CN1816534A - Oxazolidinone antibiotics and derivatives thereof - Google Patents

Oxazolidinone antibiotics and derivatives thereof Download PDF

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Publication number
CN1816534A
CN1816534A CN 200480018878 CN200480018878A CN1816534A CN 1816534 A CN1816534 A CN 1816534A CN 200480018878 CN200480018878 CN 200480018878 CN 200480018878 A CN200480018878 A CN 200480018878A CN 1816534 A CN1816534 A CN 1816534A
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phenyl
hexane
alkyl
azabicyclo
group
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米尔顿·L·哈蒙德
福田保路
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Kyorin Pharmaceutical Co Ltd
Merck and Co Inc
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Kyorin Pharmaceutical Co Ltd
Merck and Co Inc
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Abstract

This invention relates to new oxazolidinones having a cyclopropyl moiety, which are effective against aerobic and anerobic pathogens such as multi-resistant staphylococci, streptococci and enterococci, Bacteroides spp., Clostridia spp. species, as well as acid-fast organisms such as Mycobacterium tuberculosis and other mycobacterial species. The compounds are represented by structural formula I: its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof.

Description

The cross reference of oxazolidone microbiotic and derivative related application thereof
The title that the application requires on July 2nd, 2003 to submit to is the U.S. Provisional Application 60/483 of " OXAZOLIDINONEANTIBIOTICS AND DERIVATIVES THEREOF ", 905, the title that on February 2nd, 2004 submitted to is the U.S. Provisional Application 60/546 of " OXAZOLIDINONEANTIBIOTICS AND DERIVATIVES THEREOF ", 947, the title of submitting to on March 18th, 2004 is the U.S. Provisional Application 60/553 of " OXAZOLIDINONEANTIBIOTICS AND DERIVATIVES THEREOF ", 963 right of priority, it is all incorporated into this paper as a reference in full.
Background of invention
Oxazolidone has been represented the first kind novel antibacterial medicine of exploitation after quinolone.Oxazolidone is to have oral or intravenously is active, the debatable multi-drug resistant gram-positive organism of antagonism and do not have the synthetic antimicrobial compound of cross resistance with other microbiotic.Referring to people such as Riedl, Recent Developments with OXAZOLidinone Antibiotics, Exp.Opin.Ther.Patents (1999) 9 (5), people such as Ford, OXAZOLidinones:NewAntibacterial Agents, Trends in Microbiology, 196, the 5th the 5th phase of volume, in May, 1997 and WO 96/35691.Also referring to WO 03/063862, WO 01/81350, WO01/94342, WO 03/072553, EP 0352781 and US 5,565,571 and 4,053,593.
The present invention relates to have the novel oxazolidinone of cyclopropyl part, it is the aerobic and anaerobic pathogenic agent of antagonism such as multi-drug resistant staphylococcus (staphylococci), suis (streptococci) and enterococcus bacteria (enterococci), genera bacillus (Bacteroides spp.), clostridium (Clostridia spp.) effectively, and acidproof organism such as mycobacterium tuberculosis (Mycobacterium tuberculosis) and other mycobacterium.
Summary of the invention
The present invention relates to the compound of following formula I:
Figure A20048001887800121
Its enantiomer, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug, wherein:
R 1Expression:
I) hydrogen;
ii)NR 5R 6；
iii)CR 7R 8R 9、C(R) 2OR 14、CH 2NHR 14；
iv)C(＝O)R 13、C(＝NOH)H、C(＝NOR 13)H、C(＝NOR 13)R 13、C(＝NOH)R 13、C(＝O)N(R 13) 2、C(＝NOH)N(R 13) 2、NHC(＝X 1)N(R 13) 2、(C＝NH)R 7、N(R 13)C(＝X 1)N(R 13) 2、COOR 13、SO 2R 14、N(R 13)SO 2R 14、N(R 13)COR 14；
V) (C 1-6Alkyl) CN, CN, CH=C (R) 2, (CH 2) pOH, C (=O) CHR 13, C (=NR 13) R 13, NR 10C (=X 1) R 13Or
Vi) optionally by 1-3 R 7The C that group replaces 5-10Heterocycle, it can connect by carbon atom or heteroatoms;
A represents NR, O or S (O) p
Figure A20048001887800122
Expression aryl or heteroaryl, heterocycle, heterocyclic radical or heterocyclic, condition is in heteroaryl, heterocycle, heterocyclic radical or heterocyclic situation, cyclopropyl is not connected with the nitrogen-atoms that encircles;
Rx represents hydrogen or C 1-6Alkyl;
R 3Expression:
i)NR 13(C＝X 2)R 12，
ii)NR 13(C＝X 1)R 12，
iii)NR 13SO 2R 14，
Iv) N (R 13) heteroaryl,
V) NR 13(CHR 13) 0-4Aryl,
Vi) NR 13(CHR 13) 0-4Heteroaryl,
Vii) S (CHR 13) 0-4Aryl,
Viii) S (CHR 13) 0-4Heteroaryl,
Ix) O (CHR 13) 0-4Aryl,
X) O (CHR 13) 0-4Heteroaryl,
xi)NOH(C＝X 1)R 12，
Xii)-OC=N (OCO aryl) C 1-6Alkyl,
Xiii)-OC=N (OH) C 1-6Alkyl,
Xiv) can be by the C of carbon atom or heteroatoms connection 5-10Heteroaryl; Described aryl and heteroaryl are optionally by 1-3 R 7Group replaces;
R 4And R 4aExpression independently:
I) hydrogen,
Ii) halogen,
Iii) C 1-6Alkoxyl group, or
Iv) C 1-6Alkyl,
R and s are 1-3 independently, and condition is as (R 4a) s(R 4) rBe connected in Ar or HAr when ring, r and s and be less than or equal to 4;
R 5And R 6Expression independently:
I) hydrogen,
Ii) optionally by the C of 1-3 group replacement 1-6Alkyl, described substituted radical is selected from halogen, CN, OH, C 1-6Alkoxyl group, amino, imino-, hydroxylamino, alkoxy amino, C 1-6Acyloxy, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulfinyl (sulfinyl), C 1-6Alkyl sulphonyl, amino-sulfonyl, C 1-6Alkyl amino sulfonyl, C 1-6Dialkyl amino sulfonyl, 4-morpholinyl alkylsulfonyl, phenyl, pyridine, 5-isoxazolyl, vinyloxy group (ethylenyloxy) or ethynyl, described phenyl and pyridine are optionally by 1-3 halogen, CN, OH, CF 3, C 1-6Alkyl or C 1-6Alkoxyl group replaces;
Iii) optionally by the C of 1-3 group replacement 1-6Acyl group, described substituted radical is selected from halogen, OH, SH, C 1-6Alkoxyl group, naphthyloxy, phenoxy group, amino, C 1-6Acyl amino, hydroxyl amino, alkoxy amino, C 1-6Acyloxy, aralkoxy, phenyl, pyridine, C 1-6Alkyl-carbonyl, C 1-6Alkylamino, C 1-6Dialkyl amido, C 1-6Hydroxyl acyloxy, C 1-6Alkyl sulphinyl, phthalimide-based, dimaleoyl imino, succinimido, described phenoxy group, phenyl and pyridine are optionally by 1-3 halo, OH, CN, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces;
Iv) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, amino, hydroxyl amino, alkoxy amino, C 1-6The C that acyloxy or phenyl replace 1-6Alkyl sulphonyl; Described phenyl is optionally by 1-3 halo, OH, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces;
V) optionally by 1-3 halogen, C 1-6Alkoxyl group, OH or C 1-6The aryl sulfonyl that alkyl replaces;
Vi) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, C 1-6The C that acyloxy or phenyl replace 1-6Alkoxy carbonyl, described phenyl are optionally by 1-3 halo, OH, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces;
Vii) aminocarboxyl, C 1-6Alkyl amino-carbonyl or C 1-6Dialkyl amino carbonyl, described alkyl are optionally by 1-3 halogen, OH, C 1-6Alkoxyl group or phenyl replace;
Viii) optionally by 1-3 halogen, OH, CN, amino, C 1-6Acyl amino, C 1-6Alkyl sulfonyl-amino, C 1-6Alkoxycarbonyl amino, C 1-6Alkoxyl group, C 1-6Acyloxy or C 1-6Hexa-member heterocycle is arrived in five of alkyl replacement, and described alkyl is optionally by 1-3 halogen or C 1-6Alkoxyl group replaces;
Ix) optionally by 1-3 halogen, OH, C 1-6The C that alkoxyl group or CN replace 3-6Naphthene base carbonyl;
X) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, C 1-6Alkyl, CF 3, C 1-6Alkyloyl, amino or C 1-6The benzoyl that acyl amino replaces;
Xi) optionally by 1-3 C 1-6The pyrryl carbonyl that alkyl replaces;
Xii) C 1-2The acyloxy ethanoyl, wherein acyl group is optionally by amino, C 1-6Alkylamino, C 1-6Dialkyl amido, 4-morpholino, 4-aminophenyl, 4-(dialkyl amido) phenyl, 4-(glycidyl-amino) phenyl replace; Or
R 5And R 6Can form with any interval atom and to comprise carbon atom and 1-2 and independently be selected from O, S, SO, SO 2, N or NR 8Heteroatomic 3 to 7 yuan of heterocycles;
R 7Expression:
I) hydrogen, halogen, CN, CO 2R, CON (R) 2, CHO, CH 2NHAc, C (=NOR), OH, C 1-6Alkoxyl group, C 1-6Alkyl, thiazolinyl, hydroxyl C 1-6Alkyl, (CH 2) 1-3NHC (O) C 1-6Alkyl, (CH 2) 1-3N (C 1-6Alkyl) 2
Ii) (CH 2) nAmino, (CH 2) nC 1-6Alkylamino, C 1-6Dialkyl amido, hydroxyl amino or C 1-2Alkoxy amino, they all optionally on nitrogen by C 1-6Acyl group, C 1-6Alkyl sulphonyl or C 1-6Alkoxy carbonyl replaces, and described acyl group and alkyl sulphonyl are optionally replaced by 1-2 halogen or OH;
R 8And R 9Expression independently:
i)H、CN，
Ii) optionally by 1-3 halogen, CN, OH, C 1-6Alkoxyl group, C 1-6Acyloxy or the amino C that replaces 1-6Alkyl,
Iii) optionally by 1-3 halogen, OH, C 1-6The phenyl that alkoxyl group replaces; Or
R 7And R 8Can form together optionally and be selected from O, S, SO, SO by 1-2 2, NH and NR 8The 3-7 unit carbocyclic ring that interrupts of heteroatoms;
X 1Expression O, S or NR 13, NCN, NCO 2R 16, or NSO 2R 14
X 2Expression O, S, NH or NSO 2R 14
R 10Expression hydrogen, C 1-6Alkyl or CO 2R 15
R 12Expression hydrogen, C 1-6Alkyl, NH 2, OR, CHF 2, CHCl 2, CR 2Cl, (CH 2) nSR, (CH 2) nCN, (CH 2) nSO 2R, (CH 2) nS (O) R, C 1-6Alkylamino, C 5-10Heteroaryl or C 1-6Dialkyl amido, wherein said alkyl are optionally by 1-3 halo, CN, OH or C 1-6Alkoxyl group replaces, and described heteroaryl is optionally by 1-3 R 7Base replaces;
Each R 13Represent hydrogen, C independently 1-6Alkyl, C 6-10Aryl, NR 5R 6, SR 8, S (O) R 8, S (O) 2R 8, CN, OH, C 1-6Alkyl S (O) R, C 1-6Alkoxy carbonyl, hydroxycarbonyl group ,-OCO aryl, C 1-6Acyl group, optionally be selected from O, S, SO, SO by 1-4 2, NH and NR 8The C that interrupts of heteroatoms 3-7Unit's carbocyclic ring, wherein said C 1-6Alkyl, aryl or C 1-6Acyl group can be independently by 0-3 halogen, hydroxyl, N (R) 2, CO 2R, C 6-10Aryl, C 5-10Heteroaryl or C 1-6Alkoxyl group replaces;
As two R 13When group connected with identical atom or two adjacent atoms, they can form together optionally and are selected from O, S, SO, SO by 1-2 2, NH and NR 8The 3-7 unit carbocyclic ring that interrupts of heteroatoms;
R represents hydrogen, (CH 2) pCN, C 1-6Alkyl, CO 2C 1-6Alkyl, COCH 2OH, COCH 2OCOC 1-6Alkyl, SO 2C 1-6Alkyl;
R 14Expression is amino, C 1-6Alkyl, C 1-6Haloalkyl, five is to hexa-member heterocycle or phenyl, and described phenyl and heterocycle are optionally by 1-3 halo, C 1-6Alkoxyl group, C 1-6Acyl amino or C 1-6Alkyl, hydroxyl and/or amino the replacement,, described amino and hydroxyl are optionally with amino protecting group or hydroxyl protecting group protection;
R 15Be C 1-6Alkyl or benzyl, described benzyl are optionally by 1-3 halo, OH, C 1-6Alkoxyl group, amino, C 1-6Acyl amino or C 1-6Alkyl replaces;
R 16Be hydrogen, C 5-10Heteroaryl, C 6-10Aryl, described heteroaryl and aryl are optionally by 1-3 R 7Replace;
P represents 0-2; With
M, n and q represent 0-1.
