CN1816545A - Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof - Google Patents

Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof Download PDF

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Publication number
CN1816545A
CN1816545A CN 200480018905 CN200480018905A CN1816545A CN 1816545 A CN1816545 A CN 1816545A CN 200480018905 CN200480018905 CN 200480018905 CN 200480018905 A CN200480018905 A CN 200480018905A CN 1816545 A CN1816545 A CN 1816545A
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Prior art keywords
amino
pyridine
cyclopropane
ylmethyl
phenyl
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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 mycobactenial species. The compounds are represented by structural formula: (I): its enantiomer, diastereomer, or pharmaceutically acceptable salt or ester thereof.

Description

Cyclopropyl replaces De oxazolidone microbiotic and derivative thereof
The cross reference of related application
The application requires the right of priority of provisional application of submitting on July 2nd, 2,003 60/483,904 and the provisional application of submitting on February 24th, 2,004 60/546,980, and it is all incorporated into this paper as a reference in full.
Background of invention
Oxazolidone has been represented first novel antibacterial medicine of exploitation after quinolone.Oxazolidone is oral or intravenously is active, resists debatable multi-drug resistant gram-positive organism and does 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:New AntibacterialAgents, Trends in Microbiology, 196, the 5th the 5th phase of volume, in May, 1997, and WO96/35691.Also referring to WO 03/063862, WO 01/81350, WO 01/94342, WO03/072553, 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 formula I:
Figure A20048001890500151
Its enantiomer, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug, wherein:
R 1And R 2Expression independently:
I) hydrogen;
ii)(CH 2) nNR 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;
R 1aExpression (CH 2) nNR 5R 6, CR 7R 8R 9, C (R) 2OR 14, CH 2NHR 14, 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, (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 optionally by 1-3 R 7The C that group replaces 5-10Heterocycle, it can connect by carbon atom or heteroatoms;
X is selected from the group of following group:
With
Figure A20048001890500162
Z represents (O) n, H, OH or halogen;
A represent C (when---when existing, condition is Z=(O) nAnd n=0), C (when--when not existing, condition is that Z is H, OH or halogen) or N (when---when not existing and Z=(O) nAnd n=1);
---expression key;
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;
R xExpression 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 4, R 4a, R 4b, and R 4cExpression 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) rOr (R 4b) and (R 4c) sBe 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 2) 0-3NHAc, 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) 0-3N (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 optionally 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 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 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 the term that is defined as follows to describe the present invention in detail in this article.
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 A20048001890500211
Be meant the aryl or heteroaryl, heterocycle, Het, heterocyclic radical or the heterocyclic that are about to description as following.
Aryl is meant any stable monocycle or the bicyclic carbocyclic that maximum 7 atoms are arranged in each ring, wherein at least one ring is 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 A20048001890500221
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.
Unless otherwise indicated, 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 inOrganic Synthesis; 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, phenyl, 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 the compound of formula I is alkali, 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 may be owing to 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 1And R 2Represent H, NR independently 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.
At R 1aExpression NR 5R 6, CN, OH, C (R 2) OR 14, NHC (=X 1) N (R 13) 2, C (=NOH) N (R 13) 2, NR 10C (=X 1) R 13Or R 7R 8R 9, and other all variablees has been realized another embodiment of the invention as described herein the time.
When Be phenyl, pyridine, pyrimidine or piperidines, and other all variablees has been realized another embodiment of the invention as described herein the time.
When
Figure A20048001890500252
Be phenyl, pyridine, pyrimidine or piperidines, and other all variablees has been realized another embodiment of the invention as described herein the time.
Work as R 1And R 2In one be H another be NR 5R 6, and other all variablees has been realized another embodiment of the invention as described herein the time.
Work as R 1And R 2In one be H another be CN, and other all variablees has been realized another embodiment of the invention as described herein the time.
Work as R 1aBe CN or NR 5R 6, and other all variablees has been realized another embodiment of the invention as described herein the time.
Work as R 1And R 2In one be H another be NR 10C (=X 1) R 13, and other all variablees has been realized another embodiment of the invention as described herein the time.
When X is
Figure A20048001890500261
And other all variablees has been realized one embodiment of the invention as described herein the time.
When X is And other all variablees has been realized one embodiment of the invention as described herein the time.When A is C, existing---and Z=(O) n, wherein n=0, and other all variablees have realized a subscheme of the present invention as described herein the time.When A is N,---do not exist and and Z=(O) n, wherein n=1, and other all variablees has realized a subscheme of the present invention as described herein the time.When A is N,---not existing and Z=H, OH or halogen, wherein n=1, and other all variablees has realized another subscheme of the present 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 by 1-3 R aReplace.
Work as R 3Serve as reasons
Figure A20048001890500271
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, ethylenedioxy 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:
Formula II
R wherein 1a, R 4, R 4a, and R 3As described herein.
Work as R 1aBe CN or NR 5R 6The time, realized another preferred embodiment of the present invention.
When structural formula is Formula Il I, realized a preferred embodiment of the present invention:
Figure A20048001890500282
Formula III
Wherein Z, R 1, R 2, R x, R 4, R 4a, A and R 3As described herein.
Preferred compound of the present invention is:
N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[5-(1-cyano group cyclopropane-1-yl) pyridine-2-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-(dimethylamino) methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-(dimethylamino) methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-tert-butoxycarbonyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-hydroxymethyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-hydroxycarbonyl group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-(tertiary butyl oxygen carbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-amino methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
N-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-t-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-base phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone;
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone;
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles;
1-[5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole;
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole;
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyrimidine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide;
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole;
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole;
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
Or its enantiomer, diastereomer, or its 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 those comprise: 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 form 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 injectable composition, carrier comprises that typically sterilized water, salt solution or another kind of injectable liquids 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, takes place to prevent or to reduce side effect relevant with oxazolidone among the patient.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 structural 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 one or more methods with treatment or prevention infectation of bacteria in Wei ShengsuB2, vitamin B6, vitamin B12 and the folic acid group of being selected to the compound in structural 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 form 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 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-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes (borolyl)) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (400mg), 5-bromo-2-(1-cyano group cyclopropane-1-yl) pyridine (248mg) and four (triphenyl phosphine) palladium (O) mixture (128mg) in dioxane (10mL) and 2M sodium carbonate solution (2.78mL) 80 ℃ of heating 2 hours.The flash chromatography of mixture (silicon-dioxide, methylene dichloride: methyl alcohol=9: 1) obtain N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (298mg).
MS(EI +)m/z：376(M +)。
HRMS (EI +): C 21H 20N 4O 3(M +), calculated value 376.1535; Measured value 376.1533.
Embodiment 2
N-[5 (S)-3-[4-[5-(1-cyano group cyclopropane-1-yl) pyridine-2-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide.
In similarly to Example 1 mode from N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (400mg) and 2-bromo-5-(1-cyano group cyclopropane-1-yl) pyridine (248mg) preparation title compound N-[5 (S)-3-[4-(5-(1-cyano group cyclopropane-1-yl) pyridine-2-yl) phenyl)-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (266mg).
MS(EI +)m/z：376(M +)。
HRMS (EI +): C 21H 20N 4O 3(M +): calculated value 376.1535; Measured value 376.1533.
Embodiment 3
N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (400mg) and 5-bromo-2-(1-cyano group cyclopropane-1-yl) pyridine (236mg) preparation title compound N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (278mg).
MS(E)m/z：394(M +)。
HRMS (EI +): C 21H 19FN 4O 3(M +): calculated value 394.1441; Measured value 394.1412.
Embodiment 4
Figure A20048001890500372
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (575mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (500mg) preparation title compound N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (398mg).
MS(FAB +)m/z：467(MH +)。
HRMS (FAB +): C 25H 31N 4O 5(MH +): calculated value 467.2294; Measured value 467.2292.
