans-2-yl) acryl amino] and oxyethyl group } benzamide;
N-hydroxyl-4-{2R-[is trans-3-(7-methoxyl group benzo furans-2-yl) acryl amino] and butoxy } benzamide;
N-hydroxyl-4-{2S-[is trans-3-(5-methoxyl group benzo furans-2-yl) but-2-ene acyl amino] and butoxy } benzamide;
N-hydroxyl-4-[2-(trans-the 3-furans-2-base acryl amino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[4-(4-(2-morpholine-4-base ethyl) thiazol-2-yl) phenylcarbonyl group amino] oxyethyl group }-benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-hydroxyethyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-phenyl amino oxyethyl group) benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-methyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-N-thionaphthene-2-base-N-sec.-propyl amino ethoxy) benzamide;
N-hydroxyl-4-(2-N-trans-cinnamoyl-N-sec.-propyl amino ethoxy) benzamide;
N-hydroxyl-4-(3-N-trans-cinnamoyl-N-methylamino propoxy-) benzamide;
N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(1H-indoles-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(1-skatole-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[3-(thionaphthene-2-base carbonylamino) propoxy-]-benzamide;
N-hydroxyl-4-[3-(cumarone-2-base carbonylamino) propoxy-]-benzamide;
N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino)-3-methyl butoxy]-benzamide;
N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino) butoxy]-benzamide;
N-hydroxyl-4-[2S-(thionaphthene-2-base carbonylamino)-propoxy-]-benzamide;
N-hydroxyl-4-[2R-(thionaphthene-2-base carbonylamino)-propoxy-]-benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino) butoxy]-benzamide;
N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino)-1R-methyl ethoxy]-benzamide;
N-hydroxyl-4-[2-(thionaphthene-2-base carbonylamino)-1S-methyl ethoxy]-benzamide;
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-1R-methyl ethoxy]-benzamide;
N-hydroxyl-4-[2-(6-anisole thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methylbenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(3-chloro thiophene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(6-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(4-trifluoromethyl thionaphthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-fluorobenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-anisole thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-chlorobenzene and furans-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(7-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(2-morpholine-4-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(pyridin-3-yl methoxyl group) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(3-methyl cumarone-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(3-methylbenzene thiophthene-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[5-(2-hydroxyl-oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(2-N, N-dimethylamino ethoxy) cumarone-2-base carbonylamino]-oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(2-morpholine-4-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[6-(pyridin-3-yl methoxyl group) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(3-ethyl benzofuran-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-fluoro indole-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-[2-(5-methoxyl group indoles-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[3-(methoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(phenoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-[2-(5,6-dimethoxy indoles-2-base carbonylamino) oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[3-(morpholine-4-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(N, N-dimethylaminomethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(isopropoxy methyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[7-(phenoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[7-(methoxymethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[7-(morpholine-4-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[7-(N, N-dimethylaminomethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{3-[5-(methyl) thionaphthene-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{3-[6-(methoxyl group) thionaphthene-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{3-[7-(methoxymethyl) cumarone-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{3-[7-(phenoxymethyl) cumarone-2-base carbonylamino] propoxy-}-benzamide;
N-hydroxyl-4-{2-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-(2R-cumarone-2-base carbonylamino-3-methylthio group propoxy-) benzamide;
N-hydroxyl-4-(2R-cumarone-2-base carbonylamino-3-methyl sulphonyl propoxy-) benzamide;
N-hydroxyl-4-{2-[3-(2-phenylethyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-methyl-N-benzylamino-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-methyl-N-2-phenylethyl amino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxyl rosickyite ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxypropyl sulfinyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxypropyl alkylsulfonyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-methyl-N-2-indol-3-yl ethylamino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-(3-trifluoromethyl) ethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-(3-Trifluoromethoxyphen-l) ethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(N-hydroxyl amino carbonyl methylamino methyl) cumarone-2-base carbonylamino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-carboxy ethyl amino methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(cumarone-2-base carbonylamino)-1RS-phenoxymethyl oxyethyl group]-benzamide;