Another aspect of the present invention relates to the application of new antibiotic composition in the treatment infectation of bacteria.
Detailed Description Of The Invention
Unless otherwise indicated, use in this article with undefined term and describe the present invention in detail.
Compound of the present invention may have asymmetric center, chiral axis and chirality face and exist as racemic mixture, racemic mixture with as independent diastereomer, and all possible isomer comprises optical isomer, all is included among the present invention.(referring to E.L.Eliel and S.H.Wilen, Stereochemistry of Carbon Compounds, (John Wiley and Sons, New York 1994 is particularly at the 1119-1190 page or leaf).
When any variable (as aryl, heterocycle, R 5, R 6Deng) when occurring more than once, its definition in each case all is independent of other every kind situation.Also allow substituting group/or the combination of variable, as long as substituting group/or the combination results stable compound of variable.
Unless otherwise defined, term " alkyl " is meant unit price alkane (hydrocarbon) the deutero-group that comprises 1 to 15 carbon atom.It can be straight chain and side chain.Preferred alkyl comprises low alkyl group such as methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl with 1 to 6 carbon atom.When being substituted, alkyl can be replaced at any available tie point by maximum 3 substituting groups that are selected from definition herein.When the description alkyl was replaced by alkyl, it can use interchangeably with " branched-chain alkyl ".
Cycloalkyl is to comprise 3 to 15 carbon atoms, do not have between carbon atom alternately or the alkyl of the two keys of resonance.It can comprise 1 to 4 thick and ring.Preferred cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.When being substituted, cycloalkyl can be replaced by the defined substituting group of the definition of alkyl herein by maximum 3.
Alkyloyl is meant the group derived from the aliphatic carboxylic acid with 2 to 4 carbon atoms.Its example is ethanoyl, propionyl, butyryl radicals etc.
Term " alkoxyl group " if be meant have designated length, for having two or more carbon atoms on straight or branched structure and the length then they can comprise two keys or those groups of triple-linked.The example of this alkoxyl group is methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, isopentyloxy, hexyloxy, different hexyloxy, allyloxy, third alkynyloxy group etc.
Figure A20048001887800171
Be meant the aryl or heteroaryl, heterocycle, Het, heterocyclic radical or the heterocyclic that are about to description as following.
Aryl is meant in each ring any stable monocycle or the bicyclic carbocyclic of maximum 7 atoms, and wherein at least one ring is for aromaticity.The example of this aryl comprises phenyl, naphthyl, tetralyl, 2,3-dihydro indenyl, indone base, xenyl, 1,2,3, the phenyl of 4-tetralyl, naphthane ketone group, Fluorenone base, phenanthryl, anthryl, acenaphthenyl etc. and replacement etc.As definition, aryl can be substituted equally.The preferred aryl that replaces comprises phenyl and naphthyl.
Unless otherwise noted, term heterocycle as used in this article, heteroaryl, Het, heterocyclic radical or heterocyclic are represented stable 5 to 7 yuan of monocycles or bicyclic heterocyclic systems, or 8 to 11 yuan of stable bicyclic heterocyclic systems, its any ring can be saturated or unsaturated, and be selected from N by carbon atom and one to four, the heteroatoms of O and S constitutes, and wherein nitrogen and sulfur heteroatom are optionally oxidized, nitrogen heteroatom optionally by quaternized (in this case, make its suitably balance by counterion), and comprise the heterocycle of wherein any above-mentioned definition and phenyl ring is thick and any bicyclic radicals.Heterocycle can connect on any heteroatoms that produces rock steady structure or carbon atom.Term heterocycle or heterocyclic comprise heteroaryl moieties.Therefore, " heterocycle " or " heterocyclic radical " comprises above-mentioned heteroaryl, and dihydro and tetrahydro-analogue.Heterocycle, heteroaryl, Het or heterocyclic can be by 1 to 3 R 7Replace.The example of this heterocyclic unit (heterocyclicelements) includes but not limited to following: piperidyl, piperazinyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, 2-oxo azepan base, the azepan base, pyrryl, the 4-piperidone base, pyrrolidyl, pyrazolyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl (pyridyl), pyrazinyl, pyrimidyl, the pyrimidine ketone group, pyriconyl, pyridazinyl oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, quinuclidinyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl benzoxazolyl, furyl, tetrahydrofuran base, THP trtrahydropyranyl, thienyl, imidazopyridyl, triazolyl, tetrazyl, triazinyl, thienyl, benzothienyl, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, the naphthopyridine base, the dihydro-pyrimidin base, the pyrrolin base, the dihydroquinoline base, the dihydro tetrazyl, the dihydro triazolyl, dihydro-thiophene base dihydro-oxazole base, the dihydrobenzo thienyl, the dihydrofuran base, benzothiazolyl, benzothienyl, benzimidazolyl-, benzopyranyl, benzothienyl, carbolinyl, chromanyl, the cinnoline base, the benzopyrazoles base, benzo dioxane amyl group is with the oxadiazole base.The other example of heteroaryl is illustrated by following formula a, b, c and d:
Figure A20048001887800191
R wherein 16And R 17Be independently selected from hydrogen, halogen, C 1-6Alkyl, C 2-4Alkyloyl, C 1-6Alkoxyl group; R 18Expression hydrogen, C 1-6Alkyl, C 2-4Alkyloyl, C 1-6Carbalkoxy and formamyl.
Term " thiazolinyl " is meant straight chain, side chain or the cyclic hydrocarbon group that comprises 2 to 10 carbon atoms and at least one carbon-carbon double bond.Preferred thiazolinyl comprises vinyl, propenyl, butenyl and cyclohexenyl.
Term " quaternary nitrogen " and " positively charged " are meant the positively charged nitrogen-atoms of quaternary (as required by counterion balance as known in the art), it for example comprises tetra-allkylammonium (as tetramethylammonium), heteroaryl salt (as N-picoline salt), under physiology pH by the positively charged nitrogen in protonated basic nitrogen etc.Therefore, cationic group comprises positively charged nitrogen-containing group, and under physiology pH by protonated basic nitrogen.
Term " heteroatoms " is meant O, S or the N that selects independently.
Term " prodrug " is meant as the compound that discharges the prodrug of medicine after administration and absorption by some metabolic process in vivo.Exemplary prodrug comprises the acid amides such as the paraffinic acid (C of aminocompound of the present invention 1-6) acid amides, aryl acid (as phenylformic acid) and alkane (C 1-6) acid amides of dicarboxylic acid.
Halogen and " halo " are meant bromine, chlorine, fluorine and iodine.
Unless otherwise indicated, when group was expressed as " being substituted ", it was meant that this group contains 1 to 3 substituting group thereon.
When functional group was expressed as " protected ", it was meant that this functional group is in reformed form, to avoid in protected position undesirable side reaction taking place.The protecting group that is fit to that is used for The compounds of this invention can be recognized from the application based on the state of the art of this area; but and reference standard textbook such as Greene, people such as T.W., Protective Groups in OrganicSynthesis; Wiley, New York (1991).The example of the protecting group that is fit to is included in the whole specification sheets.