Embodiment 5
Figure A20048001890500381
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] add trifluoroacetic acid (5mL) in the suspension of ethanamide (370mg) in methylene dichloride (10mL), at room temperature stirred the mixture 1 hour, then vacuum concentration.Resistates is washed with the dilution of 5% hydrochloric acid and with methylene dichloride.Regulate the aqueous solution to pH10 by adding salt of wormwood, extract the mixture that obtains with methylene chloride-methanol (7: 1).With the organic extract liquid vacuum concentration.The flash chromatography of resistates (NH silicon-dioxide, methylene dichloride: methyl alcohol=20: 1) obtain N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (283mg).
MS(EI +)m/z：366(M +)。
HRMS (EI +): C 20H 22N 4O 3(M +): calculated value 366.1692; Measured value 366.1683.
Embodiment 6
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (540mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (447mg) preparation title compound N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (592mg).
MS(FAB +)m/z：485(MH +)。
HRMS (FAB +): C 25H 30FN 4O 5(MH +): calculated value 485.2200; Measured value 485.2209.
Embodiment 7
Figure A20048001890500392
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 5 mode from N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (50.0mg) preparation title compound N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (30.2mg).
MS(EI +)m/z：384(M +)。
HRMS (EI +): C 20H 21FN 4O 3(M +): calculated value 384.1598; Measured value 384.1603.
Embodiment 8
N-[5 (S)-3-[4-[2-(1-(dimethylamino) methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (575mg) and 5-bromo-2-(1-(dimethylamino) methyl cyclopropane-1-yl) pyridine (337mg) preparation title compound N-[5 (S)-3-[4-(2-(1-dimethylamino) methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (223mg).
MS(EI +)m/z：426(M +)
HRMS (EI +): C 23H 27FN 4O 3(M +): calculated value 426.2067; Measured value 426.2074.
Embodiment 9
Figure A20048001890500402
N-[5 (S)-3-[4-[2-(1-tert-butoxycarbonyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (507mg) and 5-bromo-2-(1-tert-butoxycarbonyl cyclopropane-1-yl) pyridine (400mg) preparation title compound N-[5 (S)-3-[4-[2-(1-tert-butoxycarbonyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (384mg).
MS(EI +)m/z：469(M +)
HRMS (EI +): C 25H 28FN 3O 5(M +): calculated value 469.2013; Measured value 469.1968.
Embodiment 10
N-[5 (S)-3-[4-[2-(1-hydroxymethyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (200mg) and 5-bromo-2-(1-hydroxymethyl cyclopropane-1-yl) pyridine (121mg) preparation title compound N-[5 (S)-3-[4-[2-(1-hydroxymethyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (161mg).
MS(EI +)m/z：399(M +)
HRMS (EI +): C 21H 22FN 3O 4(M +): calculated value 399.1594; Measured value 399.1628.
Embodiment 11
Figure A20048001890500421
N-[5 (S)-3-[4-[2-(1-hydroxycarbonyl group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride
With N-[5 (S)-3-[4-[2-(1-tert-butoxycarbonyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] the dioxane solution (4M of ethanamide (54.8mg) and hydrogenchloride, 1mL) at room temperature stir 4 hours, then vacuum concentration.Handle resistates with chloroform and obtain N-[5 (S)-3-[4-[2-(1-hydroxycarbonyl group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride (49.0mg).
MS (FAB +) m/z:414 (MH +) (being free alkali)
HRMS (FAB +): C 21H 21FN 3O 5(MH +): calculated value 414.1465; Measured value 414.1512.
Embodiment 12
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
Stirred down 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (500mg), two (tetramethyl ethylene ketone base) two boron (446mg), 2 ethyl hexanoic acid potassium (437mg) and [1,1 '-two (diphenyl phosphine) ferrocene] palladium chlorides (II)-mixture of methylene dichloride adducts (130mg) in dioxane (15mL) 1.5 hours at 80 ℃.In this solution, add N-[5 (S)-3-[3; 5-two fluoro-4-(trifyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (601mg), four (triphenyl phosphine) palladium (O) (166mg) and 2M sodium carbonate solution (2.2mL), mixture stirred 1.5 hours at 80 ℃.The flash chromatography of mixture (NH silicon-dioxide, ethyl acetate: methyl alcohol=9: 1) obtain N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (398mg).
MS(FAB +)m/z：503(MH +)。
HRMS (FAB +): C 25H 29F 2N 4O 5(MH +): calculated value 503.2106; Measured value 503.2085.
Embodiment 13
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 5 mode from N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (398mg) preparation title compound N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (269mg).
MS(EI +)m/z：402(M +)
HRMS (EI +): C 20H 20F 2N 4O 3(M +): calculated value 402.1503; Measured value 402.1509.
Embodiment 14
Figure A20048001890500441
N-[5 (S)-3-[4-[2-(1-amino methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃ to N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] add six hydration cobalt dichlorides (47.6mg) and sodium borohydride (37.8mg) in the suspension of ethanamide (39.4mg) in methyl alcohol (1mL), under identical temperature, stirred the mixture 1 hour.Regulate mixture pH2 by adding 1N hydrochloric acid, the mixture that obtains at room temperature stirred 30 minutes.Regulate mixture pH10, vacuum concentration then by adding ammonium hydroxide solution,stronger.The flash chromatography of resistates (NH silicon-dioxide, ethyl acetate: methyl alcohol=19: 1) obtain N-[5 (S)-3-[4-[2-(1-amino methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (25.9mg).
MS(EI +)m/z：398(M +)
HRMS (EI +): C 21H 23FN 4O 3(M +): calculated value 398.1754; Measured value 398.1789.
Embodiment 15
Figure A20048001890500442
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
To 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazole (10.5mg), 5-bromo-2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine (10.0mg), cesium carbonate (36.8mg) and three (dibenzalacetones), two palladiums (O) (6.46mg) add three (tertiary butyl) phosphine (2.86mg) in the mixture of dioxane (1mL) and water (0.1mL), mixture stirred 20 minutes at 70 ℃.Flash chromatography (the silicon-dioxide of mixture, ethyl acetate: methyl alcohol=6: 1) obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (12.6mg).
MS(FAB +)m/z：518(MH +)。
HRMS (FAB +): C 27H 32N 7O 4(MH +): calculated value 518.2516; Measured value 518.2505.
Embodiment 16
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With with embodiment 1 and 5 same modes from 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes)-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazole (372mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (300mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (261mg).
MS(EI +)m/z：394(M +)
HRMS (EI +): C 20H 19FN 6O 2(M +): calculated value 394.1554; Measured value 394.1588.
Embodiment 17
Figure A20048001890500461
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With with embodiment 1 and 5 same modes from 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes)-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazole (591mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (500mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles (231mg).
MS(EI +)m/z：376(M +)
HRMS (EI +): C 20H 20N 6O 2(M): calculated value 376.1648; Measured value 376.1662.
Embodiment 18
Figure A20048001890500462
1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-(4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (400mg), 2-(1-cyano group cyclopropane-1-yl) pyridine-5-boric acid (264mg) and four (triphenyl phosphine) palladium (0) (125mg) mixture in dioxane (15mL) and 2M sodium carbonate solution (2.7mL) stirred 2 hours at 80 ℃.The flash chromatography of mixture (silicon-dioxide, ethyl acetate: methyl alcohol=9: 1) obtain 1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles (252mg).
MS(EI +)m/z：386(M +)。
HRMS (EI +): C 21H 18N 6O 2(M +): calculated value 386.1491; Measured value 386.1469.
Embodiment 19
1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
In similarly to Example 18 mode from 1-[5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (400mg) and 2-(1-cyano group cyclopropane-1-yl) pyridine-5-boric acid (252mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (235mg).
MS(EI +)m/z：404(M +)
HRMS (EI +): C 21H 27FN 6O 2(M +): calculated value 404.1397; Measured value 404.1379.
Embodiment 20
Figure A20048001890500481
N-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 18 mode from N-[5 (S)-3-[3; 5-two fluoro-4-(trifyl) oxygen phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (418mg) and 2-(1-cyano group cyclopropane-1-yl) pyridine-5-boric acid (244mg) preparation title compound N-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (270mg).