N-hydroxyl-4-{2-[3-(3-hydroxyl propoxy-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(3-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(4-fluorophenoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(pyridin-4-yl oxygen methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2,4,6-trifluoromethoxy phenoxy ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(2-oxo pyridine-1-ylmethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-imidazoles-1-phenoxyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-[1.2.4]-triazine-1-phenoxyl methyl) cumarone-2-base carbonyl-amino] oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(tetramethyleneimine-1-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(piperidines-1-methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[3-(4-trifluoromethyl piperidines-1-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-methylpiperazine-1-methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(3,3,3-trifluoropropyl oxygen ylmethyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-[2-(4-methyl cumarone-2-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-{2-[3-(4-fluorobenzene sulfenyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-fluorophenyl sulfinyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2-[3-(4-fluorophenyl alkylsulfonyl methyl) cumarone-2-base carbonylamino]-oxyethyl group } benzamide;
N-hydroxyl-4-{2S-[3-(2,2,2-trifluoro ethoxy methyl) cumarone-2-base carbonylamino]-butoxy } benzamide;
N-hydroxyl-4-[2-(4-hydroxyl benzofuran-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-[2S-(5-chlorobenzene and furans-2-base carbonylamino) butoxy] benzamide;
N-hydroxyl-4-[2-(5-chlorobenzene and furans-2-base carbonylamino)-1R-methyl ethoxy] benzamide;
N-hydroxyl-4-[2-(4-pyridin-3-yl methoxymethyl cumarone-2-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxyl group benzo furans-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2-[4-(2-methoxy ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2-(4-pyridin-3-yl methoxyl group benzo furans-2-base carbonylamino)-oxyethyl group] benzamide;
N-hydroxyl-4-[2-(4-methoxyl group indoles-2-base carbonylamino) oxyethyl group] benzamide;
N-hydroxyl-4-{2S-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-butoxy } benzamide;
N-hydroxyl-4-{2-[3-(2-methoxy ethoxy methyl) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[3-(N, N-diethylamino methyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[5-(2-methoxy ethoxy) cumarone-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[5-(tetrahydropyran-4-base oxygen) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[5-(2,2, the 2-trifluoro ethoxy) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-{2S-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino] butoxy }-benzamide;
N-hydroxyl-4-{2-[5-(2-tetramethyleneimine-1-base oxethyl) cumarone-2-base carbonylamino]-the 1R-methyl ethoxy } benzamide;
N-hydroxyl-4-{2-[5-(piperidin-4-yl oxygen) cumarone-2-base carbonylamino] oxyethyl group }-benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-methylthio group butoxy] benzamide;
N-hydroxyl-4-[2S-(cumarone-2-base carbonylamino)-4-methyl sulphonyl butoxy] benzamide;
N-hydroxyl-3-[2-(biphenyl-4-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(biphenyl-4-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(cumarone-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(trans-cinnamoyl amino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(4-(2-ethoxyl phenenyl) phenylcarbonyl group amino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(biphenyl-3-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(biphenyl-4-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(3-methyl diphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(2 '-ethoxybiphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(3-methyl diphenyl-4-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(4-phenyl thiazole-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(naphthalene-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(naphthalene-1-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-(3-[2-(2-phenylethyl) phenylcarbonyl group amino] propoxy-} isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-1-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(cumarone-2-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(biphenyl-3-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(cumarone-2-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-3-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-3-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-4-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(4-phenyl thiazole-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-{2-[2-(2-phenylethyl) phenylcarbonyl group amino] oxyethyl group } isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(biphenyl-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(biphenyl-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(naphthalene-2-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2S-(naphthalene-1-base carbonylamino) butoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-2-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[2-(naphthalene-1-base carbonylamino)-1R-methyl ethoxy] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(cumarone-2-base carbonylamino) propoxy-] isoxzzole-5-yl-carboxamides;
N-hydroxyl-3-[3-(trans-cinnamoyl amino) propoxy-] isoxzzole-5-yl-carboxamides; With
N-hydroxyl-3-[2-(3-phenoxymethyl cumarone-2-base carbonylamino) oxyethyl group] isoxzzole-5-yl-carboxamides.
24. compound or pharmaceutically acceptable salt thereof with following structure:
25. compound or pharmaceutically acceptable salt thereof with following structure:
26. compound or pharmaceutically acceptable salt thereof with following structure:
Figure A2004800092250023C2
27. compound or pharmaceutically acceptable salt thereof with following structure:
28. compound or pharmaceutically acceptable salt thereof with following structure:
Figure A2004800092250023C4
29. a pharmaceutical composition comprises among the claim 1-28 that treats significant quantity each compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable vehicle.
30. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of the claim 24 for the treatment of significant quantity.
31. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of the claim 25 for the treatment of significant quantity.
32. a pharmaceutical composition comprises the compound or pharmaceutically acceptable salt thereof and the pharmaceutically acceptable vehicle of the claim 26 for the treatment of significant quantity.
33. the application in the medicine of the disease that each compound is mediated by HDAC in preparation is used for the treatment of animal among the claim 1-28.
34. method as claimed in claim 33, wherein said disease are cancer, described animal is behaved.
35. method as claimed in claim 34, wherein said cancer are AML or MML.