The hydroxyl that is fit to and the example of amino protecting group are: trimethyl silyl, triethylsilyl, adjacent nitro carbobenzoxy-(Cbz), to nitro carbobenzoxy-(Cbz), t-butyldiphenylsilyl, t-butyldimethylsilyl, carbobenzoxy-(Cbz), tertbutyloxycarbonyl, 2; 2,2-trichloro-ethoxycarbonyl, allyloxycarbonyl etc.The example of the carboxyl-protecting group that is fit to is: diphenyl-methyl, adjacent nitrobenzyl, to nitrobenzyl, 2-menaphthyl, allyl group, 2-chlorallyl, benzyl, 2; 2,2-three chloroethyls, trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethyl silyl) ethyl, phenacyl, to methoxy-benzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl, the tertiary butyl etc.
Of the present inventionly contain that cyclopropyl De oxazolidone compound can directly use or use, be used for the treatment of the infectation of bacteria of animal and human's main body with the form of its pharmacologically acceptable salt and ester.Term " pharmaceutically useful ester, salt or hydrate " is meant those salt, ester and the hydrate of conspicuous The compounds of this invention concerning Pharmaceutical Chemist, promptly nontoxic basically and may advantageously influence the pharmacokinetic property of described compound such as palatability, absorption, distribution, metabolism and excretory those.During selection no less important, actual other factors is the flowability of raw materials cost, crystallization easily, yield, stability, solubleness, water absorbability and the bulk drug that obtains in essence.Incidentally, can make up and the preparation pharmaceutical compositions from activeconstituents and pharmaceutically acceptable carrier.Therefore, the invention still further relates to novel cyclopropyl De oxazolidone compound is treated infectation of bacteria as activeconstituents pharmaceutical compositions and the method that contain of using.
Above-mentioned pharmacologically acceptable salt also comprises acid salt.Therefore, when compound is alkali shown in the formula I, can prepare salt, comprise mineral acid or organic acid from pharmaceutically useful non-toxic acid.The salt of this acid comprises: acetate, adipic acid ester, alginates, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecane sulfonate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, isethionate, lactic acid salt, maleate, mandelate, malate, maleate, mesylate, mucate, the 2-naphthalenesulfonate, nicotinate, nitric acid oxalate (nitric oxalate), embonate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, phosphoric acid salt, pantothenate, embonate (pamoic), vitriol, succinate, tartrate, thiocyanate-, the tosylate ester, with the undecane hydrochlorate.
When compound of the present invention was acid, suitable " pharmacologically acceptable salt " was meant from the salt of pharmaceutically useful nontoxic alkali preparation, comprises mineral alkali and organic bases.The salt that comprises aluminium, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganic, bivalent manganese, potassium, zinc, sodium etc. derived from the salt of mineral alkali.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.Salt derived from pharmaceutically useful nontoxic mineral alkali comprises primary amine, the salt of secondary amine and tertiary amine, the amine that replaces comprises the salt of the amine of naturally occurring replacement, the salt of cyclammonium and alkaline kation exchange resin, as arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl ethylene diamine, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine (hydrabamine), Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.
Pharmaceutically acceptable ester for for example for Pharmaceutical Chemist conspicuous those, be included in those of hydrolysis under the physiological condition, as " biolabile ester ", new pentane acyloxy methyl esters, acetoxyl group methyl esters, phthalidyl ester, 2,3-dihydro indenyl ester and methoxymethyl ester etc.
But biolabile ester is the biology hydrolysis, and owing to can be suitable for oral administration by stomach or good absorption, stomach juice-resistant degradation property and the other factors of intestinal mucosa.The example of biolabile ester comprises compound.
At R 1Expression H, NR 5R 6, CN, OH, C (R) 2OR 14, NHC (=X 1) N (R 13) 2, C (=NOH) N (R 13) 2, NR 10C (=X 1) R 13Or CR 7R 8R 9, and other all variablees has been realized one embodiment of the invention as described herein the time.
When
Figure A20048001887800221
Be phenyl, pyridine, pyrimidine or piperidines, and other all variablees has been realized another embodiment of the invention as described herein the time.
As a R 1Be NR 10C (=X 1) R 13, and other all variablees has been realized another embodiment of the invention as described herein the time.
As a R 1Be CN, and other all variablees has been realized another embodiment of the invention as described herein the time.
As a R 1Be NR 5R 6, and other all variablees has been realized another embodiment of the invention as described herein the time.
Work as R 3Be NR (C=X 1) R 12, C 5-10Heteroaryl, NH (CH 2) 0-4Aryl, NH (CH 2) 0-4Heteroaryl, and other all variablees realized another embodiment of the invention as described herein constantly, and described aryl and heteroaryl are optionally replaced by 1-3 Ra.
Work as R 3Serve as reasons
Figure A20048001887800222
The C of expression 5-10Heteroaryl, its expression comprise 1 to 4 nitrogen-atoms and at least one two key and during the aromatic heterocycle group of the selectivity replacement that is connected by the key on any nitrogen, have realized another embodiment of the invention.Exemplary group is a 1,2,3-triazoles, 1,2,4-triazole, oso-triazole, tetrazolium, pyrazoles and imidazoles, its any can comprise 1-3 and be selected from R 7Substituting group.
Work as R 5And R 6Be independently:
i)H；
Ii) optionally by 1-3 halogen, CN, OH, C 1-6Alkoxyl group, amino, hydroxylamino, alkoxy amino, C 1-6Acyloxy, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulfinyl, C 1-6Alkyl sulphonyl, amino-sulfonyl, C 1-6Alkyl amino sulfonyl, C 1-6The C that dialkyl amino sulfonyl, 4-morpholinyl alkylsulfonyl, phenyl, pyridine, 5-isoxazolyl, vinyloxy group or ethynyl replace 1-6Alkyl, described phenyl and pyridine are optionally by 1-3 halogen, CN, OH, CF 3, C 1-6Alkyl or C 1-6Alkoxyl group replaces;
Iii) optionally by 1-3 halogen, OH, SH, C 1-6Alkoxyl group, naphthyloxy, phenoxy group, amino, C 1-6Acyl amino, hydroxyl amino, alkoxy amino, C 1-6Acyloxy, phenyl, pyridine, C 1-6Alkyl-carbonyl, C 1-6Alkylamino, C 1-6Dialkyl amido, C 1-6Hydroxyl acyloxy, C 1-6The C that alkyl sulphinyl, phthalimide-based, dimaleoyl imino, succinimido replace 1-6Acyl group, described phenoxy group, phenyl and pyridine are optionally by 1-3 halo, OH, CN, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces; Or
Iv) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, C 1-6Alkyl, CF 3, C 1-6Alkyloyl, amino or C 1-6The benzoyl that acyl amino replaces, and other all variablees has been realized another embodiment of the invention as described herein the time.
Work as X 1Expression O, and other all variablees has been realized another embodiment of the invention as described herein the time.
When structural formula is Formula Il, realized a preferred embodiment of the present invention,
Figure A20048001887800231
Formula II
R wherein 1, R 4, R 4a, Y and R 3As described herein.
Preferred compound of the present invention is:
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methylsulfonyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3,6-dicyano-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-cyano methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyrimidine-2-base)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(4-pyridylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-1-imido grpup ethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methoxycarbonyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-S-methyl thioimines ylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group amidino groups (carboxamidyl))-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N, N '-tertbutyloxycarbonyl amidino groups)-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-amidino groups-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N-tert-butoxycarbonyl amino) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β) 3)-[3-glycyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methylsulfonyl ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(dibenzyl phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
Or its enantiomer, diastereomer, or pharmacologically acceptable salt, hydrate or prodrug.
The suitable main body that is used for preparation administration of the present invention comprises Mammals, primate, people and other animal.When predicting its activity in vivo by antibacterial activity in vitro when infecing the Mammals administration composition of susceptible bacteria organism.
The susceptibility test of use standard, measuring composition of the present invention has activity to MRSA and faecalis infection.
By compound of the present invention and pharmaceutically acceptable carrier combination are formulated as pharmaceutical compositions with compound.The example of this carrier is as described below.
Compound can be powder or crystallized form, in liquor or in suspension.They are administration in several ways, and main interested administering mode comprises: topical, oral administration and the parenterai administration by injection (intravenous injection or intramuscularly).
The composition that is used for injection (preferred route of administration) can be prepared as the unit dosage of ampoule or in multi-dose container.Injectable composition can be for example suspension, solution or the emulsion form in oiliness or aqueous medium, and may comprise multiple reagent preparation.Optionally, activeconstituents can be powder (freeze dried or non-freeze dried) form, is used for rebuilding with suitable medium such as sterilized water administration the time.In composition for injection, carrier comprises that typically sterilized water, salt solution or another kind of injection liquid are as being used for the peanut oil of intramuscular injection.In addition, can comprise numerous buffers, sanitas etc.
Topical can be formulated in carrier such as hydrophobicity or the hydrophilic matrix to form paste, creme, washing lotion; In water-based, oiliness or alcohol liquid to form paint; Or in dried thinner to form powder.
Oral compositions can be for example tablet, capsule, oral suspension and oral liquid.Oral compositions can use the reagent preparation of carrier such as routine, and may comprise sustained release property and quick form of medication.
Dosage depends on that to a great extent the situation that will treat main body and size, route of administration and frequency, pathogenic agent are to the susceptibility of selected specific compound, the virulence and the other factors of infection.Yet these things are left the doctor for and are carried out the routine judgement according to well-known principle of reatment in the antibiotic field.Except the character that infects with will treat the individual distinctive characteristic, another factor that influences accurate dosage regimen is the molecular weight of compound.
Be used for the per unit dosage to the new antibiotic composition of the present invention of people's administration, liquid or solid no matter comprises about 0.01% to up to 99% the cyclopropyl De oxazolidone compound that contains as herein described, and its preferred range is about 10-60%; With one or more other microbiotic of about 1% to about 99.99%, as herein described those, preferred about 40% to about 90%.Composition comprises as herein described the contain cyclopropyl De oxazolidone compound of about 125mg to about 3.0g usually; Yet, the preferred usually dosage that uses about 250mg to 1000mg; With the another kind of as herein described microbiotic of about 200mg to about 5g, preferably about 250mg is to about 1000mg.In parenterai administration, unit dosage can typically be included in the pure compound in the aseptic aqueous solution or be designed for the soluble powder form of solution, and it can be adjusted to neutral pH and isoosmotic.
Described herein the present invention also comprises the method for the mammiferous infectation of bacteria of this treatment of treatment needs, and it comprises the claimed composition of described Mammals administration effectively being treated the amount of described infection.