MS(EI +)m/z：412(M +)。
HRMS (EI +): C 21H 18F 2N 4O 3(M +): calculated value 412.1347; Measured value 412.1339.
Embodiment 21
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone
Step 1.
5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl] oxazolidine-2-ketone
With similarly to Example 18 mode from 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-(4-iodine substituted phenyl) oxazolidine-2-ketone (1.70g) preparation title compound 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl] oxazolidine-2-ketone (1.10g).
MS(FAB +)m/z：450(MH +)。
HRMS (FAB +): C 25HN 32O 3Si (MH +): calculated value 450.2213; Measured value 450.2214.
Step 2.
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone
In similarly to Example 28 mode from 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl] oxazolidine-2-ketone (116mg) preparation title compound 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (85.1mg).
MS(EI +)m/z：335(M +)。
HRMS (EI +): C 19H 17N 3O 3(M +): calculated value 335.1270; Measured value 335.1286.
Step 3.
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone.
To 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (50mg), 3-hydoxyisoxazole (16.5mg) and the mixture of triphenyl phosphine (58.7mg) in tetrahydrofuran (THF) (1.5mL) in adding azo-2-carboxylic acid's diisopropyl ester (39.2mg), mixture at room temperature stirred 30 minutes, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl ester: methyl alcohol=9: 1) obtain 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone (56.0mg).
MS(EI +)m/z：402(M +)
HRMS (EI +): C 22H 18N 4O 4(M +): calculated value 402.1328; Measured value 402.1296.
Embodiment 22
Figure A20048001890500501
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
To 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (70.0mg), 3-N-(tert-butoxycarbonyl) An isoxazole (46.1mg) and the suspension of tetramethyl-Cellmic C 121 (53.9mg) in toluene (2mL) adds tributylphosphine (63.3mg), and with mixture 50 ℃ of heating 2 hours.The flash chromatography of mixture (silicon-dioxide, hexane: ethyl acetate=1: 1) obtain 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (101mg).
MS(EI +)m/z：501(M +)
HRMS (EI +): C 27H 27N 5O 5(M +): calculated value 501.2012; Measured value 501.2005.
Embodiment 23
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
In similarly to Example 5 mode from 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (491mg) preparation title compound 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (322mg).
MS(EI +)m/z：401(M +)
HRMS (EI +): C 22H 19N 5O 3(M +): calculated value 401.1488; Measured value 401.1515.
Embodiment 24
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
Step 1.
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-(t-butyldimethylsilyl oxygen base) Jia Ji oxazolidine-2-ketone
In similarly to Example 1 mode from 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl] oxazolidine-2-ketone (84.8mg) and 5-bromo-2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine (58.8mg) preparation title compound 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-(t-butyldimethylsilyl oxygen base) first base oxazolidine-2-ketone (76.0mg).
MS(EI +)m/z：557(M +)
HRMS (EI +): C 29H 40FN 3O 5Si (M +): calculated value 557.2721; Measured value 557.2724.
Step 2.
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone
In similarly to Example 28 mode from 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-(t-butyldimethylsilyl oxygen base) Jia Ji oxazolidine-2-ketone (1.32g) preparation title compound 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (740mg).
MS(FAB +)m/z：444(MH +)
HRMS (FAB +): C 23H 27FN 3O 5(MH +): calculated value 444.1935; Measured value 444.1928.
Step 3.
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
In similarly to Example 22 mode from 5, (R)-3-[4-[2-, (1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone, (400mg) and 3-N-, (tert-butoxycarbonyl) An isoxazole, (203mg) preparation title compound 5, (R)-3-[4-[2-, (1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-, (tert-butoxycarbonyl)-N-, the (isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone, (554mg).
MS(FAB +)m/z：610(MH +)
HRMS (FAB +): C 31H 37FN 5O 7(MH +): calculated value 610.2677; Measured value 610.2674.
Embodiment 25
5 (R)-3-[4-[2-(1-t-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
In similarly to Example 5 mode from 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (554mg) preparation title compound 5 (R)-3-[4-[2-(1-t-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (224mg).
MS(EI +)m/z：409(M +)
HRMS (EI +): C 21H 20FN 5O 3(M +): calculated value 409.1550; Measured value 409.1565.
Embodiment 26
Figure A20048001890500532
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone
In similarly to Example 21 mode from 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (290mg) and 3-hydoxyisoxazole (72.3mg) prepare title compound 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone (335mg).
MS(EI +)m/z：510(M +)
HRMS (EI +): C 26H 27FN 4O 6(M +): calculated value 510.1915; Measured value 510.1925.
Embodiment 27
Figure A20048001890500541
5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone
In similarly to Example 5 mode from 5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone (335mg) preparation title compound 5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone (115mg).
MS(EI +)m/z：410(M +)
HRMS (EI +): C 21H 19FN 4O 4(M +): calculated value 410.1390; Measured value 410.1379.
Embodiment 28
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
Step 1.
5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-3-fluorophenyl] oxazolidine-2-ketone
In similarly to Example 1 mode from 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl] oxazolidine-2-ketone (60.8mg) and 5-bromo-2-(1-cyano group cyclopropane-1-yl) pyridine (30.0mg) preparation title compound 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl] oxazolidine-2-ketone (59.4mg).
MS(EI +)m/z：467(M +).
HRMS (EI +): C 25H 30FN 3O 3Si (M +): calculated value 467.2040; Measured value 467.2047.
Step 2.
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone
At room temperature to 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-3-fluorophenyl] oxazolidine-2-ketone (54.6mg) adds the tetrahydrofuran solution (solution of 1M of four fourth Neutral ammonium fluorides at tetrahydrofuran (THF) (2mL), 0.14mL), under identical temperature, stirred the mixture 2.5 hours.With mixture with saturated ammonium chloride solution dilution and use ethyl acetate extraction.Organic extract liquid is washed with salt, anhydrous magnesium sulfate drying, vacuum concentration obtains 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl then]-the 3-fluorophenyl]-5-hydroxyl base first base oxazolidine-2-ketone (13mg).
MS(EI +)m/z：353(M +)
HRMS (EI +): C 19H 16FN 3O 3(M +): calculated value 353.1176; Measured value 353.1197.
Step 3.
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
In similarly to Example 22 mode from 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (50.0mg) and 3-N-(tert-butoxycarbonyl) An isoxazole (31.3mg) preparation title compound 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] the basic Jia Ji of An oxazolidine-2-ketone (67.5mg).
MS(EI +)m/z：519(M +)
HRMS (EI +): C 27H 26FN 5O 5(M +): calculated value 519.1918; Measured value 519.1938.
Embodiment 29
Figure A20048001890500561
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone
In similarly to Example 5 mode from 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (64.2mg) preparation title compound 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone (49.8mg).
MS(EI +)m/z：419(M +)
HRMS (E): C 22H 18FN 5O 3(M +): calculated value 419.1394; Measured value 419.1421.
Embodiment 30
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone
In similarly to Example 21 mode from 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-Qiang base Jia Ji oxazolidine-2-ketone (13.0mg) and 3-hydoxyisoxazole (4.1mg) prepare title compound 5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone (13.6mg).
MS(EI +)m/z：420(M +)
HRMS (EI +): C 22H 17FN 4O 4(M +): calculated value 420.1234; Measured value 420.1261.
Embodiment 31
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazole (457mg), 5-bromo-2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine (400mg) and four (triphenyl phosphine) palladium (O) (196mg) mixture in toluene (5.65mL), ethanol (5.65mL), water (2.83mL) and 2M sodium carbonate solution (2.82mL) 80 ℃ of heating 3 hours.The mixture dichloromethane extraction.Organic extract liquid water and salt washing, anhydrous magnesium sulfate drying, vacuum concentration then.The flash chromatography of resistates (NH silicon-dioxide, ethyl acetate: methyl alcohol=50: 1) obtain 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (390mg).