36. the application among the claim 1-28 in the medicine of each compound cancer in preparation is used for the treatment of animal, it is independently selected from following compound in conjunction with one or more: estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent, another kind of antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors, dnmt rna inhibitor or angiogenesis inhibitor.
37. the application among the claim 1-28 in the medicine of each compound cancer in preparation is used for the treatment of animal, it is in conjunction with radiotherapy, and randomly exists one or more to be independently selected from following compound: estrogenic agents, androgen receptor modifier, retinoid receptor conditioning agent, cytotoxic agent, another kind of antiproliferative, prenyl-protein transferase inhibitor, HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors, dnmt rna inhibitor or angiogenesis inhibitor.
38. intermediate or its salt with following formula (II):
Figure A2004800092250025C1
Wherein:
R 50Be hydrogen or alkyl,
X is-O-,-NR 2-or-S (O) n-, wherein n is 0-2, R 2Be hydrogen or alkyl;
Y is an alkylidene group, and it is randomly replaced by cycloalkyl, the optional phenyl that replaces, alkylthio, alkyl sulphinyl, alkyl sulphonyl, the optional octadecyloxy phenyl sulfenyl that replaces, the optional phenylalkyl alkylsulfonyl that replaces, hydroxyl or the optional phenoxy group that replaces;
Ar 1Be phenylene or heteroarylidene, wherein said Ar 1Randomly replaced by one or two group, described group is independently selected from: alkyl, halogen, hydroxyl, alkoxyl group, halogenated alkoxy or haloalkyl;
R 3Be hydrogen, alkyl, hydroxyalkyl or the optional phenyl that replaces; With
Ar 2Be aryl, aralkyl, arylalkenyl, heteroaryl, heteroaralkyl, impure aromatic ene base, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl.
39. the application among the claim 1-28 in the medicine of each compound hepatitis C in preparation is used for the treatment of animal.
40. the application in the medicine of the compound of claim 39 hepatitis C in preparation is used for the treatment of animal.
41. the method for a preparation formula (I) compound comprises:
(i) make formula (III) compound:
Figure A2004800092250025C2
R wherein 51Be hydroxyl, alkoxyl group, halogen or succinimide ester, with formula NH 2OR " azanol reaction, wherein R " is hydrogen, alkyl or oxygen protecting group; Or
(ii) use acid treatment formula (IV) compound:
M wherein +Be basic metal; Use NH then 2" handle, wherein R " is hydrogen, alkyl or oxygen protecting group to OR;
Obtain the formula V compound;
Figure A2004800092250026C2
" base obtains formula (I) compound, wherein R (iii) randomly to remove the R in the compound (V) 1Be hydrogen;
The acid salt of the product that (iv) randomly is formed on above-mentioned steps (i), forms in (ii) or (iii);
(the free alkali of the product that v) randomly be formed on above-mentioned steps (i), forms in (ii), (iii) or (iv); Or
(vi) randomly modification in above-mentioned steps (i), (ii), (iii), (iv) or (X, Y, R in the product that forms v) 1, R 2, R 3, Ar 1And Ar 2In the group any one.
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CN102548975A (en) * 2009-07-07 2012-07-04 安瑟生物科技私人有限公司 Histone deacetylase inhibitors
CN102775368A (en) * 2011-05-10 2012-11-14 中国科学院上海药物研究所 Thiazole compound, and preparation method and application thereof
CN101674820B (en) * 2006-12-26 2013-09-25 药品循环公司 Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
CN103906732A (en) * 2011-10-28 2014-07-02 株式会社钟根堂 Hydroxamate derivatives for hdac inhibitor, and the pharmaceutical composition comprising thereof
CN103917231A (en) * 2011-09-13 2014-07-09 药品循环公司 Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101674820B (en) * 2006-12-26 2013-09-25 药品循环公司 Method of using histone deacetylase inhibitors and monitoring biomarkers in combination therapy
CN102548975A (en) * 2009-07-07 2012-07-04 安瑟生物科技私人有限公司 Histone deacetylase inhibitors
CN102775368A (en) * 2011-05-10 2012-11-14 中国科学院上海药物研究所 Thiazole compound, and preparation method and application thereof
CN102775368B (en) * 2011-05-10 2016-08-17 上海驺虞医药科技有限公司 One class thiazole compound and its production and use
CN103917231A (en) * 2011-09-13 2014-07-09 药品循环公司 Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof
CN103917231B (en) * 2011-09-13 2016-09-28 药品循环有限责任公司 Combination formulations of histone deacetylase inhibitor and bendamustine and application thereof
CN103906732A (en) * 2011-10-28 2014-07-02 株式会社钟根堂 Hydroxamate derivatives for hdac inhibitor, and the pharmaceutical composition comprising thereof

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