Yi Zhi oxazolidone causes side effect such as sideroblastic anemia, peripheral sensory neuropathy, optic neuropathy, epileptic seizures, thrombopenia, cheilosis, seborrheic dermatitis, inferior hyperplastic anemia (hypo-regenerative anemia), megaloblastic anemia or normocytic anemia often.Compound of the present invention can make up with one or more VITAMIN of significant quantity, to prevent or to reduce the generation of the patient Zhong side effect relevant Yu oxazolidone.The VITAMIN of using capable of being combined is Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid.VITAMIN can be used as independent composition Yu the oxazolidone administration, or Wei gives birth to Su with oxazolidone can be present in the same composition.
Therefore, another aspect of the present invention is for by to one or more Wei ShengsuB2s, vitamin B6, vitamin B12 and the folic acid of formula I De oxazolidone that the patient's effective dosage that needs is arranged and the significant quantity method with treatment or the Fang Zhi side effect relevant Yu oxazolidone.
Another aspect of the present invention relates to the Wei ShengsuB2 of patient's effective dosage that needs are arranged with treatment or Yu Fang normocytic anemia or the peripheral sensory neuropathic method relevant Yu oxazolidone.
Another aspect of the present invention relates to the vitamin B6 of patient's effective dosage that needs the are arranged method with treatment or Yu Fang sideroblastic anemia, peripheral sensory neuropathy, optic neuropathy, epileptic seizures, thrombopenia, cheilosis and the seborrheic dermatitis relevant Yu oxazolidone.
Another aspect of the present invention relates to the vitamin B12 of patient's effective dosage that needs are arranged and folic acid with treatment or the Yu Fang inferior hyperplastic anemia relevant Yu oxazolidone, the method for megaloblastic anemia.
Another aspect of the present invention relates to by to one or more methods with treatment or prevention infectation of bacteria in the group that is selected from Wei ShengsuB2, vitamin B6, vitamin B12 and folic acid of the compound of the formula I of patient's effective dosage that needs are arranged and significant quantity.
The preferred medication of claimed composition comprises that being formulated as every kind of activeconstituents making unit dosage comprise the treatment significant quantity or one concludes a contract or treaty that several oral administrations and parenterai administration such as intravenously (i.v.) infusion, intravenously (i.v.) pilule (bolus) and intramuscular (i.m.) inject.
For the adult, about 5-50mg/kg body weight that preferred administration every day is to four time, preferably everyone about 250mg arrives about 1000 another kind of microbiotic to the cyclopropyl De oxazolidone antimicrobial compounds that contains of about 1000mg with everyone about 250mg.More specifically, for grade and moderate infection, recommend about 250mg of twice of every day or three times to contain the another kind of microbiotic of about 250mg of twice of cyclopropyl De oxazolidone antimicrobial compounds and every day or three times.For the grade and moderate infection of extremely sensitive gram-positive organism, recommend every day three times or four every dosage to contain cyclopropyl De oxazolidone and another kind of microbiotic for about 500mg.For serious, the life-threatening infection of the organism that antibiotic susceptibility is reached the upper limit, can recommend the oxazolidone that contain cyclopropyl and the another kind of microbiotic of each dosage for about 500-2000mg, be administered three times every day four times.
For children, the dosage of preferably about 5-25mg/kg body weight, the dosage of 10mg/kg is typically recommended in administration every day 2,3 or 4 times.
Further describe the present invention with reference to following non-limiting example.
Embodiment 1
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
Step 1.
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone
Under-78 ℃ to 1-benzyloxycarbonyl amino-4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) hexane solution (1.6M of adding n-Butyl Lithium in anhydrous tetrahydro furan (25mL) solution of benzene (1.26g)], 2.51mL), under identical temperature, stirred the mixture 30 minutes.Also at room temperature stirred the mixture 2 hours-78 ℃ of following (R)-glycidyl butyric ester (0.58mL) are joined in the mixture.By after adding methyl alcohol (2.5mL) quencher reaction, at room temperature stirred the mixture 30 minutes.After with aqueous ammonium chloride solution diluted mixture thing, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate) obtains 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (995mg).
MS(EI +)m/z：298(M +)
HRMS (EI +): C 17H 18N 2O 3(M +): calculated value 298.1317; Measured value 298.1310.
Step 2.
5 (R)-azido methyl-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl] oxazolidine-2-ketone
Under 0 ℃ to 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) phenyl]]-add triethylamine (0.28mL) and methylsulfonyl chloride (0.12mL) in methylene dichloride (10mL) solution of 5-Qiang base Jia Ji oxazolidine-2-ketone (298mg), under identical temperature, stirred the mixture 15 minutes.After with the dilution of 1N hydrochloric acid, the mixture ethyl acetate extraction.Organic extract liquid water, sodium bicarbonate aqueous solution and salt washing, anhydrous sodium sulfate drying filters, then vacuum concentration.At N, the suspension in the dinethylformamide (10mL) stirred 4 hours and vacuum concentration at 70 ℃ with resistates and sodiumazide (199mg).After the dilute with water resistates, the mixture ethyl acetate extraction.Organic extract liquid water and salt washing, anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate) obtains 5 (R)-azido methyl-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl] oxazolidine-2-ketone (304mg).
MS(EI +)m/z：323(MF)
HRMS (EI +): C 17H 17N 5O 2(M +): calculated value 323.1382; Measured value 323.1363.
Step 3.
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature with 5 (R)-azido methyl-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl] oxazolidine-2-ketone (300mg) and lindlar catalyst (Lindlar catalyst) (5% palladium-CaCO3, with lead its part is poisoned, the 150mg) hydrogenation 70 minutes under 1atm of the suspension in tetrahydrofuran (THF) (2mL) and methyl alcohol (10mL).After filtering catalyst, vacuum concentrated filtrate obtains 5 (R)-amino methyl-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl] oxazolidine-2-ketone (276mg).This compound can use without being further purified.Under 0 ℃ to thick 5 (R)-amino methyl-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] add triethylamine (194 μ L) and diacetyl oxide (108 μ L) in tetrahydrofuran (THF) (10mL) solution of phenyl] oxazolidine-2-ketone (276mg), at room temperature stirred the mixture 30 minutes.After by adding 1N hydrochloric acid quencher reaction, the mixture ethyl acetate extraction.Organic extract liquid water, sodium bicarbonate aqueous solution and salt washing, anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate: methyl alcohol=15: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (276mg).
MS(EI +)m/z：339(M +)
HRMS (EI +): C 19H 21N 3O 3(M +): calculated value 339.1583; Measured value 339.1606.
Embodiment 2
Figure A20048001887800311
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 5 (R)-azido methyl-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) phenyl] oxazolidine-2-ketone (417mg) and 2], 5-norbornadiene (0.70mL) mixture heating up in dioxane (13mL) refluxed 4 hours, then vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, ethyl acetate: methyl alcohol=20: 1) obtain 1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (345mg).
MS(EI +)m/z：349(M +)
HRMS (EI +): C 19H 19FN 5O 2(M +): calculated value 349.1539; Measured value 349.1526.
Embodiment 3
Figure A20048001887800321
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
Step 1.
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone
With similarly to Example 1 method from 4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)]-1-benzyloxycarbonyl amino benzene (123mg) preparation title compound 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (102mg).
MS(EI +)m/z：399(M +)
HRMS (EI +): C 21H 25N 3O 5(M +): calculated value 399.1794; Measured value 399.1801.
Step 2.
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With similarly to Example 1 method from 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-5-Qiang base Jia Ji oxazolidine-2-ketone (98.4mg) preparation title compound N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (89.9mg).
MS(EI +)m/z：440(M +)
HRMS (EI +): C 23H 28N 4O 5(M +): calculated value 440.2060; Measured value 440.2076.
Embodiment 4
Figure A20048001887800331
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride
Under 0 ℃ to N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add the ethanolic soln (10M of hydrogenchloride in tetrahydrofuran (THF) (5mL) solution of ethanamide (378mg), 15mL), mixture at room temperature stirred 3 hours and vacuum concentration.Obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β with the Ethanol Treatment resistates)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (275mg).
MS (EI +) m/z:340 (M +) (being free alkali)
HRMS (EI +): C 18H 20N 4O 3(M +): calculated value 340.1535; Measured value 340.1553.
Embodiment 5
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl 1]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With similarly to Example 2 method from 5 (R)-azido methyl-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano-bicyclo [3.1.0] hexane-6-yl) phenyl] oxazolidine-2-ketone (425mg) preparation title compound 1-[5 (R)-3-[4-[(1 α], 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (358mg).
MS(FAB +)m/z：451(MH +)
HRMS (FAB +): C 23H 27FN 6O 4(MH +): calculated value 451.2094; Measured value 451.2098.
Embodiment 6
Figure A20048001887800342
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 1,2,3-triazoles hydrochloride
With similarly to Example 4 method from 1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (358mg) preparation 1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazolium salt hydrochlorate (267mg).
MS (EI +) m/z:350 (M +) (being free alkali)
HRMS (EI +): C 18H 18N 6O 2(M +): calculated value 350.1491; Measured value 350.1464.
Embodiment 7
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃ to N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add triethylamine (0.46mL) and alpha-Acetoxyacetyl chloride (0.15mL) in the suspension of acetamide hydrochloride (415mg) in methylene dichloride (11mL), mixture stirred 45 minutes under identical temperature.After the dilute with water resistates, the mixture dichloromethane extraction.The organic extract liquid anhydrous sodium sulfate drying filters, then vacuum concentration.Flash chromatography (the silicon-dioxide of resistates; methylene bromide: methyl alcohol=10: 1) obtain N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-(3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (378mg).
MS(FAB +)m/z：441(MH +)
HRMS (FAB +): C 22H 25N 4O 6(MH +): calculated value 441.1774; Measured value 441.1764.
Embodiment 8
Figure A20048001887800361
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature to N-[5 (S)-3-[4-[(1 α; 5 α; 6 β)-(3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add salt of wormwood (141mg) in the suspension of ethanamide (225mg) in methyl alcohol (5mL) and tetrahydrofuran (THF) (1mL), mixture stirred under identical temperature 90 minutes and vacuum concentration.Flash chromatography (the silicon-dioxide of resistates; methylene dichloride: methyl alcohol=20: 1) obtain N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-(6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (138mg).