MS(FAB +)m/z：536(MH +)
HRMS (FAB +): C 27H 31FN 7O 4(MH +): calculated value 536.2422; Measured value 536.2435.
Embodiment 32
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
In similarly to Example 5 mode from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (19.5mg) preparation title compound 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (10.3mg).
MS(FAB +)m/z：436(MH +)
HRMS (FAB +): C 22H 23FN 7O 2(MH +): calculated value 436.1897; Measured value 436.1919.
Embodiment 33
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide.
With with the same mode of embodiment 31 from N-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (9.00mg) and 5-bromo-2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine (8.00mg) preparation title compound 5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (7.00mg).
MS(EI +)m/z：507(M +)
HRMS (EI +): C 27H 33N 5O 5(M +): calculated value 507.2482; Measured value 507.2475.
Embodiment 34
Figure A20048001890500601
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide.
In similarly to Example 5 mode from 5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (90.0mg) preparation title compound 5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (40.0mg).
MS(EI +)m/z：407(M +)
HRMS (EI +): C 22H 25N 5O 3(M +): calculated value 407.1957; Measured value 407.1937.
Embodiment 35
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With with same mode 31 title compounds of embodiment from N-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (56.7mg), 5-bromo-2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine (50.0mg) preparation 5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (50.3mg).
MS(EI +)m/z：525(M +)
HRMS (EI +): C 27H 32FN 5O 5(M +): calculated value 525.2387; Measured value 525.2408.
Embodiment 36
Figure A20048001890500612
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide.
In similarly to Example 5 mode from 5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (50.0mg) preparation title compound 5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (25.0mg).
MS(FAB +)m/z：426(MH +)
HRMS (FAB +): C 22H 25FN 5O 3(MH +): calculated value 426.1941; Measured value 426.1965.
Embodiment 37
Figure A20048001890500621
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazoles.
In similarly to Example 5 mode from 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (19.5mg) preparation title compound 1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-and 6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (10.3mg).
MS(FAB +)m/z：418(MH +)
HRMS (FAB +): C 22H 24N 7O 2(MH +): calculated value 418.1991; Measured value 418.1994.
Embodiment 38
1-[5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole.
In similarly to Example 1 mode from 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (570mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (444mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (465mg).
MS(EI +)m/z：508(M +)
HRMS (EI +): C 26H 29FN 6O 4(M +): calculated value 508.2234; Measured value 508.2272.
Embodiment 39
Figure A20048001890500632
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole.
In similarly to Example 5 mode from 1-[5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (365mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (210mg).
MS(EI +)m/z：408(M +).
HRMS (EI +): C 21H 21FN 6O 2(M +): calculated value 408.1710; Measured value 408.1690.
Embodiment 40
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide.
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (570mg) and 4-bromo-1-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) benzene (471mg) preparation title compound N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (592mg).
MS(FAB +)m/z：484(MH +)
HRMS (FAB +): C 26H 31FN 3O 5(MH +): calculated value 484.2248; Measured value 484.2259.
Embodiment 41
Figure A20048001890500651
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 5 mode from N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (580mg) preparation title compound N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (345mg).
MS(EI +)m/z：383(M +)
HRMS (EI +): C 21H 22FN 3O 3(M +): calculated value 383.1645; Measured value 383.1631.
Embodiment 42
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide.
In similarly to Example 1 mode from N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (450mg) and 4-bromo-1-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) benzene (390mg) preparation title compound N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (459mg).
MS(FAB +)m/z：466(MH +)
HRMS (FAB +): C 26H 32N 3O 5(MH +): calculated value 466.2342; Measured value 466.2363.
Embodiment 43
Figure A20048001890500661
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide.
In similarly to Example 5 mode from N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (420mg) preparation title compound N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (234mg).
MS(FAB +)m/z：366(MH +)
HRMS (FAB +): C 21H 24N 3O 3(MH +): calculated value 366.1818; Measured value 366.1809.
Embodiment 44
Figure A20048001890500662
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (570mg) and 4-bromo-1-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-2-fluorobenzene (499mg) preparation title compound N-[5 (S)-3-[4-[4-(1-(5 tertiary butyl oxygen carbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (448mg).
MS(FAB +)m/z：502(MH +)
HRMS (FAB +): C 26H 30F 2N 3O 5(MH +): calculated value 502.2154; Measured value 502.2113.
Embodiment 45
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 5 mode from N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (442mg) preparation title compound N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (296mg)
MS(FAB +)m/z：402(MH +)
HRMS (FAB +): C 21H 22F 2N 3O 3(MH +): calculated value 402.1629; Measured value 402.1599.
Embodiment 46
Figure A20048001890500681
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 1 mode from N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (500mg) and 4-bromo-1-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-2-fluorobenzene (458mg) preparation title compound N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (453mg).
MS(EI +)m/z：483(M +)
HRMS (EI +): C 26H 30FN 3O 5(M +): calculated value 483.2169; Measured value 483.2151.
Embodiment 47
Figure A20048001890500682
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 5 mode from N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (420mg) preparation title compound N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (283mg).
MS(FAB +)m/z：384(MH +)。
HRMS (FAB +): C 21H 23FN 3O 3(MH +): calculated value 384.1723; Measured value 384.1728.
Embodiment 48
Figure A20048001890500691
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With with the same mode of embodiment 1 and embodiment 5 from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (411mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorine pyridine (360mg) preparation title compound N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (311mg).
MS(FAB +)m/z：403(MH +)
HRMS (FAB +): C 20H 21F 2N 4O 3(MH +): calculated value 403.1582; Measured value 403.1605.
Embodiment 49
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
In similarly to Example 12 mode from N-[5 (S)-3-[3; 5-two fluoro-4-(trifyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (121mg) and 4-bromo-1-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) benzene (100mg) preparation title compound N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-3, the 5-difluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (57.2mg).
MS(FAB +)m/z：402(MH +)
HRMS (FAB +): C 21H 22F 2N 3O 3(MH +): calculated value 402.1629; Measured value 402.1625.
Embodiment 50
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyrimidine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide
With with the same mode of embodiment 1 and embodiment 5 from N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (27.0mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyrimidine (22.4mg) preparation title compound N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyrimidine-5-yl]-the 3-fluorophenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (19.0mg).
MS(FAB +)m/z：386(MH +)
HRMS (FAB +): C 19H 21FN 5O 3(MH +): calculated value 386.1628; Measured value 386.1668.
Embodiment 51
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole
With with the same mode of embodiment 12 and embodiment 5 from 1-[5 (R)-3-(3,5-two fluoro-4-iodine substituted phenyls)-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (500mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (447mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (253mg).
MS(EI +)m/z：426(M +)
HRMS (EI +): C 21H 20F 2N 6O 2(M +): calculated value 426.1616; Measured value 426.1646.
Embodiment 52
Figure A20048001890500721
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole
With with the same mode of embodiment 12 and embodiment 5 from 1-[5 (R)-3-(3,5-two fluoro-4-iodine substituted phenyls)-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (500mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorine pyridine (434mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (298mg).
MS(EI +)m/z：444(M +)
HRMS (EI +): C 21H 19F 3N 6O 2(M +): calculated value 444.1522; Measured value 444.1534.
Embodiment 53
Figure A20048001890500722
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With with the same mode of embodiment 12 and embodiment 5 from 1-[5 (R)-3-(3,5-two fluoro-4-iodine substituted phenyls)-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazole (460mg) and 5-bromo-2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine (426mg) preparation title compound 1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (252mg).
MS(EI +)m/z：412(M +)
HRMS (EI +): C 20H 18F 2N 6O 2(M +): calculated value 412.1459; Measured value 412.1488.