MS(FAB +)m/z：399(MH +)
HRMS (FAB +): C 20H 23N 4O 5(MH +): calculated value 399.1668; Measured value 399.1681.
Embodiment 9
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methylsulfonyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With similarly to Example 7 method from N-[5 (S)-3-[4-[(1 α; 5 α; 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (226mg) and methylsulfonyl chloride (70 μ L) preparation title compound N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-(6-cyano group-3-methylsulfonyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (219mg).
MS(FAB +)m/z：419(MH +)
HRMS (FAB +): C 19H 23N 4O 5S (MH +): calculated value 419.1389; Measured value 419.1386.
Embodiment 10
Figure A20048001887800371
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature to N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add acetate (57 μ L), 35% formaldehyde (396 μ l) in the suspension of acetamide hydrochloride (188mg) in tetrahydrofuran (THF) (5mL), and sodium triacetoxy borohydride (223mg), mixture stirred 2 hours under identical temperature.After by adding sodium bicarbonate aqueous solution quencher reaction, mixture extracts with methylene chloride-methanol (5: 1).The organic extract liquid anhydrous sodium sulfate drying filters, then vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, methylene dichloride: methyl alcohol=10: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (104mg).
MS(FAB +)m/z：355(MH +)
HRMS (FAB +): C 19H 23N 4O 3(MH +): calculated value 355.1770; Measured value 355.1775.
Embodiment 11
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3,6-dicyano-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature stir N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (245mg) and the mixture of sodium acetate (373mg) in methyl alcohol (22mL) 20 minutes.(5M, 0.26mL), mixture stirred under identical temperature 40 minutes and vacuum concentration at the dichloromethane solution that adds cyanogen bromide under 0 ℃ in the suspension that obtains.Flash chromatography (the silicon-dioxide of resistates, methylene dichloride: methyl alcohol=10: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3,6-dicyano-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (207mg).
MS(FAB +)m/z：366(MH +)
HRMS (FAB +): C 19H 20N 5O 3(MH +): calculated value 366.1566; Measured value 366.1575.
Embodiment 12
Figure A20048001887800382
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-cyano methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature stir N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (245mg), sodium bicarbonate (273mg) be at N, the suspension in the dinethylformamide (6.5mL) 10 minutes.At room temperature add bromoacetonitrile (70 μ L) in the suspension that obtains, mixture stirred under identical temperature 6 hours and vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, methylene dichloride: methyl alcohol=10: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-cyano methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (219mg).
MS(FAB +)m/z：380(MH +)
HRMS (FAB +): C 20H 22N 5O 3(MH +): calculated value 380.1723; Measured value 380.1728.
Embodiment 13
Figure A20048001887800391
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone.
To 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-adding di-isopropyl azodicarboxylate (9.8 μ L) in 5-Qiang base Jia Ji oxazolidine-2-ketone (10.0mg), 3-hydoxyisoxazole (4.3mg) and the suspension of triphenyl phosphine (13.5mg) in tetrahydrofuran (THF) (0.25mL), mixture at room temperature stirs 3 hours also vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, hexane: ethyl acetate=1: 5) obtain 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone (11.7mg).
MS(FAB +)m/z：467(MH +)
HRMS (FAB +): C 24H 27N 4O 6(MH +): calculated value 467.1931; Measured value 467.1903.
Embodiment 14
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[(isoxazolyl-3-yl) oxygen base] Jia Ji oxazolidine-2-keto hydrochloride
With similarly to Example 4 method from 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-5-[(isoxazolyl-3-yl) oxygen base] Jia Ji oxazolidine-2-ketone (248mg) preparation title compound 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[(isoxazolyl-3-yl) oxygen base] Jia Ji oxazolidine-2-keto hydrochloride (199mg).
MS (EI +) m/z:366 (M +) (being free alkali)
HRMS (EI +): C 19H 18N 4O 4(M +): calculated value 366.1328; Measured value 366.1330.
Embodiment 15
Figure A20048001887800402
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone.
To 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-adding tributylphosphine (12.5 μ L) in 5-Qiang base Jia Ji oxazolidine-2-ketone (10.0mg), 3-N-(tert-butoxycarbonyl) An isoxazole (9.2mg) and the suspension of tetramethyl-Cellmic C 121 (8.6mg) in benzene (0.25mL), mixture at room temperature stirred 90 minutes.After with ethyl acetate diluted mixture thing, leach insoluble substance and with the filtrate vacuum concentration.Flash chromatography (the silicon-dioxide of mixture, hexane: ethyl acetate=3: 5) obtain 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (14.1mg).
MS(FAB +)m/z：566(MH +)
HRMS (FAB +): C 29H 36N 5O 7(MH +): calculated value 566.2615; Measured value 566.2609.
Embodiment 16
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-keto hydrochloride
With similarly to Example 4 method from (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-5-[N-(tertbutyloxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (292mg) preparation title compound 5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-keto hydrochloride (207mg).
MS (EI +) m/z:365 (M +) (being free alkali)
HRMS (EI +): C 19H 19N 5O 3(M +): calculated value 365.1488; Measured value 365.1478.
Embodiment 17
Figure A20048001887800421
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add diisopropyl ethyl amine (1.05mL) in the suspension of acetamide hydrochloride (226mg) in dimethyl sulfoxide (DMSO) (6mL), mixture at room temperature stirred 5 minutes.Add 2-chloro-5-cyanopyridine (166mg) in the mixture that obtains, mixture stirring under 40 ℃ is spent the night and was stirred 10 hours at 60 ℃.After with ethyl acetate and water diluted mixture thing, the mixture ethyl acetate extraction.Organic extract liquid is washed with sodium bicarbonate aqueous solution and salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, methylene dichloride: methyl alcohol=10: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (218mg).
MS(FAB +)m/z：443(MH +)
HRMS (FAB +): C 24H 23N 6O 3(MH +): calculated value 443.1832; Measured value 443.1841.
Embodiment 18
Figure A20048001887800431
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] add diisopropyl ethyl amine (1.22mL) in the suspension of acetamide hydrochloride (264mg) in 2-pyridyl triflate (5.49mL).Mixture at room temperature stirred 5 minutes and stirred 30.5 hours at 90 ℃.Flash chromatography (the silicon-dioxide of mixture, ethyl acetate: methyl alcohol=5: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (215mg).
MS(FAB +)m/z：418(MH +)
HRMS (FAB +): C 23H 24N 5O 3(MH +): calculated value 418.1879; Measured value 418.1885.
Embodiment 19
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (245mg) adds saturated sodium bicarbonate solution (6.5mL) in the suspension of tetrahydrofuran (THF) (6.5mL), and mixture stirred 5 minutes down at 0 ℃.In the mixture that obtains, add diacetyl oxide (70 μ L), and mixture was stirred 20 minutes down at 0 ℃.After water layer,, filter, then vacuum concentration the organic extract liquid anhydrous sodium sulfate drying that merges with methylene chloride-methanol (10: 1) extraction mixture.Handle resistates with ethyl acetate and obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (215mg).
MS(FAB +)m/z：383(MH +)
HRMS (FAB +): C 20H 23N 4O 4(MH +): calculated value 383.1719; Measured value 383.1732.
Embodiment 20
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyrimidine-2-base)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With similarly to Example 17 method from N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (283mg) and 2-chloropyrimide (181mg) preparation title compound N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyrimidine-2-base)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (198mg).
MS(FAB +)m/z：419(MH +)
HRMS (FAB +): C 22H 23N 6O 3(MH +): calculated value 419.1832; Measured value 419.1832.
Embodiment 21
Figure A20048001887800451
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(4-pyridylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add triethylamine (209 μ L) in the suspension of acetamide hydrochloride (188mg) in methylene dichloride (33mL), mixture at room temperature stirred 5 minutes.At room temperature add pyridine-4-carboxylic acid amides (98 μ L), acetate (115 μ L) and sodium triacetoxy borohydride (223mg) in the mixture that obtains, mixture at room temperature stirred 7 hours.After by adding 1N sodium hydroxide solution quencher reaction, the mixture dichloromethane extraction.The organic extract liquid anhydrous sodium sulfate drying filters, then vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, methylene dichloride: methyl alcohol=10: 1) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(4-pyridylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (181mg).
MS(FAB +)m/z：432(MH +)
HRMS (FAB +): C 24H 26N 5O 3(MH +): calculated value 432.2036; Measured value 432.2041.
Embodiment 22
Figure A20048001887800461
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-1-imido grpup ethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add diisopropyl ethyl amine (192 μ L) in the suspension of acetamide hydrochloride (207mg) in methyl alcohol (5.5mL), mixture at room temperature stirred 20 minutes.Add N-cyano group acetimide acid methyl esters (108mg) in the mixture that obtains, mixture at room temperature stirred 2 days.Obtain N-[5 (S)-3-[4-[(1 α by filtering the throw out of collecting generation, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-1-imido grpup ethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (186mg).
MS(FAB +)m/z：407(MH +)
HRMS (FAB +): C 21H 23N 6O 3(MH +): calculated value 407.1832; Measured value 407.1869.
Embodiment 23
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methoxycarbonyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add diisopropyl ethyl amine (261 μ L) in the suspension of acetamide hydrochloride (188mg) in acetonitrile (5mL), mixture at room temperature stirred 10 minutes.Adding methyl-chloroformate (61 μ L) under 0 ℃ in the mixture that obtains, mixture at room temperature stirred 25 minutes and vacuum concentration.After 1N hydrochloric acid dilution resistates, the mixture dichloromethane extraction.The organic extract liquid anhydrous sodium sulfate drying filters, then vacuum concentration.Handle resistates with ethyl acetate and obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methoxycarbonyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (161mg).
MS(FAB +)m/z：399(MH +)
HRMS (FAB +): C 20H 23N 4O 5(MH +): calculated value 399.1668; Measured value 399.1671.
Embodiment 24
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-S-methyl thioimines ylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl] phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide with similarly to Example 11 method from N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (9.4mg) and N-cyano group dithio imido grpup formic acid dimethyl ester (4.9mg) preparation title compound N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-S-methyl thioimines ylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (8.3mg).
MS(FAB +)m/z：439(MH +)
HRMS (FAB +): C 21H 23N 6O 3S (MH +): calculated value 439.1552; Measured value 439.1553.