Reference example 1
N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide
With N-[5 (S)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (2.00g), two (tetramethyl ethylene ketone base) two boron (1.61g), potassium acetate (1.56g) and [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II)-methylene dichloride adducts (432mg) mixture in dimethyl sulfoxide (DMSO) (50mL) be 80 ℃ of heating 1 hour.The mixture dilute with water is also used ethyl acetate extraction.Organic extract liquid is washed with salt, anhydrous magnesium sulfate drying, vacuum concentration then.The flash chromatography of resistates (silicon-dioxide, ethyl acetate: acetone=9: 1) obtain N-[5 (S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (889mg).
MS(EI +)m/z：378(M +).
HRMS (EI +): C 18H 24BFN 2O 5(M +): calculated value 378.1762; Measured value 378.1779.
Reference example 2
N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide
With with the same mode of reference example 1 from N-[5 (S)-3-(4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide (108mg) and two (tetramethyl ethylene ketone base) two boron (855mg) preparation title compound N-[5 (S)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (92.5mg).
MS(EI +)m/z：360(M +)。
HRMS (EI +): C 18H 25BN 2O 5(M +): calculated value 360.1857; Measured value 360.1875.
Reference example 3
1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazoles
With with the same mode of reference example 1 from 1-[5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (2.69g) and two (tetramethyl ethylene ketone base) two boron (1.86g) preparation title compound 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazoles (1.53g).
MS(EI +)m/z：388(M +)
HRMS (EI +): C 18H 22BFN 4O 4(M +): calculated value 388.1718; Measured value 388.1752.
Reference example 4
1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazoles
With with the same mode of reference example 1 from 1-[5 (R)-3-(4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (200mg) and two (tetramethyl ethylene ketone base) two boron (151mg) preparation title compound 1-[5 (R)-3-[4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-1,2,3-triazoles (147mg).
MS(EI +)m/z：370(M +)
HRMS (EI +): C 18H 23BN 4O 4(M +): calculated value 370.1812; Measured value 370.1814.
Reference example 5
5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone
Adding imidazoles (1.33g) and tert-butyldimethylsilyl chloride (1.48g) under 0 ℃ in methylene dichloride (30mL) solution of 5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone (3.00g), mixture at room temperature stirred 2 hours.Mixture water, 2N hydrochloric acid, saturated sodium bicarbonate solution and salt washing, anhydrous magnesium sulfate drying, vacuum concentration obtains 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone (3.66g) then.
MS(EI +)m/z：451(M +)。
HRMS (EI +): C 16H 23FINO 3Si (M +): calculated value 451.0476; Measured value 451.0511.
Reference example 6
5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl] oxazolidine-2-ketone
With with the same mode of reference example 1 from 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone (100mg) and two (tetramethyl ethylene ketone base) two boron (67.0mg) preparation title compound 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl] oxazolidine-2-ketone (64.4mg).
MS(CI +)m/z：452(MH +)
HRMS (CI +): C 22H 36BFNO 5Si (MH +): calculated value 452.2440; Measured value 452.2394.
Reference example 7
3,5-two fluoro-4-(methoxymethyl) oxygen base oil of mirbane.
To 2, add diisopropyl ethyl amine (50.2mL) and methoxymethyl chlorine (17.5mL) in methylene dichloride (300mL) solution of 6-two fluoro-4-nitrophenolss (35.0g) under 0 ℃, mixture at room temperature stirred 2 hours.Mixture water, 5% sodium hydrogen carbonate solution and salt washing, anhydrous magnesium sulfate drying, vacuum concentration then.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=9: 1), obtain 3,5-two fluoro-4-(methoxymethyl) oxygen base oil of mirbane (35.2g).
1H NMR(CDCl 3)δ3.59(d，J＝1.5Hz，3H)，5.30(s，2H)，7.83-7.91(m，2H)。
Reference example 8
4-benzyloxycarbonyl amino-2,6-two fluoro-1-(methoxymethyl) oxygen base benzene
With 3, and 5-two fluoro-4-(methoxymethyl) oxygen base oil of mirbane (35.0g) and palladium catalyst (10%, on charcoal, the 3.00g) hydrogenation 2 hours under 1atm at room temperature of the suspension in methyl alcohol (250mL).After filtering catalyst, vacuum concentrated filtrate obtains 4-amino-2,6-two fluoro-1-(methoxymethyl) oxygen base benzene.It is not purified to be used for next step.Under 0 ℃ to the thick 4-amino-2 that so obtains, add sodium bicarbonate (17.4g), water (100mL) and benzyl chloroformate (30.0g) continuously in the solution of 6-two fluoro-1-(methoxymethyl) oxygen base benzene in tetrahydrofuran (THF) (500mL), and at room temperature stirred the mixture 15 minutes.Mixture is with the saturated sodium bicarbonate solution dilution and use ethyl acetate extraction.Organic extract liquid is washed with salt, anhydrous magnesium sulfate drying, vacuum concentration then.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=6: 1) obtain 4-benzyloxycarbonyl amino-2,6-two fluoro-1-(methoxymethyl) oxygen base benzene (49.10g).
MS(EI +)m/z：323(M +)
HRMS (EI +): C 16H 15F 2NO 4(M +): calculated value 323.0969; Measured value 323.0963.
Reference example 9
5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-5-hydroxyl base first base oxazolidine-2-ketone
Under-78 ℃ to 4-benzyloxycarbonyl amino-2, add in the anhydrous tetrahydro furan (400mL) of 6-two fluoro-1-(methoxymethyl) oxygen base benzene (46.3g) n-Butyl Lithium hexane solution (1.6M, 90.0mL) and under identical temperature, stirred the mixture 30 minutes.Under-78 ℃, add (R)-Glycidyl butyrate (20.3mL) and mixture was at room temperature left standstill 3 hours to mixture.After adding aqueous ammonium chloride solution quencher reaction, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous magnesium sulfate drying filters, then vacuum concentration.Add salt of wormwood (20.0g) in methyl alcohol (300mL) solution of resistates, mixture at room temperature stirs 30 minutes vacuum concentration then.After the dilute with water resistates, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous magnesium sulfate drying filters and vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=1: 4) obtain 5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-5-hydroxyl base first base oxazolidine-2-ketone (36.1g).
MS(EI +)m/z：289(M +)
HRMS (EI +): C 12H 13F 2NO 5(M +): calculated value 289.0762; Measured value 289.0743.
Reference example 10
N-[5 (S)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl ethanamide
Under 0 ℃ to 5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-add triethylamine (4.82mL) in methylene dichloride (20mL) solution of 5-hydroxyl base first base oxazolidine-2-ketone (5.00g) continuously with methylsulfonyl chloride (2.53mL) and under identical temperature, stirred the mixture 1 hour.Mixture washes with water, and anhydrous magnesium sulfate drying filters vacuum concentration then, obtains 5 (R)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-5-methylsulfonyl oxygen base first base oxazolidine-2-ketone.It is used for next step without being further purified.With 5 thick (the R)-3-[3 that so obtain; 5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-5-methylsulfonyl oxygen base first base oxazolidine-2-ketone and sodiumazide (3.93g) be at N; mixture in the dinethylformamide (20mL) is at 60 ℃ of heating 8 hours, vacuum concentration then.Resistates dilutes with ethyl acetate, water and salt washing.The organic extract liquid anhydrous magnesium sulfate drying filters vacuum concentration then, obtains 5 (R)-azido methyl-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl] oxazolidine-2-ketone (5.43g).It is not purified to be used for next step.With 5 (R)-azido methyl-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl] oxazolidine-2-ketone (3.53g) and Lin Dela (Lindlar) catalyzer (5% palladium-CaCO 3, with lead its part is poisoned, the 700mg) hydrogenation 6 hours under 1atm at room temperature of the suspension in methyl alcohol (110mL).After filtering catalyst, the filtrate vacuum concentration.At room temperature in tetrahydrofuran (THF) (15mL) solution of resistates, add triethylamine (6.30mL) and diacetyl oxide (2.10mL) and under uniform temp, stirred the mixture 2 hours.After by adding saturated sodium bicarbonate solution quencher reaction, the mixture ethyl acetate extraction.The organic extract liquid anhydrous magnesium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate) obtains N-[5 (S)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (3.45g).
MS(EI +)m/z：330(M +).
HRMS (EI +): C 14H 16F 2N 2O 5(M +): calculated value 330.1027; Measured value 330.1001.
Reference example 11
N-[5 (S)-3-(3,5-two fluoro-4-hydroxy phenyls)-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide
To N-[5 (S)-3-[3,5-two fluoro-4-(methoxymethyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] and adding concentrated hydrochloric acid (0.50mL) in methyl alcohol (5mL) solution of ethanamide (200mg), mixture at room temperature stirs 1 natural final vacuum and concentrates.Use the water treatment resistates, obtain N-[5 (S)-3-(3,5-two fluoro-4-hydroxy phenyls)-2-oxygen for oxazolidine-5-ylmethyl] ethanamide (144mg).
MS(EI +)m/z：286(M +)。
HRMS (EI +): C 12H 12F 2N 2O 4(M +): calculated value 286.0765; Measured value 286.0747.
Reference example 12
N-[5 (S)-3-[3,5-two fluoro-4-(trifyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide
Under 0 ℃ to N-[5 (S)-3-(3,5-two fluoro-4-hydroxy phenyls)-2-oxygen for oxazolidine-5-ylmethyl] add trifluoromethanesulfanhydride anhydride (2.38mL) in pyridine (15mL) solution of ethanamide (2.70g), at room temperature stirred the mixture 12 hours.After the dilute with water mixture, the mixture ethyl acetate extraction.Organic extract liquid is washed with 5% hydrochloric acid and salt, and anhydrous magnesium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate: methyl alcohol=19: 1) obtain N-[5 (S)-3-[3,5-two fluoro-4-(trifyl) oxygen base phenyl]-2-oxygen is for oxazolidine-5-ylmethyl] ethanamide (3.48g).
MS(EI +)m/z：418(M +)。
HRMS (EI +): C 13H 11F 5N 2O 6S (M +): calculated value 418.0258; Measured value 418.0210.
Reference example 13
1-(5-bromopyridine-2-yl)-1-cyclopropane formonitrile HCN
The mixture of 5-bromo-2-cyano-methyl pyridine (6.00g), triethyl benzyl ammonia chloride (6.94g), glycol dibromide (3.94mL) and 50% sodium hydroxide solution (150mL) was stirred 1 hour at 80 ℃.After the dilute with water mixture, collect the throw out that obtains by filtering.Throw out divides flash chromatography (silicon-dioxide, hexane: ethyl acetate=6: 1) obtain 1-(5-bromopyridine-2-yl)-1-cyclopropane formonitrile HCN (6.21g).
MS(CI +)m/z：223(MH +).
HRMS (CI +): C 9H 8BrN 2(MH +): calculated value 222.9871; Measured value 222.9853.
Reference example 14
1-(5-bromopyridine-2-yl)-1-cyclopropane-carboxylic acid
Ethanol (60mL) solution and 25% sodium hydroxide solution (20mL) reflux 10 hours and vacuum concentration with 1-(5-bromopyridine-2-yl)-1-cyclopropane formonitrile HCN (3.00g).After the dilute with water resistates, regulate mixture pH3 and use chloroform extraction by adding 5% hydrochloric acid.The organic extract liquid anhydrous magnesium sulfate drying, filtering then, vacuum concentration obtains 1-(5-bromopyridine-2-yl)-1-cyclopropane-carboxylic acid (3.19g).
MS(CI +)m/z：242(MH +)
HRMS (CI +): C 9H 9BrNO 2(MH +): calculated value 241.9817; Measured value 241.9849.
Reference example 15
1-(5-bromopyridine-2-yl)-1-tert-butoxycarbonyl amino-cyclopropane
At room temperature in methylene dichloride (24mL) solution of 1-(5-bromopyridine-2-yl)-1-cyclopropane-carboxylic acid (1.20g), add triethylamine (1.04mL) and diphenyl phosphine trinitride (1.60mL), mixture stirred 1 hour under identical temperature, then vacuum concentration.After with the dilution with toluene resistates, mixture washes with water, and anhydrous magnesium sulfate drying filters vacuum concentration then.Dimethylbenzene (40mL) solution of resistates was stirred 2 hours at 120 ℃.Adding the trimethyl carbinol (5mL) afterwards to mixture, mixture stirred 16 hours at 140 ℃, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ether=2: 1) obtain 1-(5-bromopyridine-2-yl)-1-tert-butoxycarbonyl amino-cyclopropane (1.40g).
MS(FAB +)m/z：313(MH +).
HRMS (FAB +): C 13H 28BrN 2O 2(MH +): calculated value 313.0552; Measured value 313.0569.
Reference example 16
1-(5-bromopyridine-2-yl)-1-cyclopropane carboxylic acid tert-butyl acrylate
At room temperature in the trimethyl carbinol (40mL) solution of 1-(5-bromopyridine-2-yl)-1-cyclopropane-carboxylic acid (2.00g), add the solution of two dimethyl dicarbonate butyl esters (2.71g) in the trimethyl carbinol (20mL) and 4-(dimethylamino) pyridine (505mg), mixture stirred 6 hours under identical temperature, vacuum concentration.After with 10% solution of potassium carbonate dilution resistates, the mixture ethyl acetate extraction.With the organic extract liquid anhydrous magnesium sulfate drying, filter, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=5: 1) obtain 1-(5-bromopyridine-2-yl)-1-cyclopropane carboxylic acid tert-butyl acrylate (1.38g).
MS(EI +)m/z：297(M +)
HRMS (EI +): C 13H 16BrNO 2(M +): calculated value 297.0364; Measured value 297.0329.
Reference example 17
5-bromo-2-(1-hydroxymethyl cyclopropane-1-yl) pyridine
Adding triethylamine (104 μ L) and chloro ethyl formate (65.0 μ L) under 0 ℃ in tetrahydrofuran (THF) (4mL) solution of 1-(5-bromopyridine-2-yl)-1-cyclopropane-carboxylic acid (150mg), mixture stirred 30 minutes under identical temperature.In the mixture that obtains, adding water (3mL) solution of sodium borohydride (234mg) under 0 ℃, at room temperature stirred the mixture 30 minutes.By after adding 1N hydrochloric acid quencher reaction, regulate mixture pH8 and use ethyl acetate extraction by adding sodium bicarbonate.The organic extract liquid anhydrous magnesium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=3: 2) obtain 5-bromo-2-(1-hydroxymethyl cyclopropane-1-yl) pyridine (131mg).
MS(CI +)m/z：228(MH +).
HRMS (CI +): C 9H 21BrNO (MH +): calculated value 228.0024; Measured value 228.0020.
Reference example 18
5-bromo-2-(1-dimethylaminomethyl cyclopropane-1-yl) pyridine
Adding triethylamine (91.7 μ L) and methylsulfonyl chloride (40.7 μ L) under 0 ℃ in methylene dichloride (5mL) solution of 5-bromo-2-(1-hydroxymethyl cyclopropane-1-yl) pyridine (100mg), mixture stirred 1 hour under identical temperature.Mixture is washed with frozen water, and anhydrous magnesium sulfate drying filters vacuum concentration then.At room temperature tetrahydrofuran (THF) (2mL) solution of resistates is joined that (2M, 2.2mL), mixture stirred 12 hours at 60 ℃, then vacuum concentration in the tetrahydrofuran solution of dimethyl amine.After with saturated sodium bicarbonate solution dilution resistates, the mixture ethyl acetate extraction.The organic extract liquid anhydrous magnesium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (NH silicon-dioxide, hexane: ethyl acetate=4: 1) obtain 5-bromo-2-(1-dimethylaminomethyl cyclopropane-1-yl) pyridine (85.9mg).