Embodiment 25
Figure A20048001887800481
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group amidino groups)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃ to N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-S-methyl thioimines ylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl] phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add the methanol solution (4.1M of ammonia in dimethyl formamide (8mL) solution of ethanamide (260mg), 8mL), mixture was at room temperature left standstill 3 days and vacuum concentration.Flash chromatography (the silicon-dioxide of resistates, methylene dichloride: methyl alcohol=20: 3) obtain N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group amidino groups)-3-azabicyclo [3.1.0] hexane-6-yl] phenyl]]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (111mg).
MS(FAB +)m/z：408(MH +)
HRMS (FAB +): C 20H 22N 7O 3(MH +): calculated value 408.1784; Measured value 408.1792.
Embodiment 26
Figure A20048001887800482
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N, N '-tert-butoxycarbonyl amidino groups)-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With similarly to Example 23 method from N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (19mg) and N, N '-two (tertbutyloxycarbonyl)-1H-pyrazoles-1-formyl amidine (23mg) preparation title compound N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N, N '-tert-butoxycarbonyl amidino groups)-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl] phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (35mg).
MS(FAB +)m/z：583(MH +)
HRMS (FAB +): C 29H 39N 6O 7(MH +): calculated value 583.2880; Measured value 583.2880.
Embodiment 27
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-amidino groups-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride
Under 0 ℃ to N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N, N '-tert-butoxycarbonyl amidino groups)-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] add the dioxane solution (4.8M of hydrogenchloride in tetrahydrofuran (THF) (1.9mL) suspension of ethanamide (221mg), 5.7mL), mixture at room temperature stirs 3.7 hours, and vacuum concentration.After the dilute with water resistates, mixture washs with ethyl acetate.The water layer freeze-drying that obtains is obtained N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-amidino groups-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (157mg).
MS (FAB +) m/z:383 (MH +) (being free alkali)
HRMS (FAB +): C 19H 23N 6O 3(MH +): calculated value 383.1832; Measured value 383.1879.
Embodiment 28
Figure A20048001887800501
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N-tert-butoxycarbonyl amino) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature to N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add triethylamine (17 μ L) in dimethyl formamide (2mL) suspension of acetamide hydrochloride (19mg), N-tert-butoxycarbonyl glycine (9.6mg) and I-hydroxybenzotriazole (8.4mg), mixture at room temperature stirred 5 minutes.Adding 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (11mg) under 0 ℃ in the mixture that obtains, mixture at room temperature stirs 5.5 hours, and vacuum concentration.After with 1N hydrochloric acid dilution resistates, use the ethyl acetate extraction mixture.The organic extract liquid that merges is washed with sodium bicarbonate aqueous solution, and anhydrous sodium sulfate drying filters, then vacuum concentration.Flash chromatography (the silicon-dioxide of resistates; ethyl acetate: methyl alcohol=5: 1) obtain N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-[3-(N-tert-butoxycarbonyl amino) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (23mg).
MS(FAB +)m/z：498(MH +)
HRMS (FAB +): C 25H 32N 5O 6(MH +): calculated value 498.2353; Measured value 498.2339.
Embodiment 29
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-glycyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride
With similarly to Example 27 method from N-[5 (S)-3-[4-[(1 α; 5 α; 6 β)-[3-(N-t-butoxycarbonyl amino) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl] phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (299mg) preparation title compound N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-[3-glycyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (225mg).
MS (FAB +) m/z:398 (MH +) (being free alkali).
HRMS (FAB +): C 20H 24N 5O 4(MH +): calculated value 398.1828; Measured value 398.1826.
Embodiment 30
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methylsulfonyl ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With similarly to Example 28 method from N-[5 (S)-3-[4-[(1 α; 5 α; 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (188mg) and methylsulfonyl acetate (78mg) preparation title compound N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-[6-cyano group-3-methylsulfonyl ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (193mg).
MS(FAB +)m/z：461(MH +)
HRMS (FAB +): C 21H 25N 4O 6S (MH +): calculated value 461.1495; Measured value 461.1513.
Embodiment 31
Figure A20048001887800521
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(dibenzyl phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[(1 α; 5 α; 6 β)-(6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl) phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] add di-isopropyl azodicarboxylate's toluene solution (40 weight % in ethanamide (10mg), triphenyl phosphine (14mg) and the suspension of di(2-ethylhexyl)phosphate benzyl ester (14mg) in tetrahydrofuran (THF) (1mL); 27 μ L); mixture at room temperature stirs and spends the night, and stirs 11 hours down at 60 ℃.With the mixture vacuum concentration.Flash chromatography (the silicon-dioxide of resistates; methylene dichloride: methyl alcohol=20: 3) obtain N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-[6-cyano group-3-(dibenzyl phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (9.5mg).
MS(FAB +)m/z：659(MH +)
HRMS (FAB +): C 34H 36N 4O 8P (MH +): calculated value 659.2271; Measured value 659.2256.
Embodiment 32
Figure A20048001887800531
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
At room temperature with N-[5 (S)-3-[4-[(1 α; 5 α; 6 β)-[6-cyano group-3-(dibenzyl phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl] phenyl]]-2-Yang Dai oxazolidine-5-ylmethyl] (7.5%, methyl alcohol 24mg) (6mL) suspension stirred 4 hours under nitrogen atmosphere for ethanamide (163mg) and palladium-charcoal.After leaching insoluble substance, with the filtrate vacuum concentration.Wash the solution of resistates in water (1.5mL) with ethyl acetate; and the aqueous solution freeze-drying that obtains obtained N-[5 (S)-3-[4-[(1 α; 5 α, 6 β)-[6-cyano group-3-(phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (111mg).
MS(FAB +)m/z：479(MH +)
HRMS (FAB +): C 20H 24N 4O 8P (MH +): calculated value 479.1332; Measured value 479.1344.
Reference example 1
4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)]-1-benzyloxycarbonyl amino benzene
Step 1.
(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) benzene
(add phenylacetonitrile (3.18mL) from tetrahydrofuran (THF) (37mL) solution of diisopropylamine (3.88mL) and n-Butyl Lithium (hexane solution of 1.6M, 17.4mL) preparation), mixture stirred 3 hours at 0 ℃ to lithium diisopropylamine under-50 ℃.Add tetrahydrofuran (THF) (26mL) solution of cyclopentenes-1-base phenylsulfone under 5 ℃ in mixture, mixture stirred 40 minutes under identical temperature, and at room temperature stirred 18 hours.Mixture stirred 3 hours down at 60 ℃.After with aqueous ammonium chloride solution diluted mixture thing, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=10: 1) obtain (1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) benzene (4.44g).
MS(EI +)m/z：183(M +)
HRMS (EI +): C 13H 13N (M +): calculated value 183.1048; Measured value 183.1072.
Step 2.
4-(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)-1-oil of mirbane
Under-30 ℃, in chloroform (5mL) solution of (1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) benzene (916mg), add the vitriol oil (1.93mL) and nitric acid (is fuming, 0.28mL), mixture was stirred 1 minute under identical temperature.Mixture is poured in the frozen water, uses chloroform extraction.Organic extract liquid is washed with sodium bicarbonate aqueous solution and salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=10: 3) obtain 4-(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)-1-oil of mirbane (875mg).
MS(EI +)m/z：228(M +)
HRMS (EI +): C 13H 12N 2O 2(M +): calculated value 228.0899; Measured value 228.0889.
Step 3.
1-benzyloxycarbonyl amino-4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] benzene
At room temperature with 4-(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)-1-oil of mirbane (875mg) and palladium catalyst (10%, on charcoal, the hydrogenation 3 hours under 1atm of tetrahydrofuran (THF) 87mg) (19mL) suspension.After filtering catalyst, with the filtrate vacuum concentration, obtain 1-amino-4-(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl) benzene, at 0 ℃ to thick 1-amino-4-(1 α that so obtains, 5 α, 6 β)-and adding sodium bicarbonate (644mg), water (6mL) and benzyl chloroformate (0.69mL) in acetone (12mL) solution of (6-cyano-bicyclo [3.1.0] hexane-6-yl) benzene, mixture stirred 5 minutes under identical temperature.After by adding frozen water diluted mixture thing, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=5: 2) obtain 1-benzyloxycarbonyl amino-4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] benzene (1.27g).
MS(EI +)m/z：332(M +)
HRMS (EI +): C 21H 20N 2O 2(M +): calculated value 332.1525; Measured value 332.1543.
Reference example 2
1-tert-butoxycarbonyl-3-pyrroline-3-base phenylsulfone
At room temperature add benzenethiol (0.60mL) in methylene dichloride (6mL) suspension of N-chlorosuccinimide (781mg), mixture stirred 30 minutes under identical temperature.At methylene dichloride (1mL) solution that adds 1-tertbutyloxycarbonyl-3-pyrroline (1.00g) under-60 ℃ in the mixture that obtains, mixture at room temperature stirred 1 hour.Leach insoluble substance, with the filtrate vacuum concentration.Adding metachloroperbenzoic acid (3.65g) under 0 ℃ in methylene dichloride (29mL) solution of resistates, mixture at room temperature stirred 1 hour.Add yellow soda ash (2.19g) in the mixture that obtains, mixture at room temperature stirred 5 minutes.Leach insoluble substance, filtrate is diluted with ether.Filtrate is washed with 10% sodium bisulfate, 10% sodium carbonate solution and salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.Adding 1 under-40 ℃ in methylene dichloride (11mL) solution of resistates, 8-diazabicyclo [5.4.0] 11-7-alkene (0.92mL), mixture at room temperature stirred 5 minutes.Be poured into mixture in the 1N hydrochloric acid and use extracted with diethyl ether.Organic extract liquid water, sodium bicarbonate aqueous solution and salt washing, anhydrous sodium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=5: 2) obtain 1-tertbutyloxycarbonyl-3-pyrroline-3-base phenylsulfone (1.16g).
MS(EI +)m/z：309(M +)
HRMS (EI +): C 15H 19NO 4S (M +): calculated value 309.1035; Measured value 309.1042.
Reference example 3
1-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)]-4-oil of mirbane
Step 1.
(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) benzene
With with the same method of reference example 1 from phenylacetonitrile (1.65mL) and 1-tertbutyloxycarbonyl-3-pyrroline-3-base phenylsulfone (4.46g) preparation title compound (1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) benzene (3.83g).