MS(EI +)m/z：254(M +)
HRMS (EI +): C 11H 15BrN 2(M +): calculated value 254.0419; Measured value 254.0435.
Reference example 19
1-(2-bromopyridine-5-yl)-1-cyclopropane formonitrile HCN
With with the same mode of reference example 13 from 2-bromo-5-cyano-methyl pyridine (2.62g) preparation title compound 1-(2-bromopyridine-5-yl)-1-cyclopropane formonitrile HCN (2.19g).
MS(EI +)m/z：223(M +)
HRMS (EI +): C 9H 7BrN 2(M +): calculated value 222.9793; Measured value 222.9794.
Reference example 20
2-(1-cyano group cyclopropane-1-yl) pyridine-5-boric acid
At the hexane solution (1.6M, 690 μ L) that adds n-Butyl Lithium under-78 ℃ in tetrahydrofuran (THF) (5mL) solution of 1-(5-bromopyridine-2-yl)-1-cyclopropane formonitrile HCN (200mg) and three isopropoxy borines (169 μ L), mixture at room temperature stirred 1 hour.After with saturated ammonium chloride solution diluted mixture thing, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous magnesium sulfate drying filters, and vacuum concentration obtains 2-(1-cyano group cyclopropane-1-yl) pyridine-5-boric acid (170mg) then.
MS (EI +) m/z:510 (M +) (being tripolymer)
HRMS (EI +): C 27H 21B 3N 6O 3(M +): calculated value 510.1954; Measured value 510.1969.
Reference example 21
5-bromo-2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine
At room temperature to (1 α, 5 α, 6 α)-N of 6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane (40.0mg), add triethylamine (55.8uL) and 5-bromo-2-fluorine pyridine (25.7 μ L) in dinethylformamide (0.20mL) solution, mixture stirred 5 hours at 80-90 ℃.After the dilute with water mixture, the mixture ethyl acetate extraction.Organic extract liquid is washed with salt, and anhydrous magnesium sulfate drying filters, then vacuum concentration.The flash chromatography of resistates (silicon-dioxide, hexane: ethyl acetate=1: 1) obtain 5-bromo-2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine (51.0mg).
MS(EI +)m/z：353(M +)
HRMS (EI +): C 15H 20BrN 3O 2(M +): calculated value 353.0739; Measured value 353.0700.
Reference example 22
1-[5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
Step 1.
5 (R)-acetoxy-methyl-3-(3-fluorophenyl) oxazolidine-2-ketone
In tetrahydrofuran (THF) (53mL) solution of 5 (R)-3-(3-fluorophenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone (5.28g), add triethylamine (3.83mL), diacetyl oxide (2.55mL) and (4-dimethylamino) pyridine (152mg), and at room temperature stirred the mixture 1 hour.By after adding 1N hydrochloric acid cooling reaction, use the ethyl acetate extraction mixture.Organic extract liquid is washed with salt, anhydrous sodium sulfate drying, and filtering then, vacuum concentration obtains 5 (R)-acetoxy-methyl-3-(3-fluorophenyl) oxazolidine-2-ketone (6.33g).
Step 2.
5 (R)-acetoxy-methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone
(add iodine monochloride (1.91mL) in acetate (40mL) solution of 3-fluorophenyl) oxazolidine-2-ketone (6.33g), at room temperature stirred the mixture 18 hours, then vacuum concentration to 5 (R)-acetoxy-methyl-3-.The resistates that obtains with acetic acid ethyl dissolution, mixture is washed with sodium bicarbonate aqueous solution, 20% sodium sulfite solution and salt, anhydrous sodium sulfate drying filters vacuum concentration then, obtains 5 thick (R)-acetoxy-methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone (9.48g).
Step 3.
5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone
(add salt of wormwood (6.91g) in methyl alcohol (95mL) solution of 3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone (9.48g), and at room temperature stirred the mixture 2.5 hours to 5 thick (R)-acetoxy-methyl-3-.After leaching insoluble substance, with the filtrate vacuum concentration.The resistates acetic acid ethyl dissolution, mixture is washed with salt, and anhydrous sodium sulfate drying filters, then vacuum concentration.After handling resistates with Virahol, collect the throw out that obtains by filtering, obtain 5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone, with the filtrate vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate) obtains the product (amounting to 6.24g) of another tittle.
MS(EI +)m/z：337(M +)
1HNMR(CDCl 3)δ2.15(t，J＝6.4Hz，1H)，3.74-4.80(m，5H)，7.07(dd，J＝8.8，2.4Hz，1H)，7.48(dd，J＝10.3，2.4Hz，1H)，7.70(dd，J＝8.8，6.8Hz，1H)。
Step 4.
5 (R)-azido methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone
Adding triethylamine (1.24mL) and methylsulfonyl chloride (551 μ L) under 0 ℃ in methylene dichloride (30mL) solution of 5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone (2.00g), mixture stirred 30 minutes under identical temperature.Mixture is washed with frozen water, and anhydrous magnesium sulfate drying filters vacuum concentration then.At N, the mixture in the dinethylformamide (30mL) stirred 2 hours and vacuum concentration at 80 ℃ with resistates and sodiumazide (964mg).After the dilute with water resistates, the mixture ethyl acetate extraction.The organic extract liquid anhydrous magnesium sulfate drying, filtering then, vacuum concentration obtains 5 (R)-azido methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone (2.18g).
MS(EI +)m/z：361(M +).
HRMS (EI +): C 10H 8FIN 4O 2(M +): calculated value 361.9676; Measured value 361.9698.
Step 5.
1-[5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With 5 (R)-azido methyl-3-(3-fluoro-4-iodine substituted phenyl) oxazolidine-2-ketone (2.18g) and 2, the mixture of 5-norbornadiene (6.40mL) in dioxane (45.6mL) stirred 2 hours at 80 ℃, stirred 4 hours at 110 ℃, vacuum concentration then, obtain 1-[5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazole (1.70g).
MS(EI +)m/z：388(M +)
HRMS (EI +): C 12H 10FIN 4O 2(M +): calculated value 387.9833; Measured value 387.9835.
Reference example 23
5 (R)-azido methyl-3-(4-iodine substituted phenyl) oxazolidine-2-ketone
With with the same mode of reference example 22 from 5 (R)-3-(4-iodine substituted phenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone (70.0g) preparation title compound 5 (R)-azido methyl-3-(4-iodine substituted phenyl) oxazolidine-2-ketone (75.3g).
MS(EI +)m/z：344(M +)
HRMS (EI +): C 10H 9IN 4O 2(M +): calculated value 343.9770; Measured value 343.9740.
Reference example 24
1-[5 (R)-3-(4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles
With with the same mode of reference example 22 from 5 (R)-azido methyl-3-(4-iodine substituted phenyl) oxazolidine-2-ketone (100mg) preparation title compound 1-[5 (R)-3-(4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles (62.5mg).
MS(EI +)m/z：370(M +)
HRMS (EI +): C 12H 11IN 4O 2(M +): calculated value 369.9927; Measured value 369.9919.
Reference example 25
5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-(4-iodine substituted phenyl) oxazolidine-2-ketone
With with the same mode of reference example 5 from 5 (R)-3-(4-iodine substituted phenyl)-5-Qiang base Jia Ji oxazolidine-2-ketone (2.00g) preparation title compound 5 (R)-5-(t-butyldimethylsilyl oxygen base) methyl-3-(4-iodine substituted phenyl) oxazolidine-2-ketone (2.66g).
MS(EI +)m/z：433(M +)
HRMS (EI +): C 16H 24INO 3Si (M +): calculated value 433.0570; Measured value 433.0544.
Reference example 26
1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole
With 1-[5 (R)-3-(3-fluoro-4-iodine substituted phenyl)-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (590mg), two (tetramethyl ethylene ketone base) two boron (410mg), 2 ethyl hexanoic acid potassium (802mg) and [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride (II)-methylene dichloride adducts (120mg) mixture in dioxane (15mL) stirred 1.5 hours at 80 ℃.The flash chromatography of mixture (silicon-dioxide, ethyl acetate) obtains 1-[5 (R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl--1,3,2-two oxa-boron pentanes) phenyl]-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (581mg).