MS(CI +)m/z：285(MH +)
HRMS (CI +): C 17H 21N 2O 2(MH +): calculated value 285.1603; Measured value 285.1616.
Step 2.
1-[(1 α, 5 α, 6 β)-(6-cyano group-3-trifluoroacetyl group-3-azabicyclo [3.1.0] hexane-6-yl)]-4-oil of mirbane
Under 0 ℃ to (1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl) add trifluoroacetic acid (7mL) in methylene dichloride (7mL) solution of benzene (853mg), mixture at room temperature stirred 75 minutes and vacuum concentration.Adding triethylamine (5.01mL) and trifluoroacetic anhydride (1.06mL) under 0 ℃ in methylene dichloride (7mL) solution of resistates, mixture at room temperature stirs and spends the night and vacuum concentration.After with ethyl acetate dilution resistates, mixture is washed with 1N hydrochloric acid, water, sodium bicarbonate aqueous solution and salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.Add ammonium nitrate (372mg) and trifluoroacetic anhydride (2.19mL) in chloroform (3mL) solution of resistates, mixture at room temperature stirred 2.7 hours.After adding ice, collect the throw out that obtains and water and methylene dichloride and wash by filtering, obtain 1-[(1 α, 5 α, 6 β)-(6-cyano group-3-trifluoroacetyl group-3-azabicyclo [3.1.0] hexane-6-yl)]-4-oil of mirbane (546mg).
MS(EI +)m/z：325(M +)
HRMS (EI +): C 14H 10F 3N 3O 3(M +): calculated value 325.0674; Measured value 325.0648.
Step 3.
1-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)]-4-oil of mirbane
At room temperature stir 1-[(1 α, 5 α, 6 β)-(6-cyano group-3-trifluoroacetyl group-3-azabicyclo [3.1.0] hexane-6-yl)]-methanol solution (6.7M, mixture 0.5mL) 21 hours and the vacuum concentration of 4-oil of mirbane (9.2mg) and ammonia.Adding triethylamine (19.7 μ L) and tert-Butyl dicarbonate (9.5mg) under 0 ℃ in tetrahydrofuran (THF) (0.5mL) solution of resistates, mixture at room temperature stirred 30 minutes.The preparation thin-layer chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=4: 5) obtain 1-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)]-4-oil of mirbane (8.7mg).
MS(EI +)m/z：329(M +)
HRMS (EI +): C 17H 19N 3O 4(M +): calculated value 329.1376; Measured value 329.1401.
Reference example 4
1-benzyl oxygen carbonylamino-4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] benzene
With with the same method of reference example 1 from 1-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)]-4-oil of mirbane (98.8mg) preparation title compound 1-benzyloxycarbonyl amino-4-[(1 α, 5 α, 6 β)-(3-tert-butoxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] benzene (127mg).
MS(EI +)m/z：433(M +)
HRMS (EI +): C 25H 27N 3O 4(M +): calculated value 433.2002; Measured value 433.1989.
Anti-microbial activity
Pharmaceutically acceptable compound of the present invention can be used as the antiseptic-germicide of the good in-vitro antibacterial spectrum with anti-reference culture, and it can be used for screening the anti-microbial pathogen activity.It should be noted that pharmaceutically acceptable compound of the present invention shows the activity to the enterococcus bacteria that the resistance of vancomycin property of medicine is arranged, the pneumococcus (S.pneumoniae) that suis includes penicillin resistance, the streptococcus aureus (S.aureus) that methicillin resistance is arranged, mucous membrane catarrhalis (M.catarrhalis) and Chlamydia pneumoniae (C.pneumoniae).The antimicrobial spectrum of specific compound and effectiveness can be measured in the standard test system.
Obtain following in vitro results based on agar dilution, except Chlamydia pneumoniae.Activity is expressed as minimum inhibitory concentration (MIC).
Test streptococcus aureus and mucous membrane catarrhalis use 1 * 10 under 35 ℃ culture temperature on Mueller-Hinton agar 4The approximate inoculum that cfu/ is ordered 24 hours.MIC is defined as to observe does not have visible vegetative minimum concentration.
Test suis and enterococcus bacteria use 1 * 10 under 35 ℃ culture temperature on the Mueller-Hinton agar that is supplemented with 5% defibrinated horse blood 4The approximate inoculum that cfu/ is ordered 24 hours.MIC is defined as to observe does not have visible vegetative minimum concentration.
Use is supplemented with the minimum essential medium test Chlamydia pneumoniae of 10% heat-killed foetal calf serum, 2mM L-glutaminate, 1mg/ml cycloheximide and non-essential amino acid.With every milliliter 10 4Inclusion compound forms unitary Chlamydia pneumoniae inoculation HeLa 229 cells.With infected cell and test compounds in perfect medium under 35 ℃ at 5%CO 2Environment in cultivated 72 hours.Cell monolayer is fixing in methyl alcohol, make the dyeing of chlamydozoan inclusion compound with the anti-chlamydozoan monoclonal antibody of fluorescein conjugated.MIC is defined as the minimum concentration when not observing inclusion compound.
Bacterial strain MIC(μg/ml)
Embodiment 1 Embodiment 8 Embodiment 9 Embodiment 11 Linezolid
Streptococcus aureus (staphylococcus aureus) Smith CR MR 0.25 2 0.25 1 2 1 0.5 1 0.5 0.25 1 0.5 1 16 1
Streptococcus pneumoniae (Streptococcus pneumoniae) IID553 PRQR 0.5 0.25 0.5 0.5 0.5 0.5 0.25 0.25 2 1
Streptococcus pyogenes (Streptococcus pyogenes) IID692 0.5 0.5 0.5 0.125 1
Urine enterococcus (Enterococcus faecium) VRQR 0.25 0.5 0.5 0.25 2
Morazella catarrhalis (Moraxella catarrhalis) ATCC25238 0.5 2 2 1 4
CR=paraxin resistance
The MR=methicillin resistance
The PRQR=penicillin resistance, the quinolone resistance
The VRQR=resistance of vancomycin property of medicine, the quinolone resistance
NT=is test not
Illustrate the present invention who describes herein by following non-limiting example.The compound numerical nomenclature is according to General Guidelines for Manuscript Preparation, J.Org.Chem., the 66th volume 19A page or leaf, the 1st phase, 2001.

Claims (11)

1. the present invention relates to the compound of following formula I:
Figure A2004800188780002C1
Its enantiomer, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug, wherein:
R 1Expression:
Vi) hydrogen;
vii)NR 5R 6；
viii)CR 7R 8R 9、C(R) 2OR 14、CH 2NHR 14；
ix)C(＝O)R 13、C(＝NOH)H、C(＝NOR 13)H、C(＝NOR 13)R 13、C(＝NOH)R 13、C(＝O)N(R 13) 2、C(＝NOH)N(R 13) 2、NHC(＝X 1)N(R 13) 2、(C＝NH)R 7、N(R 13)C(＝X 1)N(R 13) 2、COOR 13、SO 2R 14、N(R 13)SO 2R 14、N(R 13)COR 14；
X) (C 1-6Alkyl) CN, CN, CH=C (R) 2, (CH 2) pOH, C (=O) CHR 13, C (=NR 13) R 13, NR 10C (=X 1) R 13Or
Vi) optionally by 1-3 R 7The C that group replaces 5-10Heterocycle, it can connect by carbon atom or heteroatoms;
A represents NR, O or S (O) p
Figure A2004800188780002C2
Expression aryl or heteroaryl, heterocycle, heterocyclic radical or heterocyclic, condition is in heteroaryl, heterocycle, heterocyclic radical or heterocyclic situation, cyclopropyl is not connected with the nitrogen-atoms that encircles;
Rx represents hydrogen or C 1-6Alkyl;
R 3Expression:
i)NR 13(C＝X 2)R 12，
ii)NR 13(C＝X 1)R 12，
iii)NR 13SO 2R 14，
Iv) N (R 13) heteroaryl,
V) NR 13(CHR 13) 0-4Aryl,
Vi) NR 13(CHR 13) 0-4Heteroaryl,
Vii) S (CHR 13) 0-4Aryl,
Viii) S (CHR 13) 0-4Heteroaryl,
Ix) O (CHR 13) 0-4Aryl,
X) O (CHR 13) 0-4Heteroaryl,
xi)NOH(C＝X 1)R 12，
Xii)-OC=N (OCO aryl) C 1-6Alkyl,
Xiii)-OC=N (OH) C 1-6Alkyl,
Xiv) can be by the C of carbon atom or heteroatoms connection 5-10Heteroaryl; Described aryl and heteroaryl are optionally by 1-3 R 7Group replaces;
R 4And R 4aExpression independently:
V) hydrogen,
Vi) halogen,
Vii) C 1-6Alkoxyl group, or
Viii) C 1-6Alkyl,
R and s are 1-3 independently, and condition is as (R 4a) s(R 4) rBe connected in Ar or HAr when ring, r and s and be less than or equal to 4;
R 5And R 6Expression independently:
Xiii) hydrogen,
Xiv) C that is optionally replaced by 1-3 group 1-6Alkyl, described substituted radical is selected from halogen, CN, OH, C 1-6Alkoxyl group, amino, imino-, hydroxylamino, alkoxy amino, C 1-6Acyloxy, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulfinyl, C 1-6Alkyl sulphonyl, amino-sulfonyl, C 1-6Alkyl amino sulfonyl, C 1-6Dialkyl amino sulfonyl, 4-morpholinyl alkylsulfonyl, phenyl, pyridine, 5-isoxazolyl, vinyloxy group or ethynyl, described phenyl and pyridine are optionally by 1-3 halogen, CN, OH, CF 3, C 1-6Alkyl or C 1-6Alkoxyl group replaces;
Xv) C that is optionally replaced by 1-3 group 1-6Acyl group, described substituted radical is selected from halogen, OH, SH, C 1-6Alkoxyl group, naphthyloxy, phenoxy group, amino, C 1-6Acyl amino, hydroxyl amino, alkoxy amino, C 1-6Acyloxy, aralkoxy, phenyl, pyridine, C 1-6Alkyl-carbonyl, C 1-6Alkylamino, C 1-6Dialkyl amido, C 1-6Hydroxyl acyloxy, C 1-6Alkyl sulphinyl, phthalimide-based, dimaleoyl imino, succinimido, described phenoxy group, phenyl and pyridine are optionally by 1-3 halo, OH, CN, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces;
Xvi) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, amino, hydroxyl amino, alkoxy amino, C 1-6The C that acyloxy or phenyl replace 1-6Alkyl sulphonyl; Described phenyl is optionally by 1-3 halo, OH, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces;
Xvii) optionally by 1-3 halogen, C 1-6Alkoxyl group, OH or C 1-6The aryl sulfonyl that alkyl replaces;