MS(EI +)m/z：402(M +)
HRMS (EI +): C 19H 24BFN 4O 4(M +): calculated value 402.1875; Measured value 402.1874.
Reference example 27
1-[5 (R)-3-(3,5-two fluoro-4-iodine substituted phenyls)-2-oxygen is for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole
Under 0 ℃ to 5 (R)-amino methyl-3-(3,5-two fluoro-4-iodine substituted phenyls) add diisopropyl ethyl amine (262 μ L) and inclined to one side Dichloro acetone tosylhydrazone (108mg) in methyl alcohol (2mL) solution of oxazolidine-2-ketone (100mg), mixture at room temperature stirred 20 hours, vacuum concentration.The flash chromatography of resistates (silicon-dioxide, ethyl acetate) obtains 1-[5 (R)-3-(3,5-two fluoro-4-iodine substituted phenyls)-2-oxygen for oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2,3-triazole (110mg).
MS(EI +)m/z：420(M +)
HRMS (EI +): C 13H 11F 2IN 4O 2(M +): calculated value 420.9895; Measured value 420.9904.
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.Form unitary Chlamydia pneumoniae inoculation HeLa 229 cells with every milliliter 104 inclusion compound.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 3 Embodiment 5 Embodiment 8 Embodiment 32 Linezolid
Staphylococcus aureus (staphylococcus aureus) Smith CR MR streptococcus pneumonia (Streptococcus pneumoniae) IID553 PRQR streptococcus pyogenes (Streptococcus pyogenes) IID692 urine enterococcus (Enterococcus faecium) VRQR morazella catarrhalis (Moraxella catarrhalis) ATCC25238 0.06 0.5 0.125 0.125 0.125 0.125 0.125 0.5 0.25 2 0.5 0.5 0.25 0.25 0.5 2 0.06 1 0.06 0.125 0.125 0.06 0.125 0.5 0.125 1 0.125 0.25 0.125 0.125 0.5 2 1 16 1 2 1 1 2 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 (17)

1. the present invention relates to the compound of following formula I:
Figure A2004800189050002C1
Its enantiomer, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug, wherein:
R 1And R 2Expression independently:
Vi) hydrogen;
vii)(CH 2)nNR 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;
R 1aExpression (CH 2) nNR 5R 6, CR 7R 8R 9, C (R) 2OR 14, CH 2NHR 14, 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, (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 optionally by 1-3 R 7The C that group replaces 5-10Heterocycle, it can connect by carbon atom or heteroatoms;
X is selected from the group of following group:
Figure A2004800189050003C1
With
Figure A2004800189050003C2
Z represents (O) n, H, OH or halogen;
A represent C (when---when existing, condition is Z=(O) nAnd n=0), C (when--when not existing, condition is that Z is H, OH or halogen) or N (when---when not existing and Z=(O) nAnd n=1);
---expression key;
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 4, R 4a, R 4b, and R 4cExpression 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) rOr (R 4b) and (R 4c) sBe 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 2) 0-3NHAc, 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) 0-3N (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, CHCl 2, CR 2C1, (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 7Group 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
N represents 0-1.
2. the compound of claim 1, wherein R 1And R 2Represent H, NR independently 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, R 1aExpression 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 2, wherein, With Be phenyl, pyridine, pyrimidine or piperidines independently.
4. the compound of claim 3, wherein X is
5. the compound of claim 3, wherein X is
6. the compound of claim 5, wherein A is C,---exist, and Z=(O) n, wherein n=0; A is C,---do not exist and Z=H, OH or halogen; Perhaps A is N,---do not exist, and Z=(O) n, wherein n=1.
7. the compound of claim 6, wherein R 1And R 2In one be H, another is NR 5R 6Perhaps R 1And R 2In one be H, another is NR 10C (=X 1) R 13
8. the compound of claim 4, wherein R 1aOne of be CN, NR 10C (=X 1) R 13, or NR 5R 6
9. the compound of claim 1, wherein R 3Be 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 by 1-3 R aGroup replaces.
10. the compound of claim 9, wherein R 3Serve as reasons 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.
11. the compound of claim 1, wherein structural formula is a Formula Il:
Figure A2004800189050008C2
Formula II
Wherein X is selected from the group of following group:
Figure A2004800189050008C3
With
Z represents (O) n, H, OH or halogen;
A represent C (when--when existing, condition is Z=(O) n and n=0), C (when--when not existing, condition is that Z is H, OH or halogen) or N (when---when not existing and Z=(O) n and n=1); And R 1a, R 1, R 2, Rx, R 4, R 4a, and R 3Definition as described above.
12. the compound of claim 11, wherein R 1aBe CN or NR 5R 6
13. following compound:
N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[5-(1-cyano group cyclopropane-1-yl) pyridine-2-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-(dimethylamino) methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-(dimethylamino) methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-tert-butoxycarbonyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-hydroxymethyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-hydroxycarbonyl group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] acetamide hydrochloride,
N-[5 (S)-3-[4-[2-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-amino methyl cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridyl-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
N-[5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl] phenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl] phenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(tert-butoxycarbonyl)-N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-5-[N-(isoxazole-3-base)] An base Jia Ji oxazolidine-2-ketone,
5 (R)-3-[4-[2-(1-cyano group cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-the 5-[(isoxazole-3-base) oxygen base] Jia Ji oxazolidine-2-ketone,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-(N-tert-butoxycarbonyl) amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-[(1 α, 5 α, 6 α)-6-amino-3-azabicyclo [3.1.0] hexane-3-yl] pyridine-5-yl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
1-[5 (R)-3-[4-[2-(1-tert-butoxycarbonyl amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole,
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole,
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-(tert-butoxycarbonyl) amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl)-3-fluorophenyl] phenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[4-(1-amino-cyclopropane-1-yl) phenyl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
N-[5 (S)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyrimidine-5-yl]-the 3-fluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl] ethanamide,
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole,
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl)-3-fluorine pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-the 4-methyl isophthalic acid, 2, the 3-triazole,
1-[5 (R)-3-[4-[2-(1-amino-cyclopropane-1-yl) pyridine-5-yl]-3, the 5-difluorophenyl]-2-Yang Dai oxazolidine-5-ylmethyl]-1,2,3-triazoles,
Or its enantiomer, diastereomer, or its pharmacologically acceptable salt, hydrate or prodrug.
14. 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.
15. treatment or prevention have the method for the infectation of bacteria of the mammalian subject that needs, it comprises the compound to the claim 1 of described patient's effective dosage.
16. 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.
17. 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 200480018905 2003-07-02 2004-06-29 Cyclopropyl group substituted oxazolidinone antibiotics and derivatives thereof Pending CN1816545A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013182070A1 (en) * 2012-06-08 2013-12-12 四川贝力克生物技术有限责任公司 Drug for preventing or treating mycobacterial diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003535860A (en) * 2000-06-05 2003-12-02 ドン・ア・ファーム・カンパニー・リミテッド Novel oxazolidinone derivative and method for producing the same
ES2248633T3 (en) * 2001-04-17 2006-03-16 MERCK & CO., INC. OXAZOLIDINONE ANTIBIOTICS CONTAINING BICYCLE (3.1, OR) HEXANE AND DERIVATIVES OF THE SAME.
US6686363B2 (en) * 2001-11-29 2004-02-03 Kyorin Pharmaceutical Co., Ltd. Cyclopropyl containing oxazolidinone antibiotics and derivatives thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013182070A1 (en) * 2012-06-08 2013-12-12 四川贝力克生物技术有限责任公司 Drug for preventing or treating mycobacterial diseases
CN104364240A (en) * 2012-06-08 2015-02-18 四川贝力克生物技术有限责任公司 Drug for preventing or treating mycobacterial diseases

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