Xviii) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, C 1-6The C that acyloxy or phenyl replace 1-6Alkoxy carbonyl, described phenyl are optionally by 1-3 halo, OH, C 1-6Alkoxyl group, amino, C 1-6Acyl amino, CF 3Or C 1-6Alkyl replaces;
Xix) aminocarboxyl, C 1-6Alkyl amino-carbonyl or C 1-6Dialkyl amino carbonyl, described alkyl are optionally by 1-3 halogen, OH, C 1-6Alkoxyl group or phenyl replace;
Xx) optionally by 1-3 halogen, OH, CN, amino, C 1-6Acyl amino, C 1-6Alkyl sulfonyl-amino, C 1-6Alkoxycarbonyl amino, C 1-6Alkoxyl group, C 1-6Acyloxy or C 1-6Hexa-member heterocycle is arrived in five of alkyl replacement, and described alkyl is optionally by 1-3 halogen or C 1-6Alkoxyl group replaces;
Xxi) optionally by 1-3 halogen, OH, C 1-6The C that alkoxyl group or CN replace 3-6Naphthene base carbonyl;
Xxii) optionally by 1-3 halogen, OH, C 1-6Alkoxyl group, C 1-6Alkyl, CF 3, C 1-6Alkyloyl, amino or C 1-6The benzoyl that acyl amino replaces;
Xxiii) optionally by 1-3 C 1-6The pyrryl carbonyl that alkyl replaces;
Xxiv) C 1-2The acyloxy ethanoyl, wherein acyl group is optionally by amino, C 1-6Alkylamino, C 1-6Dialkyl amido, 4-morpholino, 4-aminophenyl, 4-(dialkyl amido) phenyl, 4-(glycidyl-amino) phenyl replace; Or
R 5And R 6Can form with any interval atom and to comprise carbon atom and 1-2 and independently be selected from O, S, SO, SO 2, N or NR 8Heteroatomic 3 to 7 yuan of heterocycles;
R 7Expression:
Iii) hydrogen, halogen, CN, CO 2R, CON (R) 2, CHO, CH 2NHAc, C (=NOR), OH, C 1-6Alkoxyl group, C 1-6Alkyl, thiazolinyl, hydroxyl C 1-6Alkyl, (CH 2) 1-3NHC (O) C 1-6Alkyl, (CH 2) 1-3N (C 1-6Alkyl) 2
Iv) (CH 2) nAmino, (CH 2) nC 1-6Alkylamino, C 1-6Dialkyl amido, hydroxyl amino or C 1-2Alkoxy amino, they all optionally on nitrogen by C 1-6Acyl group, C 1-6Alkyl sulphonyl or C 1-6Alkoxy carbonyl replaces, and described acyl group and alkyl sulphonyl are optionally replaced by 1-2 halogen or OH;
R 8And R 9Expression independently:
iv)H、CN，
V) optionally by 1-3 halogen, CN, OH, C 1-6Alkoxyl group, C 1-6Acyloxy or the amino C that replaces 1-6Alkyl,
Vi) optionally by 1-3 halogen, OH, C 1-6The phenyl that alkoxyl group replaces; Or
R 7And R 8Can form together optionally and be selected from O, S, SO, SO by 1-2 2, NH and NR 8The 3-7 unit carbocyclic ring that interrupts of heteroatoms;
X 1Expression O, S or NR 13, NCN, NCO 2R 16, or NSO 2R 14
X 2Expression O, S, NH or NSO 2R 14
R 10Expression hydrogen, C 1-6Alkyl or CO 2R 15
R 12Expression hydrogen, C 1-6Alkyl, NH 2, OR, CHF 2, CHC1 2, CR 2Cl, (CH 2) nSR, (CH 2) nCN, (CH 2) nSO 2R, (CH 2) nS (O) R, C 1-6Alkylamino, C 5-10Heteroaryl or C 1-6Dialkyl amido, wherein said alkyl can be by 1-3 halo, CN, OH or C 1-6Alkoxyl group replaces, and described heteroaryl is optionally by 1-3 R 7Base replaces;
Each R 13Represent hydrogen, C independently 1-6Alkyl, C 6-10Aryl, NR 5R 6, SR 8, S (O) R 8, S (O) 2R 8, CN, OH, C 1-6Alkyl S (O) R, C 1-6Alkoxy carbonyl, hydroxycarbonyl group ,-OCO aryl, C 1-6Acyl group, optionally be selected from O, S, SO, SO by 1-4 2, NH and NR 8The C that interrupts of heteroatoms 3-7Unit's carbocyclic ring, wherein said C 1-6Alkyl, aryl or C 1-6Acyl group can be independently by 0-3 halogen, hydroxyl, N (R) 2, CO 2R, C 6-10Aryl, C 5-10Heteroaryl or C 1-6Alkoxyl group replaces;
As two R 13When group connected with identical atom or two adjacent atoms, they can form together optionally and are selected from O, S, SO, SO by 1-2 2, NH and NR 8The 3-7 unit carbocyclic ring that interrupts of heteroatoms;
R represents hydrogen or C 1-6Alkyl;
R 14Expression is amino, C 1-6Alkyl, C 1-6Haloalkyl, five is to hexa-member heterocycle or phenyl, and described phenyl and heterocycle are optionally by 1-3 halo, C 1-6Alkoxyl group, C 1-6Acyl amino or C 1-6Alkyl, hydroxyl and/or amino the replacement,, described amino and hydroxyl are optionally with amino protecting group or hydroxyl protecting group protection;
R 15Be C 1-6Alkyl or benzyl, described benzyl are optionally by 1-3 halo, OH, C 1-6Alkoxyl group, amino, C 1-6Acyl amino or C 1-6Alkyl replaces;
R 16Be hydrogen, C 5-10Heteroaryl, C 6-10Aryl, described heteroaryl and aryl are optionally by 1-3 R 7Group replaces;
P represents 0-2; With
M, n and q represent 0-1.
2. the compound of claim 1, wherein R 1Expression H, NR 5R 6, CN, OH, C (R) 2OR 14, NHC (=X 1) N (R 13) 2, C (=NOH) N (R 13) 2, NR 10C (=X 1) R 13Or CR 7R 8R 9
3. the compound of claim 1, wherein
Figure A2004800188780006C1
Be phenyl, pyridine, pyrimidine or piperidines.
4. the compound of claim 3, wherein R 1Be NR 5R 6Or CN, R 3Be NR 10C (=X 1) R 13, NR (C=X 1) R 12, C 5-10Heteroaryl, NH (CH 2) 0-4Aryl, NH (CH 2) 0-4Heteroaryl, described aryl and heteroaryl are optionally replaced by 1-3 Ra group.
5. the compound of claim 3, wherein R 3Serve as reasons
Figure A2004800188780007C1
The C of expression 5-10Heteroaryl, its expression comprise the fragrant heterocyclic radical of the selectivity replacement of 1 to 4 nitrogen and at least one two key, and it connects by the key on any nitrogen.
6. the compound of claim 1, wherein structural formula is a Formula Il:
Formula II
R wherein 1, R 4, R 4a, Y and R 3Definition as described above.
7. following compound:
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-bicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2, the 3-ethanamide,
1-[5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3-acetoxyl group ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano-3-hydroxy ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methylsulfonyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(3,6-dicyano-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-cyano methyl-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(3-tertbutyloxycarbonyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(tertbutyloxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[(1 α, 5 α, 6 β)-(6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl)] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(5-cyanopyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyridine-2-yl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(pyrimidine-2-base)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(4-pyridylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-1-imido grpup ethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methoxycarbonyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group-S-methyl thioimines ylmethyl)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(N-cyano group amidino groups)-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N, N '-tertbutyloxycarbonyl amidino groups)-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-amidino groups-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-(N-tert-butoxycarbonyl amino) ethanoyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[3-glycyl-6-cyano group-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-methylsulfonyl ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(dibenzyl phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[(1 α, 5 α, 6 β)-[6-cyano group-3-(phosphoryl oxygen base) ethanoyl-3-azabicyclo [3.1.0] hexane-6-yl]] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
Or its enantiomer, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug.
8. pharmaceutical compositions comprises compound and pharmaceutically acceptable carrier of claim 1 and optionally is selected from the combination of the VITAMIN in Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid group.
9. treatment or prevention have the method for the infectation of bacteria of the mammalian subject that needs, and it comprises the compound to the claim 1 of described patient's effective dosage.
10. by one or more of compound shown in the formula I of claim 1 that the patient's effective dosage that needs is arranged and significant quantity being selected from methods of vitaminization in Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid group or the prevention infectation of bacteria Huo side effect relevant Yu oxazolidone.
11. claim 16 pass through method to Wei ShengsuB2 treatment that the patient's effective dosage that needs is arranged or Yu Fang normocytic anemia, peripheral sensory neuropathy, sideroblastic anemia, peripheral sensory neuropathy, optic neuropathy, epileptic seizures, thrombopenia, cheilosis, inferior hyperplastic anemia, megaloblastic anemia and the seborrheic dermatitis relevant Yu oxazolidone.
CN 200480018878 2003-07-02 2004-06-29 Oxazolidinone antibiotics and derivatives thereof Pending CN1816534A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102131811A (en) * 2008-06-24 2011-07-20 财团法人乙卯研究所 Oxazolidinone derivative having fused ring
CN102803224A (en) * 2009-06-26 2012-11-28 万能药生物有限公司 Novel azabicyclohexanes
CN112851692A (en) * 2021-01-23 2021-05-28 中国科学院新疆理化技术研究所 Oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102131811A (en) * 2008-06-24 2011-07-20 财团法人乙卯研究所 Oxazolidinone derivative having fused ring
CN102803224A (en) * 2009-06-26 2012-11-28 万能药生物有限公司 Novel azabicyclohexanes
CN112851692A (en) * 2021-01-23 2021-05-28 中国科学院新疆理化技术研究所 Oxazolo [5,4-d ] pyrido [1,2-a ] pyrimidone derivative and application thereof

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